Hawthorn

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Crataegus monogyna Jacq., C. laevigata (Poir.) DC. (syn. C. oxyacantha auct)

[Fam. Rosaceae]

Overview

Hawthorn is a bush or small tree that includes approximately 280 species native to northern temperate zones in East Asia, Europe, and eastern North America (Hobbs and Foster, 1990). The fruit has been used as food and medicine in Europe for centuries. Over the past 20 years, several different commercially available preparations of hawthorn have been investigated in double-blind, placebo-controlled (DB, PC) clinical studies. Hawthorn preparations are among the most popularly prescribed botanical medicines in central Europe, particularly in Germany, Austria, and Switzerland. The primary approved indication is treatment of declining cardiac performance according to Stage II of the New York Heart Association (NYHA) classification. Hawthorn has become increasingly popular as a dietary supplement in the U.S., ranking 20th in sales in mainstream retail stores in 2000 (Blumenthal, 2001). Separate United States Pharmacopeia-National Formulary botanical monographs are presently under development for hawthorn leaf with flower and its preparations including extract, powder, and tablet (USP, 2002).

Description

Hawthorn leaf and flower preparations consist of whole or cut, dried, flower-bearing branches of Crataegus monogyna Jacq. or C. laevigata (Poir) DC. (syn. C. oxyacantha auct.), their hybrids, or other Crataegus species including C. piperi Bitton (syn. C. columbiana T.J. Howell var. piperi [Britt.] Egglest) and C. rivularis Nutt. (syn. C. douglasii Lindl. Var. rivularis [Nutt.] Sarg.)[Fam. Rosaceae]. Various species of hawthorn leaf and flower are recognized as official by different compendia: the German Pharmacopoeia recognizes up to five species, and the Pharmacopoeia Europa recognizes two. The American Herbal Pharmacopoeia (unofficial) recognizes C. laevigata (C. oxyacantha) and C. monogyna, or their hybrids, and other species (Upton, 1999a, 1999b).

The Pharmacopoeia Europa requires that hawthorn preparations contain not less than 1.5% flavonoids, calculated as hyperoside (Ph.Eur., 2001). Both the Austrian Pharmacopoeia and the German Pharmacopoeia, however, require not less than 0.7% flavonoids (DAB, 1999; ÖAB, 1994). The Pharmacopoeia Europa requires a flavonoid content of 1.5% based on a spectrophotometric method, while the 0.7% flavonoid concentration of the German Pharmacopoeia is based on a high-performance liquid chromatography method. Thus, the apparent differences in value are based on different analytical methods, not on differences of raw material.

Hawthorn fruit consists of the dried pome of C. monogyna Jacq. or C. laevigata (Poir) D.C. (syn. C. oxyacantha auct.), or hybrids or combinations of these species. The dried fruit contains not less than 1.0% of procyanidins calculated as cyanidin chloride (DAC, 1992; Ph.Eur., 2001).

Primary Uses

Hawthorn leaf with flower (internal)

Congestive heart failure NYHA Stage I and II (Tauchert et al., 1999; Blumenthal, et al., 1998; Loew et al., 1996; Weikl et al., 1996; Bödigheimer and Chase, 1994; Förster et al., 1994; Schmidt et al., 1994; Tauchert et al., 1994; Leuchtgens H, 1993; Weikl and Noh, 1992; Eichstädt et al., 1989; O’Conolly et al., 1986; Hanak and Brückel, 1983; Iwamoto et al., 1981)

Note: NYHA functional classification is most often used to characterize patients’ limitation from left ventricular failure. The classification has a strong association with mortality independent of left ventricular ejection fraction.

Stage I: No limitation of physical activity. Ordinary physical activity does not cause undue fatigue or dyspnea.

Stage II: Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in fatigue or dyspnea.

Other Potential Uses

Feeling of pressure and tightness in the cardiac region (Morant and Ruppanner, 2001; Braun et al., 1996)

Nervous heart complaints such as palpitations, sharp pain in the chest, rapid pulse, or vertigo (Morant and Ruppanner, 2001; Pfister-Hotz, 1997; van Hellemont, 1988; Wichtl, 1997)

Dosage

Hawthorn leaf with flower (internal)

Crude Preparations

Infusion: About 150 ml boiling water poured over approximately 1.5 g dried herb, steeped for 10–15 min., tea bag squeezed over cup, 3–4 times daily, during or after meals (Morant and Ruppanner, 2001; Braun et al., 1996).

Note: According to Kneipp^®, a properly prepared tea infusion will yield over 90% into solution of the active principles from the flavonoid and oligomeric procyanidin groups and compares dose for dose with solid-form preparations (Kneipp-Werke, 1996). Other sources report that after a 10-minute infusion, 35% of the O-glycoside bound flavonoids, and 40% of the C-glycoside bound flavonoids are released into solution (Meyer-Buchtela, 1999).

Fluid extract (DAB, 2000) [1:1 (w/v), 45% ethanol (v/v), ≥1.0% flavonoids calculated as hyperoside ethanol]: The German Commission E requires that a single- or daily-dose phytoequivalence to the native dry extract dosage must first be confirmed by a clinical-pharmacological experiment or clinical study before a dosage recommendation can be made (Blumenthal et al., 1998).

Standardized Preparations

Dry extract [4–7:1 (w/w) with defined flavonoid or procyanidins content, ethanol 45% (v/v) or methanol 70% (v/v)]: 160–900 mg, in 2–3 individual doses, corresponding to 30–168.7 mg procyanidins, calculated as epicatechin, or 3.5–19.8 mg flavonoids, calculated as hyperoside, according to Commission E (Blumenthal et al., 1998).

Hawthorn fruit (internal)

Crude Preparations

Note: The following doses for hawthorn fruit preparations are not approved by Commission E and do not correlate to clinical trials summarized in the table in this monograph. These doses are presented as guides for non-official uses of hawthorn fruit preparations that are not documented by recent clinical research but are nevertheless published in the literature as potentially useful in NYHA Stage I and possibly Stage II (Upton, 1999).

Fluid extract [1:1 (w/v) in 25% alcohol (v/v)]: 0.5–1.0 ml, 3 times daily (BHP, 1983; Karnick, 1994).

Tincture [1:5 (w/v), in 45% alcohol (v/v)]: 1–2 ml, 3 times daily (BHP, 1983).

Tincture [1:3.2 (w/v) in 49% alcohol (v/v)]: 30 drops diluted in water, 3 times daily, one-half hour before meals (Morant and Ruppanner, 2001).

Tincture [1:10 (w/v)]: 5–10 drops, 1–3 times daily (Hänsel et al., 1992–94).

Solid extract: 0.25–0.50 teaspoon daily (Upton et al., 1999a).

Syrup: 1 teaspoon, 2–3 times daily (Upton et al., 1999a).

Duration of Administration

Internal

The Commission E reports that a healthcare provider should be consulted in cases where symptoms continue unchanged for more than six weeks or in case of swelling of the legs. Medical diagnosis is absolutely necessary when pain occurs in the region of the heart, spreading out to the arms, upper abdomen, or the area around the neck, or in cases of respiratory distress (dyspnea) (Blumenthal et al., 1998).

Chemistry

Note: Fully validated methods for determining procyanidin content are lacking. Therefore, the findings provided should be taken as relative values (Upton, 1999b).

Hawthorn leaf with flower

Constituents considered most important and primarily responsible for the pharmacological activity of hawthorn include flavonoids and procyanidins. The oligomeric procyanidins with a lower degree of polymerization appear to be more active than those with a higher degree of polymerization. Various concentrations are found in different plant parts and vary from species to species (Upton, 1999b). All species and parts studied contain a wide array of flavonoids (0.5–1.5%). The primary flavonoids are hyperoside (quercetin-3-D-galactoside), vitexin-2”-O-rhamnoside, and acetylvitexin-2”-O-rhamnoside. The primary flavonoid in the flowers is hyperoside, although in the leaves, vitexin-2”-O-rhamnoside and, occasionally, acetylvitexin-2”-O-rhamnoside dominate (Rehwald, 1995). 

The leaf and flower contain to 1.78% total flavonoids (flavones and flavonols) of which approximately 0.53% are vitexin-2”-O-rhamnoside, 0.28% hyperoside, 0.17% rutin, and 0.02% acetylvitexin–2”–O–rhamnoside (Hänsel et al., 1992–94; Wagner and Tittel, 1983); 1.0–2.4% oligomeric procyanidins; 0.6% triterpene acids including ursolic, oleanolic, and crataegolic acids; and phenolic acids such as caffeic acid, chlorogenic acid, and related phenolcarboxylic acids (Hänsel et al., 1992–94).

Hawthorn fruit

The fruits contain relatively low levels of flavonoids and consist primarily of oligomeric and polymeric procyanidins (Rehwald, 1995; Tittel and Wagner, 1981). The procyanidins contained in the fruit reportedly have a higher degree of polymerization than the procyanidins in the leaves and flowers. The pulp contains the highest concentration of procyanidins followed by the skin and stalks and procyanidin content is reportedly highest in unripe fruits (decreasing from 6.9% to 0.9% to the end of summer) (Rohr, 1999).

The fruit contains up to 2.96% total procyanidins of which approximately 1.9% are oligomeric procyanidins; 0.42–0.45% triterpene acids including ursolic, oleanolic, and crataegolic acids; and flavonoids (flavone glycosides and C-glycoside flavones), mainly hyperoside (Hänsel et al., 1992–94). A small amount of quercetin derivatives and rutin are also present (Rohr, 1999).

Pharmacological Actions

Hawthorn leaf with flower

Human

The Commission E reported that in cases of cardiac insufficiency classified as NYHA Stage II, hawthorn leaf with flower improves subjective findings, increases cardiac work tolerance, decreases pressure/heart rate product, increases the ejection fraction, and raises the anaerobic threshold (Blumenthal et al., 1998).

Animal

The Commission E reported positive inotropic effect, positive dromotropic effect, negative bathmotropic effect, increases in coronary and myocardial circulatory perfusion, and a reduction in peripheral vascular resistance (Blumenthal et al., 1998). These actions are confirmed in recent reviews (Loew, 1997; Upton, 1999a, 1999b).

In vitro

The extract standardized to procyanidins blocks beta-adrenoceptors (Rácz-Kotilla et al., 1980), and has inotropic effects in isolated heart cells (Bratman and Kroll, 1999), exerts direct positive inotropic ex vivo effect in human myocardium taken from patients with congestive heart failure, increases force of contraction in human myocardium 3’, 5’-cyclic adenosine monophosphate (cAMP)-independently (Schwinger et al., 2000) and increases antioxidant activity (Da Silva et al., 2000).

Standardized Preparations

The extract standardized to procyanidins blocks beta-adrenoceptors (Rácz-Kotilla et al., 1980), lowers plasma lipids (Rajendran et al., 1996), and blocks repolarizing potassium currents in ventricular cardiac myocytes (Müller, 1999).

Hawthorn fruit

Human

Cardiotonic (BHP, 1996).

Animal

Alcoholic tincture is a hypolipidemic agent (Rajendran et al., 1996; Shanthi et al., 1994).

Note: Since hawthorn fruit contains many of the same procyanidins as the leaf and flower extract, albeit in lower concentrations, the antioxidant effect (and presumably others) are presumed to be similar (Upton, 1999b).

Mechanism of Action

The mechanism of hawthorn’s vasodilating effect remains unclear (Loew, 1997). Based on animal studies, increases in coronary blood flow do not appear to be due to the action of a single group of constituents (e.g., flavonoids) but rather to interactions between various different groups of compounds (Sticher and Meier, 1998). Because the biological activity cannot be attributed to any single substance contained in hawthorn, the entire extract must be viewed as the effective treatment (Reuter, 1994). Hawthorn’s hypotensive effect is due to its vasodilating action rather than to an effect via adrenergic, muscarinic, or histaminergic receptors (Abdul-Ghani et al., 1987). The hypotensive effect may be due to procyanidins inhibiting angiotensin-converting enzyme (ACE) (Sticher and Meier, 1998).

Human

Based on experiments on myocardium taken from terminally failing human hearts (NYHA Class IV), it is suggested that hawthorn leaf with flower extract acts in a way similar to the cAMP-independent positive inotropic action of cardiac glycosides. Additionally, hawthorn improves the force-frequency relation in failing human myocardium (Schwinger et al., 2000).

Animal

Enhances LDL-receptor activity in rats. The hypocholesterolemic effect caused by the tincture may be due to up-regulation of hepatic LDL receptors (Rajendran et al., 1996).

In vitro

One study reports that the mechanism of hawthorn’s positive inotropic effects remains elusive and the effects are not caused by phosphodiesterase inhibition or a b-sympathomimetic effect. In isolated guinea pig ventricular myocytes, hawthorn extract blocks repolarizing potassium currents in a way that is similar to the action of class III anti-arrhythmic drugs (Müller, 1999).

Inhibits cAMP phosphodiesterase activity (Schüssler et al., 1991, 1992, 1993, and 1995), which increases cardiac cAMP levels causing a positive inotropic effect (cardiac muscle contractility).

Inhibits Na⁺-/K⁺ - ATP-ase activity (Brixius et al., 1998; Leukel-Lenz, 1988).

May inhibit thromboxane (TXA2) synthesis and stimulate prostacyclin (PGI2) (Vibes et al., 1991, 1993, and 1994).

Antioxidant (Bahorun et al., 1994, 1996; Chatterjee et al., 1997). A good correlation between hawthorn total phenolic content and antioxidant capacity has been shown (Sticher and Meier, 1998).

Inhibits human neutrophil elastase (Chatterjee et al., 1997).

Contraindications

Hawthorn leaf with flower

None known (Blumenthal et al., 1998; Braun et al., 1996; ESCOP, 1999).

Hawthorn fruit

None known (Meyer-Buchtela, 1999).

Pregnancy and Lactation: No known restrictions (McGuffin et al., 1997), but further research needs to be conducted to determine safety. The Commission E reports that no experimental data are available concerning embryonic and fetal toxicity, fertility, and postnatal development (Blumenthal et al., 1998). Systematic scientific investigations have not been conducted on pregnant or lactating women. Use during pregnancy or lactation should be decided by a healthcare provider (Morant and Ruppanner, 2001).

Adverse Effects

Hawthorn leaf with flower: None known (Blumenthal et al., 1998; Braun et al., 1996; ESCOP, 1999).

Hawthorn fruit: None known (Meyer-Buchtela, 1999).

Drug Interactions

Hawthorn leaf with flower: No known documented interactions, according to the Commission E monograph of 1994 and later therapeutic reviews, including one by the European Scientific Cooperative on Phytotherapy (Blumenthal et al., 1998; Braun et al., 1996; ESCOP, 1999). Other references suggest that hawthorn preparations may potentiate drugs containing cardiac glycosides (e.g., digoxin) probably resulting from the positive inotropic and coronary vasodilating effects (Brinker, 2001). Earlier research suggested potentiation of digitalis glycosides with hawthorn (Trunzler and Schuler, 1962), and another study suggested that hawthorn preparations may potentiate the coronary artery dilating effects of theophylline, caffeine, papaverine, sodium nitrate, adenosine, and epinephrine (Hahn et al., 1960). Because of the similarity in actions, one reference suggests that hawthorn should not be used with any other heart medications without the advice of a healthcare provider (Newall et al., 1996).

Hawthorn fruit: None known (Meyer-Buchtela, 1999). Depending on dosage the same interactions for leaf and flower may be relevant (Upton, 1999a).

American Herbal Products Association (AHPA) Safety Rating

Class 1: Herbs that can be safely consumed when used appropriately (McGuffin et al., 1997).

Regulatory Status

Austria: Hawthorn leaf and flower official in the Austrian Pharmacopoeia (ÖAB, 1994).

Canada: Schedule “A” drug not suitable as a non-medicinal ingredient at any level (HPB, 1993). Permitted as a component of OTC Traditional Herbal Medicine (THM) and as a homeopathic drug monopreparation in various dilutions, in both cases requiring pre-marketing authorization and application for a Drug Identification Number (DIN) (Health Canada, 2000).

European Union: Dried false fruit containing not less than 1.0% procyanidins official in the European Pharmacopoeia, 3rd ed. Suppl. 1998 (Ph.Eur., 2001) and dried leaf and flower containing not less than 1.5% flavonoids official in Ph.Eur. Suppl. 2001 (Ph.Eur., 2001).

France: Hawthorn leaf with flower, as well as, homeopathic mother tinctures of hawthorn fresh ripe fruit and of hawthorn fresh flowering twig tips, respectively, are official in the French Pharmacopeia (Ph.Fr.X, 1982-1996). Fluid extract and tincture preparations are listed in the Codex Fr. IX (ESCOP, 1999; van Hellemont, 1988).

Germany: Hawthorn leaf with flower (DAB, 1999) and the fluid extract form (DAB, 2000) official in the German Pharmacopoeia. Hawthorn fruit (DAC, 1992) and hawthorn flower (DAC, 1990) are official in the German Drug Codex supplement to the DAB. The dry native extract of hawthorn leaf with flower is an approved drug of the Commission E monographs (Blumenthal et al., 1998), and the tea infusion of hawthorn leaf with flower is an approved drug of the German Standard License monographs (Braun et al., 1996) with sale limited to pharmacies, without prescription. The mother tincture and liquid dilutions of hawthorn fresh ripe fruit are official preparations of the German Homoeopathic Pharmacopoeia (GHP, 1993) and are approved drugs of the Commission D monographs (Hänsel et al., 1992-1994). Thirty-three Hawthorn extract preparations are listed in the German “Rote Liste 1994” (Sticher and Meier, 1998).

Italy: Dried leaf with flower containing not less than 0.7% flavonoids official in Italian Pharmacopoeia IX 1985 Supplement 1991 (Ph.Ital., 1991).

Sweden: Natural product (DeSmet et al., 1993) As of January 2001, no hawthorn products have been listed in the Medical Products Agency (MPA) “Authorised Natural Remedies” (MPA, 2001).

Switzerland: Hawthorn leaf with flower and standardized dry extract are official in the Swiss Pharmacopeia (Ph.Helv.VIII, 1998). Positive classification (List D) by the Interkantonale Konstrollstelle für Heilmittel (IKS) and corresponding sales Category D with sale limited to pharmacies and drugstores, without prescription (Morant and Ruppanner, 2001; WHO, 1998). One hawthorn Anthroposophical preparation, 27 hawthorn homoeopathic preparations and 76 hawthorn-containing phytomedicines are listed in the Swiss Codex 2000/01 (Ruppanner and Schaefer, 2001).

UK: No licensed hawthorn products on the General Sale List (GSL) (Newall et al., 1996).

U.S.: Dietary supplement (USC, 1994). The mother tincture 1:10 (w/v), 45% ethanol (v/v), of the fresh or dried fruit, is an Rx Class C drug official in the Homoeopathic Pharmacopoeia of the United States (HPUS, 1990).

Clinical Review

Fourteen studies are outlined in the following table, “Clinical Studies on Hawthorn,” conducted on 6,900 participants. All but one of the studies (Bödigheimer et al., 1994), demonstrated positive effects for cardiac insufficiency. Eight are DB, PC studies (Bödigheimer and Chase, 1994; Förster et al., 1994; Hanak and Brückel, 1983; Iwamoto et al., 1981; Leuchtgens, 1993; O’Conolly et al., 1986; Schmidt et al., 1998; Weikl et al., 1996), four are open studies (Eichstädt et al., 1989; Loew et al., 1996; Weikl and Noh, 1992), one is a large multi-center observational study (Tauchert et al., 1999), and one is a DB study comparing hawthorn to standard treatment (Tauchert et al., 1994). Note: Most clinical studies have been conducted using a dry extract of hawthorn leaf with flower standardized to a daily dose of 9 mg or more oligomeric procyanidins (Schulz et al., 2000; Hänsel et al., 1992–94).

A major international R, DB, PC study is currently investigating the influence of the standardized extract of hawthorn leaf with flower (WS 1442; Schwabe, Karlsruhe, Germany) on the mortality of patients suffering from congestive heart failure. In this trial (involving approximately 120 investigational centers in seven European countries), up to 2,300 patients with congestive heart failure, NYHA Stage II and III, and markedly impaired left ventricular function will be enrolled and treated over 24 months. The primary outcome variable is the combined end point of cardiac death, nonlethal myocardial infarction, and hospitalization due to progression of heart failure. Secondary outcome variables are total mortality, exercise duration, echocardiographic parameters, and quality of life, as well as pharmacoeconomic parameters. The first patient was enrolled in October 1998. The trial is expected to be completed at the end of 2002 (Holubarsch et al., 2000).

Branded Products*

Crataegutt^® Dragees: Dr. Willmar Schwabe Pharmaceuticals / International Division / Willmar Schwabe Str. 4 / D-76227 Karlsruhe / Germany / Tel: +49-721-4005 ext. 294 / www.schwabepharma.com / Email: melville-eaves@schwabe.de. One tablet contains 30 mg hawthorn flower, fruit and leaf hydroalcoholic dry normalized extract 5:1 (w/w), standardized to 5% (50 mg/g) oligomeric procyanidins.

Crataegutt^® forte Kapseln: Dr. Willmar Schwabe Pharmaceuticals. 1 capsule contains 80 mg hawthorn leaf and flower hydroalcoholic dry normalized extract 5:1 (w/w) standardized to 18.75% (187.5 mg/g) oligomeric procyanidins (15 mg per capsule).

Crataegutt^® novo Filmtabletten: Dr. Willmar Schwabe Pharmaceuticals. One tablet contains 60 mg hawthorn flower, fruit and leaf hydroalcoholic dry normalized extract 5:1 (w/w), standardized to 5% (50 mg/g) oligomeric procyanidins.

Crataegus Special Extract WS 1442: Dr. Willmar Schwabe Pharmaceuticals. One capsule contains 80 mg hawthorn leaf with flower dry extract 5:1 (w/w), standardized to 18.75% oligomeric procyanidins (15 mg per capsule). Solvent: ethanol 45%

Faros^® 300 Dragées: Lichtwer Pharma AG / Wallenroder Strasse 8-14 / 13435 Berlin / Germany / Tel: +49-30-40-3700 / Fax: +49-30-40-3704-49 / www.lichtwer.de. One tablet contains 300 mg hawthorn leaf with flower dry native extract 4–7:1 (w/w) (average 5.5:1), standardized to 2.25% flavonoid content. Solvent: methanol 70% (v/v).

Faros^® LI 132 Dragées: Lichtwer Pharma AG. One tablet contains 100 mg hawthorn leaf with flower dry native extract 4–7:1 (w/w), standardized to 2.25% flavonoids.

*American equivalents are found in the Product Table beginning on page 398.

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