Prevention of cisplatin-induced emesis by the oral neurokinin-1 antagonist, MK-869, in combination with granisetron and dexamethasone or with dexamethasone alone.
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PURPOSE: The NK1-receptor antagonist MK-869 (L-754,030) has demonstrated antiemetic activity in humans receiving chemotherapy. Objectives of the present trial included the first assessment of oral MK-869 plus dexamethasone compared with a 5HT(3) antagonist plus dexamethasone for prevention of acute and delayed emesis after high-dose cisplatin. Furthermore, the study sought to confirm that addition of MK-869 to a 5HT(3) antagonist plus dexamethasone was more effective than just the 5HT(3) antagonist plus dexamethasone for prevention of acute and delayed emesis. METHODS: This multicenter, double-blind, parallel-group trial in 351 cisplatin-naive patients evaluated prevention of acute (0 to 24 hours) and delayed emesis (primary efficacy parameter; days 2 to 5) after cisplatin (> or =70 mg/m(2)). Patients were randomized to four groups (I to IV) (n = number randomized; number evaluable): granisetron (10 microg/kg intravenously) pre-cisplatin followed by placebo on days 2 to 5 (group I) (n = 90; 90); granisetron and MK-869 (400 mg PO [by mouth]) pre-cisplatin, followed by MK-869 (300 mg PO) on days 2 to 5 (group II) (n = 86; 84); MK-869 (400 mg PO) the evening before and pre-cisplatin, followed by MK-869 (300 mg PO) on days 2 to 5 (group III) (n = 89; 88); or MK-869 (400 mg PO) pre-cisplatin, followed by MK-869 (300 mg PO) on days 2 to 5 (group IV) (n = 86; 84). All patients also received dexamethasone (20 mg PO) before cisplatin. Additional medication was available to treat emesis or nausea at any time. RESULTS: In the acute period, 57%, 80%, 46%, and 43% of patients were without emesis in groups I, II, III, and IV, respectively (P <.01 for group II v group I). In the delayed period, the proportion of patients without emesis in groups I, II, III, and IV was 29%, 63%, 51%, and 57%, respectively (P <.01 for groups II, III, and IV v group I). The distribution of nausea scores in the delayed period was lower when comparing group II with group I (P <.05 for days 1 to 5 and days 2 to 5). One serious adverse event (dizziness) was rated as possibly related to MK-869. CONCLUSION: Once daily oral administration of MK-869 was effective in reducing delayed emesis and nausea after high-dose cisplatin. However, the combination of the 5HT3 antagonist plus dexamethasone was numerically superior to MK-869 plus dexamethasone in reducing acute emesis. Confirming and extending previous findings, the triple combination of a 5HT(3) antagonist, MK-869, and dexamethasone provided the best control of acute emesis. (+info)
Ondansetron plus metopimazine compared with ondansetron plus metopimazine plus prednisolone as antiemetic prophylaxis in patients receiving multiple cycles of moderately emetogenic chemotherapy.
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PURPOSE: To compare the antiemetic efficacy and tolerability of ondansetron plus metopimazine with ondansetron plus metopimazine plus prednisolone during nine cycles of moderately emetogenic chemotherapy. PATIENTS AND METHODS: A total of 221 women with stage I or II breast cancer and no prior chemotherapy who were scheduled to receive adjuvant chemotherapy with intravenous cyclophosphamide, fluorouracil and methotrexate or cyclophosphamide, epirubicin, and fluorouracil given every 3 weeks were included in a double-blind parallel trial. Patients were randomized to 3 days of oral treatment with ondansetron plus metopimazine, or ondansetron plus metopimazine plus prednisolone. Ondansetron was administered as 8 mg bid, metopimazine as 30 mg qid, and prednisolone as 50 mg qd. RESULTS: In all, 216 patients (97.7%) were assessable for efficacy during a total of 1,462 cycles. In cycle 1, complete protection from emetic episodes/nausea day 1, days 2 through 5, and days 1 through 5 was achieved in 84.4%/51.4%, 82.6%/41.3%, and 79.8%/34.9% with ondansetron plus metopimazine and in 84.1%/57.0%, 86.8%/53.8%, and 79.4%/43.0% with ondansetron plus metopimazine plus prednisolone, respectively. In cycle 1, the three-drug combination was superior only in the treatment of nausea on days 2 through 5 (P =.0497). The cumulative emetic protection rate after nine cycles was 0.52 with ondansetron plus metopimazine and 0.75 with ondansetron plus metopimazine plus prednisolone. Side effects were generally few and mild with both treatments. Constipation was the only adverse event significantly more frequent with the three-drug combination (P =.029). CONCLUSION: Ondansetron plus metopimazine plus prednisolone is highly effective and superior to ondansetron plus metopimazine during nine cycles of moderately emetogenic chemotherapy. (+info)
Pharmacokinetics of granisetron in adults and children with malignant diseases.
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Granisetron (GRN) is widely used for patients with various cancers who suffer from chemotherapy-induced vomiting and nausea. The, pharmacokinetics of GRN has not been fully evaluated in such patients, however, and its dosage regimen is still controversial. In this study, we determined GRN levels in serum and urine from lung cancer patients and children suffering from cancer after intravenous infusion. In lung cancer patients, the interindividual variations in t(1/2beta), area under the concentration-time curve (AUC), and Vd(beta) were relatively smaller than expected from previous reports on healthy subjects, while t(1/2beta) was prolonged more than 5-fold in healthy subjects. Urinary excretion of unchanged GRN in lung cancer patients was ca. 15% of dose, consistent with previous reports, and one individual demonstrated an even higher urinary excretion (ca. 45%). The pharmacokinetic parameters of GRN in child cancer patients varied markedly among individuals, and some child patients had smaller t(1/2beta) than adult patients. In these cases, GRN should be administered at shorter intervals. These results suggested that a pharmacokinetic study of GRN was necessary for planning a dosage regimen and managing chemotherapy-induced vomiting and nausea. (+info)
The broad-spectrum anti-emetic activity of AS-8112, a novel dopamine D2, D3 and 5-HT3 receptors antagonist.
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The anti-emetic and pharmacological profile of AS-8112 ((R)-5-bromo-N-(1-ethyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-2-methoxy-6-methy lamino-3-pyridinecarboxamide.2 fumarate), a novel and potent dopamine D2, D3 and 5-hydroxytryptamine-3 (5-HT3) receptors ligand, was investigated in the present study. In guinea-pig isolated colon, AS-8112 produced a rightward shift of the concentration-response curves of 2-methyl-5HT, a 5-HT3 receptor agonist (pA2 value of 7.04). Other 5-HT3 receptor antagonists also produced such a shift in the following antagonistic-potency order: granisetron> ondansetron=AS-8112>>metoclopramide. In mice, AS-8112 (1.0 - 3.0 mg kg(-1) s.c.) potently inhibited hypothermia induced by the dopamine D3 receptor agonist; R(+)-7-OH-DPAT (R(+)-7-hydroxy-2-(N,N-di-n-propylamino)tetraline) (0.3 mg kg(-1) s.c.). Domperidone and haloperidol, which have affinity for dopamine D3 receptor, also inhibited R(+)-7-OH-DPAT-induced hypothermia. In ferrets or dogs, AS-8112 dose-dependently inhibited emesis induced by R(+)-7-OH-DPAT, apomorphine, morphine or cisplatin with ID50 values of 2.22 microg kg(-1) s.c., 10.5 microg kg(-1) s.c., 14.2 microg kg(-1) i.v. and 17.6 microg kg(-1) i.v., respectively. Moreover, oral administration of AS-8112 significantly inhibited emesis induced by these emetogens. AS-8112 (0.3 mg kg(-1) i.v.) significantly inhibited emesis induced by cyclophosphamide and doxorubicin. In conclusion, AS-8112 is a potent dopamine D2, D3 and 5-HT3 receptors antagonist, and a novel anti-emetic agent with a broad-spectrum of anti-emetic activity. These results suggest that this compound is worthy of clinical investigation. (+info)
Ramosetron compared with granisetron for the prevention of vomiting following strabismus surgery in children.
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BACKGROUND/AIMS: Postoperative vomiting occurs frequently after strabismus surgery in children. Granisetron, a selective 5-hydroxytryptamine type 3 receptor antagonist, is effective for the prevention of vomiting following paediatric strabismus surgery. Ramosetron, another new antagonist of 5-hydroxytryptamine type 3 receptor, has more potent and longer acting properties than granisetron against cisplatin induced emesis. This study was undertaken to compare the efficacy and safety of granisetron and ramosetron for the prevention of vomiting following strabismus surgery in children. METHODS: In a randomised, double blinded manner 80 children, aged 4-10 years, received intravenously granisetron 40 microg/kg or ramosetron 6 microg/kg (n=40 each) at the end of surgery. A standard general anaesthetic technique and postoperative analgesia were used. Emetic episodes and safety assessment were performed during the first 24 hours and the next 24 hours after anaesthesia. RESULTS: The percentage of patients who were emesis free during 0-24 hours after anaesthesia was 85% with granisetron and 90% with ramosetron, respectively (p = 0.369); the corresponding rate during 24-48 hours after anaesthesia was 70% and 95% (p = 0.003). No clinically serious adverse events caused by the study drug were observed in any of the groups. CONCLUSION: Prophylactic antiemetic therapy with ramosetron is comparable with granisetron for the prevention of vomiting during 0-24 hours after anaesthesia in children undergoing strabismus surgery. During 24-48 hours after anaesthesia, ramosetron is more effective than granisetron for prophylaxis against postoperative vomiting. (+info)
The cannabinoid agonist WIN55,212-2 suppresses opioid-induced emesis in ferrets.
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BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. (+info)
Ondansetron versus dehydrobenzoperidol and metoclopramide for management of postoperative nausea in laparoscopic surgery patients.
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BACKGROUND: In this prospective, randomized, double-blind study, we compared the efficacy of ondansetron versus dehydrobenzoperidol (droperidol) or metoclopramide in the treatment of established postoperative nausea and vomiting in 200 adult patients undergoing laparoscopic surgery under general anesthesia. METHODS: One hundred seventy-three American Society of Anesthesiologists (ASA) I and II patients satisfied inclusion criteria. Fifty-seven patients received ondansetron 4 mg (group O), 57 patients were given droperidol 1.25 mg (group D), and 59 patients received metoclopramide 10 mg (group M). Antiemetic efficacy was compared at 10 minutes and 30 minutes after the administration of the study drug. RESULTS: At 10 minutes, nausea scores in group O dropped from 8.3 to 3.7, in group D from 8.5 to 5, and in group M from 8.4 to 6.7; (P < 0.05 between the three groups). At 30 minutes, nausea scores were 1.3 in group O, 1.7 in group D, and 5 in group M; (P < 0.05 between group M and the other two groups). In the droperidol group, 25% of patients developed sedation. Patient satisfaction was best with ondansetron. CONCLUSIONS: Both ondansetron and droperidol were more effective in the treatment of established postoperative nausea and vomiting than was metoclopramide. However, patients were satisfied best with ondansetron, which acts faster and causes less sedation than droperidol. (+info)
Effects of substance P on identified neurons of the rat dorsal motor nucleus of the vagus.
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Previous evidence suggests that substance P (SP) activates subpopulations of neurons within the dorsal motor nucleus of the vagus (DMV). In this study we aimed at identifying these subpopulations in relation to their gastrointestinal projection organs or vagal branches and characterizing pharmacologically the SP response. Using whole cell patch-clamp recordings from identified gastrointestinal-projecting vagal motoneurons, we found that SP induced an inward current in all neuronal groups except for cecum-projecting cells. The lowest percentage of SP-responding neurons was found in fundus-projecting cells, where SP also had a concentration-response curve that was shifted to the left (P < 0.05). Independently from the projections, the SP response was reduced by sendide and MEN 10,376 and mimicked by a combination of [Sar(9)-Met(O(2))(11)]SP and alpha-neurokinin. SP and alpha-neurokinin also increased the frequency, but not the amplitude, of postsynaptic currents. In conclusion, we demonstrated that SP induces both pre- and postsynaptic effects on DMV neurons via activation of neurokinin NK(1) and NK(2) receptors. The magnitude of the SP response was correlated to the peripheral target organ. (+info)