Влияние полиморфизма CYP2D6*4 на профиль эффективности и безопасности миртазапина у пациентов с депрессивным расстройством, коморбидным с алкогольной зависимостью

Background: Alcohol dependence is often combined with affective disorders, in particular, depressive disorder, which adversely affects the prognosis of the course of both diseases. For the treatment of a depressive disorder, drugs from the group of tetracyclic antidepressants, of which mirtazapine is a representative, are used. Therapy with mirtazapine is associated with the risk of undesirable drug reactions and pharmacoresistance. Aim: To study the effect of CYPD6 isoenzyme activity on the efficacy and safety of mirtazapine therapy in patients with depressive disorders comorbid with alcoholism. Methods: The study was conducted on 109 Russian patients with a depressive disorder, comorbid with alcohol dependence. For the correction of depressive disorders within the framework of cyclothymia, mirtazapine was prescribed to patients at a dosage of 1545 mg/day. CYP2D6*4 genotyping (1846G A, rs3892097) was carried out using Real-time polymerase chain reaction with allele-specific hybridization. Efficacy and safety were assessed using validated psychometric scales and an assessment of the severity of adverse drug reactions. Results: By the 9th day of the study, the severity of depressive symptoms on the HAMD scale was significantly different in patients with different genotypes: (GG) 7.0 [6.0; 8.0], (GA) 4.0 [3.8; 5.0] (p0.001), safety indicator, estimated on a UKU scale: (GG) 3.0 [3.0; 3.0], (GA) 4.0 [4.0; 5.0] (p0.001). The presence of differences persisted on the 16th day: (GG) 5.0 [3.0; 6.0], (GA) 1.5 [0.8; 3.2] (p0.001), safety indicator, estimated on a UKU scale: (GG) 6.0 [6.0; 7.0], (GA) 8.5 [8.0; 10.0] (p0.001). Conclusion: In this study, the effect of CYP2D6 gene polymorphism on the efficacy and safety of therapy with mirtazapine was demonstrated. Carrying a minor allele A is associated with an increased risk of adverse drug reactions, but improving performance profile performance.Обоснование. Аффективные расстройства, в частности депрессивные расстройства, часто коморбидно сочетаются с алкогольной зависимостью, что негативно сказывается на прогнозе течения обоих заболеваний. Для лечения депрессивного расстройства используют лекарственные средства из группы тетрациклических антидепрессантов, представителем которого является миртазапин. Терапия миртазапином сопряжена с риском развития нежелательных лекарственных реакций и фармакорезистентности. Цель исследования ― оценить влияние полиморфного маркера CYPD6*4 на профиль эффективности и безопасности терапии миртазапином у пациентов с депрессивным расстройством, коморбидным с алкоголизмом. Методы. Исследование проведено на 109 русских пациентах с депрессивным расстройством, коморбидным с алкогольной зависимостью. Пациентам с целью коррекции депрессивных расстройств в рамках циклотимии был назначен миртазапин в дозировке 1545 мг/сут. Генотипирование CYP2D6*4 (1846GA, rs3892097) осуществлялось методом полимеразной цепной реакции в режиме реального времени с аллельспецифической гибридизацией. Эффективность и безопасность оценивали с помощью валидизированных психометрических шкал и шкалы оценки выраженности нежелательных лекарственных реакций. Результаты. К 9-му дню исследования выраженность депрессивной симптоматики по шкале HAMD статистически значимо отличалась у пациентов с разными генотипами: (GG) 7,0 [6,0; 8,0], (GA) 4,0 [3,8; 5,0] (p0,001), показатель безопасности, оцененный по шкале UKU: (GG) 3,0 [3,0; 3,0], (GA) 4,0 [4,0; 5,0] (p0,001). Наличие различий сохранялось и на 16-й день: (GG) 5,0 [3,0; 6,0], (GA) 1,5 [0,8; 3,2] (p0,001), показатель безопасности, оцененный по шкале UKU: (GG) 6,0 [6,0; 7,0], (GA) 8,5 [8,0; 10,0] (p0,001). Заключение. По результатам исследования было продемонстрировано влияние полиморфного маркера CYP2D6*4 на профиль эффективности и безопасности терапии миртазапином. Носительство минорного аллеля A сопряжено с повышенным риском развития нежелательных лекарственных реакций, но улучшением показателей профиля эффективности

Влияние активности CYP2D6 на эффективность и безопасность флувоксамина у пациентов с депрессивными расстройствами, коморбидными с алкогольной зависимостью

Background: Alcohol dependence is often combined with affective disorders, in particular, depressive disorder (DD), which worsens adversely affects the prognosis of the course of both diseases and their outcomes. For the treatment of DD, drugs from the group of selective serotonin reuptake inhibitors, whose representative is fluvoxamine, are used. Fluvoxamine therapy is often associated with a risk of development is shown to be ineffective, and a part of patients develop dose-dependent adverse drug reactions (ADR) and pharmacoresistance.Objective: To study the effects of CYPD6 isoenzyme activity on the efficacy and safety of fluvoxamine therapy in patients with depressive disorders, comorbid with alcoholism.Methods: The study was conducted on 117 Russian patients with DD, alcohol-dependent comorbid. For the purpose of correction of depressive disorders within the framework of cyclothymia, fluvoxamine (Fevarin) was administered to patients at a dosage of 50−150 mg/day. Genotyping was carried out by the method of polymerase chain reaction in Real-time mode with allele-specific hybridization. Efficacy and safety were assessed using validated psychometric scales and an assessment of the severity of ADR. To evaluate the activity of CYP2D6, the method of high performance liquid chromatography with mass spectrometry was used to measure the urinary content of the endogenous substrate of this isoenzyme and its metabolite, the ratio of 6-hydroxy-1,2,3,4-tetrahydro-beta-carboline.Results: By the 9th day of the study, the severity of depressive symptoms on the HAMD scale was statistically significantly different in patients with different genotypes: (GG) 7.0 [6.0; 8.0], (GA) 4.0 [3.0; 5.0] (p0.001); safety indicator, estimated on a UKU scale: 3.0 [2.0; 4.0], (GA) 4.0 [4.0; 4.2] (p0.001). The presence of differences persisted on the 16th day: (GG) 5.0 [3.0; 6.0], (GA) 1.5 [1.0; 3.0] (p0.001); safety indicator, estimated on a UKU scale: (GG) 9.0 [9.0; 10.0], (GA) 6.0 [6.0; 7.0] (p0.001). The calculation of the correlation coefficients between the difference in the number of scores on psychometric scales and the metabolic ratio showed a statistically significant inverse correlation of the average power degree between the efficiency index estimated by the HAMD scale (r=-0.467, p0.05). There was no connection with the difference on the UKU scale (r=0.173, p0.05).Conclusion: In a study of a group of 117 patients with DD, comorbid with alcohol dependence, the effect of CYP2D6 activity, estimated by the ratio of the endogenous substrate concentrations of pinolin and its metabolite 6-hydroxy-1,2,3,4-tetrahydro-beta-carboline, on the efficacy of fluvoxamine therapy. This effect was also shown using the results of genotyping. The results of genotyping also showed the existence of a difference in the safety index in patients with different genotypes from the polymorphic marker CYP2D6 1846GA.Обоснование. Алкогольная зависимость часто сочетается с аффективными расстройствами, в частности депрессивным расстройством, что отрицательно сказывается на прогнозе течения обоих заболеваний. Для лечения депрессивного расстройства используют лекарственные средства из группы селективных ингибиторов обратного захвата серотонина, представителем которого является флувоксамин. Терапия флувоксамином сопряжена с риском развития нежелательных лекарственных реакций и фармакорезистентности. В более ранних исследованиях было показано возможное влияние полиморфизма гена CYP2D6, кодирующего одноименный изофермент, на частоту и выраженность нежелательных реакций флувоксамина.Цель исследования ― изучить влияние активности изофермента CYPD6 на эффективность и безопасность терапии флувоксамином у пациентов с депрессивными расстройствами, коморбидными с алкоголизмом.Методы. Исследование проведено на 117 русских пациентах с депрессивными расстройствами, коморбидными с алкогольной зависимостью. Пациентам с целью коррекции депрессивных расстройств в рамках циклотимии был назначен флувоксамин в дозировке 50−150 мг/сут. Генотипирование CYP2D6*4 (1846GA, rs3892097) осуществлялось методом полимеразной цепной реакции в режиме реального времени с аллельспецифической гибридизацией. Эффективность и безопасность оценивали с помощью валидизированных психометрических шкал и шкалы оценки выраженности нежелательных лекарственных реакций. Для оценки активности CYP2D6 использовали метод высокоэффективной жидкостной хроматографии с масс-спектрометрией по содержанию в моче эндогенного субстрата данного изофермента и его метаболита — отношение 6-гидрокси-1,2,3,4-тетрагидро-бета-карболина.Результаты. К 9-му дню исследования выраженность депрессивной симптоматики по шкале HAMD статистически значимо отличалась у пациентов с разными генотипами: (GG) 7,0 [6,0; 8,0], (GA) 4,0 [3,0; 5,0] (p0,001); показатель безопасности, оцененный по шкале UKU: 3,0 [2,0; 4,0], (GA) 4,0 [4,0; 4,2] (p0,001). Наличие различий сохранялось и на 16-й день: (GG) 5,0 [3,0; 6,0], (GA) 1,5 [1,0; 3,0] (p0,001); показатель безопасности, оцененный по шкале UKU: (GG) 9,0 [9,0; 10,0], (GA) 6,0 [6,0; 7,0] (p0,001). Расчет показателей коэффициентов корреляции между разницей в количестве баллов по психометрическим шкалам и метаболическим отношением показал наличие статистически значимой обратной корреляции средней степени силы между показателем эффективности, оцененной с помощью шкалы HAMD (r=-0,467, p0,05). Связь с разницей по шкале UKU отсутствовала (r=0,173, p0,05).Заключение. В данном исследовании было продемонстрировано влияние активности CYP2D6, оцененной по отношению концентраций эндогенного субстрата пинолина и его метаболита 6-гидрокси-1,2,3,4-тетрагидро-бета-карболина, на показатель эффективности терапии флувоксамином. Повышение активности CYP2D6 снижает эффективность терапии флувоксамином. Влияние активности CYP2D6 на безопасность подтверждено не было. Тем не менее обнаружено влияние полиморфизма гена CYP2D6 на профиль безопасности

Lattice Study of the Equation of State of a Rotating Gluon Plasma

International audienceThe effect of uniform rotation on the equation of state of gluodynamics has been studied in lattice simulation. To this end, the system has been considered in the corotating reference frame, where the rotation can be modeled as an external gravitational field. The free energy of the studied system in the case of sufficiently slow rotation can be expanded in a power series in the angular velocity. The moment of inertia given by the second-order coefficient of this expansion has been calculated and its dependence on the temperature and the dimensions of the rotating system has been determined. Our results indicate that the moment of inertia of gluodynamics is negative up to the temperature T * ~ 1.5T$_{c}$, where T$_{c}$ is the critical temperature of the confinement/deconfinement phase transition, and becomes positive at temperatures T > T *. The negative moment of inertia has been attributed to the thermodynamic instability of the gluon plasma with respect to uniform rotation

Comparison of Quantitative Analytical Techniques for Dabigatran in Blood Plasma of Humans with Knee Replacements

Two different literature methods were used to compare the experimental efficacy and accuracy of dabigatran assays in blood of 30 patients with knee replacements. Blood plasma was collected from patients who underwent anticoagulant therapy and were administered the medicine at a dose of 220 mg. Residual and peak dabigatran concentrations were determined by HPLC-MS and HPLC-MS/MS. © 2019, Springer Science+Business Media, LLC, part of Springer Nature

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

Background: Today, it is proved that isoenzymes CYP2D6 and CYP3A4 are involved in metabolism of haloperidol. In our previous investigation, we found a medium correlation between the efficacy and safety of haloperidol and the activity of CYP3A4 in patients with alcohol abuse. Objective: The aim of this study was to evaluate the correlation between the activity of CYP2D6 and the efficacy and safety of haloperidol in patients with diagnosed alcohol abuse. Methods: The study involved 70 men (average age: 40.83±9.92 years) with alcohol addiction. A series of psychometric scales were used in the research. The activity of CYP2D6 was evaluated by high-performance liquid chromatography with mass spectrometry using the ratio of 6-hydroxy-1,2,3,4-tetrahydro-beta-carboline to pinoline. Genotyping of CYP2D6 (1846G>A) was performed using real-time polymerase chain reaction. Results: According to results of correlation analysis, statistically significant values of Spearman correlation coefficient (rs) between the activity of CYP2D6 and the difference of points in psychometric scale were obtained in patients receiving haloperidol in injection form (Sheehan Clinical Anxiety Rating Scale =−0.721 [P<0.001] and Udvald for Kliniske Undersogelser Side Effect Rating Scale =0.692 [P<0.001]) and in those receiving haloperidol in tablet form (Covi Anxiety Scale =−0.851 [P<0.001] and Udvald for Kliniske Undersogelser Side Effect Rating Scale =0.797 [P<0.001]). Conclusion: This study demonstrated the correlations between the activity of CYP2D6 isozyme and the efficacy and safety of haloperidol in patients with alcohol addiction. © 2016 Sychev et al

Adverse drug reactions of macrolide therapy: analysis of spontaneous reports according to the Pharmacovigilance system

Objective. To perform pharmacoepidemiological analysis of spontaneous reports of adverse drug reactions (ADRs) occurred during macrolide group antibiotics prescription and registered in the “Pharmacovigilance 2.0” subsystem of the Federal Service for Surveillance in Healthcare. Materials and Methods. A retrospective pharmacoepidemiological analysis of spontaneous reports of ADRs arising from the use of all macrolide and azalide antibiotics registered in Russia and registered in the electronic database of the “Pharmacovigilance 2.0” subsystem of the Federal Service for Surveillance in Healthcare for the period from 01.04.2019 to 30.11.2022 was performed. Results. Analysis of the number of spontaneous reports of ADRs, their structure, outcomes and severity criteria was performed. The most clinically significant ADRs were identified, the occurrence of which was reported to pharmacovigilance bodies. The results of a retrospective pharmacoepidemiological analysis showed that the development of complications of pharmacotherapy in most cases was associated with the use of azithromycin and clarithromycin. The main clinical manifestations of adverse drug reactions were skin and subcutaneous tissue disorders, gastrointestinal disorders, as well as general disorders and injection site reactions. Conclusions. It was found that the reported events generally corresponded to the general spectrum of ADRs typical for individual representatives of macrolide and azalide antibiotics

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

Background: Today, it is proved that isoenzymes CYP2D6 and CYP3A4 are involved in metabolism of haloperidol. In our previous investigation, we found a medium correlation between the efficacy and safety of haloperidol and the activity of CYP3A4 in patients with alcohol abuse. Objective: The aim of this study was to evaluate the correlation between the activity of CYP2D6 and the efficacy and safety of haloperidol in patients with diagnosed alcohol abuse. Methods: The study involved 70 men (average age: 40.83±9.92 years) with alcohol addiction. A series of psychometric scales were used in the research. The activity of CYP2D6 was evaluated by high-performance liquid chromatography with mass spectrometry using the ratio of 6-hydroxy-1,2,3,4-tetrahydro-beta-carboline to pinoline. Genotyping of CYP2D6 (1846G>A) was performed using real-time polymerase chain reaction. Results: According to results of correlation analysis, statistically significant values of Spearman correlation coefficient (rs) between the activity of CYP2D6 and the difference of points in psychometric scale were obtained in patients receiving haloperidol in injection form (Sheehan Clinical Anxiety Rating Scale =−0.721 [P<0.001] and Udvald for Kliniske Undersogelser Side Effect Rating Scale =0.692 [P<0.001]) and in those receiving haloperidol in tablet form (Covi Anxiety Scale =−0.851 [P<0.001] and Udvald for Kliniske Undersogelser Side Effect Rating Scale =0.797 [P<0.001]). Conclusion: This study demonstrated the correlations between the activity of CYP2D6 isozyme and the efficacy and safety of haloperidol in patients with alcohol addiction. © 2016 Sychev et al

Luminescence of ZnS:Cu particles modified by shungite nanocarbon

This paper presents a study of the luminescence properties of the commercial phosphor ZnS:Cu modified with nanoparticles of shungite carbon. It shows that even a small amount of the modifying additive causes substantial surface darkening of the phosphor and reduces the reflectance at a wavelength of 490 nm. A number of competing processes are observed: a reduction of the luminance of the electroluminescence because part of the emitted light is absorbed, and an increase of the luminance, probably because the electric field is concentrated on the phosphor particles. Besides altering the luminance, such modification alters the electroluminescence spectra. Modification by shungite-carbon nanoparticles is thus promising from the viewpoint of directed adjustment of the characteristics of commercial phosphors, and optimizing the modification conditions makes it possible to obtain luminescence whose luminance exceeds that in unmodified samples. © 2017 Optical Society of America