Biomedical subjects
Publications and source records attributed to D Skoner.
Pediatric dose selection for montelukast in 2-5-year-old children was based on a pharmacokinetic approach that was also used in previously selecting a once-daily 5-mg chewable tablet for asthmatic children 6-14 years of age. A 4-mg chewable tablet administered once daily was determined to be the correct dose and was subsequently found to be safe and effective in asthmatic children 2-5 years of age.
BACKGROUND: Inflammation plays an important role in the pathogenesis of bronchopulmonary dysplasia (BPD), but the exact nature of this inflammatory process is incompletely understood. Older infants with established BPD have higher levels of urinary leukotriene E(4) (LTE(4)) compared to healthy infants of the same age. This suggests that cysteinyl leukotrienes may play a role in the abnormalities seen in BPD. OBJECTIVES: To measure urinary LTE(4) levels during the first month of life in premature infants, and to determine whether there are significant differences in premature infants who develop BPD, as compared to those who do not develop BPD. DESIGN: Prospective, blinded, controlled study. SETTING: Neonatal ICUs of a tertiary-care university hospital. METHODS: Thirty-seven premature infants (< 33 weeks of gestational age) were enrolled prospectively at birth. Urinary LTE(4) levels were measured blinded, using a standard radioimmunoassay technique at 2 days, 7 days, and 28 days of life. At 1 month of age, infants were classified as with or without BPD, based on need for supplemental oxygen, and characteristic chest radiographs. Clinical features and urinary LTE(4) were compared between the two groups. RESULTS: Mean +/- SD gestational age was 29 +/- 2.6 weeks. None of the infants had a family history of asthma. Thirteen of 37 infants were classified as having BPD at 28 days after birth. Mean gestational age in infants who developed BPD was 27 +/- 2.4 weeks, compared to 30 +/- 2 weeks in infants who did not develop BPD (p < 0.05). In infants with BPD, mean urinary LTE(4) levels of urinary creatinine were 1,762 +/- 2,003 pg/mg, 1,236 +/- 992 pg/mg, and 5,541 +/- 5,146 pg/mg at days 2, 7, and 28, respectively, compared to 1,304 +/- 1,195 pg/mg, 1,158 +/- 1,133 pg/mg, and 2,800 +/- 2,080 pg/mg in infants without BPD. LTE(4) levels at 2 days, 7 days, and 28 days did not correlate with the subsequent development of BPD. LTE(4) levels at day 28 were significantly higher than LTE(4) levels at day 2 and day 7 in both groups, even after correcting for gestational age or birth weight (p < 0.05). There was significant inverse correlation between LTE(4) levels at day 2 with gestational age and birth weight (p < 0.05). All 13 infants with BPD received steroid pulses, compared to 3 of 26 infants without BPD. Gestational age and use of postnatal steroid pulses, diuretics, and theophylline (for apnea of prematurity) were significantly associated with each other and with the subsequent development of BPD. CONCLUSION: Urinary LTE(4) levels measured on the second day of life in very-low-birth-weight infants inversely correlate with gestational age and birth weight. Urinary LTE(4) levels may reflect lung injury and/or inflammation in premature infants, not necessarily related to BPD as it is presently defined.
Interleukin-6 (IL-6) is a pleotropic cytokine implicated in the pathogenesis of local inflammation during viral upper respiratory infections. This study determined if experimental influenza A virus infection causes local IL-6 production. Seventeen healthy, adult subjects were intranasally inoculated, by course drops, with a safety-tested strain of influenza A/Kawasaki/86 (H1N1) virus. Nasal lavage samples were collected, symptoms were recorded, and expelled nasal secretions were weighed once before and then daily for 8 days after the virus inoculation. Lavage samples were submitted for virus culture and were examined for IL-6 and IL-4 by enzyme-linked immunosorbent assay. The IL-6, but not IL-4, levels were significantly increased in the nasal lavage samples of the 12 subjects who shed virus but not in those of the 5 subjects who did not shed virus. Moreover, the elevations in IL-6 levels were related temporally to the development of nasal symptoms and secretions but not to systemic symptoms. These results suggest a role for locally produced IL-6 in the pathogenesis and expressed symptomatology of influenza A virus infection.
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Episodes of acute otitis media are commonly associated with viral upper respiratory tract infections. Rhinoviruses account for approximately 40% of these infections, and were previously shown to alter eustachian tube function and middle ear pressures. However, progression to otitis media has not been prospectively documented. In the present study, changes in tympanometric pressures and otoscopic findings resulting from experimental intranasal rhinovirus type-39 inoculation were documented in 60 adult volunteers. Fifty-seven (95%) subjects became infected and 34 (60%) of these had a clinical cold. Prior to viral inoculation, 3 (5%) subjects had middle ear pressures of less than -100 mm H2O and two of these subjects developed middle ear effusions following infection. In all, 22 (39%) subjects developed middle ear pressures of less than -100 mm H2O. No subject with normal middle ear pressures prior to infection developed evidence of effusion. This study extends the otologic manifestations of rhinovirus infection to include otitis media. Furthermore, these results support the hypothesized relationship between upper respiratory tract infections, eustachian tube dysfunction, and otitis media.
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In summary, wheezing is a common manifestation of viral respiratory tract disease in infancy. The precise pathogenetic mechanisms of virus-induced wheezing and its sequelae are not clear, although recent reports about participation of the cellular and humoral immune systems are promising. Although therapies like those used to treat asthma are employed in the treatment of virus-induced wheezing in infancy, their efficacy remains controversial in bronchiolitis. Recently developed agents with antiviral properties are promising and the choice of any of these agents in a therapeutic regimen should be individualized. Antiviral agents during acute infections may modify the long-term sequelae. Clearly, much work needs to be done to elucidate pathogenetic mechanisms, and to develop new, safe, and effective anti-inflammatory agents for the therapy of these disorders.
Studies of the efficacy of antihistamines in treating human upper airway pathology are difficult to design and conduct. In part, this is the result of a lack of objective measures of the nasal response. The purpose of this study was to develop a monkey model for the objective evaluation of antihistamine effectiveness and, using this model, to study the efficacy of cetirizine. Computer-assisted active anterior rhinomanometry was used to assess nasal airway resistance (NAR) before and after a nasal histamine provocation in conscious rhesus monkeys (Macaca mulatta). To establish dose-response relationships for oral antihistamines in monkeys, we measured the suppression of wheal-and-flare reactions by two such agents, oral cetirizine (CET) 0.1 to 1 mg/kg and chlorpheniramine (CHL) 0.07 to 0.2 mg/kg. The decreases in wheal sizes were maximal 60 to 120 minutes after CET 1.0 mg/kg (90%), and after CHL 0.2 mg/kg (70%). The four monkeys were challenged intranasally with increasing histamine doses (0.5, 1, 5, and 10 mg). The NAR was measured 15 minutes after each dose. At least three days later and 90 minutes after oral pretreatment with either CET 1 mg/kg or CHL 0.2 mg/kg, the intranasal challenges were repeated. Postchallenge NAR data are given as the percent increase from the baseline NAR values. The four monkeys studied had coefficients of variation of 13%, 15%, 16%, and 26% respectively for baseline studies. Mean percent increases in NAR +/- standard deviation were 14% +/- 0.4%, 47% +/- 10.0%, 45% +/- 3.0%, and 72% +/- 6.0% after intranasal challenge with 0.5, 1, 5, and 10 mg of histamine, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)