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PubMed2001

Ondansetron plus metopimazine compared with ondansetron plus metopimazine plus prednisolone as antiemetic prophylaxis in patients receiving multiple cycles of moderately emetogenic chemotherapy.

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.

Adult↗
PubMed1993

Cholecystokinin stimulates gonadotropin-releasing hormone release in the monkey (Macaca mulatta).

There is evidence to suggest that the arginine vasopressin release observed in association with emesis after i.v. injection of cholecystokinin (CCK) and N-methyl-D-aspartate (NMDA) is mediated by stimulation of emetic centers in the brainstem. That the GnRH-releasing action of NMDA is also sometimes accompanied by emesis led to the suggestion that stimulation of this parvocellular system by the glutamate agonist may also be mediated in part via activation of brainstem pathways. If this is the case, then other nauseogenic agents, such as CCK, should similarly elicit GnRH release. The foregoing prediction was tested in the castrated juvenile male monkey, an experimental model characterized by the absence of spontaneous GnRH release. GnRH discharges were monitored indirectly by measuring changes in circulating LH concentrations after the responsivity of the gonadotroph had been heightened by a chronic intermittent i.v. infusion of the decapeptide. An i.v. bolus of CCK at 10 and 30 micrograms/kg BW led to a distinct discharge of GnRH accompanied by emesis or other behaviors suggestive of nausea. Lower doses of CCK (1 and 3 micrograms/kg BW) failed to significantly perturb GnRH release or cause emesis, although NMDA (5 mg/kg BW; racemic form) injected i.v. 3 h after the CCK challenge led to a robust rise in GnRH. In a parallel study, three repetitive i.v. CCK injections at 2h intervals maintained intermittent GnRH release. Pretreatment with a long-acting GnRH receptor antagonist ([AcD2Nal1,4ClPhe2,DTrp3,DArg6,DAla10]GnRH -HOAc) abolished the LH response to CCK, confirming that the action of this peptide was mediated by GnRH release. Although a direct hypothalamic site of action for these agents remains the most likely possibility, since both NMDA and CCK receptors are present in the infundibular region, the present data are consistent with the notion that CCK and, by inference, NMDA may activate GnRH release in part via the stimulation of brainstem emetic centers. Plasma GH, PRL, and cortisol concentrations were also monitored during the course of some of these experiments, and the release of these hormones was observed after the administration of either the 10 or 30 micrograms/kg BW dose of CCK.

Animals↗
PubMed1989

Neurohypophyseal secretion in response to cholecystokinin but not meal-induced gastric distention in humans.

Exogenous administration of cholecystokinin octapeptide (CCK) is known to decrease food intake and slow gastric emptying in humans and animals. Recent studies have shown that CCK stimulates neurohypophyseal secretion of oxytocin (OT) in rats and arginine vasopressin (AVP) in monkeys, and that gastric distention also stimulates OT release in rats. We therefore studied AVP and OT secretion in 14 normal subjects in response to meal-induced gastric distention and administration of CCK, both separately and in combination, to assess whether these stimuli similarly activated central neurohypophyseal pathways in humans. Neither plasma AVP nor OT concentrations increased after gastric distention produced by ingestion of a large meal. However, a dose-related increase in plasma AVP, but not OT levels, occurred after CCK administration, the threshold CCK dose being 0.05 micrograms/kg body weight. The AVP secretion in response to CCK administration was significantly correlated with subjective aversive symptoms quantified by use of a numeric scale (r = 0.61, P less than 0.001). In 12 of the 14 subjects plasma AVP levels increased in association with symptoms of epigastric pressure and discomfort before the onset of overt nausea or emesis. The combination of CCK and meal-induced gastric distention did not stimulate increases in plasma AVP levels in excess of those produced by CCK administration alone. The results demonstrate that AVP secretion resulting from emetic center activation often is a graded response that can begin in association with milder degrees of visceral discomfort before symptoms of overt nausea or emesis. In addition, the stimulation of AVP secretion by CCK administration, but not by meal-induced gastric distention in association with physiological satiety, suggests that some component of the anorectic effects of exogenous CCK in man likely results from activation of brainstem emetic centers.

Adult↗
PubMed2003

The effect of dexamethasone on side effects after coronary revascularization procedures.

UNLABELLED: Corticosteroids decrease side effects after noncardiac elective surgery. We designed this randomized, double-blinded, placebo-controlled study to test the hypothesis that standard doses of dexamethasone (4 mg x2) would reduce postoperative nausea, vomiting, and pain, decrease the incidence of atrial fibrillation (AF), and improve appetite after cardiac surgery, thereby facilitating the recovery process. A total of 300 patients undergoing coronary revascularization surgery were enrolled in this clinical study. The anesthetic management was standardized in all patients. Dexamethasone (4 mg/mL) or saline (1 mL) was administered after the induction of anesthesia and a second dose of the same study drug was given on the morning after surgery. The incidence of AF was determined by analyzing the first 72 h of continuously recorded electrocardiogram records after cardiac surgery. The patients were assessed at 24- and 48-h intervals after surgery, as well as at the time of hospital discharge, to determine the incidence and severity of postoperative side effects (e.g., nausea, vomiting, pain) and patient satisfaction scores. Dexamethasone significantly reduced the need for antiemetic rescue medication on the first postoperative day (30% versus 42%), and the incidences of nausea (15% versus 26%) and vomiting (5% versus 16%) on the second postoperative day (P < 0.05). In addition, dexamethasone significantly reduced the percentage of patients with a depressed appetite on the second postoperative day. However, the corticosteroid failed to decrease the incidence of AF (27% versus 32%) or the total dosage of opioid analgesic medication administered in the postoperative period. We conclude that dexamethasone (8 mg in divided doses) was beneficial in reducing emetic symptoms and improving appetite after cardiac surgery. However, this dose of the corticosteroid does not seem to have antiarrhythmic or analgesic-sparing properties. IMPLICATIONS: Dexamethasone (8 mg IV) was beneficial in reducing emetic symptoms and increasing appetite after cardiac surgery. However, this dose of the corticosteroid failed to decrease postoperative pain or the incidence of new-onset atrial fibrillation.

Aged↗
PubMed2006

Local/cervical block anesthesia versus general anesthesia for minimally invasive parathyroidectomy: what are the advantages?

BACKGROUND: Minimally invasive parathyroidectomy (MIP) under local/cervical block anesthesia (LA) is safe and effective for patients with primary hyperparathyroidism (HPT). Advantages of LA versus general anesthesia (GA) for these focused procedures have not been clearly demonstrated. METHODS: Between 3/01 and 6/04, 177 consecutive patients with primary HPT and positive localization studies underwent MIP. Seventy-three (41%) had surgery under LA while 104 (59%) had GA. Primary endpoints were IV narcotic use, anti-emetic use, nausea, vomiting, and post-operative pain. RESULTS: Patients who had parathyroidectomy under LA were older (64 +/- 2 vs. 57 +/- 2 years, P = 0.001). Cure and complication rates were identical between the two groups. Patients who had parathyroidectomy under LA required less IV narcotic pain mediation (mean morphine equivalents 11.4 +/- 1.3 mg vs. 22.5 +/- 1.1 mg; P < 0.001) compared to GA patients. The LA patients had better pain control as shown by lower post-operative peak pain scores (2.9 +/- 0.3 vs. 5.0 +/- 0.4; P < 0.001) and lower overall pain scores (mean 1.9 +/- 0.2 vs. 3.1 +/- 0.2; P < 0.001). The LA group required fewer anti-emetic medications compared to the GA patients (mean 0.4 +/- 0.1 vs. 1.7 +/- 0.1 doses; P < 0.001). Fewer LA patients experienced post-operative nausea (16% vs. 49%; P < 0.001), and vomiting (7% vs. 24%; P = 0.002). Length of stay was similar between the groups (0.4 +/- 0 vs. 0.3 +/- 0; P = 0.22). CONCLUSIONS: In this study the choice of anesthesia did not affect surgical cure rate, morbidity, or length of stay. LA was associated with significantly lower post-operative pain, nausea, and vomiting. LA appears to offer specific advantages more than GA for patients undergoing MIP.

Anesthesia, General↗
PubMed1997

Involvement of a peripheral mechanism in the emesis induced by cardiac glycosides in Suncus murinus.

The ability of three cardiac glycosides, ouabain, digitonin and digitoxin, to induce emesis and their mechanism(s) of action were investigated in Suncus murinus. The intraperitoneal injection of ouabain but not digitonin nor digitoxin caused vomiting in a dose-dependent manner. However, the administration of ouabain into the cerebroventricle did not cause emesis. Ouabain-induced emesis was partly prevented by surgical abdominal vagotomy. Pretreatment with tropisetron, a selective 5-HT3 (5-hydroxytriptamine) receptor antagonist, did not affect the emetic response evoked by ouabain. These results suggest that ouabain exerts emetic effects via peripheral mechanism(s), but 5-HT3 receptors are not involved in the pathway.

Animals↗
PubMed1997

Antiemetic effects of morphine on motion- and drug-induced emesis in Suncus murinus.

Emetic and antiemetic effects of morphine were investigated in Suncus murinus. Subcutaneous (up to 30 mg/kg) or intracerebroventricular administration (50 micrograms) of morphine failed to cause emesis. However, pretreatment with morphine (s.c.) prevented the emesis induced by nicotine (10 mg/kg, i.p.), copper sulfate (40 mg/kg, p.o.), cisplatin (20 mg/kg, i.p.) and motion stimulus. These results suggest that morphine has only antiemetic potency and may block a common mechanism for the emetic reflex of suncus, because the antiemetic effects of the drug were exerted irrespective of the stimulus.

Animals↗
PubMed1996

[Mechanisms of cytotoxic drug-induced emesis and its prevention].

In this review, I have attempted to provide an overview of the pathways by which cytotoxic drugs induce emesis. The mechanisms of serotonin 5-HT3 antagonists and new antiemetics are also discussed. Old data especially from the experiments employing area postrema ablation must be re-evaluated because it is likely that the operation has damaged other important nucleus in the brain stem. Therefore, the concept of the chemoreceptor trigger zone and "vomiting center" proposed by Borison et al. in 1950s is questionable. Nausea and vomiting caused by cytotoxic drugs have been a serious problem in anti-cancer therapy and prompted lots of scientists to find the mechanism and to develop antiemetics. Effectiveness of 5-HT3 antagonists were shown in late 1980s, and now they are clinically available. I have investigated their mechanisms using Suncus murinus and proposed that the pathways by which cisplatin, one of most emetogenic drugs, induces emesis are as follows: 1) cisplatin is converted to an active metabolite(s), 2) the metabolite(s) somehow produces oxygen free radicals in the enterochromaffin cells, 3) the free radicals release serotonin, 4) the released serotonin stimulates 5-HT3 receptors located on the vagus afferents, 5) impulses are transmitted to the brain stem, or emetic pattern generator and initiate emetic reflex. Therefore, scavengers of free radicals and antioxidants can be a new type of antiemetic drug.

Animals↗
PubMed1988

Emesis induced by cancer chemotherapeutic agents in the Suncus murinus: a new experimental model.

Acute emetic responses to seven cancer chemotherapeutic agents (adriamycin, bleomycin, cisplatin, cyclophosphamide, 5-fluorouracil, methotrexate, mitomycin C) were studied in the Suncus murinus. Intravenous injection of the drugs caused vomiting with various latency. Cisplatin-induced emesis was prevented by the pretreatment with metoclopramide or chlorpromazine but not with domperidone. These results indicate that the Suncus murinus is a useful animal for testing emetic activities of cancer chemotherapeutics and antiemetic activities of prophylactic drugs.

Animals↗
PubMed1991

Selective blockade of cytotoxic drug-induced emesis by 5-HT3 receptor antagonists in Suncus murinus.

Antiemetic effects of serotonin 5-HT3 receptor antagonists (ICS205-930, zacopride, BRL43694, GR38032F) were investigated in Suncus murinus. Veratrine, nicotine, copper sulfate, cisplatin, cyclophosphamide and motion sickness were used as emetic stimuli. Serotonin 5-HT3 receptor antagonists did not inhibit emetic responses to veratrine, nicotine, copper sulfate and motion sickness. However, cisplatin- and cyclophosphamide-induced emesis was strongly blocked by them. Both subcutaneous and intravenous injections of 5-HT3 antagonists were effective. Serotonin 5-HT1 and 5-HT2 receptor antagonists were less effective. These results clearly indicate that a 5-HT3 receptor-mediated mechanism(s) is involved in the emesis caused by cancer chemotherapeutic agents and that 5-HT3 receptor antagonists are very effective as prophylactic drugs.

Animals↗
PubMed2001

Possible involvement of 5-HT4 receptors, in addition to 5-HT3 receptors, in the emesis induced by high-dose cisplatin in Suncus murinus.

To clarify the mechanism for the severe emesis concomitant with intensive chemotherapy, we investigated the effects of 5-HT3- and 5-HT4-receptor antagonists on the emesis induced by the high-dose of cisplatin in Suncus murinus. The emesis induced by 50 mg/kg of cisplatin was reduced by the oral pretreatment with tropisetron, which is known as a 5-HT3- and 5-HT4-receptor dual antagonist in vitro, with the ID50 value of 0.52 mg/kg. On the contrary, granisetron, a selective 5-HT3-receptor antagonist, did not markedly inhibit the emesis at up to 30 mg/kg. Moreover, GR125487, a selective 5-HT4-receptor antagonist, did not inhibit the emesis. However, co-administration of GR125487 and granisetron significantly reduced the number of emetic episodes. The study of the co-administration of GR125487 with tropisetron showed that GR125487 did not further enhance the inhibitory effect of tropisetron alone, suggesting that the anti-emetic effect of tropisetron is mediated via the blockade of both 5-HT3 and 5-HT4 receptors. These results suggest that both the 5-HT3 and 5-HT4 receptors are involved in the emesis induced by the high-dose of cisplatin in Suncus murinus.

Animals↗
PubMed2002

Effect of 6-hydroxydopamine treatment in the area postrema on morphine-induced emesis in ferrets.

To investigate the role of catecholamine release in emesis, we examined the effects of pretreatment with 6-hydroxydopamine (6-OH-DA) administered into the area postrema in morphine-induced emesis in ferrets. In the 6-OH-DA pre-treated animals, the latency to the first emetic response induced by morphine hydrochloride (1.0 mg/kg, s.c.) was significantly prolonged and the number of retches and emetic episodes was markedly reduced. In the medulla oblongata, the levels of dopamine and homovanilic acid were reduced by 6-OH-DA pretreatment. These results suggest that catecholamine release in the medulla oblongata, mainly dopamine release, may play an important role in morphine-induced emesis in ferrets.

Animals↗
PubMed2000

Advances in use of the 5-HT3 receptor antagonists.

Nausea and vomiting continue to rank as important side effects for cancer patients receiving chemotherapy. The class of drugs known as the 5-HT3 receptor antagonists have become widely used for chemotherapy-induced nausea and vomiting, and are considered a standard part of care for moderately- and highly-emetogenic chemotherapy in combination with corticosteroids. Ondansetron (Zofran, Glaxo Wellcome), granisetron (Kytril, SmithKline Beecham) and dolasetron (Anzemet, Hoechst Marion Roussel) are commercially available in the US. Intravenous forms of all three drugs have demonstrated efficacy in preventing acute (< or = 24 h following chemotherapy) nausea and emesis due to moderately- and highly-emetogenic chemotherapy. Oral forms of the drugs have been shown to be effective in prevention of nausea and emesis due to moderately-emetogenic chemotherapy. More recently, oral 5-HT3 receptor antagonists have demonstrated efficacy in the prevention of nausea and vomiting due to highly-emetogenic chemotherapy as well. Comparative trials between the three agents have shown no clinically important differences in outcome and they should be considered clinically equivalent. Optimal oral anti-emetic regimens for high-dose chemotherapy with bone marrow or stem cell transplantation remain to be determined and future oral studies should target this population. In general, the decision of which 5-HT3 receptor antagonist to select for formulary inclusion should be based on the dose of anti-emetic used and the acquisition cost of the agents being compared. The oral route should be used whenever possible.

Antiemetics↗
PubMed2005

New drugs for chemotherapy-induced nausea and vomiting: focus on palonosetron.

Significant progress has been made in the development of effective, convenient and well-tolerated means to prevent chemotherapy-induced nausea and vomiting (CINV). Nevertheless, a substantial minority of patients continue to have suboptimal antiemetic control, and additional treatment approaches are needed. One avenue of investigation being pursued involves the evaluation of a new 5-hydroxytryptamine (5-HT(3)) receptor antagonist (palonosetron) that differs from available serotonin antagonists in its markedly longer half-life (40 h) and greater binding affinity for the type-3 serotonin receptor. Analysis of available clinical data demonstrates that palonosetron is an active and well-tolerated new 5-HT(3) antagonist. Moreover, single-dose palonosetron, prior to chemotherapy, has demonstrated improved control of CINV through the full period of emetic risk with a single dose. Palonosetron is recommended as the preferred treatment of acute and delayed emesis prevention with moderate emetic risk chemotherapy in the most recently published evidence-based antiemesis consensus guidelines. Further studies incorporating dexamethasone to 5-HT(3) antagonists will be necessary to determine the relative efficacy of palonosetron compared with available agents. These trials could open a new era in the treatment of CINV.

Animals↗
PubMed2000

Potential of substance P antagonists as antiemetics.

The introduction of serotonin 5-HT3 receptor antagonists into clinical practice allowed for a dramatic improvement in the management of nausea and vomiting. Despite this, postoperative and chemotherapy-induced emesis remains a significant, unresolved issue in many patients even when a combination of antiemetic drugs is used. Numerous neurotransmitters have been implicated in triggering emesis; however, the tachykinin substance P, by virtue of its localisation within both the gastrointestinal vagal afferent nerve fibres and brainstem emetic circuitry, and its ability to induce vomiting when administered intravenously, is thought to play a key role in emetic responses. Because substance P is the most likely endogenous ligand for the neurokinin-1 (NK1) receptor, the development of nonpeptide NK1 receptor antagonists led scientists to evaluate these compounds as antiemetics. The five NK1 receptor inhibitors that have been studied initially in humans are: vofopitant (GR-205171), CP-122721, ezlopitant (CJ-11974), MK-869 (L-754030) and its prodrug L-758298. Except for monotherapy in acute cisplatin-induced emesis, this new class of drugs has proven to be highly effective in the control of both chemotherapy-induced nausea and vomiting, and postoperative nausea and vomiting. No major adverse event was reported in the preliminary trials. Further investigation is mandatory in order to assess the optimal treatment regimen and to make sure the wide spectrum activity of the NK1 receptor inhibitors does not cause significant adverse effects in the context of the treatment of nausea and vomiting.

Antiemetics↗
PubMed1990

The natural course of emesis after carboplatin treatment.

Twenty-eight patients receiving their first cycle of carboplatin treatment (300-400 mg/m2) entered a prospective study in which the natural course and intensity of postchemotherapy emesis was evaluated. Twenty-five patients (89%) experienced nausea at some time after carboplatin treatment and twenty-three patients (82%) vomited. The median number of emetic episodes was 13.5. In the 23 patients who experienced vomiting, the mean period of latency of vomiting (time from start of carboplatin administration to onset of vomiting) was 6.25 h. The period of maximum incidence of vomiting was between 8 and 12 h (71% of patients with vomiting). Between 6 and 14 h after the start of carboplatin treatment, more than 50% of patients were continuously vomiting. Vomiting declined significantly after 24 h. According to these data, carboplatin is a severely emetic drug. Prospective antiemetic trials are necessary in order to obtain antiemetic schedules which are able to increase the tolerance to carboplatin treatment.

Aged↗
PubMed1997

Oral ondansetron 8 mg twice daily is as effective as 8 mg three times daily in the prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy. S3A-376 Study Group.

The efficacy and safety of ondansetron 8 mg BID compared with 8 mg TID for 3 days in the prevention of nausea and vomiting in 402 patients on cyclophosphamide (> or = 500 mg/m2)-based chemotherapy were evaluated in a multicenter, randomized, double-blind, stratified study. The percentage of patients with no emetic episodes over the 3-day study period was 61% in the ondansetron BID group compared with 58% in the ondansetron TID group. Among patients with at least one emetic episode, the mean time to emesis was 14 hr and 17 min in the ondansetron BID group compared with 12 hr and 48 min in the ondansetron TID group. Patients' daily appetite ratings and nausea scores were not significantly different between groups. Clinical laboratory and adverse event profiles were similar between groups. This study is the first large-scale, double-blind trial to demonstrate that ondansetron 8 mg BID for 3 days, a dosing regimen that may enhance patient convenience and compliance, is as effective as ondansetron 8 mg TID for 3 days in the prevention of nausea and vomiting associated with cyclophosphamide-based chemotherapy.

Administration, Oral↗
PubMed1996

The use of ondansetron in the treatment of nausea and vomiting associated with acetaminophen poisoning.

BACKGROUND: Nausea and vomiting associated with poisoning can complicate treatment and in some cases delay potential antidote administration. Side effect such as lowering the seizure threshold may at times discourage the use of traditional phenothiazine and butyrophenone antiemetics. METHODS: We performed a prospective, single arm, observational study examining the effectiveness of the 5HT3 receptor antagonist ondansetron in the management if nausea and vomiting associated with acetaminophen poisoning. Patients with a history or laboratory evidence of acetaminophen poisoning were eligible for inclusion in the study. Exclusion criteria included age less than 18 or greater than 65, use of other antiemetic therapy within the previous 12 hours, history of preexisting hepatic or hematologic disease, pregnancy, or significant ingestion of other substances. Upon meeting entry criteria, patients were administered 8 mg of intravenous ondansetron. Nausea was graded on a 100 mm scale with number of emetic episodes recorded before and after treatment. RESULTS: Six patients were entered in the study. All patients had nausea and at least one emetic episode prior to ondansetron and prior to administration of N-acetylcysteine. All patients reported relief of nausea after ondansetron. The degree of nausea decreased by an average of 52% at 30 min and 88% at 60 min following ondansetron administration. No significant vital sign changes were recorded in any patient, and there were no complications related to therapy. Three patients were administered N-acetylcysteine, and all tolerated this therapy without vomiting after ondansetron. CONCLUSIONS: Ondansetron appears to be a potentially useful adjunct in the management of nausea and vomiting associated with acetaminophen poisoning.

Acetaminophen↗