Objectives. To identify associations between CYP3A4*22 and CYP3A5*3 genotypes, CYP2D6 phenotype, and the effectiveness and safety of antipsychotics in neurotypically developed boys with conduct disorders. Methods: The study included neurotypically developed boys aged 7–12 years who were hospitalized for conduct disorders. All patients were prescribed an antipsychotic. Patient follow-up lasted 14 days. Treatment effectiveness was assessed using a clinical aggression assessment (checklist) and the CGI-S, CGI-I, and CGAS scales. Safety was assessed using the UKU SERS and SAS scales. Patients were examined upon enrollment in the study, on day 5, and on day 14. All patients were genotyped for the CYP3A4*22 (rs35599367, C>T), CYP3A5*3 (rs776746, 6986T>C) CYP2D6*3 (rs35742686), CYP2D6*4 (G1846A, rs3892097), CYP2D6*6 (rs5030655), CYP2D6*10 (C100T, rs1065852), CYP2D6*41 (rs28371725) loci. CYP2D6 metabolism type was determined based on genotyping results, and patients were divided into two subgroups: those with normal metabolism (NM) and those with intermediate or poor metabolism (IM + PM). Results: Patients taking carbamazepine (n = 11) were excluded from the analysis of associations between treatment outcomes and the CYP3A4*22 and CYP3A5*3 polymorphisms. The analysis of associations between treatment outcomes and CYP2D6 metabolism type was conducted in two stages: the overall sample and a subsample of patients who were prescribed risperidone (n = 80). No significant associations were found between carrier status of the CYP3A4*22 and CYP3A5*3 polymorphisms and treatment effectiveness parameters. Analysis of the overall sample did not reveal any significant associations between CYP2D6 metabolism subtypes and the effectiveness parameters of drug therapy. Analysis of patients receiving risperidone revealed one statistically significant association: patients with CYP2D6 IM + PM reported headaches more frequently (16.1% vs. 2%; p = 0.03). Carrier status of the CYP3A4*22 polymorphism was significantly associated with asthenia and lethargy on day 5 (50% vs. 9.4%; p = 0.008). Conclusions: Our study identified only a few significant associations between the CYP3A4*22 polymorphism, CYP2D6 slow metabolism, and patients’ reports of early adverse reactions in a 14-day observation period. Further research is needed to identify pharmacogenetic predictors of the efficacy and safety of antipsychotics in neurotypical children with conduct disorders.

Objectives. The aim of our study was to track changes in ODQ scores in adolescents with depressive episodes taking sertraline, depending on CYP2C19 polymorphisms. Methods. This study included 88 adolescents (88% were female) aged 12-17 who were prescribed sertraline. Emotional blunting was assessed using the Oxford Depression Questionnaire (ODQ) scale when the antidepressant was prescribed, after one, three, and 8 weeks, taking into account other medications used. Part 3 of the ODQ scale assessed the changes that occurred after the prescription of an antidepressant. All patients were genotyped for CYP2C19*2, *3, and *17. Based on genotypes, the phenotypes of the CYP2C19 isoenzyme were determined. Results. The ODQ score at the time of enrollment was higher (65[50;79] points) compared with after 8 weeks (38.5[32.5;56.5] points). Part 3 of the ODQ-26 questionnaire remained approximately the same for 8 weeks. Patients with higher ODQ-26 values at enrollment (73[56;83] vs. 59[44;71] points) were more likely to be prescribed antipsychotics. Differences in ODQ scores remained significant up to 3 weeks after enrollment (50.5[41.5;68] vs. 45.5[36;54] points). The comparison of ODQ scores and their dynamics did not show significant differences depending on CYP2C19*2 or *17 polymorphisms, or the type of CYP2C19 metabolism. Conclusions. There was no increase in emotional blunting according to the ODQ score among adolescents with depression who took sertraline for eight weeks. No significant correlations were found between the carrier status of CYP2C19 gene variants and the development of apathy induced by antidepressants.

ObjectivesTo evaluate the associations of clinical and pharmacogenetic factors (CYP2C19*2, *17 polymorphisms) with the safety parameters of sertraline in adolescents with a depressive episode and suicidal intentions for 3 weeks in a psychiatric hospital.MethodsThe study included 112 adolescents, who were hospitalized due to a depressive episode and suicidal intentions. All patients received sertraline for 21 days. The safety of pharmacotherapy was assessed on the 7th and 21st day using the Antidepressant ADRs checklist. Each patient underwent genetic testing for CYP2C19*2, *3, *17. The safety of sertraline was analyzed depending on the carrier status of CYP2C19 polymorphisms, the type of CYP2C19 metabolism, as well as depending on additional pharmacotherapy.ResultsIt was found that patients with the CYP2C19*2 genotype took a slightly lower dose of sertraline compared to those with the wild-type genotype on 21st day (100 [87.5; 100] mg/day vs. 100 [100; 100], p = 0.048). Patients carrying the CYP2C19*17 allele, on the other hand, were more likely to experience vegetative and somatic ADRs on day 7 of treatment (2 vs. 1, p = 0.042). The use of anxiolytics (alimemazine and hydroxyzine) was significantly associated with an increased number of vegetative/somatic, and mental ADRs on day 7, as well as an increased total number of ADRs by day 21. Linear regression analysis confirmed that anxiolytics were the most significant predictors of ADR development on day 21 (Estimate = 0.86, 95% CI 0.32-1.41, p = 0.002).ConclusionPolypharmacy (particularly, adding a non-benzodiazepine anxiolytic) was a more significant risk factor for ADRs when taking sertraline, compared to the carrier status of CYP2C19 gene polymorphisms.

Background. An algorithm for the personalized selection of SSRIs based on pharmacogenetic testing is currently available. Personalization algorithms for adults are not applicable to teenagers. Previously, contradictory results were obtained regarding the association of “ultrarapid” CYP2C19 metabolism and poorer tolerability of sertraline and escitalopram. Our aim was to assess the relationships between CYP2C19*2, *3, and *17 polymorphisms and early adverse drug reactions to sertraline among adolescents with depressive episodes and suicidal intentions. Methods. Study design: observational prospective single-center. The study included 133 adolescents (89% female) with a depressive episode and suicidal tendencies. All patients received sertraline. On day 7, the safety of pharmacotherapy was assessed using the Antidepressant adverse drug reactions checklist. Each patient underwent genetic testing for CYP2C19*2, *3, *17. Statistical processing of the results was carried out using IBM SPSS Statistics 26.0. The safety of sertraline was analyzed depending on the carriage of CYP2C19 polymorphisms, the type of CYP2C19 metabolism, as well as depending on additional pharmacotherapy. Results. 96 patients had “normal” CYP2C19 metabolism, 27 had “intermediate” metabolism, 8 — “ultrarapid” metabolism, and 2 — a “poor” metabolism. There were no significant associations of the number of ADRs, as well as the frequency of individual ADRs, depending on the type of CYP2C19 metabolism. Carriage of CYP2C19*17 (CT+TT genotypes) was significantly associated with a large number of somatic and vegetative adverse drug reactions on day 7 (2 (1; 3) vs. 1 (1; 2); p = 0.017). On day 7, carriers of CYP2C19*2 (genotype GA+AA) were more likely to complain of sleep disorders (13 (46.4%) vs. 28 (26.7%); p = 0.044) and tremor (7(25%) vs. 9 (8.7%); p = 0.018) compared with homozygotes GG. Conclusion. Carriage of the CYP2C19*17 was significantly associated with an increase in somatic and vegetative ADRs frequency. This result is paradoxical, as carriage of CYP2C19*17 is more likely to lead to accelerated metabolism of sertraline. Carriage of the CYP2C19*2 was only associated with a higher frequency of sleep disturbances and tremor.

Objectives. To investigate the risk of developing emotional blunting in adolescents with a depressive episode who are prescribed sertraline. To establish associations of carriage of CYP2C19 gene polymorphisms with the antidepressant-induced apathy. Methods. The study included 133 adolescents (89.5% female) aged 12-17 who were prescribed sertraline. The follow-up was carried out for 8 weeks. Emotional blunting was assessed using the Oxford Depression Questionnaire scale (ODQ-26) at the time of activation, after one, three and 8 weeks. We took into account the appointment of additional pharmacotherapy. The polymorphisms CYP2C19*2, *3, *17 were genotyped for all patients. Based on the results of genotyping, the phenotypes of the CYP2C19 isoenzyme were determined. Results. The ODQ score at the time of enrollment was higher (65 [50;79]) compared to after 8 weeks (38 [32;53]). The part 3 of the ODQ-26 questionnaire remained approximately the same for 8 weeks. Patients with higher ODQ-26 values at enrollment (73 [56;83] vs. 59 [44;71], p=0.0006) were more likely to be prescribed antipsychotics. Differences in ODQ scores remained significant up to 3 weeks after enrollment (50.5 [41.5;68], vs. 45.5 [36;54], p=0.015). The comparison of ODQ scores and their dynamics did not show significant differences depending on CYP2C19*2 or *17 polymorphisms, or the type of CYP2C19 metabolism. Conclusion. A negative outcome was observed: there was no improvement in emotional blunting among adolescents with depression who took sertraline for eight weeks. No significant correlations were found between the carriage of CYP2C19 gene variants and the development of apathy induced by antidepressants.

Introduction . Polymorphisms of CYP3A4 and CYP3A5 genes are currently poorly understood as biomarkers of antipsychotic efficacy and safety. There are no studies of these factors in children taking antipsychotics for conduct disorder. Aim . To identify associations of CYP3A4*22 , CYP3A5*3 carriers with the effectiveness and safety of antipsychotics in children with conduct disorder Materials and methods . Eighty-four children aged 7–12 years hospitalised for conduct disorders were included in the study. All patients received antipsychotics for correction of conduct disorder. Observation was carried out for 14 days, the efficacy of pharmacotherapy was assessed using CGAS, CGI-S, CGI-I scales; safety was evaluated using the UKU SERS scale. All patients were genotyped for CYP3A4*22 (rs35599367) and CYP3A5*3 (rs776746) polymorphisms. Results . Carriers of the CYP3A5*1 (GA + AA) allele differed in lower severity of oppositional defiant behaviour on the CGI-S scale (3 [3; 4] vs. 4 [3; 4] points; p = 0.040) at the time of inclusion in the study. Also, CYP3A5*1 (GA + AA) was associated with less improvement on the CGI-I scale on day 5 (4 [3; 4] vs. 3 [3; 4] points; p = 0.026). CYP3A4*22 carriers reported a greater score on the UKU Mental Disorders subscale at day 5 (1 [0.25; 2] vs. 0 [0; 1], p = 0.026). Also, CYP3A4*22 carriers had higher scores on the UKU ‘Other HP’ subscale at 14 days (0 [0; 1] vs 0 [0; 0], p = 0.023). In carriers of the active CYP3A5*1 allele (genotypes GA + AA), the SAS scale score on day 5 was on average significantly higher compared to CYP3A5*3 GG carriers (0 [0; 1] vs 0 [0; 0] respectively, p = 0.019). Conclusion . It was found that carriers of the ‘wild’ allele of CYP3A5*1 responded worse to pharmacotherapy of conduct disorders after 5 days. Significant associations of CYP3A4*22 carriers with worse tolerability of pharmacotherapy were found.

Aim: To establish significant risk factors for the development of adverse drug effects (ADEs) in children and adolescents with an acute psychotic episode taking antipsychotics.Materials and Methods: The research team randomly selected 15 patient records each month for 3 years (2016-2018). Overall, 450 patient records were included (223 boys and 227 girls, mean age was 14.52 +/- 2.21 years). Adverse effects were identified using the standard algorithm of the Global Trigger Tool method. A "trigger" is an indication that an adverse reaction is likely to occur, e.g., an antihistamine prescription on a prescribing list. When a trigger was detected, the case history was studied in further detail to confirm the occurrence of ADEs. We divided patients into two groups: the "children" group (under 12 years old) and the "adolescents" group (13 years and older). Data were analyzed using the statistical package IBM SPSS Statistics 23.0.Results: Of the 450 patient records, 402 (89.3%) had at least one trigger detected. In total, 126 case histories contained evidence of ADE (28%). The total number of ADEs per 1000 patient days was 5.39 and the number of ADEs per 100 admissions was 32.0. Among adolescents, two or more triggers per patient were significantly more frequently identified (61.3% vs. 44.6%; p = 0.001). ADEs were rare in "Children" compared with "Adolescents" (13.8% vs. 30.4%; p = 0.006). The logistic regression analysis confirmed high predictive role of "Adolescence" (odds ratio [OR] = 2.58; 95% confidence interval [CI] 1.22-5.4; p = 0.013), "Polypharmacy" (OR = 1.96; 95% CI 1.23-3.1; p = 0.004), and "First-life hospitalization" (OR = 2.17; 95% CI 1.34-3.48; p = 0.001) for ADE fact in patient records.Conclusion: We found that significant risk factors for ADEs to antipsychotics in patients with acute psychotic episode were adolescence (13 years and older), polypharmacy, and first-life hospitalization. The fact that children (i.e., younger than 13 years of age) are less likely to experience ADEs was not associated with high-risk drugs or higher doses in our study.

Abstract Objectives Radioactive iodine therapy is considered for patients with certain clinicopathological factors that predict a significant risk of recurrence, distant metastases of thyroid cancer or disease-specific mortality. The aim of the study was to investigate the association between polymorphisms of genes, products of which are involved in the processes of DNA damage response and autophagy, and the adverse reactions of radioiodine therapy in thyroid cancer patients. Methods The study included 181 patients (37 men, 144 women; median age 56 [41; 66.3] years) with histologically confirmed thyroid cancer and a history of thyroidectomy who received radioiodine therapy. NFKB1, ATM, ATG16L2, ATG10, TGFB1, and TNF polymorphisms were determined by allele-specific realtime-PCR. Results The frequency of adverse reactions was the following: gastrointestinal symptoms – 57.9 %, local symptoms – 65.8 %, cerebral symptoms – 46.8 %, fatigue – 54.4 %; signs of sialoadenitis six months after radioiodine therapy – 25.2 %. TT genotype carriers of ATG10 rs1864183 had higher frequency of gastrointestinal symptoms (vs. CC+CT), the CC genotype carriers of ATG10 rs10514231 had significantly more frequent cerebral symptoms (vs. CT+TT), as well as AA genotype carriers of TGFB1 rs1800469 (vs. AG+GG). CC genotype of ATG10 rs10514231 increased the incidence of radioiodine-induced fatigue, whereas GA genotype of the ATM rs11212570 had a protective role against fatigue. TGFB1 rs1800469 was associated with signs of sialoadenitis six months after radioiodine therapy. Conclusions Genetic factors may contribute to the occurrence of adverse reactions of radioiodine therapy in thyroid cancer patients.

EDITORIAL article Front. Pharmacol., 13 June 2023Sec. Pharmacogenetics and Pharmacogenomics Volume 14 - 2023 | https://doi.org/10.3389/fphar.2023.1234219

Background. The indication for radiotherapy in oncological practice are metastases of differentiated thyroid cancer after thyroidectomy, the presence of distant metastases, or stage N1b, or negative dynamics of blood thyroglobulin levels after thyroidectomy for thyroid cancer. The mechanism of action of radiotherapy is based on provoking double-stranded DNA breaks. It is important to study the role of polymorphisms of NFKB1, ATM, ATG16L2 and ATG10 genes, products of which are involved in the processes of DNA damage response pathway and autophagy, in the formation of resistance to radioiodine therapy of thyroid cancer patients. Aim. To examine the association between NFKB1, ATM, ATG16L2 and ATG10 polymorphisms and resistance to radioiodine therapy in thyroid cancer patients. Materials and methods. The study included 181 patients (37 men, 144 women; mean age 53.515.7 years) with histologically confirmed thyroid cancer and a history of thyroidectomy who received radioiodine therapy. Carriage of single-nucleotide polymorphisms (rs230493) NFKB1, (rs11212570) ATM, (rs10898880) ATG16L2 and (rs10514231, rs1864183, rs4703533) ATG10 was determined by real-time PCR using TaqMan kits. Results. Among 181 patients, resistance to radioiodine therapy was observed in 11 (6.1%) cases. No significant associations between the individual polymorphisms and resistance to radioiodine therapy were obtained, p0.05. Haplotype analysis showed that carriage of the C-C ATG10 rs10514231-rs1864183 haplotype was associated with an increased risk of developing resistance to radioiodine therapy, p=0.04. Conclusion. Further studies on large samples of radioiodine therapy-resistant patients using whole-genome sequencing methods are required to specify the role of genetic factors in the response to 131I therapy.

The usual procedure to monitor the ion exchange of small ions utilizes a potentiometer with a selective membrane as part of the working electrode. As the next step, we have applied polyaniline electrodes to the monitoring the activity macromolecular ions during DNA hybridization. Single-strand oligonucleotide (ssODN) probes were immobilized using a nucleophilic substitution reaction of the thiolated ssODN molecules with polyaniline. The anionic phosphate groups of the probe molecules also interacted with the cationic-doped polyaniline surface. Three useful findings were observed with the potentiometric experiments. First, the binding of the complimentary target molecules with the immobilized probes revealed a substantial potential change. Further, potential change was observed neither with the non-complimentary targets nor with the samples with a mutation in the sequence. The last two experiments were important for the future evaluation of the impact of medium and potential interfering compounds: anionic groups and hydrogen bonding groups in the non-complimentary samples did not cause any interactions.

Abstract Objectives Timolol maleate is used for the treatment of glaucoma and metabolized by cytochrome CYP2D6 in the liver. The aim of this study was the evaluation of the influence of CYP2D6*4 and CYP2D6*10 gene polymorphisms on the safety of medications containing 0.5% of timolol maleate as glaucoma treatment in patients with primary open-angle glaucoma (POAG). Methods 105 patients with POAG were prescribed glaucoma medications, containing 0.5% timolol maleate. The safety of glaucoma treatment was determined by electrocardiography (ECG) (to assess heart rate (HR) and PQ interval) and blood pressure (BP) measurements. The real-time polymerase chain reaction method was used for the detection of single nucleotide polymorphisms (SNP). Results The risk of adverse drug reactions was higher in patients with the CYP2D6*4 GA genotype compared with GG: mean HR change at 1 month (2.88 ± 4.68 and 6.44 ± 5.57, p<0.001) and 6 months (5.14 ± 8.93 and 7.88 ± 5.65, p<0.001), mean PQ interval change at 1 (0.01 ± 0.031 and 0.02 ± 0.022, p=0.003) and 6 months (0.01 ± 0.032 and 0.02 ± 0.024, p=0.003). The risk of adverse drug reactions was higher in patients with the CYP2D6*10 CT genotype compared with CC: mean HR change at 1 month (2.94 ± 4.65 and 6.34 ± 5.66, p<0.001) and 6 months (5.20 ± 8.90 and 7.78 ± 5.75, p<0.001), mean PQ interval change at 1 (0.01 ± 0.032 and 0.02 ± 0.021, p=0.014) and 6 months (0.01 ± 0.033 and 0.02 ± 0.022, p=0.014). Conclusions CYP2D6*4 and CYP2D6*10 gene polymorphisms may affect a higher risk of timolol-induced bradycardia and increased PQ interval of treatment medications containing 0.5% of timolol maleate in patients with POAG.

Introduction . Antipsychotics are the main drugs for treatment of schizophrenia spectrum disorders. Pharmacodynamic genetic factors are being actively studied to improve the accuracy of antipsychotic selection based on pharmacogenetic testing. Purpose of this study : to establish associations of genetic polymorphisms of the DRD2, DRD3, DRD4, HTR2A, COMT, ZNF804A, and ANKS1B genes with the efficacy and safety of antipsychotics in adolescents with an acute psychotic episode during a 28-day follow-up. Materials and methods . The study included 68 adolescents with an established diagnosis of acute polymorphic psychotic disorder at the time of admission (F23.0-9 according to ICD-10). All patients received an antipsychotic as their main therapy. Patients were monitored for 28 days. The effectiveness of antipsychotics was assessed using the Children’s Global Assessment Scale (CGAS), Positive and Negative Symptoms Scale (PANSS), Clinical Global Impression Severity (CGI-S) and Improvement (CGI-I). The safety of pharmacotherapy was assessed using the UKU Side Effects Rating Scale (UKU SERS), Sympson-Angus Scale (SAS), Barnes Akathisia rating scale (BARS). From each patient we obtained a buccal scraped epithelium, extracted DNA from it by sorbent method and detected carriage of genetic polymorphisms DRD2 rs1800497 (C>T), DRD3 rs6280 (C>T), DRD3 rs324026 (C>T), DRD4 rs1800955 (C>T), HTR2A rs6313 (T>C), COMT rs4680 (Val158Met, G>A), ZNF804A rs1344706 (A>C), ANKS1B rs7968606 (C>T) by real-time PCR. Results . DRD2 rs1800497 T allele carriers had a stronger reduction in the PANSS subscore «Productive Symptomatics» on day 14 (Me=-7.0 [-9.0;-5.0] vs Me=-7.0 [-8.0;-2.0]; p=0.018) and day 28 of follow-up (Me=-11.0 [-9.0;-5.5] vs Me=-8.0 [-8.0;-2.0]; p=0.019). Also, greater improvement on the CGAS scale on day 14 of follow-up was seen in TC+CC HTR2A rs6313 carriers (Me=2.0 [1.0;3.0] vs. Me=2.0 [1.0;2.0]; p=0.029). DRD3 rs324026 homozygous carriers (TT) had a significantly lower SAS score (Me=0.5 [0.0; 1.0] vs. Me=1.0 [0.0; 5.0]; p=0.016) and UKU subscore «Neurological Disorders» on 28 days of antipsychotic therapy (Me=0.0 [0.0; 0.0] vs. Me=1.0 [0.0; 3.8]; p=0.005). DRD3 rs324026 TT carriers also had lower severity of akathisia according to the BARS scale. Carriers of the T DRD4 rs1800955 allele had a higher SAS scale score on day 28 of therapy compared with CC homozygotes (Me=1.0 [0.0;4.0] vs Me=0.0 [0.0;1.0]; p=0.036). Conclusion . The DRD2 rs1800497 was a predictor of better reduction of productive symptoms; HTR2A rs6313 demonstrated a similar association. The DRD2 rs1800497 polymorphic variant was a predictor of better reduction of productive symptomatology; HTR2A rs6313 demonstrated a similar association. DRD3 rs324026 and HTR2A rs6313 were associated with a lower frequency of neurological adverse reactions and akathisia. In contrast, carriers of the DRD4 rs1800955 were more prone to adverse reactions on pharmacotherapy.

Abstract Objectives To identify possible associations of CYP2D6, CYP3A4/5, and ABCB1 gene polymorphisms with the efficacy and safety of antipsychotics in adolescents with acute psychotic episodes. Methods We examined the associations of pharmacogenetic factors with the efficacy and safety of antipsychotics in 101 adolescents with acute psychotic episodes. The diagnosis on admission was “Brief psychotic disorder” (F23.0–23.9 by ICD-10). All patients were administered antipsychotics for 14 days. Treatment efficacy and safety were assessed using the PANSS, CGAS, CGI-S(I), UKU SERS, BARS, and SAS scales. Pharmacokinetic genotyping was performed for the CYP2D6*4, *10, ABCB1 1236C>T, 2677G>T, and 3435C>T genes. Results CYP2D6 intermediate metabolisers had “Micturition disturbances” more often than extensive metabolisers (24.2 vs. 7.4%; p=0.026). “Wild” homozygote ABCB1 3435C>T CC was associated with more prominent akathisia. Haplotype analysis of three ABCB1 polymorphisms revealed that the “wild” alleles “C-G-C” (ABCB1 1236-2677-3435) were associated with higher risk of “Reduced salivation” (OR=2.95; 95% CI=1.35–6.45; p=0.0078). Conclusions CYP2D6 intermediate metabolism was associated with the risk of urinary difficulties under treatment with antipsychotics. We found that “wild” homozygotes ABCB1 1236C>T, 2677G>T, and 3435C>T were predictors of adverse drug effects caused by treatment with antipsychotics.

Antipsychotics are often used to treat children and adolescents. Because of their age, there are a lot of off-label prescribed antipsychotics in that population. However, the off-label use of medications is considered to be potentially unsafe.Objective: to evaluate whether the off-label prescription of antipsychotics outside of the approved age group increased the risk of adverse drug reactions in adolescents experiencing an acute psychotic episode.Patients and methods. We analyzed 450 charts of adolescents hospitalized due to an acute psychotic episode (only completed cases). In addition, we evaluated adverse drug reactions adjusted by off-label antipsychotics prescription outside the approved age group using the Global Trigger Tool (GTT). We also registered prescriptions with duplicates drug classes and potentially dangerous drug interactions.Results and discussion. Off-label antipsychotics prescription outside the approved age group was less frequently associated with adverse drug reactions (3.2% vs. 10.5%; p=0.013). The logistic regression analysis did not show any significant associations between the off-label antipsychotic use and increased risk of adverse drug reactions (Odds ratio=0.994 (95% confidence interval 0.572-1.726), p=0.982). Although, patients with off-label use of antipsychotics were more likely to have potentially dangerous drug interactions (35.2% vs. 16.15%; p=0.0001) and prescriptions with duplicates drug classes (39.6% vs. 15.43%; p=0.0001).Conclusion. Off-label antipsychotic prescription outside the approved age group in adolescents with acute psychotic episode does not increase the risk of adverse drug reactions. However, an increase in potentially dangerous drug interactions and prescriptions with duplicates drug classes frequency could be considered red flags. Therefore, we have concluded that the concerns about off-label antipsychotics prescription outside of approved age groups in adolescents with acute psychotic episodes were overrated.

Since the early days of the COVID-19 pandemic, a long range of medications have been tried in the fight against the novel coronavirus: antivirals, antimalarial drugs, antibiotics, steroids, and numerous biologicals. None of them were licensed against COVID-19 either in the United Kingdom, the United States, or EU, or Russia. In addition to all the known challenges with the off-label use, many of those medications have significant safety issues, such as potentially dangerous drug interactions, pro-arrhythmic effects, teratogenicity, or organ toxicity. At the same time, both media and politicians have spread news about efficacy of certain medications. Such claims were not based on proper evidence and sometimes were simply factually incorrect. Navigating through this complexity, which in the setting of severe COVID-19 turned to be a true pharmacological minefield, demands high competence and broad knowledge. Russia, as well as over 10 other countries in Eastern Europe and Central Asia, historically lacks clinical pharmacists as a profession, in contrast to the United Kingdom, the United States, Canada, Australia, and majority of the European countries. Hence, the clinical pharmacologists are necessitated to deal with every aspect of rational, safe, and effective medication use alone.1 In Russia, for over 500 000 medical doctors, there are about 800 clinical pharmacologists, who are often overloaded with clinical consultations, assessing and reporting adverse drug events, and advising the hospital medication committees. Due to this high daily workload, clinical pharmacologists have to focus on controlling and adjusting the use of specific drug groups and ensuring adherence to local and national guidelines. With the off-label use of medications becoming the only option, this situation poses extra challenges to clinical pharmacologists in the frontline. It is also important to take into account that in Russia, a country spread across 11 time zones, there are many rural areas, which are remote but not isolated from the pandemic's threat, and which often have limited health care provision and do not have clinical pharmacologists present. In early March 2020, there were just about 15 000 cases of COVID-19 in Russia, yet this number was growing exponentially, and global challenges with obtaining high-quality scientific advice became apparent. A group of clinical pharmacologists based in Moscow and several other cities started a project aimed to support clinical pharmacologists and medical doctors of other specialties working across the country by establishing an online competence centre for complex pharmacological problems in patients with COVID-19 (PharmaCOVID). The concept and methodology of the centre was mainly based on our knowledge of Drug Information Centers (DIC) in Scandinavia and the United States. We performed analysis of the existing publications describing the DIC structure and methodology and adapted them to establish a makeshift specialized rapid response DIC. The main purpose of the centre was to provide evidence-based information about drugs used against COVID-19, especially in patients with multiple pre-existing conditions, polypharmacy issues, kidney or liver failure, and elderly patients. Additionally, we aimed to use clinical requests and our answers for research and teaching purposes, as well as to contribute to medication safety monitoring. PharmaCOVID was established with its core at the Russian Medical Academy of Continuous Professional Education (Academy), state-owned largest national CME institution for Russian medical doctors of all specialties. Nine clinical pharmacologists, further referred to as experts, volunteered to work at the centre pro bono, utilizing their spare time and time which had become available under the lockdown in their permanent jobs. Four experts were based in Moscow, while others worked remotely from their locations in the regions. All meetings were held online due to the geographical constraints and the social distancing imposed by the authorities. One expert was chosen as the permanent scientific leader based on work experience and academic achievements, and another member of the team had the role of the daily operational manager. Scientific leader maintained an overall advisory role, the right to approve recommendations, and a mediatory function in case of disagreements. Operational manager was responsible for the initial screening of the incoming questions, assigning urgency level and delegating the questions to the experts, as well as follow-up of the further work and timely dispatch of the recommendations to the addressees. An overview of the centre's structure and function is presented as a flow chart in Figure 1. Clinicians used online request forms at the academy web site to send their questions. During the early phase, access to the request form was provided to doctors from several major hospitals in Moscow, which were designated by health care authorities as COVID-19 specialized clinics. It has also been decided to answer selected questions from a nationwide online platform used by almost half of Russian clinical pharmacologists—mainly when it was suspected that leaving a particular pharmacological issue unresolved may have put patients at risk. The request forms included a checklist designed to make sure that we would receive only COVID-related questions, a free-text field for the doctor to provide a short summary of the problem, and a number of fields for filling in clinical details, brief case history, laboratory data, and other relevant information. Every effort has been made to de-identify health information in order to preserve patients' privacy. After initial screening and sorting, two experts were assigned to each question to assess it independently, using available clinical evidence via PubMed, Google Scholar, clinicaltrials.gov, national and foreign guidelines, drug–drug interaction databases, and information digests published by academic centres elsewhere—a standard layout of our answers is presented in Table 1. All references were included in the recommendation texts. In order to comply with the national regulations and to respect individual clinician's right to independent decision making, the answers were shaped as recommendations based on assessment of given clinical situations, rather than direct advice on how to treat a given patient. These recommendations were sent directly to the authors of the questions and published at the centre's web site fully available to the public. Importantly, the experts always had special focus on the language used in the recommendations, in order to make it as simple and concise as possible, as this has been shown as a major factor limiting the practical usefulness of DIC answers elsewhere.2 Introduction General information about the medicine (name, ATC code, regulatory status, mechanism of action, main therapeutic indications and contraindications, specific restrictions) – if any of the above are significantly different in Russia and abroada, then a brief summary is provided Preclinical and clinical rationales for potential use in patients with COVID-19 Evidence base and expert recommendations Results of relevant in silico, in vitro, in vivo and clinical studies, including (if relevant) design and dosages used in planned or ongoing clinical trials Russian and foreign guidelines and recommendations, including statements and positions of professional societies Relevant official documents from Russian and foreign authorities PharmaCOVID recommendations on the clinical use of the medicine in question During the first 3 months of its work PharmaCOVID has received a broad variety of questions—see Table 2 for the brief overview of examples. On average, our answers had 20 references and consisted of 1300 words. We have covered specific topics such as dosing regimen and choice of administration route for an interleukin-6 inhibitor, and broad ones—safety measures in patients receiving antimalarial medications. Some doctors wondered about the off-label use of globally approved medications, while others had specific inquiries about medications licensed and available only in Russia. Some physicians wanted our opinion about clinical usefulness of unlicensed supplements and unorthodox treatments. The centre has become widely known among clinical pharmacologists and other physicians in Russia and several neighbouring countries, and publicly praised for objectiveness, impartiality, and strict adherence to the principles of evidence-based medicine. By mid-July 2020 our answers have been downloaded more than 21 000 times, and the website has had over 33 000 unique visitors. We have been recognised by the Ministry of Health of Russia, which has sent a formal letter to all regional health authorities, health care institutions, and universities, advising to use the answers published by PharmaCOVID. The ministry is also using our scientific advice in revising national COVID-19 guidelines. Our centre is not entirely unique; similar initiatives have been launched in the United Kingdom, the United States, France, Australia, Canada, and elsewhere. Teams of experts performing rapid analyses of evidence and/or producing answers to the clinicians' questions are usually based at universities,3-5 or affiliated to professional societies,6 or international initiatives,7 HTA agencies,8, 9 and health care systems.10-12 However, most of them have either somewhat different functions or a different focus. Distinct features of our centre are as follows: (a) we accept questions regarding pharmacological treatment of patients with COVID-19, (b) we provide rapid answers within three timeframes (6, 24, or 72 h), and (c) we aim specifically towards clinicians and researchers rather than general public. Publicly available and thoroughly implemented system for quality control is the major strength of our centre. We believe that our model can be replicated and scaled up in practically any region or country, as it requires only a limited set of resources, is fully digitalised, and has successfully passed the test of a pandemic. Specifically, countries with limited or fragmented resources could benefit from implementation of our model. For smaller countries sharing similar challenges and health care systems, a transnational centre could be an effective resource-sparing solution. International bodies, and specifically the World Health Organisation, could consider using our model and provide the essential guidance and coordination for similar projects. While the COVID-19 outbreaks in most of Europe appear to have been stabilized, we are still seeing a significant growth in the number of cases in Russia, the United States, Central Asia, Latin America, and Africa. Many patients are still in hospitals, and more will inevitably be hospitalised, while the progress in finding effective and safe treatments has been limited, and challenges in obtaining and implementing evidence-based pharmacological advice are still acute. Working on PharmaCOVID project, we created an infrastructure and gained unique experience that will be useful for rising on similar challenges. We hope that our example may serve as an inspiration for colleagues across the globe, as our model can potentially be used in other countries or regions where rapid access to a clinical pharmacologist or a pharmacist is not always possible. The authors wish to thank Dr. Harald Christian Langaas and his colleagues from RELIS–Norwegian network of medicines information centres for sharing their experience and providing valuable methodological advice. There are no competing interests to declare. K.B.M., Y.K., and D.A.S. conceptualized the manuscript. K.B.M. and Y.K. also did the literature search, wrote the first draft, and edited every draft. D.V.I. and V.A.O. contributed to writing of the first draft. K.B.M., Y.K., D.V.I., V.A.O., and D.A.S. edited the manuscript.

Aim . To search for new pharmacogenetic biomarkers of bleeding risk in patients taking rivaroxaban and dabigatran for different indications: atrial fibrillation, endoprosthesis of large joints of lower limbs. Material and methods . The study enrolled 29 patients (17 patients received dabigatran and 12 –rivaroxaban), who had hemorrhagic complications during taking direct oral anticoagulants. To find new pharmacogenetic biomarkers of bleeding risk, a next generation sequencing (NGS) was performed for selected candidate genes. Results . Among the patients with bleeding who received dabigatran, 13 variants of the nucleotide sequence showed statistically significant deviation from the population values: 11 in the CES1 gene and 2 in the ABCB1 gene. Among the patients with bleeding who received rivaroxaban, 7 variants of nucleotide sequence showed significant deviation: 4 in the ABCG2 gene, 2 in the CYP3A4 gene, and 1 in the ABCB1 gene. Conclusion . The identified in this study polymorphisms of candidate genes ABCB1, ABCG2, CES1, CYP3A4 were associated with the risk of bleeding in patients taking rivaroxaban and dabigatran. It makes an important contribution to the pharmacogenetics of direct oral anticoagulants and require additional assessment of clinical significance in further studies.