Johannes Dr. Rer. Nat. Dr. Med. Pill

The pharmacological profile of the thromboxane A2 antagonist BM 13.177. A new anti-platelet and anti-thrombotic drug

BM 13.177 (4-[2-(benzenesulfonamido)-ethyl]-phenoxyacetic acid) is a representative of a new class of sulfonamidophenylcarboxylic acids which possess platelet-inhibitory and anti-thrombotic activity and inhibits the contraction of rabbit aorta stimulated by PG endoperoxides and TXA2. BM 13.177 5 mg/kg body weight p.o. protected rabbits from arachidonate-induced sudden death and greater than or equal to 10 mg/kg dose-dependently reduced the experimental thrombus formation induced in the rabbit aorta by perivascular administration of silver nitrate. In guinea-pigs, the collagen-induced bronchoconstriction was inhibited in a dose- and time-dependent fashion. The formation of TXA2 and the TXA2-induced platelet aggregation and smooth muscle contraction are probably crucial events in these experimental models. The protective effect of BM 13.177 may, therefore, be due to the TXA2-antagonizing effect of BM 13.177, which has been conclusively demonstrated in human platelets (PATSCHEKE and STEGMEIER, Thrombosis Res., 33, 277-288 (1984). The antagonism of TXA2 is supported by the observation that BM 13.177 also specifically inhibits the contraction of isolated arterial strips from rabbits which were stimulated with the thromboxane A2 mimetic U 46619. Schild-plot with a slope close to unity suggests a competitive type of antagonism. BM 13.177 exhibited neither anti-inflammatory nor ulcer-inducing activity of cyclooxygenase inhibitors. Furthermore it did not block the TXB2 formation in spontaneously clotting blood from rabbits and did not inhibit the release of prostacyclin-like activity from rabbit aortas. The lack of toxicological effects in long-term toxicity studies in rat and dog, together with the absence of objective and subjective side effects in the first human studies have encouraged us to initiate clinical trials in order to evaluate the therapeutic benefit of this new approach in humans.

The effect of impaired lipid metabolism on the smooth muscle cells of rabbits

SummaryOur clinical data enabled us to demonstrate a correlation between impaired lipid metabolism and vasculogenic impotent men. Our aim was to evaluate the effect of an impaired lipid metabolism on the smooth muscle of the corpus cavernosum. A total of 16 rabbits were given a cholesterol-enriched diet for 3 months, and 8 of these received additional thromboxane A2 receptor antagonist; 10 other rabbits (control) were fed a normal diet. Subsequently, cavernous tissue biopsies were taken, and tissue lipid extractions and electron microscopic evaluation were made from 3 rabbits in each group. In the untreated high-cholesterol diet group, cholesterol levels reached approx. 2.1 μg/mg body weight compared with 1.07 μg/mg b.wt. in the thromboxane A2 receptor antagonist-treated group and elevated levels compared with control group. Similar results were found for the triglyceride and free fatty acid levels. Lecithin tissue levels in treated rabbits were distinctly elevated against those of other 2 groups. Ultramorphological examination of the control group disclosed normal smooth muscle cell (SMC) architecture with numerous sites of intercellular contacts. These findings contrasted with those of the high-cholesterol diet groups which showed significant SMC degeneration with loss of intercellular contacts. Our data imply that impaired lipid metabolism causes cavernous SMC degeneration which plays a major role in the pathogenesis of erectile dysfunction. The thromboxane A2 receptor antagonist seems to produce a protective metabolic effect on the erectile tissue which may have some consequences future treatment strategies.

Thin-layer chromatography of radioactively labelled cholesterol and precursors from biological material

SummaryThe investigation methods of the action of xenobiotics on sterol biosynthesis from 14C-acetate in rat hepatocyte cultures can be developed, with regard to extraction using Extrelut and the separation of the sterol pattern by thin-layer chromatography, in such a way that they are suitable for wider application, e.g., screening. Good visualisation and recognition of changes in the sterol pattern are possible using autoradiography of the thin-layer chromatogram.