Author(s): Wilsmann K, Neugebauer G, Kessel R, Lang E
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Abstract After single i.v. (5 and 10 mg) and p.o. (10, 20 and 40 mg) administrations, 4-amino-6-methyoxy-1-phenyl-pyridazinium methyl sulfate (ameziniummetilsulfate, LU 1631, Regulton), in the following briefly called amezinium, a new antihypotensive agent, was studied by non-invasive methods for its cardiovascular action in comparison with norfenefrine (10 mg i.m. and 40 mg p.o.) and dihydroergotamine (1 mg i.m. and 4 mg p.o.) in a group of 33 volunteers. The action pattern of 10 mg amezinium i.v. consisted of a significant rise in arterial blood pressure (systolic 23\%, diastolic 14\%) with an increase in pulse pressure (38\%) and a reflex fall in heart rate (9\%). The total peripheral resistance was increased by 29\%, with a moderate reduction of cardiac output (5\%; n.s.) and an increase of the stroke volume (6\%; n.s.). A clear positive inotropic effect was discernible by the significant reduction of heart rate, corrected preejection period (delta PEP; 13 ms), left ventricular ejection time (delta LVET; 8 ms; n.s.) and a decrease of the ratio PEP/LVET (-0.028). This pattern of action points to stimulation of vascular alpha- as well as cardiac beta 1-adrenoceptors and is in accordance with the findings from animal experiments as amezinium acts via endogenous noradrenaline. The reference substance norfenefrine exhibited purely alpha-sympathomimetic action, whereas dihydroergotamine presumably exerted venoconstrictive and central sympatholytic effects. The effects of amezinium after p.o. administration on the circulation were similar to those after i.v. administration, whereas the reference substances did not reveal any definite pharmacodynamic action when given p.o. Single administrations of the various p.o. doses of amezinium gave rise to a dose-dependent increase of the systolic blood pressure, persisting over the 180 min of the investigation period. From the dose-response relationships after parenteral and oral administration a relative enteral efficacy of 50-80\% was established, which corresponds well with bioavailability data. The results show amezinium to have potent, long-lasting blood pressure increasing and positive inotropic actions in man after oral as well as parenteral administration.
This article was published in Arzneimittelforschung
and referenced in Pharmaceutica Analytica Acta