Эффективность и безопасность комбинированного применения целекоксиба, диацереина и комбинации глюкозамина и хондроитина для контроля скелетно-мышечной боли, связанной с остеоартритом и неспецифической болью в спине

   The combined use of drugs with different mechanisms of action is the main principle of musculoskeletal pain control in rheumatic diseases. However, there are few studies evaluating the efficacy of this approach in real practice.Objective: to determine the efficacy and safety of the combined use of celecoxib, diacerein, and the combination of glucosamine + chondroitin in osteoarthritis (OA) and chronic nonspecific low back pain (NSLBP).   Material and methods. Statistical analysis of data obtained during a 3-month open observational study was performed. We included 1569 patients (63.6 % women and 36.4 % men, mean age 58.7 ± 11.0 years) with knee OA (kOA), hip OA (hOA), generalized OA (gOA), and chronic NSLBP with moderate/severe pain (≥ 4 on a numeric rating scale, NRS 0–10) who required nonsteroidal anti-inflammatory drugs. Celecoxib 200 mg twice daily was prescribed, with the dose reduced to 200 mg per day or taken “as needed" after significant pain relief; diacerein 50 mg twice daily; and a medication of glucosamine 250 mg and chondroitin 200 mg, 2 capsules 2–3 times daily. Outcomes were assessed after 3 months using the dynamics of pain, fatigue, dysfunction (according to NRS), and the “Patient Acceptable Symptom State” (PASS) indicator.   Results and discussion. 80.2 % of patients completed the 3 month course of treatment, 4.4 % discontinued treatment due to adverse events (AEs), and for 15.4 % of patients there was no follow-up. After 3 months of treatment ≥ 50 % decrease (from baseline) in the severity of symptoms was noted in 83.4 % of patients for pain on movement, in 83.7 % for pain at rest, in 78.6 % for pain at night, in 80.8 % for dysfunction, and in 83.4 % for fatigue. 87.7 % of patients reported PASS. There were no significant differences in treatment outcomes for different localizations of OA and NSLBP: a ≥ 50 % pain reduction in kOA was achieved in 81.6 % of patients, in hOA – in 82.2 %, in gOA – in 85.0 %, in NSLBP – in 88.1 %. AEs were registered in 350 (22.4 %) patients, the most frequent was dyspepsia (n = 280, 17.8 %), diarrhea was recorded in 37 (2.4 %) cases. No serious AEs requiring hospitalization were registered.   Conclusion. Combination therapy with celecoxib, diacerein, and a combination of glucosamine and chondroitin significantly reduces the severity of symptoms of OA and NSLBS.   Комплексное применение препаратов с различным механизмом  действия – основной принцип контроля скелетно-мышечной боли при ревматических заболеваниях. Однако имеется лишь небольшое число работ, в которых оценивается эффективность такого подхода в реальной практике.   Цель исследования – определение эффективности и безопасности сочетанного применения целекоксиба, диацереина и комбинации глюкозамин + хондроитин при остеоартрите (ОА) и хронической неспецифической боли в спине (НБС).   Материал и методы. Выполнен статистический анализ данных, полученных в ходе 3-месячного открытого наблюдательного исследования. Было включено 1569 пациентов (63,6 % женщин и 36,4 % мужчин, средний возраст – 58,7 ± 11,0 года) с ОА коленного (КС), тазобедренного (ТБС) суставов, генерализованным ОА (ГОА) и хронической НБС, испытываваших умеренную/выраженную боль (≥ 4 по числовой рейтинговой шкале, ЧРШ 0–10) и нуждавшихся в приеме нестероидных противовоспалительных препаратов. Назначались целекоксиб 200 мг 2 раза в сутки со снижением дозы до 200 мг/сут и использованием «по требованию» после значительного уменьшения боли; диацереин 50 мг 2 раза в сутки и препарат глюкозамина 250 мг и хондроитина 200 мг по 2 капсулы 2–3 раза в день. Оценка результатов проводилась через 3 мес по динамике боли, усталости, нарушения функции (по ЧРШ), а также показателю «состояние симптомов, приемлемое для пациента» (ССПП).   Результаты и обсуждение. 3-месячный курс лечения закончили 80,2 % больных, 4,4 % прервали лечение из-за нежелательных явлений (НЯ), 15,4 % выпали из-под наблюдения. Через 3 мес уменьшение выраженности ≥ 50 % по сравнению с исходным уровнем для боли при движении отмечено у 83,4 % пациентов, боли в покое – у 83,7 %, боли ночью – у 78,6 %, нарушения функции – у 80,8 %, усталости – у 83,4 %; 87,7 % пациентов указали на ССПП. Не выявлено значимых различий результатов лечения при различной локализации ОА и НБС: ≥ 50 % уменьшение боли при ОА КС достигнуто у 81,6 % больных, при ОА ТБС – у 82,2 %, при ГОА – у 85,0 %, при НБС – у 88,1 %. НЯ зарегистрированы у 350 (22,4 %) пациентов, наиболее часто встречалась диспепсия (n = 280, 17,8 %), диарея отмечалась в 37 (2,4 %) случаях. Серьезные НЯ, потребовавшие госпитализации, не зафиксированы.   Заключение. Комбинированная терапия с использованием целекоксиба, диацереина и комбинации глюкозамина и хондроитина обеспечивает существенное уменьшение выраженности симптомов ОА и НБС

OBSERVATIONS OF TYPICAL, RARE AND UNIQUE PHENOMENA IN CLOSE BINARIES WITH EXTREMAL MASS RATIO

We present the review of different properties of several close binary systems, based on our observations. These binaries are as follow: SU UMa type stars V503 Cyg and V1504 Cyg, X-Ray novae V518 Per and V404 Cyg. They have the extremal mass ratio of the primary component to the secondary M1/M2 > 3. Some of them show the typical for the SU UMa type stars behaviour, so-called the "positive superhumps" or more rare "negative superhumps". Another display the "forbidden" variability in the ordinary outbursts or the light variation of unknown yet nature

THE INFLUENCE OF METABOLIC SYNDROME ON HEART ABNORMALITIES IN PATIENTS WITH ARTERIAL HYPERTENSION

Aim: To evaluate structural and functional heart abnormalities in patients with arterial hypertension (AH) with and without metabolic syndrome.Materials and methods: The study included 303  patients with AH I, II and III, aged from 25 to  70  years (mean±SD 52±18 years). All patients were categorized into 3 groups according to severity of AH (AH I, II and III corresponded to groups 1, 2 and 3, respectively). Within each group, patients were subdivided into 2 subgroups: without metabolic syndrome (n=151) and with metabolic syndrome (n=152). Assessments included measurements of blood glucose and lipids, 24-hour monitoring of blood pressure, echocardiography with calculation of myocardial mass index of left ventricle and the use of conventional and tissue myocardial dopplerography.Results: Already at early stage of AH (gr. I), 60% patients with metabolic syndrome and 32% patients without metabolic abnormalities had some degree of left ventricular remodeling, including concentric type of remodeling in 12 and 20%, excentric hypertrophy in 18 and 6%, concentric left ventricular hypertrophy in 30 and 6%, respectively. In AH I, an increase of myocardial mass index of left ventricle was found in 39% of patients with metabolic syndrome and in 12% patients without it. In patients with AH I, abnormalities of left ventricular diastolic function according to the results of tissue myocardial dopplerography was seen in 82% of patients with metabolic syndrome and in 42% of patients without metabolic syndrome. Patients with AH I–III and metabolic syndrome had almost 5-fold higher probability of heart abnormalities than AH patients without metabolic disturbances (odds ratio 4.8, 95% confidence interval 1.9–6.4, p< 50 and>50 years).Conclusion: Metabolic syndrome contributes to heart abnormalities irrespective of gender, age and AH grade

Synthesis of D-π-A′-π-A Chromophores with Quinoxaline Core as Auxiliary Acceptor and Effect of Various Silicon-Substituted Donor Moieties on Thermal and Nonlinear Optical Properties at Molecular and Material Level

Novel D-π-A′-π-A chromophores with quinoxaline cores as auxiliary acceptors and various donor moieties (aniline, carbazole, phenothiazine, tetrahydroquinoline) containing bulky tert-butyldimethylsilyloxy (TBDMSO) groups and tricyanofuranyl (TCF) acceptors with bulky cyclohexylphenyl substituents were synthesized via eight- to nine-step procedures, and their photo-physical and thermal properties were investigated. The values of the chromophores’ first hyperpolarizabilities were calculated in the framework of DFT at the M06-2X/aug-cc-pVDZ computational level; the effect of the introduction of the TBDMSO group into the donor fragment is shown to be inessential, as this group is not coupled to the π-conjugated system of the chromophore. The chromophore with the tetrahydroquinoline donor has a first hyperpolarizability value of 937 × 10−30 esu, which is the highest for the studied chromophores. Atomistic modeling of composite materials with the studied chromophores as guests demonstrated that the presence of bulky substituent in the donor fragment prevents notable aggregation of chromophores, even at high chromophore content (40 wt.%). The nonlinear optical performance of guest–host materials with 25 and 40 wt.% of suggested chromophore content was studied using a second harmonic generation technique to give the NLO coefficient, d33 up to 52 pm/V

Combined Inhibition of AKT and KIT Restores Expression of Programmed Cell Death 4 (PDCD4) in Gastrointestinal Stromal Tumor

The majority of gastrointestinal stromal tumor (GIST) patients develop resistance to the first-line KIT inhibitor, imatinib mesylate (IM), through acquisition of secondary mutations in KIT or bypass signaling pathway activation. In addition to KIT, AKT is a relevant target for inhibition, since the PI3K/AKT pathway is crucial for IM-resistant GIST survival. We evaluated the activity of a novel pan-AKT inhibitor, MK-4440 (formerly ARQ 751), as monotherapy and in combination with IM in GIST cell lines and preclinical models with varying IM sensitivities. Dual inhibition of KIT and AKT demonstrated synergistic effects in IM-sensitive and -resistant GIST cell lines. Proteomic analyses revealed upregulation of the tumor suppressor, PDCD4, in combination treated cells. Enhanced PDCD4 expression correlated to increased cell death. In vivo studies revealed superior efficacy of MK-4440/IM combination in an IM-sensitive preclinical model of GIST compared with either single agent. The combination demonstrated limited efficacy in two IM-resistant models, including a GIST patient-derived xenograft model possessing an exon 9 KIT mutation. These studies provide strong rationale for further use of AKT inhibition in combination with IM in primary GIST; however, alternative agents will need to be tested in combination with AKT inhibition in the resistant setting