Validation of incorporating flurbiprofen into the Pittsburgh cocktail.

BACKGROUND: We have previously shown that flurbiprofen metabolism to 4'-hydroxyflurbiprofen provides an in vivo measure of cytochrome P450 (CYP) 2C9 activity. This study evaluated the possibility of incorporating flurbiprofen into the current 5-drug Pittsburgh cocktail. METHODS: In a randomized, 3-way, Latin-square, crossover-design study, 24 healthy subjects (mean age [+/-SD], 47.8 +/- 15.1 years) received flurbiprofen (50 mg) and the Pittsburgh 5-drug cocktail (100 mg caffeine, 100 mg mephenytoin, 10 mg debrisoquin [INN, debrisoquine], 250 mg chlorzoxazone, and 100 mg dapsone) separately and in combination on 3 occasions over a period of 5 weeks. Urine was collected from 0 to 8 hours, and plasma was obtained at 4 and 8 hours after drug administration. Parent drug and metabolite concentrations were measured to determine phenotypic indices for each of the metabolizing enzymes. RESULTS: The geometric mean ratio and 90% confidence interval of the phenotypic indices were included within the 80% to 125% bioequivalence range for each of the probe drugs. There were no statistically significant differences between the phenotypic indices determined after administration of the 5-drug and 6-drug cocktails. However, there was a small but statistically significant increase (7.5%, P = .03) in the 8-hour urinary flurbiprofen recovery ratio after administration of the 6-drug cocktail compared with that after administration of flurbiprofen alone. The 6-drug cocktail was well tolerated. CONCLUSION: The results of this study show that caffeine (CYP1A2), chlorzoxazone (CYP2E1), dapsone (N-acetyltransferase 2), debrisoquin (CYP2D6), flurbiprofen (CYP2C9), and mephenytoin (CYP2C19) can be simultaneously administered in low doses without metabolic interaction.

Reversible changes in echo planar perfusion- and diffusion-weighted MRI in status epilepticus.

Perfusion imaging (PI) demonstrated increased perfusion and diffusion-weighted imaging (DWI) showed high signal limited to the left temporoparietal cortex in a 68-year-old man with nonconvulsive status epilepticus. The EEG showed a slow delta-wave focus. The patient recovered and PI, DWI and EEG changes completely resolved.

Anticonvulsant therapy in small animals.

Successful control of seizures with anticonvulsant drugs reflects a balance in achieving seizure control while minimizing undesirable drug side effects. Variability in the disposition of anticonvulsants and interaction among them are important confounders of successful therapy. This article will provide a review of selected anticonvulsants, focusing on drugs most likely to control seizures in small animals. The proper use of anticonvulsants will be discussed, with emphasis on differences in individual drug disposition, detection of these differences, and rational approaches to responding to these differences by dose modification. The primary target of discussion will be treatment of generalized, tonic clonic seizures, the most common type afflicting small animals. Opinions regarding anticonvulsive therapy vary among clinicians. Most of the comments and recommendations offered in this discussion reflect observations made from our therapeutic drug monitoring service and completed and ongoing clinical trials that focus on the use of anticonvulsants used either alone or in combination with phenobarbital.

Pharmacokinetics of R-enantiomeric normephenytoin during chronic administration in epileptic patients.

Stereoselective metabolism has been demonstrated for mephenytoin (MHT), R-MHT being demethylated to the pharmacologically active metabolite 5-phenyl-5-ethylhydantoin (PEH; nirvanol), and S-MHT undergoing aromatic hydroxylation to 4-OH-MHT, with formation of an intermediate arene oxide metabolite. PEH is responsible for the therapeutic effect, whereas 4-OH-MHT is rapidly eliminated by the kidneys. The arene oxide metabolite may have implications in MHT toxicity. The metabolism of PEH is also stereospecific. In the present study, the R-enantiomer of PEH (R-PEH; R-normephenytoin) was administered chronically during 8 weeks to four epileptic patients, as a single dose every 3 days. The half-lives of R-PEH ranged from 77.7 to 175.8 h, and correlated closely with the creatinine clearance. Mean urinary recovery of R-PEH was 86.6% of the dose at steady state, with 4-OH-PEH accounting for only 5%. This indicates that, unlike Nirvanol (a racemic mixture of R- and S-PEH), R-PEH is only minimally metabolized, even after several weeks of treatment and despite potential enzymatic autoinduction and heteroinduction by other antiepileptic drugs. Complete blood counts and liver function tests revealed no alteration, and no other adverse effects were noted. If arene oxide intermediate metabolites are indeed involved in the toxicity of MHT and nirvanol, R-PEH may represent a safer alternative.

Influence of anticonvulsant drugs on thyroid hormones in epileptic children.

Thyroid function tests were studied in epileptic children undergoing long-term anticonvulsive therapy with phenytoin, primidone or mephenytoin. Serum T4 was decreased in all three treated groups, serum T3 was diminished only in those treated with phenytoin or primidone. FT4 was also significantly decreased while serum TSH and TBG were not affected in the treated patients. The effect of anticonvulsant drugs on thyroid hormone catabolism and peripheral conversion of T4 seems to be important in these alterations.

Disposition of mephenytoin and its metabolite, nirvanol, in epileptic patients.

We investigated the conversion of mephenytoin to nirvanol in five patients with uncontrolled complex partial seizures. After a 50-mg single oral dose, mean peak mephenytoin level was 0.48 microgram/ml and nirvanol 0.37 microgram/ml. After 400 mg, peak mephenytoin level was 3.9 micrograms/ml and nirvanol 2.5 micrograms/ml. On 400 mg daily, mephenytoin reached a mean steady-state level of 1.5 micrograms/ml. Nirvanol mean steady-state level was 18 micrograms/ml. Mean plasma half-life was 17 hours for mephenytoin and 114 hours for nirvanol. Two patients had reduced seizures during mephenytoin therapy and one a transient increase during drug withdrawal. No toxicity was seen, but mephenytoin was not more effective than phenytoin.

[Changes in reactivity to halothane after administration of mephenytoin]. / Zmena reaktivity na halotan po aplikaci mephenytoinu.

In the pigs of the Belgian Landrace breed, peroral premedication removed sensitivity to halothane. When mephenytoine had been administered four hours before testing (dose of 4 mg/kg live weight), the sensitive animals ceased to differ in their reaction to halothane from non-sensitive animals.

Flash-evoked afterdischarge in rat as a model of the absence seizure: dose-response studies with therapeutic drugs.

The flash-evoked afterdischarge (FEAD) is a self-sustained burst of wave-and-spike complexes recorded from occipital cortex in the rat and other animals in response to a single light flash. On the basis of behavioral experiments and studies employing single doses of antiepileptic drugs, FEAD has been proposed as a model of the absence seizure. In order to test the validity of FEAD as an absence seizure model, the present experiments determined dose-response relationships for the suppression of FEAD by six antiepileptic drugs with established clinical profiles. It was found that phenobarbital, ethosuximide, and trimethadione suppressed FEAD in a dose-related manner, and that ethosuximide was approximately three times as potent as trimethadione. Mephenytoin produced a maximal reduction of FEAD of only 30 to 40%, which was not dose-related. Neither phenytoin nor acetazolamide suppressed FEAD. The results obtained with ethosuximide, trimethadione, and phenytoin are qualitatively similar to their therapeutic effects in absence epilepsy. The FEAD model failed, however, to unequivocally predict the therapeutic efficacy of mephenytoin or acetazolamide. In this respect, it is similar to the metrazol seizure model. It is concluded that FEAD is a valid absence seizure model with a pharmacological predictive value that is at least as good as the metrazol model.

Measurement of mephenytoin (3-methyl-5-ethyl-5-phenylhydantoin) and its demethylated metabolite by selective ion monitoring.

Mephenytoin (3-methyl-5-ethyl-5-phenylhydantoin) and its demethylated metabolite Nirvanol (5-ethyl-5-phenylhydantoin) were measured by a selective ion monitoring technique. This method was used in the analysis of both compounds in plasma from a patient receiving 50 mg and 400 mg of mephenytoin in single oral doses. Both compounds were extracted from plasma and ethylated prior to analysis by electron-impact mass spectrometry. Alkylation, using ethyl iodide in 2-butanone, occurred in the N-1 and N-3 positions of the hydantoin ring when concentrated KOH was added to the reaction mixture. The lower limits of quantitation for mephenytoin and Nirvanol were 10 ng/ml and 50 ng/ml, respectively, and were found to be reproducible within 8% upon repeated quantification.

Mephenytoin: a reappraisal.

Serum levels of mephenytoin (Mesantoin) and its metabolite nirvanol were correlated with effectiveness and side effects in 93 patients. Mean mephenytoin level was 8% of the combined mephenytoin plus nirvanol levels. "Total mephenytoin" level should be used clinically, as neither individual component is as well correlated with clinical phenomena. Serum levels of 25 to 40 mug/ml usually yield improvement in seizure control without discomfort, and three-quarters of patients had fewer seizures. Side effects frequently associated with phenytoin were absent, but drowsiness, an occasional rash, and a single, fatal case of aplastic anemia were found. Performance on psychological tests of cognitive-attentional skills showed a modest improvement during mephenytoin administration. The drug merits wider employment in refractory seizure problems, but vigilant follow-up is required.

Effect of 2 br-alpha-ergocryptin (CB 154) on serum prolactin and the clinical picture in a case of progressive gigantomastia in pregnancy.

A 24 year old woman who had epilepsy since the age of 7 years and who was still using antiepileptics, developed an excessive mamary growth (gigantomastia) during pregnancy. Treatment with CB 154 (Sandoz), 2 Br-alpha-ergocryptin in a dose of 2.5 mg three times a day from the 27th week of pregnancy, resulted in prompt improvement with a corresponding decrease in the plasma prolactin, return of the breast temperature to normal, and disappearance of the EEG-abnormalities. After parturition and subsequent mammoplasty the woman soon became pregant again. During this pregnancy, which terminated in the birth of a normal child, treatment with CB 154 was started early and continued throughout pregnancy with success and without side effects.

[Determination of phenobarbital, mephenytoin and diphenylhydantoin in the surveillance of anticonvulsant treatment]. / Dosage du phénobarbital, de la méphénytoïne et de la diphénylhydantoïne dans la surveillance du traitement des anticonvulsivants

The authors describe a method of simultaneous estimation of phenobarbitone, mephenytoin and diphenylhydantoin in the blood. After extraction with ether, the methylation of these substances by trimethylanilinium hydroxide permits their rapid separation by gas chromatography. Heptabarbitone is used as internal standard and the chromatograph used is supplied with a thermoionic detector. The technique used is simple and rapid. Its reproducibility and sensitivity are satisfactory, permitting daily application to the supervision of anticonvulsant treatment, especially in Pediatrics.

Generalized lymphadenopathy and nephrotic syndrome as a manifestation of mephenytoin (mesantoin) toxicity.

This report describes a patient who developed marked generalized adenopathy and nephrotic syndrome while receiving mephenytoin (mesantoin) for a seizure disorder. Renal biopsy showed a diffuse proliferative glomerulonephritis. Lymph node histopathology revealed replacement of parenchyma with lymphocytes, eosinophils, and reticuloendothelial cells. A hypersensitivity reaction is postulated as the etiology of both these processes.

Anticonvulsant osteomalacia.

Drug-induced osteomalacia appears to be a relatively common disorder in patients receiving long-term anticonvulsant drug therapy. The severity of clinical manifestations in any given individual appears to be a function of the combined effects of a variety of factors including drug type and total drug dose, dietary vitamin D intake, sunlight exposure, and physical activity level. Aided by the recent development of sensitive techniques such as the serum 25-hydroxyvitamin D assay and the photon absorption methods for bone mass determination, one can now detect abnormalities in vitamin D and bone metabolism with much greater precision. As a consequence, the incidence of disordered mineral metabolism in patients receiving long-term anti-convulsant therapy can be determined with greater precision and therapeutic regimens instituted to prevent the associated morbidity.