Does withdrawal of different antiepileptic drugs have different effects on seizure recurrence? Further results from the MRC Antiepileptic Drug Withdrawal Study.
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One thousand and thirteen patients, in remission of epilepsy for at least 2 years, were randomized to continued therapy or slow withdrawal over 6 months and were followed up for a median period of 5 years. At the time of randomization 83% of patients were receiving monotherapy with carbamazepine (237 patients), phenobarbitone/primidone (72 patients), phenytoin (184 patients) or valproate (228 patients) in low doses, and plasma levels were below the usual optimal range. The most important factor determining seizure recurrence was continued therapy, which was the case for barbiturates, phenytoin and valproate. There was no significant difference for patients taking carbamazepine at randomization, because of a low rate of recurrence in those withdrawing treatment. The difference between carbamazepine and other drugs was not explained by differences in covariate prognostic factors. There was no evidence that withdrawal of phenobarbitone was associated with withdrawal seizures. These data provide unique evidence for the effectiveness of standard antiepileptic drugs as monotherapy. The results for carbamazepine may be open to a number of interpretations. (+info)
Anticonvulsant-induced dyskinesias: a comparison with dyskinesias induced by neuroleptics.
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Anticonvulsants cause dyskinesias more commonly than has been appreciated. Diphenylhydantoin (DPH), carbamazepine, primidone, and phenobarbitone may cause asterixis. DPH, but not other anticonvulsants, may cause orofacial dyskinesias, limb chorea, and dystonia in intoxicated patients. These dyskinesias are similar to those caused by neuroleptic drugs and may be related to dopamine antagonistic properties possessed by DPH. (+info)
Flash-heater ethylation of some antiepileptic drugs.
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We describe a modification of the MacGee method [Anal. Chem. 42, 421 (1970)] for rapid determination of phenytoin (diphenylhydantoin) in plasma by gas-liquid chromatography, in which an ethylaing reagent is used instead of the more common methylating reagents. With this modification, several N-methylated antiepileptic drugs can be separated from their demethylated metabolites. Our results agree well with those of Butler and Waddell [Neurology 8, 106 (1958)], who showed that in patients receiving the N-methylated compounds mephenytoin and mephobarbital, the N-demethylated products, 5-ethyl-5-phenylhydantoin and phenobarbital are found in higher concentrations in plasma than are their respective parent drugs. The method is also useful for routine determinations of phenobarbital, primidone, and phenytoin in serum, cerebrospinal fluid, or saliva. (+info)
Interaction of phenytoin and primidone.
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The ratio of derived phenobarbitone to unmetabolized primidone in the serum was significantly higher in 50 epileptic patients on a combination of primidone and phenytoin than in 12 patients on primidone alone, though the dose and serum levels of primidone were similar in the two groups. Out of 253 patients attending a seizure clinic 47% were taking a combination of these two anticonvulsants. The effect of phenytoin on the metabolism of primidone may have clinical implications in view of the frequency of their combined use. (+info)
Therapeutic monitoring of anticonvulsant drugs: gas-chromatographic simultaneous determination of primidone, phenylethylmalonamide, carbamazepine, and diphenylhydantoin.
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We describe a sensitive and precise gas-chromatographic method in which benzylmalonate methylester monoamide is used as the internal standard for the simultaneous determination of primidone, phenylethylmalonamide, carbamazepine, and diphenylhydantoin. The trimethylsilyl derivatives of the anticonvulsants are well separated from each other and from normal serum constituents. The lower limit of detection for each drug is 0.5 mg/liter when 1 ml of serum is analyzed. Within-run precision (CV), established by analysis of 10 replicates, was as follows: primidone (5.4 mg/liter), 2.6%; phenylethylmalonamide (5.5 mg/liter), diphenylhydantoin (6.6 mg/liter), 3.8%; and carbamazepine (10.4 mg/liter), 3.2%. Fifty specimens were analyzed for primidone and 35 for diphenylhydantoin by a standard gas-chromatographic method involving on-column methylation and by the procedure we have developed. The mean value observed for primidone with the on-column alkylation procedure was 9.3 mg/liter and with our procedure was 9.6 mg/liter. When values for our assay were regressed against values for the standard method, the slope of the least-squares line was 0.936, the intercept was 1.00 mg/liter, and r was 0.939. The mean values observed for diphenylhydantoin by on-column methylation and with our procedure were both 12.6 mg/liter. When values for our assay were regressed against the standard method, the slope of the least-squares line was 0.944, the intercept was 0.3 mg/liter, and r was 0.988. (+info)
Determination of lamotrigine simultaneously with carbamazepine, carbamazepine epoxide, phenytoin, phenobarbital, and primidone in human plasma by SPME-GC-TSD.
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A simple and rapid analytical method is presented for the determination of lamotrigine simultaneously with primidone, carbamazepine, carbamazepine epoxide, phenobarbital, and phenytoin in human plasma using solid-phase microextraction (SPME) and gas chromatography with thermionic specific detection. The best conditions for the SPME procedure is established as following: direct extraction on a 65-microm Carbowax-divinylbenzene fiber; 1.0 mL of a sample plasma matrix modified with 15% NaCl and 3 mL of a potassium phosphate buffer (pH 7.0); extraction temperature at 30 degrees C; and stirring at a rate of 2500 rpm for 15 min. The method shows good linearity between 0.05 and 40.0 microg/mL with regression coefficients ranging between 0.9965 and 0.9995 and a coefficient of variation of the points of the calibration curve lower than 10%. The lowest limit of quantitation for the plasma-investigated drugs varies from 0.05 to 0.20 microg/mL, according to the drug. The proposed method is sensitive enough to work into subtherapeutic and therapeutic concentrations, being that it is applied in pharmacokinetic studies and patient routine therapeutic drug monitoring. (+info)
Simultaneous plasma lamotrigine analysis with carbamazepine, carbamazepine 10,11 epoxide, primidone, phenytoin, phenobarbital, and PEMA by micellar electrokinetic capillary chromatography (MECC).
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The determination of lamotrigine (LTG) simultaneously with carbamazepine (CBZ), carbamazepine 10,11 epoxide (CBZ-E), primidone (PRM), phenytoin (PHT), phenobarbital (PB), and 2-phenyl-2-ethyl-malonamide (PEMA) in human plasma was developed using micellar electrokinetic capillary chromatography (MECC) with a diode-array detector. The reproducibility of both separation and quantitation with MECC analysis were appropriate for the intra- and interassay coefficients. The evaluated drugs concentration intervals of LTG, 0.5-10.0 micro g/mL; CBZ, 1.0-16.0 micro g/mL; PEMA, 1.0-20.0 micro g/mL; PB, 1.0-60.0 micro g/mL; PRM, 1.0-20.0 micro g/mL; PHT, 0.7-40.0 micro g/mL; and CBZ-E, 1.0-14.0 micro g/mL were linear with correlation coefficients higher than 0.987 and coefficients of the variation of the points of the calibration curve lower than 10%. The limit of quantitation of the investigated drugs in plasma varied from 0.5 to 1.0 micro g/mL, depending upon the drug. The MECC technique was sensitive enough to work with microsamples into the subtherapeutic, therapeutic, and toxic concentrations, as well as showed to be simple and efficient when applied to monitoring therapeutic drugs in patients treated with a combination of lamotrigine and other antiepileptic drugs such as hepatic enzyme-inducing agents. (+info)
Prediction of adsorption from multicomponent solutions by activated carbon using single-solute parameters. Part II--Proposed equation.
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Prediction of multicomponent adsorption is still one of the most challenging problems in the adsorption field. Many models have been proposed and employed to obtain multicomponent isotherms from single-component equilibrium data. However, most of these models were based on either unrealistic assumptions or on empirical equations with no apparent definition. The purpose of this investigation was to develop a multicomponent adsorption model based on a thermodynamically consistent equation, and to validate that model using experimental data. Three barbiturates--phenobarbital, mephobarbital, and primidone--were combined to form a ternary system. The adsorption of these barbiturates from simulated intestinal fluid (without pancreatin) by activated carbon was studied using the rotating bottle method. The concentrations, both before and after the attainment of equilibrium, were determined with a high-performance liquid chromatography system employing a reversed-phase column. The proposed equation and the competitive Langmuir-like equation were both fit to the data. A very good correlation was obtained between the experimental data and the calculated data using the proposed equation. The results obtained from the original competitive Langmuir-like model were less satisfactory. These results suggest that the proposed equation can successfully predict the trisolute isotherms of the barbituric acid derivatives employed in this study. (+info)