Amiodarone toxicity *1II. Desethylamiodarone-induced phospholipidosis and ultrastructural changes during repeated administration in rats

Kannan, R.; Sarma, J. S. M.; Guha, Martin; Venkataraman, Kalyanasundaram

doi:10.1016/0272-0590(91)90139-u

Cited by 31 publications

(19 citation statements)

References 23 publications

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“…However, increased lipid peroxidation in the spleen, although secondary to phospholipidosis, may be toxicologically relevant (Kannan et al 1991).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, several pharmacokinetics and body distribution studies have described that amiodarone and its principal metabolite, desethylamiodarone, are preferentially distributed, in decreasing order, in thyroid gland, lungs, kidneys, liver, heart, adipose tissue, skeletal muscle and brain (Riva et al 1982;Plomp et al 1985aPlomp et al , 1985bPlomp et al , 1989Brien et al 1987;Kannan et al 1991). Desethylamiodarone is the only metabolite positively identified in the plasma of patients treated with amiodarone, but no data are available on its possible pharmacological activity.…”

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confidence: 99%

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Acute Renal Toxic Effect of Amiodarone in Rats

Morales

Barata

Bruges

et al. 2003

Pharmacology & Toxicology

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Amiodarone is an antiarrhythmic drug now more frequently used after a number of years in which the use had been on the decline due to a number of studies which reported side effects such as chronic toxicity, primarily in the lungs, liver and thyroid glands. Additionally, in some patients an increase in serum creatinine was noted, however the effect of amiodarone on renal function had never been closely examined. Thus, the aim of our study was to analyse the effects of amiodarone on renal function in rats. Experiments were carried out in male Wistar rats divided in two experimental groups: 1) a control group, (nΩ8), 2) a group that received a daily intraperitoneal injection of amiodarone (50 mg/kg body weight) for 6 days (nΩ5). At the end of the treatment, renal function was measured by clearance creatinine and acute clearance studies. Renal toxicity was evaluated by urinary N-acetyl-glucosamine and alkaline phosphatase. At the end of the experiment, histology studies were done. Rats treated with amiodarone had a higher serum creatinine (182%) and a lower glomerular filtration rate (53%), renal plasma flow (68%) and filtration fraction (62%) than controls. Rats treated with amiodarone also showed an increase in urinary N-acetyl-glucosamine (221%) and alkaline phosphatase (4.151%) excretion which corresponds with tubular alterations showed on electron microscopy. In conclusion our data confirm that amiodarone induces acute renal damage in the rat.

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“…However, increased lipid peroxidation in the spleen, although secondary to phospholipidosis, may be toxicologically relevant (Kannan et al 1991).…”

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Acute Renal Toxic Effect of Amiodarone in Rats

Morales

Barata

Bruges

et al. 2003

Pharmacology & Toxicology

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“…However, because it is known that desethylamiodarone, a major metabolite of amiodarone, induces pulmonary toxicity in animals like amiodarone does (29) and the serum concentration of desethylamiodarone reaches about 60°7o of those of amiodarone (30), it would be of interest to perform additional studies with desethylamiodarone to examine in more detail the mechanisms underlying amiodarone induced disorders.…”

Section: Discussionmentioning

confidence: 99%

Amiodarone Induces Two Different Types of Disorders in Mouse Alveolar Macrophages.

Futamura

1997

Jpn.J.Pharmacol

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ABSTRACT-It has been reported that amiodarone induces disorders of alveolar macrophages and pul monary fibrosis, but the mechanism is not well-understood. This study was performed to elucidate the toxic mechanism from the standpoint of cellular function. Using alveolar macrophages obtained from a male Slc:ICR mouse, several injuries caused by amiodarone were compared to those caused by amantadine and mianserin as cationic amphiphilic drugs (CADs). As parameters for the drug effects, H+-ATPase and acid sphingomylinase activities, cellular pH, cytokine and prostaglandin releases, phagocytosis and neutral red uptake were measured. Amiodarone decreased H+-ATPase activity initially and subsequently increased cellular pH and decreased acid sphingomyelinase activity. These changes, which were also observed with amantadine and mianserin, were considered to be CAD-related. Amiodarone increased cytokine and prostaglandin releases and suppressed neutral red uptake and phagocytosis. These changes, being not induced by amantadine and mianserin, were considered to be specific for amiodarone. The above data suggest that amiodarone has two types of toxic effects on alveolar macrophages.

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“…TOXICOLOGIC PATHOLOGY 1980; Heyneman and Reasor, 1986;Riva et al, 1987;Kannan et al, 1989;Reasor et al, 1990;Kannan et al, 1991) and the inability of routine toxicokinetics to monitor this type of accumulation (Hein et al, 1990) raised concern that PNU-177864 or its metabolites might accumulate in tissues, particularly in skeletal muscle, and that this accumulation would not be detected by determination of levels of PNU-177864 in plasma. Continued accumulation of the parent drug or its metabolites would then result in myocyte injury.…”

Section: Resultsmentioning

confidence: 99%

Myopathy Related to Administration of a Cationic Amphiphilic Drug and the Use of Multidose Drug Distribution Analysis to Predict its Occurrence

et al. 2004

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Many cationic amphiphilic (phospholipidosis-inducing) drugs (CADs) accumulate in tissues following repeated dosing in preclinical models, and this is sometimes associated with dose-limiting toxicities. Plasma drug levels cannot be used to estimate tissue accumulation of CADs since it occurs in tissues despite stabilization of plasma levels. Severe myopathy was found in skeletal muscles of rats during the initial safety evaluation of a dopamine D3 receptor antagonist, PNU-177864, and was associated with phospholipidosis in numerous tissues. The myopathy was observed only when plasma levels of PNU-177864 remained essentially constant throughout the 24-hour dosing period. A repeat dose drug distribution study using whole body autoradiography demonstrated that drug-related material did not accumulate in skeletal muscle or other tissues following repeated doses at levels considered within the therapeutic range and showing toxicokinetic profiles acceptable for further development. These observations provided support for the continued development of and longer-term toxicity studies with this candidate compound.

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Amiodarone toxicity *1II. Desethylamiodarone-induced phospholipidosis and ultrastructural changes during repeated administration in rats

Cited by 31 publications

References 23 publications

Acute Renal Toxic Effect of Amiodarone in Rats

Acute Renal Toxic Effect of Amiodarone in Rats

Amiodarone Induces Two Different Types of Disorders in Mouse Alveolar Macrophages.

Myopathy Related to Administration of a Cationic Amphiphilic Drug and the Use of Multidose Drug Distribution Analysis to Predict its Occurrence

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