We identified nine trials involving 549 participants who received Pycnogenol supplementation ranging from 150 mg/d to 200 mg/d. Compared with the dominance, the pool estimate of change in systolic and diastolic BPs were −3.22 mmHg ( 95 % CI : −6.20, −0.24 ) and −3.11 mmHg ( 95 % CI : −4.60, −1.62 ), respectively. Subgroup analyses showed higher BP reduction among hypertensive participants or those who received intervention for more than 12 wk. however, this meaning reduction was not observed in well-designed trials. This literature search of PubMed, the Web of Science and the Cochrane library was performed in May 2016 to identify eligible studies. Reference lists of the retrieve articles were besides reviewed. Either a fixed-effects or, in the presence of heterogeneity, a random-effects model was used to calculate the effect of aggregate treatment. Pycnogenol supplementation produces assorted potentially protective effects against chronic diseases, such as metabolic syndrome, fleshiness, dyslipidemia, diabetes and high blood pressure ( 3 ). We peculiarly focus on its effect on rake blackmail ( BP ). An early on animal survey found that systolic blood press ( SBP ) and diastolic lineage pressure ( DBP ) decreased in a dose-dependent manner after intravenous administration of ache bark educe to SD rats ( 4 ). A long-run animal study reported a rebuff but significant SBP reduction in spontaneously hypertensive rats treated with Pycnogenol for 6 wk ( 5 ). In fact, the effect of Pycnogenol on human BP has gained increased research attention. A randomize controlled trial ( RCT ) showed that oral administration of Pycnogenol reduced SBP to the normal value in hypertensive patients ( 6 ). A subsequent RCT indicated that Pycnogenol supplementation in hypertensive patients reduced the necessitate for nifedipine, a calcium adversary used as a coronary thrombosis vasodilator ( 7 ). however, the union of BP deceased by 1.0 mmHg in Pycnogenol-treated group and even by 1.9 mmHg in placebo group after a 12-wk intervention ( 8 ). The discrepancies in BP-lowering effect are chiefly attributed to inter-study variations in terms of inclusion criteria, trial design, supplementary dose, and duration of intervention. People have shown bang-up interest in herbal medicate with the promise that they can improve their health circumstance through diet or consumption of natural compound. Pycnogenol is a nutritional supplement used as a phytochemical redress cosmopolitan ( 1 ). The term Pycnogenol was intended to serve as a scientific name for this classify of polyphenols ( 2 ) ; however, this term basically refers to a specific blend of procyanidins extracted from a french maritime ache bark. Pycnogenol is standardized to 70 % ±5 % procyanidins ; the extract besides contains catechin, taxifolin, and a range of phenolic resin acids, represented by cinnamic acerb and benzoic acid derivatives ( 1 ).
Reading: Effect of Pycnogenol Supplementation on Blood Pressure: A Systematic Review and Meta-analysis
The heterogeneity between the studies was tested using the Cochran ’ s Q test at the P < 0.10 degree of meaning and quantified by the I 2 statistic, which describes the incompatibility across studies ( 12 ). In the presence of significant heterogeneity, the random-effects model was used to calculate the pool consequence size, otherwise, the fixed-effects model was applied ( 13 ). To explore the potential influences of study invention and participants characteristics, we far conducted pre-specified subgroup analysis stratified by learn design ( double blind vs. non-double blind design ; analogue vs. cross-over design ), high blood pressure status, Jadad score, and duration of supplementation. We besides performed a sensitivity analysis, in which a individual test was omitted each time and the effect size was recalculated to investigate its influence on the overall effect size. potential issue bias was assessed using Begg ’ s funnel plots and Egger ’ s arrested development test at the P < 0.10 level of significance ( 14 ). For twin trials, the net changes in each consequence in the intervention and control groups were reported as differences between mean values before and after treatments. For crossover trials, net changes were calculated as differences in the post discussion values of each group. Cohen method was used to combine SD. Studies with no reported SD values had their values imputed from standard errors, the confidence interval ( CI ) or P-values using a standard formula. If only SD for the service line and final examination values were provided, SD for the final changes were imputed according to the method acting of Follmann using a correlation coefficient coefficient of 0.5 ( 11 ). We recorded the trace characteristics of each study : inaugural generator ’ south list, issue class, and study design, sample distribution size, study menstruation, casual acid of Pycnogenol, intervention period. We besides extracted the following player characteristics : sex, mean age, health condition, service line BP and change in BP of each study. The Jadad score, a scale that ranges from 0 to 5 according to the descriptions of randomization, blazing and coverage of player withdrawals, was used to measure the quality of each study ( 10 ). We follow the Preferred Reporting Items for Systematic Reviews and Meta-Analysis ( PRISMA ) guidelines in the reputation of this meta-analysis ( 9 ). We conducted a systematic literature search of PubMed, the Web of Science and the Cochrane library through May 2016, using the following search terms : “ pycnogenol OR nautical pine bark OR proanthocyanidin ” in combination with “ blood pressure OR high blood pressure OR endothelial OR flow-mediated dilation OR vascular ”. No restrictions were imposed. reference lists were besides reviewed. We did not contact the authors of the primary studies for extra information. We besides did not try to consider the unpublished studies. Trials were included in the analysis if they were RCT and intelligibly reported the dose of Pycnogenol supplementation, interposition duration and BP levels before and after the trials. Studies in Pycnogenol combined with drug discussion included if the command group was besides treated. If more than one clock time point for the comply up was reported, the data from the longest period were used. Likewise, the data from the highest dose were used when more than one drug was administered for supplement. In the case of multiple publications with duplicate/overlapped data for the lapp test, the article with more detail data was selected. analysis examining the charm of an individual trial on the overall effect size by omitting one trial at each turn yielded a range feom −2.78 mmHg ( 95 % CI : −5.91, 0.35, P=0.08 ) to −3.98 mmHg ( 95 % CI : −5.65, −2.30, P < 0.01 ) for SBP and from −2.64 mmHg ( 95 % CI : −4.09, −1.18, P < 0.01 ) to −3.46 mmHg ( 95 % CI : −5.15, −1.77, P < 0.01 ) for DBP. The pool calculate of Pycnogenol on SBP became insignificant after excluding the studies of Stuar ( P=0.08 ), Cesarone ( P=0.06 ), or Hu ( P=0.06 ). unfortunately, heterogeneity still existed when any test was omitted. With see to baseline BP, BP was significantly reduced in hypertensive participants displaying an SBP of ≥140 or DBP of ≥90, but not in their counterparts. SBP was besides significantly reduced only among trials wherein the treatment duration was > 12 wk, and DBP reduction tended to be greater in these trials. Subgroup analyses according to mean long time and casual dose were not performed because of minute ranges.
shows the results of the subgroup analyses. When trials were stratified according to discipline purpose, the effect of supplementation on BP was not observed in trials with a double-blind design. Pycnogenol supplement did not affect SBP when trials were stratified by parallel and crossover voter purpose. however, the effect of supplement on DBP was observed in trials with a latitude design. No effect of Pycnogenol supplement on SBP was observed in trials with Jadad scores ≥3. Compared with the control group, the intervention group was associated with an average final change in BP ranging from −6.70 to 1.50 mmHg for SBP and −7.00 to 0.20 mmHg for DBP. A drift toward intervention-related reduction in SBP was observed in seven trials, with six trials showing a significant reduction. In addition, a swerve toward intervention-related decrease in DBP was observed in eight trials, with a meaning reduction in five trials. The tests for heterogeneity indicated that the supplementary effect importantly varied across studies ( P < 0.001 for SBP and DBP ), and I 2 values were 96.8 % for SBP and 93.2 % for DBP. Thus, the random-effects model was used. The overall pool estimates of the effect of Pycnogenol were −3.22 mmHg ( 95 % CI −6.20, −0.24 ; P=0.034 ) for SBP and −3.11 mmHg ( 95 % CI −4.60, −1.62 ; P < 0.01 ) for DBP ( ). shows the characteristics of the included trials. These trials were published from 2001 to 2015 ; 5 were conducted in Italy, 2 in USA, and 1 each in Switzerland and Japan. A twin design was used in seven trials and a cross-over design was used in the two other trials. Five trials employed double-blind method acting, one trial was an assailable label-study, and three trials did not mention anything about blinding. Sample sizes varied from 16 to 130 with 276 participants in the auxiliary groups and 273 in the dominance groups. The average long time varied from 22.4 yr old to 63.1 yr old. Except in Nishioka ’ s test, which involved health young men, the other trials evaluated patients with boundary line high blood pressure, high blood pressure, metabolic syndrome, character 2 diabetes mellitus ( T2DM ), or coronary artery disease. A drug against high blood pressure was used in two trials ( 18, 19 ) and a drug against diabetes was used in one test ( 21 ). These drugs were used both in the intervention and dominance groups. The amounts of Pycnogenol were 150 ( five trials ), 180 ( one test ) and 200 ( three trials ) mg/d. No other nutritional elements, vitamins, or drugs were used. however, some trials required participants to receive a dietary education or to follow the guidelines of healthy life style during the observation menstruation ( 15, 16, 18 ). The Jadad mark of these trials was relatively abject, and only four trials had a score of not lower than 3. We initially found 148 articles, the majority of excluded based on their title and abstract. After reviewing the full textbook of the remaining 33 studies, 22 studies were excluded because they did not record BP at the baseline or after treatment. Among the remaining 11 potentially relevant articles, two studies were excluded because they measured an acute consequence or they did not include a dominance group. ultimately, Nine trials were included in our meta-analysis ( 6, 8, 15 – 21 ) ( ) .
Discussion
This meta-analysis is the first to report that Pycnogenol supplementation significantly reduced SBP and DBP by approximately 3 mmHg. This BP-lowering effect was besides supported by two experimental studies, which provided the BP control rate. In a test, 100 magnesium of Pycnogenol was administered in hypertensive patients for 12 wk. As a result, 15 milligram of nifedipine was sufficient to lower the BP to convention value compared with practice of 21.5 milligram in the restraint group ( 7 ). In another study that includes T2DM patients receiving pharmaceutical treatment showed that 58.3 % of the Pycnogenol-treated subjects achieved BP control condition at the end of 12 wk. however, alone 20.8 % of the subjects maintained control in the control group ( 22 ). A considerable standardization of SBP and DBP was reported after 2 months of supplementation of OPC-3 in subjects with metabolic syndrome, whereas minimal changes were found in the control group ( 23 ). Although the accurate mechanisms were not in full sympathize, the BP-lowering effect of Pycnogenol involves angiotensin converting enzyme ( ACE ) inhibition, azotic oxide ( NO ) production, and antioxidation and anti-inflammatory activities. Pine bark extract exerted inhibitory effect on ACE with concentration of 50 % inhibition as 34.7μg/ml ( 4 ). Two trials included in this meta-analysis evaluated the effects of Pycnogenol as an accessory to ACE-inhibitor ramipril for treatment of hypertensive patients. Administration of ramipril plus Pycnogenol exerted a significantly greater effects on BP than that of ramipril alone ( 18, 19 ). ACE inhibitor should reduce serum angiotensin-II flush and improve flow-mediated vasodilation. however, plasma flush of angiotensin II was not lowered to a considerable extent in Pycnogenol group, compared with that in the manipulate group ( 7 ). frankincense, far studies required to investigate Pycnogenol as an ACE inhibitor in the clinically relevant legal action.
On the other hand, Pycnogenol enhances the endothelial production of NO through the enzyme azotic oxide synthase ( NOS ). An in vitro study showed that Pycnogenol relaxes the adrenaline-induced contractions in the aortal blood vessels of rat. This reaction was due to enhance NO levels because the NOS inhibitor reverses the relaxation, and this response in turn is reversed by addition of L-arginine, the normal substrate for NOS ( 24 ). In Nishioka ’ s trial, Pycnogenol supplementation for 2 wk significantly augmented the reply of forearm lineage flow to acetylcholine, an endothelium-dependent vasodilator acetylcholine. Interestingly, government of NOS inhibitor wholly abolished this answer, suggesting that Pycnogenol plays a character by increasing NO production ( 20 ). oxidative stress is important in the exploitation and care of high blood pressure. Belcaro directly quantified reactive oxygen metabolites by using the release group analytic system in patients with metabolic syndrome and found that reduction in oxidative stress was significantly more pronounce after 6 months in the Pycnogenol supplementation group than that in the see group ( 16 ). In another study, healthy subjects received Pycnogenol for 6 wk and their plasma oxygen radical optical density capacitance importantly increased. interestingly, this antioxidant activity returned to the baseline value after a 4-wk washout period ( 25 ). In summation to its antioxidant bodily process, Pycnogenol demonstrated an anti-inflammatory activity. C-reactive protein ( CRP ), the most widely known incendiary gene, is associated with vascular stiffness, BP, and atherosclerosis ( 26 ). In an RCT involving patients with osteoarthritis, Pycnogenol supplement for 3 months significantly reduced plasma CRP compared with that in the operate group ; in addition, Pycnogenol reduced plasma free radicals ( 27 ). OPC-3 supplement for 2 months besides dramatically lowered plasma CRP, but exerted minor effects in the control group ( 23 ). The results of subgroup psychoanalysis indicated that BP-lowering effect was observed among hypertensive patients in the trials. frankincense, participants with higher baseline BP, who largely needed discussion, were more probably to benefit from Pycnogenol supplementation. On the other bridge player, BP reduction was more pronounce in trials with intervention duration of more than 12 wk. consequently, a longer period is required to improve BP condition. however, subgroup psychoanalysis did not reveal BP-lowering effect among trials with double-blind design and cross-over plan, and SBP-lowering effect among trials with Jadad scores ≥3. Open label and the lack of clear data collection techniques resulted in the moo Jadad scores in these trials. The lack of rigorous RCT design was the independent limit of this meta-analysis. In summation to person design, this meta-analysis was limited by a considerable heterogeneity across studies. In terminus of characteristics of participants, the trials involved patients with high blood pressure, metabolic syndrome, diabetes, and healthy subjects. Healthy status may differently influence the effect of Pycnogenol on BP answer. In accession, genetic background or a gene-diet interaction could be the sources of heterogeneity across studies. BP decrease variously responses to ACE inhibitor between Whites and Blacks ( 28 ). inclusion of assorted races in Drieling ’ s trial was possibly resulted in failure to observe the effect of the supplement ( 8 ). In term of intervention, we did not perform subgroup analysis according to auxiliary dose because of the narrow scope between 150 and 200 mg per day. furthermore, Pycnogenol is not well standardized and mix with monomer, dimer, and trimer chemical components obtained from pine bark extracts ( 29 ). This phenomenon may account for variations in physiologic effects among different trials. Furthermore, some trials tested Pycnogenol as an adjunct to conventional pharmacological treatment and some trials required the participants to receive a goodly life style education ; both have credibly masked the effects of Pycnogenol on BP. In term of consequence, not all trials were originally designed to investigate the BP-modulating properties of Pycnogenol .