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)

Tropisetron is a novel selective antagonist of the type-3 serotonin (5-HT3) receptor, with proven efficacy in the control of emesis related to cancer treatment. Epirubicin in doses of > 100 mg/m2 has a high emetogenic potential. This study was designed to determine whether a single intravenous administration of tropisetron could prevent acute nausea and vomiting in patients treated with high dose epirubicin. Forty chemotherapy naive breast cancer patients treated with epirubicin at a dose of 110 mg/m2 on an outpatient basis were enrolled in the study. Tropisetron 5 mg i.v. was used as antiemetic prophylaxis. "On demand" treatment with tropisetron 5 mg p.os was used for the rescue of patients who failed on the initial i.v. dose. Complete control of acute nausea and vomiting had 62.5% (95% C.I. 47.2-77.8), partial control 15% (95% C.I. 3.8-26.2) and 22.5% (95% C.I. 9.3-35.7) insufficient control or failure. Headache was the most common adverse event reported in 3 patients (7.5%) and constipation in 2 patients (5%). Interestingly, patients with a negative experience of nausea and vomiting during pregnancy and those treated for metastatic disease, had a better control of chemotherapy-induced nausea and vomiting. In conclusion, a single 5 mg i.v. dose of tropisetron is safe and effective in preventing acute emesis in patients treated with high dose epirubicin.
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PMID:Tropisetron in the prevention of acute nausea and vomiting in patients treated with high dose epirubicin. 964 36

Tropisetron (Navoban") suppresses nausea and vomiting induced by cancer chemotherapy by antagonizing central and peripheral 5-HT3 receptors. In this open-label study, tropisetron was evaluated in 873 patients who were either refractory to antiemetic treatment during previous chemotherapy or at high risk of emesis as a result of current chemotherapy. The most commonly used agents alone or in combination were cyclophosphamide (35%), fluorouracil (30%), carboplatin (24%) and cisplatin (21%). The primary tumors were breast cancer (27%), lung cancer (16%), gynecological cancers (12%) and lymphoma (9%). Tropisetron was administered as a 15 min infusion prior to chemotherapy and an additional oral 5 mg dose was taken by 80% of the patients on subsequent days. During course 1, complete response to tropisetron was obtained in 64% of patients on day 1, 54% on day 2, 63% on day 3, 71% on day 4 and 77% on day 5. Very similar response rates were found for the six chemotherapy courses. There were few failures after complete and partial response, at maximum 3 and 15%, respectively. Moreover, 24-38% of those with partial response and 7-29% of those with failure could achieve a complete response during the following cycle. The treatment was well tolerated, the most frequently reported adverse events being constipation (3.7%) and headache (2.6%).
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PMID:Tropisetron in the prevention of acute and delayed nausea and vomiting over six courses of emetogenic chemotherapy. 984 Jul 22

Serotonin receptors are highly heterogeneous and they have been regrouped within seven different families (5-HT1-5-HT7). With the exception of the 5-HT3 which is a ligand-gated ion channel, all others are G-protein coupled receptors with each family sharing structural, pharmacological and transductional characteristics. 5-HT receptors have been implicated in the regulation of several psychiatric and neurological disorders related to serotonergic neurotransmission, and specific receptor subtypes have recently been associated with either the pathogenesis or the treatment of migraine headache. In this respect, activation of vascular 5-HT2B and/or 5-HT7 receptors, possibly as a consequence of the sudden rise in 5-HT levels reported at the onset of a migraine attack, would hypothetically result in dilation of cerebral blood vessels and concomitant activation of sensory trigeminovascular afferents, hence initiating the manifestation of head pain. At this stage in the migraine process, activation of specific subtypes of 5-HT1 receptors has proven clinically effective in relieving migraine pain. Neural 5-HT1D and/or 5-HT1F receptors localized pre-junctionally on trigeminovascular afferents appear to mediate the triptan-induced inhibition of the neurogenic inflammatory response, with possible additional sites of action for brain penetrant 5-HT1 receptor agonists in inhibiting the transmission of pain centrally. In contrast, activation of vascular 5-HT1B receptors would constrict meningeal vessels hence recovering their pre-migraine diameter. The recent availability of subtype selective 5-HT1D and 5-HT1F receptor agonists should allow a further test of the neural/vascular hypothesis and could possibly lead to antimigraine drugs with a safer cardiovascular profile.
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PMID:The biology of serotonin receptors: focus on migraine pathophysiology and treatment. 1056 26

5-HT3-receptor antagonists are potent and highly selective competitive inhibitors of the 5-HT3-receptor with negligible affinity for other receptors. They are rapidly absorbed and penetrate the blood-brain barrier easily. 5-HT3-receptor antagonists are metabolized by diverse subtypes of the cytochrome P450-system, metabolites are excreted mainly in urine. Half-lifes in healthy subjects vary from 3-4 hours (ondansetron, granisetron) to 7-10 hours (tropisetron, hydrodolasetron). 5-HT3-receptor antagonists do not modify any aspect of normal behaviour in animals or induce remarkable changes of physiological functions in healthy subjects. They are well tolerated over wide dose ranges, most common side effects in clinical use are headache and obstipation. Clinical efficacy was first established in chemotherapy-induced emesis. In this indication, 5-HT3-receptor antagonists set a new standard regarding efficacy and tolerability. Further established indications are radiotherapy-induced and post-operative emesis. Antiemetic efficacy results from a simultaneous action at peripheral and central 5-HT3-receptors. Other peripheral actions include reduction of secretion and diarrhea caused by increased intestinal serotonin content (e.g. in carcinoid syndrome), a limited antiarrhythmic activity and a reduction of experimentally induced pain. CNS effects comprise anxiolysis, attenuation of age-associated memory impairment, reduction of alcohol consumption in moderate alcohol abuse and an antipsychotic effect in patients with parkinson psychosis. In migraine, 5-HT3-receptor antagonists show moderate efficacy, as well. Repeatedly demonstrated efficacy of 5-HT3-receptor antagonists in patients suffering from fibromyalgia raises the question for the mechanism of action involved. Ligand binding at the 5-HT3-receptor causes manifold effects on other neurotransmitter and neuropeptide systems. In particular, 5-HT3-receptor antagonists diminish serotonin-induced release of substance P from C-fibers and prevent unmasking of NK2-receptors in the presence of serotonin. These observations possibly provide an approach for the causal explanation of favourable treatment results with 5-HT3-receptor antagonists in fibromyalgia.
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PMID:Preclinical and clinical pharmacology of the 5-HT3 receptor antagonists. 1102 30

The 5-HT3 receptor antagonists are a novel therapy for patients suffering from fibromyalgia, although the optimal duration of treatment is still unclear. The objective of this phase II study was to evaluate whether prolonging treatment with tropisetron to 4 weeks is tolerable and correlated with an improved clinical benefit. Thirty female patients with fibromyalgia received oral tropisetron (5 mg) daily for 28 days in an open-label fashion. Treatment resulted in significantly decreased pain as measured by visual analog scale (VAS), with a mean reduction of 59.7% and an absolute median change of -25.0 from baseline to day 28 (p<0.0001). A similar, significant reduction of 55.7% and absolute median change of -31.0 was observed in the painscore (p<0.0001). The response rate with patients showing a > or = 35% reduction in individual pain scores was 72.4% at day 28. The pressure tolerance of tender-points was slightly increased at the end of the treatment period. In addition, significant improvements were observed in the State-Trait-Anxiety-Inventory (STAI), scales of von Zerssen (Bf-S) and Beck Depression Index (BDI). Functional symptoms were compared with the results from a 10-day, randomized, double-blind phase III study of tropisetron in 418 fibromyalgia patients. In both studies several functional symptoms such as sleep disturbances and dizziness improved significantly (p<0.05). In the 28 days study, the number and extent of improvement in functional symptoms was increased compared with the shorter trial. Tolerability and safety of tropisetron was good, and typically for 5-HT3-receptor antagonists, gastrointestinal symptoms and headache were the most frequently reported events. In conclusion, 28 days treatment of fibromyalgia patients with 5 mg tropisetron resulted in significant pain reduction, which was most pronounced after 10 days with a further reduction up to day 28. Psychometric tests showed significant improvements in depression and anxiety state scores, while functional symptoms improved with extended tropisetron treatment.
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PMID:Oral treatment of fibromyalgia with tropisetron given over 28 days: influence on functional and vegetative symptoms, psychometric parameters and pain. 1102 33

Sumatriptan succinate (SMT) was a highly specific 5-HT1-receptor agonist. It showed high affinity only for 5-HT but no affinity for other neurotransmitter receptors such as muscarinic, dopamine D1, D2, adrenergic alpha 1, alpha 2, and beta. Furthermore, it was highly selective for 5-HT1B/1D-receptor and showed no affinity for 5-HT2 and 5-HT3 receptors. SMT contracted isolated cranial arteries such as basilar, midcerebral, temporal arteries and large arteries in the dura matter, but did not contract coronary, femoral, mesenteric and other arteries. Reflecting these results, SMT induced vasoconstriction of carotid artery, but produced practically no contractile responses in the other arteries mentioned above in anaesthetized animals. These pharmacological characteristics of SMT were different from those of ergot alkaloids, current anti-migraine drugs, which contracted coronary, femoral and other arteries as well. SMT inhibited neurotransmitter release, including CGRP, from trigeminal nerve terminals. Consequently protein extravasation induced by CGRP was inhibited and neurogenic inflammation could be suppressed. It was believed that SMT showed its anti-migraine activity through cranial vasoconstriction via 5-HT1B/1D receptors, since it did not show any analgesic activities. Its clinical efficacy on migraine and cluster headache had been already confirmed in about 100 western countries. Its efficacy was also shown by open trials and placebo controlled double blind tests in Japan.
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PMID:[Anti-migraine drug sumatriptan succinate, a 5-HT1B/1D-receptor agonist]. 1143 16

Cluster headache is a rare and severe pain syndrome with elusive pathophysiology. Serotonin pathways within the brainstem may be implicated in cluster headache with seasonal affective disorder and a subset of cranial nerve neuralgias. We describe and chronicle a syndrome consisting of cluster headache, seasonal affective disorder, with associated trigeminal, glossopharyngeal, superior laryngeal neuralgias in an 11-year-old female. Pharmacologic interventions for this patient were examined in conjunction with current classification, location and function of serotonin receptors. Etiology is postulated as mixed cranial nerve excitation via endogenous 5-HT (agonist) activity of 5-HT3 receptors within the nucleus tractus solitarius and trigeminal tract nucleus.
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PMID:Serotonin mediated cluster headache, trigeminal neuralgia, glossopharyngeal neuralgia, and superior laryngeal neuralgia with SAD chronicity. 1157 58

The purpose of this study was to evaluate the effectiveness of three 5-HT3 antagonists in routine clinical practice. The ultimate aim was to develop an antiemetic protocol, selecting a single 5-HT3 antagonist. Each of the drugs was studied for a 4-month period and data was collected from patients on nausea, vomiting (both acute and delayed) and side-effects by means of a diary card. A total of 274 patients were enrolled into the study. Success rates for acute emesis seen over the study period were in excess of 90%. There were no statistically significant differences between any of the three drugs investigated with respect to both acute and delayed nausea and vomiting. Similarly, there was no difference between the three groups for the incidence of constipation, diarrhoea and headache. Granisetron demonstrated a lesser deviation from the protocol in respect of the number of intravenous doses given to patients. The study allowed an effective 5-HT3 antagonist protocol to be developed for use in the management of nausea and vomiting in cancer patients.
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PMID:The development of a protocol for the use of 5-HT3 antagonists in chemotherapy-induced nausea and vomiting. 1182 78

Several 5-HT3 receptor antagonists are available (tropisetron, ondansetron, granisetron, dolasetron, and palonsetron), and further compounds are in clinical development. These substances show only minor differences in the activity profile regarding their affinity for particular receptors. 5-HT3 receptor antagonists are primarily used and found effective in the prevention and treatment of chemotherapy-induced nausea and emesis, and in postoperative nausea and vomiting (PONV). Antagonism of the 5-HT3 receptors in the peripheral and central nervous system is a probable mechanism of action. The substances are suitable as first-line therapy (combined with a corticosteroid) for the prevention of acute nausea and vomiting in patients treated with moderately to severely emetogenic chemotherapeutic agents. This combination is also moderately effective in the prevention of delayed nausea and vomiting. 5-HT3 receptor antagonists are an important constituent in the prevention and treatment of emesis and nausea caused by radiation therapy, especially in patients receiving whole body or upper abdominal treatment. Alosetron was found clinically effective in diarrhoea-predominant irritable bowel syndrome, whereas tropisetron in fibromyalgia and related pain disorders. Further indications for such treatment include anxiety disorders, alcohol dependence, drug withdrawal, and psychosis related to treatment of Parkinson's disease. 5-HT3 receptor antagonists are well tolerated with the most frequently reported adverse effects being headache, constipation, dizziness, tiredness, and gastrointestinal disturbances such as abdominal pain or constipation. Intravenous administration of serotonin induces the Bezold-Jarisch reflex and causes small reversible changes in electrocardiogram (ECG) parameters.
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PMID:Spectrum of use and tolerability of 5-HT3 receptor antagonists. 1551 6

We investigated the effect of serotonergic agonists and antagonists injected intrathecally by direct punction of the spinal cord at the lumbar level (between L5-L6) on peripheral inflammatory edema. Edema was induced by carrageenan injected subcutaneously in one hindpaw 30 min after spinal treatments. Serotonin (0.1, 1, 10 pmol) caused a graded-inhibition of the inflammatory paw edema. The corticosteroid inhibitor aminoglutethimide (100 mg/kg, p.o. 1.5 h before spinal treatment) did not modify this effect. The 5-HT1A agonist buspirone and the 5-HT1B/1D agonist sumatriptan (0.1, 1.0 and 10 nmol) also inhibited paw edema. The 5-HT1,2 antagonist methysergide (10 and 100 pmol) enhanced edema, but higher doses ( 4 and 8 nmol) diminished edema. NAN-190 (5-HT1 antagonist; 1 and 10 nmol) increased paw edema, while ritanserin (5-HT2 antagonist; 1 nmol) inhibited paw edema. Ondansetron (5-HT3 antagonist; up to 10 nmol) did not affect edema, but metoclopramide (5-HT3 antagonist / 5-HT4 agonist; 5, 10 and 30 pmol) inhibited edema. These data suggest that a tonic release of serotonin in the spinal cord may occurs during ongoing peripheral inflammation, modulating the neurogenic component of edema either by an inhibitory action on 5-HT1 receptors or by a stimulatory action on 5-HT2 receptors. A disfunction in such mechanism may be involved in the pathophysiology of certain types of headaches or migraine, which seem to depend on neurogenic vasodilation, and may also help to explain the therapeuthic effectiveness of some serotonergic agents in these conditions.
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PMID:Evidence for a spinal serotonergic control of the peripheral inflammation in the rat. 1574 28


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