Amiodarone induced phospholipidosis biochemical, morphological and functional changes in the lungs of rats chronically treated with amiodarone

Riva, Emma; Marchi, Stefano de; Pesenti, Antonio; Bizzi, A.; Cini, M.; Veneroni, E.; Tavbani, Enrico; Boeri, R; Bertani, Tullio; Latini, Roberto

doi:10.1016/0006-2952(87)90635-6

Cited by 32 publications

(20 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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

View full text Add to dashboard Cite

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.

show abstract

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

View full text Add to dashboard Cite

show abstract

“…Short-term changes in pulmonary phospholipids are a function of amiodarone dose administered. No change in lung phospholipid content was noted after 4 weeks treatment with amiodarone 50 mg daily in the CD-COBS rat [14] ; 150 mg daily for 1-2 weeks produced variable results dependant on the strain of rat [15,16] ; while 400 mg/day for 4 weeks increased pulmonary phospholipid content [17] . However, the caveats with respect to the dosage of amiodarone in humans and animals discussed above [30] are relevant to interpretation of the lung phospholipid data.…”

Section: Effect On Tissue Phospholipids and Their Major Subfractionsmentioning

confidence: 99%

“…Total phospholipid content and fractions such as phosphatidylcholine, phosphatidylethanoloamine and phosphatidylserine are increased in rats with experimental hyperthyroidism [42] . These changes occur because of T3-induced enhancement in phospholipid biosynthesis demonstrated by 14 C-labelled palmitate incorporation of into these phospholipids [42,43] . In experimentally induced hypothyroidism, there is a decrease in the level of total phospholipids and phosphatidylserine which correlates with a reduction in fatty acids incorporation into the composition of phospholipids [43] .…”

Section: Limitations Of the Studymentioning

confidence: 99%

“…In contrast, the effect of amiodarone on phospholipid biosynthesis has been unresolved as slight increases or decreases have been reported [12,13] . Amiodarone-induced phospholipidosis have been confi rmed in animal models mainly utilizing protocols with short term administration of high doses of amiodarone [14][15][16][17] . These phospholipid changes have been mainly examined in the liver or lung and there is a paucity of data in other organs especially the heart [13,18,19] which of course in the therapeutic target organ for the drug.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Effect of Amiodarone on Phospholipid Content and Composition in Heart, Lung, Kidney and Skeletal Muscle: Relationship to Alteration of Thyroid Function

Rabkin¹

2006

Pharmacology

View full text Add to dashboard Cite

To investigate the effect of chronic amiodarone treatment on tissue phospholipids, a marker of amiodarone-induced toxicity, and to test the hypothesis that tissue phospholipids changes are related to amiodarone-induced effects on thyroid function, male Wistar rats were treated with amiodarone and tissue phospholipid content and fractions were assessed. Twenty-six animals were allocated to 4 groups: (i) group 1 received amiodarone, 20 mg/kg per day, for 3 weeks (n = 6); (ii) group 2 received amiodarone for 5 weeks (n = 6); (iii) group 3 received drug for 6 weeks (n = 6), and (iv) group 4 (control group) received the diluent for 6 weeks (n = 8). Total phospholipid content of lung, kidney and skeletal muscle but not heart was increased after 3 weeks of amiodarone treatment. With longer durations of treatment, the phospholipid content was significantly (p < 0.05) reduced in all four organs. The proportion of phospholipids in different classes was modified by amiodarone treatment with the most consistent changes across different tissues being reductions in phosphatidylethanolamine and increases in phosphatidylserine. Serum thyroxine concentration was significantly (p < 0.05) reduced at 5 weeks of treatment and thereafter. There was a significant correlation between serum thyroxine and total phospholipid concentration in heart (r = 0.555; p < 0.05) and lung (r = 0.502; p < 0.05). For heart, there was a significant correlation between serum thyroxine and the distribution of phospholipid classes, mainly for phosphatidylserine even after considering amiodarone dose. The same was found in the lung. In the kidney and skeletal muscle, there was a significant (p < 0.05) correlation between serum thyroxine and the proportion of phospholipids in phosphatidylcholine and sphingomyelin. In conclusion, this study presents the novel finding of a biphasic tissue phospholipid response to amiodarone characterized by a short term increase in phospholipids in lung, kidney and skeletal muscle but not the heart followed by a long term decline in phospholipids in all four organs that is likely due to a direct action of amiodarone on phospholipid metabolism and potentially the result of amiodarone-induced reduction in thyroid function.

show abstract

“…It has been demonstrated that this drug, and its principal metabolite desethylamiodarone, inhibit lysosomal phospholipase A, and A2 activities (14)(15)(16)(17). Due to this disruption in phospholipid breakdown, treatment of rats with amiodarone significantly increases the concentration of total phospholipid in whole lung and AMs (9,18,195. In our previous studies (9,19), it was shown that this development of phospholipidosis was both dose and time dependent as well as reversible.…”

mentioning

confidence: 99%

Acute silica toxicity: attenuation by amiodarone-induced pulmonary phospholipidosis.

Antonini

McCloud²,

Reasor³

1994

Environ Health Perspect

View full text Add to dashboard Cite

Exposure to the toxic mineral dust silica has been shown to produce an acute inflammatory response in the lungs of both humans and laboratory animals. Coating silica with phospholipids reduces its toxicity when studied with in vitro systems. The drug amiodarone increases phospholipid within the cells, airways, and alveoli of the lungs. This increase in phospholipid is due to amiodarone's ability to inhibit phospholipase activity within alveolar macrophages (AMs) and whole lung. The purpose of this study was to determine whether the amiodarone-induced increase in pulmonary phospholipid would protect the lungs from acute damage caused by the intratracheal instillation of silica. Treatment of male Fischer 344 rats with amiodarone for 14 days caused an increase in phospholipid content in bronchoalveolar lavage fluid and AMs compared to vehicle-treated controls. The rats were then instilled with silica or saline vehicle. At both 1 and 14 days after silica exposure, pulmonary phospholipidosis was associated with a marked reduction in acute silica-induced pulmonary damage as assessed by biochemical parameters in bronchoalveolar lavage fluid, however, the influx of neutrophils into the airspaces was not reduced. Four times more phospholipid was bound to the silica recovered from amiodarone-treated rats compared to controls. The results of these in vivo experiments indicate that pulmonary phospholipidosis attenuates the acute damage associated with the intratracheal instillation of silica in rats. By using an in vitro cell culture system, we demonstrated that, in contrast to control AMs, phospholipidotic AMs were significantly more resistant to the cytotoxicity of surfactant-coated silica.(ABSTRACT TRUNCATED AT 250 WORDS) Images p372-a Figure 1. Figure 2. Figure 3. Figure 4. Figure 5. Figure 6. Figure 7. Figure 8.

show abstract

Amiodarone induced phospholipidosis biochemical, morphological and functional changes in the lungs of rats chronically treated with amiodarone

Cited by 32 publications

References 31 publications

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

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

Effect of Amiodarone on Phospholipid Content and Composition in Heart, Lung, Kidney and Skeletal Muscle: Relationship to Alteration of Thyroid Function

Acute silica toxicity: attenuation by amiodarone-induced pulmonary phospholipidosis.

Contact Info

Product

Resources

About