benzofurans and Lipidoses

Topics: Animals; Benzofurans; Endoplasmic Reticulum Stress; Fatty Liver; Fluorescent Dyes; HeLa Cells; Humans; Lipid Droplets; Lipidoses; Mice; Microscopy, Fluorescence; Photons

Topics: Adult; Aged; Amiodarone; Benzofurans; Female; Humans; Lipidoses; Lung Diseases; Male; Middle Aged; Pulmonary Fibrosis

We hypothesized that one of the reasons for the particular susceptibility of the lung toward the adverse effects from the antiarrhythmic agent amiodarone (A) could be a high pulmonary accumulation of this drug. This hypothesis was tested using the isolated perfused lungs of Fischer 344 and Sprague-Dawley rats and New Zealand White rabbits. Uptake of a 3 microM starting concentration of a mixture of A and [14C]A by the lung occurred rapidly in each species, and only 25.6, 19 and 16.4% of the initial concentration remained in the perfusate at the end (60 min) of the experiment in Fischer 344, Sprague-Dawley rats and rabbits, respectively. No metabolism of A was detected by the high-performance liquid chromatography technique. Raising the initial concentration of A from 0.3 to 120 microM (n = 26) in the Fischer 344 rats apparently did not saturate the uptake process, and the tissue/medium ratio averaged 122.5. The uptake of desethylamiodarone (DEA), the main metabolite of A in vivo, was more extensive (tissue/medium ratio = 506) than that of the parent compound. DEA also was not metabolized by the isolated perfused lungs. Lung homogenate incubations fortified with cofactors did not metabolize A or DEA. We conclude that in the isolated perfused lungs: A is extensively taken up by the lungs of rats and rabbits; the uptake is not saturated by raising the concentrations over a 400-fold range; DEA is taken up more readily than A; and metabolism of neither compound is observed.

Topics: Amiodarone; Animals; Benzofurans; Chromatography, High Pressure Liquid; In Vitro Techniques; Lipidoses; Lung; Male; Perfusion; Phospholipids; Rabbits; Rats; Rats, Inbred F344; Rats, Inbred Strains

Amiodarone is an amphiphilic iodinated compound that is used as a treatment for refractory ventricular arrhythmias. During evaluation for possible pulmonary toxicity, a patient receiving amiodarone was noted to have an increase in the density of his liver as seen on computed tomographic (CT) scanning of the abdomen. Six additional patients who were receiving amiodarone were subsequently evaluated to ascertain the frequency of this finding. The CT density of the liver was increased in all patients. Values obtained varied from 95 to 145 H, with a mean of 117 +/- 8.9 (normal, 30-70). The alkaline phosphatase was elevated in four patients, but only one had an elevation of either the alanine or aspartate aminotransferase. Two patients underwent liver biopsies, and both revealed membranous lamellar phospholipid-containing structures within hepatocytes. Animal studies done to recreate these findings revealed that amiodarone accumulated in the liver at concentrations 175-500 times greater than those found in serum. Quantitative measurements of iodine in samples from the same liver showed that the iodine levels were correspondingly elevated. In the treated animals, there was a small but statistically significant increase in the CT density of the liver, whereas the values for untreated animals were unchanged. Treatment with amiodarone leads to an accumulation in the liver of this iodinated compound and hence an increase in the CT density of the liver. This accumulation of the drug in hepatic lysosomes apparently causes a secondary phospholipidosis.

Topics: Aged; Amiodarone; Benzofurans; Biopsy; Humans; Lipidoses; Liver; Lysosomes; Male; Middle Aged; Phospholipids; Tomography, X-Ray Computed

Numerous amphiphilic cationic drugs cause lipid-lysosomal storage in animal tissues; one of these drugs is amiodarone, a major antiarrhythmic agent. The toxicological effects of amiodarone were studied in three animal species (rats, dogs, and monkeys). It was shown that sublethal dose levels of amiodarone induced lipid storage in a great variety of tissues in rats (Fischer and Sprague-Dawley strains) and dogs. However, this change was not observed in baboons and Wistar rats. This storage, essentially characterized by lamellated inclusions, affected foamy macrophages, and at a later phase multiple cell types. Tissue biochemical analysis provided evidence of the phospholipidic nature of the storage. In addition, amiodarone induced an increased cholesterolemia and marked modifications of the lipoproteinogram. The kinetics of lipid storage was demonstrated following oral administration of amiodarone. After jejunal absorption, lipid storage occurred in the mesenteric lymph nodes followed by widespread deposition in the other lymph nodes and tissues, particularly in the lung. A complete recovery from lipid storage as observed in dogs and rats. Finally, an investigation of a correlation between animal and man by means of long-term experiments is proposed.

Topics: Amiodarone; Animals; Benzofurans; Cholesterol; Dogs; Foam Cells; Lipidoses; Lung; Lymph Nodes; Papio; Phospholipids; Rats; Rats, Inbred F344; Rats, Inbred Strains; Triglycerides

Topics: Adolescent; Adult; Aged; Amiodarone; Benzofurans; Cataract; Color Vision Defects; Corneal Diseases; Eye Diseases; Female; Humans; Lipidoses; Male; Middle Aged; Retinal Diseases

Among 37 patients treated with amiodarone, an antiarrhythmic drug, a typical keratopathy developed in 35, none of whom had ocular complaints. The keratopathy resembled that seen with Fabry's disease and chloroquine use, as did the membrane-bound lamellar bodies detected by electron microscopy in all layers of the corneal epithelium in the one patient with marked keratopathy in whom a corneal biopsy was performed; membrane-bound bodies, mostly granular, were also noted within this patient's stromal keratocytes. The possible pathogenesis of the keratopathy as a type of drug-induced lipidosis is discussed.

Topics: Adult; Aged; Amiodarone; Benzofurans; Cornea; Corneal Diseases; Humans; Lipidoses; Microscopy, Electron; Middle Aged

Topics: Aged; Amiodarone; Benzofurans; Female; Humans; Lipidoses; Peripheral Nervous System Diseases

Topics: Aged; Amiodarone; Benzofurans; Humans; Lipidoses; Male; Peripheral Nervous System Diseases

The antianginal drug amiodarone (an amphiphilic cationic compound) causes a keratopathy in humans. In the present investigation the cytologic effects of amiodarone on ocular tissues of rats were studied. Ultrastructural alterations, which are typical of human keratopathy and characteristic of drug-induced lipidosis, could be experimentally reproduced in rats by local application of amiodarone. Repeated oral administration of high drug doses induced lipidosis-like alterations in many ocular cell types, particularly in retinal pigment epithelium. It is concluded that amiodarone has the potency to induce generalized lipidosis in rats, as do several other previously investigated amphiphilic cationic drugs. It is tentatively suggested that amiodarone-induced corneal alterations in humans might equally be interpreted as part of a generalized lipidosis.

Topics: Amiodarone; Animals; Benzofurans; Cornea; Female; Keratitis; Lipidoses; Male; Rats; Retina

Topics: Adrenal Glands; Allylamine; Amiodarone; Animals; Antidepressive Agents; Benzofurans; Cornea; Female; Lipidoses; Liver; Lung; Lymph Nodes; Male; Pyridines; Rats; Retina