소아 간질 환자에서 항경련제에 따른 체중 변화; Valproic Acid와 Topiramate의 비교

김수진(Su-Jin Kim),박혜순(Hye-Soon Park),황정숙(Jung-Sook Hwang),정영진(Young-Jin Jung),고태성(Tae-Sung Ko) 대한소아신경학회 2003 대한소아신경학회지 Vol.11 No.1

목적 : Valproic acid를 비롯한 몇몇 항경련제가 체중 증가를 유발하여 순응도 저하와 비만의 위험이 문제시되고 있다. 그러나 새로 개발된 항경련제 중 topiramate는 오히려 체중 감소를 유발하는 것으로 알려져 있으며 이러한 효과가 소아 간질 환자에서 미치는 영향에 관한 국내보고는 아직 없는 실정이다. 이에 저자들은 소아 간질환자에서 valproic acid와 topiramate의 사용에 따른 체중변화를 알아보고자 하였다. 방법 : 1999년 8월부터 2001년 12월까지 서울아산병원 소아과에서 간질의 진단을 받고 valproic acid나 topiramate를 복용하고 있는 소아환자 124명의 의무기록지를 후향적으로 조사하여 치료 전후의 체중 변화를 비교분석 하였다. 결과 : 평균 치료 기간 10개월 동안 valproic acid 복용군에서는 3.7 kg의 체중 증가를 보인 반면 topiramate를 복용한 군에서는 0.3 kg의 체중 증가를 보여 통계적으로 유의하였다. 결론 : 소아 간질 환자에서 topiramate는 체중 증가를 유발하지 않았으며 비만한 간질 환자에서 선택적인 치료약제로 고려해 볼 수 있겠다. Purpose : The use of antiepileptic drugs for the seizure control has been a remarkable breakthrough. However, excessive body weight gain is a common side effect of some antiepileptic drugs. Topiramate is a novel and highly effective antiepileptic drug that has been associated with weight loss in some patients. This study was undertaken to compare the change of body weight in children treated with valproic acid and topiramate for epilepsy. Methods : Children who took medications for epilepsy with either valproic acid or topiramate were recruited. We collected the data of the initial weight and the follow-up weight on average, 10 months documented in the medical records. We analyzed the change of body weight due to antiepileptic drugs in the study subjects. Results : Statistically significant weight gains after treatment with valproic acid were observed(mean±SD, 3.7±3.2 kg). However, there have nearly no change of body weight after the treatment with topiramate(mean±SD, -0.9±2.3 kg). There were significant difference in weight changes between two groups of two different antiepileptic drug. Conclusion : This study showed that topiramate caused little weight gain in children with epilepsy. Antiepileptic drugs should be selected by individual patient's characteristics.

새로운 간질 치료제

김수경 啓明大學校 醫科大學 1995 계명의대학술지 Vol.14 No.2

Epilepsy is one of the most common disorder of man and one of very difficult disorders to manage in medical practice. Although established drugs have been used, they have also proved a lack of efficacy for several types of seizure. A large number of candidate drug used antiepileptive drugs are undergoing preclinical and clinical evaluation throughout the world. Now, felbamate, gabapentin, lamotrigine, zonisamide, vigabatrin, clobazam are promising of new generation of drugs in epilepsy management. Our purpose in this review is to consider the basic mechanism about currently used new antiepileptic drugs and newly developed drugs. Also, through he history of discovery of new antiepileptic drugs, we are going to approach to the next generation of epilepsy in pathophysiology, pharmacology, and medical practice.

항경련제의 장기투여가 혈장 PIVKA-Ⅱ 및 간기능에 미치는 영향

방규진(Kyu-Jin Bhang),김영훈(Young-Hoon Kim),황경태(Kyung-Tai Whang) 대한소아신경학회 1993 대한소아신경학회지 Vol.1 No.2

It was reported that plasma PIVKA-Ⅱ(protein induced by vitamin K absence or antagonistⅡ) levels in infants born to mothers treated with antiepileptic d겨gs pregnancy increased markedly, but little has been studied on the effect of the drugs on plasma PIVKA-Ⅱ in epileptic patients We measured PIVKA-Ⅱ levels by means of latex agglutination method in epileptic children receiving a variety of antiepileptic drugs, and assessed the incidence of PIVKA-Ⅱ positivity(plasma levels above 1µg/ml) together with a correlation between the plasma level of PIVKA-Ⅱ and the particular anticonvulsant taken, duration of the treatment, age of patients, and the values of liver function test. The study included 97 epileptic patients(54 males, 43 females; age 5-23 years) who were divided into four antiepileptic drug-treated groups : valproic acid monotherapy(n=18), carbamazepine monotherapy(n=38), valproic acid polytherapy(n=20) and other antiepileptic drugs(n=21), and a control group ofn 52 children(33 males, 19 females; ages 8-19years). The results were as follows; 1) The incidence rate of PIVKA-Ⅱ positivity was 21.6% in 97 patients of four antiepileptic drug-teated groups. 2) There was neither correlation between PIVKA-Ⅱ positivity and any specific antiepileptic drugs nor between PIVKA-Ⅱ positivity and the duration of the treament. 3) There was an inverse correlation between the age of the patients and PIVKA-Ⅱ levels(P=0.028). 4) Among the biochemical studies of liver function, only the lvel of blood ammonia was correlated with the level of PIVKA-Ⅱ(P<0.00001). It could be concluded that the raised PIVKA-Ⅱ level in patients on antiepileptic treatment was presumptive evidence for subclinical coagulation defect, similar to that found in vitamin K deficiency, and the measurement of blood ammonia may be the useful adjuvant method to predict raised plasma PIVKA-Ⅱ level.

Modern Methods for Analysis of Antiepileptic Drugs in the Biological Fluids for Pharmacokinetics, Bioequivalence and Therapeutic Drug Monitoring

Juseop Kang,Yoo-Sin Park,Shin-Hee Kim,Sang-Hyun Kim,Min-Young Jun 대한생리학회-대한약리학회 2011 The Korean Journal of Physiology & Pharmacology Vol.15 No.2

Epilepsy is a chronic disease occurring in approximately 1.0% of the world s population. About 30% of the epileptic patients treated with availably antiepileptic drugs (AEDs) continue to have seizures and are considered therapy-resistant or refractory patients. The ultimate goal for the use of AEDs is complete cessation of seizures without side effects. Because of a narrow therapeutic index of AEDs, a complete understanding of its clinical pharmacokinetics is essential for understanding of the pharmacodynamics of these drugs. These drug concentrations in biological fluids serve as surrogate markers and can be used to guide or target drug dosing. Because early studies demonstrated clinical and/or electroencephalographic correlations with serum concentrations of several AEDs, It has been almost 50 years since clinicians started using plasma concentrations of AEDs to optimize pharmacotherapy in patients with epilepsy. Therefore, validated analytical method for concentrations of AEDs in biological fluids is a necessity in order to explore pharmacokinetics, bioequivalence and TDM in various clinical situations. There are hundreds of published articles on the analysis of specific AEDs by a wide variety of analytical methods in biological samples have appears over the past decade. This review intends to provide an updated, concise overview on the modern method development for monitoring AEDs for pharmacokinetic studies, bioequivalence and therapeutic drug monitoring.

Severe Cutaneous Adverse Reactions to Antiepileptic Drugs: A Nationwide Registry-Based Study in Korea

박찬선,강동윤,강민규,김수정,예영민,김세훈,박혜경,박정원,남영희,양민석,지영구,정재우,김상헌,김철우,김미영,김주희,이재천,이준규,김상현,나현오,김민혜,박승주,고영일,이상민,권용은,진현정,김희규,강혜련,최정희 대한천식알레르기학회 2019 Allergy, Asthma & Immunology Research Vol.11 No.5

Purpose: Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) to antiepileptic drug (AED), are rare, but result in significant morbidity and mortality. We investigated the major culprit drugs, clinical characteristics, and clinical course and outcomes of AED-induced SCARs using a nationwide registry in Korea. Methods: A total of 161 patients with AED-induced SCARs from 28 referral hospitals were analyzed. The causative AEDs, clinical characteristics, organ involvements, details of treatment, and outcomes were evaluated. We compared the clinical and laboratory parameters between SJS/TEN and DRESS according to the leading causative drugs. We further determined risk factors for prolonged hospitalization in AED-induced SCARs. Results: Carbamazepine and lamotrigine were the most common culprit drugs causing SCARs. Valproic acid and levetiracetam also emerged as the major causative agents. The disease duration and hospital stay in carbamazepine-induced SJS/TEN were shorter than those in other AEDs (P< 0.05, respectively). In younger patients, lamotrigine caused higher incidences of DRESS than other drugs (P= 0.045). Carbamazepine, the most common culprit drug for SCARs, was associated with a favorable outcome related with prolonged hospitalization in SJS (odds ratio, 0.12; 95% confidence interval, 0.02-0.63, P= 0.12), and thrombocytopenia was found to be a risk factor for prolonged hospitalization in DRESS. Conclusion: This was the first large-scale epidemiological study of AED-induced SCARs in Korea. Valproic acid and levetiracetam were the significant emerging AEDs causing SCARs in addition to the well-known offending AEDs such as carbamazepine and lamotrigine. Carbamazepine was associated with reduced hospitalization, but thrombocytopenia was a risk factor for prolonged hospitalization. Our results suggest that the clinical characteristics and clinical courses of AED-induced SCARs might vary according to the individual AEDs.

항경련제가 혈청 Carnitine 및 간 기능에 미치는 영향

이수중(Soo-Jung Lee),김종완(Jong-Wan Kim),황경태(Kyung-Tai Whang) 대한소아신경학회 1993 대한소아신경학회지 Vol.1 No.2

We measured the serum carnitine levels by means of radioisotopic assay in epileptic children receiving a various antiepileptic drugs, and assessed the effects of antiepileptic drugs on serum carnitine level together with a correlation between serum carnitine level and duration of treatment, and value of liver function. The study included 97 epileptic patients(54 males, 43 females ; ages 5-23 years) who were divided into four antiepileptic drug-treated groups : valproic acid(VPA) monotherapy, carbamazepine monotherapy, valproic acid polytherapy, and other antiepileptic drugs without VPA, and a control group of 52 children(33 males, 19 females ; ages 8-19 years). The results were as follows: 1. The serum levels of total and free carnitine were significantly reduced in the patients of VPA mono- and polytherapy groups, compared with the control group. The reduction was more significant in the patients of VPA polytherapy group than in those of VPA monotherapy group. 2. The number of patients whose serum level of total and free carnitine reduced by > 2SD below the mean of control group was 3 of 18 patients in VPA monotherapy group and 6 of 20 patients in VPA polytherapy group, respectively. 3. The duration of treatment was not correlated with the serum levels carnitine in both VPA mono- and polytherapy groups. 4. The blood level of ammonia was inversely correlated with the serum level of carnitine in both VPA mono- and polytherapy groups. It can be concluded that reduction of serum carnitine should be considered in epileptic patients taking VPA therapy, although the clinical symptoms of carnitine deficiency were not found in patients of our study, and the measurement of blood ammonia may be the useful parameter to predict hypocarnitinemia.

Phenytoin 복용과 관련된 다발성 골절과 저칼슘혈증을 동반한 골연화증 1예

김은경,이민석,정윤석,곽규성,홍지만,원예연 대한내분비학회 2009 Endocrinology and metabolism Vol.24 No.3

Many studies have shown that patients taking antiepileptic drugs are at an increased risk for metabolic bone disease and low bone mineral density. Traditionally, this has been attributed to alterations in vitamin D metabolism by antiepileptic drugs which induce hepatic microsomal cytochrome P450 enzyme. However, there appear to be multiple mechanisms for antiepileptic drug-induced bone loss including lack of physical activity, reduced sunlight exposure, increased propensity for falling, and fractures associated with seizures or loss of consciousness. We experienced a case of antiepileptic drug-induced osteomalacia in a 63-year-old woman who had been on phenytoin for 8 years and was admitted with hypocalcemic seizures and multiple pathological fractures. This patient also had other risk factors for osteomalacia including reduced sunlight exposure, prolonged immobilization, and decreased dietary vitamin D intake. We discontinued phenytoin, and started calcium and vitamin D replacement. The patient’s serum calcium and vitamin D level were normalized after treatment. Metabolic bone disease including osteomalacia should be considered in patients who are taking antiepileptic drugs especially those who are exposed to other risk factors.

Antiepileptic drug-induced severe cutaneous adverse reactions and HLA alleles: A report of five cases with lymphocyte activation test

김은영,김미영,Chan Sun Park,최재혁,Jong-Lyul Ghim,Ho-Sook Kim,신재국 대한임상약리학회 2019 Translational and Clinical Pharmacology Vol.27 No.2

Antiepileptic drugs (AEDs) can induce severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. We performed HLA genotyping and lymphocyte activation tests (LATs) for five AED-induced SCAR patients (three males and two females; aged 40-66 years old). Three patients were treated with carbamazepine (CBZ) for pain control, one was treated with phenytoin (PHT) for seizure prevention, and one was treated with valproic acid (VPA) for seizure prevention. One patient was diagnosed with CBZ-induced DRESS syndrome and the remaining patients were diagnosed with SJS. All patients recovered from SCARs after stopping suspicious drugs and supportive care. LATs were conducted to confirm the culprit drug responsible for inducing SCARs; and LAT results were positive for the suspected culprit drugs, in all except in one case. HLA-A, -B, and -C alleles were determined using PCR-sequence-based typing method. The common alleles of HLA were -A*02:01, -B*51:01, and -C*03:04 which were carried by three patients (60%) for each allele. The patient with CBZ-induced DRESS syndrome carried the HLAA* 31:01 allele. One patient with CBZ-induced SJS and one patient with VPA-induced SJS carried the HLA-B*15:11 allele. No patients carried the HLA-B*15:02 allele, which is a known risk allele of AED-induced SCARs. Further investigation of the three common alleles found in the five AED-induced SCARs patients is needed. We demonstrated the usefulness of LAT for confirming the culprit drug.

Modern Methods for Analysis of Antiepileptic Drugs in the Biological Fluids for Pharmacokinetics, Bioequivalence and Therapeutic Drug Monitoring

Kang, Ju-Seop,Park, Yoo-Sin,Kim, Shin-Hee,Kim, Sang-Hyun,Jun, Min-Young The Korean Society of Pharmacology 2011 The Korean Journal of Physiology & Pharmacology Vol.15 No.2

Epilepsy is a chronic disease occurring in approximately 1.0% of the world's population. About 30% of the epileptic patients treated with availably antiepileptic drugs (AEDs) continue to have seizures and are considered therapy-resistant or refractory patients. The ultimate goal for the use of AEDs is complete cessation of seizures without side effects. Because of a narrow therapeutic index of AEDs, a complete understanding of its clinical pharmacokinetics is essential for understanding of the pharmacodynamics of these drugs. These drug concentrations in biological fluids serve as surrogate markers and can be used to guide or target drug dosing. Because early studies demonstrated clinical and/or electroencephalographic correlations with serum concentrations of several AEDs, It has been almost 50 years since clinicians started using plasma concentrations of AEDs to optimize pharmacotherapy in patients with epilepsy. Therefore, validated analytical method for concentrations of AEDs in biological fluids is a necessity in order to explore pharmacokinetics, bioequivalence and TDM in various clinical situations. There are hundreds of published articles on the analysis of specific AEDs by a wide variety of analytical methods in biological samples have appears over the past decade. This review intends to provide an updated, concise overview on the modern method development for monitoring AEDs for pharmacokinetic studies, bioequivalence and therapeutic drug monitoring.

Modern Methods for Analysis of Antiepileptic Drugs in the Biological Fluids for Pharmacokinetics, Bioequivalence and Therapeutic Drug Monitoring

강주섭,Yoo-Sin Park,Shin-Hee Kim,Sang-Hyun Kim,전민영 대한약리학회 2011 The Korean Journal of Physiology & Pharmacology Vol.15 No.2

Epilepsy is a chronic disease occurring in approximately 1.0% of the world’s population. About 30% of the epileptic patients treated with availably antiepileptic drugs (AEDs) continue to have seizures and are considered therapy-resistant or refractory patients. The ultimate goal for the use of AEDs is complete cessation of seizures without side effects. Because of a narrow therapeutic index of AEDs, a complete understanding of its clinical pharmacokinetics is essential for understanding of the pharmacodynamics of these drugs. These drug concentrations in biological fluids serve as surrogate markers and can be used to guide or target drug dosing. Because early studies demonstrated clinical and/or electroencephalographic correlations with serum concentrations of several AEDs, It has been almost 50 years since clinicians started using plasma concentrations of AEDs to optimize pharmacotherapy in patients with epilepsy. Therefore, validated analytical method for concentrations of AEDs in biological fluids is a necessity in order to explore pharmacokinetics, bioequivalence and TDM in various clinical situations. There are hundreds of published articles on the analysis of specific AEDs by a wide variety of analytical methods in biological samples have appears over the past decade. This review intends to provide an updated, concise overview on the modern method development for monitoring AEDs for pharmacokinetic studies, bioequivalence and therapeutic drug monitoring.