piperidines and Vomiting

Chronic lymphocytic leukemia (CLL) is a rare hematological malignancy classified in the non-Hodgkin's lymphoma category. Ibrutinib, a first-in-class Bruton tyrosine kinase inhibitor has been approved for use in the treatment of CLL. This drug has shown beneficial effects including a higher overall response rate, sustained remissions, and a tolerable toxicity level. In this meta-analysis, we aimed to compare the adverse drug events which were associated with the use of ibrutinib for the treatment of patients with CLL.. A careful search was carried out through the Cochrane Central, EMBASE, MEDLINE (PubMed), and through www.ClinicalTrials.com. The following criteria for inclusion were considered: Both randomized trials and observational cohorts; Studies comparing the adverse drug events observed with the use of ibrutinib versus a control group for the treatment of CLL. The RevMan software (version 5.3) was used to carry out this analysis and the analyzed data were represented by risk ratios (RR) and 95% confidence intervals (CI).. A total number of 2456 participants with CLL were included in this analysis. One thousand one hundred thirteen participants were treated with ibrutinib whereas the remaining 1343 participants were assigned to the control (non-ibrutinib) group. Results of this current analysis showed Ibrutinib not to be associated with significantly higher risk of anemia (RR: 0.90, 95% CI: 0.67-1.21; P = .49), thrombocytopenia (RR: 0.61, 95% CI: 0.32-1.14; P = .12), neutropenia (RR: 0.50, 95% CI: 0.25-1.00; P = .05), and febrile neutropenia (RR: 0.89, 95% CI: 0.32-2.49; P = .83) in these patients with CLL. The risk for respiratory tract infection was also similarly manifested (RR: 1.01, 95% CI: 0.78-1.30; P = .96). However, ibrutinib was associated with a high risk of abdominal manifestations in comparison to the control group (RR: 1.62, 95% CI: 1.32-2.00; P = .00001). The risk for diarrhea was also significantly higher in the Ibrutinib group (RR: 2.14, 95% CI: 1.44-3.17; P = .0002).. During the treatment of CLL, ibrutinib was not associated with significantly higher risks of anemia, thrombocytopenia, or neutropenia compared to the control group. However, abdominal manifestations were significantly higher with ibrutinib. Advanced phase trials should further confirm this hypothesis.

Topics: Abdominal Pain; Adenine; Constipation; Diarrhea; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Piperidines; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Vomiting

Migraine is a common, disabling condition and a burden for the individual, health services, and society. Many sufferers choose not to, or are unable to, seek professional help and rely on over-the-counter analgesics. Naproxen is a non-steroidal anti-inflammatory drug (NSAID); its efficacy in acute migraine has not been established by systematic reviews. Co-therapy with an antiemetic should help to reduce the nausea and vomiting commonly associated with migraine headaches.. To determine the efficacy and tolerability of naproxen, alone or in combination with an antiemetic, compared with placebo and other active interventions in the treatment of acute migraine headaches in adults.. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library, MEDLINE, EMBASE, and the Oxford Pain Relief Database, together with two online databases (www.gsk-clinicalstudyregister.com and www.clinicaltrials.gov) and reference lists, for studies to 22 May 2013.. We included randomised, double-blind, placebo- or active-controlled studies, with at least 10 participants per treatment arm, using naproxen alone or with an antiemetic to treat a migraine headache episode.. Two review authors independently assessed trial quality and extracted data. We used numbers of participants achieving each outcome to calculate risk ratios and numbers needed to treat (NNT) or harm (NNH) compared with placebo or a different active treatment.. We included six studies using naproxen 275 mg, 500 mg, or 825 mg to treat attacks of moderate or severe pain intensity. Overall, 1241 participants took naproxen (275 mg to 825 mg), 229 took sumatriptan 50 mg, 173 took naratriptan 2.5 mg, and 1092 took placebo. No studies combined naproxen with an antiemetic. Studies using naproxen 275 mg provided no useable data for analysis.Naproxen (500 mg and 825 mg) was better than placebo for pain-free response and headache relief. At two hours, the NNT for pain-free response was 11 (17% response with naproxen, 8% with placebo; risk ratio 2.0 (95% CI 1.6 to 2.6), moderate quality) and for headache relief was 6.0 (45% response with naproxen, 29% with placebo; risk ratio 1.6 (1.4 to 1.8), moderate quality). The NNT for sustained pain-free response during the 24 hours post dose was 19 (12% response with naproxen, 6.7% with placebo), and for sustained headache relief during the 24 hours post dose was 8.3 (30% response with naproxen, 18% with placebo). Analysing only the lower dose of 500 mg of naproxen did not significantly change the results. Adverse events, which were mostly mild or moderate in severity and rarely led to withdrawal, were more common with naproxen than with placebo when the 500 mg and 825 mg doses were considered together, but not when the 500 mg dose was analysed alone.There were insufficient data for analysis of naproxen compared with sumatriptan, and no data suitable for analysis of naproxen compared with naratriptan.. Naproxen is statistically superior to placebo in the treatment of acute migraine, but the NNT of 11 for pain-free response at two hours suggests that it is not a clinically useful treatment. Cochrane reviews examining other commonly used analgesics for acute migraine have reported better (lower) NNT results for the same outcome. Naproxen is not clinically useful as a stand-alone analgesic in acute migraine, as it is effective in fewer than 2 people in 10.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Antiemetics; Drug Therapy, Combination; Humans; Migraine Disorders; Naproxen; Nausea; Piperidines; Randomized Controlled Trials as Topic; Sumatriptan; Tryptamines; Vomiting

Aspiration is a significant cause of anesthetic morbidity, occurring most commonly during the induction of anesthesia. For patients with a high likelihood of aspiration, rapid sequence intubation (RSI) techniques may minimize this risk by reducing the time between the loss of protective airway reflexes and the placement of a cuffed endotracheal tube. Although RSI frequently involves the administration of a neuromuscular-blocking agent (NMBA) such as succinylcholine or rocuronium, there are times when the administration of an NMBA is contraindicated or undesirable. We present an 11-year-old boy who presented with vomiting, papilledema, and a history concerning for an undiagnosed neuromuscular disorder. Deep sedation or anesthesia was required during an emergent lumbar puncture to evaluate his symptoms. Rapid sequence intubation was successfully performed with propofol and remifentanil without the use of an NMBA. We highlight the anesthetic considerations in such a clinical scenario and review the literature regarding the combination of remifentanil and propofol for RSI.

Topics: Anesthesia, Inhalation; Child; Contraindications; Deep Sedation; Emergencies; Headache; Humans; Hypnotics and Sedatives; Intracranial Hypertension; Intubation, Intratracheal; Laryngoscopy; Male; Methyl Ethers; Muscle Weakness; Neuromuscular Depolarizing Agents; Neuromuscular Diseases; Piperidines; Propofol; Remifentanil; Respiratory Aspiration of Gastric Contents; Risk; Sevoflurane; Spinal Puncture; Succinylcholine; Vision Disorders; Vomiting

The addition of neurokinin-1 receptor (NK1R) antagonists to antiemetic regimens has substantially reduced chemotherapy-induced nausea and vomiting (CINV). We sought to systematically review the overall impact of NK1R antagonists on CINV prevention.. We systematically searched the MEDLINE, EMBASE, and CENTRAL databases, and meeting proceedings for randomized controlled trials (RCTs) that evaluated NK1R antagonists plus standard antiemetic therapy for CINV prevention. Complete response (CR) to therapy was defined as the absence of emesis and the absence of rescue therapy. The endpoints were defined as CR in the overall phase (during the first 120 hours of chemotherapy), CR in the acute phase (first 24 hours), and the delayed phase (24-120 hours) after chemotherapy, nausea, and toxicity. Subgroup analyses evaluated the type of NK1R antagonist used, the emetogenic potential of the chemotherapy regimen, and prolonged use of 5-HT3 (serotonin) receptor antagonists, a class of standard antiemetic agents. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Statistical tests for heterogeneity were one-sided; statistical tests for effect estimates and publication bias were two-sided.. Seventeen trials (8740 patients) were included in this analysis. NK1R antagonists increased the CR rate in the overall phase from 54% to 72% (OR = 0.51, 95% CI = 0.46 to 0.57, P < .001). CR and nausea were improved in all phases and subgroups. The expected side effects from NK1R antagonists did not statistically significantly differ from previous reports; however, this analysis suggests that the incidence of severe infection increased from 2% to 6% in the NK1R antagonist group (three RCTs with a total of 1480 patients; OR = 3.10; 95% CI = 1.69 to 5.67, P < .001).. NK1R antagonists increased CINV control in the acute, delayed, and overall phases. They are effective for both moderately and highly emetogenic chemotherapy regimens. Their use might be associated with increased infection rates; however, additional appraisal of specific data from RCTs is needed.

Topics: Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Aprepitant; Confidence Intervals; Humans; Infections; Morpholines; Nausea; Neoplasms; Neurokinin-1 Receptor Antagonists; Odds Ratio; Piperazines; Piperidines; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Serotonin 5-HT3 Receptor Antagonists; Vomiting

In animal models of vomiting, mu-opioid (MOP, OP(3)) receptors mediate both emesis and anti-emesis. mu-receptors within the blood-brain barrier, mediating anti-emesis, are more rapidly accessible to lipid-soluble mu-opioid receptor agonists such as fentanyl than to morphine, and fentanyl has broad-spectrum anti-emetic effects in a number of species. Whether a similar situation exists in humans is not known. A search was performed for clinical studies comparing the emetic side effects of opioids administered peri-operatively in an attempt to identify differences between morphine and more lipid-soluble mu-receptor-selective agonists such as fentanyl. Overall, the evidence appears to suggest that fentanyl and other phenylpiperidines are associated with less nausea and vomiting than morphine, but not all studies support this, and fentanyl-like drugs are associated with nausea and vomiting per se. Good evidence, however, exists to show that fentanyl and alfentanil do not cause more nausea and vomiting than the ultra fast-acting remifentanil. Because remifentanil is cleared rapidly post-operatively, such trials suggest that the emetic side effects of fentanyl and alfentanil are minimal. The clinical evidence, although limited, is at least consistent with the possibility that central mu-opioid receptors may mediate anti-emesis in humans. It is possible that the role of mu-opioid agonists in anti-emesis may become clearer in the future as a result of the use of peripheral mu-opioid receptor antagonists.

Topics: Alfentanil; Analgesics, Opioid; Animals; Antiemetics; Blood-Brain Barrier; Fentanyl; Humans; Models, Animal; Morphine; Piperidines; Postoperative Nausea and Vomiting; Receptors, Opioid, mu; Remifentanil; Vomiting

Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in quality of life. The emetogenicity of the chemotherapeutic agents, repeated chemotherapy cycles, and patient risk factors significantly influence CINV. 5-hydroxytryptamine-3 (5-HT(3)) receptor antagonists plus dexamethasone have significantly improved the control of acute CINV, but delayed CINV remains a significant clinical problem. Two new agents, palonosetron and aprepitant, have been approved for the prevention of both acute and delayed CINV. Palonosetron is a second-generation 5-HT(3) receptor antagonist with a longer half-life and a higher binding affinity than first-generation 5-HT(3) receptor antagonists. Aprepitant is the first agent available in the new drug class of neurokinin-1 (NK-1) receptor antagonists. Casopitant is another NK-1 receptor antagonist that is under review by the FDA after recent completion of Phase III clinical trials. The introduction of these new agents has generated revised antiemetic guidelines for the prevention of CINV. Future studies may consider the use of palonosetron, aprepitant and casopitant with other antiemetic agents (olanzapine, gabapentin, cannabinoids) in moderately and highly emetogenic chemotherapy, as well as in the clinical settings of multiple-day chemotherapy and bone marrow transplantation.

Topics: Antiemetics; Antineoplastic Agents; Aprepitant; Clinical Trials, Phase III as Topic; Humans; Isoquinolines; Morpholines; Nausea; Palonosetron; Piperazines; Piperidines; Quinuclidines; Serotonin Antagonists; Vomiting

The effective treatment of emetic complications of cancer therapies has remained a challenging task for cancer patients and their cancer care providers. Despite striking advances in antiemetic interventions, the need for more personalized targeted treatments in those who fail to response to the currently available antiemetic agents are yet to be met. Casopitant, a potent selective inhibitor of neurokinin-1 receptors, is a product of the increasingly heightened interest in this particular subset of cancer patients. The current review examines the emerging data about the benefits and safety of casopitant for treatment of chemotherapy-induced acute and delayed emesis, as well as the postoperative nausea/vomiting. Although preclinical studies promoted the notion of a potential superiority of casopitant over the already approved aprepitant in enhancing food and fluid intake, the limited comparison in clinical settings have yet to affirm a demonstratable meaningful superiority. The prevailing view from the published prospective studies supports a single 100 or 150 mg dose schedule of casopitant, orally or intravenously, as an effective and safe prophylaxis for acute and delayed emesis. The relative inferior outcomes of "nausea" control, as compared to a more impressive "vomiting" prevention, are similarly shared by both casopitant and aprepitant. This repeated and disappointing observation has challenged the precision and accuracy of our current understandings about the exact fabric of the "emesis axis." The future efforts should be directed to identify more effective agents for managing nausea and anticipatory emesis equally in both genders.

Topics: Antiemetics; Antineoplastic Agents; Humans; Nausea; Neoplasms; Piperazines; Piperidines; Vomiting

Casopitant, an inhibitor of the neurokinin-1 receptor, and its mesylate salt, are being developed by GlaxoSmithKline plc for the potential treatment of chemotherapy-induced nausea and vomiting (CINV), post-operative nausea and vomiting (PONV), as well as for anxiety, depression and insomnia. Phase II trials are ongoing for anxiety, depression and insomnia, and further results are awaited from phase III trials of CINV and PONV. At the time of publication, it was expected that applications to the FDA for regulatory approval for CINV and PONV would be filed in 2008. Casopitant was previously being developed for the treatment of overactive bladder; however, in September 2007, this indication was no longer listed on the company's product pipeline.

Topics: Animals; Antiemetics; Anxiety Disorders; Clinical Trials as Topic; Contraindications; Depressive Disorder, Major; Drug Evaluation, Preclinical; Female; Fibromyalgia; Humans; Nausea; Neurokinin-1 Receptor Antagonists; Patents as Topic; Piperazines; Piperidines; Postoperative Nausea and Vomiting; Structure-Activity Relationship; Urinary Bladder, Overactive; Vomiting

Remifentanil is a synthetic opioid that was developed in the early 1990s and introduced into clinical use in 1996. It is a methyl ester and is metabolised by nonspecific tissue and plasma esterases. Consequently, it is a drug that undergoes rapid elimination and has a reported terminal elimination half-life of between 10 and 35 minutes. Because there is no drug accumulation, the context-sensitive half-time remains constant; thus the pharmacokinetics of the drug do not change regardless of the duration of infusion. The organ-independent elimination of remifentanil, coupled with the fact that its clearance is greater in infants and neonates compared with older age groups, make its pharmacokinetic profile different from any other opioid. In addition, its unique metabolism confers predictability in its clinical use. Like other opioid mu receptor agonists, remifentanil provides dose-dependent analgesia, while the adverse effects of this drug, e.g. respiratory depression, are also thought to be dose related. The incidence of nausea and vomiting appear similar to other opioids. Its rapid and consistent metabolism regardless of duration of infusion has made remifentanil an attractive analgesic/anaesthetic option for paediatric care providers.

Topics: Analgesics, Opioid; Anesthesia, General; Anesthetics, Intravenous; Blood Pressure; Child; Heart Rate; Humans; Nausea; Piperidines; Remifentanil; Respiratory Insufficiency; Seizures; Vomiting

Alzheimer's disease is common, incurable and disabling. It is expected to grow dramatically in prevalence over the next 50 years. At current, the standard of care for patients with mild and moderately severe Alzheimer's disease includes the use of acetylcholinesterase inhibitors. Donepezil (Aricept) is a highly selective acetylcholinesterase inhibitors with a pharmacokinetic profile allowing once-daily dosing. There is an extensive knowledge base derived from published clinical trials of donepezil in Alzheimer's disease, revealing consistent efficacy in cognition, global clinical ratings and daily function. Donepezil is also associated with additional meaningful outcomes such as reduced risk for, or delay to, nursing home placement. Despite a sense of limited efficacy of this drug class among prescribers, number needed-to-treat analyses suggest donepezil is highly effective at reducing the long-term adverse outcomes associated with Alzheimer's disease.

Topics: Alzheimer Disease; Anorexia; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition Disorders; Dementia; Diarrhea; Donepezil; Drug Interactions; Humans; Indans; Nausea; Piperidines; Treatment Outcome; Vomiting

Lerisetron is a 5-hydroxytryptamine3 receptor antagonist under development by FAES Farma for the potential treatment of emesis resulting from chemotherapy. Phase I trials of lerisetron were underway in Spain by 1994, and as of June 2000, the compound was in phase II trials in the UK. By the end of 2001, phase II trials had been completed and phase III trials had commenced.

Topics: Animals; Antineoplastic Agents; Benzimidazoles; Clinical Trials as Topic; Drugs, Investigational; Humans; Piperidines; Technology, Pharmaceutical; Vomiting

Sumatriptan is a 5-HT1B/D receptor agonist of documented efficacy in relieving migraine and associated symptoms such as nausea and vomiting. In the past decade, several studies reported an important delay of gastric emptying induced by sumatriptan in healthy humans. The impact of this gastric motor effect of sumatriptan in migraineurs is difficult to predict: a further delay in gastric emptying could be detrimental (i.e. increased nausea and epigastric symptoms) in patients already having delayed gastric emptying. However, in patients with functional dyspepsia, sumatriptan is also reported to improve gastric accommodation to a meal and reduce perception of gastric distention, hence relieving epigastric symptoms. Thus, reduced visceral perception could be a mechanism involved in reducing nausea during a migraine attack. Paradoxically, sumatriptan is reported both to relieve the nausea of a migraine attack and to have nausea as a side effect. Although careful analysis of the time of onset of nausea may offer a clue as to the origin of this symptom, available data do not support definite conclusions, all the more so because the gastric motor effect of second-generation triptans are still unexplored. Taken together, the available evidence warrants further studies to clarify the following issues: first, the mechanism responsible for the gastric motor effect of sumatriptan [receptor subtype(s) involved; central vs peripheral mechanism]; secondly, the effects on gastric motility/visceral sensitivity of second-generation triptans (which are 5-HT1B/D receptor agonists) and more recent selective 5-HT1D receptor agonists (proposed as investigational antimigraine agents with less potential to induce coronary vasoconstriction through 5-HT1B receptors); finally, the possible use of drugs improving gastric accommodation to a meal in the management of those dyspeptic patients with impaired fundic relaxation/altered visceral sensitivity.

Topics: Forecasting; Gastrointestinal Motility; Humans; Indoles; Nausea; Piperidines; Serotonin Receptor Agonists; Sumatriptan; Tryptamines; Vomiting

Topics: Animals; Cisapride; Esophagus; Gastric Emptying; Gastroesophageal Reflux; Gastrointestinal Motility; Humans; Parasympathomimetics; Piperidines; Vomiting

Tepotinib is an oral, potent, highly selective MET inhibitor. This first-in-man phase I trial investigated the MTD of tepotinib to determine the recommended phase II dose (RP2D).. Patients received tepotinib orally according to one of three dose escalation regimens (R) on a 21-day cycle: R1, 30-400 mg once daily for 14 days; R2, 30-315 mg once daily 3 times/week; or R3, 300-1,400 mg once daily. After two cycles, treatment could continue in patients with stable disease until disease progression or unacceptable toxicity. The primary endpoint was incidence of dose-limiting toxicity (DLT) and treatment-emergent adverse events (TEAE). Secondary endpoints included safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor effects.. One hundred and forty-nine patients received tepotinib (R1:. Tepotinib was well tolerated with clinical activity in MET-dysregulated tumors. The RP2D of tepotinib was established as 500 mg once daily.

Topics: Adult; Aged; Aged, 80 and over; Dose-Response Relationship, Drug; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Nausea; Neoplasms; Patient Safety; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyridazines; Pyrimidines; Tissue Distribution; Treatment Outcome; Vomiting; Young Adult

Capromorelin is a ghrelin receptor agonist that is FDA approved for appetite stimulation in dogs. The objective of this study was to evaluate the safety of daily oral administration of capromorelin to cats over a range of doses and for an extended period. Two randomized, controlled studies were conducted: in Study 1, cats (n = 6 per group) received placebo or capromorelin at a dose of 9, 15, 30 or 60 mg/kg once daily for 14 days; and in Study 2, cats received capromorelin at 6 mg/kg (n = 8) or placebo (n = 4) once daily for 91 days. Cats were evaluated using clinical observations and clinical pathology test results for both studies, with the addition of postmortem examination in Study 1 and measurements of growth hormone and insulin-like growth factor 1 in Study 2. Abnormal clinical observations were limited to emesis, hypersalivation, lethargy/depression, head shaking and lip smacking, which occurred more frequently in the capromorelin-treated groups than in the placebo group. There were no clinically relevant differences in clinical pathology test results between the capromorelin and placebo groups in either study.

Topics: Administration, Oral; Animals; Cat Diseases; Cats; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Growth Hormone; Insulin-Like Growth Factor I; Lethargy; Male; Piperidines; Pyrazoles; Sialorrhea; Vomiting

This randomized, controlled, double-blind study was designed to determine the optimal dose of remifentanil for preventing complications associated with the removal of a laryngeal mask airway (LMA) without delaying emergence.. This study randomly assigned 128 patients to remifentanil effect-site concentrations (Ce) of 0 ng/mL (group R0), 0.5 ng/mL (group R0.5), 1.0 ng/mL (group R1.0), and 1.5 ng/mL (group R1.5) during emergence. The emergence and recovery profiles were recorded. Adverse events such as coughing, airway obstruction, breath-holding, agitation, desaturation, nausea, and vomiting were also evaluated.. The number of patients with respiratory complications such as coughing and breath-holding was significantly lower in the R1.0 and R1.5 groups than in the R0 group (p<0.05). Emergence agitation also decreased in the R1.0 and R1.5 groups (p<0.0083). The time to LMA removal was significantly longer in the R1.5 group than in the other groups (p<0.05).. Maintaining a remifentanil Ce of 1.0 ng/mL during emergence may suppress adverse events such as coughing, breath-holding, and agitation following the removal of LMA without delayed awakening.

Topics: Adult; Airway Management; Anesthesia Recovery Period; Anesthetics, Intravenous; Cough; Device Removal; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Infusions, Intravenous; Laryngeal Masks; Male; Middle Aged; Piperidines; Postoperative Complications; Psychomotor Agitation; Remifentanil; Vomiting

Breech presentation occurs in up to 3% of pregnancies at term and may be an indication for caesarean delivery. External cephalic version can be effective in repositioning the fetus in a cephalic presentation, but may be painful for the mother. Our aim was to assess the efficacy of remifentanil versus placebo for pain relief during external cephalic version.. A randomized, double-blind, controlled trial that included women at 36-41 weeks of gestation with non-cephalic presentations was performed. Women were randomized to receive either a remifentanil infusion at 0.1 μg/kg/min and demand boluses of 0.1 μg/kg, or saline placebo. The primary outcome was the numerical rating pain score (0-10) after external cephalic version.. Sixty women were recruited, 29 in the control group and 31 in the remifentanil group. There were significant differences in pain scores at the end of the procedure (control 6.5 ± 2.4 vs. remifentanil 4.7 ± 2.5, P = 0.005) but not 10 min later (P = 0.054). The overall success rate for external cephalic version was 49% with no significant differences between groups (remifentanil group 54.8% vs. control group 41.3%, P = 0.358). In the remifentanil group, there was one case of nausea and vomiting, one of drowsiness and three cases of fetal bradycardia. In the control group, there were three cases of nausea and vomiting, one of dizziness and nine cases of fetal bradycardia.. Intravenous remifentanil with bolus doses on demand during external cephalic version achieved a reduction in pain and increased maternal satisfaction. There were no additional adverse effects, and no difference in the success rate of external cephalic version or the incidence of fetal bradycardia.

Topics: Adult; Analgesia; Analgesics, Opioid; Bradycardia; Breech Presentation; Dizziness; Double-Blind Method; Female; Fetal Diseases; Humans; Nausea; Pain; Pain Management; Patient Satisfaction; Piperidines; Placebos; Pregnancy; Remifentanil; Treatment Outcome; Version, Fetal; Vomiting

The primary objective was to determine if a single dose of casopitant 90 mg added to ondansetron and dexamethasone would improve the control of chemotherapy-induced nausea and vomiting (CINV) over 0-120 h following initiation of oxaliplatin-based moderately emetic chemotherapy (MEC) compared to ondansetron and dexamethasone alone.. Patients with colorectal cancer received either casopitant or placebo intravenously (IV) added to ondansetron 8 mg bid oral on study days 1 to 3 and one dose of dexamethasone 8 mg IV given prior to starting the oxaliplatin on day 1. The primary endpoint was the percentage of subjects achieving complete response (CR; no vomiting/retching or use of rescue medication) during 120 h after initiation of chemotherapy in cycle 1.. No difference in the rate of CR was noted in the casopitant group compared to the placebo group for the overall (placebo 85%, casopitant 86%, p = 0.7273), acute (placebo 96%, casopitant 97%), or delayed phases (placebo 85%, casopitant 86%). The average area under curve (0-∞) of casopitant after a single 90-mg IV dose was 8,390 ng h/mL. At 24 h after casopitant 90-mg IV dosing, the plasma casopitant concentration was 24% lower than the values noted in prior studies with 150 mg oral administration, and the plasma exposure of the major metabolite (GSK525060) was 18% lower.. Addition of single-dose casopitant 90 mg IV did not improve the control of CINV at any time during 120 h following initiation of oxaliplatin-based MEC. Excellent control of CINV was achieved in this study population with the combination of ondansetron and dexamethasone alone.

Topics: Aged; Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Colorectal Neoplasms; Dexamethasone; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Nausea; Ondansetron; Organoplatinum Compounds; Oxaliplatin; Piperazines; Piperidines; Time Factors; Treatment Outcome; Vomiting

A randomized, placebo-controlled, double-blind study to evaluate the effect of intravenously (IV) administered acetaminophen on postoperative pain in children and adolescents undergoing surgery for idiopathic scoliosis or spondylolisthesis.. To evaluate effectiveness of IV-administered acetaminophen on postoperative analgesia, opioid consumption, and acetaminophen concentrations after major spine surgery in adolescents.. Scoliosis surgery is associated with severe postoperative pain, most commonly treated with IV-administered opioids. Nonsteroidal anti-inflammatory drugs (NSAIDs), as adjuvant to opioids, improve analgesia and reduce the need for opioids. However, by inhibiting cyclo-oxygenase enzymes peripherally, NSAIDs may inhibit bone healing. Acetaminophen, a centrally acting analgesic, does not have the adverse effects of NSAIDs and has improved analgesia in children after another orthopedic surgery.. In an institutional review board approved study, 36 American Society of Anesthesiology patient classification I to III patients of 10 to 18 years of age were analyzed. Acetaminophen 30 mg/kg, administered IV or 0.9% NaCl was administered at the end of scoliosis or spondylolisthesis surgery, and thereafter twice at 8-hour intervals. Timed blood samples for acetaminophen determination were taken between 0.25 and 20 hours after the first dose. All patients received standard propofol-remifentanil anesthesia. Pain scores (visual analogue scale [VAS], 0-10), opioid consumption, and adverse effects were recorded.. In the surgical ward, 7 (39%) patients in the acetaminophen and 13 (72%) in the placebo group had a VAS pain score 6 or more (P < 0.05). There were fewer hours with VAS score 6 or more in the acetaminophen group compared with the placebo group (8.7% vs. 17.8% of the hours, P < 0.05). There was no difference in oxycodone consumption during the 24-hour follow-up between the 2 groups.. IV-administered acetaminophen 90 mg/kg/day, adjuvant to oxycodone, did improve analgesia, but did not diminish oxycodone consumption during 24 hours after major spine surgery in children and adolescents. All acetaminophen concentrations were in nontoxic levels.

Topics: Acetaminophen; Administration, Intravenous; Adolescent; Analgesics, Non-Narcotic; Analgesics, Opioid; Child; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Male; Nausea; Oxycodone; Pain, Postoperative; Piperidines; Propofol; Remifentanil; Scoliosis; Spinal Diseases; Spondylolisthesis; Treatment Outcome; Vomiting

Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare, fatal, segmental premature aging syndrome caused by a mutation in LMNA that produces the farnesylated aberrant lamin A protein, progerin. This multisystem disorder causes failure to thrive and accelerated atherosclerosis leading to early death. Farnesyltransferase inhibitors have ameliorated disease phenotypes in preclinical studies. Twenty-five patients with HGPS received the farnesyltransferase inhibitor lonafarnib for a minimum of 2 y. Primary outcome success was predefined as a 50% increase over pretherapy in estimated annual rate of weight gain, or change from pretherapy weight loss to statistically significant on-study weight gain. Nine patients experienced a ≥50% increase, six experienced a ≥50% decrease, and 10 remained stable with respect to rate of weight gain. Secondary outcomes included decreases in arterial pulse wave velocity and carotid artery echodensity and increases in skeletal rigidity and sensorineural hearing within patient subgroups. All patients improved in one or more of these outcomes. Results from this clinical treatment trial for children with HGPS provide preliminary evidence that lonafarnib may improve vascular stiffness, bone structure, and audiological status.

Topics: Adolescent; Carotid Arteries; Child; Child, Preschool; Diarrhea; Dose-Response Relationship, Drug; Drug Administration Schedule; Enzyme Inhibitors; Farnesyltranstransferase; Fatigue; Female; Humans; Male; Piperidines; Progeria; Pulse Wave Analysis; Pyridines; Treatment Outcome; Vomiting; Weight Gain

Rising life expectancies coupled with an increasing awareness of age-related cognitive decline have led to the unwarranted use of psychopharmaceuticals, including acetylcholinesterase inhibitors (AChEIs), by significant numbers of healthy older individuals. This trend has developed despite very limited data regarding the effectiveness of such drugs on non-clinical groups and recent work indicates that AChEIs can have negative cognitive effects in healthy populations. For the first time, we use a combination of EEG and simultaneous EEG/fMRI to examine the effects of a commonly prescribed AChEI (donepezil) on cognition in healthy older participants. The short- and long-term impact of donepezil was assessed using two double-blind, placebo-controlled trials. In both cases, we utilised cognitive (paired associates learning (CPAL)) and electrophysiological measures (resting EEG power) that have demonstrated high-sensitivity to age-related cognitive decline. Experiment 1 tested the effects of 5 mg/per day dosage on cognitive and EEG markers at 6-hour, 2-week and 4-week follow-ups. In experiment 2, the same markers were further scrutinised using simultaneous EEG/fMRI after a single 5 mg dose. Experiment 1 found significant negative effects of donepezil on CPAL and resting Alpha and Beta band power. Experiment 2 replicated these results and found additional drug-related increases in the Delta band. EEG/fMRI analyses revealed that these oscillatory differences were associated with activity differences in the left hippocampus (Delta), right frontal-parietal network (Alpha), and default-mode network (Beta). We demonstrate the utility of simple cognitive and EEG measures in evaluating drug responses after acute and chronic donepezil administration. The presentation of previously established markers of age-related cognitive decline indicates that AChEIs can impair cognitive function in healthy older individuals. To our knowledge this is the first study to identify the precise neuroanatomical origins of EEG drug markers using simultaneous EEG/fMRI. The results of this study may be useful for evaluating novel drugs for cognitive enhancement.

Topics: Aged; Analysis of Variance; Cholinesterase Inhibitors; Cognition; Cross-Over Studies; Diarrhea; Donepezil; Double-Blind Method; Electroencephalography; Female; Hippocampus; Humans; Indans; Magnetic Resonance Imaging; Male; Memory; Middle Aged; Nausea; Piperidines; Vomiting

Depletion of cellular nicotinamide adenine dinucleotide (NAD) by inhibition of its synthesis is a new pharmacological principle for cancer treatment currently in early phases of clinical development. We present new and previously published data on the safety and efficacy of these drugs based on early clinical trials.. A phase I clinical trial of CHS 828 in patients with advanced solid tumours was performed. Published clinical trials on NAD depleting drugs for cancer treatment were summarised for safety and efficacy.. Seven patients with previously treated solid tumours received oral administration of CHS 828 in the dose range 20-80 mg once weekly for 3 weeks in 4 weeks cycles. Toxicity was dominated by gastrointestinal symptoms including nausea, vomiting, diarrhoea, constipation, subileus and gastric ulcer. One patient had thrombocytopenia grade 2. There were two cases each of grade 3-4 hyperuricemia and hypokalemia. Safety and efficacy of the NAD depleting drugs CHS 828 and FK866 have been reported from four phase I clinical trials, including a total of 97 patients with previously treated solid tumours. Outstanding toxicity reported was thrombocytopenia and various gastrointestinal symptoms. No objective tumour remission has been observed in the total of 104 patients treated in the above early trials.. Critical toxicity from NAD depleting cancer drugs to consider in future trials seems to be thrombocytopenia and various gastrointestinal symptoms. Efficacy of NAD depleting drugs when used alone is expected to be low.

Topics: Acrylamides; Aged; Clinical Trials, Phase I as Topic; Cyanides; Dose-Response Relationship, Drug; Drug Administration Schedule; Fatigue; Female; Guanidines; Humans; Male; Meta-Analysis as Topic; Middle Aged; NAD; Nausea; Neoplasms; Nicotinamide Phosphoribosyltransferase; Piperidines; Thrombocytopenia; Treatment Outcome; Vomiting

The control of chemotherapy-induced nausea and vomiting (CINV) is critical in preventing poor health outcomes and increasing patient quality of life. The objective of this study was to evaluate the impact of the addition of casopitant to dual-combination therapy of dexamethasone and ondansetron on quality of life in patients receiving highly emetogenic chemotherapy (HEC).. In a multicenter, double-blind, randomized, placebo-controlled, add-on trial (N = 810), patients were randomized to intravenous (IV) ondansetron/dexamethasone alone (control) or in combination with either a single 150-mg oral dose of casopitant or 3-day IV/oral casopitant. Quality of life was assessed as impact of nausea and vomiting on daily life using the Functional Living Index Emesis (FLIE) questionnaire. Patients completed the FLIE questionnaire at baseline prior to receiving chemotherapy and after completion of the first cycle of HEC.. Patients in the single oral dose and 3-day IV/oral casopitant groups scored higher mean total FLIE scores (115.7 and 114.0, respectively; p ≤ 0.0332) than patients in the control group (107.5), indicating that casopitant patients experienced less impact from nausea and vomiting on daily life. The overall absolute difference in the proportion of patients reporting CINV with no impact on daily life between the single oral casopitant group and the control group was 13%; the difference between the 3-day IV/oral casopitant group and the control group was 14%.. The addition of casopitant to ondansetron and dexamethasone in patients receiving HEC was significantly more effective in reducing the impact of nausea and vomiting on all daily life activities as assessed by the FLIE compared with ondansetron/dexamethasone dual therapy.

Topics: Activities of Daily Living; Administration, Oral; Adult; Aged; Aged, 80 and over; Antiemetics; Antineoplastic Agents; Dexamethasone; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Nausea; Neoplasms; Ondansetron; Piperazines; Piperidines; Quality of Life; Surveys and Questionnaires; Vomiting; Young Adult

Drug rechallenge (or reinitiation), following an event of drug-induced liver injury, is associated with 13% mortality in prospective series. Rechallenge generally results in much more rapid injury than the initial liver event. The neurokinin-1 antagonist casopitant or its placebo was administered cyclically with ondansetron and dexamethasone in two randomized chemotherapy-induced nausea and vomiting clinical trials in nearly 3000 subjects. Grade 3 ALT elevations were observed in up to 2% of subjects receiving casopitant or placebo treatment. Similar rates of positive rechallenge were observed in the casopitant 8/29 (28%) and placebo groups 2/8 (25%), with no Grade 4 ALT elevations, hypersensitivity or liver-related serious adverse events. Publishing available rechallenge data (positive and negative) will advance our clinical understanding. Rechallenge should only be considered when the potential drug benefit exceeds the risk.

Topics: Administration, Oral; Antiemetics; Antineoplastic Agents; Dexamethasone; Dose-Response Relationship, Drug; Female; Humans; Male; Nausea; Neurokinin-1 Receptor Antagonists; Ondansetron; Piperazines; Piperidines; Serotonin Antagonists; Vomiting

The objective of this 10-week, randomized, double-blind, placebo-controlled multicenter study was to assess the efficacy and safety of donepezil for the treatment of cognitive dysfunction exhibited by children with Down syndrome (DS). Intervention comprised donepezil (2.5-10 mg/day) in children (aged 10-17 years) with DS of mild-to-moderate severity. The primary measures were the Vineland-II Adaptive Behavior Scales (VABS-II) Parent/Caregiver Rating Form (PCRF) the sum of nine subdomain standardized scores and standard safety measures. Secondary measures included the VABS-II/PCRF scores on the following domains and their respective individual subdomains: Communication (receptive, expressive, and written); Daily Living Skills (personal, domestic, and community); Socialization (interpersonal relationships, play and leisure time, and coping skills), and scores on the Test of Verbal Expression and Reasoning, a subject-performance-based measure of expressive language. At baseline, 129 participants were assigned treatment with donepezil or placebo. During the double-blind phase, VABS II/PCRF sum of the nine subdomain standardized scores, called v-scores, improved significantly from baseline in both groups (P < 0.0001), with no significant between-group differences. This trial failed to demonstrate any benefit for donepezil versus placebo in children and adolescents with DS, although donepezil appeared to be well tolerated.

Topics: Adolescent; Behavior; Caregivers; Child; Cholinesterase Inhibitors; Cognition Disorders; Diarrhea; Donepezil; Dose-Response Relationship, Drug; Double-Blind Method; Down Syndrome; Drug Tolerance; Female; Humans; Indans; Learning; Male; Neuropsychological Tests; Piperidines; Severity of Illness Index; Vomiting

Pharmacokinetic interactions between casopitant (a substrate and weak to moderate inhibitor of CYP3A), dexamethasone (a substrate and weak inducer of CYP3A), and ondansetron (a mixed CYP substrate) were evaluated in a two-part, three-period, single-sequence study in two groups of healthy subjects.. Part 1: subjects received oral casopitant (regimen A); oral dexamethasone and IV ondansetron (regimen B); and oral casopitant, a reduced dose of oral dexamethasone, and IV ondansetron (regimen C). Part 2: subjects received oral casopitant (regimen D); IV dexamethasone and oral ondansetron (regimen E); and oral casopitant, IV dexamethasone, and oral ondansetron (regimen F). Each regimen was separated by 14 days.. Casopitant AUC in regimen C was increased 28% on day 1 but decreased 34% on day 3 compared to casopitant alone in regimen A. When given with casopitant and ondansetron in regimen C, dexamethasone AUC was 17% lower on day 1, but similar on day 3, compared to regimen B (representing dose-normalized increases in exposure of 39% and 108%, respectively). Ondansetron exposure was equivalent in regimens B and C. Casopitant AUC in regimen F was similar to regimen D on days 1 and 3. Dexamethasone AUC increased 21% when given with oral casopitant and oral ondansetron (regimen F compared to regimen E). Ondansetron exposure was equivalent in regimens E and F.. When repeat-dose oral dexamethasone is to be coadministered with oral casopitant, a reduction in dexamethasone dose may be considered; however, no change in casopitant dose is required. Ondansetron exposure was not affected by coadministration with casopitant.

Topics: Adolescent; Adult; Antiemetics; Dexamethasone; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Nausea; Neurokinin-1 Receptor Antagonists; Ondansetron; Piperazines; Piperidines; Vomiting; Young Adult

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

Chemotherapy-induced nausea and vomiting (CINV) remains a clinical management problem after treatment with highly emetogenic chemotherapy (HEC). We therefore designed and carried out a multicentre, randomised, double-blind, placebo-controlled trial to assess whether a three-drug antiemetic regimen of ondansetron, dexamethasone, and the neurokinin-1-receptor antagonist casopitant mesylate was able to prevent acute and delayed CINV events in patients naive to chemotherapy with a malignant solid tumour who were scheduled to receive cisplatin-based HEC regimens.. The study was done between Nov 6, 2006, and Oct 9, 2007, in 77 participating centres in 22 countries. All 810 patients enrolled in the trial received dexamethasone and ondansetron. Patients were randomly assigned to also receive placebo (n=269), single oral dose of casopitant mesylate (150 mg oral, n=271), or 3-day intravenous plus oral casopitant mesylate (90 mg intravenous on day 1 plus 50 mg oral on days 2 and 3, n=270). Randomisation was done using a central telephone system at the study level, because some centres were expected to recruit only a few patients during the study period. The primary endpoint was the proportion of patients achieving complete response (no vomiting, retching, or use of rescue medications) in the first 120 h after receiving HEC. Efficacy analysis was done on the modified intention-to-treat population (n=800), which included all patients who received placebo or study drug and HEC (n=265 control, n=266 single-dose oral casopitant mesylate, n=269 3-day intravenous and oral casopitant mesylate). Safety was reported in 802 patients who received either placebo or study medication. This study is registered with ClinicalTrials.gov, NCT00431236.. Significantly more patients in each casopitant group achieved complete response in cycle 1 of HEC treatment than did those in the control group (175 [66%] patients in the control group, 228 [86%] in the single-dose oral casopitant mesylate group [p<0.0001 vs control], and 214 [80%] in the 3-day intravenous plus oral casopitant mesylate group (p=0.0004 vs control]). This improvement was sustained over multiple cycles of HEC. Adverse events occurred in 205 (77%) patients in the single-dose oral casopitant mesylate group and 203 (75%) patients in the 3-day intravenous and oral casopitant mesylate group compared with 194 (73%) of patients in the control group. The most common serious adverse events were neutropenia (n=5 [3%] in the control group, n=3 [1%] in the single-dose oral casopitant mesylate group, and n=11 [4%] in the 3-day intravenous plus oral casopitant mesylate group), febrile neutropenia (n=1 [<1%] in the control group, n=4 [1%] in the single-dose oral casopitant mesylate group, and n=6 [2%] in the 3-day intravenous plus oral casopitant mesylate group), and dehydration (n=4 [2%] in the control group, n=2 [<1%] in the single-dose oral casopitant mesylate group, and n=1 [<1%] in the 3-day intravenous plus oral casopitant mesylate group).. A three-drug regimen including a single oral dose or 3-day intravenous plus oral regimen of casopitant mesylate plus dexamethasone and ondansetron significantly reduced CINV events in patients receiving HEC compared with a two-drug regimen of dexamethasone and ondansetron.. GlaxoSmithKline.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Antiemetics; Antineoplastic Agents; Cisplatin; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Infusion Pumps; Male; Middle Aged; Molecular Structure; Nausea; Neoplasms; Neurokinin-1 Receptor Antagonists; Piperazines; Piperidines; Vomiting; Young Adult

Casopitant mesylate is a novel, oral neurokinin-1 receptor antagonist with demonstrated antiemetic efficacy. We conducted a randomized, double-blind, controlled phase II trial to evaluate three casopitant doses as part of a triple-therapy regimen for the prevention of nausea and vomiting associated with high-dose cisplatin. The aim of the study was to detect a dose response.. A total of 493 patients with solid tumors receiving a first cycle of cisplatin > or =70 mg/m(2) were randomly assigned among six treatment arms. The primary analysis compared a control arm [ondansetron/dexamethasone (Ond/Dex)] with three investigational treatments (Ond/Dex plus oral casopitant 50, 100, or 150 mg administered daily for 3 days). Two exploratory arms were included: one evaluating a single oral casopitant dose of 150 mg added to standard Ond/Dex and another with 3-day oral aprepitant-based therapy (Ond/Dex plus aprepitant 125 mg day 1, 80 mg days 2-3).. The complete response (CR) rate (defined as no vomiting, retching, rescue therapy, or premature discontinuation) was significantly increased in each casopitant arm relative to control over the 120-h evaluation period: 76% (50 mg), 86% (100 mg), 77% (150 mg), and 60% with control (P = 0.0036). The CR rate for the single oral dose regimen was similar to the CR rate reported for the 3-day regimens. No differences were observed in the incidence of nausea or significant nausea among groups in the primary analysis. The most common adverse events related to treatment included headache (n = 10) and hiccups (n = 14).. All doses of oral casopitant as a 3-day regimen (and likely as a 150-mg single oral dose) in combination with Ond/Dex provided significant improvement in the prevention of cisplatin-induced emesis.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antiemetics; Antineoplastic Agents; Cisplatin; Dexamethasone; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Nausea; Neoplasms; Neurokinin-1 Receptor Antagonists; Ondansetron; Piperazines; Piperidines; Receptors, Neurokinin-1; Vomiting

The purpose of this phase III trial was to evaluate the efficacy and safety of regimens containing casopitant, a novel neurokinin-1 receptor antagonist, for the prevention of chemotherapy-induced nausea and vomiting during the first cycle in patients receiving moderately emetogenic chemotherapy (MEC).. Predominantly female patients (98%) diagnosed with breast cancer (96%) who were chemotherapy-naïve and scheduled to receive an anthracycline and cyclophosphamide (AC) -based regimen were enrolled onto this multinational, randomized, double-blind, parallel-group, placebo-controlled clinical trial. All patients received dexamethasone 8 mg intravenously (IV) on day 1 and oral ondansetron 8 mg twice daily on days 1 to 3. Patients were randomly assigned to a control arm (placebo), a single oral dose casopitant arm (150 mg orally [PO] on day 1), a 3-day oral casopitant arm (150 mg PO on day 1 plus 50 mg PO on days 2 to 3), or a 3-day IV/oral casopitant arm (90 mg IV on day 1 plus 50 mg PO on days 2 to 3). The primary end point was the proportion of patients achieving complete response (no vomiting/retching or rescue medications) in the first 120 hours after the initiation of MEC.. A significantly greater proportion of patients in the single-dose oral casopitant arm, 3-day oral casopitant arm, and 3-day IV/oral casopitant arm achieved complete response (73%, 73%, and 74%, respectively) versus control (59%; P < .0001). The study did not demonstrate a reduced proportion of patients with nausea or significant nausea in those receiving casopitant. Adverse events were balanced among study arms.. All casopitant regimens studied were more effective than the control regimen. Casopitant was generally well tolerated.

Topics: Administration, Oral; Alopecia; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Constipation; Cyclophosphamide; Dexamethasone; Double-Blind Method; Drug Therapy, Combination; Female; Headache; Humans; Injections, Intravenous; Kaplan-Meier Estimate; Male; Middle Aged; Nausea; Neoplasms; Neurokinin-1 Receptor Antagonists; Neutropenia; Ondansetron; Piperazines; Piperidines; Treatment Outcome; Vomiting

This randomized, double-blind, dose-ranging, placebo-controlled, phase 2 trial evaluated the neurokinin-1 receptor antagonist casopitant mesylate in combination with ondansetron/dexamethasone (ond/dex) for the prevention of chemotherapy-induced nausea and vomiting (CINV) related to moderately emetogenic chemotherapy (MEC).. Chemotherapy-naive patients who were receiving MEC (N=723) were randomized to receive either oral placebo or casopitant at doses of 50 mg, 100 mg, or 150 mg daily (on Days 1-3) plus ondansetron (on Days 1-3) and dexamethasone (Day 1). Two exploratory arms evaluated single-dose casopitant (150 mg) plus ond/dex and a 3-day casopitant regimen with once-daily ondansetron and dexamethasone. Primary endpoints were rates of complete response (CR) (no vomiting, retching, rescue therapy, or premature discontinuation) and significant nausea (SN) (>or=25 mm on a visual analog scale) over the first 120 hours after Cycle 1 of MEC. Secondary endpoints included acute and delayed CR and SN rates, rates of nausea, vomiting, and safety.. All casopitant doses that were tested significantly increased the proportion of patients with CR: The CR rates were 80.8% with casopitant 50 mg, 78.5% with casopitant 100 mg, and 84.2% with casopitant 150 mg compared with 69.4% in the control group (P=.0127); casopitant 150 mg was identified as the minimally effective dose. In exploratory analyses, single-dose casopitant demonstrated a 79.2% CR rate, and once-daily ondansetron plus casopitant produced an 83.5% CR rate. Vomiting rates in the first 5 days after MEC were reduced with casopitant-containing regimens (from 23% to 10%-16%). Rates of SN did not differ among treatment arms (range, 28%-29%). Casopitant appeared to be well tolerated with no notable differences in overall adverse event frequency.. Casopitant plus ond/dex was more effective than ond/dex alone for the prevention of CINV.

Topics: Adult; Aged; Aged, 80 and over; Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Nausea; Neurokinin-1 Receptor Antagonists; Ondansetron; Piperazines; Piperidines; Vomiting

Rapidly acting narcotics enhance the degree of bradycardia due to the oculocardiac reflex (OCR) elicited by extraocular muscle (EOM) tension during strabismus surgery. We evaluated and compared the effects of remifentanil and sevoflurane on OCR during paediatric strabismus surgery.. One hundred and twenty children, 1-9 years old, undergoing elective strabismus surgery, were randomly assigned to receive sevoflurane or remifentanil. No anticholinergic prophylaxis was administered. Anaesthesia was induced using ketamine 1.0 mg/kg or midazolam 0.15 mg/kg with 66% N(2)O in O(2). Laryngeal mask airways were placed with rocuronium 0.5 mg/kg. Anaesthesia was maintained with sevoflurane 2.0-3.0 vol% with 66% N(2)O in O(2) or remifentanil 0.75 mug/kg over 1 min and followed by the continuous infusion of remifentanil 0.5 mug/kg/min with 66% N(2)O in O(2). Heart rate (HR) and blood pressure (BP) were measured and compared. OCR was defined as a reduction in HR of >20% induced by traction of an EOM.. During anaesthesia, HR and BP were maintained at a lower level in the remifentanil group than in the sevoflurane group (each, P<0.05). The mean percent change in HR (-23.3+/-17.0% vs. -11.2+/-13.0%; P<0.05) and the incidence of OCR (58.3% vs. 28.3%; P<0.05) following traction of an EOM were higher in the remifentanil group than in the sevoflurane group.. Remifentanil enhanced the degree of bradycardia due to OCR as compared with sevoflurane during paediatric strabismus surgery.

Topics: Anesthesia; Blood Pressure; Child; Child, Preschool; Female; Heart Rate; Humans; Infant; Male; Midazolam; Nausea; Piperidines; Reflex, Oculocardiac; Remifentanil; Strabismus; Vomiting

FK866 is a potent inhibitor or NAD synthesis. This first-in-human study was performed to determine the maximum-tolerated dose, toxicity profile, and pharmacokinetics on a 96-h continuous infusion schedule.. Twenty four patients with advanced solid tumor malignancies refractory to standard therapies were treated with escalating doses of FK866 as a continuous, 96-h infusion given every 28 days. Serial plasma samples were collected to characterize the pharmacokinetics of FK866. Further blood samples were collected for the measurement of plasma VEGF levels.. There were 12 women and 12 men with a median age of 61 (range 34-78) and a median KPS of 80%, received a 4-day of infusion of FK866 at dose levels of 0.018 mg/m2/h (n=3), 0.036 mg/m2/h (n=3), 0.072 mg/m2/h (n=3), 0.108 mg/m2/h (n=4), 0.126 mg/m2/h (n=6), and 0.144 mg/m2/h (n=5). Thrombocytopenia was the dose limiting toxicity, observed in two patients at the highest dose level and one patient at the recommended phase II dose of 0.126 mg/m2/h No other hematologic toxicities were noted other than mild lymphopenia and anemia. There was mild fatigue and grade 3 nausea; the latter was controlled with antiemetics and was not a DLT. Css (the mean of the 72 and 96 h plasma concentrations) increased in relation to the dose escalation. The study drug did not significantly affect plasma concentrations of VEGF. There were no objective responses, although four patients had stable disease (on treatment for 3 months or greater).. The recommended phase II dose is 0.126 mg/m2/h given as a continuous 96-h infusion every 28 days. The dose limiting toxicity of FK866 is thrombocytopenia. Pharmacokinetic data suggest an increase in the plasma Css in relation to the escalation of FK866.

Topics: Acrylamides; Adult; Aged; Area Under Curve; Dose-Response Relationship, Drug; Fatigue; Female; Half-Life; Humans; Infusions, Intravenous; Male; Middle Aged; NAD; Nausea; Neoplasms; Neutropenia; Nicotinamide Phosphoribosyltransferase; Piperidines; Thrombocytopenia; Vascular Endothelial Growth Factor A; Vomiting

This phase I study was conducted to evaluate the safety, tolerability, pharmacological properties and biological activity of the combination of the lonafarnib, a farnesylproteintransferase (FTPase) inhibitor, with gemcitabine and cisplatin in patients with advanced solid malignancies.. This was a single institution study to determine the maximal tolerated dose (MTD) of escalating lonafarnib (75-125 mg po BID) with gemcitabine (750-1,000 mg/m(2) on days 1, 8, 15) and fixed cisplatin (75 mg/m(2) day 1) every 28 days. Due to dose-limiting toxicities (DLTs) of neutropenia and thrombocytopenia in initial patients, these patients were considered "heavily pre-treated" and the protocol was amended to limit prior therapy and re-escalate lonafarnib in "less heavily pre-treated patients" on 28-day and 21-day schedules. Cycle 1 and 2 pharmacokinetics (PK), and farnesylation of the HDJ2 chaperone protein and FPTase activity were analyzed.. Twenty-two patients received 53 courses of therapy. Nausea, vomiting, and fatigue were frequent in all patients. Severe toxicities were observed in 91% of patients: neutropenia (41%), nausea (36%), thrombocytopenia (32%), anemia (23%) and vomiting (23%). Nine patients withdrew from the study due to toxicity. DLTs of neutropenia, febrile neutropenia, thrombocytopenia, and fatigue limited dose-escalation on the 28-day schedule. The MTD was established as lonafarnib 75 mg BID, gemcitabine 750 mg/m(2) days 1, 8, 15, and cisplatin 75 mg/m(2) in heavily pre-treated patients. The MTD in the less heavily pre-treated patients could not be established on the 28-day schedule as DLTs were observed at the lowest dose level, and dose escalation was not completed on the 21-day schedule due to early study termination by the Sponsor. No PK interactions were observed. FTPase inhibition was not observed at the MTD, however HDJ-2 gel shift was observed in one patient at the 100 mg BID lonafarnib dose. Anti-cancer activity was observed: four patients had stable disease lasting >2 cycles, one subject had a complete response, and another had a partial response, both with metastatic breast cancer.. Lonafarnib 75 mg BID, gemcitabine 750 mg/m(2) days 1, 8, 15, and cisplatin 75 mg/m(2) day 1 on a 28-day schedule was established as the MTD. Lonafarnib did not demonstrate FTPase inhibition at these doses. Despite the observed efficacy, substantial toxicity and questionable contribution of anti-tumor activity of lonafarnib to gemcitabine and cisplatin limits further exploration of this combination.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Deoxycytidine; Dose-Response Relationship, Drug; Farnesyltranstransferase; Fatigue; Female; Gemcitabine; HSP40 Heat-Shock Proteins; Humans; Male; Maximum Tolerated Dose; Middle Aged; Nausea; Piperidines; Pyridines; Treatment Outcome; Vomiting

Lonafarnib is an orally bioavailable nonpetidomimetic farnesyl transferase inhibitor with significant activity against BCR-ABL-positive cell lines and primary human chronic myeloid leukemia (CML) cells. Lonafarnib can inhibit the proliferation of imatinib-resistant cells and increases imatinib-induced apoptosis in vitro in cells from imatinib-resistant patients.. The authors conducted a phase 1 study of lonafarnib in combination with imatinib in patients with CML who failed imatinib therapy. The starting dose level for patients with chronic phase (CP) disease was imatinib, 400 mg/day, plus lonafarnib at a dose of 100 mg twice daily. The starting dose levels for accelerated phase (AP) and blast phase (BP) disease were 600 mg/day and 100 mg twice daily, respectively.. A total of 23 patients were treated (9 with CP, 11 with AP, and 3 with BP) for a median of 25 weeks (range, 4-102 weeks). Of those with CP disease, 2 patients had grade 3 (according to the National Cancer Institute Common Toxicity Criteria [version 2.0]) dose-limiting toxicities (DLTs) at the 400 + 125-mg dose, including diarrhea (2 patients), vomiting (1 patient), and fatigue (1 patient). In patients with AP/BP disease, DLTs were observed at the 600 + 125-mg dose and was comprised of diarrhea (1 patient) and hypokalemia (1 patient). Eight patients (35%) responded; 3 with CP disease achieved a complete hematologic response (CHR) (2 patients) and a complete cytogenetic response (1 patient). Three patients with AP disease responded (2 CHR, 1 partial cytogenetic response), and 2 patients with BP disease demonstrated hematologic improvement. Pharmacokinetics data suggest no apparent increase in exposure or changes in the pharmacokinetics of either lonafarnib or imatinib when they are coadministered.. The results of the current study indicate that the combination of lonafarnib and imatinib is well tolerated and the maximum tolerated dose of lonafarnib is 100 mg twice daily when combined with imatinib at a dose of either 400 mg or 600 mg daily.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Diarrhea; Dose-Response Relationship, Drug; Drug Administration Schedule; Fatigue; Female; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Piperazines; Piperidines; Pyridines; Pyrimidines; Treatment Failure; Treatment Outcome; Vomiting

Halofuginone (tempostatin) is a synthetic derivative of a quinazolinone alkaloid showing anti-angiogenic, anti-metastatic and anti-proliferative effects in preclinical studies. The objectives of this phase I study were to assess the dose-limiting toxicities (DLTs), to determine the maximum tolerated dose (MTD) and to study the pharmacokinetics (PKs) of halofuginone when administered once or twice daily orally to patients with advanced solid tumours.. Patients were treated with escalating doses of halofuginone at doses ranging from 0.5 to 3.5 mg/day. For pharmacokinetic analysis plasma sampling was performed during the first and second course and assayed using a validated high-performance liquid chromatographic assay with mass spectrometric detection.. Twenty-four patients received a total of 106 courses. The 'acute' MTD was reached at 3.5 mg/day, with nausea, vomiting, and fatigue as DLT. The recommended dose for chronic administration was defined as 0.5mg/day with the requirement of 5HT3 antagonists to control nausea and vomiting considered as DLT. Several patients experienced bleeding complications on treatment with halofuginone in which a causal relationship could not be excluded. The PKs of halofuginone were linear over the dose range studied with a large interpatient variability.. In this study the DLT of halofuginone was nausea, vomiting, and fatigue. The recommended dose for phase II studies of halofuginone is 0.5mg administered orally, once daily.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Fatigue; Humans; Maximum Tolerated Dose; Middle Aged; Nausea; Neoplasms; Piperidines; Quinazolines; Quinazolinones; Vomiting

Target-controlled infusions (TCIs) of remifentanil and fentanyl in conscious sedation regimes for extra-corporeal shock-wave lithotripsy have not been reported. We estimated the effect site concentrations of remifentanil and fentanyl needed to obtain adequate analgesia in 50% of patients (EC50) and compared both drugs in terms of intra- and post-procedure complications.. Forty-four adult patients were randomly distributed into two groups: Group R received remifentanil and Group F received fentanyl TCI with initial effect site concentrations of 1.5 and 2 ng mL(-1), respectively. Pain was assessed using a 10-point verbal analogue scale and <3 was considered adequate analgesia. Increments or decrements of 0.5 ng mL(-1) were then introduced for subsequent patients according to Dixon's up and down method. During the rest of the procedure, TCI was adjusted to maintain verbal analogue scale <3.. Remifentanil and fentanyl EC50 were 2.8 ng mL(-1) (95% confidence interval (CI): 1.8-3.7 ng mL(-1)) and 2.9 ng mL(-1) (95% CI: 1.7-4.1 ng mL(-1)), respectively (n.s.). At EC50, the probability of having a respiratory rate <10 was 4% (95% CI: 0-57%) for remifentanil and 56% (95% CI: 13-92%) for fentanyl. Hypoxaemia, vomiting and sedation were more frequent in Group F during and after the procedure (P < 0.05).. A similar EC50 but more respiratory depression, sedation and PONV were found with fentanyl TCI than with remifentanil TCI.

Topics: Adolescent; Adult; Analgesics, Opioid; Conscious Sedation; Drug Delivery Systems; Female; Fentanyl; Humans; Hypoxia; Infusions, Intravenous; Lithotripsy; Male; Middle Aged; Pain; Pain Measurement; Piperidines; Remifentanil; Respiratory Function Tests; Vomiting

To test the activity of the cyclin dependent kinase (cdk) inhibitor flavopiridol in malignant melanoma, a disease with frequent abnormalities of the cyclin dependent kinase system.. Patients had histologically proven, unidimensionally measurable malignant melanoma, incurable by standard therapy. Prior adjuvant immunotherapy was allowed, but patients were otherwise untreated for advanced disease. Flavopiridol was administered at a dose of 50 mg/m(2) IV over 1 hour daily x 3 days every 3 weeks. Patients were assessed for response every 2 cycles.. 17 patients were accrued over 5 months. No objective responses were documented in the 16 patients evaluable for response. Seven patients (44%) had stable disease after 2 cycles, with a median of 2.8 months (range 1.8-9.2). The most common treatment-related non-hematologic toxicities were diarrhea (82%), nausea (47%), fatigue (41%), anorexia (35%) and vomiting (29%). Most treatment-related toxicities were mild, except for diarrhea (grade 3 in 3 patients, grade 4 in 1 patient), nausea (grade 3 in 1 patient) and tumor pain (grade 3 in 1 patient). Hematologic toxicities were minimal, none worse than grade 2. Eighty-eight percent of patients received >/=90% planned dose intensity; 2 patients had dose reductions for gastrointestinal (GI) toxicity.. Flavopiridol is well tolerated at the dose regimen used in this study, with an acceptable (primarily GI) toxicity profile. Although 7 of the 16 patients had stable disease ranging from 1.8 to 9.2 months in duration, there was no evidence of significant clinical activity in malignant melanoma by objective response criteria.

Topics: Adult; Aged; Anorexia; Antineoplastic Agents; Cyclin-Dependent Kinases; Diarrhea; Fatigue; Female; Flavonoids; Humans; Infusions, Intravenous; Male; Maximum Tolerated Dose; Melanoma; Middle Aged; Neoplasm Metastasis; Piperidines; Treatment Outcome; Vomiting

Posture has an effect on gastric emptying. In this study, we investigated whether posture influences the delay in gastric emptying induced by opioid analgesics. Ten healthy male subjects underwent 4 gastric emptying studies with the acetaminophen method. On two occasions the subjects were given a continuous infusion of remifentanil (0.2 microg. kg(-1). min(-1)) while lying either on the right lateral side in a 20 degrees head-up position or on the left lateral side in a 20 degrees head-down position. On two other occasions no infusion was given, and the subjects were studied lying in the two positions. When remifentanil was given, there were no significant differences between the two postures in maximal acetaminophen concentration (right side, 34 micromol. L(-1); versus left side, 16 micromol. L(-1)), time taken to reach the maximal concentration (94 versus 109 min), or area under the serum acetaminophen concentration time curve from 0 to 60 min (962 versus 197 min. micromol. L(-1)). In the control situation, there were differences between the postures in maximal acetaminophen concentration (138 versus 94 micromol. L(-1); P < 0.0001) and area under the serum acetaminophen concentration time curves from 0 to 60 min (5092 versus 3793 min. micromol. L(-1); P < 0.0001), but there was no significant difference in time taken to reach the maximal concentration (25 versus 47 min). Compared with the control situation, remifentanil delayed gastric emptying in both postures. We conclude that remifentanil delays gastric emptying and that this delay is not influenced by posture.

Topics: Acetaminophen; Adult; Analgesics, Non-Narcotic; Analgesics, Opioid; Area Under Curve; Blood Gas Analysis; Blood Pressure; Dose-Response Relationship, Drug; Gastric Emptying; Heart Rate; Humans; Male; Nausea; Piperidines; Posture; Pruritus; Remifentanil; Respiratory Mechanics; Vomiting

Stapedotomy for otosclerosis presents particular anaesthesiology demands as the surgeon has to assess functional results during the operation, work with some bleeding, be ensured the collaboration of the patient, and limit the occurrence of intra- and post-operative symptoms (dizziness, nausea, vomiting and pain). Remifentanyl, a micro-opioid selective agonist characterised by short latency and duration, has been used for about 2 years at the Otolaryngological Unit of the "Federico II" University of Naples for patients with otosclerosis undergoing stapedotomy. Aim of the study was, therefore, to assess: efficacy and tolerability of Remifentanyl in combination with a local anaesthetic in surgical procedures for otosclerosis; intra- and post-operative reduction in patient symptoms of dizziness, nausea, vomiting and pain; reduction of intra-operative bleeding; degree of patient collaboration and optimisation of anaesthesiological and vital parameters monitored during surgery. The study was carried out on 92 patients with otosclerosis, (17 M, 75 F), median age 41 years (range 25-56), undergoing stapedotomy. Patients were randomly assigned to one of two groups, which were homogeneous as far as concerns age, sex and pre-operative hearing: i. Group A (50 patients), received Remifentanyl infusion in combination with canal injection for local anaesthesia with Mepivacaine 2% and Adrenalin 1/100,000; ii. Group B (42 patients), received only local anaesthetic by infiltration of the external canal ear. Remifentanyl led to an improvement over the local anaesthetic technique previously used, with a clear decrease in intra- and post-operative neurovegetative symptoms such as dizziness, nausea, vomiting and pain, as well as reduced bleeding.

Topics: Adult; Analgesics, Opioid; Dizziness; Female; Humans; Hypnotics and Sedatives; Intraoperative Complications; Male; Middle Aged; Nausea; Otosclerosis; Pain; Piperidines; Postoperative Complications; Remifentanil; Stapes Surgery; Vomiting

To determine the response rate and toxicity of flavopiridol in patients with previously untreated or relapsed mantle-cell lymphoma.. Adult patients with previously untreated or in first or second relapse of previously responsive mantle-cell lymphoma were given flavopiridol 50 mg/m2/d by intravenous bolus for 3 consecutive days every 21 days with antidiarrheal prophylaxis. Flavopiridol was continued until disease progression, unacceptable toxicity, or stable disease for four cycles. Disease was reassessed every two cycles.. From 33 registered patients, 30 were eligible after pathology review, 30 were assessable for toxicity, and 28 were assessable for response. A median of four cycles of treatment was administered; 90% of patients received at least 90% of planned dose-intensity. No complete responses were seen; three patients had a partial response (11%), 20 patients had stable disease (71%), and five patients had progressive disease (18%). The median duration of response was 3.3 months (range, 2.8 to 13.2 months). The most common toxicities were diarrhea (97%), fatigue (73%), nausea (47%), and vomiting (27%). At least one nonhematologic grade 3 or 4 toxicity was seen in 14 patients (47%). Hematologic toxicity was modest.. Flavopiridol given as a daily bolus for 3 consecutive days every 3 weeks has modest activity as a single agent for mantle-cell lymphoma. The number of stable and partial responses that was seen indicates that it is biologically active and may delay progression. Future studies in mantle-cell lymphoma should test this agent with other active agents and using different schedules.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Diarrhea; Disease Progression; Fatigue; Female; Flavonoids; Humans; Injections, Intravenous; Lymphoma, Mantle-Cell; Male; Middle Aged; Nausea; Piperidines; Treatment Outcome; Vomiting

The pharmacokinetic properties of remifentanil may allow a rapid analgesic action during painful procedures and short lasting postoperative respiratory depression.. We carried out a randomized, blind, study in 60 patients to compare remifentanil (continuous i.v. infusion starting at 0.025 micro g kg(-1) min(-1)) and sufentanil (i.v. doses of 0.15 micro g kg(-1)) during extra-corporeal shock wave lithotripsy (ESWL). Pain was assessed using a numerical pain scale (0-100), and pain relief was defined as a score < or =30. Respiratory depression was defined as a ventilatory frequency less than10 breaths min(-1) on two occasions or a peripheral oxygen saturation < or =92%, or administration of naloxone.. The quality of analgesia was similar in both groups, during and after ESWL. During ESWL, there was no significant difference in respiratory depression in the remifentanil and sufentanil groups (53 vs 73%, NS). The percentage of satisfied patients (73 vs 83%, NS) and satisfied surgeons (97 vs 100%, NS) did not significantly differ between groups. After the procedure patients given remifentanil had less respiratory depression (20 vs 53%, P<0.05) and less nausea and vomiting (3 vs 20%, P<0.05).. A continuous i.v. infusion of remifentanil provided comparable analgesia and caused less respiratory depression and nausea and vomiting than i.v. boluses of sufentanil in patients undergoing extra-corporeal shock wave lithotripsy.

Topics: Adult; Aged; Aged, 80 and over; Analgesia; Analgesics, Opioid; Double-Blind Method; Female; Humans; Lithotripsy; Male; Middle Aged; Nausea; Patient Satisfaction; Piperidines; Remifentanil; Respiratory Insufficiency; Sufentanil; Vomiting

Postoperative vomiting (POV) after strabismus surgery in children results in discomfort and prolonged hospital stays. Opioids increase the incidence of POV. Remifentanil has a context-sensitive half-life of 3 to 4 min, and how this short half-life influences POV in those patients is unknown. We conducted a prospective, double-blinded study in 81 ASA status I or II children from 2 to 12 yr of age undergoing elective strabismus surgery under general anesthesia. Patients were randomized to receive either remifentanil (bolus 1 microg/kg; infusion 0.1-0.2 microg x kg(-1) x min(-1)) or fentanyl (2 microg/kg, and 1 microg/kg every 45 min). POV episodes were recorded for 25 h. Pain scores were obtained by using an objective pain scale for 60 min during recovery. The number of patients who experienced POV did not differ significantly between groups (49% vs 48%). However, in the Remifentanil group, POV episodes were significantly less frequent (0.95 vs 2.2 episodes). In contrast, fentanyl was associated with lower pain scores during the first 30 min of recovery. We conclude that children undergoing strabismus surgery under balanced anesthesia with remifentanil, compared with fentanyl, showed less frequent POV. However, early postoperative analgesia was better with fentanyl.. Opioids increase the incidence of postoperative vomiting (POV). Remifentanil is characterized by the shortest half-life of all opioids used in anesthetic practice. Therefore, we studied the effect of remifentanil on POV compared with the longer-acting opioid fentanyl in children undergoing strabismus surgery.

Topics: Analgesics, Opioid; Child; Child, Preschool; Double-Blind Method; Female; Fentanyl; Humans; Incidence; Male; Pain, Postoperative; Piperidines; Postoperative Complications; Prospective Studies; Remifentanil; Strabismus; Vomiting

To assess the efficacy and safety of remifentanil for analgesia and sedation during subarachnoidea anesthesia, and to compare remifentanil with propofol.. Ninety ASA I-III patients undergoing orthopedic or traumatologic surgery under subarachnoid anesthesia were enrolled for prospective study and randomly assigned to two treatment groups. The propofol group (n = 45) received a single dose of 0.5 mg/kg followed by infusion at 3 mg/kg/h. The remifentanil group (n = 45) received a single dose of 0.5 microgram/kg followed by infusion at 0.1 microgram/kg/min. We evaluated quality of sedation, pain intensity during nerve blockade, hemodynamic and respiratory parameters and time until recovery.. The remifentanil group experienced less moderate-to-intense pain (13%) than did the propofol group (63%) (p < 0.01). Sedation was adequate in both groups and was easy to control by adjusting the rate of infusion. Times until recovery of consciousness and respiratory frequency after withdrawal of infusion until recovery of baseline levels were 7.87 +/- 3.54 min and 5.22 +/- 2.49 min, respectively, in the remifentanil group and 8.72 +/- 4.59 min and 5.36 +/- 2.49 min, respectively, in the propofol group, respectively. Patients in the remifentanil group experienced a significantly greater decrease in SpO2 than did those in the propofol group (20% and 4%, respectively; p < 0.05). Mean blood pressure was higher for patients treated with remifentanil. The incidence of vomiting was also higher in the remifentanil group than in the propofol group (9% vs 0%).. Remifentanil is more effective in reducing pain related to nerve blockade and level of sedation is lower; however remifentanil is associated with a higher incidence of respiratory depression and vomiting.

Topics: Adolescent; Adult; Aged; Anesthesia, Spinal; Anesthetics, General; Female; Humans; Hypnotics and Sedatives; Hypoxia; Male; Middle Aged; Orthopedic Procedures; Pain, Postoperative; Piperidines; Propofol; Prospective Studies; Remifentanil; Respiration Disorders; Safety; Vomiting

We conducted a randomized trial to compare the incidence of vomiting and the quality of emergence from anesthesia associated with the use of remifentanil versus a nonopiate. It was expected that remifentanil would provide smoother emergence from anesthesia with a comparably low rate of vomiting. The study sample consisted of 115 pediatric patients undergoing dental restoration and extraction who were randomly assigned to the nonopiate or remifentanil groups based on their hospital admission numbers. The nonopiate patients received sufficient desflurane to prevent movement, typically 7%-9%. The remifentanil group received remifentanil 0.2 microg x kg(-1) x min(-1) and enough desflurane to prevent movement, typically 3.2%-3.6%. A trained postanesthesia care unit nurse, blinded to the anesthetic technique, assessed the quality of emergence and incidence of vomiting. Sixty-three patients received remifentanil and 52 received the nonopiate. The groups were not significantly different in either quality of emergence or incidence of vomiting. Remifentanil provided results comparable to a nonopiate with no increase in emesis.. A randomized, controlled clinical trial of 115 patients undergoing dental restoration indicated that an anesthetic technique using remifentanil provided quality of emergence comparable to and no greater incidence of vomiting than a nonopiate technique.

Topics: Anesthesia; Anesthetics, Intravenous; Child; Child, Preschool; Female; Humans; Male; Piperidines; Postoperative Complications; Remifentanil; Vomiting

Remifentanil is a new rapid-acting and ultra-short acting mu-opioid receptor agonist with few reports from use in children. Therefore, we compared a propofol-remifentanil-anaesthesia (TIVA) with a desflurane-N2O-anaesthesia (DN) with particular regard to the recovery of characteristics in children.. 50 children (4-11 yr) scheduled for ENT surgery were randomly assigned to receive TIVA (n = 25) or DN (N = 25). After standardised i.v. induction of anaesthesia in both groups with remifentanil, propofol and cisatracurium, TIVA was maintained with infusion of propofol and remifentanil. Ventilation was with oxygen in air. DN was maintained with desflurane in 50% N20. The administration of volatile and intravenous anaesthetics was adjusted to maintain a surgical plane of anaesthesia. At the end of surgery all anaesthetics were terminated without tapering and early emergence and recovery were assessed. In addition, side effects were noted.. Both anaesthesia methods resulted in stable haemodynamics but significantly higher heart rate with desflurane. Recovery did not differ between the groups except for delayed spontaneous respiration after TIVA. Spontaneous ventilation occurred after 11 +/- 03.7 min versus 7.2 +/- 2.8 min (mean +/- SD, TIVA versus DN), extubation after 11 +/- 3.7 min versus 9.4 +/- 2.9 min, eye opening after 11 +/- 3.9 min versus 14 +/- 7.6 min and Aldrete score > or = 9 after 17 +/- 6.8 min versus 17 +/- 7.5 min. Postoperatively, there was a significant higher incidence of agitation in the DN group (80% vs. 44%) but a low incidence (< 10%) of nausea and vomiting in both groups.. In children, TIVA with remifentanil and propofol is a well-tolerated anaesthesia method, with a lower peroperative heart rate and less postoperative agitation compared with a desflurane-N2O based anaesthesia.

Topics: Adenoidectomy; Akathisia, Drug-Induced; Anesthesia Recovery Period; Anesthesia, Inhalation; Anesthesia, Intravenous; Anesthetics, Inhalation; Anesthetics, Intravenous; Child; Child, Preschool; Desflurane; Female; Heart Rate; Hemodynamics; Humans; Incidence; Intubation, Intratracheal; Isoflurane; Male; Middle Ear Ventilation; Nausea; Nitrous Oxide; Piperidines; Propofol; Receptors, Opioid, mu; Remifentanil; Respiration; Time Factors; Tonsillectomy; Vomiting; Wakefulness

Topics: Adult; Aged; Antiemetics; Antineoplastic Agents; Cisplatin; Female; Humans; Male; Middle Aged; Neurokinin-1 Receptor Antagonists; Piperidines; Vomiting

The well established bowel cleansing method using a polyethylene glycol-based solution (Fordtran) is limited by the necessity of large volume intake, which proves difficult for many patients. Therefore, a new method using small volumes (2 x 90 ml) of oral sodium phosphate is employed more and more frequently. Its only disadvantage is the occurrence of considerable nausea or occasional vomiting in about 25% of patients. To ascertain whether nausea could be reduced, 426 patients were given an antiemetic (ondansetron, metoclopramide, cisapride) or placebo on a randomized, double-blind basis, one hour before sodium phosphate intake.. sodium phosphate was well tolerated in 69.2% of the patients on placebo, 73.6% on cisapride, 76.5% on metoclopramide and 80.4% on ondansetron. Taking all four groups together, male patients exhibited much better tolerance (86.1%) than females (66.1%). Severe nausea and/or emesis was noted in 22.4% of patients on placebo, 21.7% on cisapride, 17% on metoclopramide and 14% on ondansetron. In over 90% of patients colon cleansing was rated as good to very good. This was largely independent of the severity of nausea. 129 patients who had undergone former polyethylene glycol-based lavage judged sodium phosphate to be more tolerable and easier to complete. Considering known contraindications (symptomatic congestive heart failure and/or renal failure), no serious adverse event was noted in any of the 426 patients investigated. In accordance with several recent studies, we consider sodium phosphate solution at present the procedure of choice for colon cleansing. Compared to Fordtran, patient acceptance is far better and cleansing quality superior. Routine antiemetic comedication for reducing possible nausea/vomiting is not worthwhile. On the other hand, this study confirms our former impression of enhanced colon cleansing after administration of an additional mild laxative before sodium phosphate, without interfering with patient acceptance.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Antiemetics; Cathartics; Cisapride; Colonoscopy; Double-Blind Method; Female; Humans; Male; Metoclopramide; Middle Aged; Nausea; Ondansetron; Phosphates; Piperidines; Prospective Studies; Vomiting

We evaluated the use of an infusion of remifentanil to provide postoperative analgesia during recovery from total intravenous anesthesia (TIVA) with remifentanil and propofol. One hundred fifty-seven patients from seven medical centers underwent abdominal, spine, joint replacement, or thoracic surgery. Remifentanil was titrated in an effort to limit pain to 0 or 1 on a 0-3 scale. At the end of the 30-min titration period, 78% of infusion rates were in the range of 0.05 to < or = 0.15 microgram.kg-1.min-1, 5% were < 0.05 microgram.kg-1.min-1, and 17% were > 0.15 microgram.kg-1.min-1. Pain scores were 0 or 1 in 64% of patients. Nausea occurred in 35% and emesis in 8% of patients; the peak incidence of nausea followed discontinuation of the remifentanil infusion at the time of administering morphine. Respiratory adverse events (oxygen saturation by pulse oximetry [Spo2] < 90% or respiratory rate < 12) affected 29% of patients. Apnea occurred in 11 patients (7.0%). There was a large variation in the incidence of respiratory depression between the centers, ranging from 0 to 75%. The explanation for the large variability in respiratory outcome was not evident.

Topics: Abdomen; Adult; Aged; Analgesics, Opioid; Anesthesia Recovery Period; Anesthesia, Intravenous; Anesthetics, Intravenous; Apnea; Female; Humans; Incidence; Infusions, Intravenous; Joint Prosthesis; Male; Middle Aged; Morphine; Nausea; Oxygen; Pain Measurement; Pain, Postoperative; Piperidines; Propofol; Remifentanil; Respiration; Spine; Thoracic Surgery; Vomiting

Pharmacologic and cognitive behavioral therapies have been advocated in the treatment of bulimia nervosa (BN). Brofaromine, a selective and reversible inhibitor of monoamine oxidase-A was selected for a double-blind, placebo-controlled evaluation because of previous demonstrated monoamine oxidase inhibitor efficacy in BN and because of its safer adverse reaction profile. Thirty-six female patients who met DSM-III-R criteria for BN were randomly assigned to the drug group (N = 19) or to the placebo group (N = 17) for an 8-week outpatient trial. Brofaromine produced a significant effect in decreasing episodes of vomiting throughout the trial, although comparable reductions in episodes of binge eating were found in both groups. Also, there were no advantages of drug over placebo on improvements in attitudinal measures and shape or on self-report ratings of depression and anxiety. However, a significant proportion of the subjects on brofaromine lost weight when compared with the placebo group. Methodologic issues including subjective assessment measures, placebo response rates, and the elucidation of responder subgroups are discussed.

Topics: Adolescent; Adult; Affect; Attitude; Body Image; Body Weight; Bulimia; Double-Blind Method; Feeding Behavior; Female; Humans; Monoamine Oxidase Inhibitors; Piperidines; Psychiatric Status Rating Scales; Vomiting

The purpose of a single-subject randomized trial is to assess objectively the efficacy of a specific therapeutic intervention in an individual patient. Treatment is randomly alternated with placebo over a number of study periods. Specific outcome measures are recorded blindly and later compared via paired statistical analysis. Single-subject trials have long been successfully performed in adults, but rarely in children. We present single-subject trials of two pediatric patients done to assess the effect of cisapride on symptoms arising from gastroesophageal reflux. In the first patient, the drug affected neither vomiting nor gagging, although stool frequency increased. Since the symptoms of concern were unaffected, cisapride was discontinued. In the second patient, use of cisapride led to a significant decrease in vomiting and wheezing; the drug was therefore incorporated into the therapeutic regimen. Single-subject randomized trials are inexpensive and simple and can be used by the family physician, pediatrician, or pediatric surgeon in daily practice. They permit the rational use of effective therapy and the abandonment of ineffective measures.

Topics: Adult; Child; Child, Preschool; Cisapride; Gagging; Gastroesophageal Reflux; Humans; Infant; Male; Piperidines; Respiratory Sounds; Treatment Outcome; Vomiting

Topics: Clinical Trials as Topic; Dehydration; Diarrhea, Infantile; Double-Blind Method; Feces; Humans; Infant; Loperamide; Male; Piperidines; Vomiting

The anti-emetic effects of domperidone were evaluated under double-blind conditions in twenty-four patients with acute vomiting randomly assigned to treatment either with 10 mg i.m. domperidone (six female, five males) or with placebo (seven females, six males). The therapeutic results were better with domperidone and the differences from placebo were statistically significant (p less than 0.02). In a second randomized, crossover, double-blind trial, domperidone (10 mg t.i.d.) evaluated according to a nine-symptom rating scale, in eighteen dyspeptic patients, proved significantly more effective than placebo. The duration of treatment was 6 weeks and the drugs were crossed-over after 3 weeks. The difference between the two groups was most marked during the second phase of the trial. No side-effects were reported.

Topics: Aged; Benzimidazoles; Clinical Trials as Topic; Domperidone; Double-Blind Method; Dyspepsia; Female; Humans; Male; Middle Aged; Piperidines; Vomiting

The antiemetic effects of domperidone in patients undergoing post-surgical cytostatic treatment for stomach and colorectal carcinoma have been evaluated. The study has been performed on 3 groups of patients treated with domperidone, metoclopramide and placebo respectively. The antiemetic activity of domperidone proved to be better than that of metoclopramide. No side effects were observed in patients treated with domperidone.

Topics: Aged; Antineoplastic Agents; Benzimidazoles; Clinical Trials as Topic; Domperidone; Female; Gastrointestinal Neoplasms; Humans; Male; Metoclopramide; Middle Aged; Nausea; Piperidines; Postoperative Care; Vomiting

In a single-blind trial of therapy in 20 patients with idiopathic Parkinson disease, domperidone prevented nausea and vomiting induced by bromocriptine without diminishing beneficial central effects. Combination of the two drugs permitted rapid increase in bromocriptine dosage from 22.5 mg per day to 148 mg per day, with 71% mean clinical improvement over baseline score; continuing efficacy of the regimen was evident for a mean follow-up of 2 months.

Topics: Benzimidazoles; Bromocriptine; Domperidone; Female; Humans; Levodopa; Male; Middle Aged; Nausea; Parkinson Disease; Piperidines; Vomiting

In a double-blind comparison of domperidone 10 mg, domperidone 4 mg, metoclopramide 10 mg and a placebo, 176 adult patients were given an intravenous injection of one of these substances after postoperative vomiting had occurred. Patients were then observed for 6 hours. Those who failed to respond sufficiently to the double-blind injection were given an open dose of domperidone 4 mg i.v. Vomiting recurred in 52% of patients in each of domperidone groups compared with 75% of patients in the metoclopramide group and 84% of patients in the placebo group. Thus domperidone was significantly more effective than the other two substances (p < 0.05). Significantly more patients in the placebo group required a supplementary injection than in the domperidone and metoclopramide groups (p < 0.05). No side effects were observed in any patient.

Topics: Adult; Aged; Antiemetics; Benzimidazoles; Clinical Trials as Topic; Domperidone; Double-Blind Method; Female; Humans; Male; Metoclopramide; Middle Aged; Piperidines; Placebos; Postoperative Complications; Vomiting

One hundred patients (14-82 years) were given either domperidone 10 mg I.V. or a placebo after they had vomited postoperatively. The patients were then observed for six hours. A supplementary injection of domperidone 10 mg I.V. from an open supply was given if required. In the placebo group 47.9% of patients needed another injection but only 25% of patients in the domperidone group (p less than 0.01). Vomiting occurred later after domperidone than after the placebo (p less than 0.01). At the end of six hours 74% of patients in the domperidone group had no recurrence of vomiting compared with 38% in the control group. In this study neither vomiting nor the efficacy of domperidone were found to be related to the type of surgery, the type of anaesthetic or the physical status (ASA I-III) of the patient (p greater than 0.05).

Topics: Adolescent; Adult; Aged; Antiemetics; Benzimidazoles; Clinical Trials as Topic; Domperidone; Double-Blind Method; Female; Humans; Male; Middle Aged; Piperidines; Postoperative Complications; Random Allocation; Vomiting

Forty patients with postprandial nausea and vomiting from a variety of underlying causes, were given either domperidone 20 mg t.d.s. or placebo in a double-blind study lasting two weeks. The tablets were taken before meals and no other anti-emetics were used. Nausea and vomiting were reduced in those patients given the active therapy, the results being recorded as excellent in 62% in the domperidone group and 18% of controls.

Topics: Adult; Aged; Antiemetics; Benzimidazoles; Chronic Disease; Clinical Trials as Topic; Double-Blind Method; Dyspepsia; Female; Food; Humans; Male; Middle Aged; Nausea; Piperidines; Vomiting

In a double-blind trial in 60 children suffering from gastroenteritis complicated by vomiting, it was found that suppositories of domperidone (30 mg) were more effective than either metoclopramide (10 mg) or placebo in reducing the severity of vomiting, nausea and other symptomatic parameters. No side effects were reported throughout the 24 hour period of the trial and the results suggest that domperidone suppositories may well prove to be the drug of choice in such cases of paediatric vomiting.

Topics: Antiemetics; Benzimidazoles; Child; Child, Preschool; Clinical Trials as Topic; Double-Blind Method; Female; Gastroenteritis; Humans; Male; Metoclopramide; Nausea; Piperidines; Suppositories; Vomiting

Forty-seven infants and children suffering from chronic vomiting or regurgitation, participated in a two-week double-blind trial comparing 1% drops of domperidone, 1% metoclopramide drops or placebo. The dose was 0.3 mg/kg given t.d.s. before meals. Both active medicaments were significantly more effective than placebo in controlling the symptoms and domperidone was also significantly superior to metoclopramide. It is concluded, in view of the good safety margin with domperidone, that this drug could become the treatment of choice in such cases.

Topics: Antiemetics; Benzimidazoles; Child; Child, Preschool; Chronic Disease; Clinical Trials as Topic; Double-Blind Method; Female; Gastroesophageal Reflux; Humans; Infant; Infant, Newborn; Male; Metoclopramide; Nausea; Piperidines; Vomiting

A small scale pilot study among 41 children with severe vomiting, showed that a single administration of domperidone either intravenously, intramuscularly or rectally, effectively controlled the symptom within 3 hours in 36 (88%) patients. The excellent results together with the safety of this new drug indicate its potential value in these patients.

Topics: Adolescent; Antiemetics; Benzimidazoles; Child; Child, Preschool; Clinical Trials as Topic; Female; Humans; Infant; Injections, Intramuscular; Injections, Intravenous; Male; Pilot Projects; Piperidines; Rectum; Time Factors; Vomiting

In a series of open pilot studies, intravenous domperidone was given to three groups of post-operative patients, at doses ranging from 10 mg to 60 mg. As a result of these studies, it was decided that a regime of 20 mg initially, followed by maintenance doses of 10 mg at 6 hourly intervals was highly effective in preventing post-operative nausea and vomiting. Consequently this regime was chosen to evaluate domperidone against placebo in a double-blind study involving 106 patients. The results showed that only three out of 53 patients (5.7%) on active treatment were having nausea and vomiting compared with 16 of 53 patients (30.2%) on placebo. It is concluded that this regime is effective in preventing post-operative nausea and vomiting.

Topics: Antiemetics; Benzimidazoles; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Male; Nausea; Pilot Projects; Piperidines; Postoperative Complications; Vomiting

Topics: Adult; Aged; Anti-Inflammatory Agents; Antiemetics; Benzimidazoles; Clinical Trials as Topic; Craniocerebral Trauma; Dihydroxyphenylalanine; Dysmenorrhea; Esophagoscopy; Female; Humans; Male; Middle Aged; Migraine Disorders; Nausea; Piperidines; Premedication; Radiotherapy; Renal Dialysis; Vomiting

One hundred and ninety-five female patients of child-bearing age were assessed for postoperative vomiting in a double-blind trial using domperidone, metoclopramide and placebo. Compared with placebo, both drugs were found to reduce vomiting in approximately half the patients who had undergone caesarean section. However, in the group of non-obstetric patients, no statistically significant difference as regards vomiting was shown.

Topics: Adult; Anesthesia, Inhalation; Anesthesia, Intravenous; Anesthesia, Obstetrical; Benzimidazoles; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Metoclopramide; Nausea; Piperidines; Placebos; Postoperative Period; Random Allocation; Vomiting

Forty seven patients received either 4 mg or 10 mg domperidone I.V. in a double blind study after they had vomited postoperatively. The patients were then observed for six hours. If necessary, the same dose of domperidone was repeated double blind but not during the first hour. When the two groups were compared there was little difference between them for the first half hour after the initial dose, thereafter both the frequency and severity of vomiting was reduced in the 10 mg group. Also fewer patients in the 10 mg group needed a second injection. These differences were statistically significant (p less than 0.05).

Topics: Adolescent; Adult; Aged; Antiemetics; Benzimidazoles; Clinical Trials as Topic; Domperidone; Double-Blind Method; Female; Humans; Male; Middle Aged; Piperidines; Postoperative Complications; Vomiting

Topics: Adolescent; Antiemetics; Antineoplastic Agents; Benzimidazoles; Child; Child, Preschool; Female; Humans; Male; Metoclopramide; Nausea; Piperidines; Vomiting

A cross-over double-blind trial was conducted in 14 patients (20 double-blind treatment courses) comparing domperidone and placebo in the treatment of vomiting due to intensive cytostatic treatment. Eight ml, containing 16 mg of domperidone or placebo was injected one hour before the start of cytostatic therapy. The efficacy of the drug was evaluated by the investigator and the duration of nausea and vomiting was registered in the majority of the patients. Domperidone was preferred to placebo 13 times, whereas the reverse preference occurred only twice. The duration of both nausea (a median of 11 hours against seven hours) and vomiting (a median of 7 1/2 hours against 6 hours) was shorter with domperidone than with the placebo.

Topics: Adolescent; Adult; Aged; Antiemetics; Antineoplastic Agents; Benzimidazoles; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Male; Middle Aged; Piperidines; Placebos; Vomiting

The effect of domperidone on vomiting due to cytostatic treatment was studied during a double-blind trial involving 41 patients. One group received the sequence domperidone-placebo and the other the reverse sequence during two consecutive courses of cytostatic therapy (chlormethine alone or in combination with other cytostatics). Domperidone 2 mg/ml or the placebo was injected IV 1 h before the start of the cytostatic treatment. A similar injection was given 4 h later. Presence, duration, and incidence of nausea and vomiting before, during, and after the peak period (period from the second up to and including the sixth hour after cytostatic injection) were measured. With respect to vomiting, domperidone was significantly superior to placebo concerning duration and effect before and after the peak period in both sequences. There was no difference during the peak period. With respect to nausea, domperidone was superior to placebo concerning duration and effect during the peak period in the placebo-domperidone sequence. No difference was observed in the reverse order. A significant superiority of domperidone was noted before the peak period.

Topics: Adult; Aged; Antiemetics; Antineoplastic Agents; Benzimidazoles; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Male; Middle Aged; Nausea; Piperidines; Placebos; Time Factors; Vomiting

The effect of domperidone on postoperative nausea and vomiting was evaluated in two consecutive studies. Fifty-eight patients with postoperative nausea and vomiting were included in an open pilot study and 38 other patients in a double-blind trial. In the first study 4 mg of domperidone was found to be significantly superior to 2 mg, in controlling nausea and vomiting. In the double-blind trial, vomiting recurred significantly later in domperidone than in placebo-treated patients. Side-effects were not seen nor reported in either study.

Topics: Antiemetics; Benzimidazoles; Double-Blind Method; Female; Humans; Male; Nausea; Piperidines; Postoperative Complications; Vomiting

The new antihistamine, HC20-511 (Sandoz), was compared with Dimetinden (Fenistil retard) in a single-blind comparative study in 42 patients with dermatoses, 28 of whom suffered from chronic urticaria. HC20-511 had a better effect, especially in chronic urticaria, where pruritus, erythema and papules quickly disappeared. The effect appeared somewhat faster than and lasted as long as that of Dimetinden, although HC20-511 is not a retard-preparation unlike the Dimetinden preparation used for comparison. HC20-511 also caused less side effects.

Topics: Adolescent; Adult; Aged; Chronic Disease; Clinical Trials as Topic; Dimethindene; Drug Therapy, Combination; Female; Fumarates; Histamine H1 Antagonists; Humans; Male; Middle Aged; Piperidines; Pruritus; Skin Diseases; Thiophenes; Urticaria; Vomiting

Topics: Analgesics; Analysis of Variance; Clinical Trials as Topic; Humans; Injections, Intramuscular; Isonipecotic Acids; Morphine; Movement; Nausea; Nitriles; Pain, Postoperative; Piperidines; Respiration; Time Factors; Vomiting

Topics: Adolescent; Adult; Aged; Blood Pressure; Cholecystectomy; Female; Humans; Isonipecotic Acids; Male; Meperidine; Middle Aged; Morphinans; Nausea; Nitriles; Pain; Piperidines; Pulse; Respiration; Vomiting

Topics: Administration, Oral; Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Female; Humans; Imides; Menopause; Morpholines; Nausea; Piperidines; Remission, Spontaneous; Vomiting

Topics: Adolescent; Child; Child, Preschool; Clinical Trials as Topic; Gastrointestinal Diseases; Humans; Infant; Pain; Parasympatholytics; Piperidines; Recurrence; Vomiting

Topics: Analgesics; Blood Pressure; Clinical Trials as Topic; Humans; Hypnotics and Sedatives; Isonipecotic Acids; Morphine; Nausea; Nitriles; Piperidines; Postoperative Complications; Vomiting

Topics: Adolescent; Adult; Aged; Antiemetics; Child; Child, Preschool; Clinical Trials as Topic; Humans; Middle Aged; Nausea; Piperidines; Vomiting

The MET inhibitor tepotinib demonstrated durable clinical activity in patients with advanced MET exon 14 (METex14) skipping NSCLC. We report detailed analyses of adverse events of clinical interest (AECIs) in VISION, including edema, a class effect of MET inhibitors.. Incidence, management, and time to first onset/resolution were analyzed for all-cause AECIs, according to composite categories (edema, hypoalbuminemia, creatinine increase, and ALT/AST increase) or individual preferred terms (pleural effusion, nausea, diarrhea, and vomiting), for patients with METex14 skipping NSCLC in the phase II VISION trial.. Of 255 patients analyzed (median age: 72 years), edema, the most common AECI, was reported in 69.8% (grade 3, 9.4%; grade 4, 0%). Median time to first edema onset was 7.9 weeks (range: 0.1-58.3). Edema was manageable with supportive measures, dose reduction (18.8%), and/or treatment interruption (23.1%), and rarely prompted discontinuation (4.3%). Other AECIs were also manageable and predominantly mild/moderate: hypoalbuminemia, 23.9% (grade 3, 5.5%); pleural effusion, 13.3% (grade ≥ 3, 5.1%); creatinine increase, 25.9% (grade 3, 0.4%); nausea, 26.7% (grade 3, 0.8%), diarrhea, 26.3% (grade 3, 0.4%), vomiting 12.9% (grade 3, 1.2%), and ALT/AST increase, 12.2% (grade ≥ 3, 3.1%). GI AEs typically occurred early and resolved in the first weeks.. Tepotinib was well tolerated in the largest trial of a MET inhibitor in METex14 skipping NSCLC. The most frequent AEs were largely mild/moderate and manageable with supportive measures and/or dose reduction/interruption, and caused few withdrawals in this elderly population.

Topics: Aged; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase II as Topic; Creatinine; Diarrhea; Edema; Exons; Humans; Hypoalbuminemia; Lung Neoplasms; Mutation; Nausea; Piperidines; Pleural Effusion; Protein Kinase Inhibitors; Pyridazines; Pyrimidines; Vomiting

HM01, a novel, orally bioavailable, brain-penetrating agonist of ghrelin receptors, ameliorates emesis in Suncus murinus. This study compared HM01's activity against motion sickness with that of the less brain-penetrating ghrelin receptor agonist, HM02.. The potential of HM01 and HM02 to relax isolated mesenteric arteries and to increase feeding was investigated. Radio telemetry was used to record gastric slow waves and body temperature. Plethysmography was used to measure respiratory function. HM01 and HM02 were administered p.o. 1 hr prior to provocative motion, and c-Fos expression in brain sections was assessed.. HM01 and HM02 both relaxed precontracted arteries, yielding EC. HM01 is more effective than HM02 in preventing motion-induced emesis. The difference in potency may relate to activation of ghrelin receptors in the PVH.

Topics: Animals; Piperidines; Receptors, Ghrelin; Shrews; Vomiting

Poly(ADP-ribose) polymerase (PARP) proteins are used by cells in several DNA repair processes. PARP inhibition can result in preferential death of cancer cells when another mechanism for repairing DNA is defective. Two PARP inhibitors, olaparib and rucaparib, have been approved by the US Food and Drug Administration (FDA) for the treatment of recurrent, BRCA-associated ovarian cancer. More recently, these two and a third PARP inhibitor, niraparib, were approved by the FDA as maintenance therapy following platinum-based chemotherapy for recurrent ovarian cancer. This has caused a paradigm shift in disease management and a challenge for clinicians, who must decide how best to use these agents in individualized treatment. The oral formulation is attractive to patients, but adverse effects such as nausea and fatigue can impact quality of life. As clinicians become comfortable selecting PARP inhibitors and managing associated toxicities, future steps will be to investigate how to safely administer them in combination with other therapies.

Topics: Anemia; Creatinine; Drug Administration Schedule; Drug Interactions; Exanthema; Fatigue; Female; Genes, BRCA1; Genes, BRCA2; Heart Rate; Humans; Hypertension; Indazoles; Leukopenia; Mutation; Myelodysplastic Syndromes; Nasopharyngitis; Nausea; Ovarian Neoplasms; Piperidines; Pneumonia; Poly(ADP-ribose) Polymerase Inhibitors; Thrombocytopenia; Transaminases; Vomiting

Nowadays, chemotherapy induced nausea and vomiting (CINV) is still common in patients with cancer. It was reported that substance P mediated CINV via neurokinin-1 (NK. Rats' kaolin intake, food intake, and bodyweight were recorded every day; gastric contraction activity was recorded in conscious rats through a force transducer implanted into the stomach; gastric emptying was monitored using the phenol red method; single unit extracellular firing in the DMNV were recorded.. DMNV microinjection of CP-99 994 reduced the changes of increased kaolin consumption and suppressed food intake in cisplatin-treated rats; enhanced the gastric contraction activity dose-dependently in control and cisplatin-treated rats but enhanced gastric emptying only in cisplatin-treated rats; reduced the firing rate of gastric distention inhibited (GD-I) neurons but increased the firing rate of GD excited (GD-E) neurons in the DMNV. The effects of CP-99 994 on gastric motility and neuronal activity were stronger in cisplatin-treated rats than those of control rats.. Our results suggested that CP-99 994 could improve emesis induced by cisplatin by regulating gastric motility and gastric related neuronal activity in the DMNV.

Topics: Animals; Antiemetics; Antineoplastic Agents; Cisplatin; Gastric Emptying; Gastrointestinal Motility; Male; Medulla Oblongata; Neurokinin-1 Receptor Antagonists; Piperidines; Rats; Rats, Wistar; Vomiting

Recent data demonstrated that activation of the muscarinic M

Topics: Allosteric Regulation; Amphetamine; Animals; Ataxia; Diarrhea; Dogs; Donepezil; Drug Design; Female; Humans; Indans; Isoindoles; Lactams; Male; Mice, Inbred C57BL; Microsomes, Liver; Oxazoles; Piperidines; Rats, Wistar; Receptor, Muscarinic M1; Scopolamine; Seizures; Structure-Activity Relationship; Sulfonamides; Thiadiazoles; Vomiting

Doses of naloxone far below those which elicit emesis increase the sensitivity to motion sickness. In order to evaluate the possible interaction with broad spectrum antiemetics, low doses of naloxone were tested alone and in combination with 8-hydroxy-2-(di-n-propylamine)tetralin (DPAT), fentanyl and the NK1 antagonist CP-99994. A modified autonomic symptom rating scale was unaffected by any drug and thus considered of little value. Fentanyl and NK1 antagonists decreased the duration of the retch/vomit sequence. Naloxone alone and in combination with each of the drugs increased the duration of retching/vomiting. Naloxone also increased the number of vomiting sequences. The results are interpreted in terms of possible site(s) of action of the antiemetic drugs.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Antiemetics; Cats; Dose-Response Relationship, Drug; Drug Interactions; Emetics; Female; Fentanyl; Models, Animal; Motion Sickness; Naloxone; Neurokinin-1 Receptor Antagonists; Physical Stimulation; Piperidines; Vomiting

Enhancement of central availability of the second messenger cAMP is a promising approach to improve cognitive function. Pharmacological inhibition of phosphodiesterase type 4 (PDE4), a group of cAMP hydrolyzing enzymes in the brain, has been shown to improve cognitive performances in rodents and monkeys. However, inhibition of PDE4 is generally associated with severe emetic side-effects. Roflumilast, an FDA-approved PDE4 inhibitor for treatment of chronic obstructive pulmonary disease (COPD), is yielding only mild emetic side effects. In the present study we investigate the potential of roflumilast as a cognition enhancer and to determine the potential coinciding emetic response in comparison to rolipram, a classic PDE4 inhibitor with pronounced emetic effects. Cognition enhancement was evaluated in mice and it was found that both roflumilast and rolipram enhanced memory in an object location task (0.03mg/kg), whereas only roflumilast was effective in a spatial Y-maze (0.1mg/kg). Emetic potential was measured using competition of PDE4 inhibition for α2-adrenergic receptor antagonism in which recovery from xylazine/ketamine-mediated anesthesia is used as a surrogate marker. While rolipram displayed emetic properties at a dose 10 times the memory-enhancing dose, roflumilast only showed increased emetic-like properties at a dose 100 times the memory-enhancing dose. Moreover, combining sub-efficacious doses of the approved cognition-enhancer donepezil and roflumilast, which did not improve memory when given alone, fully restored object recognition memory deficit in rats induced by the muscarinic receptor antagonist scopolamine. These findings suggest that roflumilast offers a more favorable window for treatment of cognitive deficits compared to rolipram.

Topics: Aminopyridines; Animals; Benzamides; Cyclopropanes; Donepezil; Indans; Male; Memory; Mice; Mice, Inbred C57BL; Nootropic Agents; Phosphodiesterase 4 Inhibitors; Piperidines; Rats, Wistar; Recognition, Psychology; Rolipram; Scopolamine; Spatial Memory; Vomiting

The use of glucagon-like peptide-1 (7-36) amide (GLP-1) receptor agonists for the treatment of type 2 diabetes mellitus is commonly associated with nausea and vomiting. Previous studies using Suncus murinus revealed that the GLP-1 receptor agonist, exendin-4, induces emesis via the brainstem and/or hypothalamus. The present study investigated the mechanism of exendin-4-induced emesis in more detail. Ondansetron (1 mg/kg, s.c.) and CP-99,994 (10 mg/kg, s.c) failed to reduce emesis induced by exendin-4 (3 nmol, i.c.v.), suggesting that 5-HT3 and NK1 receptors are not involved in the mechanism. In other studies, the GLP-1 receptor antagonist, exendin (9-39), antagonised emesis and c-Fos expression in the brainstem and the paraventricular hypothalamus induced by the chemotherapeutic drug cisplatin (30 mg/kg, i.p.; p < 0.05), but not the emesis induced by nicotine (5 mg/kg, s.c.; p > 0.05), or copper sulphate pentahydrate (120 mg/kg, p.o.; p > 0.05). GLP-1 receptors may therefore represent a potential target for drugs to prevent chemotherapy-induced emesis in situations where 5-HT3 and NK1 receptor antagonists fail.

Topics: Animals; Antiemetics; Brain; Exenatide; Glucagon-Like Peptide-1 Receptor; Male; Ondansetron; Peptide Fragments; Peptides; Piperidines; Proto-Oncogene Proteins c-fos; Receptors, Glucagon; Shrews; Venoms; Vomiting

Donepezil is a centrally-acting, reversible acetylcholinesterase inhibitor that is used in the treatment of Alzheimer disease. Altered mental status, nausea, vomiting, and bradycardia have been reported in therapeutic and supratherapeutic ingestions of donepezil, though pediatric exposures have not been well-described. We report a case of prolonged altered mental status and recurrent bradycardia in a child with a single-pill ingestion of donepezil.. A 14-month-old boy was brought to the Emergency Department 3 hours after ingesting one of his grandfather's donepezil tablets (10 mg). Upon arrival, he was somnolent and drooling, with multiple episodes of vomiting and diarrhea. Pupils were normal. Initial vitals: temperature, 36.8°C; blood pressure, 103/56 mmHg; heart rate, 140/min; respiratory rate, 36/min; oxygen saturation, 97%. His drooling, vomiting, and diarrhea resolved, but he remained intermittently agitated. Over the course of the following four days, he had intermittent, episodes of asymptomatic bradycardia to a low of 55/min, primarily when sleeping. A transient episode of junctional rhythm was observed. Serum donepezil level 97 hours post-ingestion was 10 ng/ml. He did not require atropine treatment, and was discharged in stable condition on hospital day 5.. Donepezil has a prolonged elimination of half-life in adults of approximately 70 hours. Despite its relative specificity for central AChEs, peripheral cholinergic symptoms have been described. We report a case of a symptomatic ingestion of donepezil in a child.. Even after a single-tablet ingestion, donepezil may cause prolonged altered mental status and bradycardia in young children.

Topics: Accidents, Home; Bradycardia; Cholinesterase Inhibitors; Donepezil; Emergency Service, Hospital; Humans; Indans; Infant; Male; Nootropic Agents; Piperidines; Psychoses, Substance-Induced; Severity of Illness Index; Sleep Stages; Vomiting

The role of the endocannabinoid system in vomiting has been previously studied using several animal species. These investigations have clearly demonstrated an anti-emetic role for the eCB, anandamide, in these animal models; however, research concerning the role of 2-arhachidonoylglycerol (2AG) has been less clear. The aim of the present study was to assess the effects of exogenous 2AG administration in the house musk shrew, Suncus murinus. In Experiment 1, shrews were injected with vehicle or 2AG (1, 2, 5, 10 mg/kg) 15 min prior to behavioral testing in which the frequency of vomiting episodes was observed. In Experiment 2, shrews were pre-treated with 2AG (2, 5 mg/kg) prior to being administered the emetic drug, lithium chloride (LiCl). It was found that 2AG alone did not induce emesis, but interfered with vomiting in response to LiCl administration. The anti-emetic effects of 2AG in Suncus murinus do not appear to be mediated by CB1 receptors, as concomitant pretreatment with the CB1 receptor antagonist, SR141716, did not reverse the suppressive effects of 2AG. These results confirm that manipulations that increase levels of 2AG exert anti-emetic effects in the house musk shrew.

Topics: Animals; Antiemetics; Arachidonic Acids; Cannabinoid Receptor Agonists; Data Interpretation, Statistical; Dose-Response Relationship, Drug; Endocannabinoids; Female; Glycerides; Lithium Chloride; Male; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Shrews; Vomiting

To understand how anandamide transport inhibition impacts the regulation of nausea and vomiting and the receptor level mechanism of action involved. In light of recent characterization of an anandamide transporter, fatty acid amide hydrolase-1-like anandamide transporter, to provide behavioural support for anandamide cellular reuptake as a facilitated transport process.. The systemic administration of the anandamide transport inhibitor ARN272 ([(4-(5-(4-hydroxy-phenyl)-3,4-diaza-bicyclo[4.4.0]deca-1(6),2,4,7,9-pentaen-2-ylamino)-phenyl)-phenylamino-methanone]) was used to evaluate the prevention of LiCl-induced nausea-induced behaviour (conditioned gaping) in rats, and LiCl-induced emesis in shrews (Suncus murinus). The mechanism of how prolonging anandamide availability acts to regulate nausea in rats was explored by the antagonism of cannabinoid 1 (CB1) receptors with the systemic co-administration of SR141716.. The systemic administration of ARN272 produced a dose-dependent suppression of nausea-induced conditioned gaping in rats, and produced a dose-dependent reduction of vomiting in shrews. The systemic co-administration of SR141716 with ARN272 (at 3.0 mg·kg(-1)) in rats produced a complete reversal of ARN272-suppressed gaping at 1.0 mg·kg(-1). SR141716 alone did not differ from the vehicle solution.. These results suggest that anandamide transport inhibition by the compound ARN272 tonically activates CB1 receptors and as such produces a type of indirect agonism to regulate toxin-induced nausea and vomiting. The results also provide behavioural evidence in support of a facilitated transport mechanism used in the cellular reuptake of anandamide.

Topics: Amidohydrolases; Animals; Antiemetics; Arachidonic Acids; Behavior, Animal; Biological Transport; Cannabinoid Receptor Antagonists; Disease Models, Animal; Dose-Response Relationship, Drug; Endocannabinoids; Isoenzymes; Lithium Chloride; Male; Nausea; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Rimonabant; Shrews; Vomiting

To evaluate the role of 2-arachidonoyl glycerol (2AG) in the regulation of nausea and vomiting using animal models of vomiting and of nausea-like behaviour (conditioned gaping).. Vomiting was assessed in shrews (Suncus murinus), pretreated with JZL184, a selective monoacylglycerol lipase (MAGL) inhibitor which elevates endogenous 2AG levels, 1 h before administering the emetogenic compound, LiCl. Regulation of nausea-like behaviour in rats by exogenous 2AG or its metabolite arachidonic acid (AA) was assessed, using the conditioned gaping model. The role of cannabinoid CB(1) receptors, CB(2) receptors and cyclooxygenase (COX) inhibition in suppression of vomiting or nausea-like behaviour was assessed.. JZL184 dose-dependently suppressed vomiting in shrews, an effect prevented by pretreatment with the CB(1) receptor inverse agonist/antagonist, AM251. In shrew brain tissue, JZL184 inhibited MAGL activity in vivo. In rats, 2AG suppressed LiCl-induced conditioned gaping but this effect was not prevented by AM251 or the CB(2) receptor antagonist, AM630. Instead, the COX inhibitor, indomethacin, prevented suppression of conditioned gaping by 2AG or AA. However, when rats were pretreated with a high dose of JZL184 (40 mg·kg(-1) ), suppression of gaping by 2AG was partially reversed by AM251. Suppression of conditioned gaping was not due to interference with learning because the same dose of 2AG did not modify the strength of conditioned freezing to a shock-paired tone.. Our results suggest that manipulations that elevate 2AG may have anti-emetic or anti-nausea potential.. This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7.

Topics: Animals; Arachidonic Acids; Behavior, Animal; Benzodioxoles; Brain; Endocannabinoids; Enzyme Inhibitors; Fear; Glycerides; Lithium Chloride; Male; Monoacylglycerol Lipases; Nausea; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Shrews; Vomiting

This prospective study evaluated the effects of continuous sedation using midazolam, with or without remifentanil, on postoperative nausea and vomiting (PONV) in patients undergoing myringoplasty.. Sixty patients undergoing myringoplasty were sedated with midazolam in the presence of remifentanil (group MR), or after saline injection instead of remifentanil (group M).. Three patients (10%) in group M complained of nausea; two vomited. Four patients (13%) in group MR complained of nausea and vomited within 24 h after surgery. Rescue drugs were given to the six patients who vomited. No significant difference was detected between the two groups regarding the incidence or severity of nausea, incidence of vomiting, or need for rescue drugs.. Midazolam-based continuous sedation can reduce PONV after myringoplasty. Compared with midazolam alone, midazolam with remifentanil produced no difference in the incidence or severity of nausea, incidence of vomiting, or need for rescue drugs.

Topics: Adult; Age Factors; Female; Humans; Male; Midazolam; Middle Aged; Myringoplasty; Piperidines; Postoperative Nausea and Vomiting; Prospective Studies; Remifentanil; Sex Factors; Vomiting

Significant electrophysiological and biochemical findings suggest that receptor cross-talk occurs between serotonergic 5-HT(3)- and tachykininergic NK(1)-receptors in which co-activation of either receptor by ineffective doses of their corresponding agonists (serotonin (5-HT) or substance P (SP), respectively) potentiates the activity of the other receptor to produce a response. In contrast, selective blockade of any one of these receptors attenuates the increase in abdominal vagal afferent activity caused by either 5-HT or SP. This interaction has important implications in chemotherapy-induced nausea and vomiting (CINV) since 5-HT(3)- and NK(1)-receptor antagonists are the major classes of antiemetics used in cancer patients receiving chemotherapy. The purpose of this study was to demonstrate whether the discussed interaction produces effects at the behavioral level in a vomit-competent species, the least shrew. Our results demonstrate that pretreatment with either a 5-HT(3) (tropisetron)- or an NK(1) (CP99,994)-receptor specific antagonist, attenuates vomiting caused by a selective agonist (2-methyl 5-HT or GR73632, respectively) of both emetic receptors. In addition, relative to each antagonist alone, their combined doses were 4-20 times more potent against vomiting caused by each emetogen. Moreover, combined sub-maximal doses of the agonists 2-methyl 5-HT and GR73632, produced 8-12 times greater number of vomits relative to each emetogen tested alone. However, due to large variability in vomiting caused by the combination doses, the differences failed to attain significance. The antiemetic dose-response curves of tropisetron against both emetogens were U-shaped probably because larger doses of this antagonist behave as a partial agonist. The data demonstrate that 5-HT(3)- and NK(1)-receptors cross-talk to produce vomiting, and that synergistic antiemetic effects occur when both corresponding antagonists are concurrently used against emesis caused by each specific emetogen.

Topics: Analysis of Variance; Animals; Antiemetics; Dose-Response Relationship, Drug; Drug Synergism; Female; Indoles; Male; Neurokinin-1 Receptor Antagonists; Peptide Fragments; Piperidines; Receptors, Neurokinin-1; Serotonin; Serotonin 5-HT3 Receptor Antagonists; Shrews; Substance P; Tropisetron; Vomiting

Cisplatin chemotherapy frequently causes severe vomiting in two temporally separated clusters of bouts dubbed the acute and delayed phases. Cannabinoids can inhibit the acute phase, albeit through a poorly understood mechanism. We examined the substrates of cannabinoid-mediated inhibition of both the emetic phases via immunolabeling for serotonin, Substance P, cannabinoid receptors 1 and 2 (CB(1), CB(2)), and the neuronal activation marker Fos in the least shrew (Cryptotis parva). Shrews were injected with cisplatin (10mg/kg i.p.), and one of vehicle, Delta(9)-THC, or both Delta(9)-THC and the CB(1) receptor antagonist SR141716A (2mg/kg i.p.), and monitored for vomiting. Delta(9)-THC-pretreatment caused concurrent decreases in the number of shrews expressing vomiting and Fos-immunoreactivity (Fos-IR), effects which were blocked by SR141716A-pretreatment. Acute phase vomiting induced Fos-IR in the solitary tract nucleus (NTS), dorsal motor nucleus of the vagus (DMNX), and area postrema (AP), whereas in the delayed phase Fos-IR was not induced in the AP at all, and was induced at lower levels in the other nuclei when compared to the acute phase. CB(1) receptor-IR in the NTS was dense, punctate labeling indicative of presynaptic elements, which surrounded Fos-expressing NTS neurons. CB(2) receptor-IR was not found in neuronal elements, but in vascular-appearing structures. All areas correlated with serotonin- and Substance P-IR. These results support published acute phase data in other species, and are the first describing Fos-IR following delayed phase emesis. The data suggest overlapping but separate mechanisms are invoked for each phase, which are sensitive to antiemetic effects of Delta(9)-THC mediated by CB(1) receptors.

Topics: Analgesics, Non-Narcotic; Animals; Area Postrema; Brain Stem; Cisplatin; Dronabinol; Drug Therapy, Combination; Female; Immunohistochemistry; Injections, Intraperitoneal; Microscopy, Confocal; Neurons; Oncogene Proteins v-fos; Piperidines; Presynaptic Terminals; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant; Serotonin; Shrews; Solitary Nucleus; Substance P; Time Factors; Vomiting

Considerable evidence implicates the endocannabinoid system as a neuromodulator of nausea and vomiting. The action of anandamide (AEA) can be prolonged by inhibiting its degradation, through the use of URB597 (URB), a Fatty Acid Amide Hydrolase (FAAH) enzyme inhibitor. Here we present evidence that the FAAH inhibitor, URB, interferes with cisplatin- and nicotine-induced vomiting in the Suncus murinus. In Experiment 1, shrews were injected with URB (0.9 mg/kg) or vehicle 120 min prior to the behavioral testing. They received a second injection of AEA (5 mg/kg) or vehicle 15 min prior to being injected with cisplatin (20 mg/kg) or saline and the number of vomiting episodes were counted for 60 min. In Experiment 2, shrews were injected with vehicle or URB (0.9 mg/kg) 120 min prior to receiving an injection of nicotine (5 mg/kg) or saline and the number of vomiting episodes were counted for 15 min. Experiment 3 evaluated the potential of the CB(1) antagonist, SR141716, to reverse the effect of URB on nicotine-induced vomiting. URB attenuated vomiting produced by cisplatin and nicotine and the combination of URB+AEA suppressed vomiting produced by cisplatin. The effect of URB on nicotine-induced vomiting was reversed by SR141716. These data suggest that the EC system plays a tonic role in the regulation of toxin-induced vomiting.

Topics: Amidohydrolases; Animals; Arachidonic Acids; Benzamides; Carbamates; Cisplatin; Drug Interactions; Endocannabinoids; Female; Male; Nicotine; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Shrews; Vomiting

The objective was to investigate the frequency of adverse events (AE) as a cause for discontinuation of donepezil treatment for Alzheimer's dementia (DAT) in a geriatric memory unit.. Five-year retrospective study of 123 donepezil-treated patients diagnosed with DAT or mixed dementia in a geriatric memory unit. The material covers all patients treated with donepezil and surveyed for 12 months in the memory unit during the period from 14th March 2001 to 7th April 2006.. Among the 123 patients, 106 (86%) suffered from DAT and 17 (14%) suffered from mixed dementia. A total of 100 (81%) were female while 23 (19%) were male. The median age was 84 years. In all, 26 (21%) patients discontinued treatment due to AE. The most frequent AE were nausea/vomiting, diarrhoea and loss of appetite.. In 21% of the cases treatment was discontinued within 12 months due to AE. The most frequent AEs were nausea/vomiting, diarrhoea and loss of appetite. For the most part discontinuation took place within the initial three months. However, some treatments were not discontinued until after six months; consequently, treatment should be supervised and patients should have easy access to a memory unit in the case of AE.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Appetite; Cholinesterase Inhibitors; Diarrhea; Donepezil; Female; Humans; Indans; Male; Nausea; Nootropic Agents; Piperidines; Retrospective Studies; Vomiting

U46619 is a potent thromboxane A(2) mimetic with emesis-inducing actions that are mediated via prostanoid TP receptors. We investigated its emetic mechanism of action in more detail using the ferret as model animal. The emesis induced by U46619 (30 microg/kg, intraperitoneal) was antagonized significantly by (+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine hydrochloride (CP-99,994; 1 and 10 mg/kg; P < 0.05) and metoclopramide (0.3 and 3 mg/kg), but not by domperidone (3 mg/kg), sulpiride (0.1 mg/kg), ondansetron (0.1 and 1 mg/kg) alone or combined with droperidol (3 mg/kg), GR125487 (1 mg/kg), promethazine (3 mg/kg), or scopolamine (3 mg/kg); GR 125487 (1 mg/kg) prevented the anti-emetic action of metoclopramide (3 mg/kg). U46619 0.3 microg administered into the fourth ventricle rapidly induced emesis. However, bilateral abdominal vagotomy was ineffective in reducing the emetic response (P > 0.05). Our data suggests that U46619 induces emesis via an extra-abdominal mechanism, probably within the brain. Metoclopramide probably has a mechanism of action to prevent U46619-induced emesis via 5-HT(4) receptor activation and NK(1) tachykinin receptor antagonists could be useful to prevent emesis induced by TP receptor activation in man.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Antiemetics; Disease Models, Animal; Ferrets; Metoclopramide; Piperidines; Receptors, Thromboxane; Vagotomy; Vomiting

A novel central nervous system (CNS) selective neurokinin-1 (NK(1)) receptor antagonist, (2S,3S)-3-[(1R)-6-methoxy-1-methyl-1-trifluoromethylisochroman-7-yl]-methylamino-2-phenylpiperidine 'CJ-17,493' (compound (+)-1), was synthesized stereoselectively using a kinetic resolution by lipase-PS as a key step. Compound (+)-1 displayed high and selective affinity (K(i)=0.2 nM) for the human NK(1) receptor in IM-9 cells, potent activity in the [Sar(9), Met(O(2))(11)]SP-induced gerbil tapping model (ED(50)=0.04 mg/kg, s.c.) and in the ferret cisplatin (10mg/kg, i.p.)-induced anti-emetic activity model (vomiting: ED(90)=0.07 mg/kg, s.c.), all levels of activity comparable with those of CP-122,721. In addition, compound (+)-1 exhibited linear pharmacokinetics rather than the super dose-proportionality of CP-122,721 and this result provides a potential solution for the clinical issue observed with CP-122,721.

Topics: Animals; Antiemetics; Benzopyrans; Cell Line; Cisplatin; Dose-Response Relationship, Drug; Ferrets; Gerbillinae; Humans; Molecular Structure; Neurokinin-1 Receptor Antagonists; Piperidines; Structure-Activity Relationship; Vomiting

The pharmacological properties of T-2328 were evaluated as an antagonist of the tachykinin neurokinin 1 (NK(1)) receptor. T-2328 inhibited the specific binding of [(3)H][Sar(9),Met(O(2))(11)]substance P to tachykinin NK(1) receptors in human lymphoblastic IM9 cells with K(i) of 0.08 nM. In the same assay, K(i) for aprepitant, a brain-penetrating NK(1) antagonist, was 1.3 nM. The antagonism of T-2328 is highly selective for the human NK(1) receptors since the affinities for human NK(2), NK(3) receptors, and 13 other kinds of receptors and ion channels were >1000-fold lower than for NK(1) receptors. Reduction in Bmax with no change in affinity suggests the non-competitive nature of T-2328 interaction with the NK(1) receptor. T-2328 (0.03-0.1 mg/kg, i.v.) and aprepitant (1 - 3 mg/kg, i.v.) significantly prevented the GR73632 (i.c.v.)-induced foot tapping response in gerbils. The potencies of T-2328 in both in vitro and in vivo studies were more than 10 times greater than those of aprepitant. I.v. administration of T-2328 (0.1-0.3 mg/kg) potently blocked both acute and delayed emetic responses induced by cisplatin (5 mg/kg, i.p.) in ferrets. It is concluded that T-2328 is a potent, centrally active NK(1) antagonist. T-2328 may have potential as a novel therapeutic agent for the treatment of chemotherapy-induced emesis.

Topics: Animals; Antiemetics; Antineoplastic Agents; Aprepitant; Binding Sites; Brain; Cell Line, Tumor; CHO Cells; Cisplatin; Cricetinae; Cricetulus; Disease Models, Animal; Dose-Response Relationship, Drug; Ferrets; Gerbillinae; Humans; Kinetics; Male; Morpholines; Motor Activity; Neurokinin-1 Receptor Antagonists; Peptide Fragments; Piperidines; Receptors, Neurokinin-1; Substance P; Transfection; Vomiting

We examined the therapeutic potential of a proprietary Croton palanostigma extract (Zangrado(R)) in the management of emesis and itch.. Emesis was induced in ferrets with morphine-6-glucuronide (0.05 mg/kg sc) in the presence of Zangrado (3 mg/kg, ip) and the cannabinoid receptor 1 antagonist, AM 251 (5 mg/kg, ip). Topical Zangrado (1%) was assessed for anti-pruretic actions in the 5-HT-induced scratching model in rats and evaluated in capsaicin-induced gastric hyperemia as measured by laser doppler flow. In the ApcMinmouse model of precancerous adenomatosis polyposis, mice received Zangrado (100 mug/ml in drinking water) from the age of 6 - 16 weeks for effects on polyp number. In RAW 264.7 cells Zangrado was examined for effects on lipopolysaccharide-induced nitrite production.. Zangrado was a highly effective anti-emetic, reducing morphine-induced vomiting and retching by 77%. These benefits were not associated with sedation or hypothermia and were not reversed by cannabinoid receptor antagonism. Itch responses were blocked in both the morphine and 5-HT models. Zangrado did not exacerbate the ApcMincondition rather health was improved. Capsaicin-induced hyperemia was blocked by Zangrado, which also attenuated the production of nitric oxide by activated macrophages.. Zangrado is an effective anti-emetic and anti-itch therapy that is devoid of common side-effects, cannabinoid-independent and broadly suppresses sensory afferent nerve activation. This complementary medicine represents a promising new approach to the management of nausea, itch and irritable bowel syndrome.

Topics: Animals; Antiemetics; Antipruritics; Cell Line; Croton; Ferrets; Male; Mice; Mice, Inbred C57BL; Morphine Derivatives; Nausea; Piperidines; Plant Extracts; Proanthocyanidins; Pruritus; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Vomiting

Substance P (SP) is thought to play a cardinal role in emesis via the activation of central tachykinin NK1 receptors during the delayed phase of vomiting produced by chemotherapeutics. Although the existing supportive evidence is significant, due to lack of an appropriate animal model, the evidence is indirect. As yet, no study has confirmed that emesis produced by SP or a selective NK1 receptor agonist is sensitive to brain penetrating antagonists of either NK1, NK2, or NK3 receptors. The goals of this investigation were to demonstrate: 1) whether intraperitoneal (i.p.) administration of either SP, a brain penetrating (GR73632) or non-penetrating (e.g. SarMet-SP) NK1 receptor agonist, an NK2 receptor agonist (GR64349), or an NK3 receptor agonist (Pro7-NKB), would induce vomiting and/or scratching in the least shrew (Cryptotis parva) in a dose-dependent manner; and whether these effects are sensitive to the above selective receptor antagonists; 2) whether an exogenous emetic dose of SP (50 mg/kg, i.p.) can penetrate into the shrew brain stem and frontal cortex; 3) whether GR73632 (2.5 mg/kg, i.p.)-induced activation of NK1 receptors increases Fos-measured neuronal activity in the neurons of both brain stem emetic nuclei and the enteric nervous system of the gut; and 4) whether selective ablation of peripheral NK1 receptors can affect emesis produced by GR73632. The results clearly demonstrated that while SP produced vomiting only, GR73632 caused both emesis and scratching behavior dose-dependently in shrews, and these effects were sensitive to NK1-, but not NK2- or NK3-receptor antagonists. Neither the selective, non-penetrating NK1 receptor agonists, nor the selective NK2- or NK3-receptor agonists, caused a significant dose-dependent behavioral effect. An emetic dose of SP selectively and rapidly penetrated the brain stem but not the frontal cortex. Systemic GR73632 increased Fos expression in the enteric nerve plexi, the medial subnucleus of nucleus tractus solitarius, and the dorsal motor nucleus of the vagus, but not the area postrema. Ablation of peripheral NK1 receptors attenuated the ability of GR73632 to induce a maximal frequency of emesis and shifted its percent animals vomiting dose-response curve to the right. The NK1-ablated shrews exhibited scratching behavior after systemic GR73632-injection. These results, for the first time, affirm a cardinal role for central NK1 receptors in SP-induced vomiting, and a facilitatory role for gastrointestin

Topics: Animals; Antiemetics; Brain; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Enteric Nervous System; Neurokinin-1 Receptor Antagonists; Oncogene Proteins v-fos; Peptide Fragments; Piperidines; Receptors, Neurokinin-1; Recombinant Fusion Proteins; Ribosome Inactivating Proteins, Type 1; Saporins; Shrews; Stereotyped Behavior; Substance P; Time Factors; Tissue Distribution; Vomiting

The endogenous cannabinoid system plays a vital role in the control of nausea and emesis. Because of the rapid breakdown and hydrolysis of endocannabinoids, such as anandamide, the therapeutic effects may be enhanced by prolonging their duration of action.. The present experiment evaluated the potential of various doses of URB597, a fatty acid amide hydrolase (FAAH) inhibitor, alone and in combination with systemic administration of anandamide to modulate the establishment of lithium-induced conditioned taste reactivity responses in rats.. In experiment 1, on the conditioning day, rats first received an injection of 0.3 mg/kg URB597, 0.15 mg/kg URB597, or vehicle and then received a second injection of anandamide (5 mg/kg) or vehicle, before a 3-min exposure of 0.1% saccharin by intraoral infusion. Immediately after the saccharin exposure, the rats were injected with lithium chloride. On each of three test days, rats received a 3-min intraoral infusion of saccharin solution, and the taste reactivity responses were videotaped and monitored. In experiment 2, the effects of pretreatment with the CB(1) antagonist, AM-251, on URB597 and anandamide-induced suppressed aversion was evaluated.. Administration of URB597 alone and in combination with anandamide reduced active rejection reactions elicited by a LiCl-paired saccharin solution; both effects were reversed by pretreatment with AM-251, suggesting that they were CB(1) receptor mediated.. The results suggest that prolonging the action of anandamide by pretreatment with the FAAH inhibitor, URB597, suppresses lithium-induced nausea in the rat.

Topics: Amidohydrolases; Animals; Arachidonic Acids; Association Learning; Avoidance Learning; Benzamides; Carbamates; Conditioning, Classical; Dose-Response Relationship, Drug; Endocannabinoids; Injections, Intraperitoneal; Lithium Chloride; Male; Nausea; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Long-Evans; Receptor, Cannabinoid, CB1; Vomiting

Cannabinoid (CB) agonists suppress nausea and vomiting (emesis). Similarly, transient receptor potential vanilloid-1 (TRPV1) receptor agonists are anti-emetic. Arvanil, N-(3-methoxy-4-hydroxy-benzyl)-arachidonamide, is a synthetic 'hybrid' agonist of CB1 and TRPV1 receptors. Anandamide and N-arachidonoyl-dopamine (NADA) are endogenous agonists at both these receptors. We investigated if arvanil, NADA and anandamide were anti-emetic in the ferret and their mechanism of action. All compounds reduced the episodes of emesis in response to morphine 6 glucuronide. These effects were attenuated by AM251, a CB1 antagonist that was pro-emetic per se, and TRPV1 antagonists iodoresiniferatoxin and AMG 9810, which were without pro-emetic effects. Similar sensitivity to arvanil and NADA was found for prodromal signs of emesis. We analysed the distribution of TRPV1 receptors in the ferret brainstem and, for comparison, the co-localization of CB1 and TRPV1 receptors in the mouse brainstem. TRPV1 immunoreactivity was largely restricted to the nucleus of the solitary tract of the ferret, with faint labeling in the dorsal motor nucleus of the vagus and sparse distribution in the area postrema. A similar distribution of TRPV1, and its extensive co-localization with CB1, was observed in the mouse. Our findings suggest that CB1 and TRPV1 receptors in the brainstem play a major role in the control of emesis by agonists of these two receptors. While there appears to be an endogenous 'tone' of CB1 receptors inhibiting emesis, this does not seem to be the case for TRPV1 receptors, indicating that endogenously released endocannabinoids/endovanilloids inhibit emesis preferentially via CB1 receptors.

Topics: Acrylamides; Animals; Antiemetics; Arachidonic Acids; Area Postrema; Autonomic Pathways; Brain Stem; Bridged Bicyclo Compounds, Heterocyclic; Cannabinoids; Capsaicin; Dopamine; Emetics; Endocannabinoids; Ferrets; Male; Mice; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Receptor, Cannabinoid, CB1; Solitary Nucleus; TRPV Cation Channels; Vagus Nerve; Vomiting

Topics: Animals; Cisplatin; Injections, Intraperitoneal; Kaolin; Neurokinin-1 Receptor Antagonists; Pharmacology; Pica; Piperidines; Rats; Vomiting

The action of ondansetron (1 mg/kg, i.p.) and (+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994; 10 mg/kg, i.p.) on spontaneous behavior and the emesis induced by cisplatin (10 mg/kg, i.p.) was studied in the ferret. Ondansetron was inactive to modify behavior, but CP-99,994 reduced spontaneous locomotor activity and lip licking by 48% (P<0.01) and 79% (P<0.01), respectively; CP-99,994 also abolished spontaneous burrowing activity (P<0.05). Treatment of animals with cisplatin induced an emetic response that was abolished by both ondansetron and CP-99,994 (P<0.01). However, cisplatin did not significantly modify other behavioral measures although animals that received CP-99,994, cisplatin, or CP-99,994 in combination with cisplatin exhibited more episodes of defecation than animals that received ondansetron (P<0.05). The action of CP-99,994 to modify behavior in this species is discussed in relation to animal models of nausea.

Topics: Animals; Antiemetics; Behavior, Animal; Cisplatin; Ferrets; Male; Ondansetron; Piperidines; Vomiting

Activation of vanilloid receptors has commonly been used to facilitate neurogenic inflammation and plasma exudation to model components of the pathogenesis of migraine; however, these studies have been performed mainly in species lacking the emetic reflex. In the present studies, therefore, we used Suncus murinus, a species of insectivore capable of emesis, to investigate if the vanilloid receptor agonist resiniferatoxin is capable of modeling the emesis associated with migraine. Resiniferatoxin (100 nmol/kg, s.c.) induced an emetic response that was antagonized significantly (P<0.05) by ruthenium red (1-3 micromol), (2R-trans)-4-[1-[3,5-bis(trifluromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-acetamide (S)-hydroxybutanedioate (R116301; 10-100 micromol/kg), and scopolamine (1 micromol/kg), but not by dihydroergotamine (0.3-3 micromol/kg), sumatriptan (1-10 micromol/kg), methysergide (1-10 micromol/kg), tropanyl 3,5-dichlorobenzoate (MDL72222; 3-30 micromol/kg), ondansetron (0.3-3 micromol/kg), metoclopramide (3-30 micromol/kg), domperidone (3-30 micromol/kg), diphenhydramine (1-10 micromol/kg), or indomethacin (3-30 micromol/kg). The failure of a wide range of representative anti-migraine drugs to reduce retching and vomiting limits the use of this model to identify/investigate novel treatments for the emesis (and nausea) associated with migraine attacks in humans. However, the results provide further evidence for the involvement of a novel vanilloid receptor in resiniferatoxin-induced emesis and implicate both tachykinins and acetylcholine in the pathway(s) activated by resiniferatoxin in S. murinus.

Topics: Animals; Antiemetics; Butanols; Capsaicin; Cyclooxygenase Inhibitors; Dihydroergotamine; Diphenhydramine; Diterpenes; Domperidone; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Humans; Indomethacin; Malates; Methysergide; Metoclopramide; Migraine Disorders; Ondansetron; Piperidines; Ruthenium Red; Scopolamine; Serotonin Antagonists; Serotonin Receptor Agonists; Shrews; Sumatriptan; Time Factors; Tropanes; Vomiting

Species possessing the emetic reflex are useful for anti-emetic screening. Assessing the potential of novel drugs to simultaneously reduce nausea and emesis in animals is problematic, however. In the present studies, therefore, the behavioural repertoire of Suncus murinus in response to the emetic chemotherapeutic drug cisplatin was studied in an attempt to characterize behaviours (including spontaneous locomotor activity) that may be relevant to nausea status. Cisplatin at 30 mg/kg, intraperitoneal, induced a robust emetic response but did not induce novel behaviour and failed to affect spontaneous locomotor activity. Ondansetron at 3 mg/kg, subcutaneous, and CP-99,994 at 10 mg/kg, subcutaneous, reduced emesis by 98% and 40.7%, respectively. Both ondansetron and CP-99,994, however, were inactive in modifying spontaneous locomotor activity in either cisplatin-treated or normal animals. Results are discussed in relation to other animal models of nausea and emesis.

Topics: Animals; Antineoplastic Agents; Behavior, Animal; Cisplatin; Female; Motor Activity; Ondansetron; Piperidines; Serotonin Receptor Agonists; Shrews; Vomiting

Marijuana has been reported to interfere with nausea and vomiting in chemotherapy patients. The principal cannabinoids found in marijuana include the psychoactive compound Delta-9-tetrahydrocannabinol (THC) and the non-psychoactive compound cannabidiol (CBD). The experiments reported here evaluated the potential of THC and CBD to interfere with vomiting in the Suncus murinus (house musk shrew) produced by lithium chloride (LiCl), which is the most commonly employed unconditioned stimulus for taste avoidance.. To evaluate the potential of the principal components of marijuana, THC and CBD, to suppress Li-induced vomiting in the house musk shrew.. Shrews were injected with vehicle or one of two cannabinoids [Delta-9-THC (1-20 mg/kg), or CBD (2.5-40 mg/kg)] 10 min prior to an injection of LiCl (390 mg/kg of 0.15 M) and were then observed for 45 min. The frequency of vomiting episodes and the latency to the first episode were measured. The role of the CB1 receptor in these effects was also evaluated by pretreatment with SR-141716.. Delta-9-THC produced a dose-dependent suppression of Li-induced vomiting, with higher doses producing greater suppression than lower doses. CBD produced a biphasic effect with lower doses producing suppression and higher doses producing enhancement of Li-induced vomiting. The suppression of Li-induced vomiting by THC, but not by CBD, was reversed by SR-141716.. These results indicate that two major cannabinoid compounds found in marijuana, THC and CBD, are effective treatments for Li-induced vomiting; however, only THC acts by the CB1 receptor. The effects of THC and CBD on vomiting were dose dependent; with THC the effect was linear, but with CBD the effect was biphasic.

Topics: Animals; Antiemetics; Cannabidiol; Dose-Response Relationship, Drug; Dronabinol; Female; Injections, Intraperitoneal; Lithium Chloride; Male; Piperidines; Pyrazoles; Rimonabant; Shrews; Vomiting

The 5-HT3 antagonist, ondansetron (OND), and the cannabinoid, delta9-tetrahydrocannabinol (delta9-THC), have been shown to interfere with emesis; however, their relative and/or combined effectiveness in suppressing vomiting produced by the chemotherapeutic agent, cisplatin, is unknown.. To evaluate the potential of: 1) a broad range of doses of delta9-THC and OND to prevent cisplatin-induced vomiting and retching in the Suncus murinus (house musk shrew), 2) combined treatment with ineffective individual doses of delta9-THC and OND to prevent cisplatin-induced vomiting and retching, 3) the CB1 receptor antagonist, SR141716, to reverse the antiemetic effects of OND, and 4) cannabidiol (CBD), the principal non-psychoactive component of marijuana, to reverse cisplatin-induced vomiting in the shrew.. Shrews were injected with various doses of OND (0.02-6.0 mg/kg), delta9-THC (1.25-10 mg/kg) and a combination of ineffective doses of each (0.02 mg/kg OND+1.25 mg/kg delta9-THC) prior to being injected with cisplatin (20 mg/kg) which induces vomiting. Shrews were also injected with CBD (5 mg/kg and 40 mg/kg) prior to an injection of cisplatin.. OND and delta9-THC both dose-dependently suppressed cisplatin-induced vomiting and retching. Furthermore, a combined pretreatment of doses of the two drugs that were ineffective alone completely suppressed vomiting and retching. CBD produced a biphasic effect, suppressing vomiting at 5 mg/kg and potentiating it at 40 mg/kg.. A low dose of the non-intoxicating cannabinoid CBD may be an effective anti-emetic treatment and combined doses of OND and delta9-THC that are ineffective alone suppresses cisplatin-induced emetic reactions in shrews.

Topics: Animals; Antiemetics; Antineoplastic Agents; Cannabinoids; Cisplatin; Dose-Response Relationship, Drug; Dronabinol; Drug Therapy, Combination; Female; Lithium; Male; Ondansetron; Piperidines; Psychotropic Drugs; Pyrazoles; Rimonabant; Shrews; Vomiting

Previous studies showed that diphenidol was effective on emetogens-induced pica, eating of non-nutritive substances, in rats, a model analogous to emesis in other species. We evaluated the actual antiemetic activity of diphenidol against four emetic stimuli in the dog and ferret, animals that possess an emetic reflex. In dogs, emetic responses to apomorphine were significantly prevented by diphenidol (3.2 mg/kg, i.v.), whereas diphenidol (3.2 mg/kg, i.v. x 2) showed a weak inhibition to the vomiting evoked by cisplatin. In ferrets, diphenidol (10 mg/kg, i.p.) exhibited a weak antiemetic activity on the emesis induced by copper sulfate and had no activity on emesis by loperamide. On the other hand, CP-122,721, a NK1-receptor antagonist, significantly reduced the emetic episodes to all four stimuli. These results suggest that the prediction of antiemetic activity of compounds in animals lacking an emetic reflex does not always correspond with actual antiemetic activity.

Topics: Animals; Antiemetics; Dogs; Female; Ferrets; Male; Piperidines; Species Specificity; Vomiting

Dibenzopyran (Delta(9)-tetrahydrocannabinol) and aminoalkylindole [R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrolol[1,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl) methanone mesylate; (WIN55,212-2)] cannabinoids suppress vomiting produced by cisplatin via cannabinoid CB(1) receptors. This study investigates the antiemetic potential of the "nonclassical" cannabinoid CP55,940 [1alpha,2beta-(R)-5alpha]-(-)-5-(1,1-dimethyl)-2-[5-hydroxy-2-(3-hydroxypropyl) cyclohexyl-phenol] against cisplatin-induced vomiting and assesses the presence and functionality of cannabinoid CB(1) receptors in the least shrew (Cryptotis parva) brain. CP55,940 (0.025-0.3 mg/kg) reduced both the frequency of cisplatin-induced emesis (ID(50)=0.025 mg/kg) and the percentage of shrews vomiting (ID(50)=0.09 mg/kg). CP55,940 also suppressed shrew motor behaviors (ID(50)=0.06- 0.21 mg/kg) at such doses. The antiemetic and motor-suppressant actions of CP55,940 were countered by SR141716A [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide], indicating both effects are cannabinoid CB(1) receptor-mediated. Autoradiographic studies with [3H]-SR141716A and [35S]-GTPgammaS binding revealed that the distribution of the cannabinoid CB(1) receptor and its activation pattern are similar to rodent brain and significant levels are present in brain loci (e.g., nucleus tractus solitarius (NTS)) that control emesis. The affinity rank order of structurally diverse cannabinoid ligands for cannabinoid CB(1) receptor in shrew brain is similar to rodent brain: HU-210=CP55,940=SR141716A>/=WIN55,212-2>/=delta-9-tetrahydrocannabinol>methanandamide=HU-211=cannabidiol=2-arachidonoylglycerol. This affinity order is also similar and is highly correlated to the cannabinoid EC(50) potency rank order for GTPgammaS stimulation except WIN55,212-2 and delta-9-tetrahydrocannabinol potency order were reversed. The affinity and the potency rank order of tested cannabinoids were significantly correlated with their antiemetic ID(50) potency order against cisplatin-induced vomiting (CP55,940>WIN55,212-2=delta-9-tetrahydrocannabinol) as well as emesis produced by 2-arachidonoylglycerol or SR141716A (CP55,940>WIN55,212-2>delta-9-tetrahydrocannabinol).

Topics: Animals; Antiemetics; Benzoxazines; Binding, Competitive; Brain; Cisplatin; Cyclohexanols; Dose-Response Relationship, Drug; Dronabinol; Female; GTP-Binding Proteins; Guanosine 5'-O-(3-Thiotriphosphate); Injections, Intraperitoneal; Injections, Subcutaneous; Male; Morpholines; Motor Activity; Naphthalenes; Piperidines; Pyrazoles; Radioligand Assay; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Shrews; Sulfur Radioisotopes; Tritium; Vomiting

Cisplatin (4 mg/kg, i.v.) induced both early emesis, which appears within the first 8-h period, and delayed emesis, which appears between 8 and 48 h after its administration to pigeons. GR205171 ([(2S-cis)-N-((2-methoxy-5(5-(trifluoromethyl)-1H-tetrazol-1-yl)-phenyl) methyl)-2-phenyl-3-piperidinamine dihydrochloride]) administered intramuscularly (1-10 mg/kg) reduced significantly the number of emetic response to cisplatin: this reduction was 60-81% (P < 0.05) for early emesis and 48-64% (P < 0.05) for the delayed response. Intracerebroventricularly administered GR205171 (30 microg/kg) also reduced the number of emetic responses: 53% (P < 0.05) in early emesis and 88% (P < 0.05) in the delayed response. However, the latency time to the first emesis was not affected by GR205171. Direct injection of cisplatin (10 microg/kg) into the fourth ventricle produced emesis, which was reduced by GR205171 administered via the peripheral or central route. Substance P-immunoreactive fibres were distributed throughout the dorsal vagal complex. These results suggest that the antiemetic effect of GR205171 on both emetic responses to cisplatin acts on a central site, and that the onset of the emetic response may be mediated partly via GR205171-insensitive mechanisms.

Topics: Animals; Antiemetics; Cisplatin; Columbidae; Female; Immunohistochemistry; Injections, Intramuscular; Injections, Intravenous; Injections, Intraventricular; Male; Neurokinin-1 Receptor Antagonists; Piperidines; Solitary Nucleus; Substance P; Tetrazoles; Vagus Nerve; Vomiting

Large doses (10-40 mg/kg) of the selective cannabinoid CB(1) receptor antagonist, SR 141716A, produce the head-twitch response (HTR) and scratching in rodents and vomiting in the least shrew (Cryptotis parva). Agents that increase brain serotonin (5-HT) levels induce the HTR in rodents, whereas enhancements in either brain 5-HT or dopamine concentrations can lead to production of emesis in vomiting species. The present study was undertaken to demonstrate whether large doses of SR 141716A can (1) induce the HTR and scratching in the least shrew and (2) cause concurrent biochemical changes in brain 5-HT and dopamine concentrations. SR 141716A (0, 1, 5, 10, 20 and 40 mg/kg i.p.) administration induced the HTR, scratching and vomiting. The HTR effect was bell shaped with a maximum frequency occurring at the 20 mg/kg SR 141716A dose, whereas the scratching and vomiting behaviors displayed dose-dependent effects. The selective 5-HT(2A/C) receptor antagonist, SR 46349B (0, 0.1, 0.25, 1, 3 and 6 mg/kg i.p.), differentially attenuated all SR 141716A (20 mg/kg)-induced behaviors because the HTR was relatively more potently and completely blocked. In the shrew forebrain, SR 141716A (20 and 40 mg/kg ip) caused dose- and time-dependent increases in the levels of 5-HT and dopamine and the concentrations of their major metabolites [5-hydroxyindole acetic acid (5-HIAA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanilic acid (HVA)] and the turnover of both monoamines. Although the effects of SR 141716A on brainstem concentrations of both monoamines and their metabolites were not always consistent, the CB(1) antagonist did increase the turnover of both 5-HT and dopamine. The present findings suggest that the mechanism and the neurochemical substrate for SR 141716A-induced HTR and scratching behaviors is enhancement of 5-HT release, whereas increased release of 5-HT and dopamine probably contributes to the production of emesis.

Topics: Animals; Behavior, Animal; Brain; Dopamine; Dose-Response Relationship, Drug; Female; Male; Piperidines; Pruritus; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Serotonin; Shrews; Vomiting

A 79-year-old woman with Alzheimer's disease was admitted due to acute cholinergic symptoms induced by overdose (45 mg) of donepezil (DPZ). Physical examination showed bradycardia, sinus arrhythmia, vomiting and respiratory insufficiency. She was treated with atropine intravenously and her cholinergic symptoms subsided in the next evening. After 5 days she was discharged from the hospital and DPZ was withholded for about 4 weeks. The plasma concentration of DPZ was 54.6 ng/ml on admission and gradually decreased to the normal limits in about 90 hours. The calculative half-life of DPZ was about 55 hours. Since the half-life of DPZ is long and differs between individuals, hospitalization and treatment with atropine is recommended for cholinergic side effects induced by overdose of DPZ. It is important to prevent dosing errors in cooperation with medical providers, patients and families.

Topics: Aged; Alzheimer Disease; Arrhythmia, Sinus; Bradycardia; Cholinesterase Inhibitors; Donepezil; Drug Overdose; Electrocardiography; Female; Humans; Indans; Piperidines; Vomiting

The emetic action of the prostanoid TP receptor agonist, 11alpha,9alpha-epoxymethano-15S-hydroxyprosta-5Z,13E-dienoic acid (U46619; 300 microg/kg, i.p.), was investigated in Suncus murinus. The emetic response was reduced by 76% following bilateral abdominal vagotomy (P<0.001) and by reserpine (5 mg/kg, i.p., 24 h pretreatment; P<0.05) but U46619 administered i.c.v. (30-300 ng) was not emetic, suggesting a peripheral mechanism involving monoamines. However, fenfluramine (5 mg/kg, repeated treatment) and para-chlorophenylalanine (100-400 mg/kg) and ondansetron (0.3-3 mg/kg) were inactive (P>0.05) to reduce U46619-induced emesis precluding a role of 5-HT and 5-HT(3) receptors in the mechanism. Similarly, phentolamine (0.3-3 mg/kg), propranolol (3 mg/kg), and their combination, and metoclopramide (0.3-3 mg/kg), domperidone (0.3-3 mg/kg), droperidol (0.3-3 mg/kg), scopolamine (0.3-3 mg/kg) and promethazine (0.3-3 mg/kg) were inactive (P>0.05) to reduce the retching and vomiting response. However, the tachykinin NK(1) receptor antagonist, (+)-2S,3S(-3-(2-methoxy-5-trifluoromethoxybenzyl)amino-2-phenylpiperidine) (CP-122,721; 1-10 mg/kg) antagonized emesis (P<0.01). In conclusion, U46619-induced emesis appears to be mediated via a predominant peripheral mechanism sensitive to reserpine and is not likely to involve adrenoceptors, dopamine, 5-HT(3), muscarinic or histamine (H(1)) receptors. The action of CP-122,721 to reduce U46619-induced emesis extends the spectrum of anti-emetic action tachykinin NK(1) receptor antagonists to mechanisms involving TP receptors.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Emetics; Female; Male; Piperidines; Receptors, Thromboxane; Shrews; Vagotomy; Vagus Nerve; Vomiting

The purpose of these studies was to evaluate the effect of lerisetron (1-phenyl-methyl-2-piperazinyl-1H-benzimidazole hydrochloride, CAS 143257-98-1, F-0930-RS2), a new 5-HT3 receptor antagonist, on ipecacuanha-induced nausea and vomiting. The ipecacuanha model of emesis has been used to test the anti-emetic activity of several different 5-HT3 antagonists and the anti-emetic doses that were effective in the ipecacuanha model have been found to correlate well with the clinically effective doses. Study 1 investigated oral doses of lerisetron from 4 mg to 40 mg. Study 2 evaluated the duration of effect of a single dose of 20 mg oral lerisetron. Study 3 evaluated intravenous doses of 18 mg and 12 mg lerisetron. In Study 1, the 40 mg dose of oral lerisetron inhibited emesis in all test subjects. The percentage of subjects who experienced an emetic episode increased as the dose of lerisetron decreased. At the lowest dose level tested five of six subjects had an emetic episode compared with four out of five in the placebo group. In Study 2, 20 mg oral lerisetron was effective up to 12 h after administration. When ipecacuanha was administered at 18 h post-dose three of seven subjects had an emetic episode and at 24 h post-dose the incidence of emesis was similar to the placebo treatment groups in the previous study. Study 3 demonstrated the effectiveness of intravenous doses of lerisetron. The 18 mg intravenous dose reduced the number of patients experiencing emetic episodes by 75% compared with placebo, doses below 12 mg i.v. were not evaluated because of the reduced efficacy of the compound at this dose level. In conclusion, lerisetron has been shown to be effective in the treatment of ipecacuanha-induced nausea and vomiting at intravenous doses of 18 mg and at oral doses of 20 mg for up to 12 hours.

Topics: Administration, Oral; Adolescent; Adult; Antiemetics; Benzimidazoles; Dose-Response Relationship, Drug; Emetics; Granisetron; Humans; Injections, Intravenous; Ipecac; Male; Nausea; Piperidines; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Serotonin Antagonists; Time Factors; Vomiting

Topics: Alzheimer Disease; Diarrhea; Donepezil; Humans; Indans; Nausea; Nootropic Agents; Piperidines; Vomiting

There is substantial clinical evidence that Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and its synthetic analogs (nabilone and levonantradol) can prevent emesis in cancer patients receiving chemotherapy. Limited available animal studies also support the antiemetic potential of these cannabinoids. The present study investigates the mechanism of antiemetic action of cannabinoids in an established animal model of emesis, the least shew (Cryptotis parva). Since cannabinoid agonists prevent emesis, it was hypothesized that blockade of either the cannabinoid CB(1) receptor or the cannabinoid CB(2) receptor would induce vomiting. Thus, the emetic potential of SR 141716A (CB(1) receptor antagonist) or SR 144528 (CB(2) receptor antagonist) was investigated. Both intraperitoneal (0, 1, 2.5, 5, 10 and 20 mg/kg, n = 7-15 per group) and subcutaneous (0, 10, 20 and 40 mg/kg, n = 6-9 per group) administration of SR 141716A caused emesis (ED(50) = 5.52 +/- 1.23 and 20.2 +/- 1.02 mg/kg, respectively) in the least shrew in a dose-dependent manner. Indeed, both the frequency of emesis and the percentage of animals vomiting increased with increasing doses of SR 141716A. Significant effects were seen at the 10- and 20-mg/kg doses for the IP route, while only the 40-mg/kg dose produced significant emesis via the SC route. The CB(2) antagonist failed to produce emesis via either route of administration. SR 141716A at an IP dose of 20 mg/kg was used to induce emesis for drug interaction studies. Thus, varying doses of three different classes of cannabinoid agonists [CP 55, 940 (0, 0.1, 0.5 and 1 mg/kg), WIN 55, 212-2 (0, 1, 5 and 10 mg/kg), and Delta(9)-THC (0, 5, 10 and 20 mg/kg)], were administered IP to different groups of shrews 10 min prior to SR 141716A injection. The frequency of emesis was recorded for 30 min following the administration of SR 141716A. The order of potency for redcing both the frequency of emesis and the percentage of shrews vomiting was CP 55, 940 > WIN 55, 212-2 > Delta(9)-THC which is consistent with an action on the CB(1) receptor. These results suggest that the antiemetic activity of Delta(9)-THC and its synthetic analogs reside in their ability to stimulate the cannabinoid CB(1) receptor. Furthermore, the antiemetic potency of CP 55, 940 is 45 times greater than Delta(9)-THC. On the other hand, blockade of CB(1) receptors can induce vomiting, which implicates an important role for endogenous cannabinoids in emetic circuits.

Topics: Analgesics, Non-Narcotic; Animals; Cannabinoids; Dronabinol; Female; Male; Piperidines; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Shrews; Vomiting

Cannabinoid receptor agonists reverse nausea and vomiting produced by chemotherapy and radiation therapy in animals and humans but have not been tested against opioid-induced emesis. This study tests the hypothesis that cannabinoid receptor agonists will prevent opioid-induced vomiting.. Twelve male ferrets were used. They weighed 1.2-1.6 kg at the beginning and 1.8-2.3 kg at the end of the experiments. All drugs were injected subcutaneously. WIN55,212-2, a mixed CB1-CB2 cannabinoid receptor agonist, was administered 25 min before morphine. Retches and vomits were counted at 5-min intervals for 30 min after morphine injection.. Retching and vomiting responses increased with increasing morphine doses up to 1.0 mg/kg, above which the responses decreased. Previous administration of naloxone prevented morphine-induced retching and vomiting. WIN55,212-2 dose-dependently reduced retching and vomiting. The ED50 was 0.05 mg/kg for retches and 0.03 mg/kg for vomits. At 0.13 mg/kg, retching decreased by 76% and vomiting by 92%. AM251, a CB1 receptor-selective antagonist, blocked the antiemetic actions of WIN55,212-2, but AM630, a CB2 receptor-selective antagonist, did not.. These results demonstrate that WIN55,212-2 prevents opioid-induced vomiting and suggest that the antiemetic activity of WIN55,212-2 occurs at CB1 receptors. This is consistent with findings that CB1 receptors are the predominant cannabinoid receptors in the central nervous system and that antiemetic effects of cannabinoids appear to be centrally mediated.

Topics: Analgesics, Opioid; Animals; Antiemetics; Benzoxazines; Ferrets; Male; Morphine; Morpholines; Naphthalenes; Piperidines; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Vomiting

The effects of a novel tachykinin NK1-receptor antagonist HSP-117 [(2S,3S)-3-[(5-isopropyl-2,3-dihydrobenzofuran-7-yl)methyl]amino-2-phenylpiperidine dihydrochloride] on cisplatin-induced pica, i.e., the eating of nonnutritive substances such as kaolin were examined in rats. HSP-117 inhibited kaolin intake in a dose-dependent manner for 2 days. The 5-HT3-receptor antagonist ondansetron inhibited only on the first day, but not on the second day. These results indicate that the cisplatin-induced kaolin intake on the first day is related to both 5-HT3- and NK1 receptors, while only the NK1 receptor is involved on the second day. Thus, cisplatin-induced continuous pica in rats represents a useful model of not only acute but also delayed emesis.

Topics: Animals; Antineoplastic Agents; Benzofurans; Cisplatin; Humans; Neurokinin-1 Receptor Antagonists; Pica; Piperidines; Rats; Rats, Wistar; Vomiting

The dibenzopyran cannabinoids (delta-9 (Delta9)-tetrahydrocannabinol and nabilone) are clinically used to suppress nausea and vomiting produced by chemotherapeutic agents such as cisplatin. The purpose of this investigation was to investigate the antiemetic potential of the aminoalkylindole cannabinoid receptor agonist WIN 55, 212-2 [R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl) methyl] pyrolol [1,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl) methanone mesylate] against cisplatin-induced vomiting. Different doses of WIN 55, 212-2 (0, 1, 2.5 and 5 mg/kg, i.p.) reduced both the frequency of cisplatin (20 mg/kg, i.p.)-induced emesis (ID(50)=0.5 mg/kg) as well as the percentage of shrews vomiting (ID50=1.2 mg/kg) in a dose-dependent manner. Significant reductions in emesis frequency occurred from 2.5 mg/kg dose of WIN 55, 212-2, whereas significant total protection from vomiting was afforded at its 5 mg/kg dose. The antiemetic actions of a 5-mg/kg dose of WIN 55, 212-2 against cisplatin (20 mg/kg, i.p.)-induced vomiting were reversed by nonemetic subcutaneous doses (0, 0.25, 0.5 and 1 mg/kg) of the cannabinoid CB1 receptor antagonist/inverse agonist SR 141716A [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide] (ID50=0.27 and 0.47 mg/kg, respectively) but not by a 5-mg/kg dose of the cannabinoid CB2 receptor antagonist SR 144528 [N-[(1S)-endo-1,3,3-trimethylbicyclo [2.2.1] heptan-2-yl]5-(4-chloro-3-methylphenyl)-1-(4-methybenzyl) pyrazole-3-carboxamide]. The effects of the cited doses of WIN 55, 212-2 were also investigated on several motor parameters (spontaneous locomotor activity, duration of movement and rearing frequency). Significant reductions in motor parameters were only observed at its highest tested dose (ID50=1.97, 2.75 and 2.8 mg/kg; respectively). SR 141716A (0, 0.5, 1, 5 and 10 mg/kg) also reversed the motor suppressant effects of a 5-mg/kg dose of WIN 55, 212-2 (ID50=0.39, 0.1 and 0.3 mg/kg, respectively) and significant reversals were seen from its 0.5 and 1 mg/kg doses. These results suggest that WIN 55, 212-2 reduces both emesis and indeces of locomotion via the stimulation of cannabinoid CB1 receptors. However, cannabinoid CB1 receptors in different loci are most likely responsible for the antiemetic and motor suppressive effects of WIN 55, 212-2 since reduction in the frequency of vomiting occurred at lower doses relative to its sedative actions.

Topics: Animals; Antiemetics; Benzoxazines; Cisplatin; Locomotion; Morpholines; Motor Activity; Naphthalenes; Piperidines; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Shrews; Vomiting

Microinjection and ligand binding studies have implicated NK(1) receptors in the area postrema (AP) in the emetic response to intragastric copper sulphate that is mediated by abdominal vagal afferents. Because these afferents terminate in the brainstem in the nucleus tractus solitarius in close proximity to the AP or in the AP itself, the results of such studies may be difficult to interpret. The present study has demonstrated in the dog that the emetic response to intragastric copper sulphate is unaffected by AP ablation, demonstrated functionally by absence of an emetic response to apomorphine (100 microg kg(-1) i.v.). In AP ablated animals the selective NK(1) receptor antagonist CP-99, 994 (1 mg kg(-1) i.v.) blocked the emetic response to copper sulphate as it did in intact animals. The results demonstrate that the AP is not involved in the blockade of the emetic response to intragastric copper sulphate by an NK(1) receptor antagonist and hence provides further support for other sites proposed such as the nucleus tractus solitarius and central pattern generator.

Topics: Animals; Antiemetics; Apomorphine; Chemoreceptor Cells; Copper Sulfate; Denervation; Dogs; Emetics; Fourth Ventricle; Male; Medulla Oblongata; Neurokinin-1 Receptor Antagonists; Piperidines; Receptors, Neurokinin-1; Solitary Nucleus; Vagus Nerve; Visceral Afferents; Vomiting

The site of the anti-emetic action of the neurokinin1 receptor antagonist CP-99,994 was studied in the ferret using the centrally acting opiate receptor agonist loperamide at a dose (0.5 mg/kg s.c.) which induced emesis in all animals tested. CP-99,994 (1 mg/kg, s.c.x2) abolished the emetic response (retching and vomiting) and the behaviours (licking, wet dog shakes, mouth scratching and gagging) induced by loperamide over a 2-h observation period. The enantiomer of this compound CP-100,263 (1 mg/kg, s.c.x2) did not have any significant effect on emesis or related behaviours. Loperamide (0.5 mg/kg s.c.) administration (but not its vehicle) resulted in dense fos-like immunoreactivity (FLI) mainly throughout the rostro-caudal extent of the nucleus tractus solitarius but not the area postrema. Although CP-99,994 (1 mg/kgx2) abolished the loperamide-induced emesis, it did not have any statistically significant effect on FLI in the brainstem. In loperamide and CP-100,263 (1 mg/kg, s.c.x2) treated animals FLI was comparable to that in animals treated with loperamide and CP-99,994. The results from this study taken together with those from previous studies indicate that loperamide exerts its emetic effect via nucleus tractus solitarius dendrites projecting into the area postrema. The lack of significant effect of CP-99,994 on the FLI induced by loperamide in this nucleus suggests that it is acting at a site "deep" in the nucleus tractus solitarius or elsewhere. The marked reduction in behaviours associated with loperamide administration by CP-99,994 provides a preliminary indication that NK1 receptor antagonist (as represented by CP-99,994) may in the clinic have effects on behaviours induced by emetic agents in addition to their previously described effects on retching and vomiting.

Topics: Animals; Antidiarrheals; Brain Stem; Female; Ferrets; Loperamide; Male; Neurokinin-1 Receptor Antagonists; Piperidines; Proto-Oncogene Proteins c-fos; Psychomotor Performance; Vomiting

Delayed emesis in cancer patients undergoing chemotherapy remains a significant problem. The pathogenesis of delayed emesis is still obscure. It was recently demonstrated that methotrexate (MTX), an anticancer drug, evoked delayed emesis in dogs in a manner similar to its actions in humans. We evaluated the antiemetic activity of FK1052, a potent antagonist for both the 5-hydroxytryptamine (HT)(3) and 5-HT(4) receptors, on delayed emesis induced by MTX in beagle dogs. Animal behavior was recorded for 3 days using a video camera. Delayed emesis lasting up to 72 h was observed in dogs treated with MTX (2.5 mg/kg i.v.), but acute emesis did not occur. The following antiemetics, at the dose that prevents cisplatin-induced acute emesis in dogs, were administered i.v. as multiple injections every 12 h during days 2 to 3. FK1052 (1 and 3.2 mg/kg) significantly reduced the emetic episodes caused by MTX, whereas ondansetron (1 mg/kg), a selective 5-HT(3) receptor antagonist, was not effective. The emetic episodes induced by MTX were also inhibited by another 5-HT(3/4) receptor antagonist, tropisetron (1 mg/kg). CP-122,721 (0. 1 mg/kg), a potent selective tachykinin NK(1) receptor antagonist, significantly reduced the emetic responses to MTX. Copper sulfate-induced emesis in dogs was also prevented by FK1052, tropisetron, and CP-122,721 but not by ondansetron. FK1052, tropisetron, and ondansetron had negligible affinity for the NK(1) receptor at 1 microM. These results suggest that the 5-HT(4) receptor may be in part involved in the production of delayed emesis induced by MTX in dogs and that FK1052 may be a useful drug against both acute and delayed emesis induced by cancer chemotherapy.

Topics: Animals; Antiemetics; Cisplatin; Copper Sulfate; Dogs; Female; Imidazoles; Indoles; Male; Methotrexate; Piperidines; Receptors, Neurokinin-1; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Receptors, Serotonin, 5-HT4; Serotonin Antagonists; Time Factors; Vomiting

The role of tachykinin NK-1 receptors in the area postrema (AP) in emesis was examined in ferrets. Strong c-fos-like immunoreactivity was observed in the AP and nucleus tractus solitalius (NTS) in cisplatin (10 mg/kg, i.p.)-treated animals, but not in control animals. The number of the central emetogen morphine-induced vomits and retches was remarkably reduced (95%) and that of the peripheral emetogen copper sulphate-induced vomits was significantly (54%) reduced by AP lesion. Pretreatment with the tachykinin NK-1 receptor antagonists HSP-117 (1.0 microg) and CP-99,994 (7.5 microg) into the AP decreased the numbers of vomits and retches induced by morphine and copper sulphate. These results suggest that NK-1 receptors in the AP are involved in the mechanism of emesis induced by morphine and copper sulphate.

Topics: Animals; Antiemetics; Antineoplastic Agents; Benzofurans; Chemoreceptor Cells; Cisplatin; Copper Sulfate; Drug Interactions; Ferrets; Fourth Ventricle; Male; Medulla Oblongata; Morphine; Narcotics; Neurokinin-1 Receptor Antagonists; Neurons; Piperidines; Proto-Oncogene Proteins c-fos; Radioligand Assay; Receptors, Neurokinin-1; Solitary Nucleus; Substance P; Tachykinins; Tritium; Vomiting

1. In SUNCUS: murinus the ultrapotent capsaicin analogue resiniferatoxin (RTX) induced an emetic response in the dose range 1 - 1000 microg kg(-1), s.c. The latency was inversely related to dose and ranged from 41.2+/-4.4 min. (1 microg kg(-1), s.c.) to 2.7+/-0.6 min. (1000 microg kg(-1), s.c.). 2. The emetic response to RTX (10 or 100 microg kg(-1), s.c.) was blocked or markedly reduced by pre-treatment with RTX (100 microg kg(-1), s.c.), 8-OH-DPAT (100 microg kg(-1), s.c.), morphine (2 mg kg(-1), s.c.), neonatal capsaicin (100 mg kg(-1), s.c.) and the NK(1) receptor antagonist CP-99,994 (10 - 20 mg kg(-1), s.c.) but not by the 5-HT(3) receptor antagonist tropisetron (200 microg kg(-1), s.c.). 3. RTX (100 microg kg(-1), s.c.) induced c-fos-like immunoreactivity in the area postrema and parts of the nucleus tractus solitarius. This pattern is consistent with the proposal that the emetic effect is mediated via one or both of these structures and an involvement of substance P is discussed. 4. RTX (10 and 100 microg kg(-1), s.c.) had broad-spectrum antiemetic effects in Suncus as indicated by its ability to block or markedly reduce the emetic response to motion (1 Hz, 4 cm lateral, 10 min.), cisplatin (20 mg kg(-1), i.p.), intragastric copper sulphate (40 mg kg(-1), p.o.), nicotine (10 mg kg(-1), s.c.) and RTX (100 microg kg(-1), s.c.) itself. 5. It is proposed that the site of the anti-emetic effect is in the nucleus tractus solitarius and mechanisms involving the modulation of substance P release are discussed. 6. The general utility of SUNCUS: for investigations of vanilloid receptors is reviewed in the light of the exquisite sensitivity of the emetic reflex in this species to resiniferatoxin.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Abdomen; Animals; Animals, Newborn; Antiemetics; Behavior, Animal; Capsaicin; Cisplatin; Copper Sulfate; Diterpenes; Dose-Response Relationship, Drug; Female; Indoles; Injections, Intraventricular; Male; Medulla Oblongata; Morphine; Motion Sickness; Nicotine; Piperidines; Proto-Oncogene Proteins c-fos; Serotonin Receptor Agonists; Shrews; Tropisetron; Vagotomy; Vomiting

Donepezil is an acetylcholinesterase inhibitor indicated for the symptomatic treatment of mild to moderate Alzheimer's disease. It is reported to have a relatively favourable side-effect profile. We report here on a pharmacovigilance study carried out post-marketing in England. An observational cohort study using the technique of Prescription-Event Monitoring was carried out. Some 1762 patients (mean age 72.9 years; 42% male) were followed up for 6 months minimum. The commonest adverse events were nausea, diarrhoea, malaise, dizziness and insomnia. Aggression, agitation and abnormal dreams were uncommonly associated with the drug. There were no cardiac rhythm disturbances or liver disorders causally associated. The commonest adverse drug reactions are already reported in the product information. Given the relatively small size of this cohort, the signals of abnormal dreams and psychiatric disturbance as possible adverse drug reactions need further investigation in carefully planned studies.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Cohort Studies; Donepezil; Drug Prescriptions; England; Female; Follow-Up Studies; Humans; Indans; Male; Nausea; Nootropic Agents; Piperidines; Product Surveillance, Postmarketing; Vomiting

The anti-emetic potential of CP-122,721 ((+)-2S,3S)-3-(2-methoxy-5-trifluoromethoxybenzyl)amino-2-phenylpi peridine), CP-99,994 ((+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine), CP-100,263 ((-)-(2R,3R)-3-(2-methoxybenzylamino)-2-phenylpiperidine), RP 67580 ((3R, 7aR)-7,7-diphenyl-2-[1-imino-2-(2-methoxyphenyl)ethyl] po-hydroisoindol-4-one), FK 888 (N2-[(4R)-4-hydroxy-1-(1-methyl-1H-in-dole-3-yl)carbonyl-L-propyl] -N-methyl-N-phenylmethyl-1-3-(2-naphthyl)-alaninamide) and GR 82334 ([D-Pro9[spiro-g-lactam]Leu10]-physalaemin-(1-11)) was investigated to inhibit nicotine (5 mg/kg, s.c.)-, copper sulphate pentahydrate (120 mg/kg, intragastric)- and motion (4 cm horizontal displacement at 1 Hz for 5 min)-induced emesis in Suncus murinus. A 30 min intraperitoneal pre-treatment with CP-122,721, CP-99,994, RP 67580 and FK 888 significantly (P < 0.05) antagonized nicotine-induced emesis with ID50 values of 2.1, 2.3, 13.5 and 19.2 mg/kg, respectively CP-100,263, the less active enantiomer of CP-99,994, was inactive at doses up to 10 mg/kg. Infusion of GR 82334, CP-122,721, CP-99,994 and FK 888 into the dorsal vagal complex of the hindbrain also antagonized nicotine-induced emesis yielding ID50 values of 1.1, 3.0, 3.3 and 58.0 microg/dorsal vagal complex, respectively RP 67580 and CP-100,263 were inactive. RP 67580 and FK 888 failed to antagonize copper sulphate-induced emesis but CP-122,721 and CP-99,994 were active yielding ID50 values of 2.2 and 3.0 mg/kg, i.p., respectively. CP-99,994 also completely prevented motion-induced emesis at 10 mg/kg, i.p. (P < 0.05) and RP 67580 produced a significant reduction of motion-induced emesis at 10 mg/kg, i.p. (P < 0.05). These studies provide evidence of a central site of action of tachykinin NK1 receptor antagonists to inhibit nicotine-induced emesis in S. murinus and confirm the broad profile of inhibitory action. The rank order of potency of the antagonists following the intra-dorsal vagal complex administration suggests that the S. murinus tachykinin NK1 receptor has a unique pharmacological profile.

Topics: Animals; Antiemetics; Copper Sulfate; Dipeptides; Dose-Response Relationship, Drug; Emetics; Female; Ganglionic Stimulants; Indoles; Infusions, Parenteral; Isoindoles; Male; Motion Sickness; Neurokinin-1 Receptor Antagonists; Nicotine; Physalaemin; Piperidines; Shrews; Stereoisomerism; Vomiting

Tachykinin NK1 receptor antagonists are known to act centrally and to have broad-spectrum antiemetic effects, but their precise site of action has not yet been defined. To identify this site, the effects of the NK1 receptor antagonist GR205171 on the activities of neurons comprising the central pattern generator (CPG) for vomiting were observed in decerebrate paralyzed dogs. A non-respiratory neuron in each of nine dogs was considered to be a CPG neuron based on its response to abdominal vagal stimulation, its location in the CPG area in the reticular formation dorsomedial to the retrofacial nucleus, its firing patterns in prodromal and retching phases and its response to apomorphine. In response to vagal stimulation at 3-10 Hz, the firing of these neurons transiently increased at the onset of stimulation (fast component), gradually increased again (slow component), and finally developed into rhythmic bursts synchronous with retching bursts of the phrenic and abdominal muscle nerves. GR205171 (25-50 microg/kg, i.v.) abolished the slow component and retching bursts in the neurons, and the retching activities of both nerves, but did not change the fast component. The responses of these neurons to repetitive pulse-train vagal stimulation exhibited a vigorous 'wind-up' and finally developed into retching bursts. Both the 'wind-up' phenomenon and retching bursts disappeared after the application of GR205171. These results suggest that the site of the antiemetic action of NK1 receptor antagonists is located in the CPG or in the pathway connecting the solitary nucleus to the CPG.

Topics: Animals; Antiemetics; Apomorphine; Decerebrate State; Dogs; Electric Stimulation; Emetics; Female; Male; Neurokinin-1 Receptor Antagonists; Neurons; Piperidines; Reticular Formation; Tetrazoles; Vagus Nerve; Vomiting

Emesis induced by inhibitors of type IV cyclic nucleotide phosphodiesterase (PDE IV) has been investigated in the ferret. The PDE IV inhibitors studied were: RS14203, R-rolipram and CT-2450 (i.e. (R)-N-[4-[1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethyl]phenyl ]N'-ethylurea), in addition to the less active enantiomers S-rolipram and CT-3405. Following oral administrations, different emetic profiles were observed with time. Emesis induced by RS14203 exhibited a dose-response relationship but no such relationship was seen for R-rolipram or CT-2450. The incidence of emesis was positively influenced by the dose of PDE IV inhibitors administered, allowing a rank order of potency: RS14203 > R-rolipram > S-rolipram > CT-2450 > CT-3405. PDE IV inhibitor-induced emesis was abolished by the tachykinin NK1 receptor antagonist, CP-99,994. No peripheral release of substance P by PDE IV inhibitors seems to be involved in triggering the emetic reflex since L-743,310, which only has peripheral NK1 receptor antagonist activity, was without effect. The implication of 5-HT3 receptors in PDE IV inhibitor-induced emesis was variable. Our results suggest that the PDE IV inhibitors studied are mixed peripheral-central emetogens. PDE IV inhibition itself could be plausible mechanism of action of these agents. However, whether emesis is mediated via a specific isoform of PDE IV remains to be established.

Topics: Animals; Antiemetics; Dose-Response Relationship, Drug; Emetics; Ferrets; Indoles; Molecular Structure; Nitrobenzenes; Ondansetron; Phenylurea Compounds; Phosphodiesterase Inhibitors; Piperidines; Pyridines; Pyrrolidinones; Quinolones; Rolipram; Stereoisomerism; Time Factors; Vomiting

Substance P (SP) is a member of the tachykinin family of bioactive peptides and has highest affinity for the NK-1 receptor. We have developed the non-peptide compound HSP-117 as a selective antagonist of the NK-1 receptor. Binding of 3H-SP to the membranes of IM-9 cells was inhibited by the antagonists HSP-117 and CP-99,994, the inhibitory activity of HSP-117 being 50-fold that of CP-99,994. The SP-induced firing responses of single neuron activity in slices of the nucleus tractus solitarius of ferrets were inhibited by 10 microM HSP-117. Intracerebroventricular injection of HSP-117 significantly inhibited retching and vomiting induced by copper sulphate and morphine and the inhibitory effect of HSP-117 on emesis was greater than that of CP-99,994. Moreover, emesis induced by copper sulphate and morphine were inhibited by the microinjection of HSP-117 and CP-99,994 into the area postrema and by lesion of the area postrema. These results indicate that HSP-117 is a potent anti-emetic agent, blocking NK-1 receptors in the area postrema and that NK-1 receptors in the area postrema play an important role in emesis induced by broad-spectrum emetic stimuli.

Topics: Animals; Antiemetics; Benzofurans; Copper Sulfate; Ferrets; Medulla Oblongata; Morphine; Piperidines; Receptors, Neurokinin-1; Solitary Nucleus; Stereoisomerism; Vomiting

Tachykinin NK1 receptor antagonists injected into the medulla oblongata are known to abolish vomiting induced by vagal afferent stimulation. Emetic vagal afferents have been shown to synapse with neurons in the medial solitary nucleus (mNTS), which suggests that substance P is a transmitter in the synapse. To examine this possibility, the effects of GR205171, an NK1 receptor antagonist, on retching and mNTS neuronal responses to the stimulation of abdominal vagal afferents were investigated in decerebrate dogs. GR205171 (0.05-0.7 mg kg-1, i.v.) abolished retching induced by either vagal or mNTS stimulation within 5 min. Firing of mNTS neurons in response to pulse-train and sustained vagal stimulation did not change even after the abolition of retching. Similarly, GR205171 did not have any effects on mNTS evoked potentials induced by pulse-train vagal stimulation. In about 20% of mNTS neurons, the peak firing frequency was facilitated to about 150% with repetitive pulse-train vagal stimulation. This facilitation remained even after the abolition of retching. Administration of GR205171 (1 mg ml-1, 30 microliters) into the 4th ventricle abolished retching, with latencies in excess of 120 min These results suggest that substance P does not participate in synaptic transmission between emetic vagal afferents and mNTS neurons in dogs.

Topics: Animals; Dogs; Electric Stimulation; Evoked Potentials; Female; Injections, Intravenous; Injections, Intraventricular; Male; Neurons; Neurons, Afferent; Piperidines; Receptors, Tachykinin; Solitary Nucleus; Synaptic Transmission; Tetrazoles; Vagus Nerve; Vomiting

The effects of GR205171, a selective tachykinin NK1 receptor antagonist, were investigated on both the acute and delayed phases of cisplatin-induced nausea-like behaviour and vomiting in the conscious piglet. Animals receiving cisplatin (5.5 mg kg(-1), i.v.) were observed for 60 h. Fifteen min prior to cisplatin infusion (T0(-15 min)), eight piglets acting as controls received an intravenous injection of saline solution (1 ml kg(-1)), whereas experimental animals received a single i.v. administration of GR205171 (1 ml kg(-1)) at a dose of 0.01 (n=8), 0.03 (n=8), 0.1 (n = 8), 0.3 (n = 16) or 1.0 (n = 13) mg kg(-1). In eight additional piglets, GR205171 (1 mg kg(-1)) was administered 15 min before the onset of the delayed phase (T16(-15 min)). A further five piglets received GR205171 (1 mg kg(-1)) every 6 h throughout the experiment. The latencies of the first emetic episode (EE) and nausea-like behavioural episode (NE) increased in all experimental groups treated at T0(-15 min), and the total number of both EE and NE during the 60 h was reduced in a dose-dependent manner. In piglets treated at T0(-15 min) with GR205171 1 mg kg(-1), eight out of 13 (62%) did not vomit throughout the experiment. Animals treated with GR205171 (1 mg kg(-1)) at T16(-15 min) exhibited an acute response to cisplatin but did not vomit during the delayed phase. The greatest inhibition of both nausea-like behaviour and vomiting was observed in piglets receiving multiple injections of GR205171. These results demonstrate the long-lasting anti-emetic effects of GR205171, and confirm the key role of substance P within the emetic reflex.

Topics: Animals; Antiemetics; Antineoplastic Agents; Cisplatin; Dose-Response Relationship, Drug; Female; Injections, Intravenous; Male; Nausea; Neurokinin-1 Receptor Antagonists; Piperidines; Swine; Tetrazoles; Vomiting

The roles of tachykinin neurokinin-1 (NK1) receptors in the induction of fictive retching, hypersalivation, and gastric responses associated with emesis induced by abdominal vagal stimulation were studied in paralyzed, decerebrated dogs. Vagal stimulation induced gradual increases in salivary secretion and activity of the parasympathetic postganglionic fibers to the submandibular gland, relaxation of the gastric corpus and antrum, and fictive retching. However, hypersalivation and increased nerve activity were suppressed and antral contractility was enhanced during fictive retching. An NK1 receptor antagonist, GR-205171, abolished the enhancement of antral contractility and fictive retching but had no effect on corpus and antral relaxation. Hypersalivation and increased nerve activity were inhibited by GR-205171 but were not completely abolished. Reflex salivation by lingual nerve stimulation was unaffected. These results suggest that GR-205171 acts on the afferent pathway in the bulb and diminishes hypersalivation and antral contraction related to emesis as well as fictive retching but does not affect gastric relaxation or hypersalivation induced by the vagovagal, vagosalivary, and linguosalivary reflexes.

Topics: Animals; Dogs; Electric Stimulation; Gastrointestinal Motility; Models, Biological; Muscle Contraction; Muscle, Smooth; Neurokinin-1 Receptor Antagonists; Phrenic Nerve; Piperidines; Saliva; Salivation; Stomach; Tetrazoles; Time Factors; Vagus Nerve; Vomiting

The effects of a NK1 antagonist, GR205171, and a 5-HT3 antagonist, ondansetron, in a novel model of post-anaesthesia-induced emesis in Suncus murinus is described. GR205171 (1 and 3 mg k(-1) s.c) and ondansetron (3 mg kg(-1) s.c.) each significantly inhibited emesis. This model may be useful for studying drugs to treat post-operative nausea and vomiting in man.

Topics: Anesthesia; Animals; Halothane; Humans; Male; Nausea; Neurokinin-1 Receptor Antagonists; Ondansetron; Piperidines; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Serotonin Antagonists; Shrews; Tetrazoles; Vomiting

The 5-HT3 receptor antagonists are the most potent antiemetics known at present. Lerisetron is a new 5-HT3 receptor antagonist chemically unrelated to other antagonists like Ondansetron. An emesis model in the dog induced by irradiation with 60Co was used, and 8 Gy were administered over the total body surface. An irradiated control group was established and received no medication, and two irradiated groups received treatment with either Ondansetron or Lerisetron. The 'up-down' technique was employed to determine the effective dose (ED50). A logarithmic-scale was used to increase or decrease the doses in each case. The initial doses were 300 microg/kg for Ondansetron and 100 microg/kg for Lerisetron. All animals in the control group vomited. The ED50 of Ondansetron was 178+/-151 microg/kg body wt and that of Lerisetron was 63+/-18 microg/kg. Lerisetron is more potent and presented less individual variability than Ondansetron, but its antiemetic effects were equally effective.

Topics: Animals; Antiemetics; Benzimidazoles; Cobalt Radioisotopes; Dogs; Drug Administration Schedule; Ondansetron; Piperidines; Radiotherapy; Serotonin Antagonists; Vomiting

We have developed a non-peptide compound, HSP-117, antagonist of the tachykinin NK-1 receptor. Binding of 3H-substance P (SP) to the membranes of IM-9 cells was inhibited by the antagonists HSP-117 and CP-99,994, the inhibitory activity of HSP-117 being about 50-fold that of CP-99,994. The SP-induced firing responses of single neuron activity in slices of the nucleus tractus solitarius of ferrets were inhibited by 10 microM HSP-117. Intracerebroventricular injection of HSP-117 significantly inhibited retching and vomiting induced by copper sulphate and morphine and the inhibitory effect of HSP-117 on emesis was greater than that of CP-99,994. These results indicate that (1) HSP-117 is a potent anti-emetic agent, blocking NK-1 receptors in the nucleus tractus solitarius and (2) NK-1 receptors in the nucleus tractus solitarius play an important role in emesis induced by broad-spectrum emetic stimuli.

Topics: Animals; Antiemetics; Benzofurans; Brain Stem; Cerebral Ventricles; Copper Sulfate; Emetics; Ferrets; In Vitro Techniques; Injections, Intraventricular; Male; Membrane Potentials; Morphine; Neurokinin-1 Receptor Antagonists; Piperidines; Substance P; Vomiting

Ethanol-induced emesis were investigated using Suncus murinus and the emetogenic mechanisms of ethanol were compared with those of cisplatin. Intraperitoneal injection of ethanol caused dose-dependent emesis with ED50 value of 22.3% (v/v) when injection volume was adjusted to 4 ml/kg. Intraperitoneal and subcutaneous injection of acetaldehyde also caused dose-dependent emesis (ED50 = 3.5% (v/v) with an extremely shorter latency (6% i.p.: 1.0 +/- 0.3 min cf. 40% ethanol: 13.0 +/- 1.9 min). Neither ethanol nor acetaldehyde caused emetic responses when injected intracerebroventricularly. Pretreatment with disulfiram, an inhibitor of liver aldehyde dehydrogenase, potentiated the emetogenic effects of ethanol. Surgical abdominal vagotomy, which blocks cisplatin-induced emesis completely, did not prevent ethanol-induced emesis. 5-HT3 receptor antagonists, which also cause complete inhibition of cisplatin-induced emesis, did not affect the responses. However, ethanol-induced emesis was prevented by the pretreatment with 8-hydroxy-2-(di-n-propylamino)tetrarin hydrobromide (8-OH-DPAT) and N-(2-mercaptopropionyl)-glycine (MPG) dose-dependently. The tackykinin NK1 receptor antagonist (+)-(2S, 3S)-3-(2-methoxybenzylamino)-2-phenyl-piperidine (CP-99,994) also attenuated ethanol-induced emesis. Taken together, these results suggest that 1) acetaldehyde is probably responsible for ethanol-induced emesis, 2) active site for ethanol maybe peripheral, 3) ethanol-induced emesis is mediated by free radicals, and 4) mechanism of ethanol-induced emesis and that caused by cisplatin are different in many respects, although in some they are similar and that the precise pathways remain to be identified. Therefore, the tolerance to emetogenic effects of cisplatin in alcoholic patients cannot be explained as a simple cross desensitization of the pathway.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Acetaldehyde; Alcohol Deterrents; Animals; Antiemetics; Baclofen; Benzamides; Bridged Bicyclo Compounds, Heterocyclic; Central Nervous System Depressants; Disulfiram; Dose-Response Relationship, Drug; Ethanol; Female; GABA Antagonists; Indoles; Injections, Intraperitoneal; Injections, Intraventricular; Injections, Subcutaneous; Male; Piperidines; Serotonin Antagonists; Serotonin Receptor Agonists; Shrews; Tiopronin; Tropisetron; Vagotomy; Vomiting

1. The NK1 receptor antagonist CP-99994 has been shown to prevent vomiting elicited by both peripherally and centrally acting emetogens in ferrets and dogs. These results have now been extended to another stimulus, provocative motion, and another species, the cat. 2. CP-99994 displaced [3H]-substance P from cat cortex with IC50 of 0.52 +/- 0.08 nM. Following s.c. administration, peak plasma drug levels were achieved at 30 min. The plasma drug half life was 1.4 h. 3. Subcutaneous administration of CP-99994 inhibited motion-induced vomiting in the cat with an ED50 of 144 micrograms kg-1 but did not change the epiphenomena associated with provocative motion in the cat over the dose range of 30 to 300 micrograms kg-1. The antiemetic effect of CP-99994 can be attributed to antagonism of the NK1 receptor because its enantiomer, CP-100,263, which is 900 fold weaker as an NK1 antagonist, had no effects on any response to provocative motion. 4. The inhibitory effect of CP-99994 on motion-induced retching and vomiting is consistent with a central site of antiemetic action, potentially at the level of the motor nuclei responsible for these behaviours. 5. An investigation into whether the failure of CP-99994 to alter the epiphenomena will also predict a lack of anti-nausea effects in man will provide critical information on the neural organization of the emetic reflex.

Topics: Animals; Antiemetics; Area Under Curve; Binding, Competitive; Cats; Half-Life; Injections, Subcutaneous; Motion Sickness; Neurokinin-1 Receptor Antagonists; Piperidines; Receptors, Neurokinin-1; Substance P; Vomiting

The preparation of a series of N-heteroarylpiperidine ether-based human NK1 antagonists is described. Two of the compounds 3-[-(2S,3S)-3-(((3,5-bis(trifluoromethyl)phenyl)methyl)oxy)- 2-phenylpiperidino}methyl]-1,2,4-triazole (11) and 5-[¿(2S,3S)-3-(((3,5-bis(trifluoromethyl)-phenyl)methyl)oxy)-2- phenylpiperidino}methyl]-3-oxo-1,2,4-triazolone (12)), in particular, are orally bioavailable and exhibited significant improvements in potency, both in vitro and in vivo, over the lead (carboxamidomethyl)piperidine ether 1. Rat liver microsome studies on a selected number of compounds from this series show the triazolone heterocycle to be considerably more stable than the others. Furthermore, both 11 and 12 have been profiled in a number of assays that may be predictive of the clinical utility of substance P antagonists.

Topics: Animals; Biological Availability; Drug Stability; Ferrets; Guinea Pigs; Humans; Inflammation; Macaca mulatta; Male; Microsomes, Liver; Migraine Disorders; Neurokinin-1 Receptor Antagonists; Piperidines; Rats; Receptors, Neurokinin-1; Triazoles; Vomiting

The potent, selective, tachykinin NK1 receptor antagonist, CP-122,721 ([(+)-(2S,3S)-3-(2-methoxy-5-trifluoromethoxybenzyl)amino-2- phenylpiperidine]), at 0.01-1 mg/kg, s.c. reduced retching and vomiting elicited by loperamide, copper sulfate, ipecac syrup and cisplatin in a dose-dependent manner. ID50 values after subcutaneous administration ranged from 0.02 mg/kg (loperamide) to 0.08 mg/kg (ipecac). Oral CP-122,721 reduced cisplatin-induced emesis with an ID50 of approximately 0.08 mg/kg. The less active (2R, 3R)-enantiomer, CP-132.687, did not significantly suppress retching or vomiting induced by any of the emetogens. These data support the hypothesis that CP-122,721 blocks emesis by a specific action at tachykinin NK1 receptors. Its broad spectrum of antiemetic activity suggests a central site of action.

Topics: Animals; Antiemetics; Cisplatin; Copper Sulfate; Emetics; Ferrets; Ipecac; Loperamide; Male; Neurokinin-1 Receptor Antagonists; Piperidines; Stereoisomerism; Vomiting

This paper is the first to describe aspects of the mechanics of retching in the insectivore Suncus murinus (house musk shrew) and in an animal of such a small size (approximately 50 g). In anaesthetised animals using the novel stimulus of mechanical stimulation of the upper gastrointestinal tract as the provocative stimulus the frequency of retching was found to be about 4 retches/s, a much higher frequency than in other species (dog, cat, ferret). These studies show that quantification of retching in Suncus cannot be undertaken using direct observation. The temporal pattern of the emetic response was characterised in conscious Suncus using motion (1 Hz, 5 min) and nicotine (20 mg/kg s.c.). The ultrapotent capsaicin analogue resiniferatoxin (100 micrograms/kg s.c.) was discovered to be highly emetic and comparative studies showed that nicotine and resiniferatoxin induced the most intense responses with episodes (retches and a vomit) occurring every 10-15 s. The retching response to mechanical stimulation in the anaesthetised Suncus was not blocked by a 5-HT3 receptor antagonist (granisetron, 1-5 mg/kg s.c.), a tachykinin NK1 receptor antagonist (CP-99,994 20 mg/kg s.c. dihydrochloride salt (9+) -(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine) or morphine (2 mg/kg s.c.) but was blocked by the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT 100 micrograms/kg s.c.). Suncus appears to be a suitable animal in which to study the pharmacology of the emetic response to mechanical stimulation of the gut. The results are discussed in the light of studies of the pharmacology of emesis in other species.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Digestive System Physiological Phenomena; Diterpenes; Granisetron; Male; Morphine; Motion; Neurokinin-1 Receptor Antagonists; Nicotine; Piperidines; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Serotonin Antagonists; Serotonin Receptor Agonists; Shrews; Vomiting

1. The anti-emetic effects of the NK1 tachykinin receptor antagonist, CP 99,994 (10 mg kg-1) were investigated in the ferret using a cisplatin-induced acute (day 1) and delayed (day 2 and 3) retching and vomiting model. 2. With a single cisplatin (10 mg kg-1) emetogenic challenge, the i.p. administration of CP 99,994 given as a single injection immediately following the first emetic episode, promptly abolished the retching and vomiting for a 4 h period. CP 99,994 was as efficacious as ondansetron (1.0 mg kg-1). The general toxicity of cisplatin 10 mg kg-1 precluded its use in studies of delayed emesis. 3. With a single cisplatin (5 mg kg-1) emetogenic challenge, the single administration of either CP 99,994 (10 mg kg-1) or ondansetron (1.0 mg kg-1) immediately following the first emetic episode markedly reduced or abolished the retching and vomiting for 4 h. Such single treatments failed to modify significantly the intensity of delayed emesis appearing on the second and third day. 4. With a cisplatin (5 mg kg-1) emetogenic challenge, administration of CP 99,994 (10 mg kg-1) at 8 hourly intervals, the first injection being administered 30 s post cisplatin, was associated with 4 or more abolitions of emesis during both the acute and delayed phase. A 4 hourly administration of CP 99,994 for 20 h during delayed emesis completely abolished the retching and vomiting. 5. It is concluded that cisplatin 5 mg kg-1 provides an emetogenic challenge causing an acute and delayed phase of retching and vomiting and that CP 99,994 can abolish both phases. The results may be relevant to the understanding and treatment of chemotherapy-induced emesis in man.

Topics: Animals; Antineoplastic Agents; Cisplatin; Ferrets; Male; Neurokinin-1 Receptor Antagonists; Ondansetron; Pharmaceutical Vehicles; Piperidines; Vomiting

These studies have compared the pharmacological profile of two non-peptide human type neurokinin1 (hNK1) receptor selective antagonists, L-741,671 and a quaternised compound L-743,310. In radioligand binding studies L-741,671 and L-743,310 had high affinity for ferret and cloned hNK1 receptors [Ki (nM) ferret 0.7 and 0.1; human 0.03 and 0.06, respectively] but low affinity for rodent NK1 receptors [Ki (nM) 64 and 17, respectively] suggesting that ferret receptors have hNK1-like binding pharmacology. Studies in vivo showed that L-741,671 and L-743,310 had equivalent functional activity in the periphery (ID50s of 1.6 and 2 micrograms/kg i.v., respectively) as measured by inhibition of plasma protein extravasation evoked in the oesophagus of guinea pigs by resiniferatoxin (7 nmol/kg i.v.). Using an in situ brain perfusion technique in anaesthetised rats, L-741,671 was shown to be much more brain penetrant than the quaternary compound L-743,310 which had an entry rate similar to the poorly brain penetrant plasma marker inulin. These compounds thus provided an opportunity to compare the anti-emetic effects of equi-active hNK1 receptor antagonists with and without brain penetration to central NK1 receptor sites. When tested against cisplatin-induced emesis in ferrets, L-741,671 (0.3, 1 and 3 mg/kg i.v.) produced marked dose-dependent inhibition of retching and vomiting but L-743,310 was inactive at 3 and 10 micrograms/kg i.v. In contrast, direct central injection of L-741,671 and L-743,310 (30 micrograms) into the vicinity of the nucleus tractus solitarius or L-743,310 (200 micrograms) intracisternally was shown to inhibit retching and vomiting induced by i.v. cisplatin. L-741,671 and L-743,310 had equivalent functional activity, at the same dose, against cisplatin-induced emesis when injected centrally. These observations indicated that had L-743,310 penetrated into the brain after systemic administration it would have been active in the cisplatin-induced emesis assay and so show that brain penetration is essential for the anti-emetic action of systemically administered NK1 receptor antagonists.

Topics: Animals; Antiemetics; Antineoplastic Agents; Blood Proteins; Brain Chemistry; Cell Line; Cisplatin; Diterpenes; Ferrets; Guinea Pigs; Indoles; Ligands; Male; Neurokinin-1 Receptor Antagonists; Neurotoxins; Piperidines; Radioligand Assay; Receptors, Neurokinin-1; Triazoles; Vomiting

The antiemetic, pharmacokinetic, and metabolic profile of CP-99,994, a potent NK1 receptor antagonist, has been carefully evaluated. As a result we began a medicinal chemistry program which initially identified a 3-furanyl analogue (6) with improved antiemetic potency and a methyl sulfone (5) with enhanced metabolic stability and oral bioavailability. The improved pharmacokinetic profile of methyl sulfone (5) was associated with its low lipophilicity, and a therefore a number of heterocyclic analogues with reduced log D were synthesized. Out of this program emerged 19 (GR203040), a tetrazolyl-substituted analogue. Tetrazole 19 inhibits radiation-induced emesis in the ferret with high potency when administered both subcutaneously and orally, has a long duration of action, and has high oral bioavailability in the dog. Tetrazole 19 is currently undergoing evaluation as a novel approach for the control of emesis associated with, for example, cancer chemotherapy.

Topics: Animals; Antiemetics; Biological Availability; Cell Membrane; CHO Cells; Cricetinae; Dogs; Female; Ferrets; Gerbillinae; Magnetic Resonance Spectroscopy; Male; Neurokinin-1 Receptor Antagonists; Piperidines; Tachykinins; Tetrazoles; Vomiting; Whole-Body Irradiation

Topics: Adolescent; Adult; Cisapride; Female; Gastroesophageal Reflux; Humans; Male; Parasympatholytics; Piperidines; Sympatholytics; Vomiting

1. Following our earlier observations that the tachykinin NK1 receptor antagonist CP-99,994 is an effective anti-emetic in ferrets, we have examined the anti-emetic effects of a more potent and novel NK1 receptor antagonist, GR203040, against various emetic stimuli in the ferret, dog and house musk shrew (Suncus murinus). 2. In ferrets, GR203040 (0.1 mg kg-1 s.c. or i.v.) is effective against emesis induced by radiation, cisplatin, cyclophosphamide, copper sulphate, ipecacuanha or morphine. 3. In animals in which emesis had been established with cisplatin, GR203040 (1 mg kg-1 s.c.) was fully effective as an interventional treatment. No further emesis was seen in animals treated with GR203040 whilst saline-treated animals continued to vomit. 4. GR203040 (0.1 mg kg-1 s.c.) retains anti-emetic efficacy in the ferret, even when given as a 6 h pretreatment, indicating that this compound has a long duration of action. The compound is also effective orally at the same dose, when given as a 90 min pretreatment. 5. GR203040 (0.1 mg kg-1 i.v.) is fully effective against ipecacuanha-induced emesis in the dog. 6. GR203040 is effective against motion- and cisplatin-induced emesis in Suncus murinus. These effects were seen at doses an order of magnitude greater than those shown to be effective against cisplatin in the ferret. 7. In conclusion, GR203040 is a novel anti-emetic agent, and the broad spectrum of anti-emetic activity, together with activity observed in three species, suggests that this compound is worthy of clinical investigation.

Topics: Animals; Antiemetics; Dogs; Dose-Response Relationship, Drug; Emetics; Ferrets; Male; Motion Sickness; Neurokinin-1 Receptor Antagonists; Piperidines; Radiation Injuries, Experimental; Shrews; Tetrazoles; Vomiting

Effects of the NK1 receptor antagonist CP-99,994 on nicotine-induced emesis were examined in Suncus murinus. CP-99,994 (3 and 10 mg/kg i.p.) attenuated emesis to (-)nicotine (4 mg/kg s.c.). CP-100,263 (3 and 10 mg/kg i.p.), the enantiomer of CP-99,994 with 1000 fold lower affinity for the NK1 receptor was without effect and RP67580 reduced emesis only at a dose of 30 mg/kg i.p. Responses to NK1 antagonists were ranked according to their affinities for the Suncus murinus NK1 receptor.

Topics: Animals; Antiemetics; Dose-Response Relationship, Drug; Indoles; Isoindoles; Male; Morphine; Neurokinin A; Nicotine; Piperidines; Receptors, Neurokinin-1; Shrews; Stereoisomerism; Substance P; Vomiting

Topics: Antiemetics; Humans; Neurokinin A; Piperidines; Serotonin Antagonists; Vomiting

These studies have examined the effects of the selective neurokinin1 (NK1) receptor antagonist CP-99,994 on the retching and vomiting response to apomorphine. CP-99,994 (1-3 mg/kg i.p.) attenuated retching and vomiting induced by apomorphine (0.25 mg/kg s.c.) with complete inhibition of retching and vomiting at the 3 mg/kg dose. In contrast CP-100,263 (3 mg/kg i.p.), the enantiomer of CP-99,994 with 1000-fold lower affinity for the NK1 receptor, was without effect.

Topics: Animals; Apomorphine; Dose-Response Relationship, Drug; Ferrets; Male; Neurokinin-1 Receptor Antagonists; Piperidines; Stereoisomerism; Vomiting

In the ferret, 5-HT3 receptor antagonists are effective in controlling emesis produced by cytotoxic agents or radiation. To investigate the possibility that substance P has a role, as well as 5-HT, in the emetic reflex pathway, we have examined the anti-emetic effects of a NK1 receptor antagonist (racemic CP-99,994) in the ferret. Racemic CP-99,994 was effective against a range of emetogens, comprising cytotoxic drugs, radiation, morphine, ipecacuanha and copper sulphate.

Topics: Animals; Ferrets; Male; Neurokinin A; Piperidines; Stereoisomerism; Substance P; Vomiting

The tachykinin NK1 receptor antagonist CP-99,994 ((+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine) (0.3-3 mg/kg i.v.), but not its inactive enantiomer CP-100,263, attenuated the retching and vomiting induced by cisplatin (10 mg/kg i.v.) in the ferret. CP-99,994, 3 mg/kg i.v., prevented vomiting in all ferrets tested. Since substance P is the preferred ligand at the NK1 receptor subtype these data support a role for the release of this peptide during the emetic response induced by cytotoxic chemotherapeutic agents.

Topics: Analysis of Variance; Animals; Cisplatin; Ferrets; Injections, Intravenous; Male; Neurokinin A; Piperidines; Vomiting

In this paper the authors review the main prokinetic drugs analyzing their pharmacological properties, therapeutic indications and adverse effects. In addition, some more recently introduced substances are taken into consideration which, although they were not initially used for digestive tract dyskinesias, can nevertheless be used in certain conditions. From this point of view, calcium blocking agents employed in spastic conditions of the esophagus and the new antiserotoninergic drugs for treatment of anticancer chemotherapy-induced vomiting are of particular interest.

Topics: Antineoplastic Agents; Cisapride; Domperidone; Esophageal Motility Disorders; Gastroesophageal Reflux; Gastrointestinal Motility; Humans; Metoclopramide; Piperidines; Serotonin Antagonists; Vomiting

Octadecyl-[2-(N-methylpiperidinio)ethyl]-phosphate (OMPEP, D-20133), a heterocyclic analogue of hexadecylphosphocholine (MIL), has been synthesized in an attempt to increase the therapeutic range of the parent compound. The antineoplastic activity of the novel alkylphospholipid was compared with that of MIL in dimethylbenz(a)anthracene-induced mammary carcinoma of the rat. Using tumors of different sizes and repeated daily doses as well as high single doses, we achieved marked remissions with either compound. However, the therapeutic range of OMPEP was broader than that of the parent drug. Furthermore, the emetic potential of OMPEP tested on ferrets was distinctly less pronounced than that of MIL. In vitro the new alkylphospholipid proved to be more active than MIL in all cell lines tested, and its differentiation-inducing capacity turned out to be superior to that of MIL. No hematological toxicity was observed at various OMPEP doses during a 3-week treatment period.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antineoplastic Agents; Cell Differentiation; Female; Ferrets; Mammary Neoplasms, Experimental; Phosphorylcholine; Piperidines; Rats; Rats, Sprague-Dawley; Tumor Cells, Cultured; Vomiting

The selective 5HT uptake inhibitor, litoxetine (SL 81.0385), currently under development as an antidepressant was shown to have antiemetic properties in the ferret. Litoxetine (at 1 and 10 mg/kg i.v.) dose dependently reduced the number of retches and vomiting as well as the number of emetic episodes induced by cisplatin (10 mg/kg i.v.) and delayed the onset of emesis. Fluoxetine (at 1 or 10 mg/kg i.v.) failed to inhibit cisplatin-induced emetic responses and, in contrast, significantly increased the number of retches and vomiting and accelerated the onset of emesis. The possibility that the antiemetic effects of litoxetine may be mediated through an interaction with 5HT3 receptors was studied using [3H]quipazine or [3H]BRL 43694 to label the 5HT3 receptor. Litoxetine has moderate affinity for cerebral 5HT3 receptors (Ki = 85 nM), while fluoxetine, similar to other 5HT uptake inhibitors, has only negligible affinity for this receptor (Ki = 6.5 microM). It is proposed that litoxetine inhibits cisplatin-induced emetic responses due to its moderate 5HT3 antagonist properties. The clinical use of the majority of serotonergic antidepressants (e.g. fluoxetine, fluvoxamine etc.) is associated with gastrointestinal discomfort (particularly nausea and vomiting) as a major side-effect. If nausea and vomiting associated with the use of 5 HT uptake inhibitors are due to stimulation of 5HT3 receptors, the concomitant 5HT3 antagonism of litoxetine may limit the gastrointestinal side-effects of this novel antidepressant and thus offer an important advantage.

Topics: Animals; Antiemetics; Binding, Competitive; Cerebral Cortex; Cisplatin; Dose-Response Relationship, Drug; Ferrets; Fluoxetine; Granisetron; Indazoles; Male; Piperidines; Quipazine; Rats; Rats, Sprague-Dawley; Selective Serotonin Reuptake Inhibitors; Serotonin Antagonists; Vomiting

Gastroparesis is a disabling complication in diabetic patients. It has been reported as the second most frequent cause of hospitalization in diabetic patients on continuous ambulatory peritoneal dialysis (CAPD). We analyzed infectious and noninfectious complications in our CAPD patients. We included 31 patients (12 diabetics and 19 nondiabetics) with an average time on CAPD of 14 +/- 7 months. The incidence of peritonitis was 1.68 episodes/patient/year in diabetics and 0.84 in nondiabetics. Nine (75%) diabetic patients had peritonitis, 5 (42%) had vomiting, and 4 (33%) had ischemic heart disease. The hospitalization index (days/year) was greater in diabetics: 11.83 +/- 11.36 versus 4.16 +/- 8.84 in nondiabetics (p < 0.05). Vomiting was the first cause of admission in diabetics. We were unable to control severe gastroparesis with cisapride and metoclopramide in 4 patients. Erythromycin, 100 mg/2-L bag of dialysate, improved symptoms in all of them. We concluded that gastroparesis is an important cause of morbidity in CAPD patients. Intraperitoneal erythromycin can improve symptoms if other prokinetic drugs fail.

Topics: Cisapride; Diabetes Mellitus, Type 1; Erythromycin; Female; Gastric Emptying; Hospitalization; Humans; Male; Metoclopramide; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Peritonitis; Piperidines; Serotonin Antagonists; Stomach Diseases; Vomiting

Pigeons were fed a fixed amount of grain-based feed and behavior was observed after administration of doses of ditolyguanidine (DTG), (+)-3-(3-hydroxyphenyl)-N-(1-propyl)-piperidine [(+)-3-PPP], dextromethorphan, haloperidol, (+)-N-allylnormetazocine (NANM), alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanol (BMY-14802) apomorphine, pentobarbital, propranolol, and MK-801. Of the drugs tested, DTG, dextromethorphan, and (+)-3-PPP each produced dose-related increases in the percentage of pigeons exhibiting an emetic response. The emetic response produced by DTG was antagonized by haloperidol and BMY-14802 but not by propranolol. These observations suggest that the emetic response in the pigeon may be mediated by sigma sites and is unlikely to be mediated by phencyclidine receptors.

Topics: Animals; Apomorphine; Columbidae; Dextromethorphan; Dizocilpine Maleate; Dopamine Agents; Guanidines; Haloperidol; Male; Pentobarbital; Phenazocine; Piperidines; Propranolol; Psychotropic Drugs; Pyrimidines; Receptors, Opioid; Receptors, sigma; Vomiting

Topics: Administration, Oral; Cisapride; Gastroesophageal Reflux; Humans; Infant; Kidney Failure, Chronic; Piperidines; Serotonin Antagonists; Vomiting

The pharmacological profile of bethanechol (CAS 674-38-4), metoclopramide (CAS 364-62-5), trimebutine (CAS 39133-31-8) and cisapride (CAS 81098-60-4) was studied in a series of simple pharmacological tests in rats and dogs. Bethanechol stimulated both gastric emptying and intestinal propulsion but displayed also the well-known behavioral effects of a direct muscarinic acetylcholine receptor agonist. Metoclopramide showed the profile of a centrally active dopamine D2 antagonist. In addition, metoclopramide displayed a stimulant effect on spontaneous gastric emptying in rats, an effect that could not be related to dopamine D2 antagonism. The only effect observed with trimebutine was protection from castor oil diarrhea, probably due to its reported interaction with peripheral opiate receptors. Cisapride was a potent stimulant of gastric emptying in rats, 7 times more potent than metoclopramide. Cisapride was also a very specific gastrokinetic, over a large dose range (specificity ratio: greater than or equal to 20) devoid of effects indicative for direct interaction with dopamine or acetylcholine receptors. The relationship between the differential activity profiles of the compounds in the present study and differences in their mechanism of action and side-effect liability is discussed.

Topics: Animals; Apomorphine; Bethanechol Compounds; Cisapride; Conditioning, Operant; Diarrhea; Dogs; Gastric Emptying; Gastrointestinal Agents; Gastrointestinal Motility; Metoclopramide; Motor Activity; Piperidines; Rats; Rats, Inbred Strains; Serotonin Antagonists; Species Specificity; Trimebutine; Vomiting

A patient with progressive spinal stenosis, paraplegia, chronic pain syndrome and simultaneous severe chronic constipation is described. Treatment with cisapride 10 mg, 4 times daily improved her condition, and this was associated with improved small intestinal motility during a 12-hour examination using a computer aided system.

Topics: Cisapride; Constipation; Female; Gastrointestinal Motility; Gastrointestinal Transit; Humans; Intestine, Small; Middle Aged; Neck; Piperidines; Spinal Stenosis; Time Factors; Vomiting

Selective presynaptic dopamine receptor agonists appear to offer promise as putative antipsychotic agents with a low risk of extrapyramidal side-effects, including tardive dyskinesia. However, no such agent with a reasonable degree of selectivity has yet reached the stage of clinical trial. In the present paper the particular pharmacological profile of presynaptic dopamine receptor (autoreceptor) agonists is described, and underlying mechanisms are discussed. Special attention is paid to the compound 3-(3-hydroxyphenyl-N-n-propylpiperidine(3-PPP), especially its levotatory enantiomer. This agent shows affinity for both pre- and postsynaptic dopamine receptors. Its intrinsic activity in different locations varies between virtually zero and 100%, leading to a mixture of agonist and antagonist properties. It is suggested that this variability depends on the adaptive properties of the dopamine receptor.

Topics: Animals; Binding, Competitive; Brain; Corpus Striatum; Dogs; Dopamine; Piperidines; Prolactin; Rats; Receptors, Dopamine; Stereoisomerism; Substantia Nigra; Synapses; Vomiting

Topics: Benzamides; Chemical Phenomena; Chemistry; Cisapride; Dexamethasone; Digestive System; Domperidone; Gastric Emptying; Gastroesophageal Reflux; Gastrointestinal Diseases; Gastrointestinal Motility; Humans; Kinetics; Metoclopramide; Naloxone; Phenytoin; Piperidines; Proglumide; Vomiting

Topics: Adult; Antiemetics; Basal Ganglia Diseases; Benzimidazoles; Domperidone; Female; Humans; Infant; Male; Piperidines; Vomiting

Topics: Acetylcholine; Acetylcholinesterase; Antiemetics; Benzimidazoles; Domperidone; Dyspepsia; Enzyme Inhibitors; Humans; Neuromuscular Junction; Peristalsis; Piperidines; Receptors, Dopamine; Vomiting

Cisplatin (cis-diammine-dichloro-platinum) administered at a dose of 3 mg/kg iv induced a reproducible and characteristic emetic response in the dog. It was characterized by a latency period (90-120 min) and multiple emetic episodes occuring within 5 hours following drug administration with sporadic delayed emesis later within the first 24 hours. There was a qualitative similarity between the emetic response of Cisplatin seen in dogs and cancer patients. Metoclopramide (1, 3 mg/kg sc) was found to be the most effective antagonsit of Cisplatin emesis in the dog while haloperidol (1 mg/kg sc) and chlorpromazine (0.3, 1, 3 mg/kg sc) offered a less complete protection. Nabilone (0.1 mg/kg iv) and AL-1612 (1 mg/kg sc) failed to to demonstrate any significant activity. A relationship between antagonism patterns of emetic responses induced by Cisplatin and apomorphine was discussed.

Topics: Animals; Antiemetics; Chlorpromazine; Cisplatin; Dogs; Dronabinol; Female; Haloperidol; Indoles; Male; Metoclopramide; Piperidines; Vomiting

Topics: Adolescent; Antiemetics; Antineoplastic Agents; Benzimidazoles; Child; Child, Preschool; Drug Evaluation; Female; Humans; Infant; Male; Nausea; Piperidines; Vomiting

The findings of a study into the anti-emetic properties of domperidone are reported. When the drug was given prophylactically with either morphine or pethidine the study revealed that any anti-emetic property of domperidone was of short duration and that it would not be suitable as a prophylaxis against opiate-induced emesis. Domperidone is not being introduced into clinical practice in the United Kingdom on the basis of current study.

Topics: Adolescent; Adult; Anesthesia, General; Antiemetics; Benzimidazoles; Drug Evaluation; Female; Humans; Middle Aged; Nausea; Pilot Projects; Piperidines; Postoperative Period; Surgical Procedures, Operative; Vomiting

Topics: Animals; Apomorphine; Benzimidazoles; Dogs; Domperidone; Fentanyl; Haloperidol; Morphine; Muscle Contraction; Muscle Relaxation; Muscle, Smooth; Naloxone; Piperidines; Stomach; Vomiting

The new potent anti-nauseant 5-chloro-1-(1p[3-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-propyl]-4-piperidinyl)-1.3-dihydro-2H-benzimidazol-2-one (domperidone), which in contrast to available anti-emetics does not provoke extrapyramidal or adrenolytic adverse effects, also enhances gastric emptying motility. Controlled clinical trials have confirmed its prokinetic effects on the stomach and its lack of side-effects, even at high doses. This anti-nauseant appears to be a safe and effective treatment for patients, both adults and children, with dyspepsia or vomiting.

Topics: Animals; Antiemetics; Benzimidazoles; Dogs; Dyspepsia; Gastric Emptying; Gastrointestinal Motility; Guinea Pigs; Humans; In Vitro Techniques; Piperidines; Rats; Vomiting

The effect of domperidone (R 33 812), a new antiemetic, was studied in 27 patients presenting with postoperative vomiting and staying for at least six hours in a recovery room. All patients received 4 mg domperidone intravenously because of the vomiting. Nineteen patients were fully protected during the subsequent 6 hours observation period, 8 patients required a second 4 mg-dose: only one of these 8 patients was not protected at all. No side-effects were observed.

Topics: Adult; Aged; Anesthesia; Antiemetics; Benzimidazoles; Drug Evaluation; Female; Humans; Male; Middle Aged; Piperidines; Postoperative Complications; Vomiting

Topics: Aggression; Animals; Antiemetics; Apomorphine; Behavior, Animal; Cats; Chlorpromazine; Conditioning, Operant; Copper; Dextroamphetamine; Dioxoles; Dogs; Drug Synergism; Electroencephalography; Escape Reaction; Ethanol; Haplorhini; Humans; Indoles; Male; Mice; Motor Activity; Piperidines; Postural Balance; Rats; Seizures; Species Specificity; Stereotyped Behavior; Vomiting

Topics: Antiemetics; Carbonates; Dihydroxyphenylalanine; Dinitrophenols; Humans; Nausea; Parkinson Disease; Piperidines; Vomiting

Topics: Antiemetics; Cerebral Angiography; Cerebral Ventriculography; Dihydroxyphenylalanine; Drug Hypersensitivity; Humans; Myelography; Phenothiazines; Piperidines; Vomiting

Topics: Adolescent; Brain Injuries; Child; Diseases in Twins; Humans; Intellectual Disability; Male; Nitriles; Phenothiazines; Piperidines; Psychomotor Disorders; Tranquilizing Agents; Vascular Diseases; Vomiting

Topics: Adult; Alanine Transaminase; Aspartate Aminotransferases; Autistic Disorder; Autonomic Nervous System; Catatonia; Female; Hallucinations; Humans; Hypnotics and Sedatives; Liver Function Tests; Male; Mental Disorders; Nausea; Neurotic Disorders; Paranoid Disorders; Personality Disorders; Phenothiazines; Piperidines; Schizophrenia; Sleep Wake Disorders; Stimulation, Chemical; Sweating; Tremor; Vascular Diseases; Vomiting

Topics: Female; Humans; Parasympatholytics; Piperidines; Pregnancy; Pregnancy Complications; Vomiting