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Biomedical subjects

B E Gilbert

Publications and source records attributed to B E Gilbert.

At least 55 records · Page 3Linked to original sources
PubMed1987

Ribavirin aerosol treatment of influenza.

In this article we have described the clinical and laboratory features of uncomplicated influenza in college students and its treatment with ribavirin aerosol. The disease presents as an acute febrile systemic illness of short duration that varies little from patient to patient. Peripheral blood cell changes in the infection are also quite specific and very consistent. Polymorphonuclear cell counts are slightly increased above normal early in infection at a time when lymphocyte counts were greatly reduced. As lymphocyte numbers increase at the third day of illness, polymorphonuclear cell counts diminish substantially. Eosinophil counts fluctuate in a pattern similar to that of lymphocytes. Basophil, monocyte, and band cell counts are increased at admission and thereafter decline in numbers. Reticulocytes and platelets are reduced during acute illness. We assume that changes in peripheral white blood cell counts during influenza result from migration of cells to the inflamed respiratory tract and subsequent resupply of the various types of cells to the circulation from other sites in the body. The cellular alterations in the circulation and at the site of infection are of fundamental importance in the pathogenesis of infection, and a better knowledge of them should open new avenues for prevention and treatment. Aerosol treatment was shown to alleviate the symptoms of influenza and to reduce the shedding of influenza virus from the respiratory tract. No evidence of untoward effect of ribavirin treatment on peripheral white or red blood cells was found, and a wide range of clinical chemical tests revealed no toxic effects of treatment. There was no pulmonary irritation detected from the treatment. Reference was made to prompt recovery of four patients with influenzal pneumonia treated with ribavirin aerosol. Ribavirin aerosol must produce its major therapeutic effect through inhibition of virus replication at the sites of infection in the respiratory epithelium. This appears to result mainly from interference with viral messenger RNA initiation and elongation. This is best demonstrated by the prompt decline in viral shedding in treated patients. The associated prompt clinical improvement suggests that illness results from continued virus replication, and when virus replication is retarded, improvement follows. Although treatment promptly reduces illness and virus shedding, antibody response is not reduced in treated patients. We emphasized that ribavirin aerosol had a major therapeutic effect on infections caused by both influenza A and B viruses, and the picture of illness with these types of influenza was not clinically distinguishable.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1986

Influenza virus infection induces functional alterations in peripheral blood lymphocytes.

This report describes alterations in functional responses to lectin-induced stimulation of peripheral blood lymphocytes and in the natural killer cell (NKC) activity, of college students, obtained during an outbreak of influenza A/Philippines/2/82(H3N2) virus infection. These results are compared with similar observations in college students with an acute, febrile, noninfluenzal respiratory illness that occurred during the same outbreak. The lymphopenia typical of influenza during acute illness was shown to be due to a reduction in both T and B cells without alteration in the CD4:CD8 ratio. In addition, phytohemagglutinin and concanavalin A responses were reduced and NKC activity was increased, while pokeweed mitogen reactivity was unaltered at the time of admission to the study. Patients with noninfluenzal illness showed early polymorphonuclear leukocytosis and a similar lymphopenia. Lymphocyte functions were virtually unchanged during acute illness in noninfluenza patients. The relatively specific alterations in lymphocyte responses to lectin-induced stimulation in influenza patients may indicate that the peripheral T cells are incapable of activation via the CD3 or CD2 activation pathways. In addition, increased NKC activity in the periphery may be reflective of increased NKC activity in the lung. Influenza-infected individuals with higher NKC activity at the time of admission to the study also took longer to recover. Finally, the early lymphopenia and the later neutropenia in the influenza-infected patient may represent migration of these cells from the circulation to the infected respiratory tract as a consequence of infection.

Concanavalin A↗
PubMed1986

Effects of selenazofurin and ribavirin and their 5'-triphosphates on replicative functions of influenza A and B viruses.

We studied the effects of selenazofurin alone and in combination with ribavirin on replication of influenza A and B viruses. These drugs showed little cytotoxicity as measured by leucine incorporation into protein in MDCK cells, although they were potent inhibitors of viral replication in the same cells. Selenazofurin inhibited growth of influenza A and B viruses at concentrations (50% inhibitory dose = 25 and 19 microM, respectively) which were similar to those at which growth was inhibited by ribavirin (50% inhibitory dose = 50 and 30 microM, respectively). The inhibition of replication of either influenza A or B virus was additive for any combination of ribavirin and selenazofurin. The effects of the 5'-triphosphate of selenazofurin on two replicative functions associated with the influenza virus RNA-dependent RNA polymerases, primer generation (initiation of transcription) and its subsequent elongation, were measured. Elongation was more sensitive to selenazofurin 5'-triphosphate than was primer generation, and the effects of this drug on these functions were approximately the same as those of ribavirin 5'-triphosphate. The activities of ribavirin triphosphate and selenazofurin triphosphate were additive, and combinations did not potentiate the individual inhibitory effects of these drugs on elongation.

Animals↗
PubMed1986

Protection of mice from lethal influenza virus infection with high dose-short duration ribavirin aerosol.

An aerosol generated from a reservoir containing 60 mg of ribavirin per ml given for 2 h twice daily for 4 days afforded the same high level of protection against lethal influenza virus infection of mice as a longer, conventional treatment schedule (20 mg/ml given for 11 h daily for 4 days). Incremental decreases in ribavirin concentration made while maintaining the 2-h intermittent schedule provided progressively less protection of mice. Mice exposed to the 60-mg/ml doses had significantly increased pulmonary and serum drug levels when compared with mice given 20 mg of drug per ml, these increases were transient, and no evidence of pulmonary intolerance was detected. These studies suggest that protective effects of ribavirin against influenza virus infection can be achieved without untoward effects if higher doses and shorter periods of administration are used.

Aerosols↗
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

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

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

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↗
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

Evidence that T-lymphocytes are part of the blood-brain barrier to virus dissemination.

The dissemination of a neurovirulent strain of influenza A/WSN (HON1) virus from infected lungs to brains of thymus-deficient nude and immunocompetent furred mice inoculated intranasally was compared. Nude mice were more susceptible to lethal disease following intranasal (i.n.) inoculation with A/WSN virus than furred mice based on the number of plaque-forming units (PFU) of virus required to constitute a median lethal dose (LD50). In normal mice, virus was cleared from the lungs of survivors and dissemination of virus from lung to brain was detected only rarely. Nude mice, in contrast, had frequent and early deaths with significant brain virus titers and histologic evidence of encephalitis. Adoptive immunization of recipient nude mice with suspensions of cytotoxic T-lymphocytes secondarily stimulated in vitro 24 h after i.n. challenge, reduced both brain virus titers and mortality in these animals. These data indicated that T-lymphocytes were a significant factor in preventing dissemination of neurotropic virus from lungs to the brains of infected mice.

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↗
PubMed1980

Regulation of prenatal and postnatal protein synthesis in mouse brain.

Regulation of protein synthesis during prenatal and postnatal brain development was examined using postmitochondrial supernatant (PMS) fractions and isolated ribosome-pH 5 enzyme systems from fetal, neonatal, and adult neural tissue. The rate of polyuridylic acid (poly-U)-dependent protein synthetic activity was inversely proportional to the endogenous rate of protein synthesis in either the PMS fractions or ribosomal preparations. A careful analysis of the kinetics of the poly-U-dependent polypeptide synthesis revealed that there was a lag in the time at which certain of the PMS preparations could begin to utilize the poly-U template as sole source of mRNA. The lag period was dependent upon the developmental age of the neural tissue used and the Mg2+ concentration of the protein synthesis reaction. Since previous work reported that the observed developmental decrease in the rate of polypeptide synthesis utilizing a poly-U template could not be measured by several isolation techniques to determine if the purification procedure might have affected the ribosomes in some manner by removing a specific protein(s) involved in ribosome-cytosol interactions. At 6 mM-Mg2+ the rate of poly-U-dependent protein synthesis was inversely proportional to the rate of endogenous synthesis and depended upon the method used to isolate the ribosomes: microsomes congruent to Triton X-100-treated < DOC-treated < KCl-treated. However, there was no age-dependent effect with any of the ribosomal preparations. The data suggest that there is a developmental modulating effect of ribosomal activity in PMS preparations which is not found in association with the isolated ribosome-pH 5 enzyme protein synthesizing system.

Aging↗
PubMed1977

Human ornithine transcarbamylase. Purification and characterization of the enzyme from normal liver and the liver of a Reye's syndrome patient.

Ornithine transcarbamylase was purified and characterized from normal human liver. The properties of this enzyme were compared to those of ornithine transcarbamylase purified from the liver of a patient with Reye's syndrome. The enzyme isolated from both sources appeared virtually identical for a variety of biochemical characteristics. The native molecular weight of ornithine transcarbamylase is 110,000 as determined by gel filtration. Electrophoresis of the enzyme, dissociated by sodium dodecyl sulfate, indicated that the enzyme exists as a trimer of identical or similar subunits of 36,500 daltons. Ornithine transcarbamylase from normal liver has an isoelectric point of 7.95, and the value for the enzyme from the Reye's syndrome liver was 8.05. No evidence of multiple species was found during the purification or subsequent characterization of the enzyme. The enzyme exhibited normal Michaelia-Menten kinetics, and the apparent Michaelis constants for L-ornithine and carbamyl phosphate are 0.20 mM and 0.09 mM, respectively. Inhibitor studies established the structural requirements for L-ornithine antagonists. L-Norvaline is the best competitive inhibitor of the enzyme with respect to L-ornithine. This study indicated that the reduced level of ornithine transcarbamylase activity commonly observed in Reye's syndrome is not necessarily due to structural or functional alterations of the enzyme.

Female↗