Association of CYP2D6*4 Polymorphism with the Steady-State Concentration of Haloperidol in Patients with Alcohol-Induced Psychotic Disorders.

Background: CYP2D6 subfamily isoenzymes play an important role in the biotransformation of haloperidol, and their activity may influence the efficacy and safety of haloperidol. The use of haloperidol is often associated with the occurrence of adverse drug reactions (ADRs), such as dyskinesia, acute dystonia, and orthostatic hypotension. Previous studies have demonstrated the relationship between the CYP2D6*4 genetic polymorphism and CYP2D6 activity, as well as haloperidol efficacy and safety rates. Purpose: To evaluate the association of CYP2D6*4 genetic polymorphism with the steady-state concentration of haloperidol in patients with acute alcohol-induced psychotic disorders (AIPDs). Material and methods: The study involved 100 male patients with AIPD (average age 41.4 ± 14.4 years) who received haloperidol by injections in a dose of 5-10 mg/day. The efficacy profile was assessed using a validated psychometric PANSS scale (Positive and Negative Syndrome Scale). Therapy safety was assessed using the internationally validated UKU (Side-Effect Rating Scale) and SAS (Simpson-Angus Scale for Extrapyramidal Symptoms) scales. Genotyping was performed with the real-time polymerase chain reaction. Results: We revealed the statistically significant results in terms of therapy safety evaluation (dynamics of the UKU scores: (GG) 8.00 [7.00; 10.00], (GA) 15.0 [9.25; 18.0], p < 0.001; dynamics of the SAS scores: (GG) 11.0 [9.0; 14.0], (GA) 14.50 [12.0; 18.0], p < 0.001. Pharmacokinetic study showed a statistically significant difference across the groups with different genotypes: (GG) 3.13 [2.32; 3.95], (GA) 3.89 [2.92; 5.26], p = 0.010. Conclusion: It can be concluded that patients with the GA genotype have a higher risk of ADRs compared to patients who carry the GG genotype. It was shown that CYP2D6*4 genetic polymorphism has a statistically significant effect on the steady-state concentration of haloperidol.

[CYP2D6 gene polymorphic markers role in determining the optimal treatment tactics for portal hypertension in patients with liver cirrhosis].

AIM: To study the polymorphic markers CYP2D6*4 (G1846A, rs3892097), CYP2D6*6 (T1707del, rs5030655), CYP2D6*10 (C100T, rs1065852), CYP2D6*41 (G2988A, rs28371725) and CYP2D6*3 (A2549del, rs4986774) role in treatment optimization of portal hypertension with propranolol in patients with liver cirrhosis (LC). MATERIALS AND METHODS: The study included 60 patients with LC who received propranolol therapy at a daily dose of 30 mg for 14 days. The efficacy of treatment was assessed by ultrasonography measuring the linear blood flow velocity of portal vein. Genotyping of CYP2D6*4, CYP2D6*6, CYP2D6*10, CYP2D6*41 and CYP2D6*3 was carried out by real-time polymerase chain reaction. Evaluation of the CYP2D6 activity was carried out by determining the ratio of pinoline and its metabolite concentration in morning urine using high performance liquid chromatography with mass spectrometry. RESULTS: Positive hemodynamics in the form of any increase in the mean linear blood flow velocity of the portal vein compared to baseline was observed in 41 patients. Portal vein mean linear blood flow rate increased from 10.43.9 to 14.74.3 cm/s (p0.001). Of these, 29 patients showed an increase in this indicator by 20% from the initial one with a dynamic of 5.5 cm/s (p0.001). The regression analysis constructed by us revealed the presence of a statistically significant effect of the CYP2D6 gene polymorphic marker G1846A carriage on the propranolol therapeutic effect (p0.05). There was no statistically significant effect of polymorphic markers T1707del, C100T, G2988A, and A2549del of the CYP2D6 gene (p0.05). No convincing reliable dependence of CYP2D6 activity on the severity of LC was revealed (p0.05). CONCLUSION: An association was found between CYP2D6 gene polymorphic marker G1846A carriage and the hemodynamic effect of propranolol in patients with LC of the Russian population. There is a more significant positive dynamics of manifestations of portal hypertension on the background of propranolol therapy in carriers of the homozygous GG CYP2D6*4 genotype, in contrast to patients with the heterozygous GA genotype. Based on the results of the study, an algorithm has been developed for personalizing the treatment of patients with LC with nonselective b-adrenergic blockers using the method of CYP2D6 genotyping. Carriage of polymorphic markers T1707del, C100T, G2988A and A2549del gene CYP2D6 does not affect the effectiveness of propranolol therapy in patients with LC.

[Evaluation of the association of polymorphisms of the CYP2C8 gene with the efficacy and safety of ketorolac in patients with postoperative pain syndrome].

AIM: To evaluate the possible association of CYP2C8 gene polymorphisms with the clinical efficacy and safety of ketorolac in relation to postoperative pain. MATERIALS AND METHODS: The study included 107 patients after video laparoscopic cholecystectomy, who received ketorolac (30 mg 2.0 w/m 3 r/d) as postoperative pain relief. All patients were genotyped for CYP2C8. The pain syndrome was assessed using the visual analog scale, the McGill pain questionnaire. The profile of adverse reactions was assessed by the dynamics of red blood counts, as a possible trigger for the development of gastrointestinal bleeding according to the method of global assessment of triggers (Global Trigger Tool GTT). RESULTS: According to visual analog scale data: in carriers of the genotype CYP2C8*3 (rs10509681) and CYP2C8*3 (rs11572080) after 12, 24, 36, 48 hours the intensity of pain syndrome is lower than in carriers of the wild type (p0.05). According to the McGill pain questionnaire, there were no statistically significant differences in pain intensity between the two groups. CONCLUSION: In carriers of the genotype CYP2C8*3 (rs10509681) and CYP2C8*3 (rs11572080), the effectiveness of anesthesia with ketorolac is higher than in carriers of the wild type. Carriage of the genotype CYP2C8*3 (rs10509681) and CYP2C8*3 (rs10509681) does not affect the risk of developing adverse reactions after ketorolac anesthesia.

Correlation of 1846G>A Polymorphism of CYP2D6 Gene with Haloperidol Efficacy and Safety in Patients with Alcoholic Hallucinoses.

Background: Previous studies have shown that haloperidol biotransformation occurs with participation of the CYP2D6 isoenzyme. The CYP2D6 gene is highly polymorphic, which may contribute to differences in its activity and in the haloperidol biotransformation rates across different individuals, resulting in variable drug efficacy and safety profiles. Purpose: The study aimed to investigate the correlation of the 1846G> A polymorphism of CYP2D6 gene with the efficacy and safety rates of haloperidol in patients with alcoholic hallucinoses. Material and methods: One hundred male patients received 5-10 mg/day haloperidol by injections for 5 days. The efficacy and safety assessments were performed using the validated psychometric scales PANSS, UKU, and SAS. For genotyping, the real-time polymerase chain reaction was performed. Results: We revealed no statistically significant results in terms of haloperidol efficacy in patients with different genotypes (dynamics of the PANSS scores: (GG) -13.00 [-16.00; -11.00], (GA) -15.00 [-16.75; -13.00], p = 0,728). Our findings revealed the statistically significant results in terms of treatment safety evaluation (dynamics of the UKU scores: (GG) 8.00 [7.00; 10.00], (GA) 15.0 [9.25; 18.0], p < 0.001; dynamics of the SAS scores: (GG) 11.0 [9.0; 14.0], (GA) 14.50 [12.0; 18.0], p < 0.001. Conclusion: These results suggest that genotyping for common CYP3A variants might have the potential to guide benzodiazepine withdrawal treatment. The effect of of the 1846G>A polymorphism of CYP2D6 gene on the safety profile of haloperidol was demonstrated in a group of 100 patients with alcoholic hallucinoses.

[CYP2C8, PTGS-1, 2 gene polymorphisms prevalence associated with sensitivity to non-steroidal anti-inflammatory drugs among North Caucasus ethnic groups].

AIM: Find the prevalence of CYP2C8*3 (rs10509681; rs11572080), PTGS-1 (rs10306135; rs12353214) and PTGS-2 (rs20417) alleles and genotypes in four ethnic groups among Laks, Avars, Dargins and Kumyks. MATERIALS AND METHODS: The study involved 400 volunteers from four ethnic groups living in Republic of Dagestan: 100 participants from each group. Carriage of polymorphic markers was determined by reverse transcription polymerase chain reaction. RESULTS: Minor allele frequency of the CYP2C8 (rs10509681) was 5.5% in Avars, 10% in Dargins, Laks and Kumyks 6.5% both; CYP2C8 (rs11572080) was 5.5% in Avars, 9.5% in Dargins, 6.5% in Laks, 8.5% in Kumyks; PTGS-1 (rs10306135) in Avars 10.5%, in Dargins 13.0%, in Laks 9.5% and Kumyks 7.5%; PTGS-1 (rs12353214) in Avars 9.0%, in Dargins 4.5%, in Laks 7.5%, in Kumyks 8.0%; PTGS-2 (rs20417) in Avars 1.0%, in Dargins 2.5%, in Laks 3.5%, in Kumyks 5.0%. There were no significant differences between groups. CONCLUSION: The study of CYP2C8 and PTGS-1 and 2 gene polymorphisms is promising for predicting the effectiveness and safety of non-steroidal anti-inflammatory drug therapy, due to the high prevalence of these polymorphisms in ethnic groups in the North Caucasus.

EFFECT OF CYP2C19 GENETIC POLYMORPHISMS ON THE EFFICACY OF PROTON PUMP INHIBITOR-BASED TRIPLE ERADICATION THERAPY IN SLAVIC PATIENTS WITH PEPTIC ULCERS: A META-ANALYSIS.

INTRODUCTION: Several meta-analyzes reported the effect of CYP2C19 genetic polymorphisms on the efficacy of proton pump inhibitor-based triple therapy for Helicobacter pylori eradication. Most of the studies which were included in these meta-analyzes were held on Asian population. Thus, there is lack of information about the effect of CYP2C19 genetic polymorphisms on the efficacy of proton pump inhibitor-based triple eradication therapy in Slavic patients with peptic ulcers. The aim of the study - to determine whether CYP2C19 affect the efficacy of proton pump inhibitor-based triple eradica- tion therapy in Slavic patients with peptic ulcers. METHODS: Data search was performed using Russian index of scientific citation database, Google Scholar and MEDLINE PubMed. Statistics was held in Review Manager v 5.3. The odds ratio (OR) and 95% confidence interval (95% Cl) for eradication of H.pylori was estimated in a fixed-effect model when no heterogeneity across the studies was indicated. RESULTS: Four articles published between 2008 and 2015 were included in meta-analysis (three Russian studies, one Polish study). Eradication rates were significantly lower in CYP2C19 extensive metabolizers of proton pump inhibitors than in a combined group of intermediate and poor metabolizers (OR = 1,90, CI-95% 1,08-3,34, p = 0,03; heterogeneity: 12= 0%, p = 0,74). We also found that proton pump inhibitor-based triple eradication therapy achieved higher rates in poor metabolizers than in a combined group of intermediate and extensive metabolizers of CYP2C19 (OR= 5,48 CI-95% 1,51-19,93, p = 0,01; heterogeneity: F= 0%, p = 0,66). CONCLUSION: The impact of CYP2C19 genetic polymorphisms on the efficacy of proton pump inhibitor-based triple eradication therapy in Slavic patients appears significant.

The frequency of CYP2C19 genetic polymorphisms in Russian patients with peptic ulcers treated with proton pump inhibitors.

INTRODUCTION: Proton pump inhibitors, which are widely used as acid-inhibitory agents for the treatment of peptic ulcers, are mainly metabolized by 2C19 isoenzyme of cytochrome P450 (CYP2C19). CYP2C19 has genetic polymorphisms, associated with extensive, poor, intermediate or ultra-rapid metabolism of proton pump inhibitors. Genetic polymorphisms of CYP2C19 could be of clinical concern in the treatment of peptic ulcers with proton pump inhibitors. AIM: To investigate the frequencies of CYP2C19*2, CYP2C19*3, and CYP2C19*17 alleles and genotypes in Russian patients with peptic ulcers. METHODS: We retrospectively reviewed the cases of 971 patients of Caucasian origin with Russian nationality from Moscow region with endoscopically and histologically proven ulcers, 428 males (44%) and 543 females (56%). The mean age was 44.6±11.9 years (range: 15-88 years). DNA was extracted from ethylenediaminetetraacetic acid whole blood samples (10 mL). The polymorphisms CYP2C19 681G.A (CYP2C19*2, rs4244285), CYP2C19 636 G.A (CYP2C19*3, rs4986893) and CYP2C19 -806 C.T (CYP2C19*17, rs12248560) were evaluated using real-time polymerase chain reaction. RESULTS: Regarding CYP2C19 genotype, 317 patients (32.65%) out of 971 were CYP2C19*1/*1 carriers classified as extensive metabolizers. Three hundred and eighty-six (39.75%) with CYP2C19*1/*17 or CYP2C19*17/*17 genotype were ultra-rapid metabolizers. Two hundred and fifty-one people (25.85%) were intermediate metabolizers with CYP2C19*1/*2, CYP2C19*2/*17, CYP2C19*1/*3, CYP2C19*3/*17 genotypes. Seventeen patients (1.75%) with CYP2C19*2/*2, CYP2C19*3/*3, CYP2C19*2/*3 genotypes were poor metabolizers. The allele frequencies were the following: CYP2C19*2 - 0.140, CYP2C19*3 - 0.006, CYP2C19*17 - 0.274. CONCLUSION: There is a high frequency of CYP2C19 genotypes associated with modified response to proton pump inhibitors in Russian patients with peptic ulcers. Genotyping for CYP2C19 polymorphisms is suggested to be a useful tool for personalized dosing of proton pump inhibitors.

[HIGH FREQUENCY OF CYP2C19 ULTRARAPID METABOLIZERS IN RUSSIAN PATIENTS WITH PEPTIC ULCER].

INTRODUCTION: The main enzyme responsible for metabolism of proton pump inhibitors (PPI) is cytochrome P-4502C19 (CYP2C19). Among all CYP2C19 polymorphisms ulrarapid CYP2C19*17 allele plays an important role in clinical practice as in CYP2C19*17 allele carriers acid suppression achieved with PPI including eradication regimens may be insufficient. THE AIM OF THE STUDY: To find the frequency of CYP2C19 ultrarapid metabolizers in Russian patients with peptic ulcer METHODS: We retrospectively reviewed the results of pharmacogenetic tests of 971 Russian patients with endoscopically and histologically proven ulcers, 428 male (44%) and 543 female (56%). The mean age was 44.6 ± 11.9 years (range 15-88 years). DNA was extracted from EDTA whole blood samples (10 mL). The polymorphisms CYP2C19 *2, *3 *17 were evaluated using real-time polymerase chain reaction (RT-PCR). RESULTS: We found that among 971 peptic ulcer patients ultrarapid metabolizers (CYP2C19*1/*17, CYP2C19*17/*17) were the most frequent genotype--39.75%. Extensive metabolizers with CYP2C19*1/*1 genotype were less frequent--32.65%. Frequency of poor and intermediate metabolizers was found to be 1.5% and 25.85% respectively. We were the first to investigate CYP2C19*17 allele frequency in Russian patients with peptic ulcer which was found to be 27.4%. CONCLUSION: High frequency of CYP2C19 ultrarapid metabolizers in Russian patients with peptic ulcer may be associated with insufficient response to proton pump inhibitors.

[Structural and functional changes in sympathetic ganglia following endotoxin and alpha1-antitrypsin exposure]. / Strukturno-funktsional'nye izmeneniia v simpaticheskikh gangliiakh pri deistvii v organizme éndotoksina i al'fa-antitripsina.

Structural and functional organisation of sympathetic ganglia under conditions of endotoxemia was studied in white rats, cats, and dogs. Submicroscopic characteristics of the changes occurring in the rat prevertebral sympathetic ganglia after endotoxin administration or application of endogenous proteinase inhibitor alpha 1-antitrypsin, were assessed as well as ultrastructural bases of the febrile rat ganglionic responses to antipyretic drug administration. Effects of endotoxin on synaptic transmission in inferior mesenteric plexus' ganglia of cats and on electrical activity in inferior mesenteric plexus' ganglia of dogs, were electrophysiologically demonstrated.

[Isothiorbamin possesses stress-protective action]. / Izotiorbamin obladaet stressprotektivnym deistviem.

It was shown on a model of long-term stress induced by chronic electrostimulation of the ventromedial hypothalamus of rabbits that administration of isothiorbamin in the active periods of the experiment prevents hyperactivation of lipid peroxidation in the blood and myocardium by maintaining the activity of antioxidant enzymes. Isothiorbamin also causes an antiatherogenic effect on the blood lipid spectrum, raises the efficacy of the work of the heart and decreases the stressogenic ischemic disorders of the myocardium.

[Change in lipid peroxidation depending on hormonal reactions during lengthy electric stimulation of the rabbit hypothalamic dorsomedial nucleus]. / Izmenenie perekisnogo okisleniia lipidov v zavisimosti ot gormonal'nykh reaktsii pri dlitel'noi élektrostimuliatsii dorsomedial'nykh iader gipotalamusa krolikov.

A model of chronic emotional stress (ES) induced by electrostimulation of the hypothalamic dorsomedial nucleus in 69 rabbits was used to examine the relationship of blood hormonal changes and lipid peroxidation (LPO) activity in blood and myocardial cells. The elevated concentrations of stress hormones at the initial stages of chronic ES (the first 2 series) caused LPO with high activities of antioxidative enzymes (AOEs). The subsequent stages of chronic ES (from 60 to 120 days) were associated with the decreased role of major stress hormones (adrenocorticotropic hormone, cortisol, catecholamines) and the increased significance of parathyroid hormone and active renin (angiotensin I). A significant direct correlation was found between the blood level of these hormones and the rate of LPO in the myocardium and blood. At the same time the activity of AOEs progressively decreased and all rabbits exhibited myocardial cell necrotic foci.

[Ultrastructural organization of the synapses in ganglia of the hen intestinal nerve under various conditions of its activity]. / Ul'trastrukturnaia organizatsiia sinapsov v ganglii kishechnogo nerva kuritsy v raznykh usloviiakh ego aktivnosti.

The interneuronal connections in ganglia of the caudal part of the hen intestinal nerve of Remak are presented as axodendritic and axosomatic synapses and symmetric axo-axonal, dendro-dendritic and axodendritic contacts, often forming complicated complexes. Under conditions of preliminary decentralization or under certain disturbances of nervous connections with the intestine, a part of synapses remains, and a part of them degenerates, this demonstrates participation of peripheral afferent neurons in formation of the synaptic apparatus of the ganglia mentioned. The axonal terminals differentiate by composition of the synaptic vesicles: some contain mainly light agranular vesicles, others--a large amount of granular ones. The characteristic peculiarities of the hen intestinal nerve ganglia, in contrast to analogous mammalian ganglia, are abundant axosomatic synapses in some neurons, and presynaptic terminals, containing a large number of granular vesicles.