UNKNOWN EFFECTS OF CLINICALLY USED DRUGS AS BIAS IN CLINICAL-TRIALS -ANTIHISTAMINERGIC ACTIVITY OF THE ANTIHYPERTENSIVE FIXED-DOSE COMBINATION BETATHIAZID(R)

In a controlled clinical trial on histamine release in anaesthesia, it was suspected that the antihypertensive fixed-dose combination drug B etathiazid(R) masked clinical signs of histamine release. By structure analysis of its constituents (propranolol, triamterene and hydrochlor othiazide), hydrochlorothiazide was considered to be most likely an Hi -antagonist. An aqueous solution of the whole drug tablet (2x10(-4) M propranolol 2.9 x 10(-5) M triamterene, 1.7 x 10(-5) M hydrochlorothia zide) and of the individual substances (1 mu M each) was tested in the classical H1-receptor assay using the guinea pig ileum. Betathiazid(R ) in total suppressed the contraction to histamine (78% inhibition), b ut not to carbachol. Propranolol and triamterene had depressive effect s (14% and 38% inhibition), but hydrochlorothiazide potentiated the co ntractions to histamine (75% potentiation). In all cases, the type of antagonism was not competitive. Although different mechanisms may acco unt for the modulatory effects of Betathiazid(R), they have to be cons idered in the interpretation of clinical studies, especially for relat ing mediator concentrations with clinical signs.