Digitoxin

The development of a standardized extract of hawthorn leaves and flowers in Europe has led to a novel approach to the treatment of congestive heart failure (CHF). Clinical trials with an extract standardized to oligomeric procyanidins (WS 1442) have successfully demonstrated improved cardiac function and improved quality of life in patients with early stage CHF.

Hawthorn is a small, shrub-like tree with sharp thorns, often found in woodlands. A member of the Rosaceae family, hawthorn is the popular name given to the plant genus Crataegus, which includes over 100 species. The two species used most frequently for the development of standardized extracts are Crataegus laevigata (synonym: Crataegus oxyacantha) and Crataegus monogyna. (1)

While the berries of hawthorn have been used in traditional herbal preparations, modern phytomedicinal extracts have primarily used the leaves and flowers. (2)

Active Constituents and Mechanism of Action

Modern development of hawthorn extracts began with the discovery that flavonoid and flavonoid complexes were responsible for the cardiac actions attributed to the plant. Among these are oligomeric procyanidins, vitexin, vitexin 4'-O-rhamnoside, quercetin, rutin, and hyperoside. (3) The leaves and flowers contain the highest concentration of these active constituents, especially the oligomeric procyanidins. (4)

The following pharmacodynamic effects have been demonstrated in both in vitro and in vivo studies: (5-7) 1) increased contractility of the myocardium (positive inotropic effect); 2) reduced peripheral vascular resistance (reduction in after load); 3) improved left ventricular ejection fraction; 4) improved coronary blood flow; and 5) increased tolerance of the myocardium to oxygen and substrate deficiency.

The mechanism underlying these effects is primarily attributed to a slight inhibition of Na+/K+ ATPase, which might be responsible for the positive inotropic action. There is also evidence of inhibition of angiotensin converting enzyme and of interactions with campmediated [beta]-adrenergic system, which may explain the vascular effects of the extract. (8)

Clinical Use for Congestive Heart Failure (CHF)

Clinical trials using WS 1442 have been completed primarily with patients meeting the New York Heart Association's stage II for CHI (e.g. mild limitation, symptoms only with exercise). Two earlier placebo-controlled trials found that CHF patients taking 80 mg of WS 1442 b.i.d. for 8 weeks had improved exercise tolerance and decreased heart rate during exercise (a stationary bicycle was the form of exercise).(9,10) Subjective well-being also improved in patients taking WS 1442. A more recent 12-week placebo-controlled trial found increased exercise tolerance for stage II CHF patients taking 240 mg/day of WS 1442. (11) However, the difference in exercise tolerance between the WS 1442 and placebo group failed to reach statistical significance (p = 0.06). Finally, an uncontrolled, open-label study found that 900 mg/day of WS 1442 for 24 weeks also led to improved exercise tolerance, decreased blood pressure, and improved left ventricular ejection fraction (LVEF)in 1,011 stage II CHF patients. (12)

In a small clinical trial, 40 stage II CHF patients with a LVEF of less than 55% were randomized to receive either 160 mg of WS 1442 or placebo t.i.d. for 4 weeks. (13) At the end of the trial there was a 1.5% increase in the LVEF under exercise conditions (stationary bicycle) in the WS 1442 group compared to a 0.2% decrease in LVEF in the placebo group (p = 0.0002). During rest, LVEF increased by 2.5% in the WS 1442 group compared to a 0.3% decrease in the placebo group (p = 0.0001).

Recommended Use

For the treatment of early stage CHF, the effective daily dosage of WS 1442 (standardized to 18.75% oligomeric procyanidins) has ranged from 160 to 900 mg per day. This is typically delivered in two to three divided doses. Health care professionals should note that efficacy has been shown in the 160 to 480 mg/day range and this may be an acceptable starting point for treating early stage CHF.

Side Effects/Contraindications

Clinical trials on the oral use of the WS 1442 hawthorn extract suggest that it is safe for ongoing use in patients with early stage CHF. (14) There are no known interactions with prescription cardiac drugs. Although the potential for hawthorn extracts to potentiate the effect of digoxin has been reported in the literature, (15) this has not been documented in any clinical trials to date nor has it been cited as a concern by either the German Commission E (16) or American Herbal Pharmacopoeia (17) monographs on hawthorn.

Note: WS 1442 is a standardized extract (5:1) of hawthorn leaves and flowers produced by the Dr. Wilmar Schwabe Co. of Karlsruhe, Germany. The extract is standardized to contain 18.75% oligomeric procyanidins.

References

(1.) Hamon NW. Hawthorns: The genus Crataegus. Can Pharm J 1996;121:708-9, 724.

(2.) Wichtl M: Herbal Drugs and Phytopharmaceuticals. Boca Raton, FL: CRC Press, 1994. 161-6.

(3.) Loew D. Pharmacological and clinical results with Crataegus special extracts in cardiac insufficiency. ESCOP Phytotelegrarn 1994:6:20-6.

(4.) Rewerski VW, Piechocki T. Ryiski M, Lewak S. Some pharmacological properties of oligomeric procyanidin isolaled from hawthorn (Crataegus oxyacantha). Arznemittforschung Drug Res 1967:17:490-1.

(5.) Chatterjee SS, Koch B, Jaggy H, Krzeminski T. In vitro and in vivo investigations en the cardioprotective effects of oligomeric procyanidins in a Crataegus extract from leaves with flowers. Arzneimittlforochung Drug Res 1997:47:821-5.

(6.) Weikl A, Noh HS. The influence of Crataegus on global cardiac insufficiency. Hem Gatabe 1993:11:516-24.

(7.) Schwinger RHG, Pietsch M, Frank K, Brixus K. Crataegus special extract WS 1442 Increases force of contraction in human myocardium camp-independently. J Cardiovasc Pharmacol 2000:35:700-707.

(8.) Loew D. Pharmacological and clinical results with Crataegus special extracts in cardiac insufficiency. ESCOP Phytotelegram 1994:8:29-6.

(9.) Weikl A, Assmus KD, Neukum-Schmidt A, et al. Crataegus special extract WS 1442: Objective proof of efficacy in patients with cardiac insufficiency (NYHA II). Fortschr Med 1996:114:291-6.

(10.) Leuchtgens H. Crataegus special extract (WS 1442) in cardiac Insufficiency. Fortschr Med 1993;111:352-4.

(11.) Zapfe G. Clinical efficacy of Crataegus extract WS 1442 in congestive heart failure NYHA class II. Phytomedicine 2001:8:262-6.

(12.) Tauchert M, Gildor A. Lipinski J. High-dose Crataegus extract WS 1442 in the treatment of NYHA Stage II cardiac insufficiency. Herz 1999:24:465-74.

(13.) Eichstodt, Stork T, Mockel M, et al. Efficacy and tolerability of Crataegus extract WS 1442 in patients with congestive heart failure and impaired lets-ventricular function. Perfusion 2001;14:212-7.

(14.) Busse W, Standardized Crataegus extract. Seattle, WA: Natural Product Research Consultants, 1997.

(15.) Tanzler VG, Schuler E Verleichande studein Ober wirkungen elnes Crataegus-extraktes, ven digitoxin, digaxin, und y.strophanthin am isolierten warmbluterherzen. Arzneimittforschung Drug Res 1962:12:198.

(16.) Blumenthal M, Busse WR, Goldberg A, et al, eds. The Complete Commission E Monographs. Integrative Medicine Communications, Boston, MA, 1996,142-4.

(17.) Upton R, ed. Hawthorn leaf with flower. Santa Cruz, CA: American Herbal Pharmacopoeia, 1999.

Correspondence:

Emerson Ecologics, Inc.

603-656-7887 ext. 161 / Fax 603-656-9797

Email: jmccartin@emersonecologics.com

Website: www.emersonecologics.com

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