ОПЫТ ПРИМЕНЕНИЯ мКРЛ У БОЛЬНЫХ С ЛЕКАРСТВЕННОЙ УСТОЙЧИВОЙ ТУБЕРКУЛЕЗА И ОЦЕНКА ЭФФЕКТИВНОСТИ, ТЩАТЕЛЬНОГО МОНИТОРИНГА И НЕЖЕЛАТЕЛЬНЫХ ЯВЛЕНИЙ

Objective. To study the frequency of adverse events when using new drugs in the treatment regimen for patients with MDR-TB and evaluate the effectiveness of new shorter regimens. Material and methods of research. New shortened regimens have been used for the treatment of patients with MDR- TB since September and February 2020 in two institutions (MJ and GS). 225 MDR cases were identified in the treatment regimens, Bdq, Lzd, Lfx, Cfz, Cs were prescribed to 106 patients. Gender balance: men 58 (67.4%), women 28 (32.56%).Almost 67 (79.76%) patients had a bilateral process with decay cavities, and 17 (20.24%) patients had a process without decay. The main side effect of bedaquiline is cardiotoxicity, which manifests itself in prolongation of the QT interval and an increase in QTcF (Fridericia coefficient) calculated using the Fridericia formula. The cardiotoxicity of bedaquiline persists after taking it for another 6 months, i.e. has a cumulative effect. In this connection, with the use of bedaquiline in treatment regimens, an electrocardiographic (ECG) study is initially performed. When monitoring treatment with bedaquiline in the first month, an ECG study is performed after 14 days, before the end of the course of treatment is carried out monthly, after the end of the course for 3 months. SAEs were identified in 3 patients. Hypokalemia, myelosuppression and hyperglycemia were noted accordingly in the 1 patient Peripheral neuropathy (moderate) was observed in 7 patients.Results. Culture conversion was observed in 63 patients (75%) who took Bdq, Lzd, Lfx, Cfz, Cs treatment regimens for 9 months. Time to culture conversion was ≤ mean (or median) in 10 (25%) cases, ≥ mean (or median) in 97 (75%) cases In the remaining 16 (18%) patients, the isolation of mycobacteria persisted, and additional detection of resistance to the main drugs provided a rationale for prolonging the course of treatment. In 5 patients dropped out, these patients were discharged for violations of the nosocomial regimen and took drugs only from 28 days to 2 months. There was no prolongation of the QT interval (0.48-0.51 s). All continued the course with bedaquiline. Peripheral neuropathy (moderate) occurred in 7 (8%) patients taking linezolid. All patients (with mild neuropathy) continued the course with linezolid. These patients were prescribed pyridoxine until the end of the regimen. Myelosuppression was observed in 59 patients. 10 of them had grade 1, 3 had grade 2, and only 1 had grade 3 myelosuppression. Nearly all of those treated with clofozemin had a dark brown skin tone. Treatment outcomes and course completion were 63(75%), failure 16(19%). Conclusion. The effectiveness of shortened treatment regimens for MDR/TB patients with the inclusion of new anti-TB drugs (Bdq, Lzd, Lfx, Cfz, Cs) in the treatment regimen turned out to be quite high, side effects were eliminated in time with the help of careful monitoring. In earlier terms, sputum conversion and closure of decay cavities were noted.Scop. Pentru a studia frecvența evenimentelor adverse în rezultatul utilizării a noilor medicamente în regimul de tratament al pacienților cu tuberculoză multidrogrezistentă (TB-MDR) și a evalua eficacitatea schemelor noi, scurte de tratament. Material și metode. Noi regimuri mai scurte au început să fie utilizate pentru tratarea pacienților cu TB-MDR din septembrie (MJ) și februarie (GS) 2020 în două instituții. Au fost identificate 225 de cazuri cu TB-MDR. În schemele de tratament, Bdq, Lzd, Lfx, Cfz, Cs au fost prescrise la 106 pacienți. Echilibrul de gen: bărbați 58 (67,4%), femei 28 (32,56%). Aproape 67 (79,76%) pacienți au avut un proces bilateral cu cavități, iar 17 (20,24%) pacienți au avut un proces fără cavități. Principalul efect advers al bedaquilinei este cardiotoxicitatea, care se manifestă printr-o prelungire a intervalului QT și o creștere a QTcF (coeficientul Fridericia) calculat folosind formula Fridericia. Cardiotoxicitatea bedaquilinei persistă după ce a luat-o încă 6 luni, adică, este cumulativ. Prin urmare, atunci când bedaquilina este utilizată în regimurile de tratament, este efectuat inițial un examen electrocardiografic (ECG). La monitorizarea tratamentului cu bedaquilină în prima lună, se efectuează un examen ECG după 14 zile, până la sfârșitul cursului de tratament, lunar, după terminarea cursului timp de 3 luni. SAE au fost identificate la 3 pacienți. Hipokaliemia, mielosupresia și respectiv hiperglicemia au fost observate la 1 pacient. Neuropatia periferică (moderată) a fost observată la 7 pacienţi. Rezultate. Conversia culturii a fost observată la 63 de pacienți (75%) care au primit regimuri de tratament Bdq, Lzd, Lfx, Cfz, Cs timp de 9 luni. Timpul până la conversia culturii ≤ medie (sau mediană) a fost de 10 (25%), ≥ medie (sau mediană) 97 (75%) cazuri. La restul de 16 (18%) pacienți, izolarea micobacteriilor a persistat, și detectarea suplimentară a rezistenței la principalele medicamente a oferit o justificare pentru extinderea cursului de tratament. 5 (%) pacienți au abandonat, acești pacienți au fost externați pentru încălcări ale regimului spitalicesc și au luat medicamente doar de la 28 de zile la 2 luni.Nu a existat o prelungire a intervalului QT (0,48-0,51s). Toată lumea a continuat cursul cu bedaquilină. Neuropatia periferică (moderată) a apărut la 7 (8%) pacienți care au luat linezolid. Toți pacienții (cu neuropatie ușoară) au continuat cursul cu linezolid. Acestor pacienți li s-a prescris piridoxină până la sfârșitul regimului. Mielosupresia a fost observată la 14 pacienţi. 10 dintre ei aveau gradul I, 3 pacienti gradul II, doar 1 mielosupresie gradul III. Aproape toți cei care au primit medicamentul clofazimină aveau o nuanță a pielii maro închis. Rezultatele tratamentului și finalizarea cursului au fost 63 (75%), eșec în 16 (19%).Concluzie. Eficacitatea schemelor scurte de tratament pentru pacienții cu MDR-TB atunci când noi medicamente antituberculoase (Bdq, Lzd, Lfx, Cfz, Cs) au fost incluse în regimul de tratament s-a dovedit a fi destul de mare, efectele secundare au fost eliminate în timp util prin monitorizare atentă. S-a observat conversia sputei și închiderea cavităților mai devreme.Цель. Изучить частоту побочных нежелательных явлений при применении новых препаратов в схеме лечении больных с МЛУ ТБ и оценить эффективность новых укороченных схем лечения. Материал и методы исследования. Новые укороченные схемы начали применять для лечения больных с МЛУ ТБ с сентября (МЮ) и февраля (ГС) 2020 г. в двух учреждениях. Было выявлено 225 МЛУ случаев. В схемах лечения Bdq, Lzd, Lfx, Cfz, Cs были назначены у 106 больным. Гендерный баланс: мужчины 58 (67,4%), женщины 28 (32,56%). Почти у 67 (79.76%) больных наблюдался двусторонний процесс с полостями распада, а у 17 (20,24%) больных процесс без распада. Основным побочным НЯ бедаквилина является кардиотоксичность, которая проявляется в удлинении QT интервала и увеличении QTcF (коэффициент Фридеричи) рассчитываемый при помощи формулы Фридеричи. Кардиотоксичность бедаквилина сохраняется после его приёма еще 6 месяцев, т.е. обладает кумулятивностью. В связи с чем при применении в режимах лечения бедаквилина исходно проводится электрокардиографическое (ЭКГ) исследование. При мониторинге лечения с бедаквилином в первый месяц проводится ЭКГ исследование после 14 дней, до конца курса лечения ежемесячно, после окончания курса в течение 3 месяцев. СНЯ были выявлены у 3 пациентов. Гипокалемия, миелосупрессия и гипергликемия отмечалось соотвественно у 1-го больного. Периферическая нейропатия (средней тяжести) отмечалась у 7 больных. Результаты. Конверсия культуры наблюдались у 63 больного (75%), которые принимали в режимах лечения Bdq, Lzd,Lfx, Cfz, Cs 9 месяцев. Время до конверсии посева ≤ среднего (или медианы) составляло 10 (25%), ≥ среднего (или медианы) 97 (75%) случаев. У остальных 16 (18%) больных выделение микобактерий сохранялись и дополнительное выявление резистентности к основным препаратам дали обоснование для удлинение курс лечение. Выбыли 5 (%) больных, эти больные были выписаны за нарушения внутрибольничного режима и принимали препараты лишь от 28 дней до 2 месяцев.Удлинении QT интервала (0,48-0,51с) не отмечалась. Все продолжали курс с бедаквилином. Периферическая нейропатия (средней тяжести) имела место у 7 (8%) пациентов принимающих линезолид. Все больные (с легкой степенью тяжести нейропатии) продолжали курс с линезолидом. Этим больным до конца режима было назначена пиридоксин. Миелосупрессия отмечалась у 14 больных. У 10 из них была 1-я степень, у 3 больных - 2-я степень, только у 1 - 3-я степень миелосупрессии. Практически у всех получавших препарат клофазимин отмечалась темнокоричневый оттенок кожи. Исходы излечения и завершение курса составляло 63 (75%), неудача 16 (19%).Заключение. Эффективность укороченных схем лечения больных МЛУ/ ТБ при включении в схему терапии новых противотуберкулезных препаратов - (Bdq,Lzd,Lfx,Cfz,Cs) оказалась достаточно высокой, побочные явления вовремя устранялись с помощью тщательного мониторинга. Более ранее сроки отмечались конверсия мокроты и закрытие полостей распада

Audiogenic Seizures and Social Deficits: No Aggravation Found in Krushinsky–Molodkina Rats

Epilepsy or epileptic syndromes affect more than 70 million people, often comorbid with autism spectrum disorders (ASD). Seizures are concerned as a factor for social regression in ASD. A stepwise experimental approach to this problem requires an animal model to provoke seizures and monitor subsequent behavior. We used rats of the Krushinsky–Molodkina (KM) strain as a validated inbred genetic model for human temporal lobe epilepsy, with recently described social deficiency and hypolocomotion. Generalized tonic-clonic seizures in KM rats are sound-triggered, thus being controlled events in drug-naïve animals. We studied whether seizure experience would aggravate contact deficits in these animals. Locomotor and contact parameters were registered in “the elevated plus maze”, “socially enriched open field”, and “social novelty/social preference tests” before and after sound-provoked seizures. The triple seizure provocations minimally affected the contact behavior. The lack of social drive in KM rats was not accompanied by a submissive phenotype, as tested in “the tube dominance test”, but featured with a poor contact repertoire. Here, we confirmed our previous findings on social deficits in KM rats. The contact deficiency was dissociated from hypolocomotion and anxiety and did not correlate with seizure experience. It was established that experience of rare, generalized tonic-clonic convulsions did not lead to an impending regress in contact motivation, as seen in an animal model of genetic epilepsy and comorbid social deficiency. One of the oldest animal models for epilepsy has a translational potential to study mechanisms of social behavioral deficits in future neurophysiological and pharmacological research

Striatal Patchwork of D1-like and D2-like Receptors Binding Densities in Rats with Genetic Audiogenic and Absence Epilepsies

Binding densities to dopamine D1-like and D2-like receptors (D1DR and D2DR) were studied in brain regions of animals with genetic generalized audiogenic (AGS) and/or absence (AbS) epilepsy (KM, WAG/Rij-AGS, and WAG/Rij rats, respectively) as compared to non-epileptic Wistar (WS) rats. Convulsive epilepsy (AGS) exerted a major effect on the striatal subregional binding densities for D1DR and D2DR. An increased binding density to D1DR was found in the dorsal striatal subregions of AGS-prone rats. Similar changes were seen for D2DR in the central and dorsal striatal territories. Subregions of the nucleus accumbens demonstrated consistent subregional decreases in the binding densities of D1DR and D2DR in epileptic animals, irrespective of epilepsy types. This was seen for D1DR in the dorsal core, dorsal, and ventrolateral shell; and for D2DR in the dorsal, dorsolateral, and ventrolateral shell. An increased density of D2DR was found in the motor cortex of AGS-prone rats. An AGS-related increase in binding densities to D1DR and D2DR in the dorsal striatum and motor cortex, areas responsible for motor activity, possibly reflects the activation of brain anticonvulsive loops. General epilepsy-related decreases in binding densities to D1DR and D2DR in the accumbal subregions might contribute to behavioral comorbidities of epilepsy

Striatal Patchwork of D1-like and D2-like Receptors Binding Densities in Rats with Genetic Audiogenic and Absence Epilepsies

Binding densities to dopamine D1-like and D2-like receptors (D1DR and D2DR) were studied in brain regions of animals with genetic generalized audiogenic (AGS) and/or absence (AbS) epilepsy (KM, WAG/Rij-AGS, and WAG/Rij rats, respectively) as compared to non-epileptic Wistar (WS) rats. Convulsive epilepsy (AGS) exerted a major effect on the striatal subregional binding densities for D1DR and D2DR. An increased binding density to D1DR was found in the dorsal striatal subregions of AGS-prone rats. Similar changes were seen for D2DR in the central and dorsal striatal territories. Subregions of the nucleus accumbens demonstrated consistent subregional decreases in the binding densities of D1DR and D2DR in epileptic animals, irrespective of epilepsy types. This was seen for D1DR in the dorsal core, dorsal, and ventrolateral shell; and for D2DR in the dorsal, dorsolateral, and ventrolateral shell. An increased density of D2DR was found in the motor cortex of AGS-prone rats. An AGS-related increase in binding densities to D1DR and D2DR in the dorsal striatum and motor cortex, areas responsible for motor activity, possibly reflects the activation of brain anticonvulsive loops. General epilepsy-related decreases in binding densities to D1DR and D2DR in the accumbal subregions might contribute to behavioral comorbidities of epilepsy