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1.
Eksp Klin Farmakol ; 77(10): 38-43, 2014.
Article in Russian | MEDLINE | ID: mdl-25518527

ABSTRACT

Several novel compounds were found to be potent inhibitors of the HCV (JFH-1 isolate) infection in vitro. Human serum did not significantly reduce antiviral activity of the lead compound, AVR560 (< 4-fold). The immunohistochemistry studies with the Huh7 cell line, infectable with the HCV (JFH-1 strain), demonstrated that AVR560 inhibited the early steps of viral infection and blocked the spread of the HCV infection in tissue culture. The cytotoxicity in Huh7 and Vero-76 cell lines was mild. AVR560 proved to be a specific HCV inhibitor and exhibited no activity against other flaviviruses such as yellow fever (strain 17D), West Nile (strain NY99), and dengue (New Guinea type 2) in in vitro infection experiments. AVR560 also did not inhibit any of the tested human CYP450 isozymes (3A4, 1A2, 2C19 and 2D6). In the pharmacokinetic studies in mice, rats and dogs, favorable pharmacokinetic profiles and good oral bioavailability were observed for AV560. Further pre-clinical studies with this novel HCV inhibitor are in progress.


Subject(s)
Antiviral Agents/pharmacology , Hepacivirus/drug effects , Piperazines/pharmacology , Piperidines/pharmacology , Virus Internalization/drug effects , Virus Replication/drug effects , Animals , Antiviral Agents/pharmacokinetics , Cell Line, Tumor , Cell Survival/drug effects , Chlorocebus aethiops , Cytochrome P-450 Enzyme System/metabolism , Dengue Virus/drug effects , Dengue Virus/growth & development , Dogs , Drug Evaluation, Preclinical , Hepacivirus/physiology , Hepatitis C/drug therapy , Hepatitis C/virology , Hepatocytes/drug effects , Hepatocytes/virology , Humans , Mice , Piperazines/pharmacokinetics , Piperidines/pharmacokinetics , Rats , Vero Cells , West Nile virus/drug effects , West Nile virus/growth & development , Yellow fever virus/drug effects , Yellow fever virus/growth & development
2.
Eksp Klin Farmakol ; 77(4): 33-41, 2014.
Article in Russian | MEDLINE | ID: mdl-25076758

ABSTRACT

In vitro immunohistochemical investigations on the human hepatoma cell line (Huh7) infected with hepatitis C virus (HCV) strain JFH-1 showed that AV0012 compound blocks the early stages of viral infection. AV0012 also blocked viral infection spread in tissue culture through the secreted virus and through tight cell-to-cell contact. AV0012 is a specific inhibitor of HCV but not of related pestivirus, flaviviruses and other RNA-containing viruses such as bovine diarrhea (BVDV), Venezuelan equine encephalitis (strain TC-83), dengue type 2 (New Guinea), yellow fever (strain 17D), west Nile fever, parainfluenza (type 3) virus, RSV (strain A2), and Rhinovirus (type 2 strain HGP). It is established that human serum does not significantly affect the antiviral activity of AV0012 in vitro. The drug combination studies with AV0012 and interferon alpha 2a in vitro showed that the two inhibitors act additively, which makes possible the use of this combination in clinical tests. AV0012 is highly soluble and stable in aqueous solutions and murine blood plasma, has limited metabolic stability, low binding to human plasma proteins, high permeability through biological membranes, and only interacts with isoenzymes 2D6 and 3A4 of human cytochrome P450. In animal pharmacokinetic studies, AV0012 was rapidly absorbed into the blood stream upon oral administration, showed sufficiently long half-elimination times, and had high oral bioavailability that reached 92% in monkeys. Further preclinical development of AV0012 is in progress.


Subject(s)
Antiviral Agents/pharmacology , Antiviral Agents/pharmacokinetics , Hepacivirus/metabolism , Hepatitis C/drug therapy , Hepatitis C/metabolism , Animals , Antiviral Agents/chemistry , Cattle , Cell Line , Drug Evaluation, Preclinical , Flavivirus/metabolism , Flavivirus Infections/drug therapy , Flavivirus Infections/metabolism , Haplorhini , Humans , Mice , Rats
3.
Eksp Klin Farmakol ; 77(5): 23-7, 2014.
Article in Russian | MEDLINE | ID: mdl-25033568

ABSTRACT

In the framework of preclinical testing of AV0038, ethyl 2-(dimethylaminomethyl)-5-hydroxy-1-methyl-6-(pyridin-3-yl)-1H-indole-3-carboxylate, which showed high efficiency in the prevention and treatment of influenza A/Aichi/2/69 (H3N2) in mice, we have studied the drug solubility and stability in aqueous solutions, metabolic stability in human liver microsomes, stability in blood plasma of mice and humans, binding to plasma proteins of mice and humans, pharmacokinetics and bioavailability in mice, and the acute toxicity and the maximum tolerated dose. It is established that AV0038 has attractive pharmacological properties as anti-influenza drug candidate. The therapeutic doses of AV0038 do not cause acute toxicity in mice. It is expedient to continue preclinical investigations and study the drug metabolism, metabolites, and sub-chronic toxicity in test animals.


Subject(s)
Antiviral Agents/pharmacology , Antiviral Agents/pharmacokinetics , Influenza A Virus, H3N2 Subtype , Orthomyxoviridae Infections/drug therapy , Animals , Drug Evaluation, Preclinical , Humans , Male , Maximum Tolerated Dose , Mice , Mice, Inbred BALB C , Orthomyxoviridae Infections/blood
4.
Eksp Klin Farmakol ; 77(12): 33-9, 2014.
Article in Russian | MEDLINE | ID: mdl-25739191

ABSTRACT

Pharmacological safety of a new type of HCV inhibitor, AV0012, was studied including acute, subchronic and chronic toxicity in mice, rats and monkeys. Genotoxicity was assessed using the Ames test and the chromosomal aberrations assay in the bone marrow cells of mice. It is established that AV0012 has low toxicity in SHK line mice, Wistar line rats, and monkey of Rhesus macaques species. Results obtained in the study of genetic toxicity showed that AV0012 exhibits no mutagenic activity. Data on general toxicity and mutagenicity discussed in this paper, together with data on 1 the pharmacological activity, pharmacokinetics, and metabolism published previously, allow us to consider AV0012 as a candidate drug for clinical research phase I.


Subject(s)
Antiviral Agents/toxicity , Hepatitis C/drug therapy , Indoles/toxicity , Pyridines/toxicity , Animals , Antiviral Agents/therapeutic use , Drug Evaluation, Preclinical , Female , Indoles/therapeutic use , Macaca mulatta , Male , Maximum Tolerated Dose , Mice, Inbred Strains , Molecular Structure , Mutagenicity Tests , Pyridines/therapeutic use , Rats, Wistar , Toxicity Tests, Acute , Toxicity Tests, Chronic , Toxicity Tests, Subchronic
6.
Eksp Klin Farmakol ; 73(3): 28-30, 2010 Mar.
Article in Russian | MEDLINE | ID: mdl-20408427

ABSTRACT

The influence of ethyl-3-(8-fluoro-2-methyl-2,3,4,5-tetrahydro-1H-gamma-carboline-5-yl)propionate dihydrochloride belonging to the class of gamma-carbolines on the allergic reactions (inflammation and systemic anaphylaxis) has been studied on laboratory animals. It was established that the given substance administered in a dose of 5 - 20 mg/kg exhibits a pronounced antiallergic action. Unlike many other antihistamine drugs, this gamma-carboline derivative probably does not produce sedative effect.


Subject(s)
Anti-Allergic Agents/therapeutic use , Carbolines/therapeutic use , Histamine Antagonists/therapeutic use , Anaphylaxis/drug therapy , Anaphylaxis/immunology , Animals , Guinea Pigs , Inflammation/drug therapy , Inflammation/immunology , Male , Mice , Mice, Inbred C57BL , Mice, Inbred CBA
7.
Eksp Klin Farmakol ; 73(11): 25-9, 2010 Nov.
Article in Russian | MEDLINE | ID: mdl-21254595

ABSTRACT

The properties of 2,3,4,5-tetrahydro-1H-gamma-carbolines containing acid, ether, and amido-substituents, were assessed as potential antagonists of histamine H1 receptors (H1R), capable of blocking histamine-induced calcium fluxes in SK-N-SH cells. The structure--activity relationship for their antagonistic activity is discussed. Among the gamma-carbolines used in the study, the antihistamine activity considerably depends on the nature of substituents in positions 2, 5, and 8 of the heterocycle. The most active antagonist, ethyl 3-(2-methyl-8-fluoro-2,3,4,5-tetrahydro-1H-gamma-carboline-5-yl)propionate, with high affinity to the H1R (Ki = 6.5 nM), produces no adverse effects on motor activity of mice in doses 1-40 mg/kg, which shows the absence of a sedative effect.


Subject(s)
Calcium/metabolism , Carbolines/pharmacology , Histamine H1 Antagonists/pharmacology , Motor Activity/drug effects , Receptors, Histamine H1/metabolism , Animals , Carbolines/chemistry , Cell Line , Drug Evaluation, Preclinical , Histamine H1 Antagonists/chemistry , Male , Mice , Structure-Activity Relationship
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