ah-23848 and Angina-Pectoris

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 rate-pressure 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 aggregation 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.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adult; Aged; Angina Pectoris; Biphenyl Compounds; Clinical Trials as Topic; Double-Blind Method; Humans; Male; Middle Aged; Platelet Aggregation; Prostaglandin Endoperoxides, Synthetic; Random Allocation; Receptors, Prostaglandin; Receptors, Thromboxane

Despite numerous suggestions in the literature that thromboxane A2 is involved in a variety of occlusive vascular diseases, no definitive evidence is available. Arguments have been presented to support the view that such evidence can only come from clinical studies with a highly specific thromboxane receptor-blocking drug. We have now identified such a drug, AH23848, in our laboratories. Preliminary experiments with AH23848, ([1 alpha (Z), 2 beta,5 alpha]-(+/-)-7-[5-[[(1,1'-biphenyl)-4-yl]methoxy]-2-(4-morpholin yl)-3-oxocyclopentyl]-4-heptenoic acid), show that it is a potent, specific thromboxane receptor-blocking drug that is orally active and has a long duration of action. It should be a valuable tool in elucidating any physiologic or pathologic role of thromboxane A2.

Topics: Angina Pectoris; Animals; Biphenyl Compounds; Collagen; Dogs; Dose-Response Relationship, Drug; Guinea Pigs; Humans; In Vitro Techniques; Male; Muscle, Smooth, Vascular; Platelet Aggregation; Rats; Receptors, Cell Surface; Receptors, Prostaglandin; Receptors, Thromboxane; Shock, Septic; Thromboxane A2; Thromboxane-A Synthase; Vasoconstriction