Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042963 (vomiting)
 31,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pharmacological effects of the metabolites M1 and M2 of mosapride citrate ((+/-)-4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholi nyl] methyl]benzamide citrate, AS-4370, CAS 112885-42-4), a gastroprokinetic agent with serotonin 5-HT4 receptor agonist property, were compared with those of mosapride. In isolated guinea-pig ileum treated with phenoxybenzamine, the metabolites M1 and M2 enhanced electrically-evoked contractions with EC50 values of 1.2 x 10(-7) mol/l and 1.0 x 10(-6) mol/l, respectively. The metabolite M1 was twice less potent than that of mosapride. When administered intravenously, the metabolite M1 enhanced gastric emptying of a semisolid meal in mice and rats; the potency was 3 times less than that of mosapride in mice and almost equal to that of mosapride in rats. When administered orally, the metabolite M1 enhanced gastric emptying of a semisolid meal in mice and rats, and also enhanced gastric emptying of a resin pellet meal in rats. The potency of metabolite M1 was 10 times less than that of mosapride in rats, although it was equal to that of mosapride in mice. In these experiments, the metabolite M2 was far less active. In addition to these gastroprokinetic properties, the metabolite M1 possessed a potent 5-HT3 receptor antagonist property. The metabolite M1 antagonized the 2-methyl-5-HT-induced bradycardia in anesthetized rats with an ED50 value of 10.5 micrograms/kg, i.v., and inhibited the cisplatin-induced emesis in ferrets with a potency approximately 25 times that of mosapride. These results suggest that the metabolites M1 and M2 of mosapride do not play a crucial role in the gastroprokinetic effect of mosapride.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pharmacological effects of the new gastroprokinetic agent mosapride citrate and its metabolites in experimental animals. 826 74

Involvement of ileal and circulating serotonin (5-HT) levels in cisplatin-induced emesis was examined using a microdialysis technique and an extraction method in dogs. The 5-HT levels in the ileal dialysate were increased to 232-294% of the basal level from 100 to 180 min after cisplatin administration (3 mg/kg, i.v.) and had returned to the basal level 280 min after dosing. The 5-HT levels in the blood dialysate were increased to 424-2165% from 140 to 180 min after dosing. The concentrations of 5-HT determined by HPLC following extraction were increased to 271% in the ileal mucosa and to 478% in plasma 3 hr after dosing. In immunohistochemistry, the number of 5-HT-immunoreactive cells was increased to 166% in the ileal mucosa following cisplatin treatment. These results strongly suggest that increases in the release and synthesis of 5-HT in the gut, probably in the enterochromaffin cells, are intimately involved in cisplatin-induced emesis.
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PMID:Increase in serotonin levels in the dog ileum and blood by cisplatin as measured by microdialysis. 829 18

Migraine and the eating disorders, particularly bulimia nervosa, share some common demographics, phenomenology, psychopathology, and treatments. Bulimics also appear to be more sensitive to the induction of severe migrainous headaches than controls following challenge with the 5-HT agonist, m-chlorophenylpiperazine (m-CPP), but not placebo or L-tryptophan. This supports a common pathophysiological relationship involving postsynaptic 5-HT dysfunction between these disorders. In order to further explore the possible relationship between eating disorders and migraine, we administered a modified version of the Diagnostic Survey of the Eating Disorders (DSED) and the Eating Disorders Inventory (EDI) to a group of female migraine patients attending the Medical University of South Carolina (MUSC) Neurology Clinic (n = 34). Of the 34 migraine patients surveyed, 88% reported dieting behavior, 59% reported binge eating, and 26% reported self-induced vomiting during their lifetimes. Compared to the responses of a group of normal female controls (n = 577), patients with migraine had elevated scores on four of the eight subscales of the EDI: Body Dissatisfaction (p < or = .02), Perfectionism (p < or = .01), Interpersonal Distrust (p < or = .02), and Ineffectiveness (p < or = .06). These findings support the hypothesis that common pathophysiological mechanisms, perhaps involving 5-HT dysregulation, may be involved in these two disorders.
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PMID:Is migraine related to the eating disorders? 833 2

The pharmacological activity of RS 42358-197, a novel 5-HT3 receptor antagonist has been evaluated in vitro and in vivo. In functional experiments in vitro, RS 42358-197 behaved as a competitive antagonist against 5-HT-induced contractions in the guinea pig ileum (low-potency phase), yielding a pA2 estimate of 8.1. RS 42358-197 was devoid of any agonistic or antagonistic activity at 5-HT1-like receptors (contraction of canine saphenous vein), 5-HT2 receptors (contraction of rabbit aorta) or 5-HT4 receptors (contraction of guinea pig ileum, high-potency phase). RS 42358-197 failed to affect the concentration-effect curve to substance P in guinea pig ileum. In anesthetized rats. RS 42358-197, administered by the intravenous, intraduodenal or transdermal route, dose-dependently inhibited the Bezold-Jarisch reflex induced by 2-methyl 5-HT (ID50:0.05 micrograms/kg; i.v., 5.7 micrograms/kg; i.d., and 11.6 micrograms/chamber, respectively). In this regard, when administered intraduodenally, RS 42358-197 was more potent and exhibited a longer duration of action than either ondansetron or granisetron. In dogs, RS 42358-197, administered either intravenously or orally, dose-dependently inhibited the emesis induced by cisplatin, actinomycin and cyclophosphamide, but not that induced by apomorphine. When tested at maximally effective doses against cisplatin-induced emesis in dogs, RS 42358-197 had a longer duration of antiemetic activity (> 6 h) than ondansetron (2 h). RS 42358-197, administered orally, also afforded protection against cisplatin-induced emesis in ferrets. At doses that showed marked anti-emetic activity in dogs (10-100 micrograms/kg; i.v. and 100-1000 micrograms/kg; i.d.), RS 42358-197 did not produce any hemodynamic changes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:RS 42358-197, a novel and potent 5-HT3 receptor antagonist, in vitro and in vivo. 835 89

Serotonin is a neurotransmitter involved in chemotherapy-induced emesis and ondansetron is a new drug endowed with selective antagonism against the 5HT3 receptors. Phase I-II studies have demonstrated its activity against acute emesis after single-dose cisplatin, reporting particularly low toxicity; in comparative studies with high-dose metoclopramide, it has been proved to be more effective and completely devoid of extrapyramidal side effects. Ondansetron has shown its activity and safety also in multiple-day cisplatin regimens. Its antiemetic efficacy is improved by the addition of dexamethasone. Preliminary data suggest its role also when used in single-dose administration. Its activity in the delayed phase of cisplatin emesis needs to be further explored.
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PMID:Cisplatinum based chemotherapy: role of the antiserotoninergic ondansetron in prevention of emesis. 837 Nov 30

We investigated the involvement of peripheral and central serotonin (5-HT)3 receptors in cisplatin- and 5-HT3 receptor agonist-induced emesis in ferrets. Cisplatin (10 mg/kg i.v.)-induced emesis was inhibited by intravenous YM060 (0.003-0.1 microgram/kg). A highly selective and potent 5-HT3 receptor agonist, m-chlorophenylbiguanide (1-10 mg/kg i.p.), dose dependently elicited emesis an effect which was inhibited by YM060 (0.003-0.3 microgram/kg i.v.). Vagotomy markedly reduced this emesis, and the combination of abdominal vagotomy and greater splanchnicectomy abolished emesis. Lesion of greater splanchnic nerves alone did not markedly inhibit emesis. Intracerebroventricularly (4th ventricle) administered YM060 inhibited cisplatin- and m-chlorophenylbiguanide-induced emesis only at higher doses (0.01-0.1 and 0.01-0.03 microgram, respectively). Intracerebroventricularly (4th ventricle) administered m-chlorophenylbiguanide (30-100 micrograms) produced only a weak retching response. These results indicate that stimulation of abdominal vagal afferent nerves via peripheral 5-HT3 receptors is important for triggering cisplatin- and m-chlorophenylbiguanide-induced emesis in ferrets.
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PMID:Mechanisms of cisplatin- and m-chlorophenylbiguanide-induced emesis in ferrets. 840 4

In species which vomit, elevated intestinal serotonin (5-hydroxytryptamine, 5-HT) may stimulate abdominal vagal afferent fibers, which in turn evoke the vomiting reflex. The release of 5-HT from intestinal enterochromaffin (EC) cells is regulated by polymodal mechanisms. The object of this study was to evaluate the involvement of 5-HT autoreceptors in the regulation of 5-HT release from the small intestine. Functional studies were carried out using 5-HT3 receptor agonist and antagonists, and 5-HT4 receptor agonist. Ferret and rat ileal tissue were isolated and 5-HT released into the bathing solution was determined using HPLC with an electrochemical detector (ECD). We previously reported that cisplatin produced a significant increase in cumulative 5-HT release and that ondansetron, a selective 5-HT3 receptor antagonist, did not alter the 5-HT release from the ferret ileum. In this study, a selective 5-HT3 agonist, 2-methyl-5-HT, induced a dose-dependent increase of 5-HT from the rat ileum. This release of 5-HT was significantly reduced by granisetron, a selective 5-HT3 receptor antagonist. Furthermore, a selective 5-HT4 receptor agonist, 5-methoxytryptamine induced a concentration-dependent increase of 5-HT in the rat ileum. These results suggest that both 5-HT3 and 5-HT4 receptors may be involved in intestinal 5-HT release.
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PMID:Chemical modulation of 5-HT3 and 5-HT4 receptors affects the release of 5-hydroxytryptamine from the ferret and rat intestine. 855 68

The oral toxicity of ramosetron ((R)-5-[(1-methyl-3-indolyl) carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole hydrochloride, CAS 132907-72-3, YM060), a new compound having serotonin (5-HT)3 receptor antagonist activity was investigated in beagle dogs. To evaluate the acute toxicity, two groups of beagle dogs, each comprised of one male and one female, were given YM060 bulk powder in gelatin capsules at dose of 0, 3 mg/kg or 0, 30 and 60 mg/kg in ascending order in at least 7-day intervals. After the final dose, animals were observed for 2 weeks. No deaths were observed at any dose. At 60 mg/kg, the male exhibited frequent vomiting, salivation and prone position 1-3 h after administration, when the plasma concentration of the unchanged drug reached Cmax or was close to Cmax. The female exhibited no changes except vomiting. No effects on either the male or the female were detected in body weight, food consumption, electrocardiography, hematology, plasma biochemistry or urinalysis. To evaluate the subacute toxicity of YM060, three male and 3 female beagle dogs per group received doses of 0, 1, 3, 10 and 20 mg/kg/d for 13 weeks. YM060 was triturated 10-fold using lactose and filled in gelatin capsules before use. The plasma concentration of unchanged drug increased almost dose-dependently, peaked about 2 h post-dosing and subsequently decreased with time. The plasma concentration-time profile after the final dose at week 13 was not different from that after the initial dose. No treatment-related changes were observed up to 3 mg/kg/d.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Acute, subacute and chronic oral toxicity studies of the new serotonin (5-HT)3-receptor antagonist ramosetron in beagle dogs. 857 18

Since the discovery of the biologically active platinum complexes 30 years ago, 2 agents have become widely established in clinical oncology practice. Both cisplatin and carboplatin are platinum(II) complexes with 2 ammonia groups in the cis- position. However, they differ in their solubility, chemical reactivity, dichloride or alicyclic oxygenated leaving groups, pharmacokinetics and toxicology. Cisplatin causes severe renal tubular damage and reduces glomerular filtration, and requires concurrent saline hydration and mannitol diuresis to eliminate potentially lethal and unacceptable damage to the kidneys. Carboplatin, at conventional doses, causes no decrease in glomerular filtration and only minor transient elevations in urinary enzymes. Cisplatin is the most emetic cancer drug in common use, while nausea and vomiting associated with carboplatin are moderately severe. Serotonin release from enterochromaffin gut mucosal cells and stimulation of serotonin 5-HT3-receptors mediates acute emesis. Selective inhibitors of the 5-HT3-receptor protect against cisplatin- and carboplatin-induced nausea and vomiting. Peripheral neurotoxicity is the most dose-limiting problem associated with cisplatin. Loss of vibration sense, paraesthesia and sensory ataxia comes on after several treatment cycles. Carboplatin, however, is relatively free from peripheral neurotoxicity. Audiometry shows cisplatin-induced ototoxicity in 75 to 100% of patients, which may be associated with tinnitus and hearing loss. Ototoxicity is rare with conventional dose carboplatin therapy. Monitoring hearing with audiograms may identify early signs before significant impairment occurs. Cisplatin causes mild haematological toxicity to all 3 blood lineages. Haematological toxicity is dose-limiting for carboplatin, with thrombocytopenia being a greater problem than leucopenia. Although carboplatin is not toxic to the kidney, renal function markedly affects the severity of carboplatin-induced thrombocytopenia. The major clearance mechanism of cisplatin is irreversible binding in plasma and tissues, while carboplatin is cleared by glomerular filtration. Metabolism of cisplatin to aqua, amino acid and protein species is extensive, whereas carboplatin exists mainly as the free unchanged form. Strong relationships between carboplatin renal clearance, glomerular filtration rate, area under the plasma concentration-time curve (AUC) of filterable platinum and severity of thrombocytopenia have prompted dose adjustment according to renal function. New analogues such as JM216 offer the potential advantages of oral administration and few nonhaematological toxicities. Analogues based on the diaminocyclohexane ligand have encountered problematic neurotoxicity.
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PMID:Comparative adverse effect profiles of platinum drugs. 857 96

Emesis is a common side effect of chemotherapeutic drugs. Cisplatin, nitrogen mustard and dacarbazine induce increases in urinary 5-hydroxyindoleacetic acid (5-HIAA) in parallel with the development of the period of emesis which is sensitive to 5-HT3 receptor antagonists ('acute emesis'). It is suggested that these cytotoxics release serotonin from enterochromaffin cells, which then acts on 5-HT3 receptors to trigger the emetic response. Cyclophosphamide, on the other hand, induces a modest emetic response, partly sensitive to 5-HT3 receptor antagonists, but not associated with increases in urinary 5-HIAA. It is suggested that cyclophosphamide-induced emesis is not mediated by the release of serotonin from enterochromaffin cells. Although after high-dose cisplatin most emesis is sensitive to 5-HT3 receptor antagonists, patients often present a milder, although more prolonged form of emesis which is mostly resistant to 5-HT3 receptor antagonists (also known as 'delayed emesis'). This form of emesis is not associated with increases in urinary 5-HIAA (not due to serotonin released from the enterochromaffin cells). Treatment with p-chlorophenylalanine (a serotonin synthesis inhibitor) inhibited cisplatin-induced emesis and cisplatin-induced increases in urinary 5-HIAA excretion. In summary, these results indicate that in human patients, serotonin plays a fundamental role in chemotherapy-induced emesis. Serotonin released from enterochromaffin cells seems to mediate emesis sensitive to 5-HT3 receptor antagonists induced by cisplatin, dacarbazine and nitrogen mustard. Emesis sensitive to 5-HT3 receptor antagonists associated with cyclophosphamide treatment, is not mediated by the release of serotonin from enterochromaffin cells by the cytotoxic. Therefore, cyclophosphamide could induce serotonin release either from enteric serotonin nerves or from the CNS. Cisplatin-induced emesis resistant to 5-HT3 receptor antagonists ('delayed emesis') is not mediated by serotonin released from enterochromaffin cells.
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PMID:Serotonin mechanisms in chemotherapy-induced emesis in cancer patients. 869 46


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