ABSTRACT
Effectiveness of the granulocyte colony-stimulating factor immobilized by using electronbeam synthesis nanotechnology was investigated on the model of experimental testicular failure caused by the toxic effect on stem spermatogonia. Administration of the drug to experimental paclitaxel-treated animals increased the number of sources of the proliferative pool of spermatogenesis and its productivity. The effectiveness of immobilized granulocyte colony-stimulating factor was based on its ability to stimulate reparative regeneration of the spermatogenic tissue, which manifested in a decrease in spermatogenic layer maturity and increase in the number of microenvironment cells. Effectiveness of the immobilized form of the drug was superior to that of non-immobilized form.
Subject(s)
Granulocyte Colony-Stimulating Factor/pharmacology , Immobilized Proteins/pharmacology , Infertility, Male/drug therapy , Spermatogonia/physiology , Animals , Antineoplastic Agents/adverse effects , Drug Evaluation, Preclinical , Granulocyte Colony-Stimulating Factor/therapeutic use , Immobilized Proteins/therapeutic use , Infertility, Male/chemically induced , Male , Nanotechnology , Paclitaxel/adverse effects , Rats, Wistar , Regeneration , Spermatogenesis , Spermatogonia/drug effectsABSTRACT
Course treatment with IFN-α2b immobilized on polyethylene glycol stimulates phagocytic activity of peritoneal macrophages and neutrophils, enhances humoral immune response in CBA/CaLac mice, stimulates IL-4 synthesis, and suppresses IFN-γ production by mitogenstimulated splenocytes from experimental animals.
Subject(s)
Adjuvants, Immunologic/administration & dosage , Drug Carriers/administration & dosage , Interferon-alpha/administration & dosage , Macrophages, Peritoneal/drug effects , Polyethylene Glycols/administration & dosage , Animals , Antigen Presentation/drug effects , Cells, Cultured , Drug Evaluation, Preclinical , Immunity, Cellular/drug effects , Immunity, Humoral/drug effects , Interferon alpha-2 , Macrophages, Peritoneal/immunology , Male , Mice, Inbred CBA , Neutrophils/drug effects , Neutrophils/immunology , Phagocytosis/drug effects , Spleen/drug effects , Staphylococcus aureus/immunologyABSTRACT
Within the framework of the multicenter randomized placebo-controlled double-blind clinical trial "VETTER-1" the authors carried out assessment of therapeutic efficacy and safety of oral drug Thrombovasim® possessing a thrombolytic effect in comprehensive treatment of lower-extremity deep vein thrombosis (LEDVT). The clinical study comprised a total of 154 patients. All patients received standard therapy accepted in LEDVT. The patients were subdivided into 4 groups. Patients from the three study groups received Thrombovasim® at a daily dose of 1,600, 3,200, and 4,800 IU. The control group patients were given placebo. Efficacy was assessed by the results of ultrasound duplex scanning first performed before treatment commenced and then after it terminated. The relative frequency of positive dynamics according to the findings of instrumental methods of study in patients taking Thrombovasim® amounted to 0.728 and in the group of patients receiving placebo to 0.585, p=0.0031. Comparing the degree of blood flow normalization in the zone of the compromised blood flow revealed a pronounced dose-dependent effect: in patients taking the drug at a daily dose of 1,600 IU, the relative frequency of positive dynamics amounted to 0.707 corresponding to an increase in therapeutic efficacy by 21%, for a dose of 3,200 IU these parameters amounted to 0.0257 and 24% and for 4,800 IU - 0.747 and 28%, respectively. In patients taking Thrombovasim® there were no cases of negative dynamics observed. Of the patients taking Thrombovasim®, none developed undesirable or severe adverse events. Inclusion of Thrombovasim® into the composition of comprehensive therapy for LEDVT increases efficacy of treatment at the expense of a spontaneous thrombolytic effect. The most effective dose amounted to 4,800 IU daily. Thrombovasim® turned out to be an efficient and safe agent in treatment of venous thromboses.
Subject(s)
Anticoagulants , Fibrinolytic Agents , Venous Thrombosis , Administration, Oral , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Anticoagulants/administration & dosage , Anticoagulants/adverse effects , Dose-Response Relationship, Drug , Double-Blind Method , Drug Monitoring/methods , Drug Therapy, Combination/methods , Female , Fibrinolytic Agents/administration & dosage , Fibrinolytic Agents/adverse effects , Humans , Lower Extremity/blood supply , Male , Middle Aged , Treatment Outcome , Ultrasonography, Doppler, Duplex/methods , Vascular Patency , Venous Thrombosis/diagnosis , Venous Thrombosis/drug therapy , Venous Thrombosis/physiopathologyABSTRACT
Recent years have witnessed an increased worldwide interest in medical use of unique naturally occurring enzymes - subtilisins possessing pronounced fibrinolytic and anti-inflammatory properties. The article deals with experience in clinical administration in vascular surgery of new therapeutic agent Thrombovasim® containing pegylated subtilisin as an active substance. Thrombovasim® has a favourable profile of safety, good tolerance and causes no severe haemorrhagic complications. The pharmacological action of Thrombovasim® consists in combination of the targeted effect on the fibrin carcass of the thrombus without participation of the own system of haemostasis and anti-inflammatory effect. In the Russian Federation Thrombovasim® has been used for 6 years predominantly in vascular pathology of lower limbs accompanied by the development of chronic venous insufficiency.
Subject(s)
Subtilisin/administration & dosage , Thrombolytic Therapy/methods , Vascular Surgical Procedures/methods , Venous Insufficiency/drug therapy , Venous Insufficiency/surgery , Chronic Disease , Humans , Treatment OutcomeABSTRACT
Population of spermatogonia was reduced in 2, 3, and 6 months after single intravenous injection of antitumor drug paclitaxel in maximum tolerated dose (MTD). The count of Sertoli cell increased in 3 months after the start of the experiment. The maturity of the seminiferous tubule epithelium was lower than in intact rats. Spermatogenesis productivity did not differ from that in intact animals 6 months after start of the experiment. These data indicate that regeneration of the spermatogenous tissue after paclitaxel treatment is realized via renewal of the spermatogenic epithelium, but considering the amount of spermatogonial cell population, the recovery rate would be low.
Subject(s)
Antineoplastic Agents, Phytogenic/toxicity , Paclitaxel/toxicity , Regeneration , Seminiferous Tubules/physiopathology , Sertoli Cells/physiology , Animals , Male , Maximum Tolerated Dose , Rats, Wistar , Seminiferous Tubules/drug effects , Sertoli Cells/drug effects , Spermatogenesis , Spermatogonia/drug effects , Spermatogonia/physiologyABSTRACT
Productivity of spermatogenesis and the population of spermatogonial cells were substantially reduced in male Wistar rats 3 months after administration of cytostatic drug paclitaxel, damaging stem spermatogonia. However, signs of reparative regeneration appeared in the testicular tissue. In animals receiving paclitaxel in combination with granulocyte CSF, the same period of observation, the number of spermatogonia and the efficiency of spermatogenesis at the same terms of the study did not differ from those in intact animals. Intensive recovery processes started 1 month earlier than after administration of paclitaxel alone. These data attest to pronounced potentiating effect of granulocyte CSF on reparative regeneration of the testicular tissue.
Subject(s)
Granulocyte Colony-Stimulating Factor/therapeutic use , Paclitaxel/toxicity , Regeneration/drug effects , Spermatogenesis/drug effects , Testis/pathology , Animals , Male , Rats , Rats, Wistar , Spermatogonia/metabolismABSTRACT
The effect of immobilized hyaluronidase on stem and progenitor cells of the lungs was studied on the model of partially reversible toxic bleomycin-induced pulmonary fibrosis in C57Bl/6 mice. During the inflammation phase, immobilized hyaluronidase reduced infiltration of alveolar interstitium with hemopoietic stem cells Sca-1(+), c-Kit(+), CD34(-), (CD3, CD45R (B220), Ly6C, Ly6G (Gr1), CD11b (Mac1), TER-119)(-). Improvement of histological parameters of bleomycin lungs during the phase of collagen fiber deposition after the treatment was accompanied by accumulation of mesenchymal multipotent stromal cells (CD31(-), CD34(-), CD45(-), CD44(+), CD73(+), CD90(+), CD106(+)decrease in the population of pan-hemopoietic cells (CD45(+)), accelerated restoration of the content of endothelial cells, and inhibition of clonal activity of fibroblast precursors (CD45(-)).
Subject(s)
Enzymes, Immobilized/administration & dosage , Hyaluronoglucosaminidase/administration & dosage , Pulmonary Fibrosis/pathology , Stem Cells/metabolism , Animals , Antigens, CD/metabolism , Bone Marrow/immunology , Bone Marrow/pathology , Lung/pathology , Mice, Inbred C57BL , Pulmonary Fibrosis/drug therapy , Pulmonary Fibrosis/immunology , Stem Cells/drug effectsABSTRACT
Antifibrotic activity of intranasally administered conjugates of pluronics L31 and F68 with hyaluronate-endo-ß-N-acetylhexosaminidase was studied in C57Bl/6 mice under conditions of single and repeated bleomycin-induced injury to the alveolar epithelium. Conjugates were prepared using the technique of protein immobilization with ionizing radiation. We demonstrate that in cases of single and repeated injuries to the alveolar epithelium, the conjugates administered during phases of inflammation or deposition of fibrotic masses prevent the development of pulmonary fibrosis. The conjugates demonstrated more pronounced antifibrotic activity than hyaluronate-endo-ß-N-acetylhexosaminidase. The conjugate based on hydrophobic pluronic L31 showed higher effectiveness in comparison with the conjugate based on amphiphilic pluronic F68.
Subject(s)
Enzymes, Immobilized/pharmacology , Fibrinolytic Agents/pharmacology , Hyaluronic Acid/chemistry , Poloxamer/chemistry , Pulmonary Fibrosis/prevention & control , beta-N-Acetylhexosaminidases/pharmacology , Administration, Intranasal , Animals , Bleomycin , Enzymes, Immobilized/chemistry , Fibrinolytic Agents/chemistry , Hydrophobic and Hydrophilic Interactions , Mice , Mice, Inbred C57BL , Pulmonary Alveoli/drug effects , Pulmonary Alveoli/pathology , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/pathology , Radiation, Ionizing , beta-N-Acetylhexosaminidases/chemistryABSTRACT
Hyaluronidase immobilized on polyethylenoxide obtained by electron bean synthesis was administered intranasally and intravenously to C57Bl/6 mice after intratracheal bleomycin and the enzyme effects on the development of pneumofibrosis in animals were studied. Intranasal immobilized hyaluronidase prevented connective tissue growth in the lungs exposed to bleomycin and virtually did not modulate the infiltration of the alveolar and alveolar duct interstitium by inflammatory cells (lymphocytes, macrophages, neutrophils, plasma cells). The antifibrotic effect developed sooner after intranasal inoculation of immobilized hyaluronidase and was more pronounced than after intranasal native hyaluronidase. Intravenous injection of immobilized hyaluronidase did not modify the inflammatory process and deposition of collagen fibrils in the lung parenchyma in pneumofibrosis.
Subject(s)
Connective Tissue/drug effects , Enzymes, Immobilized/therapeutic use , Hyaluronoglucosaminidase/therapeutic use , Inflammation/drug therapy , Pulmonary Fibrosis/drug therapy , Animals , Bleomycin , Connective Tissue Cells/drug effects , Hyaluronic Acid/metabolism , Hyaluronoglucosaminidase/administration & dosage , Hyaluronoglucosaminidase/metabolism , Inflammation/chemically induced , Leukocyte Count , Lung/drug effects , Lung/pathology , Lymphocyte Count , Lymphocytes/immunology , Macrophages/immunology , Mice , Mice, Inbred C57BL , Neutrophils/immunology , Plasma Cells/immunology , Polyethylene Glycols/administration & dosage , Pulmonary Fibrosis/chemically inducedABSTRACT
The possibility of boosting antifibrotic activity of testicular hyaluronidase immobilized on polyethylene oxide with spiperone was studied on the bleomycin models of a single (partially reversible pneumofibrosis) and repeated (irreversible pneumofibrosis) injuries to the alveolar epithelium in C57Bl/6 mice. The antifibrotic effect was more pronounced after successive treatment with immobilized hyaluronidase and spiperone than after individual treatment with each of the compounds: no collagen deposition in the parenchyma of bleomycin-damaged lungs was found. The decrease in inflammatory cell (lymphocytes, macrophages, neutrophils, plasma cells) infiltration of the alveoli and alveolar tracts interstitium in mice treated by immobilized hyaluronidase and spiperone did not differ from the anti-inflammatory effect of spiperone monotherapy.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Hyaluronoglucosaminidase/pharmacology , Pulmonary Fibrosis/drug therapy , Spiperone/pharmacology , Animals , Anti-Inflammatory Agents/therapeutic use , Bleomycin , Collagen/metabolism , Drug Evaluation, Preclinical , Drug Therapy, Combination , Enzymes, Immobilized/pharmacology , Enzymes, Immobilized/therapeutic use , Hyaluronoglucosaminidase/therapeutic use , Lung/drug effects , Lung/metabolism , Lung/pathology , Mice , Mice, Inbred C57BL , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/prevention & control , Spiperone/therapeutic useABSTRACT
Antifibrotic activity of testicular hyaluronidase, immobilized on polyethylenoxide and obtained by electron beam synthesis, was studied on the model of bleomycin injuries to the alveolar epithelium (irreversible pneumofibrosis) in C57Bl/6 mice and compared to the effect of testicular hyaluronidase. Intranasal therapy with immobilized and testicular hyaluronidases prevented the deposition of fibrotic mass in the parenchyma of "bleomycin" lungs. The effect of immobilized hyaluronidase was more pronounced than that of testicular hyaluronidase. The studied compounds were virtually inessential for infiltration of the alveolar interstitium and alveolar tracts by lymphocytes, macrophages, neutrophils, and plasma cells. Unchanged histoarchitectonics of bleomycin-damaged lungs in immobilized hyaluronidase therapy was due to suppression of the progenitor fibroblast cells (CD45(-)).
Subject(s)
Anti-Inflammatory Agents/administration & dosage , Hyaluronoglucosaminidase/administration & dosage , Idiopathic Pulmonary Fibrosis/drug therapy , Animals , Anti-Inflammatory Agents/chemistry , Bleomycin , Drug Carriers/administration & dosage , Drug Carriers/chemistry , Enzymes, Immobilized/administration & dosage , Enzymes, Immobilized/chemistry , Hyaluronoglucosaminidase/chemistry , Idiopathic Pulmonary Fibrosis/chemically induced , Idiopathic Pulmonary Fibrosis/pathology , Mice , Mice, Inbred C57BL , Polyethylenes/chemistry , Pulmonary Alveoli/pathology , Respiratory Mucosa/pathologyABSTRACT
We studied the effect of hyaluronate-endo-ß-N-acetylhexosaminidase on the secretory function of the liver and bone marrow microenvironment cells in chronic hepatitis. Enhanced production of substances stimulating parenchymal tissue-specific precursors and stem cell homing factors by liver cells was revealed. At the same time, production of SDF-1 and other chemoattractants and adhesion factors of progenitor cells by bone marrow elements was reduced.
Subject(s)
Bone Marrow Cells/metabolism , Chemokine CXCL12/biosynthesis , Hepatitis, Chronic/metabolism , Liver/metabolism , Polyethylene Glycols/pharmacology , Stem Cells/drug effects , beta-N-Acetylhexosaminidases/pharmacology , Animals , Bone Marrow Cells/drug effects , Cell Movement/drug effects , Cellular Microenvironment/drug effects , Hyaluronoglucosaminidase , Liver/cytology , Liver/drug effects , Male , Mice , Mice, Inbred C57BL , Stem Cells/metabolismABSTRACT
Pegylated hyaluronate-endo-ß-N-acetylhexosaminidase was shown to potentiate significantly the hemostimulatory effect of pegylated erythropoietin. It was found that enhanced production of hemopoietin by adherent and non-adherent cells of the hemopoiesis-inducing microenvironment and elevated serum content of endogenous erythropoietin along with increased susceptibility of erythroid precursors to pegylated erythropoietin underlay this phenomenon.
Subject(s)
Anemia/drug therapy , Erythropoietin/pharmacology , Hematinics/pharmacology , Polyethylene Glycols/pharmacology , beta-N-Acetylhexosaminidases/pharmacology , Anemia/chemically induced , Animals , Bone Marrow Cells/drug effects , Carboplatin , Cell Differentiation , Cell Proliferation , Cells, Cultured , Drug Synergism , Drug Therapy, Combination , Erythroid Cells/drug effects , Erythropoietin/administration & dosage , Hematinics/administration & dosage , Mice , Mice, Inbred CBA , Polyethylene Glycols/administration & dosage , Recombinant Proteins/administration & dosage , Recombinant Proteins/pharmacology , Stem Cells/drug effects , Stem Cells/physiology , beta-N-Acetylhexosaminidases/administration & dosageABSTRACT
Using the model of lung fibrosis induced by intratracheal administration of bleomycin we studied anti-fibrotic activity of combined treatment with neuroleptic haloperidol and hyaluronidase immobilized on polyethylene oxide using electron-beam synthesis. It was shown that successive administration of immobilized hyaluronidase and the neuroleptic drug inhibits deposition of collagen fibers in the bleomycin-treated lungs. Combined treatment with the test compounds reduced swelling of the alveolar epithelium, exudation and infiltration of the alveolar interstitium and alveolar passages by inflammatory cells, and desquamation of alveolocytes into alveolar lumen, so that the alveolar-capillary membrane function was preserved.
Subject(s)
Antipsychotic Agents/therapeutic use , Enzymes, Immobilized/therapeutic use , Haloperidol/therapeutic use , Hyaluronoglucosaminidase/therapeutic use , Pulmonary Fibrosis/drug therapy , Respiratory Mucosa/drug effects , Animals , Bleomycin , Capillaries/drug effects , Collagen/metabolism , Connective Tissue/drug effects , Drug Therapy, Combination , Haloperidol/pharmacology , Hyaluronoglucosaminidase/pharmacology , Inflammation/drug therapy , Lung/drug effects , Lung/pathology , Mice , Mice, Inbred C57BL , Polyethylene Glycols , Pulmonary Alveoli/drug effects , Pulmonary Alveoli/pathology , Pulmonary Fibrosis/chemically induced , Receptors, Dopamine/metabolism , Receptors, Serotonin/metabolismABSTRACT
We studied the effect of mobilization of bone marrow multipotent stem cells induced by intragastric administration of pegylated hyaluronate-endo-ß-N-acetylhexosaminidase (Peg-HEAHA) on hemopoiesis under conditions of experimental chronic hepatitis. Peg-HEAHA increased the counts of hemopoietic precursors in the hemopoietic tissue against the background of their decelerated maturation. This was paralleled by a short-term decrease in the count of neutrophilic granulocyte in the bone marrow and a slight increase of neutrophil count in the peripheral blood.
Subject(s)
Electrons , Hematopoiesis/drug effects , Hepatitis, Chronic/drug therapy , Hyaluronic Acid/chemistry , Nanoparticles/therapeutic use , beta-N-Acetylhexosaminidases/chemistry , Animals , Hepatitis, Chronic/metabolism , Male , Mice , Mice, Inbred C57BL , Nanoparticles/chemistry , Nanotechnology/methods , Regenerative Medicine/methodsABSTRACT
Pharmacological characteristics of somatotropin pegylated using electron-beam synthesis nanotechnology (PEG-STH) were studied. Oral PEG-STH stimulated the intensity of protein and lipid metabolism and endochondral bone growth without modifying the processes of periosteal and endosteal bone formation. Specific activity of this substance administered orally significantly surpassed that of parenteral non-modified growth hormone.
Subject(s)
Bone Development/drug effects , Human Growth Hormone/pharmacology , Lipid Metabolism/drug effects , Nanotechnology , Polyethylene Glycols , Proteins/metabolism , Animals , Male , Rats , Rats, WistarABSTRACT
Hypoglycemic effect of hyaluronate-endo-ß-N-acetylhexosaminidase immobilized by electron-beam synthesis nanotechnology (imHEA-HA) was studied in experimental insulin-dependent and insulin-independent diabetes mellitus. The drug exhibited a hypoglycemic effect of its own and potentiated the pharmacological effect of exogenous insulin injected in vivo. Studies on liver cell culture demonstrated an increase of cell sensitivity to insulin after treatment with imHEA-HA.
Subject(s)
Enzymes, Immobilized/therapeutic use , Glycosaminoglycans/chemistry , Hypoglycemic Agents/therapeutic use , Nanotechnology/methods , beta-N-Acetylhexosaminidases/chemistry , beta-N-Acetylhexosaminidases/therapeutic use , Animals , Diabetes Mellitus/drug therapy , Hyaluronoglucosaminidase/metabolism , Hypoglycemic Agents/chemistry , MiceABSTRACT
High hepatoprotective activity of granulocytic CSF and hyaluronidase immobilized using electron-beam immobilization technology was demonstrated on the model of CCl(4)-induced hepatitis: the preparations produced anticholestatic, anti-inflammatory, and antisclerotic effects. These effects developed against the background of stimulation of bone marrow multipotent precursor cells and their mobilization into circulation accompanied by an increase in the content of parenchymatous progenitor cells in the liver. The most pronounced positive effect was observed in combined treatment with the test preparations.
Subject(s)
Enzymes, Immobilized/therapeutic use , Granulocyte Colony-Stimulating Factor/therapeutic use , Hepatitis, Chronic/drug therapy , Hyaluronoglucosaminidase/therapeutic use , Animals , Male , Mice , Nanotechnology , Rats , Rats, Wistar , Regenerative MedicineABSTRACT
The effect of immobilized granulocyte CSF on morphological characteristics and functional state of the liver was studied during chronic toxic hepatitis. The mechanisms of the therapeutic action of this agent were evaluated. The product had a strong hepatoprotective effect and exhibited the antiinflammatory and antisclerotic properties. The mechanism of activation of reserve systems for cell renewal (involved in restoration of the liver tissue) is probably related to an increase in proliferative activity of early precursor cells in the bone marrow, mobilization of these cells into the peripheral circulation, and directed homing into the liver tissue where they activate local regenerative mechanisms and prevent hepatocyte destruction. It should be emphasized that the concentration of SDF-1 increases in the liver tissue, but decreases in the bone marrow. These changes create the concentration gradient, which determines the migration of undifferentiated precursor cells to the liver.
Subject(s)
Chemical and Drug Induced Liver Injury, Chronic/drug therapy , Chemokine CXCL12/metabolism , Granulocyte Colony-Stimulating Factor/pharmacology , Hepatitis, Chronic/metabolism , Liver/physiopathology , Animals , Bone Marrow/metabolism , Chemical and Drug Induced Liver Injury, Chronic/metabolism , Hepatocytes/metabolism , Liver/drug effects , Liver/pathology , Male , Mice , Mice, Inbred CBA , Rats , Rats, WistarABSTRACT
Immobilized hyaluronidase (nanotechnology method of electron-beam synthesis) exhibited high hepatoprotective activity on the model of Cl4-induced hepatitis. This agent produced anticholestatic, anti-inflammatory, and antisclerotic effects. These effects were shown to accompany stimulation of multipotent bone marrow precursors, mobilization of these cells into the peripheral blood, and cell migration to the target organ increasing the number of parenchymal progenitor cells in the liver. The mechanisms for targeted migration of progenitor cells suggest a decrease in SDF-1 production by bone marrow stromal cells and increase in the synthesis of this factor by microenvironmental cells of the liver tissue.