piperidines and dolasetron

The objective of this study was to characterize the impact of casopitant, a novel neurokinin-1 receptor antagonist under investigation for the prevention of postoperative and chemotherapy-induced nausea and vomiting, on the pharmacokinetics of the commonly prescribed 5-hydroxytryptamine receptor 3 receptor antagonists, dolasetron or granisetron.. In a phase I, open-label, two-part, two-period, single-sequence study, two cohorts of healthy subjects received either oral dolasetron (100 mg once daily for 3 days) or oral granisetron (2 mg once daily for 3 days) alone (period 1) and combined with oral casopitant, 150 mg day 1, 50 mg days 2 and 3 (period 2). Pharmacokinetics of hydrodolasetron and granisetron were assessed on days 1 and 3 of each period. Log-transformed area under the curve (AUC) and Cmax were statistically analyzed by performing an analysis of variance. Eighteen subjects were enrolled in the dolasetron cohort; nine subjects were CYP2D6 extensive metabolizers (EMs) and nine subjects were CYP2D6 poor metabolizers. Nineteen subjects were enrolled in the granisetron cohort.. The largest changes in hydrodolasetron exposure after coadministration with casopitant were seen in CYP2D6 EMs, with a 24% increase in hydrodolasetron AUC on day 1 and 30% increase in Cmax on days 1 and 3. All other changes in hydrodolasetron exposure were <20%, and granisetron exposure was not altered to any relevant extent (<11%).. None of the changes observed are considered clinically meaningful, and coadministration of casopitant with dolasetron or granisetron was well tolerated.

Topics: Adolescent; Adult; Antiemetics; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Granisetron; Humans; Indoles; Male; Middle Aged; Nausea; Piperazines; Piperidines; Quinolizines; Vomiting; Young Adult

Remifentanil is used as an analgesic for different procedures performed during monitored anaesthesia care. Opioid-induced nausea and vomiting can be troublesome.. This prospective, randomized, double-blind study was performed to evaluate the efficacy of prophylaxis with dolasetron in reducing the frequency of postoperative nausea and duration of discharge time. Forty urological patients, undergoing elective ambulatory extracorporeal shock wave lithotripsy (ESWL) received randomly either dolasetron 12.5 mg i.v. (Group 1) or placebo (Group 2) 10 min before a patient-adapted continuous infusion of remifentanil 0.15-0.4 micro g kg(-1) min(-1) was administered. Frequency and intensity (VAS 0-100 mm) of nausea, retching, and vomiting were assessed by patients and blinded investigators during and after the procedure.. Patient characteristics, baseline values, duration of ESWL, and total dose of remifentanil did not differ between groups. The frequency (Group 1/Group 2; 20/55%; P<0.05) and mean (SD) maximal intensity [15 (9)/45 (14) mm; P<0.05] of nausea during 24 h was significantly reduced after dolasetron and discharge times in Group 1 were less than Group 2 [22 (14)/45 (28) min; P<0.05].

Topics: Adult; Aged; Ambulatory Surgical Procedures; Analgesics, Opioid; Anesthesia Recovery Period; Anesthesia, Intravenous; Antiemetics; Double-Blind Method; Female; Humans; Indoles; Infusions, Parenteral; Lithotripsy; Male; Middle Aged; Monitoring, Intraoperative; Patient Satisfaction; Piperidines; Postoperative Nausea and Vomiting; Prospective Studies; Quinolizines; Remifentanil

1. The actions of 5-hydroxytryptamine (5-HT) on rat dentate gyrus neurones were measured with conventional intracellular recording techniques in brain slices maintained in vitro at 32 degrees C. 2. Bath application of 5-HT (0.3-100 microM) hyperpolarized the membrane potential and reduced the input resistance; these effects persisted in tetrodotoxin (1 microM) and were abolished by MDL 73,005EF, a 5-HT1A receptor antagonist. 3. Local application of 5-HT via a pressure pipette also elicited a hyperpolarization and a reduction in resistance, and evoked a transient 'burst' of spontaneous inhibitory postsynaptic potentials (IPSPs) which were blocked by tetrodotoxin or bicuculline. 4. The 'burst' of IPSPs was subject to desensitization. It was completely abolished in the presence of the 5-HT3 receptor antagonist dolasetron. 5. In some cells, a longer lasting increase in spontaneous IPSP frequency was observed during application of 5-HT; this effect was blocked by the 5-HT2 receptor antagonist MDL 100,907. 6. 5-HT (30 microM) shortened the decay time constants of the glutamatergic and GABAergic evoked EPSPs and IPSPs without changing their amplitudes. 7. It is concluded that 5-HT hyperpolarizes granule cells via postsynaptic 5-HT1A receptors and increases spontaneous GABA release from inhibitory interneurones via the activation of 5-HT3 receptors and/or 5-HT2 receptors.

Topics: Animals; Bicuculline; Dioxins; Electrophysiology; Excitatory Amino Acid Antagonists; Fluorobenzenes; GABA Antagonists; Glutamic Acid; Hippocampus; Indoles; Long-Term Potentiation; Male; Piperidines; Quinolizines; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Serotonin; Spiro Compounds; Tetrodotoxin

Several lines of evidence have suggested a link between serotonergic and dopaminergic systems in the brain. The interpretation of much of these early data needs careful reevaluation in light of the recent understanding of the plethora of serotonin receptor subtypes, their distribution in the brain and the new findings with more selective serotonin antagonists. Electrophysiological, biochemical and behavioral evidence obtained using highly selective antagonists of the 5-HT2 or 5-HT3 receptor subtypes, MDL 100,907 or MDL 73,147EF, respectively, supports the thesis that serotonin modulates the dopaminergic system. This modulation is most evident when the dopaminergic system has been activated.

Topics: Animals; Basal Ganglia Diseases; Behavior, Animal; Dopamine; Electrophysiology; Fluorobenzenes; Indoles; Male; Mice; Microdialysis; Motor Activity; N-Methyl-3,4-methylenedioxyamphetamine; Neurons; Piperidines; Quinolizines; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Serotonin Antagonists

Pre-weaning rat pups emit ultrasonic vocalizations when removed from the litter. These 'separation-induced vocalizations' (SIV) are suppressed by classical benzodiazepine anxiolytics and by non-benzodiazepine anxiolytics which lack muscle relaxant and sedative properties. The present study used the SIV model to assess potential anxiolytic properties of compounds which target different sites associated with the NMDA receptor complex. Comparison was made to drugs which affect benzodiazepine or serotonin (5-HT) receptors. Muscle relaxant potential was assessed using 'TIP' (time on an inclined plane), the amount of time a pup was able to retain its position on a steeply inclined surface. Mephenesin, a centrally acting muscle relaxant, significantly suppressed TIP but not SIV. The benzodiazepine agonist diazepam suppressed both SIV and TIP, whereas the 5-HT1A partial agonists, buspirone and MDL 73,005EF, suppressed SIV without affecting TIP. The 5-HT2 antagonist MDL 11,939 suppressed TIP but not SIV, whereas neither measure was affected by the 5-HT3 antagonist MDL 73,147EF. SIV was suppressed by NMDA antagonists including those acting at the glutamate recognition site (D,L-amino-phosphonovaleric acid (AP5) and MDL 100,453) or at the ion channel (MK-801), or by the strychnine-insensitive glycine antagonist 5,7-dichlorokynurenic acid (5,7-DCKA). TIP was suppressed even more potently by AP5, MDL 100,453 and MK-801, whereas 5,7-DCKA was inactive on this measure. Thus, antagonists acting at different sites present on the glutamate recognition site exhibit potential anxiolytic activity, but the glycine antagonist was unusual in its lack of prominent muscle relaxant side effects.

Topics: 2-Amino-5-phosphonovalerate; Animals; Anti-Anxiety Agents; Anxiety, Separation; Behavior, Animal; Buspirone; Diazepam; Dioxins; Dizocilpine Maleate; Dose-Response Relationship, Drug; Indoles; Kynurenic Acid; Maternal Deprivation; Mephenesin; Piperidines; Quinolizines; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Receptors, Serotonin; Serotonin Antagonists; Spiro Compounds; Valine; Vocalization, Animal