Addition of anticholinergic solution prolongs bronchodilator effect of beta 2 agonists in patients with chronic obstructive pulmonary disease.

A randomized, double-blind placebo-controlled clinical trial was designed to assess the safety, efficacy, and duration of the bronchodilation resulting from the addition of 500 micrograms of ipratropium bromide (Atrovent; Boehringer Ingelheim, CT) inhalation solution to standard small volume nebulizer treatments with 2.5 mg albuterol inhalation solution. A total of 195 patients (63% men, average age 64 years) with > 10 pack-year smoking histories and stable, moderate-to- severe chronic obstructive pulmonary disease (COPD; forced expiratory volume in 1 second [FEV1] 1.02 liter, 38.8% predicted) from eight university-affiliated chest clinics in seven U.S. cities were enrolled into the study. Asthma, rhinitis, and eosinophilia were exclusions, as was daily use of > 10 mg of prednisone (or 20 mg on alternate days). There was a 2-week stabilization period during which the patients were instructed in the use of the small volume nebulizers, which they used three times daily with albuterol alone. They were asked to keep daily logs of peak flow rates, pulmonary symptoms, and additional medication usage. On their test day 1 the subjects came to the pulmonary function laboratory having been off theophylline for 24 hours and beta 2-agonists for 12 hours and performed a baseline spirometry. They then received their morning small volume nebulizer treatment of albuterol to which was added either 500 micrograms if ipratropium bromide or a saline placebo. Spirometry was repeated at 15, 30, and 60 minutes, and then hourly for 8 hours. Subjects then took home a 2-week supply of albuterol and test drug for thrice daily use in their small volume nebulizer. They were evaluated for pulmonary symptoms and adverse effects every 14 days. The 8-hour spirometry was repeated on test day 43 and finally on test day 85. Primary data evaluated were the peak increase in FEV1 and the area between the FEV1 baseline value and the 8-hour FEV1 curve. Similar calculations were made for forced vital capacity (FVC) and 25-75% forced expiratory flow (FEF25-75%). On test day 1 the peak increase in FEV1 for the ipratropium bromide + albuterol subjects was 26% greater than those on placebo + albuterol (p < 0.003). The area under the 8-hour FEV1 curve was 64% greater in those given ipratropium bromide on test day 1 (p < 0.0002). Similar increases were seen in FVC and FEF25-75%. The peak improvements in FEV1 and FVC with the addition of ipratropium bromide to albuterol were maintained on test days 43 and 85. Considering the safety and efficacy profiles of this combination, the data would suggest that ipratropium bromide inhalation solution should be considered first-line therapy for those patients with COPD requiring small volume nebulizer treatments.

Effects of MK-801 on rat primary afferent neurons and fibers.

Recent evidence suggests that glutamate and its N-methyl-D-aspartate (NMDA) receptor may participate in regulating neurite morphology and peptide expression. A previous study from this laboratory showed that treatment with the NMDA receptor antagonist, MK-801, induced an apparent increase in the density of calcitonin gene-related peptide (CGRP)-immunoreactive primary afferent fibers in the dorsal spinal cord of the rat. The present study was undertaken to extend this work by: 1) quantifying the MK-801-induced increase in CGRP immunostaining in the dorsal grey commissure/medial dorsal horn region and 2) examining the effect of MK-801 on the number of CGRP-immunoreactive primary afferent cell bodies in lumbar dorsal root ganglia. Following 7 days of MK-801 treatment, a significant increase (p less than 0.001) in CGRP immunostaining was observed in the dorsal grey commissure/medial dorsal horn. However, after MK-801 treatment, no significant difference was noted in the numbers of CGRP-immunoreactive primary afferent cell bodies in dorsal root ganglia. These data suggest that MK-801 produces significant alterations in the intraspinal projection of CGRP-immunoreactive fibers without inducing immunocytochemically detectable CGRP within a new population of primary afferent neurons.