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

Multiwavelength variability of BL Lacertae measured with high time resolution

In an effort to locate the sites of emission at different frequencies and physical processes causing variability in blazar jets, we have obtained high time-resolution observations of BL Lacertae over a wide wavelength range: with the Transiting Exoplanet Survey Satellite (TESS) at 6000–10000 Å with 2 minute cadence; with the Neil Gehrels Swift satellite at optical, UV, and X-ray bands; with the Nuclear Spectroscopic Telescope Array at hard X-ray bands; with the Fermi Large Area Telescope at γ-ray energies; and with the Whole Earth Blazar Telescope for measurement of the optical flux density and polarization. All light curves are correlated, with similar structure on timescales from hours to days. The shortest timescale of variability at optical frequencies observed with TESS is ~0.5 hr. The most common timescale is 13 ± 1 hr, comparable with the minimum timescale of X-ray variability, 14.5 hr. The multiwavelength variability properties cannot be explained by a change solely in the Doppler factor of the emitting plasma. The polarization behavior implies that there are both ordered and turbulent components to the magnetic field in the jet. Correlation analysis indicates that the X-ray variations lag behind the γ-ray and optical light curves by up to ~0.4 day. The timescales of variability, cross-frequency lags, and polarization properties can be explained by turbulent plasma that is energized by a shock in the jet and subsequently loses energy to synchrotron and inverse Compton radiation in a magnetic field of strength ~3 G.Accepted manuscrip

The complex variability of blazars: time-scales and periodicity analysis in S4 0954+65

Among active galactic nuclei, blazars show extreme variability properties. We here investigate the case of the BL Lac object S4 0954+65 with data acquired in 2019–2020 by the Transiting Exoplanet Survey Satellite (TESS) and by the Whole Earth Blazar Telescope (WEBT) Collaboration. The 2-min cadence optical light curves provided by TESS during three observing sectors of nearly 1 month each allow us to study the fast variability in great detail. We identify several characteristic short-term time-scales, ranging from a few hours to a few days. However, these are not persistent, as they differ in the various TESS sectors. The long-term photometric and polarimetric optical and radio monitoring undertaken by the WEBT brings significant additional information, revealing that (i) in the optical, long-term flux changes are almost achromatic, while the short-term ones are strongly chromatic; (ii) the radio flux variations at 37 GHz follow those in the optical with a delay of about 3 weeks; (iii) the range of variation of the polarization degree and angle is much larger in the optical than in the radio band, but the mean polarization angles are similar; (iv) the optical long-term variability is characterized by a quasi-periodicity of about 1 month. We explain the source behaviour in terms of a rotating inhomogeneous helical jet, whose pitch angle can change in time.Accepted manuscrip

Multiwavelength behaviour of the blazar 3C 279: decade-long study from γ-ray to radio

We report the results of decade-long (2008–2018) γ-ray to 1 GHz radio monitoring of the blazar 3C 279, including GASP/WEBT, Fermi and Swift data, as well as polarimetric and spectroscopic data. The X-ray and γ-ray light curves correlate well, with no delay ≳ 3 h, implying general cospatiality of the emission regions. The γ-ray–optical flux–flux relation changes with activity state, ranging from a linear to a more complex dependence. The behaviour of the Stokes parameters at optical and radio wavelengths, including 43 GHz Very Long Baseline Array images, supports either a predominantly helical magnetic field or motion of the radiating plasma along a spiral path. Apparent speeds of emission knots range from 10 to 37c, with the highest values requiring bulk Lorentz factors close to those needed to explain γ-ray variability on very short time-scales. The Mg ii emission line flux in the ‘blue’ and ‘red’ wings correlates with the optical synchrotron continuum flux density, possibly providing a variable source of seed photons for inverse Compton scattering. In the radio bands, we find progressive delays of the most prominent light-curve maxima with decreasing frequency, as expected from the frequency dependence of the τ = 1 surface of synchrotron self-absorption. The global maximum in the 86 GHz light curve becomes less prominent at lower frequencies, while a local maximum, appearing in 2014, strengthens toward decreasing frequencies, becoming pronounced at ∼5 GHz. These tendencies suggest different Doppler boosting of stratified radio-emitting zones in the jet.First author draf

Broadband multi-wavelength properties of M87 during the 2017 Event Horizon Telescope campaign

High Energy AstrophysicsInstrumentatio

Broadband multi-wavelength properties of M87 during the 2017 Event Horizon Telescope campaign

In 2017, the Event Horizon Telescope (EHT) Collaboration succeeded in capturing the first direct image of the center of the M87 galaxy. The asymmetric ring morphology and size are consistent with theoretical expectations for a weakly accreting supermassive black hole of mass ∼6.5 × 109Me. The EHTC also partnered with several international facilities in space and on the ground, to arrange an extensive, quasi-simultaneous multi-wavelength campaign. This Letter presents the results and analysis of this campaign, as well as the multi-wavelength data as a legacy data repository. We captured M87 in a historically low state, and the core flux dominates over HST-1 at high energies, making it possible to combine core flux constraints with the more spatially precise very long baseline interferometry data. We present the most complete simultaneous multi-wavelength spectrum of the active nucleus to date, and discuss the complexity and caveats of combining data from different spatial scales into one broadband spectrum. We apply two heuristic, isotropic leptonic single-zone models to provide insight into the basic source properties, but conclude that a structured jet is necessary to explain M87’s spectrum. We can exclude that the simultaneous γ-ray emission is produced via inverse Compton emission in the same region producing the EHT mm-band emission, and further conclude that the γ-rays can only be produced in the inner jets (inward of HST-1) if there are strongly particle-dominated regions. Direct synchrotron emission from accelerated protons and secondaries cannot yet be excluded.http://iopscience.iop.org/2041-8205am2022Physic