Using the CYP3A Activity Evaluation to Predict the Efficacy and Safety of Diazepam in Patients With Alcohol Withdrawal Syndrome.

BACKGROUND: Diazepam is one of the most commonly prescribed tranquilizers for the therapy of alcohol withdrawal syndrome (AWS). Despite its popularity, there is currently no precise information on the effect of genetic polymorphisms on the efficacy and safety of diazepam therapy. OBJECTIVE: The objective of our study was to study the effect of CYP3A isoenzymes activity on the efficacy and safety of diazepam in patients with AWS. METHODS: The study was conducted on 30 Russian male patients suffering from the AWS who received diazepam in injections at a dosage of 30.0 mg / day for 5 days. The efficacy and safety assessment was performed using psychometric scales and scales for assessing the severity of adverse drug reactions. RESULTS: Based on the results of the study, we revealed the differences in the efficacy of therapy in patients with different CYP3A4 C>T intron 6 (rs35599367) genotypes: (CC) -9.0 [-13.0; -5.0], (CT+TT) -13.5 [-15.0; -10.0], p = 0.014. The scores on the UKU scale, which was used to evaluate the safety of therapy, were also different: (CC) 7.5 [6.0; 11.0], (CT+TT) 11.0 [8.0; 12.0], p = 0.003. CONCLUSION: Possible relationship between the CYP3A activity, evaluated by the content of the urinary endogenous substrate of the given isoenzyme and its metabolite, the 6-beta-hydroxy cortisol (6-ß-HC) / cortisol ratio, and the efficacy of diazepam was demonstrated. This possible relationship was also supported by the genotyping results. This should be taken into consideration when prescribing this drug to such patients in order to reduce the risk of pharmacoresistance.

Impact of CYP2D6 Polymorphism on Equilibrium Concentration of Fluoxetine in Patients Diagnosed With Major Depressive Disorder and Comorbid Alcohol Use Disorders.

INTRODUCTION: Fluoxetine is used in the treatment of patients with recurrent depressive disorder. Some of these patients do not achieve an adequate response to a treatment regimen containing fluoxetine, and many of these patients experience dose-dependent adverse drug reactions. The cytochrome P450 enzyme CYP2D6 is involved in the biotransformation of fluoxetine, the activity of which is quite dependent on the polymorphism of the gene encoding this enzyme. OBJECTIVE: The objective of the study was to investigate the influence of the 1846G>A polymorphism of the CYP2D6 gene on the concentration/dose indicator of fluoxetine in patients diagnosed with major depressive disorder and comorbid alcohol use disorder. METHODS: Our study included 101 patients with major depressive disorder and alcohol use disorder (average age: 41.3±14.5 y) who were treated with fluoxetine at an average dose of 26.1±8.7 mg/d. Treatment efficacy was assessed using validated psychometric scales, and the safety/tolerability of the therapy was assessed using the Udvalg for Kliniske Undersogelser Side-Effect Rating Scale. Genotyping was done using a real-time polymerase chain reaction. Therapeutic drug monitoring was performed using high-performance liquid chromatography-mass spectrometry. RESULTS: CYP2D6 genotyping by polymorphic marker 1846G>A (rs3892097) in the 101 patients found that there were 81 patients (80.2%) with the GG genotype ("wild-type," normal metabolism), 20 (19.8%) with the GA genotype (intermediate metabolism), and no subjects with the AA genotype (poor metabolism). Statistically significant results in treatment efficacy as evaluated by Hamilton Rating Scale for Depression scores at the end of the treatment course were found: GG 9.0 [confidence interval (CI): 6.0; 12.0] and GA 12.0 (CI: 9.5; 14.0), P=0.005. Statistically significant results were also obtained for the safety profile as measured by scores on the Udvalg for Kliniske Undersogelser Side-Effect Rating Scale: GG 3.0 (CI 2.0; 4.0) and GA 5.0 (CI: 4.0; 5.0), P<0.001. Finally, a statistically significant difference was found in concentration/dose indicators of fluoxetine in patients with the different genotypes: GG 4.831 (CI: 3.654; 6.204) and GA 7.011 (CI: 5.431; 8.252), P<0.001. CONCLUSION: The effect of the genetic polymorphism of the CYP2D6 gene on the efficacy and safety profiles of fluoxetine was demonstrated in a group of 101 patients with major depressive disorder and alcohol use disorder.

How do CYP2C19*2 and CYP2C19*17 genetic polymorphisms affect the efficacy and safety of diazepam in patients with alcohol withdrawal syndrome?

Background Diazepam is one of the most commonly prescribed tranquilizers for therapy of alcohol withdrawal syndrome (AWS). Despite its popularity, there is currently no precise information on the effect of genetic polymorphisms on its efficacy and safety. The objective of our study was to investigate the effect of CYP2C19*2 and CYP2C19*17 genetic polymorphisms on the efficacy and safety of diazepam in patients with AWS. Methods The study was conducted on 30 Russian male patients suffering from the AWS who received diazepam in injections at a dosage of 30.0 mg/day for 5 days. The efficacy and safety assessment was performed using psychometric scales and scales for assessing the severity of adverse drug reactions. Results Based on the results of the study, we revealed the differences in the efficacy of therapy in patients with different CYP2C19 681G>A (CYP2C19*2, rs4244285) genotypes: (CYP2C19*1/*1) -8.5 [-15.0; -5.0], (CYP2C19*1/*2 and CYP2C19*2/*2) -12.0 [-13.0; -9.0], p = 0.021. The UKU scale scores, which were used to evaluate the safety of therapy, were also different: (CYP2C19*1/*1) 7.0 [6.0; 12.0], (CYP2C19*1/*2 and CYP2C19*2/*2) 9.5 [8.0; 11.0], p = 0.009. Patients carrying different CYP2C19 -806C>T (CYP2C19*17, rs12248560) genotypes also demonstrated differences in therapy efficacy and safety rates. Conclusions Thus, the effects of CYP2C19*2 and CYP2C19*17 genetic polymorphisms on the efficacy of diazepam were demonstrated.