ABSTRACT
Here we developed a model of chronic thromboembolic pulmonary hypertension (CTEPH) using repeated intravenous administration of microencapsulated thrombi with a controlled rate of biodegradation. Autologous thrombi encapsulated in alginate microspheres with a diameter of 190±48 µm were intravenously injected to rats 8 times every 4 days. In the comparison group, nonmodified thrombi were injected. After 6 weeks, a significant increase in systolic pressure in the right ventricle, a decrease in exercise tolerance, and an increase in the index of vascular wall hypertrophy were revealed in the group receiving injections of microencapsulated thrombi in comparison with the group receiving nonmodified thrombi and healthy animals. Thus, the developed representative CTEPH model can be used to test promising pharmacological substances.
Subject(s)
Hypertension, Pulmonary , Pulmonary Embolism , Animals , Rats , Hypertension, Pulmonary/metabolism , Pulmonary Artery/metabolism , Pulmonary Embolism/metabolism , Chronic DiseaseABSTRACT
Prospects for the development of a transdermal dosage form (DF) based on microneedles were considered. Methods for obtaining such systems, the application areas, and data from the pharmaceutical market were examined. A wide sample of INNs that are used to reduce pain in osteoarthritis patients was formed based on clinical guidelines. The market capacity, sales by Anatomical Therapeutic Chemical (ATC-2) groups, and sales depending on the DF were discussed. Criteria for the choice of active ingredients with market potential were defined. An analysis of a short list revealed that meloxicam has sufficient market potential to create a microneedle DF. A forecast of meloxicam consumption based on time series models indicated stable sales-growth dynamics and a potential market size of 4.6 billion Russian rubles by 2030. Results of the study indicated good market prospects and justification of pharmaceutical development of a new transdermal DF including meloxicam microneedles as the active ingredient.
ABSTRACT
We studied the effects of apoptotic bodies of cardiomyocytes (ApBc) and fibroblasts (ApBf) on myocardial regeneration and contractility in rats and the dynamics of RNA concentrations in cardiomyocytes and fibroblasts at different stages of apoptosis. ApBc increase the contractility of rat myocardium, while ApBf reduce it. ApBc stimulate the development of clones of cardiomyocyte precursors in the myocardium, while ApBf stimulate the formation of endothelial precursor clones. In doxorubicin cardiomyopathy, ApBc, similar to the reference drug (ACE inhibitor) improve animal survival, while ApBf produce no such effect. RNA concentrations in cardiomyocytes and fibroblasts before apoptosis and at the beginning of cell death significantly differed, while in apoptotic bodies of these cells, it was practically the same. It has been hypothesized that RNA complex present in ApBc and ApBf represents an "epigenetic code" of directed differentiation of cardiac stem cells.
Subject(s)
Aging/metabolism , Cardiomyopathies/metabolism , Culture Media/pharmacology , Extracellular Vesicles/metabolism , Fibroblasts/metabolism , Myocytes, Cardiac/metabolism , Stem Cells/metabolism , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , Apoptosis/drug effects , Cardiomyopathies/chemically induced , Cardiomyopathies/drug therapy , Cardiomyopathies/pathology , Cell Differentiation , Clone Cells , Culture Media/chemistry , Doxorubicin/toxicity , Extracellular Vesicles/chemistry , Fibroblasts/cytology , Fibroblasts/drug effects , Fosinopril/pharmacology , Male , Myocardial Contraction/drug effects , Myocardium/metabolism , Myocardium/pathology , Myocytes, Cardiac/cytology , Myocytes, Cardiac/drug effects , Primary Cell Culture , RNA/metabolism , Rats , Rats, Wistar , Signal Transduction , Stem Cells/cytology , Stem Cells/drug effectsABSTRACT
Acute myocardial infarction remains to be one of the most important problems of health care. Cardiac cell therapy is a new therapeutic strategy focused on repair of the injured cardiac muscle. Mesenchymal stem cells (MSC) are considered as the most suitable candidates for cardiac cell therapy. MSC transplantation in the myocardium after ischemic injury has been shown to be cardioprotective in animal models and clinical trials. However, the beneficial effects of MSC in humans are limited because of both poor survival and impaired function of the cells in ischemic tissue. To address these issues, a number of approaches to the modification of MSCs with the aim to improve their survival and proliferation, reduce the immune reaction, enhance transdifferentiation, and optimize the profile of secreted paracrine factors have been tested. In this review, we provide detailed discussion of different methods of MSCs modification, including targeted gene overexpression, conditioning of MSCs using physical and chemical factors, and application of multicellular units for transplantation. The effectiveness of these strategies in preclinical studies is also discussed.
Subject(s)
Cell- and Tissue-Based Therapy/methods , Immunologic Factors/pharmacology , Mesenchymal Stem Cell Transplantation/methods , Mesenchymal Stem Cells/drug effects , Myocardial Infarction/therapy , Animals , Cell Proliferation/drug effects , Cell Survival/drug effects , Cell Transdifferentiation/drug effects , Cytokines/genetics , Cytokines/immunology , Disease Models, Animal , Gene Expression , Humans , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/immunology , Mesenchymal Stem Cells/metabolism , Myocardial Infarction/genetics , Myocardial Infarction/immunology , Myocardial Infarction/pathology , Myocardium/immunology , Myocardium/metabolism , Myocardium/pathology , Paracrine Communication , Receptors, Cytokine/genetics , Receptors, Cytokine/immunology , TransgenesABSTRACT
Using the cell model of regenerative cardiomyogenesis (formation of contracting cardiomyocyte colonies from resident stem cells), we found that the addition of cardiomyocyte-derived apoptotic bodies to the culture of neonatal myocardial cells stimulated proliferation and differentiation of cardiomyocyte precursors and the frequency of their contraction was 1.5-fold higher than in the control. Systemic administration of cardiomyocyte-derived apoptotic bodies to Wistar rats with chronic postinfarction heart failure during the early period of myocardial remodeling considerably improved the contractile function of the heart.