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)

H2-antagonists such as cimetidine and ranitidine are metabolized by cytochrome P-450. In this way they may interfere with theophylline metabolism. Cimetidine is known to have this effect and frequently to induce a theophylline toxic effect, while data concerning ranitidine are more uncertain. In this paper, we report the case of a 67-year-old woman with non-insulin dependent diabetes. She was taking aminophylline for respiratory failure and after ranitidine infusion exhibited generalized convulsions. Theophylline values which were monitored within the therapeutic range, increased toxic levels after ranitidine therapy and epileptic episodes. The increase in theophylline levels was associated with a further reduction in the clearance rate of the bronchodilator. We think that ranitidine may combine with other clinical factors known to reduce theophylline metabolism mainly in the elderly and severely ill patients. Theophylline-induced seizures may occur when theophylline serum levels are slightly above the therapeutic range, as in our case report.
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PMID:Seizures during concomitant treatment with theophylline and ranitidine: a case report. 209 63

Theophylline, with its narrow therapeutic margin, is a common cause of iatrogenic and deliberate overdose. Most cases of self-poisoning are with sustained release preparations, with peak concentrations occurring up to 12 or more hours after overdose. Toxic symptoms are often seen at concentrations above 15 mg/L. Theophylline is metabolised within the cytochrome P-450 system, with an average total body clearance of 50 to 60 ml/min. Clearance is, however, affected by many factors such as other drugs or disease, and in overdose zero order kinetics may result in prolonged half-lives. Toxicity is characterised by agitation, tremor, nausea, vomiting, abdominal pains, seizures, and tachyarrhythmias. Hypokalaemia and metabolic acidosis are more profound in acute toxicity, and hypercalcaemia is usually present. Seizures occur at lower concentrations after chronic over-medication than after acute overdose. Gastric lavage should be performed in all patients presenting early, and an oral multiple dose charcoal regimen started with 50 to 100g charcoal, repeating with 50g doses and checking theophylline concentrations at 2- to 4-hour intervals. Multiple dose charcoal can be expected to double the clearance of theophylline, being as effective as a haemodialysis. Of the invasive techniques available, charcoal haemoperfusion is the most effective, increasing clearance 4- to 6-fold. Supportive care is particularly important. The aggressive supplementation of potassium, treatment of emesis with droperidol and ranitidine, and treatment of tachyarrhythmias and hypotension (possibly with propranolol), together with oral multiple dose charcoal may obviate the need for haemoperfusion. Seizures suggest increased morbidity and mortality. Charcoal haemoperfusion should be considered if plasma concentrations are greater than 100 mg/L in an acute intoxication or greater than 60 mg/L in a chronic intoxication. The decision to haemoperfuse should not be based on plasma concentrations alone, but an overall evaluation of the patient's laboratory and clinical status.
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PMID:Role of extracorporeal drug removal in acute theophylline poisoning. A review. 330 69

The [(biphenylyloxy)alkyl]imidazoles were found to be potent anticonvulsants. The most potent compound of the series, 1-[2- ([1,1'-biphenyl]-2-yloxy)ethyl]-1H-imidazole (4), had an ED50 of 15.5 mg/kg against maximal-electroshock-induced seizures in mice after oral administration; the horizontal screen ED50 was 320 mg/kg, revealing that the compound has a protective index of 21. Homologues bearing three- and four-carbon tethers between the imidazole and biphenylyloxy moieties were also active, but their potency was attenuated relative to 4. Congeners with the imidazolylalkoxy moiety at the meta or para positions of biphenyl were also less active. All these compounds were potent potentiators of hexobarbital-induced sleeping time in mice, presumably via the well-known imidazole-mediated inhibition of cytochrome P-450. The structural features governing the anticonvulsant and sleeping-time activities appear to be distinct, but a complete dissociation of these two effects has not been achieved. Thus, the potential of these compounds as clinically useful antiepileptic drugs would appear to be limited.
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PMID:Imidazole anticonvulsants: structure-activity relationships of [(biphenylyloxy)alkyl]imidazoles. 357 83

A recently discovered and structurally distinct class of antiepileptic drugs is the (arylalkyl)imidazoles. Two independently discovered representatives of this class, denzimol (alpha-[4-(2-phenylethyl)phenyl]-1H-imidazole-1-ethanol) and nafimidone (2-(1H-imidazol-1-yl)-1-(2-naphthalenyl)ethanone), are undergoing clinical evaluation. Our structure-activity relationship (SAR) studies revealed that in addition to the naphthalenyl and phenethylphenyl aryl moieties of nafimidone and denzimol, respectively, fluorenyl, benzo[b]thienyl, and benzofuranyl aryl groups provided several highly active (arylalkyl)imidazole anticonvulsants. These structurally diverse aryl moieties, and comparable anticonvulsant activities, lend credence to the hypothesis that the pharmacophore of this class of anticonvulsants is the alkylimidazole portion of the molecule, with the lipophilic aryl portion enabling penetration of the blood-brain barrier. We focused our SAR studies on the (fluorenylalkyl)imidazole series. A representative compound from this series is 1-(9H-fluoren-2-yl)-2-(1H-imidazol-1-yl)ethanone. This agent was twice as potent as nafimidone in inhibiting maximal electroshock seizures in mice (po ED50's = 25 and 56 mg/kg, respectively) and considerably less toxic in the rat (po LD50's = 4550 and 504 mg/kg, respectively). The tertiary alcohol alpha-(9H-fluoren-2-yl)-alpha-methyl-1H-imidazole-1-ethanol was as potent as denzimol in mice (po ED50's = 10 and 12 mg/kg, respectively). This series of imidazole anticonvulsants was highly selective; while many compounds displayed potent antielectroshock activity, little or not activity was observed against pentylenetetrazole-induced clonic seizures or in the horizontal screen test for ataxia. All active compounds that we tested in this series, as well as denzimol and nafimidone, potentiated hexobarbital-induced sleeping time in mice, probably by imidazole-mediated inhibition of cytochrome P-450. The SAR's for the anticonvulsant activity and the sleeping time potentiation were similar. The propensity of these (arylalkyl)imidazole anticonvulsants to interact strongly with cytochrome P-450 and thereby impair the metabolism of other antiepileptic drugs may severely limit their clinical utility as anticonvulsants.
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PMID:Structure-activity relationships of (arylalkyl)imidazole anticonvulsants: comparison of the (fluorenylalkyl)imidazoles with nafimidone and denzimol. 374 10

Serum concentrations of the anticonvulsants phenytoin, phenobarbital, and carbamazepine were compared before and after patients received influenza vaccine. Serum drug concentrations were measured in patients at a state school for the mentally retarded who were receiving continuous anticonvulsant therapy with only one of the study drugs and taking no other medication regularly. Patients with hepatic or renal disease or other medical problems were excluded. All study patients had steady-state serum concentrations of the anticonvulsants before they were vaccinated with Influenza Virus Vaccine, USP, Types A and B, Whole Virus. Trough serum concentrations of anticonvulsants were measured by enzyme-mediated immunoassay technique immediately before vaccination and on days 7, 14, and 28. Data were excluded for patients who required dosage adjustments because of toxicity or seizures. On day 7, mean serum concentrations of phenytoin (15.16 +/- 5.52 micrograms/mL, n = 8) and phenobarbital (17.25 +/- 6.77 micrograms/mL, n = 27) were significantly higher than at baseline. Mean carbamazepine concentrations on day 7 (6.89 +/- 2.18 micrograms/mL, n = 20) were not significantly greater than baseline; however, there was a significant increase from day 7 to day 14. In patients who are receiving phenytoin, phenobarbital, or other drugs metabolized by the cytochrome P-450 system, serum concentrations of these drugs may increase as a result of influenza vaccination, and dosage adjustments may be necessary.
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PMID:Effect of influenza vaccine on serum anticonvulsant concentrations. 378 Jan 49

It has not yet been determined whether human liver contains inducible cytochromes P-450 similar to those that catalyze the oxidative metabolism of foreign substances in animals. We carried out immunoblot analyses of liver microsomes isolated from eight patients and found that each contained a cytochrome P-450, termed HLp, that reacted with antibodies directed against P-450p, a rat liver cytochrome that is inducible by the anti-glucocorticoid pregnenolone-16 alpha-carbonitrile, by glucocorticoids, by anti-seizure drugs, and by such macrolide antibiotics as triacetyloleandomycin. In the two patients who received dexamethasone and anti-seizure medications and in the one patient who was given triacetyloleandomycin, the concentrations of immunoreactive HLp and the ability to demethylate erythromycin and/or to convert triacetyloleandomycin to a metabolite that forms a spectral complex with cytochrome P-450 heme (catalytic properties unique to P-450p in rat liver) were significantly higher as compared to the values for patients who received no inducing drugs. We purified HLp to homogeneity and found that it was immunochemically related to P-450p and to its homologue in the rabbit (LM3c), actively demethylated erythromycin in a reconstituted system, exhibited electrophoretic mobility identical to that of P-450p, and shared 57% homology in its NH2-terminal amino acid sequence with that of a pregnenolone-16 alpha-carbonitrile-inducible rat cytochrome P-450. We conclude that HLp is a human representative of the multigene family of the glucocorticoid-inducible cytochromes P-450.
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PMID:Identification of an inducible form of cytochrome P-450 in human liver. 389 85

This study was designed to assess the strain differences in pentobarbital toxicity, narcosis, the development of tolerance and physical dependence, the half-life of pentobarbital and the activities of hepatic microsomal electron transfer chain in DBA/2J, C57BL/6J and ICR mice. The comparisons of responses to acute pentobarbital-induced narcosis with two different doses revealed that DBA was most sensitive among these strains. When continuous administration of pentobarbital by pentobarbital pellet implantation is concerned, four criteria were used to assess strain differences: 1) determination of the duration of the loss of righting reflex during pentobarbital pellet implantation; 2) cumulative mortality after pentobarbital pellet implantation; 3) degree of tolerance development after 3 days of s.c. implantation of a 75-mg pentobarbital pellet by the relative decrease in the pentobarbital sleeping time; and 4) assessment of hyperexcitability by pentylenetetrazol- and audiogenic-induced seizures after pellet removal. The order of susceptibility to continuous pentobarbital pellet implantation was found to be as follows: DBA/2J > C57BL/6J > ICR. The biochemical data also revealed that the half-life of pentobarbital in DBA/2J mice was significantly longer than that of C57BL/6J or ICR mice in both brain and serum. Further studies also showed that DBA/2J mice have lower hepatic cytochrome P-450 and cytochrome b5 levels and NADPH dehydrogenase and NADPH-cytochrome c reductase activities as compared with the other strains of mice. However, these parameters were markedly induced in DBA/2J mice after the development of tolerance to pentobarbital. It appears that the differences in genetic variation could be of importance for further studies in gaining insight of the mechanism of barbiturate tolerance and dependence.
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PMID:Pharmacological responses to pentobarbital in different strains of mice. 719 35

Carbamazepine (Tegretol, CBZ) is an anticonvulsant drug that is very effective in the treatment of tonic-clonic seizures and is gaining acceptance as a treatment for various psychiatric disorders. The drug is embryotoxic in rodents and has been reported to produce neural tube defects in approximated 1% of prenatally exposed human offspring. It is metabolized by the cytochrome P-450 system to a stable, pharmacologically active epoxide intermediate, carbamazepine-10, 11-epoxide. It is currently unknown whether the parent compound, the epoxide intermediate or some other metabolite is the embryotoxic agent. The present study was designed to determine the embryotoxicity of CBZ and its epoxide intermediate (CBZ-E) in a rodent whole embryo culture system. Rat embryos were cultured beginning on day 9 of gestation (GD 9), and mouse embryos were cultured beginning in GD 8. All embryos were cultured for 48 hr in medium containing various concentrations of either CBZ or CBZ-E. Mice were more sensitive to the effects of CBZ than were rats. The parent compound was embryotoxic to mouse embryos at concentrations as low as 12 micrograms, but it was only embryotoxic at 60 micrograms/ml to rat embryos. CBZ-E was not embryotoxic to either species at concentrations as high as 48 micrograms/ml. These results suggest that the parent compound is the embryotoxic agent and that the epoxide intermediate plays no role in the drug's embryotoxic mechanism.
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PMID:In vitro embryotoxicity of carbamazepine and carbamazepine-10, 11-epoxide. 891 69

Oxcarbazepine (OXC, trade names Timox, Trileptal is a new antiepileptic drug (AED) for treatment of mono- and adjunctive therapy of partial seizures with or without secondary generalization for adults and children older than 6 years of age. Although OXC was developed through structural variation of carbamazepine in order to avoid side effects from metabolites, significant differences have emerged between the two drugs. The mechanism of action mainly involves blockade of sodium currents but differs from CBZ by modulating different types of calcium channels. In contrast to CBZ, which is oxidized by the cytochrome P-450 system, OXC undergoes reductive metabolism at its ketomoiety to form MHD, which is glucuronidated and excreted in the urine. Involvement of the hepatic cytochrome P450-dependent enzymes in the metabolism of OXC is minimal. This allows for better combining of OXC with other AEDs such as valproate. In postmarketing experience of over 800,000 patient-years, OXC also showed an advantageous risk-benefit ratio. Oxcarbazepine should be preferred over CBZ and other older AEDs due to its very good efficacy and better side effect profile in children, adolescents, and adults with partial seizures.
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PMID:[How is oxcarbazepine different from carbamazpine?]. 1477 Feb 87

Oxcarbazepine (OXC, Trileptal) is a modern antiepileptic drug (AED) used as both monotherapy and adjunctive therapy for the treatment of partial seizures with or without secondary generalization in adults and children above 4 years (USA) or 6 years (Europe) of age. Although OXC has been developed through structural variation of carbamazepine (CBZ) with the intent to avoid metabolites causing side effects, significant differences have emerged between the two drugs. The mechanism of action of OXC involves mainly blockade of sodium currents but differs from CBZ by modulating different types of calcium channels. In contrast to CBZ, which is oxidized by the cytochrome P-450 system, OXC undergoes reductive metabolism at its keto moiety to form the monohydroxy derivative (MHD), which is glucuronidated and excreted in the urine. The involvement of the hepatic cytochrome P-450-dependent enzymes in the metabolism of OXC is minimal. Although it does not prevent interaction with oral contraceptives, it explains why OXC can be more effectively combined with other AEDs such as valproate compared with CBZ. Switching from CBZ to OXC normalized CBZ-associated thyroid and sexual hormone abnormalities and pathological lipid values in small patient samples. OXC is often better tolerated than CBZ and causes fewer rashes than CBZ. Add-on or substitution treatment with OXC was effective in controlled trials even when CBZ did not achieve sufficient seizure control. This constitutes compelling clinical evidence that OXC and CBZ are distinctly different medications. From postmarketing experience in over 1,000,000 patient years, OXC had an advantageous risk-benefit balance also in comparison to other new AEDs. OXC should be preferred over CBZ and other older AEDs because of its proven efficacy and excellent side effect profile in children, adolescents, and adults with partial seizures.
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PMID:What is the evidence that oxcarbazepine and carbamazepine are distinctly different antiepileptic drugs? 1538 Jan 12


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