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

As part of an open dose-ranging study, the pharmacokinetics of granisetron (BRL 43694A), a selective 5-HT3 receptor antagonist given by the i.v. route, was studied in 18 patients receiving highly emetogenic cytotoxic drugs, predominantly cisplatin, either alone or in combination with other cytostatic agents. All patients received 30-min infusions of granisetron at a dose of 40 micrograms/kg. Nine showed complete absence of the gastrointestinal side effects normally associated with cisplatin, and in the majority of the remaining patients, the onset and severity of nausea was significantly modified. No acute side effects were observed at this dose and the drug was well tolerated in all cases. Peak plasma concentrations and area under the curve (AUC) values for granisetron showed considerable inter-patient variation. Higher plasma levels of granisetron were observed at 5 h in responding patients compared with those in whom the drug was ineffective in controlling emesis (P less than 0.05). AUC values were higher in responding patients, but this difference was not statistically significant. There was apparently no defined plasma concentration threshold for the drug's anti-emetic effect in these patients. Granisetron seems to be an effective and safe anti-emetic in patients receiving cytotoxic chemotherapy. Further exploration of its dose scheduling and pharmacokinetic profile is warranted.
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PMID:A pharmacokinetic study of granisetron (BRL 43694A), a selective 5-HT3 receptor antagonist: correlation with anti-emetic response. 254 37

Loading therapy consisting of the ACNU regimen was instituted as postoperative anticancer chemotherapy for malignant gliomas. The efficacy rate of the regimen was 25% at a dose of 3 mg/kg. A high incidence of hematological changes, such as leukopenia (neutropenia) and thrombocytopenia, were observed after chemotherapy. The former could be prevented by the administration of G-CSF, but platelet infusions were necessary in some patients for amelioration of thrombocytopenia. Gastroenterological symptoms, such as nausea and vomiting, were also frequently noted. Granisetron (Kytril), which is a recently developed selective competitive inhibitor of the 5-HT3 receptor, was used for the treatment of these adverse effects, and was found to be clinically effective.
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PMID:[Effective measures against side effects by increasing ACNU dose for malignant glioma: effects on digestive organs]. 752 1

At cancer treatment, the use of antiemetics are often needed due to induction of nausea and vomiting. Some antiemetics have been shown to interact with the direct cytotoxic effects. The newly developed antiemetics have, as far as we know, not been studied in this respect. In the present study, the effects of the 5-HT3 receptor antagonists ondansetron and granisetron were evaluated on the cytotoxicity, induced by irradiation, bleomycin, epirubicin, estramustine, and cisplatin using fibroblasts (V79) and lung cancer cells (P31) in vitro. Ondansetron or granisetron (10(-5) mol/l) had no effect on the survival of irradiated cells. Granisetron (10(-5) mol/l) significantly potentiated cytotoxicity of 2.5 mg/l epirubicin on fibroblasts whereas the effect of granisetron (10(-7) mol/l) on the cytotoxic effect of 25 mg/l bleomycin, and estramustine (80 mg/l) seemed additive to lung cancer cells. Ondansetron was non-interactive with the cytotoxicity induced by any of the anti-cancer drugs. Although the encountered observation with an enhancing effect of granisetron on the epirubicin-induced cytotoxicity is seen in a specific experimental situation in vitro, the fact that 5-HT3 receptor antagonists are routinely used during cancer treatment indicate that attention should be given to a possible interaction with the antineoplastic action of cancer treatment.
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PMID:Interaction of the antiemetics ondansetron and granisetron with the cytotoxicity induced by irradiation, epirubicin, bleomycin, estramustine, and cisplatin in vitro. 757 57

1. In isolated detrusor strips from the guinea-pig urinary bladder, contractile responses to electrical field stimulation were mostly mediated by neurally released acetylcholine (ACh) and adenosine 5'-triphosphate (ATP). 2. 5-Hydroxytryptamine (5-HT) produced a concentration-dependent increase in the amplitude of stimulated detrusor strip contractions. The 5-HT concentration-response curve showed a biphasic profile: the high potency phase was obtained at sub-micromolar concentrations (10-300 nM), while the low potency phase in the range 1-30 microM. The maximum response of the first phase was 30% of the total 5-HT response. 3. Like 5-HT, the 5-HT3 receptor agonist, 2-methyl-5-hydroxytryptamine (2-methyl-5-HT: 0.3-100 microM), the 5-HT2 receptor agonist, (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI: 30 nM-3 microM) and the 5-HT4 receptor agonist, 5-methoxytryptamine (5-MeOT: 0.1-30 microM) potentiated, though with lower potency, detrusor contractions. The resulting concentration-response curves were monophasic in nature. 2-Methyl-5-HT had a maximum effect comparable to that of 5-HT. By contrast, the maximal effects of DOI and 5-MeOT were only 20% and 30% of that elicited by 30 microM 5-HT, respectively. 4. The 5-HT3 receptor antagonist, granisetron (0.3 microM) had no effect on the high potency phase, but caused a rightward parallel shift of the low potency phase of the 5-HT curve (pKB = 7.3). Granisetron(0.3 microM) antagonized with comparable affinity (pKB = 7.1) 5-HT-induced responses after pharmacological isolation of 5-HT3 receptors with the 5-HT1/5-HT2 receptor antagonist, methiothepin (0.3 microM) and the 5-HT4 receptor antagonist, GR 125487 (30 nM). Granisetron (0.1, 0.3 and 1 microM) competitively antagonized the potentiating effect of 2-methyl-5-HT with an estimated pA2 of 7.3.5. Methiothepin (0.3 microM) and the 5-HT2A receptor antagonist, ketanserin (0.3 microM) produced a slight inhibition of the first phase of the 5-HT curve. In the presence of ketanserin, an equimolar concentration of methiothepin was ineffective in further reducing the effect of 5-HT. Similarly, the 5-HT4 receptor antagonist, GR 125487 (30 nM) slightly inhibited the first phase of the 5-HT curve. Conversely, this phase was suppressed when detrusor strips were coincubated with ketanserin (or methiothepin) and GR125487.6. In a separate set of experiments, the interactions of 5-HT with either the purinergic or cholinergic components of excitatory neuromuscular transmission were investigated. In the presence of hyoscine(1 microM), 5-HT was mostly effective at sub-micromolar concentrations, while in the presence of the P2-purinoceptor antagonist, suramin (300 microM), 5-HT-induced potentiation was mainly obtained with micromolar concentrations.7. Thus, in electrically stimulated detrusor strips from guinea-pig, 5-HT potentiated excitatory neuromuscular transmission by activating at least three separate neural 5-HT receptors. These include the 5-HT2A and 5-HT4 receptors, which mediate the 5-HT high potency phase mainly by activation of purinergic transmission. On the other hand, the potentiating effect caused by micromolar concentrations of 5-HT mostly involves cholinergic transmission and is mediated by the 5-HT3 receptors.
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PMID:5-Hydroxytryptamine receptors that facilitate excitatory neuromuscular transmission in the guinea-pig isolated detrusor muscle. 758 90

Cholera toxin and Escherichia coli heat labile toxin (LT) induced intestinal secretion has in the past been attributed exclusively to an increase in intracellular cAMP whereas E coli heat stable toxin (ST) induced secretion is mediated through cGMP. Evidence is accumulating on the importance of 5-hydroxytryptamine (5-HT) in cholera toxin induced secretion, but its role in LT and ST is not well established. This study therefore investigated in vivo the effect of 5-HT3 receptor antagonist, granisetron, on intestinal fluid and electrolyte secretion induced by cholera toxin, LT, and ST. 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. In situ small intestinal perfusion was performed with an iso-osmotic plasma electrolyte solution (PES) to assess fluid movement. 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. Cholera toxin induced net fluid secretion (median -50.1 microliters/min/g (interquartile range -59.5 to -29.8)) was found to be dose dependently decreased or abolished by granisetron (plateau effect at 75 micrograms/kg: 18 (-7.8 to 28), p < 0.01). Granisetron in high dose (300 micrograms/kg), however, failed to prevent LT or ST induced secretion (-52 (-121 to -71) v -31 (-44 to -18), and (-39 (-49 to 17) v (-22 (-39 to -3)), respectively). Sodium and chloride movement paralleled that of fluid. In conclusion, these data show that 5-HT and 5-HT3 receptors play an important part in cholera toxin induced secretion but are not involved in E coli heat stable or heat labile toxin induced secretion.
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PMID:Role of 5-hydroxytryptamine type 3 receptors in rat intestinal fluid and electrolyte secretion induced by cholera and Escherichia coli enterotoxins. 759 Apr 28

In urethananesthetized ferrets, basal lower esophageal sphincter pressure (LESP) was unaffected by the 5-hydroxytryptamine3 (5-HT3) receptor antagonist granisetron (0.5 mg/kg) or by greater splanchnic nerve section (GSX), but increased after bilateral vagotomy. Peripheral vagal nerve stimulation caused LES relaxation, often followed by a brief contraction and a prolonged inhibition of LESP. Close intra-arterial injection of 5-HT (5-100 micrograms) had a biphasic effect on LESP, with a brief drop followed by a prolonged increase. Granisetron (0.5 mg/kg i.v.) abolished the initial relaxation and revealed an earlier peak of excitation. This was not influenced by subsequent vagotomy and GSX. In a series of eight additional experiments (series 2), granisetron was given after vagotomy and GSX. In series 2, 5-HT-induced relaxation was unaffected by vagotomy but was significantly reduced after GSX and was further reduced after granisetron, indicating that 5-HT3 receptor mechanisms may lie on a sympathetic neural pathway. Vagotomy had no effect on the excitatory component. GSX had no effect on the amplitude of excitation, but reduced its latency. Granisetron had no further effect on excitation in series 2. In a separate series of 13 experiments (series 3), the excitatory component of the LES response to 5-HT was abolished by ketanserin (2.5 mg/kg i.v.) , after which only relaxation occurred. Both 5-HT2 and 5-HT3 antagonists in combination abolished all effects of 5-HT on LESP. Atropine (400 micrograms/kg i.v., n = 7) had no effect on 5-HT-induced LES responses.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Responses of ferret lower esophageal sphincter to 5-hydroxytryptamine: pathways and receptor subtypes. 761 99

Typical neuroleptics (e.g. haloperidol) can induce a cataleptic state in rodents by means of striatal DA receptor blockade. It has been shown that drugs which influence central serotonergic (5-HTergic) mechanisms can modify neuroleptic-induced catalepsy, suggesting that dopaminergic transmission is under 5-HTergic modulation. The aim of this study was to examine the effects of bemesetron and granisetron, two selective 5-HT3 receptor antagonists, on this catalepsy in mice. Catalepsy was induced with haloperidol (1.5 mg/kg, i.p.) and measured at 30-min intervals by means of a bar test. Drugs (or saline, for the controls) were injected i.p. 20 min before haloperidol, with each animal used only once. Bemesetron significantly reduced catalepsy at a dose of 1 mg/kg, whilst 10 mg/kg potentiated the phenomenon and 0.1 mg/kg was found to be without effect. Granisetron inhibited catalepsy at doses of 0.04 and 0.1 mg/kg while 4 mg/kg of the antagonist significantly increased the duration of catalepsy. These data suggest that 5-HT3 receptors play a role in neuroleptic-induced catalepsy. Considering the high affinities of both antagonists for 5-HT3 receptors, it is tempting to speculate that the potentiation of catalepsy by high doses of them is due to non 5-HT3 receptor mechanisms.
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PMID:Effects of 5-HT3 receptor antagonists on neuroleptic-induced catalepsy in mice. 762 68

1. Noxious colo-rectal distension was applied in conscious rats by acute balloon inflation and the effects observed as abdominal muscle contraction with the threshold typically between 10-40 mmHg. The effects of 5-HT3 receptor antagonists on responses to noxious colo-rectal distension were then studied in both normal rats and those pretreated with 5-hydroxytryptophan (5-HTP). 2. Granisetron and ondansetron (10 micrograms kg-1 and 1 mg kg-1, s.c.) had no effect on visceromotor thresholds to colo-rectal distension in normal rats. 3. Hypersensitivity of the colo-rectum was achieved by systemic administration of a low dose of 5-HTP (10 mg kg-1, s.c.) which lowered the distension pressure required to induce the visceromotor reflex; analysis of variance showed a highly significant treatment effect (F1,11 = 84.26, P < 0.001). 4. Granisetron, zatosetron, bemesetron and renzapride equi-potently increased the threshold values at which distension evoked a visceromotor reflex after dosing with 5-HTP, with a maximal response 3.6 to 4.2 fold above saline controls, at 10 micrograms kg-1, s.c. Metoclopramide (10 micrograms kg-1) also raised the level of distension required to elicit a response. By comparison, tropisetron caused a small, non-significant increase in visceromotor threshold values and only at high doses (1 mg kg-1), whilst ondansetron and BRL 46470 had no significant effects at doses up to 10 mg kg-1. 5. The response to granisetron (10 micrograms kg-1, s.c.) in 5-HTP-treated rats was unaltered by pre-administration of naloxone (5 mg kg-1, s.c.). 6. These results suggest that a 5-HT3-like receptor modulates 5-HTP- evoked visceral hypersensitivity.However, the rank order of antagonist potency does not correlate with their order of potency against the classically defined 5-HT3 receptor.
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PMID:Differences between 5-HT3 receptor antagonists in modulation of visceral hypersensitivity. 788 56

In ferrets, the highly selective 5-HT3 receptor antagonist, granisetron, abolished or reduced emesis induced by cisplatin (10 mg/kg i.v.) or whole body X-irradiation (50 Gy in 10.4 min) in a dose-dependent manner when administered by a variety of routes (intravenous, per os, subcutaneous, intramuscular). Complete protection from vomiting and retching was achieved with 0.5 mg/kg i.v. or p.o. granisetron. Granisetron (0.5 mg/kg i.v.) was also effective when given 6 h before cisplatin, completely protecting 50% of ferrets for a total of 10 h. Following repeat dosing, for either 4 days i.v. or 10 days p.o. before emetic challenge, granisetron (0.5 mg/kg) still retained its antiemetic activity on the 5th or 11th day. Prior treatment with cyclophosphamide (80 mg/kg i.v.) resulted in a significantly shorter time to the onset of vomiting after exposure to X-irradiation. Granisetron, but not saline, abolished vomiting and nausea when given as intervention after this combined emetic regimen. These results show that granisetron has potential flexibility for administration via a variety of different routes and also a long duration of action when used as an antiemetic against a wide range of cytostatic agents.
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PMID:Further studies of the antiemetic activity of granisetron against whole body X-irradiation or cisplatin-induced emesis in the ferret. 801 89

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.
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PMID:Pharmacokinetics and tolerability of ascending intravenous doses of granisetron, a novel 5-HT3 antagonist, in healthy human subjects. 803 36


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