Estudio del índice nivel/dosis de la fenitoína en pacientes epilépticos voluntarios de Mérida / Study of the level/dose index of phenytoin in volunteer epileptic patients from Mérida

INTRODUCCIÓN La fenitoína es usada con mucha frecuencia en nuestro medio, por lo que se requiere hacer estudios de monitorización terapéutica, que contribuya a minimizar los efectos adversos y optimizar la terapia farmacológica. En ese contexto, nuestro objetivo ha sido determinar el índice nivel/dosis de la fenitoína en pacientes epilépticos voluntarios de Mérida. MÉTODOS Se realizó un estudio descriptivo, observacional y por reclutamiento consecutivo concurrente, conformado por 30 pacientes voluntarios con diagnóstico de epilepsia. Las muestras de suero se obtuvieron en niveles mínimos de pacientes que estaban en tratamiento con fenitoína durante 1 mes. Los niveles del fármaco se cuantificaron por el método de Inmunoensayo de enzima donante clonada en el equipo Indiko Thermo Scientific. RESULTADOS El índice nivel/dosis fue de 1,4 y 1,6, la concentración plasmática de 4,8mg/l y 8,0mg/l, la capacidad metabólica de 388,4 y 462,9mg/día, respectivamente en mujeres y hombres. Mientras que el nivel de la concentración plasmática en el estado estacionario fue de 6,5mg/l y 5,5mg/l, la dosis de carga máxima de 237,3mg y de 395,6mg, respectivamente en mujeres y hombres con epilepsia de la ciudad de Mérida. CONCLUSIONES Nuestros resultados sugieren que se debe individualizar la dosis en base al índice nivel/dosis de cada paciente, ya que no se puede extrapolar para todos los pacientes con epilepsia, debido a diversos factores como al fenotipo metabólico y al uso de fármacos inductores e inhibidores enzimáticos.

INTRODUCTION Phenytoin is used very frequently in our environment, so it is necessary to do studies of therapeutic monitoring, which helps to minimize adverse drug reaction and optimize pharmacological therapy. In this context, our objective was to determine the level/dose index of phenytoin in volunteer epileptic patients from Mérida. METHODS A descriptive, observational and consecutive concurrent recruitment study was carried out, consisting of 30 volunteer patients with a diagnosis of epilepsy. The serum samples were obtained in minimum levels from patients who were in treatment with phenytoin for 1 month. The levels of the drug were quantified by the method of donor enzyme immunoassay cloned in the Indiko Thermo Scientific equipment. RESULTS The level/dose index was 1,4 and 1,6, the plasma concentration of 4,8mg/l and 8,0mg/l, the metabolic capacity of 388,4 and 462,9mg/day, respectively in women and men. While the level of plasma concentration at steady state was 6,5mg/l and 5,5mg/l, the maximum loading dose of 237,3mg and 395,6mg, respectively in women and men with epilepsy of the city of Mérida. CONCLUSIONS Our results suggest that the dose should be individualized based on the level/dose index of each patient, since it can not be extrapolated for all patients with epilepsy, due to various factors such as the metabolic phenotype and the use of enzyme-inducing drugs and inhibitors.

MDR1 gene polymorphism and phenytoin pharmacokinetics in epilepsy

Background: Pharmacokinetics is a widely used anti-epileptic drug phenytoin, which exhibits noticeable inter-individual variations in efficacy. Genetic factors, such as MDR1 gene polymorphism may play a crucial role in drug response

Objective: To investigate the influence of MDR1 variant genotypes on Phenytoin Pharmacokinetics in epileptic patients

Design: A Case-Control Genetic Study

Setting: College of Medicine and Pharmacy, King Khalid University, Abha, Saudi Arabia

Method: Twenty-five epileptic patients non-responders to phenytoin monotherapy and 25 epileptic patients' responders to phenytoin monotherapy were recruited. DNA was isolated by conventional phenol-chloroform method. MDR1 [3435C>T] gene polymorphism was assessed using the Polymerase Chain Reaction-Restriction Fragment Length Polymorphisms [PCR-RFLP] method. Allelic and genotypic frequency were calculated. Reversed-phase High-Performance Liquid Chromatography [HPLC] method was used to determine the plasma levels of Phenytoin drug. PK Solutions was used for non-compartmental analysis to estimate the pharmacokinetic parameters

Result: The MDR1 [3435C>T] polymorphism was found to be in Hardy-Weinberg equilibrium and displayed significant allelic and genotypic association between non-responders and responders to phenytoin [P<0.01]. The finding of pharmacokinetics analysis demonstrated that longer halflife [t1/2 = 33.26 hours] and less clearance rate [CL = 0.42 L/hour] in the homozygous variant group compared to wild-type genotype group [t 1/2 = 19.2hrs, CL = 0.8 L/hour]

Conclusion: The finding suggests that the genetic polymorphism in the C3435T location of MDR1 gene might determine pharmacokinetics variability of phenytoin drug. Therefore, pharmacokinetics parameters along with genotyping of MDR1 [C3435T] genotype might be valuable in the perspective of personalized medicine in epileptic patients

The Anticonvulsant Effect of Eupatorium Birmanicum DC Leave Extract Alone and in Combination with Phenytoin Against MES Seizure in Albino Mice.

To evaluate the anticonvulsant activity of aqueous extract of Eupatorium birmanicum DC leave (EB) alone and in combination with phenytoin against MES seizure in albino mice. Method: Aqueous extract of EB was prepared using Soxhlet apparatus. The anticonvulsant effect of the extract was tested on prescreened albino mice at 3 doses (200, 400 & 800 mg/kg). After 1 hr of oral administration of EB the animals were subjected to MES seizures by convulsiometer with a current of 45 mA for 0.2 sec via transauricular electrodes and the duration of the THLE was recorded. Sub-anticonvulsant dose of phenytoin was also determined and the effect of its combination with the most effective dose of EB tested. Results: EB aqueous extract exhibited significant anticonvulsant activity in the MES model at doses 400 mg/ kg (p<0.01) & 800 mg/kg (p<0.001). This reduction in the duration of THLE at 800mg/kg of EB was further reduced significantly (p<0.001) when combined with subanticonvulsant doses of phenytoin (10mg/kg). Conclusion: The aqueous extract of E. birmanicum leaves showed significant anticonvulsant activity in MES seizure model in albino mice and it significantly increased the anticonvulsant effect of phenytoin in the same animal model.

Effect of total parenteral nutrition on the pharmacokinetics of digoxin and phenytoin in male rabbits

Total parenteral nutrition [TPN] is a therapeutic intervention designed to provide sufficient calories and nitrogen to sustain patients who are unable to consume adequate nourishment by mouth and are therefore at risk of developing malnutrition. Unfortunately, alterations in both hepatic and intestinal function accompany therapy with TPN. TPN depresses both hepatic oxidative and conjugative biotransformation, consequently, the metabolism and elimination rate of drugs may be affected. To give insight about this situation, the present study was designed to investigate the effect of total parenteral nutrition on single dose pharmacokinetics of digoxin and phenytoin in male rabbits. Thirty six rabbits were divided into six groups as follow: the first three groups[I,II and III] were fed dry food and water, and the other three groups [IV, V and VI] received a total parenteral nutrition for ten days. Each group received a single IV dose of one drug as follow: group I and IV received digoxin [0.02 mg/kg,iv], group II and V received phenytoin [10 mg/ kg, iv],and group III and VI received midazolam [1 mg/kg, iv]. Serum alanine aminotrasnferase [ALT], aspartate aminotransferase [AST] and total bilirubin were determined. Plasma nitric oxide was estimated by Griess reaction. Sleeping time induced by midazolam was recorded. To study the pharrnacokinetic behaviour of digoxin or phenytoin, blood was collected 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0 and /or 24.0 hours after digoxin or phenytoin administration for determination of their blood levels. Total parenteral nutrition induced a significant increase in liver functions, plasma nitric oxide levels, and sleeping time of midazolam. In addition, Total parenteral nutrition induced a significant increase in the area under plasma digoxin or phenytoin concentration-time curves [AUC]and half life [t 1/2] of both drugs. Moreover, TPN induced a significant decrease in the clearance rate [Cl] for both drugs. The present study revealed that, in case of TPN,it is necessary to take in consideration the possibility of significant pharmacokinetic changes of some drugs, especially those having a narrow therapeutic index as digoxin and phenytoin. Therefore. digoxin and phenytoin blood levels must be monitored carefully in patients under TPN, and the doses of digoxin and phenytoin may need readjustment in those patients

Evaluation of phenytoin utilization based on key pharmacokinetic parameters in patients with head trauma

Phenytoin is commonly administered as an anticonvulsant agent to critically traumatic patients for seizure prophylaxis and treatment. It exhibits non-linear pharmacokinetic characteristic and requires frequent plasma level monitoring and dose adjustment. Based on the previous study, it is often difficult to achieve therapeutic levels in patients with head trauma using the recommended phenytoin dosing strategies. Therefore, we conducted a prospective, randomized study to evaluate pharmacokinetic parameters of phenytoin in patients with head trauma. In this prospective randomized study, eighty-three patients were enrolled. The dosing regimen of phenytoin was designed and individualized for each patient based on available population pharmacokinetic data and was compared with the administered dose. The peak and trough concentrations of collected blood samples were determined by TDX. Statistical analysis of the findings indicated that there were significant differences between administered doses of phenytoin and calculated doses based on peak and trough [P<0.0001]. Additonally, our findings indicate the significant difference between previous population Vmax and Vmax obtained from this study. Furthermore, this study showed that phenytoin plasma concentrations were sub therapeutic in the majority of cases [71%].It seems that blood level monitoring ot phenytoin in patients with neurosurgical trauma on the basis of drug pharmacokinetic parameters such as Vmax is necessary

Pharmacokinetics of phenytoin: unaltered by enalapril and amlodipine in rhesus monkeys.

A cross over single and multiple dose study was carried out to find out pharmacokinetic interactions between diphynylhydantoin (DPH) (35 mg/kg, p.o.) and antihypertensives enalapril (1.6 mg/kg; p.o.) and amlodipine (0.4 mg/kg, p.o.) in rhesus monkeys. Neither the plasma concentrations nor the pharmacokinetic parameters of DPH were altered by coadministration of enalapril or amlodipine, suggesting that enalapril and amlodipine can be safely administered to epileptic patients receiving phenytoin.

Effect of ciprofloxacin on steady state pharmacokinetics of phenytoin in rabbits.

Present study was undertaken to determine if an interaction exists during co-administration of ciprofloxacin with phenytoin. Eight healthy male rabbits received oral phenytoin, 40 mg/kg, od, for 7 days. On day 7, phenytoin blood sampling was done at times 0, 0.1, 1, 2, 3, 4, 5, 6, 8 and 24 hr. From day 8 to 14, phenytoin was co-administered with oral ciprofloxacin, 70 mg/kg, od. On day 14, blood samples were collected as previously described. Pharmacokinetic analysis revealed significant decrease in steady state maximum concentration (Cmax), through concentration (Cmin), elimination half life (t 1/2 e) and the area under plasma time concentration curve (AUC0-24) of phenytoin when co-administered with ciprofloxacin. It warrants close monitoring of levels when these two agents are given simultaneously.

Bioavailability of phenytoin sodium capsules available in Thailand. Part II: In vivo study.

Four phenytoin brands, dilantin and three local brands (brand A, B and C) were selected for the bioavailability study. The study was carried out in 16 healthy male Thai volunteers with the average age of 21 years old. A single oral dose of 300 mg (three capsules of 100-mg) phenytoin sodium was given to subjects following an 8 hour-overnight fast. The tested drugs were given in a single-blind randomized crossover with at least 2 weeks of washout period. Venous blood samples of approximately 5 ml were drawn before medication and at 1, 2, 4, 6, 8, 10, 12, 24, 48 and 72 hours post dosing. Plasma phenytoin concentrations were determined by HPLC assay. The pharmacokinetic parameters were calculated from the plasma-concentration time curve of an innovator brand, dilantin, by PCNONLIN program. Elimination rate constant and half-life were 0.2 h-1 and 19 h, respectively. The maximum concentration (Cmax) and time to peak (Tmax) were 1.98 micrograms/ml and 9.6 h, respectively. Bioavailability study was determined by comparing the area under the plasma concentration time curve (AUC), maximum plasma concentration (Cmax) and time to reach maximum plasma concentration (Tmax) by using ANOVA. The result indicated that two local brands (brand A and brand C) were not bioequivalent to the innovator in terms of Cmax and AUC0-alpha, whereas Tmax was not significantly different among these 4 brands. Cmax and AUC of brand A and C were significantly higher than the innovator brand. In addition, the plasma concentration time profile of brand C was also different from other brands with the steep peak which yielded a Cmax value double that of the Cmax of the innovator. However, brand B (from Research and Development Institute, Government Pharmaceutical Organization) was bioequivalent to dilantin after 4 times of product formulation adjustment. This present study demonstrated that the local products (brand A and brand C) were not bioequivalent with the innovator. Thus, the interchange from one brand to another must be performed cautiously or should be avoided, otherwise phenytoin blood levels should be monitored closely together with the clinical signs and symptoms of the patients.

Variaciones farmacocinéticas de anticonvulsivantes en mujeres epilépticas mexicanas durante las diferentes etapas del postparto / Pharmakocinetic variation of anticonvulsants in Mexican epileptic women during different parts of puerperium

Durante el embarazo existen una serie de cambios fisiológicos que influyen en la cinética de los medicamentos administrativos durante esta etapa: Estos cambios fisiológicos no se restauran inmediatamente en el parto, de tal manera que su concentración en los fluidos biológicos es diferente cuando se administra inmediatamente después del parto que varias semanas posterior al mismo. El presente trabajo tiene como propósito identificar los cambios en las constantes farmacocinéticas de fenitoína y carbamacepina, en pacientes epilépticas cuando se mantiene una misma dosis durante diferentes etapas del postparto. En 20 mujeres mexicanas epilépticas se determinó la concentración en plasma y leche de fenitoína durante 60 días postparto y en 14 se determinó carbamacepina. A todas las pacientes se les realizó la farmacocinética de los anticonvulsivantes en cada periodo de estudio (5, 15, 30, 45 y 60 días posparto) y se determinó el índice de excreción en leche materna. Las concentraciones plasmáticas de fenitoína no presentaron variaciones, sin embargo la carbanacepina fue más alta en el periodo tardió, también se observaron diferencias en las áreas bajo la curva y vida media de eliminación y en los índices de excreción

Terapêutica em epilepsia / Therapeutics in epilepsy

Esta revisão sumária sobre terapêutica em epilepsia aborda questões tais como quando começar o tratamento, qual a droga antiepilética (DAE) indicada para os diversos tipos de crise, quando retirar a DAE, sua posologia, frequência de tomadas, efeitos colaterais e idução/inibição enzimática da DAE, monitorização do tratamento e epilepsia refratária. Várias dessas questões são dependentes do conhecimento de farmacocinética e farmacodinâmica, fatos que também são considerados.

Determination of pharmacokinetic parameters of phenytoin in Iranian epileptic patients

Adjustment of phenytoin dosage in patients is very difficult due to its nonlinear metabolism and patient to patient variation in its kinetics. It has been recommended that the dosage of phenytoin should be adjusted according to its plasma concentration and requirements of the patients. Therefore, the present study was carried out to identify the various factors which may influence the plasma level of this drug. The phenytoin plasma concentration was determined in 91 patients with steady-state concentrations according to the EMIT method. In a further 14 patients, who had recieved at least two different doses of phenytoin, the Km and Vmax of phenytoin metabolism were determined according to Mullen's direct linear plot. The results of this study showed that the plasma level of phenytoin was below the therapeutic level in 62 [68.2%] of the patients and above the therapeutic level in 8 [8.8%]. Statistical analysis did not show any correlation between plasma level and factors such as sex, age, or type of drug administered. Only a small correlation was found between dosage and plasma level. The Km of phenytoin metabolism in the group studied was found to be in the range of 1.8-26micro g/ml and that of Vmax in the range of 5.33-13.88 mg/kg/day. The mean values of Km [8.4 +/- 1.7 micro g/ml] and Vmax [7.3 +/- 0.58 mg/kg/day] were slightly higher than reported values in the literature [5.7 +/- 2.9 micro g/ml and 5.9 +/- 1.2 mg/kg/day, respectively]. However, this difference was not statistically significant

Concentraciones de fármacos en sangre. Utilidad clínica en el embarazo y recién nacido / Drug concentration in blood: clinical utiliry during pregnancy and in the new born

En elpresente trabajo se analizan los resultados de 2,168 exámenes de laboratorio que se realizaron en 50 pacientes (78 en mujeres embarazadas y 26 en recién nacidos) para determinar los niveles de teofilina, fenobarbital, difenilhidantoína o digoxina. El 62.7%(1,359) de las concentraciones estuvieron entre los niveles terapéuticos recomendados para cada fármaco; el 21.8%(472) presentaron concentraciones subterapéuticas; y el 15.5%(337) fueron altas. En algunos pacientes se determinó la vida media de eliminación del medicamento. Estas actividades tienen como objetivo evaluar los resultados de las concentraciones con la información clínica para recomendar ajuste de dosis cuando es necesario, lo que permite controlar con mayor eficacia los esquemas de dosificación y aumentar el beneficio clínico de fármacos con índice terapéutico reducido y/o de aquellos en que la respuesta terapéutica es muy variable por factores diversos que afectan su cinética.