• Clinical data 90%
  • Efficacy 80%
  • Security 70%
  • Toxicity 30%

Crataegus oxyacantha
Folium cum Flore Crataegi

Synonyms

Crataegus monogyna Jacq. (Lindm): C. apiifolia Medik. non Michx., C. oxyacantha L. ssp. monogyna Lev., Mespilus elegans Poir., M. monogyna All., M. monogyna Ehrh.
Crataegus laevigata (Poir.) DC: C. oxyacantha L., C. oxyacantha L. ssp. polygala Lev., C. oxyacanthoides Thuill, Mespilus oxyacantha (Gartn.) Crantz.

General appearance

Crataegus monogyna: leaves bright green with 3 or 5 acute lobes, deeper and further apart than those of C. laevigata, with secondary venation curved outwards. Flowers, grouped into branchy corymbs, have 5 triangular sepals, 5 white petals, and an androecium of 15–20 stamens inserted on the edge of a monocarpellate, brownish-green receptacle; floral peduncles and sepals pubescent, anthers black with 1 style; sepals lanceolate, acuminate, falling over the ovary after flowering. Crataegus laevigata: leaves bright green with 3, 5 or 7 shallow, obtuse, converging lobes, with secondary venation curved inward. Flowers, grouped into branchy corymbs, have 5 triangular sepals, 5 white petals, and an androecium of 15–20 stamens inserted on the edge of a bi- or tricarpellate receptacle; floral peduncles and sepals glabrous, stamens with red anthers and 2–3 styles.

Major chemical constituents

The major constituents are flavonoids (rutin, hyperoside, vitexin, vitexin-2≤ rhamnoside, acetylvitexin-2≤ rhamnoside) and related proanthocyanidins. In the inflorescence, flavonol glycosides, mainly in the form of hyperoside, spiraeoside and rutin, are present. The primary flavonoid derivatives in the leaves are epi-catechin (epi-catechol) and/or catechin (catechol), and the related procyanidins formed during condensation of 28 monomeric units of the above catechins, together with oligomeric procyanidins. The presence of simple phenolic acids (e.g. chlorogenic and caffeic acids) has also been reported. Of the non-phenolic constituents, pentacyclic triterpenes (e.g. ursolic and oleanolic acids) and the 2-a-hydroxy derivative of oleanolic acid, known as crataegolic acid, are among the characteristic components.

Medicinal uses

Uses supported by clinical data
Crataegus oxyacantha: Treatment of chronic congestive heart failure stage II, as defined by the New York Heart Association.
Uses described in pharmacopoeias and in traditional systems of medicine
Support of cardiac and circulatory functions.
Uses described in folk medicine, not supported by experimental or clinical data
As an antispasmodic agent in the treatment of asthma, diarrhoea, gall bladder disease and uterine contractions, and as a sedative for the treatment of insomnia.

Pharmacology

Experimental pharmacology

Inotropic effects

Positive inotropic effects of Folium cum Flore Crataegi and its constituents have been demonstrated both in vitro and in vivo. These effects are generally attributed to the flavonoid and procyanidin constituents of the leaves with flowers. A hydroalcoholic extract of the flowers with leaves, flavonoid and procyanidin fractions of the extract, and isolated constituents (e.g. biogenic amines, crataegolic acid, epi-catechin, hyperoside, luteolin 7-glucoside, rutin and vitexin) all have positive inotropic effects, and prolong the refractory period in cardiac myocytes, isolated papillary muscles and isolated guinea-pig hearts. In isolated guinea-pig hearts perfused at constant pressure, 3mg/ml of a standardized extract increased the contractility of the heart by 9.5%. In isolated, electrically stimulated strips of failing human left ventricular myocardium, a standardized extract (18.75% oligomeric procyanidins) increased the force of contraction at concentrations higher than 10mg/ml; a 100mg/ml extract improved the force–frequency relationship (39). A standardized extract of the leaves and flowers increased the contractility of myocardial cells by 153%, at a concentration of 120mg/ml. An aqueous extract of the leaves with flowers, two proanthocyanidin fractions and two flavonoid fractions of the extract dilated coronary blood vessels, and had positive inotropic effects on isolated guinea-pig hearts (extract or fraction: 0.05mg/ml).

Chronotropic effects

Intragastric administration of a macerate or fluidextract of the shoots, flowers or leaves to rats (12.5–25.0 mg/kg body weight) significantly inhibited arrhythmias induced by aconitine, calcium chloride or chloroform/epinephrine Folium cum Flore Crataegi 71 (P < 0.05). The extracts also reduced blood pressure in rats at the same dosage. Aconitine-induced arrythmias were also inhibited after intravenous administration of a 95% ethanol extract of the bark and leaves (50mg/kg body weight) to rabbits. Intravenous administration of a flavonoid enriched extract of the leaves and flowers to rabbits (20mg/kg body weight) or rats (2 mg/kg body weight) inhibited barium chloride-induced arrhythmias. Intravenous administration of a standardized extract (containing 18.75% oligomeric procyanidins) to anaesthetized dogs (7.5–30.0 mg/kg body weight) increased maximum left ventricular contraction velocity by 16.8–31.1%. An aqueous extract improved cardiac performance during reperfusion, reduced lactate levels and accelerated energy metabolism in reperfused ischaemic rat heart. No increase in coronary blood flow was observed. Intragastric administration of single doses of a standardized extract (containing 18.75% oligomeric procyanidins) of the leaves with flowers (100mg/kg body weight) or an oligomeric procyanidin-enriched fraction (20mg/kg body weight) daily to rats protected against perfusion-induced arrhythmias, hypotensive crisis and mortality. The oligomeric procyanidin-enriched fraction did not decrease the reperfusion-induced elevation of creatine kinase plasma levels. Administration of powdered leaves and flowers to rats (2% of diet) reduced the release of lactate dehydrogenase after perfusion-induced heart ischemia.

Effect on coronary blood flow

Intragastric administration of an oligomeric procyanidin fraction of a standardized leaf and flower extract to dogs at a dose of 12–70mg/kg body weight, three times daily for 60 days, increased myocardial blood flow (59, 60). Intravenous injection of an aqueous or 95% ethanol extract of the flowers increased coronary blood flow and cardiac output, and decreased peripheral resistance in both dogs and guinea-pigs. Administration of a flavonoid-enriched
extract to cats and rabbits increased coronary blood flow by 48% and 163%, respectively, and reduced pituitrin induced coronary insufficiency in rabbits. Intravenous administration of a leaf with flower extract to cats (10mg/kg
body weight) or rabbits (20 mg/kg body weight) dilated coronary blood vessels, and improved coronary blood flow.

Effect on action potential

A leaf preparation (10 mg/l) prolonged the duration of the action potential and delayed the recovery of Vmax in isolated guinea-pig papillary muscle. The electrophysiological correlation between the increase in the contraction amplitude of isolated canine papillary muscles, and vasodilation in isolated human coronary arteries, was measured after application of an extract of the leaves with flowers. The cardiac action potential significantly increased in duration and overshoot, and maximal depolarization (P < 0.001). Hyperpolarization of the resting membrane of normal and arteriosclerotic vascular smooth muscle cells of the human coronary artery was observed after treatment with flavonoids isolated from the extract (0.1 and 100mmol/l). The isometric wall tension decreased in both normal and arteriosclerotic vessels. The increase of peak-to-plateau repolarization in cardiac action potential and hyperpolarization of vascular smooth muscle suggest that the extract acts as a potassium channel agonist.

Antihypertensive effects

In various animal models, a decrease in peripheral vascular resistance and hypertension occurred after treatment with leaf and/or flower extracts. Intravenous administration of a standardized fluidextract of the leaves with flowers (equivalent to 6 mg of procyanidins/kg body weight) to anaesthetized normotensive dogs decreased norepinephrine induced elevation of blood pressure. The extract (equivalent to 0.03 mg procyanidins/ml) also had b-blocking activity and inhibited epinephrine-induced tachycardia in isolated frog hearts. Hyperoside, isolated from an extract of the leaves and flowers, administered either intravenously at a dose of 1mg/kg body weight or by infusion
at 0.1 mg/kg body weight/min for 30 min, decreased blood pressure in anaesthetized dogs. Intravenous administration of an aqueous extract of the leaves (average dose 31 mg/kg body weight) decreased the systolic, diastolic and mean blood pressure in normotensive anaesthetized rats. Acute or chronic intragastric administration of a fluidextract or a glycerol/ethanol extract reduced arterial blood pressure in normotensive rats and in rats with desoxycorticosterone acetate-induced hypertension. Intragastric administration of a standardized extract (300 mg/kg body weight daily) decreased blood pressure by 9mmHg (1.20 kPa). Intravenous administration of a standardized extract (containing 18.75% oligomeric procyanidins) to anaesthetized rats (30 mg/kg body weight) or dogs (15 mg/kg body weight) decreased total peripheral resistance and arterial blood pressure.

Anti-inflammatory effects 

Both free radical production and lipid peroxidation are involved in various pathological processes, including cardiac ischaemia. As determined by in vitro studies, Folium cum Flore Crataegi has free radical scavenging and antioxidant activities. A standardized extract (containing 18.75% oligomeric procyanidins) and an oligomeric procyanidin-fraction of the extract inhibited lipid peroxidation (IC50 0.48mg/ml (extract), 0.3mg/ml (fraction)), and the activity of human neutrophil elastase (IC50 4.75mg/ml (extract), 0.84mg/ml (fraction)). A 70% methanol extract of the flower buds inhibited lipid peroxidation in rat liver microsomes (IC50 23mg/l). Both phenolic and flavonoid-enriched fractions of extracts of the leaves and flowers had antioxidant activity in vitro.

Effect on signal transduction

An aqueous or methanol extract of the leaves with flowers, as well as hyperoside, vitexin and vitexin rhamnoside, inhibited the activity of cyclic AMPdependent phosphodiesterase isolated from guinea-pig or rat heart.
Both luteolin 7-glucoside and rutin were also active. Hydroalcoholic extracts of the flowers and flower heads inhibited the formation of thromboxane A2 and prostaglandin I2 in rabbit cardiac tissues in vitro, thus indicating an anti-inflammatory effect of the extracts. A standardized extract (containing 18.75% oligomeric procyanidins) displaced 3H-ouabain bound to sodium- and potassium-activated adenosine triphosphatase.

Anticontractile effects

An aqueous extract of the flowers inhibited barium chloride-induced contractions in rabbit intestine in vitro. A flavonoid-enriched extract of the leaves with flowers inhibited both histamine- and nicotine-induced contractions in rabbit intestine in vitro and partially inhibited contractions induced by barium chloride, acetylcholine or serotonin (ED50 0.02 mg/ml). Intravenous administration of a flavonoid-enriched extract of the leaves with flowers to cats (20 mg/kg body weight) inhibited contractions in intestinal smooth muscle, and intraperitoneal injection (400 mg/kg body weight) inhibited acetic acid-induced writhing in mice.

Sedative effects

Sedative effects have been observed in various animal models after intragastric administration of leaf with flower extracts. A 60% ethanol extract of the flowers increased hexobarbital-induced sleeping times, and decreased spontaneous motility and exploratory behaviour in female mice (800mg/kg body weight).

Diuretic effects

A flavonoid-enriched fraction of a flower extract had diuretic activity in dogs (50 mg/kg body weight).

Toxicology

Single-dose toxicity studies have demonstrated that rats and mice tolerate 3g/kg body weight, by gastric lavage, of a standardized hydroalcoholic extract of the leaves with flowers (containing 18.75% oligomeric procyanidins) without any clinical symptoms of toxicity. The intraperitoneal median lethal dose (LD50) was 1.17 g/kg body weight in rats and 750 mg/kg body weight in mice. No toxic effects were observed in a repeat-dose toxicity study in which rats and dogs were given a standardized extract (containing 18.75% oligomeric procyanidins) at doses of 30, 90 and 300 mg/kg body weight daily by the intragastric route for 26 weeks.
Clinical pharmacology

Cardiac insufficiency

Review of the pharmacological and clinical data indicates that standardized extracts of Folium cum Flore Crataegi increase myocardial performance, improve myocardial circulatory perfusion and tolerance in cases of oxygen deficiency, have antiarrhythmic effects and reduce afterload. Positive therapeutic effects of Folium cum Flore Crataegi in patients with characteristic symptoms of an activated sympathoadrenergic system, such as hypertension, tachycardia and arrhythmia (also characteristic of cardiac insufficiency stage II, as defined by the New York Heart Association), have also been demonstrated. Furthermore, numerous clinical trials with and without controls have assessed the therapeutic efficacy of Folium cum Flore Crataegi extracts for the treatment of cardiac insufficiency stage II. The investigations were performed with a dried 70% methanol or 45% ethanol standardized extract (containing 2.2% flavonoids or 18.75% oligomeric procyanidins, respectively) of the leaves with flowers. The dosage ranged from 160 to 900 mg extract daily for 4–8 weeks. Evaluation of efficacy of the extracts was based on the following criteria: anaerobic threshold; Clinical Global Impression Scale; exercise tolerance; ventricular ejection fraction; quality of life and improvement of subjective symptoms (defined by the New York Heart Association) and pressure/rate product. Although improvements were seen, no long-term trials have assessed the effects of Folium Cum Flore Crataegi on mortality rates in patients with chronic congestive heart failure.

Exercise tolerance

A randomized, double-blind, placebo-controlled trial assessed the efficacy of the extract containing 2.2% flavonoids on exercise-induced anaerobic threshold, as measured by spiroergometry, in 72 patients. Patients were administered an oral dose of 900 mg extract or placebo daily for 8 weeks. After treatment, oxygen uptake increased significantly in the treated group (P < 0.05), and exercise time to anaerobic threshold increased by 30 seconds in the treated group, but by only 2 seconds in the placebo group. Significant improvements in subjective symptoms were also noted in the treated group, as compared with the placebo group (P < 0.01).
The efficacy of the extract containing 2.2% flavonoids on the improvement of exercise tolerance was assessed by bicycle ergometry in patients with cardiac insufficiency stage II, in three clinical trials. In a double-blind, placebocontrolled trial of 85 patients, oral administration of 300mg extract daily for 4–8 weeks improved working capacity; however, the difference was not significant when compared with the placebo. A double-blind, placebocontrolled trial assessed the efficacy of oral administration of 600 mg extract daily for 8 weeks in 78 patients. Patients in the treatment group had a significant improvement in exercise tolerance as compared with the placebo group (P < 0.001). Patients who received the extract also had lower blood pressure and heart rate during exercise, and had fewer overall symptoms, such as dyspnoea and fatigue. In the third trial, 132 patients were treated orally with 900mg extract or 37.5 mg captopril daily for 8 weeks in a double-blind comparative study. Exercise tolerance, measured after 56 days of treatment, improved significantly in both groups (P < 0.001). In addition, the pressure/rate product was reduced, and the incidence and severity of symptoms such as dyspnoea and fatigue decreased by approximately 50%. Pressure/rate product Two double-blind, placebo-controlled trials assessed the efficacy of the extract containing 18.75% oligomeric procyanidins in a total of 156 patients with stage II cardiac insufficiency. Patients were treated orally with 160 mg extract or placebo daily for 8 weeks. The main parameters measured were the pressure/rate product using a bicycle ergometer, and the score of subjective symptom status. Patients treated with the extract exhibited a significant improvement in exercise tolerance, as compared with the placebo group (P < 0.05), and also a decrease in subjective complaints. In addition, a slight reduction in the systolic and diastolic blood pressure was noted in both groups.

Ventricular ejection fraction

In a trial without controls involving seven patients with stages II and III cardiac insufficiency, with an angiographically determined left ventricular ejection fraction of less than 55% over a period of 4 weeks, oral administration of 240mg extract containing 18.75% oligomeric procyanidins daily for 4 weeks increased the ventricular ejection fraction from 29.80 to 40.45%, as measured by angiography. Symptomatic complaints (Complaint List as defined by von Zerssen) also showed improvements. The effects of the extract containing 18.75%
oligomeric procyanidins on haemodynamics were also investigated by radionuclide angiocardiography in a study without controls. Twenty patients with stage II cardiac insufficiency, with an angiographically determined left ventricular ejection fraction of less than 55% over a period of 4 weeks, were treated with 480 mg extract. After treatment, the ejection fraction increased from 40.18 to 43.50% at rest, and from 41.51 to 46.56% under exercise conditions. Ergometric tolerance to exercise improved, blood pressure decreased and subjective complaints were reduced.

Pharmacokinetics

Absorption of a 14C-labelled oligomeric procyanidin fraction of standardized extracts of leaves with flowers was measured in mice after intragastric administration (0.6 mg). The results demonstrated that 20–30% of the total fraction, 40–81% of the trimeric procyanidins and 16–42% of the oligomeric procyani-dins were absorbed within 1–7 hours after administration. After 7 hours, 0.6% of the radioactivity of the total fraction was eliminated by expiration and 6.4% was eliminated in the urine. Daily intragastric administration of 0.6mg of a radiolabelled oligomeric procyanidin fraction to mice for 7 days led to an accumulation of radioactivity that was 2–3 times that in mice given a single dose.

Contraindications

None.

Warnings

Accurate diagnosis of stage II congestive heart failure should be obtained prior to use of Folium cum Flore Crataegi. Consult a physician if symptoms worsen, remain unchanged for longer than 6 weeks, or if water accumulates in the legs. Medical attention is absolutely necessary if pain occurs in the region of the heart, spreading out to the arms, upper abdomen or neck area, or in cases of respiratory distress (e.g. dyspnoea).

Precautions

Drug interactions
None.

News and Journals

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