Therapeutic drug monitoring of antiepileptic drugs.

Commonly used conventional antiepileptic drugs for pharmacotherapy in epilepsy are phenytoin, carbamazepine and valproic acid. These drugs have complex pharmacokinetic properties leading to fluctuation in their plasma level at given same therapeutic dose. The present study was done to monitor their plasma levels. A prospective observational study was conducted at National Public Health Laboratory. After taking detail history, blood samples were taken from epileptic patients of all age groups and both gender who were on usual therapeutic dose of one or two combined antiepileptic drugs. Plasma level of these drugs were analyzed by using Fluorescence Polarization Immuno Assay (FPIA) technique. Out of total 417 testing, 81 were tested for phenytoin , 241 for carbamazepine and 95 for valproic acid. Their levels were further analyzed to find therapeutic, subtherapeutic and toxic levels. Out of total 81 blood samples tested for phenytoin, 38.8% had plasma drug at therapeutic level, 38.8% at subtherapeutic level and 28.4% had toxic level. Carbamazepine was tested in 241 samples and 79.3% cases had at therapeutic drug level, 15.8% had subtherapeutic drug level and 4.9% had toxic level. Out of 95 samples tested for valproic acid, 62% had therapeutic level and 20% had subtherapeutic and 18% had toxic level of drug. Therapeutic drug monitoring of phenytoin showed wide fluctuation in its plasma level. Its toxic and subtherapeutic levels were quite high. It is suggested that the dose of phenytoin should be adjusted after regular plasma level monitoring only. Monitoring of carbamazepine and valproic acid were also helpful when their toxicity and efficacy are doubtful.

Relación entre niveles de carbamazepina en saliva y plasma: Estudio piloto / Saliva and plasma levels of carbamazepine have a poor correlation: a pilot study

Abstract: Carbamazepine is one of the most commonly used anticonvulsants for the treatment of epilepsy and its plasma concentrations must be monitored periodically to obtain a useful and safe clinical effect. There is not a good relationship between the dose of the carbamazepine and their effects in humans, but the effects of this drug have been well correlated with its plasma levels. Aim: To measure the correlation between plasma and saliva levels of carbamazepine in children with epilepsy. Material and Methods: Saliva and plasma levels of carbamazepine were measured by using instrumental planar chromatography in 11 epileptic children aged 8 to 15 years treated with the drug for at least six months. Results: The mean saliva/plasma ratio was 0.18±0.05 and the mean of carbamazepine concentration in saliva, expressed as a percentage of concentrations in plasma, was 17.97±5.40. There was a poor linear correlation (r =0.37) between the concentrations of carbamazepine in both fluids. Conclusions: In this group of epileptic children the correlation between saliva and plasma carbamazepine levels was weak.

Antiepileptic TDM pattern at a tertiary care hospital in India.

Therapeutic drug monitoring, a comparatively new investigational procedure in clinical pharmacology, is considered very beneficial to epilepsy patients though it increase the health care cost. Aim of this study was to determine the pattern of use of antiepileptic drug level monitoring over the last 7 years in our tertiary care centre and to critically comment on its utility. Retrospective data audit of archived data from 1998 to 2004 and age, sex, estimated levels of phenytoin, carbamazepine and phenobarbitone by HPLC were noted down, tabulated and compared. Chi square test was used for analysis. Three thousand five jundred thirty four blood samples of patients requesting for 4213 estimations of phenytoin, phenobarbitone or carbamazepine were received. Among the obtained samples, 44.0% (1058) were of children, 68.0% (2402) were of males, 0.6% (22) patients were getting 3 and 18.0% (635) getting 2, antiepileptic medications. 13.0% (546) samples showed level in the toxic range and 39.0% (1653) in lower range. There was increasing demand observed for estimation of antiepileptic drugs, over the 7 years. The number of abnormal values of phenytoin, phenobarbitone and carbamazepine did not show any significant difference over the years. The pattern was similar to that observed in other countries.

Systemic and presystemic conversion of carbamazepine to carbamazepine-10, 11-epoxide during long term treatment / Conversão da carbamazepina para 10, 11-epóxido-carbamazepina no tratamento prolongado

INTRODUCTION: Carbamazepine (CBZ) undergoes biotransformation, being CYP3A4 the major cytocrome P450 (CYP) enzyme catalyzing the carbamazepine-10,11-epoxide (EPOX) formation, which is quantitatively the most important pathway in CBZ metabolism. There is evidence of dose-dependent elimination of this drug due to its autoinduction capacity. Moreover, published data showed an incomplete bioavailability of CBZ since its absorption increases when grapefruit juice was administered. Both CYP3A4 and MRP2 (located in the enterocyte) are autoinduced during long term use of CBZ. As the other enzymes involved in CBZ metabolism are negligible in the gut, presystemic biotransformation through CYP3A4 could be responsible for the bioavailability of the drug as well as EPOX formation. OBJECTIVE: The purpose of our study was to assess the importance of presystemic formation of EPOX during the autoinduction of CBZ versus the daily administered dose. PATIENTS AND METHODS: 40 adults (average age: 28 years) and 29 children (average age: 9 years) receiving CBZ as monotherapy were included in the study. CBZ and EPOX plasma concentrations were analyzed by a previous validated HPLC method. RESULTS AND CONCLUSION: The results obtained confirmed the metabolic induction after chronic administration and provided new elements to suggest a strong contribution of dose-dependent bioavailability in the non linear kinetics of CBZ.

Disminución de ácido fólico y alteraciones cognitivas en pacientes con epilepsia tratados con fenitoína o carbamazepina, estudio piloto / Decrease of folic acid and cognitive alterations in patients with epilepsy treated with phenytoin or cartnabazepine, pilot study

Introduction. Phenytoin and carbamazepine were the antiepileptic drugs most frequently used in Mexico and throughout the world. Epileptic patients who take these drugs have a variety of collateral effects including the decrease of Mates plas-matic level. Low serie folie acid concentration has been associated with a decline in cognitive functions. The administration of a combined treatment with folie acid could ameliorate these difficulties. Objective.To describe the effect of the folie acid in the cognitive function in epileptic patients who take phenytoin and carbamazepine. Methods. We chose patient who have epilepsy and that are being treated with phenytoin, carbamazepine or both and formed two groups. The study group was treated with a daily dose of 5 mg of folie acid and the control group was administered placebo for a period of six months, with nine patients in each group of same age, sex, education level, epilepsy's evolution, frequency of seizures, EEG abnormalities and antiepileptic drugs plasma levels. We registered data at the beginning (basal) and at the end of the study. Results.Measurements of basal folie acid plasma levels in both groups were under the referential value. The neuropsychological assessment at the beginning (Mini-Barcelona test) showed a deficit in the verbal memory skills in both groups. After six months of treatment with folie acid (study group), the folie acid plasma level was 12.2 mg/mL (p < 0.01) higher than the basal value. Verbal memory test has improved with respect to the basal value (p < 0.05). The numbers of seizures and the plasma levels of the antiepileptic drugs remained unchanged. On the other hand, the group treated with placebo did not improve. Conclusion.Treatment with folie acid is safe and without side effects, it improved the cognitive function in patients with epilepsy treated with phenytoin and carbamazepine.

Introducción. La difenilhidantoína (DFH) y la carbamazepina (CBZ) son los antiepilépticos más empleados en México y en el mundo, los pacientes con epilepsia que emplean estos fármacos presentan una disminución en las concentraciones séricas de ácido fólico, una de las causas que pueden contribuir a un deterioro cognitivo, por lo que la terapia sustitutiva con ácido fólico pudiera mejorar estas alteraciones. Objetivo. Describir el efecto de la disminución del ácido fólico en la cognición de pacientes con epilepsia tratados con difenilhidantoína y carbamazepina. Material y métodos. Incluimos pacientes tratados con carbamazepina, fenitoína o ambos, con epilepsia. Formamos dos grupos: Un grupo experimental recibió ácido fólico 5 mg/día y otro grupo control recibió placebo durante seis meses, nueve pacientes en cada grupo; pareados en la edad, sexo, escolaridad, tiempo de evolución, námero de crisis, alteraciones EEG, niveles séricos de anticonvulsivos, realizamos estudios neuropsicológicos al inicio (básales) y al final del estudio a ambos grupos. Resultados. Las básales del ácido fólico en ambos grupos estuvieron por debajo del valor de referencias. En las pruebas neuropsicológicas (básales) (prueba de Mini-Barcelona) se halló un déficit en el área de la memoria verbal en ambos grupos. Después de seis meses de tratamiento con ácido fólico (grupo experimental) los niveles de ácido fólico alcanzaron 12.2 ng/mL (p < 0.01) con respecto a su basal; las pruebas de memoria verbal mejoraron con respecto a su basal (p < 0.05); el námero de crisis y los niveles séricos de los anticonvulsivos no se modificaron. El grupo con placebo no presentó ninguna mejoría. Conclusiones. El tratamiento coadyuvante con ácido fólico es seguro, libre de efectos adversos y mejoró las alteraciones cognitivas (memoria verbal) de estos pacientes.

Effect of nimodipine, a dihydropyridine calcium channel antagonist on the pharmacokinetics of carbamazepine in rhesus monkeys.

Calcium channel antagonists have been shown to have an anticonvulsant activity in a variety of seizure models and also to potentiate the anticonvulsant activity of other standard antiepileptic drugs like carbamazepine, phenytoin and valporoate. A pharmacokinetic interaction may be involved in such potentiation. This cross over single dose study was carried out to find out if there was a pharmacokinetic interaction between carbamazepine, a commonly used antiepileptic drug and nimodipine, a dihydropyridine calcium channel antagonist in rhesus moneys. Carbamazepine 46 mg/kg and nimodipine 9.6 mg/kg was administered through a nasogastric tube and blood samples were collected at 0.5, 1, 2, 3, 6, 9, 12, 24, 48, 72 and 96 hours after drug administration and were assayed for carbamazepine. Nimodipine caused a significant increase in peak plasma concentration (C(max)) of carbamazepine and a decrease in plasma absorption half life (t1/2 alpha). There was no significant change in other pharmacokinetic parameters between the two groups. The results of the study suggest that concurrent administration of carbamazepine and nimodipine may cause a significant rise in carbamazepine concentration as may contribute to a potentiation of anticonvulsant effect of carbamazepine and an increase in the incidence of adverse effects warranting that nimodipine should be prescribed cautiously in epileptic patients receiving carbamazepine and it might be very appropriate to do therapeutic drug monitoring of carbamazepine in such patients.

Association of drug levels & pharmacokinetics of carbamazepine with seizure control.

BACKGROUND & OBJECTIVES: A sizeable number of epilepsy patients remain uncontrolled with carbamazepine (CBZ) monotherapy. While the therapeutic plasma concentration range of CBZ is only vaguely defined, pharmacokinetic differences in the disposition of CBZ among subjects could be responsible for the inadequate control of seizures in some. This study was aimed at associating serum CBZ levels with seizure control and elucidating any pharmacokinetic differences between patients with controlled and uncontrolled epilepsy. METHODS: The study was conducted in 16 controlled and 15 uncontrolled adult epileptic patients receiving CBZ monotherapy for the previous 3 or more months, without any dosage change. Blood samples were drawn from the patients before and 0.5, 1, 2, 3, 4, 8, 12 and 24 h after ingestion of their total daily dose of CBZ. Serum CBZ levels were measured by HPLC and the pharmacokinetic parameters were calculated. RESULTS: The uncontrolled epileptic patients were receiving a higher daily dose of CBZ (difference not significant). The trough and peak serum CBZ levels were relatively higher in the uncontrolled group, and at no time point were the drug levels lower in these patients compared to the controlled group. The absorption kinetics, volume of distribution and plasma half life of CBZ were similar in the two groups. Thus, non-attainment or non-maintenance of therapeutic CBZ level or other pharmacokinetic difference was not responsible for occurrence of seizures in the uncontrolled patients. A high percentage of patients with generalised tonic clonic seizures (73%) and simple partial seizures (SPS) with generalisation (66%) were controlled by CBZ, while SPS and complex partial seizures (CPS) were largely uncontrolled. INTERPRETATION & CONCLUSIONS: It appears that pharmacodynamic resistance of the seizure to CBZ rather than pharmacokinetic factors is responsible for lack of efficacy of CBZ in nonresponding epileptic patients.

Adult epileptics; correlation of serum carbamazepine and gamma glutamyl transferase

A study was conducted to determine serum carbamazepine [CBZ] levels by high performance liquid chromatography [HPLC] and gamma glutamyl transferase [GGT] activity in already diagnosed 40 epileptic patients [20 males and 20 females] on CBZ therapy more than six months. Twenty normal healthy controls [10 males and 10 females] were included in the study. The mean +/- standard deviation of CBZ level in all subjects, males [young and old and females young and old[were 4.2 +/- 2.76, 3.47 +/- 2.15, 3.65 +/- 3.21 and 4.80 +/- 3.27, 3.86 +/- 3.65 ug/ml respectively. While the GGT level in all the subjects were 50.57 +/- 23.36, in male 52.42 +/- 23.86 and in female 48.5 +/- 23.28 IU. It was observed that the serum GT activity in relation to daily dosage of CBZ was more in old than young groups. The comparison between daily dosage and CBZ was weakly positive [r=0.2951] while serum CBZ versus serum GGT activity [0.09820] shows no correlation. Hence it was concluded that there is no significant correlation between serum CBZ level and serum GGt activity to avoid toxic effects of drug over dosage and to obtain therapeutic results drug monitoring is essential

rapid high performance liquid chromatographic determination of lansoprazole in human serum

A simple and rapid reverse phase high-performance liquid chromatographic [RP-HPLC] method with UV detection has been described for the determination of lansoprazole in human serum. Carbamazepine was used as internal standard. The drug and the internal standard in serum were extracted twice with diethyl ether, followed by evaporation, reconstitution in the mobile phase and injection into the chromatographic system. The method utilized a Nova-Pak CI8 4-micro m column [150x3.9 mm i.d.] together with an isocratic mobile phase consisted of 0.02M sodium dihydrogenphosphate- acetonitrile- methanol [58: 23: 19%, v/v/v]. The mobile phase was adjusted to pH 7.3 with 5M NaOH and pumped at a flow rate of 1.8 mI/min. The UV detector was set at 285 Rm. Running time per single analysis was less than four minutes. The response of the assay was linear with a correlation coefficient, r = 0.9993. The within and between-day coefficients of variation for three different concentrations [50-1500 ng/ml] ranged from 1.14 to 8.26% and from 1.66 to 8.02%, respectively. The average recovery of the concentration range stated was better than 96.5%. Stability testing revealed that lansoprazole was stable in serum at -20°C for two weeks. The method was successfully applied in a bioassay study of two products each in the form of enteric-coated granules in capsules containing 30 mg lansoprazole, administered orally to eighteen healthy male volunteers

Anti-epileptic drug intake adherence: the value of the blood drug level measurement and the clinical approach

It was evaluated the patient antiepileptic drug (AED) intake adherence in a pilot cross-sectional study carried out at a neurologic out-patient clinic of a university hospital. Ninety-three AED blood concentration (phenobarbital, phenytoin, carbamazepine) were analyzed from 24 patients. The variability of the AED blood level was measured (in the steady state period by means of the variation coefficient) and compared with the self-reported antiepileptic medication non-adherence. AED blood level according to the range (therapeutic or not), and the seizure control. It was not observed any strong correlation between the higher value of variability and the other three parameters of no adherence. The highest correlation was with the blood drug level (therapeutic or not). The evaluation of blood drug measurement alone, except in cases of extreme low adherence and variability of drug intake, is not enough for the recognition of incorrect drug intake, but the clinical markers and the self-reported adherence have to be also considered for this sort of evaluation.

Effect of Septilin--a herbal preparation on pharmacokinetics of carbamazepine in rabbits.

The study was carried out in rabbits, to see the effects of Septilin, a herbal preparation on the single and multiple dose kinetics of carbamazepine. Single dose treatment of Septilin significantly decreased t 1/2a. t 1/2e. AUCo-alpha of carbamazepine. Steady state Cmax and AUC0-24 of carbamazepine were also reduced significantly in comparison to those of control rabbits after 7 days co-administration of Septilin. We conclude that Septilin decrease/hinder the absorption process of carbamazepine through an unknown mechanism.

Correlation of serum carbamazepine and gamma glutamyle transferase in adult epileptics

A study was conducted to determine serum carbamazepine [CBZ] levels by high performance liquid chromatography [HPLC] and gamma glutamyl transferase [GGT] activity in 40, already diagnosed epileptic patients [20 males and 20 females] on CBZ therapy for more than six months. Twenty normal healthy controls [10 males and 10 females] were included in the study. The mean +/- standard deviation of CBZ level in all subjects, males [young and old, females young and old] were 4.2 +/- 2.76, 3.47 +/- 2.15, 3.65 +/- 3.21 and 4.80 +/- 3.27, 3.86 +/- 3.65 micro g/ml respectively. While the GGT level in all the subjects were 50.57 +/- 23.36, in male 52.42 +/- 23.68 IU/L and in female 48.5 +/- 23.28 IU/L. It was observed that the serum GT activity in relation to daily dosage of CBZ was more in old than young groups. The comparison between daily dosage and CBZ was weakly positive [r=0.2951] while serum CBZ versus serum GGT activity [0.09820], shows no correlation. Hence it was concluded that there is no significant correlation between serum CBZ level and serum GGT activity. To avoid toxic effects of drug overdosage and to obtain therapeutic results drug monitoring is essential

Carbamazepine-induced sinus node dysfunction

Carbamazepine, a drug used for the treatment of epilepsy and neuralgias, may exert hazardous effects on the cardiac conduction system. We report such a case of symptomatic brady-arrhythmia occurring in a 43-years-old male while on therapy with carbamazepine. Additionally, a literature review is made of previous cases of carbamazepine-induced sinus mode, AV node and His-Purkinje conduction disturbances

High doses of carbamazepine for refractory partial epilepsy

Forty-eight patients with partial seizures were analysed during treatment with 1200 mg/d or more of carabamazepine (CBZ). Thirty-three were on monotherapy and fifteen on polytherapy. The other drugs, were kept unchanged in the patients on polytherapy. The dose of CBZ was increased if no control was observed and the patient had no side effects. The doses used ranged between 1200 and 1900 mg/day 91200 mg/day, n=18; 1300 mg/day, n=l: 1400 mg/day, n=7: 1600 mg/day, n=9; 1700 mg/day, n=4; 1800 mg/day, n=8; 1900 mg/day, n=1). Anticonvulsant plasma levels were taken to confirm patient compliance. The average plasma level was 9.6 ug/mL. The period of follow up varied from 3 to 96 months (M=25,6). Seizure's control was observed in 7 (14.48 per cent) patients taking 1200 mg/day and in 2 (4.16 per cent patients taking 1400 mg/day of CBZ. Thirty-nine patients did not show any control (81.21 per cent). Ten patients (20.81 per cent) had signs of intoxication. When patients have no improvement with 1400 mg/day, it is difficult to obtain any control despite the use of higher doses of CBZ, which frequently expose the patient to signiflcant side effects.

Correlation of the serum levels of carbamazepine and the severity of the clinical manifestations of its acute toxicity

A clinical study was carried out on all cases, acutely poisoned by carbamazepine [CBMZ] [26 cases] presented to [P. C. C.] during the period from January to April 1994 and compared with equal number of non exposed subjects with similar age and sex. Cases were evaluated clinically by history and examination and by laboratory investigation in the form of ECG. serum sodium levels and CBMZ serum levels at admission and when needed thereafter. It was observed that 20 cases [13 males and 7 females] were suicidal poisoning, all of them were above age of 15 years and 6 cases [4 males and 2 females] were accidental, all of them were below age of 15 years. It was also observed that grade of coma, hypotension respiratory depression, presence of convulsions, vomiting, ECG changes and dilatation of the pupils correlated well with CBMZ serum levels. On the other hand, serum sodium and pulse changes did not correlate with it. Moreover, the line of treatment needed for each case for most cases correlated well with CBMZ serum levels

Determination of phenobarbital, phenytoin and carbamazepine in human serum: comparison of fluorescence polarization immunoassay with high performance liquid chromatography

A simple high performance-liquid chromatography [HPLC] method for simultaneous determination of antiepileptic drugs i.e., carbamazepine, phenobaebital and phenytion in human serum is described. The procedure involves deproteinization of serum with acetonitrile containing phenacetin as an internal standard prior to injection onto the chromatograph. The drugs were eluted from a resolve 5 micro spherical c18 column with a mobile phase consisting of 0.01 m potassium dihydrogen phosphate: methanol [55:54%, v/v] adjusted to PH 6.0 with potassium hydroxide. The drugs and the internal standard were eluted at a flow rate of 1.5 ml per minute, and the optimum detector wavelength was 220 nm. The chromatography time was ten minutes and the resolution between the drugs and internal standard was excellent. Quantitation was achieved by the measurement of peak height ratios and the minimum detectable concentration was less than 0.1 mg/l. the calibration curve of the assay was linear over the range of 0.1-25 mg/l, 0.5-120mg/L and 0.1-80 mg/L for carbamazepine, Phenobarbital and phenytoin respectively respectively. The Abbott TDX FLXTM fluorescence polarization immunoassay [FPIA] has been evaluated and compared with the developed HPLC method for precision, calibration curve stability, specificity and accuracy. Using control samples in the subtherapeutic, therapeutic and toxic concentrations resulted in mean analytical recoveries which varied from 95.3 to 99.8% for HPLC and 96.8 to 101.2 for FPIA. Within run coefficient of variation was in the range of 1.66-4.47% for HPLC and 1.50-3.75% for FPIA. Between run precision ranged from 2.10-4.71% for HPLC and 1.21-4.28% for FPIA. Serum specimens from 270 patients taking carnamazepine, 191 patients taking Phenobarbital and 225 patients taking phenytion were analyzed by both methods, with good correlation. The HPLC method offered reproducibility and accuracy when compared with an established method for routine analysis of carbamazepine, Phenobarbital and phenytoin

O uso da carbamazepina no tratamento agudo da mania / Use of carbamazepine in acute treatment of mania

A carbamazepina (CBZ) é a droga de escolha na neuralgia do trigêmio e na epilepsia do lobo temporal. Seu uso em Psiquiatria iniciou-se no início dos anos 70 com relatos de pesquisadores japoneses descrevendo seus efeitos positivos no tratamento da PMD. Nosso objetivo é através de uma revisäo bibliográfica relatar o uso da CBZ na fase maníaca da doença afetiva, sua associaçäo com lítio, sua farmacodinâmica, administraçäo clínica e seus efeitos colaterais

Drogas anticonvulsivantes en suero y líquido cefalorraquideo de pacientes epilépticos: cuantificación por cromatografía líquida / Anticonvulsant drugs in serum and crebrospinal fluid of epileptical patients: liquid chromatography measurement

Se desarrolló un procedimiento de cromatografía líquida de alta presión para cuantificar simultáneamente varias drogas anticonvulsivantes en el suero y líquido cefalorraquídeo de 20 pacientes. Los coeficientes de correlación para las concentraciones en ambos líquidos decarbamazepina, fenobarbital y fenitoína fueron r=0,8588 (p<0,01), r=0,9721 (p<0,01) y r=0,9289 (p<0,01), respectivamente. Las concentraciones de cada droga en líquido cefalorraquídeo representaron porcentajes de la concentración en suero, comparables a los referidos en la literatura. Las concentraciones séricas de carbamazepina en los pacientes sin barbitúricos asociados fueron mayores que las de aquellos bajo politerapia con barbitúricos, independientemente de la dosis. La fenitoína y las concentraciones de fenobarbital en suero y líquido cefalorraquídeo. Estos resultados aqpoyan el uso de la monoterapia para tratar las epilepsias

Dosagens séricas repetidas de anticonvulsivantes em pacientes epiléticas / Repetitive serum dosages of anticonvulsants in epileptic patients

Para avaliaçäo da aderência ao tratamento em epilépticas crônicas estudamos 38 pacientes através de 144 dosagens séricas repetidas de anticonbulsivantes a intervalos semanais. Todas as pacientes apresentavam crises supostamente de dificil controle, isto é, tiveram crises no mês anterior à última consulta. O nível sérico da droga antiepiléptica estava abaixo da faixa terapêutica em 34// das amostras analisadas. Houve ainda variaçöes semanais importantes do nível terapêutico para subterapêutico das drogas e vice-versa. Baseados nestes achados sugere-se que a estratégia de dosagens séricas repetidas possa diferenciar as pacientes resistentes à droga daquelas que näo fazem uso regular do medicamento