Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027497 (nausea)
 23,468 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Depression is a heterogeneous disease state characterised by complex alterations in several CNS neurotransmitter and receptor systems. All antidepressants are thought to act by causing postsynaptic adaptive changes (e.g. in transducers or second messengers) within these systems. Thus, the mechanism of action of selective serotonin reuptake inhibitors (SSRIs) cannot simply be explained in terms of inhibition of serotonin (5-hydroxytryptamine) [5-HT] reuptake. Fluvoxamine, sertraline and fluoxetine downregulate central beta-adrenoceptors, and all SSRIs are believed to normalise central 5-HT1A- and 5-HT2-receptor density and function in patients with depression. SSRIs are as effective as tricyclic antidepressants in the treatment of depression, but have distinct tolerability advantages--they are not associated with anticholinergic adverse effects, cardiotoxicity, sedation or weight gain. However, gastrointestinal reactions (e.g. nausea, diarrhoea/loose stools, constipation) are relatively common during SSRI therapy. Additionally, in contrast to tricyclic antidepressants, SSRI dosage adjustments appear to be unnecessary in elderly depressed patients. Fluvoxamine has a much shorter elimination half-life than fluoxetine and its active metabolite, norfluoxetine, and therefore a reduced potential for drug interactions. Only small amounts of fluvoxamine and fluoxetine, but large quantities of paroxetine, are secreted in breast milk. Furthermore, genetic polymorphism has not been documented for fluvoxamine metabolism, whereas slow and fast metabolisers of paroxetine, and fast metabolisers of fluoxetine have been identified. SSRIs have a better tolerability profile than tricyclic antidepressants, as indicated by lower mean rank scores for behavioural toxicity. Moreover, SSRIs are associated with a much lower incidence of fatal toxicity than tricyclics, and appear to be relatively safe in overdosage.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pharmacological differences of serotonin reuptake inhibitors and possible clinical relevance. 137 71

Serotonin (5-hydroxytryptamine; 5-HT) is found in the enteric nervous system where it has been implicated in controlling gastrointestinal motor function. A number of receptor or recognition sites have been identified in the gut, but recently most attention has focused on the 5-HT3 and 5-HT4 receptors. The functional role of the 5-HT3 receptor remains incompletely understood, but it is probably involved in the modulation of colonic motility and visceral pain in the gut. A number of selective 5-HT3 antagonists have been developed including ondansetron, granisetron, tropisetron renzapride and zacopride. While the substituted benzamide prokinetics (for example, metoclopramide, cisapride) also block 5-HT3 receptors in high concentrations, their prokinetic action is believed to be on the basis of their agonist effects on the putative 5-HT4 receptor. Some 5-HT3 antagonists have 5-HT4 agonist activity (for example, renzapride, zacopride) and others do not (for example, ondansetron, granisetron), while tropisetron in high concentrations is a 5-HT4 antagonist. Based on the pharmacological data, it has been suggested that specific 5-HT antagonists and agonists may prove to be beneficial in a number of gastrointestinal disorders including the irritable bowel syndrome, functional dyspepsia, non-cardiac chest pain, gastrooesophageal reflux and refractory nausea. In this review, the rationale for the use of these compounds is discussed, and the available experimental evidence is summarized.
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PMID:Review article: 5-hydroxytryptamine agonists and antagonists in the modulation of gastrointestinal motility and sensation: clinical implications. 160 46

Radiotherapy-induced emesis is poorly controlled with existing antiemetics. 5-Hydroxytryptamine (5HT3) receptor antagonists are a new class of antiemetics which have been demonstrated to be effective in controlling cytotoxic-induced emesis. We have prospectively studied the antiemetic efficacy of the 5HT3 receptor antagonist granisetron in an open non-randomized efficacy and toxicity study, at two dose levels, in patients receiving lower hemibody radiotherapy for multiple bone metastases. Of the 22 patients studied, 13 patients received 20 micrograms/kg and nine patients 40 micrograms/kg of granisetron, administered as an intravenous infusion 1 h before radiotherapy. Radiotherapy was administered as a single exposure to the lower half body to a midline dose of 8 Gy. A complete response (no nausea or vomiting) was observed in 9/13 patients at the lower dose level and 6/9 patients at the higher level. No major adverse events were recorded. We conclude that granisetron is a well-tolerated and effective antiemetic agent in radiotherapy-induced emesis. Formal comparison with conventional antiemetic agents in this situation is required.
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PMID:The antiemetic effect of granisetron in lower hemibody radiotherapy. 165 14

The efficacy and tolerability of the selective 5-HT reuptake inhibitor fluvoxamine were compared with the tricyclic dothiepin in 52 elderly (age greater than 64 years) hospital patients in a multi-centre double-blind randomised trial. Patients met DSM-III criteria for 'major depressive episode' and scored greater than 29 on the Montgomery Asberg Depression Rating Scale (MADRS) after a one-week placebo baseline. Active treatment was for six weeks. The dosage of both drugs was 50 mg nocte for three days, 100 mg nocte for the remainder of the first week, thereafter increasing to a maximum of 200 mg/day according to response/tolerance. MADRS scores improved by 63.5% with fluvoxamine and 60.0% with dothiepin; there were no significant differences between treatments at any assessment. Nausea, dizziness, headache, somnolence and constipation in both groups, plus dry mouth and asthenia in the dothiepin group were more frequent than single reports. Two patients in each group discontinued treatment owing to unwanted effects. There were no clinically significant changes in haematological, biochemical or cardiovascular parameters.
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PMID:A double-blind, randomised comparison of fluvoxamine with dothiepin in the treatment of depression in elderly patients. 181 Mar 58

Paroxetine is a novel antidepressant drug with selective serotonin (5-HT) reuptake inhibitory properties. In a double-blind placebo-controlled crossover sleep laboratory study the single-dose effects on objective and subjective sleep and awakening qualities were investigated after paroxetine 20, 30 and 40 mg morning doses (PX 20, 30, 40), paroxetine 30 mg evening dose, fluoxetine 40 mg morning dose (FX 40) and placebo in 18 healthy young volunteers. The drugs were orally administered in 2-wk intervals. In addition to each drug night, the adaptation night and washout night were recorded. Polysomnographic investigations (10:30 p.m. to 6:00 a.m.) showed a delayed sleep onset only after the morning intake of paroxetine, PX 40 being statistically different from placebo. Total sleep time and sleep efficiency deteriorated under morning PX 30, PX 40 and evening PX 30 as compared to placebo. The nocturnal wake time and sleep stage 1 increased under the paroxetine. Rapid eye movement (REM) reduction (min and %) occurred dose dependently after all paroxetine doses, but the REM latency was lengthened only after the morning intake. The suppressant effect on REM sleep is characteristic for antidepressants and was still significant in the washout nights following PX 40 and evening PX 30. The only statistically relevant finding under 40 mg fluoxetine referred to the increase of REM latency in both drug and washout nights. In contrast to objective results, subjective sleep quality remained generally unchanged. Attention, concentration and reaction performance improved under paroxetine as compared to baseline. The deterioration of well-being under PX 40 might be related to the appearance of drowsiness and nausea. Blood pressure and pulse rate were unaffected.
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PMID:Sleep laboratory studies on the single-dose effects of serotonin reuptake inhibitors paroxetine and fluoxetine on human sleep and awakening qualities. 183 94

In those subjects genetically susceptible to migraine, biological rhythms or excessive afferent stimulation trigger an episodic neurovascular reaction with focal neurological symptoms, headache and nausea as its most common manifestations. Mood changes and a craving for sweet foods point to a preliminary hypothalamic disturbance. The referral of ice-cream headache and ice-pick pains to the habitual site of migraine headache (even in the intervals between attacks) indicate defective control of trigeminal pathways. Laboratory experiments have demonstrated that projections from the brainstem, releasing monoamines and peptides as transmitter agents, can mimic the vascular changes of migraine. Serotonin released from platelets may sensitize vessels to respond to distension by generating pain-producing afferent discharges. Central depletion of monoamines can accentuate the perception of pain by reducing the efficacy of the endogenous pain control system. The intravenous injection of serotonin relieves migraine headache but produces side-effects. A new drug, sumatriptan, acting on a subtype of serotonin receptors, the 5HT1-like receptor, is undergoing clinical trial for the relief of acute attacks of migraine. Antagonist of the 5HT2 receptor are beneficial in interval therapy for the prevention of migraine. Increased knowledge of physiological mechanisms and neurotransmitters that can mediate the various components of the migraine attack opens the way for improvements in pharmacotherapy.
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PMID:[Physiopathology of migraine]. 196 76

Neuronal 5-hydroxytryptamine3 (5-HT3) receptors mediate the excitatory effects of 5-HT. They are located in pain- and nausea-modulating areas in the central nervous system and on C-fibre primary afferents in the peripheral nervous system. Consequently, these receptors mediate the painful and emetic effects of 5-HT. Selective and potent 5-HT3 receptor antagonists have been shown to block inflammatory and 5-HT induced and potentiated "vascular pain". Based on the hypothesis that 5-HT3 receptor antagonists may block neurogenic dural inflammation in the distribution area of the trigeminal nerve and, thus, could potentially prevent migraine (pain), four highly selective and potent 5-HT3 receptor antagonists have been tested in both the acute and prophylactic treatment of migraine. Unfortunately, except for a clear anti-emetic effect, none of these drugs has shown unequivocal efficacy in the treatment of migraine. This may be partly due to the complex (bell-shaped) dose-response relationship of these compounds, making exact titration of the correct dose difficult. Moreover, most 5-HT3 receptor antagonists have proved to be toxic in man on chronic administration thereby preventing further trials in migraine with adjusted doses. Short-term treatment for cytotoxic drug-induced emesis so far appears to be the only proven indication for 5-HT3 receptor antagonists.
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PMID:5-HT3 receptor antagonists and migraine therapy. 204 32

Seventy-five breast cancer patients scheduled to receive a first course (in a new cycle) of cyclophosphamide, fluorouracil, and doxorubicin (FAC) or epirubicin (FEC) participated in a double-blind crossover study to compare the antiemetic efficacy and safety of ondansetron (GR38032), a 5-hydroxytryptamine3 (5-HT3) receptor antagonist, and metoclopramide. Ondansetron was given as an 8 mg loading dose (4 mg intravenously [IV] plus 4 mg orally) before chemotherapy followed by 8 mg every 8 hours orally for 3 to 5 days. Metoclopramide was given as an 80 mg loading dose (60 mg IV plus 20 mg orally) before chemotherapy followed by 20 mg every 8 hours orally for 3 to 5 days. A "period" interaction in the analysis of emetic response in the first 24 hours necessitated a parallel group analysis of first treatments only, 68 patients being assessable for this parameter. In the first 24 hours, complete or major control (zero to two emetic episodes) of emesis was achieved in 30 of 35 (86%) patients receiving ondansetron and in 14 of 33 (42%) patients receiving metoclopramide (P less than .001). Ondansetron was also more effective in reducing acute nausea. On days 2 to 3, the complete or major responses were significantly better with ondansetron (81% v 65%; P = .033), but there was no statistical difference in the control of nausea. There was a significant patient preference for ondansetron (63% v 26%; P = .001). Extrapyramidal reactions were observed in two metoclopramide treatments; both treatments were otherwise well tolerated. These results are consistent with serotonin (5-HT), being a significant neurotransmitter of cyclophosphamide/doxorubicin- or epirubicin/fluorouracil-induced emesis.
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PMID:A randomized double-blind comparison of ondansetron and metoclopramide in the prophylaxis of emesis induced by cyclophosphamide, fluorouracil, and doxorubicin or epirubicin chemotherapy. 214 Aug 54

Emesis in chemotherapy containing Cisplatinum (DDP) is still a therapeutical dilemma. Emesis and nausea cause the cessation of a potential curative therapy in up to 10% of patients treated with DDP. We studied the antiemetic effectiveness of the selective Serotonin (5HT3)-receptor-antagonist Ondansetron (GR 38032F, Glaxo) in patients receiving high dose platinum chemotherapy. All patients suffered from severe emesis and were refractory to any standard antiemetic regimen (Metoclopramid). We studied the efficacy of the new drug against acute and delayed emesis following platinum chemotherapy. All adverse events are listed. Thirty four courses (n = 17 patients) of a platinum-containing regimen were analyzed so far. A sufficient antiemetic efficacy was observed in 56% of the courses. In 32 of 34 course (94%) the patients preferred the new drug compared with the standard antiemetic regime (Metoclopramid). In most cases only minor adverse events--which do not require any medical therapy--occurred. The most common adverse events were headache, constipation, dry mouth, abdominal discomfort and elevation of liver enzyme level without any clinical symptoms. One patient needed bowel surgery for severe constipation based on widespread intra-abdominal carcinosis.
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PMID:[Refractory vomiting with cisplatin therapy. Prospective study with the serotonin receptor antagonist GR 38032F]. 215 May 51

Three major areas of medicine are identified in which there is a need for new antiemetic drugs. These are the nausea and vomiting arising from gastrointestinal motility disturbances (functional dyspepsia, diabetic neuropathy, classical migraine), the sickness evoked by abnormal motion, and the severe emesis experienced by cancer patients as a result of certain cytotoxic therapies. For gastrointestinal-related nausea, selective stimulants of gut motility are suggested to form the basis for a new type of antiemetic therapy. In motion sickness, there has been progress in the understanding of the illness, but little advance in the development of new drugs that selectively prevent this type of sickness. In cancer chemo- and radio-therapy, the discovery that selective 5-HT3 (5-HT, 5-hydroxytryptamine) receptor antagonists can prevent severe cytotoxic-evoked emesis now promises to radically change the type of antiemetic therapy given to these patients. This type of antiemetic compound and the pharmacology of the new 5-HT3 receptor antagonists are, therefore, discussed in detail.
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PMID:New antiemetic drugs. 217 55


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