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Excerpt:

6.1. Asthma

From the peer-reviewed literature, two main important studies deal with the use of PYC for the management of chronic asthma. In the first one appearing on PubMed [17] authors evaluated the efficiency of this agent in a randomized, double-blinded, placebo-controlled, crossover study in patients with varying asthma severity. For that twenty-six patients who fulfilled the American Thoracic Society criteria for asthma were enrolled in the study. The patients were randomly assigned to receive either 1 mg/lb/day (maximum 200 mg/day) PYC or a placebo for the first period of 4 weeks and then crossed over to the alternate regimen for the next 4 weeks. No adverse effects were observed related to the study drug. Contrary to placebo almost all responded favorably to PYC, moreover, compared with placebo PYC treatment also significantly reduced serum leukotrienes. Anyway, the same authors recommend that further clinical trials should be conducted in larger groups of asthmatics to establish this type of efficacy. In the second study [16] a randomized, placebo-controlled, double-blind study involv- ing 60 subjects, aged 6–18 years old, was conducted over a period of 3 months to determine the effect of PYC. Compared with subjects taking placebo, the group who took PYC showed a remarkable improvement both in pulmonary functions and asthma symptoms. Moreover, the PYC group was able to reduce or discontinue their use of rescue inhalers more often than the placebo group. Also in this case there was also a significant reduction of urinary leukotrienes in the PYC group.

6.2. Chronic venous insufficiency

In this case at least ten supportive studies are available and among these the most cited according Goole Scholar (keywords: pycnogenol chronic venous insufficiency) is the one reported by Arcangeli [61] where forty patients with chronic venous insufficiency (CVI) and legs varices were selected and double-blindly randomly assigned to a treat- ment with PYC 100 mg × 3/day or a placebo for 2 months, according to a double-blind experimental design. The effects of the treatment were evaluated by scoring the symptom- atology with a semi-quantitative scale, and the venous blood flow by means of a hand-held Doppler ultrasound. The tolerability was evaluated by recording the adverse effects and by means of hematology and blood chemistry para- meters, before and at the end of the treatment. PYC treatment induced a significant reduction in subcutaneous edema as well as heaviness and pain in the legs, on both the evaluation time periods (i.e. after 30 and 60 days). Approximately 60% of patients treated with PYC experienced a complete disappear- ance either of the edema (the most rapidly disappearing symptom) and of the pain at the end of the treatment, while almost all the patients reported a reduction in leg heaviness which disappeared in approximately 33% of patients. These changes were statistically significant. No effect was observed in the placebo-treated subjects. No outcome on the venous blood flow in either of the experimental groups was observed. However, more recent studies do confirm the efficacy of PYC in the management of CVI, in particular, and more specifically, the one by Cesarone et al. [62].

6.3. Attention deficient hyperactivity disorder (ADHD)

Until nowadays a dozen of articles from PubMed are available concerning the use pycnogenol in the treatment of ADHD being the study reported by Trebatická et al. [63] the more cited with 15 citations (Google Scholar, GS) and also the more definite. In this study PYC has shown improvement of ADHD in case reports and in an open study. In particular, sixty-one children were supplemented with 1 mg/kg/day PYC or placebo over a period of 4 weeks in a randomized, placebo- controlled, double-blind study. Results show that 1-month PYC administration caused a significant reduction of hyperactivity and improved attention and visual-motoric coordination and concentration of children with ADHD. In the placebo group no positive effects were found. However, three very recent and interesting reviews support, although with mixed evidence, the use of PYC in management of ADHD [24,64,65].

6.4. Cramps and muscular pain

Although quite large and statistically valid with different groups of subjects and patients examined, really just one study is found on PubMed indicating that PYC is effective in reducing pain and cramps [66]. Globally, the results suggest that the use of PYC prevents cramps, muscular pain at rest, and pain after/during exercise in normals, in athletes prone to cramps, in patients with venous disease, in claudicants, and in diabetics with microangiopathy.

6.5. Diabetes

The PubMed entries pycnogenol human diabetes gives 12 articles, among these the most cited in GS (28 citations) and the most authoritative is that of Liu et al. [67] where a double- blind, placebo-controlled, randomized, multi-center study was performed with 77 diabetes type II patients. The study reports that conventional diabetes treatment supplementa- tion with 100 mg PYC for 12 weeks, lowers glucose levels and improves endothelial function.

6.6. Diabetic microangiopathy

Less than ten references appear on PubMed concerning the treatment of this pathology with PYC. Taking into account the more remarkable study [68] a group of 30 patients showing severe microangiopathy and a group of 30 comparable patients as controls (no treatment during the observation period) received oral PYC (50 mg capsules) 3 times daily for a total of 150 mg daily for 4 weeks. After 4 weeks, microcirculatory and clinical evaluations showed a progressive decrease in skin flux at rest in the foot (indicating an improvement in the level of microangiopathy), a significant decrease in capillary filtration, and a significant improvement in the venoarteriolar response in all treated subjects. Interestingly, this study confirms the clinical efficacy of PYC in patients with diabetic microangiopathy.

6.7. Dysmenorrhea (painful menstruation)

From PubMed, two articles and a replay letter published on the same journal deal with PYC and dysmenorrhea. Both studies [18,69] claim that women with dysmenorrhea had a significantly lower pain score and required statistically significantly less analgesic medication during supplementa- tion with PYC that control subjects. However, authors have clearly demonstrated the safety and efficacy of PYC as a novel, new and highly potent natural analgesic agent. For that PYC is rapidly emerging as a major player in the management of other systemic diseases besides dysmenorrhea.

6.8. Edema (in patients with high blood pressure)

In this case although four articles can be found on PubMed, only one has a remarkable importance [70]. This 8-week study evaluated capillary filtration in 2 comparable treatment groups with hypertension treated with a calcium antagonist (nifedipine) or angiotensin-converting enzyme inhibitor to define PYC efficacy in preventing edema caused by anti- hypertensives. Noteworthy, a significant decrease in filtration was observed in the PYC treated groups. As authors claim, PYC controls this type of edema, helps to prevent and limit long- term damage in the microcirculation in hypertensive patients, and allows the dose of anti-hypertensive drugs to be reduced in most patients.

6.9. Erectile dysfunction (ED)

Two studies only by the same research group report that oral administration of L-arginine in combination with PYC causes a significant improvement in sexual function in men with ED without any side effects [21,22]. In particular the first study (highly cited: 32 citations from GS) included 40 men, aged 25–45 years, without confirmed organic erectile dys- function. Throughout the 3-month trial period, patients received 3 ampoules Sargenor a day, a drinkable solution of the dipeptide arginyl-aspartate (equivalent to 1.7 g L-arginine per day). Remarkably, after the third month of treatment, 92.5% of the men experienced a normal erection.

Regarding the second study [22] in a randomly allocated, double-blind, placebo-controlled, crossover design, 50 patients with mild to moderate ED were treated for 1month with placebo or a combination of L-arginine aspartate and PYC (Prelox). In this case, intake of PYC for 1 month restored erectile function to normal. Anyway, it is not known what effect each of the individual compounds may have directly on this condition.

6.10. Gingival bleeding/plaque

The PubMed results with pycnogenol gingival bleeding/ plaque entries give just one reference [71]. This study compares the effects of chewing gums with and without PYC on gingival bleeding and plaque formation in 40 human subjects. In this double-blind study, subjects were assigned randomly to receive either control gums without PYC or experimental gums containing 5mg PYC. Subjects used chewing gums for 14 days. The data of this study suggest that the use of PYC chewing gums can minimize gingival bleeding and plaque accumulation. Interestingly, PYC has also been added to toothpaste for a potential antioxidant effect [72].

6.11. High blood pressure

About ten articles are present on PubMed concerning this issue. Certainly, the most important, and the most cited (also because the first appearing in this area) with 61 citations (from GS) is that of Pütter et al. [73]. In this case, the effects of PYC were assessed on platelet function in humans. In particular, increased platelet reactivity yielding aggregation 2 h after smoking was prevented by 500 mg aspirin or 100 mg G. D'Andrea / Fitoterapia 81 (2010) 724–736 731

732 G. D'Andrea / Fitoterapia 81 (2010) 724–736 PYC in 22 German heavy smokers. In a group of 16 American smokers, blood pressure increased after smoking. It was unchanged after intake of 500 mg aspirin or 125 mg PYC. In another group of 19 American smokers, increased platelet aggregation was more significantly reduced by 200 mg than either 150 mg or 100 mg of PYC supplementation. This study showed that a single, high dose, 200 mg PYC, remained effective for over 6 days against smoking-induced platelet aggregation. Globally, all the observations suggest an advan- tageous risk–benefit ratio in PYC treated subjects.

6.12. High cholesterol

Although quite authoritative, only one specific study is found on PubMed with regard this treatment with PYC [74]. In this study, the possibility that this supplement might produce vascular effects by stimulation of nitric oxide (NO) released from the vascular endothelial cells was investigated. The results indicate that PYC, in addition to its antioxidant activity, stimulates constitutive endothelial NOS (eNOS) activity thus to increase NO levels, which could counteract the vasoconstrictor effects of epinephrine and norepineph- rine. Furthermore, additional protective effects could result from the well-established properties of NO in decreasing platelet aggregation and adhesion, as well as in inhibiting low-density lipoprotein (LDL) cholesterol oxidation, all circumstances which could protect against atherogenesis and thrombus formation.

6.13. Male infertility

Pycnogenol male infertility entries in PubMed give four references, of which one very recent and exciting [75] being the research group the same who studied the effects of PYC upon erectile dysfunction. In particular, in a randomly allocated, double-blind, placebo-controlled, crossover design, 50 infertile patients were treated for 1 month with placebo or a combina- tion of L-arginine aspartate and PYC (Prelox). Data support the evidence that treatment with Prelox increased significantly the semen volume, concentration of spermatozoa, percentage of motile spermatozoa and percentage of spermatozoa with normal morphology compared with placebo. Moreover, no unwanted effects were reported. However, in this field the most cited article (with 28 citations on GS) is the one from Comhaire and Mahmoud [76] where it was shown that inhibiting the cyclo-oxygenase enzyme, and reducing prostaglandin produc- tion and inflammatory reaction, Pycnogenol improves sperm morphology and concentration.

6.14. Melasma (chloasma)

Melasma (or chloasma) is a common disorder of cutane- ous hyperpigmentation predominantly affecting sun-exposed areas in women. The pathogenesis of melasma is not fully understood and treatments are frequently disappointing and often associated with side effects. Two articles are reported by PubMed when pycnogenol melasma (chloasma) are used as entries [20,77] the most specific (and most cited with 27 citations by GS) being the first published [20]. In this latter study, 30 women with melasma completed a 30-day clinical trial in which they took one 25 mg tablet of PYC with meals three times daily, i.e. 75 mg PYC per day. In general, no side effects were observed. Moreover, several other associated symptoms such as fatigue, constipation, pains in the body and anxiety were also improved, concluding that PYC was shown to be therapeutically effective and safe in patients suffering from melasma.

6.15. Menopausal symptoms

Although statistically relevant just one paper is reported by PubMed concerning this treatment [78]. In this study 200 peri-menopausal women were enrolled in a double-blind, placebo-controlled study, and treated with PYC (200 mg) daily, but a total of 155 women completed the study. In general, PYC was found to alleviate menstrual pain and reduce hyperactivity, improving all climacteric symptoms, increasing the antioxidative status and LDL/HDL ratio. Noteworthy, no side effects were reported.

6.16. Migraine

Pycnogenol migraine PubMed entries do not display any reference, only pine bark extract migraine entries give just one reference [79]. In this study PYC was used in combination with vitamin C and vitamin E. More precisely, twelve patients with a long-term history of migraine with and without aura who had failed to respond to multiple treatments with β- blockers, antidepressants, anticonvulsants, and 5-hydroxy- tryptamine receptor agonists were selected for the study. They were treated with 10 capsules of an antioxidant formulation of 120 mg pine bark extract, 60 mg vitamin C, and 30 IU vitamin E in each capsule daily for 3 months. Taken together, data suggest that the antioxidant therapy used in this study may be beneficial in the treatment of migraine possibly reducing headache frequency and severity; anyway, further clinical investigation demonstrating the efficacy of antioxidant as therapy for chronic migraine is warranted.

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