Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018681 (headache)
 56,091 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two randomised single-blind comparative studies were carried out in patients receiving 5-day fractionated chemotherapy. The first which has been reported previously [1] compared granisetron (40 micrograms/kg) (n = 103) with alizapride (12 mg/kg) plus dexamethasone (8 mg) (n = 94) while the second compared granisetron (40 micrograms/kg) (n = 143) with metoclopramide (7 mg/kg) plus dexamethasone (12 mg) (n = 141). Granisetron, unlike alizapride or metoclopramide is a specific 5-HT3 antagonist. The percentage of complete responders (patients with no vomiting and no worse than mild nausea) over the 5-day treatment period was higher for granisetron than for alizapride/dexamethasone (54% vs. 42.7%) (P = 0.121) or for metoclopramide/dexamethasone (46.8% vs. 43.9%). The percentage of complete responders in the first 24 h was significantly higher for granisetron (90.3%) than for alizapride/dexamethasone (65.9%) (P less than 0.001) or for metoclopramide/dexamethasone (87.4% vs. 67.9% P less than 0.0001). Granisetron was also superior to both comparators in terms of the time to the first episode of moderate/severe nausea and to less than a complete response. Significantly fewer granisetron patients were withdrawn than in the alizapride/dexamethasone group (P = 0.017) or the metoclopramide/dexamethasone group (P less than 0.0001). In both studies more comparator patients were withdrawn due to lack of efficacy and adverse events. Significantly fewer granisetron patients experienced adverse events than in either the alizapride/dexamethasone group (47.6% vs. 61.7%, P = 0.047) or the metoclopramide/dexamethasone group (60.8% vs. 77.3% P = 0.003). Granisetron patients experienced a significantly higher occurrence of constipation in both studies (10.7% vs. 3.2% and 12.6% vs. 2.8%). Headache and fever were also more frequent in the granisetron group, while extrapyramidal effects, reported by 5.3% of the alizapride/dexamethsone group and 20.6% of the metoclopramide/dexamethasone group, were not reported in any granisetron patients.
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PMID:Fractionated chemotherapy--granisetron or conventional antiemetics? The Granisetron Study Group. 132 Sep 16

After the synthetic serotonin 5-hydroxytryptamine (5-HT) became available in the early 1950s, attempts were soon under way to study the nature of 5-HT receptors. Using the guinea-pig isolated ileum, Gaddum and Picarelli (1957) suggested that 5-HT-induced contractions were mediated by a morphine-sensitive "M" receptor located on the parasympathetic ganglion and a dibenzyline-sensitive "D" receptor located on the smooth muscle. Though this classification ws used during the next three decades, it was realized that some effects of serotonin, for example vasoconstriction within the carotid vascular bed, were not mediated by either "M" or "D" receptors. When radioligand binding studies led to the identification of 5-HT1 and 5-HT2 "receptors" in the rat brain membranes, it became increasingly apparent that the two receptor classifications were not identical. Thus, a new framework for serotonin receptor nomenclature and classification was proposed: 5-HT1-like (5-HT1), 5-HT2 (formerly "D") and 5-HT3 (formerly "M") receptors. At the present time, several subtypes of 5-HT1 receptors as well as a 5-HT4 receptor are also recognized. As the serotonin receptor classification was emerging to indicate that carotid vasoconstriction by serotonin is mediated by a subtype of 5-HT1 receptors, on the migraine front it was being suggested that the disease is associated with vasodilation within the cranial extracerebral circulation and deranged serotonin metabolism and that certain antimigraine drugs caused a selective carotid vasoconstriction, probably via serotonin receptors. Therefore, Humphrey and colleagues conceived that synthesis of serotonin derivatives may lead to a compound that would elicit highly selective carotid vasoconstriction and abort migraine attacks. Indeed, via the synthesis of 5-carboxamidotryptamine and AH25086, sumatriptan was designed. The drug acts as an agonist at the vasoconstrictor 5-HT1 receptor subtype and has proved highly effective in the therapy of migraine attacks.
Cephalalgia 1992 Aug
PMID:From serotonin receptor classification to the antimigraine drug sumatriptan. 132

Neurogenic plasma extravasation, endothelial cell activation (increase in vesicle number and vacuole formation), platelet aggregation and adhesion, and mast cell degranulation occur selectively in post-capillary venules of the dura mater following electrical trigeminal ganglion stimulation, and are mediated by release of neuropeptides from perivascular unmyelinated C fibres. Pre-treatment with the antimigraine drugs dihydroergotamine and sumatriptan, two drugs that bind with high affinity to 5-HT1B/1D receptors, markedly attenuated plasma protein extravasation induced by electrical trigeminal ganglion stimulation. Trigeminal stimulation increased plasma calcitonin gene-related peptide levels in rat superior sagittal sinus. Pre-treatment with dihydroergotamine and, to a lesser extent, sumatriptan, attenuated this increase. Both drugs reduced morphological changes in post-capillary venules and mast cells within dura mater following electrical trigeminal ganglion stimulation. Plasma protein extravasation was selectively blocked in dura mater (but not in extracranial tissues) by pre-treatment with those receptor agonists showing a rank order of potency suggesting a 3-HT1B/1D interaction (5-CT greater than 5-BT greater than DHE greater than sumatriptan greater than 8-OH-DPAT). Pre-treatment with 5-HT2 and 5-HT3 antagonists was not effective. Taken together, these data are consistent with the interpretation that putative 5-HT-1B/1D receptors located on sensory fibres are coupled to inhibition of peptide release and blockade of neurogenic inflammation. An important therapeutic action of ergot alkaloids and sumatriptan in migraine headaches is so defined.
Cephalalgia 1991 Sep
PMID:Evidence for 5-HT1B/1D receptors mediating the antimigraine effect of sumatriptan and dihydroergotamine. 166 Mar 51

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 chemistry, pharmacokinetics, adverse effects, stability, compatibility, and dosage of ondansetron hydrochloride are described, and clinical studies of the use of ondansetron for the prophylaxis of nausea and vomiting induced by antineoplastic therapy are reviewed. Ondansetron hydrochloride is a specific antagonist of serotonin type 3 (5-HT3) receptors, both in the chemoreceptor trigger zone and in the GI tract. Peak plasma concentrations of ondansetron occur approximately one hour after an oral dose and 6 to 20 minutes after an i.v. dose. The mean elimination half-life is approximately 3.5 hours in healthy volunteers, but it is extended in elderly patients (mean of 7.9 hours). In clinical trials, ondansetron has been shown to provide excellent control of nausea and vomiting in patients treated with cisplatin. Comparisons of ondansetron with metoclopramide in patients treated with various types of chemotherapy have shown better response rates with ondansetron. Ondansetron has also been shown to be effective in controlling nausea and vomiting in patients receiving cyclophosphamide with an anthracycline and in patients receiving combination therapy with cyclophosphamide, methotrexate, and fluorouracil. Adverse effects appear to be mild and include headache, constipation, diarrhea and transient abnormalities in liver function tests. The dose of ondansetron (as the hydrochloride salt) for the prophylaxis of chemotherapy-induced nausea and vomiting in adults is 0.15 mg/kg i.v. every four hours for three doses, beginning 30 minutes before antineoplastic therapy. The efficacy of ondansetron is comparable to that of metoclopramide, and the adverse-effect profile is much less problematic. The cost of ondansetron is much higher than that of metoclopramide; thus its use should be limited to patients at high risk for metoclopramide-induced adverse effects and patients in whom metoclopramide is ineffective.
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PMID:Ondansetron--the first of a new class of antiemetic agents. 182 68

Ondansetron is a selective 5-HT3 antagonist with significant antiemetic properties in patients receiving cytotoxic chemotherapy. Patients who had suffered severe vomiting on carboplatin alone (23 patients with ovarian carcinoma) or in combination (two patients with testicular cancer) despite intensive antiemetic regimens were treated with ondansetron, given as 8 mg immediately prior to carboplatin followed by 8 mg orally, 8 hourly for 5 days. Twenty-five patients received 58 courses of ondansetron. In the first 24 h after the first course of chemotherapy with ondansetron, 17 patients (68%) experienced no vomiting, five patients (20%) had almost complete control and the other three patients had partial control. During the subsequent 4 days slightly lesser control was achieved. Nausea was similarly controlled in most patients. Twenty-two patients stated a preference for ondansetron with future chemotherapy. Fourteen patients received additional chemotherapy with ondansetron and in only three patients did the efficacy of therapy lessen. Toxicity was mild and transient with headache and constipation predominant. No extrapyramidal reaction was seen. Sedation was absent. Ondansetron is highly effective in refractory vomiting associated with carboplatin chemotherapy. It may be particularly beneficial when an extrapyramidal reaction has occurred on previous antiemetics and when sedation is unacceptable.
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PMID:Reduction of carboplatin induced emesis by ondansetron. 182 54

Preparation for bone marrow transplantation (BMT) uses the extremely emetogenic combination of chemotherapy and total body irradiation (TBI). Ondansetron is a selective 5-HT3 antagonist and has clear anti-emetic capabilities. The efficacy of the drug was assessed in 15 children (aged 2-17 years) who received high dose cyclophosphamide (on days -6 and -5) and TBI (days -3 to 0 inclusive). During days -6 to -4 when the emetic effect of cyclophosphamide would be most pronounced, 12 of the 15 patients (80%) had fewer than five emetic episodes during their worst 24-h period, 11 (73%) had fewer than three vomits whilst nine (60%) experienced no vomiting or retching. Eleven patients progressed to TBI and 10 (91%) had fewer than five emetic events in the worst 24-h period (days -3 to +2), six (55%) had no vomiting at all. Of 100 evaluable 'patient-days' 83 (83%) were without any vomiting or retching and a further 10 'patient-days' had only one or two emetic episodes. There were no significant side-effects noted and in particular no extrapyramidal reactions. Headaches and constipation, which have been seen in adult studies, were not reported by patient or parent on any of the study days and transient elevation of liver enzymes were noted in only two patients. Ondansetron has a major role in preparing patients for BMT.
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PMID:Effective emetic control during conditioning of children for bone marrow transplantation using ondansetron, a 5-HT3 antagonist. 183 95

Ondansetron represents a new class of drugs that exert their antiemetic activity by selective inhibition of a serotonin receptor subtype (5-HT3). Ondansetron has marked activity against emesis associated with cisplatin and other highly emetogenic drugs. Compared with high doses of metoclopramide, the antiemetic "gold standard," it demonstrates equal or superior efficacy. Although ondansetron is moderately well absorbed after oral administration, only a parenteral formulation will initially be available. Ondansetron is eliminated almost entirely by hepatic metabolism; less than five percent of an intravenously administered dose is recovered intact in urine. The half-life of ondansetron is approximately 3.5 hours; slightly shorter in children and prolonged in the elderly. Neither clinical efficacy nor adverse effects have correlated with serum concentrations. Ondansetron is generally well tolerated. Clinically relevant adverse effects include headache, diarrhea or constipation, sedation, and transient minor elevations of liver function tests. It is not associated with extrapyramidal reactions. Ondansetron is indicated as prophylaxis for nausea and vomiting associated with emetogenic chemotherapy. Studies to further evaluate and define its use are ongoing.
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PMID:Ondansetron: a serotonin receptor (5-HT3) antagonist for antineoplastic chemotherapy-induced nausea and vomiting. 183 88

The efficacy and safety of two dose schedules of the 5-HT3 antagonist ondansetron (Zofran) were studied in 35 patients (group A: 19 patients, group B: 16 patients) previously refractory to standard antiemetics after non-cisplatin-based chemotherapy (greater than 5 emetic episodes). The maintenance of the antiemetic efficacy of ondansetron was further studied in 28 patients (13 A, 15 B) in respectively 36 and 48 retreatment courses. Ondansetron was administered as an 8 mg loading dose (A: 4 mg i.v. + 4 mg orally; B: 8 mg i.v.), followed by oral treatment for 5 days (A: 6-hourly; B: 8 mg 8-hourly). In the first treatment cycle acute emesis was completely controlled in 53% of the patients in group A and in 50% of the patients in group B. Delayed emesis was absent in 75% and 38% of the patients in group A and B respectively. In a second treatment cycle acute antiemetic control was achieved in 54% and 53% of the patients in group A and B respectively. Over the third and fourth subsequent treatments, complete control occurred in 56% and 38% of the patients in group A, and in 46% and 56% of the patients in group B respectively. Delayed emesis did not occur over the following courses in 62%, 89% and 75% of the patients on regimen A, in 57%, 60% and 63% of the patients on regimen B. The observed adverse effects were headache (37%) and constipation (42%). No extrapyramidal reactions were seen. Ondansetron is able to re-establish an acceptable antiemetic control in previously refractory patients on non-cisplatin-based chemotherapy, without major toxicity. This efficacy is maintained over the three following retreatment courses.
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PMID:The 5-HT3 receptor antagonist ondansetron re-establishes control in refractory emesis induced by non-cisplatin chemotherapy. 183 61


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