Low-Temperature Polymorphic Phase Transition in a Crystalline Tripeptide L-Ala-L-Pro-Gly·H2O Revealed by Adiabatic Calorimetry

We demonstrate application of precise adiabatic vacuum calorimetry to observation of phase transition in the tripeptide l-alanyl-l-prolyl-glycine monohydrate (APG) from 6 to 320 K and report the standard thermodynamic properties of the tripeptide in the entire range. Thus, the heat capacity of APG was measured by adiabatic vacuum calorimetry in the above temperature range. The tripeptide exhibits a reversible first-order solid-to-solid phase transition characterized by strong thermal hysteresis. We report the standard thermodynamic characteristics of this transition and show that differential scanning calorimetry can reliably characterize the observed phase transition with <5 mg of the sample. Additionally, the standard entropy of formation from the elemental substances and the standard entropy of hypothetical reaction of synthesis from the amino acids at 298.15 K were calculated for the studied tripeptide.National Institute of Biomedical Imaging and Bioengineering (U.S.) (EB-003151)National Institute of Biomedical Imaging and Bioengineering (U.S.) (EB-001960)National Institute of Biomedical Imaging and Bioengineering (U.S.) (EB-002026

РЕЦЕПТОР ДОФАМИНА D2 (DRD2) ЛИМФОЦИТОВ ПЕРИФЕРИЧЕСКОЙ КРОВИ КАК БИОМАРКЕР ПРОГНОЗА АНТИПСИХОТИЧЕСКОЙ ТЕРАПИИ

Introduction. Despite the evolution of antipsychotic drugs, the problem of the therapy effectiveness and safety of schizophrenia spectrum disorders and comorbid conditions is very acute. The dopamine receptor D2 gene (DRD2) is one of the key targets of modern pharmacogenetic studies of mental disorders.The objective of the study was to analyze the DRD2 mRNA level in peripheral blood lymphocytes and to identify genetic variations of –141С Ins/Del as potential biomarkers for antipsychotic therapy prognosis.Methods and materials. The study included 112 patients with mental disorders: 61 – with a diagnosis of schizophrenia spectrum disorder, 51 – with a comorbid disease course with alcohol dependence syndrome, and 112 people as a control group. Psychometric evaluation was carried out using PANSS scale. The material was peripheral blood lymphocytes (PBLs). The DRD2 mRNA level was determined by real-time polymerase chain reaction with TaqMan probe. Genotyping –141С Ins/Del was performed by the restriction fragment length polymorphism assay.Results. –141C Ins/Del DRD2 genetic variations are not associated with a risk of mental disorder development, and they did not affect the DRD2 mRNA level in PBLs. There were no significant differences in the gene expression of DRD2 in the control group and patients (p=0.194). Despite the improvement of the mental state in all patients included in the study, the studied DRD2 parameters did not affect either the mental disorder symptoms or the normalization of the patient status against the background of antipsychotic therapy. Ins/Ins genetic variation of –141C Ins/Del was significantly associated with an increase weight gain of more than 7 % on the 28th day of antipsychotic therapy.Conclusion. Ins/Ins genetic variation of –141C Ins/Del can be considered as a biomarker for the prognosis of antipsychotic-induced weight gain. Введение. Несмотря на эволюцию антипсихотических препаратов, проблема эффективности и безопасности терапии расстройств шизофренического спектра и коморбидных с ними состояний стоит очень остро. Ген рецептора дофамина Д2 (DRD2) – один из объектов современных фармакогенетических исследований в психиатрии.Цель исследования – определение биомаркеров прогноза антипсихотической терапии на основе молекулярно-генетических характеристик гена DRD2 в лимфоцитах периферической крови (уровня мРНК и генетических вариантов –141С Ins/Del).Методы и материалы. В исследование включены 112 пациентов с психическими патологиями: 61 – с диагнозом «Расстройство шизофренического спектра», 51 – с коморбидным течением расстройства шизофренического спектра и синдрома алкогольной зависимости и 112 лиц контрольной группы. Психометрическую оценку проводили на основании шкалы PANSS. Материалом служили лимфоциты периферической крови (ЛПК). Уровень мРНК гена DRD2 определяли методом ПЦР в реальном времени с использованием зонда TaqMan. Генотипирование –141С Ins/Del – методом полиморфизма длины рестрикционных фрагментов.Результаты. Генетические варианты –141С Ins/Del DRD2 не ассоциированы с риском развития психических патологий и уровнем мРНК гена DRD2 в ЛПК. Экспрессия гена DRD2 у лиц контрольной группы и психически больных не различалась (р=0,194). Несмотря на улучшение психического состояния у всех пациентов, включенных в исследование, изучаемые показатели DRD2 не оказывали влияния ни на симптоматику психических патологий, ни на нормализацию статуса пациентов на фоне антипсихотической терапии. Генетический вариант Ins/Ins –141С Ins/Del статистически значимо ассоциировался с увеличением массы тела более 7 % на 28-й деньтерапии антипсихотиками.Выводы. Генетический вариант Ins/Ins –141С Ins/Del может быть рассмотрен в качестве биомаркера прогноза антипсихотик-индуцированного набора массы тела.

Экспрессия рецептора дофамина DRD1 (мРНК, белок) в лимфоцитах периферической крови и прогноз антипсихотической терапии

Introduction. There is a problem in predicting the efficacy and safety of antipsychotic therapy. Dopamine receptor D1 is one of the targets of antipsychotics. Peripheral blood lymphocytes (PBL) are the research object of neurotransmission receptors.The objective was to study DRD1 gene expression (mRNA, protein level) in PBL as a possible biomarker of olanzapine and haloperidol therapy prognosis.Methods and Materials. Sample: 106 patients diagnosed with schizophrenic spectrum disorder. Study design: prospective longitudinal follow-up with drug administration by randomization. Assessment of mental status and development of Parkinsonism: Positive and Negative Syndrome Scale (PANSS) and Simpson-Agnus Scale (SAS), respectively. PBL was study material. DRD1 mRNA level was determined by real-time PCR. DRD1 protein concentration in PBL was measured by enzyme immunoassay.Results. Haloperidol (but not olanzapine) treatment for 28 days, leads to DRD1 protein concentration decrease in PBL in a manner dependent on its initial level. DRD1 mRNA level in PBL remained unchanged during the treatment. Patients with effective therapy by olanzapine had lower DRD1 mRNA levels. Side effects of the therapy (Parkinsonism, weight gain) were not associated with studied DRD1 parameters.Conclusions. Haloperidol treatment leads to a decrease of DRD1 protein concentration in PBL, which depends on the initial protein level. Effective olanzapine therapy is associated with reduced DRD1 mRNA level in PBL before the treatment. Введение. Существует проблема прогноза эффективности и безопасности терапии антипсихотическими препаратами, одна из мишеней которых – рецептор дофамина D1. Лимфоциты периферической крови (ЛПК) – объект исследования рецепторов нейротрансмиссии.Цель – изучение экспрессии гена DRD1 (мРНК, белок) в ЛПК как возможного биомаркера прогноза терапии оланзапином и галоперидолом.Методы и материалы. Выборка: 106 пациентов с диагнозом «Расстройство шизофренического спектра». Дизайн исследования: проспективное лонгитудинальное наблюдение с назначением препарата путем рандомизации. Оценка психического статуса и развития паркинсонизма: шкалы Позитивных и негативных синдромов (PANSS) и Симпсона Агнуса (SAS). Материал исследования – ЛПК. Уровень мРНК гена DRD1 определяли методом полимеразной цепной реакции в режиме реального времени. Концентрацию белка DRD1 в ЛПК измеряли методом иммуноферментного анализа.Результаты. При воздействии галоперидола (но не оланзапина) в течение 28 дней концентрация белка DRD1 в ЛПК снижалась зависимо от его начального уровня. Уровень мРНК гена DRD1 в ЛПК оставался неизменным при действии препаратов. Пациенты с эффективной терапией оланзапином имели более низкие значения уровня мРНК DRD1. Побочные эффекты терапии (паркинсонизм, набор веса) не были ассоциированы с изучаемыми характеристиками DRD1.Заключение. Действие галоперидола приводит к снижению концентрации белка DRD1 в ЛПК, которое зависит от начального уровня белка. Эффективная терапия оланзапином ассоциирована с пониженным уровнем мРНК DRD1 в ЛПК до начала лечения.

Сравнительное исследование эффективности и безопасности препарата Хондрогард ® при комбинированном (внутрисуставное и внутримышечное) и внутримышечном введении у пациентов с остеоартритом коленных суставов

Objective: to evaluate the efficacy and safety of Chondroguard® in the combined (intra-articular (IA) + intramuscular (IM)) and IM injection in patients with knee osteoarthritis (OA).Patients and methods. The study enrolled 150 patients with knee OA who were divided into two groups with 75 patients in each group. Group 1 received the drug (100 mg/ml) intramuscularly: 25 injections every other day, the first three injections at a dose of 100 mg, the fourth injection was started with a dose of 200 mg. Group 2 had five IA injections into the target joint at a daily dose of 200 mg with an interval of 3 days between injections, then 16 IM injections at 200 mg every other day. All the patients were prescribed nonsteroidal anti-inflammatory drugs (NSAIDs), such as meloxicam 15 mg. To determine the efficiency of treatment, the investigators estimated the following parameters: pain intensity on a visual analogue scale (VAS), the total WOMAC index and its components (pain, stiffness, and functional insufficiency), sensory and affective-emotional pain characteristics (for the target joint) according to McGill Pain Questionnaire (MPQ) scores. Clinical and biochemical blood tests, clinical urinalysis, coagulogram, and electrocardiography were performed in all the patients at the beginning and the end of the study.Results and discussion. Comparison of two Chondroguard® regimens showed that by the end of treatment, the pain intensity on VAS was significantly lower in Group 2 (IA + IM administration) than in Group 1 (16.81±13.49 and 21.88±13.24, respectively; p&lt;0.0001). Analysis revealed that there were no significant differences between Groups 1 and 2 in the changes of the overall WOMAC index and its components (pain, stiffness, and functional performance), as well as in MPQ pain scores. No serious adverse events (AEs) were recorded in the study. There were 11 AEs in 3.3% (n = 5/150) of the patients throughout the study. By its end, resolution/termination of AEs was noted in 100% of cases. There were no clinically significant pathological laboratory and ECG findings.Conclusion. The test drug during any (IM or combined) route of administration quickly and effectively reduces pain syndrome and stiffness and improves joint functional performance and at the same time it is a safe drug. Its important advantage is a quick effect achieved by IA and IM administration. This makes it possible to reduce the dose of NSAIDs or to discontinue the latter, which is very important for OA patients with comorbidity. Цель – оценить эффективность и безопасность препарата Хондрогард® при комбинированном (внутрисуставное, в/с + внутримышечное, в/м) и внутримышечном введении у пациентов с остеоартритом (ОА) коленных суставов.Пациенты и методы. В исследование были включены 150 пациентов с ОА коленных суставов. Пациенты были разделены на две группы (по 75 пациентов в каждой группе). Первая группа (R) получала изучаемый препарат (100 мг/мл) внутримышечно: 25 инъекций через день, первые три инъекции в дозе 100 мг, начиная с 4-й инъекции – в дозе 200 мг. Вторая группа (N) получала 5 внутрисуставных инъекций в целевой сустав по 200 мг с перерывом 3 дня между введениями, далее 16 внутримышечных инъекций по 200 мг через день. Всем пациентам назначали нестероидные противовоспалительные препараты (НПВП, мелоксикам 15 мг). Для определения эффективности лечения оценивали следующие параметры: интенсивность боли по визуальной аналоговой шкале (ВАШ), индекс WOMAC общий и его составляющие (боль, скованность и функциональная недостаточность), сенсорные и аффективно-эмоциональные характеристики боли (для целевого сустава) по опроснику MPQ (McGiIl Pain Questionnaire). Всем пациентам в начале и в конце исследования выполняли клинический и биохимический анализы крови, клинический анализ мочи и анализ показателей коагулограммы, электрокардиографию.Результаты и обсуждение. При сравнении двух режимов введения Хондрогарда® интенсивность боли по ВАШ к концу лечения в группе N (в/с + в/м введение) была достоверно ниже, чем в группе R (16,81±13,49 и 21,88±13,24; р&lt;0,0001 соответственно). Анализ динамики общего индекса WOMAC и его составляющих (боль, скованность, функциональное состояние), а также оценки боли по опроснику MPQ достоверных различий между группами N и R не выявил. Серьезных нежелательных явлений (НЯ) в исследовании не зарегистрировано. За весь период исследования выявлено 11 НЯ у 3,3% (5/150) пациентов. К концу исследования разрешение/прекращение НЯ отмечено в 100% случаев. Клинически значимых отклонений лабораторных показателей и данных ЭКГ не наблюдалось.Выводы. Изучаемый препарат при любом способе введения (в/м или комбинированный) быстро и эффективно уменьшает болевой синдром и скованность, улучшает функциональное состояние суставов и при этом является безопасным препаратом. Важное его преимущество – быстрый эффект за счет в/с и в/м введения. Это позволяет снизить дозу НПВП или отменить их, что очень важно для больных ОА с коморбидностью.

POSSIBILITY OF ANTIDESTRUCTIVE EFFECT OF LOW DOSES OF CORTICOSTEROIDS IN RHEUMATOID ARTHRITIS: PRELIMINARY INFORMATION

Summary Aim of study: Control ofpossible antidestructive effect of low doses of corticosteroids (CS) on the background of basic therapy of rheumatoid arthritis (RA) by methotrexate (MT). Materials and methods: Preliminary results from 38 out of planned 80 patients (all females) aged 23-68 and disease duration from 0.5 to 20 years with reliable RA (ARA criteria, 1987) observed during a year. Exclusion criteria for the study were: ulceral disease ofstomach or duodenum and patients with IV radiological stage of the disease. Patients were divided into 2 groups: 1st group included 19 pts who had MT and CS in dosage of 10 mg/ day and the 2tul -19 pts having as the basic therapy only MT. Taking NSAID was allowed in both groups. To assess therapeutic effect clinical, laboratory&gt; and radiological indices were used. Results: In the 1st group 5 out of 19 pts demonstrated decrease of Larsen index mainly on account of the decrease or disappearing of cystic clearings and of periarticular osteoporosis. In the 2nd group such decrease was observed only in one patient. But Larsen index decrease did not correlate with expected disappearing of erosions, growing of erosions in both groups practically did not differ (2.0 and 2.4 correspondingly). Conclusion: Low doses of corticosteroids taken by RA pts in combination with MT promote the regression of bone-cartilage destruction assessed by Larsen index

Potential diagnostic markers of olanzapine efficiency for acute psychosis: a focus on peripheral biogenic amines

Abstract Background Biomarkers are now widely used in many fields of medicine, and the identification of biomarkers that predict antipsychotic efficacy and adverse reactions is a growing area of psychiatric research. Monoamine molecules of the peripheral bloodstream are possible prospective biomarkers based on a growing body of evidence indicating that they may reflect specific changes in neurotransmitters in the brain. The aim of this study was to detect peripheral biogenic amine indicators of patients with acute psychosis and to test the correlations between the biological measures studied and the psychopathological status of the patients. Methods This research included 60 patients with acute psychosis treated with olanzapine (n = 30) or haloperidol (n = 30). Here, we measured biogenic amine indicators, including mRNA levels of dopamine receptor D4 (DRD4) and the serotonin 2A receptor (5HTR2A), in peripheral blood mononuclear cells (PBMCs) using quantitative real-time polymerase chain reaction and serum dopamine concentrations by enzyme linked immunosorbent assay (ELISA). Psychopathological status was evaluated using psychometric scales. The assessments were conducted prior to and after 14 and 28 days of treatment. Results The administration of haloperidol, but not olanzapine, up-regulated 5HTR2A mRNA in a linear manner, albeit without statistical significance (p = 0.052). Both drugs had non-significant effects on DRD4 mRNA levels. Nevertheless, a positive correlation was found between DRD4 and 5HTR2A mRNA levels over a longitudinal trajectory, suggesting co-expression of the two genes. A significant positive correlation was observed between 5HTR2A mRNA levels and total Positive and Negative Syndrome Scale (PANSS) scores in both groups of patients before treatment. A significant correlation between baseline 5HTR2A mRNA levels and PANSS scores on days 14 and 28 of treatment remained for patients treated with olanzapine only. Moreover, a significant positive correlation was observed between blood serum dopamine levels and scores on extrapyramidal symptom scales in the olanzapine group. Conclusions The DRD4 and 5HTR2A genes are co-expressed in PBMCs during antipsychotic administration. Despite a correlation between the studied biogenic amine indicators and the psychopathological status of patients, reliable biomarkers of treatment response could not be determined

Comparative study of the efficacy and safety of Chondroguard® during its combined (intra-articular and intramuscular) and intramuscular injection in patients with knee osteoarthritis

Objective: to evaluate the efficacy and safety of Chondroguard® in the combined (intra-articular (IA) + intramuscular (IM)) and IM injection in patients with knee osteoarthritis (OA).Patients and methods. The study enrolled 150 patients with knee OA who were divided into two groups with 75 patients in each group. Group 1 received the drug (100 mg/ml) intramuscularly: 25 injections every other day, the first three injections at a dose of 100 mg, the fourth injection was started with a dose of 200 mg. Group 2 had five IA injections into the target joint at a daily dose of 200 mg with an interval of 3 days between injections, then 16 IM injections at 200 mg every other day. All the patients were prescribed nonsteroidal anti-inflammatory drugs (NSAIDs), such as meloxicam 15 mg. To determine the efficiency of treatment, the investigators estimated the following parameters: pain intensity on a visual analogue scale (VAS), the total WOMAC index and its components (pain, stiffness, and functional insufficiency), sensory and affective-emotional pain characteristics (for the target joint) according to McGill Pain Questionnaire (MPQ) scores. Clinical and biochemical blood tests, clinical urinalysis, coagulogram, and electrocardiography were performed in all the patients at the beginning and the end of the study.Results and discussion. Comparison of two Chondroguard® regimens showed that by the end of treatment, the pain intensity on VAS was significantly lower in Group 2 (IA + IM administration) than in Group 1 (16.81±13.49 and 21.88±13.24, respectively; p&lt;0.0001). Analysis revealed that there were no significant differences between Groups 1 and 2 in the changes of the overall WOMAC index and its components (pain, stiffness, and functional performance), as well as in MPQ pain scores. No serious adverse events (AEs) were recorded in the study. There were 11 AEs in 3.3% (n = 5/150) of the patients throughout the study. By its end, resolution/termination of AEs was noted in 100% of cases. There were no clinically significant pathological laboratory and ECG findings.Conclusion. The test drug during any (IM or combined) route of administration quickly and effectively reduces pain syndrome and stiffness and improves joint functional performance and at the same time it is a safe drug. Its important advantage is a quick effect achieved by IA and IM administration. This makes it possible to reduce the dose of NSAIDs or to discontinue the latter, which is very important for OA patients with comorbidity