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Safety and tolerability of a natural supplement containing glucosinolates, phytosterols and citrus flavonoids in adult women: a randomized phase I, placebo-controlled, multi-arm, double-blinded clinical trial.
Villar-López, M, Soto-Becerra, P, Curse Choque, R, Al-Kassab-Córdova, A, Bernuy-Barrera, F, Palomino, H, Rojas, PA, Vera, C, Lugo-Martínez, G, Mezones-Holguín, E
Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology. 2021;(10):906-913
Abstract
OBJECTIVE To evaluate the safety and tolerability of an oral herbal supplement containing glucosinolates, phytosterols, and citrus flavonoids (Warmi®, Lima Perú;) in otherwise healthy adult women. METHODS This was a phase-I, randomized parallel three arms, double-blinded, and a placebo-controlled clinical trial. A total of 55 participants aged 18-40 were randomly assigned to one of three groups to receive for three months: (1) an oral herbal supplement of 1650 mg/day; (2) an oral herbal supplement of 3300 mg/day; or (3) an oral placebo 3300 mg/day. The primary endpoints were oral safety and tolerability of the supplement. The secondary endpoint was its effect on vital functions, anthropometrics, and laboratory tests. We used an exploratory approach by covariance analysis (ANCOVA) adjusted for the variables' baseline value for the secondary outcomes. RESULTS All women completed three months of follow-up, reporting no side effects. Our exploratory analysis revealed that treatment with the herbal supplement of 1650 mg/day was associated with increased glucose and uric acid levels. In comparison, the herbal supplement 3300 mg/day was associated with reduced breathing rate, increased basal temperature, and systolic blood pressure, both compared to the placebo group. However, despite significant differences, none of these was clinically significant. CONCLUSION The oral herbal supplement had a favorable safety and tolerability profile in studied women. There is a need to study its potential as an option to treat menopausal symptoms.
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The COFU3 Study. Improvement in cognitive function, attention, mental performance with Pycnogenol® in healthy subjects (55-70) with high oxidative stress.
Belcaro, G, Dugall, M, Ippolito, E, Hu, S, Saggino, A, Feragalli, B
Journal of neurosurgical sciences. 2015;(4):437-46
Abstract
AIM: This 12-month product registry study evaluated the effects of supplementation with French pine bark extract (Pycnogenol(®)) on cognitive function, attention, and mental performance in healthy subjects with high oxidative stress. METHODS Healthy subjects (age range 55-70) were screened - within a cardiovascular screening program - for oxidative stress. Out of 150 subjects, high oxidative stress was present in 44; the use of the supplement Pycnogenol(®) was suggested (100 mg/day). These subjects decided to use Pycnogenol(®) and accepted to be evaluated by assessing cognitive functions. A group of subjects with comparable oxidative stress was followed as a reference. IQ Code (Informant Questionnaire on Cognitive Decline in the Elderly), daily tasks, cognitive function, oxidative stress and the short Blessed tests (SBT) were used (in defined scales) to evaluate cognitive functions (COFU). RESULTS As for the IQ Code, at 12 months there was a significantlty total lower score in Pycnogenol(®) patients and also a lower value (P<0.05) for 14 out of 16 items in the questionnaire. Daily tasks: all items were improved (P<0.05) with supplementation in comparison with controls. The improvement was seen for all 12 items (P<0.05) with the supplement. Cognitive function values (visual scale line) indicated a significant improvement (P<0.05) in all elements present in the questionnaire with the 12-month supplementation (no significant variations in controls). Oxidative stress was comparable in both groups at inclusion. It was significantly decreased with Pycnogenol(®) (-28.07%; P<0.05) at 12 months; there was no decrease in controls. The short blessed test (SBT) value was significantly increased in controls (P<0.05); but significantly decreased in the Pycnogenol(®) group (P<0.05). Values for supplemented patients at 12 months were almost within the normal range (21 out or 38 were below the normal value of 4). Tolerability and compliance for Pycnogenol(®) were optimal with >97% of the doses of the supplement correctly used. No side effects were observed, recorded or described. CONCLUSION Pycnogenol(®) supplementation for 12 months appears to improve cognitive function and oxidative stress in normal subjects between 55 and 70 years of age.
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Pycnogenol® improves cognitive function, attention, mental performance and specific professional skills in healthy professionals aged 35-55.
Belcaro, G, Luzzi, R, Dugall, M, Ippolito, E, Saggino, A
Journal of neurosurgical sciences. 2014;(4):239-48
Abstract
AIM: This 12-week, product-evaluation registry study aimed to compare the effects of supplementation with French Pine Bark Extract (Pycnogenol®) on cognitive function, attention, and mental performance in healthy professionals with increased oxidative stress in a professional context. METHODS Professionals were screened for increased oxidative stress: 60 subjects (range 35-55 years, no risk conditions, no addictions) voluntarily decided to be followed-up. Diet, alcohol and lifestyle patterns, including exercise, were controlled. Pycnogenol® (150 mg/day) was used in combination with a health plan to enhance mental performance and control oxidative stress. RESULTS A group of 30 professionals used Pycnogenol®, and 29 acted as comparable controls for a period of 12 weeks. The two registry groups were comparable. Cognitive function, attention, mental performance, sustained attention, memory, executive functions, mood and oxidative stress values were comparable at inclusion. At 12 weeks the improvement in Pycnogenol® subjects was more significant than in controls. Plasma-free radicals (oxidative stress) were significantly decreased (median -30.4%) at 12 weeks in Pycnogenol® subjects in comparison with a non-significant variation observed in controls (+0.9%; difference between groups). Considering the cognitive test battery (PASAT, pattern recognition memory, spatial recognition memory, spatial working memory), Pycnogenol® subjects showed a small but significant improvement with spatial recognition memory unchanged. Mood parameters (alertness, anxiety, contentedness) also improved in professionals using the supplement. In the evaluation of 12 professional daily tasks all items were improved with Pycnogenol® supplementation. The score relative to semi-professional minitasks was improved more in Pycnogenol® subjects. Tolerability and compliance were optimal with >94% of the doses of supplement correctly used. CONCLUSION Pycnogenol® supplementation for 12 weeks appears to improve cognitive function and oxidative stress in healthy professionals.
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Clinical assessment of a supplement of Pycnogenol® and L-arginine in Japanese patients with mild to moderate erectile dysfunction.
Aoki, H, Nagao, J, Ueda, T, Strong, JM, Schonlau, F, Yu-Jing, S, Lu, Y, Horie, S
Phytotherapy research : PTR. 2012;(2):204-7
Abstract
A double-blind parallel group comparison design clinical study was conducted in Japanese patients with mild to moderate erectile dysfunction to investigate the efficacy of a supplement containing Pycnogenol® and L-arginine. Subjects were instructed to take a supplement (Pycnogenol® 60 mg/day, L-arginine 690 mg/day and aspartic acid 552 mg/day) or an identical placebo for 8 weeks, and the results were assessed using the five-item erectile domain (IIEF-5) of the International Index of Erectile Function. Additionally, blood biochemistry, urinalysis and salivary testosterone were measured. Eight weeks of supplement intake improved the total score of the IIEF-5. In particular, a marked improvement was observed in 'hardness of erection' and 'satisfaction with sexual intercourse'. A decrease in blood pressure, aspartate transaminase and γ-glutamyl transpeptidase (γ-GTP), and a slight increase in salivary testosterone were observed in the supplement group. No adverse reactions were observed during the study period. In conclusion, Pycnogenol® in combination with L-arginine as a dietary supplement is effective and safe in Japanese patients with mild to moderate erectile dysfunction.
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Dietary flavonoids and risk of stroke in women.
Cassidy, A, Rimm, EB, O'Reilly, EJ, Logroscino, G, Kay, C, Chiuve, SE, Rexrode, KM
Stroke. 2012;(4):946-51
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Abstract
BACKGROUND AND PURPOSE To date, few studies have examined associations between the wide range of flavonoid subclasses and risk of ischemic, hemorrhagic, and total stroke. METHODS We conducted a prospective study among 69 622 women from the Nurses' Health Study. Total flavonoid and subclass intakes were calculated from semiquantitative food frequency questionnaires collected every 4 years using an updated and extended US Department of Agriculture flavonoid database. RESULTS During 14 years of follow-up, 1803 incident strokes were confirmed. After adjusting for potential confounders, women in the highest compared with the lowest quintile of flavanone intake had a relative risk of ischemic stroke of 0.81 (95% CI, 0.66-0.99; P=0.04). Citrus fruits/juices, the main dietary source of flavanones, tended to be associated with a reduced risk for ischemic stroke (relative risk, 0.90; 95% CI, 0.77-1.05) comparing extreme quintiles. CONCLUSIONS Total flavonoid intake was not inversely associated with risk of stroke; however, increased intake of the flavanone subclass was associated with a reduction in the risk of ischemic stroke. Citrus fruit consumption may be associated with a reduction in stroke risk, and experimental data support these epidemiological associations that the flavanone content of citrus fruits may potentially be cardioprotective. Further prospective studies are needed to confirm these associations.
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The addition of raspberries and blueberries to a starch-based food does not alter the glycaemic response.
Clegg, ME, Pratt, M, Meade, CM, Henry, CJ
The British journal of nutrition. 2011;(3):335-8
Abstract
It is now known that health benefits associated with diets rich in fruit and vegetables may be partly derived from intake of polyphenols. Berry polyphenols may influence carbohydrate metabolism and absorption and hence postprandial glycaemia. To date, studies related to polyphenol effects on the glycaemic response have been completed only in liquids using either monosaccharides or disaccharides. It remains to be determined whether berries known to be rich in polyphenols can reduce the glycaemic response (GR) to a solid polysaccharide meal. The aim of the present study was to investigate whether berries alter postprandial hyperglycaemia and consequently the GR to a starchy food. Blood glucose was tested on seven occasions, on three occasions using a reference food and on four occasions using pancakes supplemented with either raspberries or blueberries or control pancakes containing similar amounts of fructose and glucose. Results showed that there were no differences in GR (blueberry 51·3 (SEM 5·7); raspberry 54·7 (SEM 5·6); blueberry control 43·9 (SEM 4·2); raspberry control 41·8 (SEM 6·4)), GR area under the curve or satiety index between any of the tests. The present study indicates that the ability of berries to reduce blood glucose from starch-based foods is unsubstantiated.
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Investigation of Pycnogenol® in combination with coenzymeQ10 in heart failure patients (NYHA II/III).
Belcaro, G, Cesarone, MR, Dugall, M, Hosoi, M, Ippolito, E, Bavera, P, Grossi, MG
Panminerva medica. 2010;(2 Suppl 1):21-5
Abstract
AIM: In this study we investigated benefits of a Pycnogenol - coenzyme Q10 combination (PycnoQ10) taken as an adjunct to medical treatment in stable heart failure patients. The aim of this single-blinded, 12-week observational study was to provide functional parameters such as exercise capacity, ejection fraction and distal edema. METHODS The essential element for inclusion was a stable level of heart failure within the past three months and stable NYHA class II or III (6 months). The heart failure management was in accordance with AHA guidelines for "best treatment." The treatment and control groups were comparable at baseline. The mean age of the PycnoQ10-treated patients was 61.3+/-7.1 years and 62.1+/-3.7 in the control group. All patients were taking medication and most patients (>75%) used three or more drugs for heart failure treatment. There were two dropouts in the PycnoQ10 treatment group and 6 in the control group (5 NYHA III patients). RESULTS Nine PycnoQ10 treated patients (out of 32) and 3 (out of 21) taking placebo improved NYHA class. Systolic and diastolic pressure as well as heart rate and respiratory rate were significantly lowered with PycnoQ10 as compared to the control group (P<0.05). No significant changes were observed in controls. Heart ejection fraction increased by 22.4% in the treatment group (P<0.05) versus 4.0% in controls. Walking distance on treadmill increased 3.3-fold in PycnoQ10 treated patients (P<0.05) but marginally improved in the control group. Distal edema decreased significantly in PycnoQ10 treated patients and only slightly in controls. CONCLUSION The association of Pycnogenol and CoQ10 may offer an important therapeutic option with a very good tolerability that improves heart failure management without side effects.
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Phase I study of flavopiridol with oxaliplatin and fluorouracil/leucovorin in advanced solid tumors.
Rathkopf, D, Dickson, MA, Feldman, DR, Carvajal, RD, Shah, MA, Wu, N, Lefkowitz, R, Gonen, M, Cane, LM, Dials, HJ, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2009;(23):7405-11
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PURPOSE Flavopiridol, a cyclin-dependent kinase inhibitor, has promising clinical activity when combined with chemotherapy. Preclinical data indicate that flavopiridol enhances oxaliplatin- and fluorouracil (5FU)-induced apoptosis in a sequence-dependent manner. EXPERIMENTAL DESIGN We conducted a phase I trial of flavopiridol + FOLFOX (folinic acid, 5FU, and oxaliplatin) for advanced solid tumors. Flavopiridol was administered every 2 weeks with oxaliplatin before 5FU, based on sequence-dependent growth inhibition. Flavopiridol pharmacokinetics and p53 status were evaluated. RESULTS Forty-eight patients were treated on study. With dose escalation of oxaliplatin (85 mg/m(2)) and 5FU (2,400 mg/m(2)), dose-limiting toxicities included hyponatremia, thrombocytopenia, and neutropenia. 5FU was subsequently reduced to allow for dose escalation of flavopiridol. Dose-limiting toxicities with escalation of flavopiridol were nausea, vomiting, and neutropenia. The maximum tolerated dose was 70 mg/m(2) flavopiridol, 85 mg/m(2) oxaliplatin, and 1,800 mg/m(2) 5FU continuous infusion over 48 hours. Clinical activity was noted in platinum-refractory germ cell tumors: 3 of 9 (33%) evaluable patients showed a partial response on imaging and 7 of 10 (70%) had a decline in serum tumor markers. Responses were also observed in pancreatic, gastric, and sweat gland tumors. Flavopiridol pharmacokinetics had significant interpatient variability. At the maximum tolerated dose, tumor samples were p53 mutant (>30% positive cells) for responders and p53 wild-type for nonresponders. CONCLUSIONS Flavopiridol with FOLFOX is a safe and tolerable regimen. Promising clinical activity was seen across tumor types. Encouraging results in the platinum-refractory germ cell tumor population has prompted a phase II trial that is currently open for accrual.
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Phenotyping tea consumers by nutrikinetic analysis of polyphenolic end-metabolites.
van Velzen, EJ, Westerhuis, JA, van Duynhoven, JP, van Dorsten, FA, Grün, CH, Jacobs, DM, Duchateau, GS, Vis, DJ, Smilde, AK
Journal of proteome research. 2009;(7):3317-30
Abstract
An integration of metabolomics and pharmacokinetics (or nutrikinetics) is introduced as a concept to describe a human study population with different metabolic phenotypes following a nutritional intervention. The approach facilitates an unbiased analysis of the time-response of body fluid metabolites from crossover designed intervention trials without prior knowledge of the underlying metabolic pathways. The method is explained for the case of a human intervention study in which the nutrikinetic analysis of polyphenol-rich black tea consumption was performed in urine over a period of 48 h. First, multilevel PLS-DA analysis was applied to the urinary 1H NMR profiles to select the most differentiating biomarkers between the verum and placebo samples. Then, a one-compartment nutrikinetic model with first-order excretion, a lag time, and a baseline function was fitted to the time courses of these selected biomarkers. The nutrikinetic model used here fully exploits the crossover structure in the data by fitting the data from both the treatment period and the placebo period simultaneously. To demonstrate the procedure, a selected set of urinary biomarkers was used in the model fitting. These metabolites include hippuric acid, 4-hydroxyhippuric acid and 1,3-dihydroxyphenyl-2-O-sulfate and derived from microbial fermentation of polyphenols in the gut. Variations in urinary excretion between- and within the subjects were observed, and used to provide a phenotypic description of the test population.
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Tea polyphenols decrease serum levels of prostate-specific antigen, hepatocyte growth factor, and vascular endothelial growth factor in prostate cancer patients and inhibit production of hepatocyte growth factor and vascular endothelial growth factor in vitro.
McLarty, J, Bigelow, RL, Smith, M, Elmajian, D, Ankem, M, Cardelli, JA
Cancer prevention research (Philadelphia, Pa.). 2009;(7):673-82
Abstract
The purpose of this study was to determine the effects of short-term supplementation with the active compounds in green tea on serum biomarkers in patients with prostate cancer. Twenty-six men with positive prostate biopsies and scheduled for radical prostatectomy were given daily doses of Polyphenon E, which contained 800 mg of (-)-epigallocatechin-3-gallate (EGCG) and lesser amounts of (-)-epicatechin, (-)-epigallocatechin, and (-)-epicatechin-3-gallate (a total of 1.3 g of tea polyphenols), until time of radical prostatectomy. Serum was collected before initiation of the drug study and on the day of prostatectomy. Serum biomarkers hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF)-I, IGF binding protein-3 (IGFBP-3), and prostate-specific antigen (PSA) were analyzed by ELISA. Toxicity was monitored primarily through liver function enzymes. Changes in serum components were analyzed statistically using the Wilcoxon signed rank test. Cancer-associated fibroblasts were treated with EGCG, and HGF and VEGF protein and mRNA levels were measured. HGF, VEGF, PSA, IGF-I, IGFBP-3, and the IGF-I/IGFBP-3 ratio decreased significantly during the study. All of the liver function tests also decreased, five of them significantly: total protein, albumin, aspartate aminotransferase, alkaline phosphatase, and amylase. The decrease in HGF and VEGF was confirmed in prostate cancer-associated fibroblasts in vitro. Our results show a significant reduction in serum levels of PSA, HGF, and VEGF in men with prostate cancer after brief treatment with EGCG (Polyphenon E), with no elevation of liver enzymes. These findings support a potential role for Polyphenon E in the treatment or prevention of prostate cancer.