Phenytoin (PHT) is an antiepileptic drug widely used in the treatment of focal epilepsy and status epilepticus, and effective in controlling focal seizures with and without tonic–clonic generalization and status epilepticus. The metabolization of PHT is carried out by two oxidative cytochrome P450 enzymes CYP2C9 and CYP2C19; 90% of this metabolization is done by CYP2C9 and the remaining 10% by CYP2C19. Genetic polymorphism of CYP2C9 may reduce the metabolism of PHT by 25–50% in patients with variants *2 and *3 compared to those with wild-type variant *1. The frequency distribution of CYP2C9 polymorphism alleles in patients with epilepsy around the world ranges from 4.5 to 13.6%, being less frequent in African-Americans and Asians. PHT has a narrow therapeutic range and a nonlinear pharmacokinetic profile; hence, its poor metabolization has significant clinical implications as it causes more frequent and more serious adverse effects requiring discontinuation of treatment, even if it had been effective. There is evidence that polymorphisms of CYP2C9 and the use of PHT are associated with an increase in the frequency of some side effects, such as cerebellar atrophy, gingival hypertrophy or acute cutaneous reactions. The presence of HLA-B*15:02 and CYP2C9 *2 or *3 in the same patient increases the risk of Stevens–Johnson syndrome and toxic epidermal necrolysis; hence, PHT should not be prescribed in these patients. In patients with CYP2C9 *1/*2 or *1/*3 alleles (intermediate metabolizers), the usual PHT maintenance dose (5–10 mg/kg/day) must be reduced by 25%, and in those with CYP2C9 *2/*2, *2/*3 or *3/*3 alleles (poor metabolizers), the dose must be reduced by 50%. It is controversial whether CYP2C9 genotyping should be done before starting PHT treatment. In this paper, we aim to review the influence of CYP2C9 polymorphism on the metabolization of PHT and the clinical implications of poor metabolization in the treatment of epilepsies.

Our study is the first to report evidence linking CYP2C9 polymorphism and a reduction in cerebellar volume in epileptic users of phenytoin.

Objective: CYP2C9 is a major enzyme in human drug metabolism and the polymorphism observed in the corresponding gene may affect therapeutic outcome during treatment. The distribution of variant CYP2C9 alleles and prevalence of phenytoin adverse reactions were hereby investigated in a population of patients diagnosed with epilepsy. Method: Allele-specific PCR analysis was carried out in order to determine frequencies of the two most common variant alleles, CYP2C9*2 and CYP2C9*3 in genomic DNA isolated from 100 epileptic patients. We also analyzed the frequency of phenytoin adverse reactions among those different genotypes groups. The data was presented as mean±standard deviation. Results: The mean age at enrollment was 39.6±10.3 years (range, 17-72 years) and duration of epilepsy was 26.5±11.9 years (range 3-48 years). The mean age at epilepsy onset was 13.1±12.4 years (range, 1 month-62 years). Frequencies of CYP2C9*1 (84%), CYP2C9*2 (9%) and CYP2C9*3 (7%) were similar to other published reports. Phenytoin adverse reactions were usually mild and occurred in 15% patients, without correlation with the CYP2C9 polymorphism (p=0.34). Conclusion: Our findings indicate an overall similar distribution of the CYP2C9 alleles in a population of patients diagnosed with epilepsy in the South of Brazil, compared to other samples. This sample of phenytoin users showed no drug related adverse reactions and CYP2C9 allele type correlation. The role of CYP2C9 polymorphism influence on phenytoin adverse reaction remains to be determined since some literature evidence and our data found negative results. Key words: CYP2C9, polymorphism, Brazilian population, phenytoin, adverse reactions.Polimorfismo do CYP2C9 em pacientes com epilepsia: estudo da frequência genotípica e correlação com os efeitos colaterais da fenitoína RESUMO Objetivo: A CYP2C9 é uma das principais enzimas do metabolismo de drogas humano e o polimorfismo observado no respectivo gene pode afetar o resultado terapêutico durante o tratamento. Neste trabalho investigamos em uma população de pacientes portadores de epilepsia a distribuição dos alelos variantes do CYP2C9 e a frequência de efeitos adversos da fenitoína tentando estabelecer uma correlação. Método: Realizamos uma análise através de uma PCR alelo específica para determinar a frequência dos alelos variantes mais comuns, CYP2C9*2 e CYP2C9*3, isolados da amostra de 100 pacientes com epilepsia. Também levantamos a frequência de reações adversas da fenitoína nestes diferentes grupos genotípicos. Os dados são apresentados na forma de média e desviopadrão. Resultados: A idade média na inclusão foi 39,6±10,3 anos (variando de 17-72 anos) e a duração da epilepsia era 26,5±11,9 anos (variando de 3-48 anos). A idade média dos pacientes no início da epilepsia era 13,1±12,4 anos (variando de 1 mês-62 anos). As frequências do CYP2C9*1 (84%), CYP2C9*2 (9%) e CYP2C9*3 (7%) foram similares Correspondence Carlos Silvado Hospital de Clínicas / UFPR Rua General Carneiro 181 / 3° andar 80060-900 Curitiba PR -Brasil

-Hyponatremia is a significant complication of treatment with serotonin selective re u p t a k e inhibitors (SSRI). We describe a case of a 53-year-old woman that was started on fluoxetine 20 mg/day for d e p ression. Nine days later, the patient started with weakness, nausea, pro g ressing to confusion, inapetence and vomit. Three hours later she became unresponsive and had a generalized seizure. She was b rought to our emergency service. On admission, the patient was normovolemic, without focal motor deficits, but had mild generalized muscle rigidity and Babinski`s sign bilaterally. Serum sodium was 105 mmol/L, serum osmolality, 220 mmol/L, and urinary osmolality, 400 mmol/L. The other laboratory exams, chest X-ray, cere b rospinal fluid and cranium tomography were normal. She was found to have fluoxetineinduced SIADH and it was descontinued. We started the hyponatremia correction and, in 5 days, the mental status of the patient gradually re t u rned to a normal baseline, paralleling the resolution of her hyponat remia, without re c u rrence. Hyponatremia and SIADH should be considered if a patient experiences deterioration in his or her clinical condition while taking SSRI. The use of SSRI antidepressants should be re m e mbered in the differential diagnosis of drug-induced hyponatremia.KEY WORDS: antidepressive agents, fluoxetine, inappropriate ADH syndrome.Hiponatremia grave e síndrome da secreção inapropriada de hormônio antidiurético (SSIHAD) associada com fluoxetina: relato de caso RESUMO -A hiponatremia é complicação significativa do tratamento com inibidores seletivos da re c a ptação da serotonina (ISRS). Descrevemos o caso de uma paciente de 53 anos de idade que iniciou uso de fluoxetina 20 mg/dia para depressão. Nove dias depois, a paciente apresentou fraqueza, náusea, pro g re d i ndo para confusão, inapetência e vômitos. Três horas depois ela tornou-se irresponsiva e teve uma crise convulsiva generalizada. Foi então trazida ao nosso serviço de emergência. Na admissão, a paciente estava n o rmovolêmica, sem déficits motores focais, mas apresentava leve rigidez muscular generalizada e sinal de Babinski bilateralmente. O sódio sérico era 105 mmol/L, osmolaridade sérica, 220 mmol/L, e osmolaridade urinária, 400 mmol/L. Os outros exames laboratoriais, Raio-X do pulmão, líquido cefalorraqueano e tomografia do crânio eram normais. Ela foi diagnosticada como tendo SSIHAD induzida por fluoxetina sendo esta descontinuada. Nós iniciamos a correção da hiponatremia e, em 5 dias, o estado mental da paciente gradualmente re t o rnou ao normal, paralelamente a resolução da hiponatremia. SSIHAD e hiponat remia devem ser consideradas em um paciente que apresenta deterioração de sua condição clinica quando estiver em uso de ISRS. O uso de antidepressivos ISRS deve ser lembrado no diagnóstico diferencial de hiponatremia induzida por drogas. PALAVRAS-CHAVE: antidepressivos, fluoxetina, síndrome da secreção inapropriada de hormônio antidiurético, inibidores de recaptação de serotonina.

Improvement in post-CME scores confirms that the program had a significant immediate impact on the PCPs knowledge directly affecting the patient's health.