Unknown effects of clinically used drugs as bias in clinical trials: antihistaminergic activity of the antihypertensive fixed-dose combination Betathiazid.

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