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)

We have evaluated the analgesic effect of continuous intrathecal administration of midazolam in 4 patients using a three-level score (no change, amelioration, and marked improvement). The secondary effects of this drug were also investigated (sedation, nausea, vomiting, respiratory depression, urinary retention, motor dysfunction). In one patient midazolam was the only drug administered, whereas in three patients this drug was associated with morphine. In one patient with a peripheral arteriopathy, midazolam at a dose of 12 mg/day was unable to equal the analgesic effect achieved with 0.4 mg of morphine. The remaining three patients had carcinoma and received a continuous intrathecal perfusion of morphine at increasing daily doses up to 12; 4,8; and 6 mg/day, respectively without pain relief. In these patients the association of midazolam at respective doses of 9; 4-8; and 6 mg/day induced amelioration in one patient and marked improvement in the two other patients. Midazolam did not change the heart rate, respiratory rate, arterial blood pressure, nor body temperature. We believe that the analgesic effect of intrathecal administration of midazolam is due to its coupling with the ionophore complex GABA-spinal benzodiazepine that in turn produces an increment of the GABA amino butyric acid at this level.
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PMID:[Intrathecal administration of morphine, midazolam, and their combination in 4 patients with chronic pain]. 159 51

Monoamine oxidase inhibitors (MAOIs) are being used more frequently in the treatment of various psychiatric and neurological disorders. Although adverse effects of MAOI treatment are widely known, withdrawal symptoms are less well known. They include nausea, sweating, palpitations, nightmares, and psychosis. Withdrawal reactions from combination therapy with an MAOI and another agent are seldom described. Reported here is the occurrence of myoclonic seizures after the abrupt discontinuation of phenelzine and alprazolam. Alterations in the GABA and serotonin neurotransmitter systems as a result of withdrawal of the MAOI and the benzodiazepine may account for the seizures.
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PMID:Myoclonic seizures after abrupt withdrawal from phenelzine and alprazolam. 380 75

Activation of supraspinal gamma-aminobutyric acid-A (GABAA) receptors is known to result in antagonism of opioid analgesia. Since benzodiazepines enhance the action of GABA at GABAA receptors, we hypothesized that administration of these agents for preoperative sedation might antagonize the analgesic effects of opioids administered postoperatively. If so, then administration of the benzodiazepine antagonist flumazenil should enhance postoperative morphine analgesia. In a double-blind, placebo-controlled study of patients who received a preoperatively administered benzodiazepine (diazepam) for sedation and a postoperatively administered opioid (morphine) for analgesia, we investigated opioid-benzodiazepine interactions affecting postoperative dental pain. We found that flumazenil significantly enhanced morphine analgesia consistent with the hypothesis that the preoperatively administered benzodiazepine exerts an ongoing antianalgesic effect. In addition, we followed these patients over the first and second postoperative days to determine if there were differences between the drug groups in post-discharge pain, analgesic consumption, or side-effects. Participants receiving flumazenil reported significantly less post-discharge nausea and used significantly less ibuprofen. Since post-discharge pain levels were not significantly different, these results suggest that the patients receiving flumazenil required less analgesic medication to achieve a comparable level of pain control. In summary, our results indicate that the benzodiazepine antagonist flumazenil enhances morphine analgesia and decreases post-discharge side-effects as well as post-discharge need for analgesic medication.
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PMID:Benzodiazepine mediated antagonism of opioid analgesia. 920 Jan 70

Tiagabine (TGB) is a recently approved antiepileptic drug (AED) that inhibits y-aminobutyric acid (GABA) reuptake into neurons and glia, a mechanism of action that is specific and unique among the AEDs. TGB is potent and has linear and predictable pharmacokinetics. It has no clinically relevant effects on hepatic metabolism or serum concentrations of other AEDs, effects on laboratory values, or interactions with common non-AEDs. TGB is effective as add-on therapy for partial seizures in patients with medically refractory epilepsy in doses ranging from 30 to 56 mg daily. Conversion to TGB monotherapy can be achieved in patients with medically refractory epilepsy, although additional controlled studies are needed to confirm the efficacy of TGB as monotherapy and to establish the effective dosage range. In controlled studies, the most common adverse events of TGB are dizziness, asthenia, somnolence, accidental injury, infection, headache, nausea, and nervousness. These are usually mild to moderate in severity and almost always resolve without medical intervention.
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PMID:Tiagabine. 1053 Jun 90

Besides their binding to cognate intracellular receptors gonadal steroids may also act as functional antagonists at the 5-HT3 receptor. A structure-activity relationship for the actions of a variety of steroids at the 5-HT3 receptor was elaborated that differed considerably from that known for GABA(A) receptors. Steroids appear to interact allosterically with ligand-gated ion channels at the receptor membrane interface. The functional antagonism of gonadal steroids at the 5-HT3 receptor may play a role for the development and course of nausea during pregnancy and of psychiatric disorders. Moreover, we could demonstrate that 3alpha-reduced neuroactive steroids concurrently modulate the GABA(A) receptor and regulate gene expression via the progesterone receptor after intracellular oxidation. Animal studies showed that progesterone is converted rapidly into GABAergic neuroactive steroids in vivo. Progesterone reduces locomotor activity in a dose dependent fashion in male Wister rats. Moreover, progesterone and 3alpha,5alpha-tetrahydroprogesterone produce a benzodiazepine-like sleep EEG profile in rats and humans. In addition, there is a dysequilibrium of such 3alpha-reduced neuroactive steroids during major depression which is corrected by successful treatment with antidepressants. Neuroactive steroids may further be involved in the treatment of depression and anxiety with antidepressants in patients during ethanol withdrawal. First studies in patients with panic disorder suggest that neuroactive steroids may also play a pivotal role in human anxiety. The genomic and non-genomic effects of steroids in the brain contribute to the pathophysiology of psychiatric disorders and the mechanisms of action of antidepressants. Neuroactive steroids affect a broad spectrum of behavioral functions through their unique molecular properties and may constitute a yet unexploited class of drugs.
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PMID:Neuroactive steroids: molecular mechanisms of action and implications for neuropsychopharmacology. 1174 74

As a foundation for evaluating potential mechanisms of the neurological effects (e.g. headache, nausea, dizziness) of some octane boosters, we studied the gamma-aminobutyric acid(A) (GABA(A)) receptor in a series of binding assays in membranes from rat brain. The GABA(A) receptor was probed using the radioligand [3H]t-butylbicycloorthobenzoate ([3H]TBOB) which binds to the convulsant recognition site of the receptor. The results demonstrated that the short-chain t-ethers and their t-alcohol metabolites inhibit binding at the convulsant site of the GABA(A) receptor. The potency of the inhibition tended to correlate with carbon chain length. For agents having an equal number of carbon atoms, potency of inhibition of [3H]TBOB binding was greater in magnitude for the alcohols than for the ethers. The descending rank order of potency for the ethers and alcohols were as follows, t-amyl alcohol (TAA); t-amyl-methyl ether (TAME); ethyl-t-butyl ether (ETBE)>t-butyl alcohol (TBA)>methyl-t-butyl ether (MTBE)>ethanol. In additional saturation binding assays, MTBE reduced apparent density of convulsant binding (B(max)).
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PMID:Influence of oxygenated fuel additives and their metabolites on the binding of a convulsant ligand of the gamma-aminobutyric acid(A) (GABA(A)) receptor in rat brain membrane preparations. 1188 5

ASTA Medica is developing retigabine, a carbamic acid ethyl ester and a selective potassium channel opener, for the treatment of complex partial seizures. Phase II trials have commenced [249117], and a multicenter placebo-controlled dosage-finding study has begun in Europe and Australia [392702]. Retigabine is also undergoing phase II testing in Germany, Switzerland, Russia and the US for the potential treatment of epilepsy [323383]. Phase II trials have shown >50% reduction in seizure frequency in 12 of 35 patients with refractory epilepsy [373379]. Phase I clinical trials for epilepsy were successfully completed in Germany in 1995 [180371]. Single and multiple dose trials demonstrated the tolerability and favorable pharmacokinetic behavior of the compound [264306]. The compound showed good compatibility and exhibits an antisense anticonvulsive effect in various preclinical epilepsy models [250565,299344]. Side effects of mild to moderate tiredness, fatigue and nausea were observed [276123]. The spectrum of activity of retigabine resembles that of valproate, but its potency is greater and toxicity is reduced [373379]. The mechanism of action of retigabine is probably multifactorial. Research has shown that retigabine acts as a selective K+ channel opener in neuronal cells and this can be expected to contribute to its anticonvulsant effect [273670]. In addition it demonstrates potentiation of GABA transmission and possibly also weak modulation of sodium and calcium channels [299344]. Retigabine also has neuroprotective activity with potential for the treatment of stroke and neurodegenerative diseases, such as Alzheimer's disease, Huntington's disease and multiple sclerosis [249381]. In February 2000, Lehman Brothers predicted product launch could be as early as 2002 for epilepsy in the US [357788]. In February 1999, Lehman Brothers predicted that the first major launch date of the drug would be 2003, and the year of peak sales to be 2011 [319225].
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PMID:Retigabine (ASTA Medica). 1603 7

The first pyrethroid pesticide, allethrin, was identified in 1949. Allethrin and other pyrethroids with a basic cyclopropane carboxylic ester structure are type I pyrethroids. The insecticidal activity of these synthetic pyrethroids was enhanced further by the addition of a cyano group to give alpha-cyano (type II) pyrethroids, such as cypermethrin. The finding of insecticidal activity in a group of phenylacetic 3-phenoxybenzyl esters, which lacked the cyclopropane ring but contained the alpha-cyano group (and hence were type II pyrethroids) led to the development of fenvalerate and related compounds. All pyrethroids can exist as at least four stereoisomers, each with different biological activities. They are marketed as racemic mixtures or as single isomers. In commercial formulations, the activity of pyrethroids is usually enhanced by the addition of a synergist such as piperonyl butoxide, which inhibits metabolic degradation of the active ingredient. Pyrethroids are used widely as insecticides both in the home and commercially, and in medicine for the topical treatment of scabies and headlice. In tropical countries mosquito nets are commonly soaked in solutions of deltamethrin as part of antimalarial strategies. Pyrethroids are some 2250 times more toxic to insects than mammals because insects have increased sodium channel sensitivity, smaller body size and lower body temperature. In addition, mammals are protected by poor dermal absorption and rapid metabolism to non-toxic metabolites. The mechanisms by which pyrethroids alone are toxic are complex and become more complicated when they are co-formulated with either piperonyl butoxide or an organophosphorus insecticide, or both, as these compounds inhibit pyrethroid metabolism. The main effects of pyrethroids are on sodium and chloride channels. Pyrethroids modify the gating characteristics of voltage-sensitive sodium channels to delay their closure. A protracted sodium influx (referred to as a sodium 'tail current') ensues which, if it is sufficiently large and/or long, lowers the action potential threshold and causes repetitive firing; this may be the mechanism causing paraesthesiae. At high pyrethroid concentrations, the sodium tail current may be sufficiently great to prevent further action potential generation and 'conduction block' ensues. Only low pyrethroid concentrations are necessary to modify sensory neurone function. Type II pyrethroids also decrease chloride currents through voltage-dependent chloride channels and this action probably contributes the most to the features of poisoning with type II pyrethroids. At relatively high concentrations, pyrethroids can also act on GABA-gated chloride channels, which may be responsible for the seizures seen with severe type II poisoning. Despite their extensive world-wide use, there are relatively few reports of human pyrethroid poisoning. Less than ten deaths have been reported from ingestion or following occupational exposure. Occupationally, the main route of pyrethroid absorption is through the skin. Inhalation is much less important but increases when pyrethroids are used in confined spaces. The main adverse effect of dermal exposure is paraesthesiae, presumably due to hyperactivity of cutaneous sensory nerve fibres. The face is affected most commonly and the paraesthesiae are exacerbated by sensory stimulation such as heat, sunlight, scratching, sweating or the application of water. Pyrethroid ingestion gives rise within minutes to a sore throat, nausea, vomiting and abdominal pain. There may be mouth ulceration, increased secretions and/or dysphagia. Systemic effects occur 4-48 hours after exposure. Dizziness, headache and fatigue are common, and palpitations, chest tightness and blurred vision less frequent. Coma and convulsions are the principal life-threatening features. Most patients recover within 6 days, although there were seven fatalities among 573 cases in one series and one among 48 cases in another. Management is supportive. As paraesthesiae usually resolve in 12-24 hours, specific treatment is not generally required, although topical application of dl-alpha tocopherol acetate (vitamin E) may reduce their severity.
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PMID:Poisoning due to pyrethroids. 1618 Sep 29

The past 20 years have seen notable advances in our understanding of the physiology and pharmacology of the emetic reflex leading to the identification of the anti-emetic effects of 5-hydroxytryptamine(3) (5-HT(3)) and neurokinin(1) receptor (NK(1)) antagonists. The introduction of 5-HT(3) and NK(1) receptor antagonists into the clinic has had a major impact in alleviating the nausea and vomiting associated with the treatment of cancer and the sequelae to anaesthesia and surgery (post-operative nausea and vomiting, PONV). Despite these advances there are major gaps in our understanding. Interestingly, one of these is the relatively poor ability to treat nausea. Additional gaps in our knowledge are highlighted to provide a framework within which directions for research can be proposed. Particular attention is drawn to: lacunae in knowledge of some currently used anti-emetics such as the source of dopamine required to initiate emesis; the theoretical assumptions and mechanisms underlying the concept of a "universal anti-emetic"; the variety of receptors at which agonists act to have anti-emetic effects (GABA (B), CB(1), 5-HT(1A), ghrelin, opioid); issues of translation from animals to humans and the relationship between the pathways involved in emesis and certain gastrointestinal disorders such as dyspepsia and gastroesophageal reflux, with the latter being of particular interest as some agents affecting reflux are also anti-emetic. Together, the unmet clinical need to adequately control nausea, possibly by new drugs acting within the brainstem, and the significant gaps in understanding key aspects of the emetic reflex, suggest an important need to focus and re-direct research into the distressing and sometimes life-threatening symptoms of nausea and vomiting.
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PMID:Treatment of nausea and vomiting: gaps in our knowledge. 1693 36

GABA has been implicated in both the aetiology and treatment of anxiety. Tiagabine is currently the only selective GABA reuptake inhibitor available in US markets; it exerts its action via GAT-1 transporter blockade presynaptically, facilitating GABA neurotransmission. Preclinical studies and current human studies suggest tiagabine possesses anxiolytic properties. The anxiolytic properties of tiagabine have also been suggested in a number of case series, open-label studies and placebo-controlled studies in patients with different anxiety disorders. Throughout these studies, tiagabine has been reasonably tolerated; the most commonly reported adverse events include dizziness, headache and nausea. Tiagabine may be a useful addition to currently available drugs for anxiety; however, the data from small open-label investigations remain to be confirmed in larger controlled studies.
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PMID:Tiagabine in anxiety disorders. 1702 Apr 23


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