Investigating the Use of Pharmacogenetic and Pharmacometabolomic Markers to Predict Haloperidol Efficacy and Safety Rates.

Background: Haloperidol is commonly prescribed to patients with alcohol-induced psychotic disorder (AIPD). Notably however, individuals differ extensively with regards to therapeutic response and adverse drug reactions (ADRs). Previous studies have shown that haloperidol biotransformation is mainly metabolized by CYP2D6. Objective: The objective of our study was to investigate the use of pharmacogenetic (CYP2D6*4 genetic polymorphism) and pharmacometabolomic biomarkers to predict haloperidol efficacy and safety rates. Material and Methods: The study enrolled 150 patients with AIPD. Therapy included haloperidol in a daily dose of 5 to 10 mg/day by injections for 5 days. Efficacy and safety of treatment were evaluated using the validated psychometric scales PANSS, UKU, and SAS. Results: No association of the urinary 6-НО-ТНВС/pinoline ratio values which could be evidence of the CYP2D6 activity level with both the efficacy and safety rates of haloperidol was demonstrated. However, a statistically significant association between haloperidol safety profile and CYP2D6*4 genetic polymorphism was demonstrated (P < .001). Conclusion: To predict haloperidol efficacy and safety rates, utilization of pharmacogenetic testing that defines CYP2D6*4 genetic polymorphism is found preferable over the use of the pharmacometabolomic marker in a clinical setting.

Acute Alcoholic Hallucinosis: A Review.

Acute alcoholic hallucinosis is a psychotic disorder characterized by a predominance of auditory hallucinations with delusions and affective symptoms in the clinical picture. Classically, it develops as part of the alcohol withdrawal syndrome. The prevalence of acute alcoholic hallucinosis ranks second among alcohol-related psychoses after alcohol delirium. The study aimed to systematize the scientific data on the history of alcoholic hallucinosis, its pathogenesis, clinical presentation, and treatment approaches. A literature search was performed in PubMed, Scopus, Google Scholar, and eLibrary. The following words and combinations were used as search strings: (alcoholic hallucinosis OR alcoholic psychosis OR alcohol-related psychosis OR alcohol-induced psychosis OR alcohol-induced psychotic disorder OR complicated alcohol withdrawal syndrome) NOT (animal OR rat OR mouse). The relevant information concerning the history of acute alcoholic hallucinosis, its pathogenesis, clinical picture, and treatment approaches was systematized and summarized. This review presents relevant findings regarding acute alcoholic hallucinosis. Limitations of the review include the use of heterogeneous and mostly descriptive studies and studies on small cohorts of patients.

CYP3A4*22 and CYP3A5*3 impact efficacy and safety of diazepam in patients with alcohol withdrawal syndrome.

BACKGROUND: Diazepam is one of the most commonly prescribed pharmaceuticals for the treatment of alcohol withdrawal syndrome (AWS). However, diazepam sometimes is ineffective, and some patients experience dose-dependent adverse drug reactions (ADR). Previous studies have shown that diazepam metabolism involves the CYP3A4 and CYP3A5 isoenzymes, whose activity is highly variable between individuals, which may contribute to differences in clinical response. PURPOSE: The study aimed to investigate the effects of the genetic polymorphisms CYP3A4*22 and CYP3A5*3 on the efficacy and safety of diazepam in patients with AWS. MATERIALS AND METHODS: One hundred male AWS patients received 30 mg/day diazepam by intramuscular injections for 5 days. Genotyping for CYP3A4*22 (rs35599367) and CYP3A5*3 (rs776746) was performed by real-time polymerase chain reaction with allele-specific hybridization. The efficacy and safety assessments were performed using psychometric scales. RESULTS: Patients who carry CT and TT genotypes by polymorphic marker C > T intron 6 (rs35599367) of the CYP3A4 gene had a higher risk for ADR and demonstrated lower safety of diazepam therapy (p < 0.001; two-way ANOVA). CONCLUSION: These results suggest that genotyping for common CYP3A variants might have the potential to guide benzodiazepine withdrawal treatment.

Time trends in tuberculosis mortality across the BRICS: an age-period-cohort analysis for the GBD 2019.

Background: Tuberculosis is the leading cause of death from a single infectious agent among the HIV-negative population and ranks first among the HIV-positive population. However, few studies have assessed tuberculosis trends in Brazil, Russia, India, China and South Africa (BRICS) or with an emphasis on HIV status. This study assesses the time trends of tuberculosis mortality across the BRICS with an emphasis on HIV status from 1990 to 2019. Methods: We obtained tuberculosis data from the Global Burden of Disease 2019 study (GBD 2019). We calculated the relative proportion of tuberculosis to all communicable, maternal, neonatal, and nutritional diseases by HIV status across the BRICS. We used age-period-cohort modelling to estimate cohort and period effects in tuberculosis from 1990 to 2019, and calculated net drift (overall annual percentage change), local drift (annual percentage change in each age group), longitudinal age curves (expected longitudinal age-specific rate), and period (cohort) relative risks. Findings: There were 549,522 tuberculosis deaths across the BRICS in 2019, accounting for 39.3% of global deaths. Among HIV-negative populations, the age-standardised mortality rate (ASMR) of tuberculosis in BRICS remained far higher than that of high-income Asia Pacific countries, especially in India (36.1 per 100 000 in 2019, 95% UI [30.7, 42.6]) and South Africa (40.1 per 100 000 in 2019, 95% UI [36.8, 43.7]). China had the fastest ASMR reduction across the BRICS, while India maintained the largest tuberculosis death numbers with an annual decrease much slower than China's (-4.1 vs -8.0%). Among HIV-positive populations, the ASMR in BRICS surged from 0.24 per 100 000 in 1990 to 5.63 per 100 000 in 2005, and then dropped quickly to 1.70 per 100 000 in 2019. Brazil was the first country to reverse the upward trend of HIV/AIDS-tuberculosis (HIV-TB) mortality in 1995, and achieved the most significant reduction (-3.32% per year). The HIV-TB mortality in South Africa has realised much progress since 2006, but still has the heaviest HIV-TB burden across the BRICS (ASMR: 70.0 per 100 000 in 2019). We also found unfavourable trends among HIV-negative middle-aged (35-55) adults of India, men over 50 in the HIV-negative population and whole HIV-positive population of South Africa, and women aged 45-55 years of Russia. China had little progress in its HIV-positive population with worsening period risks from 2010 to 2019, and higher risks in the younger cohorts born after 1980. Interpretation: BRICS' actions on controlling tuberculosis achieved positive results, but the overall improvements were less than those in high-income Asia Pacific countries. BRICS and other high-burden countries should strengthen specified public health approaches and policies targeted at different priority groups in each country. Funding: National Natural Science Foundation of China (82073573; 72074009), Peking University Global Health and Infectious Diseases Group.

CYP3A subfamily activity affects the equilibrium concentration of Phenazepam® in patients with anxiety disorders and comorbid alcohol use disorder.

Phenazepam® is prescribed to relieve anxiety and sleep disorders during alcohol withdrawal, although it is associated with undesirable side effects. Aim: To demonstrate changes in the safety and efficacy profiles of Phenazepam in patients with anxiety disorders and comorbid alcohol use disorder. Materials & methods: A total of 94 Russian patients with alcohol use disorder received 4.0 mg of Phenazepam per day in tablets. We used a urinary 6-beta-hydroxycortisol/cortisol ratio to evaluate CYP3A activity. Results: A statistically significant inverse correlation between Phenazepam plasma concentration and CYP3A activity was found (r = -0.340 and p = 0.017). Correlation between the concentration/dose ratio and phenotyping results was also statistically significant (r = 0.301 and p = 0.026). Conclusion: The safety and efficacy of Phenazepam depend on CYP3A genetic polymorphisms.

Effects of CYP2D6 genetic polymorphisms on the efficacy and safety of fluvoxamine in patients with depressive disorder and comorbid alcohol use disorder.

BACKGROUND: Fluvoxamine therapy is used for treatment of patients with depressive disorder, but it is often ineffective, and some patients suffer from dose-dependent undesirable side effects such as vertigo, headache, indigestion, xerostomia, increased anxiety, etc. CYP2D6 is involved in the biotransformation of fluvoxamine. Meanwhile, the genes encoding these isoenzymes have a high level of polymorphism, which may affect the protein synthesis. OBJECTIVE: The primary objective of our study was to investigate the effects of CYP2D6 genetic polymorphisms on the efficacy and safety of fluvoxamine in patients with depressive disorder and comorbid alcohol use disorder, in order to develop the algorithms of optimization of fluvoxamine therapy for reducing the risk of dose-dependent undesirable side effects and pharmacoresistance. METHODS: The study involved 45 male patients (average age: 36.44±9.96 years) with depressive disorder and comorbid alcohol use disorder. A series of psychometric scales was used in the research. Genotyping of CYP2D6 (1846G>A) was performed using real-time polymerase chain reaction. RESULTS: According to results of Mann-Whitney U-test, statistically significant differences between the efficacy and safety of fluvoxamine were obtained on 9th and 16th days of therapy in patients with GG and GA genotypes (The Hamilton Rating Scale for Depression: 10.0 [10.0; 23.0] vs 25.0 [24.0; 16.0] (P<0.001) on the 9th day and 4.0 [2.0; 5.0] vs 6.0 [6.0; 7.0] on the 16th day; The UKU Side Effect Rating Scale: 6.0 [4.0; 6.0] vs 9.0 [9.0; 10.0] (P<0.001) on the 9th day and 5.0 [1.0; 9.0] vs 19.0 [18.0; 22.0] on the 16th day). CONCLUSION: This study demonstrated the lower efficacy and safety of fluvoxamine in patients with depressive disorder and comorbid alcohol use disorders with GA genotype in CYP2D6 1846G>A polymorphic marker.

The influence of CYP3A5 polymorphisms on haloperidol treatment in patients with alcohol addiction.

BACKGROUND: Isoenzymes CYP2D6 and CYP3A4, the activity of which varies widely, are involved in metabolism of haloperidol and may influence its profile of efficacy and safety. OBJECTIVE: The primary aim of this study was to estimate the relationship between CYP3A5 gene polymorphism, activity of the CYP3A isoenzyme, and the risk of development of adverse drug reactions by haloperidol in patients with alcohol abuse. METHODS: Sixty-six male alcohol-addicted patients participated in the study. The safety of haloperidol was evaluated by Udvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU) and Simpson-Angus Scale for extrapyramidal symptoms (SAS). The activity of CYP3A was evaluated by determining the concentrations of an endogenous substrate of this isoenzyme (cortisol) and its urinary metabolite (6-beta-hydroxycortisol, 6-B-HC). Genotyping of CYP3A5*3 was performed by real-time polymerase chain reaction with allele-specific hybridization. RESULTS: The frequency of A-allele occurrence in Russian population was very poor (2.27%). CYP3A5*3 polymorphism had no influence on safety profile indicators of haloperidol (UKU scale: p=0.55, SAS scale: p=0.64). In addition, there was no statistical significant difference between the values of indexes of the metabolic ratio (6-B-HC/cortisol) in groups with different genotypes of CYP3A5*3: GG 5.00 (3.36; 6.39) vs AG 5.26 (2.10; 6.78) (p=0.902). CONCLUSION: The frequency of A-allele occurrence of CYP3A5*3 in Russian population is very poor, and it has no high influence on the safety of haloperidol treatment; therefore, there are no reasons to take this polymorphism into account in patients with alcohol addiction who receive haloperidol.

Pharmacodynamic genetic polymorphisms affect adverse drug reactions of haloperidol in patients with alcohol-use disorder.

BACKGROUND: Antipsychotic action of haloperidol is due to blockade of D2 receptors in the mesolimbic dopamine pathway, while the adverse drug reactions are associated with striatal D2 receptor blockade. Contradictory data concerning the effects of genetic polymorphisms of genes encoding these receptors and associated structures (catechol-O-methyltransferase [COMT], glycine transporter and gene encoding the density of D2 receptors on the neuronal membrane) are described. OBJECTIVE: The objectives of this study were to evaluate the correlation between DRD2, SLC6A3 (DAT) and COMT genetic polymorphisms and to investigate their effect on the development of adverse drug reactions in patients with alcohol-use disorder who received haloperidol. PATIENTS AND METHODS: The study included 64 male patients (average age 41.38 ± 10.14 years, median age 40 years, lower quintile [LQ] 35 years, upper quintile [UQ] 49 years). Bio-Rad CFX Manager™ software and "SNP-Screen" sets of "Syntol" (Russia) were used to determine polymorphisms rs4680, rs1800497, rs1124493, rs2242592, rs2298826 and rs2863170. In every "SNP-Screen" set, two allele-specific hybridizations were used, which allowed to determine two alleles of studied polymorphism separately on two fluorescence channels. RESULTS: Results of this study detected a statistically significant difference in the adverse drug reaction intensity in patients receiving haloperidol with genotypes 9/10 and 10/10 of polymorphic marker SLC6A3 rs28363170. In patients receiving haloperidol in tablets, the increases in the UKU Side-Effect Rating Scale (UKU) score of 9.96 ± 2.24 (10/10) versus 13 ± 2.37 (9/10; p < 0.001) and in the Simpson-Angus Scale (SAS) score of 5.04 ± 1.59 (10/10) versus 6.41 ± 1.33 (9/10; p = 0.006) were revealed. CONCLUSION: Polymorphism of the SCL6A3 gene can affect the safety of haloperidol, and this should be taken into account during the choice of drug and its dosage regimen.

The correlation between CYP2D6 isoenzyme activity and haloperidol efficacy and safety profile in patients with alcohol addiction during the exacerbation of the addiction.

BACKGROUND: Today, it is proved that isoenzymes CYP2D6 and CYP3A4 are involved in metabolism of haloperidol. In our previous investigation, we found a medium correlation between the efficacy and safety of haloperidol and the activity of CYP3A4 in patients with alcohol abuse. OBJECTIVE: The aim of this study was to evaluate the correlation between the activity of CYP2D6 and the efficacy and safety of haloperidol in patients with diagnosed alcohol abuse. METHODS: The study involved 70 men (average age: 40.83±9.92 years) with alcohol addiction. A series of psychometric scales were used in the research. The activity of CYP2D6 was evaluated by high-performance liquid chromatography with mass spectrometry using the ratio of 6-hydroxy-1,2,3,4-tetrahydro-beta-carboline to pinoline. Genotyping of CYP2D6 (1846G>A) was performed using real-time polymerase chain reaction. RESULTS: According to results of correlation analysis, statistically significant values of Spearman correlation coefficient (rs) between the activity of CYP2D6 and the difference of points in psychometric scale were obtained in patients receiving haloperidol in injection form (Sheehan Clinical Anxiety Rating Scale =-0.721 [P<0.001] and Udvald for Kliniske Undersogelser Side Effect Rating Scale =0.692 [P<0.001]) and in those receiving haloperidol in tablet form (Covi Anxiety Scale =-0.851 [P<0.001] and Udvald for Kliniske Undersogelser Side Effect Rating Scale =0.797 [P<0.001]). CONCLUSION: This study demonstrated the correlations between the activity of CYP2D6 isozyme and the efficacy and safety of haloperidol in patients with alcohol addiction.