Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The novel 5-HT3 antagonist, BRL 46470A (endo-N-(8-methyl-8-azabicyclo [3.2.1]oct-3-yl)2,3-dihydro-3,3 dimethyl-indole-1-carboxamide, hydrochloride), has been investigated in a series of in vitro and in vivo tests, including the effect of the drug in models of anxiolysis. In classical tests for 5-HT3 receptor antagonism, BRL 46470A was shown to antagonise 5-HT3 mediated responses in the guinea-pig ileum [pA2 8.3 +/- 0.5, slope 0.98 +/- 0.20, mean +/- SEM (5)], the rabbit isolated heart (pA2 10.1 +/- 0.1, slope 1.2 +/- 0.2, n = 5) and the rat Bezold-Jarisch model (ID50 0.7 microgram/kg IV +/- 0.1, n = 8), with a long duration of action (> 3 h). BRL 46470A selectively displaced [3H]-BRL 43694 from 5-HT3 binding sites in rat brain membranes (Ki 0.32 nM +/- 0.04, n = 4) without displacing (at concentrations greater than 1 microM) a wide variety of ligands binding to other neurotransmitter receptors, opioid receptors and to neurotransmitter gated ion channel complexes. In vivo, BRL 46470A showed anxiolytic-like activity in two animal models predictive of antianxiety effects-elevated X-maze and social interaction in rats. In both models, BRL 46470A showed significant activity over a wide dose-range following both oral (0.0001-0.1 mg/kg PO) and systemic administration. The unique level of potency of BRL 46470A was apparent in the rat social interaction test and was shown to be 100 fold more potent than the 5-HT3 receptor antagonist ondansetron, with no evidence of a bell-shaped dose response curve over 4 orders of magnitude.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:BRL 46470A: a highly potent, selective and long acting 5-HT3 receptor antagonist with anxiolytic-like properties. 783 18

The pharmacokinetics of lerisetron, a novel 5HT(3) antagonist, are studied together with its efficacy in inhibiting the serotonin (5-HT)-evoked transient bradycardia reflex (von Bezold-Jarisch reflex) in Sprague Dawley rats. [(14)C]Lerisetron (50, 100, and 200 microg/kg) was given to rats by intravenous (iv) injection and plasma levels of unchanged (UL) and total (unchanged + changed, TL) drug were measured by liquid chromatography with radioactivity monitoring and scintillation counting, respectively. Linearity of UL and TL pharmacokinetics over the dose range was established by noncompartmental analysis. Protein binding of lerisetron was measured in vitro by ultrafiltration. The unbound fraction was 14.4 +/- 1.4%. A nonlinear mixed effects ("population") bicompartmental pharmacokinetic analysis showed that volume of distribution and clearance (CL) were high for both forms of the drug, but CL was significantly smaller for TL [(mean +/- SEM) 0.014 +/- 0.03 L/min for UL versus 0.006 +/- 0.03 L/min for TL, p < 0.05)]. Large interindividual variabilities were observed for both forms. The response to lerisetron administration (inhibition of bradycardia) was evaluated at different doses (2, 3, 5, 6, and 10 microg/kg, iv) at times 2-180 min after dose administration and related to simulated concentrations. Inhibition was 100% 5 min after the 10-microg/kg dose and, 3 h later, it was still > 10%. Response to lerisetron was dose related in the range studied. Pharmacodynamic parameters were estimated by a sigmoid E(max) naive-pooled model. The parameters were also different between the two forms: EC(50) was 0.44 ng/mL (CV = 5.9%) for UL and 0.88 ng/mL (CV = 4.9%) for TL. We conclude that UL and TL pharmacokinetics were linear and that the differences in the kinetics and dynamics between the two forms suggest the presence of at least one metabolite.
 ...
PMID:Pharmacokinetics and pharmacological effect of lerisetron, a new 5-HT3 antagonist, in rats. 1178 96

Vasovagal syncope (VVS) is mediated by arterial mechanoreceptors, resulting in reflexive changes in heart rate and vascular tone. The Bezold-Jarisch reflex was originally described as enhanced contraction and activation of left ventricular mechanoreceptors, but later studies implicated other triggers, including coronary, carotid, and cerebral arterial mechanoreceptors. VVS is uncommon in patients with left ventricular dysfunction. We hypothesized that VVS could occur in this subset and examined patient characteristics and hemodynamic responses during tilt table testing. From 1996 through 1998, 128 consecutive patients with ejection fraction <40% underwent tilt table testing (70 degrees , 45 min). A total of 15 patients (11.7%) had a positive neurocardiogenic response thought to be the cause of syncope. Clinical data and hemodynamic responses were reviewed. Mean patient age (+/-SEM) was 70.1 +/- 12.2 years. Nine patients were male. Mean ejection fraction was 27.7% +/- 7.1%. Thirteen had electrophysiologic studies with normal findings or abnormal findings insufficient to account for syncope. Hemodynamic analysis of 14 patients who had a vasovagal response during passive tilt table testing showed a mean time to positive response of 17.6 +/- 12.7 min. Cardioinhibitory responses (pauses >3 sec or heart rate < 40 beats/min for > or =10 sec) were not observed. Five responses were classified as mixed type (>10% decrease in heart rate without a cardioinhibitory response) and 9 as vasodepressor type (< or =10% decrease in heart rate). VVS occurs in patients who have clinically significant left ventricular dysfunction. Although this study had a small cohort size, the predominantly vasodepressor response without a cardioinhibitory component warrants further investigation into mechanisms of VVS in these patients.
 ...
PMID:Vasovagal syncope in patients with reduced left ventricular function. 1721 53