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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: NCT02063477


Systolic blood pressure


Cardiovascular biomarkers

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 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 ( 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.

Sample size

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.

Statistical analyses

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.

Blood pressure

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).

Lipid profile

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.

Dietary intake

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.


Article history:

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

Title and          la    Identification as a           1
  abstract                 randomised trial in the

                   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

                   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


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

                         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

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

Objectives         5     Specific objectives or        6

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

                         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

                         Any changes to trial          --
                           outcomes after the trial
                           commenced, with reasons

Sample size        7     How sample size was           11

                         When applicable,
                           explanation of any
                           interim analyses and        --
                           stopping guidelines

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

Implementation     10    Who generated the
                           allocation sequence, who
                           enrolled participants,
                           and who assigned
                           participants to their

Blinding           11a   Whether or not participants,
  (Masking)                those administering the
                           interventions, and those
                           assessing the outcomes
                           were blinded to group

                         When relevant, how the
                           success of blinding was

                         If done, who was blinded
                           after assignment to
                           interventions (for
                           example, participants,
                           care providers, those
                           assessing outcomes) and

                         If relevant, description
                           of the similarity of

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


Participant        13    Flow of participants          12. (Fig. 1)
  flow (a                  through each stage (a
  diagram is               diagram is strongly
  strongly                 recommended)
                         Specifically, for each
                           group report the numbers
                           of participants randomly
                           assigned, receiving
                           treatment.completing the
                           study protocol, and
                           analyzed for the primary

                         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

Baseline data      15    Baseline demographic and      12
                           clinical characteristics      (Supplemental
                           of each group.                Table 2)

                         Including concomitant
                           medication, herbal and
                           complementary medicine

                         A table showing baseline
                           demographic and clinical
                           characteristics for each

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
                           State the results in
                           absolute numbers when
                           feasible (eg, 10/20, not

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

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


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

                         Trial limitations,
                           addressing sources of
                           potential bias,
                           imprecision, and. if
                           relevant, multiplicity of

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

                         Discussion of the trial
                           results in relation to
                           trials of other available

                         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

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

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
                                     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

                                   3.Whether the           9
                                     product used is
                                     registered) in the
                                     country in which
                                     the study was

                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),

                                   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

                                   2. The content (eg.     8
                                     as weight,
                                     concentration may
                                     be given as range
                                     where appropriate)
                                     of all quantified
                                     constituents, both
                                     native and added,
                                     per dosage unit
                                     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

                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 (eg. heavy
                                     metal or other
                                     undertaken. Which
                                     unwanted components
                                     were removed and
                                     how (ie, methods)

                                   3. Standardization:     --
                                     what to (eg, which
                                     component(s) of the
                                     product) and how
                                     (eg. chemical
                                     processes or
                                     functional measures
                                     of activity)

                4.E. Placebo/      The rationale for       8
                  control group      the type of

                4.F.               A description of the    --
                  Practitioner       practitioners (eg,
                                     training and
                                     experience) who are
                                     a part of
                                     the intervention

Standard        Standard           Row      Text
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.
                                   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
                                                la liste des plantes,
                                                autres que les
                                                autorisees dans les
                                                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

                4.B.                          Bark
                  of the product

                                              Fresh bark coming from
                                                saw mills

                                   --         Extraction solvent =

                                              Purification solvent =
                                                ethyl acetate
                                              Ratio raw material
                                                (bark) / final
                                                extract: 1000 : 1

                                   --       According to the USP


                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

                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
                                              Mercury content <0.1
                                              Cadmium content < 1
                                              Pesticides: complies
                                                with Ph Eur 2.8.13
                                              Benzo(a)pyrene: <2
                                              Sum of benzo(a)-
                                                and chrysene : < 10
                                              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
                                                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

Supplementary materials

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.phymed.2016.08.007.


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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: (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)
    (mm Hg)
               Oligopin   150.20 (12.41)   143.84(12.26)

Diastolic      Placebo    82.63 (10.72)    80.89 (8.83)
    (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
    (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
    (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
    (mm Hg)

Diastolic      Placebo    -0.57     [-5.3: 4.2]   -0.69%     0.8048
    (mm Hg)


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)
  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
  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
HDL-c (mmol/l)     Placebo    0.22     [0.1; 0.4]     14.06%   0.0119
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)
Apolipoprotein     Placebo   -2.67     [-10.9; 5.6]   -2.58%   0.5079
  B-100 (mg/dl)
Ratio              Placebo   -0.08     [-0.2; -0.0)  -10.26%   0.0460
  B-100 A-1

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
Article Type:Report
Geographic Code:4EUSP
Date:Nov 15, 2016
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