First-in-human trials of gamtbvac, a recombinant subunit tuberculosis vaccine candidate: Safety and immunogenicity assessment
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01.12.2019 |
Vasina D.
Kleymenov D.
Manuylov V.
Mazunina E.
Koptev E.
Tukhovskaya E.
Murashev A.
Gintsburg A.
Gushchin V.
Tkachuk A.
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Vaccines |
10.3390/vaccines7040166 |
0 |
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© 2019, MDPI AG. All rights reserved. Tuberculosis is known to be the biggest global health problem, causing the most deaths by a single infectious agent. Vaccine-development efforts are extremely important. This paper represents the results of the first-in-human trial of recombinant subunit tuberculosis vaccine GamTBvac in a Phase I study. GamTBvac is a new BCG booster candidate vaccine containing dextran-binding domain modified Ag85a and ESAT6-CFP10 MTB antigens and CpG ODN adjuvant, formulated with dextrans. Safety and immunogenicity of GamTBvac were estimated in an open-label clinical trial on 60 Mycobacterium tuberculosis uninfected (MTB-uninfected) volunteers previously-vaccinated with Bacillus Calmette—Guérin vaccine (BCG). The candidate vaccine had an acceptable safety profile and was well-tolerated. Three different vaccine doses with a double-immunization scheme were assessed for immunogenicity and induced a significant increase in IFN-γ in-house IGRA response and IgG ELISA analysis. Among them, the half dose vaccine group (containing DBD-ESAT6-CFP10, 12.5 μg; DBD-Ag85a, 12.5 μg; CpG (ODN 2216), 75 μg; DEAE-Dextran 500 kDa, 250 μg; and Dextran 500 kDa, 5 mg) provided high, early and stable in time immune response specific to both protein antigen fusions and is proposed for the further studies.
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Olesoxime in neurodegenerative diseases: Scrutinising a promising drug candidate
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01.10.2019 |
Weber J.
Clemensson L.
Schiöth H.
Nguyen H.
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Biochemical Pharmacology |
10.1016/j.bcp.2019.07.002 |
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© 2019 Elsevier Inc. Over the last years, the experimental compound olesoxime, a mitochondria-targeting cholesterol derivative, has emerged as a promising drug candidate for neurodegenerative diseases. Numerous preclinical studies have successfully proved olesoxime's neuroprotective properties in cell and animal models of clinical conditions such as amyotrophic lateral sclerosis, Huntington disease, Parkinson disease, peripheral neuropathy and spinal muscular atrophy. The beneficial effects were attributed to olesoxime's potential impact on oxidative stress, mitochondrial permeability transition or cholesterol homoeostasis. Although no significant benefits have been demonstrated in patients of amyotrophic lateral sclerosis, and only the first 12 months of a phase II/III clinical trial showed an improvement in motor symptoms of spinal muscular atrophy, this orphan drug may still offer undiscovered potential in the treatment of neurological diseases. In our earlier preclinical studies, we demonstrated that administration of olesoxime in mouse and rat models of Huntington disease improved psychiatric and molecular phenotypes. Aside from stabilising mitochondrial function, the drug reduced the overactivation of calpains, a class of calcium-dependent proteases entangled in neurodegenerative conditions. This observation may be credited to olesoxime's action on calcium dyshomeostasis, a further hallmark in neurodegeneration, and linked to its targets TSPO and VDAC, two proteins of the outer mitochondrial membrane associated with mitochondrial calcium handling. Further research into the mode of action of olesoxime under pathological conditions, including its effect on neuronal calcium homeostasis, may strengthen the untapped potential of olesoxime or other similar compounds as a therapeutic for neurodegenerative diseases.
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Possible Ways of Studying Pharmacokinetic Parameters of Calcium Preparations
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01.06.2018 |
Eremenko N.
Shikh E.
Serebrova S.
Goryachev D.
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Pharmaceutical Chemistry Journal |
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0 |
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© 2018, Springer Science+Business Media, LLC, part of Springer Nature. Issues pertaining to determination of the pharmacokinetic parameters of calcium preparations are examined using their comparative bioavailability as an example. Pharmacokinetic parameters of calcium such as area under the concentration—time curve (AUC) and maximum concentration (Cmax) are calculated considering the background calcium contents in volunteers. Calcium excretion with urine is assessed as clearance of creatinine, a calcium elimination factor. The dynamics of the content of parathormone (PTH), the main hormone regulating calcium homeostasis, are studied. The results can be used to plan clinical trials for assessing the pharmacokinetics of drug analogs of endogenous compounds.
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Current state of the problem of allotransplantation of Langerhans cells (achievements and prospects)
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01.01.2018 |
Alekberzade A.
Krylov N.
Adzhun Z.
Laftavi M.
Shakhbazov R.
Zuykova K.
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Khirurgiia |
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0 |
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Literature data devoted to transplantation of Langerhans cells have been analyzed. The main stages, indications, dissection of islets, immunosuppressive therapy, complications and data of the latest clinical trials were discussed.
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The modern therapy of systemic vasculitides: Perspectives and challenges
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01.01.2018 |
Novikov P.
Zykova A.
Moiseev S.
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Terapevticheskii Arkhiv |
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0 |
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© 2018 Media Sphera Publishing Group. All rights reserved. Systemic vasculitis is a heterogeneous group of inflammatory diseases, which are classified according to the diameter of the affected vessels. The treatment of systemic vasculitis is no longer empirical, because of increasing number of randomized clinical trials in this field. In recent years, there was a trend to limit the cumulative dose of glucocorticosteroids and immunosuppressive drugs, partially through biological drugs usage. However, biologic therapy is not always superior to combination of glucocorticosteroids and cytotoxic drugs. The efficacy of different biologic drugs varies in patients with different forms of systemic vasculitis, which creates the ground for personalized therapy of these diseases. Another serious problem is the absence of strict criteria to immunosuppressive therapy intensification, especially in vasculitis, affecting large vessels, due to the lack of reliable laboratory markers of disease activity. The article reviews modern approaches to the treatment of some types of systemic vasculitis, including ANCA-associated vasculitides, giant cell arteritis, Takayasu`s arteritis and cryoglobulinemic vasculitis.
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Mesenchymal stem cell therapy for ischemic heart disease: Advances and challenges
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01.01.2018 |
Konoplyannikov M.
Kotova S.
Baklaushev V.
Konoplyannikov A.
Kalsin V.
Timashev P.
Troitskiy A.
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Current Pharmaceutical Design |
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3 |
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© 2018 Bentham Science Publishers. Ischemic Heart Disease (IHD) has been recognized as the main cause of mortality in the modern world. Application of cell therapy technologies for the IHD treatment has been actively studied from the beginning of 2000s. The review is dedicated to the use of mesenchymal stem cells (MSC) in the therapy of IHD. The strategies of the MSC modification in vitro for improvement of their regenerative potential are extensively discussed, including preconditioning to enhance the cell survival, boosting their paracrine effect and manipulating their car-diomyogenic differentiation. The optimization of the MSC delivery and opportunities related to the use of biomaterials as cell carriers are also discussed. The results of the most important clinical studies on the MSC-based IHD therapy are presented, including those completed and published in the literature and the ongoing clinical trials registered at clinicaltrials.gov by June 2018.
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