The effect of anti-emetic drugs on rat embryonic heart activity.

Nausea and vomiting of pregnancy (NVP) is the most common medical complaint during pregnancy affecting up to 70% of pregnant women worldwide. Some antiemetic medications (AEM) (droperidol, domperidone, granisetron, metoclopramide and trifluoperazine) used to treat NVP have the unwanted side effect of hERG blockade. The hERG potassium channel is essential for normal heart rhythm in both the adult human and the human and rat embryo. Animal studies show hERG blockade in the embryo causes bradycardia and arrhythmia leading to cardiovascular malformations and other birth defects. Whole rat embryo in vitro culture was used to determine the effect of the above listed AEM and meclizine on the heart rate of Gestational day 13 rat embryos. These embryos are similar in size and heart development to 5-6-week human embryo. The results showed that all of the AEMs caused a concentration-dependent bradycardia. Droperidol had the lowest margin of safety.

Carbon monoxide contributes to the constipating effects of granisetron in rat colon.

AIM: To investigate the mechanisms underlying the potential contribution of the heme oxygenase/carbon monoxide (HO/CO) pathway in the constipating effects of granisetron. METHODS: For in vivo studies, gastrointestinal motility was evaluated in male rats acutely treated with granisetron [25, 50, 75 µg/kg/subcutaneous (sc)], zinc protoporphyrin IX [ZnPPIX, 50 µg/kg/intraperitoneal (ip)] and hemin (50 µmol/L/kg/ip), alone or in combination. For in vitro studies, the contractile neurogenic response to electrical field stimulation (EFS, 3, 5, 10 Hz, 14 V, 1 ms, pulse trains lasting 10 s), as well as the contractile myogenic response to acetylcholine (ACh, 0.1-100 µmol/L) were evaluated on colon specimens incubated with granisetron (3 µmol/L, 15 min), ZnPPIX (10 µmol/L, 60 min) or CO-releasing molecule-3 (CORM-3, 100, 200, 400 µmol/L) alone or in combination. These experiments were performed under co-treatment with or without atropine (3 µmol/L, a muscarinic receptor antagonist) or NG-nitro-L-Arginine (L-NNA, 100 µmol/L, a nitric oxide synthase inhibitor). RESULTS: Administration of granisetron (50, 75 µg/kg) in vivo significantly increased the time to first defecation (P = 0.045 vs vehicle-treated rats), clearly suggesting a constipating effect of this drug. Although administration of ZnPPIX or hemin alone had no effect on this gastrointestinal motility parameter, ZnPPIX co-administered with granisetron abolished the granisetron-induced constipation. On the other hand, co-administration of hemin and granisetron did not modify the increased constipation observed under granisetron alone. When administered in vitro, granisetron alone (3 µmol/L) did not significantly modify the colon's contractile response to either EFS or ACh. Incubation with ZnPPIX alone (10 µmol/L) significantly reduced the colon's contractile response to EFS (P = 0.016) but had no effect on contractile response to ACh. Co-administration of ZnPPIX and atropine (3 µmol/L) abolished the ZnPPIX-mediated decrease in contractile response to EFS. Conversely, incubation with CORM-3 (400 µmol/L) alone increased both the contractile response to EFS at 10 Hz (10 Hz: 71.02 ± 19.16 vs 116.25 ± 53.70, P = 0.01) and the contractile response to ACh (100 µmol/L) (P = 0.012). Co-administration of atropine abolished the CORM-3-mediated effects on the EFS-mediated response. When granisetron was co-incubated in vitro with ZnPPIX, the ZnPPIX-mediated decrease in colon contractile response to EFS was lost. On the other hand, co-incubation of granisetron and CORM-3 (400 µmol/L) further increased the colon's contractile response to EFS (at 5 Hz: P = 0.007; at 10 Hz: P = 0.001) and to ACh (ACh 10 µmol/L: P = 0.001; ACh 100 µmol/L: P = 0.001) elicited by CORM-3 alone. L-NNA co-administered with granisetron and CORM-3 abolished the potentiating effect of CORM-3 on granisetron on both the EFS-induced and ACh-induced contractile response. CONCLUSION: Taken together, findings from in vivo and in vitro studies suggest that the HO/CO pathway is involved in the constipating effects of granisetron.

Evaluating the potential effect on fetal tissue after exposure to granisetron during pregnancy.

The objective of this study was to elucidate the possible toxic effects on the fetal tissues after exposure to two clinically relevant concentrations of granisetron. Primary cells were isolated from human fetal organs of 16-19 weeks gestational age and treated with 3 ng/mL or 30 ng/mL of granisetron. Cell cycle progression was evaluated by flow cytometry. ELISA was used to detect alterations in major apoptotic proteins. Up to 10% apoptosis in cardiac tissue was observed following treatment with 30 ng/mL granisetron. Neither concentration of granisetron caused alteration in cell cycle progression or alterations in apoptotic proteins in any of the other tissues. At 30 ng/mL granisetron concentration had the potential to induce up to 10% apoptosis in cardiac tissue; clinical significance needs further evaluation. At granisetron 3 ng/mL there was no detectable toxicity or on any fetal tissue in this study. Further research is needed to confirm these preliminary findings and determine if clinically significant.

Granisetron plus dexamethasone versus granisetron alone in the prevention of vomiting induced by conditioning for stem cell transplantation: a prospective randomized study.

This prospective randomized study compared the efficacy and toxicity of granisetron and dexamethasone to those of granisetron alone for antiemetic control in patients receiving high-dose chemotherapy with or without total body irradiation (TBI) for stem cell transplantation. Patients were divided randomly into 2 groups. Groups received granisetron twice daily at a dose of 40 microg/kg with or without 4 mg dexamethasone (GS group and G group, respectively), starting 30 minutes before each dose of chemotherapeutic agent or TBI, or 12 hours after the first dose if TBI or a drug was given once a day. Fifty patients were evaluated for the analysis. During the first 24 hours of conditioning, 23 of 25 patients (92.0%) in the GS group achieved complete control of emesis (no emetic episodes over the course of a day), compared with 72.0% in the G group (P = .06). For patients receiving TBI on the first day of conditioning, complete emetic control was achieved in all patients (100.0%) in the GS group, compared with 63.2% in the G group (P = .02). The same degree of emetic control was maintained throughout the conditioning period in 38.8% of the GS group and 29.9% of the G group (P = .10). Adverse reactions were observed more frequently in the GS group (68.0% versus 5.0% in the G group). These reactions included insomnia, headache, flushing, and hyperglycemia. None of the events were serious. We conclude that granisetron with dexamethasone seems superior to granisetron alone for the prevention of emesis resulting from the conditioning regimen; however, the more frequent side effects may limit the wide use of this combination.

Comparison of tropisetron and granisetron in the control of nausea and vomiting in children receiving combined cancer chemotherapy.

Tropisetron and granisetron are selective serotonin (5-HT3) antagonists that have been proven effective in the prevention of nausea and vomiting in adults and children receiving cancer chemotherapy. This prospective, randomised study was designed to compare the efficacy of the two agents in the prevention of vomiting and nausea in children receiving highly emetogenic chemotherapy for various malignancies. A total of 51 children (mean age: 7.7 +/- 4.8 year) were studied in 133 chemotherapy cycles. In 66 chemotherapy cycles, the children received tropisetron as an antiemetic agent in a dose of 0.2 mg/kg/24 h intravenously and, in 67 cycles, they received granisetron 40 micrograms/kg/24 h intravenously before cytotoxic drug administration during the days they received chemotherapy. The response per 24 h of chemotherapy was defined as complete (no nausea and vomiting), partial (1-4 events of vomiting and/or nausea), and failure (more than 4 events of vomiting and/or nausea). Efficacy of antiemetic therapy was evaluated as acute (Day 1) and overall was based on the worst day during the chemotherapy. Complete control of acute vomiting was achieved in 74% of tropisetron and 88% of granisetron patients (P = 0.04), and complete control of acute nausea in 56% and 82% respectively (p = 0.002). Overall response by means of complete control of both vomiting and nausea during the whole therapy period was 29% of tropisetron group and 55% of granisetron group (p = 0.007). The statistical analysis (depending on the emetogenicity of the chemotherapy cycles) showed increased efficacy of granisetron in highly (grade 3) emetogenic chemotherapy cycles (p = 0.002), whereas there was no difference in the very highly emetogenic cycles (p = 0.7). Also, granisetron was found to be more effective than tropisetron, especially in patients heavier than 25 kg (p = 0.02). The adverse reactions were few and mild. There were no differences in the tolerability of the two antiemetic therapy modalities. In conclusion, granisetron was found to be more effective than tropisetron in controlling nausea and vomiting in children receiving highly emetogenic chemotherapy. This increased antiemetic efficacy of ganisetron might have been related to maximal dose differences according to body weight.

Double-blind, randomized, parallel-group study on the efficacy and safety of oral granisetron and oral ondansetron in the prophylaxis of nausea and vomiting in patients receiving hyperfractionated total body irradiation.

The efficacy and safety of granisetron and ondansetron for the prophylaxis of nausea and vomiting resulting from hyperfractionated total body irradiation (TBI) were assessed. Thirty-four patients randomly received double-blind, oral granisetron (2 mg, 1 h before first daily fraction of radiation) or ondansetron (8 mg, 1.5 h prior to each fraction of TBI). Ninety patients who received the same TBI regimen prior to bone marrow transplantation (BMT), but no 5-HT3-receptor antagonist, were identified and comprised the historical control group. By design, this study was only powered to show a difference between each of the active treatment groups and the historical control group. Significantly more patients given granisetron (33.3%) or ondansetron (26.7%) had zero emetic episodes over 4 days, the primary efficacy end point, than those in the historical control group (0%) (P < 0.01; intent-to-treat). Secondary efficacy end points were also evaluated. During the first 24 h, significantly more patients taking granisetron (61.1%) or ondansetron (46.7%) had zero emetic episodes than patients in the historical control group (6.7%) (P < 0.01). Complete emetic control (no emesis or rescue antiemetic) over 4 days was more frequent in patients taking granisetron (27.8%) or ondansetron (26.7%) compared with the historical control group (0%) (P < 0.01). Significantly fewer patients taking granisetron (18/18), but not those taking ondansetron (12/15), experienced more than five emetic episodes during the 4 days of the study compared with the historical control group (40/90; P < 0.01). Oral granisetron and ondansetron are safe and effective for the prevention of nausea and vomiting resulting from TBI.

Pharmacokinetics and tolerability of ascending intravenous doses of granisetron, a novel 5-HT3 antagonist, in healthy human subjects.

The pharmacokinetics and tolerance of granisetron, a novel 5HT3-receptor antagonist which is under development as an anti-emetic agent have been studied after administration of single 30 min intravenous infusions to three groups of 8 healthy male subjects, in a series of placebo-controlled ascending dose studies (50, 80, 100 and 130 micrograms.kg-1 to group 1; 150, 180, 200 and 230 micrograms.kg-1 to group 2 and 270 and 300 micrograms.kg-1 to group 3). Plasma and urine samples were analysed for granisetron by HPLC with fluorimetric detection. Administration of granisetron was well tolerated by the volunteers and there were no serious adverse effects reported. Pharmacokinetic parameters and dose-normalised plasma levels appeared to be independent of dose in the range 50 to 300 micrograms.kg-1, although there was extensive inter-subject variability. Granisetron was extensively distributed, with mean volumes of distribution ranging from 186-264 l at the various doses. Total plasma clearance was, in general, rapid (mean values of 37.0 to 49.9 l.h-1) and predominantly non-renal, with most subjects excreting less than 20% of the dose unchanged in urine. Mean t1/2 values ranged from 4.1 to 6.3 h and MRT from 5.2 to 8.1 h.