Abstract
A rat model of amiodarone-induced pulmonary toxicity is described. The rats were fed, by gavage, 175 mg/kg/day of amiodarone hydrochloride suspended in methyl cellulose. Controls received methyl cellulose alone. Groups of rats were examined after 1, 3, 6, 9, and 12 weeks of feeding. We found that drug-fed rats had significantly more macrophages, neutrophils, and lymphocytes in the bronchoalveolar lavage (BAL). The early increase in cellularity was due to an increase in macrophages, and the macrophage count peaked after 6 weeks of drug treatment. The number of neutrophils in the experimental animals remained high throughout the course of the experiment. An increasing number of lymphocytes was seen in the BAL between 6 and 12 weeks of drug treatment. Protein in the lavage fluid was significantly elevated after 12 weeks of amiodarone exposure. Histologic sections were abnormal after 3 weeks of drug treatment, characterized by interstitial thickening with accumulation of mononuclear cells and alveoli packed with large foamy macrophages. There was only minimal evidence of fibrosis. This model appears to be very similar to human amiodarone-induced pulmonary toxicity and should be useful for the study of the pathogenesis of amiodarone-induced toxicity.
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Akoun GM, Gauthier-Rahman S, Milleron BJ, Perrot JY, Mayaud CM (1984) Amiodarone-induced hypersensitivity pneumonitis: evidence of an immunological cell-mediated mechanism. Chest 85:133–135
Camus P, Jeannin L (1984) Speculation on the mechanism for amiodarone-induced pneumonitis. Radiology 150:279–280
Cantor JO, Osman M, Cerreta JM, Suarez R, Mandl I, Turino GM (1984) Amiodarone-induced pulmonary fibrosis in hamsters. Exp Lung Res 6:1–10
Costa-Jussa FR, Corrin B, Jacobs JM (1984) Amiodarone lung toxicity: a human and experimental study. J Pathol 143:73–79
Dake MD, Madison JM, Montgomery CK, Shellito JD, Hinchcliffe WA, Winkler ML, Bainton DF (1985) Electron microscopic demonstration of lysosomal inclusion bodies in lung, liver, lymph nodes, and blood leukocytes of patients with amiodarone pulmonary toxicity. Am J Med 78:506–512
Falik R, Flores BT, Shaw L, Gibson GA, Josephson ME, Marchlinski FE (1987) Relationship of steady-state serum concentrations of amiodarone and desethylamiodarone to therapeutic efficacy and adverse effects. Am J Med 82:1102–1108
Fogoros RN, Anderson KP, Winkle RA, Swerdlow CD, Mason JW (1983) Amiodarone: clinical efficacy and toxicity in 96 patients with recurrent, drug-refractory arrhythmias. Circulation 68:88–948
Haffajee CI, Love JC, Canada AT, Lesko LJ, Asdourian G, Alpert JS (1983) Clinical pharmacokinetics and efficacy of amiodarone for refractory tachyarrhythmias. Circulation 67:1347–1355
Harris L, McKenna WJ, Rowland E, Krikler DM (1983) Side effects and possible contraindications of amiodarone use. Am Heart J 106:916–923
Heath MK, Costa-Jussa FR, Jacobs JM, Jacobson W (1985) The induction of pulmonary phospholipidosis and the inhibition of lysosomal phospholipases by amiodarone. Br J Exp Pathol 66:391–397
Hostetler KY, Giordano JR, Jellison, EJ (1988) In vitro inhibition of lysosomal phospholipase A1 of rat lung by amiodarone and desethylamiodarone. Biochem Biophys Acta 959:316–321
Hostetler KY, Reasor MJ, Walker ER, Yazaki PJ (1986) Role of phospholipase A inhibition in amiodarone pulmonary toxicity in rats. Biochem Biophys Acta 875:400–405
Israel-Biet D, Venet A, Caubarrere I, Bonan G, Danel C, Chretien J, Hance AJ (1987) Bronchoalveolar lavage in amiodarone pneumonitis. Cellular abnormalities and their relevance to pathogenesis. Chest 91:214–221
Israel-Biet D, Venet A, Caubarrere I, Bonan G, Dennewald G, Pechaud, D, Danel C, Chretien J (1985) Amiodarone pneumonitis mechanism: evaluation by bronchoalveolar lavage (BAL). Am Rev Respir Dis 131:74A
Kennedy JI, Myers JL, Plumb VJ, Fulmer JD (1987) Amiodarone pulmonary toxicity. Clinical, radiologic, and pathologic correlations. Arch Intern Med 147:50–56
Kudenchuk PJ, Pierson DJ, Greene HL, Graham EL, Sears GK, Trobaugh GB (1984) Prospective evaluation of amiodarone pulmonary toxicity. Chest 86:541–548
Marcus FI, Fontaine GH, Frank R, Grosgogeat Y (1981) Clinical pharmacology and therapeutic applications of the antiarryhythmic agent, amiodarone. Am Heart J 101:480–493
Martin WJ II, Howard DM (1986) Amiodarone-induced lung toxicity: in vitro evidence for the direct toxicity of the drug. Am J Pathol 120:344–35018.
Martin WJ II, Osborn MJ, Douglas WW (1985) Amiodarone pulmonary toxicity: assessment by bronchoalveolar lavage. Chest 88:630–631
Mazue G, Vic P, Gouy D, Remandet B, Lacheretz F, Berthe J, Barchewitz G, Gagnol JP (1984) Recovery from amiodarone-induced lipidosis in laboratory animals: a toxicological study. Fundam Appl Toxicol 4:992–999
Mason JW (1987) Amiodarone. N Engl J Med 316:455–465
McGovern B, Garan H, Kelly E, Ruskin JN (1983) Adverse reactions during treatment with amiodarone hydrochloride. Br Med J 287:175–180
Rakita L, Sobol SM, Mostow N, Vrobel T (1983) Amiodarone pulmonary toxicity. Am Heart J 106:906–916
Reasor MJ, Ogle CL, Walker ER, Kacew S (1988) Amiodarone-induced phospholipidosis in rat alveolar macrophages. Am Rev Respir Dis 137:510–518
Riley SA, Williams SE, Cooke NJ (1982) Alveolitis after treatment with amiodarone. Br Med J 284:161–162
Riva E, Marchi S, Pesenti A, Bizzi A, Cini M, Veneroni E, Tavbani E, Boeri R, Bertani T, Latini R (1987) Amiodarone induced phospholipidosis: biochemical, morphological and functional changes in the lungs of rats chronically treated with amiodarone. Biochem Pharmacol 19:3209–3214
Rosenbaum MB, Chiale PA, Halpern MS (1976) Clinical efficacy of amiodarone as an antiarrhythmic agent. Am J Cardiol 38:934–944
Rotmensch HH, Belhassen B, Swanson BN, Shoshani D, Spielman SR, Greenspon AJ, Vlasses PH, Horowitz LN (1984) Steady-state serum amiodarone concentrations: relationships with antiarrhythmic efficacy and toxicity. Ann Intern Med 101:462–469
Sobol SM, Rakita L (1982) Pneumonitis and pulmonary fibrosis associated with amiodarone treatment: a possible complication of a new antiarrhythmic drug. Circulation 65:819–824
Woessner JF (1961) The determination of hydroxyproline in tissue and protein samples containing small proportions of the imino acid. Arch Biochem Biophys 93:440–447
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Wilson, B.D., Jaworski, A.J., Donner, M.E. et al. Amiodarone-induced pulmonary toxicity in the rat. Lung 167, 301–311 (1989). https://doi.org/10.1007/BF02714959
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DOI: https://doi.org/10.1007/BF02714959