Dose Of Granisetron Research Articles

Effects of N-methyl- d-aspartate receptor antagonists on cisplatin-induced emesis in the Ferret

Glutamate may be a key transmitter in the emetic reflex arc. The present investigation focussed on the involvement of the NMDA subtype of glutamate receptors in cisplatin-induced emesis. Ferrets were injected with cisplatin (10 mg/kg i.v.) and either of the non-competitive NMDA receptor antagonists dextrometorphan or memantine, or the competitive receptor antagonist CGS 19755. In order to determine whether there is a synergism between NMDA blockers and 5-HT 3 receptor antagonists, a submaximal dose of granisetron (0.05 mg/kg) was given alone or in combination with either dextromethorphan or memantine. The latency for the onset of emesis as well as the total number of vomits and retches over 3 hr were determined. In controls, the latency for emesis was 73 ± 6 min and the total number of vomits and retches 143 ± 17. The corresponding figures for animals treated with dextromethorphan, 10 and 20 mg/kg, were 89 ± 19 min( p > 0.05) and 50 ± 17 ( p = 0.008), and 113 ± 18 min ( p > 0.05) and 22 ± 9 ( p = 0.004), respectively. At 10 mg/kg, dextromethorphan failed to enhance the antiemetic effect of granisetron which by itself provided 90% inhibition. While memantine (2.5 or 5.0 mg/kg) did not have an effect per se, it tended to reduce the antiemetic effect of granisetron. CGS 19755 (10 mg/kg) provided a partial protection against cisplatin-induced emesis (latency:111 ± 23, number of vomits and retches 30 ± 11). None of the NMDA receptor antagonists was free of behavioural effects (e.g. some sedation) at antiemetic doses. It is concluded that NMDA receptor antagonists may afford protection against cisplatin-induced emesis but the specificity of this effect is uncertain since it may relate to general CNS depression.

Control of Carboplatin-Induced Emesis with a Fixed Low Dose of Granisetron (0.5 mg) plus Dexamethasone

In an effort to develop a cost-effective antiemetic regimen for carboplatin-based chemotherapy, we examined a fixed (0.5 mg) low dose of granisetron (a new 5-HT3(serotonin) antagonist) plus dexamethasone (20 mg) in 23 patients with gynecologic malignancies receiving this antineoplastic drug. Nineteen (83%) patients experienced complete control of acute emesis (nausea and vomiting) while 22 (96%) individuals demonstrated complete or major control (≤2 episodes of vomiting, ≤5 episodes of retching, minimal interference with eating) of emetic events. We conclude that this fixed low-dose granisetron plus dexamethasone regimen is a safe, convenient, and cost-effective antiemetic program for individuals receiving carboplatin-based chemotherapy.

A pilot study to evaluate the cost-effectiveness of ondansetron and granisetron in fractionated total body irradiation

The duration of the antiemetic effect of granisetron was examined in a pilot study of patients ( n = 26) undergoing a standard emetogenic stimulus in the form of total body irradiation fractionated over 3–4 days, in a randomized comparison with twice-daily ondansetron. A single intravenous dose of granisetron at the onset of therapy was effective over the entire follow-up period in 50% (6/12) of patients, compared with 77% (10/13) prescribed twice-daily oral ondansetron for 3 or 4 days. The response rate within the first 24 hours from the start of irradiation was 67% (8/12) for granisetron and 77% (10/13) for ondansetron. Granisetron and ondansetron were therefore of similar efficacy within the first 24-hour period, but granisetron was less efficaceous more than 24 hours after the onset of therapy. Patients who required a second dose of granisetron did so at intervals of 12, 42, 47 and 48 hours following the first fraction of radiotherapy. The cost per patient in this study was £48 for granisetron and £54 for ondansetron, but the dose scheduling we used cannot be recommended in view of the lower effectiveness of granisetron.

Efficacy and safety of different doses of granisetron for the prophylaxis of cisplatin-induced emesis

Efficacy and safety of different doses of granisetron for the prophylaxis of cisplatin-induced emesis

Granisetron: the second serotonin-receptor antagonist.

To review the pharmacology, pharmacokinetics, clinical efficacy, and adverse effects of granisetron, focusing on critical analysis of published clinical trials and comparison with other antiemetic agents, including ondansetron. MEDLINE (1966-1995) and CANCERLIT (1991-1995) searches of English-language literature using the terms "granisetron" and "granisetron (rn)" were performed. All articles were considered for possible inclusion in this review. Abstracts of clinical trials were included only when they were judged to add critical information not otherwise available in the medical literature. For studies published more than once, the most recent publication was cited. Nausea and vomiting are rated by patients as the most distressing chemotherapy-related adverse effects and may produce potentially life-threatening complications. The discovery of the role of serotonin in nausea and vomiting and the development of selective serotonin3-receptor (5-HT3) antagonists has significantly diminished the incidence and consequences of chemotherapy-related nausea and vomiting. Granisetron is the second 5-HT3-receptor antagonist to be marketed in the US. Granisetron has been compared with other antiemetic agents, including ondansetron, against highly and moderately emetogenic chemotherapy. The results of these trials have shown granisetron to be superior to conventional antiemetics and as effective as ondansetron in the prevention of chemotherapy-induced nausea and vomiting. The optimal dose of granisetron has yet to be determined. Formulary decisions should be based on a cost comparison among the 5-HT3-receptor antagonists at individual institutions. Granisetron is a safe, effective antiemetic agent for the management of nausea and vomiting caused by cancer chemotherapy.

1231 Comparison of dexamethasone (DXM) + granisetron (G) or + ondansetron (O) in cancer patients treated with moderately emetic cytotoxics

Anti-5HT3 drugs are potent but expensive anti-emetics. Since its introduction, ondansetron has currently been used at 3 × 8 mg. More recently, a unique 3 mg dose of granisetron, found as effective as higher doses in dose-finding studies, came as a challenger. According to these different dosages, 3rd-party reimbursement in Belgium endorses a 6 fold cost G > 0 difference per mg. We compared 8 mg O with 3 mg G in naive cancer patients treated with moderately emetic drugs (combination therapy with CPA > 600 mg or IFO > 1 g/m2). DXM 10 mg IV was used in both arms as an anti-5HT3 potentiator. Treatment allocation was randomized in blocks of four. After the block, G and O were simply alternated. The patients were kept blind of the study. To-date, 12 patients (9 F) have been enrolled for 53 treatments. No difference in efficacy could be demonstrated on D1: complete response O:18, G:16; partial response (light nausea) O:7, G:6; failure (vomiting) O:2, G:4. No patient perceived any difference between G and O in acute or late emesis. Post-D1 nausea was easily controlled with po alizapride or metoclopramide. Since DXM 10 mg + G 3 mg or + O 8 mg are clinically equivalent, opting fur DXM + O could save ± 1100 Bef/treatment. Anti-5HT3 drugs are potent but expensive anti-emetics. Since its introduction, ondansetron has currently been used at 3 × 8 mg. More recently, a unique 3 mg dose of granisetron, found as effective as higher doses in dose-finding studies, came as a challenger. According to these different dosages, 3rd-party reimbursement in Belgium endorses a 6 fold cost G > 0 difference per mg. We compared 8 mg O with 3 mg G in naive cancer patients treated with moderately emetic drugs (combination therapy with CPA > 600 mg or IFO > 1 g/m2). DXM 10 mg IV was used in both arms as an anti-5HT3 potentiator. Treatment allocation was randomized in blocks of four. After the block, G and O were simply alternated. The patients were kept blind of the study. To-date, 12 patients (9 F) have been enrolled for 53 treatments. No difference in efficacy could be demonstrated on D1: complete response O:18, G:16; partial response (light nausea) O:7, G:6; failure (vomiting) O:2, G:4. No patient perceived any difference between G and O in acute or late emesis. Post-D1 nausea was easily controlled with po alizapride or metoclopramide. Since DXM 10 mg + G 3 mg or + O 8 mg are clinically equivalent, opting fur DXM + O could save ± 1100 Bef/treatment.

Granisetron (Kytril): a survey of use in clinical practice in Switzerland.

Data on the use of intravenous grainsetron (Kytril) were collected during a surveillance exercise amongst Swiss oncologists. The data were analysed to ascertain how grainsetron was used, and to document the incidence of adverse experiences in a clinical setting. Forty-nine oncologists at 40 Swiss centres were surveyed for their use of granisetron for the prevention and treatment of chemotherapy-induced nausea and vomiting. All were advised to follow the Swiss prescribing instructions for granisetron. They were invited to return data on patient demography, chemotherapy duration, granisetron dosing and adverse experiences. From 285 patients it was deduced that the mean daily dose of granisetron was 1.3 ampoules (3.9 mg) and the median daily dose was 1 ampoule (3 mg). The average number of doses of granisetron per patient per session was 3.8. There were 44 reports of adverse experiences by 34 patients, the most common report being headache. The survey confirmed that the large majority of patients undergoing chemotherapy required only a single dose of granisetron per day, and that the adverse experience profile was good.

Review of the preclinical pharmacology and comparative efficacy of 5-hydroxytryptamine-3 receptor antagonists for chemotherapy-induced emesis.

This analysis was undertaken to review published reports of the comparative efficacy and safety of 5-hydroxytryptamine-3 (5-HT3) receptor antagonists in the prophylaxis of acute chemotherapy-induced emesis. Comparison data used are the preclinical pharmacology as well as the design and results of clinical trials. Seven comparative studies that used granisetron, ondansetron, or tropisetron in patients who received either moderately or highly emetogenic chemotherapy are reviewed. As the study designs, patient population, chemotherapy, antiemetic doses and schedule, and methods of assessment were slightly different, the results of each study are analyzed independently. Effectiveness is assessed by emetic episodes, nausea, and patient preference. The preclinical pharmacologic profile is different among the 5-HT3 antagonists in terms of potency, selectivity, dose response, and duration of action. The comparative clinical trials show that a single intravenous (i.v.) dose of granisetron 3 mg is as effective as multiple (8 mg x 3) or single (32 mg) i.v. doses of ondansetron for the prevention of acute nausea and emesis due to cisplatin. In the two moderately emetogenic clinical trials, granisetron 3 mg i.v. was at least as effective as ondansetron 8 mg i.v. +/- 24 mg orally and tropisetron 5 mg i.v. Patient preference was evaluated in three of the four crossover trials: granisetron was preferred in three of four, and no preference was reported in the fourth. The one trial to compare ondansetron 0.15 mg/kg x 3 versus granisetron 10 micrograms/kg x 1 or granisetron 40 micrograms/kg i.v. demonstrated equivalent control of nausea and vomiting in patients who received cisplatin-based chemotherapy. The 5-HT3 receptor antagonists compared are highly effective antiemetic agents that have now become the standard of care for preventing chemotherapy-induced emesis. Whether the described preclinical differences among these agents are also clinically significant remains to be seen. In the comparative trials analyzed, the 5-HT3 receptor antagonists demonstrated relatively equivalent clinical efficacy. Cost analysis may favor the use of one agent over another depending on the emetogenic challenge, dose of the 5-HT3 antagonists, and number of doses recommended. Patient preference may be an important factor to be considered in future antiemetic trials.

An open study to assess the safety, tolerance and pharmacokinetics of an intravenous infusion of granisetron given at 3 mg over 30 s in patients receiving chemotherapy for malignant disease.

Granisetron is a highly potent and selective 5-hydroxytryptamine3 (5-HT3) receptor antagonist indicated for the prevention of cytotoxic-induced nausea and vomiting. Clinical trials have demonstrated granisetron to be effective and well tolerated at a standard dose of 40 micrograms/kg or 3 mg given i.v. as a 5-min infusion. In this study, the efficacy and safety of granisetron given as a 30-s infusion was assessed. A total of 21 patients, scheduled to undergo chemotherapy, received a single 3-mg i.v. dose of granisetron over 30 s, completed at 1 h before chemotherapy administration. Patients were allowed two further i.v. doses of granisetron at 3 mg within the 24-h assessment period. Changes from baseline values in vital signs were analysed prior to granisetron administration and at 30 s as well as 1, 10, 15, 30 and 60 min after granisetron administration. Holter ECG recordings were taken for 6 h prior to and 1 h after administration. No significant change was found in vital signs at 30 s or 1 min after granisetron infusion. There was a small but statistically significant fall in diastolic blood pressure as compared with baseline and a non-significant trend in favour of a reduction in heart rate at 10 and 15 min. No ECG abnormality was recorded post-infusion that had not been present pre-infusion. None of these changes was considered to be clinically relevant. The treatment was well tolerated. The most frequently reported adverse events were constipation (n = 6) and headache (n = 5). Maximal plasma levels of granisetron were within the range of 44.57-410 ng/ml except in one patient. The median values recorded for peak concentration (Cmax) and area under the curve (AUC) were 195 ng/ml and 71.2 ng h ml-1, respectively. In conclusion, granisetron at 3 mg was shown to be safe and well tolerated when given as a 30-s i.v. infusion to patients receiving chemotherapy for malignant disease.

Antiemetic treatment with oral granisetron in patients receiving moderately emetogenic chemotherapy: a dose-ranging study

The antiemetic efficacy and tolerability of four different oral doses of granisetron (0.25, 0.5, 1, and 2 mg twice daily [BID]) were compared in a randomized, double-blind, parallel-group, multi-center study involving 930 patients with malignant disease receiving moderately emetogenic chemotherapy over a 7- or 14-day period. On the first day of granisetron treatment, a statistically significant association between complete response and dose was seen ( P = 0.001), with the maximum response (81.1%) achieved at a dose of 1 mg BID. The 24-hour complete response rate with granisetron 1 mg BID was significantly higher than with 0.25 mg BID (61.1%) or 0.5 mg BID (70.2%) ( P < 0.009). The complete response rate for days 0 to 6 was significantly higher with granisetron at 1 mg BID (58.8%) than with 0.25 mg BID (43.7%) or 0.5 mg BID (53.6%) ( P < 0.009). No advantage in terms of complete response rate was shown for 2 mg BID over 1 mg BID. Granisetron was well tolerated, and few patients required additional treatment with other antiemetics.

Role of 5-hydroxytryptamine in gastrointestinal chemosensitivity

The present electrophysiological investigation examines the effect of 5-hydroxytryptamine (5-HT) on gastrointestinal afferent fiber discharge. 5-HT markedly and specifically stimulated vagal mucosal chemosensitive afferents. The response was mediated by 5-HT3 receptors as demonstrated by the action of 2-methyl-5-HT and antagonism by granisetron. At doses of granisetron that completely block the response to 5-HT, the afferent fibers still responded to both mechanical and chemical stimulation of the mucosa. This sensitivity of extrinsic afferents is in marked contrast to that reported for intrinsic afferents, suggesting fundamental differences in the organization of enteric and vagal reflexes.

Efficacy and safety of granisetron, a selective 5-hydroxytryptamine-3 receptor antagonist, in the prevention of nausea and vomiting induced by high-dose cisplatin.

To assess the antiemetic effects and safety profile of four different doses of granisetron (Kytril; SmithKline Beecham Pharmaceuticals, Philadelphia, PA) when administered as a single intravenous (IV) dose for prophylaxis of cisplatin-induced nausea and vomiting. One hundred eighty-four chemotherapy-naive patients receiving high-dose cisplatin (81 to 120 mg/m2) were randomized to receive one of four granisetron doses (5, 10, 20, or 40 micrograms/kg) administered before chemotherapy. Patients were observed on an inpatient basis for 18 to 24 hours, and vital signs, nausea, vomiting, retching, and appetite were assessed. Safety analyses included incidence of adverse experiences and laboratory parameter changes. After granisetron doses of 5, 10, 20, and 40 micrograms/kg, a major response (< or = two vomiting or retching episodes, and no antiemetic rescue) was recorded in 23%, 57%, 58%, and 60% of patients, respectively, and a complete response (no vomiting or retching, and no antiemetic rescue) in 18%, 41%, 40%, and 47% of patients, respectively. There was a statistically longer time to first episode of nausea (P = .0015) and vomiting (P = .0001), and fewer patients were administered additional antiemetic medication in the 10-micrograms/kg dosing groups than in the 5-micrograms/kg dosing group. As granisetron dose increased, appetite return increased (P = .040). Headache was the most frequently reported adverse event (20%). A single 10-, 20-, or 40-micrograms/kg dose of granisetron was effective in controlling vomiting in 57% to 60% of patients who received cisplatin at doses greater than 81 mg/m2 and totally prevented vomiting in 40% to 47% of patients. There were no statistically significant differences in efficacy between the 10-micrograms/kg dose and the 20- and 40-micrograms/kg doses. Granisetron was well tolerated at all doses.

Optimal anti-emetic dose of granisetron for preventing post-operative nausea and vomiting

In order to determine the optimal effective dose of granisetron for preventing postoperative nausea and vomiting, the drug was administered in doses of either 20, 40 or 60 micrograms.kg-1. The efficacy of granisetron was evaluated in a randomized, double-blind comparison with placebo in 100 patients undergoing general anaesthesia for major gynaecological surgery. The patients received a single dose of either granisetron or placebo (saline) iv immediately after recovery from anaesthesia. The effects were assessed during the 24 hr after recovery from anaesthesia by means of a nausea and vomiting score; 0 = no emetic symptoms, 1 = nausea, 2 = vomiting. The treatment groups were similar for patient characteristics, surgical procedures and anaesthetics administered. The mean scores were 0.7, 0.6, 0.2 and 0.2 after administration of placebo, granisetron 20, 40 and 60 micrograms.kg-1, respectively. Granisetron 40 micrograms.kg-1 was as effective as 60 micrograms.kg-1 and both resulted in reduction of the scores compared with placebo and granisetron 20 micrograms.kg-1 (P < 0.05). In conclusion, granisetron 40 micrograms.kg-1 is considered to be the appropriate dosage for preventing postoperative emesis after anaesthesia.

The Efficacy and Safety of Granisetron in Pediatric Cancer Patients Who Had Failed Standard Antiemetic Therapy During Anticancer Chemotherapy

This study was undertaken to evaluate the safety and efficacy of granisetron (a 5-hydroxytryptamine. antagonist) in children with malignant disease who had previously experienced unacceptable nausea and vomiting and/or adverse effects associated with standard antiemetic therapy. Thirty children 3-18 years of age who were receiving anticancer chemotherapy were enrolled in the study. Patients received a prophylactic dose of granisetron before chemotherapy and two subsequent doses as needed. If further antiemetics were required, standard therapy was given and those patients were classified as treatment failures. Patients received granisetron during one to three cycles of chemotherapy; a total of 66 courses were given. Eighty-seven percent of patients had good control of nausea and vomiting with granisetron alone; 90% of patients elected to receive granisetron with subsequent chemotherapy. No loss of efficacy was noted with repeated cycles in 21 patients. No serious adverse events occurred. Intravenous granisetron (20 micrograms/kg/dose) appears to be a safe and effective drug for pediatric patients receiving emetogenic chemotherapy.

Clinical experience with intravenous granisetron

This review discusses the development and use of 5-hydroxytryptamine3 (5-HT3) antagonists, especially granisetron, for the treatment of chemotherapy-induced emesis. Following recent evidence suggesting that high-dose chemotherapy is more effective in increasing tumor response rate and median survival time, more effective antiemetic control is essential. Granisetron, a new 5-HT3, is approximately 400 times more potent than metoclopramide and, unlike metoclopramide, does not produce extrapyramidal side effects. Granisetron has been shown to be effective as a single prophylactic dose, over 5 days and in patients receiving repeated cycles of chemotherapy. Patients with nausea and vomiting within the first 24 h after chemotherapy are more likely to experience delayed symptoms; however, episodes of breakthrough nausea and vomiting can be controlled by intervention with one, and in some cases more, doses of granisetron. The development of granisetron represents an important advance in the control of chemotherapy induced emesis.

Dose finding study of granisetron in patients receiving high-dose cisplatin chemotherapy

The efficacy and safety of three different doses of granisetron (2 micrograms kg-1, group A; 10 micrograms kg-1, group B; 40 micrograms kg-1, group C) were compared in a randomised, double-blind study of 157 patients due to receive high-dose cisplatin therapy (mean dose > 97 mg m-2). In each group, up to two 3 mg rescue doses of granisetron were allowed if more than mild nausea or vomiting occurred. In group A 30.8%, in group B 61.5% and in group C 67.9% of patients were complete responders (i.e. no vomiting or nothing worse than mild nausea) during the first 24 h. These differences are significant between groups A and B, and A and C. There were no statistically significant differences in any efficacy variable between the 10 micrograms kg-1 and 40 micrograms kg-1 groups, although in each case the trend favoured the higher dose. Additional rescue doses resulted in resolved or improved symptoms in 95.3% for the first rescue dose and 93.3% for the second. Over the 7 days of the study, 82.7%, 82.7% and 86.8% of patients in groups A, B and C respectively were treated with granisetron alone. Headache was the most common side-effect, reported by 9.6% of patients; the majority of headaches were mild. There was no difference between the treatment groups regarding the adverse event rate. We concluded that prophylactic doses of 10 or 40 micrograms kg-1 lead to a safe and satisfactory degree of control of nausea and vomiting induced by high-dose cisplatin.

A double-blind, randomised, crossover comparison of granisetron and ondansetron in 5-day fractionated chemotherapy: Assessment of efficacy, safety and patient preference

We report the first double-blind, randomised, crossover study comparing granisetron and ondansetron as anti-emetics in cancer chemotherapy. Patients receiving two cycles of identical chemotherapy fractionated over 5 days were given either granisetron (3 mg/day) or ondansetron (24 mg/day) on each day of chemotherapy, using a double-dummy technique to preserve study blindness. Patients then crossed over to the other therapy. 309 patients (237 male) completed the crossover: 260 received cisplatin (mean dose 19.2 mg/m 2/day) and 49 received ifosfamide (mean dose 1415 mg/m 2/day). Primary efficacy variables were prospectively defined as complete response (no vomiting and mild or absent nausea) over 5 days, and patient preference. Both agents achieved good control of emetic symptoms with 5-day complete response rates of 44.0% on granisetron and 39.8% on ondansetron [95% confidence interval (CI) for odds ratio 0.8, 1.9]. Complete response rates were very similar in patients receiving either cisplatin (40.8% granisetron, 37.6% ondansetron) or ifosfamide (61.2% granisetron, 51.0% ondansetron). There was a statistically significant difference in patient preference in favour of granisetron, 105 patients preferred granisetron, 79 preferred ondansetron, 121 had no preference ( P = 0.048: 95% CI for odds ratio 1.00, 1.84). Single daily doses of granisetron (3 mg/day) appeared similarly effective and well tolerated to three daily doses of ondansetron (8 mg three times daily) in prevention of emesis induced by 5-day fractionated chemotherapy, however, significantly more patients preferred granisetron.

The control of acute cisplatin-induced emesis – a comparative study of granisetron and a combination regimen of high-dose metoclopramide and dexamethasone

The anti-emetic efficacy and safety of granisetron, a highly selective and potent 5-HT3 receptor antagonist, was compared with that of high-dose metoclopramide plus dexamethasone in 281 patients due to receive single-day cisplatin chemotherapy (> or = 49 mg m-2). In this single-blind, multicentre study, granisetron (40 micrograms kg-1) was administered as a single prophylactic 5-min infusion. Dexamethasone (12 mg) was administered as a 30-min infusion followed by a loading dose of 3 mg kg-1 metoclopramide. A maintenance dose of metoclopramide 4 mg kg-1 was then infused over 8 h. A single prophylactic dose of granisetron was as effective as the combination regimen in the prevention of cisplatin-induced emesis. Of 143 granisetron-treated patients, 100 (70%) were complete responders (no vomiting and no or only mild nausea) compared with 93/138 (67%) patients who received the comparator regimen. Twenty-three percent of granisetron-treated patients experienced one of more adverse events compared with 33% of patients in the comparator group. No extrapyramidal reactions were reported in the granisetron group compared with 13 in comparator-treated patients (8%). This difference was significant (P < 0.05). The commonest adverse event in the granisetron group, headache (9.8%) described by the majority of patients as mild, was significantly higher than that reported in the comparator group (3% P = 0.02). Granisetron appears to be a safe and effective agent which can be used as a single agent for the prophylaxis of cisplatin-induced emesis. The simplicity of administration, a single 5-min infusion prior to chemotherapy, and the lack of somnolence or extrapyramidal reactions offer clear advantages over the comparator combination regimen.

5-HT 3 receptor antagonists inhibit morphine-induced stimulation of mesolimbic dopamine release and function in the rat

The effects of three different 5HT 3 receptor antagonists, granisetron, ICS 205–930 and ondansetron (0.01, 0.1 and 1 mg/kg, s.c.) were tested on changes in mesolimbic dopamine function produced by 1 mg/kg of morphine in the rat. Increases of in vivo dopamine release and stimulation of behavioural activity (grooming, locomotion, rearing and sniffing) were monitored. Morphine (0.5 and 1 mg/kg, s.c.) increased dose-dependently the concentration of dopamine in dialysates obtained from the nucleus accumbens. This action of morphine was inhibited by the opiate antagonist naloxone (1 mg/kg, s.c.). Morphine (0.5 and 1 mg/kg) stimulated behavioural activity, which in the early part of the time course corresponded closely with the increase of dopamine in the nucleus accumbens. Pretreatment with 1 mg/kg (s.c.) of granisetron resulted in moderate inhibition (28%) of the morphine-induced stimulation of the extracellular dopamine levels, while doses of 0.01 and 0.1 mg/kg (s.c.) had no effect. The highest dose of granisetron (1 mg/kg, s.c.) also significantly reduced the morphine-induced enhancement of behavioural activity. The fact that granisetron attenuated morphine-induced effects on mesolimbic DA only at the highest dose tested (1 mg/kg, s.c.) was also true for ICS 205–930 and ondansetron. It is concluded that 5HT 3 receptor antagonists partially inhibit, with low potency, the morphine-induced stimulation of dopamine release in the nucleus accumbens and the corresponding behavioural activation.

A comparison of granisetron as a single agent with conventional combination antiemetic therapies in the treatment of cytostatic-induced emesis

The safety and efficacy of intravenous granisetron were compared with combinations of conventional antiemetics in two single-blind, parallel-group studies which have been reported previously [1, 2]. In this review updated data from both studies is presented. In both studies granisetron (40 μg/kg) was given as a single 5-min infusion before chemotherapy with two additional doses allowed to control subsequent nausea and vomiting. All patients were naive to chemotherapy. Patients due to receive cisplatin (> 49 mg/m 2) were randomly assigned to receive either granisetron alone or metoclopramide (3 mg/kg) plus dexamethasone (12 mg) given prophylactically followed by an 8-h infusion of metoclopramide (4 mg/kg). In the 24 h after the start of chemotherapy 70% of granisetron-treated patients and 67% of comparator group were complete responders. In patients due to receive moderately emetogenic chemotherapy, granisetron was compared with chlorpromazine (up to 200 mg/24 h) plus dexamethasone (12 mg). Twenty-four hour efficacy was significantly higher in the granisetron group with complete response in 68% of patients compared to 47% in the comparator group ( P < 0.001). A subset of 40 patients in this study were crossed over to receive the alternative antiemetic on their next cycle of chemotherapy. A significant majority of patients ( 32 34 ; 94%) preferred granisetron ( P < 0.001). Around 80% of the granisetron-treated patients in both groups required only a single prophylactic dose of granisetron. Following the first additional dose of granisetron, around 87% of patients reported symptoms to be improved or resolved. Adverse experience reporting was higher in the comparator groups with somnolence and extrapyramidal reactions representing the most common events. Headache was the most commonly reported adverse experience in granisetron-treated patients. Granisetron has proved safe and effective in controlling chemotherapy-induced emesis and is more convenient to administer than conventional antiemetics.