Pildralazine

Abstract: Studies of the binding and release of the new antihypertensive drug (+/-)-1-[(6-hydrazinopyridazin-3-yl)methylamino]-2-propanol (pildralazine, PD) were performed on isolated perfused guinea pig hearts according to the Langendorff technique. Extensive binding to and accumulation in the tissue were recorded. Even after 30 min of washout considerable PD concentrations were detected both in the myocardium (900 ng/g w.w.) and the effluent (17 ng/ml = 100 ng/min). The calculation of elimination half-life yielded a nearly identical value in the myocardial tissue and the effluent. Coronary vasodilation mediated by PD ran in close parallel to the drug concentrations. As the washout of [3H]-sucrose as an extracellular space marker was half-maximal already after 1.6 min rediffusion of PD originated from tissue sites and not only by dilution of the fluid in the extracellular space. In addition the results indicated that the observed binding of PD to cell structures prevented its normally rapid chemical destruction, already evident in aqueous solutions. The back diffusion of PD from the binding and storage sites into the coronary perfusate was very slow, explaining its long-lasting biological availability and action in vivo. The release kinetics may be described by an exponential function which obeys the criterions of a first order elimination process.

Abstract: Pildralazine, a hydralazinelike antihypertensive vasodilator containing a free hydrazine group, was administered in the drinking water to male and female B6C3F1 and to female BALB/c mice at 100, 200, and 400 ppm dose levels for 80 weeks. The animals were kept under observation until 130–133 weeks of age, when the experiment was terminated. A transplacentalinfantile bioassay was also carried out with pildralazine administered in the drinking water at 200 and 400 ppm dose levels to female C57BL/6J mice for 1 week before mating with C3Hf males and during mating and pregnancy. The progeny received the same doses for 10 weeks after birth and were kept under observation until 80–85 weeks of age, when the experiment was terminated. In both long-term and transplacental-infantile assays, control and treated groups developed the pattern of tumors usually observed in the strains used and no tumor type at any site appeared to be related to treatment.