Effects of low molecular weight procyanidin rich extract from French maritime pine bark on cardiovascular disease risk factors in stage-1 hypertensive subjects: Randomized, double-blind, crossover, placebo-controlled intervention trial.
Background: Oligopin (OP) is a quantified extract from French Maritime Pine bark (FMPB) with low molecular weight procyanidins. The cardioprotective effects of OP need to be tested in human clinical intervention trials with an appropriate design.
Purpose: The aim of the present study was to assess the effect of subchronic consumption of OP on cardiovascular disease risk factors such as lipid profile, systolic blood pressure (BP) and oxidized-Low Density Lipoprotein (ox-LDL) in stage-1 -hypertensive subjects.
Methods: Between February 14 and May 31, 2014, eligible subjects were recruited from the outpatient clinics of Hospital Universitari Sant Joan (Reus, Spain). A total of 24 participants (mean age [+ or -] DS; 57.36 [+ or -] 11.25; 17 men) with stage-1-hypertension who were not receiving BP-lowering medication and LDL cholesterol < 4.88 mmol/l were randomized in a double-blind, placebo-controlled, crossover study. The subjects received 2 capsules/day with 75 mg of OP or placebo for 5-weeks.
Results: At 5-weeks, compared to the placebo, OP raised High Density Lipoprotein-cholesterol (HDL-c) by 14.06% (p = 0.012) and apolipoprotein A-l by 8.12% (p = 0.038) and reduced the ratio of apolipoprotein B-100/A-1 by 10.26% (p = 0.046). Moreover, at 5-weeks, compared to the baseline, OP reduced the systolic BP by 6.36 mmHg (p = 0.014), and decreased ox-LDL concentrations by 31.72 U/l (p = 0.015).
Conclusion: At 5-weeks, the consumption of 150 mg/day of OP improve lipid cardiovascular profile and represents one of the scarce ways to increase HDL-c in stage-1 -hypertensive subjects.
Trial Registration: ClinicalTrials.gov: NCT02063477
Systolic blood pressure
Low weight molecular procyanidin
Hypertension is a leading risk factor for cardiovascular disease (CVD), which is the major cause of premature death in the world Games et ai., 2014; Perk et al., 2012). The reduction of blood pressure (BP) levels in hypertensive subjects is associated with a decrease in cardiovascular events (James et al., 2014; Perk et al., 2012). According to the Lifestyle Work Group, recommendations of lifestyle modifications have a potential role in improving BP (Reidlinger et al., 2015), specially, in early stages of hypertension or in subjects with grade-1-hypertension Qames et al., 2014).
In the approach to reduce BP in subjects with hypertension, other CVD risk factors such as lipids or emergent CVD risk factors as oxidized-Low Density Lipoprotein (ox-LDL) should be lowered additionally to BP. In this line, phenolic compounds present in a healthy dietary pattern may have a beneficial impact on all these CVD risk factors (Rosa Cde et al., 2015).
Among phenolic compounds, procyanidins (condensed oligomeric catechin and epicatechin) are proanthocyanidin biopolymers classified in the flavonoid subgroup. These bioactive compounds have been related to different beneficial health properties, such as hypolipidemic, antihypertensive, anti-inflammatory and antioxidant effects, thus improving different CVD risk factors (Gonzalez-Abuin et al., 2015). The French Maritime Pine (Pinus pinaster) bark (FMPB) extract is a natural extract rich in specific oligomeric procyanidins and other phenolic compounds that have been related to beneficial CVD risk factors effects (Schoonees et al., 2012). Pycnogenol[R] is one of the most studied quantified FMPB extracts, and it has been observed to inhibit the activity of angiotensin-converting enzyme (ACE), decreasing BP levels (Hosseini et al., 2001; Liu et al., 2004). The consumption of 150 mg/day of Pycnogenol[R] during a 6-month period has also been observed to improve other CVD risk factors in subjects with metabolic syndrome, such as waist circumference (WC), glucose and triglycerides (TG) levels and high density lipoprotein cholesterol (HDL-c) levels, compared to the baseline (Belcaro et al., 2013). These interesting results need to be verified, as no control product was consumed in Belcaro et al., 2013 study thus representing a methodological limitation (Belcaro et al., 2013). Moreover, two different placebo-controlled studies reported no improvement in BP or other CVD risk factors at 6 and 12 weeks following FPBE intake (Drieling et al., 2010; Enseleit et al., 2012). Therefore, the beneficial health effects of FMPB extract, including its possible hypotensive effect, its ability to modulate plasma lipids levels, or antioxidant lipid activity are inconsistent, and methodological aspects are hindering the interpretation. Recent systematic reviews stated that the current evidence of FMPB extract value is insufficient, and that well-designed, high quality and adequately powered trials are needed (Sahebkar, 2014; Schoonees et al., 2012).
Oligopin[R] (OP) is a quantified extract, commercially available, with a specific selective extraction and purification process of FMPB, and its effects on CVD risk factors have not previously been evaluated in human trials (Assoud and Piriou, 2007). OP is characterized by a practical absence of tannins (<1%) and a high content in low molecular weight oligomeric procyanidins (OPC > 70%; dimers about 20%), a distinctive feature of other proanthocyanidin-rich extracts such as Pycnogenol[R] which contained about 5% of dimers (Assoud and Piriou, 2007). Furthermore, although the insoluble products in water are low in both products, lower and more adequate concentrations are present in OP (OP: typically 2 to 4% to a maximum at 5% versus Pycnogenol[R]: 6%-8.1%). The degree of polymerization of OPC can determine its absorption across cell membranes and, as it has been observed in rats, only a certain OPC of a lower degree of polymerization is absorbed during transit in the gut (Cheah et al., 2014). Consequently, the effect of FMPB extract could be determined, in part, by the quality of its OPC. In this context, we hypothesized that OP that contain an originally low weight molecular procyanidin rich quantified extract from FMPB can improve, in hypertensive patients, not only BP, but also other CVD risk factors such as lipid profile or ox-LDL The aim of the present study was to assess the effect of subchronic consumption of OP on several CVD risk factors, such as lipid profile, systolic BP and ox-LDL in stage-1-hypertensive subjects.
Materials and methods
The study was randomized, double-blind, placebo-controlled and crossover. After a run-in week for dietary stabilization of all participants, they were randomly assigned to placebo or OP periods of 5-weeks each, with a 3 week washout period between the first and second periods of the study to test possible interactions between treatment and sequence order (carryover effect). Thus, the duration of the study was 14-weeks (1 + 5 + 3 + 5 weeks).
The study was approved by the Clinical Research Ethical Committee of Hospital Universitari Sant Joan (HUSJ) de Reus (Spain) on May 13, 2013. The protocol and the trial were conducted in accordance to the Helsinki Declaration and good clinical practice guidelines of the International Conference of Harmonization (ICH GCP) and reported as CONSORT criteria. The trial was registered with Clinical-Trials.gov: number NCT02063477. There have not been any deviations from the study protocol. We declare that there are no restrictions on the sharing of data and/or materials.
Participants and recruitment
Between February 14 and May 31, 2014, eligible patients were recruited from the outpatient clinics of HUSJ Reus. The follow-up of the participants was conducted on the Nutrition and Health Technology Centre (CTNS) and the HUSJ and lasted until September 30, 2014. The trial registration was completed on February 13, 2014. The end of study was October 31, 2014 for the final data collection for primary outcome measure. All the participants provided written informed consent prior to participation in the study.
The participants were community-dwelling men and women > 18 years of age with stage 1 hypertension (systolic BP [greater than or equal to] 140 and [less than or equal to] 159 mm Hg) and/or diastolic BP [greater than or equal to] 90 and [less than or equal to] 99 mm Hg and were not receiving BP-lowering medication. The exclusion criteria were Body Mass Index (BMI) > 30 kg/[m.sup.2], consumption of anti-hypertensive medications, smoking, persons with a self-reported history of clinical CVD, cancer, chronic kidney disease (or a serum creatinine [greater than or equal to] 1.7 mg/dl for men and [greater than or equal to] 1.5 mg/dl for women), hypercholesterolemia (LDL-c [greater than or equal to] 4.88 mmol/l), diabetes mellitus (or serum glucose [greater than or equal to] 126 mg/dl), consumption of more than 14 drinks of alcoholic beverages per week, pregnancy, or with the intention to breastfeed or become pregnant.
Participant eligibility or exclusion was assessed by the attending physician and was based on review of clinical records, followed by a screening visit.
Randomization and intervention
The randomization allocation sequence was generated by a statistician with SAS 9.2 (Cary, NC: SAS Institute Inc.) statistical software PROC PLAN. The statistician responsible for the randomization did not participate in the study. Because all participants received both interventions (OP and placebo), restrictions such as blocking were unnecessary. Participant assignment to treatment or placebo arm was at a ratio of 1:1. The sequence number for the subject and treatment assignment was allocated through an interactive electronic response system hosted by the Nutrition and Health Technology Centre (CTNS). Subjects complying with selection criteria were assigned a randomization number taken from a randomization list following the chronological order by which they were included, after verifying compliance with inclusion and exclusion criteria. The participant enrollment was conducted by a researcher, and participants' assignment to interventions according to the random sequence was done by a physician. The randomization list remained closed until the end of the experimental intervention and the data registering had finished.
The randomized patients receive a placebo (250 mg maltodextrine plus 30 mg magnesium stearate: 280 mg of total content per capsule; 2 times a day) or OP quantified extract (75 mg Oligopin plus 175 mg maltodextrine plus 30 mg magnesium stearate: 280 mg of total content per capsule; 2 times a day) for 5 weeks each. During the intervention, patients consume one capsule of placebo or OP in the morning and the other one in the afternoon, being indifferent if taken before, during or after meals as the product is soluble in water so its biodisponibility is not affected by food consumption. These products were provided by Les Derives Resiniques 8i Terpeniques (DRT); 40105 DAX CEDEX--FRANCE. Pine bark extract from Pinus pinaster is positively listed in annex 1 of the French Plant decree (Arrete du 24 juin 2014 etablissant la liste des plantes, autres que les champignons, autorisees dans les complements alimentaires et les conditions de leur emploi). By mutual recognition it should be authorized in Spain unless a specific legislation applies. We are not aware of any restriction in Spain. The polyphenol composition of Oligopin[R] is described in Supplemental Table 1.
Blinding was maintained using matching placebo capsules that did not differ from the OP with respect to appearance or any other physical characteristics. A total of 45 capsules were presented in opaque bottle plastic packaging, and 2 bottles were delivered face-to-face at the beginning of each intervention period by the physician.
Compliance treatment monitoring was measured with a questionnaire filled-in by patients at a clinical interview in all visits, and the capsule bottles were returned afterwards. Consumption of > 80% was considered an acceptable level of adherence.
The stabilization diet had a 13% of saturated fatty acid content. During the intervention, dietary recommendations were disseminated according to the guidelines of the Adult Treatment Panel (ATP) III (Stone et al., 2014) and Dietary Approaches to Stop Hypertension (DASH) diet (Saneei et al., 2014). At the basal level and at the end of each intervention, dietary compliance was monitored using 3 DAY dietary records and was confirmed in interviews with the dietician. In addition, the follow-up of the dietary recommendations was verified through a 24 h record by trained dieticians in each follow-up visit.
The systolic BP was defined as a primary outcome measure. BP was measured twice after subjects respite 2-5 min seated, with a 1 -min interval in between, using an automatic sphygmomanometer (OMRON HEM-907; Peroxfarma, Barcelona, Spain) by a physician. The mean values were employed in the statistical analyses.
The anthropometric measurements, lipid profile, ox-LDL and other CVD risk biomarkers were defined as secondary outcome measures.
Screening chemistries and haemograms were performed with appropriate clinical chemistry quality controls in the HUSJ. A fasting blood sample was obtained at 0 and after 5 weeks of each intervention. Samples were stored at -80 [degrees]C in the central laboratory's Biobanc (firstname.lastname@example.org) until required for batch analyses.
Total cholesterol, HDL-c, TG, Apolipoprotein A-1 (Apo A-1), Apolipoprotein B-100 (Apo B-100) and glucose were measured in serum by standardized enzymatic automated methods in a PENTRA-400 autoanalyzer (ABX-Horiba Diagnostics, Montpellier, France). LDL-c was calculated by the Friedewald formula (Friedewald et al., 1972). High sensitivity C-reactive protein (hsCRP) was determined by standardized methods in a Cobas Mira Plus autoanalyzer (Roche Diagnostics Systems, Madrid, Spain). Insulin was measured using a specific ELISA kit (Mercodia AB, Uppsala, Sweden).
EDTA plasma ox-LDL was measured with an ELISA kit (Mercodia AB, Uppsala, Sweden), and Heparin-lithium plasma GSH and GSSG were analyzed by fluorimetric methods.
Endothelin-1, nitric oxide, ACE, vascular endothelial growth factor (VEGF), Intercellular Adhesion Molecule type 1 (ICAM-1), Vascular Cell Adhesion Molecule type 1 (VCAM-1) and e-Selectin, which were measured in serum using ELISA kits (R&D Systems, Minneapolis, USA).
Standard anthropometric data were obtained while participants were wearing lightweight clothing and no shoes at each visit. Trained dieticians measured weight and body composition using a body composition analyzer (Tanita SC 330-S; Tanita Corp., Barcelona, Spain) and height using a well-mounted stadiometer (Tanita Leicester Portable; Tanita Corp., Barcelona, Spain). WC was measured midway between the lowest rib and the iliac crest using an anthropometric tape. All participants were advised to maintain their usual physical activity throughout the study.
Adverse events were coded according to the Medical Dictionary for Regulatory Activities (MedDra dictionary; version 16.1) and described per subject, including their characteristics, listed by visit and study intervention. Relationship to the intervention was also listed in those adverse events catalogued as serious. The number of individuals with at least one adverse event and the number of adverse events per study intervention were analyzed.
To detect differences between the two interventions (OP and placebo) of 10 mm Hg under an [alpha] = 0.05 bilateral significance level, a power of 80% and assumption that the common standard deviation (SD) was 12.15 mm Hg, the sample size was 24 participants.
Descriptive results were expressed as the mean [+ or -] SD or percentages, according to the type of variable. The efficacy analysis was evaluated by paired Student's t-test using employing the Baseline Observation Carried Forward (BOCF) approach on the Intention to Treat population (ITT). The analysis was performed using the Available Data Only (ADO) approach on the same population. The primary efficacy variable was also analyzed using the Per Protocol population (PP) to test the robustness of the results with both approximations (BOCF and ADO). The Kolmogorov-Smirnov test was used to verify the distributions of the variables. Carryover effect determined by a period-by-treatment interaction was discarded. Student's T-Test and Mann-Whitney's U were applied according to the variables' nature. Exploratory analysis was determined by the primary outcome by gender on ITT population using ADO approach.
The possible interaction between the treatments and the treatment sequence (carryover effect) was discarded in all variables of the study. The level of statistical significance was set at p < 0.05. Data were analyzed using the SAS software package version 9.2 (SAS Institute Inc., Cary, NC, USA).
Characteristics of subjects
From the 45 eligible volunteers, 25 were randomized, and finally, data from 24 were analyzed by ITT (Fig. 1). The baseline characteristics from the 24 participants (17 men and 7 women) included in the study are described in Supplemental Table 2. No relevant differences between sequences were observed at the baseline.
The changes in BP are shown in Table 1. At 5-weeks, systolic BP had been significantly reduced by 6.36 mm Hg (p = 0.014) compared with its baseline during the OP intervention. However, this decrease was not significantly different when compared to the placebo intervention, because the placebo also reduced systolic BP levels by 3.98 mm Hg (p = 0.426) after 5-weeks. Moreover, after OP intervention and stratifying by gender, the female participants significantly reduced their systolic BP by 14.75 mm Hg (p = 0.002) compared to the placebo intervention. Additionally, diastolic BP had been reduced by 1.82 mm Hg compared with its baseline during the 5-weeks OP intervention, although this reduction did not reach the significance level (p = 0.259). Likewise, this decrease was not significantly different when compared to the placebo intervention, because the placebo also reduced diastolic BP levels by 1.74 mm Hg (p = 0.805).
At 5-weeks with OP intervention, the HDL-c concentrations significantly increased by 14.06% (0.22 mmol/1; p = 0.011) and Apo A-l concentrations by 8.12% (p = 0.038); the Apo B-100/Apo A-l ratio was significantly reduced by 10.25% (p = 0.046) compared with the placebo intervention. The changes in lipid profiles are described in Table 2.
Anthropometric variables and other CVD risk biomarkers
The changes in anthropometric variables and other CVD risk biomarkers analyzed are shown in Supplemental Table 3. At 5 weeks, ox-LDL was significantly reduced by 31.72 U/l (-29.4%) (p = 0.015) compared with its baseline during the OP intervention. Moreover, a reduction trend in ox-LDL values was also observed when compared with the placebo intervention group (p = 0.077). After OP intervention and stratifying by gender, the male participants' trend for ox-LDL was significantly reduced by 33.96 U/l (p = 0.059) compared with the placebo intervention.
BMI and waist circumference of the participants remain stable during the study. No significant changes were observed between the OP and placebo interventions for anthropometric variables and other CVD risk biomarkers.
Supplemental Table 4 summarizes the dietary intake of study participants. The intake of energy, macronutrients, dietary cholesterol, fiber, sodium, potassium, magnesium and calcium did not change after 5-weeks between interventions, except toward a lower alcohol consumption in the placebo intervention by -5.23 g (p = 0.025) compared to the OP intervention.
Adverse events and product tolerance
There were no statistically significant differences between the 2 interventions with respect to the adverse events reported. The OP product was well tolerated.
The present study is the first randomized, double-blind, placebo-controlled and crossover study performed with OP in stage-1-hypertensive subjects. The present results reveal that the consumption of 150 mg/day of OP during 5-weeks, compared to the control group, produced beneficial effects on CVD risk factor, not only by the significant clinical increase of HDL-c (0.22 mmol/1, 14.06%), but also by the increase of its main apolipoprotein Apo A-l (11.1 mg/dl, 8.12%), and the reduction of the Apo B-100/A-1 ratio (10.26%). Moreover, at 5-weeks and compared to baseline, OP significantly reduced systolic BP by 6.36 mm Hg, and decreased oxLDL concentrations by 31.72 U/l in stage-1 -hypertensive subjects.
Our results are in line with the results of Belcaro et al. (2013) (Belcaro et al., 2013), who also observed an increase in HDL-c levels after Pycnogenol[R] consumption. Moreover, the increment observed in our OP study (14%) was more intense than those observed in the METS-GREECE study, in which an increment of 7% was described after a 3-year therapy with atorvastatin (Athyros et al., 2004). HDL-c levels have long been inversely associated with the risk of coronary heart disease, being a key component in predicting CVD risk. Gordon et al. suggested in 1989 (Gordon et al., 1989) that for each 1 mg/dl of HDL-c increase, a reduction of 3% in coronary heart disease risk was expected. The increment of Apo A-l observed after OP intervention could lead to the possible improvement of HDL functionality by enhancing HDL-c efflux and HDL antioxidative properties, because Apo A-l is the major HDL component involved in these activities (Rached et al., 2014). Thus, HDL particle is a major target for novel therapeutic approaches to decrease atherosclerosis. The increase in HDL-c levels and Apo A-l could occurs due to a mechanism of action of the components present in the OP quantified extract, particularly, the low molecular weight procyanidins. In this line, procyanidin B2 and procyanidin CI, present in cacao, have been shown to influence the regulation of Apo A-1 in HepG2 and Caco2 cells by increasing their mRNA expression and consequently, Apo A-1 protein levels. This mechanism has been suggested as a possibility by which HDL-c levels become elevated after cocoa intake, and it could also be the mechanism by which the OP quantified extract produced the increase in HDL-c and its major Apo lipoprotein (Sarria et al., 2015). The Apo B-100/Apo A-l ratio could predict cardiovascular heart disease and stroke risk more accurately than conventional lipid measurements such as total cholesterol or LDL-c levels (Sola et al., 2011). Moreover, an Apo B-100/Apo A-1 ratio value less than 1 has been recommended to improve the lipid cardiovascular profile (McQueen et al., 2008). In the present study, after 5-weeks of OP intervention, compared to placebo, the Apo B-100/Apo A-1 ratio was significantly reduced after 5-weeks of OP intervention by 10.26% with a final value of 0.75.
The systolic BP reduction of 6.46 mm Hg observed after OP consumption compared to the baseline is similar to that observed after the DASH diet, which is based in the consumption of fruits, vegetables, whole grains, low fat products, low sodium and low total and saturated fats; it produced a reduction in systolic BP of 6.74 mm Hg in healthy and hypertensive subjects (Saneei et al., 2014). Similarly, a Mediterranean diet also significantly reduced systolic BP by 7.8 mm Hg, as described in the meta-analysis of Rees, (Rees et al., 2013). High polyphenol intake has been associated with an improvement in systolic and diastolic BP (Medina-Remon et al., 2016). Systematic reviews indicate that dietary intakes of polyphenol-rich foods, herbs and beverages, specifically rich in flavonoids, including flavonols (cocoa or tea), anthocyanidins (berry), oligomeric proanthocyanidins (red wine or FMPB), flavones (thyme), flavanones (citrus fruits), isoflavones (soy) and flavan-3-ols (berry and green tea), significantly decrease the risk of hypertension (Hugel et al., 2016). Moreover, the evidence resulted from several recent reviews summarizing the effect of polyphenols and polyphenol-rich foods on BP has resulted in one of the few current European Food Safety Authority (EFSA) allowed health claims on maintenance of normal BP and related to cocoa flavanols (EFSA, 2010). The magnitude of systolic BP reduction observed after OP quantified extract intervention was the same as that achieved by hypotensive drugs (Morgan et al., 2001). However, no significant differences were observed when compared to the placebo, as after taking the placebo, volunteers also obtained a small reduction (-3.98 mm Hg) in systolic BP. This surprising reduction in systolic BP after placebo consumption can be explained by the psychological reactivity of subjects included in an intervention study that produces modifications as a result of knowing that they are being studied and not in response to the experimental intervention (Grufferman, 1999). The placebo effect on systolic BP has been previously described and quantified, that is, approximately 6.5 [+ or -] 11.1 mm Hg in mild-to-moderate hypertension subjects (Asmar et al., 2001).
However, when we stratified the results by gender, we could observe a strong significant decrease in systolic BP (-14.75 mm Hg) compared to the placebo in female participants after 5-weeks of intervention with OP. This preliminary result suggests a sex-dependent response to the FMPB extract present in OP, which must be explored in future studies with a large female sample size.
Consumption of 200 mg/day of Pycnogenol[R] during 8-weeks has also been observed in another study to significantly decrease (-7 mm Hg) systolic BP compared to placebo consumption and was more effective in subjects with higher pressure (Hosseini et al., 2001). In the context of the same commercial FMPB, Liu et al. (2004) showed that Pycnogenol[R] has a significant antihypertensive effect in subjects with mild hypertension compared to the placebo, as they could reduce their hypotensive drug treatment dose after consuming 100 mg/day of Pycnogenol[R] during 12-weeks. They suggest that a lowered concentration of plasma endothelin could contribute to this antihypertensive effect; how ever, we did not observe changes in endothelin concentrations after intervention with the OP standardize extract.
Subjects under OP quantified extract intervention also show a significant decrease in ox-LDL compared to the baseline, indicating a protective antioxidant effect. Similarly, a cocoa powder rich in procyanidins has been related to a reduction in ox-LDL in hypercholesterolemic subjects (Baba et al., 2007). The low molecular weight procyanidin rich extract from FMPB could contribute to the resistance of LDL to oxidation, such as evidence that reported catechin and quercetin may be incorporated onto the surface of LDL particles, producing an increase of resistance of ox-LDL by either scavenging chain-initiating oxygen radicals or chelating transitional metal ions (Hayek et al., 1997).
The changes detected in lipid profile and in systolic BP after OP quantified extract consumption cannot be attributed to dietary modifications as no significant differences were observed between the placebo and OP intervention at 5-weeks. Moreover, the differences between the basal and final interventions were due to dietary recommendations given to the participants. Besides, as the anthropometric parameters (BMI and waist circumference) were unchanged during the study, the results observed can be specifically attributed to OP consumption.
One of the strengths of the present study is its design as a randomized, placebo-controlled, clinical trial that is able to provide the first level of scientific evidence using a product without FMPB as a placebo. In addition, the crossover design, in which each subject acts as the corresponding control, minimizes the interference of possible confounding variables.
One potential limitation of the study is the unknown FMPB extract bioavailability, which was supported by the significantly increased antioxidant capacity of plasma in OP intervention, the same extract used in the present study, compared with grape seed extract or a high-degree polymerized pine bark extract consumed during 8 weeks in rats (Busserolles et al., 2006).
In conclusion, at 5-weeks. the consumption of 150 mg/day of OP improve lipid cardiovascular profile and represents one of the scarce ways to increase HDL-c in stage-1-hypertensive subjects. In addition, OP also tends to improve systolic BP and LDL oxidation. Moreover, as no significant differences were reached compared to placebo, further studies are needed to elucidate this trend and to ensure systolic BP and oxidation improvement after OP consumption.
Funding sources and conflict of interest
LES DERIVES RESINIQUES & TERPENIQUES (DTR, France) provided a grant to the Centre Tecnologic de Nutricio i Salut (Nutrition and Health Technology Centre; CTNS)-TECNIO CT09-1-0019), Reus (Spain). The funding bodies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Logistic support, analysis and interpretation of the data were provided by CTNS; Hospital Universitari Sant Joan and Facultat de Medicina i Ciencies de la Salut, Universitat Rovira i Virgili, Reus (Spain). No conflict of interests declared.
Received 23 April 2016
Revised 26 July 2016
Accepted 20 August 2016
We thank the following for their enthusiastic support in the conduct of the study: Lluisa Iniesta, Miguel Querol, Lorena Torrado, Eva Ribas and Cristina Sevilla.
Table. Proposed Elaborations of CONSORT Items for Randomized. Controlled Trials of Herbal Medicine Interventions * Section/Topic Item Descriptor Reported no on page No Title and la Identification as a 1 abstract randomised trial in the title lb Structured summary of 3 Introduction trial design, methods, results, and Background 2a Scientific background and 5-6 explanation of the rationale conclusions (for specific guidance see CONSORT for abstracts) 2b Including a brief 6 statement of reasons for the trial with reference to the specific herbal medicinal product being tested and. if applicable, whether new or traditional indications are being investigated. Specific objectives or hypotheses Methods Trial design Description of trial 7.8 design (such as parallel, factorial) including allocation ratio Important changes to methods after trial commencement (such as eligibility criteria), with reasons Participants 3 Eligibility criteria for 7-8 participants and the settings and locations where the data were collected If a traditional indication is being tested, a description of how the traditional theories and concepts were maintained. For example, participant inclusion criteria should reflect the theories and concepts underlying the traditional indication Settings and locations where the data were collected Interventions 4 Precise details of the 9-10 (A interventions intended detailed for each group and how description and when they were of this item actually administered. (item 4) for The interventions for reporting each group with Randomized sufficient details to Controlled allow replication, Trials of including how and when Herbal they were actually Medicine administered Interventions on CONSORT appears in the other supplemental cheklist attached. Oligopin Consort Herbal Extension checklist) Objectives 5 Specific objectives or 6 hypotheses Outcomes 6 Clearly defined primary 10-11 and secondary outcome measures and. when applicable, any methods used to enhance the quality of measurements (e.g.. multiple observations, training of assessors) Outcome measures should reflect the intervention and indications tested, considering, where applicable, underlying theories and concepts Completely defined pre-specified primary and secondary outcome measures, including how and when they were assessed Any changes to trial -- outcomes after the trial commenced, with reasons Sample size 7 How sample size was 11 determined When applicable, explanation of any interim analyses and -- stopping guidelines Randomization 8 Sequence 8 Method used to generate allocation the random allocation sequence, including details of any restriction (eg. blocking, stratification) Sequence 8b Method used to generate 8 generation the random allocation sequence, including details of any restriction (eg. blocking, stratification Type of randomization; details of any restriction (such as blocking and block size) Allocation 9 Method used to implement 8 concealment the random allocation sequence(eg. numbered containers or central telephone), clarifying whether the sequence was concealed until interventions were assigned Implementation 10 Who generated the allocation sequence, who enrolled participants, and who assigned participants to their groups Blinding 11a Whether or not participants, (Masking) those administering the interventions, and those assessing the outcomes were blinded to group assignment. When relevant, how the success of blinding was evaluated If done, who was blinded after assignment to interventions (for example, participants, care providers, those assessing outcomes) and how If relevant, description of the similarity of interventions Statistical 12 Statistical methods used 11-12 methods to compare groups for primary outcome(s); Methods for additional analyses, such as subgroup analyses and adjusted analyses Statistical methods used to compare groups for primary and secondary outcomes Methods for additional analyses, such as subgroup analyses and adjusted analyses Results Participant 13 Flow of participants 12. (Fig. 1) flow (a through each stage (a diagram is diagram is strongly strongly recommended) recommended) Specifically, for each group report the numbers of participants randomly assigned, receiving intended treatment.completing the study protocol, and analyzed for the primary outcome. Describe protocol deviations from study as planned, together with reasons For each group, losses and exclusions after randomization, together with reasons Dates defining the periods of recruitment and follow-up Recruitment 14 Dates defining the 7 periods of recruitment and follow-up. Why the trial ended or was stopped Baseline data 15 Baseline demographic and 12 clinical characteristics (Supplemental of each group. Table 2) Including concomitant medication, herbal and complementary medicine use. A table showing baseline demographic and clinical characteristics for each group Numbers 16 Number of participants 12. Table 1 analyzed (denominator) in each and 2, group included in each Supplemental analysis and whether the Table 3 and 4 analysis was by "intention-to-treat." State the results in absolute numbers when feasible (eg, 10/20, not 50%) Outcomes and 17 For each primary and 12-14 estimation secondary outcome, a summary of results for each group, and the estimated effect size and its precision (eg. 95* confidence interval) For binary outcomes, -- presentation of both absolute and relative effect sizes is recommended Ancillary 18 Address multiplicity by analyses reporting any other analyses performed, including subgroup analyses and adjusted analyses, indicating those prespecified and those exploratory Harms 19 All important adverse 14 events or side effects in each intervention group Discussion Limitations 20 Interpretation of 18 results, taking into account study hypotheses, sources of potential bias or imprecision, and the dangers associated with multiplicity of analyses and outcomes Interpretation of the results in light of the product and dosage regimen Trial limitations, addressing sources of potential bias, imprecision, and. if relevant, multiplicity of analyses Ceneralisability 21 Ceneralizability 14 (external validity) of trial results (applicability) of the trial findings Where possible, discuss how the herbal product and dosage regimen used relate to what is used in self-care and/or practice Overall evidence 22 General interpretation of 14-18 the results in the context of current evidence. Discussion of the trial results in relation to trials of other available products Interpretation consistent with results, balancing benefits and harms, and considering other relevant evidence Other information 3.7 Registration 23 Registration number and name of trial registry Protocol 24 Where the full trial -- protocol can be accessed, if available Funding 25 Sources of funding and 19 other support (such as supply of drugs), role of funders * Cagnier, J et al. REPORTING RANDOM CONTROLLED TRIALS OF HERBAL MEDICINES. Explore 2006; 2:143-149. We strongly recommend reading trials. We strongly recommend reading this statement in conjunction with the CONSORT 2010 Explanation and Elaboration for important clarifications on all the items. If relevant, we also recommend reading CONSORT extensions for cluster randomised trials, non-inferiority and equivalence trials, non-pharmacological treatments, herbal interventions, and pragmatic trials. Additional extensions are forthcoming: for those and for up to date references relevant to this checklist, see www.consort-statement.org. Oligopin[R] that contains an original low molecular weight procyanidin rich extract from French Maritime Pine (Pinus pinaster) bark description according to Consort Herbal Extension checklist Standard Standard Descriptor Reported CONSORT CONSORT on page checklist: checklist: number paper section item and topic Methods 4. Where applicable, the description of a herbal intervention should include Interventions 4.A. 1. The Latin -- Product name binomial name together with botanical authority and family name for each herbal ingredient: common name(s) should also be included 2. The proprietary 8 product name (ie, brand name) or the extract name (eg. EGb-761) and the name of the manufacturer of the product 3.Whether the 9 product used is authorized (licensed, registered) in the country in which the study was conducted 4.B. 1. The part(s) used Characteristics to produce the of the product product or extract. 2. The type of product used (eg. raw [fresh or dry), extract) 3. The type and -- concentration of extraction solvent used (eg. 80% ethanol. [H.sub.2]O 100%. 90% glycerine, and others) and the herbal drug to extract ratio (drug: extract: eg. 2:1) 4. The method of -- authentication of raw material (ie. how done and by whom) and the lot number of the raw material. State whether a voucher specimen (ie. retention sample) was retained and. if so. where it is kept or deposited and the reference number 4.C. Dosage l. The dosage of the 8 regimen and duration of quantitative administration. and description how these were determined 2. The content (eg. 8 as weight, concentration may be given as range where appropriate) of all quantified product constituents, both native and added, per dosage unit form. Added materials, such as binders, fillers, and other excipients: eg. 17% maltodextrin. 3% silicon dioxide per capsule, should also be listed 3. For standardized Supplemental products, the Table 1 quantity of active/ marker constituents per dosage unit form 4.D.Qualitative 1. Product's -- testing chemical fingerprint and methods used (equipment and chemical reference standards) and who performed it (eg. the name of the laboratory used). Whether or not a sample of the product (ie. retention sample) was retained and. if so. where it is kept or deposited 2. Description of -- any special testing/purity testing (eg. heavy metal or other contaminant testing) undertaken. Which unwanted components were removed and how (ie, methods) 3. Standardization: -- what to (eg, which chemical component(s) of the product) and how (eg. chemical processes or biological/ functional measures of activity) 4.E. Placebo/ The rationale for 8 control group the type of control/placebo used 4.F. A description of the -- Practitioner practitioners (eg, training and practice experience) who are a part of the intervention Standard Standard Row Text CONSORT CONSORT checklist: checklist: paper section item and topic Methods 4. Interventions 4.A. Pinus pinaster Aiton (or Product name Pinus pinaster Ait.) Family: Pinaceae synonyms : Pinus maritima Lam. Old name: Pinus pinaster Soland Common names: French Maritime Pine Pinus pinaster Aiton subsp. Atlantica 154-155 Brand name: Oligopin Manufacturer: Les Derives Resiniques & Terpeniques (DRT)/ Purextract: 40.105 DAX CEDEX--FRANCE 158-159 Pine bark extract from Pinus pinaster is positively listed in annex 1 of the French Plant decree (Arrete du 24 juin 2014 etablissant la liste des plantes, autres que les champignons. autorisees dans les complements alimentaires et les conditions de leur emploi). By mutual recognition it should be authorized in Spain unless a specific legislation applies. We are not aware of any restriction in Spain 4.B. Bark Characteristics of the product Fresh bark coming from saw mills -- Extraction solvent = water Purification solvent = ethyl acetate Ratio raw material (bark) / final extract: 1000 : 1 -- According to the USP monography Text 4.C. Dosage 151-154 As it was described in regimen and the manuscript: The quantitative randomized patients description receive a placebo (250 mg maltodextrine plus 30 mg magnesium stearate: 280 mg of total content per capsule: 2 times a day) or OP standardized extract (75 mg Oligopin plus 175 mg maltodextrine plus 30 mg magnesium stearate: 280 mg of total content per capsule: 2 times a day). for 5 weeks each. 151-154 Content per capsule : Oligopin = 75 mg; maltodextrine = 175 mg; magnesium stearate = 30 mg; 2 capsules /day Minimum 67% OPC of active material, determined by GPC analysis 4.D.Qualitative According to the USP testing method and internal DRT methods (CPC) Heavy metals: Lead content: <3 mg/kg Arsenic content : <0.5 mg/kg Mercury content <0.1 mg/kg Cadmium content < 1 mg/kg Pesticides: complies with Ph Eur 2.8.13 Benzo(a)pyrene: <2 Mg/kg Sum of benzo(a)- pyrene. benz(a)anthracene. benzo(b)fluoranthene and chrysene : < 10 Mg/kg Sum of dioxins (WHO-PCDD/ F-TEQ) : <0.75 pg/g Sum of dioxins and dioxin-iike PCB (WHO- PCDD/F-PCB- TEQ): <1.25 pg/g Sum of PCBs 28-52-101-138-153- 180 : <40 ng/g Standardization to 67-75% OPC content (GPC analysis) 4.E. Placebo/ 143.144 Participant assignment control group to treatment or placebo arm was at a ratio of 1:1 The researchers 4.F. included dietitians Practitioner are experimented in nutritional trial Reporting RCTs of Herbal Medicines EXPLORE March 2006. Vol. 2. No. 2147
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Rosa-M Vails (a), Elisabet Llaurado (a), Sara Fernandez-Castillejo (a), Francesc Puiggros (b), Rosa Sola (a), *, Lluis Arola (b), Anna Pedret (a)
(a) NFOC-Salut group. URLA, CTNS, CIBERDEM. Hospital Universitari Sant Joan. Servei de Medicina Interna, IISPV, Facultar de Medicina i Ciencies de la Salut, Universitat Rovirn i Virgili, St. Uorenc, 21, 43201, Reus, Spain
(b) CTNS-TECNIO-Technology Center of Nutrition and Health. Avda. Universitat, 1, 43204, Reus, Spain
Abbreviations: ACE. angiotensin convening enzyme; ADO. Available Data Only; Apo A-l, Aplipoprotein A-1; Apo B-100. Aplipoprotein B-100; ATP III. Adult Treatment Panel III; BMI, body mass index; BOCF. Baseline Observation Carried Forward; BP, Blood Pressure; CTNS. Nutrition and Health Technology Centre; CVD. cardiovascular disease; DASH, Dietary Approaches to Stop Hypertension; FMPB. Freeh Maritime Pine Bark; GSH, reduced glutathione; GSSC, oxidized glutathione; HDL, High Density Lipoprotein; hsCRP. high sensitivity C-reactive protein; HSUJ. Hospital Universitari Sant Joan; ICAM-1, Intercellular Adhesion Molecule type 1; ICH GCP. International Conference of Harmonization Good Clinical Practice; ITT. Intention to Treat population; LDL. Low Density Lipoprotein; OP, Oligopin; OPC. oligomeric procyanidins; ox-LDL. oxidized LDL; PP. Protocol population: SD. standard deviation; TC, triglycerides; VCAM-1, Vascular Cell Adhesion Molecule type 1; VECF, vascular endothelial growth factor; WC. waist circumference.
* Corresponding author at: NFOC-Salut group, URLA. CTNS. CIBERDEM. Hospital Universitari Sant Joan, Servei de Medicina Interna, IISPV. Facultat de Medicina i Ciencies de la Salut, Universitat Rovira i Virgili. St. Llorenc, 21, 43201, Reus, Spain; fax: +34 977 75 93 22.
E-mail address: email@example.com (R. Sola).
Table 1 Changes in blood pressure through the study. Variable Baseline Final Mean (SD) Mean (SD) Systolic Placebo 145.76(13.97) 141.78(12.90) Blood Pressure (mm Hg) Oligopin 150.20 (12.41) 143.84(12.26) Diastolic Placebo 82.63 (10.72) 80.89 (8.83) Blood Pressure (mm Hg) Oligopin 83.70 (8.05) 81.89 (9.65) Variable Change at 5 weeks relative to baseline Change (95%CI] % Change P from from Baseline Baseline Systolic Placebo -3.98 [-10.2: 2.2] -2.73% 0.1974 Blood Pressure (mm Hg) Oligopin -6.36 [-11.3; -1.4] -4.23% 0.0138 Diastolic Placebo -1.74 [-5.6: 2.1] -2.11% 0.3588 Blood Pressure (mm Hg) Oligopin -1.82 [-5.1:1.4] -2.17% 0.2594 Variable Treatment difference Change (95% CI] % Change P from from Placebo Placebo Systolic Placebo -2.98 [-10.6:4.7] -2.01% 0.4264 Blood Pressure (mm Hg) Oligopin Diastolic Placebo -0.57 [-5.3: 4.2] -0.69% 0.8048 Blood Pressure (mm Hg) Oligopin Data calculated on the per-protocol (PP) population (n = 21). Results from the ANCOVA model. Abbreviations: SD, standard deviation. Table 2 Changes in lipid profile variables through the study. Variable Baseline Final Mean (SD) Mean (SD) Cholesterol Placebo 5.44 (0.65) 5.27 (0.58) (mmol/l) Oligopin 5.56 (0.77) 5.43 (0.69) LDL-c (mmol/l) Placebo 3.28 (0.45) 3.16 (0.54) Oligopin 3.41 (0.63) 3.18 (0.57) HDL-c (mmol/l) Placebo 1.58 (0.25) 1.47 (0.19) Oligopin 1.55 (0.29) 1.62 (0.32) Triglycerides Placebo 1.27 (0.72) 1.43 (0.83) (mmol/l) Oligopin 1.36 (0.74) 1.40 (0.95) Apolipoprotein Placebo 137.35 (18.36) 131.91 (14.57) A-l (mg/dl) Oligopin 135.91 (21.88) 139.64 (19.76) Apolipoprotein Placebo 101.26 (15.02) 100.04 (16.97) B-100 (mg/dl) Oligopin 105.82 (21.22) 101.09 (16.07) Ratio Placebo 0.75 (0.17) 0.77 (0.19) Apolipoprotein B-100 A-1 Oligopin 0.81 (0.25) 0.75 (0.21) Variable Change at 5 weeks relative to baseline Change [95% CI] % Change P from from Baseline Baseline Cholesterol Placebo -0.16 [-0.4; 0.1] -2.94% 0.1913 (mmol/l) Oligopin -0.14 [-0.5; 0.2] -2.52% 0.4219 LDL-c (mmol/l) Placebo -0.12 [-0.3; 0.1] -3.66% 0.1637 Oligopin -0.23 [-0.5; 0.0] -6.74% 0.0659 HDL-c (mmol/l) Placebo -0.11 [-0.2; 0.0] -6.96% 0.0731 Oligopin 0.07 [-0.0; 0.2] 4.52% 0.2092 Triglycerides Placebo 0.16 [-0.1; 0.4] 12.60% 0.1929 (mmol/l) Oligopin 0.04 [-0.1; 0.2] 2.94% 0.6692 Apolipoprotein Placebo -5.43 [-12.7: 1.8] -3.95% 0.1351 A-l (mg/dl) Oligopin 3.73 [-3.4: 10.9] 2.74% 0.2914 Apolipoprotein Placebo -1.22 [-6.1; 3.7] -1.20% 0.6106 B-100 (mg/dl) Oligopin -4.73 [-11.8; 2.3] -4.47% 0.1773 Ratio Placebo 0.02 [-0.0; 0.1] 2.67% 0.3515 Apolipoprotein B-100 A-1 Oligopin -0.06 [-0.1; 0.0) -7.41% 0.0538 Variable Treatment difference Change [95% CI] % Change P from from Placebo Placebo Cholesterol Placebo 0.07 [-0.3; 0.5] 1.27% 0.7287 (mmol/l) Oligopin LDL-c (mmol/l) Placebo -0.08 [-0.3; 0.2] -2.39% 0.5454 Oligopin HDL-c (mmol/l) Placebo 0.22 [0.1; 0.4] 14.06% 0.0119 Oligopin Triglycerides Placebo -0.16 [-0.5; 0.2] -12.17% 0.3026 (mmol/l) Oligopin Apolipoprotein Placebo 11.10 [0.7; 21.5] 8.12% 0.0380 A-l (mg/dl) Oligopin Apolipoprotein Placebo -2.67 [-10.9; 5.6] -2.58% 0.5079 B-100 (mg/dl) Oligopin Ratio Placebo -0.08 [-0.2; -0.0) -10.26% 0.0460 Apolipoprotein B-100 A-1 Oligopin Data calculated on the per-protocol (PP) population (n = 21). Results from the ANCOVA model. Abbreviations: SD. standard deviation; LDL-c. low density lipoprotein cholesterol; HDl-c, high density lipoprotein cholesterol.
Please note: Some tables or figures were omitted from this article.
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|Title Annotation:||Original Article|
|Author:||Vails, Rosa-M.; Llaurado, Elisabet; Fernandez-Castillejo, Sara; Puiggros, Francesc; Sola, Rosa; Arol|
|Publication:||Phytomedicine: International Journal of Phytotherapy & Phytopharmacology|
|Date:||Nov 15, 2016|
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