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)

The pharmacokinetics of antiepileptic drugs may be altered during pregnancy, resulting in decline of serum concentrations and subsequent suboptimal control of seizures. We investigated changes which may occur during pregnancy in hepatic drug handling by comparing metabolic ratios of 15 pregnant epileptic women to 15 nonpregnant epileptic women, as well as 10 pregnant nonepileptic and 10 nonpregnant nonepileptic controls. We used the caffeine test to describe several enzyme activities: P450 1A2, xanthine oxidase, n-acetyltransferase and hydroxylation. For this end, ratios were calculated among a number of metabolites of the main demethylation pathway of caffeine. In addition, we measured D-glucaric acid excretion for specific characterization of antiepileptic drug metabolism. Paired comparison of epileptic women in late pregnancy and six to eight weeks post partum revealed statistically significant decreases in P450 1A2, xanthine oxidase and n-acetyltransferase activities, and a significantly increased hydroxylation activity during pregnancy. Twenty-one of the 30 epileptic women (70%) were found to be fast acetylators, whereas the normal distribution in the nonepileptic control groups was 50%. Excretion of D-glucaric acid was significantly increased in all epileptic patient groups as compared to the matched nonepileptic control groups. Importantly, it was also significantly increased in the pregnant nonepileptic control group as compared to the nonpregnant nonepileptic women. Overall, our results suggest that enzymatic pathways involved in antiepileptic drug metabolism tend to be increased during pregnancy as a potential cause for observed lower serum concentrations of these drugs.
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PMID:Pregnancy-induced changes in drug metabolism in epileptic women. 203 16

Topiramate [TPM, 2,3:4,5-bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate] (RWJ-17021-000, formerly McN-4853) is a structurally novel antiepileptic drug (AED). The preclinical anticonvulsant profile suggests that TPM acts primarily by blocking the spread of seizures. TPM was highly effective in the maximal electroshock (MES) seizure test in rats and mice. Activity was evident < or = 0.5 h after oral administration and lasted at least 16 h. The ED50 values 4 h after oral dosing were 13.5 and 40.9 mg/kg in rats and mice, respectively. TPM blocked pentylenetetrazol (PTZ)-induced clonic seizures at high doses in mice (ED50 = 1,030 mg/kg orally, p.o.). With motor incoordination and loss of righting reflex used as indicators of neurologic impairment, the neuroprotective index (TD50/MES ED50) for TPM was equivalent or superior to that of several approved AEDs. In mice pretreated with SKF-525A (a P450 enzyme inhibitor), the anticonvulsant potency was either increased or unaffected when TPM was tested 0.5, 1, or 2 h after i.p. administration, suggesting that TPM rather than a metabolite was the active agent. In mice pretreated with reserpine or tetrabenazine, the activity of TPM in the MES test was markedly reduced. TPM was inactive in a variety of receptor binding, neurotransmitter uptake, and ion channel tests. TPM weakly inhibited erythrocyte carbonic anhydrase (CA) activity. However, the anticonvulsant activity of TPM appears to differ mechanistically from that of acetazolamide.
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PMID:Topiramate: preclinical evaluation of structurally novel anticonvulsant. 815 72

Basic haematologic parameters and serum gamma-glutamyl-transferase (GGT) activity were evaluated in a five-year prospective follow-up study of 25 patients with newly diagnosed epilepsy starting treatment with carbamazepine. In addition, we evaluated the effects of replacing carbamazepine by oxcarbazepine on these parameters, erythrocyte folate concentrations and serum vitamin B12 levels in 12 male patients with epilepsy. The mean white blood cell count (WBC) and red blood cell count decreased after 2 months carbamazepine therapy, and remained at this lower level during the first 5 years of medication. The mean erythrocyte volume (MCV) and the serum GGT activity increased progressively during carbamazepine treatment. The serum GGT activity decreased after replacing carbamazepine by oxcarbazepine indicating a normalization of the liver P450 enzyme system induction. Concomitantly, the erythrocyte folate concentrations and serum levels of vitamin B12 increased, and the WBC increased and MCV decreased. It is probable that the changes in folate metabolism and serum vitamin B12 concentrations are due to normalization of the liver P450 enzyme system induction after the change of medication. The haematologic changes during carbamazepine medication, and their normalization after replacing carbamazepine by oxcarbazepine are possibly related to changes in folate and vitamin B12 metabolism.
Seizure 1997 Jun
PMID:Basic haematological parameters, serum gamma-glutamyl-transferase activity, and erythrocyte folate and serum vitamin B12 levels during carbamazepine and oxcarbazepine therapy. 920 49

Some six or so physiological systems, essential to normal mammalian life, are involved in poisoning; an intoxication that causes severe injury to any one of them could be life threatening. Reversible chemical reactions showing Scatchard-type binding are exemplified by CO, CN- and cyclodiene neurotoxin insecticide intoxications, and by antigen-antibody complex formation. Haemoglobin (Hb) molecular biology accounts for the allosteric co-operativity and other characteristics of CO poisoning, CN- acts as a powerful cytochrome oxidase inhibitor, and antigen binding in a deep antibody cleft between two domains equipped with epitopes for antigen-binding groups explains hapten-specific immune reactions. Covalent chemical reactions with second-order (SN2) kinetics characterize Hg and Cd poisonings, the reactions of organophosphates and phosphonates with acetylcholinesterase and neurotoxic esterase and the reaction sequence whereby Paraquat accepts electrons and generates superoxide under aerobic conditions. Indirect carcinogens require cytochrome P450 activation to form DNA adducts in target-organ DNA and cause cancer, but a battery of detoxifying enzymes clustered with the P450 system must be overcome. Thus, S-metabolism competes ineffectively with target DNA for reactive vinyl chloride (VC) metabolites, epoxide hydrolase is important to the metabolism and carcinogenicity of alfatoxins and polycyclic aromatic hydrocarbons (benzo[a]pyrene, etc.), and the non-toxic 2-naphthylhydroxylamine N-glucuronide acts as a transport form in 2-naphthylamine bladder cancer. VC liver-cancer pathogenesis is explicable in terms of the presence of the glutathione S-transferase detoxifying system in hepatocytes and its absence from the fibroblastic elements, and of the VC concentrations reaching the liver by different administrative routes. In VC carcinogenicity, chemical reactions give imidazo-cyclization products with nucleoside residues of target DNA, and in benzene leukaemia, Z,Z-muconaldehyde forms cyclic products containing a pyrrole residue linked to purine. Increased HbCO concentrations reduce the O2-carrying capacity of the blood, and the changed shape of the O2-Hb dissociation curve parallels disturbance in O2 unloading. CN- acts on electron transport and paralyses respiration. In telodrin poisoning, preconvulsive glutamine formation abstracts tricarboxylic acid intermediates incommensurately with normal cerebral respiration. Antigen-antibody complexing depletes the antibody titre, available against infection. At high doses of Cd, Cd-thionein filtered through the kidneys is reabsorbed and tubular lesions produced. Some organophosphate insecticides promote irreversible acetylcholinesterase phosphorylation and blockade nerve function, and others react with neurotoxic esterase to cause delayed neuropathy. The evidence for Paraquat pulmonary poisoning suggests a radical mechanism involving three interrelated cyclic reaction stages. The action of N- and O8 (O substituent in 6-position of the purine) demethylases explains deletion mechanisms for DNA-alkyl adducts. DNA-directed synthesis in the presence of ultimate carcinogens provides for an estimation of misincorporations, which implicate the same transversions as those found by direct mutagenicity testing. Chemical carcinogens recognize tissue-sensitive cells and modify their heritable genetic complement. Oncoproteins encoded by activated oncogenes signal the transformation of normal cells into cancer cells. The importance of the H-ras oncogene and p53 tumour-suppressor gene is stressed. Antidotal action is analysed; for example, parenteral glutamine administration to telodrin-intoxicated rats restores the depleted cerebral glutamate level and prevents seizures. Glutamate acts as anticonvulsant in petit mal epilepsy. In general, therefore, the reaction of the toxicant-related substance with the relevant target-tissue macromolecule accounts for the biochemical/biological events at a cellular level a
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PMID:Toxic action/toxicity. 1074 Aug 94

The frequency of oestrus cycles in female mice was significantly reduced by the implantation of a pellet of subcutaneous ketoconazole (50 mg every 6 days). The effect was more pronounced after 22 days than after 13 days and it was probably related with the progressive reduction in steroid synthesis induced by the inhibition of key steroidogenic P450 cytochromes by the drug. In addition, the influence of ketoconazole on the incidence of seizures after the administration of intraperitoneal pentylenetetrazol was evaluated in female mice. Pentylenetetrazol produced a higher percentage of seizures during dioestrus than during oestrus. Pretreatment with ketoconazole significantly increased the percentage of animals with induced seizures in oestrus but not in dioestrus as compared to controls, probably through reduced progesterone levels. The reduced seizure threshold confirm the modulatory role exerted by progesterone on central nervous system excitability, and may be relevant in epileptic patients undergoing antifungal therapy.
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PMID:Effects of ketoconazole on oestrus cycle and convulsant action of pentylenetetrazol in mice. 1190 57

The clinical aspect of porphyria has been investigated, and it is well known that porphyrinogens such as estrogens and alcohol or other inducers of P450 isoenzymes exacerbate the porphyric state. However, there can be a delay in diagnosing porphyria and a difficulty in selecting safe medicine for it even today. A 21-year-old woman developed epilepsy, disturbance of mental state, and spastic tetraparesis during the convalescent period after acute viral encephalitis. She was diagnosed with porphyria after the fifth hospitalization. In the course of modifying her anticonvulsant regimen, the authors examined the 6beta-hydroxycortisol/cortisol ratio (6beta-OHF/F) in her urine, which can be the index of hepatic CYP3A4 activity, with electrospray ionization/mass spectrometry/mass spectrometry (ESI/MS/MS). Generalized and partial complex seizures, other neurological signs and symptoms, and laboratory data were improved after modification of her anticonvulsant regimen. This is the first report of evaluating the urinary 6beta-hydroxycortisol/cortisol ratio in a case of porphyria.
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PMID:Microsomal enzyme induction and clinical aggravation of porphyria: the evaluation of human urinary 6beta-hydroxycortisol/cortisol ratio as the index of hepatic CYP3A4 activity. 1246 33

Cancer and epilepsy commonly co-occur, and concomitant administration of antiepileptic (AEDS) and chemotherapeutic drugs (CTDs) is necessary in many cases. Many drugs are metabolised by the hepatic cytochrome P450 (CYP) isoenzyme system, and coadministration of AEDs and CTDs can lead to clinically relevant interactions by induction or inhibition of enzymes in shared metabolic pathways. These interactions can cause insufficient tumour and seizure control or lead to unforeseen toxicity. Enzyme-inducing AEDs reduce the effects of taxanes, vinca alkaloids, methotrexate, teniposide, and camptothecin analogues. Inhibition of the metabolism of nitrosoureas or etoposide by valproic acid can lead to CTD toxicity. Poor seizure control may result from the combinations of phenytoin with cisplatin or corticosteroids, and valproic acid with methotrexate. Increased toxicity of AEDs can occur when phenytoin is combined with 5-fluorouracil. Use of enzyme-inducing AEDs should be avoided in patients with cancer, particularly in association with chemotherapy. Generally, valproic acid-although not free from interactions-would be the agent of first choice. Some of the newer AEDs not metabolised by the P450 system may prove to be good alternatives.
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PMID:Interactions between antiepileptic and chemotherapeutic drugs. 1284 18

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

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

N-methyl-tetramethylcyclopropanecarboxamide (MTMCD) is a new antiepileptic drug (AED) structurally related to valproic acid (VPA) that has a broad spectrum of anticonvulsant activity including models of therapy-resistant epilepsy. The purpose of this study was to identify in vivo metabolites of MTMCD that could contribute to its anticonvulsant efficacy. The metabolism of MTMCD was studied in mice, in human liver microsomes (HLM), and in recombinant human CYP isoforms with focus on formation of the hydroxylation product, N-hydroxymethyl-tetramethylcyclopropanecarboxamide (OH-MTMCD) and the N-demethylation product tetramethylcyclopropanecarboxamide (TMCD). The anticonvulsant activity of MTMCD's metabolites was evaluated in the maximal electroshock (MES), subcutaneous metrazole (s.c. Met), and in the 6Hz model in mice. In mice, OH-MTMCD was identified as a phase I metabolite of MTMCD and detected in plasma and brain after administration of MTMCD. In human liver microsomes MTMCD was biotransformed to OH-MTMCD but not to TMCD. Chemical inhibition studies suggested that MTMCD hydroxylation is mainly mediated by CYP 2A6 and CYP 2C19, which was confirmed using cDNA-expressed P450 isozymes. OH-MTMCD was a broad-spectrum anticonvulsant and possessed significant anticonvulsant activity in mouse models of partial and generalized seizures (ED50 values 75-220mg/kg), but was less potent than MTMCD. As OH-MTMCD was also present at lower concentrations than MTMCD in mouse brain, it is likely that MTMCD itself and not one of its metabolites is responsible for its activity in therapy-resistant epilepsy.
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PMID:Metabolism of a new antiepileptic drug, N-methyl-tetramethylcyclopropanecarboxamide, and anticonvulsant activity of its metabolites. 1506 69


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