Pycnogenol^®

(French Maritime Pine Bark Extract)

Pinus pinaster Aiton subsp. atlantica

[Fam. Pinaceae]

Overview

French maritime pine bark extract, sold under the trade name Pycnogenol^® (manufactured by Horphag Research, Geneva, Switzerland) was ranked 15th among the top-selling herbal dietary supplements in the U.S. in mainstream retail outlets (food, drug, and mass market stores) with total sales in this channel of trade exceeding $3 million in 2000 (Blumenthal, 2001). Sales in natural food store, multi-level marketing, and mail order channels are presumably much higher, but accurate statistics for aggregate sales in these markets are not available. Traditionally, North American pine bark has been used by Native American Indians to treat colds and rheumatism, and for wound healing (Moerman, 1998; Chandler et al., 1979).

Recent research suggests significant antioxidant activity for this extract, based primarily on its proanthocyanidin content. Currently, Pycnogenol^® is used primarily to help prevent edema formation of the lower legs (Gulati, 1999) and capillary bleeding, especially in cases of retinopathy (Spadea and Balestrazzi, 2001). Pycnogenol^® has been shown to prevent platelet aggregation in smokers (Pütter et al., 1999) and in cardiovascular patients (Wang et al., 1999). It has been used in reducing pain associated with menstrual disorders (Kohama and Suzuki, 1999) and has demonstrated improved lung function and symptom scores in asthmatics (Hosseini et al., 2001b), normalized blood pressure in mild hypertensives (Hosseini et al., 2001a), and improved symptoms in patients with systemic lupus erythematosus (SLE) (Stefanescu et al., 2001).

Description

French maritime pine bark extract is made by extraction of the outer bark of Pinus pinaster Ait. subsp. atlantica. The French subspecies atlantica of P. pinaster differs from the Iberian (Spanish) and Moroccan subspecies by its resistance against salt (Saur et al., 1993) and in the profile of its phytochemical constituents (Bahrman et al., 1994).

The fresh bark is powdered and extracted with ethanol and water in patented equipment allowing an automated continuous process (Rohdewald, 2002). After purification of the raw extract, the aqueous solution of the extracted constituents is spray-dried. The resulting fine brownish powder is stable if stored in a dry, dark environment. The extract is standardized to a procyanidin content of 70 5%, primarily catechins and epicatechins.

Primary Uses

Cardiovascular

Venous insufficiency, chronic (Arcangeli, 2000; Petrassi et al., 2000; Schmidtke and Schoop, 1995; Sirnelli-Walter and Weil-Masson, 1988; Doucet et al., 1987; Schmidtke and Schoop, 1984; Feine-Haake, 1975)

Other Potential Uses

Abdominal and menstrual pain (Kohama and Suzuki, 1999)

Asthma (Hosseini et al., 2001b)

Endometriosis (Kohama and Suzuki, 1999)

Enhanced sperm quality in case of man diagnosed with malformed sperm (Roseff and Gulati, 1999)

Mild hypertension (Hosseini et al., 2001a)

Prevention of platelet aggregation (Pütter et al., 1999)

Retinal disorder, vascular (Spadea and Balestrazzi, 2001)

Retinopathy, diabetic (Magnard et al., 1970)

Systemic lupus erythematusus (SLE), second line therapy (Stefanescu et al., 2001)

Dosage

For prevention and treatment of chronic venous disorders: daily doses ranging from 100–300 mg per day were effective in controlled clinical trials (Gulati, 1999).

For prevention and treatment of retinal vascular disorders: doses from 40–150 mg have been used in clinical trials (Spadea and Balestrazzi, 2001; Magnard et al., 1970).

For treatment of endometriosis and menstrual disorders: 30–60 mg have been found to be effective (Kohama and Suzuki, 1999).

To normalize platelet function doses of 150–200 mg are needed (Pütter et al., 1999).

To normalize blood pressure 200 mg were given (Hosseini et al., 2001a).

To reduce asthma symptoms, 1 mg/lb body weight were taken (Hosseini et al., 2001b).

Duration of Administration

Clinical experience demonstrated that beneficial effects can be substantiated after 4 weeks of treatment with Pycnogenol^® in cases of chronic venous disorders and retinal vascular disorders. However, results improved significantly when the treatment period was extended to 2 months (Gulati, 1999).

Blood pressure in mild hypertensive patients was normalized following treatment period of 8 weeks (Hosseini et al., 2001a).

For prevention of menstrual disorders treatment periods will vary from individual to individual; however, one study noted beneficial effects after 14–30 days (Kohama and Suzuki, 1999).

Asthma symptoms were improved after 4 weeks treatment (Hosseini et al., 2001b).

For improvement of sperm quality, treatment period was 9 months (Roseff and Gulati, 1999).

Continuous intake of Pycnogenol^® as a dietary supplement can be recommended to protect the cardiovascular system from the development of atherosclerosis and thrombus formation in moderate doses from 50–100 mg. (This effect is the result of Pycnogenol^®’s ability to normalize platelet aggregation and thromboxane levels, to antagonize vasoconstriction induced by adrenaline, to inactivate free radicals, and the anti-oxidative effect influencing the oxidation of lipids.)

Chemistry

Pycnogenol^® is prepared from the bark of French maritime pine trees (P. pinaster) by a standardized process. The trees are cultivated as a monoculture exclusively in one narrow area in Southwest France and the bark is harvested from 30-year old trees; therefore, chemical studies indicate that there is little variation in the composition of the extract over the years.

French maritime pine bark extract contains procyanidins, catechin, epicatechin, taxifolin, phenolic acids, and glucosides or glucose esters of its constituents.

Procyanidins

The procyanidins consist of units of catechin and epicatechin. The chain length of the procyanidins in Pycnogenol^® range from dimers up to octamers. The dimers had been identified as the isomeric forms B1, B3, B6, and B7. A trimer C2, consisting of catechin-epicatechin-catechin is also identified (Rohdewald, 2002). The presence of tetramers to octamers was demonstrated by mass spectrometry (MALDI-TOF) (Rohdewald, 1998). The total amount of procyanidins in Pycnogenol^® is standardized to 70 5%. Catechin, epicatechin, and taxifolin represent the so-called “monomeric” procyanidins. Taxifolin was found as its glycoside and in its free form (Rohdewald, 1998).

Phenolic acids

Phenolic acids, also called fruit acids, in French maritime pine bark extract are derivates from benzoic acid (p-hydroxybenzoic acid, protocatechic acid, gallic acid, vanillic acid) and from cinnamic acid (caffeic acid, ferulic acid, p-cumaric acid).

Additionally, the glucose ester of ferulic acid and p-cumaric acid were identified and the glucoside of vanillic acid (Rohdewald, 1998).

Other constituents

Free glucose is present in small amounts, rhamnose, xylose, and arabinose could be detected, but not quantified. Vanillin is also found in very small quantities (Rüve, 1996).

Pharmacological Actions

Humans

Symptoms of chronic venous insufficiency including edema of the lower legs, feeling of heaviness in the lower legs, cramps, and pain were significantly reduced (Arcangeli, 2000; Petrassi et al., 2000; Schmidtke and Schoop, 1995, 1984); vision was improved in cases of retinal vascular disorder (Spadea and Balestrazzi, 2001; Magnard et al, 1970); smoking-induced platelet aggregation was prevented (Pütter et al., 1999); in patients with cardiovascular diseases, platelet aggregation was reduced (Wang et al., 1999); mild hypertension was reduced to normal (Hosseini et al., 2001a); asthma symptoms and lung function were improved (Hosseini et al., 2001b); reduction of menstrual cramps and pain have been reported (Kohama and Suzuki, 1999); and malformation of human sperm have been normalized (Roseff and Gulati, 1999).

Animal

Increased capillary resistance (Gábor et al., 1993); anti-inflammatory (Blazsó et al., 1997); anti-hypertensive (Blaszó et al., 1996); immunomodulation (Liu et al., 1998; Cheshier et al., 1996); improvement of cognitive function (Liu et al., 1999); UV-protection (Blazsó et al., 1995); spasmolytic activity of ferulic acid on rat uterus (Ozaki and Ma, 1990).

In vitro

Radical scavenging activity (Packer et al., 1999; Rohdewald, 1998; Elstner and Kleber, 1990); protection of DNA (Nelson et al., 1998); increased production of superoxide dismutase (SOD), catalase, and glutathione (Wei et al., 1997); protection of brain cells against amyloid--protein toxicity (Rohdewald, 1998) and glutamate-induced toxicity (Kobayashi, 2000; Rohdewald, 1998); inhibition of adrenalin-induced platelet aggregation (Rüve, 1996); inhibition of angiotensin-converting enzyme (ACE) (Blaszó et al., 1996); inhibition of adrenalin-induced vasoconstriction (Fitzpatrick et al., 1998); UV-protection (Guochang, 1993); apoptosis of human mammary cancer cells (Huynh and Teel, 2000); and spasmolytic action of constituents of Pycnogenol^®, caffeic, and protocatechic acid on smooth muscles (de Urbina et al., 1990). Pycnogenol^® has been shown to exhibit anticalgranulin activity in human keratinocytes (in vitro), suggesting potential use for treatment of psoriasis and various dermatoses (Rihn et al., 2001). Pycnogenol^® increases human growth hormone secretion (Buz’Zard et al., 2002).

Mechanism of Action

High affinity to proteins (Packer et al., 1999) decreases capillary permeability thereby reducing microbleeding and preventing edema formation (Gabór et al., 1993).

Stimulates production of the endothelium-derived factor (nitric oxide, NO) causing vasorelaxation (Fitzpatrick et al., 1998) leading to increased microcirculation (Wang et al., 1999). Pycnogenol^®, in addition to its antioxidant activity, stimulates constitutive endothelial NO synthase activity to increase NO levels, which could counteract the vasoconstrictor effects of epinephrine (E) and norepinephrine (NE) (Fitzpatrick et al., 1998). Furthermore, additional protective effects could result from the well-established properties of NO to decrease platelet aggregation and adhesion, as well as to inhibit low-density lipoprotein (LDL) cholesterol oxidation, all of which could protect against atherogenesis and thrombus formation. Pycnogenol^® stimulates NO production (Fitzpatrick et al., 1998) and inhibits thromboxane formation (Watson, 1999), both effects leading to reduced platelet-aggregation (Pütter et al., 1999).

Antioxidant activity is closely related to anti-inflammatory effects (Blázso et al., 1995). [Because anti-inflammatory processes generate free radicals, the inhibition of the superoxide radical by fractions of Pycnogenol^® in vitro is closely related to the anti-inflammatory activity of the same fractions in vivo. In addition to the inhibition of prostaglandins and leukotrienes (Hosseini et al., 2001b), the scavenging of free radicals is a contributing factor to an anti-inflammatory activity].

Phenolic acids possess spasmolytic activity on uterine muscles in vivo (Ozaki and Ma, 1990; de Urbina et al., 1990).

Contraindications

None known.

Pregnancy and lactation: As a general precaution, Pycnogenol^® should not be taken during the first 3 months of pregnancy. Safety pharmacology demonstrated absence of mutagenic and teratogenic effects, no perinatal toxicity, and no negative effects on fertility (Rohdewald, 2002).

Adverse Effects

Gastric upset, diarrhea, constipation. To avoid these small side effects, Pycnogenol^® should be taken with meals. The average frequency of minor adverse effects including headache and dizziness is 1.6%. Adverse effects are not related to dose or total duration of treatment. Data are based on documentation of reports on 2000 patients (Rohdewald, 2002).

Drug Interactions

None known.

Because of its mechanism of action of inhibiting platelet aggregation, Pycnogenol^® should not be added to treatment with antiplatelet drugs; however, this interaction is theoretical and has not been demonstrated in clinical experience.

American Herbal Products Association (AHPA) Safety Rating

There is no listing for P. pinaster, Pycnogenol^®, or French maritime pine bark extract in the American Herbal Products Association’s Botanical Safety Handbook (McGuffin et al., 1997), probably due to the fact that most of the herbs rated for safety in this volume are based on those herbs previously listed in the AHPA Herbs of Commerce (Foster, 1992). At that time, pine bark extract was only beginning to be marketed in the U.S.

Regulatory status

Canada: Decision pending.

France: A French maritime pine bark extract is approved as a non-prescription herbal drug for treatment of venous disorders.

Germany: Not reviewed by the German Commission E (Blumenthal et al., 1998).

Greece: Non-prescription herbal drug for treatment and prevention of chronic venous insufficiency.

Japan: Food supplement; also approved as cosmetic ingredient.

People’s Republic of China & Hong Kong: Health food.

Sweden: No pine bark extract products are presently registered in the Medical Products Agency’s (MPA) “Authorised Natural Remedies” listings (MPA, 2001).

Switzerland: Non-prescription herbal drug for treatment and prevention of chronic venous insufficiency. One purified pine bark extract product is listed in the Codex 2000/01 (Ruppanner and Schaefer, 2000).

U.K.: Food supplement. For adults only. Not to be used by children or pregnant women (FAC, 2000; Crates, 2000). (This is consistent with the labelling of other food supplements in the UK).

U.S.: Dietary supplement (USC, 1994).

Clinical Review

Fourteen clinical studies are included in the following table, “Clinical Studies on Pycnogenol^® (French Maritime Pine Bark Extract).” Nine double-blind, placebo-controlled studies (DB, PC) have been conducted on a total of 244 patients. Four DB, PC studies (Arcangeli, 2000; Petrassi et al., 2000; Schmidtke and Schoop, 1995, 1984) focused on chronic venous insufficiency and confirmed results of three open studies with 255 patients in total (Sirnelli-Walter and Weil-Masson, 1988; Doucet et al., 1987; Feine-Haake, 1975). One DB, PC study conducted by Spadea and Balestrazzi (2001) confirmed preliminary findings of a previous open study (Magnard et al., 1970) on the effects of retinopathy. One PC study demonstrated complete inhibition of smoking-induced platelet aggregation (Pütter et al., 1999), and a DB, PC study with cardiovascular patients showed a significant decrease in platelet aggregation and improved microcirculation (Wang et al., 1999). A DB, PC, crossover (CO) study showed reduction of asthma symptoms and improvement of lung function (Hosseini et al., 2001b). Blood pressure of mild hypertensives was normalized in a DB, PC, CO study (Hosseini et al., 2001a). Pycnogenol^® supplementation contributed to improvement of symptoms of SLE in a DB, PC pilot study (Stefanescu et al., 2001).