今日の臨床サポート

サプリメント(ミネラルとビタミン以外)

著者: 青島周一 医療法人社団 徳仁会 中野病院

監修: 名郷直樹 武蔵国分寺公園クリニック

著者校正済:2022/03/16
現在監修レビュー中
患者向け説明資料

概要・推奨   

  1. 認知機能正常者もしくは軽度認知機能障害を有する患者において、イチョウ抽出物の投与で認知症発症を予防するという方法論的妥当性の高い研究は報告されておらず推奨しないが、患者が希望すれば1日240㎎の摂取は許容できる(推奨度3)
  1. 認知症患者におけるイチョウ抽出物の有効性を検討した方法論的妥当性の高い研究は少なく、推奨しないが複数のシステマティックレビューで、わずかながら認知機能低下の抑制効果が報告されており、患者が希望すれば1日240㎎の摂取は許容できる(推奨度3)
  1. 変形性関節症に対するグルコサミン硫酸塩の疼痛軽減、機能改善に対する効果は極めて小さく、積極的な投与を推奨しないが、患者が希望すれば1日1,500㎎の摂取は許容できる(推奨度3)
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、 著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適応の査定において保険適応及び保険適応外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適応の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
青島周一 : 特に申告事項無し[2022年]
監修:名郷直樹 : 特に申告事項無し[2022年]

改訂のポイント:
  1. 定期レビューを行い、最新のエビデンスを反映させるともに、細部の文章表現を訂正した。特に「研究の質」という表現は「方法論的妥当性」に統一した。n-3系不飽和脂肪酸については、2018年以降に大規模臨床試験が相次いで報告されたため、当該試験の結果をレビューするとともに、それ以前の小規模研究に関するレビューは削除した。加えて、最新のシステマティックレビューの結果を反映させた。また、感染性下痢症に対するプロバイオティクスについて、2018年に報告されたランダム化比較試験と最新のシステマティックレビューの結果を反映させ、レビューの結論を「有効性は極めて小さい」と変更した。

まとめ

まとめ  
  1. サプリメントとは「dietary supplement」の訳語であり、わが国では健康食品と同じ意味で用いられることが多い。
  1. 法律上の定義は無く、ビタミン、ミネラル、ハーブ類や生薬など健康の保持および増進に資する食品として販売・利用されるもの全般を指す。そのうち、国の制度としては、国が定めた安全性や有効性に関する基準等を満たした「保健機能食品制度」がある。
  1. サプリメントの利用状況について、内閣府・消費者委員会が2012年に報告した『消費者の「健康食品」の利用に関する実態調査』によれば、消費者の約6割が健康食品(サプリメント)を利用しており、50代以上の約3割が健康食品をほぼ毎日利用している。
  1. 『消費者の「健康食品」の利用に関する実態調査』によれば、健康食品利用者の約4割が2種類以上の健康食品(サプリメント)を利用しており、年齢が上がるほど、複数の健康食品(サプリメント)を利用する割合が増える傾向がある。
  1. 現状で積極的に奨められるサプリメントは抗菌薬関連下痢症の対症療法としてのプロバイオティクスであるが、保険診療でも対応可能である(ビオフェルミン錠、もしくはビオフェルミンR錠)。

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

最新のエビデンスに基づいた二次文献データベース「今日の臨床サポート」。
常時アップデートされており、最新のエビデンスを各分野のエキスパートが豊富な図表や処方・検査例を交えて分かりやすく解説。日常臨床で遭遇するほぼ全ての症状・疾患から薬剤・検査情報まで瞬時に検索可能です。

まずは15日間無料トライアル
本サイトの知的財産権は全てエルゼビアまたはコンテンツのライセンサーに帰属します。私的利用及び別途規定されている場合を除き、本サイトの利用はいかなる許諾を与えるものでもありません。 本サイト、そのコンテンツ、製品およびサービスのご利用は、お客様ご自身の責任において行ってください。本サイトの利用に基づくいかなる損害についても、エルゼビアは一切の責任及び賠償義務を負いません。 また、本サイトの利用を以て、本サイト利用者は、本サイトの利用に基づき第三者に生じるいかなる損害についても、エルゼビアを免責することに合意したことになります。  本サイトを利用される医学・医療提供者は、独自の臨床的判断を行使するべきです。本サイト利用者の判断においてリスクを正当なものとして受け入れる用意がない限り、コンテンツにおいて提案されている検査または処置がなされるべきではありません。 医学の急速な進歩に鑑み、エルゼビアは、本サイト利用者が診断方法および投与量について、独自に検証を行うことを推奨いたします。

文献 

Thammanard Charemboon, Kankamol Jaisin
Ginkgo biloba for prevention of dementia: a systematic review and meta-analysis.
J Med Assoc Thai. 2015 May;98(5):508-13.
Abstract/Text OBJECTIVE: To determine the efficacy of Ginkgo biloba for the prevention of dementia in individuals without dementia.
MATERIAL AND METHOD: English databases including Medline, Embase, Cochrane Library and PsycINFO, were searched, and randomized double-blind controlled studies comparing Ginkgo biloba with placebo in prevention of dementia were considered. Two trials met inclusion criteria. Methodological quality was assessed using the Jadad criteria.
RESULTS: Meta-analysis of the two trials involving 5,889 participants indicated no significant difference in dementia rate between Ginkgo biloba and the placebo (347/2,951 vs. 330/2,938, odds ratio = 1.05, 95% CI 0.89-1.23) and there was no considerable heterogeneity between the trials. The two studies revealed no statistically significant differences in the rate of serious adverse effect between Ginko biloba and the placebo.
CONCLUSION: There is no convincing evidence from this review that demonstrated Ginkgo biloba in late-life can prevent the development of dementia. Using it for this indication is not suggested at present.

PMID 26058281
Meng-Shan Tan, Jin-Tai Yu, Chen-Chen Tan, Hui-Fu Wang, Xiang-Fei Meng, Chong Wang, Teng Jiang, Xi-Chen Zhu, Lan Tan
Efficacy and adverse effects of ginkgo biloba for cognitive impairment and dementia: a systematic review and meta-analysis.
J Alzheimers Dis. 2015;43(2):589-603. doi: 10.3233/JAD-140837.
Abstract/Text BACKGROUND: Research into Ginkgo biloba has been ongoing for many years, while the benefit and adverse effects of Ginkgo biloba extract EGb761 for cognitive impairment and dementia has been discussed controversially.
OBJECTIVE: To discuss new evidence on the clinical and adverse effects of standardized Ginkgo biloba extract EGb761 for cognitive impairment and dementia.
METHODS: MEDLINE, EMBASE, Cochrane, and other relevant databases were searched in March 2014 for eligible randomized controlled trials of Ginkgo biloba EGb761 therapy in patients with cognitive impairment and dementia.
RESULTS: Nine trials met our inclusion criteria. Trials were of 22-26 weeks duration and included 2,561 patients in total. In the meta-analysis, the weighted mean differences in change scores for cognition were in favor of EGb761 compared to placebo (-2.86, 95%CI -3.18; -2.54); the standardized mean differences in change scores for activities in daily living (ADLs) were also in favor of EGb761 compared to placebo (-0.36, 95%CI -0.44; -0.28); Peto OR showed a statistically significant difference from placebo for Clinicians' Global Impression of Change (CGIC) scale (1.88, 95%CI 1.54; 2.29). All these benefits are mainly associated with EGb761 at a dose of 240 mg/day. For subgroup analysis in patients with neuropsychiatric symptoms, 240 mg/day EGb761 improved cognitive function, ADLs, CGIC, and also neuropsychiatric symptoms with statistical superiority than for the whole group. For the Alzheimer's disease subgroup, the main outcomes were almost the same as the whole group of patients with no statistical superiority. Finally, safety data revealed no important safety concerns with EGb761.
CONCLUSIONS: EGb761 at 240 mg/day is able to stabilize or slow decline in cognition, function, behavior, and global change at 22-26 weeks in cognitive impairment and dementia, especially for patients with neuropsychiatric symptoms.

PMID 25114079
Guoyan Yang, Yuyi Wang, Jin Sun, Kang Zhang, Jianping Liu
Ginkgo Biloba for Mild Cognitive Impairment and Alzheimer's Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
Curr Top Med Chem. 2016;16(5):520-8.
Abstract/Text BACKGROUND: Ginkgo biloba is a natural medicine used for cognitive impairment and Alzheimer's disease. The objective of this review is to explore the effectiveness and safety of Ginkgo biloba in treating mild cognitive impairment and Alzheimer's disease.
METHODS: Electronic search was conducted from PubMed, Cochrane Library, and four major Chinese databases from their inception up to 1(st) December, 2014 for randomized clinical trials on Ginkgo biloba in treating mild cognitive impairment or Alzheimer's disease. Meta-analyses were performed by RevMan 5.2 software.
RESULTS: 21 trials with 2608 patients met the inclusion criteria. The general methodological quality of included trials was moderate to poor. Compared with conventional medicine alone, Ginkgo biboba in combination with conventional medicine was superior in improving Mini-Mental State Examination (MMSE) scores at 24 weeks for patients with Alzheimer's disease (MD 2.39, 95% CI 1.28 to 3.50, P<0.0001) and mild cognitive impairment (MD 1.90, 95% CI 1.41 to 2.39, P<0.00001), and Activity of Daily Living (ADL) scores at 24 weeks for Alzheimer's disease (MD -3.72, 95% CI -5.68 to -1.76, P=0.0002). When compared with placebo or conventional medicine in individual trials, Ginkgo biboba demonstrated similar but inconsistent findings. Adverse events were mild.
CONCLUSION: Ginkgo biloba is potentially beneficial for the improvement of cognitive function, activities of daily living, and global clinical assessment in patients with mild cognitive impairment or Alzheimer's disease. However, due to limited sample size, inconsistent findings and methodological quality of included trials, more research are warranted to confirm the effectiveness and safety of ginkgo biloba in treating mild cognitive impairment and Alzheimer's disease.

PMID 26268332
Steven T DeKosky, Jeff D Williamson, Annette L Fitzpatrick, Richard A Kronmal, Diane G Ives, Judith A Saxton, Oscar L Lopez, Gregory Burke, Michelle C Carlson, Linda P Fried, Lewis H Kuller, John A Robbins, Russell P Tracy, Nancy F Woolard, Leslie Dunn, Beth E Snitz, Richard L Nahin, Curt D Furberg, Ginkgo Evaluation of Memory (GEM) Study Investigators
Ginkgo biloba for prevention of dementia: a randomized controlled trial.
JAMA. 2008 Nov 19;300(19):2253-62. doi: 10.1001/jama.2008.683.
Abstract/Text CONTEXT: Ginkgo biloba is widely used for its potential effects on memory and cognition. To date, adequately powered clinical trials testing the effect of G. biloba on dementia incidence are lacking.
OBJECTIVE: To determine effectiveness of G. biloba vs placebo in reducing the incidence of all-cause dementia and Alzheimer disease (AD) in elderly individuals with normal cognition and those with mild cognitive impairment (MCI).
DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled clinical trial conducted in 5 academic medical centers in the United States between 2000 and 2008 with a median follow-up of 6.1 years. Three thousand sixty-nine community volunteers aged 75 years or older with normal cognition (n = 2587) or MCI (n = 482) at study entry were assessed every 6 months for incident dementia.
INTERVENTION: Twice-daily dose of 120-mg extract of G. biloba (n = 1545) or placebo (n = 1524).
MAIN OUTCOME MEASURES: Incident dementia and AD determined by expert panel consensus.
RESULTS: Five hundred twenty-three individuals developed dementia (246 receiving placebo and 277 receiving G. biloba) with 92% of the dementia cases classified as possible or probable AD, or AD with evidence of vascular disease of the brain. Rates of dropout and loss to follow-up were low (6.3%), and the adverse effect profiles were similar for both groups. The overall dementia rate was 3.3 per 100 person-years in participants assigned to G. biloba and 2.9 per 100 person-years in the placebo group. The hazard ratio (HR) for G. biloba compared with placebo for all-cause dementia was 1.12 (95% confidence interval [CI], 0.94-1.33; P = .21) and for AD, 1.16 (95% CI, 0.97-1.39; P = .11). G. biloba also had no effect on the rate of progression to dementia in participants with MCI (HR, 1.13; 95% CI, 0.85-1.50; P = .39).
CONCLUSIONS: In this study, G. biloba at 120 mg twice a day was not effective in reducing either the overall incidence rate of dementia or AD incidence in elderly individuals with normal cognition or those with MCI. Trial Registration clinicaltrials.gov Identifier: NCT00010803.

PMID 19017911
Bruno Vellas, Nicola Coley, Pierre-Jean Ousset, Gilles Berrut, Jean-François Dartigues, Bruno Dubois, Hélène Grandjean, Florence Pasquier, François Piette, Philippe Robert, Jacques Touchon, Philippe Garnier, Hélène Mathiex-Fortunet, Sandrine Andrieu, GuidAge Study Group
Long-term use of standardised Ginkgo biloba extract for the prevention of Alzheimer's disease (GuidAge): a randomised placebo-controlled trial.
Lancet Neurol. 2012 Oct;11(10):851-9. doi: 10.1016/S1474-4422(12)70206-5. Epub 2012 Sep 6.
Abstract/Text BACKGROUND: Prevention strategies are urgently needed to tackle the growing burden of Alzheimer's disease. We aimed to assess efficacy of long-term use of standardised ginkgo biloba extract for the reduction of incidence of Alzheimer's disease in elderly adults with memory complaints.
METHODS: In the randomised, parallel-group, double-blind, placebo-controlled GuidAge clinical trial, we enrolled adults aged 70 years or older who spontaneously reported memory complaints to their primary-care physician in France. We randomly allocated participants in a 1:1 ratio according to a computer-generated sequence to a twice per day dose of 120 mg standardised ginkgo biloba extract (EGb761) or matched placebo. Participants and study investigators and personnel were masked to study group assignment. Participants were followed-up for 5 years by primary-care physicians and in expert memory centres. The primary outcome was conversion to probable Alzheimer's disease in participants who received at least one dose of study drug or placebo, compared by use of the log-rank test. This study is registered with ClinicalTrials.gov, number NCT00276510.
FINDINGS: Between March, 2002, and November, 2004, we enrolled and randomly allocated 2854 participants, of whom 1406 received at least one dose of ginkgo biloba extract and 1414 received at least one dose of placebo. By 5 years, 61 participants in the ginkgo group had been diagnosed with probable Alzheimer's disease (1·2 cases per 100 person-years) compared with 73 participants in the placebo group (1·4 cases per 100 person-years; hazard ratio [HR] 0·84, 95% CI 0·60-1·18; p=0·306), but the risk was not proportional over time. Incidence of adverse events was much the same between groups. 76 participants in the ginkgo group died compared with 82 participants in the placebo group (0·94, 0·69-1·28; p=0·68). 65 participants in the ginkgo group had a stroke compared with 60 participants in the placebo group (risk ratio 1·12, 95% CI 0·77-1·63; p=0·57). Incidence of other haemorrhagic or cardiovascular events also did not differ between groups.
INTERPRETATION: Long-term use of standardised ginkgo biloba extract in this trial did not reduce the risk of progression to Alzheimer's disease compared with placebo.
FUNDING: Ipsen.

Copyright © 2012 Elsevier Ltd. All rights reserved.
PMID 22959217
Mengmeng Yang, Dan Dan Xu, Yan Zhang, Xinyou Liu, Robin Hoeven, William Chi Shing Cho
A systematic review on natural medicines for the prevention and treatment of Alzheimer's disease with meta-analyses of intervention effect of ginkgo.
Am J Chin Med. 2014;42(3):505-21. doi: 10.1142/S0192415X14500335.
Abstract/Text We performed a systematic review to evaluate the efficacy of natural medicines for the treatment of Alzheimer's disease (AD) in randomized controlled trials (RCTs). Disease-specific and intervention terms were searched in MEDLINE, EMBASE, the Cochrane Library and PsycINFO to identify RCTs for the AD intervention of natural medicines, and searched for literatures in English language. The RCTs compared natural medicines and either placebo or orthodox medication in AD patients. The quality of literature was evaluated by Jadad's score and the Cochrane assessing tool to reduce the risk of bias. Meta-analysis and the heterogeneity of results across the trials were performed. Out of the literatures, 21 clinical reports were included in this review that satisfied the particular selection criteria. Apart from Ginkgo, other treatments we came across had minimal benefits and/or the methodological quality of the available trials was poor. The meta-analyses showed that Ginkgo had better outcomes than the placebo, with the standardized mean difference (SMD) between Ginkgo and the placebo on cognition being -1.62 (95% CI: -2.69 to -0.56) and on activities of daily living being -1.55 (95% CI: -2.55 to -0.55), with the existence of significant heterogeneity across studies. The meta-analysis for assessing the prevention effect of Ginkgo against AD suggested that risk ratio (RR) is 1.06 (95% CI: 0.92 to 1.22) between Gingko and the placebo, with no significant heterogeneity across studies (test for heterogeneity, p = 0.49). Our results suggest that Ginkgo may help established AD patients with cognitive symptoms but cannot prevent the neurodegenerative progression of the disease.

PMID 24871648
Jacqueline Birks, John Grimley Evans
Ginkgo biloba for cognitive impairment and dementia.
Cochrane Database Syst Rev. 2009 Jan 21;(1):CD003120. doi: 10.1002/14651858.CD003120.pub3. Epub 2009 Jan 21.
Abstract/Text BACKGROUND: Extracts of the leaves of the maidenhair tree, Ginkgo biloba, have long been used in China as a traditional medicine for various disorders of health. A standardized extract is widely prescribed for the treatment of a range of conditions including memory and concentration problems, confusion, depression, anxiety, dizziness, tinnitus and headache. The mechanisms of action are thought to reflect the action of several components of the extract and include increasing blood supply by dilating blood vessels, reducing blood viscosity, modification of neurotransmitter systems, and reducing the density of oxygen free radicals.
OBJECTIVES: To assess the efficacy and safety of Ginkgo biloba for dementia or cognitive decline.
SEARCH STRATEGY: The Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (CDCIG), The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL and LILACS were searched on 20 September 2007 using the terms: ginkgo*, tanakan, EGB-761, EGB761, "EGB 761" and gingko*. The CDCIG Specialized Register contains records from all major health care databases (The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS) as well as from many trials databases and grey literature sources.
SELECTION CRITERIA: Randomized, double-blind studies, in which extracts of Ginkgo biloba at any strength and over any period were compared with placebo for their effects on people with acquired cognitive impairment, including dementia, of any degree of severity.
DATA COLLECTION AND ANALYSIS: Data were extracted from the published reports of the included studies, pooled where appropriate and the treatment effects or the risks and benefits estimated.
MAIN RESULTS: 36 trials were included but most were small and of duration less than three months. Nine trials were of six months duration (2016 patients). These longer trials were the more recent trials and generally were of adequate size, and conducted to a reasonable standard. Most trials tested the same standardised preparation of Ginkgo biloba, EGb 761, at different doses, which are classified as high or low. The results from the more recent trials showed inconsistent results for cognition, activities of daily living, mood, depression and carer burden. Of the four most recent trials to report results three found no difference between Ginkgo biloba and placebo, and one found very large treatment effects in favour of Ginkgo biloba.There are no significant differences between Ginkgo biloba and placebo in the proportion of participants experiencing adverse events.A subgroup analysis including only patients diagnosed with Alzheimer's disease (925 patients from nine trials) also showed no consistent pattern of any benefit associated with Ginkgo biloba.
AUTHORS' CONCLUSIONS: Ginkgo biloba appears to be safe in use with no excess side effects compared with placebo. Many of the early trials used unsatisfactory methods, were small, and publication bias cannot be excluded. The evidence that Ginkgo biloba has predictable and clinically significant benefit for people with dementia or cognitive impairment is inconsistent and unreliable.

PMID 19160216
Stefan Weinmann, Stephanie Roll, Christoph Schwarzbach, Christoph Vauth, Stefan N Willich
Effects of Ginkgo biloba in dementia: systematic review and meta-analysis.
BMC Geriatr. 2010 Mar 17;10:14. doi: 10.1186/1471-2318-10-14. Epub 2010 Mar 17.
Abstract/Text BACKGROUND: The benefit of Ginkgo biloba has been discussed controversially. The aim of this review was to assess the effects of Ginkgo biloba in Alzheimer's disease as well as vascular and mixed dementia covering a variety of outcome domains.
METHODS: We searched MEDLINE, EMBASE, the Cochrane databases, CINAHL and PsycINFO for controlled trials of ginkgo for Alzheimer's, vascular or mixed dementia. Studies had to be of a minimum of 12 weeks duration with at least ten participants per group. Clinical characteristics and outcomes were extracted. Meta-analysis results were expressed as risk ratios or standardized mean differences (SMD) in scores.
RESULTS: Nine trials using the standardized extract EGb761(R) met our inclusion criteria. Trials were of 12 to 52 weeks duration and included 2372 patients in total. In the meta-analysis, the SMDs in change scores for cognition were in favor of ginkgo compared to placebo (-0.58, 95% confidence interval [CI] -1.14; -0.01, p = 0.04), but did not show a statistically significant difference from placebo for activities in daily living (ADLs) (SMD = -0.32, 95% CI -0.66; 0.03, p = 0.08). Heterogeneity among studies was high. For the Alzheimer subgroup, the SMDs for ADLs and cognition outcomes were larger than for the whole group of dementias with statistical superiority for ginkgo also for ADL outcomes (SMD = -0.44, 95% CI -0.77; -0.12, p = 0.008). Drop-out rates and side effects did not differ between ginkgo and placebo. No consistent results were available for quality of life and neuropsychiatric symptoms, possibly due to the heterogeneity of the study populations.
CONCLUSIONS: Ginkgo biloba appears more effective than placebo. Effect sizes were moderate, while clinical relevance is, similar to other dementia drugs, difficult to determine.

PMID 20236541
Young Ho Lee, Jin-Hyun Woo, Seong Jae Choi, Jong Dae Ji, Gwan Gyu Song
Effect of glucosamine or chondroitin sulfate on the osteoarthritis progression: a meta-analysis.
Rheumatol Int. 2010 Jan;30(3):357-63. doi: 10.1007/s00296-009-0969-5. Epub 2009 Jun 21.
Abstract/Text The aim of this study was to assess the structural efficacies of daily glucosamine sulfate and chondroitin sulfate in patients with knee osteoarthritis (OA). The authors surveyed randomized controlled studies that examined the effects of long-term daily glucosamine sulfate and chondroitin sulfate on joint space narrowing (JSN) in knee OA patients using the Medline and the Cochrane Controlled Trials Register, and by performing manual searches. Meta-analysis was performed using a fixed effect model because no between-study heterogeneity was evident. Six studies involving 1,502 cases were included in this meta-analysis, which consisted of two studies on glucosamine sulfate and four studies on chondroitin sulfate. Glucosamine sulfate did not show a significant effect versus controls on minimum JSN over the first year of treatment (SMD 0.078, 95% CI -0.116 to -0.273, P = 0.429). However, after 3 years of treatment, glucosamine sulfate revealed a small to moderate protective effect on minimum JSN (SMD 0.432, 95% CI 0.235-0.628, P < 0.001). The same was observed for chondroitin sulfate, which had a small but significant protective effect on minimum JSN after 2 years (SMD 0.261, 95% CI 0.131-0.392, P < 0.001). This meta-analysis of available data shows that glucosamine and chondroitin sulfate may delay radiological progression of OA of the knee after daily administration for over 2 or 3 years.

PMID 19544061
Jos Runhaar, Rianne M Rozendaal, Marienke van Middelkoop, Hans J W Bijlsma, Michael Doherty, Krysia S Dziedzic, L Stefan Lohmander, Timothy McAlindon, Weiya Zhang, Sita Bierma Zeinstra
Subgroup analyses of the effectiveness of oral glucosamine for knee and hip osteoarthritis: a systematic review and individual patient data meta-analysis from the OA trial bank.
Ann Rheum Dis. 2017 Nov;76(11):1862-1869. doi: 10.1136/annrheumdis-2017-211149. Epub 2017 Jul 28.
Abstract/Text OBJECTIVE: To evaluate the effectiveness of oral glucosamine in subgroups of people with hip or knee osteoarthritis (OA) based on baseline pain severity, body mass index (BMI), sex, structural abnormalities and presence of inflammation using individual patient data.
METHODS: After a systematic search of the literature and clinical trial registries, all randomised controlled trials (RCTs) evaluating the effect of any oral glucosamine substance in patients with clinically or radiographically defined hip or knee OA were contacted. As a minimum, pain, age, sex and BMI at baseline and pain as an outcome measure needed to be assessed.
RESULTS: Of 21 eligible studies, six (n=1663) shared their trial data with the OA Trial Bank. Five trials (all independent of industry, n=1625) compared glucosamine with placebo, representing 55% of the total number of participants in all published placebo-controlled RCTs. Glucosamine was no better than placebo for pain or function at short (3 months) and long-term (24 months) follow-up. Glucosamine was also no better than placebo among the predefined subgroups. Stratification for knee OA and type of glucosamine did not alter these results.
CONCLUSIONS: Although proposed and debated for several years, open trial data are not widely made available for studies of glucosamine for OA, especially those sponsored by industry. Currently, there is no good evidence to support the use of glucosamine for hip or knee OA and an absence of evidence to support specific consideration of glucosamine for any clinically relevant OA subgroup according to baseline pain severity, BMI, sex, structural abnormalities or presence of inflammation.

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
PMID 28754801
Xiaoyue Zhu, Lingli Sang, Dandong Wu, Jiesheng Rong, Liying Jiang
Effectiveness and safety of glucosamine and chondroitin for the treatment of osteoarthritis: a meta-analysis of randomized controlled trials.
J Orthop Surg Res. 2018 Jul 6;13(1):170. doi: 10.1186/s13018-018-0871-5. Epub 2018 Jul 6.
Abstract/Text OBJECTIVE: To assess the symptomatic effectiveness and safety of oral symptomatic slow-acting drugs (SYSADOAs) on the treatment of knee and/or hip osteoarthritis, such as chondroitin, glucosamine, and combination treatment with chondroitin plus glucosamine.
METHODS: We searched electronic database including PubMed, Embase, Cochrane Library, and the reference lists of relevant articles published from inception to May 22, 2018. An updated meta-analysis was performed to assess the effectiveness of these slow-acting drugs for osteoarthritis.
RESULTS: Twenty-six articles describing 30 trials met our inclusion criteria and were included in the meta-analysis. The estimates between chondroitin and placebo showed that chondroitin could alleviate pain symptoms and improve function. Compared with placebo, glucosamine proved significant effect only on stiffness improvement. However, the combination therapy did not have enough evidence to be superior to placebo. Additionally, there was no significant difference in the incidence of AEs and discontinuations of AEs when compared with placebo.
CONCLUSIONS: Given the effectiveness of these symptomatic slow-acting drugs, oral chondroitin is more effective than placebo on relieving pain and improving physical function. Glucosamine showed effect on stiffness outcome. Regarding on the limited number of combination therapy, further studies need to investigate the accurate effectiveness. This information accompanied with the tolerability and economic costs of included treatments would be conducive to making decisions for clinicians.

PMID 29980200
O Bruyere, K Pavelka, L C Rovati, J Gatterová, G Giacovelli, M Olejarová, R Deroisy, J Y Reginster
Total joint replacement after glucosamine sulphate treatment in knee osteoarthritis: results of a mean 8-year observation of patients from two previous 3-year, randomised, placebo-controlled trials.
Osteoarthritis Cartilage. 2008 Feb;16(2):254-60. doi: 10.1016/j.joca.2007.06.011. Epub 2007 Jul 27.
Abstract/Text OBJECTIVE: To assess the incidence of Total Joint Replacement (TJR) during the long-term follow-up of patients with knee osteoarthritis (OA) formerly receiving treatment with glucosamine sulphate or placebo.
METHODS: Knee OA patients participating in two previous randomised, placebo-controlled, double-blind, 3-year trials of glucosamine sulphate and receiving treatment for at least 12 months, were systematically contacted to participate in a long-term follow-up retrospective assessment of the incidence of total knee replacement.
RESULTS: Out of 340 patients with at least 12 months of treatment, 275 (i.e., 81%) could be retrieved and interviewed for the present evaluation: 131 formerly on placebo and 144 on glucosamine sulphate. There were no differences in baseline disease characteristics between groups or with the patients lost to follow-up. The mean duration of follow-up was approximately 5 years after trial termination and treatment discontinuation, making up a total of 2178 patient-years of observation (including treatment and follow-up). Total knee replacement had occurred in over twice as many patients from the placebo group, 19/131 (14.5%), than in those formerly receiving glucosamine sulphate, 9/144 (6.3%) (P=0.024, chi-square test), with a Relative Risk that was therefore 0.43 (95% confidence interval (CI): 0.20-0.92), i.e., a 57% decrease compared with placebo. The Kaplan Meier/Log-Rank test survival analysis confirmed a significantly decreased (P=0.026) cumulative incidence of total knee replacements in patients who had received glucosamine sulphate. A pharmacoeconomic analysis in a subgroup of subjects suggested that patients formerly on glucosamine sulphate had recurred to less symptomatic medications and use of other health resources than those from the placebo group during the last year of follow-up.
CONCLUSIONS: Treatment of knee OA with glucosamine sulphate for at least 12 months and up to 3 years may prevent TJR in an average follow-up of 5 years after drug discontinuation.

PMID 17681803
Florent Richy, Olivier Bruyere, Olivier Ethgen, Michel Cucherat, Yves Henrotin, Jean-Yves Reginster
Structural and symptomatic efficacy of glucosamine and chondroitin in knee osteoarthritis: a comprehensive meta-analysis.
Arch Intern Med. 2003 Jul 14;163(13):1514-22. doi: 10.1001/archinte.163.13.1514.
Abstract/Text OBJECTIVE: To assess the structural and symptomatic efficacy of oral glucosamine sulfate and chondroitin sulfate in knee osteoarthritis through independent meta-analyses of their effects on joint space narrowing, Lequesne Index, Western Ontario MacMaster University Osteoarthritis Index (WOMAC), visual analog scale for pain, mobility, safety, and response to treatment.
METHODS: An exhaustive systematic research of randomized, placebo-controlled clinical trials published or performed between January 1980 and March 2002 that assessed the efficacy of oral glucosamine or chondroitin on gonarthrosis was performed using MEDLINE, PREMEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Current Contents, BIOSIS Previews, HealthSTAR, EBM Reviews, manual review of the literature and congressional abstracts, and direct contact with the authors and manufacturers of glucosamine and chondroitin. Inclusion, quality scoring, and data abstraction were performed systematically by 2 independent reviewers who were blinded to sources and authors. Conservative approaches were used for clear assessment of potential efficacy.
RESULTS: Our results demonstrated a highly significant efficacy of glucosamine on all outcomes, including joint space narrowing and WOMAC. Chondroitin was found to be effective on Lequesne Index, visual analog scale pain, mobility, and responding status. Safety was excellent for both compounds.
CONCLUSIONS: Our study demonstrates the structural efficacy of glucosamine and indistinguishable symptomatic efficacies for both compounds. Regarding the relatively sparse data on glucosamine and joint space narrowing and the absence of data on structural effects of chondroitin, further studies are needed to investigate the relationship among time, dose, patient baseline characteristics, and structural efficacy for an accurate, disease-modifying characterization of these 2 compounds.

PMID 12860572
Nalinee Poolsup, Chutamanee Suthisisang, Patchareeya Channark, Wararat Kittikulsuth
Glucosamine long-term treatment and the progression of knee osteoarthritis: systematic review of randomized controlled trials.
Ann Pharmacother. 2005 Jun;39(6):1080-7. doi: 10.1345/aph.1E576. Epub 2005 Apr 26.
Abstract/Text OBJECTIVE: To investigate the structural and symptomatic efficacy and safety of glucosamine in knee osteoarthritis (OA).
DATA SOURCES: Clinical trials of glucosamine were identified through electronic searches (MEDLINE, EMBASE, BIOSIS, EMB review, the Cochrane Library) using the key words glucosamine, osteoarthritis, degenerative joint disease, degenerative arthritis, osteoarthrosis, gonarthrosis, knee, disease progression, and clinical trial. The bibliographic databases were searched from their respective inception dates to August 2004. We also hand-searched reference lists of relevant articles.
STUDY SELECTION AND DATA EXTRACTION: Studies were included if they were double-blind, randomized, controlled trials that evaluated oral glucosamine long-term treatment in knee OA; lasting at least one year; and reporting as outcome measures the symptom severity and disease progression as assessed by joint space narrowing. Two authors interpreted data independently. Disagreements were resolved through discussion.
DATA SYNTHESIS: Glucosamine sulfate was more effective than placebo in delaying structural progression in knee OA. The risk of disease progression was reduced by 54% (pooled RR 0.46; 95% CI 0.28 to 0.73; p = 0.0011). The number-needed-to-treat was 9 (95% CI 6 to 20). The pooled effect sizes for pain reduction and improvement in physical function were 0.41 (95% CI 0.21 to 0.60; p < 0.0001) and 0.46 (95% CI 0.27 to 0.66; p < 0.0001), respectively, in favor of glucosamine sulfate. Glucosamine sulfate caused no more adverse effects than placebo.
CONCLUSIONS: The available evidence suggests that glucosamine sulfate may be effective and safe in delaying the progression and improving the symptoms of knee OA. Due to the sparse data on structural efficacy and safety, further studies are warranted.

PMID 15855241
Daniel O Clegg, Domenic J Reda, Crystal L Harris, Marguerite A Klein, James R O'Dell, Michele M Hooper, John D Bradley, Clifton O Bingham, Michael H Weisman, Christopher G Jackson, Nancy E Lane, John J Cush, Larry W Moreland, H Ralph Schumacher, Chester V Oddis, Frederick Wolfe, Jerry A Molitor, David E Yocum, Thomas J Schnitzer, Daniel E Furst, Allen D Sawitzke, Helen Shi, Kenneth D Brandt, Roland W Moskowitz, H James Williams
Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis.
N Engl J Med. 2006 Feb 23;354(8):795-808. doi: 10.1056/NEJMoa052771.
Abstract/Text BACKGROUND: Glucosamine and chondroitin sulfate are used to treat osteoarthritis. The multicenter, double-blind, placebo- and celecoxib-controlled Glucosamine/chondroitin Arthritis Intervention Trial (GAIT) evaluated their efficacy and safety as a treatment for knee pain from osteoarthritis.
METHODS: We randomly assigned 1583 patients with symptomatic knee osteoarthritis to receive 1500 mg of glucosamine daily, 1200 mg of chondroitin sulfate daily, both glucosamine and chondroitin sulfate, 200 mg of celecoxib daily, or placebo for 24 weeks. Up to 4000 mg of acetaminophen daily was allowed as rescue analgesia. Assignment was stratified according to the severity of knee pain (mild [N=1229] vs. moderate to severe [N=354]). The primary outcome measure was a 20 percent decrease in knee pain from baseline to week 24.
RESULTS: The mean age of the patients was 59 years, and 64 percent were women. Overall, glucosamine and chondroitin sulfate were not significantly better than placebo in reducing knee pain by 20 percent. As compared with the rate of response to placebo (60.1 percent), the rate of response to glucosamine was 3.9 percentage points higher (P=0.30), the rate of response to chondroitin sulfate was 5.3 percentage points higher (P=0.17), and the rate of response to combined treatment was 6.5 percentage points higher (P=0.09). The rate of response in the celecoxib control group was 10.0 percentage points higher than that in the placebo control group (P=0.008). For patients with moderate-to-severe pain at baseline, the rate of response was significantly higher with combined therapy than with placebo (79.2 percent vs. 54.3 percent, P=0.002). Adverse events were mild, infrequent, and evenly distributed among the groups.
CONCLUSIONS: Glucosamine and chondroitin sulfate alone or in combination did not reduce pain effectively in the overall group of patients with osteoarthritis of the knee. Exploratory analyses suggest that the combination of glucosamine and chondroitin sulfate may be effective in the subgroup of patients with moderate-to-severe knee pain. (ClinicalTrials.gov number, NCT00032890.).

Copyright 2006 Massachusetts Medical Society.
PMID 16495392
Steven C Vlad, Michael P LaValley, Timothy E McAlindon, David T Felson
Glucosamine for pain in osteoarthritis: why do trial results differ?
Arthritis Rheum. 2007 Jul;56(7):2267-77. doi: 10.1002/art.22728.
Abstract/Text OBJECTIVE: Investigators in trials of glucosamine report a range of estimates for efficacy, making conclusions difficult. We undertook this study to identify factors that explain heterogeneity in trials of glucosamine.
METHODS: We searched for reports of trial results in Ovid Medline, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and proceedings of scientific conferences. We selected reports of randomized, double-blind, placebo-controlled trials of glucosamine for pain from osteoarthritis of the knee or hip. We extracted data regarding features of design, subjects, and markers of industry involvement, including industry funding, whether a drug was supplied by industry, industry participation, and industry-affiliated authorship. We examined which factors best accounted for differences in the effect sizes of studies grouped by these characteristics, and we examined changes in I(2), a measure of heterogeneity.
RESULTS: Fifteen trials met our inclusion criteria. The summary effect size was 0.35 (95% confidence interval 0.14, 0.56). I(2) was 0.80. Except for allocation concealment, no feature of study design explained this substantial heterogeneity. Summary effect sizes ranged from 0.05 to 0.16 in trials without industry involvement, but the range was 0.47-0.55 in trials with industry involvement. The effect size was 0.06 for trials using glucosamine hydrochloride and 0.44 for trials using glucosamine sulfate. Trials using Rottapharm products had an effect size of 0.55, compared with 0.11 for the rest.
CONCLUSION: Heterogeneity among trials of glucosamine is larger than would be expected by chance. Glucosamine hydrochloride is not effective. Among trials with industry involvement, effect sizes were consistently higher. Potential explanations include different glucosamine preparations, inadequate allocation concealment, and industry bias.

PMID 17599746
Simon Wandel, Peter Jüni, Britta Tendal, Eveline Nüesch, Peter M Villiger, Nicky J Welton, Stephan Reichenbach, Sven Trelle
Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: network meta-analysis.
BMJ. 2010 Sep 16;341:c4675. Epub 2010 Sep 16.
Abstract/Text OBJECTIVE: To determine the effect of glucosamine, chondroitin, or the two in combination on joint pain and on radiological progression of disease in osteoarthritis of the hip or knee. Design Network meta-analysis. Direct comparisons within trials were combined with indirect evidence from other trials by using a Bayesian model that allowed the synthesis of multiple time points.
MAIN OUTCOME MEASURE: Pain intensity. Secondary outcome was change in minimal width of joint space. The minimal clinically important difference between preparations and placebo was prespecified at -0.9 cm on a 10 cm visual analogue scale.
DATA SOURCES: Electronic databases and conference proceedings from inception to June 2009, expert contact, relevant websites. Eligibility criteria for selecting studies Large scale randomised controlled trials in more than 200 patients with osteoarthritis of the knee or hip that compared glucosamine, chondroitin, or their combination with placebo or head to head. Results 10 trials in 3803 patients were included. On a 10 cm visual analogue scale the overall difference in pain intensity compared with placebo was -0.4 cm (95% credible interval -0.7 to -0.1 cm) for glucosamine, -0.3 cm (-0.7 to 0.0 cm) for chondroitin, and -0.5 cm (-0.9 to 0.0 cm) for the combination. For none of the estimates did the 95% credible intervals cross the boundary of the minimal clinically important difference. Industry independent trials showed smaller effects than commercially funded trials (P=0.02 for interaction). The differences in changes in minimal width of joint space were all minute, with 95% credible intervals overlapping zero. Conclusions Compared with placebo, glucosamine, chondroitin, and their combination do not reduce joint pain or have an impact on narrowing of joint space. Health authorities and health insurers should not cover the costs of these preparations, and new prescriptions to patients who have not received treatment should be discouraged.

PMID 20847017
Toru Ogata, Yuki Ideno, Masami Akai, Atsushi Seichi, Hiroshi Hagino, Tsutomu Iwaya, Toru Doi, Keiko Yamada, Ai-Zhen Chen, Yingzi Li, Kunihiko Hayashi
Effects of glucosamine in patients with osteoarthritis of the knee: a systematic review and meta-analysis.
Clin Rheumatol. 2018 Sep;37(9):2479-2487. doi: 10.1007/s10067-018-4106-2. Epub 2018 Apr 30.
Abstract/Text Osteoarthritis (OA) of the knee is one of the main causes of mobility decline in the elderly. Non-surgical treatments such as administration of supplements to strengthen the joint cartilage matrix have become popular not only for pain relief but also for joint preservation. Glucosamine has been used in many countries based on the increasing evidence of its effectiveness for OA. Although there are many previous studies and systematic reviews, the findings vary and different conclusions have been drawn. We aimed to review recent randomized controlled trials on glucosamine for knee OA to reveal up-to-date findings about this supplement. We also performed a meta-analysis of some of the outcomes to overcome the unsolved bias in each study. Eighteen articles written between 2003 and 2016 were analyzed. Many used visual analogue scale (VAS) pain scores and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), which were assessed in our meta-analysis. We found a marginally favorable effect of glucosamine on VAS pain scores. The effect on knee function, as measured by the WOMAC, was small and not significant. A newly established knee OA scale, the Japanese Knee Osteoarthritis Measure (JKOM), is commonly used in Japan. Although the number of subjects was small, the JKOM meta-analysis indicated that glucosamine is superior to a placebo in alleviating knee OA symptoms. Given this, we concluded that glucosamine has the potential to alleviate knee OA pain. Further studies are needed to evaluate the effect of glucosamine on knee function and joint preservation, as well as to evaluate the combined effect with other components, such as chondroitin.

PMID 29713967
Marlene Fransen, Maria Agaliotis, Lillias Nairn, Milana Votrubec, Lisa Bridgett, Steve Su, Stephen Jan, Lyn March, John Edmonds, Robyn Norton, Mark Woodward, Richard Day, LEGS study collaborative group
Glucosamine and chondroitin for knee osteoarthritis: a double-blind randomised placebo-controlled clinical trial evaluating single and combination regimens.
Ann Rheum Dis. 2015 May;74(5):851-8. doi: 10.1136/annrheumdis-2013-203954. Epub 2014 Jan 6.
Abstract/Text OBJECTIVE: To determine if the dietary supplements, glucosamine and/or chondroitin, result in reduced joint space narrowing (JSN) and pain among people with symptomatic knee osteoarthritis.
METHODS: A double-blind randomised placebo-controlled clinical trial with 2-year follow-up. 605 participants, aged 45-75 years, reporting chronic knee pain and with evidence of medial tibio-femoral compartment narrowing (but retaining >2 mm medial joint space width) were randomised to once daily: glucosamine sulfate 1500 mg (n=152), chondroitin sulfate 800 mg (n=151), both dietary supplements (n=151) or matching placebo capsules (n=151). JSN (mm) over 2 years was measured from digitised knee radiographs. Maximum knee pain (0-10) was self-reported in a participant diary for 7 days every 2 months over 1 year.
RESULTS: After adjusting for factors associated with structural disease progression (gender, body mass index (BMI), baseline structural disease severity and Heberden's nodes), allocation to the dietary supplement combination (glucosamine-chondroitin) resulted in a statistically significant (p=0.046) reduction of 2-year JSN compared to placebo: mean difference 0.10 mm (95% CI 0.002 mm to 0.20 mm); no significant structural effect for the single treatment allocations was detected. All four allocation groups demonstrated reduced knee pain over the first year, but no significant between-group differences (p=0.93) were detected. 34 (6%) participants reported possibly-related adverse medical events over the 2-year follow-up period.
CONCLUSIONS: Allocation to the glucosamine-chondroitin combination resulted in a statistically significant reduction in JSN at 2 years. While all allocation groups demonstrated reduced knee pain over the study period, none of the treatment allocation groups demonstrated significant symptomatic benefit above placebo.
TRIAL REGISTRATION CLINICALTRIALSGOV IDENTIFIER: NCT00513422; http://www.clinicaltrials.gov.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
PMID 24395557
Alexander G Schauss, Amy Clewell, Lajos Balogh, Ilona Pasics Szakonyi, Istvan Financsek, János Horváth, Julianna Thuroczy, Erzsébet Béres, Adél Vértesi, Gabor Hirka
Safety evaluation of an açai-fortified fruit and berry functional juice beverage (MonaVie Active(®)).
Toxicology. 2010 Nov 28;278(1):46-54. doi: 10.1016/j.tox.2010.04.017. Epub 2010 May 7.
Abstract/Text The safety of an açai (Euterpe oleracea Mart.) pulp enriched fruit and berry juice, MonaVie Active®, fortified with the functional ingredient, glucosamine, was studied. The beverage was found not to be mutagenic, clastogenic, cytotoxic, or genotoxic, as determined by the bacterial reverse mutation assay, chromosomal aberration assay, mouse micronucleus assay, and mammalian cell gene mutation (L5178Y) assay. The single dose LD50 based on a 14-day acute oral toxicity study is greater than 20,000 mg/kg bw, the highest dose tested. In a repeat dose 90-day oral subchronic toxicity study by gavage, 220 animals were randomly assigned to a control group, an untreated group, or one of three experimental groups (10, 20 and 40 g/kg bw). No treatment-related significant changes in body weight, food and water consumption, ophthalmology, organ weights, urinanalysis, hematological and clinical chemistry, or gross pathology, were observed in surviving animals compared to the control groups. Three animals died midway through the observation period (male, 20 g/kg bw/day; male 40 g/kg bw/day; and, female, 10 g/kg bw/day). These animals died without preceding clinical symptoms, histopathological lesions, or evidence of injury to tissue or organs except for signs of suffocation/aspiration congestion, which was concluded to be due to problems with the gavage administration of the fluid test article, and not due to the test article itself. The NOEAL was determined to be 40 g/kg bw/day for male and female rats, which was the highest dose tested. Phylloquinone (vitamin K1) content averaged 21.7 μg/100 g, comparable to amounts found in iceberg lettuce. In conclusion, the results provide additional experimental evidence that MonaVie Active® juice is non-toxic.

Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.
PMID 20452390
E Sadowska-Krępa, B Kłapcińska, T Podgórski, B Szade, K Tyl, A Hadzik
Effects of supplementation with acai (Euterpe oleracea Mart.) berry-based juice blend on the blood antioxidant defence capacity and lipid profile in junior hurdlers. A pilot study.
Biol Sport. 2015 Jun;32(2):161-8. doi: 10.5604/20831862.1144419. Epub 2015 Mar 15.
Abstract/Text The purpose of this pilot study was to examine whether regular consumption of an acai berry-based juice blend would affect sprint performance and improve blood antioxidant status and lipid profile in junior athletes. Seven junior hurdlers (17.5±1.2 years) taking part in a pre-season conditioning camp were supplemented once a day, for six weeks, with 100 ml of the juice blend. At the start and the end of the camp the athletes performed a 300-m sprint running test on an outdoor track. Blood samples were taken before and immediately after the test and after 1 h of recovery. Blood antioxidant status was evaluated based on activities of antioxidant enzymes (superoxide dismutase [SOD], catalase [CAT], glutathione peroxidase [GSH-Px], glutathione reductase [GR]), concentrations of non-enzymatic antioxidants (reduced glutathione [GSH], uric acid), total plasma polyphenols, ferric reducing ability of plasma (FRAP), thiobarbituric acid reactive substances (TBARS) and activities of creatine kinase (CK) and lactate dehydrogenase (LDH) as muscle damage markers. In order to evaluate potential health benefits of the acai berry, the post-treatment changes in lipid profile parameters (triglycerides, cholesterol and its fractions) were analysed. Six weeks' consumption of acai berry-based juice blend had no effect on sprint performance, but it led to a marked increase in the total antioxidant capacity of plasma, attenuation of the exercise-induced muscle damage, and a substantial improvement of serum lipid profile. These findings strongly support the view of the health benefits of supplementation with the acai berry-based juice blend, mainly attributed to its high total polyphenol content and the related high in vivo antioxidant and hypocholesterolaemic activities of this supplement.

PMID 26060341
Randah M Alqurashi, Laura A Galante, Ian R Rowland, Jeremy Pe Spencer, Daniel M Commane
Consumption of a flavonoid-rich açai meal is associated with acute improvements in vascular function and a reduction in total oxidative status in healthy overweight men.
Am J Clin Nutr. 2016 Nov;104(5):1227-1235. doi: 10.3945/ajcn.115.128728. Epub 2016 Sep 28.
Abstract/Text BACKGROUND: Açai (Euterpe oleracea) is a polyphenol-rich fruit marketed as beneficial for health. Experimental data showing improvements in health markers arising from açai consumption in humans is limited.
OBJECTIVE: The objective of the present study was to investigate the effect of açai consumption on acute changes in vascular function and on other disease risk markers, including postprandial plasma insulin, glucose, and oxidative stress.
DESIGN: Twenty-three healthy male volunteers, aged 30-65 y and with a body mass index (in kg/m(2)) of 25-30, completed a randomized, controlled, high-fat challenge, double-blind, crossover, acute dietary intervention trial. The volunteers consumed either an açai-based smoothie (AS) or a macronutrient-matched control smoothie (PS) together with a high-fat breakfast meal challenge. The primary endpoint was the assessment of endothelial function in the brachial artery by flow-mediated dilatation (FMD).
RESULTS: The acute consumption of an AS containing 694 mg total phenolics improved vascular function, with postprandial increases in FMD from baseline of 1.4% at 2 h compared with 0.4% after consumption of the PS (P = 0.001) and increases at 6 h of 0.8% for the AS compared with -0.3% for the PS (P < 0.001). There was also a significantly lower incremental area under the curve (iAUC) for total peroxide oxidative status after açai consumption relative to the control. No significant changes were observed in blood pressure, heart rate, or postprandial glucose response. However, the first postprandial insulin peak (after breakfast) and the iAUC for insulin were elevated for the AS relative to the PS.
CONCLUSIONS: In this acute study in overweight men, açai consumption was associated with improvements in vascular function, which may lower the risk of a cardiovascular event. Future intervention studies, perhaps with a chronic design, in wider populations and with other biomarkers of disease risk are needed to fully elucidate the benefits of açai to health. This trial was registered at clinicaltrials.gov as NCT02292329.

© 2016 American Society for Nutrition.
PMID 27680990
Hyemee Kim, Sunday Y Simbo, Chuo Fang, Lilly McAlister, Andrea Roque, Nivedita Banerjee, Stephen T Talcott, Hongwei Zhao, Richard B Kreider, Susanne U Mertens-Talcott
Açaí (Euterpe oleracea Mart.) beverage consumption improves biomarkers for inflammation but not glucose- or lipid-metabolism in individuals with metabolic syndrome in a randomized, double-blinded, placebo-controlled clinical trial.
Food Funct. 2018 Jun 20;9(6):3097-3103. doi: 10.1039/c8fo00595h.
Abstract/Text Açaí (Euterpe oleracea Mart.) berries, characterized by high polyphenol concentrations (predominantly anthocyanins), have demonstrated anti-inflammatory and anti-diabetic activities. The study objective was to determine the modulation of lipid and glucose-metabolism, as well as oxidative stress and inflammation, by an açaí-beverage (containing 1139 mg L-1 gallic acid equivalents of total polyphenolics) in 37 individuals with metabolic syndrome (BMI 33.5 ± 6.7 kg m-2) who were randomized to consume 325 mL twice per d of a placebo control or açaí-beverage for 12 weeks. Anthropometric measurements, dietary intake, and blood and urine samples were collected at baseline and after 12 weeks of consumption. Two functional biomarkers, plasma level of interferon gamma (IFN-γ) and urinary level of 8-isoprostane, were significantly decreased after 12 weeks of açaí consumption compared to the placebo control (p = 0.0141 and 0.0099, respectively). No significant modification of biomarkers for lipid- and glucose-metabolism was observed in this study. Findings from this small pilot study provide a weak indication that the selected dose of açaí polyphenols may be beneficial in metabolic syndrome as only two biomarkers for inflammation and oxidative stress were improved over 12 weeks. Follow-up studies should be conducted with higher polyphenol-doses before drawing conclusions regarding the efficacy of açaí polyphenols in metabolic syndrome.

PMID 29850709
Chih-Hung Wang, Cheng-Chung Fang, Nai-Chuan Chen, Sot Shih-Hung Liu, Ping-Hsun Yu, Tao-Yu Wu, Wei-Ting Chen, Chien-Chang Lee, Shyr-Chyr Chen
Cranberry-containing products for prevention of urinary tract infections in susceptible populations: a systematic review and meta-analysis of randomized controlled trials.
Arch Intern Med. 2012 Jul 9;172(13):988-96. doi: 10.1001/archinternmed.2012.3004.
Abstract/Text BACKGROUND: Urinary tract infection (UTI) is one of the most commonly acquired bacterial infections. Cranberry-containing products have long been used as a folk remedy to prevent UTIs. The aims of this study were to evaluate cranberry-containing products for the prevention of UTI and to examine the factors influencing their effectiveness.
METHODS: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were systemically searched from inception to November 2011 for randomized controlled trials that compared prevention of UTIs in users of cranberry-containing products vs placebo or nonplacebo controls. There were no restrictions for language, population, or publication year.
RESULTS: Thirteen trials, including 1616 subjects, were identified for qualitative synthesis from 414 potentially relevant references; 10 of these trials, including a total of 1494 subjects, were further analyzed in quantitative synthesis. The random-effects pooled risk ratio (RR) for cranberry users vs nonusers was 0.62 (95% CI, 0.49-0.80), with a moderate degree of heterogeneity (I(2) = 43%) after the exclusion of 1 outlier study. On subgroup analysis, cranberry-containing products seemed to be more effective in several subgroups, including women with recurrent UTIs (RR, 0.53; 95% CI, 0.33-0.83) (I(2) = 0%), female populations (RR, 0.49; 95% CI, 0.34-0.73) (I(2) = 34%), children (RR, 0.33; 95% CI, 0.16-0.69) (I(2) = 0%), cranberry juice drinkers (RR, 0.47; 95% CI, 0.30-0.72) (I(2) = 2%), and subjects using cranberry-containing products more than twice daily (RR, 0.58; 95% CI, 0.40-0.84) (I(2) = 18%).
CONCLUSIONS: Our findings indicate that cranberry-containing products are associated with protective effect against UTIs. However, this result should be interpreted in the context of substantial heterogeneity across trials.

PMID 22777630
Ruth G Jepson, Gabrielle Williams, Jonathan C Craig
Cranberries for preventing urinary tract infections.
Cochrane Database Syst Rev. 2012 Oct 17;10:CD001321. doi: 10.1002/14651858.CD001321.pub5. Epub 2012 Oct 17.
Abstract/Text BACKGROUND: Cranberries have been used widely for several decades for the prevention and treatment of urinary tract infections (UTIs). This is the third update of our review first published in 1998 and updated in 2004 and 2008.
OBJECTIVES: To assess the effectiveness of cranberry products in preventing UTIs in susceptible populations.
SEARCH METHODS: We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL in The Cochrane Library) and the Internet. We contacted companies involved with the promotion and distribution of cranberry preparations and checked reference lists of review articles and relevant studies.Date of search: July 2012
SELECTION CRITERIA: All randomised controlled trials (RCTs) or quasi-RCTs of cranberry products for the prevention of UTIs.
DATA COLLECTION AND ANALYSIS: Two authors independently assessed and extracted data. Information was collected on methods, participants, interventions and outcomes (incidence of symptomatic UTIs, positive culture results, side effects, adherence to therapy). Risk ratios (RR) were calculated where appropriate, otherwise a narrative synthesis was undertaken. Quality was assessed using the Cochrane risk of bias assessment tool.
MAIN RESULTS: This updated review includes a total of 24 studies (six cross-over studies, 11 parallel group studies with two arms; five with three arms, and two studies with a factorial design) with a total of 4473 participants. Ten studies were included in the 2008 update, and 14 studies have been added to this update. Thirteen studies (2380 participants) evaluated only cranberry juice/concentrate; nine studies (1032 participants) evaluated only cranberry tablets/capsules; one study compared cranberry juice and tablets; and one study compared cranberry capsules and tablets. The comparison/control arms were placebo, no treatment, water, methenamine hippurate, antibiotics, or lactobacillus. Eleven studies were not included in the meta-analyses because either the design was a cross-over study and data were not reported separately for the first phase, or there was a lack of relevant data. Data included in the meta-analyses showed that, compared with placebo, water or not treatment, cranberry products did not significantly reduce the occurrence of symptomatic UTI overall (RR 0.86, 95% CI 0.71 to 1.04) or for any the subgroups: women with recurrent UTIs (RR 0.74, 95% CI 0.42 to 1.31); older people (RR 0.75, 95% CI 0.39 to 1.44); pregnant women (RR 1.04, 95% CI 0.97 to 1.17); children with recurrent UTI (RR 0.48, 95% CI 0.19 to 1.22); cancer patients (RR 1.15 95% CI 0.75 to 1.77); or people with neuropathic bladder or spinal injury (RR 0.95, 95% CI: 0.75 to 1.20). Overall heterogeneity was moderate (I² = 55%). The effectiveness of cranberry was not significantly different to antibiotics for women (RR 1.31, 95% CI 0.85, 2.02) and children (RR 0.69 95% CI 0.32 to 1.51). There was no significant difference between gastrointestinal adverse effects from cranberry product compared to those of placebo/no treatment (RR 0.83, 95% CI 0.31 to 2.27). Many studies reported low compliance and high withdrawal/dropout problems which they attributed to palatability/acceptability of the products, primarily the cranberry juice. Most studies of other cranberry products (tablets and capsules) did not report how much of the 'active' ingredient the product contained, and therefore the products may not have had enough potency to be effective.
AUTHORS' CONCLUSIONS: Prior to the current update it appeared there was some evidence that cranberry juice may decrease the number of symptomatic UTIs over a 12 month period, particularly for women with recurrent UTIs. The addition of 14 further studies suggests that cranberry juice is less effective than previously indicated. Although some of small studies demonstrated a small benefit for women with recurrent UTIs, there were no statistically significant differences when the results of a much larger study were included. Cranberry products were not significantly different to antibiotics for preventing UTIs in three small studies. Given the large number of dropouts/withdrawals from studies (mainly attributed to the acceptability of consuming cranberry products particularly juice, over long periods), and the evidence that the benefit for preventing UTI is small, cranberry juice cannot currently be recommended for the prevention of UTIs. Other preparations (such as powders) need to be quantified using standardised methods to ensure the potency, and contain enough of the 'active' ingredient, before being evaluated in clinical studies or recommended for use.

PMID 23076891
Monique A A Caljouw, Wilbert B van den Hout, Hein Putter, Wilco P Achterberg, Herman J M Cools, Jacobijn Gussekloo
Effectiveness of cranberry capsules to prevent urinary tract infections in vulnerable older persons: a double-blind randomized placebo-controlled trial in long-term care facilities.
J Am Geriatr Soc. 2014 Jan;62(1):103-10.
Abstract/Text OBJECTIVES: To determine whether cranberry capsules prevent urinary tract infection (UTI) in long-term care facility (LTCF) residents.
DESIGN: Double-blind randomized placebo-controlled multicenter trial.
SETTING: Long-term care facilities (LTCFs).
PARTICIPANTS: LTCF residents (N = 928; 703 women, median age 84).
MEASUREMENTS: Cranberry and placebo capsules were taken twice daily for 12 months. Participants were stratified according to UTI risk (risk factors included long-term catheterization, diabetes mellitus, ≥ 1 UTI in preceding year). Main outcomes were incidence of UTI according to a clinical definition and a strict definition.
RESULTS: In participants with high UTI risk at baseline (n = 516), the incidence of clinically defined UTI was lower with cranberry capsules than with placebo (62.8 vs 84.8 per 100 person-years at risk, P = .04); the treatment effect was 0.74 (95% confidence interval (CI) = 0.57-0.97). For the strict definition, the treatment effect was 1.02 (95% CI = 0.68-1.55). No difference in UTI incidence between cranberry and placebo was found in participants with low UTI risk (n = 412).
CONCLUSION: In LTCF residents with high UTI risk at baseline, taking cranberry capsules twice daily reduces the incidence of clinically defined UTI, although it does not reduce the incidence of strictly defined UTI. No difference in incidence of UTI was found in residents with low UTI risk.

PMID 25180378
Kevin C Maki, Kerrie L Kaspar, Christina Khoo, Linda H Derrig, Arianne L Schild, Kalpana Gupta
Consumption of a cranberry juice beverage lowered the number of clinical urinary tract infection episodes in women with a recent history of urinary tract infection.
Am J Clin Nutr. 2016 Jun;103(6):1434-42. doi: 10.3945/ajcn.116.130542.
Abstract/Text BACKGROUND: Urinary tract infections (UTIs) are among the most common bacterial infections and are often treated with antibiotics. Concerns about multidrug-resistant uropathogens have pointed to the need for safe and effective UTI-prevention strategies such as cranberry consumption.
OBJECTIVE: We assessed the effects of the consumption of a cranberry beverage on episodes of clinical UTIs.
DESIGN: In this randomized, double-blind, placebo-controlled, multicenter clinical trial, women with a history of a recent UTI were assigned to consume one 240-mL serving of cranberry beverage/d (n = 185) or a placebo (n = 188) beverage for 24 wk. The primary outcome was the clinical UTI incidence density, which was defined as the total number of clinical UTI events (including multiple events per subject when applicable) per unit of observation time.
RESULTS: The dates of the random assignment of the first subject and the last subject's final visit were February 2013 and March 2015, respectively. The mean age was 40.9 y, and characteristics were similar in both groups. Compliance with study product consumption was 98%, and 86% of subjects completed the treatment period in both groups. There were 39 investigator-diagnosed episodes of clinical UTI in the cranberry group compared with 67 episodes in the placebo group (antibiotic use-adjusted incidence rate ratio: 0.61; 95% CI: 0.41, 0.91; P = 0.016). Clinical UTI with pyuria was also significantly reduced (incidence rate ratio: 0.63; 95% CI: 0.40, 0.97; P = 0.037). One clinical UTI event was prevented for every 3.2 woman-years (95% CI: 2.0, 13.1 woman-years) of the cranberry intervention. The time to UTI with culture positivity did not differ significantly between groups (HR: 0.97; 95% CI: 0.56, 1.67; P = 0.914).
CONCLUSION: The consumption of a cranberry juice beverage lowered the number of clinical UTI episodes in women with a recent history of UTI. This study was registered at clinicaltrials.gov as NCT01776021.

© 2016 American Society for Nutrition.
PMID 27251185
Jia-Yue Xia, Chao Yang, Deng-Feng Xu, Hui Xia, Li-Gang Yang, Gui-Ju Sun
Consumption of cranberry as adjuvant therapy for urinary tract infections in susceptible populations: A systematic review and meta-analysis with trial sequential analysis.
PLoS One. 2021;16(9):e0256992. doi: 10.1371/journal.pone.0256992. Epub 2021 Sep 2.
Abstract/Text The efficacy of cranberry (Vaccinium spp.) as adjuvant therapy in preventing urinary tract infections (UTIs) remains controversial. This study aims to update and determine cranberry effects as adjuvant therapy on the recurrence rate of UTIs in susceptible groups. According to PRISMA guidelines, we conducted a literature search in Web of Science, PubMed, Embase, Scopus, and the Cochrane Library from their inception dates to June 2021. We included articles with data on the incidence of UTIs in susceptible populations using cranberry-containing products. We then conducted a trial sequential analysis to control the risk of type I and type II errors. This meta-analysis included 23 trials with 3979 participants. We found that cranberry-based products intake can significantly reduce the incidence of UTIs in susceptible populations (risk ratio (RR) = 0.70; 95% confidence interval(CI): 0.59 ~ 0.83; P<0.01). We identified a relative risk reduction of 32%, 45% and 51% in women with recurrent UTIs (RR = 0.68; 95% CI: 0.56 ~ 0.81), children (RR = 0.55; 95% CI: 0.31 ~ 0.97) and patients using indwelling catheters (RR = 0.49; 95% CI: 0.33 ~ 0.73). Meanwhile, a relative risk reduction of 35% in people who use cranberry juice compared with those who use cranberry capsule or tablet was observed in the subgroup analysis (RR = 0.65; 95% CI: 0.54 ~ 0.77). The TSA result for the effects of cranberry intake and the decreased risk of UTIs in susceptible groups indicated that the effects were conclusive. In conclusion, our meta-analysis demonstrates that cranberry supplementation significantly reduced the risk of developing UTIs in susceptible populations. Cranberry can be considered as adjuvant therapy for preventing UTIs in susceptible populations. However, given the limitations of the included studies in this meta-analysis, the conclusion should be interpreted with caution.

PMID 34473789
Wilbert B van den Hout, Monique A A Caljouw, Hein Putter, Herman J M Cools, Jacobijn Gussekloo
Cost-effectiveness of cranberry capsules to prevent urinary tract infection in long-term care facilities: economic evaluation with a randomized controlled trial.
J Am Geriatr Soc. 2014 Jan;62(1):111-6.
Abstract/Text OBJECTIVES: To investigate whether the preventive use of cranberry capsules in long-term care facility (LTCF) residents is cost-effective depending on urinary tract infection (UTI) risk.
DESIGN: Economic evaluation with a randomized controlled trial.
SETTING: Long-term care facilities.
PARTICIPANTS: LTCF residents (N = 928, 703 female, median age 84), stratified according to UTI risk.
MEASUREMENTS: UTI incidence (clinically or strictly defined), survival, quality of life, quality-adjusted life years (QALYs), and costs.
RESULTS: In the weeks after a clinical UTI, participants showed a significant but moderate deterioration in quality of life, survival, care dependency, and costs. In high-UTI-risk participants, cranberry costs were estimated at €439 per year (1.00 euro = 1.37 U.S. dollar), which is €3,800 per prevented clinically defined UTI (95% confidence interval = €1,300-infinity). Using the strict UTI definition, the use of cranberry increased costs without preventing UTIs. Taking cranberry capsules had a 22% probability of being cost-effective compared with placebo (at a willingness to pay of €40,000 per QALY). In low-UTI-risk participants, use of cranberry capsules was only 3% likely to be cost-effective.
CONCLUSION: In high-UTI-risk residents, taking cranberry capsules may be effective in preventing UTIs but is not likely to be cost-effective in the investigated dosage, frequency, and setting. In low-UTI-risk LTCF residents, taking cranberry capsules twice daily is neither effective nor cost-effective.

PMID 25180379
Judith E Bosmans, Mariëlle A J Beerepoot, Jan M Prins, Gerben ter Riet, Suzanne E Geerlings
Cost-effectiveness of cranberries vs antibiotics to prevent urinary tract infections in premenopausal women: a randomized clinical trial.
PLoS One. 2014;9(4):e91939. doi: 10.1371/journal.pone.0091939. Epub 2014 Apr 4.
Abstract/Text BACKGROUND: Urinary tract infections (UTIs) are common and result in an enormous economic burden. The increasing prevalence of antibiotic-resistant microorganisms has stimulated interest in non-antibiotic agents to prevent UTIs.
OBJECTIVE: To evaluate the cost-effectiveness of cranberry prophylaxis compared to antibiotic prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX) over a 12 month period in premenopausal women with recurrent UTIs.
MATERIALS AND METHODS: An economic evaluation was performed alongside a randomized trial. Primary outcome was the number of UTIs during 12 months. Secondary outcomes included satisfaction and quality of life. Healthcare utilization was measured using questionnaires. Missing data were imputed using multiple imputation. Bootstrapping was used to evaluate the cost-effectiveness of the treatments.
RESULTS: Cranberry prophylaxis was less effective than TMP-SMX prophylaxis, but the differences in clinical outcomes were not statistically significant. Costs after 12 months in the cranberry group were statistically significantly higher than in the TMP-SMX group (mean difference €249, 95% confidence interval 70 to 516). Cost-effectiveness planes and cost-effectiveness acceptability curves showed that cranberry prophylaxis to prevent UTIs is less effective and more expensive than (dominated by) TMP-SMX prophylaxis.
CONCLUSION: In premenopausal women with recurrent UTIs, cranberry prophylaxis is not cost-effective compared to TMP-SMX prophylaxis. However, it was not possible to take into account costs attributed to increased antibiotic resistance within the framework of this randomized trial; modeling studies are recommended to investigate these costs. Moreover, although we based the dosage of cranberry extract on available evidence, this may not be the optimal dosage. Results may change when this optimal dosage is identified.
TRIAL REGISTRATION: ISRCTN.org ISRCTN50717094.

PMID 24705418
Samantha J Eells, Kiran Bharadwa, James A McKinnell, Loren G Miller
Recurrent urinary tract infections among women: comparative effectiveness of 5 prevention and management strategies using a Markov chain Monte Carlo model.
Clin Infect Dis. 2014 Jan;58(2):147-60. doi: 10.1093/cid/cit646. Epub 2013 Sep 24.
Abstract/Text BACKGROUND: Recurrent urinary tract infections (UTIs) are a common problem among women. However, comparative effectiveness strategies for managing recurrent UTIs are lacking.
METHODS: We performed a systematic literature review of management of women experiencing ≥3 UTIs per year. We then developed a Markov chain Monte Carlo model of recurrent UTI for each management strategy with ≥2 adequate trials published. We simulated a cohort that experienced 3 UTIs/year and a secondary cohort that experienced 8 UTIs/year. Model outcomes were treatment efficacy, patient and payer cost, and health-related quality of life.
RESULTS: Five strategies had ≥2 clinical trials published: (1) daily antibiotic (nitrofurantoin) prophylaxis; (2) daily estrogen prophylaxis; (3) daily cranberry prophylaxis; (4) acupuncture prophylaxis; and (5) symptomatic self-treatment. In the 3 UTIs/year model, nitrofurantoin prophylaxis was most effective, reducing the UTI rate to 0.4 UTIs/year, and the most expensive to the payer ($821/year). All other strategies resulted in payer cost savings but were less efficacious. Symptomatic self-treatment was the only strategy that resulted in patient cost savings, and was the most favorable strategy in term of cost per quality-adjusted life-year (QALY) gained.
CONCLUSIONS: Daily antibiotic use is the most effective strategy for recurrent UTI prevention compared to daily cranberry pills, daily estrogen therapy, and acupuncture. Cost savings to payers and patients were seen for most regimens, and improvement in QALYs were seen with all. Our findings provide clinically meaningful data to guide the physician-patient partnership in determining a preferred method of prevention for this common clinical problem.

PMID 24065333
Ann E Stapleton, James Dziura, Thomas M Hooton, Marsha E Cox, Yuliya Yarova-Yarovaya, Shu Chen, Kalpana Gupta
Recurrent urinary tract infection and urinary Escherichia coli in women ingesting cranberry juice daily: a randomized controlled trial.
Mayo Clin Proc. 2012 Feb;87(2):143-50. doi: 10.1016/j.mayocp.2011.10.006.
Abstract/Text OBJECTIVE: To compare the time to urinary tract infection (UTI) and the rates of asymptomatic bacteriuria and urinary P-fimbriated Escherichia coli during a 6-month period in women ingesting cranberry vs placebo juice daily.
PATIENTS AND METHODS: Premenopausal women with a history of recent UTI were enrolled from November 16, 2005, through December 31, 2008, at 2 centers and randomized to 1 of 3 arms: 4 oz of cranberry juice daily, 8 oz of cranberry juice daily, or placebo juice. Time to UTI (symptoms plus pyuria) was the main outcome. Asymptomatic bacteriuria, adherence, and adverse effects were assessed at monthly visits.
RESULTS: A total of 176 participants were randomized (120 to cranberry juice and 56 to placebo) and followed up for a median of 168 days. The cumulative rate of UTI was 0.29 in the cranberry juice group and 0.37 in the placebo group (P=.82). The adjusted hazard ratio for UTI in the cranberry juice group vs the placebo group was 0.68 (95% confidence interval, 0.33-1.39; P=.29). The proportion of women with P-fimbriated urinary E coli isolates during the intervention phase was 10 of 23 (43.5%) in the cranberry juice group and 8 of 10 (80.0%) in the placebo group (P=.07). The mean dose adherence was 91.8% and 90.3% in the cranberry juice group vs the placebo group. Minor adverse effects were reported by 24.2% of those in the cranberry juice group and 12.5% in the placebo group (P=.07).
CONCLUSION: Cranberry juice did not significantly reduce UTI risk compared with placebo. The potential protective effect we observed is consistent with previous studies and warrants confirmation in larger, well-powered studies of women with recurrent UTI. The concurrent reduction in urinary P-fimbriated E coli strains supports the biological plausibility of cranberry activity.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00128128.

Copyright © 2012 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.
PMID 22305026
Christine H Paeng, Michael Sprague, Cynthia A Jackevicius
Interaction between warfarin and cranberry juice.
Clin Ther. 2007 Aug;29(8):1730-5. doi: 10.1016/j.clinthera.2007.08.018.
Abstract/Text INTRODUCTION: Warfarin is commonly used to treat or prevent thromboembolic events. Cranberry juice has been suggested to have an interaction with warfarin. However, there have been few reported cases of warfarin-cranberry juice interaction.
CASE SUMMARY: A 78-year-old, 86-kg man receiving warfarin at a total weekly dose of 45 mg for atrial fibrillation presented at the Bakersfield Healthcare Center of the VA Greater Los Angeles Healthcare System with an international normalized ratio (INR) of 6.45, having reported drinking a half gallon of cranberry/apple juice in the week prior to the elevated INR. After discontinuation of the cranberry juice, maintaining the warfarin dose for 5 days, and resuming the warfarin at a total weekly dose of 40 mg, the INR returned to the therapeutic range of 2 to 3.
DISCUSSION: Possible warfarin-cranberry juice interactions have been reported in the literature. Case reports illustrate INR elevation associated with cranberry juice ingestion concomitantly with warfarin administration and may be associated with bleeding (eg, pericardial, gastrointestinal). In the present case report, cranberry juice was the most likely cause of the patient's elevated INR. The Naranjo probability scale score was 3, suggesting that there was a possible interaction between warfarin and cranberry juice, while the modified Naranjo scale score adapted for anticoagulants was 5, rating the interaction as probable.
CONCLUSION: The combination of warfarin administration and cranberry juice ingestion appeared to be associated with an elevated INR without bleeding in this elderly patient.

Copyright 2007 Excerpta Medica, Inc.
PMID 17919554
Gale L Hamann, Jennifer D Campbell, Christa M George
Warfarin-cranberry juice interaction.
Ann Pharmacother. 2011 Mar;45(3):e17. doi: 10.1345/aph.1P451. Epub 2011 Mar 1.
Abstract/Text OBJECTIVE: To report a case of warfarin-cranberry juice interaction, which resulted in an international normalized ratio (INR) elevation on 2 separate occasions.
CASE SUMMARY: A 46-year-old female was receiving a total weekly dose of 56 mg of warfarin. During the 4 months prior to the incident INR, her average INR was 2.0, with a range of 1.6-2.2, while taking the same weekly dose of warfarin. Her INR increased to 4.6 after drinking approximately 1.5 quarts (1420 mL) of cranberry juice cocktail daily for 2 days. Her INR 14 days later without cranberry juice cocktail consumption was 2.3. For the next 3 months, while taking warfarin 56 mg per week, her average INR was 2.1, with a range of 1.4-2.5. At a subsequent visit, after drinking approximately 2 quarts (1893 mL) of cranberry juice cocktail daily for 3-4 days, her INR had increased to 6.5. Her INR after holding warfarin for 3 days was 1.86. Her INR 7 days after resuming the weekly dose of warfarin 56 mg was 3.2. During both of the elevated INR episodes, no other factors were identified that would have resulted in an elevated INR, such as drug, herbal, disease, or other food interactions. An objective causality assessment revealed the interaction was highly probable.
DISCUSSION: Warfarin is the most commonly used anticoagulant for chronic therapy. There have been several case reports of cranberry juice or cranberry sauce potentiating the effects of warfarin by elevating the INR; however, clinical trials evaluating this interaction have failed to demonstrate a significant effect on an INR.
CONCLUSIONS: Our case report describes INR elevations in a patient previously stable on warfarin after ingestion of cranberry juice cocktail daily for several days. This elevation occurred on 2 separate occasions, which distinguishes our case from other published literature.

PMID 21364039
Stacy L Haber, Kimberly A B Cauthon, Erin C Raney
Cranberry and warfarin interaction: a case report and review of the literature.
Consult Pharm. 2012 Jan;27(1):58-65. doi: 10.4140/TCP.n.2012.58.
Abstract/Text This case reports on a patient whose International Normalized Ratio (INR) increased after ingestion of cranberry sauce while stabilized on warfarin. It is followed by a review of the published literature on the potential interaction between the two.An 85-year-old woman on chronic warfarin therapy for atrial fibrillation experienced INR elevations of two- to three-fold after two separate ingestions of cranberry sauce. In each case, her INR values decreased after withholding three to four doses and resuming a similar maintenance dose of warfarin. Although the majority of the pharmacokinetic and pharmacodynamic studies did not find a significant interaction between cranberry and warfarin, several case reports indicate that cranberry products may increase INR values in patients on warfarin. Practitioners should consider cranberry usage as a potential contributor in the evaluation of supratherapeutic INR values in patients on warfarin.

PMID 22231999
Afa K Palu, Brett J West, Jarakae Jensen
Noni-based nutritional supplementation and exercise interventions influence body composition.
N Am J Med Sci. 2011 Dec;3(12):552-6. doi: 10.4297/najms.2011.3552.
Abstract/Text BACKGROUND: The prevalence of obesity and overweight in the Unites States has reached unprecedented levels, and so has the need for effective exercise and nutritional programs for prevention of unhealthy weight gain or safe weight loss.
AIMS: The present study was conducted in overweight men and women to assess the impact of noni-based nutritional supplementation and exercise interventions on body composition.
MATERIALS AND METHODS: Twenty two participants (16 women and 6 men), ages 18-65, were enrolled in a 12-week, open-label trial of a weight-loss program involving noni-based dietary supplements, gender-specific daily calorie restriction, and exercise interventions. Weight, percent body fat, and body mass index were measured before and after the trial.
RESULTS: All participants experienced weight loss. The average decrease in fat mass was highly significant (P < 0.0001), as were decreases in percent body fat and body mass index. Individual weight and fat mass losses were 17.55 ± 9.73 and 21.78 ± 8.34 lbs., respectively, and individual percent body fat and body mass index decreases were 8.91 ± 3.58 % and 2.6 ± 1.32, respectively.
CONCLUSION: The nutritional and exercise interventions significantly influenced body composition among participants.

PMID 22363077
Petra Algenstaedt, Alexandra Stumpenhagen, Johannes Westendorf
The Effect of Morinda citrifolia L. Fruit Juice on the Blood Sugar Level and Other Serum Parameters in Patients with Diabetes Type 2.
Evid Based Complement Alternat Med. 2018;2018:3565427. doi: 10.1155/2018/3565427. Epub 2018 Aug 6.
Abstract/Text Background: The effect of the daily consumption of Morinda citrifolia (Noni) fruit juice on the physiological status of patients with diabetes type 2 (DT2) was tested over a period of two months.
Methods: Morinda citrifolia (Noni) fruit juice (NFJ), 2 ml per kg bw per day, was consumed by twenty patients with DT2 after they underwent a standard treatment regimen including carbohydrate reduced diet and treatment with an antidiabetic drug and/or insulin. NFJ consumption started only after no further improvement was achieved. The intake of NFJ was terminated after eight weeks. The fasting blood sugar level was monitored every morning during the entire treatment period. Blood samples were taken before, at, and four and eight weeks after the start of NFJ intake. The analysis of the blood samples included the concentration of blood glucose, HbA1c, C-peptide, hs-CRP, triglycerides, total cholesterol, LDL, and HDL.
Results: The consumption of NFJ by 20 patients with DT2 resulted in a significant mean decrease of the morning blood sugar level monitored over a period of eight weeks. While NFJ reduced the blood glucose level in several but not all hyperglycemic patients, it did not cause hypoglycemia in normoglycemic patients. NFJ consumption also reduced the mean HbA1c value significantly (p= 0.033). Significant decreases (p= 0.01) were also achieved for high sensitive CRP values in patients starting with high levels (>2 mg/L), whereas no change was observed in patients with normal values (< 2 mg/L). The level of C-peptide showed a significant mean increase after four weeks of NFJ consumption in those patients who started with low levels (<3 μg/l, p=0.004, N=11) but not in patients with higher levels (> 3 μg/L).
Conclusion: The daily consumption of NFJ has the potential to regulate elevated blood sugar levels and some other pathological parameters in patients with DT2. NFJ therefore serves as a suitable additive to the diet of diabetic patients.

PMID 30158993
B Yuce, V Gulberg, J Diebold, A L Gerbes
Hepatitis induced by Noni juice from Morinda citrifolia: a rare cause of hepatotoxicity or the tip of the iceberg?
Digestion. 2006;73(2-3):167-70. doi: 10.1159/000094524. Epub 2006 Jul 11.
Abstract/Text A 24-year-old female patient presented to her community hospital with mild elevations of serum transaminase and bilirubin levels. Because of multiple sclerosis, she was treated with interferon beta-1a for 6 weeks. After exclusion of viral hepatitis due to hepatitis A-E, interferon beta-1a was withdrawn under the suspicion of drug-induced hepatitis. One week later, she was admitted again to her community hospital with severe icterus. The transaminase and bilirubin levels were highly elevated, and a beginning impairment of the liver synthesis was expressed by a reduced prothrombin time. The confinement to our department occurred with a fulminant hepatitis and the suspicion of beginning acute liver failure. There was no evidence for hepatitis due to potentially hepatotoxic viruses, alcoholic hepatitis, Budd-Chiari syndrome, hemochromatosis, and Wilson's disease. In her serum there were high titers of liver-kidney microsomal type 1 autoantibody; the serum gamma globulin levels were in the normal range. Fine-needle aspiration biopsy of the liver ruled out an autoimmune hepatitis but showed signs of drug-induced toxicity. During the interview, she admitted that for 'general immune system stimulation' she had been drinking Noni juice, a Polynesian herbal remedy made from a tropical fruit (Morinda citrifolia), during the past 4 weeks. After cessation of the Noni juice ingestion, her transaminase levels normalized quickly and were in the normal range within 1 month.

Copyright 2006 S. Karger AG, Basel.
PMID 16837801
Vanessa Stadlbauer, Sabine Weiss, Franz Payer, Rudolf E Stauber
Herbal does not at all mean innocuous: the sixth case of hepatotoxicity associated with morinda citrifolia (noni).
Am J Gastroenterol. 2008 Sep;103(9):2406-7. doi: 10.1111/j.1572-0241.2008.02010_8.x.
Abstract/Text
PMID 18844633
Vanessa Stadlbauer, Peter Fickert, Carolin Lackner, Jutta Schmerlaib, Peter Krisper, Michael Trauner, Rudolf E Stauber
Hepatotoxicity of NONI juice: report of two cases.
World J Gastroenterol. 2005 Aug 14;11(30):4758-60.
Abstract/Text NONI juice (Morinda citrifolia) is an increasingly popular wellness drink claimed to be beneficial for many illnesses. No overt toxicity has been reported to date. We present two cases of novel hepatotoxicity of NONI juice. Causality of liver injury by NONI juice was asses-sed. Routine laboratory tests and transjugular or percutaneous liver biopsy were performed. The first patient underwent successful liver transplantation while the second patient recovered spontaneously after cessation of NONI juice. A 29-year-old man with previous toxic hepatitis associated with small doses of paracetamol developed sub-acute hepatic failure following consumption of 1.5 L NONI juice over 3 wk necessitating urgent liver transplantation. A 62-year-old woman without evidence of previous liver disease developed an episode of self-limited acute hepatitis following consumption of 2 L NONI juice for over 3 mo. The most likely hepatotoxic components of Morinda citrifolia were anthraquinones. Physicians should be aware of potential hepatotoxicity of NONI juice.

PMID 16094725
Gunda Millonig, Sylvia Stadlmann, Wolfgang Vogel
Herbal hepatotoxicity: acute hepatitis caused by a Noni preparation (Morinda citrifolia).
Eur J Gastroenterol Hepatol. 2005 Apr;17(4):445-7.
Abstract/Text A 45-year-old patient was sent to our department because of highly elevated transaminases and elevated lactate dehydrogenase. His medical history was unremarkable and he took no medication on regular basis. Physical examination did not detect any abnormalities. There was no evidence for viral hepatitis, Epstein-Barr virus or cytomegalovirus, autoimmune hepatitis, Budd-Chiari syndrome, haemochromatosis or Wilson's disease. During the interview he admitted that for 'prophylactic reasons' he had been drinking the juice of Noni (Morinda citrifolia), a Polynesian herbal remedy made from a tropical fruit, during the preceding 3 weeks. This gave rise to the suspicion of herbal toxicity, which was confirmed by a liver biopsy. After ceasing the ingestion of Noni, transaminase levels normalized quickly and were within normal ranges 1 month after the first presentation. To our knowledge, this is the first report of hepatotoxicity caused by this herbal remedy, which has been highly praised in the tabloid press.

PMID 15756098
Elizabeth L Yu, Mamata Sivagnanam, Linda Ellis, Jeannie S Huang
Acute hepatotoxicity after ingestion of Morinda citrifolia (Noni Berry) juice in a 14-year-old boy.
J Pediatr Gastroenterol Nutr. 2011 Feb;52(2):222-4. doi: 10.1097/MPG.0b013e3181eb69f0.
Abstract/Text We present a case of a 14-year-old previously healthy boy with acute hepatotoxicity after noni berry juice consumption. As the popularity of noni berry consumption continues to increase, heightened awareness of the relation between noni berry consumption and acute hepatotoxicity is important.

PMID 21119544
Anna Mrzljak, Iva Kosuta, Anita Skrtic, Tajana Filipec Kanizaj, Radovan Vrhovac
Drug-Induced Liver Injury Associated with Noni (Morinda citrifolia) Juice and Phenobarbital.
Case Rep Gastroenterol. 2013 Jan;7(1):19-24. doi: 10.1159/000343651. Epub 2013 Jan 10.
Abstract/Text Noni (Morinda citrifolia) juice is a popular herbal dietary supplement globally used for preventive or therapeutic purposes in a variety of ailments, claiming to exhibit hepatoprotective properties as well. Herein we present the case of a 38-year-old woman who developed acute liver injury associated with noni juice consumption on a long-term (9 months) anticonvulsant therapy. Clinical presentation and liver biopsy were consistent with severe, predominantly hepatocellular type of injury. Both agents were stopped and corticosteroids were initiated. Five months later the patient had fully recovered. Although in the literature the hepatotoxicity of noni juice remains speculative, sporadic but emerging cases of noni juice-associated liver injury address the need to clarify and investigate potential harmful effects associated with this supplement.

PMID 23467452
Ahsan Shoeb, M C Alwar, Preethi J Shenoy, P Gokul
Effect of Morinda citrifolia (Noni) Fruit Juice on High Fat Diet Induced Dyslipidemia in Rats.
J Clin Diagn Res. 2016 Apr;10(4):FF06-10. doi: 10.7860/JCDR/2016/17900.7650. Epub 2016 Apr 1.
Abstract/Text INTRODUCTION: The medicinal value of Morinda citrifolia L. (commonly known as Noni) has been explored in ancient folk remedies with a wide range of therapeutic utility, including antibacterial, antiviral, antifungal, antitumour, analgesic, hypotensive, anti-inflammatory and immune enhancing effects.
AIM: The present study was designed to evaluate the effects of Noni fruit juice on serum lipid profile in high fat diet induced murine model of dyslipidemia.
MATERIALS AND METHODS: Hyperlipidemia was induced by feeding a cholesterol rich high fat diet for 45 days in wistar albino rats of either sex (n=8). Noni fruit juice administered at 50mg/kg/day and 100mg/kg/day, per oral, was compared with the standard drug Atorvastatin (10mg/kg/day, oral) fed for the latter 30 days. The blood samples were then sent for complete blood lipid profile, after 30 days of treatment. The data presented as mean ± SEM was analyzed using one-way ANOVA followed by Tukey's post-hoc test. The p <0.05 was considered as statistically significant.
RESULTS: The Noni fruit juice treated group showed a significant decrease in the total cholesterol, triglycerides and very low density lipoprotein - Cholesterol at both the doses when compared to the disease control (p<0.05). However, the decrease in the TC (102.75±9.79 mg/dL) and LDL-C (47.87±7.47 mg/dL) levels observed with the noni fruit juice at the 50mg/kg dose employed, failed to show a statistical significance when compared to atorvastatin.
CONCLUSION: The present study provides evidence for the hypolipidemic activity of Noni fruit juice in high fat diet induced hyperlipidemia in rats.

PMID 27190827
So-Young Lee, So-Lim Park, Jin-Taek Hwang, Sung-Hun Yi, Young-Do Nam, Seong-Il Lim
Antidiabetic Effect of Morinda citrifolia (Noni) Fermented by Cheonggukjang in KK-A(y) Diabetic Mice.
Evid Based Complement Alternat Med. 2012;2012:163280. doi: 10.1155/2012/163280. Epub 2012 Aug 27.
Abstract/Text Antidiabetic effects of Morinda citrifolia (aka Noni) fermented by Cheonggukjang (fast-fermented soybean paste) were evaluated using a T2DM (type 2 diabetes mellitus) murine model. Six-week-old KK-Ay/TaJcl mice were randomly divided into four groups: (1) the diabetic control (DC) group, provided with a normal mouse diet; (2) the positive control (PC) group, provided with a functional health food diet; (3) the M. citrifolia (MC) group, provided with an MC-based diet; (4) the fermented M. citrifolia (FMC) group, provided with an FMC-based diet. Over a testing period of 90 days, food and water intake decreased significantly in the FMC and PC groups compared with the DC group. Blood glucose levels in the FMC group were 211.60-252.20 mg/dL after 90 days, while those in the control group were over 400 mg/dL after 20 days. In addition, FMC supplementation reduced glycosylated hemoglobin (HbA1c) levels, enhanced insulin sensitivity, and significantly decreased serum triglycerides and low-density lipoprotein (LDL) cholesterol. Furthermore, a fermented M. citrifolia 70% ethanolic extract (FMCE) activated peroxisome proliferator-activated receptor-(PPAR-) γ and stimulated glucose uptake via stimulation of AMP-activated protein kinase (AMPK) in cultured C2C12 cells. These results suggest that FMC can be employed as a functional health food for T2DM management.

PMID 22969823
Vijayapandi Pandy, Megala Narasingam, Zahurin Mohamed
Antipsychotic-like activity of noni (Morinda citrifolia Linn.) in mice.
BMC Complement Altern Med. 2012 Oct 19;12:186. doi: 10.1186/1472-6882-12-186. Epub 2012 Oct 19.
Abstract/Text BACKGROUND: Noni fruit is widely consumed in tropical regions of Indonesia to the Hawaiian Islands. The noni plant has a long history of use as a medicinal plant to treat a wide variety of ailments including CNS disorders. The present investigation was designed to evaluate the antipsychotic effect of noni fruits (Morinda citrifolia Linn.) using mouse models of apomorphine-induced climbing behaviour and methamphetamine-induced stereotypy (licking, biting, gnawing and sniffing).
METHODS: In acute study, the methanolic extract of Morinda citrifolia (MMC) at different doses 1, 3, 5, 10 g/kg was administered orally one hour prior to apomorphine (5 mg/kg, i.p) and methamphetamine (5 mg/kg, i.p) injection respectively in Swiss albino mice. In chronic studies, (TAHITIAN NONI® Juice, TNJ) was made available freely in daily drinking water at 30, 50 and 100% v/v for 7 days; 30 and 50% v/v for 21 days respectively. On the test day, an equivalent average daily divided dose of TNJ was administered by oral gavage one hour prior to apomorphine treatment. Immediately after apomorphine/ methamphetamine administration, the animals were placed in the cylindrical metal cages and observed for climbing behaviour/ stereotypy and climbing time.
RESULTS: The acute treatment of MMC (1, 3, 5, 10 g/kg, p.o) significantly decreased the apomorphine-induced cage climbing behaviour and climbing time in mice in a dose dependent manner. The MMC also significantly inhibited methamphetamine-induced stereotypy behaviour and climbing time in mice dose-dependently. The 7 and 21 days treatment of TNJ in drinking water at 50 and 100%v/v significantly alleviated the apomorphine-induced climbing behaviour and climbing time in mice.
CONCLUSIONS: The present study results demonstrated the antidopaminergic effect of Morinda citrifolia Linn. in mice, suggesting that noni has antipsychotic-like activity which can be utilized in the treatment of psychiatric disorders. However further studies are warranted to identify the active principles responsible for the antipsychotic activity of noni.

PMID 23082808
Brett J West, Leland D White, C Jarakae Jensen, Afa K Palu
A double-blind clinical safety study of noni fruit juice.
Pac Health Dialog. 2009 Nov;15(2):21-32.
Abstract/Text A safety study of TAHITIAN NONI Juice from Tahiti was conducted with ninety-six healthy volunteers. For 28 days, participants consumed one of four daily quantities of noni juice: 0 mL (placebo), 30 mL, 300 mL, or 750 mL. All daily dose formulations were standardized to 750 mL by making up any volume differences with the placebo. Hematology, biochemistry, urinalysis, vital signs, and adverse events measurements were made at 0 (baseline), 2, and 4 weeks, as well as during a two-week follow up (week 6). Electrocardiogram (ECG) measurements were also made for each volunteer during the pre-study screen and at week 6. During the trial, those in the noni groups experienced 20 to 50% fewer total adverse events than those in the placebo group. A marginally significant (P<0.1) reduction in the number of constant adverse events experienced by the volunteers was also found in the 300 mL noni juice group. A similar trend was observed in the other noni juice groups, as well. No other clinically significant differences between any of the groups were noted in the parameters and measurements of this study, nor was there evidence suggesting any adverse dose-related effects. The results of this study indicate that drinking up to 750 mL TAHITIAN NONI Juice per day is safe.

PMID 20443518
Kai Liu, Rui Zhou, Bin Wang, Man-Tian Mi
Effect of resveratrol on glucose control and insulin sensitivity: a meta-analysis of 11 randomized controlled trials.
Am J Clin Nutr. 2014 Jun;99(6):1510-9. doi: 10.3945/ajcn.113.082024. Epub 2014 Apr 2.
Abstract/Text BACKGROUND: The results of human clinical trials investigating the effects of resveratrol on glucose control and insulin sensitivity are inconsistent.
OBJECTIVE: We aimed to quantitatively evaluate the effects of resveratrol on glucose control and insulin sensitivity.
DESIGN: We performed a strategic literature search of PubMed, Embase, MEDLINE, and the Cochrane Library (updated to March 2014) for randomized controlled trials that estimated the effects of resveratrol on glucose control and insulin sensitivity. Study quality was assessed by using the Jadad scale. Weighted mean differences were calculated for net changes in glycemic measures by using fixed-effects or random-effects models. We performed prespecified subgroup and sensitivity analyses to evaluate potential heterogeneity. Meta-regression analyses were conducted to investigate dose effects of resveratrol on fasting glucose and insulin concentrations in nondiabetic subjects.
RESULTS: Eleven studies comprising a total of 388 subjects were included in this meta-analysis. Resveratrol consumption significantly reduced fasting glucose, insulin, glycated hemoglobin, and insulin resistance (measured by using the homeostatic model assessment) levels in participants with diabetes. No significant effect of resveratrol on glycemic measures of nondiabetic participants was found in the meta-analysis. Subgroup and sensitivity analyses indicated that the pooled effects of resveratrol on fasting glucose and insulin concentrations in nondiabetic participants were not affected by body mass index, study design, resveratrol dose, study duration, or Jadad score.
CONCLUSIONS: Resveratrol significantly improves glucose control and insulin sensitivity in persons with diabetes but does not affect glycemic measures in nondiabetic persons. Additional high-quality studies are needed to further evaluate the potential benefits of resveratrol in humans.

© 2014 American Society for Nutrition.
PMID 24695890
Heather A Hausenblas, Jennifer A Schoulda, James M Smoliga
Resveratrol treatment as an adjunct to pharmacological management in type 2 diabetes mellitus--systematic review and meta-analysis.
Mol Nutr Food Res. 2015 Jan;59(1):147-59. doi: 10.1002/mnfr.201400173. Epub 2014 Oct 9.
Abstract/Text The red wine polyphenol, resveratrol, is highly effective in treating type 2 diabetes mellitus (T2DM) in animal models, but there is no consensus regarding its efficacy in humans. We conducted a systematic review, which included searches in nine scholarly databases and six clinical trial registries, and identified randomized controlled clinical trials whereby resveratrol was used as an adjunct to pharmaceutical interventions in T2DM. Meta-analysis on clinical parameters was performed for available data. Of 764 articles originally identified, data from six unique datasets, examining a total of 196 T2DM patients (104 resveratrol, 92 control/placebo) ultimately met inclusion criteria. Statistically significant (p < 0.05) positive effects, indicating that resveratrol supplementation was more effective than placebo/control, were identified for systolic blood pressure, hemoglobin A1c, and creatinine, but not for fasting glucose, homeostatic model assessment of insulin resistance, diastolic blood pressure, insulin, triglycerides, LDL, or HDL cholesterol. No major adverse events were reported and side effects of resveratrol were not different than placebo/control. Though limitations in sample size and treatment duration preclude definitive changes in clinical practice, significant improvements in multiple cardiometabolic biomarkers and an excellent safety profile support resveratrol as a leading candidate as an adjunct to pharmacological management of T2DM.

© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
PMID 25138371
Richard D Semba, Luigi Ferrucci, Benedetta Bartali, Mireia Urpí-Sarda, Raul Zamora-Ros, Kai Sun, Antonio Cherubini, Stefania Bandinelli, Cristina Andres-Lacueva
Resveratrol levels and all-cause mortality in older community-dwelling adults.
JAMA Intern Med. 2014 Jul;174(7):1077-84. doi: 10.1001/jamainternmed.2014.1582.
Abstract/Text IMPORTANCE: Resveratrol, a polyphenol found in grapes, red wine, chocolate, and certain berries and roots, is considered to have antioxidant, anti-inflammatory, and anticancer effects in humans and is related to longevity in some lower organisms.
OBJECTIVE: To determine whether resveratrol levels achieved with diet are associated with inflammation, cancer, cardiovascular disease, and mortality in humans.
DESIGN: Prospective cohort study, the Invecchiare in Chianti (InCHIANTI) Study ("Aging in the Chianti Region"), 1998 to 2009 conducted in 2 villages in the Chianti area in a population-based sample of 783 community-dwelling men and women 65 years or older.
EXPOSURES: Twenty-four-hour urinary resveratrol metabolites.
MAIN OUTCOMES AND MEASURES: Primary outcome measure was all-cause mortality. Secondary outcomes were markers of inflammation (serum C-reactive protein [CRP], interleukin [IL]-6, IL-1β, and tumor necrosis factor [TNF]) and prevalent and incident cancer and cardiovascular disease.
RESULTS: Mean (95% CI) log total urinary resveratrol metabolite concentrations were 7.08 (6.69-7.48) nmol/g of creatinine. During 9 years of follow-up, 268 (34.3%) of the participants died. From the lowest to the highest quartile of baseline total urinary resveratrol metabolites, the proportion of participants who died from all causes was 34.4%, 31.6%, 33.5%, and 37.4%, respectively (P = .67). Participants in the lowest quartile had a hazards ratio for mortality of 0.80 (95% CI, 0.54-1.17) compared with those in the highest quartile of total urinary resveratrol in a multivariable Cox proportional hazards model that adjusted for potential confounders. Resveratrol levels were not significantly associated with serum CRP, IL-6, IL-1β, TNF, prevalent or incident cardiovascular disease, or cancer.
CONCLUSIONS AND RELEVANCE: In older community-dwelling adults, total urinary resveratrol metabolite concentration was not associated with inflammatory markers, cardiovascular disease, or cancer or predictive of all-cause mortality. Resveratrol levels achieved with a Western diet did not have a substantial influence on health status and mortality risk of the population in this study.

PMID 24819981
Amirhossein Sahebkar
Effects of resveratrol supplementation on plasma lipids: a systematic review and meta-analysis of randomized controlled trials.
Nutr Rev. 2013 Dec;71(12):822-35. doi: 10.1111/nure.12081. Epub 2013 Oct 1.
Abstract/Text A systematic review and meta-analysis of available evidence was conducted to obtain a conclusive result on the lipid-modulating effects of resveratrol. Seven randomized controlled trials with a total of 282 subjects (141 in each group) met the eligibility criteria. Overall, resveratrol supplementation had no significant effect on any of the lipid parameters assessed: total cholesterol (weighted mean difference [WMD] -8.70; 95% confidence interval [95% CI] -21.54-4.14; P = 0.18), low-density lipoprotein cholesterol (WMD -3.22; 95% CI -12.56-6.12); P = 0.50), high-density lipoprotein cholesterol (WMD -0.26; 95% CI -4.25-3.73; P = 0.90), and triglycerides (WMD -4.30; 95% CI -20.22-11.63; P = 0.60). These results were robust in sensitivity analysis and were not dependent on the resveratrol dose, the duration of supplementation, or the cardiovascular risk status of the population studied. While future large-scale, well-designed trials are warranted, the current evidence suggests that mechanisms other than hypolipidemic effects account for the established cardioprotective properties of resveratrol.

© 2013 International Life Sciences Institute.
PMID 24111838
Yanxia Liu, Wanqiang Ma, Po Zhang, Shunchuan He, Daifa Huang
Effect of resveratrol on blood pressure: a meta-analysis of randomized controlled trials.
Clin Nutr. 2015 Feb;34(1):27-34. doi: 10.1016/j.clnu.2014.03.009. Epub 2014 Mar 31.
Abstract/Text BACKGROUND & AIMS: The results of human clinical trials that have investigated the effects of resveratrol on blood pressure are inconsistent. We aimed to quantitatively evaluate the effects of resveratrol on systolic blood pressure (SBP) and diastolic blood pressure (DBP).
METHODS: We conducted a strategic literature search of PubMed, EMBASE, MEDLINE, and the Cochrane Library (updated to January, 2014) for randomized controlled trials that evaluate the effects of resveratrol on SBP and DBP. Study quality was assessed using the Jadad scale. Weighted mean differences were calculated for net changes in SBP and DBP using fixed-effects or random-effects models. We performed pre-specified subgroup, sensitivity and meta-regression analyses to evaluate potential the heterogeneity. Dose effects of resveratrol on SBP and DBP were estimated using meta-regression analyses.
RESULTS: Six studies comprising a total of 247 subjects were included in our meta-analysis. The overall outcome of the meta-analysis indicates that resveratrol consumption can not significantly reduce SBP and DBP. Subgroup analyses indicated that higher-dose of resveratrol consumption (≥ 150 mg/d) significantly reduces SBP of -11.90 mmHg (95% CI: -20.99, -2.81 mmHg, P = 0.01), whereas lower dose of resveratrol did not show a significant lowering effect on SBP. The meta-regression analyses did not indicate dose effects of resveratrol on SBP or DBP.
CONCLUSIONS: The present meta-analysis indicates that resveratrol consumption significantly decreases the SBP level at the higher dose, while resveratrol has no significant effects on DBP levels. Additional high-quality studies are needed to further evaluate the causal conclusions.

Copyright © 2014 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
PMID 24731650
Haohai Huang, Guangzhao Chen, Dan Liao, Yongkun Zhu, Rong Pu, Xiaoyan Xue
The effects of resveratrol intervention on risk markers of cardiovascular health in overweight and obese subjects: a pooled analysis of randomized controlled trials.
Obes Rev. 2016 Dec;17(12):1329-1340. doi: 10.1111/obr.12458. Epub 2016 Jul 26.
Abstract/Text BACKGROUND: Potential effects of resveratrol consumption on cardiovascular disease risk factors and body weight in overweight/obese adults have not been fully elucidated. Our present analysis was to evaluate the effects of resveratrol consumption on risk markers related to cardiovascular health in overweight/obese Individuals.
METHODS: Multiple literature databases were systematically searched, and 21 studies were included. Effect sizes were expressed as weighted mean difference (WMD) and 95% confidence interval (CI), and heterogeneity was assessed with the I2 test. Publication bias and subgroup analyses were also performed.
RESULTS: There were variations in reporting quality of included studies. Resveratrol intervention significantly lowered total cholesterol (WMD, -0.19 mmol/L; 95% CI, -0.32 to -0.06; P = 0.004), systolic blood pressure (WMD, -2.26 mmHg; 95% CI, -4.82 to -0.49; P = 0.02), and fasting glucose (WMD, -0.22 mmol/L; 95% CI, -0.42 to -0.03; P = 0.03). Heterogeneity was noted for these outcomes (35.6%, 38.7% and 71.4%, respectively). Our subgroup analysis showed significant reductions in total cholesterol, systolic blood pressure, diastolic blood pressure, glucose, and insulin in subjects ingesting higher dose of resveratrol (≥300 mg/day).
CONCLUSION: Our finding provides evidence that daily resveratrol consumption might be a candidate as an adjunct to pharmacological management to better prevent and control cardiovascular disease in overweight/obese individuals.

© 2016 World Obesity Federation.
PMID 27456934
Wolfgang Marx, Jaimon T Kelly, Skye Marshall, Jennifer Cutajar, Brigitte Annois, Andrew Pipingas, Audrey Tierney, Catherine Itsiopoulos
Effect of resveratrol supplementation on cognitive performance and mood in adults: a systematic literature review and meta-analysis of randomized controlled trials.
Nutr Rev. 2018 Mar 27;. doi: 10.1093/nutrit/nuy010. Epub 2018 Mar 27.
Abstract/Text Context: The aim of this systematic review was to evaluate clinical trial data regarding the effect of resveratrol supplementation on cognitive performance and mood in populations that are healthy and in the clinical setting.
Data Sources: Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic literature review of randomized controlled trials was conducted.
Data Extraction: A meta-analysis was also conducted to determine treatment effect on the following cognitive domains and mental processes: processing speed, number facility, memory, and mood. Risk of bias was assessed using the Cochrane Collaboration Risk of Bias tool. Quality of the body of evidence was assessed by evidence for each outcome related to cognitive function for which data was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE).
Results: Ten studies were included. Three studies found resveratrol supplementation significantly improved some measures of cognitive performance, 2 reported mixed findings, and 5 found no effect. When data were pooled, resveratrol supplementation had a significant effect on delayed recognition (standardized mean difference [SMD], 0.39; 95% confidence interval [CI], 0.08-0.70; I2 = 0%; P = 0.01; n = 3 studies; n = 166 participants) and negative mood (SMD, -0.18; 95%CI, -0.31 to -0.05; I2 = 0%; P = 0.006; n = 3 studies; n = 163 participants). Included studies generally had low risk of bias and were of moderate or high quality.
Conclusions: The results of this review indicate that resveratrol supplementation might improve select measures of cognitive performance; however, the current literature is inconsistent and limited.

PMID 29596658
Małgorzata Chudzińska, Daniel Rogowicz, Łukasz Wołowiec, Joanna Banach, Sławomir Sielski, Robert Bujak, Anna Sinkiewicz, Grzegorz Grześk
Resveratrol and cardiovascular system-the unfulfilled hopes.
Ir J Med Sci. 2021 Aug;190(3):981-986. doi: 10.1007/s11845-020-02441-x. Epub 2020 Nov 21.
Abstract/Text INTRODUCTION: Resveratrol is a natural polyphenolic compound with a stilbene structure endowed with multiple health-promoting effects. Among phenolic compounds, resveratrol is assigned a leading role in the health-promoting effects of red wine.
METHODS: The aim of the study was to assess the effect of resveratrol on the cardiovascular system in the experimental and clinical studies conducted so far. Moreover, the paper discusses the results of the most recent meta-analyses assessing resveratrol's therapeutic effect on the cardiovascular system in humans.
RESULTS: In animal and preclinical studies, resveratrol has demonstrated a wide physiological and biochemical spectrum of activity, including antioxidant, anti-inflammatory, antiplatelet, and anticoagulant activities, which translated into its health-promoting effects on the cardiovascular system. The performed meta-analyses allow to confirm such an impact, however, after the assessment with the use of the SYRCLE's tool, these studies are burdened with a high risk of bias, and the results are not clearly presented.
CONCLUSION: Despite numerous articles and clinical studies, the convincing beneficial mechanisms of resveratrol as well as its health-promoting effects in cardiovascular diseases have not been clearly confirmed in humans. Therefore, there is a need for further clinical studies, especially randomized, double-blind, placebo-controlled trials to objectively confirm the possible health-promoting effects of this substance and to determine both the efficacy and safety, and possible therapeutic potential.

© 2020. Royal Academy of Medicine in Ireland.
PMID 33219913
Giacomo Novara, Gianluca Giannarini, Antonio Alcaraz, José-M Cózar-Olmo, Aurelien Descazeaud, Francesco Montorsi, Vincenzo Ficarra
Efficacy and Safety of Hexanic Lipidosterolic Extract of Serenoa repens (Permixon) in the Treatment of Lower Urinary Tract Symptoms Due to Benign Prostatic Hyperplasia: Systematic Review and Meta-analysis of Randomized Controlled Trials.
Eur Urol Focus. 2016 Dec;2(5):553-561. doi: 10.1016/j.euf.2016.04.002. Epub 2016 Apr 23.
Abstract/Text CONTEXT: A recent Cochrane Collaboration meta-analysis of randomized controlled trials (RCTs) evaluating the efficacy of different extracts of Serenoa repens in relieving lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) concluded that these extracts were no more effective than placebo. However, among all Serenoa repens extracts, Permixon (Pierre Fabre Medicament, Paris, France) has the highest activity and the most accurate standards of drug preparation and extraction.
OBJECTIVE: To evaluate the efficacy and safety of Permixon in the treatment of LUTS/BPH.
EVIDENCE ACQUISITION: A systematic review and meta-analysis of the literature was performed in January 2016 using the Medline, Scopus, and Web of Science databases, searching for the term Serenoa repens in all fields of the records. Only RCTs reporting on efficacy and safety of Permixon in the treatment of LUTS/BPH were selected.
EVIDENCE SYNTHESIS: The systematic search identified 12 RCTs: 7 compared Permixon with placebo; 2 compared Permixon with tamsulosin; 2 compared Permixon plus tamsulosin with, respectively, placebo plus tamsulosin and tamsulosin alone; and 1 compared Permixon with finasteride. Permixon was significantly more effective than placebo in reducing the number of nocturnal voids (weighted mean difference [WMD] -0.31; p=0.03) and increasing maximum flow rate (Qmax; WMD 3.37; p<0.0001). The rates of overall adverse events (odds ratio [OR] 1.12; p=0.92) and withdrawal (OR 1.52; p=0.60) were similar for Permixon and placebo. Permixon was as effective as tamsulosin monotherapy and short-term therapy with finasteride in improving International Prostate Symptom Score (WMD 1.15; 95% confidence interval [CI], -1.11 to 3.40; p=0.32) and Qmax (WMD -0.16; 95% CI, -0.60 to 0.28; p=0.48). The combination of Permixon and tamsulosin was more effective than Permixon alone for relieving LUTS (WMD 0.31; 95% CI, 0.13-0.48; p<0.01) but not for improving Qmax (WMD 0.10; 95% CI -0.02 to 0.21; p=0.10). Permixon had a favorable safety profile, with a very limited impact with regard to ejaculatory dysfunction compared with tamsulosin (0.5% vs 4%; p=0.007) and with regard to decreased libido and impotence compared with short-term finasteride (2.2% and 1.5% vs 3% and 2.8%, respectively).
CONCLUSIONS: The conclusions of the recent Cochrane meta-analysis on Serenoa repens in the treatment of LUTS/BPH apparently do not apply to Permixon. Our meta-analysis showed that Permixon decreased nocturnal voids and Qmax compared with placebo and had efficacy in relieving LUTS similar to tamsulosin and short-term finasteride. Moreover, Permixon had a favorable safety profile with a very limited impact on sexual function, which is significantly affected by all other drugs used to treat LUTS/BPH.
PATIENT SUMMARY: A systematic review of the literature showed that Permixon was effective for relieving urinary symptoms due to prostate enlargement and improving urinary flow compared with placebo. Permixon had efficacy similar to tamsulosin and short-term finasteride in relieving urinary symptoms. Permixon was well tolerated and had a very limited impact on sexual function.

Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.
PMID 28723522
Young Woo Ryu, Song Won Lim, Jung Hoon Kim, Seung Hyun Ahn, Jae Duck Choi
Comparison of tamsulosin plus serenoa repens with tamsulosin in the treatment of benign prostatic hyperplasia in Korean men: 1-year randomized open label study.
Urol Int. 2015;94(2):187-93. doi: 10.1159/000366521. Epub 2015 Jan 23.
Abstract/Text INTRODUCTION: In Korea, increasing attention has recently been given to the use of phytotherapeutic agents to alleviate the symptoms of BPH. Serenoa repens has been shown to have an equivalent efficacy to Finasteride or Tamsulosin in the treatment of BPH in previous studies. The present study was designed to compare the efficacy and safety of Serenoa repens plus tamsulosin with tamsulosin only over 12 months in men with LUTS secondary to BPH.
MATERIALS AND METHODS: One hundred forty men with symptomatic BPH (IPSS≥10) were recruited in our hospital for a 12-month, open-label, randomized trial. Patients were randomly assigned to either tamsulosin 0.2 mg/day plus Serenoa repens 320 mg/day (n=60) or tamsulosin 0.2 mg/day only (n=60). Prostate volume and PSA were measured at baseline and at end-point, whereas total IPSS, and its storage and voiding subscores, LUTS-related QoL, Qmax, and PVR were evaluated at baseline and later every 6 months.
RESULTS: Total 103 patients were finally available: 50 in the TAM+SR group and 53 in the TAM group. At 12 months, total IPSS decreased by 5.8 with TAM+SR and 5.5 with TAM (p=0.693); the storage symptoms improved significantly more with TAM+SR (-1.7 vs. -0.8 with TAM, p=0.024). This benefit with regard to storage symptom in the TAM+SR group lasts at 12 months (-1.9 vs. -0.9, p=0.024). The changes of voiding subscore, LUTS-related QoL, Qmax, PVR, PSA, and prostate volume showed no significant differences between the TAM+SR and TAM groups. During the treatment period, 8 patients (16.9%) with TAM and 10 (20%) with TAM+SR had drug-related adverse reactions, which included ejaculatory disorders, postural hypotension, dizziness, headache, gastro-intestinal disorders, rhinitis, fatigue and asthenia.
CONCLUSIONS: The combination treatment of Serenoa repens and tamsulosin was shown to be more effective than tamsulosin monotherapy in reducing storage symptoms in BPH patients after 6 months and up to 12 months of treatment.

© 2015 S. Karger AG, Basel.
PMID 25614155
Ismaila Jibrin, Ayodele Erinle, Abdulfattah Saidi, Zakari Y Aliyu
Saw palmetto-induced pancreatitis.
South Med J. 2006 Jun;99(6):611-2. doi: 10.1097/01.smj.0000215642.76198.44.
Abstract/Text Saw palmetto is a frequently used botanical agent in benign prostatic enlargement (BPH). Although it has been reported to cause cholestatic hepatitis and many medical conditions, Saw palmetto has not been implicated in acute pancreatitis. We report a case of a probable Saw palmetto induced acute hepatitis and pancreatitis. A 55-year-old reformed alcoholic, sober for greater than 15 years, presented with severe non-radiating epigastric pain associated with nausea and vomiting. His only significant comorbidity is BPH for which he intermittently took Saw palmetto for about four years. Physical examination revealed normal vital signs, tender epigastrium without guarding or rebound tenderness. Cullen and Gray Turner signs were negative. Complete blood count and basic metabolic profile were normal. Additional laboratory values include a serum amylase: 2,152 mmol/L, lipase: 39,346 mmol/L, serum triglyceride: 38 mmol/L, AST: 1265, ALT: 1232 and alkaline phosphatase was 185. Abdominal ultrasound and magnetic resonance cholangiography revealed sludge without stones. A hepatic indole diacetic acid scan was negative. Patient responded clinically and biochemically to withdrawal of Saw palmetto. Two similar episodes of improvements followed by recurrence were noted with discontinuations and reinstitution of Saw Palmetto. Simultaneous and sustained response of hepatitis and pancreatitis to Saw palmetto abstinence with reoccurrence on reinstitution strongly favors drug effect. "Natural" medicinal preparations are therefore not necessarily safe and the importance of detailed medication history (including "supplements") cannot be over emphasized.

PMID 16800417
Kurt A Wargo, Elena Allman, Farrah Ibrahim
A possible case of saw palmetto-induced pancreatitis.
South Med J. 2010 Jul;103(7):683-5. doi: 10.1097/SMJ.0b013e3181e1e3ee.
Abstract/Text A 65-year-old male with a history of diabetes, hypertension, hyperlipidemia, gout, Barrett esophagitis, and chronic gastritis developed acute pancreatitis after taking one week of the herbal medicine, saw palmetto, for symptoms related to benign prostatic hyperplasia (BPH). Ultrasound and computed tomography ruled out cholelithiasis and obstruction, triglycerides were normal, and he had no recent infection or trauma. He had a history of occasional alcohol consumption, though there was no recent increased intake. The most likely cause of pancreatitis in this case was saw palmetto. Saw palmetto (Serenoa repens) is an herbal medication used primarily in the treatment of symptoms related to BPH. It has a high content of fatty acids and phytosterols which are thought to exert their effects by inhibiting the enzyme 5-alpha-reductase, thereby preventing the conversion of testosterone into dihydrotestosterone (DHT). It has been postulated that saw palmetto directly stimulates estrogenic receptors and inhibits progesterone receptors in the prostate tissue. A previous report implicated the estrogen/antiandrogen properties of saw palmetto as inducing hepatotoxicity in a patient. Additionally, it has also been postulated that stimulation of the estrogenic receptors may lead to increased triglyceride levels or induction of a hypercoagulable state that leads to pancreatic necrosis. Finally, inhibition of cyclooxygenase, a property of saw palmetto, may be linked to acute pancreatitis. Acute pancreatitis, a serious and sometimes fatal disorder may occur secondary to medications. Although the mechanism is not fully known, this is the second case of acute pancreatitis that has been documented secondary to the herbal medication saw palmetto. It is important for clinicians to obtain detailed medication histories, including over-the-counter and herbal medications, in order to prevent further complications from occurring.

PMID 20531057
Jackrapong Bruminhent, Perliveh Carrera, Zhongzhen Li, Raymond Amankona, Ingram M Roberts
Acute pancreatitis with saw palmetto use: a case report.
J Med Case Rep. 2011 Aug 25;5:414. doi: 10.1186/1752-1947-5-414. Epub 2011 Aug 25.
Abstract/Text INTRODUCTION: Saw palmetto is a phytotherapeutic agent commercially marketed for the treatment of benign prostatic hyperplasia. Evidence suggests that saw palmetto is a safe product, and mild gastrointestinal adverse effects have been reported with its use. We report a case of acute pancreatitis, possibly secondary to the use of saw palmetto.
CASE PRESENTATION: A 61-year-old Caucasian man with a history of benign prostatic hyperplasia and gastroesophageal reflux disease developed epigastric pain associated with nausea 36 hours prior to presentation. He denied drinking alcohol prior to the development of his symptoms. His home medications included saw palmetto, lansoprazole and multivitamins. Laboratory results revealed elevated lipase and amylase levels. An abdominal ultrasound demonstrated a nondilated common bile duct, without choledocholithiasis. Computed tomography of his abdomen showed the pancreatic tail with peripancreatic inflammatory changes, consistent with acute pancreatitis. Our patient's condition improved with intravenous fluids and pain management. On the fourth day of hospitalization his pancreatic enzymes were within normal limits: he was discharged home and advised to avoid taking saw palmetto.
CONCLUSION: It is our opinion that a relationship between saw palmetto and the onset of acute pancreatitis is plausible, and prescribers and users of saw palmetto should be alert to the possibility of such adverse reactions.

PMID 21867545
Francesco Lapi, Eugenia Gallo, Elisa Giocaliere, Michele Vietri, Roberto Baronti, Giuseppe Pieraccini, Alessandro Tafi, Francesca Menniti-Ippolito, Alessandro Mugelli, Fabio Firenzuoli, Alfredo Vannacci
Acute liver damage due to Serenoa repens: a case report.
Br J Clin Pharmacol. 2010 May;69(5):558-60. doi: 10.1111/j.1365-2125.2010.03618.x.
Abstract/Text
PMID 20573093
Minako Hanaka, Chiharu Yoshii, Kazuhiro Yatera, Chiyo Ito, Yasuo Chojin, Shuya Nagata, Kei Yamasaki, Chinatsu Nishida, Toshinori Kawanami, Yukiko Kawanami, Hiroshi Ishimoto, Hiroshi Mukae
[A case of rhabdomyolysis caused by saw palmetto of healthy foods].
J UOEH. 2012 Jun 1;34(2):193-9.
Abstract/Text An 82-year-old man visited our hospital when he developed a fever of over 38 degrees C after having consumed 5 types of health foods. He had previously been treated for chronic obstructive pulmonary disease, hypertension and hyperuricemia. Blood examination on admission revealed renal dysfunction, marked elevation of C-reactive protein, and an elevated level of serum creatine kinase. According to the laboratory data and his clinical history, rhabdomyolysis complicated by acute renal failure was suspected, but his condition improved and his fever was reduced with fluid infusion. As a drug lymphocyte stimulation test was positive for only saw palmetto in the 5 health foods, we diagnosed the case as rhabdomyolysis induced by saw palmetto. We believe that this is the first case of a health food being the cause of rhabdomyolysis.

PMID 22768426
Marco Miroddi, Antonio Carnì, Carmen Mannucci, Mariacarla Moleti, Michele Navarra, Gioacchino Calapai
Hot flashes in a young girl: a wake-up call concerning Serenoa repens use in children.
Pediatrics. 2012 Nov;130(5):e1374-6. doi: 10.1542/peds.2011-2679. Epub 2012 Oct 1.
Abstract/Text Extracts of the plant Serenoa repens are widely used in male adults for the treatment of benign prostatic hyperplasia. Recently, therapy with S repens has been proposed as a "natural" alternative to conventional treatments for male androgenetic alopecia as well as for other hair disorders. Telogen effluvium is a form of alopecia characterized by abnormality of hair cycling, resulting in excessive loss of telogen hair. We report the case of an 11-year-old girl presenting hot flashes that appeared after treatment of telogen effluvium with a food supplement containing S repens that lasted for ~2 months. When use of the product was discontinued, the hot flashes no longer occurred. Four months after the start of S repens intake and 45 days from the cessation of therapy, the girl experienced menarche at the age of 11 years. The Naranjo adverse drug reaction probability scale indicated a probable relationship (score of 6) between the appearance of hot flashes and the intake of S repens. A correlation between exposure to S repens and the onset of menarche is not certain, but it cannot be excluded. Medicinal products or food supplements containing S repens are generally well tolerated in male adults, but we believe that their use in pediatric patients should be better evaluated.

PMID 23027164
Paolo Morabito, Marco Miroddi, Salvatore Giovinazzo, Edoardo Spina, Gioacchino Calapai
Serenoa repens as an Endocrine Disruptor in a 10-Year-Old Young Girl: A New Case Report.
Pharmacology. 2015;96(1-2):41-3. doi: 10.1159/000431327. Epub 2015 Jun 2.
Abstract/Text Serenoa repens, commonly known as saw palmetto, is the sole species currently classified in the genus Serenoa. The plant is a low shrubby palm that is native of West Indies, and it grows in the coastal lands of North America and other European mediterranean countries. Its fruits contain high concentrations of fatty acids and phytosterols. S. repens extracts have been studied for the symptomatic treatment of benign prostatic hyperplasia. Recently, they have been proposed to treat androgenic alopecia and other hair disorders. We report a new case of hot flashes in a 10-year-old girl using a food supplement containing the extract of S. repens for the treatment of hirsutism. When the girl discontinued the treatment, the hot flashes stopped. A 'rechallenge' of the supplement was tried and symptoms reappeared. About 4 months after starting therapy, the girl experienced menarche. Exposure to the plant-derived product could be responsible for the appearance of menarche. In our opinion, use of phytotherapeutic agents in pediatric patients should be associated to a better evaluation of benefit/risk profile taking in account the physiological changes that occurs at different ages in this subgroup of population.

© 2015 S. Karger AG, Basel.
PMID 26043832
Frans Debruyne, Gary Koch, Peter Boyle, Fernando Calais Da Silva, Jay G Gillenwater, Freddie C Hamdy, Paul Perrin, Pierre Teillac, Remigio Vela-Navarrete, Jean-Pierre Raynaud
Comparison of a phytotherapeutic agent (Permixon) with an alpha-blocker (Tamsulosin) in the treatment of benign prostatic hyperplasia: a 1-year randomized international study.
Eur Urol. 2002 May;41(5):497-506; discussion 506-7.
Abstract/Text OBJECTIVE: While the lipido-sterolic extract of Serenoa repens (LSESr)-Permixon((R))-has been shown to have an equivalent efficacy to finasteride in patients with benign prostatic hyperplasia (BPH), to date, there has been no valid comparison of phytotherapy with alpha-blockers. The aim of this study was to assess the equivalent efficacy of Permixon and tamsulosin.
METHODS: Eight hundred and eleven men with symptomatic BPH (I-PSS> or =10) were recruited in 11 European countries for a 12-month, double-blind randomized trial. After a 4-week run-in period, 704 patients were randomly assigned to either tamsulosin 0.4mg/day (N=354) or Permixon 320mg/day (N=350). I-PSS, QoL and Q(max) were evaluated at baseline and periodically for 1 year. Prostate volume and serum prostate-specific antigen (PSA) were measured at selection and at endpoint. The endpoint analysis was performed on the per-protocol population of 542 patients (tamsulosin: N=273; Permixon: N=269).
RESULTS: At 12 months, I-PSS decreased by 4.4in each group and no differences were observed in either irritative or obstructive symptom improvements. The increase in Q(max) was similar in both treatment groups (1.8ml/s Permixon, 1.9ml/s tamsulosin). PSA remained stable while prostate volume decreased slightly in the Permixon-treated patients. The two compounds were well tolerated, however, ejaculation disorders occurred more frequently in the tamsulosin group.
CONCLUSION: This study demonstrates that Permixon and tamsulosin are equivalent in the medical treatment of lower urinary tract symptoms in men with BPH, during and up to 12 months of therapy.

PMID 12074791
Stephen Bent, Christopher Kane, Katsuto Shinohara, John Neuhaus, Esther S Hudes, Harley Goldberg, Andrew L Avins
Saw palmetto for benign prostatic hyperplasia.
N Engl J Med. 2006 Feb 9;354(6):557-66. doi: 10.1056/NEJMoa053085.
Abstract/Text BACKGROUND: Saw palmetto is used by over 2 million men in the United States for the treatment of benign prostatic hyperplasia and is commonly recommended as an alternative to drugs approved by the Food and Drug Administration.
METHODS: In this double-blind trial, we randomly assigned 225 men over the age of 49 years who had moderate-to-severe symptoms of benign prostatic hyperplasia to one year of treatment with saw palmetto extract (160 mg twice a day) or placebo. The primary outcome measures were changes in the scores on the American Urological Association Symptom Index (AUASI) and the maximal urinary flow rate. Secondary outcome measures included changes in prostate size, residual urinary volume after voiding, quality of life, laboratory values, and the rate of reported adverse effects.
RESULTS: There was no significant difference between the saw palmetto and placebo groups in the change in AUASI scores (mean difference, 0.04 point; 95 percent confidence interval, -0.93 to 1.01), maximal urinary flow rate (mean difference, 0.43 ml per minute; 95 percent confidence interval, -0.52 to 1.38), prostate size, residual volume after voiding, quality of life, or serum prostate-specific antigen levels during the one-year study. The incidence of side effects was similar in the two groups.
CONCLUSIONS: In this study, saw palmetto did not improve symptoms or objective measures of benign prostatic hyperplasia. (ClinicalTrials.gov number, NCT00037154.).

Copyright 2006 Massachusetts Medical Society.
PMID 16467543
Michael J Barry, Sreelatha Meleth, Jeannette Y Lee, Karl J Kreder, Andrew L Avins, J Curtis Nickel, Claus G Roehrborn, E David Crawford, Harris E Foster, Steven A Kaplan, Andrew McCullough, Gerald L Andriole, Michael J Naslund, O Dale Williams, John W Kusek, Catherine M Meyers, Joseph M Betz, Alan Cantor, Kevin T McVary, Complementary and Alternative Medicine for Urological Symptoms (CAMUS) Study Group
Effect of increasing doses of saw palmetto extract on lower urinary tract symptoms: a randomized trial.
JAMA. 2011 Sep 28;306(12):1344-51. doi: 10.1001/jama.2011.1364.
Abstract/Text CONTEXT: Saw palmetto fruit extracts are widely used for treating lower urinary tract symptoms attributed to benign prostatic hyperplasia (BPH); however, recent clinical trials have questioned their efficacy, at least at standard doses (320 mg/d).
OBJECTIVE: To determine the effect of saw palmetto extract (Serenoa repens, from saw palmetto berries) at up to 3 times the standard dose on lower urinary tract symptoms attributed to BPH.
DESIGN, SETTING, AND PARTICIPANTS: A double-blind, multicenter, placebo-controlled randomized trial at 11 North American clinical sites conducted between June 5, 2008, and October 10, 2010, of 369 men aged 45 years or older, with a peak urinary flow rate of at least 4 mL/s, an American Urological Association Symptom Index (AUASI) score of between 8 and 24 at 2 screening visits, and no exclusions.
INTERVENTIONS: One, 2, and then 3 doses (320 mg/d) of saw palmetto extract or placebo, with dose increases at 24 and 48 weeks.
MAIN OUTCOME MEASURES: Difference in AUASI score between baseline and 72 weeks. Secondary outcomes included measures of urinary bother, nocturia, peak uroflow, postvoid residual volume, prostate-specific antigen level, participants' global assessments, and indices of sexual function, continence, sleep quality, and prostatitis symptoms.
RESULTS: Between baseline and 72 weeks, mean AUASI scores decreased from 14.42 to 12.22 points (-2.20 points; 95% CI, -3.04 to -1.36) [corrected]with saw palmetto extract and from 14.69 to 11.70 points (-2.99 points; 95% CI, -3.81 to -2.17) with placebo. The group mean difference in AUASI score change from baseline to 72 weeks between the saw palmetto extract and placebo groups was 0.79 points favoring placebo (upper bound of the 1-sided 95% CI most favorable to saw palmetto extract was 1.77 points, 1-sided P = .91). Saw palmetto extract was no more effective than placebo for any secondary outcome. No clearly attributable adverse effects were identified.
CONCLUSION: Increasing doses of a saw palmetto fruit extract did not reduce lower urinary tract symptoms more than placebo.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00603304.

PMID 21954478
James Tacklind, Roderick Macdonald, Indy Rutks, Judith U Stanke, Timothy J Wilt
Serenoa repens for benign prostatic hyperplasia.
Cochrane Database Syst Rev. 2012 Dec 12;12:CD001423. doi: 10.1002/14651858.CD001423.pub3. Epub 2012 Dec 12.
Abstract/Text BACKGROUND: Benign prostatic hyperplasia (BPH) is a nonmalignant enlargement of the prostate, which can lead to obstructive and irritative lower urinary tract symptoms (LUTS). The pharmacologic use of plants and herbs (phytotherapy) for the treatment of LUTS associated with BPH is common. The extract of the berry of the American saw palmetto, or dwarf palm plant, Serenoa repens (SR), which is also known by its botanical name of Sabal serrulatum, is one of several phytotherapeutic agents available for the treatment of BPH.
OBJECTIVES: This systematic review aimed to assess the effects and harms of Serenoa repens in the treatment of men with LUTS consistent with BPH.
SEARCH METHODS: We searched for trials in general and in specialized databases, including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE®, EMBASE, CINAHL®, Web of Science, SCOPUS, BIOSIS Previews®, LILACS, ClinicalTrials.gov, Controlled-Trials.com, World Health Organization (WHO), and Google Scholar. We also handsearched systematic reviews, references, and clinical practice guidelines. There were no language restrictions.
SELECTION CRITERIA: Trials were eligible if they randomized men with symptomatic BPH to receive preparations of SR (alone or in combination) for at least four weeks in comparison with placebo or other interventions, and included clinical outcomes, such as urologic symptom scales, symptoms, and urodynamic measurements. Eligibility was assessed by at least two independent observers (JT, RM).
DATA COLLECTION AND ANALYSIS: One review author (JT) extracted Information on patients, interventions, and outcomes which was then checked by another review author (RM). The main outcome measure for comparing the effectiveness of SR with active or inert controls was change in urologic symptom-scale scores, with validated scores taking precedence over non validated ones. Secondary outcomes included changes in nocturia and urodynamic measures. The main outcome measure for harms was the number of men reporting side effects.
MAIN RESULTS: In a meta-analysis of two high quality long-term trials (n = 582), Serenoa repens therapy was not superior to placebo in reducing LUTS based on the AUA (mean difference (MD) 0.25 points, 95% confidence interval (CI) -0.58 to 1.07). A 72 week trial with high quality evidence, using the American Urological Association Symptom Score Index, reported that SR was not superior to placebo at double and triple doses. In the same trial the proportions of clinical responders (≥ three-point improvement) were nearly identical (42.6% and 44.2% for SR and placebo, respectively), and not significant (RR 0.96, 95% CI 0.76 to 1.22).This update, which did not change our previous conclusions, included two new trials with 444 additional men, an 8.5% (5666/5222) increase from our 2009 updated review, and a 28.8% (1988/1544) increase for our main comparison, SR monotherapy versus placebo control (17 trials). Overall, 5666 men were assessed from 32 randomized, controlled trials, with trial lengths from four to 72 weeks. Twenty-seven trials were double blinded and treatment allocation concealment was adequate in 14.In a trial of high quality evidence (N = 369), versus placebo, SR did not significantly decrease nightly urination on the AUA Nocturia scale (range zero to five) at 72 weeks follow-up (one-sided P = 0.19).The three high quality, moderate-to-long term trials found peak urine flow was not improved with Serenoa repens compared with placebo (MD 0.40 mL/s, 95% CI -0.30 to 1.09).Comparing prostate size (mean change from baseline), one high quality 12-month trial (N = 225) reported no significant difference between SR and placebo (MD -1.22 cc, 95% CI -3.91 to 1.47).
AUTHORS' CONCLUSIONS: Serenoa repens, at double and triple doses, did not improve urinary flow measures or prostate size in men with lower urinary tract symptoms consistent with BPH.

PMID 23235581
Aleksandar Argirović, Djordje Argirović
Does the addition of Serenoa repens to tamsulosin improve its therapeutical efficacy in benign prostatic hyperplasia?
Vojnosanit Pregl. 2013 Dec;70(12):1091-6.
Abstract/Text BACKGROUND/AIM: It has been observed that a large number of patients with low urinary tract symptoms due to benign prostatic hyperplasia (LUTS/BPH)) has been treated with a combination of tamsulosin (TAM) + Serenoa repens (SR) (TAM + SR). The aim of this study was to compare a combination TAM + SR with TAM and SR alone, to see if there was any difference in efficacy and tolerance of each in patients with LUTS/BPH.
METHODS: In this prospective study patients had to have prostate volume (PV) < 50 mL, International Prostate Symptom Score (IPSS) of 7-18, Quality of Life score (QoLs) > 3, a maximal flow rate (Qmax) of 5-15 mL/s, with post voiding residual volume (PVR) < 150 mL and serum prostatic antigen (PSA) < 4 ng/mL. TAM (0.4 mg) was administered once a day, SR (320 mg) daily or SR (320 mg) + TAM (0.4 mg) daily for a median period of 6 months.
RESULTS: A total of 297 patients were recruited, whereas 265 patients were fully available: 87 into the group TAM, 97 into the group SR and 81 into the group TAM + SR. There was no statistically significant difference between the treatment groups in the sense of demographic and other baseline parameters. No difference was found among the 3 treatment groups, neither in the major endpoint of the study in the sense of a change between baseline and final evaluation in total IPSS, obstructive and irritative subscores, improvement of QoLs, increase in Qmax, nor for the second endpoint including diminution of PV, PSA and PVR. During the treatment period 20 (23%) of the patients managed with TAM and 17 (21%) with TAM + SR had drug- treated with related adverse reactions. No adverse effect was detected in the group SR.
CONCLUSION: Treatment of BPH by both SR and TAM seems to be efficacious alone. None of them had superiority over another and, additionally, a combined therapy (TAM + SR) does not provide extra benefits. Furthermore, SR is a well-tolerated agent that can be used alternatively in the treatment of LUTS/BPH.

PMID 24450252
Andrew L Avins, Stephen Bent, Suzanne Staccone, Evelyn Badua, Amy Padula, Harley Goldberg, John Neuhaus, Esther Hudes, Katusto Shinohara, Christopher Kane
A detailed safety assessment of a saw palmetto extract.
Complement Ther Med. 2008 Jun;16(3):147-54. doi: 10.1016/j.ctim.2007.10.005. Epub 2008 Feb 20.
Abstract/Text BACKGROUND: Saw palmetto is commonly used by men for lower-urinary tract symptoms. Despite its widespread use, very little is known about the potential toxicity of this dietary supplement.
METHODS: The Saw palmetto for Treatment of Enlarged Prostates (STEP) study was a randomized clinical trial performed among 225 men with moderate-to-severe symptoms of benign prostatic hyperplasia, comparing a standardized extract of the saw palmetto berry (160 mg twice daily) with a placebo over a 1-year period. As part of this study, detailed data were collected on serious and non-serious adverse events, sexual functioning, and laboratory tests of blood and urine. Between-group differences were assessed with mixed-effects regression models.
RESULTS: There were no significant differences observed between the saw palmetto and placebo-allocated participants in the risk of suffering at least one serious adverse event (5.4% vs. 9.7%, respectively; p=0.31) or non-serious symptomatic adverse event (34.8% vs. 30.1%, p=0.48). There were few significant between-group differences in sexual functioning or for most laboratory analyses, with only small differences observed in changes over time in total bilirubin (p=0.001), potassium (p=0.03), and the incidence of glycosuria (0% in the saw palmetto group vs. 3.7% in the placebo group, p=0.05).
CONCLUSIONS: Despite careful assessment, no evidence for serious toxicity of saw palmetto was observed in this clinical trial. Given the sample size and length of this study, however, these data do not rule out potential rare adverse effects associated with the use of saw palmetto.

PMID 18534327
Andrew L Avins, Jeannette Y Lee, Catherine M Meyers, Michael J Barry, CAMUS Study Group
Safety and toxicity of saw palmetto in the CAMUS trial.
J Urol. 2013 Apr;189(4):1415-20. doi: 10.1016/j.juro.2012.10.002. Epub 2012 Oct 9.
Abstract/Text PURPOSE: Extracts of the saw palmetto berry are used by many men in the United States as self-treatment for lower urinary tract symptoms due to benign prostatic hyperplasia. While the most recent data from double-blind clinical trials do not support efficacy superior to that of placebo, there are sparse data on saw palmetto toxicity.
MATERIALS AND METHODS: A total of 369 patients were randomized in the CAMUS (Complementary and Alternative Medicine for Urological Symptoms) trial, of whom 357 were included in this modified intent to treat analysis. Participants were randomized to 320, 640 and 960 mg daily of an ethanolic saw palmetto extract or to an identical-appearing placebo in an escalating manner at 6-month intervals for a total of 18 months of followup. Adverse event assessments, vital signs, and blood and urine laboratory tests were obtained at regular intervals.
RESULTS: There were no statistically significant differences between the groups in the rates of serious or nonserious adverse events, changes in vital signs, digital prostate examination findings or study withdrawal rates. Overall, there were no significant intergroup differences in laboratory test abnormalities, while differences in individual laboratory tests were rare and small in magnitude. No evidence of significant dose-response phenomena was identified.
CONCLUSIONS: The saw palmetto extract used in the CAMUS trial showed no evidence of toxicity at doses up to 3 times the usual clinical dose during an 18-month period.

Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
PMID 23063633
Howard N Hodis, Wendy J Mack, Herbert J Meiselman, Vijay Kalra, Howard Liebman, Juliana Hwang-Levine, Laurie Dustin, Naoko Kono, Melissa Mert, Rosalinda B Wenby, Emiliano Huesca, Leanne Rochanda, Yanjie Li, Mingzhu Yan, Jan A St John, Lora Whitfield
Nattokinase atherothrombotic prevention study: A randomized controlled trial.
Clin Hemorheol Microcirc. 2021;78(4):339-353. doi: 10.3233/CH-211147.
Abstract/Text BACKGROUND: Described to be antithrombotic and antihypertensive, nattokinase is consumed for putative cardiovascular benefit. However, no large-scale, long-term cardiovascular study has been conducted with nattokinase supplementation.
OBJECTIVE: To determine the effect of nattokinase on subclinical atherosclerosis progression and atherothrombotic biomarkers.
METHODS: In this double-blinded trial, 265 individuals of median age 65.3 years, without clinical evidence of cardiovascular disease (CVD) were randomized to oral nattokinase 2,000 fibrinolytic units or matching placebo. Primary outcome was rate of change in subclinical atherosclerosis measured by serial carotid ultrasound every 6 months as carotid artery intima-media thickness (CIMT) and carotid arterial stiffness (CAS). Additional outcomes determined at least every 6 months were clinical parameters including blood pressure and laboratory measures including metabolic factors, blood rheology parameters, blood coagulation and fibrinolysis factors, inflammatory markers and monocyte/macrophage cellular activation markers.
RESULTS: After median 3 years of randomized treatment, annualized rate of change in CIMT and CAS did not significantly differ between nattokinase supplementation and placebo. Additionally, there was no significant effect of nattokinase supplementation on blood pressure or any laboratory determination.
CONCLUSIONS: Results of this trial show that nattokinase supplementation has a null effect on subclinical atherosclerosis progression in healthy individuals at low risk for CVD.

PMID 33843667
Yuko Kurosawa, Shinsuke Nirengi, Toshiyuki Homma, Kazuki Esaki, Mitsuhiro Ohta, Joseph F Clark, Takafumi Hamaoka
A single-dose of oral nattokinase potentiates thrombolysis and anti-coagulation profiles.
Sci Rep. 2015 Jun 25;5:11601. doi: 10.1038/srep11601. Epub 2015 Jun 25.
Abstract/Text Our aim was to determine the quantitative effects of a single-dose of Nattokinase (NK) administration on coagulation/fibrinolysis parameters comprehensively in healthy male subjects. A double-blind, placebo-controlled cross-over NK intervention study was carried out in 12 healthy young males. Following the baseline blood draw, each subject was randomized to receive either a single-dose of 2,000 FU NK (NSK-SD, Japan Bio Science Laboratory Co., Ltd) or placebo with subsequent cross-over of the groups. Subjects donated blood samples at 2, 4, 6 and 8 hours following administration for analysis of coagulation/fibrinolysis parameters. As a result, D-dimer concentrations at 6, and 8 hours, and blood fibrin/fibrinogen degradation products at 4 hours after NK administration elevated significantly (p < 0.05, respectively). Factor VIII activity declined at 4 and 6 hours (p < 0.05, respectively), blood antithrombin concentration was higher at 2 and 4 hours (p < 0.05, respectively), and the activated partial thromboplastin time prolonged significantly at 2 and 4 hours following NK administration (p < 0.05 and p < 0.01, respectively). All the changes, however, were within the normal range. In conclusion, thus, a single-dose of NK administration appears enhancing fibrinolysis and anti-coagulation via several different pathways simultaneously.

PMID 26109079
Ji Young Kim, Si Nae Gum, Jean Kyung Paik, Hyo Hee Lim, Kyong-Chol Kim, Kazuya Ogasawara, Kenichi Inoue, Sungha Park, Yangsoo Jang, Jong Ho Lee
Effects of nattokinase on blood pressure: a randomized, controlled trial.
Hypertens Res. 2008 Aug;31(8):1583-8. doi: 10.1291/hypres.31.1583.
Abstract/Text The objective of this study was to examine the effects of nattokinase supplementation on blood pressure in subjects with pre-hypertension or stage 1 hypertension. In a randomized, double-blind, placebo-controlled trial, 86 participants ranging from 20 to 80 years of age with an initial untreated systolic blood pressure (SBP) of 130 to 159 mmHg received nattokinase (2,000 FU/capsule) or a placebo capsule for 8 weeks. Seventy-three subjects completed the protocol. Compared with the control group, the net changes in SBP and diastolic blood pressure (DBP) were -5.55 mmHg (95% confidence interval [CI], -10.5 to -0.57 mmHg; p<0.05) and -2.84 mmHg (CI, -5.33 to -0.33 mmHg; p<0.05), respectively, after the 8-week intervention. The corresponding net change in renin activity was -1.17 ng/mL/h for the nattokinase group compared with the control group (p<0.05). In conclusion, nattokinase supplementation resulted in a reduction in SBP and DBP. These findings suggest that increased intake of nattokinase may play an important role in preventing and treating hypertension.

PMID 18971533
N N Ren, H J Chen, Y Li, G W Mcgowan, Y G Lin
[A clinical study on the effect of nattokinase on carotid artery atherosclerosis and hyperlipidaemia].
Zhonghua Yi Xue Za Zhi. 2017 Jul 11;97(26):2038-2042.
Abstract/Text Objective: To evaluate the efficacy of oral nattokinase (NK) in the reduction of common carotid artery intimal medial thickness (CCA-IMT) and carotid artery plaque size and in lowering blood lipids, and to explore the underlying mechanism of actions of NK and its potential clinical use. Methods: All enrolled patients were from the Out-Patient Clinic of the Department of TCM at the 3(rd) Affiliated Hospital of Sun Yat-sen University. Using randomised picking method, all patients were randomly assigned to one of two groups, NK and Statin (ST) group. NK Group-patients were given NK at a daily dose of 6 000 FU and ST Group-patients were treated with statin (simvastatin 20 mg) daily. The treatment course was 26 weeks. CCA-IMT, carotid plaque size and blood lipid profile of the patients were measured before and after treatment. Results: A total of 82 patients were enrolled in the study and 76 patients (NK 39, ST 37) completed the study. Following the treatments for 26 weeks, there was a significant reduction in CCA-IMT and carotid plaque size in both groups compared with the baseline before treatment. The carotid plaque size and CCA-IMT reduced from(0.25±0.12)cm(2) to (0.16±0.10)cm(2) and from (1.13±0.12)mm to (1.01±0.11)mm, repectively. The reduction in the NK group was significantly profound (P<0.01, 36.6% reduction in plaque size in NK group versus 11.5% change in ST group). Both treatments reduced total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG). While the reduction in both groups was shown to be statistically significant (P<0.01), the reduction of TC, LDL-C and TG in ST group was significantly greater (P<0.05). In addition, NK significantly increased the level of high-density lipoprotein cholesterol (HDL-C) (P<0.05), in contrast, HDL-C in the ST group did not change. The lipid lowering effect observed in the NK group was not correlated to the reduction of CCA-IMT and carotid artery plaque size (r=0.35, P=0.09). Conclusions: Our findings from this pioneer clinical study suggests that daily NK supplementation is an effective way to manage the progression of atherosclerosis and potentially may be a better alternative to statins which are commonly used to reduce atherosclerosis and further to prevent cardiovascular attack and stroke in patients. The mechanism underlying the reduction of carotid atherosclerosis by NK may be independent from its lipid-lowering effect, which is different from that of statins.

PMID 28763875
Yung-Yee Chang, Jia-Shou Liu, Shung-Lon Lai, Hsiu-Shan Wu, Min-Yu Lan
Cerebellar hemorrhage provoked by combined use of nattokinase and aspirin in a patient with cerebral microbleeds.
Intern Med. 2008;47(5):467-9. Epub 2008 Mar 3.
Abstract/Text Nattokinase is used as a health-promoting medicine for preventing thrombosis due to its fibrinolytic activity. Cerebral microbleed is remnant of blood extravasations from the damaged vessels related to cerebral microangiopathies. We report a patient, having used aspirin for secondary stroke prevention, who had an acute cerebellar hemorrhage after taking nattokinase 400 mg daily for 7 consecutive days. In addition to the hemorrhagic lesion, multiple microbleeds were demonstrated on brain MR images. We suggest that nattokinase may increase risk of intracerebral hemorrhage in patients who have bleeding-prone cerebral microangiopathy and are receiving other antithrombotic agent at the same time.

PMID 18310985
Chieko Yatagai, Masugi Maruyama, Tomoko Kawahara, Hiroyuki Sumi
Nattokinase-promoted tissue plasminogen activator release from human cells.
Pathophysiol Haemost Thromb. 2008;36(5):227-32. doi: 10.1159/000252817. Epub 2009 Dec 9.
Abstract/Text When heated to a temperature of 70 degrees C or higher, the strong fibrinolytic activity of nattokinase in a solution was deactivated. Similar results were observed in the case of using Suc-Ala-Ala-Pro-Phe-pNA and H-D-Val-Leu-Lys-pNA, which are synthetic substrates of nattokinase. In the current study, tests were conducted on the indirect fibrinolytic effects of the substances containing nattokinase that had been deactivated through heating at 121 degrees C for 15 min. Bacillus subtilis natto culture solutions made from three types of bacteria strain were heat-treated and deactivated, and it was found that these culture solutions had the ability to generate tissue plasminogen activators (tPA) from vascular endothelial cells and HeLa cells at certain concentration levels. For example, it was found that the addition of heat-treated culture solution of the Naruse strain (undiluted solution) raises the tPA activity of HeLa cells to about 20 times that of the control. Under the same conditions, tPA activity was raised to a level about 5 times higher for human vascular endothelial cells (HUVEC), and to a level about 24 times higher for nattokinase sold on the market. No change in cell count was observed for HeLa cells and HUVEC in the culture solution at these concentrations, and the level of activity was found to vary with concentration.

Copyright 2009 S. Karger AG, Basel.
PMID 19996631
Yunqi Weng, Jian Yao, Sawyer Sparks, Kevin Yueju Wang
Nattokinase: An Oral Antithrombotic Agent for the Prevention of Cardiovascular Disease.
Int J Mol Sci. 2017 Feb 28;18(3). doi: 10.3390/ijms18030523. Epub 2017 Feb 28.
Abstract/Text Natto, a fermented soybean product, has been consumed as a traditional food in Japan for thousands of years. Nattokinase (NK), a potent blood-clot dissolving protein used for the treatment of cardiovascular diseases, is produced by the bacterium Bacillus subtilis during the fermentation of soybeans to produce Natto. NK has been extensively studied in Japan, Korea, and China. Recently, the fibrinolytic (anti-clotting) capacity of NK has been recognized by Western medicine. The National Science Foundation in the United States has investigated and evaluated the safety of NK. NK is currently undergoing a clinical trial study (Phase II) in the USA for atherothrombotic prevention. Multiple NK genes have been cloned, characterized, and produced in various expression system studies. Recombinant technology represents a promising approach for the production of NK with high purity for its use in antithrombotic applications. This review covers the history, benefit, safety, and production of NK. Opportunities for utilizing plant systems for the large-scale production of NK, or for the production of edible plants that can be used to provide oral delivery of NK without extraction and purification are also discussed.

PMID 28264497
Gitte S Jensen, Miki Lenninger, Michael P Ero, Kathleen F Benson
Consumption of nattokinase is associated with reduced blood pressure and von Willebrand factor, a cardiovascular risk marker: results from a randomized, double-blind, placebo-controlled, multicenter North American clinical trial.
Integr Blood Press Control. 2016;9:95-104. doi: 10.2147/IBPC.S99553. Epub 2016 Oct 13.
Abstract/Text OBJECTIVE: The objective of this study is to evaluate the effects of consumption of nattokinase on hypertension in a North American hypertensive population with associated genetic, dietary, and lifestyle factors. This is in extension of, and contrast to, previous studies on Asian populations.
MATERIALS AND METHODS: A randomized, double-blind, placebo-controlled, parallel-arm clinical study was performed to evaluate nattokinase (NSK-SD), a fermented soy extract nattō from which vitamin K2 has been removed. Based on the results from previous studies on Asian populations, 79 subjects were enrolled upon screening for elevated blood pressure (BP; systolic BP ≥130 or diastolic BP ≥90 mmHg) who consumed placebo or 100 mg nattokinase/d for the 8-week study duration. Blood collections were performed at baseline and 8 weeks for testing plasma renin activity, von Willebrand factor (vWF), and platelet factor-4. Seventy-four people completed the study with good compliance.
RESULTS: Consumption of nattokinase was associated with a reduction in both systolic and diastolic BP. The reduction in systolic BP was seen for both sexes but was more robust in males consuming nattokinase. The average reduction in diastolic BP in the nattokinase group from 87 mmHg to 84 mmHg was statistically significant when compared to that in the group consuming placebo, where the average diastolic BP remained constant at 87 mmHg (P<0.05), and reached a high level of significance for males consuming nattokinase, where the average diastolic BP dropped from 86 mmHg to 81 mmHg (P<0.006). A decrease in vWF was seen in the female population consuming nattokinase (P<0.1). In the subpopulation with low plasma renin activity levels at baseline (<0.29 ng/mL/h), an increase was seen for 66% of the people after 8-week consumption of nattokinase (P<0.1), in contrast to only 8% in the placebo group.
CONCLUSION: The data suggest that nattokinase consumption in a North American population is associated with beneficial changes to BP in a hypertensive population, indicating sex-specific mechanisms of action of nattokinase's effect on vWF and hypertension.

PMID 27785095
Tomohiro Sugino, Tomoko Shirai, Yoshitaka Kajimoto, Osami Kajimoto
L-ornithine supplementation attenuates physical fatigue in healthy volunteers by modulating lipid and amino acid metabolism.
Nutr Res. 2008 Nov;28(11):738-43. doi: 10.1016/j.nutres.2008.08.008.
Abstract/Text We examined the effects of L-ornithine administration on physical fatigue. In a double-blind, placebo-controlled, 2-way crossover study, 17 healthy volunteers were randomized to L-ornithine (2000 mg/d for 7 days and 6000 mg/d for 1 day as L-ornithine hydrochloride) or placebo for 8 days. The fatigue-inducing physical task consisted of workload trials on a cycle ergometer at fixed workloads for 2 hours on 2 occasions. We found that oral L-ornithine administration promoted lipid metabolism and activated the urea cycle from serum triacylglycerol, ketone bodies, free fatty acids, and blood ammonia level changing. L-ornithine significantly attenuated the subjective feeling of fatigue (measured by visual analog scale at postrecovery) compared with postload (P < .01). Moreover, in female subjects, the subjective feeling of fatigue was significantly lower compared with the placebo group (P < .05). In the physical performance test in female subjects, the decrease in mean speed for 10 seconds maximum pedaling from 0.5- to 3.5-hour trials in the group receiving L-ornithine was smaller than that in the group receiving placebo (P < .05). These results suggest that L-ornithine has an antifatigue effect by increasing the efficiency of energy consumption and promoting the excretion of ammonia. L-ornithine is a free amino acid and is not rich in meats or fish, so it is difficult to obtain amounts of L-ornithine from ordinary meals that would be sufficient to promote the antifatigue effect. We recommend L-ornithine intake as a nutritional supplement in cases of physical fatigue.

PMID 19083482
Mika Miyake, Takayoshi Kirisako, Takeshi Kokubo, Yutaka Miura, Koji Morishita, Hisayoshi Okamura, Akira Tsuda
Randomised controlled trial of the effects of L-ornithine on stress markers and sleep quality in healthy workers.
Nutr J. 2014 Jun 3;13:53. doi: 10.1186/1475-2891-13-53. Epub 2014 Jun 3.
Abstract/Text BACKGROUND: L-ornithine is a non-essential, non-protein amino acid. Although L-ornithine is contained in various foods, the amount is usually small.Recently, studies have shown that orally administered L-ornithine reduced the stress response in animals.From these findings, we speculated that L-ornithine may play a role in the relieve of stress and improve sleep and fatigue symptoms in humans. Through a randomised, double-blind, placebo-controlled clinical study, we asked if L-ornithine could be beneficial to stress and sleep in healthy workers.
METHOD: Fifty-two apparently healthy Japanese adults who had previously felt slight stress as well as fatigue were recruited to be study participants and were randomly divided into either the L-ornithine (400 mg/day) or placebo group. They orally consumed the respective test substance every day for 8 weeks. Serum was collected for the assessment of cortisol and dehydroepiandrosterone-sulphate (DHEA-S). Perceived mood and quality of sleep were measured by the Profile of Mood States (POMS), Athens Insomnia Scale (AIS), and Ogri-Shirakawa-Azumi sleep inventory MA version (OSA-MA).
RESULTS: Serum cortisol levels and the cortisol/DHEA-S ratio were significantly decreased in the L-ornithine group in comparison with the placebo group. Also, anger was reduced and perceived sleep quality was improved in the L-ornithine group.
CONCLUSION: L-ornithine supplementation has the potential to relieve stress and improve sleep quality related to fatigue, both objectively and subjectively.

PMID 24889392
Takeshi Kokubo, Emiko Ikeshima, Takayoshi Kirisako, Yutaka Miura, Masahisa Horiuchi, Akira Tsuda
A randomized, double-masked, placebo-controlled crossover trial on the effects of L-ornithine on salivary cortisol and feelings of fatigue of flushers the morning after alcohol consumption.
Biopsychosoc Med. 2013 Feb 18;7(1):6. doi: 10.1186/1751-0759-7-6. Epub 2013 Feb 18.
Abstract/Text UNLABELLED:
BACKGROUND: Residual alcohol effects on physiological and psychological symptoms are commonly experienced the morning after alcohol consumption. The purpose of this study was to assess the effects of L-ornithine on subjective feelings and salivary stress markers the morning after alcohol consumption and to investigate whether L-ornithine acutely accelerates ethanol metabolism.
METHODS: This study had a randomized, placebo-controlled, double-masked crossover design. Subjects were all healthy Japanese adults with the 'flusher' phenotype for alcohol tolerance. In experiment 1, 11 subjects drank 0.4 g/kg body weight alcohol 1.5 h before their usual bedtime. Half an hour after drinking, they ingested either a placebo or 400 mg ornithine. The next morning on awakening, subjects completed a questionnaire containing a visual analog scale (VAS), the Oguri-Shirakawa-Azumi sleep inventory MA version (OSA-MA), and a profile of mood states (POMS) and collected a saliva sample for measurement of salivary stress markers (cortisol, secretory immunoglobulin A, and α-amylase). In experiment 2, placebo or 400 mg ornithine were administrated to 16 subjects both before and after drinking, and the feeling of drunkenness, breath ethanol concentration and one-leg standing time were repeatedly investigated until 180 min after alcohol consumption.
RESULTS: There were significant decreases in "awareness", "feeling of fatigue" and "lassitude" VAS scores and in "anger-hostility" and "confusion" POMS scores and a significant increase in "sleep length" in the OSA-MA test. Salivary cortisol concentrations on awakening were reduced after ornithine supplementation. There were no differences between ornithine and placebo in any of the subjective or physiological parameters of acute alcohol metabolism.
CONCLUSIONS: Taking 400 mg ornithine after alcohol consumption improved various negative feelings and decreased the salivary stress marker cortisol the next morning. These effects were not caused by an increase in acute alcohol metabolism.

PMID 23414576
Ayano Imai, Yuriko Oda, Naoki Ito, Shinobu Seki, Kiyotaka Nakagawa, Teruo Miyazawa, Fumitaka Ueda
Effects of Dietary Supplementation of Astaxanthin and Sesamin on Daily Fatigue: A Randomized, Double-Blind, Placebo-Controlled, Two-Way Crossover Study.
Nutrients. 2018 Feb 28;10(3). doi: 10.3390/nu10030281. Epub 2018 Feb 28.
Abstract/Text Severe fatigue can negatively affect quality of life, and oxidative stress may play a role in its mechanism. The aim of this study was to evaluate the effect of dietary supplementation of astaxanthin and sesamin (AS), strong food-derived antioxidants, on fatigue. Twenty-four healthy volunteers were supplemented with AS and placebo, each for four weeks. After each supplementation period, participants underwent tasks inducing mental and physical fatigue (visual display terminal task and ergometer task, respectively). Subjective fatigue was evaluated using a visual analogue scale during and after the mental and physical tasks, and daily subjective fatigue was evaluated by the Chalder fatigue questionnaire. Secondary outcomes included other subjective feelings, work efficiency, autonomic nerve activity, levels of an oxidative stress marker (plasma phosphatidylcholine hydroperoxide (PCOOH)) and safety. AS supplementation was associated with significantly improved recovery from mental fatigue compared with placebo. Increased PCOOH levels during mental and physical tasks were attenuated by AS supplementation. No differences between AS and placebo were detected in secondary outcomes, and no adverse effects of AS supplementation were observed. In conclusion, AS supplementation may be a candidate to promote recovery from mental fatigue which is experienced by many healthy people.

PMID 29495607
Naoki Ito, Hitomi Saito, Shinobu Seki, Fumitaka Ueda, Takashi Asada
Effects of Composite Supplement Containing Astaxanthin and Sesamin on Cognitive Functions in People with Mild Cognitive Impairment: A Randomized, Double-Blind, Placebo-Controlled Trial.
J Alzheimers Dis. 2018;62(4):1767-1775. doi: 10.3233/JAD-170969.
Abstract/Text BACKGROUND: Dementia and its first or transitional stage, mild cognitive impairment (MCI), is a major concern for the aging Japanese society. Thus, the use of dietary supplements to improve or maintain cognitive function has become a topic of public interest.
OBJECTIVE: In this study, we evaluated the effects of a composite supplement containing food-derived antioxidants, specifically astaxanthin and sesamin (AS), on cognitive function in people with MCI.
METHOD: Twenty-one healthy participants with MCI were recruited in our double-blind placebo-controlled pilot study. They were assigned to either an AS group, who received ingestible capsules containing AS, or a placebo group, who received identical placebo capsules. To assess cognitive functions, we performed the Japanese version of the Central Nervous System Vital Signs (CNSVS) test and the Alzheimer's Disease Assessment Scale-Cog test at baseline, after 6 weeks, and after 12 weeks of dietary supplementation.
RESULTS: The CNSVS test revealed significant improvements in psychomotor speed and processing speed in the AS group compared with the placebo group, suggesting that the daily supplementation of AS improved cognitive functions related to the ability to comprehend, and perform complex tasks quickly and accurately.
CONCLUSION: Our results provide support for the use of AS as a dietary supplementation for improving cognitive functions.

PMID 29614679
Carolina Alves Cardoso, Gláucia Maria Moraes de Oliveira, Luciana de Almeida Vittori Gouveia, Annie Seixas Bello Moreira, Glorimar Rosa
The effect of dietary intake of sesame (Sesamumindicum L.) derivatives related to the lipid profile and blood pressure: A systematic review.
Crit Rev Food Sci Nutr. 2016 Feb 6;:1-10. doi: 10.1080/10408398.2015.1137858. Epub 2016 Feb 6.
Abstract/Text In this systematic review, we discuss the scientific evidence about the effect of dietary intake of seeds and sesame derivatives on lipid profile and blood pressure (BP) of hypertensive and dyslipidemic individuals. Clinical trials published in English, Portuguese or Spanish were searched on the following databases: Lilacs, PubMed, Isi Web of Knowledge, Cochrane Library, Scopus, Trip Data Base and Scielo. The bibliographic search period was started in September 2013 and ended in January 2014. The biases of risk analysis were carried out considering 6 of the 8 criteria of the Cochrane Handbook for Systematic Reviews of Interventions Version 5.1. Of the 7 clinical trials included, five evaluating individuals with hypertension observed a significant reduction in systolic and/or diastolic blood pressure. The two articles that evaluated individuals with dyslipidemia showed improvement in lipid profile. The mechanisms of action are still being studied. Regarding the bias risk analysis, clinical trials included showed few descriptions of the methods applied. There are few studies about sesame ingestion, and it was observed high risk for bias in the selected studies. More standardized methods with attention to the design of studies are needed to improve the level of the evidence.

PMID 26853814
Saman Khalesi, Ernesta Paukste, Elham Nikbakht, Hossein Khosravi-Boroujeni
Sesame fractions and lipid profiles: a systematic review and meta-analysis of controlled trials.
Br J Nutr. 2016 Mar;115(5):764-73. doi: 10.1017/S0007114515005012. Epub 2016 Jan 13.
Abstract/Text Increased plasma lipid profiles are among the most important risk factors of CHD and stroke. Sesame contains considerable amounts of vitamin E, MUFA, fibre and lignans, which are thought to be associated with its plasma lipid-lowering properties. This study aimed to systematically review the evidence and identify the effects of sesame consumption on blood lipid profiles using a meta-analysis of controlled trials. PubMed, CINAHL and Cochrane Library databases were searched (from 1960 to May 2015). A total of ten controlled trials were identified based on the eligibility criteria. Both the Cochrane Collaboration tool and the Rosendal scale were used to assess the risk of bias of the included studies. The meta-analysis results showed that consumption of sesame did not significantly change the concentrations of total blood cholesterol (-0·32 mmol/l; 95 % CI -0·75, 0·11; P=0·14, I 2=96 %), LDL-cholesterol (-0·15 mmol/l; 95 % CI -0·50, 0·19; P=0·39, I 2=96 %) or HDL-cholesterol (0·01 mmol/l; 95 % CI -0·00, 0·02; P=0·16, I 2=0 %). However, a significant reduction was observed in serum TAG levels (-0·24 mmol/l; 95 % CI -0·32, -0·15; P<0·001, I 2=84 %) after consumption of sesame. It was concluded that sesame consumption can significantly reduce blood TAG levels but there is insufficient evidence to support its hypocholesterolaemic effects. Further studies are required to determine the potential effect of sesame consumption on lipid profiles and cardiovascular risk factors.

PMID 26758593
B Helli, K Mowla, M Mohammadshahi, M T Jalali
Effect of Sesamin Supplementation on Cardiovascular Risk Factors in Women with Rheumatoid Arthritis.
J Am Coll Nutr. 2015 Jul 7;:1-8. doi: 10.1080/07315724.2015.1005198. Epub 2015 Jul 7.
Abstract/Text OBJECTIVE: Rheumatoid arthritis (RA) is an inflammatory disease with increased mortality from cardiovascular disease (CVD). Oxidative stress has a critical role in the pathogenesis of RA and CVD. Sesamin, the main lignin constituent of sesame, has several antioxidant and anti-inflammatory effects. This study aimed to investigate the effects of sesamin supplementation on anthropometric indices, lipid profile, blood pressure, and oxidative stress markers in women with RA.
METHODS: In this randomized, double-blind, placebo-controlled clinical trial, 44 patients with RA were randomly divided into 2 groups (intervention and control). Patients consumed 200 mg/day sesamin supplement and placebo in the intervention and control groups, respectively, for 6 weeks (spring 2014). At baseline and at the end of the study, anthropometric indices and blood pressure were assessed. Serum concentrations of lipid profile, malondialdehyde (MDA), and total antioxidant capacity (TAC) were also determined.
RESULTS: At the end of study, sesamin supplementation significantly decreased serum levels of MDA (p = 0.018) and increased TAC and high-density lipoprotein cholesterol (HDL-C) levels in patients with RA (p = 0.020 and p = 0.007, respectively). In the sesamin group, the mean of weight, body mass index, waist-to-hip ratio, body fat, systolic blood pressure, and the concentration of other lipid profiles (triglycerides, total cholesterol, and low-density lipoprotein cholesterol [LDL-C]) were also significantly decreased at the end of study compared to baseline values (p < 0.05). However, the difference between the 2 groups was not statistically significant in this regard (p > 0.05).
CONCLUSION: Sesamin exhibited a protective effect on cardiovascular risk factors in patients with RA. However, further investigation is suggested.

PMID 26151734
Hossein Khosravi-Boroujeni, Elham Nikbakht, Ernesta Natanelov, Saman Khalesi
Can sesame consumption improve blood pressure? A systematic review and meta-analysis of controlled trials.
J Sci Food Agric. 2017 Aug;97(10):3087-3094. doi: 10.1002/jsfa.8361. Epub 2017 May 12.
Abstract/Text Hypertension is a major risk factor for cardiovascular disease, myocardial infarction, stroke and renal failure. Sesame consumption may benefit blood pressure (BP) owing to its high polyunsaturated fatty acid, fibre, phytosterol and lignan contents. To clarify this, a systematic review and meta-analysis of controlled trials was conducted. The PubMed (MEDLINE), Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Cochrane Library (Central) databases were systematically searched until August 2016. Eight controlled trials with a total of 843 participants met the eligibility criteria. A random effect meta-analysis showed that sesame consumption can reduce systolic BP (-7.83 mmHg, 95% CI: -14.12, -1.54; P < 0.05, I2  = 99%) and diastolic BP (-5.83 mmHg, 95% CI: -9.58, -2.08; P < 0.01, I2  = 98%). To reduce the heterogeneity, the meta-analysis was limited to high methodology quality trials (n = 4), which resulted in a significant reduction in systolic BP (-3.23 mmHg, 95% CI: -5.67, -0.79; I2  = 33%) and a non-significant reduction in diastolic BP (-2.08 mmHg, 95% CI: -4.85, 0.69; I2  = 62%). This study concluded that sesame consumption can reduce systolic and diastolic BP. However, further investigations with larger sample sizes and better methodology quality are required to confirm the BP-lowering effect of sesame consumption. © 2017 Society of Chemical Industry.

© 2017 Society of Chemical Industry.
PMID 28387047
Shabnam Rafiee, Roghaye Faryabi, Alireza Yargholi, Mohammad Ali Zareian, Jessie Hawkins, Nitin Shivappa, Laila Shirbeigi
Effects of Sesame Consumption on Inflammatory Biomarkers in Humans: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
Evid Based Complement Alternat Med. 2021;2021:6622981. doi: 10.1155/2021/6622981. Epub 2021 Nov 1.
Abstract/Text Objectives: Existing evidence produces conflicting findings regarding the effect of sesame intake on inflammatory biomarkers; this knowledge gap has yet to be met through systematic review and meta-analysis. This meta-analysis of randomized, controlled clinical trials (RCTs) was conducted to evaluate the effects of sesame consumption on markers of inflammation in humans.
Methods: PubMed, Scopus, and the Cochrane Database of Systematic Reviews were searched through August 2020 to identify relevant papers for inclusion. Using the random-effects model, data were evaluated as weighted mean differences (WMD) with 95% confidence intervals (CI). Cochrane's Q and I-squared (I2) tests were used to identify within-studies heterogeneity.
Results: Seven RCTs with 310 participants (157 intervention and 153 control) were included in the meta-analysis. Sesame consumption reduced serum level interleukin-6 (IL-6) (WMD - 0.90; 95% CI (-1.71, -0.09), I2 = 80.4%) compared to the control group. However, sesame intake had no significant effects on C-reactive protein (CRP) and tumor necrosis factor-α (TNF-α) compared to the control group. Subgroup analysis identified a reduction in serum CRP, TNF-α, and IL-6 concentration among studies with participants who had a higher level of these biomarkers at baseline, those which used sesamin capsules, and those with a bigger sample size, those conducted in Asia, and studies on females.
Conclusion: Sesame consumption reduced serum levels of IL-6 but did not affect CRP and TNF-α in humans. Additional trials should be conducted utilizing a larger and longer treatment duration, along with studies using different sesame formulations (capsule, oil, and seed) and conducting on participants with varied health conditions.

Copyright © 2021 Shabnam Rafiee et al.
PMID 34760018
Muneyoshi Kuroyama, Hiroyuki Kagawa, Seigo Kitada, Ryoji Maekura, Masahide Mori, Hiroshi Hirano
Exogenous lipoid pneumonia caused by repeated sesame oil pulling: a report of two cases.
BMC Pulm Med. 2015 Oct 30;15:135. doi: 10.1186/s12890-015-0134-8. Epub 2015 Oct 30.
Abstract/Text BACKGROUND: Exogenous lipoid pneumonia is a rare disease caused by aspiration or inhalation of oily substances.
CASE PRESENTATION: A 66-year-old male with dry cough (Case 1) and a 38-year-old female with shortness of breath (Case 2) demonstrated ground-glass opacities on chest computed tomography and were diagnosed with lipoid pneumonia based on the confirmation of lipid-laden alveolar macrophages. Both patients habitually performed sesame oil pulling via nasal or mouth washing for several months prior to the diagnosis.
CONCLUSION: Steroid therapy and bronchoalveolar lavage resulted in improvement in Case 1, and no intensive therapy was required for Case 2. Sesame oil pulling has been rarely been reported to cause lipoid pneumonia.

PMID 26518258
Stephan Reichenbach, Rebekka Sterchi, Martin Scherer, Sven Trelle, Elizabeth Bürgi, Ulrich Bürgi, Paul A Dieppe, Peter Jüni
Meta-analysis: chondroitin for osteoarthritis of the knee or hip.
Ann Intern Med. 2007 Apr 17;146(8):580-90.
Abstract/Text BACKGROUND: Previous meta-analyses described moderate to large benefits of chondroitin in patients with osteoarthritis. However, recent large-scale trials did not find evidence of an effect.
PURPOSE: To determine the effects of chondroitin on pain in patients with osteoarthritis.
DATA SOURCES: The authors searched the Cochrane Central Register of Controlled Trials (1970 to 2006), MEDLINE (1966 to 2006), EMBASE (1980 to 2006), CINAHL (1970 to 2006), and conference proceedings; checked reference lists; and contacted authors. The last update of searches was performed on 30 November 2006.
STUDY SELECTION: Studies were included if they were randomized or quasi-randomized, controlled trials that compared chondroitin with placebo or with no treatment in patients with osteoarthritis of the knee or hip. There were no language restrictions.
DATA EXTRACTION: The authors extracted data in duplicate. Effect sizes were calculated from the differences in means of pain-related outcomes between treatment and control groups at the end of the trial, divided by the pooled SD. Trials were combined by using random-effects meta-analysis.
DATA SYNTHESIS: 20 trials (3846 patients) contributed to the meta-analysis, which revealed a high degree of heterogeneity among the trials (I2 = 92%). Small trials, trials with unclear concealment of allocation, and trials that were not analyzed according to the intention-to-treat principle showed larger effects in favor of chondroitin than did the remaining trials. When the authors restricted the analysis to the 3 trials with large sample sizes and an intention-to-treat analysis, 40% of patients were included. This resulted in an effect size of -0.03 (95% CI, -0.13 to 0.07; I2 = 0%) and corresponded to a difference of 0.6 mm on a 10-cm visual analogue scale. A meta-analysis of 12 trials showed a pooled relative risk of 0.99 (CI, 0.76 to 1.31) for any adverse event.
LIMITATIONS: For 9 trials, the authors had to use approximations to calculate effect sizes. Trial quality was generally low, heterogeneity among the trials made initial interpretation of results difficult, and exploring sources of heterogeneity in meta-regression and stratified analyses may be unreliable.
CONCLUSIONS: Large-scale, methodologically sound trials indicate that the symptomatic benefit of chondroitin is minimal or nonexistent. Use of chondroitin in routine clinical practice should therefore be discouraged.

PMID 17438317
Mario Simental-Mendía, Adriana Sánchez-García, Félix Vilchez-Cavazos, Carlos A Acosta-Olivo, Víctor M Peña-Martínez, Luis E Simental-Mendía
Effect of glucosamine and chondroitin sulfate in symptomatic knee osteoarthritis: a systematic review and meta-analysis of randomized placebo-controlled trials.
Rheumatol Int. 2018 Aug;38(8):1413-1428. doi: 10.1007/s00296-018-4077-2. Epub 2018 Jun 11.
Abstract/Text Although glucosamine and chondroitin sulfate have showed beneficial effects on joint tissues in osteoarthritis (OA), their therapeutic use in the clinical setting is still debatable. Hence, a systematic review and meta-analysis of randomized placebo-controlled trials was conducted to investigate the efficacy of glucosamine and chondroitin sulfate on knee OA symptoms. Medline, SCOPUS, Web of Science, and Google Scholar databases were searched for randomized placebo-controlled trials evaluating the effect of orally administered glucosamine and/or chondroitin sulfate on OA symptoms using the Western Ontario and McMaster Universities Osteoarthritis index (WOMAC) and/or the Visual Analog Scale (VAS). Meta-analysis was conducted using a random-effects model and generic inverse-variance method. Heterogeneity was tested using the I2 statistic index. Treatments with glucosamine and chondroitin were found to significantly reduce pain in VAS [weighted mean difference (WMD) - 7.41 mm, 95% CI - 14.31, - 0.51, p = 0.04 and WMD - 8.35 mm, 95% CI - 11.84, - 4.85, p < 0.00001, respectively]. Their combination did not show this behavior (WMD - 0.28 mm, 95% CI - 8.87, 8.32, p = 0.95). None of the glucosamine, chondroitin or their combination had a significant positive effect on the total WOMAC index and its subscores. Oral supplementation with glucosamine or chondroitin sulfate reduces pain in knee OA. However, there is no additional effect using both therapeutic agents in combination for the management of symptomatic knee OA.

PMID 29947998
Jean-Yves Reginster, Jean Dudler, Tomasz Blicharski, Karel Pavelka
Pharmaceutical-grade Chondroitin sulfate is as effective as celecoxib and superior to placebo in symptomatic knee osteoarthritis: the ChONdroitin versus CElecoxib versus Placebo Trial (CONCEPT).
Ann Rheum Dis. 2017 Sep;76(9):1537-1543. doi: 10.1136/annrheumdis-2016-210860. Epub 2017 May 22.
Abstract/Text OBJECTIVES: Chondroitin sulfate 800 mg/day (CS) pharmaceutical-grade in the management of symptomatic knee osteoarthritis consistent with the European Medicines Agency guideline.
METHODS: A prospective, randomised, 6-month, 3-arm, double-blind, double-dummy, placebo and celecoxib (200 mg/day)-controlled trial assessing changes in pain on a Visual Analogue Scale (VAS) and in the Lequesne Index (LI) as coprimary endpoints. Minimal-Clinically Important Improvement (MCII), Patient-Acceptable Symptoms State (PASS) were used as secondary endpoints.
RESULTS: 604 patients (knee osteoarthritis) diagnosed according to American College of Rheumalogy (ACR) criteria, recruited in five European countries and followed for 182 days. CS and celecoxib showed a greater significant reduction in pain and LI than placebo. In the intention-to-treat (ITT) population, pain reduction in VAS at day 182 in the CS group (-42.6 mm) and in celecoxib group (-39.5 mm) was significantly greater than the placebo group (-33.3 mm) (p=0.001 for CS and p=0.009 for celecoxib), while no difference observed between CS and celecoxib. Similar trend for the LI, as reduction in this metric in the CS group (-4.7) and celecoxib group (-4.6) was significantly greater than the placebo group (-3.7) (p=0.023 for CS and p=0.015 for celecoxib), no difference was observed between CS and celecoxib. Both secondary endpoints (MCII and PASS) at day 182 improved significantly in the CS and celecoxib groups. All treatments demonstrated excellent safety profiles.
CONCLUSION: A 800 mg/day pharmaceutical-grade CS is superior to placebo and similar to celecoxib in reducing pain and improving function over 6 months in symptomatic knee osteoarthritis (OA) patients. This formulation of CS should be considered a first-line treatment in the medical management of knee OA.

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
PMID 28533290
Jorge A Roman-Blas, Santos Castañeda, Olga Sánchez-Pernaute, Raquel Largo, Gabriel Herrero-Beaumont, CS/GS Combined Therapy Study Group
Combined Treatment With Chondroitin Sulfate and Glucosamine Sulfate Shows No Superiority Over Placebo for Reduction of Joint Pain and Functional Impairment in Patients With Knee Osteoarthritis: A Six-Month Multicenter, Randomized, Double-Blind, Placebo-Controlled Clinical Trial.
Arthritis Rheumatol. 2017 Jan;69(1):77-85. doi: 10.1002/art.39819.
Abstract/Text OBJECTIVE: To assess the efficacy and safety of combination therapy with chondroitin sulfate (CS) and glucosamine sulfate (GS) compared to placebo in patients with symptomatic knee osteoarthritis (OA).
METHODS: A multicenter, randomized, double-blind, placebo-controlled study was performed in 164 patients with Kellgren/Lawrence grade 2 or grade 3 radiographic knee OA and moderate-to-severe knee pain (mean ± SD global pain score 62.1 ± 11.3 mm on a 100-mm visual analog scale [VAS]). Patients were randomized to receive either combined treatment with CS (1,200 mg) plus GS (1,500 mg) or placebo in a single oral daily dose for 6 months. The mean change from baseline in the VAS global pain score was set as the primary end point. Secondary outcomes included the mean change in the investigator's global assessment of disease activity, total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), pain and function subscale scores on the WOMAC, responder rates based on the Outcome Measures in Rheumatology (OMERACT)-Osteoarthritis Research Society International (OARSI) 2004 response criteria, and rescue medication use. Adverse events were also recorded. A Data and Safety Monitoring Board was instituted to ensure patient safety and data accuracy.
RESULTS: Intriguingly, in the modified intent-to-treat (mITT) population, CS/GS combination therapy was inferior to placebo in the reduction of joint pain (mean ± SD change in VAS global pain score over 6 months -11.8 ± 2.4 mm [19% reduction] in patients receiving CS plus GS versus -20.5 ± 2.4 mm [33% reduction] in patients receiving placebo; peak between-group difference in global pain score at 6 months 8.7 mm [14.2%], P < 0.03), but no between-group differences were seen in the per-protocol completers. Both placebo treatment and CS/GS combination treatment improved to a similar extent the total WOMAC score as well as the pain and function WOMAC subscale scores, both in the mITT population and in the per-protocol completers. Neither the OMERACT-OARSI responder rate nor the frequency of rescue medication use differed between the treatment groups. Severe adverse events were uncommon and equally distributed.
CONCLUSION: The results of this trial demonstrate a lack of superiority of CS/GS combination therapy over placebo in terms of reducing joint pain and functional impairment in patients with symptomatic knee OA over 6 months. Further research might fully elucidate the suitability of CS/GS combination therapy in patients with OA.

© 2016, American College of Rheumatology.
PMID 27477804
Marc C Hochberg, Min Zhan, Patricia Langenberg
The rate of decline of joint space width in patients with osteoarthritis of the knee: a systematic review and meta-analysis of randomized placebo-controlled trials of chondroitin sulfate .
Curr Med Res Opin. 2008 Nov;24(11):3029-35. doi: 10.1185/03007990802434932. Epub 2008 Oct 2.
Abstract/Text BACKGROUND: Chondroitin sulfate has been shown to relieve pain and improve functional limitation in patients with osteoarthritis (OA) of the knee in numerous clinical trials and meta-analyses. Its role as a potential structure-modifying drug for knee OA, however, remains controversial.
OBJECTIVE: To perform a meta-analysis of randomized double-blind placebo-controlled clinical trials to assess the efficacy of chondroitin sulfate as a structure-modifying drug for knee OA.
RESEARCH DESIGN AND METHODS: A Medline search was conducted from 1996 through 2007 and five articles that reported results from three trials were identified; one additional trial was identified through review of presentations at annual rheumatology meetings. There was no evidence of heterogeneity across the trials and results were pooled using a fixed effects meta-analysis.
RESULTS: Pooled results demonstrated a small significant effect of chondroitin sulfate on the reduction in rate of decline in minimum joint space width of 0.07 mm/year (95% CI 0.03, 0.10) that corresponded to an effect size of 0.26 (95% CI 0.14, 0.38) (p < 0.0001). This result was robust in sensitivity analyses.
LIMITATIONS: The individual studies included in the meta-analysis varied in the number of patients enrolled and the techniques used to acquire knee radiographs and to measure joint space width.
CONCLUSION: These results demonstrate that chondroitin sulfate is effective for reducing the rate of decline in minimum joint space width in patients with OA of the knee. Chondroitin sulfate may have a role as a structure-modifying agent in the management of patients with knee OA.

PMID 18826751
Jasvinder A Singh, Shahrzad Noorbaloochi, Roderick MacDonald, Lara J Maxwell
Chondroitin for osteoarthritis.
Cochrane Database Syst Rev. 2015 Jan 28;1:CD005614. doi: 10.1002/14651858.CD005614.pub2. Epub 2015 Jan 28.
Abstract/Text BACKGROUND: Osteoarthritis, a common joint disorder, is one of the leading causes of disability. Chondroitin has emerged as a new treatment. Previous meta-analyses have shown contradictory results on the efficacy of chondroitin. This, in addition to the publication of more trials, necessitates a systematic review.
OBJECTIVES: To evaluate the benefit and harm of oral chondroitin for treating osteoarthritis compared with placebo or a comparator oral medication including, but not limited to, nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, opioids, and glucosamine or other "herbal" medications.
SEARCH METHODS: We searched seven databases up to November 2013, including the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, CINAHL, EMBASE, Science Citation Index (Web of Science) and Current Controlled Trials. We searched the US Food and Drug Administration (FDA) and European Medicines Agency (EMEA) websites for adverse effects. Trial registers were not searched.
SELECTION CRITERIA: All randomized or quasi-randomized clinical trials lasting longer than two weeks, studying adults with osteoarthritis in any joint, and comparing chondroitin with placebo, an active control such as NSAIDs, or other "herbal" supplements such as glucosamine.
DATA COLLECTION AND ANALYSIS: Two review authors independently performed all title assessments, data extractions, and risk of bias assessments.
MAIN RESULTS: Forty-three randomized controlled trials including 4,962 participants treated with chondroitin and 4,148 participants given placebo or another control were included. The majority of trials were in knee OA, with few in hip and hand OA. Trial duration varied from 1 month to 3 years. Participants treated with chondroitin achieved statistically significantly and clinically meaningful better pain scores (0-100) in studies less than 6 months than those given placebo with an absolute risk difference of 10% lower (95% confidence interval (CI), 15% to 6% lower; number needed to treat (NNT) = 5 (95% CI, 3 to 8; n = 8 trials) (level of evidence, low; risk of bias, high); but there was high heterogeneity between the trials (T(2) = 0.07; I(2) = 70%, which was not easily explained by differences in risk of bias or study sample size). In studies longer than 6 months, the absolute risk difference for pain was 9% lower (95% CI 18% lower to 0%); n = 6 trials; T(2) = 0.18; I(2) = 83% ), again with low level of evidence.For the Western Ontario and McMaster Universities Osteoarthritis Index Minimal Clinically Important Improvement (WOMAC MCII Pain subscale) outcome, a reduction in knee pain by 20% was achieved by 53/100 in the chondroitin group versus 47/100 in the placebo group, an absolute risk difference of 6% (95% CI 1% to 11%), (RR 1.12, 95% CI 1.01 to 1.24; T(2) = 0.00; I(2) = 0%) (n = 2 trials, 1253 participants; level of evidence, high; risk of bias, low).Differences in Lequesne's index (composite of pain,function and disability) statistically significantly favoured chondroitin as compared with placebo in studies under six months, with an absolute risk difference of 8% lower (95% CI 12% to 5% lower; T(2)= 0.78; n = 7 trials) (level of evidence, moderate; risk of bias, unclear), also clinically meaningful. Loss of minimum joint space width in the chondroitin group was statistically significantly less than in the placebo group, with a relative risk difference of 4.7% less (95% CI 1.6% to 7.8% less; n = 2 trials) (level of evidence, high; risk of bias, low). Chondroitin was associated with statistically significantly lower odds of serious adverse events compared with placebo with Peto odds ratio of 0.40 (95% CI 0.19 to 0.82; n = 6 trials) (level of evidence, moderate). Chondroitin did not result in statistically significant numbers of adverse events or withdrawals due to adverse events compared with placebo or another drug. Adverse events were reported in a limited fashion, with some studies providing data and others not.Comparisons of chondroitin taken alone or in combination with glucosamine or another supplement showed a statistically significant reduction in pain (0-100) when compared with placebo or an active control, with an absolute risk difference of 10% lower (95% CI 14% to 5% lower); NNT = 4 (95% CI 3 to 6); T(2) = 0.33; I(2) = 91%; n = 17 trials) (level of evidence, low). For physical function, chondroitin in combination with glucosamine or another supplement showed no statistically significant difference from placebo or an active control, with an absolute risk difference of 1% lower (95% CI 6% lower to 3% higher with T(2) = 0.04; n = 5 trials) (level of evidence, moderate). Differences in Lequesne's index statistically significantly favoured chondroitin as compared with placebo, with an absolute risk difference of 8% lower (95% CI, 12% to 4% lower; T(2) = 0.12; n = 10 trials) (level of evidence, moderate). Chondroitin in combination with glucosamine did not result in statistically significant differences in the numbers of adverse events, withdrawals due to adverse events, or in the numbers of serious adverse events compared with placebo or with an active control.The beneficial effects of chondroitin in pain and Lequesne's index persisted when evidence was limited to studies with adequate blinding or studies that used appropriate intention to treat (ITT) analyses. These beneficial effects were uncertain when we limited data to studies with appropriate allocation concealment or a large study sample (> 200) or to studies without pharmaceutical funding.
AUTHORS' CONCLUSIONS: A review of randomized trials of mostly low quality reveals that chondroitin (alone or in combination with glucosamine) was better than placebo in improving pain in participants with osteoarthritis in short-term studies. The benefit was small to moderate with an 8 point greater improvement in pain (range 0 to 100) and a 2 point greater improvement in Lequesne's index (range 0 to 24), both seeming clinically meaningful. These differences persisted in some sensitivity analyses and not others. Chondroitin had a lower risk of serious adverse events compared with control. More high-quality studies are needed to explore the role of chondroitin in the treatment of osteoarthritis. The combination of some efficacy and low risk associated with chondroitin may explain its popularity among patients as an over-the-counter supplement.

PMID 25629804
Chao Zeng, Jie Wei, Hui Li, Yi-lun Wang, Dong-xing Xie, Tuo Yang, Shu-guang Gao, Yu-sheng Li, Wei Luo, Guang-hua Lei
Effectiveness and safety of Glucosamine, chondroitin, the two in combination, or celecoxib in the treatment of osteoarthritis of the knee.
Sci Rep. 2015 Nov 18;5:16827. doi: 10.1038/srep16827. Epub 2015 Nov 18.
Abstract/Text This study aimed to investigate the effectiveness and safety of glucosamine, chondroitin, the two in combination, or celecoxib in the treatment of knee osteoarthritis (OA). PubMed, Embase and Cochrane Library were searched through from inception to February 2015. A total of 54 studies covering 16427 patients were included. Glucosamine plus chondroitin, glucosamine alone, and celecoxib were all more effective than placebo in pain relief and function improvement. Specifically, celecoxib is most likely to be the best treatment option, followed by the combination group. All treatment options showed clinically significant improvement from baseline pain, but only glucosamine plus chondroitin showed clinically significant improvement from baseline function. In terms of the structure-modifying effect, both glucosamine alone and chondroitin alone achieved a statistically significant reduction in joint space narrowing. Although no significant difference was observed among the five options with respect to the three major adverse effects (withdrawal due to adverse events, serious adverse events and the number of patients with adverse events), the additional classical meta-analysis showed that celecoxib exhibited a higher rate of gastrointestinal adverse effect comparing with the placebo group. The present study provided evidence for the symptomatic efficacy of glucosamine plus chondroitin in the treatment of knee OA.

PMID 26576862
Marc C Hochberg, Johanne Martel-Pelletier, Jordi Monfort, Ingrid Möller, Juan Ramón Castillo, Nigel Arden, Francis Berenbaum, Francisco J Blanco, Philip G Conaghan, Gema Doménech, Yves Henrotin, Thomas Pap, Pascal Richette, Allen Sawitzke, Patrick du Souich, Jean-Pierre Pelletier, MOVES Investigation Group
Combined chondroitin sulfate and glucosamine for painful knee osteoarthritis: a multicentre, randomised, double-blind, non-inferiority trial versus celecoxib.
Ann Rheum Dis. 2016 Jan;75(1):37-44. doi: 10.1136/annrheumdis-2014-206792. Epub 2015 Jan 14.
Abstract/Text OBJECTIVES: To compare the efficacy and safety of chondroitin sulfate plus glucosamine hydrochloride (CS+GH) versus celecoxib in patients with knee osteoarthritis and severe pain.
METHODS: Double-blind Multicentre Osteoarthritis interVEntion trial with SYSADOA (MOVES) conducted in France, Germany, Poland and Spain evaluating treatment with CS+GH versus celecoxib in 606 patients with Kellgren and Lawrence grades 2-3 knee osteoarthritis and moderate-to-severe pain (Western Ontario and McMaster osteoarthritis index (WOMAC) score ≥301; 0-500 scale). Patients were randomised to receive 400 mg CS plus 500 mg GH three times a day or 200 mg celecoxib every day for 6 months. The primary outcome was the mean decrease in WOMAC pain from baseline to 6 months. Secondary outcomes included WOMAC function and stiffness, visual analogue scale for pain, presence of joint swelling/effusion, rescue medication consumption, Outcome Measures in Rheumatology Clinical Trials and Osteoarthritis Research Society International (OMERACT-OARSI) criteria and EuroQoL-5D.
RESULTS: The adjusted mean change (95% CI) in WOMAC pain was -185.7 (-200.3 to -171.1) (50.1% decrease) with CS+GH and -186.8 (-201.7 to -171.9) (50.2% decrease) with celecoxib, meeting the non-inferiority margin of -40: -1.11 (-22.0 to 19.8; p=0.92). All sensitivity analyses were consistent with that result. At 6 months, 79.7% of patients in the combination group and 79.2% in the celecoxib group fulfilled OMERACT-OARSI criteria. Both groups elicited a reduction >50% in the presence of joint swelling; a similar reduction was seen for effusion. No differences were observed for the other secondary outcomes. Adverse events were low and similarly distributed between groups.
CONCLUSIONS: CS+GH has comparable efficacy to celecoxib in reducing pain, stiffness, functional limitation and joint swelling/effusion after 6 months in patients with painful knee osteoarthritis, with a good safety profile.
TRIAL REGISTRATION NUMBER: NCT01425853.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
PMID 25589511
Alfred F Tallia, Dennis A Cardone
Asthma exacerbation associated with glucosamine-chondroitin supplement.
J Am Board Fam Pract. 2002 Nov-Dec;15(6):481-4.
Abstract/Text BACKGROUND: Although dietary supplements are in widespread use, and some have been endorsed by the medical community and complementary and alternative practitioners, not much is known about their potential side effects or drug interactions.
METHODS: A case of asthma exacerbated by the use of a glucosamine-chondroitin supplement for osteoarthritis pain is described. The literature was searched from 1980 to 2002 using the terms "glucosamine," "chondroitin sulfate," "alternative medicine," and "dietary supplements," combined with "asthma."
RESULTS AND CONCLUSIONS: The biological link between both chondroitin and glucosamine and secretions from the respiratory tree of persons with asthma lends biologic plausibility to the hypothesis that the patient's asthmatic episode was related to the dietary substance. Physicians would be wise to question their patients about use of dietary supplements as self-medication and consider the possibility of such supplements causing exacerbations of underlying conditions.

PMID 12463294
Svend A Mortensen, Franklin Rosenfeldt, Adarsh Kumar, Peter Dolliner, Krzysztof J Filipiak, Daniel Pella, Urban Alehagen, Günter Steurer, Gian P Littarru, Q-SYMBIO Study Investigators
The effect of coenzyme Q10 on morbidity and mortality in chronic heart failure: results from Q-SYMBIO: a randomized double-blind trial.
JACC Heart Fail. 2014 Dec;2(6):641-9. doi: 10.1016/j.jchf.2014.06.008. Epub 2014 Oct 1.
Abstract/Text OBJECTIVES: This randomized controlled multicenter trial evaluated coenzyme Q10 (CoQ10) as adjunctive treatment in chronic heart failure (HF).
BACKGROUND: CoQ10 is an essential cofactor for energy production and is also a powerful antioxidant. A low level of myocardial CoQ10 is related to the severity of HF. Previous randomized controlled trials of CoQ10 in HF were underpowered to address major clinical endpoints.
METHODS: Patients with moderate to severe HF were randomly assigned in a 2-year prospective trial to either CoQ10 100 mg 3 times daily or placebo, in addition to standard therapy. The primary short-term endpoints at 16 weeks were changes in New York Heart Association (NYHA) functional classification, 6-min walk test, and levels of N-terminal pro-B type natriuretic peptide. The primary long-term endpoint at 2 years was composite major adverse cardiovascular events as determined by a time to first event analysis.
RESULTS: A total of 420 patients were enrolled. There were no significant changes in short-term endpoints. The primary long-term endpoint was reached by 15% of the patients in the CoQ10 group versus 26% in the placebo group (hazard ratio: 0.50; 95% confidence interval: 0.32 to 0.80; p = 0.003) by intention-to-treat analysis. The following secondary endpoints were significantly lower in the CoQ10 group compared with the placebo group: cardiovascular mortality (9% vs. 16%, p = 0.026), all-cause mortality (10% vs. 18%, p = 0.018), and incidence of hospital stays for HF (p = 0.033). In addition, a significant improvement of NYHA class was found in the CoQ10 group after 2 years (p = 0.028).
CONCLUSIONS: Long-term CoQ10 treatment of patients with chronic HF is safe, improves symptoms, and reduces major adverse cardiovascular events. (Coenzyme Q10 as adjunctive treatment of chronic heart failure: a randomised, double-blind, multicentre trial with focus on SYMptoms, BIomarker status [Brain-Natriuretic Peptide (BNP)], and long-term Outcome [hospitalisations/mortality]; ISRCTN94506234).

Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
PMID 25282031
Ahmed Negida, Ahmed Menshawy, Gehad El Ashal, Yasmin Elfouly, Yasmein Hani, Yasmin Hegazy, Samar El Ghonimy, Samar Fouda, Yomna Rashad
Coenzyme Q10 for Patients with Parkinson's Disease: A Systematic Review and Meta-Analysis.
CNS Neurol Disord Drug Targets. 2016;15(1):45-53.
Abstract/Text INTRODUCTION: Coenzyme Q10 (CoQ10) is an antioxidant that enhances the activity of complex I and II in the Electron Transport Chain. Many preclinical and clinical studies evaluated CoQ10 for neuroprotection against Parkinson's disease (PD). The aim of this study is to synthesize evidence from published randomized controlled trials (RCTs) about the benefit of CoQ10 supplementation for patients with Parkinson's disease.
METHODS: We followed the PRISMA statement guidelines during the preparation of this systematic review and metaanalysis. A computer literature search for (PubMed, EBSCO, Web of science and Ovid Midline) was carried out. We included RCTs comparing CoQ10 with placebo in terms of motor functions and quality of life. Outcomes of total Unified Parkinson's Disease Rating Scale (UPDRS), UPDRS I, UPDRS II, UPDRS III and Schwab and England scores were pooled as standardized mean difference (SMD) between two groups from baseline to the endpoint.
RESULTS: Five RCTs (981 patients) were included in this study. The overall effect did not favor either of the two groups in terms of: total UPDRS score (SMD -0.05, 95%CI [-0.10, 0.15]), UPDRS I (SMD -0.03, 95% CI [-0.23, 0.17]), UPDRS II (SMD -0.10, 95%CI [-0.35, 0.15]), UPDRS III (SMD -0.05, 95%CI [-0.07, 0.17]) or Schwab and England score (SMD 0.08, 95%CI [-0.13, 0.29]).
CONCLUSION: CoQ10 supplementation does not slow functional decline nor provide any symptomatic benefit for patients with Parkinson's disease.

PMID 26553164
Zhen-Guo Zhu, Miao-Xuan Sun, Wan-Li Zhang, Wen-Wen Wang, Yi-Mei Jin, Cheng-Long Xie
The efficacy and safety of coenzyme Q10 in Parkinson's disease: a meta-analysis of randomized controlled trials.
Neurol Sci. 2017 Feb;38(2):215-224. doi: 10.1007/s10072-016-2757-9. Epub 2016 Nov 9.
Abstract/Text The objective of this meta-analysis was to evaluate the effects of coenzyme Q10 (CoQ10) for the treatment of Parkinson's disease (PD) patients in order to arrive at qualitative and quantitative conclusions about the efficacy of CoQ10. Databases searched included PubMed, Google scholar, CNKI, Wan-Fang, and the Cochrane Library from inception to March 2016. We only included sham-controlled, randomized clinical trials of CoQ10 intervention for motor dysfunction in patients with PD. Relevant measures were extracted independently by two investigators. Weighted mean differences (WMD) were calculated with random-effects models. Eight studies with a total of 899 patients were included. Random-effects analysis revealed a pooled WMD of 1.02, indicating no significant difference when CoQ10 treatment compared with placebo in terms of UPDRS part 3 (p = 0.54). Meanwhile, the effect size of UPDRS part 1, UPDRS part 2, and total UPDRS scores were similar in CoQ10 group with in placebo group (p > 0.05). Moreover, we found CoQ10 was well tolerated compared with placebo group. Subgroup analysis showed that the effect size of CoQ10 in monocentric studies was larger than in multicenter studies. Using the GRADE criteria, we characterized the quality of evidence presented in this meta-analysis as moderate to high level. The current meta-analysis provided evidence that CoQ10 was safe and well tolerated in participants with PD and no superior to placebo in terms of motor symptoms. According to these results, we cannot recommend CoQ10 for the routine treatment of PD right now.

PMID 27830343
Mohammed E Madmani, Ahmad Yusuf Solaiman, Khalil Tamr Agha, Yasser Madmani, Yasser Shahrour, Adib Essali, Waleed Kadro
Coenzyme Q10 for heart failure.
Cochrane Database Syst Rev. 2014 Jun 2;6:CD008684. doi: 10.1002/14651858.CD008684.pub2. Epub 2014 Jun 2.
Abstract/Text BACKGROUND: Coenzyme Q10, or ubiquinone, is a non-prescription nutritional supplement. It is a fat-soluble molecule that acts as an electron carrier in mitochondria and as a coenzyme for mitochondrial enzymes. Coenzyme Q10 deficiency may be associated with a multitude of diseases including heart failure. The severity of heart failure correlates with the severity of coenzyme Q10 deficiency. Emerging data suggest that the harmful effects of reactive oxygen species are increased in patients with heart failure and coenzyme Q10 may help to reduce these toxic effects because of its antioxidant activity. Coenzyme Q10 may also have a role in stabilising myocardial calcium-dependent ion channels and preventing the consumption of metabolites essential for adenosine-5'-triphosphate (ATP) synthesis. Coenzyme Q10, although not a primary recommended treatment, could be beneficial to patients with heart failure. Several randomised controlled trials have compared coenzyme Q10 to other therapeutic modalities, but no systematic review of existing randomised trials has been conducted.
OBJECTIVES: To review the safety and efficacy of coenzyme Q10 in heart failure.
SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2012, Issue 12); MEDLINE OVID (1950 to January Week 3 2013) and EMBASE OVID (1980 to 2013 Week 03) on 24 January 2013; Web of Science with Conference Proceedings (1970 to January 2013) and CINAHL Plus (1981 to January 2013) on 25 January 2013; and AMED (Allied and Complementary Medicine) (1985 to January 2013) on 28 January 2013. We applied no language restrictions.
SELECTION CRITERIA: We included randomised controlled trials of either parallel or cross-over design that assessed the beneficial and harmful effects of coenzyme Q10 in patients with heart failure. When cross-over studies were identified, we considered data only from the first phase.
DATA COLLECTION AND ANALYSIS: Two authors independently extracted data from the included studies onto a pre-designed data extraction form. We then entered the data into Review Manager 5.2 for analysis. We assessed study risk of bias using the Cochrane 'Risk of bias' tool. For dichotomous data, we calculated the risk ratio and for continuous data the mean difference (MD). Where appropriate data were available, we performed meta-analysis. For this review we prioritised data from pooled analyses only. Where meta-analysis was not possible, we wrote a narrative synthesis. We provided a QUOROM flow chart to show the flow of papers.
MAIN RESULTS: We included seven studies with 914 participants comparing conenzyme Q10 versus placebo. There were no data on clinical events from published randomised trials. The included studies had small sample sizes. Meta-analysis was only possible for a few physiological measures and there was substantial heterogeneity.Only one study reported on total mortality, major cardiovascular events and hospitalisation. Five trials reported on the New York Heart Association (NYHA) classification of clinical status, but it was impossible to pool data due to heterogeneity. None of the included trials considered quality of life, exercise variables, adverse events or cost-effectiveness as outcome measures. Pooled analysis suggests that the use of coenzyme Q10 has no clear effect on left ventricular ejection fraction (MD -2.26; 95% confidence interval (CI) -15.49 to 10.97, n = 60) or exercise capacity (MD 12.79; 95% CI -140.12 to 165.70, n = 85). Pooled data did indicate that supplementation increased blood levels of coenzyme Q10 (MD 1.46; 95% CI 1.19 to 1.72, n = 112). However, there are only a small number of small studies with a risk of bias, so these results should be interpreted with caution.
AUTHORS' CONCLUSIONS: No conclusions can be drawn on the benefits or harms of coenzyme Q10 in heart failure at this time as trials published to date lack information on clinically relevant endpoints. Furthermore, the existing data are derived from small, heterogeneous trials that concentrate on physiological measures: their results are inconclusive. Until further evidence emerges to support the use of coenzyme Q10 in heart failure, there might be a need to re-evaluate whether further trials testing coenzyme Q10 in heart failure are desirable.

PMID 24049047
Li Lei, Yan Liu
Efficacy of coenzyme Q10 in patients with cardiac failure: a meta-analysis of clinical trials.
BMC Cardiovasc Disord. 2017 Jul 24;17(1):196. doi: 10.1186/s12872-017-0628-9. Epub 2017 Jul 24.
Abstract/Text BACKGROUND: The therapeutic efficacy of coenzyme Q10 on patients with cardiac failure remains controversial. We pooled previous clinical studies to re-evaluate the efficacy of coenzyme Q10 in patients with cardiac failure.
METHODS: We searched PubMed, Cochrane Library, EMBASE, and Clinical Trials.gov databases for controlled trials. The endpoints were death, left heart ejection fraction, exercise capacity, and New York Heart Association (NYHA) cardiac function classification after treatment. The pooled risk ratios (RRs) and standardized mean difference (SMD) were used to assess the efficacy of coenzyme Q10.
RESULTS: A total of 14 RCTs with 2149 patients met the inclusion criteria and were included in the analysis. Coenzyme Q10 decreased the mortality compared with placebo (RR = 0.69; 95% CI = 0.50-0.95; P = 0.02; I (2)  = 0%). A greater improvement in exercise capacity was established in patients who used coenzyme Q10 than in those who used placebo (SMD = 0.62; 95% CI = 0.02-0.30; P = 0.04; I (2)  = 54%). No significant difference was observed in the endpoints of left heart ejection fraction between patients who received coenzyme Q10 and the patients in whom placebo was administered (SMD = 0.62; 95% CI = 0.02-1.12; P = 0.04; I (2)  = 75%). The two types of treatment resulted in obtaining similar NYHA classification results (SMD = -0.70; 95% CI = -1.92-0.51; P = 0.26; I (2)  = 89%).
CONCLUSION: Patients with heart failure who used coenzyme Q10 had lower mortality and a higher exercise capacity improvement than the placebo-treated patients with heart failure. No significant differences between the efficacy of the administration of coenzyme Q10 and placebo in the endpoints of left heart ejection fraction and NYHA classification were observed.

PMID 28738783
Nadine Flowers, Louise Hartley, Daniel Todkill, Saverio Stranges, Karen Rees
Co-enzyme Q10 supplementation for the primary prevention of cardiovascular disease.
Cochrane Database Syst Rev. 2014;12:CD010405. doi: 10.1002/14651858.CD010405.pub2. Epub 2014 Dec 4.
Abstract/Text BACKGROUND: Cardiovascular disease (CVD) remains the number one cause of death and disability worldwide and public health interventions focus on modifiable risk factors, such as diet. Coenzyme Q10 (CoQ10) is an antioxidant that is naturally synthesised by the body and can also be taken as a dietary supplement. Studies have shown that a CoQ10 deficiency is associated with cardiovascular disease.
OBJECTIVES: To determine the effects of coenzyme Q10 supplementation as a single ingredient for the primary prevention of CVD.
SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2013, Issue 11); MEDLINE (Ovid, 1946 to November week 3 2013); EMBASE (Ovid, 1947 to 27 November 2013) and other relevant resources on 2 December 2013. We applied no language restrictions.
SELECTION CRITERIA: Randomised controlled trials (RCTs) lasting at least three months involving healthy adults or those at high risk of CVD but without a diagnosis of CVD. Trials investigated the supplementation of CoQ10 alone as a single supplement. The comparison group was no intervention or placebo. The outcomes of interest were CVD clinical events and major CVD risk factors, adverse effects and costs. We excluded any trials involving multifactorial lifestyle interventions to avoid confounding.
DATA COLLECTION AND ANALYSIS: Two authors independently selected trials for inclusion, abstracted data and assessed the risk of bias.We contacted authors for additional information where necessary.
MAIN RESULTS: We identified six RCTs with a total of 218 participants randomised, one trial awaiting classification and five ongoing trials. All trials were conducted in participants at high risk of CVD, two trials examined CoQ10 supplementation alone and four examined CoQ10 supplementation in patients on statin therapy; we analysed these separately. All six trials were small-scale, recruiting between 20 and 52 participants; one trial was at high risk of bias for incomplete outcome data and one for selective reporting; all studies were unclear in the method of allocation and therefore for selection bias. The dose of CoQ10 varied between 100 mg/day and 200 mg/day and the duration of the interventions was similar at around three months.No studies reported mortality or non-fatal cardiovascular events. None of the included studies provided data on adverse events.Two trials examined the effect of CoQ10 on blood pressure. For systolic blood pressure we did not perform a meta-analysis due to significant heterogeneity. In one trial CoQ10 supplementation had no effect on systolic blood pressure (mean difference (MD) -1.90 mmHg, 95% confidence interval (CI) -13.17 to 9.37, 51 patients randomised). In the other trial there was a statistically significant reduction in systolic blood pressure (MD -15.00 mmHg, 95% CI -19.06 to -10.94, 20 patients randomised). For diastolic blood pressure we performed a random-effects meta-analysis, which showed no evidence of effect of CoQ10 supplementation when these two small trials were pooled (MD -1.62 mmHg, 95% CI -5.2 to 1.96).One trial (51 patients randomised) looked at the effect of CoQ10 on lipid levels. The trial showed no evidence of effect of CoQ10 supplementation on total cholesterol (MD 0.30 mmol/L, 95% CI -0.10 to 0.70), high-density lipoprotein (HDL)-cholesterol (MD 0.02 mmol/L, 95% CI -0.13 to 0.17) or triglycerides (MD 0.05 mmol/L, 95% CI -0.42 to 0.52).Of the four trials that investigated CoQ10 supplementation in patients on statin therapy, three of them showed that simultaneous administration of CoQ10 did not significantly influence lipid levels or systolic blood pressure levels between the two groups. The fourth trial showed a significant increase in the change in total and low-density lipoprotein (LDL)-cholesterol at three months across the four arms of the trial (α-tocopherol, CoQ10, CoQ10 + α-tocopherol and placebo), however the way in which the data were presented meant that we were unable to determine if there was any significant difference between the CoQ10 only and placebo arms. In contrast, there was no significant difference in the change in HDL-cholesterol and triglycerides after three months between the four arms of the trial.
AUTHORS' CONCLUSIONS: There are very few studies to date examining CoQ10 for the primary prevention of CVD. The results from the ongoing studies will add to the evidence base. Due to the small number of underpowered trials contributing to the analyses, the results presented should be treated with caution and further high quality trials with longer-term follow-up are needed to determine the effects on cardiovascular events.

PMID 25474484
Meghan J Ho, Edmond C K Li, James M Wright
Blood pressure lowering efficacy of coenzyme Q10 for primary hypertension.
Cochrane Database Syst Rev. 2016 Mar 3;3:CD007435. doi: 10.1002/14651858.CD007435.pub3. Epub 2016 Mar 3.
Abstract/Text BACKGROUND: Blood pressure is a commonly measured risk factor for non-fatal and fatal cardiovascular adverse events such as heart attacks and strokes. Clinical trials have suggested that coenzyme Q10, a non-prescription nutritional supplement, can effectively lower blood pressure (BP). When this review was completed and published in October 2009, it concluded that "due to the possible unreliability of the 3 included studies, it is uncertain whether or not coenzyme Q10 reduces blood pressure in the long-term management of primary hypertension."
OBJECTIVES: To determine the blood pressure lowering effect of coenzyme Q10 in primary hypertension.
SEARCH METHODS: We searched the Hypertension Group Specialised Register (1946 to November 2015), The Cochrane Central Register of Controlled Trials (The Cochrane Library 2015, Issue 10), MEDLINE (1946 to November 2015), MEDLINE In-Process (accessed 10 November 2015), EMBASE (1974 to November 2015), Web of Science (1899 to November 2015), CINAHL (1970 to November 2015), and ClinicalTrials.gov (accessed 10 November 2015). We also searched reference lists of articles for relevant clinical trials in any language.
SELECTION CRITERIA: Double blind, randomized, placebo-controlled parallel or cross-over trials evaluating the blood pressure (BP) lowering efficacy of coenzyme Q10 for a duration of at least three weeks, in patients with primary hypertension.
DATA COLLECTION AND ANALYSIS: The primary author determined trial inclusion, extracted the data and assessed the risk of bias. The second author independently verified trial inclusion and data extraction.
MAIN RESULTS: In this update of the review, one new randomized, controlled cross-over trial with a total of 30 participants was added, and one trial included in the initial review was excluded. Only two of the three included trials were pooled in the meta-analysis, as one trial was judged to have an unacceptably high risk of bias. In the meta-analysis of two RCTs (50 participants), coenzyme Q10 did not significantly change systolic BP: -3.68 mm Hg (95% confidence interval (CI) -8.86 to 1.49), or diastolic BP: -2.03 mm Hg (95% CI -4.86 to 0.81] ), based on clinic data.
AUTHORS' CONCLUSIONS: This review provides moderate-quality evidence that coenzyme Q10 does not have a clinically significant effect on blood pressure. In one of three trials reporting adverse effects, coenzyme Q10 was well tolerated. Due to the small number of individuals and studies available for analysis, more well-conducted trials are needed.

PMID 26935713
Urban Alehagen, Peter Johansson, Mikael Björnstedt, Anders Rosén, Ulf Dahlström
Cardiovascular mortality and N-terminal-proBNP reduced after combined selenium and coenzyme Q10 supplementation: a 5-year prospective randomized double-blind placebo-controlled trial among elderly Swedish citizens.
Int J Cardiol. 2013 Sep 1;167(5):1860-6. doi: 10.1016/j.ijcard.2012.04.156. Epub 2012 May 23.
Abstract/Text BACKGROUND: Selenium and coenzyme Q10 are essential for the cell. Low cardiac contents of selenium and coenzyme Q10 have been shown in patients with cardiomyopathy, but inconsistent results are published on the effect of supplementation of the two components separately. A vital relationship exists between the two substances to obtain optimal function of the cell. However, reports on combined supplements are lacking.
METHODS: A 5-year prospective randomized double-blind placebo-controlled trial among Swedish citizens aged 70 to 88 was performed in 443 participants given combined supplementation of selenium and coenzyme Q10 or a placebo. Clinical examinations, echocardiography and biomarker measurements were performed. Participants were monitored every 6th month throughout the intervention. The cardiac biomarker N-terminal proBNP (NT-proBNP) and echocardiographic changes were monitored and mortalities were registered. End-points of mortality were evaluated by Kaplan-Meier plots and Cox proportional hazard ratios were adjusted for potential confounding factors. Intention-to-treat and per-protocol analyses were applied.
RESULTS: During a follow up time of 5.2 years a significant reduction of cardiovascular mortality was found in the active treatment group vs. the placebo group (5.9% vs. 12.6%; P=0.015). NT-proBNP levels were significantly lower in the active group compared with the placebo group (mean values: 214 ng/L vs. 302 ng/L at 48 months; P=0.014). In echocardiography a significant better cardiac function score was found in the active supplementation compared to the placebo group (P=0.03).
CONCLUSION: Long-term supplementation of selenium/coenzyme Q10 reduces cardiovascular mortality. The positive effects could also be seen in NT-proBNP levels and on echocardiography.

Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
PMID 22626835
Abstract/Text BACKGROUND: Selenium and coenzyme Q10 are important antioxidants in the body. As the intake of selenium is low in Europe, and the endogenous production of coenzyme Q10 decreases as age increases, an intervention trial using selenium and coenzyme Q10 for four years was performed. As previously reported, the intervention was accompanied by reduced cardiovascular mortality. The objective of the present study was to analyze cardiovascular mortality for up to 10 years after intervention, to evaluate if mortality differed in subgroups differentiated by gender, diabetes, ischemic heart disease (IHD), and functional class.
METHODS: Four-hundred forty-three healthy elderly individuals were included from a rural municipality in Sweden. All cardiovascular mortality was registered, and no participant was lost to the follow-up. Based on death certificates and autopsy results mortality was registered.
FINDINGS: Significantly reduced cardiovascular mortality could be seen in those on selenium and coenzyme Q10 intervention. A multivariate Cox regression analysis demonstrated a reduced cardiovascular mortality risk in the active treatment group (HR: 0.51; 95%CI 0.36-0.74; P = 0.0003). The reduced mortality could be seen to persist during the 10-year period. Subgroup analysis showed positive effects in both genders. An equally positive risk reduction could be seen in those with ischemic heart disease (HR: 0.51; 95%CI 0.27-0.97; P = 0.04), but also in the different functional classes.
CONCLUSIONS: In a 10-year follow-up of a group of healthy elderly participants given four years of intervention with selenium and coenzyme Q10, significantly reduced cardiovascular mortality was observed. The protective action was not confined to the intervention period, but persisted during the follow-up period. The mechanism explaining the persistency remains to be elucidated. Since this was a small study, the observations should be regarded as hypothesis-generating.

PMID 26624886
Evangelos C Rizos, Georgios Markozannes, Apostolos Tsapas, Christos S Mantzoros, Evangelia E Ntzani
Omega-3 supplementation and cardiovascular disease: formulation-based systematic review and meta-analysis with trial sequential analysis.
Heart. 2021 Jan;107(2):150-158. doi: 10.1136/heartjnl-2020-316780. Epub 2020 Aug 20.
Abstract/Text BACKGROUND: Omega-3 supplements are popular for cardiovascular disease (CVD) prevention. We aimed to assess the association between dose-specific omega-3 supplementation and CVD outcomes.
DESIGN: We included double-blind randomised clinical trials with duration ≥1 year assessing omega-3 supplementation and estimated the relative risk (RR) for all-cause mortality, cardiac death, sudden death, myocardial infarction and stroke. Primary analysis was a stratified random-effects meta-analysis by omega-3 dose in 4 a priori defined categories (<1, 1, 2, ≥3 of 1 g capsules/day). Complementary approaches were trial sequential analysis and sensitivity analyses for triglycerides, prevention setting, intention-to-treat analysis, eicosapentaenoic acid, sample size, statin use, study duration.
RESULTS: Seventeen studies (n=83 617) were included. Omega-3 supplementation as ≤1 capsule/day was not associated with any outcome under study; futility boundaries were crossed for all-cause mortality and cardiac death. For two capsules/day, we observed a statistically significant reduction of cardiac death (n=3, RR 0.55, 95% CI 0.33 to 0.90, I2=0%); for ≥3 capsules/day we observed a statistically significant reduction of cardiac death (n=3, RR 0.82, 95% CI 0.68 to 0.99, I2=0%), sudden death (n=1, RR 0.70, 95% CI 0.51 to 0.97) and stroke (n=2, RR 0.74, 95% CI 0.57 to 0.95, I2=0%).
CONCLUSION: Omega-3 supplementation at <2 1 g capsules/day showed no association with CVD outcomes; this seems unlikely to change from future research. Compared with the robust scientific evidence available for low doses, the evidence for higher doses (2-4 1 g capsules/day) is weak. The emerging postulated benefit from high-dose supplementation needs replication and further evaluation as to the precise formulation and indication.

© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.
PMID 32820013
Asmaa S Abdelhamid, Tracey J Brown, Julii S Brainard, Priti Biswas, Gabrielle C Thorpe, Helen J Moore, Katherine Ho Deane, Carolyn D Summerbell, Helen V Worthington, Fujian Song, Lee Hooper
Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease.
Cochrane Database Syst Rev. 2020 Feb 29;3:CD003177. doi: 10.1002/14651858.CD003177.pub5. Epub 2020 Feb 29.
Abstract/Text BACKGROUND: Omega-3 polyunsaturated fatty acids from oily fish (long-chain omega-3 (LCn3)), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)), as well as from plants (alpha-linolenic acid (ALA)) may benefit cardiovascular health. Guidelines recommend increasing omega-3-rich foods, and sometimes supplementation, but recent trials have not confirmed this.
OBJECTIVES: To assess the effects of increased intake of fish- and plant-based omega-3 fats for all-cause mortality, cardiovascular events, adiposity and lipids.
SEARCH METHODS: We searched CENTRAL, MEDLINE and Embase to February 2019, plus ClinicalTrials.gov and World Health Organization International Clinical Trials Registry to August 2019, with no language restrictions. We handsearched systematic review references and bibliographies and contacted trial authors.
SELECTION CRITERIA: We included randomised controlled trials (RCTs) that lasted at least 12 months and compared supplementation or advice to increase LCn3 or ALA intake, or both, versus usual or lower intake.
DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, extracted data and assessed validity. We performed separate random-effects meta-analysis for ALA and LCn3 interventions, and assessed dose-response relationships through meta-regression.
MAIN RESULTS: We included 86 RCTs (162,796 participants) in this review update and found that 28 were at low summary risk of bias. Trials were of 12 to 88 months' duration and included adults at varying cardiovascular risk, mainly in high-income countries. Most trials assessed LCn3 supplementation with capsules, but some used LCn3- or ALA-rich or enriched foods or dietary advice compared to placebo or usual diet. LCn3 doses ranged from 0.5 g a day to more than 5 g a day (19 RCTs gave at least 3 g LCn3 daily). Meta-analysis and sensitivity analyses suggested little or no effect of increasing LCn3 on all-cause mortality (risk ratio (RR) 0.97, 95% confidence interval (CI) 0.93 to 1.01; 143,693 participants; 11,297 deaths in 45 RCTs; high-certainty evidence), cardiovascular mortality (RR 0.92, 95% CI 0.86 to 0.99; 117,837 participants; 5658 deaths in 29 RCTs; moderate-certainty evidence), cardiovascular events (RR 0.96, 95% CI 0.92 to 1.01; 140,482 participants; 17,619 people experienced events in 43 RCTs; high-certainty evidence), stroke (RR 1.02, 95% CI 0.94 to 1.12; 138,888 participants; 2850 strokes in 31 RCTs; moderate-certainty evidence) or arrhythmia (RR 0.99, 95% CI 0.92 to 1.06; 77,990 participants; 4586 people experienced arrhythmia in 30 RCTs; low-certainty evidence). Increasing LCn3 may slightly reduce coronary heart disease mortality (number needed to treat for an additional beneficial outcome (NNTB) 334, RR 0.90, 95% CI 0.81 to 1.00; 127,378 participants; 3598 coronary heart disease deaths in 24 RCTs, low-certainty evidence) and coronary heart disease events (NNTB 167, RR 0.91, 95% CI 0.85 to 0.97; 134,116 participants; 8791 people experienced coronary heart disease events in 32 RCTs, low-certainty evidence). Overall, effects did not differ by trial duration or LCn3 dose in pre-planned subgrouping or meta-regression. There is little evidence of effects of eating fish. Increasing ALA intake probably makes little or no difference to all-cause mortality (RR 1.01, 95% CI 0.84 to 1.20; 19,327 participants; 459 deaths in 5 RCTs, moderate-certainty evidence),cardiovascular mortality (RR 0.96, 95% CI 0.74 to 1.25; 18,619 participants; 219 cardiovascular deaths in 4 RCTs; moderate-certainty evidence), coronary heart disease mortality (RR 0.95, 95% CI 0.72 to 1.26; 18,353 participants; 193 coronary heart disease deaths in 3 RCTs; moderate-certainty evidence) and coronary heart disease events (RR 1.00, 95% CI 0.82 to 1.22; 19,061 participants; 397 coronary heart disease events in 4 RCTs; low-certainty evidence). However, increased ALA may slightly reduce risk of cardiovascular disease events (NNTB 500, RR 0.95, 95% CI 0.83 to 1.07; but RR 0.91, 95% CI 0.79 to 1.04 in RCTs at low summary risk of bias; 19,327 participants; 884 cardiovascular disease events in 5 RCTs; low-certainty evidence), and probably slightly reduces risk of arrhythmia (NNTB 91, RR 0.73, 95% CI 0.55 to 0.97; 4912 participants; 173 events in 2 RCTs; moderate-certainty evidence). Effects on stroke are unclear. Increasing LCn3 and ALA had little or no effect on serious adverse events, adiposity, lipids and blood pressure, except increasing LCn3 reduced triglycerides by ˜15% in a dose-dependent way (high-certainty evidence).
AUTHORS' CONCLUSIONS: This is the most extensive systematic assessment of effects of omega-3 fats on cardiovascular health to date. Moderate- and low-certainty evidence suggests that increasing LCn3 slightly reduces risk of coronary heart disease mortality and events, and reduces serum triglycerides (evidence mainly from supplement trials). Increasing ALA slightly reduces risk of cardiovascular events and arrhythmia.

Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
PMID 32114706
Mitsuhiro Yokoyama, Hideki Origasa, Masunori Matsuzaki, Yuji Matsuzawa, Yasushi Saito, Yuichi Ishikawa, Shinichi Oikawa, Jun Sasaki, Hitoshi Hishida, Hiroshige Itakura, Toru Kita, Akira Kitabatake, Noriaki Nakaya, Toshiie Sakata, Kazuyuki Shimada, Kunio Shirato, Japan EPA lipid intervention study (JELIS) Investigators
Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.
Lancet. 2007 Mar 31;369(9567):1090-8. doi: 10.1016/S0140-6736(07)60527-3.
Abstract/Text BACKGROUND: Epidemiological and clinical evidence suggests that an increased intake of long-chain n-3 fatty acids protects against mortality from coronary artery disease. We aimed to test the hypothesis that long-term use of eicosapentaenoic acid (EPA) is effective for prevention of major coronary events in hypercholesterolaemic patients in Japan who consume a large amount of fish.
METHODS: 18 645 patients with a total cholesterol of 6.5 mmol/L or greater were recruited from local physicians throughout Japan between 1996 and 1999. Patients were randomly assigned to receive either 1800 mg of EPA daily with statin (EPA group; n=9326) or statin only (controls; n=9319) with a 5-year follow-up. The primary endpoint was any major coronary event, including sudden cardiac death, fatal and non-fatal myocardial infarction, and other non-fatal events including unstable angina pectoris, angioplasty, stenting, or coronary artery bypass grafting. Analysis was by intention-to-treat. The study was registered at ClinicalTrials.gov, number NCT00231738.
FINDINGS: At mean follow-up of 4.6 years, we detected the primary endpoint in 262 (2.8%) patients in the EPA group and 324 (3.5%) in controls-a 19% relative reduction in major coronary events (p=0.011). Post-treatment LDL cholesterol concentrations decreased 25%, from 4.7 mmol/L in both groups. Serum LDL cholesterol was not a significant factor in a reduction of risk for major coronary events. Unstable angina and non-fatal coronary events were also significantly reduced in the EPA group. Sudden cardiac death and coronary death did not differ between groups. In patients with a history of coronary artery disease who were given EPA treatment, major coronary events were reduced by 19% (secondary prevention subgroup: 158 [8.7%] in the EPA group vs 197 [10.7%] in the control group; p=0.048). In patients with no history of coronary artery disease, EPA treatment reduced major coronary events by 18%, but this finding was not significant (104 [1.4%] in the EPA group vs 127 [1.7%] in the control group; p=0.132).
INTERPRETATION: EPA is a promising treatment for prevention of major coronary events, and especially non-fatal coronary events, in Japanese hypercholesterolaemic patients.

PMID 17398308
ASCEND Study Collaborative Group, Louise Bowman, Marion Mafham, Karl Wallendszus, Will Stevens, Georgina Buck, Jill Barton, Kevin Murphy, Theingi Aung, Richard Haynes, Jolyon Cox, Aleksandra Murawska, Allen Young, Michael Lay, Fang Chen, Emily Sammons, Emma Waters, Amanda Adler, Jonathan Bodansky, Andrew Farmer, Roger McPherson, Andrew Neil, David Simpson, Richard Peto, Colin Baigent, Rory Collins, Sarah Parish, Jane Armitage
Effects of n-3 Fatty Acid Supplements in Diabetes Mellitus.
N Engl J Med. 2018 Oct 18;379(16):1540-1550. doi: 10.1056/NEJMoa1804989. Epub 2018 Aug 26.
Abstract/Text BACKGROUND: Increased intake of n-3 fatty acids has been associated with a reduced risk of cardiovascular disease in observational studies, but this finding has not been confirmed in randomized trials. It remains unclear whether n-3 (also called omega-3) fatty acid supplementation has cardiovascular benefit in patients with diabetes mellitus.
METHODS: We randomly assigned 15,480 patients with diabetes but without evidence of atherosclerotic cardiovascular disease to receive 1-g capsules containing either n-3 fatty acids (fatty acid group) or matching placebo (olive oil) daily. The primary outcome was a first serious vascular event (i.e., nonfatal myocardial infarction or stroke, transient ischemic attack, or vascular death, excluding confirmed intracranial hemorrhage). The secondary outcome was a first serious vascular event or any arterial revascularization.
RESULTS: During a mean follow-up of 7.4 years (adherence rate, 76%), a serious vascular event occurred in 689 patients (8.9%) in the fatty acid group and in 712 (9.2%) in the placebo group (rate ratio, 0.97; 95% confidence interval [CI], 0.87 to 1.08; P=0.55). The composite outcome of a serious vascular event or revascularization occurred in 882 patients (11.4%) and 887 patients (11.5%), respectively (rate ratio, 1.00; 95% CI, 0.91 to 1.09). Death from any cause occurred in 752 patients (9.7%) in the fatty acid group and in 788 (10.2%) in the placebo group (rate ratio, 0.95; 95% CI, 0.86 to 1.05). There were no significant between-group differences in the rates of nonfatal serious adverse events.
CONCLUSIONS: Among patients with diabetes without evidence of cardiovascular disease, there was no significant difference in the risk of serious vascular events between those who were assigned to receive n-3 fatty acid supplementation and those who were assigned to receive placebo. (Funded by the British Heart Foundation and others; Current Controlled Trials number, ISRCTN60635500 ; ClinicalTrials.gov number, NCT00135226 .).

PMID 30146932
JoAnn E Manson, Nancy R Cook, I-Min Lee, William Christen, Shari S Bassuk, Samia Mora, Heike Gibson, Christine M Albert, David Gordon, Trisha Copeland, Denise D'Agostino, Georgina Friedenberg, Claire Ridge, Vadim Bubes, Edward L Giovannucci, Walter C Willett, Julie E Buring, VITAL Research Group
Marine n-3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer.
N Engl J Med. 2019 Jan 3;380(1):23-32. doi: 10.1056/NEJMoa1811403. Epub 2018 Nov 10.
Abstract/Text BACKGROUND: Higher intake of marine n-3 (also called omega-3) fatty acids has been associated with reduced risks of cardiovascular disease and cancer in several observational studies. Whether supplementation with n-3 fatty acids has such effects in general populations at usual risk for these end points is unclear.
METHODS: We conducted a randomized, placebo-controlled trial, with a two-by-two factorial design, of vitamin D3 (at a dose of 2000 IU per day) and marine n-3 fatty acids (at a dose of 1 g per day) in the primary prevention of cardiovascular disease and cancer among men 50 years of age or older and women 55 years of age or older in the United States. Primary end points were major cardiovascular events (a composite of myocardial infarction, stroke, or death from cardiovascular causes) and invasive cancer of any type. Secondary end points included individual components of the composite cardiovascular end point, the composite end point plus coronary revascularization (expanded composite of cardiovascular events), site-specific cancers, and death from cancer. Safety was also assessed. This article reports the results of the comparison of n-3 fatty acids with placebo.
RESULTS: A total of 25,871 participants, including 5106 black participants, underwent randomization. During a median follow-up of 5.3 years, a major cardiovascular event occurred in 386 participants in the n-3 group and in 419 in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.80 to 1.06; P=0.24). Invasive cancer was diagnosed in 820 participants in the n-3 group and in 797 in the placebo group (hazard ratio, 1.03; 95% CI, 0.93 to 1.13; P=0.56). In the analyses of key secondary end points, the hazard ratios were as follows: for the expanded composite end point of cardiovascular events, 0.93 (95% CI, 0.82 to 1.04); for total myocardial infarction, 0.72 (95% CI, 0.59 to 0.90); for total stroke, 1.04 (95% CI, 0.83 to 1.31); for death from cardiovascular causes, 0.96 (95% CI, 0.76 to 1.21); and for death from cancer (341 deaths from cancer), 0.97 (95% CI, 0.79 to 1.20). In the analysis of death from any cause (978 deaths overall), the hazard ratio was 1.02 (95% CI, 0.90 to 1.15). No excess risks of bleeding or other serious adverse events were observed.
CONCLUSIONS: Supplementation with n-3 fatty acids did not result in a lower incidence of major cardiovascular events or cancer than placebo. (Funded by the National Institutes of Health and others; VITAL ClinicalTrials.gov number, NCT01169259 .).

PMID 30415637
Deepak L Bhatt, P Gabriel Steg, Michael Miller, Eliot A Brinton, Terry A Jacobson, Steven B Ketchum, Ralph T Doyle, Rebecca A Juliano, Lixia Jiao, Craig Granowitz, Jean-Claude Tardif, Christie M Ballantyne, REDUCE-IT Investigators
Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia.
N Engl J Med. 2019 Jan 3;380(1):11-22. doi: 10.1056/NEJMoa1812792. Epub 2018 Nov 10.
Abstract/Text BACKGROUND: Patients with elevated triglyceride levels are at increased risk for ischemic events. Icosapent ethyl, a highly purified eicosapentaenoic acid ethyl ester, lowers triglyceride levels, but data are needed to determine its effects on ischemic events.
METHODS: We performed a multicenter, randomized, double-blind, placebo-controlled trial involving patients with established cardiovascular disease or with diabetes and other risk factors, who had been receiving statin therapy and who had a fasting triglyceride level of 135 to 499 mg per deciliter (1.52 to 5.63 mmol per liter) and a low-density lipoprotein cholesterol level of 41 to 100 mg per deciliter (1.06 to 2.59 mmol per liter). The patients were randomly assigned to receive 2 g of icosapent ethyl twice daily (total daily dose, 4 g) or placebo. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina. The key secondary end point was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.
RESULTS: A total of 8179 patients were enrolled (70.7% for secondary prevention of cardiovascular events) and were followed for a median of 4.9 years. A primary end-point event occurred in 17.2% of the patients in the icosapent ethyl group, as compared with 22.0% of the patients in the placebo group (hazard ratio, 0.75; 95% confidence interval [CI], 0.68 to 0.83; P<0.001); the corresponding rates of the key secondary end point were 11.2% and 14.8% (hazard ratio, 0.74; 95% CI, 0.65 to 0.83; P<0.001). The rates of additional ischemic end points, as assessed according to a prespecified hierarchical schema, were significantly lower in the icosapent ethyl group than in the placebo group, including the rate of cardiovascular death (4.3% vs. 5.2%; hazard ratio, 0.80; 95% CI, 0.66 to 0.98; P=0.03). A larger percentage of patients in the icosapent ethyl group than in the placebo group were hospitalized for atrial fibrillation or flutter (3.1% vs. 2.1%, P=0.004). Serious bleeding events occurred in 2.7% of the patients in the icosapent ethyl group and in 2.1% in the placebo group (P=0.06).
CONCLUSIONS: Among patients with elevated triglyceride levels despite the use of statins, the risk of ischemic events, including cardiovascular death, was significantly lower among those who received 2 g of icosapent ethyl twice daily than among those who received placebo. (Funded by Amarin Pharma; REDUCE-IT ClinicalTrials.gov number, NCT01492361 .).

PMID 30415628
Federico Popoff, Giselle Balaciano, Ariel Bardach, Daniel Comandé, Vilma Irazola, Hugo Norberto Catalano, Ariel Izcovich
Omega 3 fatty acid supplementation after myocardial infarction: a systematic review and meta-analysis.
BMC Cardiovasc Disord. 2019 Jun 4;19(1):136. doi: 10.1186/s12872-019-1086-3. Epub 2019 Jun 4.
Abstract/Text BACKGROUND: The purpose of this review is to examine the effect of Omega-3 Fatty acids on mortality, morbidity, and adverse events in patients with acute myocardial infarction (AMI).
METHODS: Data Sources: MEDLINE, EMBASE, and the Cochrane Library through May 2018.
STUDY SELECTION: Randomized Controlled trials (RCT). Certainty of evidence was assessed with the GRADE system.
INTERVENTIONS: omega 3 fatty acids against placebo or no treatment. Primary and secondary outcomes: All-cause death, cardiovascular death, new AMI, stroke, need for therapeutic angioplasty or By-pass, new diagnosis of cancer and incidence of adverse events.
RESULTS: For the efficacy endpoints we included 10 RCT (24,414 patients). Omega 3 fatty acids probably make little or no difference to all-cause mortality (4 studies 9141 patients RR 1.06 - CI95% 0.90 to 1.27, moderate certainty), cardiovascular mortality (3 studies 4304 patients RR 0.93 - CI95% 0.63 to 1.37, moderate certainty), new AMI (RR 1.24 CI95% 0.71 to 2.14 - moderate certainty), any cardiovascular event (RR 0.95 95%CI 0.86 to 1.05; low certainty due to risk of bias and imprecision), and stroke (RR 1.2 95%CCI 0,66-2,19 - moderate certainty). Regarding adverse events, we are uncertain if Omega 3 fatty acids improve/reduce non severe adverse events (RR 1.39 95% CI 0.36 to 5.34; very low certainty). There is probably little or no difference in the outcome suspension due to adverse events (RR 1.19 CI 95% 0.97 to 1.47; moderate certainty).
CONCLUSIONS: For adult patients with AMI, omega 3 fatty-acids probably yield no benefit to patient important outcomes.

PMID 31164089
Stephen J Nicholls, A Michael Lincoff, Michelle Garcia, Dianna Bash, Christie M Ballantyne, Philip J Barter, Michael H Davidson, John J P Kastelein, Wolfgang Koenig, Darren K McGuire, Dariush Mozaffarian, Paul M Ridker, Kausik K Ray, Brian G Katona, Anders Himmelmann, Larrye E Loss, Martin Rensfeldt, Torbjörn Lundström, Rahul Agrawal, Venu Menon, Kathy Wolski, Steven E Nissen
Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk: The STRENGTH Randomized Clinical Trial.
JAMA. 2020 Dec 8;324(22):2268-2280. doi: 10.1001/jama.2020.22258.
Abstract/Text Importance: It remains uncertain whether the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) reduce cardiovascular risk.
Objective: To determine the effects on cardiovascular outcomes of a carboxylic acid formulation of EPA and DHA (omega-3 CA) with documented favorable effects on lipid and inflammatory markers in patients with atherogenic dyslipidemia and high cardiovascular risk.
Design, Setting, and Participants: A double-blind, randomized, multicenter trial (enrollment October 30, 2014, to June 14, 2017; study termination January 8, 2020; last patient visit May 14, 2020) comparing omega-3 CA with corn oil in statin-treated participants with high cardiovascular risk, hypertriglyceridemia, and low levels of high-density lipoprotein cholesterol (HDL-C). A total of 13 078 patients were randomized at 675 academic and community hospitals in 22 countries in North America, Europe, South America, Asia, Australia, New Zealand, and South Africa.
Interventions: Participants were randomized to receive 4 g/d of omega-3 CA (n = 6539) or corn oil, which was intended to serve as an inert comparator (n = 6539), in addition to usual background therapies, including statins.
Main Outcomes and Measures: The primary efficacy measure was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization.
Results: When 1384 patients had experienced a primary end point event (of a planned 1600 events), the trial was prematurely halted based on an interim analysis that indicated a low probability of clinical benefit of omega-3 CA vs the corn oil comparator. Among the 13 078 treated patients (mean [SD] age, 62.5 [9.0] years; 35% women; 70% with diabetes; median low-density lipoprotein [LDL] cholesterol level, 75.0 mg/dL; median triglycerides level, 240 mg/dL; median HDL-C level, 36 mg/dL; and median high-sensitivity C-reactive protein level, 2.1 mg/L), 12 633 (96.6%) completed the trial with ascertainment of primary end point status. The primary end point occurred in 785 patients (12.0%) treated with omega-3 CA vs 795 (12.2%) treated with corn oil (hazard ratio, 0.99 [95% CI, 0.90-1.09]; P = .84). A greater rate of gastrointestinal adverse events was observed in the omega-3 CA group (24.7%) compared with corn oil-treated patients (14.7%).
Conclusions and Relevance: Among statin-treated patients at high cardiovascular risk, the addition of omega-3 CA, compared with corn oil, to usual background therapies resulted in no significant difference in a composite outcome of major adverse cardiovascular events. These findings do not support use of this omega-3 fatty acid formulation to reduce major adverse cardiovascular events in high-risk patients.
Trial Registration: ClinicalTrials.gov Identifier: NCT02104817.

PMID 33190147
Débora Finger, Fernanda Reistenbach Goltz, Daniel Umpierre, Elisabeth Meyer, Luis Henrique Telles Rosa, Cláudia Dornelles Schneider
Effects of protein supplementation in older adults undergoing resistance training: a systematic review and meta-analysis.
Sports Med. 2015 Feb;45(2):245-55. doi: 10.1007/s40279-014-0269-4.
Abstract/Text BACKGROUND: Older individuals present reductions in muscle mass and physical function, as well as a blunted muscle protein synthesis response to amino acid administration and physical activity. Although resistance training is an effective intervention to slow down muscle impairments in the elderly, there is no consensus whether a combination with protein supplementation could offer additional benefits to an older population.
OBJECTIVE: We aimed to systematically summarize and quantify whether protein supplementation could optimize the effects of resistance training on muscle mass and strength in an aged population.
DESIGN: A structured literature search was conducted on MEDLINE (PubMed), Cochrane, EMBASE and LILACS databases. The search had no period or language restrictions. Inclusion criteria comprised study design (randomized controlled trials-RCTs), sample mean age (60 years and over) and intervention (a resistance training program for a period of 6 weeks or longer combined with protein or amino acids supplementation). Two independent reviewers performed the study selection and data extraction. Continuous data on fat-free mass, muscle mass and muscle strength were pooled using a random-effects model.
RESULTS: Of the 540 articles reviewed, 29 eligible articles underwent full-text evaluation. Nine RCTs (462 subjects) met the inclusion criteria and were included in the study. The mean age of the participants ranged from 61 to 79 years old. Protein supplementation protocols varied widely throughout the studies. Three studies used quantities related to the body mass of the participants and the other six trials provided supplements in daily amounts, independently of subjects' body masses. Overall, protein supplementation in combination with resistance training was associated with gains in fat-free mass, resulting in a standardized mean difference (SMD) of 0.23 [95% confidence interval (CI), 0.05-0.42]. However, protein supplementation was not associated with changes in muscle mass (0.14, 95% CI -0.05 to 0.32) or muscle strength (0.13, 95% CI -0.06 to 0.32).
LIMITATIONS: Studies among the very elderly population are scarce. The variation regarding the supplementation protocol, namely the different protein sources, amounts and timing of ingestion, also made it harder to compare the results. The general quality of the studies was low, reflecting increased risk of bias in some studies. Despite these limitations, this systematic review provides a general overview of the role of protein supplementation with no other added macronutrients to augment muscle mass and strength during resistance training in older adults.
CONCLUSION: Combining protein supplementation with resistance training is effective for eliciting gains in fat-free mass among older adults, but does not seem to increase muscle mass or strength.

PMID 25355074
Jürgen M Bauer, Sjors Verlaan, Ivan Bautmans, Kirsten Brandt, Lorenzo M Donini, Marcello Maggio, Marion E T McMurdo, Tony Mets, Chris Seal, Sander L Wijers, Gian Paolo Ceda, Giuseppe De Vito, Gilbert Donders, Michael Drey, Carolyn Greig, Ulf Holmbäck, Marco Narici, Jamie McPhee, Eleonora Poggiogalle, Dermot Power, Aldo Scafoglieri, Ralf Schultz, Cornel C Sieber, Tommy Cederholm
Effects of a vitamin D and leucine-enriched whey protein nutritional supplement on measures of sarcopenia in older adults, the PROVIDE study: a randomized, double-blind, placebo-controlled trial.
J Am Med Dir Assoc. 2015 Sep 1;16(9):740-7. doi: 10.1016/j.jamda.2015.05.021. Epub 2015 Jul 10.
Abstract/Text BACKGROUND: Age-related losses of muscle mass, strength, and function (sarcopenia) pose significant threats to physical performance, independence, and quality of life. Nutritional supplementation could positively influence aspects of sarcopenia and thereby prevent mobility disability.
OBJECTIVE: To test the hypothesis that a specific oral nutritional supplement can result in improvements in measures of sarcopenia.
DESIGN: A multicenter, randomized, controlled, double-blind, 2 parallel-group trial among 380 sarcopenic primarily independent-living older adults with Short Physical Performance Battery (SPPB; 0-12) scores between 4 and 9, and a low skeletal muscle mass index. The active group (n = 184) received a vitamin D and leucine-enriched whey protein nutritional supplement to consume twice daily for 13 weeks. The control group (n = 196) received an iso-caloric control product to consume twice daily for 13 weeks. Primary outcomes of handgrip strength and SPPB score, and secondary outcomes of chair-stand test, gait speed, balance score, and appendicular muscle mass (by DXA) were measured at baseline, week 7, and week 13 of the intervention.
RESULTS: Handgrip strength and SPPB improved in both groups without significant between-group differences. The active group improved more in the chair-stand test compared with the control group, between-group effect (95% confidence interval): -1.01 seconds (-1.77 to -0.19), P = .018. The active group gained more appendicular muscle mass than the control group, between-group effect: 0.17 kg (0.004-0.338), P = .045.
CONCLUSIONS: This 13-week intervention of a vitamin D and leucine-enriched whey protein oral nutritional supplement resulted in improvements in muscle mass and lower-extremity function among sarcopenic older adults. This study shows proof-of-principle that specific nutritional supplementation alone might benefit geriatric patients, especially relevant for those who are unable to exercise. These results warrant further investigations into the role of a specific nutritional supplement as part of a multimodal approach to prevent adverse outcomes among older adults at risk for disability.

Copyright © 2015 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.
PMID 26170041
Abstract/Text BACKGROUND: Even though the positive effects of whey protein-containing supplements for optimizing the anabolic responses and adaptations process in resistance-trained individuals have been supported by several investigations, their use continues to be controversial. Additionally, the administration of different multi-ingredient formulations where whey proteins are combined with carbohydrates, other protein sources, creatine, and amino acids or derivatives, has been extensively proposed as an effective strategy to maximize strength and muscle mass gains in athletes.
OBJECTIVE: We aimed to systematically summarize and quantify whether whey protein-containing supplements, administered alone or as a part of a multi-ingredient, could improve the effects of resistance training on fat-free mass or lean body mass, and strength in resistance-trained individuals when compared with other iso-energetic supplements containing carbohydrates or other sources of proteins.
METHODS: A structured literature search was conducted on PubMed, Science Direct, Web of Science, Cochrane Libraries, US National Institutes of Health clinicaltrials.gov, SPORTDiscus, and Google Scholar databases. Main inclusion criteria comprised randomized controlled trial study design, adults (aged 18 years and over), resistance-trained individuals, interventions (a resistance training program for a period of 6 weeks or longer, combined with whey protein supplementation administered alone or as a part of a multi-ingredient), and a calorie equivalent contrast supplement from carbohydrates or other non-whey protein sources. Continuous data on fat-free mass and lean body mass, and maximal strength were pooled using a random-effects model.
RESULTS: Data from nine randomized controlled trials were included, involving 11 treatments and 192 participants. Overall, with respect to the ingestion of contrast supplements, whey protein supplementation, administered alone or as part of a multi-ingredient, in combination with resistance training, was associated with small extra gains in fat-free mass or lean body mass, resulting in an effect size of g = 0.301, 95% confidence interval (CI) 0.032-0.571. Subgroup analyses showed less clear positive trends resulting in small to moderate effect size g = 0.217 (95% CI -0.113 to 0.547) and g = 0.468 (95% CI 0.003-0.934) in favor of whey and multi-ingredient, respectively. Additionally, a positive overall extra effect was also observed to maximize lower (g = 0.316, 95% CI 0.045-0.588) and upper body maximal strength (g = 0.458, 95% CI 0.161-0.755). Subgroup analyses showed smaller superiority to maximize strength gains with respect to the contrast groups for lower body (whey protein: g = 0.343, 95% CI -0.016 to 0.702, multi-ingredient: g = 0.281, 95% CI -0.135 to 0.697) while in the upper body, multi-ingredient (g = 0.612, 95% CI 0.157-1.068) seemed to produce more clear effects than whey protein alone (g = 0.343, 95% CI -0.048 to 0.735).
LIMITATIONS: Studies involving interventions of more than 6 weeks on resistance-training individuals are scarce and account for a small number of participants. Furthermore, no studies with an intervention longer than 12 weeks have been found. The variation regarding the supplementation protocol, namely the different doses criteria or timing of ingestion also add some concerns to the studies comparison.
CONCLUSIONS: Whey protein alone or as a part of a multi-ingredient appears to maximize lean body mass or fat-free mass gain, as well as upper and lower body strength improvement with respect to the ingestion of an iso-energetic equivalent carbohydrate or non-whey protein supplement in resistance-training individuals. This enhancement effect seems to be more evident when whey proteins are consumed within a multi-ingredient containing creatine.

PMID 26403469
Robert W Morton, Kevin T Murphy, Sean R McKellar, Brad J Schoenfeld, Menno Henselmans, Eric Helms, Alan A Aragon, Michaela C Devries, Laura Banfield, James W Krieger, Stuart M Phillips
A systematic review, meta-analysis and meta-regression of the effect of protein supplementation on resistance training-induced gains in muscle mass and strength in healthy adults.
Br J Sports Med. 2017 Jul 11;. doi: 10.1136/bjsports-2017-097608. Epub 2017 Jul 11.
Abstract/Text OBJECTIVE: We performed a systematic review, meta-analysis and meta-regression to determine if dietary protein supplementation augments resistance exercise training (RET)-induced gains in muscle mass and strength.
DATA SOURCES: A systematic search of Medline, Embase, CINAHL and SportDiscus.
ELIGIBILITY CRITERIA: Only randomised controlled trials with RET ≥6 weeks in duration and dietary protein supplementation.
DESIGN: Random-effects meta-analyses and meta-regressions with four a priori determined covariates. Two-phase break point analysis was used to determine the relationship between total protein intake and changes in fat-free mass (FFM).
RESULTS: Data from 49 studies with 1863 participants showed that dietary protein supplementation significantly (all p<0.05) increased changes (means (95% CI)) in: strength-one-repetition-maximum (2.49 kg (0.64, 4.33)), FFM (0.30 kg (0.09, 0.52)) and muscle size-muscle fibre cross-sectional area (CSA; 310 µm(2) (51, 570)) and mid-femur CSA (7.2 mm(2) (0.20, 14.30)) during periods of prolonged RET. The impact of protein supplementation on gains in FFM was reduced with increasing age (-0.01 kg (-0.02,-0.00), p=0.002) and was more effective in resistance-trained individuals (0.75 kg (0.09, 1.40), p=0.03). Protein supplementation beyond total protein intakes of 1.62 g/kg/day resulted in no further RET-induced gains in FFM.
SUMMARY/CONCLUSION: Dietary protein supplementation significantly enhanced changes in muscle strength and size during prolonged RET in healthy adults. Increasing age reduces and training experience increases the efficacy of protein supplementation during RET. With protein supplementation, protein intakes at amounts greater than ~1.6 g/kg/day do not further contribute RET-induced gains in FFM.

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
PMID 28698222
Fui-Ching Lam, Tahir Mehmood Khan, Hani Faidah, Abdul Haseeb, Amer Hayat Khan
Effectiveness of whey protein supplements on the serum levels of amino acid, creatinine kinase and myoglobin of athletes: a systematic review and meta-analysis.
Syst Rev. 2019 May 31;8(1):130. doi: 10.1186/s13643-019-1039-z. Epub 2019 May 31.
Abstract/Text BACKGROUND: Consuming whey protein supplements, along with physiotherapy and psychotherapy, have been recognised in sports performance. Whey protein supplements (WPS) is one of the commonly used supplements as ergogenic aids for athletes to enhance their muscle performance and recovery during sport-related injuries. The purpose of this systematic review is to investigate the effectiveness of WPS over the blood biochemistry mainly amino acids, creatinine kinase and myoglobin which influence performance and recovery among athletes.
METHOD: A comprehensive literature search was conducted to identify randomised control trials (RCTs) and non-RCTs that investigated the effectiveness of WPS on amino acids, creatinine kinase and myoglobin among athletes. Risk of Bias in Non-Randomised Studies of Interventions tool (ROBINS-I) and Cochrane Risk of Bias Assessment tool were used to rule out the quality of studies. Meta-analysis was performed using a random effect model with STATA version 14.2. The weighted mean difference was used to estimate the effectiveness of WPS against other supplements.
RESULTS: A total of 333,257 research articles were identified; of these, 15 records were included to proceed with the analysis. Meta-analysis has shown that WPS has significantly overall increased the level of essential amino acids level by 624.03 nmol/L (CI = 169.27, 1078.8; I2 = 100%; p = 0.00) and branched-chain amino acids level by 458.57 nmol/L (CI = 179.96, 737.18; I2 = 100%; p = 0.00) compared to the control group (without WPS). Moreover, was observed to decrease myoglobin level by 11.74 ng/ml (CI = - 30.24, 6.76; I2 = 79.6%; p = 0.007) and creatine kinase level by 47.05 U/L (CI = - 129.47, 35.37; I2 = 98.4%; p = 0.000) compared to the control group.
CONCLUSION: The findings revealed that the clinical evidence supports the effectiveness of WPS as a positive ergogenic aid on athletes' amino acids, creatinine kinase and myoglobin.

PMID 31151484
Filipe J Teixeira, Heitor O Santos, Scott L Howell, Gustavo D Pimentel
Whey protein in cancer therapy: A narrative review.
Pharmacol Res. 2019 Jun;144:245-256. doi: 10.1016/j.phrs.2019.04.019. Epub 2019 Apr 18.
Abstract/Text Cancer remains a public health challenge in the identification and development of ideal pharmacological therapies and dietary strategies. The use of whey protein as a dietary strategy is widespread in the field of oncology. The two types of whey protein, sweet or acid, result from several processing techniques and possess distinct protein subfraction compositions. Mechanistically, whey protein subfractions have specific anti-cancer effects. Alpha-lactalbumin, human α-lactalbumin made lethal to tumor cell, bovine α-lactalbumin made lethal to tumor cell, bovine serum albumin, and lactoferrin are whey protein subfractions with potential to hinder tumor pathways. Such effects, however, are principally supported by studies performed in vitro and/or in vivo. In clinical practice, whey protein intake-induced anti-cancer effects are indiscernible. However, whey protein supplementation represents a practical, feasible, and cost-effective approach to mitigate cancer cachexia syndrome. The usefulness of whey protein is evidenced by a greater leucine content and the potential to modulate IGF-1 concentrations, representing important factors towards musculoskeletal hypertrophy. Further clinical trials are warranted and needed to establish the effects of whey protein supplementation as an adjuvant to cancer therapy.

Copyright © 2019 Elsevier Ltd. All rights reserved.
PMID 31005617
Abstract/Text
PMID 22570464
Joshua Z Goldenberg, Lyubov Lytvyn, Justin Steurich, Patricia Parkin, Sanjay Mahant, Bradley C Johnston
Probiotics for the prevention of pediatric antibiotic-associated diarrhea.
Cochrane Database Syst Rev. 2015 Dec 22;(12):CD004827. doi: 10.1002/14651858.CD004827.pub4. Epub 2015 Dec 22.
Abstract/Text BACKGROUND: Antibiotics are frequently prescribed in children. They alter the microbial balance within the gastrointestinal tract, commonly resulting in antibiotic-associated diarrhea (AAD). Probiotics may prevent AAD via restoration of the gut microflora.
OBJECTIVES: The primary objectives were to assess the efficacy and safety of probiotics (any specified strain or dose) used for the prevention of AAD in children.
SEARCH METHODS: MEDLINE, EMBASE, CENTRAL, CINAHL, AMED, and the Web of Science (inception to November 2014) were searched along with specialized registers including the Cochrane IBD/FBD review group, CISCOM (Centralized Information Service for Complementary Medicine), NHS Evidence, the International Bibliographic Information on Dietary Supplements as well as trial registries. Letters were sent to authors of included trials, nutraceutical and pharmaceutical companies, and experts in the field requesting additional information on ongoing or unpublished trials. Conference proceedings, dissertation abstracts, and reference lists from included and relevant articles were also searched.
SELECTION CRITERIA: Randomized, parallel, controlled trials in children (0 to 18 years) receiving antibiotics, that compare probiotics to placebo, active alternative prophylaxis, or no treatment and measure the incidence of diarrhea secondary to antibiotic use were considered for inclusion.
DATA COLLECTION AND ANALYSIS: Study selection, data extraction as well as methodological quality assessment using the risk of bias instrument was conducted independently and in duplicate by two authors. Dichotomous data (incidence of diarrhea, adverse events) were combined using a pooled risk ratio (RR) or risk difference (RD), and continuous data (mean duration of diarrhea, mean daily stool frequency) as mean difference (MD), along with their corresponding 95% confidence interval (95% CI). For overall pooled results on the incidence of diarrhea, sensitivity analyses included available case versus extreme-plausible analyses and random- versus fixed-effect models. To explore possible explanations for heterogeneity, a priori subgroup analysis were conducted on probiotic strain, dose, definition of antibiotic-associated diarrhea, as well as risk of bias. We also conducted post hoc subgroup analyses by patient diagnosis, single versus multi-strain, industry sponsorship, and inpatient status. The overall quality of the evidence supporting the outcomes was evaluated using the GRADE criteria.
MAIN RESULTS: Twenty-three studies (3938 participants) met the inclusion criteria. Trials included treatment with either Bacillus spp., Bifidobacterium spp., Clostridium butyricum, Lactobacilli spp., Lactococcus spp., Leuconostoc cremoris, Saccharomyces spp., orStreptococcus spp., alone or in combination. Eleven studies used a single strain probiotic, four combined two probiotic strains, three combined three probiotic strains, one combined four probiotic strains, two combined seven probiotic strains, one included ten probiotic strains, and one study included two probiotic arms that used three and two strains respectively. The risk of bias was determined to be high or unclear in 13 studies and low in 10 studies. Available case (patients who did not complete the studies were not included in the analysis) results from 22/23 trials reporting on the incidence of diarrhea show a precise benefit from probiotics compared to active, placebo or no treatment control. The incidence of AAD in the probiotic group was 8% (163/1992) compared to 19% (364/1906) in the control group (RR 0.46, 95% CI 0.35 to 0.61; I(2) = 55%, 3898 participants). A GRADE analysis indicated that the overall quality of the evidence for this outcome was moderate. This benefit remained statistically significant in an extreme plausible (60% of children loss to follow-up in probiotic group and 20% loss to follow-up in the control group had diarrhea) sensitivity analysis, where the incidence of AAD in the probiotic group was 14% (330/2294) compared to 19% (426/2235) in the control group (RR 0.69; 95% CI 0.54 to 0.89; I(2) = 63%, 4529 participants). None of the 16 trials (n = 2455) that reported on adverse events documented any serious adverse events attributable to probiotics. Meta-analysis excluded all but an extremely small non-significant difference in adverse events between treatment and control (RD 0.00; 95% CI -0.01 to 0.01). The majority of adverse events were in placebo, standard care or no treatment group. Adverse events reported in the studies include rash, nausea, gas, flatulence, abdominal bloating, abdominal pain, vomiting, increased phlegm, chest pain, constipation, taste disturbance, and low appetite.
AUTHORS' CONCLUSIONS: Moderate quality evidence suggests a protective effect of probiotics in preventing AAD. Our pooled estimate suggests a precise (RR 0.46; 95% CI 0.35 to 0.61) probiotic effect with a NNT of 10. Among the various probiotics evaluated, Lactobacillus rhamnosus or Saccharomyces boulardii at 5 to 40 billion colony forming units/day may be appropriate given the modest NNT and the likelihood that adverse events are very rare. It is premature to draw conclusions about the efficacy and safety of other probiotic agents for pediatric AAD. Although no serious adverse events were observed among otherwise healthy children, serious adverse events have been observed in severely debilitated or immuno-compromised children with underlying risk factors including central venous catheter use and disorders associated with bacterial/fungal translocation. Until further research has been conducted, probiotic use should be avoided in pediatric populations at risk for adverse events. Future trials would benefit from a standard and valid outcomes to measure AAD.

PMID 26695080
Clare Goodman, Georgia Keating, Ekavi Georgousopoulou, Charlotte Hespe, Kate Levett
Probiotics for the prevention of antibiotic-associated diarrhoea: a systematic review and meta-analysis.
BMJ Open. 2021 Aug 12;11(8):e043054. doi: 10.1136/bmjopen-2020-043054. Epub 2021 Aug 12.
Abstract/Text OBJECTIVE: To evaluate existing evidence for the use of probiotics in preventing antibiotic-associated diarrhoea (AAD) in adults.
DESIGN: Systematic review and meta-analysis of randomised controlled trials (RCTs).
DATA SOURCES: We performed a literature search of the electronic databases CINAHL Plus, EMBASE, MEDLINE (Ovid) and Web of Science from database inception to May 2021 as well as hand searching of trial registries and reference lists of related reviews.
STUDY SELECTION: Two reviewers identified whether RCTs met the following inclusion criteria: adult population to whom antibiotics were administered; a probiotic intervention; a placebo, alternative dose, alternative probiotic strain or no treatment control; and incidence of AAD as the outcome.
DATA EXTRACTION AND SYNTHESIS: Two reviewers independently collected data and assessed risk of bias using preconstructed data extraction forms. We used a random effects model for all analyses. Subgroup analyses were performed to evaluate species-specific and dose-specific response.
RESULTS: Forty-two studies (11,305 participants) were included in this review. The pooled analysis suggests that co-administration of probiotics with antibiotics reduces the risk of AAD in adults by 37% (risk ratio (RR)=0.63 (95% CI 0.54 to 0.73), p<0.00001). The overall quality of the evidence using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) criteria was found to be moderate. In subgroup analyses, high dose compared with low dose of the same probiotic demonstrated a positive protective effect (RR 0.54 (95% CI 0.38 to 0.76), p<0.01), and only certain species, mainly of the lactobacillus and bifidobacteria genera, were found to be effective. Studies with a low baseline AAD risk did not show any difference in risk but studies with moderate or high baseline AAD risk demonstrated a significant risk reduction.
CONCLUSIONS: Probiotics are effective for preventing AAD. Secondary analyses of higher dosages and certain species have shown increased effectiveness. Our results may not be applicable in clinical scenarios of lower baseline AAD risk.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
PMID 34385227
Shelui Collinson, Andrew Deans, April Padua-Zamora, Germana V Gregorio, Chao Li, Leonila F Dans, Stephen J Allen
Probiotics for treating acute infectious diarrhoea.
Cochrane Database Syst Rev. 2020 Dec 8;12:CD003048. doi: 10.1002/14651858.CD003048.pub4. Epub 2020 Dec 8.
Abstract/Text BACKGROUND: Probiotics may be effective in reducing the duration of acute infectious diarrhoea.
OBJECTIVES: To assess the effects of probiotics in proven or presumed acute infectious diarrhoea.
SEARCH METHODS: We searched the trials register of the Cochrane Infectious Diseases Group, MEDLINE, and Embase from inception to 17 December 2019, as well as the Cochrane Controlled Trials Register (Issue 12, 2019), in the Cochrane Library, and reference lists from studies and reviews. We included additional studies identified during external review.
SELECTION CRITERIA: Randomized controlled trials comparing a specified probiotic agent with a placebo or no probiotic in people with acute diarrhoea that is proven or presumed to be caused by an infectious agent.
DATA COLLECTION AND ANALYSIS: Two review authors independently applied inclusion criteria, assessed risk of bias, and extracted data. Primary outcomes were measures of diarrhoea duration (diarrhoea lasting ≥ 48 hours; duration of diarrhoea). Secondary outcomes were number of people hospitalized in community studies, duration of hospitalization in inpatient studies, diarrhoea lasting ≥ 14 days, and adverse events.
MAIN RESULTS: We included 82 studies with a total of 12,127 participants. These studies included 11,526 children (age < 18 years) and 412 adults (three studies recruited 189 adults and children but did not specify numbers in each age group). No cluster-randomized trials were included. Studies varied in the definitions used for "acute diarrhoea" and "end of the diarrhoeal illness" and in the probiotic(s) tested. A total of 53 trials were undertaken in countries where both child and adult mortality was low or very low, and 26 where either child or adult mortality was high. Risk of bias was high or unclear in many studies, and there was marked statistical heterogeneity when findings for the primary outcomes were pooled in meta-analysis. Effect size was similar in the sensitivity analysis and marked heterogeneity persisted. Publication bias was demonstrated from funnel plots for the main outcomes. In our main analysis of the primary outcomes in studies at low risk for all indices of risk of bias, no difference was detected between probiotic and control groups for the risk of diarrhoea lasting ≥ 48 hours (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.91 to 1.09; 2 trials, 1770 participants; moderate-certainty evidence); or for duration of diarrhoea (mean difference (MD) 8.64 hours shorter, 95% CI 29.4 hours shorter to 12.1 hours longer; 6 trials, 3058 participants; very low-certainty evidence). Effect size was similar and marked heterogeneity persisted in pre-specified subgroup analyses of the primary outcomes that included all studies. These included analyses limited to the probiotics Lactobacillus rhamnosus GG and Saccharomyces boulardii. In six trials (433 participants) of Lactobacillus reuteri, there was consistency amongst findings (I² = 0%), but risk of bias was present in all included studies. Heterogeneity also was not explained by types of participants (age, nutritional/socioeconomic status captured by mortality stratum, region of the world where studies were undertaken), diarrhoea in children caused by rotavirus, exposure to antibiotics, and the few studies of children who were also treated with zinc. In addition, there were no clear differences in effect size for the primary outcomes in post hoc analyses according to decade of publication of studies and whether or not trials had been registered. For other outcomes, the duration of hospitalization in inpatient studies on average was shorter in probiotic groups than in control groups but there was marked heterogeneity between studies (I² = 96%; MD -18.03 hours, 95% CI -27.28 to -8.78, random-effects model: 24 trials, 4056 participants). No differences were detected between probiotic and control groups in the number of people with diarrhoea lasting ≥ 14 days (RR 0.49, 95% CI 0.16 to 1.53; 9 studies, 2928 participants) or in risk of hospitalization in community studies (RR 1.26, 95% CI 0.84 to 1.89; 6 studies, 2283 participants). No serious adverse events were attributed to probiotics.
AUTHORS' CONCLUSIONS: Probiotics probably make little or no difference to the number of people who have diarrhoea lasting 48 hours or longer, and we are uncertain whether probiotics reduce the duration of diarrhoea. This analysis is based on large trials with low risk of bias.

Copyright © 2020 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.
PMID 33295643
Qiukui Hao, Bi Rong Dong, Taixiang Wu
Probiotics for preventing acute upper respiratory tract infections.
Cochrane Database Syst Rev. 2015 Feb 3;(2):CD006895. doi: 10.1002/14651858.CD006895.pub3. Epub 2015 Feb 3.
Abstract/Text BACKGROUND: Probiotics may improve a person's health by regulating their immune function. Some trials have shown that probiotic strains can prevent respiratory infections. Even though the previous version of our review showed benefits of probiotics for acute upper respiratory tract infections (URTIs), several new studies have been published.
OBJECTIVES: To assess the effectiveness and safety of probiotics (any specified strain or dose), compared with placebo, in the prevention of acute URTIs in people of all ages, at risk of acute URTIs.
SEARCH METHODS: We searched CENTRAL (2014, Issue 6), MEDLINE (1950 to July week 3, 2014), EMBASE (1974 to July 2014), Web of Science (1900 to July 2014), the Chinese Biomedical Literature Database, which includes the China Biological Medicine Database (from 1978 to July 2014), the Chinese Medicine Popular Science Literature Database (from 2000 to July 2014) and the Masters Degree Dissertation of Beijing Union Medical College Database (from 1981 to July 2014). We also searched the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov for completed and ongoing trials on 31 July 2014.
SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing probiotics with placebo to prevent acute URTIs.
DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the eligibility and quality of trials, and extracted data using the standard methodological procedures expected by The Cochrane Collaboration.
MAIN RESULTS: We included 13 RCTs, although we could only extract data to meta-analyse 12 trials, which involved 3720 participants including children, adults (aged around 40 years) and older people. We found that probiotics were better than placebo when measuring the number of participants experiencing episodes of acute URTI (at least one episode: odds ratio (OR) 0.53; 95% confidence interval (CI) 0.37 to 0.76, P value < 0.001, low quality evidence; at least three episodes: OR 0.53; 95% CI 0.36 to 0.80, P value = 0.002, low quality evidence); the mean duration of an episode of acute URTI (mean difference (MD) -1.89; 95% CI -2.03 to -1.75, P value < 0.001, low quality evidence); reduced antibiotic prescription rates for acute URTIs (OR 0.65; 95% CI 0.45 to 0.94, moderate quality evidence) and cold-related school absence (OR 0.10; 95% CI 0.02 to 0.47, very low quality evidence). Probiotics and placebo were similar when measuring the rate ratio of episodes of acute URTI (rate ratio 0.83; 95% CI 0.66 to 1.05, P value = 0.12, very low quality evidence) and adverse events (OR 0.88; 95% CI 0.65 to 1.19, P value = 0.40, low quality evidence). Side effects of probiotics were minor and gastrointestinal symptoms were the most common. We found that some subgroups had a high level of heterogeneity when we conducted pooled analyses and the evidence level was low or very low quality.
AUTHORS' CONCLUSIONS: Probiotics were better than placebo in reducing the number of participants experiencing episodes of acute URTI, the mean duration of an episode of acute URTI, antibiotic use and cold-related school absence. This indicates that probiotics may be more beneficial than placebo for preventing acute URTIs. However, the quality of the evidence was low or very low.

PMID 25927096
Laodong Li, KangKang Hong, Qixiang Sun, Huan Xiao, Lejin Lai, Moyu Ming, Chaoqian Li
Probiotics for Preventing Upper Respiratory Tract Infections in Adults: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
Evid Based Complement Alternat Med. 2020;2020:8734140. doi: 10.1155/2020/8734140. Epub 2020 Oct 26.
Abstract/Text Background: Upper respiratory tract infections (URTIs) are common and burdensome infectious illness. Several trials have reported that probiotics can prevent URTIs in adults.
Objectives: To evaluate the efficacy and safety of probiotics in the prevention of URTIs in adults.
Methods: PubMed, Web of Science, Embase, and Cochrane Library were searched for reports published from database inception to May 14, 2020. Randomized controlled trials (RCTs) comparing probiotics with placebo for the prevention of URTIs in adults were included.
Results: Six RCTs with 1551 participants were included. Compared with the placebo group, the probiotics intervention group significantly reduced the incidence of URTI episodes (RR: 0.77; 95% CI: 0.68 to 0.87; P < 0.0001; I2 = 26%), the episode rate of URTIs (rate ratio: 0.72; 95% CI: 0.60 to 0.86; P = 0.0002; I2 = 99%), and the mean duration of one episode of URTI (MD: -2.66; 95% CI: -4.79 to -0.54; P = 0.01; I2 = 80%). The adverse events of probiotics were mainly mild gastrointestinal symptoms. There were no significant differences in occurrence rate of adverse effects between probiotics intervention and placebo group (rate ratio: 1.01; 95% CI: 0.80 to 1.26; P = 0.96; I2 = 99%).
Conclusion: Low-quality evidence provides support that probiotics have potential efficacy for preventing URTI episodes in adults. More trials are required to confirm this conclusion.

Copyright © 2020 Laodong Li et al.
PMID 33293995
Abirami Pararajasingam, Juliet Uwagwu
Lactobacillus: the not so friendly bacteria.
BMJ Case Rep. 2017 Sep 13;2017. doi: 10.1136/bcr-2016-218423. Epub 2017 Sep 13.
Abstract/Text We present a 65-year-old diabetic patient with a complex liver abscess and bacteraemia from Lactobacillus paracasei The abscess resulted in a prolonged hospital stay due to ongoing sepsis despite ultrasound-guided drainage and broad-spectrum antibiotics. Furthermore, the patient developed several secondary complications including a right-sided pleural effusion, an inferior vena cava thrombus and septic lung emboli. The abscess was eventually managed successfully with a prolonged course of antibiotics and multiple ultrasound-guided drainage procedures.To our knowledge, this is the first reported case of probiotic consumption, confirmed by strain identification, as the likely source of a liver abscess. Probiotic products have been widely used for many years and are advocated to the general public for their health benefits with no warning of side effects. Lactobacilli are one group of bacteria commonly used in these products. Although rare, complications have been reported. Susceptible patients, such as those who are immunocompromised, should be advised against excessive consumption.

© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
PMID 28903972
Michael H Land, Kelly Rouster-Stevens, Charles R Woods, Michael L Cannon, James Cnota, Avinash K Shetty
Lactobacillus sepsis associated with probiotic therapy.
Pediatrics. 2005 Jan;115(1):178-81. doi: 10.1542/peds.2004-2137.
Abstract/Text Probiotic strains of lactobacilli are increasingly being used in clinical practice because of their many health benefits. Infections associated with probiotic strains of lactobacilli are extremely rare. We describe 2 patients who received probiotic lactobacilli and subsequently developed bacteremia and sepsis attributable to Lactobacillus species. Molecular DNA fingerprinting analysis showed that the Lactobacillus strain isolated from blood samples was indistinguishable from the probiotic strain ingested by the patients. This report indicates, for the first time, that invasive disease can be associated with probiotic lactobacilli. This report should not discourage the appropriate use of Lactobacillus or other probiotic agents but should serve as a reminder that these agents can cause invasive disease in certain populations.

PMID 15629999
Leila Haghighat, Nancy F Crum-Cianflone
The potential risks of probiotics among HIV-infected persons: Bacteraemia due to Lactobacillus acidophilus and review of the literature.
Int J STD AIDS. 2016 Nov;27(13):1223-1230. doi: 10.1177/0956462415590725. Epub 2015 Jun 30.
Abstract/Text Lactobacillus sp. are commensal organisms that are increasingly reported to cause invasive infections among immunosuppressed persons. However, few data exist regarding the occurrence and risk factors of these infections among HIV-infected persons. Further, the safety of products that contain lactobacilli (e.g. probiotics) in certain populations, including those with HIV/AIDS, is unclear. We report a case of Lactobacillus acidophilus bacteraemia in a patient with AIDS temporally related to excessive consumption of probiotic-enriched yogurt, and provide a comprehensive review of the literature of Lactobacillus sp. infections among HIV-infected persons.

© The Author(s) 2015.
PMID 26130690
Claire Bertelli, Trestan Pillonel, Anaïs Torregrossa, Guy Prod'hom, Céline Julie Fischer, Gilbert Greub, Eric Giannoni
Bifidobacterium longum bacteremia in preterm infants receiving probiotics.
Clin Infect Dis. 2015 Mar 15;60(6):924-7. doi: 10.1093/cid/ciu946. Epub 2014 Dec 3.
Abstract/Text Administration of probiotics to premature newborns has been shown to prevent necrotizing enterocolitis and reduce all-cause mortality. In our hospital, we documented 2 cases of Bifidobacterium longum subspecies infantis bacteremia in newborns receiving probiotics. By comparative genomics, we confirmed that the strains isolated from each patient originated from the probiotics.

© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
PMID 25472946
Bradley C Johnston, Stephanie S Y Ma, Joshua Z Goldenberg, Kristian Thorlund, Per O Vandvik, Mark Loeb, Gordon H Guyatt
Probiotics for the prevention of Clostridium difficile-associated diarrhea: a systematic review and meta-analysis.
Ann Intern Med. 2012 Dec 18;157(12):878-88. doi: 10.7326/0003-4819-157-12-201212180-00563.
Abstract/Text BACKGROUND: Antibiotic treatment may disturb the resistance of gastrointestinal flora to colonization. This may result in complications, the most serious of which is Clostridium difficile–associated diarrhea (CDAD).
PURPOSE: To assess the efficacy and safety of probiotics for the prevention of CDAD in adults and children receiving antibiotics.
DATA SOURCES: Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL, Allied and Complementary Medicine Database, Web of Science, and 12 gray-literature sources.
STUDY SELECTION: Randomized, controlled trials including adult or pediatric patients receiving antibiotics that compared any strain or dose of a specified probiotic with placebo or with no treatment control and reported the incidence of CDAD.
DATA EXTRACTION: Two reviewers independently screened potentially eligible articles; extracted data on populations, interventions, and outcomes; and assessed risk of bias. The Grading of Recommendations Assessment, Development and Evaluation guidelines were used to independently rate overall confidence in effect estimates for each outcome.
DATA SYNTHESIS: Twenty trials including 3818 participants met the eligibility criteria. Probiotics reduced the incidence of CDAD by 66% (pooled relative risk, 0.34 [95% CI, 0.24 to 0.49]; I(2) = 0%). In a population with a 5% incidence of antibiotic-associated CDAD (median control group risk), probiotic prophylaxis would prevent 33 episodes (CI, 25 to 38 episodes) per 1000 persons. Of probiotic-treated patients, 9.3% experienced adverse events, compared with 12.6% of control patients (relative risk, 0.82 [CI, 0.65 to 1.05]; I(2) = 17%).
LIMITATIONS: In 13 trials, data on CDAD were missing for 5% to 45% of patients. The results were robust to worst-plausible assumptions regarding event rates in studies with missing outcome data.
CONCLUSION: Moderate-quality evidence suggests that probiotic prophylaxis results in a large reduction in CDAD without an increase in clinically important adverse events.
PRIMARY FUNDING SOURCE: None.

PMID 23362517
Abstract/Text
PMID 26365389
Qin Guo, Joshua Z Goldenberg, Claire Humphrey, Regina El Dib, Bradley C Johnston
Probiotics for the prevention of pediatric antibiotic-associated diarrhea.
Cochrane Database Syst Rev. 2019 Apr 30;4:CD004827. doi: 10.1002/14651858.CD004827.pub5. Epub 2019 Apr 30.
Abstract/Text BACKGROUND: Antibiotics alter the microbial balance commonly resulting in antibiotic-associated diarrhea (AAD). Probiotics may prevent AAD via providing gut barrier, restoration of the gut microflora, and other potential mechanisms of action.
OBJECTIVES: The primary objectives were to assess the efficacy and safety of probiotics (any specified strain or dose) used for the prevention of AAD in children.
SEARCH METHODS: MEDLINE, Embase, CENTRAL, CINAHL, and the Web of Science (inception to 28 May 2018) were searched along with registers including the ISRCTN and Clinicaltrials.gov. We also searched the NICE Evidence Services database as well as reference lists from relevant articles.
SELECTION CRITERIA: Randomized, parallel, controlled trials in children (0 to 18 years) receiving antibiotics, that compare probiotics to placebo, active alternative prophylaxis, or no treatment and measure the incidence of diarrhea secondary to antibiotic use were considered for inclusion.
DATA COLLECTION AND ANALYSIS: Study selection, data extraction, and risk of bias assessment were conducted independently by two authors. Dichotomous data (incidence of AAD, adverse events) were combined using a pooled risk ratio (RR) or risk difference (RD), and continuous data (mean duration of diarrhea) as mean difference (MD), along with corresponding 95% confidence interval (95% CI). We calculated the number needed to treat for an additional beneficial outcome (NNTB) where appropriate. For studies reporting on microbiome characteristics using heterogeneous outcomes, we describe the results narratively. The certainty of the evidence was evaluated using GRADE.
MAIN RESULTS: Thirty-three studies (6352 participants) were included. Probiotics assessed included Bacillus spp., Bifidobacterium spp., Clostridium butyricum, Lactobacilli spp., Lactococcus spp., Leuconostoc cremoris, Saccharomyces spp., orStreptococcus spp., alone or in combination. The risk of bias was determined to be high in 20 studies and low in 13 studies. Complete case (patients who did not complete the studies were not included in the analysis) results from 33 trials reporting on the incidence of diarrhea show a precise benefit from probiotics compared to active, placebo or no treatment control.After 5 days to 12 weeks of follow-up, the incidence of AAD in the probiotic group was 8% (259/3232) compared to 19% (598/3120) in the control group (RR 0.45, 95% CI 0.36 to 0.56; I² = 57%, 6352 participants; NNTB 9, 95% CI 7 to 13; moderate certainty evidence). Nineteen studies had loss to follow-up ranging from 1% to 46%. After making assumptions for those lost, the observed benefit was still statistically significant using an extreme plausible intention-to-treat (ITT) analysis, wherein the incidence of AAD in the probiotic group was 12% (436/3551) compared to 19% (664/3468) in the control group (7019 participants; RR 0.61; 95% CI 0.49 to 0.77; P <0.00001; I² = 70%). An a priori available case subgroup analysis exploring heterogeneity indicated that high dose (≥ 5 billion CFUs per day) is more effective than low probiotic dose (< 5 billion CFUs per day), interaction P value = 0.01. For the high dose studies the incidence of AAD in the probiotic group was 8% (162/2029) compared to 23% (462/2009) in the control group (4038 participants; RR 0.37; 95% CI 0.30 to 0.46; P = 0.06; moderate certainty evidence). For the low dose studies the incidence of AAD in the probiotic group was 8% (97/1155) compared to 13% (133/1059) in the control group (2214 participants; RR 0.68; 95% CI 0.46 to 1.01; P = 0.02). Again, assumptions for loss to follow-up using an extreme plausible ITT analysis was statistically significant. For high dose studies the incidence of AAD in the probiotic group was 13% (278/2218) compared to 23% (503/2207) in control group (4425 participants; RR 0.54; 95% CI 0.42 to 0.70; P <0.00001; I² = 68%; moderate certainty evidence).None of the 24 trials (4415 participants) that reported on adverse events reported any serious adverse events attributable to probiotics. Adverse event rates were low. After 5 days to 4 weeks follow-up, 4% (86/2229) of probiotics participants had an adverse event compared to 6% (121/2186) of control participants (RD 0.00; 95% CI -0.01 to 0.01; P < 0.00001; I² = 75%; low certainty evidence). Common adverse events included rash, nausea, gas, flatulence, abdominal bloating, and constipation.After 10 days to 12 weeks of follow-up, eight studies recorded data on our secondary outcome, the mean duration of diarrhea; with probiotics reducing diarrhea duration by almost one day (MD -0.91; 95% CI -1.38 to -0.44; P <0.00001; low certainty evidence). One study reported on microbiome characteristics, reporting no difference in changes with concurrent antibiotic and probiotic use.
AUTHORS' CONCLUSIONS: The overall evidence suggests a moderate protective effect of probiotics for preventing AAD (NNTB 9, 95% CI 7 to 13). Using five criteria to evaluate the credibility of the subgroup analysis on probiotic dose, the results indicate the subgroup effect based on high dose probiotics (≥ 5 billion CFUs per day) was credible. Based on high-dose probiotics, the NNTB to prevent one case of diarrhea is 6 (95% CI 5 to 9). The overall certainty of the evidence for the primary endpoint, incidence of AAD based on high dose probiotics was moderate due to the minor issues with risk of bias and inconsistency related to a diversity of probiotic agents used. Evidence also suggests that probiotics may moderately reduce the duration of diarrhea, a reduction by almost one day. The benefit of high dose probiotics (e.g. Lactobacillus rhamnosus orSaccharomyces boulardii) needs to be confirmed by a large well-designed multi-centered randomized trial. It is premature to draw firm conclusions about the efficacy and safety of 'other' probiotic agents as an adjunct to antibiotics in children. Adverse event rates were low and no serious adverse events were attributable to probiotics. Although no serious adverse events were observed among inpatient and outpatient children, including small studies conducted in the intensive care unit and in the neonatal unit, observational studies not included in this review have reported serious adverse events in severely debilitated or immuno-compromised children with underlying risk factors including central venous catheter use and disorders associated with bacterial/fungal translocation.

PMID 31039287
Jennifer A Applegate, Christa L Fischer Walker, Ramya Ambikapathi, Robert E Black
Systematic review of probiotics for the treatment of community-acquired acute diarrhea in children.
BMC Public Health. 2013;13 Suppl 3:S16. doi: 10.1186/1471-2458-13-S3-S16. Epub 2013 Sep 17.
Abstract/Text BACKGROUND: Oral rehydration salts (ORS), zinc, and continued feeding are the recommended treatments for community-acquired acute diarrhea among young children. However, probiotics are becoming increasingly popular treatments for diarrhea in some countries. We sought to estimate the effect of probiotics on diarrhea morbidity and mortality in children < 5 years of age.
METHODS: We conducted a systematic review of randomized controlled trials to estimate the effect of probiotic microorganisms for the treatment of community-acquired acute diarrhea in children. Data were abstracted into a standardized table and study quality was assessed using the Child Health Epidemiology Reference Group (CHERG) adaption of the GRADE technique. We measured the relative effect of probiotic treatment in addition to recommended rehydration on hospitalizations, duration and severity. We then calculated the average percent difference for all continuous outcomes and performed a meta-analysis for discrete outcomes.
RESULTS: We identified 8 studies for inclusion in the final database. No studies reported diarrhea mortality and overall the evidence was low to moderate quality. Probiotics reduced diarrhea duration by 14.0% (95% CI: 3.8-24.2%) and stool frequency on the second day of treatment by 13.1% (95% CI: 0.8 - 25.3%). There was no effect on the risk of diarrhea hospitalizations.
CONCLUSION: Probiotics may be efficacious in reducing diarrhea duration and stool frequency during a diarrhea episode. However, only few studies have been conducted in low-income countries and none used zinc (the current recommendation) thus additional research is needed to understand the effect of probiotics as adjunct therapy for diarrhea among children in developing countries.

PMID 24564646
Elaheh Ahmadi, Reza Alizadeh-Navaei, Mohammad Sadegh Rezai
Efficacy of probiotic use in acute rotavirus diarrhea in children: A systematic review and meta-analysis.
Caspian J Intern Med. 2015 Fall;6(4):187-95.
Abstract/Text BACKGROUND: Probiotic therapies with different strains demonstrated some beneficial effects, although some studies did not show any significant effects. This study assessed systematically the current knowledge on the effect of probiotic bacteria on duration of acute rotavirus diarrhea in children compared with control.
METHODS: The PubMed, Cochrane Controlled Trial Register (CCTR) and Ovid (Wolters Kluwer Health) were searched between 1980 to June 15, 2013. Randomized controlled trials including the administration of probiotics for treatment of rotavirus diarrhea in infants and children were reviewed.
RESULTS: A total number of 1244 articles were found through the aforementioned search. 203 articles were selected after the first screening of title and abstract. The intervention group included subjects who received probiotic strains and dosage in any conditions. Placebo or any similar vehicle without probiotic was used in the controlled trials. Finally, 14 articles were selected. The outcomes from each study were considered in the duration of diarrhea. Statistical analyses were performed with Stata software. The pooled estimate of efficacy of probiotics in prevention or treatment of disease yielded in all studies a mean difference of 0.41 (CI 95%: -0.56 to -0.25; p<0.001). The pooled estimate of efficacy of lactobacillus rhamnosus GG and other probiotics significantly reduced the duration of diarrhea. Among trials, the overall reduction of LGG was 0.47 (CI 95%: -0.80 to -0.14; P= 0.020).
CONCLUSION: In conclusion, probiotics exert positive effect in reducing the duration of acute rotavirus diarrhea compared with control.

PMID 26644891
Stephen B Freedman, Sarah Williamson-Urquhart, Ken J Farion, Serge Gouin, Andrew R Willan, Naveen Poonai, Katrina Hurley, Philip M Sherman, Yaron Finkelstein, Bonita E Lee, Xiao-Li Pang, Linda Chui, David Schnadower, Jianling Xie, Marc Gorelick, Suzanne Schuh, PERC PROGUT Trial Group
Multicenter Trial of a Combination Probiotic for Children with Gastroenteritis.
N Engl J Med. 2018 Nov 22;379(21):2015-2026. doi: 10.1056/NEJMoa1802597.
Abstract/Text BACKGROUND: Gastroenteritis accounts for approximately 1.7 million visits to the emergency department (ED) by children in the United States every year. Data to determine whether the use of probiotics improves outcomes in these children are lacking.
METHODS: We conducted a randomized, double-blind trial involving 886 children 3 to 48 months of age with gastroenteritis who presented to six pediatric EDs in Canada. Participants received a 5-day course of a combination probiotic product containing Lactobacillus rhamnosus R0011 and L. helveticus R0052, at a dose of 4.0×109 colony-forming units twice daily or placebo. The primary outcome was moderate-to-severe gastroenteritis, which was defined according to a post-enrollment modified Vesikari scale symptom score of 9 or higher (scores range from 0 to 20, with higher scores indicating more severe disease). Secondary outcomes included the duration of diarrhea and vomiting, the percentage of children who had unscheduled physician visits, and the presence or absence of adverse events.
RESULTS: Moderate-to-severe gastroenteritis within 14 days after enrollment occurred in 108 of 414 participants (26.1%) who were assigned to probiotics and 102 of 413 participants (24.7%) who were assigned to placebo (odds ratio, 1.06; 95% confidence interval [CI], 0.77 to 1.46; P=0.72). After adjustment for trial site, age, detection of rotavirus in stool, and frequency of diarrhea and vomiting before enrollment, trial-group assignment did not predict moderate-to-severe gastroenteritis (odds ratio, 1.06; 95% CI, 0.76 to 1.49; P=0.74). There were no significant differences between the probiotic group and the placebo group in the median duration of diarrhea (52.5 hours [interquartile range, 18.3 to 95.8] and 55.5 hours [interquartile range, 20.2 to 102.3], respectively; P=0.31) or vomiting (17.7 hours [interquartile range, 0 to 58.6] and 18.7 hours [interquartile range, 0 to 51.6], P=0.18), the percentages of participants with unscheduled visits to a health care provider (30.2% and 26.6%; odds ratio, 1.19; 95% CI, 0.87 to 1.62; P=0.27), and the percentage of participants who reported an adverse event (34.8% and 38.7%; odds ratio, 0.83; 95% CI, 0.62 to 1.11; P=0.21).
CONCLUSIONS: In children who presented to the emergency department with gastroenteritis, twice-daily administration of a combined L. rhamnosus-L. helveticus probiotic did not prevent the development of moderate-to-severe gastroenteritis within 14 days after enrollment. (Funded by the Canadian Institutes of Health Research and others; PROGUT ClinicalTrials.gov number, NCT01853124 .).

PMID 30462939
David Schnadower, Phillip I Tarr, T Charles Casper, Marc H Gorelick, J Michael Dean, Karen J O'Connell, Prashant Mahajan, Adam C Levine, Seema R Bhatt, Cindy G Roskind, Elizabeth C Powell, Alexander J Rogers, Cheryl Vance, Robert E Sapien, Cody S Olsen, Melissa Metheney, Viani P Dickey, Carla Hall-Moore, Stephen B Freedman
Lactobacillus rhamnosus GG versus Placebo for Acute Gastroenteritis in Children.
N Engl J Med. 2018 Nov 22;379(21):2002-2014. doi: 10.1056/NEJMoa1802598.
Abstract/Text BACKGROUND: Acute gastroenteritis develops in millions of children in the United States every year, and treatment with probiotics is common. However, data to support the use of probiotics in this population are limited.
METHODS: We conducted a prospective, randomized, double-blind trial involving children 3 months to 4 years of age with acute gastroenteritis who presented to one of 10 U.S. pediatric emergency departments. Participants received a 5-day course of Lactobacillus rhamnosus GG at a dose of 1×1010 colony-forming units twice daily or matching placebo. Follow-up surveys were conducted daily for 5 days and again 14 days after enrollment and 1 month after enrollment. The primary outcome was moderate-to-severe gastroenteritis, which was defined as an illness episode with a total score on the modified Vesikari scale of 9 or higher (scores range from 0 to 20, with higher scores indicating more severe disease), within 14 days after enrollment. Secondary outcomes included the duration and frequency of diarrhea and vomiting, the duration of day-care absenteeism, and the rate of household transmission (defined as the development of symptoms of gastroenteritis in previously asymptomatic household contacts).
RESULTS: Among the 971 participants, 943 (97.1%) completed the trial. The median age was 1.4 years (interquartile range, 0.9 to 2.3), and 513 participants (52.9%) were male. The modified Vesikari scale score for the 14-day period after enrollment was 9 or higher in 55 of 468 participants (11.8%) in the L. rhamnosus GG group and in 60 of 475 participants (12.6%) in the placebo group (relative risk, 0.96; 95% confidence interval, 0.68 to 1.35; P=0.83). There were no significant differences between the L. rhamnosus GG group and the placebo group in the duration of diarrhea (median, 49.7 hours in the L. rhamnosus GG group and 50.9 hours in the placebo group; P=0.26), duration of vomiting (median, 0 hours in both groups; P=0.17), or day-care absenteeism (median, 2 days in both groups; P=0.67) or in the rate of household transmission (10.6% and 14.1% in the two groups, respectively; P=0.16).
CONCLUSIONS: Among preschool children with acute gastroenteritis, those who received a 5-day course of L. rhamnosus GG did not have better outcomes than those who received placebo. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; ClinicalTrials.gov number, NCT01773967 .).

PMID 30462938
Abstract/Text OBJECTIVE: To systematically review the effectiveness of administering Lactobacillus rhamnosus GG (LGG) for preventing respiratory infections in children.
DESIGN: Systematic Review and Meta-analysis.
DATA SOURCES: Electronic databases and trial registries.
RESULTS: Four RCTs involving 1805 participants met the inclusion criteria. Compared with placebo, LGG administration was associated with a reduced incidence of acute otitis media (four RCTs, n=1805, RR 0.76, 95% CI 0.64-0.91, fixed effects model, NNT 17, 95% CI 11-46), a reduced risk of upper respiratory infections (one RCT, n=281, RR 0.62, 95% CI 0.50-0.78, NNT 4, 95% CI 3-8) and antibiotic treatments (four RCTs, n=1805, RR 0.80, 95% CI 0.71-0.91, fixed effects model). There was no significant difference between the LGG and the control groups in the risk of overall respiratory infections and the incidence of lower respiratory infections. However, subgroup analysis of two studies on children older than 1 year showed significant reduction in the risk of overall respiratory infections (two RCTs, n=794, RR 0.73, 95% CI 0.57-0.92, random effects model, NNT 8, 95% CI 5-14). Adverse effects were similar in both groups. No serious adverse events were reported.
CONCLUSION: The administration of Lactobacillus rhamnosus GG compared with placebo has the potential to reduce the incidence of acute otitis media, the upper respiratory infections and antibiotic use in children.

PMID 23665598
En-Jin Kang, Soo Young Kim, In-Hong Hwang, Yun-Jeong Ji
The effect of probiotics on prevention of common cold: a meta-analysis of randomized controlled trial studies.
Korean J Fam Med. 2013 Jan;34(1):2-10. doi: 10.4082/kjfm.2013.34.1.2. Epub 2013 Jan 28.
Abstract/Text BACKGROUND: Probiotics are currently under focus for their immune improvement function. Many studies have been performed to assess the potential efficacy of probiotics in allergic disease, viral disease, respiratory disease, as well as gastrointestinal disease. This study performed a systematic review to determine the effects of probiotics on the prevention of the common cold.
METHODS: We searched MEDLINE (PubMed), EMBASE, CINAHL, and Cochrane CENTRAL for studies released through June 2011. Two authors independently extracted the data. To assess the risk of bias of included literatures, Cochrane Collaboration's risk of bias tool was used.
RESULTS: We identified 10 studies in 7 articles. A total 2,894 participants, 1,588 in the probiotics group and 1,306 in the control group, were included. The effect of probiotics on the prevention of the common cold had a relative risk (RR) of 0.92 (95% CI, 0.85 to 1.00, I(2) = 26%). In the subgroup analysis, the RR of administration of probiotics for 3 months or less was 0.82 (95% CI, 0.70 to 0.97). The RR of administration of probiotics over 3 months was 1.00 (95% CI, 0.92 to 1.09). The RR of administration of probiotics without any active intervention (vitamin and mineral) was 0.87 (95% CI, 0.78 to 0.97).
CONCLUSION: In this meta-analysis, there was marginal effect of probiotics on the prevention of the common cold. The results implied that probiotics had a modest effect in common cold reduction. The balance of benefit and harms needs to be considered when using probiotics for common cold prevention.

PMID 23372900
Sarah King, Julie Glanville, Mary Ellen Sanders, Anita Fitzgerald, Danielle Varley
Effectiveness of probiotics on the duration of illness in healthy children and adults who develop common acute respiratory infectious conditions: a systematic review and meta-analysis.
Br J Nutr. 2014 Jul 14;112(1):41-54. doi: 10.1017/S0007114514000075. Epub 2014 Apr 29.
Abstract/Text Recent systematic reviews have reported a positive, although modest, effect of probiotics in terms of preventing common cold symptoms. In this systematic review, the effect of probiotics, specifically Lactobacillus and Bifidobacterium strains, on the duration of acute respiratory infections in otherwise healthy children and adults was evaluated. To identify relevant trials, eight databases, including MEDLINE, Embase, the Cochrane Database of Systematic Reviews (CDSR), the Cochrane Central Register of Controlled Trials (CENTRAL), the Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment (HTA), Science Citation Index (SCI) and OAISTER, were searched from inception to 20 July 2012. Details regarding unpublished studies/databases were also obtained from probiotic manufacturers. Study selection, data extraction and quality assessment were carried out by two reviewers. Risk of bias was assessed using criteria adapted from those published by the Centre for Reviews and Dissemination. In this review, twenty randomised controlled trials (RCT) were included, of which twelve were considered to have a low risk of bias. Meta-analysis revealed significantly fewer numbers of days of illness per person (standardised mean difference (SMD) - 0·31 (95% CI - 0·41, - 0·11), I²= 3%), shorter illness episodes by almost a day (weighted mean difference - 0·77 (95% CI - 1·50, - 0·04), I²= 80%) (without an increase in the number of illness episodes), and fewer numbers of days absent from day care/school/work (SMD - 0·17 (95% CI - 0·31, - 0·03), I²= 67%) in participants who received a probiotic intervention than in those who had taken a placebo. Reasons for heterogeneity between the studies were explored in subgroup analysis, but could not be explained, suggesting that the effect sizes found may differ between the population groups. This systematic review provides evidence from a number of good-quality RCT that probiotics reduce the duration of illness in otherwise healthy children and adults.

PMID 24780623
I E Emre, Y Eroğlu, A Kara, E C Dinleyici, M Özen
The effect of probiotics on prevention of upper respiratory tract infections in the paediatric community - a systematic review.
Benef Microbes. 2020 May 11;11(3):201-211. doi: 10.3920/BM2019.0119. Epub 2020 Apr 21.
Abstract/Text Prevention of acute upper respiratory tract infections (URTIs) is becoming an increasingly important concept in public health application due to the increase in antibiotic resistance. Probiotics have been shown to have some effect on prevention in various reviews. In this study we aimed to re-asses the effect of probiotics as there has been a substantial increase in literature regarding the effects and safety of probiotics in the paediatric population. Two major databases were systematically searched to identify clinical trials eligible for inclusion. Study selection, data extraction and quality assessment were carried out by two reviewers. This review comprises 33 randomised controlled trials (RCTs) applied to a paediatric population with high-quality methodology. The primary outcome for this review was the incidence of respiratory tract infections. Secondary outcomes were severity of symptoms, missed days of school, incidence of antibiotic use and safety of prebiotic use. This review showed that probiotics have an impact on decreasing the incidence of URTIs and the severity of symptoms. The use of probiotics is extremely safe and as studies increase in evaluation of the effect of probiotics more and more show a significant beneficiary effect. Although still a long way from becoming a unanimous treatment modality, the small positive changes that probiotics have on URTIs is important to consider and the use of probiotics should be encouraged more.

PMID 32314937
Maja Strauss, Dušanka Mičetić-Turk, Maja Šikić Pogačar, Sabina Fijan
Probiotics for the Prevention of Acute Respiratory-Tract Infections in Older People: Systematic Review.
Healthcare (Basel). 2021 Jun 7;9(6). doi: 10.3390/healthcare9060690. Epub 2021 Jun 7.
Abstract/Text The aim of this systematic review was to present the indirect influence of probiotics on the incidence and duration of acute upper respiratory-tract infections in older people, by regulating the immune system. Eight randomized, placebo-controlled clinical trials met the inclusion criteria, considering the threshold of older people being 60 years and over. Single strain probiotics were used in all studies, including three probiotic strains used in fermented foods: Lactobacillus delbrueckii subsp. bulgaricus OLL1073R-1, Lacticaseibacillus paracasei subsp. paracasei CNCM I-1518 and Lacticaseibacillusparacasei Shirota, and three probiotic strains used as food supplements: Loigolactobacillus coryniformis K8 CECT5711, Bacillus subtilis CU1 and Lacticaseibacillus rhamnosus GG. Current evidence showed that certain probiotic strains were better than a placebo in lowering the incidence or number of older people experiencing acute upper respiratory tract infections; however, not all probiotic strains were efficient, and not all studies reported statistically significant outcomes. More high quality large-scale properly controlled clinical studies focusing on older people are warranted.

PMID 34200435

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