Disease relevance of BRL 43694

• Moreover, combining L-754,030 with granisetron plus dexamethasone improves the prevention of acute emesis [1].
• The effects of the 5-hydroxytryptamine2 (5-HT2) and 5-HT3 receptor antagonists, ketanserin and granisetron, respectively, on water movement during intestinal anaphylaxis were studied [2].
• Granisetron is an effective antiemetic in children undergoing highly emetogenic chemotherapy, and effectively controls radiotherapy-induced and postoperative nausea and vomiting [3].
• The most frequently reported adverse event associated with granisetron administration is headache which occurs in about 10 to 15% of patients while constipation, somnolence, diarrhoea and minor transient changes in blood pressure have been reported less frequently [4].
• In addition, granisetron totally abolishes allodynia/hyperalgesia [5].

Psychiatry related information on BRL 43694

• The effect on mechanical pain threshold over human muscles by oral administration of granisetron and diclofenac-sodium [6].
• During the digestive state, GR38032F, BRL 43694 and ICS 205-930 did not affect GI motor activity at all at doses up to 1 mg/kg, whereas BRL 24924 at 1.0 mg/kg i.v. significantly stimulated GI motor activity from the stomach to the colon [7].
• An ethological study of the effects of buspirone and the 5-HT3 receptor antagonist, BRL 43694 (granisetron) on behaviour during social interactions in female and male mice [8].
• Effects of granisetron and lorazepam, alone and in combination, on psychometric performance [9].
• Lack of efficacy of the 5-HT3 receptor antagonist granisetron in the treatment of acute neuroleptic-induced akathisia [10].

High impact information on BRL 43694

• Using these models, selective 5-HT3 receptor antagonists such as MDL 72222 (ref. 5), ICS 205-930 (ref. 6), GR38032F (ref. 7) and BRL 43694 (ref. 8) have been developed [11].
• The 5-HT(3) antagonists, granisetron and ondansetron, are useful in combating the nausea associated with cancer chemotherapy, and alosetron is employed in the treatment of IBS with diarrhea [12].
• The LGA flow responses to motilin were not inhibited by granisetron, C6, alpha-adrenergic, beta-adrenergic, or H2 blockers [13].
• The effects of IV injection of 5-hydroxytryptamine 3 receptor antagonists (BRL 43694 and GR38032F) on gastrointestinal contractile activity were studied in dogs with vagally denervated fundic pouch in the conscious state by means of chronically implanted force transducers in the gastrointestinal tract and the pouch [14].
• CONCLUSION: The administration of a 5-hydroxytryptamine3, receptor (5-HT3) antagonist, in this case granisetron, after 24 hours conferred no benefit [15].

Chemical compound and disease context of BRL 43694

• Comparative clinical trial of granisetron and ondansetron in the prophylaxis of cisplatin-induced emesis. The Granisetron Study Group [16].
• PURPOSE: To evaluate the roles of granisetron and dexamethasone for emesis control on days 2 through 7 after the administration of cisplatin in doses of 50 mg/m2 or greater to patients who had not previously received chemotherapy [15].
• PURPOSE: To compare the efficacy and safety of granisetron and ondansetron, serotonin (5-HT3) receptor antagonists shown to be effective in the prevention of chemotherapy-induced emesis [16].
• Compared with 5-HT3 antagonists such as GR 38032F, BRL 43694, and metoclopramide, (S)-28 was most active in (a) inhibiting binding to 5-HT3 receptor binding sites in rat entorhinal cortex with an Ki value of 0.19 nM and (b) blocking cisplatin-induced emesis in the ferret with an ED50 value determined to be 9 micrograms/kg po [17].
• Serotonin receptor antagonists (ondansetron, granisetron, tropisetron, dolasetron, and ramosetron), compared with traditional antiemetics, are highly efficacious for PONV [18].

Biological context of BRL 43694

• We have used a homology model of the extracellular domain of the 5-HT(3) receptor to dock granisetron, a 5-HT(3) receptor antagonist, into the binding site using AUTODOCK [19].
• The complete control rates were 92.9% in TT subjects (n = 14) in comparison to homozygote (47.6%, n = 21, P = .009) or heterozygote (56.1%, n = 41, P = .02) carriers of the 3435 C allele in granisetron-treated patients [20].
• Scatchard analysis of [3H]granisetron binding resulted in KD values lower than the IC50 values of granisetron and a decreasing number of binding sites at higher temperatures [21].
• METHOD: Thirty-one outpatients who were currently experiencing sexual dysfunction associated with SRIs were randomly assigned to double-blind treatment with granisetron (1-1.5 mg) or placebo for use 1 to 2 hours prior to sexual activity [22].
• Granisetron was very well tolerated, and there were no clinically important changes in pulse rate, blood pressure or Holter electrocardiogram [23].

Anatomical context of BRL 43694

• Granisetron (30, 75, 150, or 300 micrograms/kg) was given subcutaneously to adult male Wistar rats 90 minutes before instillation of 75 micrograms cholera toxin or 50 micrograms LT in isolated whole small intestine [24].
• We have also reported that injection of the 5-HT(3) receptor antagonist granisetron (GRA) into the masseter muscle of healthy subjects reduced pain induced by 5-HT and abolished allodynia/hyperalgesia [25].
• Granisetron (BRL 43694) is a highly selective 5-HT3 receptor antagonist which possesses significant antiemetic activity, likely mediated through antagonism of 5-HT3 receptors on abdominal vagal afferents and possibly in or near the chemoreceptor trigger zone [4].
• Total body irradiation prior to bone marrow transplantation: efficacy and safety of granisetron in the prophylaxis and control of radiation-induced emesis [26].
• [3H]-BRL 43694 (Granisetron), a specific ligand for 5-HT3 binding sites in rat brain cortical membranes [27].

Associations of BRL 43694 with other chemical compounds

• PATIENTS AND METHODS: 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 [28].
• Seven comparative studies that used granisetron, ondansetron, or tropisetron in patients who received either moderately or highly emetogenic chemotherapy are reviewed [29].
• Thus, granisetron is an effective, well tolerated and easily administered agent for the prophylaxis of nausea and vomiting induced by cancer chemotherapy which appears to be devoid of extrapyramidal side effects associated with metoclopramide [4].
• In conclusion, the results of this study indicate that injection of granisetron and propranolol into the human masseter muscle reduces pain induced by local administration of 5-HT, but that the effect of granisetron is stronger than that of propranolol [5].
• Resolution of fluoxetine-induced sexual dysfunction with the 5-HT3 antagonist granisetron [30].

Gene context of BRL 43694

• CONCLUSION: These results suggest that ABCB1 3435C>T polymorphism is associated with antiemetic treatment efficacy in patients with cancer treated with 5-HT(3) antagonists, particularly in granisetron-treated patients, during the short-term phase of chemotherapy [20].
• The i.p. injection of ketanserin (a 5-HT2 receptor antagonist, 0.1 and 1 mg/kg) or granisetron (a 5-HT3 receptor antagonist, 0.1 and 1 mg/kg) had no effect on emotional stress-induced colonic hyperkinesia [31].
• Correlation data were consistent with the role of CYP3A3/4 in granisetron 9'-desmethylation but indicated that a different enzyme was involved in the 7-hydroxylation [32].
• 5. Studies using chemical inhibitors selective for individual P450 enzymes indicated the involvement of cytochrome P450 3A (CYP3A), both pathways of granisetron metabolism being very sensitive to ketoconazole inhibition [32].
• The pharmacokinetics of granisetron, when administered as a single dose, appeared to be unaltered by cimetidine, an inhibitor of multiple hepatic enzymes (CYP1A2, CYP2D6 and CYP3A4) [33].

Analytical, diagnostic and therapeutic context of BRL 43694

• Use of dexamethasone and granisetron in the control of delayed emesis for patients who receive highly emetogenic chemotherapy. National Cancer Institute of Canada Clinical Trials Group [15].
• Site-directed mutagenesis at position Trp-89 markedly reduces the affinity of the 5HT3R for the antagonists curare and granisetron but has little effect on the affinity for the agonist serotonin [34].
• In a second group of animals, granisetron (300 micrograms/kg) was given subcutaneously and two hours later small intestinal perfusion with PES containing 200 micrograms/l ST was performed [24].
• Effects on muscle pain by intramuscular injection of granisetron in patients with fibromyalgia [25].
• In this double-blind study, the efficacy and safety of a novel anti-emetic, granisetron, was assessed at two dose levels (40 micrograms/kg; n = 149 and 160 micrograms/kg; n = 147) in 296 patients undergoing high-dose cisplatin chemotherapy [35].

References