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Pine bark (Pinus spp.) extract for treating chronic disorders.
Robertson, NU, Schoonees, A, Brand, A, Visser, J
The Cochrane database of systematic reviews. 2020;(9):CD008294
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Abstract
BACKGROUND Pine bark (Pinus spp.) extract is rich in bioflavonoids, predominantly proanthocyanidins, which are antioxidants. Commercially-available extract supplements are marketed for preventing or treating various chronic conditions associated with oxidative stress. This is an update of a previously published review. OBJECTIVES To assess the efficacy and safety of pine bark extract supplements for treating chronic disorders. SEARCH METHODS We searched three databases and three trial registries; latest search: 30 September 2019. We contacted the manufacturers of pine bark extracts to identify additional studies and hand-searched bibliographies of included studies. SELECTION CRITERIA Randomised controlled trials (RCTs) evaluating pine bark extract supplements in adults or children with any chronic disorder. DATA COLLECTION AND ANALYSIS Two authors independently assessed trial eligibility, extracted data and assessed risk of bias. Where possible, we pooled data in meta-analyses. We used GRADE to evaluate the certainty of evidence. Primary outcomes were participant- and investigator-reported clinical outcomes directly related to each disorder and all-cause mortality. We also assessed adverse events and biomarkers of oxidative stress. MAIN RESULTS This review included 27 RCTs (22 parallel and five cross-over designs; 1641 participants) evaluating pine bark extract supplements across 10 chronic disorders: asthma (two studies; 86 participants); attention deficit hyperactivity disorder (ADHD) (one study; 61 participants), cardiovascular disease (CVD) and risk factors (seven studies; 338 participants), chronic venous insufficiency (CVI) (two studies; 60 participants), diabetes mellitus (DM) (six studies; 339 participants), erectile dysfunction (three studies; 277 participants), female sexual dysfunction (one study; 83 participants), osteoarthritis (three studies; 293 participants), osteopenia (one study; 44 participants) and traumatic brain injury (one study; 60 participants). Two studies exclusively recruited children; the remainder recruited adults. Trials lasted between four weeks and six months. Placebo was the control in 24 studies. Overall risk of bias was low for four, high for one and unclear for 22 studies. In adults with asthma, we do not know whether pine bark extract increases change in forced expiratory volume in one second (FEV1) % predicted/forced vital capacity (FVC) (mean difference (MD) 7.70, 95% confidence interval (CI) 3.19 to 12.21; one study; 44 participants; very low-certainty evidence), increases change in FEV1 % predicted (MD 7.00, 95% CI 0.10 to 13.90; one study; 44 participants; very low-certainty evidence), improves asthma symptoms (risk ratio (RR) 1.85, 95% CI 1.32 to 2.58; one study; 60 participants; very low-certainty evidence) or increases the number of people able to stop using albuterol inhalers (RR 6.00, 95% CI 1.97 to 18.25; one study; 60 participants; very low-certainty evidence). In children with ADHD, we do not know whether pine bark extract decreases inattention and hyperactivity assessed by parent- and teacher-rating scales (narrative synthesis; one study; 57 participants; very low-certainty evidence) or increases the change in visual-motoric coordination and concentration (MD 3.37, 95% CI 2.41 to 4.33; one study; 57 participants; very low-certainty evidence). In participants with CVD, we do not know whether pine bark extract decreases diastolic blood pressure (MD -3.00 mm Hg, 95% CI -4.51 to -1.49; one study; 61 participants; very low-certainty evidence); increases HDL cholesterol (MD 0.05 mmol/L, 95% CI -0.01 to 0.11; one study; 61 participants; very low-certainty evidence) or decreases LDL cholesterol (MD -0.03 mmol/L, 95% CI -0.05 to 0.00; one study; 61 participants; very low-certainty evidence). In participants with CVI, we do not know whether pine bark extract decreases pain scores (MD -0.59, 95% CI -1.02 to -0.16; one study; 40 participants; very low-certainty evidence), increases the disappearance of pain (RR 25.0, 95% CI 1.58 to 395.48; one study; 40 participants; very low-certainty evidence) or increases physician-judged treatment efficacy (RR 4.75, 95% CI 1.97 to 11.48; 1 study; 40 participants; very low-certainty evidence). In type 2 DM, we do not know whether pine bark extract leads to a greater reduction in fasting blood glucose (MD 1.0 mmol/L, 95% CI 0.91 to 1.09; one study; 48 participants;very low-certainty evidence) or decreases HbA1c (MD -0.90 %, 95% CI -1.78 to -0.02; 1 study; 48 participants; very low-certainty evidence). In a mixed group of participants with type 1 and type 2 DM we do not know whether pine bark extract decreases HbA1c (MD -0.20 %, 95% CI -1.83 to 1.43; one study; 67 participants; very low-certainty evidence). In men with erectile dysfunction, we do not know whether pine bark extract supplements increase International Index of Erectile Function-5 scores (not pooled; two studies; 147 participants; very low-certainty evidence). In women with sexual dysfunction, we do not know whether pine bark extract increases satisfaction as measured by the Female Sexual Function Index (MD 5.10, 95% CI 3.49 to 6.71; one study; 75 participants; very low-certainty evidence) or leads to a greater reduction of pain scores (MD 4.30, 95% CI 2.69 to 5.91; one study; 75 participants; very low-certainty evidence). In adults with osteoarthritis of the knee, we do not know whether pine bark extract decreases composite Western Ontario and McMaster Universities Osteoarthritis Index scores (MD -730.00, 95% CI -1011.95 to -448.05; one study; 37 participants; very low-certainty evidence) or the use of non-steroidal anti-inflammatory medication (MD -18.30, 95% CI -25.14 to -11.46; one study; 35 participants; very low-certainty evidence). We do not know whether pine bark extract increases bone alkaline phosphatase in post-menopausal women with osteopenia (MD 1.16 ug/L, 95% CI -2.37 to 4.69; one study; 40 participants; very low-certainty evidence). In individuals with traumatic brain injury, we do not know whether pine bark extract decreases cognitive failure scores (MD -2.24, 95% CI -11.17 to 6.69; one study; 56 participants; very low-certainty evidence) or post-concussion symptoms (MD -0.76, 95% CI -5.39 to 3.87; one study; 56 participants; very low-certainty evidence). For most comparisons, studies did not report outcomes of hospital admissions or serious adverse events. AUTHORS' CONCLUSIONS Small sample sizes, limited numbers of RCTs per condition, variation in outcome measures, and poor reporting of the included RCTs mean no definitive conclusions regarding the efficacy or safety of pine bark extract supplements are possible.
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A Greater Flavonoid Intake Is Associated with Lower Total and Cause-Specific Mortality: A Meta-Analysis of Cohort Studies.
Mazidi, M, Katsiki, N, Banach, M
Nutrients. 2020;(8)
Abstract
Introduction: The links between flavonoid intake and mortality were previously evaluated in epidemiological studies. The aim of the present study was to perform a systematic review and meta-analysis of cohort studies evaluating the link of flavonoid consumption with total and cause-specific mortality. Methods: Prospective cohort studies reporting flavonoid intake and mortality data published up to 30th April 2019 (without language restriction) were searched using PubMed, Scopus and EMBASE database. Generic inverse variance methods and random effects models were used to synthesize pooled and quantitative data. Sensitivity analysis was also performed by a leave-one-out method. Results: Overall, 16 articles met the inclusion criteria (nine studies were performed in Europe, five in the USA, one in Asia and one in Oceania); a total of 462,194 participants (all adults aged >19 years) with 23,473 mortality cases were included in the final analysis. The duration of follow-up ranged from 4.8 to 28 years. Most of the studies assessed flavonoid intake using food frequency questionnaires, whereas four studies used interviews and 1 study used 4-day food records. The meta-analysis showed that flavonoid consumption was inversely and significantly associated with total (relative risk (RR): 0.87, 95% confidence interval (CI) = 0.77-0.99) and cardiovascular disease mortality risk (RR: 0.85, 95%CI = 0.75-0.97), but not cancer (0.86, 95%CI = 0.65-1.14) mortality risk. These findings remained robust in sensitivity analyses. Conclusions: The present findings highlight the potential protective role of flavonoids against total and cause-specific mortality. These results support the recommendations for flavonoid-rich foods intake to prevent chronic diseases.
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Dietary intakes of flavan-3-ols and cardiometabolic health: systematic review and meta-analysis of randomized trials and prospective cohort studies.
Raman, G, Avendano, EE, Chen, S, Wang, J, Matson, J, Gayer, B, Novotny, JA, Cassidy, A
The American journal of clinical nutrition. 2019;(5):1067-1078
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Abstract
BACKGROUND Although available data suggest that some dietary flavan-3-ol sources reduce cardiometabolic risk, to our knowledge no review has systematically synthesized their specific contribution. OBJECTIVE We aimed to examine, for the first time, if there is consistent evidence that higher flavan-3-ol intake, irrespective of dietary source, reduces cardiometabolic risk. METHODS MEDLINE, Cochrane Central, and Commonwealth Agricultural Bureau abstracts were searched for prospective cohorts and randomized controlled trials (RCTs) published from 1946 to March 2019 on flavan-3-ol intake and cardiovascular disease (CVD) risk. Random-effects models meta-analysis was used. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach assessed the strength of evidence. RESULTS Of 15 prospective cohorts (23 publications), 4 found highest compared with lowest habitual intakes of flavan-3-ols were associated with a 13% reduction in risk of CVD mortality and 2 found a 19% reduction in risk of chronic heart disease (CHD) incidence. Highest compared with lowest habitual intakes of monomers were associated with a reduction in risk of type 2 diabetes mellitus (T2DM) (n = 5) and stroke (n = 4) (10% and 18%, respectively). No association was found for hypertension. Of 156 RCTs, flavan-3-ol intervention resulted in significant improvements in acute/chronic flow-mediated dilation (FMD), systolic (SBP) and diastolic blood pressure (DBP), total cholesterol (TC), LDL and HDL cholesterol, triglycerides (TGs), hemoglobin A1c (HbA1c), and homeostasis model assessment of insulin resistance (HOMA-IR). All analyses, except HbA1c, were associated with moderate/high heterogeneity. When analyses were limited to good methodological quality studies, improvements in TC, HDL cholesterol, SBP, DBP, HOMA-IR, and acute/chronic FMD remained significant. In GRADE evaluations, there was moderate evidence in cohort studies that flavan-3-ol and monomer intakes were associated with reduced risk of CVD mortality, CHD, stroke, and T2DM, whereas RCTs reported improved TC, HDL cholesterol, SBP, and HOMA-IR. CONCLUSIONS Available evidence supports a beneficial effect of flavan-3-ol intake on cardiometabolic outcomes, but there was considerable heterogeneity in the meta-analysis. Future research should focus on an integrated intake/biomarker approach in cohorts and high-quality dose-response RCTs. This review was registered at www.crd.york.ac.uk/PROSPERO/ as CRD42018035782.
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Flavonoids intake and risk of type 2 diabetes mellitus: A meta-analysis of prospective cohort studies.
Xu, H, Luo, J, Huang, J, Wen, Q
Medicine. 2018;(19):e0686
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Epidemiological studies exploring the role of flavonoids intake in preventing type 2 diabetes mellitus (T2DM) showed inconsistent results. Therefore, we performed a meta-analysis of relevant studies to examine the relationship between flavonoids intake and risk of T2DM. We hypothesized that flavonoids intake may decrease the risk of developing T2DM.A systematical search in PubMed and Embase until September 2017 was performed to identify eligible prospective cohort studies. The summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated using random-effect models. Dose-response pattern between total flavonoids intake and T2DM risk was also estimated.Eight prospective studies were included with 312,015 participants, of whom 19,953 developed T2DM during the follow-up periods of 4 to 28 years. Compared with lower consumption, high intake of total flavonoids was associated with a decreased risk of T2DM (RR: 0.89, 95% CI: 0.82-0.96). Among flavonoid subclasses, inverse correlations with T2DM were achieved for intakes of anthocyanidins, flavan-3-ols, flavonols, and isoflavones. Dose-response meta-analysis indicated a curvilinear relationship between total flavonoids intake and incident T2DM (P for nonlinearity = .042), with a significant risk reduction at an intake of ≥550 mg/day. When assuming a linear pattern, the risk of T2DM was decreased by 5% for each 300-mg/day increment in total flavonoids intake (RR: 0.95, 95% CI: 0.93-0.97).Our study suggests that higher intakes of total flavonoids and subclasses (anthocyanidins, flavan-3-ols, flavonols, and isoflavones) are associated with lower risk of T2DM.
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Dietary Flavonoids and the Risk of Colorectal Cancer: An Updated Meta-Analysis of Epidemiological Studies.
Chang, H, Lei, L, Zhou, Y, Ye, F, Zhao, G
Nutrients. 2018;(7)
Abstract
Aim: The aim of this study was to perform an up-to-date meta-analysis of the association between the intake of dietary flavonoids and the risk of colorectal cancer. Methods: The PubMed and EMBASE databases were searched to identify eligible studies. The risk of colorectal cancer for the highest versus the lowest categories of flavonoids intake were assessed. Results: A total of 12 studies (5 cohort and 7 case-control studies) involving 17,481 cases and 740,859 controls were eligible for meta-analysis. High intake of dietary flavonols, flavones and anthocyanidins may decrease the risk of colorectal cancer; the pooled odds ratio (OR) for the highest intake compared with the lowest was 0.70 (0.54⁻0.90), 0.79 (0.83⁻0.99) and 0.78 (0.64⁻0.95), respectively. No association between the intake of total flavonoids, flavanones or flavan-3-ols and the risk of colorectal cancer was observed. Furthermore, the data showed that high intake of flavonols may decrease the risk of colon cancer [0.80 (0.68⁻0.94)] but not rectal cancer [0.93 (0.74⁻1.18)], while on the contrary, the intake of flavones may decrease rectal cancer risk [0.82 (0.70⁻0.97)] but not colon cancer risk [0.88 (0.69⁻1.13)]. Conclusions: The present study suggested that high intake of flavonols (such as quercetin) may reduce the risk of colon cancer, and high intake of flavones (such as apigenin) may reduce the risk of rectal cancer.
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Flavonoids, Flavonoid Subclasses, and Esophageal Cancer Risk: A Meta-Analysis of Epidemiologic Studies.
Cui, L, Liu, X, Tian, Y, Xie, C, Li, Q, Cui, H, Sun, C
Nutrients. 2016;(6)
Abstract
Flavonoids have been suggested to play a chemopreventive role in carcinogenesis. However, the epidemiologic studies assessing dietary intake of flavonoids and esophageal cancer risk have yielded inconsistent results. This study was designed to examine the association between flavonoids, each flavonoid subclass, and the risk of esophageal cancer with a meta-analysis approach. We searched for all relevant studies with a prospective cohort or case-control study design published from January 1990 to April 2016, using PUBMED, EMBASE, and Web of Science. Pooled odds ratios (ORs) were calculated using fixed or random-effect models. In total, seven articles including 2629 cases and 481,193 non-cases were selected for the meta-analysis. Comparing the highest-intake patients with the lowest-intake patients for total flavonoids and for each flavonoid subclass, we found that anthocyanidins (OR = 0.60, 95% CI: 0.49-0.74), flavanones (OR = 0.65, 95% CI: 0.49-0.86), and flavones (OR = 0.78, 95% CI 0.64-0.95) were inversely associated with the risk of esophageal cancer. However, total flavonoids showed marginal association with esophageal cancer risk (OR = 0.78, 95% CI: 0.59-1.04). In conclusion, our study suggested that dietary intake of total flavonoids, anthocyanidins, flavanones, and flavones might reduce the risk of esophageal cancer.
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Dietary flavonoid intake and the risk of digestive tract cancers: a systematic review and meta-analysis.
Bo, Y, Sun, J, Wang, M, Ding, J, Lu, Q, Yuan, L
Scientific reports. 2016;:24836
Abstract
Several epidemiological studies have investigated the association between dietary flavonoid intake and digestive tract cancers risk; however, the results remain inconclusive. The aim of our study was to evaluate this association. PubMed and the Web of Knowledge were searched for relevant publications from inception to October 2015. The risk ratio (RR) or odds ratio (OR) with the 95% confidence interval (95% CI) for the highest versus the lowest categories of flavonoid intake were pooled using a fixed-effects model. A total of 15 articles reporting 23 studies were selected for the meta-analysis. In a comparison of the highest versus the lowest categories of dietary flavonoid intake, we found no significant association between flavonoid intake and oesophageal cancer (OR = 0.91, 95% CI = 0.75-1.10; I(2) = 0.0%), colorectal cancer (OR = 1.02, 95% CI = 0.92-1.14, I(2) = 36.2%) or gastric cancer (OR = 0.88; 95% CI = 0.74-1.04, I(2) = 63.6%). The subgroup analysis indicated an association between higher flavonoid intake and a decreased risk of gastric cancer in the European population (OR = 0.78, 95% CI = 0.62-0.97). In conclusion, the results of this meta-analysis do not strongly support an association between dietary flavonoid intake and oesophageal or colorectal cancer. Furthermore, the subgroup analysis suggested an association between higher dietary flavonoid intake and decreased gastric cancer risk in European population.
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Dietary flavonoid intake and the risk of stroke: a dose-response meta-analysis of prospective cohort studies.
Tang, Z, Li, M, Zhang, X, Hou, W
BMJ open. 2016;(6):e008680
Abstract
OBJECTIVE To clarify and quantify the potential association between intake of flavonoids and risk of stroke. DESIGN Meta-analysis of prospective cohort studies. DATA SOURCE Studies published before January 2016 identified through electronic searches using PubMed, Embase and the Cochrane Library. ELIGIBILITY CRITERIA FOR SELECTING STUDIES Prospective cohort studies with relative risks and 95% CIs for stroke according to intake of flavonoids (assessed as dietary intake). RESULTS The meta-analysis yielded 11 prospective cohort studies involving 356 627 participants and more than 5154 stroke cases. The pooled estimate of the multivariate relative risk of stroke for the highest compared with the lowest dietary flavonoid intake was 0.89 (95% CI 0.82 to 0.97; p=0.006). Dose-response analysis indicated that the summary relative risk of stroke for an increase of 100 mg flavonoids consumed per day was 0.91 (95% CI 0.77 to 1.08) without heterogeneity among studies (I(2)=0%). Stratifying by follow-up duration, the relative risk of stroke for flavonoid intake was 0.89 (95% CI 0.81 to 0.99) in studies with more than 10 years of follow-up. CONCLUSIONS Results from this meta-analysis suggest that higher dietary flavonoid intake may moderately lower the risk of stroke.
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Dietary flavonoid intake and weight maintenance: three prospective cohorts of 124,086 US men and women followed for up to 24 years.
Bertoia, ML, Rimm, EB, Mukamal, KJ, Hu, FB, Willett, WC, Cassidy, A
BMJ (Clinical research ed.). 2016;:i17
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Abstract
OBJECTIVE To examine whether dietary intake of specific flavonoid subclasses (including flavonols, flavones, flavanones, flavan-3-ols, anthocyanins, and flavonoid polymers) is associated with weight change over time. DESIGN Three prospective cohort studies. SETTING Health professionals in the United States. PARTICIPANTS 124,086 men and women participating in the Health Professionals Follow-up Study (HPFS), Nurses' Health Study (NHS), and Nurses' Health Study II (NHS II). MAIN OUTCOME MEASURE Self reported change in weight over multiple four year time intervals between 1986 and 2011. RESULTS Increased consumption of most flavonoid subclasses, including flavonols, flavan-3-ols, anthocyanins, and flavonoid polymers, was inversely associated with weight change over four year time intervals, after adjustment for simultaneous changes in other lifestyle factors including other aspects of diet, smoking status, and physical activity. In the pooled results, the greatest magnitude of association was observed for anthocyanins (-0.23 (95% confidence interval -0.30 to -0.15) lbs per additional standard deviation/day, 10 mg), flavonoid polymers (-0.18 (-0.28 to -0.08) lbs per additional SD/day, 138 mg), and flavonols (-0.16 (-0.26 to -0.06) lbs per additional SD/day, 7 mg). After additional adjustment for fiber intake, associations remained significant for anthocyanins, proanthocyanidins, and total flavonoid polymers but were attenuated and no longer statistically significant for other subclasses. CONCLUSIONS Higher intake of foods rich in flavonols, flavan-3-ols, anthocyanins, and flavonoid polymers may contribute to weight maintenance in adulthood and may help to refine dietary recommendations for the prevention of obesity and its potential consequences.
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Combined therapy of diabetic peripheral neuropathy with breviscapine and mecobalamin: a systematic review and a meta-analysis of Chinese studies.
Zheng, C, Ou, W, Shen, H, Zhou, Z, Wang, J
BioMed research international. 2015;:680756
Abstract
OBJECTIVE A meta-analysis on combined therapy of diabetic peripheral neuropathy (DPN) with breviscapine and mecobalamin was performed to evaluate the efficacy of this therapy. METHODS Six English databases (Medline, Cochrane Library, PubMed, EMBASE, Web of Science, and CINAHL) and four Chinese databases (China National Knowledge Infrastructure, VIP Journals Database, CBM, and Wanfang database) were searched for studies on the clinical trials in which DPN was treated with breviscapine and mecobalamin, and RevMan 5.1 package was employed for analyzing pooled trials and publication bias. RESULTS A total of 17 articles including 1398 DPN patients were identified. Homogeneity was observed among different studies (P = 0.74). The efficacy of combined therapy with breviscapine and mecobalamin was significantly better than that in control group [P < 0.0001 (OR = 5.01, 95% CI: 3.70-6.78)]. CONCLUSION Available findings suggest that the therapeutic efficacy of breviscapine combining mecobalamin is superior to mecobalamin alone, and this strategy is required to be popularized in clinical practice.