RESUMO
One of the problem in the selection of the most effective antiviral preparations with a broad spectrum of antiviral protective activity, is the "continuity" of assays of different level of complexity so, that the most effective antiviral therapeutic, selected by in vitro assays would be the most effective in vivo. Comparative study of the efficacy of the influenza virus inhibitor in the assays of inhibition of virus binding with fetuin, inhibition of infectious focus forming units in MDCK cells, inhibition of virus yield in infected MDCK cells, and inhibition of influenza virus infectivity in mice infected by viral aerosol are presented. The value of 50% inhibiting concentration IC50 for the pare "influenza virus strain A/NIB/23/89-MA-inhibitor tetra-Aca6-6'SLN" corresponded to 6-10 microM and was invariant for three different tests--in vitro assay of inhibition of virus binding with fetuin, inhibition of yield in infected MDCK cell culture, and inhibition of virus infectivity in mice, but not for the assay of inhibition of infectious focus forming units in cell culture.
Assuntos
Antivirais/metabolismo , Glicoproteínas de Hemaglutininação de Vírus da Influenza/metabolismo , Vírus da Influenza A/metabolismo , Testes de Sensibilidade Microbiana/métodos , Oligossacarídeos/metabolismo , Infecções por Orthomyxoviridae/virologia , Administração Intranasal , Animais , Antígenos Virais/metabolismo , Antivirais/administração & dosagem , Antivirais/uso terapêutico , Linhagem Celular , Vírus da Influenza A/crescimento & desenvolvimento , Vírus da Influenza A/patogenicidade , Camundongos , Camundongos Endogâmicos ICR , Oligossacarídeos/administração & dosagem , Oligossacarídeos/uso terapêutico , Infecções por Orthomyxoviridae/prevenção & controle , Ligação Proteica/efeitos dos fármacos , alfa-Fetoproteínas/metabolismoRESUMO
Course intragastric administration of ultralow doses of human gamma-interferon antibodies (ULD anti-IFN-gamma) to intact mice resulted in an increase of endogenous IFN-gamma production by the animal lymphocytes. Oral prophylactic administration of ULD anti-IFN-gamma significantly lowered the influenza virus concentration in the animal lungs at the initial stage of the aerogenous infection: in 2 (p = 0.05) and 3 (p = 0.07) days after the contamination. The therapeutic antiviral effect of ULD anti-IFN-gamma in mice with influenza was evident from a significant decrease of the influenza virus concentration in the lungs of the animals on the 4th (p = 0.05) and 5th (p = 0.07) days after the contamination. The antiviral effect of ULD anti-IFN-gamma after the prophylactic and therapeutic use is likely provided by induction of endogenous IFN-gamma.
Assuntos
Anticorpos/uso terapêutico , Antivirais/uso terapêutico , Vírus da Influenza A , Interferon gama/imunologia , Infecções por Orthomyxoviridae/prevenção & controle , Animais , Vírus da Influenza A/isolamento & purificação , Interferon gama/biossíntese , Pulmão/imunologia , Pulmão/virologia , Linfócitos/imunologia , Masculino , Camundongos , Infecções por Orthomyxoviridae/terapia , Infecções por Orthomyxoviridae/virologia , Baço/imunologia , Fatores de TempoRESUMO
Preventive effect in influenza can be attained by intramuscular injections of fir (Abies) polyprenols. One of 5 tested polyprenol preparations (No. 1), injected 2 days before aerogenic infection with influenza virus, reliably protected mice from disease. Mice pretreated with polyprenol preparations or Hanks' solution did not differ by accumulation of interferon in the lungs One day after aerogenic infection. Three days after injection of polyprenol preparation No. 1 the weights of the spleen and thymus significantly decreased. One day after injection cell count in the bronchoalveolar tract of mice was almost 2-fold higher than in the control at the expense of lymphocytes and macrophages. After 3 days the relative and absolute counts of macrophages decreased and those of lymphocytes decreased significantly. Three days after injection macrophages were 2-fold more active in absorption of zymosan granules. Preparation No. 1 affected the production of superoxide anion radicals, whose production by all macrophages in the bronchoalveolar tract of mice was significantly higher on day 1 postinjection than on day 3 and higher than on days 1 and 3 after injection of preparation No. 2.
Assuntos
Álcoois Graxos/farmacologia , Infecções por Orthomyxoviridae/prevenção & controle , Orthomyxoviridae/efeitos dos fármacos , Animais , Álcoois Graxos/imunologia , Álcoois Graxos/uso terapêutico , Feminino , Imunidade Inata/efeitos dos fármacos , Masculino , Camundongos , Infecções por Orthomyxoviridae/imunologia , ÁrvoresRESUMO
Humoral and cellular mechanisms of Abies sibirica polyprenol effects on nonspecific resistance of mice to influenza A/Aichi/2/68 virus were investigated. Two aerosol doses of polyprenols had a high protective effect in mice challenged with influenza virus. Aerosol polyprenol preparations in the studied doses induced no interferon or tumor necrosis factor production in the lungs. Lung macrophage counts and capacity to produce superoxide anion radicals increased in survivors after influenza in comparison with intact animals. Double aerosol administration of polyprenols prior to influenza infection promoted an increase in the thymus weight, bronchoalveolar tract cell counts (predominantly at the expense of lymphocytes), and of superoxide-producing potential of macrophages, which, in turn, can contribute to improvement of the defense potential of the organism towards influenza virus.
Assuntos
Antivirais/farmacologia , Infecções por Orthomyxoviridae/tratamento farmacológico , Pentanóis/farmacologia , Pinaceae/química , Aerossóis , Animais , Antivirais/isolamento & purificação , Antivirais/uso terapêutico , Hemiterpenos , Pulmão/metabolismo , Pulmão/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Pentanóis/isolamento & purificação , Pentanóis/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Polydispersed aerosols from allantoic fluid of chick embryos induced with influenza virus with different median weight aerodynamic diameters of corpuscles (0.5, 0.8, 1.1, 2.2, and 6.0 mu are effectively deposited in respiratory organs of mice weighing 18-19 g. The sensitivity of mice of different weight to aerogenic infection with influenza virus (strain A/Aichi/2/68) was virtually the same. The efficacies of aerogenic 50% infective and lethal doses (1.8-2.5 lg) for mice of the same weight were different. The sensitivity of mice to aerogenic infection and of developing chicken embryos to the virus (ID50 = EID50) is the same. Mice weighing 10-19 g can be infected via airways with adapted influenza virus in studies of therapeutic and prophylactic effects of drugs.
Assuntos
Vírus da Influenza A/patogenicidade , Aerossóis , Animais , Embrião de Galinha , Exposição por Inalação , Camundongos , Sistema Respiratório/virologiaRESUMO
Changes in the virulence of influenza virus A/Aichi/2/68 LD50 were studied in albino mice with immunosuppression induced by long-acting glucocorticoid kenalog (Kn). In high doses (5 and 10 micrograms/g) Kn induced a decrease in the adrenal, thymic, and splenic weight, which is typical of steroid immunosuppression. The susceptibility of mice preinjected with Kn to the virus increased more than ten-fold, judging by a decrease in LD50. The detected shifts may be due to disorders in lung tissue resistance and reactivity of alveolar macrophages and neutrophils observed previously in induced glucocorticism.
Assuntos
Suscetibilidade a Doenças/imunologia , Glucocorticoides/farmacologia , Imunossupressores/farmacologia , Vírus da Influenza A/imunologia , Infecções por Orthomyxoviridae/imunologia , Triancinolona Acetonida/farmacologia , Animais , Terapia de Imunossupressão , CamundongosAssuntos
Glucocorticoides/farmacologia , Imunossupressores/farmacologia , Vírus da Influenza A/efeitos dos fármacos , Infecções por Orthomyxoviridae/imunologia , Triancinolona Acetonida/farmacologia , Animais , Relação Dose-Resposta a Droga , Imunidade Inata/efeitos dos fármacos , Vírus da Influenza A/patogenicidade , Dose Letal Mediana , Camundongos , Infecções por Orthomyxoviridae/virologia , Virulência/efeitos dos fármacosRESUMO
The time dependence of interferon production in blood, tissues of the respiratory tract, brain and olfactory tract of mice BALB/c was investigated after administration of the interferon inductor ridostin by various routes. Intraperitoneal injection of ridostin in a dose of 5 mg/kg induced intensive accumulation of interferon in the blood serum with the peak in 8 hours (2560 U/0.2 ml) while no interferon was detected in the tissues of the respiratory tract and brain of the animals. Intracerebral injection of ridostin in the same dose induced accumulation of interferon in both the tissues of the brain (maximum 160 U/0.2 ml in 24 hours) and the blood serum (maximum 1280 U/0.2 ml in 8 hours). After respiratory administration of ridostin interferon was detected only in the site of the administration in the tissues of the upper respiratory tract and lungs of the mice.
Assuntos
Indutores de Interferon/farmacologia , Interferons/biossíntese , RNA de Cadeia Dupla/farmacologia , RNA Fúngico/farmacologia , Administração por Inalação , Animais , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Injeções Intraperitoneais , Injeções Intraventriculares , Indutores de Interferon/administração & dosagem , Interferons/sangue , Interferons/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Condutos Olfatórios/metabolismo , RNA de Cadeia Dupla/administração & dosagem , RNA Fúngico/administração & dosagem , Sistema Respiratório/metabolismoRESUMO
White mice weighing 14-16 g were intranasally infected with LD50 of influenza virus (A/Aichi/2/68 strain). High levels both of virus and interferon were detected in the lung. Sufficient virus accumulation in the nasal cavity occurred with low interferon induction. At the same time high blood interferon levels corresponded to sporadic low viremia. Intraperitoneal injection of the interferon inducer ridostin (a pharmacological formulation of dsRNA) to BALB/c mice (18-20 g) in a dose of 5 mg/kg induced intensive blood accumulation of interferon with its peak at 8 hours postadministration (2560 U/0.2 ml), but interferon was not detected in the respiratory tract and brain of these mice. Intranasal (15 mg/kg) and aerogenic (0.4-0.6 mg/kg) administration of ridostin induced interferon mainly in the upper respiratory tract and lung. The regularities found are in agreement with the data on interferon induction by other dsRNA preparations, which makes it necessary to design dosage forms of interferon inducers for respiratory application in influenza.
Assuntos
Interferons/biossíntese , Infecções por Orthomyxoviridae/metabolismo , Animais , Vias de Administração de Medicamentos , Seguimentos , Indutores de Interferon/administração & dosagem , Interferons/agonistas , Interferons/genética , Pulmão/metabolismo , Pulmão/virologia , Camundongos , Camundongos Endogâmicos BALB C , Orthomyxoviridae/crescimento & desenvolvimento , Orthomyxoviridae/isolamento & purificação , Infecções por Orthomyxoviridae/virologia , RNA/biossíntese , RNA de Cadeia Dupla/administração & dosagem , RNA Fúngico/administração & dosagemRESUMO
Influenza virus strain A/Aichi/2/68 replicated only in the lungs, nasal cavity, and trachea after intranasal challenge of white mice weighing 14-16 g. Rapid accumulation of the virus was associated with a somewhat delayed accumulation of endogenous interferon in the lungs, the concentration of interferon gradually decreasing by the end of the disease. An appreciable accumulation of the virus in the nasal cavity was coupled with weak interferon induction in this organ. On the other hand, a high level of interferon in the blood was concomitant with the development of slight sporadic viraemia.
Assuntos
Vírus da Influenza A/fisiologia , Interferons/sangue , Infecções por Orthomyxoviridae/sangue , Animais , Pulmão/virologia , Camundongos , Cavidade Nasal/virologia , Infecções por Orthomyxoviridae/virologia , Traqueia/virologia , Viremia , Replicação ViralRESUMO
Therapeutic and prophylactic effects of immunomodifiers ridostin, reaferon, and polyribonate used alone and in various combinations were assessed in experiments on guinea pigs infected with Venezuelan equine encephalomyelitis (VEE) (strain Trinidad), Marburg (strain Popp), and Ebola (M/C-8 variant of Zaire strain) viruses at doses 5 to 20 respiratory LD50 through the respiratory airways. Urgent prophylactic simultaneous intramuscular and intranasal administration of ridostin protected the animals infected with Marburg virus (p = 0.1) and prolonged their life span by 2.4 days (p = 0.15). In Ebola infection a combination of ridostin and reaferon appreciably prolonged the mean life span: by 2.9 days (p = 0.04). In VEE ridostin alone or in combination with reaferone appreciably increased the share of survivors; ridostin with reaferon and polyribonate notably prolonged the mean life span of infected animals. None of these drugs or combinations produced an appreciable therapeutic effect in any of the studied infections.
Assuntos
Adjuvantes Imunológicos/uso terapêutico , Encefalomielite Equina Venezuelana/tratamento farmacológico , Doença pelo Vírus Ebola/tratamento farmacológico , Doença do Vírus de Marburg/tratamento farmacológico , Animais , Células Cultivadas , Embrião de Galinha , Encefalomielite Equina Venezuelana/prevenção & controle , Cobaias , Doença pelo Vírus Ebola/prevenção & controle , Dose Letal Mediana , Doença do Vírus de Marburg/prevenção & controleRESUMO
Based on the dose-response dependence represented as a generating distribution function of infecting doses of a pathogen, a value for the epidemiological efficiency rate of preventive agents was derived. For an arbitrary distribution of infecting doses, EEC mean values is shown to always no greater than 1: ED50v/ED50w where ED50v and ED50w are 50% of the infective doses of the pathogen assessed for those treated with the agent and intact persons, respectively. This relation is also valid when differences in pathogenic resistance are determined not only due to the use of drugs, but for any other variables (age-, sex-specific and other factors). This was verified by experiments.
Assuntos
Antivirais/administração & dosagem , Viroses/epidemiologia , Viroses/prevenção & controle , Vírus/patogenicidade , Animais , Relação Dose-Resposta a Droga , Modificador do Efeito Epidemiológico , Fatores Epidemiológicos , Humanos , Camundongos , Resultado do Tratamento , Vírus/efeitos dos fármacosRESUMO
Time course of Marburg virus (strain Popp) accumulation and changes in hematological parameters were studied in aerosol infected M.rhesus monkeys. The lungs were the first organ in which the virus was detected after respiratory infection of monkeys. Four days after inoculation the virus was detected in the liver, spleen, blood, and thymus. Six days after inoculation the virus was present in virtually all organs and secretions. The period of fever was associated with manifest leukopenia in primates. Blood clotting time drastically increased by the moment of animal death.
Assuntos
Microbiologia do Ar , Doença do Vírus de Marburg/transmissão , Marburgvirus/patogenicidade , Animais , Fígado/virologia , Pulmão/virologia , Macaca mulatta , Doença do Vírus de Marburg/patologia , Doença do Vírus de Marburg/virologia , Marburgvirus/isolamento & purificação , Baço/virologia , Timo/virologia , ViremiaRESUMO
Aerogenic infection of M. rhesus with Ebola virus causes in them a disease similar in the principal clinical and virological parameters a grave form of Ebola fever in humans, as it is described in literature. Rapid development of symptoms of total intoxication in the presence of fever, hemorrhagic diathesis, and high viremia are indicative of the infection severity in monkeys.
Assuntos
Microbiologia do Ar , Ebolavirus/patogenicidade , Febres Hemorrágicas Virais/fisiopatologia , Animais , Modelos Animais de Doenças , Febres Hemorrágicas Virais/transmissão , Febres Hemorrágicas Virais/virologia , Macaca mulatta , Índice de Gravidade de DoençaRESUMO
Marburg virus (strain Popp) was found to accumulate in various organs of guinea pigs after aerogenic infection. At the initial stage of the infection primary multiplication of the virus took place in the lungs. The presence of the virus in bronchopulmonary washings 2-3 days after infection, leukopenia and hyperthermia 4 days after infection are the earliest virological and clinical signs of disease in aerogenically infected guinea pigs.
Assuntos
Microbiologia do Ar , Líquido da Lavagem Broncoalveolar/virologia , Pulmão/virologia , Doença do Vírus de Marburg/fisiopatologia , Animais , Febre/fisiopatologia , Cobaias , Leucopenia/fisiopatologia , Linfonodos/virologia , Doença do Vírus de Marburg/transmissão , Doença do Vírus de Marburg/virologia , Marburgvirus/fisiologia , Replicação ViralRESUMO
The study of the preventive and therapeutic action of some immunomodulators (ridostin, reaferon and polyribonate) used alone and in combinations was conducted on laboratory animals infected aerogenically by Marburg or Ebola virus. It was found that special preventive intranasal and intramuscular administration of ridostin provided protection of the animals infected by Marburg virus (p = 0.1) and an increase in their mean lifespan by 2.4 days (p = 0.15). In the Ebola infection combined administration of ridostin and reaferon caused an essential increase in the mean lifespan of the animals by 2.9 days (p = 0.04). None of the tested drugs had any significant positive effect when used in various combinations according to the treatment schemes in Marburg and Ebola infections in guinea pigs.