INFLUENCE OF THE SCN1A IVS5N + 5 G>A POLYMORPHISM ON THERAPY WITH CARBAMAZEPINE FOR EPILEPSY
Sterjev Z1,*, Kiteva G2, Cvetkovska E2, Petrov I2, Kuzmanovski I2, Ribarska TJ3, Nestorovska KA1, Matevska N1,Trajkovik-Jolevska S3, Dimovski AJ1, Suturkova, Lj1
*Corresponding Author: Zoran Sterjev, M. Sei. Pharm Institute of Pharmaceutical Chemistry, Faculty of Pharmacy, University “St. Cyril and Methodius,” str. Vodnjanska 17, 1000 Skopje, Republic of Macedonia; Tel./Fax:+38-923-120-229; E-mail: zost@ff.ukim.edu.mk
page: 19

RESULTS

The genotypes of drug-resistant and drugresponsive groups and of control group were in Hardy-Weinberg equilibrium. The genotypic frequencies of the polymorphism in all patients were 0.20 for GG, 0.52 for AG and 0.28 for the AA genotype, respectively (Table 3). In the control group, the distribution was 0.21, 0.49 and 0.29 for GG, AG and AA, respectively. There were no signifi cant differences in the allelic frequencies and genotype distribution between patients and controls (p = 0.94). Genotype frequencies in the CBZ-responsive group were 0.23, 0.47 and 0.30, while those in the CBZ-resistant patients were 0.15, 0.59 and 0.26 for the GG, GA and AA, respectively. There were no statistically signifi cant difference between these two groups (p = 0.55) (Table 3). Patients with the AA genotype needed a higher average maintenance dose of CBZ (608  273 mg/ day) than patients with the AG and GG genotypes (542  241 and 468  241 mg/day, respectively) (Figure 1). The values modes of CBZ doses were: 394 mg/day for GG, 400 mg/ day for AG and 450 mg/day for AA genotypes. These values were interdependent [2 = 4.965 >2 4;0;30 = 4.878;  = 0.30 and k = (3-1)(3-1) = 4) but the differences were not statistically signifi cant (p = 0.05). We found a signifi cant statistical difference when we compared AA+AG vs. GG genotype (z = 1.57073 >z1– = 1.435;  = 0.15) (Table 4). These results indicate that the likelihood of a positive response to CBZ therapy at an initial dose of 400 mg is 41.67, 57.89 and 73.68% in patients with AA, AG and GG genotypes, respectively. These differences persist only up to a dose of 1000 mg/day, after which there is no difference between patients with different genotypes (Figure 2). The total CBZ plasma concentrations and their correlation with the patients’ genotype showed interdependence (x2 = 11.610 >2 10;0;32 = 11.5;  = 0.32 and k = (6-1) (3-1) = 10). Distribution of dose ratios (PDD/DDD) in patients with different genotypes are presented in Figure 3. The ratio of daily doses of CBZ divided by plasma CBZ levels (dose/level) of patients with the AA genotype was 24.95  11.08, and 22.09  8.45 and 20.62  8.59 for the AG and GG genotypes, respectively. These results also showed interdependence (2 = 11.88 >2 10;0;30 =11.781;  =0.30 and k = (6-1) (3-1) = 10), indicating that the differences were primarily exerted at the level of target responsiveness. This was further strengthened by the lack of statistically signifi cant difference in CBZ plasma levels between patients with different genotypes treated with the same CBZ dose (Figure 4).



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