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Biomedical subjects

F G Hayden

Publications and source records attributed to F G Hayden.

At least 37 records · Page 2Linked to original sources
PubMed2000

In vitro activity of pleconaril and AG7088 against selected serotypes and clinical isolates of human rhinoviruses.

BACKGROUND: We tested the in vitro activity of pleconaril and AG7088 against five numbered human rhinovirus (HRV) serotypes and 46 clinical HRV isolates of undefined serotype recovered from patients with common colds. Antiviral effect of pleconaril and AG7088 were assessed by cytophathic effect (CPE) inhibition assays in Ohio HeLaI cells using microscopic and spectrophotometric methods. Both compounds were tested at concentrations of 1.0, 0.1 and 0.01 microg/ml. For the numbered HRV serotypes, the median EC(50) value determined by the microscopic CPE inhibition was slightly better for AG7088 compared to pleconaril (P=0.02) but was similar by spectrophotometric assay (P=0.15). For clinical HRV isolates the median EC(50) value determined microscopically was 0.01 microg/ml range, <0.01-0.04 microg/ml) for AG7088 compared to 0.07 microg/ml (range, <0.01->1 microg/ml) for pleconaril (P<0.001). The median EC(50) value determined by spectrophotometric assay was 0.01 microg/ml (range, <0.01-0.04 microg/ml) for AG7088 compared to 0.04 microg/ml (range, <0.01->1 microg/ml) for pleconaril (P<0.001). By either the microscopic or spectrophotometric methods the median EC(50) value of AG7088 was <1.0 microg/ml for all isolates and was >10.0 microg/ml of pleconaril for approximately 9% of isolates. In vitro AG7088 appeared to be more potent and to have a broader antirhinoviral spectrum than pleconaril among clinical HRV isolates. The clinical relevance of these in vitro results needs to be determined in controlled clinical trials.

Antiviral Agents↗
PubMed2000

Short-term treatment with zanamivir to prevent influenza: results of a placebo-controlled study.

We explored the prophylactic activity of zanamivir after presumed exposure to influenza in the community. After close contacts with index cases of influenza-like illnesses, 575 subjects were randomized in 4 treatment groups: 144 received placebo, 141 received intranasal zanamivir, 144 received inhaled zanamivir, and 146 received inhaled plus intranasal zanamivir for 5 days. Of 25 subjects (4%) who developed symptomatic influenza during the 5 days of prophylaxis, 9 (36%) were in the placebo group, 8 (32%) were in the intranasal zanamivir group (odds ratio [OR], 0.90; 95% confidence interval [CI], 0.30-2.72; P=.855), 3 (12%) were in the inhaled zanamivir group (OR, 0.27; 95% CI, 0.07-1.05; P=.058), and 5 (20%) were in the inhaled plus intranasal zanamivir group (OR, 0.52; 95% CI, 0.17-1.58; P=.247). Short-term treatment with intranasal zanamivir was ineffective. However, inhaled zanamivir treatment reduced the rate of influenza, which was 2%-3% among zanamivir recipients versus 6% among placebo recipients. Additional studies assessing a longer duration of postcontact prophylaxis are warranted.

Administration, Inhalation↗
PubMed2000

Correlates of immune protection induced by live, attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine.

The authors conducted a 2-year, multicenter, double-blind, placebo-controlled efficacy field trial of live, attenuated, cold-adapted, trivalent influenza vaccine administered by nasal spray to children 15-71 months old. Overall, vaccine was 92% efficacious at preventing culture-confirmed infection by influenza A/H3N2 and influenza B. Because influenza A/H1N1 did not cause disease during the years in which this study was conducted, the authors sought to determine vaccine efficacy and correlates of immune protection against experimental challenge with 107 TCID50 of attenuated H1N1 (vaccine strain) by intranasal spray. Prechallenge assessments included serum hemaglutination-inhibiting (HAI) antibody and nasal wash IgA antibody to H1N1. Vaccine was 83% efficacious (95% confidence interval, 60%-93%) at preventing shedding of H1N1 virus after challenge. Any serum HAI antibody or any nasal wash IgA antibody was correlated with significant protection from H1N1 infection as indicated by vaccine-virus shedding, and high efficacy against H1N1 challenge was demonstrated.

Administration, Intranasal↗
PubMed2000

Oral oseltamivir in human experimental influenza B infection.

Oseltamivir is the prodrug of Ro64-0802 (GS4071), a potent and selective inhibitor of influenza A and B virus neuraminidases. Three randomized, double-blind, placebo-controlled, parallel-group studies evaluated oral oseltamivir for early treatment (75 or 150 mg twice daily for 5 days) or prevention (75 mg once or twice daily for 7 days) of experimental influenza B virus infection in healthy susceptible adults. Treatment study A (n=60) demonstrated similar trends to treatment study B (n=117), in which 75 mg doses of oseltamivir introduced 24 h after inoculation reduced median area under curve (AUC) virus titre (oseltamivir, 22.7; placebo, 131.1 log10 TCID50 x h/ml; P=0.002) and duration of viral shedding (oseltamivir, 23.9 h; placebo, 95.8 h; P=0.0005). In prevention study C (n=58), oseltamivir did not reduce infection rates (85 versus 84%) but significantly reduced median AUC virus titre (10.0 versus 66.9 log10 TCID50 x h/ml; P=0.03) and duration of viral shedding (36 versus 84 h; P=0.03) compared with placebo. Oseltamivir was well tolerated. No emergence of drug-resistant variants was detected by testing last-day isolates (n=112) in neuraminidase inhibition assays. These results indicate that oseltamivir has significant antiviral activity in experimental human influenza B virus infection when used for prophylaxis or early treatment.

Acetamides↗
PubMed1999

Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza.

BACKGROUND: Safe and effective antiviral agents are needed to prevent infection with influenza A and B virus. Oseltamivir (GS4104), which can be administered orally, is the prodrug of GS4071, a potent and selective inhibitor of influenzavirus neuraminidases. We studied the use of oseltamivir for long-term prophylaxis against influenza in two placebo-controlled, double-blind trials at different U.S. sites during the winter of 1997-1998. METHODS: We randomly assigned 1559 healthy, nonimmunized adults 18 to 65 years old to receive either oral oseltamivir (75 mg given once or twice daily, for a total daily dose of 75 or 150 mg) or placebo for six weeks during a peak period of local influenzavirus activity. The primary end point with respect to efficacy was laboratory-confirmed influenza-like illness (defined as a temperature of at least 37.2 degrees C accompanied by at least one respiratory and at least one systemic symptom). RESULTS: In the two studies combined, the risk of influenza among subjects assigned to either once-daily or twice-daily oseltamivir (1.2 percent and 1.3 percent, respectively) was lower than that among subjects assigned to placebo (4.8 percent; P<0.001 and P=0.001 for the comparison with once-daily and twice-daily oseltamivir, respectively). The protective efficacy of oseltamivir in the two active-treatment groups combined was 74 percent (95 percent confidence interval, 53 to 88 percent) at all the sites combined and 82 percent (95 percent confidence interval, 60 to 93 percent) at sites in Virginia, where the rate of influenza infection was higher than the overall rate. For culture-proved influenza, the rate of protective efficacy in the two oseltamivir groups combined was 87 percent (95 percent confidence interval, 65 to 96 percent). The rate of laboratory-confirmed influenza infection was lower with oseltamivir than with placebo (5.3 percent vs. 10.6 percent, P<0.001). Oseltamivir was well tolerated but was associated with a greater frequency of nausea (12.1 percent and 14.6 percent in the once-daily and twice-daily groups, respectively) and vomiting (2.5 percent and 2.7 percent, respectively) than was placebo (nausea, 7.1 percent; vomiting, 0.8 percent). However, the frequency of premature discontinuation of drug or placebo was similar among the three groups (3.1 to 4.0 percent). CONCLUSIONS: Oseltamivir administered daily for six weeks by the oral route is safe and effective for the prevention of influenza.

Administration, Oral↗
PubMed1999

Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza: randomized controlled trials for prevention and treatment.

CONTEXT: Influenza virus neuraminidase is thought to be essential for virus replication in humans; however, to date, available neuraminidase inhibitors are limited to zanamivir, which is topically administered. OBJECTIVE: To determine the safety, tolerability, and antiviral activity of oral neuraminidase inhibitor oseltamivir (GS4104/Ro64-0796) for prevention and the early treatment of influenza in experimentally infected humans. DESIGN: Two randomized, double-blind, placebo-controlled trials conducted between June and July 1997. SETTING: Individual hotel rooms; 2 large US university medical schools. PARTICIPANTS: A total of 117 healthy adult volunteers (aged 18-40 years; median age, 21 years) who were susceptible (hemagglutination-inhibition antibody titer < or =1:8). INTERVENTIONS: All subjects were inoculated intranasally with influenza A/Texas/36/91 (H1N1) virus. For the prophylaxis study, oral oseltamivir (100 mg once daily [n = 12], 100 mg twice daily [n = 12], or matching placebo [n = 13], starting 26 hours before virus inoculation) was administered. For the treatment study, the same drug was given (20 mg, 100 mg, or 200 mg twice daily, 200 mg once daily, or matching placebo [n = 16], in each group starting 28 hours after inoculation). All regimens were continued for 5 days. MAIN OUTCOME MEASURES: Comparing placebo groups with pooled treatment groups, for prophylaxis, outcomes included frequency of infection and viral shedding; for treatment, viral shedding in titers. RESULTS: In the prophylaxis study, 8 (67%) of 12 placebo and 8 (38%) of 21 oseltamivir recipients became infected (P = .16; efficacy, 61%); 6 (50%) placebo compared with 0 oseltamivir recipients shed virus (P<.001; efficacy, 100%), and 33% of placebo but no oseltamivir recipient had infection-related respiratory illness (P<.01). Among infected subjects in the treatment study (n = 69), the viral titer area under the curve of the combined oseltamivir groups (n = 56) was lower (median [interquartile range [IQR]], 80 [23-151] vs 273 [79-306] log10 tissue culture-infective doses50 per milliliter x hour; P = .02) than the placebo group (n = 13), and the median (IQR) duration of viral shedding with therapy was reduced from 107 (83-131) to 58 (35-59) hours (P = .003). Oseltamivir treatment also reduced symptom scores (median [IQR] score-hours, 225 [97-349] vs 400 [189-645]; P = .05), and nasal proinflammatory cytokine levels. Transient mild to moderate nausea after dosing was observed in 15 (17%) of 88 oseltamivir and 2 (7%) of 29 placebo recipients (95% confidence interval for difference, -11% to 68%), which was largely prevented by ingestion with food. CONCLUSIONS: In these trials, prophylaxis and early treatment with oral oseltamivir were both associated with significant antiviral and clinical effects in experimental human influenza.

Administration, Oral↗
PubMed1999

Efficacy of tremacamra, a soluble intercellular adhesion molecule 1, for experimental rhinovirus infection: a randomized clinical trial.

CONTEXT: Attachment of most rhinovirus subtypes to cells depends on a cellular receptor, the intercellular adhesion molecule 1 (ICAM-1). A recombinant soluble ICAM-1 (tremacamra, formerly BIRR 4) has shown possible efficacy in early studies. OBJECTIVE: To determine the efficacy and safety of intranasal administration of tremacamra in experimental rhinovirus colds in humans. DESIGN: Four randomized, double-blind, placebo-controlled trials conducted in January to March 1996. SETTING AND SUBJECTS: Volunteers between the ages of 18 and 60 years who had an antibody titer of 1:4 or less to the challenge virus. Subjects were isolated in a hotel room during study days 0 to 8; symptoms were recorded through day 14. A total of 198 subjects were randomized, of whom 196 received drug or placebo and were included in the safety analysis. A total of 177 subjects were included in the efficacy analysis. INTERVENTIONS: Tremacamra or placebo was given beginning 7 hours before inoculation with rhinovirus type 39 (preinoculation studies) or 12 hours after (postinoculation studies). Tremacamra as an inhaled solution or as a powder (each given preinoculation and postinoculation for a total of 4 studies) and placebo were given in 6 doses at 3-hour intervals daily during days 1 through 7. Recipients of active treatment received 367 microg of tremacamra per nostril per dose for a total of 4.4 mg/d. MAIN OUTCOME MEASURES: Effect of tremacamra on infection, as determined by virus isolation and seroconversion, and on illness, as determined by symptom scores, clinical colds, and nasal mucus weights. Treatment-by-study interaction was not significant, so results were pooled for the main analysis. RESULTS: A total of 88 (92%) of the 96 subjects in the placebo groups and 69 (85%) of the 81 subjects in the active treatment groups were infected (P=.19). For placebo vs tremacamra, respectively, the total symptom score (+/- 95% confidence interval [CI]) was 17.6 (+/- 2.7) vs 9.6 (+/- 2.9), the proportion of clinical colds was 64/96 (67% +/- 9%) vs 36/81 (44% +/- 11%), and the nasal mucus weight was 32.9 (+/- 8.8) g vs 14.5 (+/- 9.4) g (P<.001 for all comparisons). Tremacamra was not associated with adverse effects or evidence of absorption through the nasal mucosa and did not interfere with development of neutralizing antibody. CONCLUSION: Tremacamra reduced the severity of experimental rhinovirus colds. Whether tremacamra will be useful clinically will require further study.

Administration, Intranasal↗
PubMed1999

Performance of virus isolation and Directigen Flu A to detect influenza A virus in experimental human infection.

BACKGROUND: Few data exist to assess the sensitivity of different specimen types for viral detection during the course of influenza virus infection. OBJECTIVES: This study assessed the relationships between quantitative influenza A virus replication and antigen detectability by the enzyme immunosorbent assay (EIA) Directigen Flu A in different type of samples during experimental human infection. STUDY DESIGN: Fourteen volunteers were inoculated with influenza A virus A/Texas/36/91 (H1N1). Four specimens types were collected in sequence for quantitative isolation in cell culture and antigen testing from days 1 to 8 after inoculation. RESULTS: Seventy-one (63%) of nasopharyngeal wash specimens were culture positive, compared to 51 (46%) of throat gargles, 51 (46%) of nasal swabs, and 27 (24%) of throat swabs. All subjects shed virus in their nasopharyngeal wash at least one day and 86% of subjects had a positive nasopharyngeal wash culture on day 2 after inoculation. The mean viral titers were highest on day 2 post inoculation for all specimen types and averaged 3.6 log10 TCID50/ml for nasal washes, 1.2 log10 TCID50/ml for throat gargles, 1.8 log10 TCID50/ml for the nasopharyngeal swabs, and 0.6 log10 TCID50/ml for the throat swabs. Mean viral titers in the nasal washes were significantly different (P<0.05) compared to other specimen types. The peak of sensitivity of EIA (compared to culture) was the second day after inoculation. Nasopharyngeal and throat swab results were combined for this analysis and considered positive by culture if positive in either or both samples. Thus, on day 2 the number of EIA positive samples relative to the number culture positive was 9/12 (75%) for nasopharyngeal wash specimens, 2/9 (22%) for throat gargles, and 7/11 (64%) for the combined throat and nasal swabs specimens. CONCLUSIONS: Nasopharyngeal washes are the most sensitive sample type detecting influenza A virus in adults. For rapid diagnosis the Directigen Flu A is an alternative with a sensitivity compared to culture ranging between 64 and 78% if performed on nasopharyngeal specimens on day two or three after experimental infection in adults. However, if performed on other specimens or later in the course of infection the sensitivity is lower.

Adult↗
PubMed1999

Nasal cytokine and chemokine responses in experimental influenza A virus infection: results of a placebo-controlled trial of intravenous zanamivir treatment.

The local immune response to influenza virus infection was characterized by determining cytokine and chemokine levels in serial nasal lavage fluid samples from 15 volunteers experimentally infected with influenza A/Texas/36/91 (H1N1). The study was part of a randomized double-blind placebo-controlled trial to determine the prophylactic effect of intravenous zanamivir (600 mg 2x/day for 5 days), a highly selective inhibitor of influenza A and B virus neuraminidases, on the clinical symptoms of influenza infection. Nasal lavage fluid levels of interleukin (IL)-6, tumor necrosis factor-alpha, interferon-gamma, IL-10, monocyte chemotactic protein-1, and macrophage inflammatory protein-1alpha and -1beta increased in response to influenza virus infection and correlated statistically with the magnitude and time course of the symptoms. Treatment with zanamivir prevented the infection and abrogated the local cytokine and chemokine responses. These results reveal a complex interplay of cytokines and chemokines in the development of symptoms and resolution of influenza.

Antiviral Agents↗
PubMed1999

Safety and efficacy of intravenous zanamivir in preventing experimental human influenza A virus infection.

Zanamivir is a potent inhibitor of influenza A and B virus neuraminidases and is active topically in experimental and natural human influenza. We conducted this double-blinded, placebo-controlled study to evaluate the safety and efficacy of intravenously administered zanamivir. Susceptible volunteers were randomized to receive either saline or zanamivir (600 mg) intravenously twice daily for 5 days beginning 4 h prior to intranasal inoculation with approximately 10(5) 50% tissue culture infectious doses (TCID50) of influenza A/Texas/36/91 (H1N1) virus. Reductions in the frequency of viral shedding (0% versus 100% in placebo, P < 0.005) and seroconversion (14% versus 100% in placebo, P < 0.005) and decreases in viral titer areas under the curve (0 versus 11.6 [median] log10 TCID50. day/ml in placebo, P < 0.005) were observed in the zanamivir group, as were reductions in fever (14% versus 88% in placebo, P < 0.05), upper respiratory tract illness (0% versus 100% in placebo, P < 0.005), total symptom scores (1 versus 44 [median] in placebo, P < 0.005), and nasal-discharge weight (3.9 g versus 17.5 g [median] in placebo, P < 0.005). Zanamivir was detectable in nasal lavage samples collected on days 2 and 4 (unadjusted median concentrations, 10.5 and 12.0 ng/ml of nasal wash, respectively). This study demonstrates that intravenously administered zanamivir is distributed to the respiratory mucosa and is protective against infection and illness following experimental human influenza A virus inoculation.

Adolescent↗
PubMed1999

Rhinovirus and respiratory syncytial virus in wheezing children requiring emergency care. IgE and eosinophil analyses.

This cross-sectional emergency department study of 70 wheezing children and 59 control subjects (2 mo to 16 yr of age) examined the prevalence of respiratory viruses and their relationship to age, atopic status, and eosinophil markers. Nasal washes were cultured for respiratory viruses, assayed for respiratory syncytial virus (RSV) antigen, and tested for coronavirus and rhinovirus RNA using reverse transcription-PCR (RT-PCR). Also evaluated were eosinophil numbers and eosinophil cationic protein (ECP) in both nasal washes and serum, along with total IgE and specific IgE antibody in serum. Respiratory viruses were detected in 82% (18 of 22) of wheezing infants younger than 2 yr of age and in 83% (40 of 48) of older wheezing children. The predominant pathogens were RSV in infants (detected in 68% of wheezing subjects) and rhinovirus in older wheezing children (71%), and both were strongly associated with wheezing (p < 0.005). RSV was largely limited to wheezing children younger than 24 mo of age, but rhinovirus was detected by RT-PCR in 41% of all infants and in 35% of nonwheezing control subjects older than 2 yr of age. After 2 yr of age the strongest odds for wheezing were observed among those who had a positive RT-PCR test for rhinovirus together with a positive serum radioallergosorbent testing (RAST), nasal eosinophilia, or elevated nasal ECP (odds ratios = 17, 21, and 25, respectively). Results from this study demonstrate that a large majority of emergent wheezing illnesses during childhood (2 to 16 yr of age) can be linked to infection with rhinovirus, and that these wheezing attacks are most likely in those who have rhinovirus together with evidence of atopy or eosinophilic airway inflammation.

Adolescent↗
PubMed1999

Safety and efficacy of once daily intranasal zanamivir in preventing experimental human influenza A infection.

Zanamivir, a potent inhibitor of influenza A and B virus neuraminidases, is protective against experimental human influenza when given intranasally twice daily. We conducted two studies to assess the pharmacokinetics and protective efficacy of a reduced frequency dosing regimen of topical zanamivir. In the first study, 36 uninfected volunteers received a single dose of zanamivir by intranasal spray (6.4 mg), intranasal drops (16 mg) or dry powder oral inhalation (10 mg). At 4 h, median nasal wash concentrations were 50-fold higher after intranasal dosing than after inhalation. Substantial levels (spray group, median 4,596 ng/ml; drop group, 1,239 ng/ml) were detected in nasal wash 48 h after intranasal dosing. In the double-blinded efficacy study, 47 sero-susceptible volunteers were randomized to receive either placebo or zanamivir intranasal spray (6.4 mg). Among the 43 subjects evaluated, decreases in viral shedding occurred in the group receiving one dose of zanamivir 4 h prior to inoculation, whereas no significant benefit was observed in those receiving a single dose 48 h prior to challenge. In the group given three daily doses, reductions were seen in viral shedding and infection. In the two regimens providing zanamivir 4 h prior to inoculation, significant reductions in nasal mucus weight were observed. Decreases in total symptom scores and the incidence of upper respiratory illness also occurred, but they did not reach statistical significance. The efficacy of a single dose of zanamivir given 4 h prior to inoculation supports the hypothesis that influenza virus neuraminidase is essential for initial virus spread through respiratory secretions. These findings indicate that once daily dosing of zanamivir is protective against experimental influenza A infection.

Administration, Intranasal↗