RESUMEN
Mice infected with influenza A/Aichi/2/68 (H3N2) virus or Sendai/960 paramyxovirus were treated by inhalations of aerosol aprotinin, a broad spectrum inhibitor of proteinases. A course of inhalations of finely dispersed aerosol aprotinin including 4 exposures of 35-40 min each daily for 6 days provided respiratory administration of aprotinin in a dose about 100 kallikrein-inhibiting U/mouse per day. In mice treated by aprotinin inhalations, histological examinations showed decreased pulmonary pathology, and their body weights increased as much as in uninfected animals. In the placebo group, the weight decreased until the death of the animals. The protective effect of aprotinin inhalations was 40-80% with inoculation doses 10-100 MLD50/mouse. The treated animals died 2-4 days later than those in the placebo group. The results indicate the expedience of inhalation therapy with aerosol aprotinin in influenza and paramyxovirus respiratory infections.
Asunto(s)
Aprotinina/administración & dosificación , Virus de la Influenza A , Infecciones por Orthomyxoviridae/tratamiento farmacológico , Virus de la Parainfluenza 1 Humana , Infecciones por Paramyxoviridae/tratamiento farmacológico , Administración por Inhalación , Animales , Peso Corporal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Pulmón/efectos de los fármacos , Pulmón/patología , Ratones , Infecciones por Orthomyxoviridae/patología , Infecciones por Paramyxoviridae/patologíaRESUMEN
Parenteral administration of an inhibitor of chymotrypsin-like proteases (TPCK) to mice infected with alphavirus (Sindbis AR/339 strain) blocked virus replication in the brain and inhibited the development of viremia in the infected animals. The most likely mechanism of TPCK antiviral effect seems to consist in disturbance of proteolytic processing of viral proteins.
Asunto(s)
Quimotripsina/antagonistas & inhibidores , Desoxiuridina/análogos & derivados , Inhibidores de Proteasas/uso terapéutico , Infecciones por Togaviridae/tratamiento farmacológico , Replicación Viral/efectos de los fármacos , Animales , Encéfalo/microbiología , Desoxiuridina/uso terapéutico , Evaluación Preclínica de Medicamentos , Ratones , Virus Sindbis/efectos de los fármacos , Virus Sindbis/fisiología , Factores de Tiempo , Infecciones por Togaviridae/microbiología , Viremia/tratamiento farmacológico , Viremia/microbiologíaRESUMEN
The effect of protease inhibitors (gordox, contrycal, epsilon-aminocapronic acid) on the development of influenza virus-induced infectious process was studied. Administration of the above-mentioned drugs exerted a marked antiviral and therapeutic effect both in animal experiments and in treatment of children suffering from influenza. Electron microscopic examinations of lungs from influenza virus-infected animals treated with protease inhibitors revealed definite decrease in the number of virus particles and significant diminution of pathological lesions; the changes were noted which indicated activation of the body immune response. The use of a protease inhibitor, epsilon-aminocapronic acid, in children with influenza shortened the duration of influenza virus antigens persistence in the nasopharyngeal epithelium and reduced the duration of the disease symptoms by 1 1/2-2-fold. Administration of epsilon-aminocapronic acid in inhalations exerted most effective antiviral and therapeutic effect. The results obtained demonstrate the possibility of influenza treatment with inhibitors of proteolytic enzymes.
Asunto(s)
Antivirales/uso terapéutico , Gripe Humana/tratamiento farmacológico , Inhibidores de Proteasas/uso terapéutico , Adolescente , Ácido Aminocaproico/uso terapéutico , Animales , Aprotinina/uso terapéutico , Niño , Preescolar , Evaluación de Medicamentos , Evaluación Preclínica de Medicamentos , Humanos , Lactante , Gripe Humana/patología , Pulmón/ultraestructura , Ratones , Inhibidores de Tripsina/uso terapéuticoRESUMEN
Administration of the protease inhibitors, epsilon-aminocaproic acid or aprotinins, to mice infected with mouse-adapted influenza virus strain A/PR/8/34 (HON1) and A/Aichi/2/68 (H3N2) reduced virus replication in the lungs. Up to 100-fold reduction of virus titre and virus-induced neuraminidase activity were revealed in mouse lungs under protease inhibitor treatment. As a result, drug-treated mice rapidly cleared the virus from their lungs. The predominant synthesis was of non-infectious virions with uncleaved haemagglutinin in the lungs of drug-treated mice, in contrast to the production of highly infectious virions with proteolytically cleaved haemagglutinin in untreated mice. These observations suggest that protease inhibitors suppress influenza virus replication in mouse lungs due to prevention of haemagglutinin cleavage and virus proteolytic activation.