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.

[HOMEOSTASIS AS A TOOL FOR STUDYING TECHNOLOGICAL IMPACTS ON HUMAN HEALTH].

The analysis of homeostasis as a tool for restraining, saving, security and rehabilitation technologies which ensures the sustainable functioning of the human organism through the cultivation of health-saving and rehabilitation technologies, as well as health programs, preventive (anti-alcohol, anti-nicotine, drug addicts) and recreational activities, upbringing of health culture and also environmental, medical treatment practices and correctional technologies. The cyclic mechanism of homeostasis is described, which works on the principle of alternating modes of behavior of the social system - structures for generating order and structures for maintaining order. The functioning stability of the human organism is relative and has the nature of a dynamic balance, fluctuating around a certain average value and constantly deviating from it either in the direction of positive, strengthening changes, or in the direction of negative and destructive ones.

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.

Influence of CYP2C19*17 Genetic Polymorphism on the Steady-State Concentration of Escitalopram in Patients with Recurrent Depressive Disorder.

Introduction: Escitalopram is commonly prescribed to patients with recurrent depressive disorder. Some of them do not show adequate response to treatment with escitalopram, while many of them experience adverse drug reactions. Objective: The objective of our study was to evaluate the impact of -806C>T polymorphism of CYP2C19 (CYP2C19*17) on the concentration/dose ratio of escitalopram in patients with recurrent depressive disorder. Material and methods: Our study enrolled 267 patients with recurrent depressive disorder (average age -40.2 ± 16.4 years). Treatment regimen included escitalopram in an average daily dose of 12.5 ± 5.0 mg per day. The efficacy and safety rates of treatment were evaluated using the international psychometric scales. For genotyping, we performed the real-time polymerase chain reaction. Therapeutic drug monitoring has been performed using HPLC-MS/MS. Results: Our findings revealed the statistically significant results in terms of both treatment efficacy evaluation (HAMD scores at the end of the treatment course): (CC) 9.0 [7.0; 11.0], (CT) 4.0 [2.0; 6.0] and (TT) 2.0 [1.0; 4.0], p < 0.001; and safety profile (the UKU scores): (CC) 7.0 [7.0; 8.0], (CT) 3.0 [3.0; 4.0] and (TT) 3.0 [2.0; 3.0], p < 0.001. We revealed no statistically significant results for the concentration/dose ratio of escitalopram in patients with different genotypes: (CC) 5.762 [3.939; 9.076], (CT) 5.714 [3.485; 8.533] and (TT) 7.388 [4.618; 10.167], p = 0.268). Conclusion: The CYP2C19*17 genetic variant significantly affected the efficacy and safety profiles of escitalopram in a group of 267 patients with recurrent depressive disorder but did not greatly affect its equilibrium plasma concentration.

[Human body composition during extended stay in microgravity].

According to the Sprut-2 protocol, bio-impedancemetry of ISS cosmonauts was performed once a month and also before and after mission. Multiple non-invasive body measurements were carried out in 15 cosmonauts in real time. Relocation of extracellular liquid along the body axis led to its reduction in legs and, on the contrary, an increase in the abdomen. Volumes of total body liquid as well as intra- and extracellular liquids decreased in comparison with pre-flight levels. Lean body mass also became less in microgravity, whereas fat mass showed an increase.

[Functional load tests for the investigation of the kidneys and water-electrolyte metabolism].

The paper deals with the application of functional load tests to assess the renal function and water-salt metabolism in human subjects during spaceflight simulating experiments and in cosmonauts in orbit and in the course of postflight recovery. The tests gave insight into mechanisms of the osmotic and volumetric regulation systems and enabled the development upon this knowledge of countermeasures to correct shifts in water-salt homeostasis.

[Water-salt metabolism in space flights].

The article centres on the water-salt metabolism properties in space flights of varying duration. To assess the water and mineral turnover, renal function and their hormonal regulation in flight, a series of experiments was carried out with participation of Russian and international cosmonauts. These experiments and ground model investigations shed light on the mechanisms of osmotic and volumetric regulation in microgravity and guided the development of countermeasures and methods for correcting the negative shifts as a result of body adaptation to the novel environment.

[Adaptation of water-electrolytes metabolism to space flight and in its imitation].

50-years study of water-electrolytes exchange, the condition of water environments of the organism and the hormonal regulation in space flights, and also in postflight period or in its on ground modeling (hypokinesia, bed rest, immersion etc.) has shown the important role of the water-salt homeostasis in adaptation of the human and animal organisms to weightlessness. It has been revealed, that in weightlessness conditions for development of negative balance of a liquid (hypohydration) and the basic electrolytes are created. After the termination of long space flights attributes of development adaptive reactions compensating for extracellular liquid's volume come to light. In order to assess the state of the kidneys and water-electrolyte metabolism in cosmonauts and investigators, functional load tests and especial methods of diagnostic were developed. This is the basis for researches directed on improvement of the scheme of correction hydrogenous the status of an organism of the cosmonauts at the different stages of flight.

[Space flight and modeling experiments: new approaches to evaluation and prophylaxis].

The article dwells on the general issues of orthostatic tolerance and new impedance methods of orthostatic test evaluation in spaceflight and simulated microgravity. The results imply that OT requires adequate body hydration and functioning of volume-regulating hormones. New pharmacological compensators of orthostatic intolerance were tested in modeling experiments. It was shown that desmopressin and water-salt supplements retain body liquid and electrolytes during bed rest and improve tolerance of the orthostatic test Therefore, simultaneous control of the hydration status and OT can be best provided through physiologically reasonable prescription of synthetic ADH analogs.

[Dynamics of the body composition, neurohumoral and psychophysiological status of humans in the conditions of 105-day isolation and confinement].

Before, in and after the experiment with 105-day isolation and confinement, 6 male volunteers from 25 to 40 years of age rationed NaCl and performed integral impedancimetric, psychological and hormonal investigations. Every 30 days blood collection for hormonal measurements was combined with filling of Cattell's 16 personal factor questionnaire. Parameters of total body fluid, body mass, basic exchange, specific hydration and basic exchange were determined. The results showed that the experimental conditions did not affect significantly body composition, metabolism or neurohumoral regulation; the metabolic variations were largely associated with motivation for and value orientation in accommodation, to the permissible extent, of the controlled diet and work/rest schedule to personal needs. In addition, it was found that evolution of the psychophysiological status of humans in isolation and confinement is governed primnarily by personality characteristics and, to a less degree, specifics and length of exposure to the artificial environment; thus, in the opinion of the volunteers normoxic, normobaric and slightly hypercapnic (0.15-0.65% CO2) atmosphere was comfortable and harmless to health. Analysis of the whole data array verified the expressed interrelation of neuroendocrine and psychophysiological parameters as well as shifts in body basic exchange and mass, salt intake and hydration rate in the conditions of isolation and confinement.

[Redistribution of body liquids in the conditions of microgravity and simulation of its effects].

The review is devoted to shifting of blood and other liquids along the body axis toward the cranium end in microgravity and during simulation of the zero-g physiological effects. The body liquids redistribution excites a number of consistent physiological reactions as well as a cascade of secondary adaptation processes. Changes occur in central venous pressure and size of the heart cavities, renal function and hormonal volumoregulation entailing the adaptive shifts in body liquid segments. Hemodynamic changes in the splanchnic vascular system affect functioning of the abdominal organs. Measures of pharmacological correction expedite human adaptation to unusual environments.

[Renal functioning and human body liquids during 5-day dry immersion].

Renal function and body composition, including liquids, were investigated in 14 essentially healthy male subjects during simulation of some spaceflight effects by 5-d dry immersion (DI). Noninvasive measurement of water spaces of organism was performed with the methods of bio-impedance analysis (BIA). Increase of renal excretion of liquids and appearance of negative water balance were observed. BIA revealed reductions of total body and extracellular liquids and a decrease of circulating plasma volume. This means, that DI induced hypohydration of organism. In the post-DI period, the hydration status regained its baseline level fairly soon. Lean body mass slightly decreased; adipose mass, on the contrary, exceeded baseline values. Moreover, the experiment evidenced technical impossibility to obtain valid impedansimetry data in DI.

[Evaluation of synthetic antidiuretic hormone as a corrective substance following head-down tilt].

Effects of synthesized desmopressin, analog of antidiuretic hormone, and water-salt supplement on the renal function and orthostatic stability were studied in 6 normal male subjects after 12-hr. head-down tilt (12 degrees). The combination of water-salt homeostasis normalizing methods was effective in retaining excessive liquid and salts. Moreover, tolerance of the standard 20-min. passive standing test improved significantly. Hence, it was demonstrated that intake of synthetic vasopressin analog combined with WSS counteracted hypohydration of organism due to HDT and improved orthostatic tolerance.

[Outcomes of prolonged anticoagulant prevention of thrombosis of deep veins of the crus in closed comminuted fractures of tibial bones].

Analysed herein are the outcomes of treating a total of 96 patients with closed comminuted fractures of crural bones. By the duration of antithrombotic prevention, the patients were subdivided into two groups: the Comparison Group comprising 45 patients with a brief course of anticoagulant treatment (mean 5.8 +/- 1.3 days) and the Study Group consisting of 51 patients receiving anticoagulant treatment till achieving full restoration of the supporting function of the limb (averagely 21.2 +/- 2.1 days). In the Comparison Group, thrombosis of the deep veins localizing exclusively on the crus was registered by the results of duplex scanning in 13 patients (28.9%). In two thirds of the cases (10 cases, 76.9%) thrombosis occurred predominantly on days 6 - 14, while in 3 cases (7.7%) it occurred on days 15 -21 after the injury. In the Study Group patients with protracted anticoagulation prevention, thrombosis of the deep veins was revealed in 9.8% of cases (5 patients). Of the five Study Group patients with thromboses of tibial veins four were subjected to prolonged prevention with indirect anticoagulants and only one - with fraxiparine. It was found that the development of venous thrombi in fractures significantly (p <0.05) makes the terms of consolidation 1.6-fold longer. A conclusion was made that because a high risk of the development of thrombosis of the deep veins preserves during the whole period of restoration of the supporting function of the extremity in fractures of the crural bones, the patients concerned should, based on early (within the first 3-7 days) stable osteosynthesis making it possible to activate the patient and to restore the function of the limb, be subjected to a prolonged course of anticoagulant preventive treatment till the final changeover of the patient to the full load on the affected extremity.

[Desmopressin effect on water-salt homeostasis and orthostatic tolerance during head-down tilting].

Effects of desmopressin, a synthetic analog of antidiuretic hormone (ADH), on water-salt metabolism and orthostatic tolerance were evaluated in human subjects during 24-hr HDT (-15 degrees). Consumption of the preparation was found to dampen losses in total body and extracellular liquids and to slow down diuresis as well as establishment of a positive water balance as compared with control series without ADH. In addition, tolerance of the standard standing test improved noticeably. To conclude, desmopressin precluded hypohydration of the tilted subjects and, consequently, prevented loss of orthostatic tolerance.

[Hormonal control of human hydratation status in space flight].

In long-lasting stay in state of weightlessness the astronaut develops a moderate hypophydratation of the organism accompanied by increase production of vasopressin. Most changes of the water-salt balance and kidney function will be fast enough normalised. The synthetic agonist of vasopressin V2-receptors proved to be able to control human hydratation status. The data obtained indicate a certain efficacy of Desmopressin thus opening prospects for development of a simple pharmacological means of prophylactics of the weightlessness effect.

[Hemoglobin mass in humans during space flight and its simulation].

The review is a retrospective of the studies of body liquids and blood formation system in long-duration space missions and physiological modeling with, specifically, the non-invasive carbon monoxide method of hemoglobin mass determination. The method is used to assess protein synthesis in general and mass of circulating blood. In the micro-g environments the humans reduce the amount of intracellular liquid including blood plasma and hydration level in addition to hemoglobin and hematocrit decreases. The number of erythrocytes decreases and abnormal forms appear. These alterations are responsible for the so-called erythrocytopenic syndrome observed in microgravity. The article discusses possible factors and mechanisms of the syndrome and dependence on the level of body hydration. The review tries to generalize and interpret the known results and state of the art of these investigations.