Relevance. Coenzyme Q10 is one of the main components that maintain the balance of the body's redox regulatory system. Although some studies have examined plasma concentrations of CoQ10 in various diseases, the distribution of ubiquinol and ubiquinone, as well as the redox state of CoQ10, remain largely unexplored. The purpose of the study. The purpose of the study was to study the ratio of ubiquinone and ubiquinol concentrations in patients with chronic heart failure (CHF) administrating the antioxidant ethylmethylhydroxypyridine malate and the domestic drug ubidecarenone (CoQ10 drug). Methods. The study included 58 patients with functional class (FC) of CHF 0−III (according to NYHA), who were divided into 2 groups for subsequent assessment of the effect of ethylmethylhydroxypyridine malate and ubidecarenone on endogenous plasma concentrations of total CoQ10, ubiquinol and ubiquinone. The concentrations of the studied substances were determined by HPLC-MS/MS in the multiple reaction monitoring mode. Results. The study revealed that with additional administration of the drug ubidecarenone, there was an increase in the concentration of coenzyme Q10 (+25.0 Δ%), a significant increase in the concentration of ubiquinol (+43.4 Δ%), as well as a sharp increase in redox state (+74.6 Δ%) compared to the control group. During administration of ethylmethylhydroxypyridine malate in addition to standard therapy, patients experienced a statistically significant increase in the concentration of coenzyme Q10 (+20.22 Δ%), a significant increase in the concentration of ubiquinol (+25.0 Δ%) and ubiquinone (+17.7 Δ%) according to compared with a control group receiving standard therapy. Conclusion. With the additional administration of ethylmethylhydroxypyridine malate and ubidecarenone to standard therapy, a statistically significant increase in the concentration of total CoQ10 is observed. However, when administrating ubidecarenone, a sharp increase in the redox state of CoQ10 is observed due to its reduced form — ubiquinol. While during administration of ethylmethylhydroxypyridine malate, it is observed an unreliable but positive trend towards an increase in the redox state of CoQ10 due to a statistically significant increase in the concentration of both ubiquinone and ubiquinol.

OBJECTIVES:To evaluate the role of ABCB1 (C3435T rs1045642, rs1128503, rs2032582, rs4148738), SLCO1B1 T521C rs4149056 genetic polymorphisms in the development of major types of methotrexate (MTX) toxicities and the occurrence of a terminal event (death, relapse) in pediatric АLL. METHODS:The study included 124 patients diagnosed with pediatric ALL. All patients treated according to the protocols of the German BFM group (2002/2009) with high-dose (1,000, 2,000 and 5,000 mg/m2) methotrexate. MTX-related toxicities, including hematologic, hepatic and renal, were evaluated according to the common terminology criteria for adverse events version 5.0 (CTCAE v.5.0). Real-time PCR method was used to investigate polymorphisms of ABCB1 and SLCO1B1 genes. The study material was peripheral blood. RESULTS:A competitive analysis demonstrated significant relationships between MTX ADRs. The results of the study support the existence of relationships between some ADRs and MTX kinetics. An associative analysis showed association with the development of AEs to methotrexate indicating their clinical significance from different genetic polymorphisms protein-transporters. The available results confirm the associations of the studied genes with the increased risk of high doses MTX toxic ADRs and terminal events. CONCLUSIONS:Complementing the existing criteria for pediatric ALL risk groups with pharmacogenetic indicators will allow further individualization of therapy.

Background: Coenzyme Q10 is a key component of the mitochondrial respiratory chain and a fat-soluble endogenous antioxidant performing many vital functions in the human body. Many researchers studied the plasma concentrations of ubiquinol, ubiquinone, total CoQ10 and the redox state (ubiquinol/ubiquinone ratio) of CoQ10 in healthy volunteers. However, these parameters in the plasma of patients with chronic heart failure (CHF) remain almost uninvestigated. Objective: The aim of this case-control study was to investigate the effect of atorvastatin, amlodipine and ethoxidol on endogenous plasma concentrations of ubiquinol, ubiquinone, total CoQ10 and its redox state in patients with CHF. Methods: The study included 62 patients with CHF divided into four groups depending on the prescribed therapy. For the quantitative determination of ubiquinol, ubiquinone, and total CoQ10 in the plasma of patients, HPLCMS/ MS was used. Results: It was established that the endogenous plasma concentration of total CoQ10 in patients with CHF is significantly lower than in healthy volunteers, and the ratio of reduced and oxidized forms of CoQ10 is shifted towards ubiquinone. It was a statistically significant effect of drugs with different physicochemical structures and pharmacological action on the plasma concentrations of ubiquinol, ubiquinone and total CoQ10: atorvastatin administration led to a decrease in the concentration of ubiquinol (-33.3Δ%), and total CoQ10 (-15Δ%), administration of amlodipine contributed to an increase in the levels of ubiquinol (+27.7Δ%) and total CoQ10 (+18.2Δ%), and the administration of ethoxidol caused an increase in the concentration of ubiquinol (+25Δ%), ubiquinone (+17.7Δ%) and total CoQ10 (+20.2Δ%). Conclusion: Amlodipine is able to neutralize the negative effect of atorvastin on the redox balance of CoQ10 in patients with CHF. An additional prescription of the antioxidant ethoxidol to standard therapy for patients with CHF was substantiated. Determination of the redox state of CoQ10 in plasma can be used to diagnose and assess the degree of oxidative stress in patients with cardiovascular diseases, as well as to assess the efficacy and safety of ongoing pharmacotherapy.

Objectives The present study investigated the analysis of adverse drug reactions (ADRs) to tamoxifen (TAM) in breast cancer patients in relation to the carriage of genetic polymorphisms of genes encoding enzymes of CYP system and transporters of P-glycoprotein (Pg) and predictive models based on it. Methods A total of 120 women with breast cancer taking adjuvant TAM were examined for the gene polymorphisms such as CYP2D6*4 , CYP3A5*3 , CYP2C9*2 , CYP2C9*3 , CYP2C19*2 , CYP2C19*3 and ABCB1 ( C3435T ). Allelic variants were determined using the real-time polymerase chain reaction method. The research material was double sampling of buccal epithelium. Medical history data and extracts from case histories were used as sources of medical information, on the basis of which questionnaires specially created by us were filled out. Results An associative analysis showed association with the development of ADRs to TAM indicating their clinical significance from different genetic polymorphisms of CYP2D6 , CYP3A5 , CYP2C9 and ABCB1 . The complex associative analysis performed using mathematical modeling made it possible to build predictive risk models for the development of ADRs such as hot flashes, dyspepsia, bone pain, and asthenia. Conclusions Models that include both genetic and non-genetic determinants of ADRs of TAM may further improve the prediction of individual response to TAM.

Abstract Objectives The present study investigated the stability of furosemide under space-flight conditions on board the International Space Station, as well as its pharmacokinetics and pharmacodynamics under conditions simulating exposure to some space-flight factors. Methods Quantitative analysis of furosemide tablets by HPLC was performed before spaceflight (background), then after six months storage under normal ground conditions (control) and under spaceflight conditions (SF). The pharmacokinetics and pharmacodynamics of furosemide were studied in six healthy volunteers after a single oral dose of 40 mg under normal conditions (background) and under anti-orthostatic hypokinesia (ANOH). Results Quantitative content of furosemide in tablets before SF was 40.19 ± 0.28 mg (100.47 ± 0.71%), after 6 months storage: under normal conditions (control) – 39.9 ± 0.39 mg (99.73 ± 0.98%), under SF – 39.24 ± 0.72 mg (98.11 ± 1.80%), which was within the prescribed limits. Studying basic hemodynamic parameters showed that in ANOH conditions 6 h after furosemide administration there was a statistically significant increase of the stroke volume (SV) (+36.5 Δ%), a tendency for increasing of the stroke index (SI) (+36.5 Δ%) and decreasing of the total peripheral resistance (TPR) (−21.9 Δ%) compared to baseline study. Conclusions It has been established that various factors of space flight (overloading, excessive vibration, microgravity, etc.) do not negatively influence the stability of furosemide in tablet form during storage for 6 months on board the International Space Station.

BACKGROUND:Despite CoQ10 being a powerful antioxidant and its redox state that may characterize the body's antioxidant system, the latter remains unstudied in patients with cardiovascular diseases. OBJECTIVE:This prospective case-control study aimed to investigate the concentrations of ubiquinol, ubiquinone, total CoQ10 and its redox state in patients with ischemic heart disease (IHD) and arterial hypertension (AH) during standard therapy and with the additional prescription of CoQ10. METHODS:The study included 54 healthy individuals and 26 patients, who were divided into a control group receiving standard therapy and a test group receiving CoQ10 in addition to standard therapy. Quantitative determination of COQ10, ubiquinone and ubiquinol was carried out by HPLC-MS/MS. RESULTS:It was found that the CoQ10 level in patients was significantly lower than in healthy individuals (on average -32Δ%). In the test group, after treatment, the concentrations of ubiquinol (+53 Δ%), ubiquinone (-28 Δ%), total CoQ10 (+27 Δ%) and redox state (+112 Δ%) were significantly different from the baseline, while in the control group no significant differences were noticed. In the test group after treatment, the levels of total CoQ10 (+25 Δ%), ubiquinol (+43 Δ%), and redox state (+86 Δ%) were statistically significantly higher than in the control group and total CoQ10 concentration did not significantly differ from that in healthy individuals (-12 Δ%). CONCLUSION:The additional prescription of CoQ10 for patients with IHD significantly increases the level of total CoQ10, which leads to the increase of body antioxidant potential.

Abstract Objectives To study the pharmacokinetics and relative bioavailability of drugs of different chemical structure and pharmacological action under conditions simulating the effects of some factors of spaceflight, as well as the peculiarities of the pharmacokinetics of acetaminophen under long-term spaceflight conditions. Methods The pharmacokinetics of verapamil (n=8), propranolol (n=8), etacizine (n=9), furosemide (n=6), and acetaminophen (n=7) in healthy volunteers after a single oral administration under normal conditions (background) and under antiorthostatic hypokinesia (ANOH), the pharmacokinetics of acetaminophen in spaceflight members under normal ground conditions (background) (n=8) and under prolonged spaceflight conditions (SF) (n=5) were studied. Results The stay of volunteers under antiorthostatic hypokinesia had different effects on the pharmacokinetics and bioavailability of drugs: Compared to background, there was a decreasing trend in Vz for verapamil (−54 Δ%), furosemide (−20 Δ%), propranolol (−8 Δ%), and acetaminophen (−9 Δ%), but a statistically significant increase in Vz was found for etacizine (+39 Δ%); there was an increasing trend in Clt for propranolol (+13 Δ%) and acetaminophen (+16 Δ%), and a decreasing trend in Clt for etacizine, verapamil, and furosemide (−22, −23 and −9 Δ% respectively) in ANOH. The relative bioavailability of etacizine, verapamil, and furosemide in ANOH increased compared to background (+40, +23 and +13 Δ%, respectively), propranolol and acetaminophen decreased (−5 and −12 Δ% accordingly). The relative rate of absorption of etacizine and furosemide in ANOH decreased (−19 and −20 Δ%, respectively) while that of verapamil, propranolol, and acetaminophen increased (+42, +58 and +26 Δ%, respectively). A statistically significant decrease in AUC0-∞ (−57 Δ%), Cmax (−53 Δ%), relative bioavailability of acetaminophen (−52 Δ%) and a sharp increase in Clt (+147 Δ%), Tmax (+131 Δ%) as well as a trend towards a significant decrease in T1/2 (−53 Δ%), MRT (−36 Δ%) and a moderate increase in Vz (+24 Δ%) were found under control compared to background. Unidirectional changes in AUC0-∞, Clt, T1/2, MRT and relative bioavailability of acetaminophen, which are more pronounced in SF and opposite dynamics for Cmax, Tmax, Vz were found in ANOH and SP compared to background studies. Conclusions The data obtained allow recommending the studied drugs for rational pharmacotherapy in the possible development of cardiovascular disease in manned spaceflight.

We studied pharmacokinetics and bioavailability of verapamil, propranolol, and ethacizine in healthy volunteers after single oral administration under normal conditions and on the second day of simulated antiorthostatic hypokinesia modeling some effects of microgravity. Under conditions of antiorthostatic hypokinesia, a tendency to a decrease in half-elimination period, mean retention time, and volume of distribution and an increase in the rate of absorption, ratio of maximum concentrations, and relative rate of absorption of verapamil and propranolol were revealed. For ethacizine, a statistically significant increase in the time of attaining maximum concentration and volume of distribution and a decrease in the maximum concentration, rate of absorption, ratio of maximum concentrations, and relative rate of absorption under conditions of antiorthostatic hypokinesia were found.

Abstract Objectives Coenzyme Q10 (CoQ10) has many vital functions in human body and its endogenous level can be affected either by various diseases or by administrated drugs. This study reveals the effect of atorvastatin, amlodipine and ethoxidol on the endogenous CoQ10 plasma concentration. Methods It was determined the total plasma concentration of endogenous CoQ10 in the plasma of 54 healthy individuals and 62 patients with cardiovascular diseases during treatment with various drugs using high performance liquid chromatography with mass spectrometric detection (HPLC-MS/MS). Results It was found that CoQ10 plasma concentration in patients is statistically significantly lower (on average −49.0 Δ%) than in practically healthy individuals. The total CoQ10 plasma level in patients receiving atorvastatin in the complex therapy is statistically significantly lower (−15.2 Δ%), and in patients taking amlodipine or ethoxidol is statistically significantly higher (+18.2 and +20.2 Δ%, respectively) than in patients of control groups (a group of patients who receive the same drugs, except for the studied one). Conclusions The study showed that in patients with CVDs treated with various drugs the CoQ10 plasma level is statistically significantly lower than in practically healthy individuals. So, to avoid the adverse reactions connected with low CoQ10 plasma levels, it is recommended to adjust the therapy to maintain its constant level.

The purpose of this work was to study the pharmacokinetics of the Ca ion antagonist verapamil (a single dose of 80 mg) and hemodynamics in nine volunteers with normal life activities (experiment 1) and on the second day of head-down (–8°) bed rest (experiment 2). The plasma concentration of verapamil was measured using high-performance liquid chromatography with fluorometric detection. Heart rate (HR), cardiac output (CO), stroke volume (SV) and general peripheral vascular resistance (GPVR) were measured using integral rheography according to Tishchenko (Mingograf-410, Russia); blood pressure (BP) was measured by Korotkoff sounds. Analysis of verapamil pharmacokinetics in both experiments showed identity of the averaged curve profiles that did not differ significantly. The pharmacokinetic parameters were comparable. Based on hemodynamics analysis, HR elevation 1 h after verapamil administration was the most common reaction in both experiments; a short CO rise and GPVR decrease were observed in experiment 2 1 h after administration. These hemodynamic shifts were not pathologic and did not deviate from the physiological range in healthy people; changes in verapamil pharmacokinetics were also not detected. These findings provide the grounds to recommend verapamil for rational pharmacotherapy of cardiovascular diseases that may develop in piloted space missions.

The pharmacokinetics of two fluoxetine capsulated dosage forms and two amitriptyline tablet forms after a single oral intake was studied in dogs and healthy volunteers. High significant correlations were detected between plasma concentrations of fluoxetine (r=0.96, p<0.00001, n=11) and amitriptyline (r=0.78, p<0.0224, n=8) in dogs and volunteers. A correlation of medium strength (though insignificant) was detected between nortriptyline concentrations in the plasma of dogs and volunteers (r=0.69, p<0.199, n=5). The bioavailability parameters of the test drugs in dogs and volunteers did not differ. Similar trends of fluoxetine and amitriptyline pharmacokinetic parameters were revealed in volunteers and animals. Methods for extrapolation of experimental pharmacokinetics parameters of fluoxetine and amitriptyline obtained on dogs for humans are proposed and validated.

The pharmacokinetics of propranolol were studied in healthy volunteers after a single peroral administration at a dose of 80 mg under normal conditions, on the second day of antiorthostatic hypokinesia, and on the first day after termination of the hypokinesia. The maximum propranolol concentration (–6 ∆%), area under the pharmacokinetic curve (–13 ∆%), elimination half-life (–15 ∆%), mean residence time in the body (–17 ∆%), and distribution volume (–8 ∆%) tended to decrease with antiorthostatic hypokinesia whereas the total clearance (+13 ∆%), ratio of maximum concentrations (125 ± 23%), and relative absorption rate of the drug (158 ± 48%) increased.

Purpose of the work was to study pharmacokinetics of beta adrenoblocker propranolol, and hemodynamic indices in volunteers for simulation of some effects of microgravity The study involved 8 essentially healthy subjects and the head-down tilt (-80) bedrest model reproducing the effects of microgravity (BD). This was designed as three series of investigations, i.e. before BD, on BD day-2 and on the first day of BD completion. Propranolol concentration in blood plasma was determined using high performance liquid chromatography with fluorescence detection. Hemodynamic indices including heart rate (HR), stroke volume, cardiac output, cardiac index and total peripheric resistance were measured using integral rheography; average blood pressure (BPav) Was assessed by Korotkovs method. Statistical deviations in propranolol pharmacokinetics were found in none of the three series. The most characteristic reactions to propranolol were BPav reductions in all series and HR decreases 2 hours after intake in the first and second series. These deviations were not pathologic but physiological variations typical of healthy people. Therefore, propranolol can be advised for rational pharmacotherapy of acute cardiovascular diseases in piloted space missions.

It was shown that multiple spaceflight factors (i.e., acceleration, overvibration, microgravity etc.) do not impact stability of acetaminophen and furosemide tablets stored onboard the International space station over 6 months. Acetaminophen dose in a tablet was 496.44 ± 6.88 mg (99.29 ± 1.38%) before spaceflight (SF) and 481.77 ± 1 2.40 mg (96.35 ± 0.48%) after 6 mos. of storage; furosemide dose in a tablet was 40.19 ± 0.28 mg (100.47 ± 0.71%) before and 39.24 ± 0.72 mg (98.105 ± 1.80%) after SF remaining within the established limits.

A simple, specific, sensitive and reproducible good method for quantitative determination of Levofloxacin in plasma using HPLC with UV-spectrophotometric detection. With this technique the pharmacokinetics and relative bioavailability of domestic generic of levofloxacin in 18 healthy volunteers after a single oral dose of 500 mg. Found that the drug being tested, levofloxacin (OOO «Ozone», Russia) is bioequivalent to the reference drugs Tavanic® («Sanofi Winthrop Industry», France).

A rapid, simple, specific, sensitive, and reproducible method for qualitative determination of fenotropil and piracetam in the drug substances, dosage forms, and blood plasma that used an original modification of a mercury-free polarograph with differential voltammetric recording and oscillographic monitoring of the electrochemical process was developed. This method could be used for analysis of drugs (original and generic) in order to identify and detect counterfeit drugs in various dosage forms and for analysis in human biological fluids, e.g., for monitoring doping.

A simple, specific, sensitive and reproducible good method for quantitative determination of Levofloxacin in plasma using HPLC with UV-spectrophotometric detection. With this technique the pharmacokinetics and relative bioavailability of domestic generic of levofloxacin in 18 healthy volunteers after a single oral dose of 500 mg. Found that the drug being tested, levofloxacin (OOO «Ozone», Russia) is bioequivalent to the reference drugs Tavanic® («Sanofi Winthrop Industry», France).

A simple, specific, sensitive and reproducible assay has been developed for the qualitative determination of piracetam and fenotropil in parent substances, dosage forms, and blood plasma using a modification of the original mercury-free polarograph with a differential voltammetric method of registration and oscillographic variant of monitoring of the electrochemical process. This method can be used for the analysis of drugs (original and generic), identification of falsified drugs in various dosage forms, and monitoring drug content in human biological fluids, for example, in the course of doping control.

The pharmacokinetics of two tablet formulations of amiodarone – Amiodarone and Amiodaron-Akri – were studied in 12 rabbits and 18 healthy human volunteers after single p.o. doses of 200 mg. A highly statistically significant correlation was found between plasma amiodarone concentrations in rabbits and volunteers (r = 0.8263, p < 0.001). Normalized C max and AUC 0−∞ values were significantly greater in volunteers than rabbits, while specific V Z and Cl t values were lower and MRT was significantly higher; rate coefficients of absorption and measures of relative bioavailability showed no statistically significant differences between rabbits and healthy humans.