Biomedical subjects

V Knight

Publications and source records attributed to V Knight.

At least 37 records · Page 2Linked to original sources

PubMed1986

Chemotherapy of respiratory viruses.

We have described positive clinical effects of seven different anti-viral drugs in the treatment of viral respiratory diseases; three of these agents are approved for clinical use--amantadine, acyclovir, and vidarabine. Of the remaining four, the most consistent and broadest range of effect was observed with ribavirin while rimantadine was similar to amantadine in its effect. Interferon and enviroxime, under the conditions in which they were tested, showed a range of effect from moderate to no effect. A feature of the use of ribavirin was its administration by inhalation over several hour periods as a small-particle aerosol. This allowed a total dosage not much less than might have been given by other routes, but with the advantage that it was evenly deposited over the surface of the infected respiratory tract beginning within seconds of the start of treatment and reached higher concentration in nasal secretions than in serum. It may be that aerosol administration can be used with other drugs, as suggested by preliminary results with amantadine. We regard the results presented in this chapter as very encouraging, but just a beginning. Effective therapy will set in motion a reexamination of many problems of viral respiratory tract infection, including how to develop more rapid and more precise viral diagnosis, the need for further characterization of both short- and long-term consequences of infection in the untreated host and their modification by treatment. The structure for rapid progress in treatment of viral diseases is in place, and with it should come a resolution of many long-standing problems in this area of medicine.

Acyclovir↗

PubMed1985

Effect of repeated intraperitoneal injections of soman on schedule-controlled behavior in the rat.

Intraperitoneal (IP) administration of the acetylcholinesterase inhibitor, soman (10-40 micrograms/kg), suppressed in a dose-related manner response rates in rats maintained under a multiple fixed-interval 50-s fixed-ratio 25 schedule of food delivery. Chronic administration of soman at weekly intervals resulted in tolerance to the response. When soman administration was separated by 2-5 weeks in individual rats, the suppressive effects of the agent again became apparent. Analysis of acetylcholinesterase activity revealed that enzyme inhibition was limited to gastrointestinal areas near the site of injection. There was no significant effect on brain acetylcholinesterase even following IP injection of doses which completely suppressed responding. The IP route may be useful for studying tolerance and other chronic effects of soman without producing generalized toxicity.

Acetylcholinesterase↗

PubMed1985

Mode of action of ribavirin: effect of nucleotide pool alterations on influenza virus ribonucleoprotein synthesis.

Ribavirin, a guanosine analogue, is a broad spectrum antiviral agent which is effective in the treatment of influenza. In this study, the effect of ribavirin on influenza virus ribonucleoprotein (RNP) synthesis and nucleotide pool sizes was simultaneously measured. Ribavirin (100 microM) reduced viral RNP synthesis 94% as measured by UTP incorporation. Intracellular GTP pools, measured by high performance liquid chromatography, were reduced approximately 45% in ribavirin treated cells, while other nucleotides remained near control values. Attempts to reverse ribavirin's inhibitory effects on viral RNP synthesis by addition of exogenous guanosine (50 microM) resulted in only a partial restoration of viral RNP synthesis, despite full restoration of the GTP pool. Dose-response experiments indicated that the GTP pool was significantly reduced (65% of control) at 25 microM ribavirin, and increasing concentrations of the drug caused only a small further reduction in the GTP pool (5-10% at 100 microM). In contrast, RNP synthesis was inhibited by 50% at 25 microM ribavirin and was further decreased to 5% of control at 100 microM ribavirin. Thus, ribavirin's antiviral activity may result from a reduction of the GTP pool size combined with direct effects on viral replicative enzymes.

Guanosine↗

PubMed1985

Effect of ribavirin triphosphate on primer generation and elongation during influenza virus transcription in vitro.

These studies examine the effect of ribavirin triphosphate (RTP) on two replicative functions associated with influenza virus nucleocapsids, primer generation and its subsequent elongation. To study primer generation influenza virus cores were added to beta-globin mRNA in the presence of only [32P]GTP. To examine elongation, ATP and CTP were added to the reaction mixture to permit limited elongation, and products from both reactions were separated on polyacrylamide gels and quantified. Under these conditions, the 50% inhibitory concentration of RTP for primer generation was 3.0 mM, and the 50% inhibitory concentration for elongation was 0.6 mM. RNA polymerase activity associated with cores isolated from clinical strains of influenza A and B viruses reacted as did the laboratory strain of influenza virus and was equally susceptible to inhibition by RTP.

Antiviral Agents↗

PubMed1985

Duration of effect of interferon aerosol prophylaxis of vesicular stomatitis virus infection in mice.

Mice were exposed for 8 h to continuous small-particle aerosols containing natural mouse alpha interferon (estimated dosage 100 U per mouse) or one of two concentrations of hybrid recombinant alpha interferon A/D bgl (estimated dosages of 100 and 10,000 U per mouse, respectively). On days 1, 3, 5, 7, and 9 after exposure to these interferons, three mice from each group were inoculated intranasally with 100 PFU of vesicular stomatitis virus. Control mice were exposed to aerosols of saline or inoculated intraperitoneally with either natural mouse alpha interferon (350 U) or one of two doses of hybrid recombinant alpha interferon A/D bgl (350 or 35,000 U) and challenged similarly. Of mice injected intraperitoneally, only those given 35,000 U of hybrid recombinant alpha interferon A/D bgl 24 h before virus challenge were protected from pulmonary infection, compared with the saline-treated control mice. Of mice given 100 U of either interferon by small-particle aerosol, only those exposed 24 h before inoculation of vesicular stomatitis virus had reduced pulmonary titers of the virus. However, of mice given ca. 10,000 U of hybrid recombinant alpha interferon A/D bgl by small-particle aerosol, all groups except those exposed 9 days before virus inoculation had significantly reduced lung virus titers.

Aerosols↗

PubMed1985

Ribavirin small-particle aerosol treatment of infections caused by influenza virus strains A/Victoria/7/83 (H1N1) and B/Texas/1/84.

In a double-blind study of influenza in a population of college students in 1984, ribavirin small-particle aerosol treatment of 38 patients (18 treated, 20 control) infected with a new antigenic variant, influenza virus strain A/Victoria/7/83 (H1N1), was associated with statistically significant reductions in the height and duration of fever, systemic symptoms, and virus shedding. Patients received a total of 2.4 g of ribavirin over 42 h during 68 h of hospitalization without any side effects. In addition, in a study of patients infected with influenza virus strain B/Texas/1/84 (seven treated, eight control) treated with ribavirin aerosol showed a trend of more rapid recovery than control patients.

Aerosols↗

PubMed1984

Efficacy of aerosolized recombinant interferons against vesicular stomatitis virus-induced lung infection in cotton rats.

Cotton rats (Sigmodon hispidus) were inoculated intranasally with vesicular stomatitis virus (VSV) and exposed to different regimens of small particle aerosols of either recombinant human alpha interferon A (rIFN-alpha A) or hybrid recombinant human alpha interferon A/D (rIFN-alpha A/D). Preliminary in vitro tests indicated that both recombinant IFNs were effective in protecting primary cotton rat pulmonary cells against VSV replication. However, rIFN-alpha A/D was 20-fold more active than rIFN-alpha A in these tests. In the in vivo tests, in contrast to control animals inoculated with VSV, but not treated, or treated only with aerosols of saline, animals exposed to either rIFN-alpha A or -alpha A/D for 8 h per day before and/or following VSV inoculation had no detectable virus titers in their lungs. In experiments in which groups of animals were treated for shorter periods, rIFN-alpha A was less effective than rIFN-alpha A/D in suppressing replication of VSV in lungs of these animals.

Aerosols↗

PubMed1984

The hypertensive response to soman and its relation to brain acetylcholinesterase inhibition.

Intravenous injection of soman in the rat produced a rapid and dose related increase in blood pressure. The dose response curve was very steep, threshold responses occurring after intravenous injection of 10 micrograms/kg, and maximum increases of about 50 mmHg occurring after 40 micrograms/kg. Heart rate also generally increased. An increase in blood pressure also followed injection of soman subcutaneously, intramuscularly, intraperitoneally and into the cerebral ventricles, although the onset was slower and higher doses were required. The magnitude of the pressor response was correlated with the degree of AChE activity in the cortex, hypothalamus and brain stem, but not in the striatum. The pressor response was aborted or prevented by atropine, but not by methylatropine. It also was prevented by phenoxybenzamine. Atropine increased survival following an LD50 dose of soman; phenoxybenzamine prevented the pressor response but did not alter the survival rate.

Acetylcholinesterase↗

PubMed1984

Pulmonary deposition and clearance of aerosolized interferon.

Small particle aerosols of a hybrid DNA recombinant human alpha interferon, A/D bgl, and a related DNA recombinant leukocyte interferon, A, were generated and delivered to mice for 23.5 h a day for 4 consecutive days. The antiviral activity of these interferons in delivery reservoirs, in the aerosols generated, and in the lungs of test mice was monitored during and after aerosol administration in cytopathic effect inhibition assays, using vesicular stomatitis virus as the indicator virus. In addition, the activity of these interferons in primary mouse embryo cells against influenza A/HK/68 (H3N2) virus was determined. The results obtained indicated that the interferon particles generated in the continuous aerosol therapy system used in these studies remained biologically active and could be readily detected in both aerosol mists and lungs of test mice; levels of exogenous interferon in the lungs equalled or exceeded levels of interferons produced endogenously during experimentally induced influenza virus infection. Titers of the exogenously administered interferons decreased gradually and disappeared from the lungs between 24 and 48 h after cessation of aerosolization. Recombinant human alpha interferon A/D, but not recombinant leukocyte alpha interferon A, significantly inhibited replication of A/HK/68 virus in primary mouse embryo cells in the in vitro studies.

Aerosols↗

PubMed1984

Treatment of influenza A (H1N1) virus infection with ribavirin aerosol.

In a randomized, controlled study of ribavirin aerosol treatment of influenza A(H1N1) virus infection among college students, treated patients had a significantly shorter duration of fever than control patients. There was a trend of more rapid recovery in treated patients. Virus shedding was similar in treated and control patients, declining gradually from a 50% tissue culture infective dose of 3.5 log10 per ml at admission to 1.8 log10 per ml at 53 h after admission. There was no local or systemic intolerance and no hematological or biochemical abnormalities associated with ribavirin treatment.

Aerosols↗

PubMed1984

Interferon aerosol suppression of vesicular stomatitis virus replication in the lungs of infected mice.

Mice were inoculated intranasally with vesicular stomatitis virus 16 to 22 h after being exposed to small-particle aerosols of saline, natural mouse alpha interferon, recombinant human alpha interferon A, or hybrid recombinant human alpha interferon A/D bgl for 2, 4, or 8 h. Compared with comparably inoculated, untreated mice, significantly reduced levels of vesicular stomatitis virus were observed in the lungs of animals treated with any interferon preparation for 8 h and in groups treated with mouse alpha interferon or hybrid recombinant human alpha interferon A/D bgl for 4 h. No significant reductions in lung virus titers were observed in any group treated with interferon for 2 h or in any of the groups treated with saline.

Aerosols↗

PubMed1983

Ribavirin aerosol treatment of influenza B virus infection.

In a randomized, controlled study, ribavirin small-particle aerosol was found to be effective in the treatment of influenza B virus infection in a group of college students. Eleven treated patients experienced significantly more rapid defervescence, disappearance of systemic illness, and reduction of virus shedding in nasal secretions than ten control patients treated with a saline aerosol. Antibody response to infection was similar in both groups. The treatment was well tolerated, and hematologic and clinical chemical tests demonstrated no toxicity. The estimated dose of ribavirin aerosol retained was about 2 g in 39 hours of treatment during the first 60 hours in the hospital.

Adult↗

PubMed1983

Cell-mediated cytotoxic responses in lungs of cotton rats infected with respiratory syncytial virus.

Pneumonia induced in cotton rats (Sigmodon hispidus) after inoculation of respiratory syncytial virus (RSV) was accompanied by the appearance of leukocytes in infected lungs. The number of these leukocytes increased until Day 5 after inoculation when sixfold more leukocytes were recovered from infected lungs using transpleural lavage than were recovered from lungs of uninfected control animals. Although macrophages and lymphocytes constituted approximately 65 and 25%, respectively, of the cells observed in lavage suspensions from both infected and uninfected lungs, only leukocytes in suspensions from infected animals appeared to be activated, as judged by cellular morphologic examination, cytochemical staining, and bactericidal activity. Leukocytes from lungs and adjacent lymph nodes of infected cotton rats, but not similar cells from uninfected animals, caused significant chromium release when they were added to primary cotton rat embryo and Hep-2 tissue culture cells infected with RSV in cytotoxicity assays. Cytotoxic activity peaked 5 days after inoculation, was neither virus-specific nor H-2 restricted, and was associated with both adherent and nonadherent fractions of lung cells. There was a close temporal relationship between the appearance of cytotoxic activity in the lung and termination of virus replication in this organ, suggesting a role for cytotoxic effector cells in recovery from respiratory syncytial virus infection of cotton rats.

Animals↗

PubMed1983

Correlation of cytotoxic activity in lungs to recovery of normal and gamma-irradiated cotton rats from respiratory syncytial virus infection.

Cotton rats (Sigmodon hispidus) that were exposed to 300, 600, or 900 rads of gamma irradiation and inoculated intranasally 2 days later with respiratory syncytial virus (RSV) exhibited prolonged virus shedding and delayed humoral and cytotoxic immune responses compared with comparably inoculated nonirradiated control rats. In nonirradiated animals and in animals exposed to 300 and 600 rads, levels of virus declined and then disappeared from the lungs during the period in which cytotoxic activity was maximal in the lungs of these animals. In contrast, in the group of cotton rats exposed to 900 rads of irradiation, local cytotoxic activity remained low throughout the 11-day observation period, and virus was not eliminated from the lungs. Although virus-neutralizing antibodies in serum and lavage fluids from these animals may have been involved, correlation of antibody concentrations with virus clearance from lungs was not as evident. These data suggest that cytotoxic effector cells have a positive role in eliminating RSV from the lungs of unprimed cotton rats.

Animals↗

PubMed1983

Ribavirin aerosol treatment of influenza B virus infection.

In a randomized, controlled study, ribavirin small particle aerosol was found to be effective in the treatment of influenza B virus infection in a group of college students. Eleven treated patients experienced significantly more rapid defervescence, disappearance of systemic illness, and reduction of virus shedding in nasal secretions than 10 control patients treated with a saline aerosol. Antibody response to infection was similar in both groups. The treatment was well tolerated and hematologic and clinical chemical tests revealed no toxicity. The estimated dose of ribavirin aerosol retained was about 2 g in 35.5 hr of treatment during the first 60 hr in the hospital.

Adult↗

PubMed1983

Ribavirin aerosol treatment of bronchiolitis associated with respiratory syncytial virus infection in infants.

In a double-blind study, bronchiolitis associated with respiratory syncytial virus infection in 12 randomly selected patients treated with ribavirin aerosol improved more rapidly than in 14 control patients given saline aerosol (P = .044, Wilcoxon rank sum test, two-tailed). An estimated 10 mg of ribavirin per kilogram of body weight was administered in daily 12-hour treatments over a five-day period. Respiratory syncytial virus disappeared from secretions at about the same rate in treated and control patients. There was no local or systemic intolerance, and there was no evidence of hematologic or other organ toxicity in the ribavirin-treated patients.

Aerosols↗

PubMed1983

Replication of respiratory syncytial virus in lungs of immunodeficient mice.

Respiratory syncytial virus was frequently isolated during a 10-day test period from the lungs of 4- to 6-week-old immunodeficient nude (nu/nu) mice and from gamma-irradiated C3H mice inoculated intranasally with this virus, but not from similar aged and comparably inoculated normal littermates of these mice. Virus isolation rates and levels of virus in lungs in both groups of immunodeficient mice were similar. No extrapulmonary dissemination of virus was observed in any test group of mice.

Animals↗

PubMed1982

Selective inhibition of functional lymphocyte subpopulations by ribavirin.

The present studies were designed to examine the effects of ribavirin (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide), a broad-spectrum antiviral agent, on the generation of murine antibody responses in vitro. Whereas primary and secondary sheep erythrocyte-specific, plaque-forming cell responses by normal murine spleen cells were enhanced by low concentrations of ribavirin (1 microgram per culture), they were strongly inhibited by higher concentrations of ribavirin (5 to 10 micrograms per culture). Both phenomena occurred with the greatest magnitude when spleen cells were exposed to ribavirin 48 to 72 h after culture initiation. Enhancement appeared to result from selective interference with suppressor T cells, since ribavirin failed to augment lipopolysaccharide-specific plaque-forming cell responses in T cell-depleted spleen cell cultures but inhibited concanavalin A-induced lymphocyte proliferation and suppressor T cell generation in cultures of normal spleen cells. The immunosuppressive properties of ribavirin were mediated by a direct antiproliferative effect and, at higher concentrations, a cytotoxic effect for B lymphocytes, since the drug inhibited plaque-forming cell responses in T cell-depleted spleen cell cultures, suppressed lipopolysaccharide-induced lymphocyte proliferation and reduced viable spleen cell recoveries.

Animals↗