Pharmakologisch-toxikologische und klinische Untersuchungen mit Koloquinthenfruchtextrakten (Extr. colocynthidis fructus)

Abstract

Colocynth pulp extract is a long-serving laxative. Contesting the official characterizations "drastic irritant action, no longer defensible" by suitable pharmacotoxicologic studies, extracts of the drug with increasing concentrations of the effective constituant "Cucurbitacins" were prepared in order to define efficacy ranges lethal to rats and mice. The extract Koloquinthentrockenextrakt Alpha with the highest content of Cucurbitacins (23,2 % delta 232,64 mg/g) permitted the definition of the LD50 for female (tentative because of death inhibition under maximal doses) and male rats; the mean LD50 = 281,8 and 525,6 mg/kg extract, respectively, equivalent to 66 and 122 mg/kg Cucurbitacins. This corresponds to 660- to 1220-fold therapeutic doses. Repeated administrations of 10- and 50-fold therapeutic doses to rats for 30 days produced no negative effects. The symptoms of rodent poisoning are described in detail. Pharmacologic doses were not toxic on rat liver slices, did not influence breathing and circulation parameters in guinea pigs (under the maximal dose of 41,6 mg/kg Cucurbitacins, 3/10 animals died of breathing failure) nor the behaviour of mice, nor were they mutagen (Ames test). Colocynth pulp extract weakly inhibited the growth of MDA-MB435 mamma carcinoma cells, but had no influence on the growth of B16 mouse melanoma cells. P388 mouse leukemia cells and L 929 mouse fibroblasts were not significantly influenced. High doses of Colocynth pulp extract inhibited diuresis and electrolyte excretion in rats. The Cucurbitacins E and I were rapidly metabolized in S9-supernatants of rat livers. A dried ethanolic Salvia fruit extract alleviated the toxicity of lethal doses of Colocynth pulp extract when administered simultaneously. A field study with 200 patients and a phase I study with 60 volunteers were conducted in Germany with Colocynth pulp extract from April to October 1998, andfrom December 2002 to March 2003, respectively. Data on the tolerance of the highest allowed dose and of a half-maximal dose administered to volunteers for 14 days in comparison to placebo, as well as data on the efficacy of a treatment course of 3 days of patients with obstipation, were to be gained. Clinical laboratory investigations of volunteers gave no indication of pathological changes even under the highest dose. In patients with obstipation and associated complaints, the administration for 3 days at maximum led to an increased frequency of bowel movements. At the same time, the discomforts accompanying obstipation were significantly relieved. Patients with obstipation defined tolerance as good. Volunteers, on the other hand, judged the tolerance of the drug significantly inferior ("good" - "average") to that of placebo ("very good" - "good"). The low risk potential of Colocynth pulp extract documented in pharmaco-toxicological studies was confirmed during administration to humans.