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)

All adverse drug reaction reports labelled seizures or myoclonus during treatment with antidepressants and stored in the Swedish national database for spontaneous reporting of adverse drug reactions were reviewed in order to evaluate possible risk factors. The reporting physicians were contacted and asked for complementary information, and blood samples for determination of the CYP2D6 and CYP2C19 genotypes were obtained from patients available. In total, 25 cases of seizures and 7 cases of myoclonus were studied. The drugs included were maprotiline (n=8), mianserin (n=7), fluvoxamine (n=6), amitriptyline (n=3), clomipramine (n=3), citalopram (n=2), paroxetine (n=2) and lofepramine (n=1). Previously suggested predisposing factors were identified in all but four cases (87%). None of the 11 patients genotyped were found to be poor metabolizers with respect to the enzymes CYP2D6 or CYP2C19. Thus, neither the CYP2D6 nor the CYP2C19 genotype were found to be associated with the occurrence of seizures/myoclonus during treatment with antidepressants. However, 15 patients (47%) were concomitantly treated with drugs with potential inhibitory effects on CYP2D6, such as neuroleptics and dextropropoxyphene, and the patients might thus have been converted from the extensive metabolizer to the poor metabolizer phenotype during this treatment. Concomitant treatment with drugs decreasing the seizure threshold and/or inhibiting the metabolism of antidepressants appeared to be an important risk factor for the occurrence of seizures/myoclonus.
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PMID:Seizures and myoclonus associated with antidepressant treatment: assessment of potential risk factors, including CYP2D6 and CYP2C19 polymorphisms, and treatment with CYP2D6 inhibitors. 939 57

The elderly have a relatively high risk of developing adverse drug reactions. Phenytoin continues to be a preferred drug for treating generalised tonic-clonic seizures in the elderly and simple partial seizures that generalise. Phenytoin is eliminated almost entirely by hepatic oxidation. The principle enzymes responsible are cytochrome P450 (CYP)2C9 and CYP2C19. CYP2C9 is saturated by therapeutic doses of phenytoin, and at steady state both enzymes are probably operant in most people. The nonlinear pharmacokinetics of phenytoin make it a difficult drug for which to establish safe and effective administration regimens. An important area of inquiry is whether the differential disposition kinetics of phenytoin in the elderly render its administration an even more difficult challenge. Moreover, since the elderly are generally subject to more polypharmacy than younger adults, are they, as a result, subject to either more frequent or more severe drug interactions with phenytoin than younger adults? In order to examine these issues we were interested in learning the extent to which old age might affect the plasma protein binding of phenytoin, its hepatic metabolism and, ultimately, its pharmacokinetic profile. With regard to the latter we looked carefully at the methods that have been used to characterise the disposition kinetics of phenytoin in general, and in the elderly, in particular. There are many conflicting findings with regard to the effect of age on the disposition kinetics of phenytoin. However, the strategies used for estimating kinetic parameters for phenytoin [viz the maximum rate of metabolism/elimination (Vmax) and the Michaelis-Menton constant (Km)] exhibit deficiencies that could account for some of the disparate findings. Certainly, more careful prospective studies focusing on the effects of age on phenytoin disposition kinetics are warranted. However, in light of the information currently available, no special attention need be paid to the initiation of phenytoin administration in elderly patients who are taking multiple anticonvulsants. On the other hand, for the elderly receiving phenytoin monotherapy, the initiation of phenytoin administration should occur at lower doses than would be customary for younger adults, and phenytoin blood concentrations should be appropriately monitored in order to evaluate individual Vmax and Km values for informed dosage adjustments.
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PMID:Differential kinetics of phenytoin in elderly patients. 1050 15

The authors report on a Japanese adult male patient with a long history of partial seizures that were poorly controlled by conventional doses of phenytoin and other drugs. His treatment was complicated by toxic symptoms and an excessive serum phenytoin concentration, 32.6 microg/mL at a dose of 187.5 mg/day. Polymerase chain reaction-restriction fragment length polymorphism analysis disclosed heterozygosity involving cytochrome P450 subfamilies 2C9 (*1/*3) and 2C19 (*1/*3). Currently, it is generally accepted that the former mutation is responsible for the CYP2C9 poor metabolizer phenotype. Pharmacokinetic parameters were estimated by a kinetic analysis, MULTI, using 17 observed dose-concentration data sets: a lower Vmax (5.6 mg/kg/day) and a higher Km (11.5 microg/mL) were observed. Although phenytoin is metabolized predominantly by CYP2C9 with a minor contribution of CYP2C19, patients with the Leu359 variant should be monitored closely when treated with a moderate to high daily dose of phenytoin.
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PMID:Genetic polymorphism of the CYP2C subfamily and excessive serum phenytoin concentration with central nervous system intoxication. 1077 39

A 31-year-old woman who had a severe head injury was treated with oral phenytoin (100 mg 3 times a day) to prevent posttraumatic seizures. On day 10 of phenytoin treatment, 3 hours after the morning dose, the patient manifested neurologic signs compatible with phenytoin intoxication. Thus drug serum concentrations were monitored daily for 12 days. The elimination half-life was 103 hours, namely, about 5 times longer than the mean value generally quoted (22 hours). In the absence of any acquired predisposing factor for phenytoin toxicity, genetic mutations in the cytochrome P450 (CYP) enzymes responsible for phenytoin metabolism (CYP2C9 and CYP2C19) were suspected. Genotyping revealed that the patient was homozygous for the CYP2C9*3 allele (CYP2C9*3/*3) and heterozygous for the CYP2C19*2 allele (CYP2C19*1/*2). In view of the markedly reduced metabolic activity of CYP2C*3 in comparison with the wild-type enzyme (about one fifth) and of the minor role of CYP2C19 in phenytoin metabolism, it is likely that CYP2C9*3 mutation was largely responsible for drug overdose.
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PMID:Severe phenytoin intoxication in a subject homozygous for CYP2C9*3. 1167 55

Moclobemide is a reversible inhibitor of monoamine-oxidase-A (RIMA) and has been extensively evaluated in the treatment of a wide spectrum of depressive disorders and less extensively studied in anxiety disorders. Nearly all meta-analyses and most comparative studies indicated that in the acute management of depression this drug is more efficacious than placebo and as efficacious as tricyclic (or some heterocyclic) antidepressants or selective serotonin reuptake inhibitors (SSRIs). There is a growing evidence that moclobemide is not inferior to other antidepressants in the treatment of subtypes of depression, such as dysthymia, endogenous (unipolar and bipolar), reactive, atypical, agitated, and retarded depression as with other antidepressants limited evidence suggests that moclobemide has consistent long-term efficacy. However, more controlled studies addressing this issue are needed. For patients with bipolar depression the risk of developing mania seems to be not higher with moclobemide than with other antidepressants. The effective therapeutic dose range for moclobemide in most acute phase trials was 300 to 600 mg, divided in 2 to 3 doses. While one controlled trial and one long-term open-label study found moclobemide to be efficacious in social phobia, three controlled trials subsequently revealed either no effect or less robust effects with the tendency of higher doses (600 - 900 mg/d) to be more efficacious. Two comparative trials demonstrated moclobemide to be as efficacious as fluoxetine or clomipramine in patients suffering from panic disorder. Placebo-controlled trials in this indication are, however, still lacking. A relationship between the plasma concentration of moclobemide and its therapeutic efficacy is not apparent but a positive correlation with adverse events has been found. Dizziness, nausea and insomnia occurred more frequently on moclobemide than on placebo. Due to negligible anticholinergic and antihistaminic actions, moclobemide has been better tolerated than tri- or heterocyclic antidepressants. Gastrointestinal side effects and, especially, sexual dysfunction were much less frequent with moclobemide than with SSRIs. Unlike irreversible MAO-inhibitors, moclobemide has a negligible propensity to induce hypertensive crisis after ingestion of tyramine-rich food ("cheese-reaction"). Therefore, dietary restrictions are not as strict. However, with moclobemide doses above 900 mg/d the risk of interaction with ingested tyramine might become clinically relevant. After multiple dosing the oral bioavailability of moclobemide reaches almost 100%. At therapeutic doses, moclobemide lacks significant negative effects on psychomotor performance, cognitive function or cardiovascular system. Due to the relative freedom from these side effects, moclobemide is particularly attractive in the treatment of elderly patients. Moclobemide is a substrate of CYP2C19. Although it acts as an inhibitor of CYP1A2, CYP2C19, and CYP2D6, relatively few clinically important drug interactions involving moclobemide have been reported. It is relatively safe even in overdose. The drug has a short plasma elimination half-life that allows switching to an alternative agent within 24 h. Since it is well tolerated, therapeutic doses can often be reached rapidly upon onset of treatment. Steady-state plasma levels are reached approximately at one week following dose adjustment. Patients with renal dysfunction require no dose reduction in contrast to patients with severe hepatic impairment. Cases of refractory depression might improve with a combination of moclobemide with other antidepressants, such as clomipramine or a SSRI. Since this combination has rarely been associated with a potentially lethal serotonin syndrome, it requires lower entry doses, a slower dose titration and a more careful monitoring of patients. Combination therapy with moclobemide and other serotonergic agents, or opioids, should be undertaken with caution, although no serious adverse events have been published with therapeutic doses of moclobemide to date. On the basis of animal data the combined use of moclobemide with pethidine or dextropropoxyphene should be avoided. There is no evidence that moclobemide would increase body weight or produce seizures. Some preclinical data suggest that moclobemide may have anticonvulsant property.
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PMID:Moclobemide: therapeutic use and clinical studies. 1504 13

Oxcarbazepine (Trileptal, Timox) is structurally related to carbamazepine and has anticonvulsant activity. Studies suggest that the anticonvulsant activity of oxcarbazepine is mediated via the blocking of neuronal ion channels. In patients aged <18 years, the efficacy of oxcarbazepine monotherapy was similar to that of phenytoin in children with partial onset or generalized tonic-clonic seizures in a 48-week trial. Additional supporting findings demonstrated that 43-71% of patients with partial onset, generalized or undetermined epilepsy were seizure free after oxcarbazepine monotherapy (mean dosage 27.7-50 mg/kg/day; duration 1-5 years). In contrast, one small nonblind trial showed more patients treated with oxcarbazepine monotherapy than with carbamazepine monotherapy had recurrent seizures during 16 months of therapy (although the conclusions that can be drawn from this trial are limited). As adjunctive therapy, oxcarbazepine was significantly better than placebo at reducing seizure frequency in children and adolescents with refractory partial onset seizures with or without secondary generalization: the median percentage change in partial onset seizure frequency was 35% vs 9%, respectively, during 16 weeks of therapy. In noncomparative trials of adjunctive oxcarbazepine (mean dosage of 34.5-56.7 mg/kg/day), 7-11% of patients with partial onset or generalized seizures were seizure free during treatment, and 20-54% had seizure reductions of > or=50%. Oxcarbazepine was generally well tolerated during monotherapy and adjunctive therapy; 2.5% and 10% of patients withdrew from well controlled trials of oxcarbazepine monotherapy and adjunctive therapy. Oxcarbazepine monotherapy was better tolerated than phenytoin and events observed in oxcarbazepine-treated patients were transient. Oxcarbazepine metabolism is largely unaffected by induction of the cytochrome (CYP) P450 system. However, oxcarbazepine can inhibit CYP2C19 and induce CYP3A4 and CYP3A5, thereby interfering with the metabolism of other drugs (e.g. phenytoin). In addition, oxcarbazepine decreases plasma levels of oral contraceptives and alternative contraceptive methods should be used. In conclusion, oxcarbazepine (as both monotherapy and adjunctive therapy) has shown efficacy in the treatment of partial onset seizures in children with epilepsy. Nevertheless, the generally favorable tolerability profile and relatively low potential for drug interactions of oxcarbazepine make it a valuable option in the treatment of childhood epilepsy.
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PMID:Oxcarbazepine: a review of its use in children with epilepsy. 1289 38

We describe the case of a 10-year-old girl with two epileptic seizures and subcontinuous spike-waves during sleep, who presented unusual side-effects related to clobazam (CLB) monotherapy. High plasma levels of N-desmethyl-clobazam (N-CLB), the major metabolite of CLB were detected. The patient and her parents underwent molecular analysis of the CYP2C19 gene, which may be implicated in the metabolism of this drug. Our patient presents one copy of the most common mutation (CYP2C19*2) affecting the activity of the isoenzyme and probably another rare or private mutation. CLB and N-CLB plasma level dosages and molecular analysis may be useful when a poor metabolic condition is suspected.
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PMID:Unusual side-effects due to clobazam: a case report with genetic study of CYP2C19. 1472 19

Oxcarbazepine (Trileptal, Timox) is structurally related to carbamazepine and has anticonvulsant activity. Studies suggest that the anticonvulsant activity of oxcarbazepine is mediated via the blocking of neuronal ion channels. In patients aged <18 years, the efficacy of oxcarbazepine monotherapy was similar to that of phenytoin in children with partial onset or generalised tonic-clonic seizures in a 48-week trial. Additional supporting findings demonstrated that 43-71% of patients with partial onset, generalised or undetermined epilepsy were seizure free after oxcarbazepine monotherapy (mean dosage 27.7-50 mg/kg/day; duration 1-5 years). In contrast, one small nonblind trial showed more patients treated with oxcarbazepine monotherapy than with carbamazepine monotherapy had recurrent seizures during 16 months of therapy (although the conclusions that can be drawn from this trial are limited). As adjunctive therapy, oxcarbazepine was significantly better than placebo at reducing seizure frequency in children and adolescents with refractory partial onset seizures with or without secondary generalisation: the median percentage change in partial onset seizure frequency was 35% versus 9%, respectively, during 16 weeks of therapy. In noncomparative trials of adjunctive oxcarbazepine (mean dosage of 34.5-56.7 mg/kg/day), 7-11% of patients with partial onset or generalised seizures were seizure free during treatment, and 20-54% had seizure reductions of > or =50%. Oxcarbazepine was generally well tolerated during monotherapy and adjunctive therapy; 2.5% and 10% of patients withdrew from well controlled trials of oxcarbazepine monotherapy and adjunctive therapy. Oxcarbazepine monotherapy was better tolerated than phenytoin and events observed in oxcarbazepine-treated patients were transient. Oxcarbazepine metabolism is largely unaffected by induction of the cytochrome (CYP) P450 system. However, oxcarbazepine can inhibit CYP2C19 and induce CYP3A4 and CYP3A5, thereby interfering with the metabolism of other drugs (e.g. phenytoin). In addition, oxcarbazepine decreases plasma levels of oral contraceptives and alternative contraceptive methods should be used. In conclusion, oxcarbazepine (as both monotherapy and adjunctive therapy) has shown efficacy in the treatment of partial onset seizures in children with epilepsy. Nevertheless, the generally favorable tolerability profile and relatively low potential for drug interactions of oxcarbazepine make it a valuable option in the treatment of childhood epilepsy.
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PMID:Spotlight on oxcarbazepine in epilepsy. 1473 Oct 60

One of the major differences between the older antiepileptic drugs (AEDs) and the newer AEDs is the potential of the older AEDs for significant interactions with other medications. Many of the drug-drug interactions involving the older AEDs are reciprocal, i.e., both drugs affect each other. In contrast, the newer AEDs have either no or limited drug interaction potential. Despite our extensive understanding of and our ability to predict drug-drug interactions, serious drug interactions still occur. More than 30% of all new seizures occur in the elderly, and because this population may be taking a variety of other medications the addition of an AED can have profound impact on these other therapies. In women, the use of enzyme-inducing AEDs can cause significant alterations of sex hormones and can decrease the efficacy of oral contraceptives. In children and adults, the use of enzyme inducers may result in long-term endocrine effects, including bone loss and lipid, thyroid, and sex hormone abnormalities. Phenytoin and phenobarbital are metabolized by cytochrome P450 isozymes, with activity dependent on genetic polymorphism (CYP2C9, CYP2C19). The dosing of the newer AEDs is not affected by genetic polymorphism. The decreased induction and inhibition effects and the lack of significant genetic polymorphism of the newer AEDs allow increased ease of use and perhaps greater safety, especially for patients taking multiple medications.
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PMID:Pharmacogenetics and enzyme induction/inhibition properties of antiepileptic drugs. 1555 48

Alternative therapy including herbal drugs and complementary medicine is becoming increasingly popular. However, the rise in the incidence of herb-drug interactions is causing concern, especially in the absence of warning labels addressing potential adverse effects. We present the case of a 55-year-old male who suffered a fatal breakthrough seizure, with no evidence of non-compliance with his anticonvulsant medications. The autopsy report revealed subtherapeutic serum levels for both anticonvulsants Depakote and Dilantin. Concomitant with his prescribed medications, the decedent was also self-medicating with a cornucopia of herbal supplements and nutraceuticals, prominent among which was Ginkgo biloba. Ginkgo, an herbal extract from the leaves of the Ginkgo biloba tree, has been used medicinally for centuries and has been touted as a cure for a variety of medical conditions. The induction of Cytochrome P450 enzymes by components of herbal drugs has been known to affect the metabolism of various drugs. Dilantin is primarily metabolized by CYP2C9, and secondarily metabolized by CYP2C19. Valproate metabolism is also modulated in part by CYP2C9 and CYP2C19. A recent study revealed significant inductive effect of ginkgo on CYP2C19 activity. CYP2C19 induction by ginkgo could be a plausible explanation for the subtherapeutic levels of Dilantin and Depakote. Additionally, ginkgo nuts contain a potent neurotoxin, which is known to induce seizure activity. Evidence of other herbal drugs diminishing the efficacy of anticonvulsant medication does exist; however, there has been only one other documented instance of ginkgo potentiating seizure activity in the presence of anticonvulsant therapy. Highlighting the potential adverse effects and drug interactions of ginkgo on the packaging of the drug may help prevent inadvertent use in vulnerable individuals.
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PMID:Fatal seizures due to potential herb-drug interactions with Ginkgo biloba. 1641 14


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