[Effects of carbamazepine on plasma concentrations of valproic acid and its toxic metabolite in epileptic patients].

To investigate the effects of carbamazepine (CBZ) on the plasma concentrations of valproic acid (VPA) and its toxic metabolite 2-propyl-4-pentenoic acid (4-ene VPA) in epileptic patients, the plasma concentrations of VPA and 4-ene VPA were determined, and the effect of CBZ on pharmacokinetics of VPA was evaluated. All patients had been divided into two groups (VPA group, n = 87; and VPA+CBZ group, n = 19). As compared to VPA group, the combination of CBZ significantly (P < 0.01) decreased the trough concentration of VPA [VPA group, (69.5 +/- 28.8) microg x mL(-1); VPA+CBZ group, (46.3 +/- 25.6) microg x mL(-1)] and does-adjusted VPA trough concentration [VPA group, (4.89 +/- 2.21) microg x mL(-1) x mg(-1) x kg(-1); VPA+CBZ group, (3.14 +/- 1.74) microg x mL(-1) x mg(-1) x kg(-1)]. However, the addition of CBZ did not influence the concentration of 4-ene VPA. The present study revealed that coadministration of CBZ can reduce VPA plasma concentration and may impact VPA clinical effect, therefore therapeutic drug mornitoring of VPA should be used when combined use of CBZ and VPA.

HLA-A*24:02 as a common risk factor for antiepileptic drug-induced cutaneous adverse reactions.

OBJECTIVE: To investigate the involvement of human leukocyte antigen (HLA) loci in aromatic antiepileptic drug-induced cutaneous adverse reactions. METHODS: A case-control study was performed to detect HLA loci involved in aromatic antiepileptic drug-induced Stevens-Johnson syndrome in a southern Han Chinese population. Between January 1, 2006, and December 31, 2015, 91 cases of Stevens-Johnson syndrome induced by aromatic antiepileptic drugs and 322 matched drug-tolerant controls were enrolled from 8 centers. Important genotypes were replicated in cases with maculopapular eruption and in the meta-analyses of data from other populations. Sequence-based typing determined the HLA-A, HLA-B, HLA-C, and HLA-DRB1 genotypes. RESULTS: HLA-B*15:02 was confirmed as strongly associated with carbamazepine-induced Stevens-Johnson syndrome (p = 5.63 × 10-15). In addition, HLA-A*24:02 was associated significantly with Stevens-Johnson syndrome induced by the aromatic antiepileptic drugs as a group (p = 1.02 × 10-5) and by individual drugs (carbamazepine p = 0.015, lamotrigine p = 0.005, phenytoin p = 0.027). Logistic regression analysis revealed a multiplicative interaction between HLA-B*15:02 and HLA-A*24:02. Positivity for HLA-A*24:02 and/or HLA-B*15:02 showed a sensitivity of 72.5% and a specificity of 69.0%. The presence of HLA-A*24:02 in cases with maculopapular exanthema was also significantly higher than in controls (p = 0.023). Meta-analysis of data from Japan, Korea, Malaysia, Mexico, Norway, and China revealed a similar association. CONCLUSIONS: HLA-A*24:02 is a common genetic risk factor for cutaneous adverse reactions induced by aromatic antiepileptic drugs in the southern Han Chinese and possibly other ethnic populations. Pretreatment screening is recommended for people in southern China.

Polycystic ovary syndrome in patients with epilepsy: a study in 102 Chinese women.

PURPOSE: The incidence of polycystic ovary syndrome (PCOS) increases in women with epilepsy (WWE), which appears to vary with ethnicity. This study was conducted to determine the incidence and risk factors of PCOS in Chinese WWE. METHODS: The study was carried out in 102 of 139 Chinese WWE at reproductive ages, with 32 receiving valproic acid (VPA), 40 receiving other antiepileptic drugs (AEDs), and 30 without AEDs therapy. PCOS was defined as having 2 or more of the following components: polycystic ovaries, hyperandrogenism, and amenorrhoea or oligomenorrhoea (a/oligomenorrhoea). RESULTS: One or more isolated components of PCOS were found in 56 (54.9%) patients, with 29 (28.4%) having polycystic ovaries, 20 (19.6%) with a/oligomenorrhea, 7 (6.9%) with hyperandrogenism, and 13 (12.7%) with defined PCOS. Their average age at the start of seizure was 13.8±6.5 years, younger than that of patients without these disorders (16.9±8.6 years, p<0.05). VPA therapy increased the incidence of PCOS (11/32, 34.4%), in addition to increased blood levels of testosterone and luteinizing hormone (LH) as well as LH to FSH (follicle-stimulating hormone) ratio. No significant relationship was found between the incidence of PCOS and the type, duration, or frequency of seizures in these WWE. CONCLUSION: There is an increased incidence of PCOS in Chinese WWE at reproductive ages, by more than 2 times of that in the general population. Risk factors include seizures starting at a young age and VPA therapy.

Association between HLA and Stevens-Johnson syndrome induced by carbamazepine in Southern Han Chinese: genetic markers besides B*1502?

Previous studies have demonstrated a strong association between carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (CBZ-induced SJS/TEN) and HLA-B*1502 in Chinese, and HLA-A*3101 but not HLA-B*1502 in Caucasians and Japanese. Cases with CBZ-induced SJS/TEN negative for HLA-B*1502 were reported recently in Southeast Asia. Negative correlations between CBZ-induced SJS/TEN and B*0702 or B*4001 have also been reported, suggesting a possible protective role. Here, we genotyped HLA-B and HLA-A in 18 cases with CBZ-induced SJS/TEN, in comparison with CBZ-tolerant and normal controls in Southern Han Chinese. A strong association between HLA-B*1502 and CBZ-induced SJS/TEN was found, with 72.2% sensitivity and 87.1% specificity. However, we also found five patients with SJS (5/18, 27.78%) who were negative for HLA-B*1502. HLA-A*2402 was present in nine of 16 cases with SJS (56.25%, including three of five cases negative for HLA-B*1502), which was significantly more frequent than that of CBZ-tolerant controls or the general southern population. Only one case with SJS carried HLA-A*3101. No statistical difference in the mean age, sex ratio and CBZ usage was found between the CBZ-induced SJS/TEN group and the CBZ-tolerant group. In search for possible protective genetic markers in HLA-B*1502-positive but CBZ-tolerant patients, we failed to find any significant factors in the HLA alleles observed. Given the association between HLA-B*1502 and CBZ-induced SJS/TEN, genetic testing before initiating CBZ therapy is suggested in Han Chinese population. However, physicians should also be vigilant about SJS/TEN in those negative for HLA-B*1502. Other factors for the development of CBZ-induced SJS/TEN in HLA-B*1502-negative patients and protective factors in CBZ-tolerant patients should be investigated further.

Simultaneous determination of valproic acid and 2-propyl-4-pentenoic acid for the prediction of clinical adverse effects in Chinese patients with epilepsy.

Valproic acid (VPA) is a well-established anticonvulsant drug that has been increasingly used in the treatment of many forms of generalized epilepsy. Although there are many reports of adverse effects of VPA, studies focusing on the concentration-response relationships of VPA and its metabolites in patients with epilepsy are extremely limited. In this study, a rapid and specific high performance liquid chromatography-ultraviolet (HPLC-UV) method to simultaneously detect the concentrations of VPA and its major hepatotoxic metabolite 2-propyl-4-pentenoic acid (4-ene VPA) in human plasma has been established, using 2,4'-dibromoacetophenone and octanoic acid as the derivatization reagent and internal standard, respectively. This method was used to analyze plasma samples (n=64) of Chinese patients with epilepsy. The results revealed that 4-ene VPA concentrations in Chinese patients were much higher than those in patients in other countries such as United States and Iran. Significant correlations between aspartate aminotransferase (AST), alanine aminotransferase (ALT) and 4-ene VPA concentration suggest that the simultaneous determination of VPA and 4-ene VPA is an effective tool for the prediction of clinical hepatotoxicity in epileptic patients. Furthermore, the present study describes a less costly and complex technique for the clinical monitoring of VPA plasma levels and the risk of hepatotoxicity which may be of particular interest in developing countries like China.

Analyzing clinical and electrophysiological characteristics of Paroxysmal Dyskinesia.

The classification, clinical and electrophysiological characteristics, treatment outcome and pathogenesis of paroxysmal dyskinesia were summarized and analyzed. Paroxysmal dyskinesia was classified into three types. Different types had different incentives in clinical practice. Patients were mostly male adolescents, and the attacks, which were in various forms, manifested as dysmyotonia of choreoathetosis, body torsion and facemaking; no disturbance of consciousness during attacks. Electroencephalogram and other examinations showed no specific abnormalities during both the attacks and interictal period. Paroxysmal dyskinesia was an independent disease and different from epilepsy.

Association between HLA-B*1502 allele and carbamazepine-induced severe cutaneous adverse reactions in Han people of southern China mainland.

Previous studies have found a strong association between HLA-B*1502 and carbamazepine-induced Stevens-Johnson syndrome in Asian areas including Taiwan, Hongkong and Thailand. This study explores the association between HLA-B*1502 allele and carbamazepine-induced cutaneous adverse reactions in Han Chinese of southern China mainland, and find the genetic marker that can predict carbamazepine-induced cutaneous adverse reactions. HLA-B*1502 allele genotyping was performed by a polymerase chain reaction-sequence specific primers (PCR-SSP) method in 48 Han Chinese subjects who had carbamazepine-induced cutaneous adverse reactions, including 9 severe cutaneous adverse reaction patients with Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) and 39 cutaneous adverse reaction patients with maculopapular eruption (MPE). Meanwhile 80 carbamazepine-tolerant controls and 62 healthy individuals were also tested. The frequency of HLA-B*1502 allele among SJS/TEN patients (100%) is significantly higher than carbamazepine-tolerant controls (13.75%, P<0.001) and healthy individuals (17.74%, P<0.001). But the frequency between MPE patients and carbamazepine-tolerant controls (25.64% vs.13.75%, P=0.110) did not have any significant difference. The data showed that HLA-B*1502 allele is strongly associated with carbamazepine-induced SJS/TEN but not MPE in Han Chinese of southern China mainland.