American journal of respiratory and critical care medicine
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Am. J. Respir. Crit. Care Med. · Apr 1998
Effect of dexfenfluramine treatment in rats exposed to acute and chronic hypoxia.
The anorexiant dexfenfluramine, which inhibits 5-hydroxytryptamine (5-HT) uptake, has been associated with an increase in the relative risk of developing primary pulmonary hypertension. The aim of this study was to investigate in rats whether dexfenfluramine (1) alters the pulmonary vasomotor effects of 5-HT and (2) aggravates the development of pulmonary hypertension during exposure to various levels of chronic hypoxia. In isolated lungs from normoxic rats, dexfenfluramine up to 10(-4) M did not elicit any vasoactive effects, and neither did pretreatment with dexfenfluramine (10[-5] M in the perfusate) modify the vasoactive effects of 5-HT. ⋯ In contrast, a continuous 5-HT infusion providing a sustained increase in plasma 5-HT levels was associated with increased muscularization of distal pulmonary arteries in response to 10% O2. Simultaneous administration of dexfenfluramine prevented the effect of exogenous 5-HT on vascular remodeling. Our findings show that dexfenfluramine does not potentiate the development of pulmonary hypertension in rats exposed to chronic hypoxia, despite its effect on plasma 5-HT concentrations.
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Am. J. Respir. Crit. Care Med. · Mar 1998
Antibody to E- and L-selectin does not prevent lung injury or mortality in septic baboons.
Recruitment of polymorphonuclear leukocytes (PMN) through upregulation of cellular adhesion molecules is a proposed mechanism of injury in sepsis and acute respiratory distress syndrome (ARDS). We hypothesized that pretreatment of baboons with a monoclonal antibody to human E- and L-selectin (EL-246) during sepsis would decrease PMN influx into tissues and result in less organ injury during gram-negative sepsis. We studied 14 anesthetized, ventilated adult baboons; six animals received 1 mg/kg of EL-246 before infusion of an LD100 of live Escherichia coli and six received the E. coli infusion without antibody therapy. ⋯ The antibody partly blocked PMN migration, but there were few significant physiologic or biochemical differences between the EL-246-treated and untreated animals. In the antibody-treated animals, UOP was decreased, metabolic acidosis was worsened, and median survival time was decreased significantly. We conclude that treatment with an antibody to E- and L-selectin in gram-negative sepsis does not improve gas exchange or protect against lung injury, and is associated with decreased survival time in primates.
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To test the respiratory effects of benzodiazepines in an established animal model of central apnea, we administered nonhypnotic and hypnotic doses of diazepam to nine adult male Sprague-Dawley rats chronically instrumented for sleep staging. In random order on separate days, rats were recorded following intraperitoneal injection of: (1) saline; (2) 0.05 mg/kg diazepam; or (3) 5 mg/kg diazepam. Normalized inspiratory minute ventilation increased significantly during wakefulness and non-rapid eye movement (non-REM) sleep following each dose of diazepam (p < 0.003 in each case) and following the highest dose during rapid eye movement (REM) sleep (p = 0.01). ⋯ The durations of non-REM and REM sleep were unaffected by the low dose, but following 5 mg/kg of diazepam non-REM sleep was increased (p = 0.03) and REM sleep was decreased (p = 0.009). We conclude that both hypnotic and non-hypnotic doses of benzodiazepines may be associated with suppression of sleep-related central apnea. We further conclude that non-REM and REM-related apneas arise from at least partially distinct mechanisms.
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Am. J. Respir. Crit. Care Med. · Mar 1998
Randomized Controlled Trial Clinical TrialInhaled flunisolide for acute severe asthma.
This randomized, double-blind trial was designed to determine the benefit of high and cumulative doses of flunisolide added to salbutamol in patients with acute asthma in the emergency room (ER). Ninety-four patients who presented to an ER for treatment of an acute exacerbation of asthma were assigned in a randomized, double-blind fashion to receive salbutamol and placebo (n = 47) or salbutamol combined with flunisolide (n = 47). Both drugs were administered successively through a metered-dose inhaler and spacer at 10-min intervals for 3 h (400 microg of salbutamol and 1 mg of flunisolide every 10 min). ⋯ Results in the flunisolide group were significantly different from those in the placebo group at 90, 120, 150, and 180 min. Data analyzed separately in accord with the duration of the attack before presenting at the ER (< 24 or > or = 24 h) showed that the placebo > or = 24 h group produced a significantly lower FEV1 at 120, 150, and 180 min (p = 0.041) than did the remaining groups. Our data support the theory that high and cumulative doses of inhaled flunisolide administered by metered-dose inhaler with spacer and added to salbutamol are an effective therapy for patients with acute asthma and a prolonged duration of symptoms before ER presentation.
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Am. J. Respir. Crit. Care Med. · Mar 1998
Comparative StudyCD8+ T-lymphocytes in peripheral airways of smokers with chronic obstructive pulmonary disease.
To investigate whether the inflammatory process in peripheral airways is different in smokers who develop symptoms of chronic bronchitis and chronic airflow limitation and in asymptomatic smokers who do not develop chronic airflow limitation, we examined surgical specimens obtained from 16 smokers undergoing lung resection for localized pulmonary lesions. Nine had symptoms of chronic bronchitis and chronic airflow limitation and seven were asymptomatic with normal lung function. ⋯ The number of CD8+ T-lymphocytes and the smooth muscle area were increased in smokers with symptoms of chronic bronchitis and chronic airflow limitation as compared with asymptomatic smokers with normal lung function, while the number of neutrophils, macrophages, and CD4+ T-lymphocytes were similar in the two groups of subjects examined. We concluded that smokers who develop symptoms of chronic bronchitis and chronic airflow limitation have an increased number of CD8+ T-lymphocytes and an increased smooth muscle area in the peripheral airways as compared with asymptomatic smokers with normal lung function, supporting the important role of CD8+ T-lymphocytes and airway remodeling in the pathogenesis of chronic obstructive pulmonary disease.