[Carfilzomib, lenalidomide and dexamethasone in relapsed/refractory multiple myeloma patients: the real-life experience].

BACKGROUND: Carfilzomib, lenalidomide, and dexamethasone (KRd) have been approved for the treatment of relapsed and refractory multiple myeloma (RRMM) based on ASPIRE clinical trial. AIM: Analysis of efficacy and safety of KRd in routine clinical practice. MATERIALS AND METHODS: The prospective analysis included patients with MM who received at least one line of previous therapy. The inclusion criteria were relapse/progression; refractoriness; lack of very good partial response (VGPR) and more after the first line of therapy. Since February 2016, we used KRd like in ASPIRE trial, since October 2019, carfilzomib has been used at a dose of 56 mg/m2 on days 1, 8 and 15. Autologous hematopoietic stem cell transplantation (autoHSCT), consolidation (KRd) and maintenance therapy (Rd) were regarded as one line of therapy. RESULTS AND DISCUSSION: We evaluated 77 patients with median age at the time of diagnosis is 55 (3072) years. For 56% (n=43) of patients KRd was applied as the second line (group 1), for 44% (n=34) as the third and more (group 2). In 23/43 patients from group 1, an early change in therapy was made due to insufficient effectiveness (after 24 courses of VCD or PAD). KRd served as a "bridge" to autoHSCT in 25 (32%) patients (21 of 25 in group 1). Another 7 patients underwent collection of autoHSC (all from group 1). The overall response rate (ORR) was 80.5%, with 33.8% complete response (CR) and 26% VGPR. ORR in group 1 was 98% versus 65.6% in group 2; 24-month overall survival (OS) was 70%, progression free survival (PFS) 49.8%. In group 1, 24-month OS was 85.6% versus 50.0% in group 2, 24-month PFS was 67.8% versus 25.5% (p=0.01). CONCLUSION: Our analysis confirmed the high efficiency of KRd in the treatment of RRMM in real-life practice. Early correction of therapy with insufficient effectiveness of the first line made it possible to implement the strategy of high-dose consolidation and autoHSCT in a larger percentage of patients with MM.

[Neuroprotective potential of pyrimidine-4-H1-OHa derivatives in experimental cerebral ischemia]. / Neiroprotektivnyi potentsial proizvodnykh pirimidin-4-H1-OHa pri eksperimental'noi ishemii golovnogo mozga.

OBJECTIVE: To evaluate the effect of ten pyrimidine-4-H1-OH derivatives on the change in the activity of mitochondrial respiratory chain complexes and tricarboxylic acid cycle enzymes in rats under experimental brain ischemia. MATERIAL AND METHODS: Cerebral ischemia in rats was modeled by irreversible occlusion of the middle cerebral artery. Two hundred and sixty male Wistar rats were administered studied compounds at a dose of 50 mg/kg (orally) and the reference - L-carnitine at a dose of 200 mg/kg (orally) for 72 hours after ischemia modeling (once a day). The activity of mitochondrial complexes (I, II, IV and V) was evaluated by the respirometric method. The activity of complex III and the enzymes of the tricarboxylic acid cycle (aconitase, citrate synthase, α-ketoglutarate dehydrogenase) was evaluated by spectrophotometric method. The analysis was performed in the mitochondrial fraction of the animal brain. RESULTS: The use of pyrimidine-4-H1-OH derivatives containing a conjugated double bond and substituted phenol in the side chain, equally with the reference, contributed to the restoration of the activity of respiratory complexes and enzymes of the tricarboxylic acid cycle. The use of the remaining test compounds did not have a significant effect on the change in the estimated indicators. CONCLUSION: It is possible to assume the relevance of further study of pyrimidine-4-H1-OH derivatives as neuroprotective agents of metabolic action.

[Epidemiology of multiple myeloma in city Moscow].

AIM: To study the epidemiology of multiple myeloma in the city of Moscow and compare the results obtained with data from similar studies in other countries. MATERIALS AND METHODS: The study is based on information from a database of case histories of 3942 patients suffering from symptomatic MM, residents of the city of Moscow, which is maintained at the Hematologic Moscow City Center of S.P. Botkin Municipal Clinical Hospital. The control of the completeness of inclusion was carried out by cross - comparison with the data of the Moscow Cancer Register and the Register of Program 7 (beginning in 2019 - 12) of Highly Expensive Nosologies. The assessment was made according to data as of January 1, 2019. The calculations were carried out taking into account the data of Rosstat at the beginning of 2019 on the population of Moscow in different gender and age categories. RESULTS: Among the 3942 patients with active MM 1707 men - 43% and 2241 women - 57%, the median of the current age was 68 (28-94) years. The median time of observation of patients since the diagnosis of the disease 34 (1-423) months. The peak incidence was in the age range of more than 60 years. There were no significant differences in gender ratio in different age strata with a breakdown of 10 years. The number of cases of newly diagnosed MM per year for the period from 2009 (n=219) to 2018 (n=385) increased by 75.8%. At the same time, the demonstrated increase in the incidence rate for the described period turned out to be fair only for groups of patients over 50 years old, with the maximum increase in this indicator over the described period in the age range of 60-69 years. This is mainly due to the increase in life expectancy in Moscow in recent years. The study demonstrated that over the past 10 years, the average annual mortality rate from MM has decreased in Moscow, and as a result, its prevalence has increased. The rate of 2-year overall survival of patients with MM was 76%, 5-year - old - 49%, 10-year - old - 27%. The median overall survival of patients under the age of 65 when diagnosing the disease was 79 months, and 48 months. The distribution of patients within international classifications was consistent with international data. CONCLUSIONS: The study revealed a significant dynamic of the epidemiological situation concerning MM in Moscow. Over the past 10 years there has been an increase in the incidence of MM, as a result of an increase in the life expectancy of the population. The use of modern diagnostics and therapy of MM in real clinical practice has led to a significant reduction in mortality. Due to these factors, an increase in the prevalence of MM in Moscow has taken place, and this process will no doubt progress in the future.

Thrombopoietin Receptor Agonists in the Treatment of Chronic Resistant Primary Immune Thrombocytopenia: Efficacy and Safety Data in Real Clinical Practice.

AIM: To analyze the long-term efficacy and safety of ATR in adult patients with primary resistant ITP in real-world clinical practice. MATERIALS AND METHODS: The article contains long-term results analysis of ATR application under real clinical practice conditions in 138 patients (40 men and 98 women) whose median age at the beginning of therapy was 59 (18-86) years. Two ATR medicines-romiplostim (100 patients) and eltrombopag (38 patients) were used. RESULTS: During the first month of therapy, the median platelet count in the romiplostim group increased from 17·109 / L to 60·109 / L (9-600·109 / L), and the elethrombopag from 16.109 / L to 56.109 / L (9-400·109 / L). The minimal response (reaching platelet counts over 30·109 / L) was achieved in 92% of cases in both groups. Partial response (achievement of platelet count more than 50·109 / L) was achieved in 91 and 84% of patients in the rhombostim and eltrombopag groups, respectively. The frequency of complete response (an increase in platelet counts above 100·109 / L) was noted somewhat more often in the rhy- ploistim group-69% compared to 47% in the eltrombopag group (P = NS). Most patients demonstrated a long-term stable effect in the form of an increase in blood platelet count to a safe level during months and years of ATR treatment. The achievement of at least partial remission for 3 months or more was 70 and 71% in romiplostim and elthrombopag groups, respectively. Patients who started ATR- therapy are currently continuing treatment: 51% - in romiplostim group and in eltrombopag group-39%. The main reason of discontinuation the initially effective therapy were the loss of platelet response, toxicity, withdrawal from treatment (withdrawal with preservation of remission) and patients death. The tolerability of drugs with long-term admission was satisfactory. The most common AE were headache, bone pain, thrombosis, increased blood pressure and petechial hemorrhagic eruptions. The overall incidence of complications did not differ significantly between the romiplostim and eltrombopag groups -15.6 and 15.8%, respectively. CONCLUSION: Long-term ATR-therapy using in patients with resistant chronic ITP is an effective and largely safe treatment option.

[Efficacy and safety of bisoprololal in hypertensive patients with cardiovascular disease and chronic obstructive pulmonary disease].

Efficacy and safety of bisoprolol in hypertensive patients with cardiovascular disease and chronic obstructive pulmonary disease. A comparative study on the efficacy and safety of bisoprolol and sustained release metoprolol succinate in patients with arterial hypertension (AH), cardiovascular disease (CVD) and chronic obstructive pulmonary disease (COPD) was conducted. High antihypertensive efficacy and good tolerability of bisoprolol and metoprolol succinate sustained release was shown in hypertensive patients with CVD and COPD. Bisoprolol versus metoprolol succinate sustained release was more effective in reducing the number of PVCs in hypertensive patients with CVD and COPD. After 12 weeks of therapy of bisoprolol there was a trend to reduce the number of patients with concentric left ventricular hypertrophy by 16.6 % (from 83.3% at baseline vs 66.7% after 12 weeks of treatment, p < 0.1). Despite the fact that the identified changes in respiratory function (ERF) in both groups did not reach certainty bisoprolol versus metoprolol succinate sustained-release was a lesser extent influenced the performance of ERF and more - to reduce dyspnea to the evaluation scales Borg and mMRC (delta% = -7.1 in fixed vs delta% = -3.8 in control groups and delta% = -5.6 vs delta% = 0 respectively) in patients with AH, CVD and COPD.

[Molecular targets for searching of endothelial-protective substances].

Endothelial dysfunction underlies the development of many cardiovascular diseases. Thus endothelium becomes an independent therapeutic target, and the search of new substances with endothelial-protective action to date is one of the promising tasks for pharmacotherapy and medicinal chemistry. Molecular modeling is an effective tool for solving this problem. Computer chemistry methods use is only possible in combination with detailed information on three dimensional structure and functions of molecular targets: receptors and enzymes, involved in signal transduction inside and outside of endothelial cells. Information on structure and function of various macromolecules involved in vascular tone regulation is collected in the review. The structure of endothelial NO-synthase (EC 1.14.13.39) (eNOS)--enzyme, responsible for the nitric oxide synthesis and involved in vascular tone regulation process is reviewed. The importance of eNOS substrate--L-arginine is underlined in the review in terms of this enzyme activity, regulation, the information on structure and functions of L-arginine transport system is provided. Also different ways of eNOS activity regulation are reviewed, among which are enzyme activation and concurrent inhibition by substances interaction with active center of enzyme, inhibition by caveoline binding with oxigenase domain, and also regulation by phosphorylation of certain amino acids of eNOS by proteinkinase and dephoshphorylation of them by phosphatases. The importance of membrane receptors of endothelial cells as targets for endothelial-protective substances is underlined. Among them are receptors of endothelin, platelet activation factor, prostanoids, bradykinin, histamine, serotonin and protease activated receptors. The important role of potassium and calcium ion channels of vascular cells in endothelial-protective activity is underlined. Macromolecules presented in the review finally are considered as targets for searching for medicinal substances with endothelial-protective activity using proposed ways and methods of molecular modeling.

Effects of misoprostol and taurine on monochloramine ulcerogenesis in rats.

We compared gastroprotective characteristics of synthetic prostaglandin E1 misoprostol and amino acid taurine on rat model of monochloramine injury to the gastric mucosa. Both substances exhibited a pronounced gastroprotective effect.

Analgesic activity of 5-HT3 receptor antagonists.

The effects of 5-HT3 receptor antagonists tropisetron and condensed derivative of benzimidazole (laboratory code 64B) on nociceptive threshold were examined on models with activation of peripheral and central nociceptive mechanisms. The examined substances demonstrated pronounced analgesic effects in peripheral pain.

[Gastroprotective effects of histamine H2-receptor blockers in Helicobacter-like gastric mucosa lesions].

This study was designed as a comparative experimental analysis of the gastroprotective effects of two H2-blocking agents--famotidine and benzimidazole compound 64--on the model rat stomach Helicobacter-like mucous lesions. Both substances demonstrated dose-dependent gastroprotective effects both on the macro- and microscopic levels. ED50 made up 21.8 mg/kg and 13.5 mg/kg, respectively.

Comparative controlled study of Andrographis paniculata fixed combination, Kan Jang and an Echinacea preparation as adjuvant, in the treatment of uncomplicated respiratory disease in children.

A three-arm study comparing the efficacy of Kan Jang, a fixed herbal combination containing standardized Andrographis paniculata (N.) SHA-10 extract, with Immunal, a preparation containing Echinacea purpurea (L.) extract, in uncomplicated common colds was carried out in 130 children aged between 4 and 11 years over a period of 10 days. The study was designed as an adjuvant treatment of Kan Jang and Immunal with a standard treatment. The patients were assigned to one of the three groups. In control group C; 39 patients received only standard treatment. Kan Jang and Immunal were used as an adjuvant to this therapy in the other two groups. Adjuvant group A; 53 patients treated with Kan Jang tablets concomitant to standard treatment, and adjuvant control group B; 41 patients treated with concomitant Immunal. It was found that the adjuvant treatment with Kan Jang, was significantly more effective than Immunal, when started at an early stage of uncomplicated common colds. The symptoms of the disease were less severe in the Kan Jang group. The effect of Kan Jang was particularly pronounced in two objective parameters, amount of nasal secretion g/day and nasal congestion. Kan Jang also accelerated the recovery time, whereas Immunal did not show the same efficacy. The use of standard medication was significantly less in the Kan Jang adjuvant group than in either the Immunal or standard treatment group. Kan Jang treatment was well tolerated and no side effects or adverse reactions were reported.

[Effectiveness of using the drug Kan-Yang in children with acute respiratory viral infection (clinico-functional data)]. / Effektivnost' primeneniia preparata Kan-Iang u detei s ostroi respiratornoi virusnoi infektsiei, po dannym kliniko-funktsional'nogo issledovaniia.

A randomized trial of the effectiveness of the preparation Kan-Yang (Sweden) consisting of andrographis and eleutherococcus extracts was performed in 53 children with acute respiratory viral infection (ARVI). 40 ARVI children given conventional treatment served control. It is shown that in early acute noncomplicated respiratory disease Kan-Yang tablets relieves considerably the treatment course and promoted cure in good tolerance.