To investigate the hypotheses that amiodarone-induced pulmonary inflammation may be related to direct drug toxicity, groups of 10 or more Wistar rats were fed amiodarone by gavage at concentrations of 175, 300, 400, and 500 mg/kg/day, or vehicle alone. After 6 wk of drug feeding, the rats were examined for histologic and cellular evidence of pulmonary inflammation. In addition, the amounts of amiodarone, the major metabolite of amiodarone N-desethylamiodarone (N-des), and phospholipid in the lungs were determined. We found that rats fed 175 mg/kg of amiodarone were essentially no different from control animals. The 175 mg/kg group had normal lung histologies, no change in lavage cell counts or differential counts, and very little amiodarone, N-des, or phospholipid in the lungs. In contrast, the three high-dose groups had abnormal lung histologies along with increases in lavage cell counts and change in differential counts. There were also significant increases in the amounts of amiodarone, N-des, and phospholipid in the lung. We conclude that the development of amiodarone-induced pulmonary inflammation is dose dependent, and that there is a direct correlation between the amount of amiodarone, N-des, and phospholipid in the lung with the development of inflammation. It therefore appears that the drug is directly toxic to lung tissue.
We have developed a panel of mouse monoclonal antibodies (MAbs) that recognize ivermectin and abamectin, the major avermectins used in veterinary and agricultural formulations. Conjugates of ivermectin 4"-hemisuccinate on three different proteins were used to raise the antibodies and develop a quantitative competition enzyme immunoassay (EIA) for avermectins. The five MAbs that gave the lowest detection limits for ivermectin and abamectin were used to optimize the EIA. Several types of EIA plates, plate coating conditions, blocking agents, incubation times and temperatures, and enzymeconjugated detecting antibodies were compared to determine acceptable assay conditions. One of the MAbs, C4D6, bound ivermectin in buffers containing up to 30% (v/v) of organic solvent. The lower limit of detection for standards in this EIA was approximately 0.5 ppb for ivermectin and 1 ppb for abamectin, with half-maximal inhibition (/50) around 3 ppb for ivermectin and 7 ppb for abamectin. The MAbs and EIA appear to be usable for quantifying avermectin residues in agricultural and environmental matrices.
Amiodarone can cause pulmonary toxicity along with an increase in phospholipid in macrophages, lymphocytes, and other cell types. Phospholipid accumulates because amiodarone inhibits the lysosomal phospholipases A1 and A2. Since a wide array of cells are affected by amiodarone and because amiodarone might inhibit other phospholipases, we postulated that cellular functions might be affected. Therefore, the major focus of this study was to determine whether amiodarone inhibited cellular functions. We found that alveolar macrophages isolated from drug-fed rats were significantly less phagocytic, and that the rats had significantly depressed delayed-type hypersensitivity responses. Spleen cells isolated from the drug-fed rats also had severely depressed mitogen responses. Since the spleen cell proliferative response could be partially restored by stimulating the cells with ionomycin and phorbol myristate acetate, we postulated that amiodarone was inhibiting phospholipase C. To substantiate this hypothesis, we found that amiodarone could directly inhibit phospholipase C in vitro. We conclude that amiodarone affects both phagocytic responses and the development of cell-mediated immunity and that the lack of these normal responses could exacerbate amiodarone toxicity. One possible mechanism for decreased cellular functions may be the inhibition of phospholipase C. However, further studies are necessary to confirm this finding.
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