Maritime Pine

Scientific Name(s): Pinus pinaster Aiton. Family: Pinaceae (Pine)

Common Name(s): Maritime pine extract , pine bark extract , Pycnogenol

Uses of Maritime Pine

Pine bark extract demonstrates antioxidant and anti-inflammatory actions and has been studied for a wide range of clinical conditions, including chronic venous insufficiency, cardiovascular conditions, and erectile dysfunction. However, many clinical studies have been limited in size, with nonrandomized or open-label designs conducted by a limited pool of researchers.

Maritime Pine Dosing

Doses of pine bark extract have been studied in clinical trials, most commonly at 150 mg of Pycnogenol per day.

Contraindications

Contraindications have not been identified.

Pregnancy/Lactation

Information regarding safety and efficacy during pregnancy and lactation is lacking.

Maritime Pine Interactions

None well documented.

Maritime Pine Adverse Reactions

Pine bark extract is generally well tolerated, with minor gastric discomfort, dizziness, nausea, and headache occasionally noted. Clinical studies using Pycnogenol report no clinically important adverse events.

Toxicology

Pine bark extract is generally recognized as safe (GRAS), based on data from clinical trials. Limited toxicological data are available.

Botany

P. pinaster Aiton (previously termed P. maritima Mill.) is a medium-sized pine growing up to 30 m tall with bright red-brown, deeply fissured bark. It has stout needles occurring in pairs, and the plant produces oval cones 10 to 20 cm long. The tree is native to the western and southwestern Mediterranean regions but has rapidly naturalized to other countries, including the United States, England, South Africa, and Australia. 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 . 1 , 2

History

In 1535, a French explorer is reputed to have used tea made from the bark of the maritime pine to treat scurvy among his sailors when his ship became icebound. Pycnogenol is a term used to describe a class of flavonoids and is derived from the Greek puknos (condensed) and genos (class, family). 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. pinaster , which grows along the coast of southwest France in Gascogne.

Pine bark extract is available without a prescription in the United States in health food stores and pharmacies. Product literature indicates that the dietary supplement is a free radical scavenger, and claims for its effects include improving circulation, reducing inflammation, and protecting collagen from natural degradation. 2 , 3

Chemistry

Pycnogenol is composed of 80% to 85% proanthocyanidins, the monomers catechin and taxifolin (5%), and phenolic acids, including derivatives of benzoic and cinnamic acids (2% to 4%). 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. In some studies, Pycnogenol -related compounds are designated procyanidiol oligomers (PCOs). The oligomers range from monomers to dodecamers. The phenolic acids are derivatives of benzoic and cinnamic acids. Tablets and capsules must contain a minimum of 20 mg of Pycnogenol for the right to use the Pycnogenol trademark on the label or as a product name. Confusion previously arose when grape seed extract was marketed as containing Pycnogenol . Maritime pine extract is monographed in the United States Pharmacopeia . 2 , 3 , 4 , 5

Maritime Pine Uses and Pharmacology

Antioxidant properties of Pycnogenol have been well described in laboratory studies and are considered to be responsible for the majority of clinical effects of the extract. 2 , 3 However, clinical studies evaluating changes in antioxidant status after Pycnogenol administration in humans have produced equivocal results. 6 , 7 , 8 Many published clinical studies have been limited in size, with nonrandomized or open-label designs conducted by a small pool of researchers. 2 , 3

Cardiovascular effects
Animal data

Studies in spontaneously hypertensive rats suggest a protective effect on microvasculature by Pycnogenol , thought to be due to antioxidant effects. Small decreases in systolic blood pressure were also observed. 9 , 10 Cardiomyopathy in diabetic rats was reduced by Pycnogenol , also considered to be due to antioxidant activity, but theoretically also due to improved cardiac energy metabolism via observed lowered plasma glucose. 11 Inhibition of angiotensin-converting enzyme (ACE) in vitro by Pycnogenol was linked to a hypertensive effect seen in rats. 12

Clinical data
Chronic venous insufficiency

Reviews of clinical trials evaluating pine bark extract in chronic venous insufficiency (CVI) have been published. 2 , 3 Positive effects, including reductions in edema, pain, capillary leakage and perivascular inflammation, and improved venous ulcer healing rates, have been demonstrated in several studies. 13 , 14 , 15 , 16 , 17 Head-to-head studies of Pycnogenol versus comparator must be interpreted carefully, because in at least 1 study the dose of the comparator was too low to be effective. 2 , 16 In another clinical study evaluating the efficacy of Pycnogenol versus stockings in CVI, 150 mg of Pycnogenol daily provided an additive positive effect on ambulatory venous pressure and clinical symptom scores over stockings alone. 18

Heart failure

A 12-week, single-blind study evaluated the efficacy of Pycnogenol in combination with coenzyme Q 10 as adjunctive therapy in cardiac failure. Patients receiving the combination adjunctive therapy improved New York Heart Association class through decreased systolic and diastolic blood pressure, heart and respiratory rate, and improved heart ejection fraction and walking distances. 19

Hypertension

A 16-week study in a small cohort of mildly hypertensive patients found a statistically insignificant reduction of diastolic blood pressure with 200 mg/day of Pycnogenol . 20 Another small pilot study (N = 55) found improvements in systolic and diastolic renal cortical flow velocity with Pycnogenol as an adjunct to ACE inhibitors in hypertensive patients with decreased renal function. Improved renal function was also observed; however, the study did not use randomization or blinding methodology. 21 A small, nonrandomized clinical study evaluated the effect of 150 mg of Pycnogenol daily in metabolic syndrome as an adjunct to ramipril over 6 months. Decreases were observed in blood pressure, serum creatinine, urinary albumin, and fasting blood sugar. 22

Platelet function

The effect of Pycnogenol on the platelet function of smoking and nonsmoking patients with coronary artery disease was evaluated in 3 studies, 23 , 24 , 25 with Pycnogenol decreasing platelet aggregation ex vivo in all 3 studies. In the nonsmoker study, platelet activating factor (PAF)–stimulated aggregation was not affected, eliminating a role for PAF in the mechanism. 26 A 16-week study in a small cohort of mildly hypertensive patients found a statistically insignificant reduction of diastolic blood pressure and a statistically significant drop in serum thromboxane with 200 mg/day of Pycnogenol . 20

Erectile dysfunction
Animal data

Research reveals no animal data regarding the use of pine bark extract in erectile dysfunction.

Clinical data

Limited clinical trials have evaluated the efficacy of pine bark extract in combination with L-arginine in mild/moderate erectile dysfunction. Indices of erectile function were improved with 60 to 80 mg of pine bark extract and 700 mg of L-arginine daily. Measurements of salivary and plasma testosterone levels showed slight increases. 27 , 28 , 29

Diabetes

In vitro studies suggest pine bark extract exhibits a number of relevant effects, including inhibition of lipid accumulation in adipocytes, 30 , 31 stimulation of lipolysis, 32 , 33 and increased glucose uptake. 34

Animal data

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 a different route, and no combination effect was noted. 35 Antioxidant effects have also been observed in other experiments in diabetic rats. 2 , 36

Clinical data

A small, nonrandomized clinical study evaluated the effect of 150 mg of Pycnogenol daily in metabolic syndrome as an adjunct to ramipril over 6 months. Decreases were observed in blood pressure, serum creatinine, urinary albumin, and fasting blood sugar. 22 Another trial found lowered plasma glucose in type 2 diabetic patients with Pycnogenol administration. 37

Inflammation

Pycnogenol appears capable of inhibiting inflammatory mediators. 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. 38 Pycnogenol reduced the production of the proinflammatory cytokine interleukin-1 in 2 macrophage cell lines, blocked activation of nuclear factor kappa beta (NF-kappa-B) and activator protein (AP)–1, and abolished lipopolysaccharide-stimulated (LPS)–induced IkB destruction. 39 , 40

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 41 and had a protective effect in a rat model of inflammatory bowel disease. 42

Clinical studies

Similarly, human volunteers administered Pycnogenol demonstrated fewer incidents of erythema and NF-kappa-B expression in keratinocytes than did controls. 43 Inhibition of NF-kappa-B activation and matrix metalloproteinase (MMP)-9 secretion was found in human plasma after 5 days of oral Pycnogenol administration. 44 In a small clinical study, allergic rhinitis symptoms were reduced with administration of 100 mg/day of Pycnogenol for at least 5 weeks. 45 Limited clinical studies suggest a role in the management of osteoarthritis with improved Western Ontario and McMaster Universities Osteoarthritis Index scores after 3 months of Pycnogenol 100 mg daily. 2

Other effects
Cancer

Pycnogenol induced apoptosis in MCF-7 breast cancer cells and in HL-60 leukemia cells and reduced the adverse effects of chemotherapy and radiation therapy in a clinical study and in rats. 2 , 46 , 47 , 48 , 49 , 50

Diabetic retinopathy

Diabetic retinopathy has also been studied in clinical trials with varying methodological quality. 51 , 52

Hemorrhoids

A small clinical trial (N = 84) evaluated the effect of oral and topical Pycnogenol on pain and bleeding, and found improvements with 300 mg daily for 4 days and then 150 mg daily for a further 3 days. The cream was used at 0.5%. 53

Tinnitus

A small pilot study (N = 50) found increased systolic and diastolic cochlear artery flow with administration of 100 and 150 mg of Pycnogenol daily for 2 weeks. 54

Other

Pycnogenol has been tested in clinical trials of varying quality for other indications, including attention deficit hyperactivity disorder, hyperpigmentation in melasma, motion sickness, and traveler's thrombosis, as well as for the control of inflammation in lupus patients, as an adjunct for childhood asthma, and in a chewing gum for gingival bleeding and plaque. 55 , 56 , 57 , 58 , 59 , 60 , 61

Dosage

The pharmacokinetics of maritime pine bark extract constituents have been studied in human volunteers. A total of 15 compounds were found to be rapidly absorbed and metabolized by phase 2 enzymes. 62 Doses of 60 to 300 mg daily of Pycnogenol have been studied in clinical trials, most commonly at 150 mg/day. 2 , 3

Pregnancy/Lactation

Information regarding safety and efficacy during pregnancy and lactation is lacking. Pycnogenol has been studied for pain in the third trimester of pregnancy at a dose of 30 mg/day. 63

Interactions

None well documented, although a risk of interaction with antiplatelet therapy is possible. 24

Adverse Reactions

Pine bark extract is generally well tolerated, with minor gastric discomfort, dizziness, nausea, and headache occasionally noted. Clinical studies using Pycnogenol report no clinically important adverse events at doses of 150 mg of Pycnogenol daily. 2 , 16 , 21 , 54

Toxicology

Pine bark extract is generally recognized as safe (GRAS), based on data from clinical trials. Limited toxicological data are available. 2 , 3

Bibliography

1. Pinus pinaster . USDA, NRCS. 2011. The PLANTS Database ( http://plants.usda.gov , August 2011). National Plant Data Team, Greensboro, NC 27401-4901 USA.
2. Maimoona A, Naeem I, Saddiqe Z, Jameel K. A review on biological, nutraceutical and clinical aspects of French maritime pine bark extract. J Ethnopharmacol . 2011;133(2):261-277.
3. D'Andrea G. Pycnogenol : a blend of procyanidins with multifaceted therapeutic applications? Fitoterapia . 2010;81(7):724-736.
4. 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.
5. 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.
6. Devaraj S , Vega-López S , Kaul N , Schönlau 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(10):931-934.
7. 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(1):67-72.
8. Dvořáková M, Paduchová Z, Muchová J, Duračková Z, Collins AR. How does Pycnogenol influence oxidative damage to DNA and its repair ability in elderly people? Prague Med Rep . 2010;111(4):263-271.
9. Rezzani R, Porteri E, De Ciuceis C, et al. Effects of melatonin and Pycnogenol on small artery structure and function in spontaneously hypertensive rats. Hypertension . 2010;55(6):1373-1380.
10. van der Zwan LP, Scheffer PG, Teerlink T. Reduction of myeloperoxidase activity by melatonin and Pycnogenol may contribute to their blood pressure lowering effect. Hypertension . 2010;56(3):e34.
11. Klimas J, Kmecova J, Jankyova S, et al. Pycnogenol improves left ventricular function in streptozotocin-induced diabetic cardiomyopathy in rats. Phytother Res . 2010;24(7):969-974.
12. 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.
13. Arcangeli P . Pycnogenol in chronic venous insufficiency . Fitoterapia . 2000;71(3):236-244.
14. Petrassi C , Mastromarino A , Spartera C . Pycnogenol in chronic venous insufficiency . Phytomedicine . 2000;7(5):383-388.
15. Koch R. Comparative study of Venostasin and Pycnogenol in chronic venous insufficiency. Phytother Res . 2002;16(suppl 1):S1-S5.
16. 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(2):205-212.
17. Belcaro G , Cesarone MR , Errichi BM , et al. Venous ulcers: microcirculatory improvement and faster healing with local use of Pycnogenol . Angiology . 2005;56(6):699-705.
18. Cesarone MR, Belcaro G, Rohdewald P, et al. Improvement of signs and symptoms of chronic venous insufficiency and microangiopathy with Pycnogenol : a prospective, controlled study. Phytomedicine . 2010;17(11):835-839.
19. Belcaro G, Cesarone MR, Dugall M, et al. Investigation of Pycnogenol in combination with coenzymeQ10 in heart failure patients (NYHA II/III). Panminerva Med . 2010;52(2)(suppl 1):21-25.
20. 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.
21. Cesarone MR, Belcaro G, Stuard S, et al. Kidney flow and function in hypertension: protective effects of Pycnogenol in hypertensive participants—a controlled study. J Cardiovasc Pharmacol Ther . 2010;15(1):41-46.
22. Stuard S, Belcaro G, Cesarone MR, et al. Kidney function in metabolic syndrome may be improved with Pycnogenol . Panminerva Med . 2010;52(2)(suppl 1):27-32.
23. 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.
24. Pütter M , Grotemeyer KH , Würthwein G , et al. Inhibition of smoking-induced platelet aggregation by aspirin and Pycnogenol . Thromb Res . 1999;95(4):155-161.
25. Araghi-Niknam M , Hosseini S , Larson D , Rohdewald P , Watson RR . Pine bark extract reduces platelet aggregation . Integr Med . 2000;2(2):73-77.
26. 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.
27. Ledda A, Belcaro G, Cesarone MR, Dugall M, Schönlau F. Investigation of a complex plant extract for mild to moderate erectile dysfunction in a randomized, double-blind, placebo-controlled, parallel-arm study. BJU Int . 2010;106(7):1030-1033.
28. Aoki H, Nagao J, Ueda T, et al. Clinical assessment of a supplement of Pycnogenol and l-arginine in Japanese patients with mild to moderate erectile dysfunction. Phytother Res . 2011 May 27. doi: 10.1002/ptr.3462. [Epub ahead of print]
29. 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.
30. Lee OH, Seo MJ, Choi HS, Lee BY. Pycnogenol inhibits lipid accumulation in 3T3-L1 adipocytes with the modulation of reactive oxygen species (ROS) production associated with antioxidant enzyme responses. Phytother Res . 2011 Jul 27. doi:10.1002/ptr.3568. [Epub ahead of print]
31. Hasegawa N . Inhibition of lipogenesis by Pycnogenol . Phytother Res . 2000;14(6):472-473.
32. Hasegawa N . Stimulation of lipolysis by Pycnogenol . Phytother Res . 1999;13(7):619-620.
33. Mochizuki M , Hasegawa N . Pycnogenol stimulates lipolysis in 3t3-L1 cells via stimulation of beta-receptor mediated activity . Phytother Res . 2004;18(12):1029-1030.
34. Lee HH, Kim KJ, Lee OH, Lee BY. Effect of Pycnogenol on glucose transport in mature 3T3-L1 adipocytes. Phytother Res . 2010;24(8):1242-1249.
35. Berryman AM , Maritim AC , Sanders RA , Watkins JB III . 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(6):345-352.
36. Koláček M, Muchová J, Vranková S, et al. Effect of natural polyphenols, Pycnogenol on superoxide dismutase and nitric oxide synthase in diabetic rats. Prague Med Rep . 2010;111(4):279-288.
37. Liu X , Wei J , Tan F , Zhou S , Würthwein G , Rohdewald P . Antidiabetic effect of Pycnogenol French maritime pine bark extract in patients with diabetes type II . Life Sci . 2004;75(21):2505-2513.
38. Sharma SC , Sharma S , Gulati OP . Pycnogenol inhibits the release of histamine from mast cells . Phytother Res . 2003;17(1):66-69.
39. 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(1):64-71.
40. 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.
41. Blazsó G , Gábor M , Rohdewald P . Antiinflammatory activities of procyanidin-containing extracts from Pinus pinaster Ait. after oral and cutaneous application . Pharmazie . 1997;52(5):380-382.
42. Mochizuki M , Hasegawa N . Therapeutic efficacy of Pycnogenol in experimental inflammatory bowel diseases . Phytother Res . 2004;18(12):1027-1028.
43. 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(2):154-160.
44. Grimm T , Chovanová Z , Muchová 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 (Lond) . 2006;3:1.
45. Wilson D, Evans M, Guthrie N, et al. A randomized, double-blind, placebo-controlled exploratory study to evaluate the potential of Pycnogenol for improving allergic rhinitis symptoms. Phytother Res . 2010;24(8):1115-1119.
46. Huynh HT , Teel RW . Selective induction of apoptosis in human mammary cancer cells (MCF-7) by Pycnogenol . Anticancer Res . 2000;20(4):2417-2430.
47. 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(6):685-692.
48. 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(5):414-418.
49. de Moraes Ramos FM , Schönlau F , Novaes PD , Manzi FR , Bóscolo 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(8):676-679.
50. Sime S , Reeve VE . Protection from inflammation, immunosuppression and carcinogenesis induced by UV radiation in mice by topical Pycnogenol . Photochem Photobiol . 2004;79(2):193-198.
51. Spadea L , Balestrazzi E . Treatment of vascular retinopathies with Pycnogenol . Phytother Res . 2001;15(3):219-223.
52. Schönlau F , Rohdewald P . Pycnogenol for diabetic retinopathy: a review . Int Ophthalmol . 2001;24(3):161-171.
53. Belcaro G, Cesarone MR, Errichi B, et al. Pycnogenol treatment of acute hemorrhoidal episodes. Phytother Res . 2010;24(3):438-444.
54. Grossi MG, Belcaro G, Cesarone MR, et al. Improvement in cochlear flow with Pycnogenol in patients with tinnitus: a pilot evaluation. Panminerva Med . 2010;52(2)(suppl 1):63-67.
55. Ni Z , Mu Y , Gulati O . Treatment of melasma with Pycnogenol . Phytother Res . 2002;16(6):567-571.
56. Trebatická J , Kopasová S , Hradecná Z , et al. Treatment of ADHD with French maritime pine bark extract, Pycnogenol . Eur Child Adolesc Psychiatry . 2006;15(6):329-335.
57. 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(9):687-695.
58. Cesarone MR , Belcaro G , Rohdewald P , et al. Prevention of edema in long flights with Pycnogenol . Clin Appl Thromb Hemost . 2005;11(3):289-294.
59. Stefanescu M , Matache C , Onu A , et al. Pycnogenol efficacy in the treatment of systemic lupus erythematosus patients . Phytother Res . 2001;15(8):698-704.
60. 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(8):825-832.
61. Kimbrough C , Chun M , dela Roca G , Lau BH . Pycnogenol chewing gum minimizes gingival bleeding and plaque formation . Phytomedicine . 2002;9(5):410-413.
62. Grimm T , Skrabala R , Chovanová 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.
63. Kohama T , Inoue M . Pycnogenol alleviates pain associated with pregnancy . Phytother Res . 2006;20(3):232-234.

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