Comparison of the efficacy and safety of combinations of metopimazine or ondansetron with methylprednisolone in the prevention of delayed emesis in patients receiving chemotherapy.

BACKGROUND: Delayed emesis following chemotherapy in cancer patients remains an important challenge for treatment and contributes to poor quality of life and treatment compliance. OBJECTIVES: To compare the efficacy and tolerability of associations of metopimazine and ondansetron with methylprednisolone for the prevention of delayed chemotherapy-induced nausea and emesis. METHODS: A randomised, open-label, observational, cross-over design was used to compare two treatment strategies following two consecutive sessions of chemotherapy separated by at least 1 week. Patients were randomised to treatment with sublingual metopimazine (15 mg tid) or ondansetron lyophilisate (8 mg bid) for 5 days. All patients received oral methylprednisolone (48 mg). Patients reported episodes of nausea and emesis in a diary, and completed the Functional Living Index Emesis quality of life questionnaire. Adverse events were also evaluated. RESULTS: Ninety-nine patients were included in the study, 79.5% of whom were women, with a mean age of 52.7 years. Breast cancer was the most common individual cancer and most patients were receiving combinations of cytotoxic drugs. Treatment was successful at preventing delayed emesis in 73.6% of patients during treatment with the metopimazine-methylprednisolone association and 57.5% during the ondansetron-methylprednisolone association. Analysis of discordant pairs revealed a significant benefit in favour of the methopimazine-methylprednisolone association (p = 0.006). No significant difference was observed between treatments for the overall quality of life score. The incidence of gastrointestinal disorders, particularly constipation, was significantly higher during ondansetron-methylprednisolone treatment (p = 0.0112). CONCLUSION: Methopimazine is an effective and well-tolerated alternative to setrons for the treatment of delayed nausea and emesis in patients undergoing chemotherapy.

Anileridine-induced delirium.

Delirium is a common complication in hospitalized patients and is often associated with significant morbidity. It is important to recognize this syndrome early so that potential causes can be identified and properly managed. Although the etiology of delirium in critically or terminally ill patients is often multifactorial, opioid analgesics are often implicated as a potential underlying cause. Certain opioids, such as meperidine, have been identified as having a greater potential for causing delirium than others. There have been no published reports of anileridine-induced delirium and an illustrative case is presented.

The effect of food on serum concentrations of metopimazine.

1. Six healthy volunteers were given single oral doses of the antiemetic metopimazine (MPZ), starting with trial (a) 20 mg preprandially and followed by trial (b) 50 mg preprandially. In trials (c) and (d) the doses were similar to those in trials (a) and (b), but MPZ was given postprandially. To evaluate intra-individual variation in serum concentrations, trial (a) was repeated three times in four of the volunteers (trial (e)). 2. Blood samples were drawn and the serum concentrations of MPZ and its acid metabolite (AMPZ) were measured by h.p.l.c. 3. There was no evidence of dose-dependent kinetics at the dose levels studied. 4. Median AUC values were 22.6, 16.2, 52.4 and 35.2 (trials (a), (b), (c) and (d), ng ml-1 h). Food intake decreased the serum concentrations of MPZ, suggesting that MPZ should be taken preprandially.

[Nalbuphine and piritramid in the postoperative period in young children. 2. External respiration]. / Nalbuphin und Piritramid in der postoperativen Phase beim Kleinkind. Teil 2. Aussere Atmung.

The use of opioid analgesics often seems to be necessary for postoperative analgesia in small children. There is a risk however, that interactions between anesthetics and the opioid analgesics may cause significant respiratory depression. There is no reliable information about the influence of nalbuphine and piritramide on respiration in small children. Therefore, the actions of nalbuphine and piritramide versus placebo on the respiratory patterns of 46 children in ASA groups I and II and aged between 1 and 4 years were tested in a randomized double blind trial. METHODS. Selection criteria were: no disturbed development, no signs or symptoms of neurological disease, uncomplicated operation, no pain at time of admission, no indication for urgent operation, written parental consent. Operations, premedication and anesthesia were standardized as mentioned in the comparison paper. Anesthesia was induced and maintained with oxygen in nitrous oxide and halothane (FiO2:0.3). Intubation was performed without the use of any relaxant. Postoperatively the ventilation was continued with the same FiO2 and with 0.5 vol% of halothane over a period of at least 20 min until spontaneous breathing was reestablished and stable ventilatory parameters were obtained. A single bolus injection of either nalbuphine or piritramide 0.1 mg/kg or a placebo was then given i.v.. The breathing parameters VT, VI, respiratory rate, maximal inspiratory flow and the inspiratory/expiratory time ratio were evaluated using the computer-assisted pneumotachometric device with hot wire anemometers (Büttner et al.). They were measured before and 2, 5, 10 and 15 min after the drugs were administered. Capillary blood-gas values were sampled before and 10 min after administration of the drug and again 5 min after extubation. Heart rate and blood pressure were recorded by means of a Dinamap monitor. Statistical analysis of the data was carried out by means of the chi 2-test or Fisher's exact test when appropriate. For the metric data analysis of variance was performed. A full factorial design was calculated with drugs and time after injection as factors and baseline values as a covariate. Multiple comparisons were performed using the Tukey test. The level of significance was set at P less than 0.05. Homogeneity was considered when p greater than 0.2. RESULTS. In spite of randomization the 3 groups could not be regarded as homogeneous for weight. In 4 of the 46 children apnea developed after drug administration and controlled ventilation was needed. These were all in the piritramide group. This result was significant against nalbuphine and placebo. There was no significant correlation between the apnea and any anamnestic, demographic or respiratory parameters. Since apnea and breathing constitute different qualities, a pooling of the apnea data and the non-apnea data within the piritramide group is not allowed...

Randomized trial of AT-1015 for treatment of intermittent claudication. A novel 5-hydroxytryptamine antagonist with no evidence of efficacy.

AT-1015 is a novel selective 5-HT2A serotonin receptor antagonist that is known to impair platelet aggregation and vasoconstriction. Serotonin has been hypothesized to contribute to claudication symptoms in individuals with peripheral arterial disease (PAD) via microvascular vasoconstrictor and thrombotic effects. AT-1015 was thus evaluated in 439 patients with claudication who were randomized in a double-blind, placebo-controlled trial comparing 10 mg, 20 mg, and 40 mg BID versus placebo for 24 weeks. Treadmill walking performance was assessed by peak walking time (PWT) and pain-free walking time (PFWT). Quality of life (QoL) was measured by the Walking Impairment Questionnaire (WIQ) and the Health Status Survey SF-36. Limb hemodynamics was assessed with the ankle-brachial index (ABI). The 40 mg arm was terminated prematurely by recommendation of the Data Safety Monitoring Committee due to an excess number of non-fatal myocardial infarctions. At study conclusion, there were no statistically significant differences in the mean change of PWT, PFWT, ABI and QoL between the 10 mg and 20 mg BID treatment groups compared with placebo. The proportion of patients who experienced an adverse event (AE) was similar across all treatment groups. Antimuscarinic and gastrointestinal AEs were more common in the AT-1015 treatment groups. Two deaths occurred: one in the placebo group and the other in the AT-1015 20 mg group. Although a prolongation of the QTc interval was observed in all groups, this was not clinically significant (QTc > 500 ms). Mean supine pulse rates were significantly increased in all AT-1015 treatment groups, consistent with predicted antimuscarinic effects. Population pharmacokinetic analysis fit a one-compartment model with first-order absorption and elimination. These data indicate that selective serotonin receptor blockade does not improve exercise tolerance or quality of life in individuals with claudication.

Character neuroses and behavioural disorders in children: their treatment with pipamperone (Dipiperon). A clinical study.

Dipiperon drops 30-180 mg/day were given for eight weeks to 29 children with character neuroses and behavioural disorders. A 16-item rating-scale covering several features of behaviour disorder was completed by a psychologist and a teacher independent from each other. The individual number of pathological scores showed a decrease already within the first treatment week and a further decrease by the end of the trial, especially for the items of capriciousness, obstinacy, irritability and restlessness. The therapeutic benefit was not accompanied by an adverse effect on the school performance of the children. No side-effects were reported or observed.

The constipating effect of diphenoxylate (Retardinr) in ulcerative colitis. A double-blind controlled trial.

A double-blind study of 20 patients with ulcerative colitis during treatment with diphenoxylate 5 mg three times daily and placebo is reported. There were two treatment periods of 14 days each, with cross-over technique and randomized sequence. Test variable for constipating effect was the mean number of defaecations per day. The criterion for inclusion of patients was the presence of 4 or more daily bowel movements; 2 patients did not complete the investigation. Significant difference (p less than 0.01) in constipating effect between diphenoxylase and placebo was demonstrated both during a period of 12 days and a period of 6 days (Tables II and III). The average number of bowel movements were reduced by 0.7 and 1.3 per day respectively. Side-effects during treatment with diphenoxylate were seen in 53% (Table III) with significant difference against placebo (p less than 0.05). On the basis of the small absolute reduction of defaecation frequency side-effects, it is concluded that diphenoxylate has no place in the routine treatment of ulcerative colitis.

Ondansetron plus metopimazine compared with ondansetron alone in patients receiving moderately emetogenic chemotherapy.

BACKGROUND AND METHODS: The serotonin (5-hydroxytryptamine3) antagonists have improved the treatment of acute chemotherapy-induced nausea and vomiting, but their ability to prevent delayed nausea and vomiting seems less pronounced. The results of a preliminary open trial suggested that the addition of a selective dopamine D2 antagonist could improve the antiemetic efficacy of the serotonin antagonists. In a randomized, double-blind, crossover trial, we compared oral treatment with ondansetron (8 mg twice a day) and the dopamine D2 antagonist metopimazine (30 mg four times a day) with treatment with ondansetron alone for three days in 30 patients who had vomited during the previous cycle of chemotherapy. All the patients received moderately emetogenic chemotherapy. RESULTS: Combination treatment with ondansetron and metopimazine significantly reduced the incidence of acute (P = 0.006) and delayed (P = 0.02) nausea and acute (P = 0.02) and delayed (P = 0.006) vomiting, as compared with treatment with ondansetron alone. Patients had significantly fewer days of nausea (P = 0.03) and vomiting (P = 0.003) if they received combination therapy. Sixty-seven percent of the patients preferred ondansetron and metopimazine, and 33 percent favored ondansetron alone (P = 0.10). Adverse reactions were mild with both regimens. With the exception of constipation, which was reported more frequently with combination therapy (P = 0.03), there were no significant differences in adverse reactions. CONCLUSIONS: Ondansetron plus metopimazine is a highly effective and safe antiemetic regimen that is markedly superior to treatment with ondansetron alone in patients receiving moderately emetogenic chemotherapy.

Comparison of anileridine and pethidine in patients with pain following upper abdominal surgery.

The analgesic potency of anileridine compared with pethidine was found to be 4:1 by measuring the effect on withdrawal movements resulting from pinching of the skin or surgery during N2O + O2 anaesthesia. The potency ratio was examined postoperatively as well. Sixty patients who had undergone upper abdominal surgery with standard anaesthesia were studied in a double-blind, between-patient two dose comparison. Each patient and an observer graded the degree of pain relief. Here again, anileridine proved 4 times as potent as pethidine. With higher doses the response to anileridine was of shorter duration than was the response to pethidine. Respiratory depression was very similar after equianalgesic doses. Blood pressure and pulse rate remained stable. The total incidence of side effects was higher after pethidine.

Comparison of anileridine and pethidine in preventing pain responses during nitrous oxide-oxygen anaesthesia.

The analgesic potency of anileridine and pethidine was compared in 28 patients by measuring their effect on withdrawal movements caused by pinching of the skin or by surgery during N2O + O2 anaesthesia. It appeared that anileridine is 3.5 to 4 times as potent as pethidine on a weight basis. In equianalgesic doses the incidence of side effects was equal after both drugs.

Dose-finding study of oral metopimazine.

A few studies indicate a dose-response effect of the antiemetic metopimazine. The aim of this study was therefore to investigate the tolerability of increasing doses of metopimazine given orally every 4 h for eleven doses. The dose levels 20 mg, 30 mg, 40 mg, 50 mg and 60 mg were studied in 36 patients completing 46 cycles of chemotherapy. Serum concentrations of metopimazine and the acid metabolite AMPZ were measured by HPLC in 13 patients (15 cycles). The dose-limiting toxicity was moderate to severe dizziness caused by orthostatic hypotension as seen in 0, 0, 17%, 42% and 50% of patients at the respective dose levels. Other side effects were few and mild, and only a single possible extrapyramidal adverse event was observed in a patient at the 60-mg dose. High serum concentrations were not predictive for toxicity, as found on comparison of patients with and without symptoms, but in individual patients symptoms were seen at the time of Cmax. We found that metopimazine was safe with a dosage of 30 mg x 6. This dose is four times higher than that previously recommended for antiemetic use.