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Selective Receptor Antagonist (selective + receptor_antagonist)
Selected AbstractsThe neurokinin-1 antagonist activity of maropitant, an antiemetic drug for dogs, in a gerbil modelJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 4 2007V. DE LA PUENTE-REDONDO Maropitant is a novel synthetic nonpeptide neurokinin type 1 (NK1) selective receptor antagonist, recently developed for use in the dog as an antiemetic. The in vivo functional activity of maropitant was investigated in the gerbil foot-tapping model, to determine the ability of maropitant to penetrate the central nervous system and inhibit foot-tapping induced by the selective NK1 agonist GR73632. In comparison with CP-122,721, a previously characterized NK1 receptor antagonist, maropitant (1 mg/kg by s.c. injection) was found to inhibit foot-tapping for significantly longer (P < 0.01). Inhibition of foot-tapping by maropitant was 100% at 2 h and approximately 50% at 8 h postdosing. The mean brain:plasma concentration ratio at 8 h post-treatment was 3.59. These data demonstrate the central functional action of maropitant as a selective and potent NK1 receptor antagonist and help to support and explain its clinical potential as a broad-spectrum antiemetic agent. [source] An investigation of dose titration with darifenacin, an M3 -selective receptor antagonistBJU INTERNATIONAL, Issue 4 2005William Steers OBJECTIVES To evaluate the efficacy, tolerability and safety of a flexible-dosing strategy with darifenacin, an M3 -selective receptor antagonist, in patients with symptoms of overactive bladder (OAB). PATIENTS AND METHODS In this multicentre double-blind 12-week study, 395 patients (aged 22,89 years; 84% female) with OAB symptoms for >6 months were randomized (2 : 1) and received once-daily treatment with darifenacin controlled-release tablets 7.5 mg (268 patients) or matching placebo (127). After 2 weeks of treatment, the efficacy, safety and tolerability were assessed and the dose increased to 15 mg once daily (pseudo-increase for placebo recipients) if additional efficacy was required by both the patient and physician. In the week before clinic visits (at 2 and 12 weeks), patients recorded incontinence episodes (primary efficacy endpoint) and several secondary efficacy variables in an electronic daily diary. Safety and tolerability were evaluated from withdrawal rates and adverse-event reports. RESULTS The treatment groups had comparable baseline characteristics. Similar proportions of darifenacin (59%) and placebo (68%) recipients increased the dose at 2 weeks; at 12 weeks patients on darifenacin (overall group) had a significantly greater reduction in the median number of incontinence episodes per week than had those on placebo, at ,,8.2 (,62.9%) and ,,6.0 (,48.1%), respectively (P = 0.035). There were also significant improvements in voiding frequency (P = 0.001), bladder capacity (volume voided; P=,0.036), frequency of urgency (P < 0.001), severity of urgency (P = 0.013) and number of significant leaks/week (i.e. incontinence episodes needing a change of clothing or pads, per week; P = 0.010) for darifenacin over placebo. Subset analysis suggested that some patients (those remaining on darifenacin 7.5 mg) were more sensitive to darifenacin than those who increased the dose, based on both efficacy and adverse events. Continued treatment with 7.5 mg for ,sensitive' patients, and an increased dose (to 15 mg) for remaining patients, resulted in comparable outcomes by 12 weeks. The most common treatment-related adverse events were mild-to-moderate dry mouth and constipation, which led to discontinuation in <,3.0% of darifenacin-treated patients and <1.0% of the placebo group. Central nervous system and cardiovascular adverse events were comparable to those with placebo. CONCLUSIONS Darifenacin appears to be an effective, well-tolerated and flexible treatment for patients with OAB, allowing individualized dosing according to patient needs. [source] Bidirectional modulation of visual plasticity by cholinergic receptor subtypes in the frog optic tectumEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 6 2003Chuan-Jiang Yu Abstract Cholinergic input to the optic tectum is necessary for visual map maintenance. To understand why, we examined the effects of activation of the different cholinergic receptor subtypes in tectal brain slices and determined whether the retinotectal map was affected by manipulations of their activity in vivo. Both ,-bungarotoxin sensitive and insensitive nicotinic receptor agonists increased spontaneous postsynaptic currents (sPSCs) in a subpopulation of patch-clamped tectal cells; application of subtype selective receptor antagonists reduced nicotine-induced increases in sPSCs. Activation of ,-bungarotoxin insensitive nicotinic receptors also induced substantial inward current in some cells. Muscarinic receptor mediated outward current responses were blocked by the M2-like muscarinic receptor antagonists himbacine or AF-DX 384 and mimicked by application of the M2-like agonist oxotremorine. A less frequently observed muscarinic response involving a change in sPSC frequency appeared to be mediated by M1-like muscarinic receptors. In separate experiments, pharmacological manipulation of cholinergic receptor subtype activation led to changes in the activity-dependent visual map created in the tectum by retinal ganglion cell terminals. Chronic exposure of the tectum to either ,-bungarotoxin insensitive, ,-bungarotoxin sensitive or M1-like receptor antagonists resulted in map disruption. However, treatment with the M2-like receptor antagonist, AF-DX 384, compressed the map. We conclude that nicotinic or M1-like muscarinic receptors control input to tectal cells while ,-bungarotoxin insensitive nicotinic receptors and M2-like muscarinic receptors change tectal cell responses to that input. Blockade of the different cholinergic receptor subtypes can have opposing effects on map topography that are consistent with expected effects on tectal cell activity levels. [source] Review article: proteinase-activated receptors , novel signals for gastrointestinal pathophysiologyALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 3 2000Vergnolle Proteinase-activated receptors (PARs) have the common property of being activated by the proteolytic cleavage of their extracellular N-terminal domain. The new NH2 -terminus acts as a ,tethered ligand' binding and activating the receptor itself. Four members of this family have been cloned, three of which are activated by thrombin (PAR-1, PAR-3 and PAR-4) while the fourth (PAR-2) is activated by trypsin or mast cell tryptase. In physiological or pathophysiological conditions, the gastrointestinal tract is exposed more than other tissues to proteinases (digestive enzymes, proteinases from pathogens or proteinases from inflammatory cells) that can activate PARs. Since PARs are highly expressed throughout the gastrointestinal tract, the study of the role of PARs in these tissues appears to be particularly important. It has already been shown that PAR-2 activation induces calcium mobilization and eicosanoid production in enterocytes as well as changes in ion transport in jejunal tissue segments. PAR-2 activation also causes calcium mobilization and stimulates amylase release from pancreatic acini. Moreover, both PAR-1 and PAR-2 activation can alter the gastrointestinal motility. In inflammatory or allergic conditions, the proteinases that constitute the major agonists for PARs (thrombin, trypsin and mast cell tryptase) are usually released. The activation of PARs by these proteinases might contribute to the gastrointestinal disorders associated with these pathologies. A complete understanding of the role of PARs in the gastrointestinal tract will require the development of selective receptor antagonists that are not yet available. Nonetheless, the use of PAR agonists has already highlighted new potential functions for proteinases in the gastrointestinal tract, thus the control of PAR activation might represent a promising therapeutic target. [source] Characterization of the 5-hydroxytryptamine receptors mediating contraction in the pig isolated intravesical ureterBRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2003Medardo Hernández This study was designed to investigate the effect of 5-hydroxytryptamine (5-HT) and to characterize the 5-HT receptors involved in 5-HT responses in the pig intravesical ureter. 5-HT (0.01,10 ,M) concentration-dependently increased the tone of intravesical ureteral strips, whereas the increases in phasic contractions were concentration-independent. The 5-HT2 receptor agonist ,-methyl 5-HT, mimicked the effect on tone whereas weak or no response was obtained with 5-CT, 8-OH-DPAT, m -chlorophenylbiguanide and RS 67333, 5-HT1, 5-HT1A, 5-HT3 and 5-HT4 receptor agonists, respectively. 5-HT did not induce relaxation of U46619-contracted ureteral preparations. Pargyline (100 ,M), a monoaminooxidase A/B activity inhibitor, produced leftward displacements of the concentration-response curves for 5-HT. 5-HT-induced tone was reduced by the 5-HT2 and 5-HT2A receptor antagonists ritanserine (0.1 ,M) and spiperone (0.2 ,M), respectively. However, 5-HT contraction was not antagonized by cyanopindolol (2 ,M), SDZ,SER 082 (1 ,M), Y-25130 (1 ,M) and GR 113808 (0.1 ,M), which are respectively, 5-HT1A/1B, 5-HT2B/2C, 5-HT3, and 5-HT4 selective receptor antagonists. Removal of the urothelium did not modify 5-HT-induced contractions. Blockade of neuronal voltage-activated sodium channels, ,-adrenergic receptors and adrenergic neurotransmission with tetrodotoxin (1 ,M), phentolamine (0.3 ,M) and guanethidine (10 ,M), respectively, reduced the contractions to 5-HT. However, physostigmine (1 ,M), atropine (0.1 ,M) and suramin (30 ,M), inhibitors of cholinesterase activity, muscarinic- and purinergic P2 -receptors, respectively, failed to modify the contractions to 5-HT. These results suggest that 5-HT increases the tone of the pig intravesical ureter through 5-HT2A receptors located at the smooth muscle. Part of the 5-HT contraction is indirectly mediated via noradrenaline release from sympathetic nerves. British Journal of Pharmacology (2003) 138, 137,144. doi:10.1038/sj.bjp.0705019 [source] | ||||||||||