Pycnogenol
Pinus maritima Mill.; Pinus pinaster Ait. Family: Pinaceae
Pycnogenol
 
Clinical Overview
Uses
  Pycnogenol has been studied for the treatment of chronic venous insufficiency (CVI) and inflammation, and for use as an antioxidant. It has been promoted for the treatment of attention deficit hyperactivity disorder (ADHD). However, there is limited clinical information regarding   Pycnogenol and these uses.

Dosing
Pycnogenol has been studied in clinical trials with oral doses ranging from 60 to 300 mg daily.

Contraindications
Contraindications have not been identified.

Pregnancy/Lactation
Information regarding safety and efficacy during pregnancy and lactation is lacking.

Interactions
None well documented.

Adverse Reactions
Some children taking   Pycnogenol for ADHD became irritable and showed decreased energy; however, pycnogenol is generally well tolerated.

Toxicology
No data.

 
Botany
The name   Pycnogenol is a trademark of the British company Horphag Research, Ltd. for a complex proprietary mixture of water-soluble proanthocyanidins derived from the bark of the European coastal pine, P. maritima , also known as Pinus nigra var. maritima (Aiton) Melville or P. pinaster Ait., which grows along the coast of southwest France in Gascogne. The largest man-made forest in the world, the 900,000 hectare Les Landes on the Atlantic coast of southwestern France, is populated almost entirely by P. pinaster .
 
History
  Pycnogenol is available OTC in the United States in health food stores and pharmacies. Product literature indicates that   Pycnogenol , when taken as a dietary supplement, is a free radical scavenger. The compound may improve circulation, reduce inflammation, and protect collagen from natural degradation.   Pycnogenol has been available in Europe for some time, where it is taken as a supplement or incorporated into topical antiaging creams. 1
 
Chemistry
  Pycnogenol is a mixture of bioflavonoids predominantly composed of proanthocyanidins. 2 Using a patented process, pine bark is boiled with saturated sodium chloride, cooled, and extracted with ethyl acetate. After concentration, the solution is precipitated with chloroform. This process is repeated several times to remove condensed tannins from the product. In some studies, pycnogenol-related compounds are designated procyanidiol oligomers (PCOs). The oligomers range from monomers to dodecamers. 3   Pycnogenol is primarily composed of proanthocyanidins (80% to 85%), the monomers catechin and taxifolin (5%), and phenolic acids (2% to 4%). The phenolic acids are derivatives of benzoic and cinnamic acids. Tablets and capsules must contain a minimum of 20 mg   Pycnogenol for the right to use the   Pycnogenol trademark on the label or as a product name. When acidified and boiled, the solution turns bright red due to formation of anthocyanidins. 3 Maritime pine extract is monographed in the United States Pharmacopeia .
 
Uses and Pharmacology
The pharmacokinetics of   Pycnogenol constituents have been studied in human volunteers. A total of 15 compounds were found to be rapidly absorbed and metabolized by phase 2 enzymes. 4 Other studies of   Pycnogenol bioavailability and efficacy have been reviewed. 5
Antioxidant   A United States patent for   Pycnogenol describes a mixture of proanthocyanidins that are effective in combating the deleterious effects of free radicals. The patent claims that the product assists in the treatment of hypoxia following atherosclerosis and cardiac or cerebral infarction, and reduces tumor promotion, inflammation, ischemia, alterations of synovial fluid, and collagen degradation. 6 Two metabolites of catechin in   Pycnogenol were found to inhibit matrix metalloproteinases more potently than the parent compound. 7 Inhibition of xanthine oxidase by   Pycnogenol was found to be a selective effect on the enzyme, 8 which is not mediated by redox activity as was initially proposed. 9 An electron spin resonance study of procyanidin B3 observed formation of a free radical species. 10 An ex vivo study with human plasma showed that pycnogenol could enhance the antioxidative capacity of the plasma if combined with whey proteins. 11
Effects in defined cellular systems have also been detected.   Pycnogenol was capable of quenching nitric oxide radical formation in activated macrophages and inhibited both induced nitric oxide synthase (iNOS) mRNA expression and iNOS activity. 12 It protected endothelial cells from oxidant-induced injury, possibly by upregulating radical scavenging systems. 13 Similar effects were seen in macrophages, with inhibition of oxidative burst, lipoprotein oxidation, and hydroxyl radical-induced DNA damage. 14 HT-4 neuronal cells were protected against glutamate-induced cytotoxicity. 15   Pycnogenol preparations have even been used in toothpastes 16 and to limit lipid oxidation in cooked beef products. 17 A large number of studies on cultured cells have demonstrated that   Pycnogenol can limit damage caused by nitrosamine metabolites in liver and lung microsomes, 18 maintain tocopherol levels in endothelial cells in the face of reactive nitrogen species, 19 and scavenge free radicals in macrophages. 20 Rat cerebellar granule cells were protected against ethanol-induced apoptosis, 21 and the protective mechanisms were found to involve reduction of reactive oxygen species and a variety of other biochemical effects. 22   Pycnogenol also protected PC12 rat cells from amyloid-beta peptide-induced apoptosis, 23 as well as from hydrogen peroxide injury. 24
Animal studies   Apolipoprotein E-deficient mice fed   Pycnogenol and a combination of other antioxidants demonstrated longer life span and reduction of hippocampal inclusion bodies, as well as a reduction in apoptosis. 25 Streptozotocin-induced diabetic rats given   Pycnogenol demonstrated reduced blood glucose and altered biochemical markers of oxidative stress. 26
Clinical studies   In 25 healthy volunteers, polyphenol blood levels increased after 6 weeks of treatment with   Pycnogenol and returned to basal levels after washout. Treatment resulted in a 40% increase over baseline. A small drop in low-density lipoprotein cholesterol was not mirrored by changes in total cholesterol or triglycerides. 27 Another study with 2-week treatment periods found no effect of   Pycnogenol on antioxidant capacity or vitamin C levels. 28
Inflammation     Pycnogenol is capable of inhibiting inflammatory mediators. For instance, histamine release from rat mast cells was induced by either a calcium ionophore (A-23187) or a compound 48/80, and   Pycnogenol reversed the action of these 2 secretogogues. 29   Pycnogenol reduced the production of the proinflammatory cytokine interleukin-1 in 2 macrophage cell lines, blocked activation of nuclear factor kappa beta (NFκB) and activator protein (AP)-1, and abolished lipopolysaccharide-stimulated (LPS)-induced IkB destruction. 30 , 31
Animal studies   Dietary   Pycnogenol decreased edema in mouse ears treated with croton oil. Similarly, rat hind paw edema due to compound 48/80 was decreased. Topical administration of   Pycnogenol blocked ultraviolet damage to capillaries. 32 Pycnogenol had a protective effect in a rat model of inflammatory bowel disease. 33
Clinical studies   Similarly, human volunteers administered   Pycnogenol demonstrated fewer incidents of erythema and NFκB expression in keratinocytes than controls. 34 Inhibition of NFκB activation and matrix metalloproteinase (MMP)-9 secretion was found in plasma of humans after 5 days of oral   Pycnogenol administration. 35
Chronic venous insufficiency (CVI)   Early pharmacology of   Pycnogenol focused on its effects on capillary fragility and permeability. This effect may be mediated by both antioxidant effects and effects on inflammatory pathways.
Animal studies   There are no valid animal models for CVI; as a consequence, most of the work reported on   Pycnogenol for this indication has been conducted with human subjects.
Clinical studies   Older European trials have been summarized in a review. Seven open studies and 8 double-blind studies were summarized, covering a total of 784 patients. 36 More recently, 40 CVI patients were treated with   Pycnogenol 100 mg 3 times daily or placebo for 2 months, with the treatment group showing reductions in edema, pain, and heaviness of the legs but no effect on venous blood flow. 37 A similar trial had the same results, with additional measures of capillary leakage and perivascular inflammation reduced. 38 A 16-week study in a small cohort of mildly hypertensive patients found a statistically insignificant reduction of diastolic blood pressure and a significant drop in serum thromboxane with of   Pycnogenol 200 mg/day. 39 Head-to-head clinical studies of   Pycnogenol versus   Venostatin (horse chestnut extract) 40 and   Daflon (combination of diosmin and hesperidin) 41 in patients with CVI found   Pycnogenol to have superior efficacy. Venous ulcers due to CVI healed more rapidly under   Pycnogenol treatment in a small study. 42
Diabetic retinopathy has also been studied, with positive results in a mixed open, double-blind format with   Pycnogenol 150 mg/day. 43 The topic has been reviewed in detail, with efficacy claimed to be equal or superior to standard agents in 5 trials involving 1,289 patients. 44
Platelet function   The effect of   Pycnogenol on the platelet function of smoking and nonsmoking patients with coronary artery disease has been studied. 45 , 46 , 47   Pycnogenol decreased platelet aggregation ex vivo in all 3 studies. In the nonsmoker study, platelet activating factor (PAF)-stimulated aggregation was not affected, ruling out a role for PAF in the mechanism. This work is also the subject of a patent. 48
Other indications
In vitro studies     Pycnogenol has induced apoptosis in MCF-7 breast cancer cells 49 and has induced differentiation and apoptosis in HL-60 leukemia cells. 50 It prevented hemolytic injury in G6PD deficient erythrocytes, 51 inhibited lipogenesis in 3T3 cells, 52 and stimulated lipolysis after differentiation, 53 possibly by a beta-adrenegic mechanism. 54   Pycnogenol increased human growth hormone secretion in engineered keratinocytes. 55 Its modest antimicrobial activity has been suggested as a use in candidiasis and dental plaque. 56 Last, inhibition of angiotensin converting enzyme in vitro by   Pycnogenol was linked to a hypertensive effect seen in rats. 57
Animal studies   In a diabetic rat model, antioxidant effects of   Pycnogenol in combination with beta-carotene and alpha-lipoic acid were studied. Each antioxidant appeared to act by different routes, and no combination effects were noted. 58   Pycnogenol reversed learning impairment and memory deficits in a strain of genetically senescence-accelerated mice. 59 A study of immune and hematopoetic function in the same strain of mice after 2 months of   Pycnogenol administration found enhanced T- and B-cell function. 60 Rats with experimental wounds healed more rapidly with topical   Pycnogenol than controls and showed reduced scarring. 61   Pycnogenol had a variety of positive immunomodulatory effects in mice infected with a murine retrovirus or dosed with ethanol. 62 It also reduced the toxicity of antitumor drugs to mice 63 and protected rats from ionizing radiation damage. 64 , 65
Clinical studies     Pycnogenol has been tested in various clinical trials for other indications. Oral treatment with   Pycnogenol 100 mg for 12 weeks improved endothelial function in patients with hypertension. 66 A trial conducted by the same group found lowered plasma glucose in type 2 diabetic patients with   Pycnogenol . 67 Oral treatment with   Pycnogenol 75 mg daily for 30 days reduced hyperpigmentation in melasma patients. 68 A study in patients with ADHD found a positive effect after 1 month of treatment with   Pycnogenol 1 mg/kg. The effect was reversed when therapy was discontinued. 69 In combination with ginger root extract,   Pycnogenol was studied for treatment of traveler's thrombosis and motion sickness. 70 A second study by a different group also found   Pycnogenol given alone to be beneficial against edema caused by long airplane flights. 71   Pycnogenol has been studied for the control of inflammation in lupus patients, 72 for pain in the third trimester of pregnancy, 73 as an adjunct for childhood asthma, 74 in a chewing gum for gingival bleeding and plaque, 75 to improve sperm quality, 76 and for erectile dysfunction. 77
 
Administration & Dosage
Doses of   Pycnogenol 60 to 300 mg daily have been studied in clinical trials for the treatment of lupus, chronic venous insufficiency, vascular retinopathy, and asthma.
 
Pregnancy/Lactation
Information regarding safety and efficacy during pregnancy and lactation is lacking.
 
Interactions
None well documented.
 
Adverse Reactions
No reports of clinically important adverse reactions from   Pycnogenol have been published. Some children treated for ADHD with   Pycnogenol became irritable and showed decreased energy. Most clinical studies report that   Pycnogenol is well-tolerated, with minor gastric discomfort occasionally noted.
 
Toxicology
Research reveals little or no information regarding toxicology with the use of this product.
 
References
 

1. Rohdewald P . Pycnogenol . In: Rice-Evans CA, Packer L. Flavonoids in Health and Disease . New York, NY: Marcel Dekker; 1998:405-419.

 

2. Masquelier J , inventor; Societe Civile de Recherche Pharmaceutique et Therapeutique, assignee. Hydroxyflavin 3,4-diols, a method of producing them and medicament based thereon . US patent 3,436,407. April 1, 1969.

 

3. Suzuki N , Kohama T , inventors; Medicinal Tradepia Co. Ltd., Horphag Research Limited, assignees. Medicinal composition for treating dysmenorrhea and endometriosis industrial use . US patent 6,372,266. April 16, 2002.

 

4. Grimm T , Skrabala R , Chovanova Z , et al. Single and multiple dose pharmacokinetics of maritime pine bark extract (pycnogenol) after oral administration to healthy volunteers . BMC Clin Pharmacol . 2006;6:4.

 

5. Williamson G , Manach C . Bioavailability and bioefficacy of polyphenols in humans. II. Review of 93 intervention studies . Am J Clin Nutr . 2005;81:243S-255S.  PubMed

 

6. Masquelier J , inventor; Societe Civile d'Investigations Pharmacologiques d'Aquitaine, Horphag Overseas Ltd, assignees. Plant extract with a proanthocyanidins content as therapeutic agent having radical scavenger effect and use thereof . US patent 4,698,360. October 6, 1987.

 

7. Grimm T , Schafer A , Hogger P . Antioxidant activity and inhibition of matrix metalloproteinases by metabolites of maritime pine bark extract (pycnogenol) . Free Radic Biol Med . 2004;36:811-822.  PubMed

 

8. Moini H , Guo Q , Packer L . Enzyme inhibition and protein-binding action of the procyanidin-rich french maritime pine bark extract, pycnogenol: effect on xanthine oxidase . J Agric Food Chem . 2000;48:5630-5639.  PubMed

 

9. Elstner EF , Kleber E . Radical scavenger properties of leucocyanidine . Presented at: 3rd International Symposium on Flavonoids in Biology & Medicine; November 13-17, 1989; Singapore.

 

10. Guo Q , Zhao B , Packer L . Electron spin resonance study of free radicals formed from a procyanidin-rich pine ( Pinus maritima ) bark extract, pycnogenol . Free Radic Biol Med . 1999;27:1308-1312.  PubMed

 

11. Janisch K , Hippeli S , Dornisch K , Kern S , Elstner EF . Determination of the antioxidative potential of human plasma after supplementation with pycnogenol and whey . Food Res Int . 2002;35:257-266.

 

12. Packer L , Rimbach G , Virgili F . Antioxidant activity and biologic properties of a procyanidin-rich extract from pine ( Pinus maritima ) bark, pycnogenol . Free Radic Biol Med . 1999;27:704-724.  PubMed

 

13. Wei ZH , Peng QL , Lau BH . Pycnogenol enhances endothelial cell antioxidant defenses . Redox Rep . 1997;3:219-224.

 

14. Nelson AB , Lau BH , Ide N , Rong Y . Pycnogenol inhibits macrophage oxidative burst, lipoprotein oxidation, and hydroxyl radical-induced DNA damage . Drug Dev Ind Pharm . 1998;24:139-144.  PubMed

 

15. Kobayashi MS , Han D , Packer L . Antioxidants and herbal extracts protect HT-4 neuronal cells against glutamate-induced cytotoxicity . Free Radic Res . 2000;32:115-124.  PubMed

 

16. Battino M , Ferreiro MS , Armeni T , et al. In vitro antioxidant activities of antioxidant-enriched toothpastes . Free Radic Res . 2005;39:343-350.  PubMed

 

17. Ahn J , Grun IU , Mustapha A . Effects of plant extracts on microbial growth, color change, and lipid oxidation in cooked beef . Food Microbiol . 2006;24:7-14.

 

18. Huynh HT , Teel RW . Effects of pycnogenol on the microsomal metabolism of the tobacco-specific nitrosamine NNK as a function of age . Cancer Lett . 1998;132:135-139.  PubMed

 

19. Virgili F , Kim D , Packer L . Procyanidins extracted from pine bark protect alpha-tocopherol in ECV 304 endothelial cells challenged by activated RAW 264.7 macrophages: role of nitric oxide and peroxynitrite . FEBS Lett . 1998;431:315-318.  PubMed

 

20. Virgili F , Kobuchi H , Packer L . Procyanidins extracted from Pinus maritima (Pycnogenol): scavengers of free radical species and modulators of nitrogen monoxide metabolism in activated murine RAW 264.7 macrophages . Free Radic Biol Med . 1998;24:1120-1129.  PubMed

 

21. Siler-Marsiglio KI , Shaw G , Heaton MB . Pycnogenol and vitamin E inhibit ethanol-induced apoptosis in rat cerebellar granule cells . J Neurobiol . 2004;59:261-271.  PubMed

 

22. Siler-Marsiglio KI , Paiva M , Madorsky I , Serrano Y , Neeley A , Heaton MB . Protective mechanisms of pycnogenol in ethanol-insulted cerebellar granule cells . J Neurobiol . 2004;61:267-276.  PubMed

 

23. Peng QL , Buz'Zard AR , Lau BH . Pycnogenol protects neurons from amyloid-beta peptide-induced apoptosis . Brain Res Mol Brain Res . 2002;104:55-65.  PubMed

 

24. Horakova L , Licht A , Sandig G , Jakstadt M , Durackova Z , Grune T . Standardized extracts of flavonoids increase the viability of PC12 cells treated with hydrogen peroxide: effects on oxidative injury . Arch Toxicol . 2003;77:22-29.  PubMed

 

25. Veurink G , Liu D , Taddei K , et al. Reduction of inclusion body pathology in ApoE-deficient mice fed a combination of antioxidants . Free Radic Biol Med . 2003;34:1070-1077.  PubMed

 

26. Maritim A , Dene BA , Sanders RA , Watkins ΙΙΙ JB . Effects of pycnogenol treatment on oxidative stress in streptozotocin-induced diabetic rats . J Biochem Mol Toxicol . 2003;17:193-199.  PubMed

 

27. Devaraj S , Vega-Lopez S , Kaul N , Schonlau F , Rohdewald P , Jialal I . Supplementation with a pine bark extract rich in polyphenols increases plasma antioxidant capacity and alters the plasma lipoprotein profile . Lipids . 2002;37:931-934.  PubMed

 

28. Silliman K , Parry J , Kirk LL , Prior RL . Pycnogenol does not impact the antioxidant or vitamin C status of healthy young adults . J Am Diet Assoc . 2003;103:67-72.  PubMed

 

29. Sharma SC , Sharma S , Gulati OP . Pycnogenol inhibits the release of histamine from mast cells . Phytother Res . 2003;17:66-69.

 

30. Cho KJ , Yun CH , Yoon DY , et al. Effect of bioflavonoids extracted from the bark of Pinus maritima on proinflammatory cytokine interleukin-1 production in lipopolysaccharide-stimulated RAW 264.7 . Toxicol Appl Pharmacol . 2000;168:64-71.

 

31. Cho KJ , Yun CH , Packer L , Chung AS . Inhibition mechanisms of bioflavonoids extracted from the bark of Pinus maritima on the expression of proinflammatory cytokines . Ann N Y Acad Sci . 2001;928:141-156.  PubMed

 

32. Blazso G , Gabor M , Rohdewald P . Antiinflammatory activities of procyanidin-containing extracts from Pinus pinaster Ait. after oral and cutaneous application . Pharmazie . 1997;52:380-382.  PubMed

 

33. Mochizuki M , Hasegawa N . Therapeutic efficacy of pycnogenol in experimental inflammatory bowel diseases . Phytother Res . 2004;18:1027-1028.

 

34. Saliou C , Rimbach G , Moini H , et al. Solar ultraviolet-induced erythema in human skin and nuclear factor- kappa-B-dependent gene expression in keratinocytes are modulated by a French maritime pine bark extract . Free Radic Biol Med . 2001;30:154-173.  PubMed

 

35. Grimm T , Chovanova Z , Muchova J , et al. Inhibition of NF-kappaB activation and MMP-9 secretion by plasma of human volunteers after ingestion of maritime pine bark extract (Pycnogenol) . J Inflamm . 2006;3:1-6.

 

36. Gulati OP .   Pycnogenol in venous disorders: A review . Eur Bull Drug Res . 1999;7:8-13.

 

37. Arcangeli P . Pycnogenol in chronic venous insufficiency . Fitoterapia . 2000;71:236-244.  PubMed

 

38. Petrassi C , Mastromarino A , Spartera C . Pycnogenol in chronic venous insufficiency . Phytomed . 2000;7:383-388.  PubMed

 

39. Hosseini S , Lee J , Sepulveda RT , Rhodewald P , Watson RR . A randomized, double-blind, placebo-controlled, prospective, 16 week crossover study to determine the role of Pycnogenol in modifying blood pressure in mildly hypertensive patients . Nutr Res . 2001;21:1251-1260.

 

40. Koch R . Comparative study of   Venostasin and   Pycnogenol in chronic venous insufficiency. Phytother Res . 2002;16:S1-S5.  PubMed

 

41. Cesarone MR , Belcaro G , Rohdewald P , et al. Comparison of   Pycnogenol and   Daflon in treating chronic venous insufficiency: a prospective, controlled study . Clin Appl Thromb Hemost . 2006;12:205-212.

 

42. Belcaro G , Cesarone MR , Errichi BM , et al. Venous ulcers: microcirculatory improvement and faster healing with local use of pycnogenol . Angiology . 2005;56:699-705.  PubMed

 

43. Spadea L , Balestrazzi E . Treatment of vascular retinopathies with pycnogenol . Phytother Res . 2001;15:219-223.  PubMed

 

44. Schonlau F , Rohdewald P . Pycnogenol for diabetic retinopathy. A review . Int Ophthalmol . 2001;24:161-171.  PubMed

 

45. Wang S , Tan D , Zhao Y , Guankai G , Gao X , Hu L . The effect of pycnogenol on the microcirculation, plaatelet function and ischemic mycardium in patients with coronary artery diseases . Eur Bull Drug Res . 1999;7:19-25.

 

46. Pütter M , Grotemeyer KH , Wurthwein G , et al. Inhibition of smoking-induced platelet aggregation by aspirin and pycnogenol . Thromb Res . 1999;95:155-161.  PubMed

 

47. Araghi-Niknam M , Hosseini S , Larson D , Rohdewald P , Watson RR . Pine bark extract reduces platelet aggregation . Integr Med . 2000;2:73-77.  PubMed

 

48. Rohdewald P , inventor. Method of controlling the reactivity of human blood platelets by oral administration of the extract of the maritime pine (pycnogenol) . US patent 5,720,956. February 21, 1998.

 

49. Huynh HT , Teel RW . Selective induction of apoptosis in human mammary cancer cells (MCF-7) by pycnogenol . Anticancer Res . 2000;20:2417-2430.  PubMed

 

50. Huang WW , Yang JS , Lin CF , Ho WJ , Lee MR . Pycnogenol induces differentiation and apoptosis in human promyeloid leukemia HL-60 cells . Leuk Res . 2005;29:685-692.  PubMed

 

51. Sharma SC , Sharma S , Gulati OP . Pycnogenol prevents haemolytic injury in G6PD deficient human erythrocytes . Phytother Res . 2003;17:671-674.  PubMed

 

52. Hasegawa N . Inhibition of lipogenesis by pycnogenol . Phytother Res . 2000;14:472-473.  PubMed

 

53. Hasegawa N . Stimulation of lipolysis by pycnogenol . Phytother Res . 1999;13:619-620.  PubMed

 

54. Mochizuki M , Hasegawa N . Pycnogenol stimulates lipolysis in 3T3-L1 cells via stimulation of beta-receptor mediated activity . Phytother Res . 2004;18:1029-1030.

 

55. Buz'Zard AR , Peng Q , Lau BH . Kyolic and   Pycnogenol increase human growth hormone secretion in genetically-engineered keratinocytes . Growth Horm IGF Res . 2002;12:34-40.  PubMed

 

56. Torras MA , Faura CA , Schonlau F , Rohdewald P . Antimicrobial activity of pycnogenol . Phytother Res . 2005;19:647-648.  PubMed

 

57. Blaszó G , Gaspar R , Gabor M , Ruve HJ , Rohdewald P . ACE inhibition and hypotensive effect of a procyanidins containing extract from the bark of Pinus pinaster Sol . Pharm Pharmacol Lett . 1996;6:8-11.

 

58. Berryman AM , Maritim AC , Sanders RA , Watkins JB, 3rd . Influence of treatment of diabetic rats with combinations of pycnogenol, beta-carotene, and alpha-lipoic acid on parameters of oxidative stress . J Biochem Mol Toxicol . 2004;18:345-352.  PubMed

 

59. Liu F , Zhang Y , Lau BH . Pycnogenol improves learning impairment and memory deficit in senescent-accelerated mice . J Anti Aging Med . 1999;2:349-355.

 

60. Liu FJ , Zhang YX , Lau BH . Pycnogenol enhances immune and haemopoietic functions in senescence-accelerated mice . Cell Mol Life Sci . 1998;54:1168-1172.  PubMed

 

61. Blazso G , Gabor M , Schonlau F , Rohdewald P . Pycnogenol accelerates wound healing and reduces scar formation . Phytother Res . 2004;18:579-581.  PubMed

 

62. Cheshier JE , Ardestani-Kaboudanian S , Liang B , et al. Immunomodulation by pycnogenol in retrovirus-infected or ethanol-fed mice . Life Sci . 1996;58:87-96.

 

63. Feng WH , Wei HL , Liu GT . Effect of pycnogenol on the toxicity of heart, bone marrow and immune organs as induced by antitumor drugs . Phytomed . 2002;9:414-418.  PubMed

 

64. de Moraes Ramos FM , Schonlau F , Novaes PD , Manzi FR , Boscolo FN , de Almeida SM . Pycnogenol protects against Ionizing radiation as shown in the intestinal mucosa of rats exposed to X-rays . Phytother Res . 2006;20:676-679.  PubMed

 

65. Sime S , Reeve VE . Protection from inflammation, immunosuppression and carcinogenesis induced by UV radiation in mice by topical pycnogenol . Photochem Photobiol . 2004;79:193-198.  PubMed

 

66. Liu X , Wei J , Tan F , Zhou S , Wurthwein G , Rohdewald R . Pycnogenol, French maritime pine bark extract, improves endothelial function of hypertensive patients . Life Sci . 2004;74:855-862.

 

67. Liu X , Wei J , Tan F , Zhou S , Wurthwein G , Rohdewald P . Antidiabetic effect of Pycnogenol French maritime pine bark extract in patients with diabetes type II . Life Sci . 2004;75:2505-2513.

 

68. Ni Z , Mu Y , Gulati O . Treatment of melasma with Pycnogenol . Phytother Res . 2002;16:567-571.  PubMed

 

69. Trebaticka J , Kopasova S , Hradecna Z , et al. Treatment of ADHD with French maritime pine bark extract,   Pycnogenol . Eur Child Adolesc Psychiatry . 2006;15:329-335.  PubMed

 

70. Scurr JH , Gulati OP .   Zinopin —the rationale for its use as a food supplement in Traveller's thrombosis and motion sickness . Phytother Res . 2004;18:687-695.  PubMed

 

71. Cesarone MR , Belcaro G , Rohdewald P , et al. Prevention of edema in long flights with pycnogenol . Clin Appl Thromb Hemos . 2005;11:289-294.

 

72. Stefanescu M , Matache C , Onu A , et al. Pycnogenol efficacy in the treatment of systemic lupus erythematosus patients . Phytother Res . 2001;15:698-704.  PubMed

 

73. Kohama T , Inoue M . Pycnogenol alleviates pain associated with pregnancy . Phytother Res . 2006;20:232-234.  PubMed

 

74. Lau BH , Riesen SK , Truong KP , Lau ES , Rohdewald P , Barreta RA . Pycnogenol as an adjunct in the management of childhood asthma . J Asthma . 2004;41:825-832.  PubMed

 

75. Kimbrough C , Chun M , dela Roca G , Lau BH . Pycnogenol chewing gum minimizes gingival bleeding and plaque formation . Phytomed . 2002;9:410-416.  PubMed

 

76. Roseff SJ , Gulati R . Improvement of sperm quality by   Pycnogenol . Eur Bull Drug Res . 1999;7:33-36.

 

77. Durackova Z , Trebaticky B , Novotny V , Zitnanova I , Breza J . Lipid metabolism and erectile function improvement by pycnogenol, extract from the bark of Pinus pinaster in patients suffering from erectile dysfunction-a pilot study . Nutr Res . 2003;23:1189-1198.