Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxcarbazepine is the 10-keto analogue of carbamazepine but has a distinct pharmacokinetic profile. In contrast to the oxidative metabolism of carbamazepine, oxcarbazepine is rapidly reduced to its active metabolite, 10,11-dihydro-10-hydroxy-carbamazepine. With the possible exception of the P450IIIA isozyme of the cytochrome P450 family, neither oxcarbazepine nor its monohydroxy derivative induce hepatic oxidative metabolism. Direct comparison of oxcarbazepine and carbamazepine has shown no difference in efficacy between these 2 agents in terms of reducing seizure frequency in patients with partial epilepsy with or without secondary generalisation, or with tonic-clonic seizures. Substitution of oxcarbazepine for carbamazepine in multiple antiepileptic drug regimens improved seizure control in some patients with refractory epilepsy; however, the rise in serum concentrations of concurrent antiepileptic agents secondary to elimination of carbamazepine-associated hepatic enzyme induction may have also played a role. Substitution of oxcarbazepine for carbamazepine was associated with improved cognition and alertness in some patients with epilepsy. Limited data indicate that oxcarbazepine may be a useful alternative to carbamazepine in the management of trigeminal neuralgia. Experience in patients with acute mania is promising, but the value of oxcarbazepine in managing affective disorders, particularly as a prophylactic agent, is not established. Oxcarbazepine may be better tolerated than carbamazepine; however, the current published database is small and the potential for oxcarbazepine to induce the type of serious idiosyncratic reactions occasionally associated with carbamazepine is unknown. Hyponatraemia has been reported in patients treated with oxcarbazepine. Although apparently asymptomatic, fluid restriction may be deemed necessary in some patients to reduce the risk of precipitating seizures secondary to low serum sodium. Thus, oxcarbazepine appears to be an effective substitute for carbamazepine in those patients intolerant of this agent, or experiencing significant drug interactions. Wider clinical experience should help clarify the long term efficacy and tolerability of oxcarbazepine. Pharmacokinetic advantages over current antiepileptic drugs, carbamazepine in particular, may then favour oxcarbazepine for consideration as a first-line agent in the management of partial and tonic-clonic epilepsy.
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PMID:Oxcarbazepine. A review of its pharmacology and therapeutic potential in epilepsy, trigeminal neuralgia and affective disorders. 137 59

In the past decade, several new antiepileptic drugs have been tested. Most recently, 5 new antiepileptic drugs have been launched onto European and US markets. These include vigabatrin, oxcarbazepine and lamotrigine in Europe, and felbamate and gabapentin in the US. In addition to these, 3 additional drugs are in the clinical investigational stage: flunarizine, fosphenytoin and stiripentol. A fourth agent is midazolam, which was originally introduced in 1986, but recently has shown effectiveness in the treatment of status epilepticus. Flunarizine is a selective calcium channel blocker that has shown anticonvulsant properties in both animal and human studies. It is a long-acting anticonvulsant that clinical studies have shown to have effects similar to those of phenytoin and carbamazepine in the treatment of partial, complex partial and generalised seizures. Fosphenytoin was developed to eliminate the poor aqueous solubility and irritant properties of intravenous phenytoin. It is rapidly converted to phenytoin after intravenous or intramuscular administration. In clinical studies, this prodrug showed minimal evidence of adverse events and no serious cardiovascular or respiratory adverse reactions. It may have a clear advantage over the present parenteral formulation of phenytoin. Midazolam is a benzodiazepine that is more potent than diazepam as a sedative, muscle relaxant and in its influence on electroencephalographic measures. It has been shown to be an effective treatment for refractory seizures in status epilepticus. Stiripentol has anticonvulsant properties as well as the ability to inhibit the cytochrome P450 system. There are significant metabolic drug interactions between stiripentol and phenytoin, carbamazepine and phenobarbital (phenobarbitone). Stiripentol has been studied in patients with partial seizures, refractory epilepsy and refractory absence seizures with some efficacious results.
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PMID:New anticonvulsant drugs. Focus on flunarizine, fosphenytoin, midazolam and stiripentol. 752 21

Major depression is a common and disabling disorder with far-reaching social and economic implications. Nonetheless, major depression is treatable by one of the many currently available antidepressants with response rates of approximately 65-70%. Treatment of depression has improved in recent years because of the availability of effective and well-tolerated antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs). The currently available antidepressants are generally equally effective and are distinguished primarily by side-effect profiles. The side effects of tricyclic antidepressants (TCAs) are attributed to their nonspecific interaction with cholinergic, histaminergic, serotonergic, and dopaminergic receptors in the central nervous system. The secondary amine TCAs, nortriptyline and desipramine, are preferred among the TCAs because of a more favorable side-effect profile. The TCAs are cardiotoxic, and overdoses are frequently fatal. Adverse effects, including potentially fatal drug and food interactions, limit the use of the monoamine oxidase inhibitors (MAOIs); however, these agents have a role in the treatment of depression with comorbid anxiety, refractory depression, atypical depression, and bulimia. The SSRIs possess a class side-effect profile of headache, nausea, and sexual dysfunction. Individual differences in side effects may distinguish fluoxetine (nervousness, restlessness), sertraline (diarrhea, loose stools), and paroxetine (dry mouth). The SSRIs all inhibit certain cytochrome P450 isoenzymes involved in the metabolism of drugs, such as the TCAs, and each SSRI has been reported to increase plasma concentrations of concomitantly administered TCAs. Bupropion therapy is associated with a risk of seizure development, which can be minimized by multiple daily doses. Trazodone is sedating and can rarely cause priapism. The related compound, nefazodone, does not cause sexual dysfunction or priapism, but is associated with sedation. Venlafaxine, a recently available antidepressant that appears to have efficacy in treatment-refractory depression, may cause nausea that requires gradual upward dosage titration. Higher doses of venlafaxine may also cause elevations in blood pressure, heart rate, and serum cholesterol. As more is learned about the pathophysiology of depression, even more specific and well-tolerated antidepressants will be developed.
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PMID:Contemporary management of depression. 799 23

Tiagabine (TGB) hydrochloride, a nipecotic acid derivative linked to a lipophilic anchor, potently and specifically inhibits uptake of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) into astrocytes and neurons. With microdialysis, TGB has been shown to increase extracellular overflow of GABA in the midbrain of awake rats. TGB administration prolongs neuronal depolarization induced by iontophoretically applied GABA in hippocampal slices. TGB is effective in a wide range of seizure models, including pentylenetetrazol-induced, methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM)-induced tonic, amygdala-kindled and picrotoxin-induced convulsions, and maximal electroshock seizures in rodents. In humans, TGB absorption is rapid and complete. It is metabolized in the liver, largely by isoform 3A of the cytochrome P450 family of enzymes. The process of elimination is linear, with a half-life of 5-8 h. TGB does not induce or inhibit metabolic processes, although it provides a target for enzyme inducers that can lower its elimination half-life to 2-3 h. Accordingly, TGB does not alter the concentrations of other antiepileptic drugs (AEDs), with the possible exception of a small decrease in valproate levels. A controlled-release formulation of TGB would offset any potential clinical disadvantage of the short elimination half-life, particularly in patients receiving concurrent treatment with enzyme-induced AEDs.
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PMID:Tiagabine pharmacology in profile. 859 91

Nonketotic hyperglycinaemia (NKH) is an inborn error of the glycine cleavage system resulting in seizures and mental retardation. Two prior reports noted an anticonvulsant effect from high-dose dextromethorphan (DM) in this disorder, although the two reported patients demonstrated widely disparate DM requirements and drug levels. We report two children with NKH who also demonstrated disparate and variable DM metabolism which markedly influenced the dose-concentration-response relationship. Levels of DM and its primary metabolite dextrorphan (DX) were utilized to guide DM therapy and exhibited patterns reflective of the extensive and poor metabolizer phenotypes for CYP2D6, the cytochrome P450 isoform responsible for DM metabolism. In the patient who appeared to represent the extensive metabolizer (EM) phenotype, treatment with the non-specific cytochrome P450 inhibitor cimetidine was required to reduce biotransformation of DM to DX and, thus, to increase DM plasma concentrations. In the patient with the apparent poor metabolizer (PM) phenotype, a change in the DM preparation to a sustained-release form and increase in the dosing interval was required to lower DM plasma concentrations. These cases demonstrate the importance of CYP2D6 phenotype in providing safe and effective DM therapy to patients with NKH.
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PMID:Dextromethorphan in nonketotic hyperglycinaemia: metabolic variation confounds the dose-response relationship. 906 64

Since its introduction in 1987, zidovudine monotherapy has been the treatment of choice for patients with HIV infection. Unfortunately it has been established that the beneficial effects of zidovudine are not sustained due to the development of resistant viral strains. This has led to the strategy of combination therapy, and in 1995 treatment with zidovudine plus didanosine, or zidovudine plus zalcitabine, was demonstrated to be more effective than zidovudine monotherapy in preventing disease progression and reducing mortality in patients with HIV disease. Recent work demonstrates an even greater antiviral effect from triple therapy with 2 nucleosides, zidovudine plus zalcitabine with the addition of saquinavir, a new protease inhibitor drug. The HIV protease enzyme is responsible for the post-translational processing of gag and gag-pol polyprotein precursors, and its inhibition by drugs such as saquinavir, ritonavir, indinavir and VX-478 results in the production of non-infectious virions. As resistance may also develop to the protease inhibitors they may be used in combination, and future strategies may well include quadruple therapy with 2 nucleoside analogues plus 2 protease inhibitors. Administration of protease inhibitors alone or in combination with other drugs does raise a number of important pharmacokinetic issues for patients with HIV disease. Some protease inhibitors (e.g. saquinavir) have kinetic profiles characterised by reduced absorption and a high first pass effect, resulting in poor bioavailability which may be improved by administrating with food. Physiological factors including achlorhydria, malabsorption and hepatic dysfunction may influence the bioavailability of protease inhibitors in HIV disease. Protease inhibitors are very highly bound to plasma proteins (> 98%), predominantly to alpha 1-acid glycoprotein. This may influence their antiviral activity in vitro and may also predispose to plasma protein displacement interactions. Such interactions are usually only of clinical relevance if the metabolism of the displaced drug is also inhibited. This is precisely the situation likely to pertain to the protease inhibitors, as ritonavir may displace other protease inhibitor drugs, such as saquinavir, from plasma proteins and inhibit their metabolism. Protease inhibitors are extensively metabolised by the cytochrome P450 (CYP) enzymes present in the liver and small intestine. In vitro studies suggest that the most influential CYP isoenzyme involved in the metabolism of the protease inhibitors is CYP3A, with the isoforms CYP2C9 and CYP2D6 also contributing. Ritonavir has an elimination half-life (t1/2 beta) of 3 hours, indinavir 2 hours and saquinavir between 7 and 12 hours. Renal elimination is not significant, with less than 5% of ritonavir and saquinavir excreted in the unchanged form. As patients with HIV disease are likely to be taking multiple prolonged drug regimens this may lead to drug interactions as a result of enzyme induction or inhibition. Recognised enzyme inducers of CYP3A, which are likely to be prescribed for patients with HIV disease, include rifampicin (rifampin) [treatment of pulmonary tuberculosis], rifabutin (treatment and prophylaxis of Mycobacterium avium complex), phenobarbital (phenobarbitone), phenytoin and carbamazepine (treatment of seizures secondary to cerebral toxoplasmosis or cerebral lymphoma). These drugs may reduce the plasma concentrations of the protease inhibitors and reduce their antiviral efficacy. If coadministered drugs are substrates for a common CYP enzyme, the elimination of one or both drugs may be impaired. Drugs which are metabolised by CYP3A and are likely to be used in the treatment of patients with HIV disease include the azole antifungals, macrolide antibiotics and dapsone; therefore, protease inhibitors may interact with these drugs. (ABSTRACT TRUNCATED)
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PMID:Protease inhibitors in patients with HIV disease. Clinically important pharmacokinetic considerations. 908 59

Nefazodone hydrochloride is a phenylpiperazine antidepressant with a mechanism of action that is distinct from those of other currently available drugs. It potently and selectively blocks postsynaptic serotonin (5-hydroxytryptamine; 5-HT) 5-HT2A receptors and moderately inhibits serotonin and noradrenaline (norepinephrine) reuptake. In short term clinical trials of 6 or 8 weeks' duration, nefazodone produced clinical improvements that were significantly greater than those with placebo and similar to those achieved with imipramine, and the selective serotonin reuptake inhibitors (SSRIs) fluoxetine, paroxetine and sertraline. The optimum therapeutic dosage of nefazodone appears to be between 300 and 600 mg/day. Limited long term data suggest that nefazodone is effective in preventing relapse of depression in patients treated for up to 1 year. Analyses of pooled clinical trial results indicate that nefazodone and imipramine produces similar and significant improvements on anxiety- and agitation-related rating scales compared with placebo in patients with major depression. Short term tolerability data indicate that nefazodone has a lower incidence of adverse anticholinergic, antihistaminergic and adrenergic effects than imipramine. Compared with SSRIs, nefazodone causes fewer activating symptoms, adverse gastrointestinal effects (nausea, diarrhoea, anorexia) and adverse effects on sexual function, but is associated with more dizziness, dry mouth, constipation, visual disturbances and confusion. Available data also suggest that nefazodone is not associated with abnormal weight gain, seizures, priapism or significant sleep disruption, and appears to be relatively safe in overdosage. Nefazodone inhibits the cytochrome P450 3A4 isoenzyme and thus has the potential to interact with a number of drugs. Further long term and comparative studies will provide a more accurate assessment of the relative place of nefazodone in the management of major depression. Nonetheless, available data suggest that nefazodone is a worthwhile treatment alternative to tricyclic antidepressants and SSRIs in patients with major depression.
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PMID:Nefazodone. A review of its pharmacology and clinical efficacy in the management of major depression. 921 Oct 88

Midazolam is a familiar agent commonly used in the emergency department to provide sedation prior to procedures such as laceration repair and reduction of dislocations. Midazolam is also effective in the treatment of generalized seizures, status epilepticus, and behavioral emergencies, particularly when intravenous access is not available. Midazolam is often employed as an induction agent for rapid sequence endotracheal intubation. Midazolam has a rapid onset of action following intravenous, intramuscular, oral, nasal, and rectal administration. Only 50% of an orally administered dose reaches the systemic circulation due to extensive first-pass metabolism. Midazolam is metabolized by the cytochrome P450 enzyme system to several metabolites including an active metabolite, alpha-hydroxymidazolam. Cytochrome P450 inhibitors such as cimetidine can profoundly reduce the metabolism of midazolam. Midazolam has a half-life of approximately 1 h, but this half-life may be prolonged in patients with renal or hepatic dysfunction. Midazolam has been associated with respiratory depression and cardiac arrest when used in combination with an opioid, particularly in the elderly, although all ages are at risk for respiratory depression. Midazolam is relatively free of side effects when used alone and offers several advantages over traditional pharmacological agents such as chloral hydrate and the combination of meperidine, chlorpromazine, and promethazine. Hiccups, cough, nausea, and vomiting are the most commonly reported adverse effects. Many of the adverse effects associated with midazolam can be reversed rapidly by the administration of flumazenil, a competitive benzodiazepine receptor antagonist. Midazolam is a safe and effective agent for providing sedation in the emergency department.
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PMID:Midazolam: a review of therapeutic uses and toxicity. 925 87

Therapy of HIV infection is changing rapidly as new drugs are introduced. Many patients with HIV infection require anticonvulsants for therapy or prophylaxis of seizures. Antiretroviral drugs, above all protease inhibitors, and anticonvulsants may cause interactions since they are metabolised through common hepatic pathways and may substantially modulate the activity of numerous cytochrome P450 isoenzymes. We describe known interactions between anticonvulsants and antiretroviral drugs and advise on possible combinations.
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PMID:[Anti-retroviral therapy and antiepileptics. Case report and discussion]. 971 1

Tiagabine exerts its antiepileptic drug (AED) activity by selectively inhibiting the uptake of gamma-aminobutyric acid (GABA) onto the transporter molecules, and thus, increasing extracellular concentrations of GABA in the brain. The absorption and elimination of tiagabine follow linear pharmacokinetics. Tiagabine is metabolized by hepatic cytochrome P450 enzymes and enzyme-inducing AEDs increase tiagabine clearance by 50-65%. Tiagabine has shown no clinically important interactions with other drugs, including oral contraceptives. In the perforant pathway stimulation model of status epilepticus, tiagabine reduced the seizure number and severity, and also prevented the loss of pyramidal cells in the hippocampus as well as alleviated impairment of the spatial memory impairment associated with hippocampal damage. Tiagabine has both antiepileptogenic and anticonvulsant effects in the kindling model of epilepsy. Based on the data from the short- and long-term add-on studies, tiagabine is effective adjunctive therapy for all partial seizure types in adolescents and adults. Conversion to tiagabine monotherapy has been also possible in substantial amount of patients with partial seizures in three trials. Tiagabine is generally well-tolerated. The most common adverse events in controlled studies involve the central nervous system; for example, dizziness, asthenia, nervousness, tremor, depressed mood and emotional lability. Special safety analyses with formal neuropsychological testing suggest that tiagabine does not adversely affect cognition or mood. Tiagabine represents an important new therapeutic option for patients with treatment-refractory partial seizures. The role of tiagabine in the management of partial epilepsy of patients with intellectual disability is especially emphasized since tiagabine has a low side-effect profile in the cognitive area.
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PMID:Tiagabine: a new therapeutic option for people with intellectual disability and partial epilepsy. 1003 Apr 35


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