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Khan O.,Wayne State University | Rieckmann P.,University of Bamberg | Boyko A.,Russian National Research Medical University | Selmaj K.,Medical University of Lódz | Zivadinov R.,State University of New York at Buffalo
Annals of Neurology | Year: 2013

Objective To assess the efficacy and safety of glatiramer acetate (GA) 40mg administered 3× weekly (tiw) compared with placebo in patients with relapsing-remitting multiple sclerosis (RRMS). Methods This randomized, double-blind study was conducted in 142 sites in 17 countries. Patients with RRMS with at least 1 documented relapse in the 12 months before screening, or at least 2 documented relapses in the 24 months before screening, and an Expanded Disability Status Scale score ≤ 5.5, were randomized 2:1 to receive either subcutaneous (sc) GA 40mg tiw (1ml) or placebo for 12 months. Results Of 1,524 patients screened, 1,404 were randomized to receive GA 40mg sc tiw (n = 943) or placebo (n = 461). Ninety-three percent and 91% of patients in the placebo and GA groups, respectively, completed the 12-month study. GA 40mg tiw was associated with a 34.0% reduction in risk of confirmed relapses compared with placebo (mean annualized relapse rate = 0.331 vs 0.505; p < 0.0001). Patients who received GA 40mg tiw experienced highly significant reduction (p < 0.0001) in the cumulative number of gadolinium-enhancing T1 (44.8%) and new or newly enlarging T2 lesions (34.7%) at months 6 and 12. GA 40mg tiw was safe and well tolerated. The most common adverse events in the GA group were injection site reactions (35.5% with GA vs 5.0% with placebo). Interpretation GA 40mg sc tiw is a safe and effective regimen for the treatment of RRMS, providing the convenience of fewer sc injections per week. © 2013 American Neurological Association.


Allegri R.F.,Institute Neurologia Raul Carrea FLENI | Guekht A.,Russian National Research Medical University
Drugs of Today | Year: 2012

Dementia is the result of various cerebral disorders, leading to an acquired loss of memory and impaired cognitive ability. The most common forms are Alzheimer's disease (AD) and vascular dementia (VaD). Neurotrophic factors are essential for the survival and differentiation of developing neurons and protecting them against damage under pathologic conditions. Cerebrolysin is a peptide preparation that mimics the pleiotropic effects of neurotrophic factors. Several clinical trials investigating the therapeutic efficacy of Cerebrolysin in AD and VaD have confirmed the proof of concept. The results of these trials have shown statistically significant and clinically relevant treatment effects of Cerebrolysin on cognitive, global and functional domains in mild to moderately severe stages of dementia. Doses of 10 and 30 mL were the most effective, but higher doses of up to 60 mL turned out to be most effective in improving neuropsychiatric symptoms, which become relevant at later stages of the disease. Combining treatment with cholinesterase inhibitors and Cerebrolysin indicated long-term synergistic treatment effects in mild to moderate AD. The efficacy of Cerebrolysin persisted for up to several months after treatment suggesting Cerebrolysin has not merely symptomatic benefits, but a disease-delaying potential. This paper reviews the clinical efficacy of Cerebrolysin in the treatment of dementia. Data were obtained from international, multicenter, randomized clinical trials performed in compliance with Good Clinical Practice and the principles of the Declaration of Helsinki (1964) and subsequent revisions. Copyright © 2012 Prous Science, S.A.U. or its licensors. All rights reserved.


Kappos L.,University of Basel | Hartung H.-P.,Heinrich Heine University Düsseldorf | Freedman M.S.,Ottawa Hospital Research Institute | Boyko A.,Russian National Research Medical University | And 7 more authors.
The Lancet Neurology | Year: 2014

Background: Depletion of B lymphocytes is associated with suppression of inflammatory activity in multiple sclerosis. We aimed to assess the safety and efficacy of atacicept, a recombinant fusion protein that suppresses B-cell function and antibody production. Methods: In this placebo-controlled, double-blind, 36-week, phase 2 trial (ATAMS) in Australia, Canada, Europe, and the USA, patients aged 18-60 years with relapsing multiple sclerosis were randomly assigned via an interactive voice response system in a 1:1:1:1 ratio, stratified by geographical region, to receive weekly subcutaneous injections with atacicept (25, 75, or 150 mg) or placebo. Both patients and study personnel were masked to treatment assignment. The primary endpoint was the change in mean number of gadolinium-enhancing lesions on T1-weighted MRI per patient per scan between weeks 12 and 36. Efficacy endpoints were analysed in the intention-to-treat population. Patients who completed week 36 were eligible to participate in a long-term extension study (ATAMS EXT), consisting of a double-blind phase followed by an open-label phase, for a total study time of up to 5 years. The study was terminated early after the independent data and safety monitoring board noted an increased annualised relapse rate with atacicept. The protocol was subsequently amended to include a 60-week safety follow-up, to allow treatment with approved multiple sclerosis drugs, and to change the primary endpoint to gadolinium-enhancing T1 lesions per scan during the entire double-blind period of ATAMS. Both the trial and the extension are registered with ClinicalTrials.gov, numbers NCT00642902 (ATAMS) and NCT00853762 (ATAMS EXT). Findings: Between April 23, 2008, and early study termination on Sept 11, 2009, 255 patients were randomly assigned: 63 to placebo, 63 to atacicept 25 mg, 64 to 75 mg, and 65 to 150 mg. 90 (35%) patients completed the week 36 treatment visit, 26 (10%) discontinued before study termination (including one who dropped out before receiving study treatment), and 139 (55%) discontinued because of study termination. During the double-blind period of ATAMS, annualised relapse rates were higher in the atacicept groups than in the placebo group (atacicept 25 mg, 0·86, 95% CI 0·43-1·74; 75 mg, 0·79, 0·40-1·58; 150 mg, 0·98, 0·52-1·81; placebo, 0·38, 0·17-0·87). Mean numbers of gadolinium-enhancing T1 lesions per scan were similar in all groups (25 mg, 2·26, 0·97-5·27; 75 mg, 2·30, 1·08-4·92; 150 mg, 2·49, 1·18-5·27; placebo, 3·07, 1·40-6·77). Seven patients (one taking placebo and six atacicept) discontinued treatment because of adverse events. One death occurred in the placebo group. During the safety follow-up, immunoglobulin concentrations and B-cell counts returned towards predose values and annualised relapse rates in the atacicept groups decreased until they were similar to that of the placebo group. Interpretation: Increased clinical disease activity associated with atacicept suggests that the role of B cells and humoral immunity in multiple sclerosis is complex. For studies that explore therapeutic immunomodulation in multiple sclerosis, rigorous monitoring for negative effects on clinical and MRI outcomes is warranted. Funding: Merck Serono (Merck KGaA) and EMD Serono (Merck KGaA). © 2014 Elsevier Ltd.


Alipieva K.,Bulgarian Academy of Science | Korkina L.,Russian National Research Medical University | Orhan I.E.,Gazi University | Georgiev M.I.,Bulgarian Academy of Science
Biotechnology Advances | Year: 2014

Phenylethanoid glycosides are naturally occurring water-soluble compounds with remarkable biological properties that are widely distributed in the plant kingdom. Verbascoside is a phenylethanoid glycoside that was first isolated from mullein but is also found in several other plant species. It has also been produced by in vitro plant culture systems, including genetically transformed roots (so-called 'hairy roots'). Verbascoside is hydrophilic in nature and possesses pharmacologically beneficial activities for human health, including antioxidant, anti-inflammatory and antineoplastic properties in addition to numerous wound-healing and neuroprotective properties. Recent advances with regard to the distribution, (bio)synthesis and bioproduction of verbascoside are summarised in this review. We also discuss its prominent pharmacological properties and outline future perspectives for its potential application. © 2014 Elsevier Inc.


Buchachenko A.L.,Moscow State University | Orlov A.P.,Russian National Research Medical University | Kuznetsov D.A.,Moscow State University | Breslavskaya N.N.,RAS Institute of Chemistry
Nucleic Acids Research | Year: 2013

Magnetic isotope and magnetic field effects on the rate of DNA synthesis catalysed by polymerases β with isotopic ions 24Mg2+, 25Mg2+ and 26Mg2+ in the catalytic sites were detected. No difference in enzymatic activity was found between polymerases β carrying 24Mg2+ and 26Mg2+ ions with spinless, non-magnetic nuclei 24Mg and 26Mg. However, 25Mg2+ ions with magnetic nucleus 25Mg were shown to suppress enzymatic activity by two to three times with respect to the enzymatic activity of polymerases β with 24Mg2+ and 26Mg2+ ions. Such an isotopic dependence directly indicates that in the DNA synthesis magnetic mass-independent isotope effect functions. Similar effect is exhibited by polymerases β with Zn2+ ions carrying magnetic 67Zn and non-magnetic 64Zn nuclei, respectively. A new, ion-radical mechanism of the DNA synthesis is suggested to explain these effects. Magnetic field dependence of the magnesium-catalysed DNA synthesis is in a perfect agreement with the proposed ion-radical mechanism. It is pointed out that the magnetic isotope and magnetic field effects may be used for medicinal purposes (trans-cranial magnetic treatment of cognitive deceases, cell proliferation, control of the cancer cells, etc). © 2013 The Author(s). Published by Oxford University Press.


Terentiev A.A.,Russian National Research Medical University | Moldogazieva N.T.,Russian National Research Medical University
Tumor Biology | Year: 2013

Alpha-fetoprotein (AFP) is a major mammalian embryo-specific and tumor-associated protein that is also present in small quantities in adults at normal conditions. Discovery of the phenomenon of AFP biosynthesis in carcinogenesis by G. Abelev and Yu. Tatarinov 50 years ago, in 1963, provoked intensive studies of this protein. AFPs of some mammalian species were isolated, purified and physico-chemically and immunochemically characterized. Despite the significant success in study of AFP, its three-dimensional structure, mechanisms of receptor binding along with a structure of the receptor itself and, what is the most important, its biological role in embryo- and carcinogenesis remain still obscure. Due to difficulties linked with methodological limitations, research of AFP was to some extent extinguished by the 1990s. However, over the last decade a growing number of investigations of AFP and its usage as a tumor-specific biomarker have been observed. This was caused by the use of new technologies, primarily, computer-based and genetic engineering approaches in studying of this very important oncodevelopmental protein. Our review summarizes efforts of different scientific groups throughout the world in studying AFP for 50 years with emphasis on detailed description of recent achievements in this field. © 2013 International Society of Oncology and BioMarkers (ISOBM).


Abramochkin D.V.,Russian National Research Medical University | Vornanen M.,University of Eastern Finland
Comparative Biochemistry and Physiology -Part A : Molecular and Integrative Physiology | Year: 2014

KB-R7943 (2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea) was developed as a specific inhibitor of the sarcolemmal sodium-calcium exchanger (NCX) with potential experimental and therapeutic use. However, in cardiomyocytes KB-R7943 also effectively blocks several K+ currents including the delayed rectifier, IKr, and background inward rectifier, IK1. In the present study we analyze the effects of KB-R7943 on the ATP-dependent potassium current (IKATP) recorded by whole-cell patch-clamp in ventricular cardiomyocytes from a mammal (mouse) and a fish (crucian carp). IKATP was induced by external application of a mitochondrial uncoupler CCCP (3×10-7M) and internal perfusion of the cell with ATP-free pipette solution. A weakly inwardly rectifying current with a large outward component, recorded in the presence of CCCP, was blocked with 10-5M glibenclamide by 56.1±4.6% and 56.9±3.6% in crucian carp and mouse ventricular myocytes, respectively. In fish cardiomyocytes IKATP was blocked by KB-R7943 with an IC50 value of 3.14×10-7M, while in mammalian cells IC50 was 2.8×10-6M (P<0.05). 10-5M KB-R7943 inhibited CCCP-induced IKATP by 99.9±0.13% and 97.5±1.2% in crucian carp and mouse ventricular myocytes, respectively. In crucian carp the IKATP is about an order of magnitude more sensitive to KB-R7943 than the background IK1, but in mammals IKATP and IK1 are almost equally sensitive to KB-R7943. Therefore, the ability of KB-R7943 to block IKATP should be taken into account together with INCX inhibition when investigating possible cardioprotective effects of this compound. © 2014 Elsevier Inc.


Bazykin G.A.,Russian National Research Medical University
Biology Letters | Year: 2015

The fitness landscape-the function that relates genotypes to fitness-and its role in directing evolution are a central object of evolutionary biology. However, its huge dimensionality precludes understanding of even the basic aspects of its shape. One way to approach it is to ask a simpler question: what are the properties of a function that assigns fitness to each possible variant at just one particular site-a single position fitness landscape-and how does it change in the course of evolution? Analyses of genomic data from multiple species and multiple individuals within a species have proved beyond reasonable doubt that fitness functions of positions throughout the genome do themselves change with time, thus shaping protein evolution. Here, I will briefly review the literature that addresses these dynamics, focusing on recent genome-scale analyses of fitness functions of amino acid sites, i.e. vectors of fitnesses of 20 individual amino acid variants at a given position of a protein. The set of amino acids that confer high fitness at a particular position changes with time, and the rate of this change is comparable with the rate at which a position evolves, implying that this process plays a major role in evolutionary dynamics. However, the causes of these changes remain largely unclear. © 2015 The Author(s) Published by the Royal Society. All rights reserved.


Chekhonin V.P.,Russian National Research Medical University | Shein S.A.,Russian National Research Medical University | Korchagina A.A.,Russian National Research Medical University | Gurina O.I.,Serbsky National Research Center for Social and Forensic Psychiatry
Current Cancer Drug Targets | Year: 2013

Progression of solid tumors depends on vascularization and angiogenesis in a malignant tissue. Among a whole range of proangiogenic factors, a vascular endothelial growth factor A (VEGF-A) plays a key role. Blockade of VEGF may lead to regression of vascular network and inhibition of a tumor growth. In the present time, bevacizumab has been introduced into wide clinical practice in therapy of breast cancer, colorectal cancer and recurrent high-grade gliomas (HGGs). Coadministration of antiangiogenic therapy with irinotecan may increase probability of the response to the treatment and prolong progression-free survival rate (PFS). Moreover, bevacizumab is well tolerated and significantly improves patient's quality of life. However, in the case of brain tumors, the efficiency of such an approach is controversial. The antiangiogenic therapy can slightly delay tumor growth and does not lead to complete recovery. In addition, it contributes to enhanced tumor cell invasion into the normal brain. The mechanisms of resistance include activation of alternative proangiogenic signaling pathways, of an invasive population of tumor cells, metabolic change toward glycolysis and recruitment of myeloid bone marrow-derived cells to tumors. Obviously, that anti-VEGF therapy as monotherapy was not effective against HGGs. To enhance the antitumor treatment efficacy, it is necessary to develop a multi-target strategy to inhibit critical processes in malignancy progression such as angiogenesis, invasion, autophagy, metastatic spread, recruitment of bone marrow-derived endothelial cells and tumor stem-like cells. In addition, anti-VEGF antibodies have shown a promising result as a tumor-targeting vector for delivery therapeutic and diagnostic drugs in brain tumors. © 2013 Bentham Science Publishers.


Abramochkin D.V.,Russian National Research Medical University | Lozinsky I.T.,Russian National Research Medical University | Kamkin A.,Russian National Research Medical University
Journal of Molecular and Cellular Cardiology | Year: 2014

Cardiac fibroblasts are an essential component of cardiac tissue. These cells not only produce the extracellular matrix, but also are electrically and mechanically coupled with cardiomyocytes. In this way, fibroblasts can influence the electrical activity of cardiomyocytes. Cardiac fibroblasts cannot generate action potentials, but their membrane potential is controlled by mechanical stretch or compression of the surrounding myocardium which in turn affects their interaction with myocytes and the way myocytes respond to mechanical stress. This review discusses the electrical properties of cardiac fibroblasts, the present evidence of fibroblast-myocyte coupling and the way in which these cells respond to mechanical stress. This article is part of a Special Issue entitled "Myocyte-Fibroblast Signalling in Myocardium.". © 2013 Elsevier Ltd.

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