ABSTRACT
Information was needed on effects of possible occupational inhalation exposure to an M1-receptor agonist (xanomeline) such as might occur during the manufacturing process. Both acute and repeated inhalation exposures to xanomeline were carried out in six male rhesus monkeys using a head-dome exposure system. Exposure concentrations ranged from 0.3 to 10 mg/m3. The exposure durations were up to 2 weeks. Decreases in tidal volume and increases in respiratory frequency were both time and concentration related during acute exposures. These effects were blocked with atropine pre-treatment. Correlation with pulmonary resistance measurements in two monkeys suggested that these were bronchoconstrictive changes that increased with severity with time at a given concentration and with concentration when measured after a constant exposure time. The dose-response was relatively steep with 10 mg/m3 becoming intolerable to the monkeys after approximately 15 minutes, but no measurable effects were observed at 0.3 mg/m3 after up to 4 hours of exposure. To investigate the effects of repeated exposures, monkeys were exposed for 4 hr/day, 5 days/wk for 2 weeks to 0.0 (air only), 0.3, and 1.2 mg xanomeline/m3 of air. When compared to the air-only exposure, 0.3 mg/m3 caused no significant changes in tidal volume. In contrast, 1.2 mg/m3 caused a rapid and significant decrease in tidal volume that was sustained throughout the 4-hr exposure. A slower rise in breathing frequency also occurred. Repeated exposures did not alter the effects seen after a single exposure. It is concluded that xanomeline, a M1-receptor agonist, can acutely alter normal ventilation in non-human primates at airborne concentrations > or = 0.6 mg/m3 and should be carefully controlled in a manufacturing environment. The no-observed-effect concentration was 0.3 mg/m3.
Subject(s)
Muscarinic Agonists/toxicity , Pulmonary Ventilation/drug effects , Pyridines/toxicity , Thiadiazoles/toxicity , Administration, Inhalation , Airway Resistance/drug effects , Animals , Atmosphere Exposure Chambers , Atropine/pharmacology , Bronchoconstriction , Dose-Response Relationship, Drug , Drug Administration Schedule , Macaca mulatta , Male , Muscarinic Agonists/administration & dosage , Pulmonary Ventilation/physiology , Pyridines/administration & dosage , Respiration/drug effects , Thiadiazoles/administration & dosage , Tidal Volume/drug effectsABSTRACT
The dose-response relationship between aerosolized leukotriene B4 (LTB4 and pulmonary neutrohilia was examined in a group of five rhesus monkeys. The effects of an oral dose of LY293111Na on LTB4-aerosol-induced pulmonary neutrophilia were also examined. Ex vivo expression of CD11b receptors on polymorphonuclear leukocytes from bronchoalveolar lavage fluid and peripheral whole blood were also assessed. Up-regulation of CD11b adhesion receptors by LTB4 was assessed ex vivo on the peripheral whole blood. Pulmonary neutrophilia was linearly associated with dose of inhaled LTB4. LY293111Na, at 10 mg/kg, significantly blocked the profound bronchoalveolar lavage neutrophilia produced by LTB4 aerosol inhalation. A large (48%), but not statistically significant, reduction was seen for CD11b expression on bronchoalveolar lavage polymorphonuclear leukocytes after pretreatment with LY293111Na. LY293111Na did not significantly change the number of white blood cells in peripheral blood. LY293111Na did significantly attenuate the LTB4-induced up-regulation of CD11b receptors on peripheral blood neutrophils. We conclude that LY293111Na may be an effective oral treatment for diseases that involve neutrophilic inflammation.
