Аннотация:
Background. Diazepam is one of the most commonly prescribed tranquilizers for the therapy of alcohol withdrawal syndrome, which includes the symptoms of anxiety, fear and emotional tension. However, diazepam therapy often turns out to be ineffective, and some patients experience the dose-dependent adverse drug reactions: dizziness, drowsiness, slowed reaction, decreased mental and physical activity, muscle weakness, ataxia, dyspepsia, etc., which reduce the efficacy of therapy in this cohort of patients. The results of previous studies revealed that CYP2C19 isoenzyme participates in the metabolism of diazepam, and CYP2C19 activity is highly dependent on the polymorphism of the encoding gene Aim: to study the effect of CYP2C19 genetic polymorphism on diazepam plasma concentration, as well as its efficacy and safety profiles in patients with alcohol withdrawal syndrome. Methods. The study was conducted on 35 male patients suffering from the alcohol withdrawal syndrome. For the therapy of psychomotor agitation, anxiety, fear and emotional tension, patients received diazepam in injections at a dosage of 30.0 mg/day for 5 days. Genotyping was performed by real-time polymerase chain reaction with allelespecific hybridization. The efficacy and safety assessment was performed using psychometric scales and scales for assessing the severity of adverse drug reactions: the Clinical Institute Withdrawal Assessment for Alcohol scale, the visual-analogue scale of the craving for alcohol, the side-effect scale. HPLC-MS/MS method was used for the therapeutic drug monitoring. Results. We revealed the statistically significant differences in the efficacy of therapy in patients with different CYP2C19C>T – 806C>T genotypes: (CC) – (CC) – 12.0 [-15.0; – 8.0], (CT+TT) – 7.0 [-14.0; – 5.0], p=0.001. The scores on the UKU scale, which was used to evaluate the safety of therapy, were also different, but we revealed no statistically significant difference: (CC) 250.70 [213.34; 308.53], (CT+TT) 89.12 [53.26; 178.07], p = 0.002. Therapeutic drug monitoring demonstrated the statistically significant difference in diazepam steady-state plasma concentrations: (CC) 250.70 [213.34; 308.53], (CT+TT) 89.12 [53.26; 178.07], p = 0.002. Conclusion. Thus, the relationship between the CYP2C19 genetic polymorphism and the efficacy and safety of diazepam was demonstrated in 35 patients with alcohol withdrawal syndrome. In addition, the statistically significant difference in diazepam steady-state plasma concentrations in patients carrying different genotypes was revealed.