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Amiodarone-induced pulmonary toxicity (AIPT) in F344 rats.

Taylor-MD; VanDyke-K; Hubbs-AF; Bowman-L; Miles-PR; Reasor-MJ
Toxicologist 1999 Mar; 48(1-S):118
Amiodarone (AD) is a very effective antiarrhythmic drug, but its side effects limit its clinical application. AIPT involves both pulmonary inflammation and fibrosis in humans. The goal of this study was to develop. an animal model of AIPT and examine the possible mechanisms leading to its development. F344 rats were intratracheaIly instilled with AD (6.25 mg/kg with a 3.125 mg/ml solution) in sterile water or the sterile water vehicle on the first day and then again 48 hours later. Animals were killed 5 days after the initial treatment and bronchoalveolar lavage (BAL) was performed. AD-treated rats had increased neutrophils and eosinophils recovered in the BAL fluid. BAL cells from AD-treated rats produced more integrated phorbol-myristate-acetate-stimulated luminol-dependent chemiluminescent (LDCL) counts over 20 minutes than BAL cells from control rats. Experiments using specific inhibitors implicate peroxynitrite in at least part of the LDCL response. When rats were examined 28 days after the initial AD or vehicle treatments, lung fibrosis was present both biochemically and histopathologically in only the AD-treated animals. Hydroxyproline, an amino acid found in collagen and used as a biochemical indicator of fibrosis, was elevated in AD-treated rats compared to controls. Examination of sections of lung tissue revealed minimal to mild, multifocal, interstitial fibrosis in the AD-treated animals. These findings indicate this model exhibits the pulmonary inflammation and fibrosis similar to that occurring in human patients and that elevated immune and oxidative processes may be involved in the development of AIPT in this model.
Animal-studies; Laboratory-animals; Statistical-analysis; Analytical-methods; Analytical-chemistry; Exposure-assessment; Toxicology; Toxins; Toxic-materials; Pulmonary-system-disorders; Pulmonary-disorders; Respiratory-system-disorders; Respiratory-irritants; Particulate-dust; Particulates; Dust-exposure; Dust-inhalation; Dust-particles; Airborne-dusts; Airborne-fibers; Airborne-particles; Silica-dusts; Silicates; Lung-disorders; Lung-fibrosis; Lung-irritants
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The Toxicologist. Society of Toxicology 38th Annual Meeting, March 14-18, 1999, New Orleans, Louisiana