Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P46098 (5-HT3 receptor)
 2,290 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In an open ascending-dose study, granisetron, a specific 5-HT3 receptor antagonist, was administered to 24 paediatric patients (17 male, 7 female, mean age 6.2, range 3-15 years) who were receiving moderately or highly emetogenic chemotherapy for malignant disease. Single doses of 10, 20 and 40 micrograms/kg were administered by intravenous infusion 1 h before chemotherapy. Each dose level was studied in a group of 8 patients. With the 40 micrograms/kg dose, 5 of 8 patients experienced no nausea or vomiting in the 24 h after granisetron treatment. With 20 micrograms/kg, a similar response was seen, but with 10 micrograms/kg only 2 of 8 patients experienced complete antiemetic protection despite additional prophylactic chlorpromazine in this group. Granisetron was very well tolerated, and there were no clinically important changes in pulse rate, blood pressure or Holter electrocardiogram. It is concluded that granisetron was very well tolerated by paediatric patients. In addition, there was clear evidence of a major antiemetic effect for at least 24 h after a single intravenous dose of 20 or 40 micrograms/kg.
Eur J Cancer 1991
PMID:Efficacy and safety of granisetron in the prevention of chemotherapy-induced emesis in paediatric patients. 165 48

Both radiotherapy and chemotherapy for cancer are capable of causing severe nausea and vomiting, which formerly often interfered with the patient's compliance to treatment. The basic pathway and pharmacological mechanisms involved in this are still poorly understood. The recent discovery, however, that 5-HT3 receptor antagonists can prevent or greatly reduce chemotherapy-induced emesis led to a re-evaluation of the sequence of events occurring in the protective emetic reflex, which are reviewed in this paper. The vomiting centre co-ordinates the incoming and outgoing information, and is thought to be represented by complex interactions between different adjacent areas in the brainstem. Whether the main role in the emetic reflex arch is accomplished by either the central part (chemoreceptor trigger zone) or the peripheral part (gastro-intestinal tract) needs further confirmation A more important role, however, of the vagal nerve and the gastro-intestinal tract is generally accepted. The neurotransmitter serotonin (5-HT) appears to play a major role in chemotherapy-induced emesis via the 5-HT receptor. These indications could form the basis for further investigations into the involvement of other neurotransmitters, and the character of their interactions.
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PMID:Pathophysiology of cytotoxic drug-induced emesis: far from crystal-clear. 167

A total of 24 patients who were receiving combination chemotherapy (POMB) including cisplatin at a dose of 100-120 mg/m2 were treated with the 5HT3 antagonist GR38032F (GR) as an anti-emetic prophylaxis. GR was given as a 15-min loading infusion followed by a 24-h infusion at three escalating dose levels of 1, 2 and 4 mg/h. In the first 24 h after commencing treatment, six patients had complete control of nausea and vomiting (CR), two had 1-2 emetic episodes (MR) and five had 3-5 emetic episodes (mR). The major response rate (CR + MR) was thus 35%. Eight responding patients (CR or MR) went on to receive oral GR at 8 or 12 mg t.i.d. for 5 days. In this group there was one CR, one MR, two mRs and four failures (F). There was no evidence of an improved therapeutic effect with increasing dose in either the infusion or the oral section of the study, although numbers were limited in the latter part of the trial. Toxicity was mild, with low-grade headache affecting 25% of patients being the most frequent side effect. Pharmacokinetic data was obtained in six patients at each dose level. There was a progressive rise in clearance with increasing dose, indicating that the kinetics are non-linear. However, there was no evidence of an association between high plasma levels and therapeutic efficacy. GR38032F is well tolerated and has promising single-agent activity in preventing vomiting induced by high-dose cisplatin.
Cancer Chemother Pharmacol 1990
PMID:A phase I/II study of the 5-HT3 antagonist GR38032F in the anti-emetic prophylaxis of patients receiving high-dose cisplatin chemotherapy. 168 16

Isolated segments of the guinea-pig small intestine were vascularly perfused and the release of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) into the portal venous effluent determined by high pressure liquid chromatography with electrochemical detection. Release of acetylcholine from isolated superfused intestinal segments was determined as outflow of [3H]radioactivity from preparations preincubated with [3H]choline. Cisplatin (3 microM) increased the outflow of 5-HT and 5-HIAA by about 90%. At 30 and 100 microM cisplatin decreased the outflow of 5-HT and its metabolite by 40%-50%. The stimulatory effect of cisplatin was consistently observed only when the bicarbonate-phosphate buffer of the Tyrode's solution was replaced by HEPES-buffer. The stimulatory effect of cisplatin was abolished in the absence of extracellular calcium or presence of tetrodotoxin (1 microM). The stimulatory effect of cisplatin was also prevented by hexamethonium (100 microM) or scopolamine (100 nM). The 5-HT3 receptor antagonists ondansetron and ICS 205-930 in concentrations as low as 1 pM also abolished the stimulatory effect of cisplatin. The 5-HT3 receptor antagonist MDL 72222 prevented the stimulatory effect of cisplatin only at a concentration of 1 microM. None of the 5-HT3 receptor antagonists alone significantly altered the outflow of 5-HT and 5-HIAA. Cisplatin (3 microM) enhanced the outflow of [3H]radioactivity from intestinal segments and caused longitudinal muscle contractions that were abolished by 100 nM scopolamine. In conclusion, cisplatin, at concentrations which occur during anti-cancer therapy in humans and induce emesis, increases the release of 5-HT from the enterochromaffin cells of the small intestine of the guinea-pig.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cisplatin increases the release of 5-hydroxytryptamine (5-HT) from the isolated vascularly perfused small intestine of the guinea-pig: involvement of 5-HT3 receptors. 171 32

The serotonin (5-hydroxytryptamine, 5-HT) antagonists, which bind at the type 3 receptor (5-HT3 receptor), have been evaluated in several preclinical models and found to be effective in alleviating cancer therapy-related emesis. The antiemetic efficacy of ondansetron (GRF-38032F, odanserin), granisetron (BRL-43694), tropisetron (ICS-205930), MDL-72222 and MDL-73147EF, batanopride (BMY-25801-01) and several others is at various stages of investigation. Ondansetron is currently marketed in several countries and the same will soon be true for granisetron. At this stage it is not yet possible to evaluate the comparative efficacy of each of these compounds, although recent preclinical data reveal some differences in the affinity of these compounds, for other receptors. Side effects related to these agents have been minor, consisting mainly of slight headaches; possible rises in liver enzymes related to some compounds need further evaluation. Future studies will need to determine the exact role of 5-HT3 antagonists, although their cost may confine their use to patients at high risk for side effects from metoclopramide.
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PMID:5-HT3 receptor antagonists. An overview of their present status and future potential in cancer therapy-induced emesis. 172 61

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. Clinical trials in cancer patients demonstrate that, compared with placebo, granisetron significantly reduces the incidence of nausea and vomiting for 24 hours after administration of high-dose cisplatin. In large comparative trials, 70% of patients who received granisetron prior to cisplatin or other chemotherapy experienced complete inhibition of vomiting with little or no nausea for 24 hours after antineoplastic administration; these results were similar to those obtained with high-dose metoclopramide plus dexamethasone, and superior to a combination of chlorpromazine plus dexamethasone, or prochlorperazine plus dexamethasone, or methylprednisolone monotherapy. 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. Extrapyramidal effects, which can occur with high-dose metoclopramide and may be a limiting factor in its use, have not been noted with granisetron administration. 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. As a member of a new class of drugs, the selective 5-HT3 receptor antagonists, granisetron provides the medical oncologist with a new, potentially more acceptable antiemetic therapy.
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PMID:Granisetron. A review of its pharmacological properties and therapeutic use as an antiemetic. 172 76

The locations of serotonin-3 (5-HT3) receptors involved in initiating vomiting (emesis) were assessed by cutting visceral afferents or lesioning the area postrema. The 5-HT3 receptor agonists phenylbiguanide (PBG) and 2-methyl-5-HT were shown to induce vomiting and related prodromal signs (e.g., licking, swallowing) in nonoperated cats. Two-methyl-5-HT, but not PBG, also usually produced defecation and sometimes urination. Most studies were conducted using PBG, which induced vomiting in 40/49 (82%) cats at doses of 8.0 mg/kg i.p. or less (thresholds ranged from 2-8 mg/kg, median 5 mg/kg). Latencies to the first episode ranged from 4 to 21 min (median 7.5 min). PBG-induced vomiting was blocked by the 5-HT3 receptor antagonist MDL 72222. Lesions of the area postrema had no apparent effect on vomiting induced by PBG or by electrical stimulation of abdominal vagal afferents. In contrast, the threshold of PBG-induced vomiting was increased by supradiaphragmatic vagotomy and greatly increased by splanchnic nerve section. Thus, abdominal visceral afferents, but not the area postrema, play an important role in mediating vomiting induced by i.p. injection of the 5-HT3 receptor agonist PBG. The mechanisms by which vomiting is induced by PBG as compared to the cancer chemotherapeutic drug cisplatin are discussed.
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PMID:Mechanisms of vomiting induced by serotonin-3 receptor agonists in the cat: effect of vagotomy, splanchnicectomy or area postrema lesion. 173 1

Ligands of various chemical classes (e.g., indoles, indazoles, benzamides, carbazoles, and quinolines) have demonstrated high affinity for the 5-HT3 receptor in radiolabeled ligand-binding studies, and have shown 5-HT3 receptor antagonistic activity in functional assays which utilize the excitatory effects of 5-HT on enteric neurons and autonomic afferents. Several 5-HT3 antagonists are currently being evaluated for potential use in the treatment of migraine, schizophrenia, and anxiety, and a few have already demonstrated high efficacy as antiemetics in cancer chemotherapy. The purpose of this presentation is to highlight the significant structure-affinity relationships (SAFIR) and common geometrical features among 5-HT3 receptor ligands, and to describe the three-dimensional pharmacophore for the 5-HT3 recognition site derived from computational techniques. The chemical template containing the recognition elements (functional groups) for the 5-HT3 receptor are: an aromatic or heteroaromatic ring system, a coplanar carbonyl group, and a nitrogen center, interrelated by well-defined distances. Two "binding shapes" or "active shapes" for 5-HT3 ligands have been identified from detailed conformational analyses.
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PMID:Molecular modeling of 5-HT3 receptor ligands. 181 57

Combinations of dopamine antagonists or high-dose metoclopramide with steroids can provide complete control of chemotherapy-related nausea and vomiting in up to 60-70% of patients undergoing high-dose cisplatin-based chemotherapy. High-dose metoclopramide probably acts as a 5-HT3 receptor antagonist, but because of its dopamine-receptor antagonism it is the cause of extrapyramidal side-effects. These compounds, and the agents used in combination with them, tend to cause sedation, an undesirable effect in the outpatient setting. Specific 5-HT3 receptor antagonists (ondansetron, granisetron, tropisetron) give a similar control of chemotherapy related nausea and vomiting, with minimum side-effects. These drugs can cause headaches and constipation and some have been related to transient liver enzyme abnormalities in cancer patients; however, disease and chemotherapy might also be the cause of the enzyme anomalies. Combinations of 5-HT3 receptor antagonists with steroids may provide a very high degree of protection.
Eur J Cancer 1991
PMID:Controlling emesis related to cancer therapy. 182 31

Ondansetron, a new 5-HT3 receptor antagonist, has been compared with high-dose metoclopramide in the control of acute emesis (24 h) induced by cisplatin (greater than or equal to 100 mg/m2). Ondansetron, given as three intravenous doses (0.15 mg/kg) 4-hourly, was superior to six intravenous doses of metoclopramide (2.0 mg/kg) in the control of acute emesis. Complete control of emesis was achieved in 40% of patients receiving ondansetron compared to 30% of patients receiving metoclopramide (P = 0.07); complete or major control (0-2 emetic episodes) was achieved in 65% and 51% of the patients receiving the two treatments respectively (P = 0.016). Patients entered in the acute emesis study who experienced no emesis or up to two episodes were randomised between placebo and ondansetron on day 2 to evaluate the control of delayed emesis up to day 5. Complete control of persistent or delayed emesis over days 2-5 was achieved in 59-78% of patients with oral ondansetron (16 mg t.d.s.) compared to 39-50% of patients receiving oral placebo. These differences failed to reach statistical significance except on day 4. Some patients with complete or major control of emesis on their first course of chemotherapy subsequently received further courses of ondansetron (median 3 courses; range 2-10) on a non-comparative basis. Similar control was achieved in 85% of courses. There may be some reduction in the degree of control with subsequent courses. Of 44 patients with complete control at cycle 1, 19 (44%) were emesis free and 3 (7%) experienced 1-2 episodes with cycle 3, though patients were sometimes withdrawn before cycle 3 for reasons other than inadequate anti-emetic control. Efficacy with successive courses can only be established in a prospective comparative trial. Both treatments were well tolerated but ondansetron caused significantly greater transient asymptomatic elevations in ALT/AST (P = 0.003/0.005). Acute dystonic reactions (2 patients) and akathisia (10 patients) occurred with metoclopramide only (P = 0.002). The role of ondansetron in the control of delayed emesis requires further study.
Eur J Cancer 1991
PMID:Progress in the control of acute and delayed emesis induced by cisplatin. 183 33


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