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)

This study examined the interaction characteristics between loreclezole (LCZ) and various conventional antiepileptic drugs (phenytoin--PHT, carbamazepine--CBZ, valproate--VPA and phenobarbital--PB) in the mouse maximal electroshock (MES)-induced seizure model using isobolographic analysis. Drug-related adverse effects were ascertained by use of the chimney test (motor impairment) and the step-through passive avoidance task (learning and retrieval). It was observed that the combination of LCZ with VPA or PB, at the fixed ratio of 1:1, was supra-additive (synergistic) and the combination of LCZ with CBZ, at all fixed ratios tested (1:3, 1:1 and 3:1), was supra-additive against electroconvulsions. The remaining combinations evaluated, i.e., LCZ with PB or VPA at fixed ratios of 1:3 and 3:1, as well as all fixed-ratio combinations between LCZ and PHT, were additive in the MES test in mice. Pharmacokinetic characterization revealed that LCZ significantly increased both free plasma and brain concentrations of CBZ and PHT, but was without effect on PB. Moreover, a bi-directional pharmacokinetic interaction between LCZ and VPA was observed in that while LCZ increased free plasma, but not total brain VPA concentrations, VPA increased the total brain, but not free plasma LCZ concentrations. Adverse-effect testing revealed that for all antiepileptic drug combinations neither motor performance nor long-term memory was altered. Of the drug combinations investigated, only that of LCZ and PB at the fixed ratio of 1:1 was not associated with any pharmacokinetic interactions, and thus it may be concluded that the supra-additive (synergistic) isobolographic interaction was pharmacodynamic in nature. Furthermore, the fact that LCZ and PB have similar mechanisms of action would suggest that drugs with similar mechanisms of action may provide rational polytherapy regimens.
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PMID:Isobolographic analysis of interactions between loreclezole and conventional antiepileptic drugs in the mouse maximal electroshock-induced seizure model. 1660 39

Pharmacoresistance in epileptic patients may be ascribed to at least two, not mutually exclusive, mechanisms: a pharmacokinetic mechanism and a decreased sensitivity or availability of targets to antiepileptic drugs (AEDs; i.e., carbamazepine and phenytoin (CBZ, PHT)). Brain:plasma drug concentration ratios were determined intraoperatively during lobectomies performed to alleviate drug-resistant seizures. The brain:plasma ratio of CBZ was 1.48 when therapeutic serum levels (15-34 microM) were achieved. When concentrations of CBZ found in multiple-drug-resistant brain were directly applied to human cortical slices from drug-resistant patients made hyperexcitable and hypersynchronous by Mg(2+)-free media, bursting frequency was not significantly affected and overall excitability was reduced by 40%. Similar results were obtained for PHT. At higher AED concentrations (60-200 microM), a dose-dependent decrease of bursting frequency and amplitude was observed. Slices from drug-resistant epileptic patients made hypersynchronous/hyperexcitable by elevated potassium or inhibition of GABA-A receptors behaved similarly. Of note is the response of slices from human multiple-drug-resistant brain, which was greater than in rodent cortex from naive animals. Taken together, our results support the hypothesis that multiple drug resistance to AEDs involves cerebrovascular changes that impede the achievement of appropriate drug levels in the central nervous system.
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PMID:In vitro responsiveness of human-drug-resistant tissue to antiepileptic drugs: insights into the mechanisms of pharmacoresistance. 1663 25

To report two unrelated patients with a new phenotype of nonketotic hyperglycinemia associated with idiopathic pulmonary hypertension. Clinical findings included rapidly progressive neurological deterioration with onset in the first year of life characterized by developmental regression without seizures or electroencephalogram abnormalities during follow-up. Both patients died before the age of 18 months. Glycine cleavage system deficiency was confirmed by enzymatic studies in frozen liver. Molecular analysis in the related genes showed no pathogenic mutation. Radiological and pathological findings were consistent with progressive vacuolating encephalopathy. Our patients with biochemical and enzymatic parameters consistent with atypical nonketotic hyperglycinemia. The clinical and radiological evolution, as progressive vacuolating leukoencephalopathy and the association with pulmonary hypertension constitute a previously unrecognized variant.
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PMID:Progressive vacuolating glycine leukoencephalopathy with pulmonary hypertension. 1680 95

7-Nitroindazole (7NI, a nitric oxide synthase [NOS] inhibitor) administered intraperitoneally (ip), 30 min before the test, at doses ranging between 50-200 mg/kg, raised the threshold for electroconvulsions in mice. Linear regression analysis revealed that the doses increasing the threshold by 50% (TID50) and 100% (TID100) over the control value for 7NI were 115.2 and 173.4 mg/kg, respectively. Moreover, 7NI dose-dependently potentiated the anticonvulsant effects of four conventional antiepileptic drugs (AEDs: carbamazepine - CBZ, phenobarbital - PB, phenytoin - PHT, and valproate - VPA) in the mouse maximal electroshock-induced seizure (MES) model. 7NI at 50 mg/kg enhanced only the anticonvulsant effect of PB, whereas the drug at 75 and 100 mg/kg potentiated the antiseizure effects of PB, PHT and VPA, but not those of CBZ against MES-induced seizures. Only 7NI at 150 mg/kg enhanced considerably the antielectroshock action of all studied AEDs in the MES test. Pharmacokinetic evaluation of interactions between 7NI and the investigated AEDs revealed that 7NI (150 mg/kg; ip) did not alter total brain concentrations of conventional AEDs in mice. L-arginine (L-Arg - a natural precursor of NO; administered ip, 500 mg/kg, 60 min before electroconvulsions) did not reverse the activity of 7NI (150 mg/kg), but in contrast, it significantly potentiated the anticonvulsant action of conventional AEDs combined with 7NI (150 mg/kg). Pharmacokinetic increase in total brain AED concentrations was observed for the combinations of L-Arg (500 mg/kg) with 7NI (150 mg/kg) and PHT (by 32%; p<0.01) or VPA (by 22%; p<0.05). Neither total brain CBZ nor PB concentrations were altered following the co-administration of L-Arg (500 mg/kg) with 7NI (150 mg/kg). 7NI at doses of 100-200 mg/kg significantly impaired spontaneous ambulatory activity in mice subjected to the Y-maze task. The NOS inhibitor at doses of 50 and 75 mg/kg had no significant effect on locomotor activity of animals, although the number of arm entries within the 5 min of observational time was reduced. Finally, it can be concluded that the enhancement of anticonvulsive efficacy of CBZ, PB, PHT and VPA by 7NI alone or in combination with L-Arg in the MES test, deserves more attention and further neurochemical studies are required to elucidate the exact role of NO in the brain.
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PMID:7-Nitroindazole enhances dose-dependently the anticonvulsant activities of conventional antiepileptic drugs in the mouse maximal electroshock-induced seizure model. 1708 58

Most infants born to women with epilepsy are healthy, but there are increased risks related to in utero antiepileptic drug (AED) exposure and seizures. Emerging data from pregnancy registries and other studies allow us to better balance the anatomic teratogenic and neurodevelopmental effects of AEDs against the need to maintain maternal seizure control. Several large prospective pregnancy registries demonstrate a consistent pattern of increased risk for major congenital malformations (MCMs) with valproate (VPA) use as monotherapy, compared to nonexposed populations and to other AEDs used in monotherapy. AED polytherapy likely increases risk for MCMs, but the risk is more pronounced if VPA is included. Reduced cognitive outcomes have been reported with AED polytherapy, and with use of VPA, phenobarbital (PB), and PHT as monotherapy. Dose-dependent risk has been demonstrated with VPA for MCMs and cognitive consequences. CBZ groups show normal neurodevelopment. Increased clearance of most of the AEDs occurs during pregnancy. Use of therapeutic drug monitoring during pregnancy with LTG reduces the risk for seizure worsening. The consistent findings of increased teratogenic risk for VPA should discourage use of this medication as first-line treatment in women of childbearing age.
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PMID:Antiepileptic drugs during pregnancy: what is known and which AEDs seem to be safest? 1908 17

Action of antiepileptic drugs in immature brain may differ from that in adult brain. The aim of our study was to study an anticonvulsant action of lamotrigine and phenytoin, i.e. two drugs active against partial seizures in adult experimental animals as well as human patients, in a model of simple partial seizures in immature rats. Epileptic foci were induced by local application of bicuculline methiodide on sensorimotor cortical area of 12-day-old rat pups. The animals were pretreated with lamotrigine (LTG, 10 or 20 mg/kg i.p.) or phenytoin (PHT, 15, 30 or 60 mg/kg i.p.). Control rats for LTG received saline, controls for PHT solvent composed of propyleneglycol, ethanol and water. Influence of either drug on interictal activity was negligible. High doses of both LTG and PHT suppressed the transition into ictal phases and shortened the duration of persisting seizures. The tricomponent solvent exhibited moderate activity against ictal activity if compared with saline controls. The two drugs exhibited similar action in our model, i.e. the suppression of secondary generalization from epileptic focus. This action is comparable to that described for human patients and adult experimental animals. In favor of lamotrigine speaks the absence of serious side effects.
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PMID:Similar effects of lamotrigine and phenytoin against cortical epileptic foci in immature rats. 1924 15

Some studies suggest a higher risk of hypertension in people with epilepsy. Captopril, a potent and selective angiotensin-converting enzyme (ACE) inhibitor, is a well known antihypertensive drug. Besides the peripheral renin-angiotensin system (RAS), ACE inhibitors are also suggested to affect the brain RAS which might participate in the regulation of seizure susceptibility. The purpose of the current study was to evaluate the effect of captopril on the protective action of numerous antiepileptic drugs (carbamazepine [CBZ], phenytoin [PHT], valproate [VPA], phenobarbital [PB], oxcarbazepine [OXC], lamotrigine [LTG] and topiramate [TPM]) against maximal electroshock-induced seizures in mice. This study was accompanied by an evaluation of adverse effects of combined treatment with captopril and antiepileptic drugs in the passive avoidance task and chimney test. Captopril (25 and 50 mg/kg i.p.) did not influence the threshold for electroconvulsions. Among the tested antiepileptics, captopril (25 and 50 mg/kg i.p.) potentiated the antiseizure action of CBZ, decreasing its ED(50) value from 12.1 to 8.9 and 8.7 mg/kg, respectively. Moreover, captopril (50 mg/kg i.p.) enhanced the anticonvulsant activity of LTG. ED(50) value for LTG was lowered from 5.1 to 3.5 mg/kg. The observed interactions between captopril and CBZ or LTG were pharmacodynamic in nature as captopril did not alter plasma and total brain concentrations of these antiepileptics. The combinations of captopril with antiepileptic drugs did not lead to retention deficits in the passive avoidance task or motor impairment in the chimney test. Based on the current preclinical data, it is suggested that captopril may positively interact with CBZ and LTG in epileptic patients. The combinations of captopril with the remaining antiepileptics (PHT, VPA, PB, OXC and TPM) seem neutral.
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PMID:Captopril potentiates the anticonvulsant activity of carbamazepine and lamotrigine in the mouse maximal electroshock seizure model. 2071 8

Cognition is a complex mental function that involves attention, concentration, recognition, judgment, and memory and relates to emotion to some extent. Cognitive dysfunction in epilepsy probably results from various factors such as frequent seizures themselves, an underlying brain lesion, and antiepileptic drugs (AEDs). However, the contribution of these factors remains ambiguous in many cases. From the therapeutic perspective, simplifying the use of AEDs, avoiding polypharmacy, and avoiding overdosing are important in almost all cases. Most classical AEDs (PB, PHT, CBZ, and SV) have some untoward effect on cognition, particularly, PB. On the other hand, many new drugs (GBP, LTG, and LEV) do not have such effects but they do affect emotions. TPM seems to have some untoward effect on cognition and emotion.
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PMID:[Cognitive dysfunction and antiepileptic drugs]. 2144 41

Gingival overgrowth is a common adverse effect of therapy with Phenytoin, having important medical and cosmetic implications. Poor periodontal hygiene is an important risk factor for severity of Phenytoin-induced gingival overgrowth (PIGO), which is a time-dependent process. There is complex interplay of altered fibroblast biology, connective tissue turnover, inflammatory processes, and growth factors on a background of genetic susceptibility to produce increase in various components of interstitial matrix in PIGO tissue. Treatment options have included change of PHT to another anti-seizure drug, measures to improve periodontal hygiene and gingivectomy. There is conclusive evidence that folic acid supplementation significantly decreases the incidence of PIGO.
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PMID:Phenytoin-induced gingival overgrowth. 2165 5

Continuous electroencephalography (cEEG) is increasingly used to detect both clinical and subclinical seizures in patients with traumatic brain injury (TBI) or subarachnoid hemorrhage (SAH). We assess whether EEG findings predict outcomes in TBI/SAH patients enrolled in a levetiracetam (LEV) vs. fosphenytoin (fos-PHT) seizure prevention trial (NCT00618436). This prospective, single-blinded, comparative trial randomized 52 patients with TBI or SAH to receive prophylactic LEV or fos-PHT. Continuous video EEG monitoring was conducted for the initial 72 h of medication administration. The association between EEG findings (degree of generalized and focal slowing, presence and frequency of epileptiform discharges and seizures) and outcomes (Glasgow Outcomes Scale-Extended (GOS-E) and Disability Rating Scale (DRS)) at discharge, 3 and 6 months was assessed using a generalized linear model. Severity of generalized slowing tended to be associated with outcomes in both treatment groups (discharge DRS, p=0.042; discharge GOS-E, p=0.026; 3 month DRS, p=0.051). The presence of focal slowing, the presence and frequency of epileptiform discharges and the presence of seizures were not predictive of outcome in either treatment group (all p>0.15). While it has been shown that LEV is associated with better outcome than fos-PHT when used as seizure prophylaxis in brain injury, aside from severity of generalized slowing, electrographic findings of focal slowing, epileptiform discharges, and seizures were not themselves associated with outcomes in patients with TBI or SAH enrolled in a randomized clinical trial.
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PMID:Initial EEG predicts outcomes in a trial of levetiracetam vs. fosphenytoin for seizure prevention. 2234 34


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