Benefit-Risk Assessment of Crataegus Extract WS 1442

An Evidence-Based Review

Christian J. F. Holubarsch; Wilson S. Colucci; Jaan Eha


Am J Cardiovasc Drugs. 2018;18(1):25-36. 

In This Article

Pharmacology and Nonclinical Data, Mode of Action

In vitro experiments with human myocardial tissue demonstrated a positive inotropic effect of WS 1442 and a concentration-dependent increase of myocardial contractility accompanied by a transient rise in intracellular calcium.[11,12] The effect is likely mediated by cyclic adenosine monophosphate (cAMP)-independent inhibition of sodium-potassium-ATPase, and is accompanied by an improved energy turnover of myocytes.[12–14] In contrast to cardiac glycosides, WS 1442 prolongs the action potential and the refractory period, and possesses pronounced anti-arrhythmic properties.[15] WS 1442 enhances the relaxant effect of the nitric oxide (NO) donor nitroprusside and increases the release of NO from the endothelium while possibly inhibiting the NO degradation due to the antioxidative properties of WS 1442.[16] The extract causes endothelium-dependent vasorelaxation by an NO-mediated mechanism via endothelial NO synthase (eNOS)-phosphorylation at serine 1177.[17,18] Increased endothelial NO availability delays activation of the local angiotensin system and endothelial senescence.[19] Endothelium-derived hyperpolarizing factor contributes to the vasorelaxing activity of WS 1442, most likely due to reduced vascular oxidative stress.[20] Moreover the compound enhances microcirculation by reducing endothelial surface layer height and stiffness[21] as well as by increasing red blood cell (RBC) NO formation[22] and RBC surface negativity.[23] Chronic administration of WS 1442 leads to a dose-dependent increase in myocardial basal vessel blood flow[24] and prevents deoxycorticosterone acetate (DOCA) salt-induced hypertension and alterations of cardiac, vascular, and renal structure and function.[25]

In animal models of short-term ischemia and reperfusion, WS 1442 caused a significant reduction of ventricular fibrillation, tachycardia, and hypotensive crisis.[15,26] Protection against reperfusion injury as well as reduction of ST segment elevation after reperfusion and ventricular fibrillation, infarct size, and mortality were also observed in rats.[27] An increased coronary blood flow as well as reduced endothelial dysfunction, inhibition of lipid oxidation and anti-inflammatory properties may contribute to the cardioprotective effects of WS 1442.[28] Sustained, maladaptive cardiac hypertrophy related to physiological stimuli, such as hypertension, valvular disease, or myocardial infarction, has been recognized as a leading cause of cardiac insufficiency.[20] WS 1442 lowered the hypertensive blood pressure and inhibited the development of cardiac hypertrophy in rats, while it had no effect in normotensive control animals.[25,29] In pressure overload-related cardiac hypertrophy, a reduction of enlarged left ventricular chamber volume and augmented wall thickness was observed.[30,31]

In a rat model of endotoxin shock, WS 1442 significantly reduced the deterioration of cardiac output and prevented an increase in peripheral resistance. Since the extract did not affect peripheral blood pressure or heart rate, the increased cardiac output is presumably related to improved ventricular diastolic filling and enhanced myocardial contractility.[32] There is pre-clinical evidence that WS 1442 may have a beneficial effect on human lipid metabolism.[9] For example, an in vitro experiment using human Hep-G2 cells showed that WS 1442 causes a dose-dependent inhibition of apolipoprotein-B secretion and thereby decreases the formation of oxygenated low-density lipoprotein (LDL), from which a prophylactic effect against atherosclerosis may be expected.[33,34]

Most of the beneficial effects of WS 1442 on the myocardium, notably its cardioprotective properties, are closely related to the OPC to which the extract is adjusted.[16,27,28]

Hecker-Niediek[35] determined the absorption and distribution of the radioactivity of 14C-labeled catechins, a trimeric procyanide, an OPC total fraction and higher OPCs after intravenous and oral administration in mice. Total radioactivity was measured in blood and different organs without determination of individual metabolites. One hour after oral administration, absorption of radioactivity could already be detected for all labeled substances. The absorption rate for the OPC total fraction was about 31%, and the rates for individual substances ranged from 16 to 40%. After repeated oral administration, the accumulation of radioactivity was higher than after a single dose.

In studies conducted with rats, WS 1442 doses of up to 3000 mg/kg body weight did not cause any chemical, hematological, morphological, or histological abnormalities or genotoxicity and had no influence on peri- or post-natal development.[9]