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PubMed2006

Randomized, double-blind trial comparing the antiemetic effect of tropisetron plus metopimazine with tropisetron plus placebo in patients receiving multiple cycles of multiple-day cisplatin-based chemotherapy.

PURPOSE: To compare the antiemetic efficacy and tolerability of tropisetron plus metopimazine with tropisetron plus placebo during 4 cycles of multiple-day, cisplatin-based chemotherapy. MATERIALS AND METHODS: 82 chemotherapy-naive patients with germ cell cancer scheduled to 4 cycles of multiple-day cisplatin-based chemotherapy (20 or 40 mg/m(2)/day for 5 days) given every 3 weeks were included. A double-blind parallel trial design was used and patients randomized to tropisetron plus metopimazine or tropisetron plus placebo. Tropisetron was administered as a single 5 mg intravenous dose on days 1-5 and a single 5 mg oral dose on day 6, and metopimazine as 30 mg orally t.i.d. on day 1, and q.i.d on days 2-6. RESULTS: Patients were evaluable for efficacy during a total of 195 cycles. Small, but certain advantages were obtained with the combination. In cycle 1, complete protection from emetic episodes on day 1, days 1-5, days 6-9 and days 1-9 was achieved in 85.7%, 42.9%, 86.2% and 40.5% with tropisetron plus metopimazine and in 90.0%, 22.5%, 64.3% and 17.5% with tropisetron plus placebo, respectively. This difference achieved statistical significance in the overall period, days 1-9 (P = 0.029). During the entire period (days 1-9), significantly less nausea was seen in patients receiving tropisetron plus metopimazine (P = 0.027), whereas other nausea parameters did not reach statistical significance. The cumulative emetic protection rate after 4 cycles was 0.51 with tropisetron plus metopimazine and 0.25 with tropisetron plus placebo (P = 0.037). Side effects were generally few and mild with both treatments and no significant differences were seen. CONCLUSION: Tropisetron plus metopimazine is superior to tropisetron during 4 cycles of multiple-day cisplatin-based chemotherapy, but both treatments are ineffective in a number of patients. The effect of the combination seems comparable to that of ondansetron plus dexamethasone. Newer drugs such as the neurokinin(1) receptor antagonist, aprepitant, should be investigated to optimize antiemetic therapy in patients receiving multiple-day chemotherapy.

Adolescent↗

PubMed1994

Efficacy and tolerability of tropisetron in comparison with a combination of tropisetron and dexamethasone in the control of nausea and vomiting induced by cisplatin-containing chemotherapy.

In a double-blind, randomised, multicentre study, the efficacy and tolerability of tropisetron and a combination of tropisetron and dexamethasone were compared for the control of nausea and vomiting induced by cisplatin in patients previously not entirely protected by tropisetron monotherapy. In all, 160 women with gynaecological cancers were studied during two consecutive courses of cisplatin-containing chemotherapy. During the first course (the screening course), all patients received tropisetron monotherapy [5 mg intravenous (i.v.) on day 1 and 5 mg orally on days 2-6] as antiemetic treatment. During the second course (the test course), tropisetron was compared with a combination of tropisetron and dexamethasone (20 mg i.v. on day 1 and 4.5 mg twice daily on days 2-6). This part of the study was double-blind, randomised and placebo-controlled. Candidates for randomisation were patients with partial control of nausea (< 12 h of nausea) or partial control of vomiting (1-4 episodes of vomiting) during the screening course. Patients with complete control of nausea and vomiting in the screening course continued with tropisetron monotherapy; patients with treatment failure received open rescue treatment in course 2. Total control of acute nausea was achieved in 37% of the tropisetron + placebo group and in 75% of the tropisetron + dexamethasone group (P = 0.001). Significantly more patients on tropisetron-dexamethasone than on tropisetron-placebo were also free of delayed nausea. Acute vomiting was prevented in 40% of the patients in the placebo group and in 75% in the dexamethasone group (P = 0.001). Delayed vomiting was also significantly less frequent in dexamethasone-treated patients than in placebo-treated patients. Tropisetron was well tolerated both as monotherapy and in combination with dexamethasone. The most frequent adverse events were headache (34%), constipation (12.5%) and fatigue (12.5%). Adding high doses of a corticosteroid did not induce further adverse events or disregulate concurrent diseases.

Adult↗

PubMed2006

Prophylactic tropisetron versus rescue tropisetron in fractionated radiotherapy to moderate or high emetogenic areas: a prospective randomized open label study in cancer patients.

AIM: A prospective randomized open label study was carried out to evaluate the efficacy and effectiveness of prophylactic tropisetron versus rescue tropisetron in fractionated radiotherapy. PATIENTS AND METHODS: The study sample consisted of 288 cancer patients randomly allocated (3:4 ratio) into two treatment groups: 120 patients received prophylactic antiemetic treatment with tropisetron and 168 patients received rescue tropisetron. To determine the efficacy of prophylactic antiemetic treatment, nausea and vomiting were evaluated 1 d before radiation therapy (RT), at 24 and 72 h, at the end of every week during RT, and finally 1 wk after RT. Diary cards were used to record the intensity of nausea and vomiting as well as the incidence of adverse effects. RESULTS: In the odds of nausea and vomiting, statistically significant differences were found between the two treatment groups over time. The incidence of nausea and vomiting were 1.89 (p = 0.009) and 2.19 (p = 0.001) times higher in the rescue tropisetron group than in the prophylactic tropisetron group. Factors that related significantly with increased nausea were primary cancer, rescue tropisetron, and radical RT. Moreover, factors for vomiting were primary cancer type, metastasis, palliative RT, and rescue tropisetron. CONCLUSIONS: Higher numbers of patients receiving prophylactic tropisetron completed RT with lower incidence of nausea and vomiting than those in the rescue tropisetron group.

Aged↗

PubMed2000

Tropisetron plus dexamethasone is more effective than tropisetron alone for the prevention of postoperative nausea and vomiting in children undergoing tonsillectomy.

The 5-HT3 antagonists are effective in reducing postoperative nausea and vomiting (PONV) associated with paediatric tonsillectomy. Although prophylactic tropisetron can reduce the incidence of PONV by half, the resulting level of over 40% is still unacceptably high. The aim of this study was to evaluate the effect of adding dexamethasone to tropisetron. In a blinded study, 59 children (mean age 6.1 years) were administered 0.1 mg.kg-1 up to 2 mg of tropisetron and 66 children (mean age 5.7 years) received the same dose of tropisetron plus 0.5 mg.kg-1 up to 8 mg of dexamethasone. Both drugs were given intravenously during induction of anaesthesia for tonsillectomy. During the inpatient stay of 24 h, the incidence of postoperative vomiting in the tropisetron alone group was 53% compared with 26% in the combination group (P=0.002, chi-squared). A significant reduction in nausea from 53% to 30% was also observed (P=0.02). Parents completed a daily diary for 5 days following discharge. Delayed vomiting occurred in 27% and 11% of the tropisetron and combination therapy groups, respectively (P=0.025) Sixteen percent and 9%, respectively, required medical attention (P=0.27). Tropisetron plus dexamethasone is more effective than tropisetron alone in reducing the incidence of PONV following paediatric tonsillectomy.

Adolescent↗

PubMed1995

[Pharmacokinetic investigation of 5-day multiple dose of tropisetron capsule in patients who had received cisplatin and the usefulness of tropisetron capsule in the treatment of nausea and vomiting].

We have investigated the pharmacokinetics of a 5-day multiple oral dose of 5 mg tropisetron capsule in patients with malignant tumour who had received cisplatin single administration. Its anti-emetic effects on acute and delayed emesis and vomiting were also investigated. During the 5 days after this administration, changes in the release and metabolism of serotonin were investigated. The results may be summarized as follows: 1) The pharmacokinetic parameters of tropisetron revealed no significant change in the data between day 1 and day 5. Also, the parameters were almost similar to those observed in healthy adult males (clinical phase I study); Cmax. T1/2 and AUC 0-24 hrs on day 1 were 9.1 +/- 2.1 ng/ml, 12.5 +/- 4.2 hrs, 85.5 +/- 22.7 ng.hr/ml, respectively. The urinary excretion of the parent drug up until 24 hours after administration on day 1 was 3.8% of the dose administered and 2.9% of the total dose after the last administration; no difference in the urinary excretion rate was observed in healthy subjects. It was thus suggested that hydration accompanied by cisplatin administration did not affect the pharmacokinetics of tropisetron. 2) The changes in the amount of urinary excretion of 5-hydroxy-indoleacetic acid (5-HIAA) during 5 days after cisplatin administration were observed; urinary excretion of 5-HIAA increased 2.3 times (1.3-5.4 times) the baseline on the average during 6 to 12 hours on day 1. In 6 out of 10 patients, the increases in urinary excretion of 5-HIAA showed double or more the baseline during 2 to 5 days after cisplatin administration. Serotonin was thus deemed to be related to the development of delayed emesis. 3) The anti-emetic effects of tropisetron on acute and delayed emesis and vomiting were rated as "markedly effective" in 6 out of 11 patients (54.6%) and "effective" in 1 out of 11 patients (9.1%) on day 1; vomiting did not occur in any of these 7 patients. Tropisetron also controlled emesis and vomiting during days 2-5, and was rated as "almost favorable" in 6 out of 11 patients (54.5%). Further, in 4 out of 6 patients, in whom the urinary excretion of 5-HIAA was increased on day 2 onwards, vomiting did not occur during the time when the urinary excretion of 5-HIAA was increasing. On the basis of the above results, tropisetron is deemed to have certain antiemetic effects on delayed vomiting as well. Its 5-HT3 receptor mediated mechanism was similarly seen to inhibit acute nausea and vomiting.

Adult↗

PubMed1999

Effects of anti-emetic drug (tropisetron) on quality of life during chemotherapy: use of a diary-type questionnaire and application of summary measures for assessment in a randomized, multicentre study. Joint Research Group for Tropisetron Double-Blind Comparative Study.

The role of tropisetron as an anti-emetic drug in the prevention of delayed nausea and vomiting remains unclear. Therefore, effectiveness of tropisetron in patients receiving cancer chemotherapy was evaluated by application of summary measures using a quality of life (QOL) questionnaire. The diary-type QOL self-rating questionnaire was constituted by seven scales. A double-blind randomized, multicentre study was performed in 33 hospitals. Quality of life was measured in 98 patients. Patients receiving cisplatin were randomized to group T (administration of tropisetron before and 4 days after cisplatin treatment) and group P (administration of tropisetron before cisplatin treatment and followed by placebo for 4 days). The rate of complete protection from delayed emesis in the groups T and P was 46.3 and 36.5%. All scales, except social wellbeing changed immediately in both groups and reached a nadir on days 2-3, after that returning to the control levels during 2 weeks after cisplatin treatment. Group T was significantly better than group P in physical wellbeing, mental wellbeing, functional wellbeing and global QOL scores summarized by area under the curve and Difmax (maximum differences of QOL scales' score from the best score throughout the entire period). These results indicate that continuous administration of tropisetron could contribute to preventing patient QOL influenced by cisplatin treatment, and the combined use of summary measures may be useful for the evaluation of QOL in cancer clinical trial.

Adult↗

PubMed1996

[Effects of an anti-emetic tropisetron capsule on QOL of patients with delayed nausea and vomiting induced by cancer chemotherapy. Group for Investigation of QOL Questionnaire for Anti-Emetics used in Cancer Chemotherapy. Joint Research Group for Tropisetron Double-Blind Comparative Study].

We have reported our "new questionnaire of QOL (quality of life) in anti-emetic therapies during cancer chemotherapy" and demonstrated its reliability and validity. In the present study we investigated the utility of tropisetron capsules for delayed nausea and vomiting induced by cancer chemotherapies with CDDP single administration in a placebo-controlled double-blind comparative study using the questionnaire. The questionnaire was composed of the following scales: a physiological scale (appetite, feeling, vomiting, nausea), a psychological scale (sleep, mental fatigue, anxiety, pain, abdominal condition), a respiratory condition related scale (sputum, respiratory distress), an active scale (daily life in a hospital), a social relation scale (understanding of the family), a linear analogue scale for evaluation of the influence of nausea and vomiting in patient's life during 24 hours, and a face scale as the global scale. First, all patients were administered a preventive dose of tropisetron capsule on day 1 (the day of CDDP administration) and then allotted to once-daily oral administration of either a tropisetron (T group) or a placebo (P group) capsule during days 2 to 5 by a double-blind method. Chronological changes of QOL during the study period were measured by the area under the curve (AUC) generally used for calculation of blood levels of drugs. The maximum fluctuation (Difmax) of QOL scores throughout the whole study period was also evaluated. The data were collected from 114 cases, and 98 cases (51 in P group, 47 in T group) were analyzed. 1) The total score or 13 items (a modified linear analogue scale with 5 graduations), the face scale and linear analogue scale of T group were higher (better) than those of P group. 2) As for the total score of each scale, the physiological, psychological and active scales in the T group showed higher (better) levels than the P group. 3) As for the AUC values, the T group was lower (better) than the P group in most items. In AUC of the total score of 13 items, the face scale, the physiological and the psychological scales, the T group was significantly superior to the P group. 4) AUC levels of each item belonged to the physiological and the psychological scales in the T group tended to be lower (better) than the P group, and "sleep" and "pain" in the psychological scale were significantly lower (better) in T group than P group. 5) In Difmax values, all scales except respiratory condition related scale showed lower levels (better) in T group and the total score of 13 items, the face scale and the physiological and psychological scales showed significantly lower levels than P group. 6) Difmax values in each item belonging to the physiological and psychological scales showed lower levels in the T group, while "appetite" and "vomiting" in the physiological scale and "sleep" in the psychological scale showed significantly lower levels (better) than those of the P group. 7) In the stratified analysis performed for patients without nausea and vomiting on the 1st day of chemotherapy, there was no significance in AUC levels of all items in both groups. In patients with nausea and vomiting on the 1st day, the total score of 13 items, the face scale, the physiological and the psychological scales in the T group were significantly better than in the P group. 8) It was suggested that the anti-emetic efficacy of tropisetron for delayed nausea and vomiting might reduce the undesirable influence of chemotherapy on QOL, especially on the physiological and the psychological effects. These results suggested that this new questionnaire is applicable for evaluation of the utility of anti-emetics in patients in cancer chemotherapy, and that tropisetron capsules could reduce the decrease of QOL in delayed nausea and vomiting induced by chemotherapy.

Adolescent↗

PubMed1994

Tropisetron (Navoban) alone and in combination with dexamethasone in the prevention of chemotherapy-induced emesis: the Nordic experience.

Three Nordic multicenter studies were performed between 1988 and 1992 to evaluate the efficacy of tropisetron (Navoban; Sandoz Pharma Ltd, Basel, Switzerland) as an antiemetic agent in patients undergoing various types of chemotherapy. More than 1,050 patients were recruited from cancer centers in Sweden, Finland, and Denmark. In the first two studies, chemotherapy-naive patients were studied for 6-day periods over two consecutive treatment cycles. The first study comparing tropisetron with a metoclopramide cocktail was performed as an open, randomized, multicenter, parallel-group study. All 259 chemotherapy-naive patients received cisplatin > or = 50 mg/m2 on the first day of chemotherapy; other cytostatic agents were allowed on days 1 to 6 of therapy. Patients received either tropisetron or an antiemetic cocktail of metoclopramide, dexamethasone, and lorazepam over the study period. Total control of acute vomiting during the first course of chemotherapy was achieved in 63% of patients in the tropisetron treatment group and in 64% of patients in the antiemetic cocktail group. Acute nausea was prevented completely in 40% of patients in the tropisetron group and in 61% of the metoclopramide cocktail group during course 1 (P < .001). For delayed nausea and vomiting, there were no significant differences between the two antiemetic regimens. Both antiemetic regimens were well tolerated. The second study compared the efficacy of tropisetron plus placebo with tropisetron plus dexamethasone for the prevention of acute and delayed nausea and vomiting during cisplatin-containing chemotherapy in patients not fully controlled by tropisetron monotherapy during course 1. One hundred sixty patients were involved in this double-blind, randomized, placebo-controlled trial. Acute vomiting was completely prevented in 40% of patients treated with tropisetron plus placebo compared with 75% of patients treated with tropisetron plus dexamethasone (P = .001). The results for acute nausea were similar. Delayed vomiting and delayed nausea were completely prevented in significantly more patients receiving the tropisetron-dexamethasone combination than in those receiving the tropisetron-placebo combination (P < .05). Adverse events were reported less frequently in patients receiving tropisetron together with dexamethasone. The third study was an open, nonrandomized multicenter trial designed to investigate the long-term antiemetic effect of tropisetron on various types of chemotherapy and on various types of patients. An interim analysis of this study has been reported previously (Ann Oncol 4:539-542, 1993). Six hundred thirty patients were studied over a mean number of 4.6 courses (range, 1 to 19 courses) of chemotherapy. Each received tropisetron daily on days 1 to 6 of therapy. Complete protection from nausea and vomiting was achieved in 67% of the complete series. The long-term effects of tropisetron therapy remained consistent over 10 consecutive courses of chemotherapy. Tropisetron was more effective during noncisplatin treatment compared with cisplatin treatment; it was also more effective in men and in older patients (> 50 years of age). The most frequent adverse events were headache (18%) and constipation (8%).

Adult↗

PubMed1994

Prevention of chemotherapy-induced nausea and vomiting by tropisetron (Navoban) alone or in combination with other antiemetic agents.

We report an open, three-armed, multicenter study being carried out to assess the optimum treatment for acute and delayed emesis and nausea in patients undergoing highly emetogenic chemotherapy. Eighty-seven patients were randomized to receive tropisetron (Navoban; Sandoz Pharma Ltd, Basel, Switzerland), tropisetron plus dexamethasone, or tropisetron plus metoclopramide during chemotherapy. Tropisetron in combination with dexamethasone produced the best control of both acute and delayed emesis. Acute vomiting was prevented in 69% of patients by tropisetron monotherapy, and the addition of dexamethasone significantly increased the total control of vomiting to 92% (P < .01). Similarly for delayed vomiting, total control of emesis was seen in approximately 70% of patients on tropisetron alone during days 2 and 3; this control rate increased to almost 90% with combined tropisetron/ dexamethasone treatment. In all patients receiving cisplatin, the tropisetron/dexamethasone combination produced total control of acute emesis. The tropisetron and dexamethasone combination also provided the best control of acute and delayed nausea. Tropisetron produced total control of acute nausea in 69% of patients. The addition of dexamethasone increased this control rate to 81%. Similarly for delayed nausea, on days 2 and 3 of treatment, dexamethasone plus tropisetron provided total control of nausea in more than 80% of patients compared with a control rate of more than 60% achieved using tropisetron. The combination of tropisetron and metoclopramide did not improve significantly on the control of nausea and vomiting achieved using tropisetron alone. Evaluation of quality of life events by patients indicated no appreciable change in their mental or physical condition during chemotherapy, irrespective of antiemetic therapy. In the tropisetron and tropisetron plus metoclopramide treatment groups, a decreased food intake was observed due to delayed nausea while the addition of dexamethasone prevented loss of appetite. The antiemetic treatments were similarly well tolerated. The most common adverse events were constipation (15%) and tiredness (7%).

Adult↗

PubMed2000

Tropisetron: an update of its use in the prevention of chemotherapy-induced nausea and vomiting.

UNLABELLED: Tropisetron is a serotonin (5-hydroxytryptamine; 5-HT) antagonist that is primarily used in the prevention of chemotherapy-induced nausea and vomiting. Antagonism of 5-HT3 binding sites in the peripheral and central nervous system is the probable mechanism of prevention of acute nausea and vomiting. Effects on delayed nausea and vomiting are less well understood as these are probably not mediated solely by 5-HT3 receptors. Tropisetron monotherapy is effective for the control of acute, and to a lesser extent delayed, nausea and vomiting in patients receiving moderately to severely emetogenic chemotherapy. The combination of dexamethasone and tropisetron is more effective than monotherapy. Complete control of cisplatin-induced nausea and vomiting was obtained in 69 to 97% of patients receiving the combination compared with 46 to 80% receiving tropisetron monotherapy in randomised trials. There were generally no significant differences between the control of acute or delayed nausea and vomiting provided by tropisetron, ondansetron or granisetron in randomised, comparative trials. The antiemetic efficacy of tropisetron was maintained over multiple cycles of chemotherapy. Most comparative studies showed tropisetron monotherapy to be more effective than metoclopramide in controlling acute nausea and vomiting, with the exception of 1 study which showed similar efficacy. However, high dose metoclopramide plus dexamethasone provided similar control of delayed emesis to tropisetron plus dexamethasone. Tropisetron is also effective in children, including those who responded poorly to previous antiemetic treatment. Tropisetron and ondansetron generally have similar efficacies in this population. The drug enhanced patients' quality of life and was well tolerated by adults and children alike. The recommended oral and IV dosage of tropisetron is 5 mg once daily; there is no increase in efficacy with doses >5 mg. CONCLUSIONS: Tropisetron is similar to other 5-HT3 receptor antagonists for the prevention of chemotherapy-induced nausea and vomiting in both adults and children. It is suitable as first-line therapy (combined with a corticosteroid) for the prevention of acute nausea and vomiting in patients treated with moderately to severely emetogenic chemotherapeutic agents. This combination is also moderately effective in the prevention of delayed nausea and vomiting.

Animals↗

PubMed2000

Efficacy and tolerability of tropisetron in primary fibromyalgia--a highly selective and competitive 5-HT3 receptor antagonist. German Fibromyalgia Study Group.

OBJECTIVE: Based on a potential role for serotonin receptors in fibromyalgia, we investigated the efficacy and tolerability of treatment with tropisetron, a highly selective, competitive inhibitor of the 5-HT3 receptor. METHODS: In this prospective, multicenter, double-blind, parallel-group, dose-finding study, 418 patients suffering from primary fibromyalgia (ACR criteria) were randomly assigned to receive either placebo, 5 mg, 10 mg or 15 mg tropisetron once daily, respectively. The duration of treatment was 10 days. The clinical response was measured by changes in pain-score, visual analog scale (VAS), and the number of painful tender-points. RESULTS: Treatment with 5 mg tropisetron resulted in a significantly higher response rate (39.2%) when compared with placebo (26.2%) (p=0.033). The absolute reduction in pain-score was -13.5% for 5 mg tropisetron, -13.0% for 10 mg tropisetron, and -6.3% for placebo (p<0.05). The effects of 15 mg tropisetron were similar to placebo, thus suggesting a bell-shaped dose-response curve. Compared with placebo, treatment with 5 mg tropisetron led to a significant improvement (p<0.05) in VAS, while a clear trend in terms of clinical benefit was seen with 10 mg tropisetron. The number of painful tender-points was also reduced significantly (p=0.002) in the 5 mg tropisetron group. Of interest, during the 12-month follow-up period, pain intensity of responders on 5 mg and 10 mg tropisetron was still markedly below baseline. The treatment was well tolerated, with gastro-intestinal complaints being the most frequently reported side effects, in keeping with the known safety profile for 5-HT3 receptor antagonists. CONCLUSIONS: This study demonstrates the efficacy of short-term treatment with 5 mg tropisetron once daily in primary fibromyalgia. Treatment was well tolerated and prolonged clinical benefits were seen.

Adolescent↗

PubMed1997

Comparison of tropisetron, droperidol, and saline in the prevention of postoperative nausea and vomiting after gynecologic surgery.

This study was performed to compare the efficacy of tropisetron, droperidol, and saline in the prevention of postoperative nausea and vomiting (PONV) and to compare the possible adverse effects of these drugs in gynecologic incontinence surgery. Using a randomized, double-blind study design, we studied 150 women undergoing gynecologic incontinence surgery with standardized general anesthesia. At the end of surgery, the patients received either tropisetron 5 mg, droperidol 1.25 mg, or 0.9% saline intravenously (i.v.). As a rescue antiemetic, the patients received metoclopramide 10 mg i.v.. The episodes of nausea, retching, and vomiting; the need for rescue treatment; and the type and severity of adverse events were recorded at four occasions during the 48-h observation period. Pain, anxiety, drowsiness, and general satisfaction were also evaluated on a linear numerical scale of 0-10. Complete response (no PONV within the 48-h observation period) occurred similarly in the study groups (tropisetron 25%, droperidol 22%, and placebo 18%). Tropisetron and droperidol had no effect on the incidence of nausea and retching. However, the incidence of vomiting was significantly less in the tropisetron group than in the placebo group (tropisetron 19%, droperidol 45%, and placebo 57%). The number of emetic episodes (retching and/or vomiting) per patient within 48 h was significantly decreased under tropisetron when compared with placebo (tropisetron 2.5 +/- 3.4, droperidol 4.2 +/- 6.1, placebo 5.9 +/- 7.1). With regard to adverse events, the patients in the droperidol group had significantly more anxiety than the placebo group (2-6 h postoperatively), more drowsiness than the tropisetron and placebo groups (0-2 h postoperatively), and more dissatisfaction than the tropisetron (0-6 h postoperatively) and placebo groups (2-6 h postoperatively). We conclude that tropisetron given 5 mg i.v. during anesthesia in gynecologic incontinence surgery effectively prevents vomiting but not nausea and retching, while 1.25 mg i.v. droperidol fails to prevent any of these emetic symptoms and results in adverse events.

Antiemetics↗

PubMed2006

Tropisetron modulation of the glycine receptor: femtomolar potentiation and a molecular determinant of inhibition.

The 5-hydroxytryptamine type-3 receptor antagonist tropisetron is in clinical use as an anti-emetic drug. This compound also exerts both potentiating and inhibitory effects on the glycine receptor chloride channel. The inhibitory effects occur at micromolar concentrations, whereas the potentiating effects are shown here to occur at femtomolar concentrations at the homomeric alpha1 receptor. Potentiation occurred only when tropisetron was applied in the presence of glycine. We also sought to identify molecular determinants of tropisetron inhibition at the alpha1 glycine receptor by serially mutating residues located in or near known ligand-binding sites. We discovered that conservative mutations to N102 ablated tropisetron inhibition without affecting the magnitude or sensitivity of tropisetron potentiation. Several lines of evidence, including a structure-activity analysis of tropisetron, atropine and SB203186, suggest that N102 may bind to the tropisetron tropane nitrogen via H-bonding. Mutation of the N125 residue in the beta subunit, which corresponds to N102 in the alpha1 subunit, had little effect on tropisetron inhibitory potency. These results show that N102 is required for tropisetron inhibition but not potentiation and that inhibitory tropisetron binds in different orientations at different subunit interfaces. To our knowledge, tropisetron is the most exquisitely sensitive modulator yet identified for a cys-loop receptor.

Binding Sites↗

PubMedDate not supplied

The polymorphic cytochrome P-4502D6 is involved in the metabolism of both 5-hydroxytryptamine antagonists, tropisetron and ondansetron.

Tropisetron and ondansetron, which are potent and selective 5-hydroxytryptamine (5-HT3) receptor antagonists, were both metabolized by human liver microsomes to several metabolites. These metabolites include the major metabolites found in humans, which are the 5-, 6-, and 7-hydroxy tropisetron and the 7- and 8-hydroxy ondansetron. The cytochrome P-450 (CYP) 2D6 inhibitor quinidine (1 microM) reduced the hydroxylation of tropisetron (67%) and ondansetron (18%). Confirmation of CYP2D6 involvement in the hydroxylation of tropisetron and ondansetron was obtained by the formation of these metabolites in recombinant V79 cells expressing human CYP2D6. The CYP3A substrate/inhibitor, cyclosporine A (CsA) had little effect on tropisetron hydroxylation (< 10%), whereas CsA and triacetyloleandomycin reduced ondansetron 7- and 8-hydroxylation up to 27%. Substrates for CYP1A (phenacetin and acetanilide), CYP2C (mephenytoin), and CYP2E (chlorzoxazone) had negligible inhibitory effects on the hydroxylation of either tropisetron or ondansetron. For the CYP2D6-dependent O-demethylation of dextromethorphan, tropisetron and ondansetron were competitive inhibitors with Ki values of 14 and 29 microM, respectively. The CYP3A specific metabolism of CsA was also competitively inhibited by tropisetron (Ki = 2.1 mM) and ondansetron (Ki = 31 microM). Other metabolites, which are only minor in vivo were also inhibited by CsA, 47-60% for tropisetron metabolism and 43% for ondansetron metabolism. To summarize, this study has identified the involvement of CYP2D6 in the formation of the hydroxylated metabolites of tropisetron and ondansetron and in addition of CYP3A in ondansetron hydroxylation. Because these are the major pathways in vivo, coadministration of drugs competing for CYP2D6 and possibly CYP3A4 could influence the human kinetics of tropisetron and ondansetron.

Animals↗

PubMedDate not supplied

Biotransformation of the antiemetic 5-HT3 antagonist tropisetron in liver and kidney slices of human, rat and dog with a comparison to in vivo.

Species differences in the biotransformation of the antiemetic tropisetron, a potent 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist, were evident in liver slice incubates of human, rat and dog, and reflected the species differences observed in vivo with respect to the relative importance of individual pathways. The dominant biotransformation pathway of tropisetron (10 microM) in human liver slices was formation of 6-hydroxy-tropisetron, whereas in rat liver slices it was 5-hydroxy-tropisetron, and in dog liver slices N-oxide formation. Initial rates of tropisetron metabolite formation in the liver slices (8 mm in diameter, 200 +/- 25 microns thickness) of human (83 +/- 61 pmol/h/mg slice protein), rat (413 +/- 98 pmol/h/mg slice protein) and dog (426 +/- 38 pmol/h/mg slice protein) would predict less of a first-pass effect in humans compared to the rat or the dog. For human and rat, the prediction matched well with the species ranking of tropisetron bioavailability; however, for dog the in vitro data overestimated the apparent first-pass effect. The jejunum is not expected to contribute to the first-pass effect in humans, since human jejunum microsomes did not metabolize tropisetron. The major organ of excretion for tropisetron and its metabolites is the kidney, but the contribution of the kidney to the overall metabolism of tropisetron would be small. Species independent N-oxide formation (2-12 pmol/h/mg slice protein) was the major pathway in human, rat and dog kidney slices, and was comparable to N-oxide formation in the rat and human liver slices but was 1/10 the rate in dog liver slices. This study has demonstrated that the liver is the primary site of tropisetron biotransformation, and the usefulness of organ slices to characterize cross species differences in the dominant biotransformation pathways.

Administration, Oral↗

PubMed1991

Tropisetron plus haloperidol to ameliorate nausea and vomiting associated with high-dose alkylating agent cancer chemotherapy.

Tropisetron is a novel antiserotoninergic drug with potent and specific activity against cancer chemotherapy-induced emesis. High-dose cyclophosphamide or high-dose melphalan are chemotherapeutic regimens associated with severe nausea and vomiting refractory to current antiemetic medications. We compared in a randomised open label study the antiemetic efficacy of tropisetron and alizapride in a first group of 32 consecutive patients treated with high-dose alkylating agent chemotherapy with or without autologous bone marrow transplantation. Tropisetron was more effective than alizapride in reducing vomiting episodes. In the first 24 h of treatment the median number of episodes in patients treated with tropisetron was 5 compared with 9 episodes in the alizapride group (P = 0.005). In the 72 h study period the median number of emetic episodes was 6 in the tropisetron group and 12 in the alizapride group (P = 0.004). In a second group of 26 consecutive patients, a combination of tropisetron plus haloperidol, a dopamine antagonist, was employed for prevention of emesis. This combination was more effective than tropisetron as single agent in preventing emetic episodes, as the median number of emetic episodes in the 72 h of observation was only 3, while they were 6 in the tropisetron group. The side-effects of tropisetron were mild and reversible upon discontinuation of the drug. We conclude that tropisetron is an effective antiemetic drug when employed in high-dose alkylating agent chemotherapy, and that its activity is potentiated by the association with haloperidol.

Adult↗

PubMed2002

Oral ondansetron, tropisetron or metoclopramide to prevent postoperative nausea and vomiting: a comparison in high-risk patients undergoing thyroid or parathyroid surgery.

BACKGROUND: Oral antiemetic prophylaxis may be a practical alternative to intravenous administration. Intravenous ondansetron and tropisetron prevent postoperative nausea and vomiting (PONV) at least as efficiently as traditional antiemetics, droperidol and metoclopramide. We tested the hypothesis that the incidence of PONV after oral ondansetron or tropisetron prophylaxis is lower compared with metoclopramide among high-risk patients. METHODS: In a prospective, double-blind study we studied 179 high-risk patients who received either ondansetron 16 mg, tropisetron 5 mg, or metoclopramide 10 mg orally 1 h before the operation. A standard general anesthetic technique and postoperative analgesia were used. The incidence of PONV and the need for rescue antiemetic medication was recorded for 24 h. RESULTS: In the postanesthesia care unit, the incidence of PONV was lower after premedication with tropisetron compared with ondansetron and metoclopramide (15%, 32% and 39%, respectively). The incidence of PONV during 0-24 h was the same in each group (68%, 58% and 75% in the ondansetron, tropisetron and metoclopramide group, respectively), but the incidence of vomiting was significantly lower after ondansetron (34%) and tropisetron (22%) prophylaxis compared with metoclopramide (53%). The need for additional antiemetics was significantly lower after tropisetron prophylaxis compared with metoclopramide. Patient satisfaction was significantly higher after tropisetron than after metoclopramide. CONCLUSIONS: In the initial period, the incidence of PONV was lower after premedication with oral tropisetron than after ondansetron or metoclopramide. Considering the entire 24-h postoperative period, the incidence of PONV was the same after all three premedications, but the incidence of vomiting was lower after oral ondansetron and tropisetron than after metoclopramide.

Adult↗

PubMed1998

Single-dose tropisetron for preventing postoperative nausea and vomiting after breast surgery.

UNLABELLED: In this randomized, double-blind, placebo-controlled study, we compared the efficacy of tropisetron 5 mg with tropisetron 2 mg for the prevention of postoperative nausea and vomiting (PONV) after breast surgery. One hundred forty-eight female patients were randomized to receive either tropisetron 5 mg (n = 49), tropisetron 2 mg (n = 49), or saline (n = 50) before the induction of anesthesia with thiopental and morphine. Anesthesia was maintained with nitrous oxide and isoflurane. Postoperative analgesia was provided by patient-controlled analgesia with i.v. morphine. The incidence of PONV, the pain score, and the analgesic requirement were recorded for 48 h. There was no difference among groups in patient characteristics, risk factors for PONV, morphine consumption, or side effects. During the first 6 h postoperatively, the incidence of PONV after tropisetron 2 mg and 5 mg were similar and were superior to placebo (P < 0.001). After 6 h, the incidence of PONV increased significantly in patients who had received tropisetron 2 mg (P = 0.01) and was greater than that in patients who had received tropisetron 5 mg (P = 0.001). We conclude that single-dose tropisetron 5 mg is more effective than tropisetron 2 mg in the prevention of PONV after breast surgery. IMPLICATIONS: Breast surgery is associated with a high incidence of postoperative nausea and vomiting. A single dose of i.v. tropisetron 5 mg is well tolerated and decreases the number of vomiting and nausea episodes after surgery.

Adolescent↗