Publications

We examined the changes in airway responsiveness to increasing doses of an acetylcholine aerosol in anesthetized and ventilated guinea pigs 2, 6, or 24 h after exposure to 2 ppm toluene diisocyanate (TDI) or 2 h after exposure to air or 1 ppm TDI. Pulmonary resistance (RL) after the animals inhaled a buffered saline aerosol was used as baseline and was similar for air and TDI groups. The concentration of acetylcholine calculated to cause a 200% increase in RL was significantly lower for animals studied at 2 h (0.68%) or at 6 h (0.77%), but not at 24 h (2.39%), after TDI than for air animals (3.07%). The increase in airway responsiveness in the TDI-exposed animals was associated with histologic changes in the trachea and intrapulmonary airways. Exposure to 2 ppm TDI caused a patchy loss of cilia, shedding of epithelial cells into the airway lumen, and an influx of inflammatory cells into the trachea and other airways. In the lamina propria of the trachea, the concentration of extravascular polymorphonuclear leukocytes (PMN) was 13- to 26-fold greater in animals studied 2 or 6 h after exposure to 2 ppm TDI or at 2 h after 1 ppm TDI than in animals exposed to air. The concentration of PMN in the epithelium was significantly increased only in animals examined 2 h after 2 ppm TDI. Exposure to TDI also caused an influx of eosinophils into the tracheal mucosa. This influx occurred later and was more persistent than the influx of PMN. These results indicate that a single exposure to TDI can cause an increase in airway responsiveness that is associated with epithelial injury and acute airway inflammation.

Short-term therapy with oral hydralazine can favorably affect abnormal hemodynamics in patients with congestive heart failure, but the range of dosage is large. To investigate whether this variability in effective dose is a result of altered systemic availability, we studied 10 patients with congestive heart failure. Bioavailability (F) was calculated as the ratio of the blood AUC for a single 75 mg oral dose to the AUC of a 0.3 mg/kg iv dose. Acetylation capability was determined by sulfamethazine metabolic clearance (CLsmz). The F value in six subjects with CLsmz greater than 100 ml/min was 9.9% +/- 6.0% (means +/- SD) and was lower than the value of 26.2% +/- 13.0% (P less than 0.05) in the four patients with CLsmz less than 60 ml/min. Thus acetylation ability is an important consideration during low-dose hydralazine therapy (less than or equal to 225 mg/day). The clearance of the single intravenous dose of hydralazine averaged 29.5 +/- 8.0 ml/min/kg, which is not different than that reported in populations without heart failure. After oral dosage titration to induce maximum hemodynamic changes, the dose-normalized hydralazine AUC rose from 53.5 +/- 50.5 to 247.2 +/- 213.4 min/L X 10(3). Thus large oral doses of hydralazine result in disproportionate increases in systemic availability compatible with saturation of the first-pass effect or systemic clearance. In the doses required for maximum hemodynamic effects in our patients (225 to 3000 mg/day), this saturation phenomenon was a prominent determinant of systemic availability.