Tiodazosin (BL-5111)

Comparative first dose effects of prazosin and tiodazosin (BL-5111) in spontaneously hypertensive rats

Prazosin produces a "first-dose" phenomenon in man clinically characterized by an exaggerated hypotensive response to the initial dose of the drug, with subsequent doses not producing this exaggerated effect. In spontaneously hypertensive rats (SHR), prazosin (1 mg kg po) produced a similar effect, appreciably reducing systolic blood pressure at 12 hours after the first dose but having little or no effect at 12 hours after the subsequent doses. In contrast, BL-5111, an antihypertensive agent similar in chemical structure and shown in previous studies to be slightly less potent than prazosin but with appreciably less alpha-adrenergic receptor antagonist activity, had no effect on blood pressure at 12 hours after dosing (1 and 2 mg/kg po). Pretreatment of rats with an ineffective blood pressure lowering dose of prazosin (0.03 mg/kg po) significantly attenuated the first dose effect of prazosin, resembling the clinical observations seen in patients. Thus, the SHR may be a useful model for predicting the prazosin-like "first-dose" phenomenon with related analogs.

The bioavailability and disposition of tiodazosin levulinate in beagle dogs with a comparison to prazosin hydrochloride

Tiodazosin is a recently developed compound that is currently undergoing investigation for use in hypertension. It is structurally and pharmacologically similar to prazosin, the prototype of the aminoquinazoline class of vasodilators. Lacking an intravenous dosage form for use in human subjects, our study concentrated on the determination of the bioavailability and disposition parameters of tiodazosin in dogs, with a comparison to those parameters for prazosin, obtained from previous work in our laboratory. Tiodazosin was administered to five male beagle dogs at a dose of 1 mg/kg both intravenously and as an oral solution. Plasma and whole blood samples were taken serially over 24 hr and analyzed with a new specific and sensitive HPLC assay. The half-life of tiodazosin was significantly shorter than that of prazosin. The tiodazosin-calculated bioavailability was 3-fold less than predicted, whereas prazosin-calculated bioavailability was the same as predicted. Assumptions necessary to predict the bioavailability of compounds cleared by the hepatic route appear to be incorrect for tiodazosin. Possible mechanisms for the unpredictable low tiodazosin bioavailability in dogs are presented.

Non-competitive antagonism of the alpha-adrenoceptor-mediated fast component of contraction of rat aorta, by doxazosin and prazosin

alpha-Adrenoceptor antagonists have been compared for their effects on dose-response curves of fast and slow components of contraction of the rat aorta to noradrenaline (NA). All agents caused a competitive antagonism of the slow component of contraction to NA. The order of potency was: prazosin greater than WB4101 = doxazosin greater than tiodazosin greater than phentolamine greater than corynanthine greater than trimazosin greater than rauwolscine. For the fast component, doxazosin, prazosin, tiodazosin and WB4101 caused some depression of the maximum response. Doxazosin (25 nM) and prazosin (25 nM) produced a complete and unsurmountable antagonism of the maximum fast component. Phentolamine, corynanthine, trimazosin and rauwolscine all competitively antagonized the fast component. The degree of antagonism of the fast component by prazosin and its analogues appeared to be directly related to the potency of individual agents for the slow component. WB4101, which was equipotent with doxazosin and more potent than tiodazosin was less effective than either in reducing the fast component. The antagonism of the fast component by prazosin or doxazosin was easily reversed by washing and prevented by phentolamine (2.5 microM). Neither prazosin nor doxazosin in concentrations of up to 2.5 microM has any effect on contractions of the aorta to 5-hydroxytryptamine (5-HT, 0.25-250 microM) or caffeine (20mM). It is concluded that the ability of some alpha-adrenoceptor antagonists to produce a non-competitive antagonism of the fast component of contraction is (a) dependent upon blockade of alpha-adrenoceptors; (b) unrelated to selectivity for alpha 1-adrenoceptors; (c) related to potency and structure. 8 EGTA (3.0 mM) caused a selective suppression of the slow component of contraction to NA. Both doxazosin and prazosin caused a non-competitive antagonism of EGTA-resistant contractions to NA whereas corynanthine showed competitive antagonism. These observations, together with those above imply that prazosin and doxazosin non-competitively antagonize alpha-adrenoceptorinduced release of calcium in the rat aorta, but competitively antagonize alpha-adrenoceptor-induced calcium entry.

Effects of tiodazosin, praxosin, trimazosin and phentolamine on blood pressure, heart rate and on pre- and postsynaptic alpha-adrenergic receptors in the rat

Subcutaneous administration of tiodazosin (0.1-3 mg/kg), prazosin (0.01-1 mg/kg), trimazosin (10-30 mg/kg) and phentolamine (0.1-3 mg/kg) to conscious spontaneously hypertensive rats (SHR) produced graded decreases in blood pressure with the order of potency being prazosin > tiodazosin > phentolamine > trimazosin. Heart rate was elevated predominantly only by phentolamine and this was consistent with the activity of this agent for both pre- and postsynaptic alpha-adrenergic receptors. In contrast, tiodazosin, prazosin and trimazosin showed selectivity only for postsynaptic alpha-adrenergic receptors. Acute oral administration of tiodazosin and prazosin indicated tiodazosin to be about 1/2 as potent as prazosin. However, chronic administration of equivalent doses of the two compounds for 25 and 52 days via the drinking water indicated approxiately equivalent, sustained reductions in blood pressure. Furthermore, at the end of the 52-day chronic dosing period tiodazosin caused appreciably less alpha-adrenergic receptor antagonist activity than prazosin as assessed by the norepinephrine dose-pressor response profiles. These results indicate that following chronic dosing with tiodazosin in the rat other mechanisms besides alpha-adrenergic receptor antagonist activity are probably contributing to the antihypertensive effect in the rat.

The effect of alpha 1-acid glycoprotein on the pharmacological activity of alpha 1-adrenergic antagonists in rabbit aortic strips

The pharmacological activity of three alpha 1-adrenergic antagonists, prazosin, tiodazosin and WB4101 has been studied in the presence and absence of 20 microM alpha 1-acid glycoprotein (AAG) in rabbit aortic strips, and measured as the ability to increase the EC50 value of the alpha 1-adrenergic agonist phenylephrine. For all three drugs, the presence of AAG diminished the pharmacological activity when compared with equivalent unbound concentrations in the absence of AAG. In the presence of AAG the EC50 value of phenylephrine at 5.69 nM unbound prazosin was on average 47% lower than in the absence of AAG (P less than 0.002), at 122 nM unbound tiodazosin, 39% lower (P less than 0.01), and at 25.6 nM unbound WB4101, 68% lower (P less than 0.002). Albumin showed no ability to modify the alpha 1-adrenergic blocking activity of prazosin (P greater than 0.7). The EC50 value for phenylephrine in the absence of antagonists was not affected by AAG. The effect of AAG on the antagonistic activity of prazosin was concentration-dependent with a maximum suppression of prazosin activity of 79% and with a half-maximum concentration of 1.1 microM AAG. AAG significantly decreased prazosin's ability to reduce alpha 1-adrenergic stimulation of calcium influx (P less than 0.05), while it had no effect on prazosin's ability to decrease alpha 1-adrenergic-stimulated formation of inositol phosphate. These results suggest that the effect of AAG on adrenoceptors appears to act selectively via alpha 1 a-receptors. Consistent with these observation was the observation that WB4101, a selective alpha 1a-antagonist was more affected by AAG than was prazosin or tiodazosin.