ABSTRACT
INTRODUCTION: Combination antiretroviral therapy is currently the main component of treatment for human immunodeficiency virus (HIV) infected patients. At the same time, the high mutational potential of the virus and the frequency of side effects of existing drugs dictate the need for the development and preclinical study of new, more effective and safer compounds.The aim of the study is to evaluate the specific types of toxicity of a new non-nucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RNA-dependent DNA revertase) (NNRTI) based on the substance 1-[2-(2-benzoylphenoxy)ethyl]-6-methyluracil, a benzophenone derivative. MATERIAL AND METHODS: The study investigated reproductive toxicity, embryotoxicity, immunotoxicity, genotoxic (in micronucleus test in and comet assay) and allergenic properties of the test itemcompound. It was tested on three species of animals in two doses: the estimated therapeutic dose (1 TD) and its tenfold equivalent (10 TD). Taking into account the metabolic coefficients, the doses for rats (Rattus) were 9 and 90 mg/kg, for mice (Mus musculus), 21 and 210 mg/kg, and for guinea pigs (Cavia porcellus), 8 and 80 mg/kg, respectively. RESULTS AND DISCUSSION: According to the obtained results, a favorable safety profile of the tested compound was established. Negative effects on the immune system, reproductive function, the body of pregnant animals and the fetus were not observed, as well as the compound did not have genotoxic and allergenic properties. CONCLUSION: These data allows to consider the studied compound as a promising therapeutic candidate for the treatment of HIV-1 infection.
Subject(s)
Anti-HIV Agents , HIV Infections , HIV-1 , Animals , Anti-HIV Agents/therapeutic use , Anti-HIV Agents/toxicity , Guinea Pigs , HIV Infections/drug therapy , HIV Reverse Transcriptase/genetics , HIV Reverse Transcriptase/pharmacology , HIV Reverse Transcriptase/therapeutic use , HIV-1/genetics , Humans , Lentivirus , Mice , RNA-Directed DNA Polymerase/pharmacology , RNA-Directed DNA Polymerase/therapeutic use , Rats , Retroviridae , Reverse Transcriptase Inhibitors/therapeutic use , Reverse Transcriptase Inhibitors/toxicity , Uracil/analogs & derivativesABSTRACT
Male infertility represents a severe social and medical challenge. In recent years the progress in regenerative medicine promoted the development of novel options to overcome this medical condition. We are elaborating a promising approach to restore spermatogenesis using mesenchymal stromal cell (MSC) secretome components as a novel class of cell-free cell therapy medicinal products for regenerative medicine. However, the choice of the representative in vivo model of spermatogenesis failure to evaluate the effectiveness of regenerative drugs remains challenging. Using the rat model of bilateral abdominal cryptorchidism, we studied the contribution of MSC conditioned medium contained bioactive cell secreted products to the spermatogenesis recovery. The feasibility of this model to evaluate the drug-driven regenerative effects on spermatogenesis restoration after the injury was demonstrated. We revealed significant correlations between the extent of spermatogonial stem cell niche recovery, spermatozoa count and serum concentration of androgens as an indicator of Leydig cell function. The obtained results can be applied in preclinical studies to choose the proper criteria to appraise the specific activity of novel regenerative drugs developed for the treatment of non-obstructive spermatogenesis disorders.
Subject(s)
Cryptorchidism/pathology , Mesenchymal Stem Cells/pathology , Regeneration/physiology , Androgens/metabolism , Animals , Cryptorchidism/metabolism , Culture Media, Conditioned/metabolism , Disease Models, Animal , Humans , Leydig Cells/metabolism , Leydig Cells/pathology , Male , Mesenchymal Stem Cells/metabolism , Rats , Rats, Wistar , Regenerative Medicine/methods , Spermatogenesis/physiology , Spermatozoa/metabolism , Spermatozoa/pathologyABSTRACT
Capillary zone electrophoresis (CZE) was used for determination of rifabutin (RFB), an anti-tuberculosis antibiotic drug, in various pharmaceutical formulations. Apart from that, simultaneous determination of RFB and human serum albumin (HSA) was performed. Electrophoretic behaviour of RFB was examined at various pH levels. CE conditions: a quartz capillary tube (internal diameter 75mm, effective length 50cm, total length 60cm), the capillary temperature was 25°Ð¡, the voltage applied to the capillary tube was +20kV, the UV detection wavelength was 214nm, hydrodynamic injection of the sample was performed at 30mbar for 5s, tetraborate buffer solution (0.01Ð, ÑÐ9.2). The obtained results are characterized by high efficiency (number of theoretical plates up to 260,000) and sufficient sensitivity (LOQ starting from 0.02µg/ml for RFB). The obtained data are in good accord with both HPLC results (for RFB) and spectrophotometry (for HSA).
Subject(s)
Chemistry, Pharmaceutical/methods , Rifabutin/analysis , Serum Albumin, Human/analysis , Anti-Bacterial Agents/analysis , Anti-Bacterial Agents/chemistry , Drug Compounding , Electrophoresis, Capillary/methods , Humans , Rifabutin/chemistry , Serum Albumin, Human/chemistryABSTRACT
Rifapentine belongs to the most potent antituberculosis drugs. Nevertheless, there are some limitations for its clinical use because of the low aqueous solubility and side effects. A technological approach to development of rifapentine intravenous formulation based on human serum albumin was described earlier and its efficacy against experimental tuberculosis was estimated. Toxicological evaluation of that water-compatible form of rifapentine revealed its low acute toxicity (LD50 340 mg/kg). Chronic toxicity tests of both the oral substance and the injectable formulation of rifapentine demonstrated similar adverse effects. However, in contrast to the conventional oral formulations, the intravenous formulation of rifapentine had no gastrointestinal toxic effects or cardiotoxicity, thus suggesting its usefulness for clinical application.
Subject(s)
Antitubercular Agents/toxicity , Heart/drug effects , Rifampin/analogs & derivatives , Serum Albumin, Human/chemistry , Stomach/drug effects , Administration, Oral , Alkaline Phosphatase/blood , Animals , Antitubercular Agents/chemistry , Bilirubin/blood , Female , Humans , Injections, Intravenous , Kidney/drug effects , Lethal Dose 50 , Liver/drug effects , Male , Mice , Rats , Rifampin/chemistry , Rifampin/toxicity , Serum Albumin, Human/administration & dosage , Solubility , Sonication , Spleen/drug effects , Toxicity Tests, Acute , Toxicity Tests, ChronicABSTRACT
Human recombinant erythropoietin adsorbed on poly(butyl)cyanoacrylate nanoparticles and administered intraperitoneally in a dose of 0.05 mg/kg exhibited a neuroprotective effect in experimental intracerebral posttraumatic hematomas (hemorrhagic stroke) and reduced animal mortality. Human recombinant erythropoietin, native and adsorbed on lactic and glycolic acid copolymer-based nanoparticles, exhibited no antistroke effect on this model. Analysis of reverse transcription PCR products showed that human recombinant erythropoietin adsorbed on poly(butyl)cyanoacrylate nanoparticles more than 2-fold increased the expression of BDNF and NGF neurotrophins in the rat brain frontal cortex and hippocampus.
