1.

Arcangeli, 2000 1

CVI

R, DB, PC
n=40 with CVI (13 men, 27 women; aged 30-74 years)

2 months

300 mg/day Pycnogenol (1 capsule tid); or placebo.

100-mg capsules

Pycnogenol-treated patients had significant reductions in heaviness, swelling, and pain compared with placebo at day 30 (P<0.01, P<0.01, and P<0.05, respectively) and day 60 (P<0.01, P<0.01, and P<0.05, respectively). At study end, Pycnogenol-treated patients reported a 54% reduction in heaviness, a 64% reduction in swelling, and a 64% reduction in pain, compared with reductions of 3%, 7%, and 18%, respectively, in placebo-treated patients (P<0.01, P<0.01, and P<0.05, respectively). In both groups, there was no apparent change in venous blood flow, measured via Doppler ultrasound.

2.

Belcaro et al., 2005 2

Venous ulcers

PC
n=18 with severe CVI causing ulcerations (10 men and 8 women; mean age, 56.6 years)

6 weeks

[1] 150 mg/day Pycnogenol (3 capsules/day); [2]150 mg/day Pycnogenol (3 capsules/day) and topical application of 100 mg Pycnogenol powder covered with dressing and reapplied every 2 days; or [3] placebo. Standard compression stockings were supplied for all patients.

50-mg capsules

Starting at 2 weeks of treatment, oral plus local Pycnogenol treatment decreased ulcer size more efficiently than oral Pycnogenol alone and oral placebo (P<0.05 for both). At 6 weeks, microcirculation (pO2 and pCO2) was significantly improved with local and/or oral treatment (P<0.05 for both).

3.

Belcaro et al., 2017 3

Postpartum varicose veins

P, OL, Cm n=133 healthy women with postpartum varicose veins after the second pregnancy (mean age, 31 years)

6 months

100 mg/day Pycnogenol (2 tablets/day); or compression stockings alone.

50-mg capsules

At 6 months, the number of varicose veins and participants with edema were significantly less in the Pycnogenol group compared to the compression stockings group (P<0.05 for both). No participant in the Pycnogenol group had to stop treatment, while 35 out of 69 participants in the control group had to stop using the compression stockings or used them only irregularly.

4.

Belcaro et al., 2015a 4

CVI

OL, Cm
n=166 with symptomatic CVI awaiting surgery (89 men and 77 women; mean age, 43 years)

8 weeks

[1] 100 mg/day Pycnogenol; [2] 720 mg/day Antistax® (red vine [grape; Vitis vinifera var. tinctoria, Vitaceae] leaf extract; Sanofi; Paris, France) (2 tablets/day); or [3] compression stockings only.

100-mg Pycnogenol capsules; 360-mg Antistax tablets

Pycnogenol significantly improved microcirculatory parameters (rate of ankle swelling, resting flux, transcutaneous pO2, and morning ankle circumference) compared with baseline (P<0.05 for all) and comparedwith compression stockings and Antistax (P<0.05 for all).

5.

Cesarone et al., 2005 5

Travel-related edema in asymptomatic individuals

R, DB, PC
n=211 with mild-to-moderate thrombotic risk (mean age, 45 years; sex NR)

2 days

200 mg Pycnogenol 2-3 hours before flight (2 capsules), 200 mg Pycnogenol 6 hours later (2 capsules), and 100 mg Pycnogenol the following day (1 capsule); or placebo.

100-mg capsules

After the flight, edema score increased by 18% in the Pycnogenol-treated group and by 58% in the placebo-treated group (P<0.05). Ankle circumference increased by 6% in the Pycnogenol group and by 11% in the placebo group (P<0.05). Rate of ankle swelling increased by 36% in the Pycnogenol group and by 91% in the placebo group (P<0.05).

6.

Cesarone et al., 2006a 6

Venous micro-angiopathy

OL, C
n=39 with severe CVI (21 patients treated with Pycnogenol [11 men and 10 women; aged 42-60 years; mean age, 53 years]; 18 patients in the untreated control group [age and sex NR])

8 weeks

150 mg/day Pycnogenol (3 capsules/day); or no treatment (control). Compression stockings were not used.

50-mg capsules

Blood microcirculation was improved and capillary filtration and edema decreased significantly after 2 weeks of treatment compared with baseline (P<0.05 for all), and after 8 weeks compared with the control group (P<0.05 for all).

7.

Cesarone et al., 2006b 7

CVI

R, C
n=86 with CVI (48 men, 38 women; aged 40-61 years)

8 weeks

[1] 150 mg/day Pycnogenol (3 capsules/day); [2] 300 mg/day Pycnogenol (6 capsules/day); or [3] 1000 mg/day Daflon® (a combination formula containing 450 mg diosmin and 50 mg hesperidin that is used to treat CVI; Servier; Suresnes, France) (2 tablets/day).

50-mg Pycnogenol capsules; 500-mg Daflon tablets

Compared with baseline and Daflon, after 8 weeks of treatment, both doses of Pycnogenol resulted in significantly greater improvements in CVI signs, symptoms, and microcirculatory parameters (resting flux, rate of ankle swelling, edema, subjective symptoms, pO2, and pCO2) (P<0.05 for all, except edema, P<0.001 vs baseline).

8.

Cesarone et al., 2010a 8

CVI

R, OL, C, Cm
n=98 with CVI and edema (53 men and 45 women; mean age, 48 years)

8 weeks

[1] 150 mg/day Pycnogenol (3 capsules/day); [2] elastic stockings only; or [3] 150 mg/day Pycnogenol plus elastic stockings.

50-mg capsules

Pycnogenol alone was significantly more effective than stockings alone in relieving rate of ankle swelling, resting flux, transcutaneous pO2, and clinical symptom scores (P<0.05 for all); Pycnogenol plus stockings was the most efficacious group (P<0.05 for all).

9.

Koch, 2002 9

CVI

R, OL, C, Cm
n=40 with CVI (7 men and 33 women; aged 34-71 years)

4 weeks

360 mg Pycnogenol (3 tablets tid); or 600 mg HCSE (Venostasin® retard; Klinge Pharma GmbH; Holzkirchen, Germany; corresponding to 100 mg aescin/day) (2 capsules/day).

40-mg Pycnogenol tablets; 300-mg Venostasin capsules

Compared with HCSE, Pycnogenol produced a significantly greater decrease in heaviness, cramps, and nighttime swelling (edema) of both legs (P<0.05). Pycnogenol significantly reduced lower leg edema from baseline (P<0.01).

10.

Petrassi et al., 2000 10

CVI

Part 1: R, DB, PC
n=20 with CVI (3 men and 17 women; mean age, 42.2 years) Part 2: OL
n=20 with CVI (3 men and 17 women; mean age, 44.9 years)

2 months for each study part

300 mg Pycnogenol (1 capsule tid); or placebo.

100-mg capsules

Heaviness and swelling significantly declined in Pycnogenol-treated patients compared with placebo-treated patients (P<0.05) and compared with baseline (P<0.01). By day 60, there was a 60% decline in heaviness and a 74% decline in swelling in Pycnogenol-treated patients. Similar findings were apparent in patients treated with OL Pycnogenol.

11.

Riccioni et al., 2004 11

Venous insufficiency

OL, C, Cm
n=70 with CVI (22 men and 48 women; mean age, 47.5 years)

60 days

940 mg/day troxerutin with 40 mg/day Pycnogenol (2 sachets); or 1200 mg troxerutin (2 tablets bid).

Sachets with 470 mg troxerutin plus 20 mg Pycnogenol powder as instant drink (490-mg Flebil® Plus sachets); 300-mg troxerutin tablets (300-mg Flebil tablets) (Bracco; Milan, Italy)

After 60 days, there was complete absence of nocturnal cramps, itching, and pain in 96% of patients taking troxerutin/Pycnogenol (P<0.001); 80% troxerutin-treated patients reported complete symptom recovery (P<0.005). Three months after discontinuation, 88% of patients previously on Pycnogenol/troxerutin and 50% of patients who had taken troxerutin remained symptom free.

12.

Schmidtke & Schoop, 1995 12

Hydrostatic edema of lower limbs

R, DB, PC
n=40 with venous circulation problems in their legs (22 men and 18 women; age NR)

6 days

360 mg/day Pycnogenol (Pygenol®; Horphag Research; Geneva, Switzerland); or placebo. No compression therapy during the study.

20-mg tablets

After 6 days of treatment, patients treated with Pycnogenol had a significantly lower leg volume (measured after lying down and 2 hours of sitting) compared to that of placebo-treated patients (P<0.001).

13.

Belcaro et al., 2004 13

Venous thrombosis

R, DB, PC
n=198 with a moderate to high risk for DVT or superficial vein thrombosis (age and sex NR)

2 days

200 mg Pycnogenol 2-3 hours before flight (2 capsules), 200 mg Pycnogenol 6 hours later (2 capsules), and 100 mg Pycnogenol the following day (1 capsule); or placebo.

100-mg capsules

Significantly fewer superficial vein thrombosis events were reported in the Pycnogenol group compared to the placebo group (0 vs 4, respectively; P<0.05). None of the Pycnogenol-treated participants had a DVT, while 1 participant in the placebo group had a DVT. There was a significantly lower rate of events in the treatment group compared with placebo (0% vs 5.15%, respectively; P<0.025).

14.

Errichi et al., 2011a 14

Postthrombotic syndrome

OL, C
n=156 with a single major episode of proximal DVT (66 men and 90 women; aged 35-50 years)

12 months

[1] Compression stockings; [2] 150 mg/day Pycnogenol (1 tablet tid); or [3] compression stockings plus 150 mg/day Pycnogenol (1 tablet tid).

50-mg tablets

At 6 months, all 3 treatments significantly improved edema, limb volume, and ankle circumference compared with baseline (P<0.05). Both Pycnogenol groups had significantly more improvement than the compression stockings-only group (P<0.05). The Pycnogenol plus stockings group was significantly more effective than Pycnogenol alone (P<0.05). All improvements persisted to 12 months. Pycnogenol was well-tolerated.

15.

Rodriguez et al., 2015 15

Nonischemic retinal vein thrombosis

P, OL
n=77 with a single episode of retinal vein thrombosis (43 men and 34 women; mean age, 45 years)

9 months

[1] 100 mg/day Pycnogenol plus standard management; [2] 100 mg/day aspirin plus standard management; [3] standard management only.

50-mg capsules

Recurrent retinal vein thrombosis was observed in 17.39% of controls, 15.38% of the aspirin group, and 3.56% of the Pycnogenol group. Pycnogenol was significantly better at reducing the edema score, and resulted in better improvement of visual acuity (P<0.05).

16.

Belcaro et al., 2006a 16

Diabetic ulcers

R, OL, C
n=30 with diabetic ulcers (14 men and 16 women; mean age, 54 years)

6 weeks

[1] 150 mg/day oral Pycnogenol (3 capsules/day) plus 100 mg topical Pycnogenol powder from capsules placed on ulcerated skin; [2] 150 mg/day oral Pycnogenol; [3] 100 mg topical Pycnogenol powder; or [4] no Pycnogenol (standard care only). All groups received standard ulcer care.

50-mg capsules

Oral and/or local treatment was significantly more effective than standard compression treatment for reducing ulcer size (P<0.05 and P<0.01, respectively). Combination therapy was more effective than local or oral therapy alone. Microcirculation (pO2 and pCO2) and microvascular response (laser Doppler) were significantly improved with oral or oral plus topical treatment compared with baseline (P<0.05 for both).

17.

Cesarone et al., 2006c 17

Diabetic micro-angiopathy

PC
n=60 with stable diabetes and severe microangiopathy with edema (34 men and 26 women; aged 55-68 years; mean age, 59 years)

4 weeks

150 mg/day Pycnogenol (3 capsules/day); or placebo. Diabetic treatment was continued.

50-mg capsules

Pycnogenol significantly decreased capillary filtration vs baseline and control (P<0.05 for both). Venoarteriolar response significantly increased with Pycnogenol vs baseline and control (P<0.05 for both). Foot skin flux at rest significantly decreased with Pycnogenol vs baseline and control (P<0.05 for both). There was a clinically significant, rapid (5-8 days) decrease in edema in Pycnogenol-treated patients with the most severe, visible foot and ankle edema (n=14). No AEs were observed.

18.

Liu et al., 2004a 18

Type 2 diabetes

R, DB, PC
n=77 with type 2 diabetes (44 men and 23 women; aged 45-66 years)

12 weeks

100 mg/day Pycnogenol (2 tablets/day); or placebo. Patients continued their antidiabetic medication.

50-mg tablets

Median fasting plasma glucose had a maximum reduction after 8 weeks of treatment (−1.97 mmol/L), which was maintained throughout the rest of the trial. Pycnogenol significantly decreased fasting plasma glucose greater than did placebo at all time intervals (P<0.01 for all); HbA1c was lowered (P<0.01) significantly but only until 1 month; and plasma endothelin-1 decreased and prostacyclin metabolites increased significantly compared with placebo (P<0.01 for both).

19.

Liu et al., 2004b 19

Type 2 diabetes

OL
n=30 with type 2 diabetes (18 men and 12 women; aged 28-64 years)

12 weeks

50, 100, 200, and 300 mg/day Pycnogenol (1 tablet/day, 2 tablets/day, 4 tablets/day, 6 tablets/day, respectively). Each dosage for 3 weeks.

50-mg tablets

There was dose-dependent lowering of fasting and postprandial blood glucose and HbA1c. There was significant lowering of postprandial blood glucose beginning at 50 mg (P<0.05). Fasting blood glucose was lowered significantly from 100 mg (P<0.05). Maximum effects were seen with 200 mg Pycnogenol.

20.

Steigerwalt et al., 2009 20

Early diabetic retinopathy

R, DB, PC
n=46 with controlled diabetes mellitus type 2 for ≥ 4 years and a moderate degree of diabetic retinopathy (29 men and 17 women; mean age, 51.5 years)

3 months

150 mg/day Pycnogenol (1 tablet tid); or placebo.

50-mg tablets

Of the patients with moderate macular edema (n=21), Pycnogenol significantly improved visual acuity, retinal edema, retinal flow, diastolic flow relative to maximal systolic flow, and retinal thickness, compared with placebo (P<0.05 for all). Of the patients with mild macular edema (n=25), Pycnogenol significantly improved visual acuity (at 2 months only), retinal edema, retinal flow, and diastolic flow relative to maximal systolic flow, compared with placebo treatment (P<0.05 for all). No AEs were observed.

21.

Belcaro et al., 2006b 21

Antihypertensive treatment-induced edema

B, PC
n=53 with edema after treatment with ACE inhibitors or the calcium antagonist nifedipine (29 men and 24 women; mean age, 47.7 years)

8 weeks

150 mg/day Pycnogenol (3 capsules/day); or placebo.

50-mg capsules

There was significant lowering of abnormal capillary filtration in Pycnogenol-treated patients medicated with nifedipine or ACE inhibitors compared with baseline and placebo (P<0.05 for all). No significant effects were seen with placebo.

22.

Cesarone et al., 2010b 22

Hypertension-associated kidney disease

OL, C
n=55 with hypertension who were symptomatic for cardiovascular disease and had altered kidney function (34 men and 21 women; mean age, 53.5 years)

6 months

10 mg/day ramipril (2 tablets/day); or 10 mg/day ramipril (2 tablets/day) plus 150 mg/day Pycnogenol (3 tablets/day).

50-mg Pycnogenol tablets; 5-mg ramipril

Ramipril was effective for all parameters compared to baseline. Ramipril plus Pycnogenol was significantly more effective than ramipril alone in decreasing diastolic BP (P<0.05), heart rate (P<0.05), serum creatinine (P<0.05), leukocyte count (P<0.05), CRP (P<0.05), and 24-hour urinary albumin excretion (P=0.002), and increasing kidney blood flow and perfusion (P<0.05). Pycnogenol was well-tolerated.

23.

Hosseini et al., 2001a 23

Mild hypertension

R, DB, PC, CO
n=11 with systolic BP of 140-159 mmHg and/or diastolic BP of 90-99 mmHg (7 men and 4 women; mean age, 50 years)

16 weeks

200 mg/day Pycnogenol (2 capsules bid); or placebo.

50-mg capsules

Systolic BP decreased from a mean of 140 mmHg to 133 mmHg after 8 weeks of Pycnogenol treatment. The decrease was significantly more than that of placebo treatment (P<0.05). Pycnogenol was less effective in patients with BP < 140 mmHg. Decrease of diastolic BP did not reach significance. Thromboxane levels decreased from baseline with Pycnogenol (P<0.05).

24.

Liu et al., 2004c 24

Assess whether Pycnogenol can reduce dose of nifedipine used to treat hypertension

R, DB, PC, PG
n=58 with hypertension (33 men and 25 women; mean age, 57 years)

12 weeks

100 mg/day Pycnogenol (2 tablets/day); or placebo. All patients were given ≥ 20 mg of sustained-release nifedipine (Shanghai Pharmaceuticals Co., Ltd.; Shanghai, China) (dose adjusted in 5-mg increments until stable BP reached).

50-mg tablets

Supplementation with Pycnogenol significantly reduced the dose of nifedipine needed to normalize BP compared with placebo (P<0.001). Pycnogenol-treated patients had a significantly greater increase in 6-keto-prostaglandin F1α values than placebo-treated patients (12% vs 8% increase, respectively; P<0.05), which shows significant improvement in endothelial function.

25.

Stuard et al., 2010 25

Hypertension with metabolic syndrome-associated kidney disease

OL, C
n=58 with hypertension, metabolic syndrome, and early kidney function impairment (31 men and 27 women; mean age, 58.5 years)

6 months

10 mg/day ramipril (2 tablets/day); or 10 mg/day ramipril (2 tablets/day) plus 150 mg/day Pycnogenol (3 tablets/day).

50-mg Pycnogenol tablets; 5-mg ramipril tablets

Ramipril plus Pycnogenol was significantly more effective than ramipril alone for decreasing systolic and diastolic BP, fasting glucose, HbA1c, urinary albumin, serum creatinine, CRP, and fibrinogen, and improving kidney blood flow and perfusion (P<0.05 for all). Pycnogenol was well-tolerated.

26.

Zibadi et al., 2008 26

Hypertension with non-insulin-dependent type 2 diabetes

R, DB, PC
n=48 with non-insulin-dependent type 2 diabetes and hypertension (treated with ACE inhibitors) (27 men and 21 women; mean age, 59.5 years)

12 weeks

125 mg/day Pycnogenol (1 tablet 5x/day); or placebo.

25-mg tablets

Significantly more Pycnogenol-treated patients (58.3%) vs placebo-treated patients (20.8%) reduced their dose of BP medication by 50% (P<0.05). Pycnogenol-treated patients vs placebo-treated patients had significant reductions in plasma endothelin-1 (P<0.001), mean HbA1c (P<0.05), fasting plasma glucose (P<0.0001), LDL cholesterol (P<0.001), and urinary albumin (P<0.05, at 8 weeks only). AEs were NR.

27.

Enseleit et al., 2012 27

Endothelial function

DB, PC, CO
n=23 with stable coronary artery disease receiving optimal standard therapy (19 men and 4 women; aged 49-73 years)

8 weeks

200 mg/day Pycnogenol; or placebo.

NR

FMD significantly increased with Pycnogenol treatment vs placebo treatment (P<0.0001). 15-F2t-isoprostanes significantly decreased after Pycnogenol treatment but not after placebo treatment (P=0.012). There were no significant changes between groups in BP, markers of inflammation, or platelet adhesion.

28.

Hu et al., 2015 28

Endothelial function

OL, P
n=32 with borderline hypertension, n=30 with borderline hyperglycemia, n=31 with borderline hyperlipidemia, and n=31 untreated controls

12 weeks

[1] 150 mg/day Pycnogenol plus diet and exercise modification; [2] diet and exercise modification only; or [3] no treatment.

NR

With Pycnogenol, FMD and flux increased at 8 and 12 weeks (P<0.05 vs baseline). No effects were found in controls or normal participants; however, there was no significant difference between Pycnogenol and control. Pycnogenol significantly normalized BP in participants with borderline hypertension (P<0.05), reduced cholesterol levels in participants with borderline hyperlipidemia (P<0.05), and improved fasting glucose in participants with borderline hyperglycemia (P<0.05). No AEs were observed during the study period.

29.

Belcaro et al., 2013a 29

Asymptomatic metabolic syndrome

OL, C
n=130 with all 5 risk factors of metabolic syndrome (64 men and 66 women; aged 45-55 years)

6 months

150 mg/day Pycnogenol (3 tablets/day); or no treatment. All patients received diet and weight management programs.

50-mg tablets

There were significant improvements in the Pycnogenol group vs the control group in waist circumference, plasma free radicals, fasting glucose, triglyceride levels, HDL levels, and BP (P<0.05 for all). No AEs were observed. Compliance and tolerability were good. No significant changes were seen in ALT, AST, GGT, ALP, CRP, serum creatinine, blood cell count, fibrinogen, INR for prothrombin time, or hematocrit.

30.

Belcaro et al., 2011 30

Allergic asthma

OL, C
n=65 with mild-to-moderate allergic asthma (house dust mite) (34 men and 31 women; aged 25-45 years)

6 months

100 mg/day Pycnogenol (1 tablet tid) plus 100-500 µg/day fluticasone propionate steroid inhalation; or 100-500 µg/day fluticasone propionate steroid inhalation only (control).

50-mg tablets

More Pycnogenol-treated patients compared with steroid-only-treated patients had an improvement in steroid dose steps (55% vs 6.3%, respectively; P=0.25). Significantly more of the steroid-only group deteriorated to a higher-dose step vs the Pycnogenol group (18.8% vs 0%, respectively; P<0.02). There was a significant improvement in the number of days with a peak expiratory flow < 80% in the Pycnogenol group vs the steroid-only group (P<0.05). Compared with baseline, the Pycnogenol group had significant improvements in nighttime awakenings, dry cough, chest tightness, wheezing, dyspnea, and daytime asthma symptoms (P<0.05 for all); the steroid-only group had no significant improvement in any of these parameters. No AEs occurred.

31.

Hosseini et al., 2001b 31

Asthma

R, DB, PC, CO
n=22 with asthma (10 men and 12 women; aged 18-60 years)

8 weeks

1 mg/lb/day Pycnogenol (maximum 200 mg/day); or placebo.

20-mg capsules

Lung function (FEV1/forced vital capacity) significantly improved with Pycnogenol compared to placebo (P=0.003). Leukotriene levels significantly decreased with Pycnogenol compared to placebo (P<0.001).

32.

Lau et al., 2004 32

Childhood asthma

R, DB, PC
n=60 children with asthma (35 boys and 25 girls; aged 6-18 years)

3 months

1 mg/lb/day Pycnogenol in 2 divided doses; or placebo.

20-mg tablets

Lung function (peak expiratory flow), asthma symptom score, frequency of albuterol usage (rescue medication), and urinary leukotriene levels were significantly improved beginning from 1 month of Pycnogenol treatment compared with baseline (P<0.001). All parameters further improved after 2 and 3 months of treatment.

33.

Trebatická et al., 2006 33

Childhood ADHD

R, DB, PC
n=61 children with clinically diagnosed ADHD for at least 6 months (50 boys and 11 girls; aged 6-14 years)

1 month, followed by 1-month washout

1 mg/kg/day Pycnogenol; or placebo.

20-mg tablets

Pycnogenol was effective according to 2 of 4 ADHD assessments. On the Child Attention Problems Rating Scale, teachers reported significant improvements in hyperactivity and inattention compared with baseline (P<0.01) and placebo (P<0.05). After a 1-month washout period, the scores returned to baseline values. On the Conners’ Teacher Rating Scale, improvement for inattention was significantly different from baseline and placebo, but not for hyperactivity. ADHD symptoms as evaluated by parents did not significantly decline compared with baseline or placebo. Psychologist assessment of visual-motor coordination and concentration revealed significant improvements compared with baseline (P=0.019) and placebo (P=0.05).

34.

Errichi et al., 2011b 34

Menopause transition

R, B, PC
n=70 healthy perimenopausal women (aged 41-49 years)

8 weeks

100 mg/day Pycnogenol (1 tablet tid); or placebo.

50-mg tablets

The following symptoms were significantly improved in the Pycnogenol group vs the placebo group (P<0.05): hot flashes, bloating, irregular heartbeat, pain feeling like electric shocks, and digestive problems. The following symptoms were significantly improved in the Pycnogenol group vs baseline (P<0.05): night sweats, irregular periods, loss of libido, vaginal dryness, mood swings, fatigue, hair loss, brittle nails, difficulty concentrating, memory lapses, dizziness, weight gain, depression, anxiety, irritability, panic disorder, breast pain, headaches, joint pain, gum problems, muscle tension, itchy skin, and tingling extremities. The control group did not have any significant change in any of these symptoms. There were no AEs.

35.

Kohama & Negami, 2013 35

Menopause transition

R, DB, PC, PG
n=170 healthy perimenopausal women (aged 42-58 years)

12 weeks

60 mg/day Pycnogenol (1 tablet tid); or placebo.

30-mg tablets

There were significant improvements in the Pycnogenol group vs the placebo group in vasomotor symptoms (P=0.036; hot flashes, sweating, cold sensation of the body and limbs, and shortness of breath), insomnia/sleeping problems (P=0.003; difficulty falling asleep, easily awaking during the night, awakening too early in the morning with the inability to return to sleep, and tired when getting up), and feeling tired and worthless (P=0.048). There were no significant changes in BP, HDL, LDL, triglycerides, total cholesterol, IGF-1, IGFBP-3, E2, FSH, or DHEA sulfate in either group.

36.

Maia et al., 2014a 36

Endometriosis

P, OL, C, R
n=45 women with endometriosis and pelvic pain (aged 22-37 years)

3 months

[1] 75 µg/day gestodene and 30 µg/day ethinylestradiol; [2] 75 µg/day gestodene, 30 µg/day ethinylestradiol, and 100 mg/day Pycnogenol; [3] 3 mg/day drospirenone and 30 µg/day ethinylestradiol; or [4] 3 mg/day drospirenone, 30 µg/day ethinylestradiol, and 100 mg/day Pycnogenol.

50 mg Pycnogenol

All groups had a significant decrease in pain scores after 3 months of treatment (P<0.001 vs baseline); however, the reduction was significantly greater in the groups using Pycnogenol (P<0.01 for both). Most patients taking Pycnogenol with an oral contraceptive (56%) had complete resolution of pain.

37.

Maia et al., 2014b 37

Dysmenorrhea

R, OL, C
n=24 women with severe dysmenorrhea and pelvic pain who failed to respond to treatment with 21-day/7-day oral contraceptives (aged 17-38 years; mean age, 29 years)

3 months

Oral contraceptive containing 60 mg gestodene and 15 μg ethinylestradiol in a 24-day/4-day regimen alone or with 100 mg/day Pycnogenol.

Pycnogenol: Flebon® (Farmoquímica S.A.; Rio de Janeiro, Brazil); Oral contraceptive: Adoless® (Farmoquímica S.A.)

Both treatments significantly reduced pain by the end of the third cycle; however, the reduction in pain scores was significantly greater in the Pycnogenol combination group compared to the oral contraceptive-only group (P<0.0001 in the abstract; P=0.0001 in the text). A total of 27% of the patients in the Pycnogenol combination group became pain-free during the hormone-free interval, while none of the patients in the oral contraceptive-only group became pain-free. The number of bleeding days also was lower in the Pycnogenol combination group.

38.

Yang et al., 2007 38

Menopause transition

R, DB, PC
n=200 healthy perimenopausal women (who had no menstrual cycles for 3-11 months and then normal cycles reappeared) (mean age, 46.9 years)

6 months

200 mg/day Pycnogenol (1 capsule bid); or placebo.

100-mg capsules

Compared with baseline and placebo, Pycnogenol-treated participants had significant improvements in the severity and frequency of the following climacteric symptoms: somatic problems, depression, vasomotor problems, memory/concentration, feelings of attractiveness, anxiety, sexual behavior, sleep, and menstrual problems (P<0.01 for all). Improvements were evident at 1 month.

39.

Kohama et al., 2004 39

Dysmenorrhea

OL
n=47 women with symptoms of dysmenorrhea (aged 21-45 years)

3 complete menstrual cycles; 64 days

60 mg/day Pycnogenol (1 capsule bid).

30-mg capsules

Compared with baseline, abdominal pain scores declined after Pycnogenol intake (P<0.05 for cycle 1; P<0.01 for cycle 2). Back pain scores significantly declined only after Pycnogenol was taken over 2 menstrual cycles (P<0.01). There was no significant change in the number of days with abdominal pain.

40.

Suzuki et al., 200840

Dysmenorrhea

R, DB, PC
n=116 women with symptoms of menstrual pain (aged 18-48 years)

4 menstrual cycles

60 mg/day Pycnogenol (2 capsules/day); or placebo for 2 menstrual cycles.

30-mg capsules

Menstrual pain decreased more in the Pycnogenol group than in the placebo group. Compared with placebo, Pycnogenol treatment reduced both the quantity of analgesics used by patients with dysmenorrhea (4.4 pills vs 2.6 pills, respectively) and the number of days during which analgesic medication was required for dysmenorrhea (1.7 days vs 1.2 days, respectively). These effects persisted after Pycnogenol treatment ceased (P<0.05 for both). The quality-of-life assessment (SF-36) and the physical and mental component summaries of the SF-36 revealed no significant differences between groups, except for the bodily pain score (P<0.05 for Pycnogenol vs placebo).

41.

Kohama et al., 2007 41

Endometriosis

R, OL, Cm
n=58 women who had undergone conservative operations for endometriosis within the previous 6 months but still had recurrent moderate-to-severe dysmenorrhea or other pelvic pain or disorders (aged 21-39 years)

48 weeks Pycnogenol; 24 weeks leuprorelin, followed by 24-week washout

60 mg/day Pycnogenol (1 capsule bid); or GnRH-a therapy as injected leuprorelin acetate depot, 3.75 mg intracutaneously, 6x every 4 weeks for 24 weeks.

30-mg Pycnogenol capsules; 3.75-mg leuprorelin acetate depot injections

Treatment with Pycnogenol slowly reduced all of the following symptom scores from severe (at baseline) to moderate: menstrual pain (P<0.01 at all time points), pelvic pain (P value not significant at 4 weeks; P<0.01 at 12, 24, and 48 weeks), pelvic tenderness (P<0.05 at 4 weeks; P<0.01 at 12, 24, and 48 weeks), and pelvic induration (P<0.05 at 4 weeks; P<0.01 at 12, 24, and 48 weeks). GnRH-a therapy also reduced all scores, but did so more quickly, and lowered the scores significantly more than Pycnogenol. However, patients treated with GnRH-a had a recurrence of symptoms following discontinuation of treatment. GnRH-a suppressed menstruation during treatment and lowered estrogen levels; Pycnogenol did not. The serum marker CA-125 for endometriosis decreased in both groups.

42.

Kohama & Inoue, 2006 42

Pain in pregnancy

OL, C
n=140 women in the third trimester of pregnancy with lower back, hip, pelvic, or calf pain (mean age, 29.8 years)

Throughout the third trimester of pregnancy until delivery

30 mg/day Pycnogenol (1 tablet/day); or no treatment (control).

30-mg tablets

After 2 and 6 weeks of Pycnogenol treatment, there was significant improvement of pain scores related to hip joint pain, lower back pain, inguinal pain, pain due to varices, and calf cramps (P<0.01 for all vs baseline). There were no significant effects in the untreated control group.

43.

Belcaro et al., 2008a 43

OA

R, DB, PC

n=156 with primary OA grade 1 or 2 in 1 or both knees (78 men and 78 women; mean age, 48 years)

3 months

100 mg/day Pycnogenol

(2 tablets/day); or placebo.

50-mg tablets

The global WOMAC score showed a 50% decrease from baseline in OA symptoms in Pycnogenol-treated patients (P<0.05), which was significantly better than placebo treatment (P<0.05). Pycnogenol treatment resulted in a significant mean increase in muscular/walking performance compared with placebo (P<0.05). At the end of treatment, 79% of Pycnogenol-treated patients and 1% of placebo-treated patients had a decrease in edema.

44.

Cisar et al., 2008 44

OA

R, DB, PC

n=100 with primary knee OA grade 1 or 2 and pain (32 men and 68 women; mean age, 54 years)

3 months

150 mg/day Pycnogenol

(1 tablet tid); or placebo.

50-mg tablets

For Pycnogenol-treated patients, pain and the WOMAC score characterizing ability to perform daily activities were not significantly different from placebo at inclusion. However, the overall WOMAC score was significantly different between groups at 1.5, 2, and 3 months (P<0.05 for all). Compared with placebo, stiffness significantly improved with Pycnogenol at 2 and 3 months (P<0.05 for both). Use of analgesics was decreased by 38% in the Pycnogenol group and by 8% in the placebo group.

45.

Farid et al., 2007 45

OA

R, DB, PC, PG

n=37 with primary knee OA grade 1 or 2 and pain (3 men and 34 women; aged 25-65 years; mean age, 48 years)

3 months

150 mg/day Pycnogenol

(1 tablet tid); or placebo.

50-mg tablets

At 3 months, there were “relevant” and significant reductions in pain (43% reduction), stiffness (35% reduction), physical dysfunction (52% reduction), and composite score (49% reduction) with Pycnogenol treatment; there were no significant changes with placebo. Pycnogenol treatment resulted in a significant decrease in the use of pain medicine, in both the number of pills and number of days compared with baseline (P<0.001 for both).

46.

Ďuračková et al., 2003 46

Erectile dysfunction and

hypercholesterolemia

R, DB, PC
n=21 men with erectile dysfunction (mean age,

46.5 years)

3 months, followed by

1-month washout

120 mg Pycnogenol (2

tablets tid); or placebo.

20-mg tablets

Erectile function score improved from moderate dysfunction to mild dysfunction after 3 months of Pycnogenol treatment. Placebo treatment did not cause an improvement.

47.

Spadea & Balestrazzi, 2001 47

Retinal vascular disorders

R, DB, PC
n=40 with vascular disorders of the retina secondary to atherosclerosis, diabetes, hypertension, or thrombosis of the central retinal vein (age and sex unclear)

2 months

150 mg Pycnogenol (1

tablet tid); or placebo.

50-mg capsules

Pycnogenol slowed deterioration

of visual acuity compared

with placebo (P<0.05). [Note:

After commencing the study,

the authors added 20 additional

patients treated with OL

Pycnogenol for 3 months. They

combined much of the data,

which is not methodologically

appropriate.]

48.

Kimbrough et al., 2002 48

Gingival bleeding and dental plaque

DB, PC, R
n=40 dental students (20 men and 20

women; aged

22-35 years)

2 weeks

30 mg Pycnogenol (6 chewing gums daily); or control chewing gum (Trident® gum; Mondelēz International, Inc.; Deerfield, Illinois).

5-mg chewing gums

Pycnogenol gum produced a significant lowering of gingival bleeding compared with baseline (P<0.05) and did not alter plaque formation. Trident gum (placebo) did not alter gingival bleeding, and increased plaque formation compared with baseline (P<0.05).

49.

Belcaro et al., 2014a 49

Plaque psoriasis

OL, P

n=73 with

moderate-to-severe plaque

psoriasis (47 men and 26

women; aged

30-45 years)

12 weeks

150 mg/day Pycnogenol (1 tablet tid) plus standard care; or standard care alone (control).

50-mg tablets

The Pycnogenol group had a significantly greater decrease in the area of skin affected by psoriasis in all body regions compared with control (P<0.05). Pycnogenol significantly improved erythema, induration, and desquamation (P<0.05 for all). The Pycnogenol group had significantly greater skin hydration compared to control (P<0.05).

50.

Marini et al., 2012 50

Skin elasticity and hydration

OL

n=20 healthy postmenopausal women (aged 55-68 years)

12 weeks

75 mg/day Pycnogenol (3 capsules/day).

25-mg Pycnogenol capsules

At 6 weeks, but not at 12 weeks, women with dry skin (n=13) had a 21% increase in hydration (P=0.02). At 6 and 12 weeks, all women had a significant increase in skin elasticity (P≤0.02).

51.

Ni et al., 2002 51

Hyper-pigmentation (melasma)

OL
n=30 women with melasma for a mean of 8 years (aged 29-59 years; mean age, 41 years)

30 days

75 mg Pycnogenol (1 tablet tid).

25-mg tablets

Pigmentary intensity and size of affected skin were significantly reduced (P<0.001 for both).

52.

Saliou et al., 2001 52

UV light-induced erythema (sunburn)

OL

n=22 fair-skinned participants (3 men and 19 women; mean age, 23.6 years)

8 weeks (4 weeks/dose)

1.10 mg/kg/day Pycnogenol for 4 weeks and then 1.66 mg/kg/day Pycnogenol for another 4 weeks.

NR

The minimal erythema dose, the dose of UV light required to induce erythema, dose-dependently and significantly increased vs baseline (P<0.05). This indicates Pycnogenol reduced the risk of sunburn.

53.

Vinciguerra et al., 2006 53

Muscle cramps and pain

Part 1: OL

n=66 (22 normal participants with cramps ≥ 4x/week [11 men and 11 women; mean age, 38.7 years], 21 patients with venous diseases and cramps 4-6x/week [10 men and 11 women; mean age, 47.4 years], and 23 athletes with frequent cramps during exercise [12 men and 11 women; mean age, 28.4 years])

Part 2: DB, PC

n=47 (25 patients with intermittent claudication and 22 patients with diabetic microangiopathy; 33 men and 14 women; mean age, 60 years)

4 weeks, followed by 1-week washout

200 mg/day Pycnogenol (two 50-mg capsules or

one 100-mg capsule bid); or placebo.

50-mg capsules or 100-mg capsules

Frequency of cramps and muscle pain score decreased significantly after 4 weeks of treatment and after 1 week of discontinuation in athletes, normal participants, and patients with venous problems (P<0.05 for all). Frequency of cramps and muscle pain score decreased significantly in patients with intermittent claudication or diabetic microangiopathy after 4 weeks of treatment and 1 week of discontinuation compared with baseline (P<0.05 for all). There was no effect in placebo-treated patients.

54.

Belcaro et al., 2010a 54

Acute hemorrhoids

R, B, PC
n=84 with an acute episode of external hemorrhoids (47 men and 37 women; mean age, 49

years)

7 days

[1] 300 mg/day oral Pycnogenol for 4 days (6 tablets/day) followed by 150 mg/day Pycnogenol for 3 days (3 tablets/day); [2] oral placebo for 7 days; [3] oral Pycnogenol as described for [1] plus topical 0.5% Pycnogenol cream (dosage not indicated) for 7 days; or [4] oral Pycnogenol as described for [1] plus a sham cream for 7 days.

50-mg tablets

Compared with the placebo group, the 3 Pycnogenol groups had significantly greater decreases in signs/symptoms (P<0.05). The patients treated with oral plus topical Pycnogenol had a significantly faster and better improvement than the other groups (P<0.05). Hemorrhoidal bleeding completely resolved in all patients taking Pycnogenol but was not resolved in the placebo-treated patients. Compared with placebo, the Pycnogenol groups had significant improvements in social quality of life (P<0.021).

55.

Belcaro et al., 2014b 55

Postpartum hemorrhoids

OL, C, P

n=70 women with third- or fourth-degree hemorrhoids after their second pregnancy (mean age, 32 years)

6 months

4-6 tablets Pycnogenol (1 tablet/12 kg) for 1 week and then 150 mg Pycnogenol (3 tablets, 1 tablet every 8 hours) plus standard best management; or standard best management only (control).

50-mg tablets

In the third-degree hemorrhoid group, 75% of the Pycnogenol group and 56% of the control group were symptom-free at 6 months (P<0.05). In the fourth-degree hemorrhoid group, 70% of the Pycnogenol group and 36% of the control group were symptom-free at 6 months (P<0.05).

56.

Wilson et al., 2010 56

Allergic rhinitis

R, DB, PC, P
n=60 with a positive allergy response to birch pollen

(21 men and 39

women; aged

18-65 years)

12 weeks (including 3-4 weeks prior to birch pollen season; n=19) or 14 weeks (including 7-8 weeks prior to birch pollen season; n=41)

100 mg Pycnogenol

(1 tablet bid); or placebo.

50-mg tablets

Pycnogenol taken for more than 5 weeks before onset of birch allergy season decreased nasal and ocular symptoms compared with placebo; however, the difference was not statistically significant.

57.

Belcaro et al., 2013b 57

Common cold

C, OL, P

Part 1: n=73 with first signs of a probable cold (35 men and 38 women; aged 25-70 years).

Part 2: n=73 with first signs of a probable cold (35 men and 38 women; aged 25-70 years).

Part 1: Approximately 1 week (varied with duration of symptoms)

Part 2:
5 days

Part 1: 100 mg Pycnogenol (1 tablet bid); or no Pycnogenol (control).

Part 2: [1] 100 mg Pycnogenol (1 tablet bid) plus 200 mg/day vitamin C; [2] 100 mg Pycnogenol (1 tablet bid) plus 30 mg/day zinc gluconate; or [3] supplement containing 100 mg Pycnogenol, 30 mg zinc gluconate, and 200 mg vitamin C. All treatments were in addition to standard care.

50-mg tablets

Part 1: Days with disease were significantly decreased in the Pycnogenol group compared with control (6.5 days vs 8.2 days, respectively; P<0.05).

Part 2: The tricomplex supplement was the most effective treatment at decreasing days with disease, lost days of work, and use of other on-demand treatment. There were no AEs.

58.

Belcaro et al., 2008b 58

AEs associated with oncologic treatment

P, B, PC

[1] n=64 post surgery for solid tumor cancer and scheduled for chemotherapy (32 men and 32 women; mean age, 50.5 years); [2] n=46 post surgery for solid tumor cancer and scheduled for radiotherapy (18 men and 28 women; mean age, 51.5 years)

2 months

150 mg/day Pycnogenol (1 tablet tid), starting the

day after the first cycle of

chemotherapy/radiotherapy; or placebo.

50-mg tablets

No statistical analyses were conducted. The Pycnogenol group had fewer AEs (especially nausea, vomiting, diarrhea, edema, weakness, mouth/throat soreness and ulceration, dry mouth, and dry eyes) associated with cancer treatment vs placebo.

59.

Grossi et al., 2010 59

Idiopathic tinnitus

P, C
n=82 with mild-to-moderate idiopathic, unilateral tinnitus for ≥ 2 weeks (27 men and 55 women; aged 35-55 years)

4 weeks

[1] 150 mg/day Pycnogenol (1 tablet tid); [2] 100 mg/day Pycnogenol (1 tablet bid); or [3] no treatment (control).

50-mg tablets

Pycnogenol significantly improved diastolic and systolic flow velocity vs baseline (P<0.05), but was not significantly different from control. Pycnogenol significantly improved subjective severity of tinnitus vs control (P<0.05), with the 150-mg dose significantly more effective than the 100-mg dose (P<0.05). The 100-mg and 150-mg dose groups had a significant improvement on the tinnitus scale vs baseline (P<0.05), but not the controls.

60.

Belcaro et al., 2014c 60

Cognitive function, attention, and mental performance

P, OL, C

n=59 healthy professionals with high oxidative stress (34 men and 25 women; aged 35-55 years)

12 weeks

150 mg/day Pycnogenol (3 tablets/day); or no treatment (control).

50-mg tablets

The Pycnogenol group performed significantly better than the control group on measures of attention, mental performance, sustained attention, memory, executive functions, mood, and cognitive function (P<0.05 for all, except mood, P<0.01).

61.

Belcaro et al., 2015b 61

Cognitive function, attention, and mental performance

P, OL, C

n=77 healthy participants with high oxidative stress (41 men and 36 women; aged 55-70 years)

12 months

100 mg/day Pycnogenol (2 capsules/day); or no treatment (control).

50-mg capsules

At 12 months, the Pycnogenol group had significant increases in attention, mental performance, sustained attention, memory, executive functions, mood, daily tasks, and the IQCODE compared with control (P<0.05 for all).

62.

Luzzi et al., 2011 62

Cognitive function, attention, and mental performance

OL, C

n=108 healthy university students with “average” test performance (53 men and 55 women; aged 18-27 years)

8 weeks

100 mg/day Pycnogenol (2 tablets/day); or no treatment (control).

50-mg tablets

Pycnogenol vs untreated control and vs baseline significantly improved sustained attention, items recalled, pattern recognition memory, mental flexibility, planning ability, and mood (P<0.05 for all). Significantly fewer Pycnogenol-treated participants vs control participants failed the university exam (P=0.043).

63.

Ryan et al., 2008 63

Cognition

R, DB, PC

n=101 elderly participants without chronic disease (46 men and 55 women; aged 60-85 years; mean age, 67.8 years)

3 months

150 mg/day Pycnogenol (bid, divided dose); or placebo.

50-mg tablets

At 3 months, Pycnogenol vs placebo significantly improved spatial working memory and quality of working memory (P<0.05 for both). There were no significant improvements for other aspects of cognitive performance, namely, concentration/attention, episodic memory, and psychomotor abilities. The Pycnogenol group had a significant decrease in plasma F2-isoprostane concentrations compared with placebo (P<0.01). There were no significant differences between groups in hepatic enzymes, cholesterol, triglycerides, HDL, LDL, postprandial glucose, or human growth hormone. AEs were NR.