Amiodarone Pulmonary Toxicity After Lung Transplantation

Diaz-Guzman, Enrique; Mireles-Cabodevila, Eduardo; Arrossi, Andrea V.; Kanne, Jeffrey P.; Budev, Marie

doi:10.1016/j.healun.2008.05.023

Cited by 17 publications

(4 citation statements)

References 24 publications

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“…, 1987; Vassallo and Trohman, 2007; Zimetbaum, 2007; Ammoury et al. , 2008; Diaz‐Guzman et al. , 2008; Ruangchira‐Urai et al.…”

Section: Introductionmentioning

confidence: 99%

“…The therapeutic plasma range for amiodarone and its metabolite is 0.7-3.7 mM (Vassallo and Trohman, 2007), but it is widely acknowledged that the tissues accumulate the drug during chronic dosing. Amiodarone produces a constellation of side effects, many of which may be related to drug-induced phospholipidosis and/or vacuolar sequestration: concentric inclusions in peripheral blood leukocytes (Adams et al, 1986;Somani et al, 1986); corneal microdeposits (>90% incidence); blue-gray skin discoloration with photosensitivity (4-9%); non-alcoholic steatohepatitis that can lead to cirrhosis (<3%); and a serious pulmonary toxicity that includes interstitial pneumonia, fibrosis and 'foamy macrophages' that are vacuolar cells containing the typical multilamellar bodies (Myers et al, 1987;Vassallo and Trohman, 2007;Zimetbaum, 2007;Ammoury et al, 2008;Diaz-Guzman et al, 2008;Ruangchira-Urai et al, 2008). Similarly, intracytoplasmic inclusions (termed primary lipidosis) have been observed in the optic nerve axons of patients with slow-onset amiodarone-induced optic neuropathy (Li et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Intracellular sequestration of amiodarone: role of vacuolar ATPase and macroautophagic transition of the resulting vacuolar cytopathology

Morissette

Ammoury

Rusu

et al. 2009

British J Pharmacology

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Background and purpose:Tissue deposits of the anti-arrhythmic drug amiodarone are a major source of side effects (skin discoloration, etc.). We addressed the mechanism of the concentration of amiodarone in cells, and characterized the resulting vacuolar cytopathology and its evolution towards macroautophagy. Experimental approach: Sequestration of amiodarone in human cells (macrophages, smooth muscle cells, HEK 293a cells) was evaluated using its violet fluorescence and cytopathology using GFP-conjugated subcellular markers. Autophagic signalling was probed by immunoblotting for the effector protein LC3. A patient biopsy of amiodarone-induced blue-gray skin discoloration was investigated for the presence of macroautophagy (immunofluorescence for LC3). Key results: Most of the amiodarone (1-20 mM, 4-24 h) captured by cultured cells (macrophages were most avid) was present in enlarged vacuoles. The specific vacuolar ATPase (V-ATPase) inhibitors, bafilomycin A1 or FR167356, prevented vacuolization and drug uptake. Vacuoles in HEK 293a cells were positive for markers of late endosomes and lysosomes (GFP-Rab7, -CD63) and for an effector of macroautophagy, GFP-LC3. The vacuoles accumulated endogenous LC3 and filled with lipids (Nile red staining) following longer amiodarone treatments (Ն24 h). The electrophoretic mobility of both GFP-LC3 and endogenous LC3 changed, showing activation in response to amiodarone. Paraffin tissue sections of the pigmented skin exhibited granular LC3 accumulation in superficial dermis macrophages. Conclusion and implications: Vacuolar sequestration of amiodarone occurs at concentrations close to therapeutic levels, is mediated by V-ATPase and evolves towards persistent macroautophagy and phospholipidosis. This cytopathology is not cell type specific, but tissue macrophages appear to be particularly susceptible.

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“…, 1987; Vassallo and Trohman, 2007; Zimetbaum, 2007; Ammoury et al. , 2008; Diaz‐Guzman et al. , 2008; Ruangchira‐Urai et al.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Intracellular sequestration of amiodarone: role of vacuolar ATPase and macroautophagic transition of the resulting vacuolar cytopathology

Morissette

Ammoury

Rusu

et al. 2009

British J Pharmacology

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“…Because immunosuppression is likewise the treatment for OP, it could be reasonably hypothesized that OHT surgery would be a rare inciting event for AAPT. On the other hand, there does exist a case report of APT following lung transplantation [ 21 ]. This raises the possibility that certain post-transplant medications like tacrolimus, which is metabolized by the liver, could potentiate toxicity from amiodarone.…”

Section: Discussionmentioning

confidence: 99%

Acute amiodarone pulmonary toxicity in the form of organizing pneumonia triggered by orthotopic heart transplantation

Kozlova

Lanier

Kleinman

et al. 2021

Respiratory Medicine Case Reports

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We report a case of a 60-year-old man who underwent orthotopic heart transplantation after short-term receipt of low-dose oral amiodarone for the management of ventricular tachycardia. Prior to transplant surgery, he had a normal chest radiograph and was free of supplemental oxygen. His initial postoperative chest radiograph showed subtle infiltrates, and thereafter his chest imaging continued to worsen. Although he was eventually able to wean off mechanical ventilation via a tracheostomy, he remained dyspneic and oxygen-dependent with persistently abnormal chest imaging as his post-transplant corticosteroid regimen was being tapered. In light of progressively worsening diffuse lung disease, he underwent bronchoscopy with transbronchial biopsies. Histology revealed foamy macrophages in association with foci of organizing pneumonia, a picture consistent with amiodarone pulmonary toxicity. Given these findings, corticosteroid dosing was increased for the clinical diagnosis of acute amiodarone pulmonary toxicity with subsequent normalization of oxygen saturation and chest radiography. Our case is the first to identify orthotopic heart transplantation as a potential trigger for acute amiodarone pulmonary toxicity. It is also only the second documented example of organizing pneumonia as the histological substrate of amiodarone pulmonary toxicity, which is an association that has therapeutic implications.

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“…There is also a case report of amiodarone toxicity in a patient with AAs after lung transplantation. 10 The bottom line from the study by D'Angelo and colleagues 1 is that the development of AAs after lung transplant is associated with a longer intensive care unit stay, longer hospital stay, and worse survival. Why the survival is worse cannot be adequately addressed in the current analysis.…”

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confidence: 99%

Atrial arrhythmias after lung transplant: A call to action starting with the electrocardiogram

Gleva

Huddleston

2016

The Journal of Thoracic and Cardiovascular Surgery

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Amiodarone Pulmonary Toxicity After Lung Transplantation

Cited by 17 publications

References 24 publications

Intracellular sequestration of amiodarone: role of vacuolar ATPase and macroautophagic transition of the resulting vacuolar cytopathology

Intracellular sequestration of amiodarone: role of vacuolar ATPase and macroautophagic transition of the resulting vacuolar cytopathology

Acute amiodarone pulmonary toxicity in the form of organizing pneumonia triggered by orthotopic heart transplantation

Atrial arrhythmias after lung transplant: A call to action starting with the electrocardiogram

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