An investigation of potential protection by spin trapping agents against amiodarone-induced pulmonary toxicity

Amiodarone (AM), a highly efficacious antidysrhythmic drug, and desethylamiodarone (DEA), a major AM metabolite, can cause adverse effects including AM-induced pulmonary toxicity (AIPT). It has been suggested that AM and DEA form radicals that target the mitochondria, resulting in cell death and initiating AIPT. The cytoprotective potential of radical spin-trapping nitrones against AM toxicity in a human lung cell line and in a hamster animal model was assessed.; HPL1A cells were incubated with AM or DEA for 4 or 24 h and cell viability was determined using the lactate dehydrogenase (LDH) release assay and the 3-[4,4-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) reduction assay. Concentrations of 0.01 to 0.5 mM AM were cytotoxic to HPL1A cells in a time- and concentration-dependent manner. Concentrations of 0.005 to 0.2 mM DEA were cytotoxic to HPL1A cells in a concentration-dependent manner, but not time dependent between 4 and 24 h. The nitrones alpha-phenyl-N- t-butylnitrone (PBN), alpha-(4-pyridyl-1-oxide)-N-t-butylnitrone (POBN) and 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) were tested for their potential cytoprotective effects. Incubation with 1.0 or 10 mM PBN, 5.0 mM POBN, or 50 mM DMPO for 30 min prior to addition of AM or DEA did not offer protection.; Male golden Syrian hamsters were treated with 150 mg/kg (0.846 mmol/kg) PBN, 164 mg/kg (0.846 mmol/kg) POBN, or 192 mg/kg (1.70 mmol/kg) DMPO by intraperitoneal (i.p.) injection 24 h and 30 min prior to intratracheal (i.t.) administration of 1.83 mumol AM. Spin trapping agents were also administered 24, 48, and 72 h post i.t. AM instillation. Animals were assessed for histological and biochemical evidence of fibrosis 21 days post AM administration. Spin trapping agents were not found to offer protection against fibrosis; however they did diminish the negative effect of AM on body weight gain.; The results of this thesis do not support the hypothesis that free radicals are major contributors to AIPT.