Effect of the specific thromboxane receptor blocking drug AH23848 in patients with angina pectoris.

Abstract

HertfordshireSUMMARY The effect of the specific thromboxane receptor blocking drug AH23848 was investigated in two double blind placebo controlled studies in male patients with exercise induced angina pectoris and angiographically verified coronary lesions. In the first study cardiac pacing was performed in twenty patients after coronary angiography. Patients were then randomised into two groups and received either AH23848 (70 mg orally) or placebo. One hour later cardiac pacing was repeated. Neither treatment had any significant effect upon time to angina or the ratepressure product at the onset of chest pain in these patients. In the second study twenty male patients were randomised to seven days' treatment with AH23848 (70 mg three times a day) or placebo followed by a crossover to the other treatment for a further seven days. Clinical assessment was performed before treatment and at the end of each treatment period. There was no significant difference between the placebo and AH23848 treatment periods in exercise tolerance, the rate-pressure product at angina after exercise testing, the number of ischaemic attacks as determined from 24 hour ambulatory electrocardiograms, the number of attacks of pain, or the number of glyceryl trinitrate tablets consumed. This lack of a clinical effect with AH23848 was seen despite a profound inhibition of ex vivo platelet aggregration stimulated by the thromboxane A2-mimetic U-46619. Because in experimental animals in vivo AH23848 blocks vascular thromboxane receptors as well as platelet thromboxane receptors the lack of effect of AH23848 in cardiac pacing and exercise induced angina is unlikely to be the result of inadequate blockade of -thromboxane receptors. The lack of effect of the drug is more likely to indicate that thromboxane A2 is not a factor in the aetiology of the pain experienced by these patients during exercise or cardiac pacing.

A Specific Thromboxane Receptor Blocking Drug, AH23848, Reduces Platelet Deposition on Vascular Grafts in Man

“…Although aorto-bifemoral grafts rarely occlude, the important finding of a reduction in platelet interaction with prosthetic grafts warrants the testing of thromboxane receptor blocking drugs in maintaining patency under conditions of low flow, high resistance, such as found in femoropopliteal or aorta-coronary bypass grafts and where thrombosis represents a major problem (40)(41)(42). Thromboxane receptor blocking drugs such as AH23848 and the recently described compound GR32191 (43)(44)(45) have to date, proved free of serious adverse effects (25,26,46). Such drugs may therefore prove to have wide indications throughout arterial thrombo-embolic disease and great potential in arterial bypass surgery.…”

The effect of the thromboxane A2 receptor antagonist SQ 29,548 on the severity of pacing-induced ischemia

“…TXA2-receptor blockade may be of potential therapeutic benefit in some forms of angina pectoris. Experimental and clinical studies have shown mixed results for TXA2 synthetase or receptor antagonists in angina (6,12,13,22), but the present study indicates further investigations in this area are warranted.…”

“…Studies by Lewy et al (16), have indicated that TXAz is produced rapidly in patients with angina pectoris who were subjected to atrial pacing, thus suggesting a role for TXA2 in angina pectoris. Early clinical trials with TXA2 synthetase inhibitors and receptor antagonists have given mixed results (6,13). A study by Hoeft et al (12) has indicated that inhibition of TXA2 synthesis appears to reduce severity of ischemia in a model of transient ischemia, though again, possible alterations in production of other arachidonic acid metabolites may cloud interpretation of the results.…”