The Tree of Life "Pine Tree"

Pycnogenol
Scientific Name(s): Pinus maritima Mill.; Pinus pinaster

Clinical Overview

Uses of Pycnogenol
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)

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 .

Pycnogenol 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

Bibliography

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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.
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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.
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.
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29. Sharma SC , Sharma S , Gulati OP . Pycnogenol inhibits the release of histamine from mast cells . Phytother Res . 2003;17:66-69.
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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.
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.
38. Petrassi C , Mastromarino A , Spartera C . Pycnogenol in chronic venous insufficiency . Phytomed . 2000;7:383-388.
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.
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.
43. Spadea L , Balestrazzi E . Treatment of vascular retinopathies with pycnogenol . Phytother Res . 2001;15:219-223.
44. Schonlau F , Rohdewald P . Pycnogenol for diabetic retinopathy. A review . Int Ophthalmol . 2001;24:161-171.
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.
47. Araghi-Niknam M , Hosseini S , Larson D , Rohdewald P , Watson RR . Pine bark extract reduces platelet aggregation . Integr Med . 2000;2:73-77.
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.
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.
51. Sharma SC , Sharma S , Gulati OP . Pycnogenol prevents haemolytic injury in G6PD deficient human erythrocytes . Phytother Res . 2003;17:671-674.
52. Hasegawa N . Inhibition of lipogenesis by pycnogenol . Phytother Res . 2000;14:472-473.
53. Hasegawa N . Stimulation of lipolysis by pycnogenol . Phytother Res . 1999;13:619-620.
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.
56. Torras MA , Faura CA , Schonlau F , Rohdewald P . Antimicrobial activity of pycnogenol . Phytother Res . 2005;19:647-648.
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.
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.
61. Blazso G , Gabor M , Schonlau F , Rohdewald P . Pycnogenol accelerates wound healing and reduces scar formation . Phytother Res . 2004;18:579-581.
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.
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.
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.
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.
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.
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.
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.
73. Kohama T , Inoue M . Pycnogenol alleviates pain associated with pregnancy . Phytother Res . 2006;20:232-234.
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.
75. Kimbrough C , Chun M , dela Roca G , Lau BH . Pycnogenol chewing gum minimizes gingival bleeding and plaque formation . Phytomed . 2002;9:410-416.
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.