Epristeride SmithKline Beecham.

Epristeride is a transition-state, noncompetitive steroid 5-alpha-reductase inhibitor under development by SmithKline Beecham for the treatment of benign prostatic hyperplasia and acne. Phase III trials for prostatic hypertrophy with an oral formulation, have been initiated in the UK, the US and Japan [188478], [219166]. In healthy male volunteers, epristeride caused a reduction in serum dihydrotestosterone levels but serum testos-terone levels remained stable. In animal studies, it showed a similar potency to finasteride for the inhibition of 5-alpha-reductase [164200]. Epristeride is licensed to Ono which has exclusive rights in Japan, South Korea and Taiwan. Recordati has co-marketing rights for epristeride [162547], [162519]. Analysts at Yamaichi estimate that epristeride will be launched in Japan between 1999 and 2000 and peak annual sales have been predicted to be over ten billion Yen [216018].

Evidence for the involvement of 5-hydroxytryptamine 4 receptors in 5-hydroxytryptophan-induced diarrhea in mice.

The objective of this study was to characterize the receptor(s) to 5-HT mediating 5-HTP-induced diarrhea in mice. The severity of diarrhea in mice was assessed using an arbitary scoring scale ranging from 0 (normal stools) to 3 (watery diarrhea). Administration of 5-HTP (1-30 mg/kg i.p.) produced a dose-dependent increase in diarrhea score (ED50, 1.47 mg/kg i.p.). 5-HTP (10 mg/kg i.p.)-induced diarrhea was unaffected by atropine (3 mg/kg i.p.) but was completely abolished by the aromatic L-amino acid decarboxylase inhibitor benserazide (10 mg/kg i.p.). Pretreatment (5 min before 5-HTP) with DAU 6285, a marginally selective 5-HT4 receptor antagonist, significantly inhibited 5-HTP-induced diarrhea (ID50, 0.58 mg/kg i.p.). Pretreatment (5 min before 5-HTP) with GR 113808 or SB 204070, two highly selective 5-HT4 antagonists, significantly inhibited 5-HTP-induced diarrhea with ID50 estimates of 0.31 and 0.003 mg/kg i.p., respectively. The maximal inhibition produced by DAU 6285, GR 113808 and SB 204070 was 63%, 68% and 36%, respectively. Neither GR 113808 (1 and 3 mg/kg i.p.) nor SB 204070 (0.1 and 1 mg/kg i.p.) had any effect on 16,16-dimethyl prostaglandin E2 (30 micrograms/kg i.p.)-induced diarrhea in mice. DAU 6285 significantly inhibited 16,16-dimethyl prostaglandin E2-induced diarrhea at the highest dose (3 mg/kg i.p.). Pretreatment (30 min before 5-HTP) with methysergide (0.1-3 mg/kg i.p.), metergoline (0.01-0.1 mg/kg i.p.), ketanserin (0.01-1 mg/kg i.p.), YM 060 (0.01-0.1 mg/kg i.p.) or ondansetron (0.01-3 mg/kg i.p.) had no significant effects on 5-HTP-induced diarrhea.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence from functional and autoradiographic studies for the presence of tubular dopamine-1 receptors and their involvement in the renal effects of fenoldopam.

Evidence from receptor-ligand binding and biochemical studies seems to suggest the possible existence of tubular dopamine DA-1 receptors in the rat kidney. However, it is not yet clear whether these putative tubular DA-1 receptors are involved in the functional renal responses elicited during the administration of DA and DA receptor agonists. In the present study we have examined the renal effects of several doses of selective DA-1 receptor agonist fenoldopam in pentobarbital-anesthetized rats in an attempt to unmask a direct tubular DA-1 receptor-mediated diuresis and natriuresis. Additionally, we have performed receptor-ligand binding and autoradiographic studies to examine the presence and localization of DA-1 receptors in various regions of the rat kidney. At the highest dose studied (2 micrograms/kg/min), fenoldopam produced diuresis and natriuresis, which was accompanied by a significant decrease in blood pressure and also a significant increase in glomerular filtration rate. At 1 micrograms/kg/min, the diuretic and natriuretic effects of fenoldopam were observed in the absence of any changes in blood pressure and glomerular filtration rate, but there was a significant increase in renal blood flow. However, at 0.5 micrograms/kg/min, fenoldopam-induced natriuresis and diuresis was not accompanied by any changes in blood pressure, renal blood flow or glomerular filtration rate, implying a direct tubular effect. These effects of fenoldopam appear to be mediated via activation of DA-1 receptors, because they were antagonized by the selective DA-1 antagonist SCH 23390.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of atrial natriuretic factor on cyclic GMP content in the rat aortic smooth muscle: studies on the role of membrane Na+,K+-ATPase.

1. These studies were conducted to determine whether preservation of the functional integrity of the membrane, Na+,K+-stimulated ATPase is essential for the atrial natriuretic factor (r-ANF-8-33) to enhance guanosine 3',5'-monophosphate (cGMP) content in the rat aortic smooth muscle. In freshly dissected rat aortic tissues, levels of cGMP were estimated using radioimmunoassay. 2. ANF (0.1 mumol/L in Krebs-Henseleit media) produced significant elevation in cGMP levels in the aortic smooth muscle when compared with that incubated in the control media, whereas suppression of Na+-pump with ouabain (1.0 mmol/L) and/or K+-free media did not produce any significant changes in the basal cGMP level; these two experimental manoeuvres did not prevent enhancement of cGMP by ANF. 3. Incubation of the tissues in the media containing ouabain plus vasoconstrictor concentrations of norepinephrine (0.3 mumol/L) also did not alter basal cGMP levels and did not prevent the ability of ANF to elevate cGMP. 4. These studies demonstrate that the antagonism by ouabain, of vasorelaxant effects of ANF (as reported in the literature) are not due to the prevention of the ability of ANF to enhance cGMP levels in the arterial smooth muscle. It is proposed that such an antagonism may be related to the actions of ouabain and ANF on diverse, and perhaps independent, mechanisms which affect Ca2+-fluxes across the cell membrane.