title: Phospholipidosis in neurons caused by posaconazole, without evidence for functional neurologic effects.
abstract: The azole antifungal drug posaconazole caused phospholipidosis in neurons of the central nervous system, dorsal root ganglia of the spinal cord, and myenteric plexus in chronic toxicity studies in dogs. The time of onset, light and electron microscopic features, neurologic and electrophysiologic effects on the central and peripheral nervous systems, and potential for regression were investigated in a series of studies with a duration of up to one year. Nuclei of the medulla oblongata were the prominently affected areas of the brain. Neurons contained cytoplasmic vacuoles with concentrically whorled plasma membrane-like material (i.e., multilamellar bodies) morphologically identical to that commonly caused in other tissues by cationic amphiphilic drugs. Some axons in the brain and spinal cord were swollen and contained granular eosinophilic, electron-dense lysosomes. There were no features suggesting degeneration or necrosis of neurons or any associated elements of nervous tissue. The earliest and most consistent onset was in neurons of dorsal root ganglia. The observed neural phospholipidosis did not result in any alteration in the amplitude or latency of the auditory, visual, or somatosensory evoked potentials. The histopathologic changes did not progress or regress within the three-month postdose period. The results indicate that phospholipidosis can be induced in central and peripheral neurons of dogs by administration of posaconazole, but this change is not associated with functional effects in the systems evaluated.
authors.affiliation: Schering-Plough Research Institute, Lafayette, NJ 07848-0032, USA. mark.cartwright@spcorp.com
authors.forename: Mark E
authors.initials: ME
authors.lastname: Cartwright
authors.forename: Janet
authors.initials: J
authors.lastname: Petruska
authors.forename: Joseph
authors.initials: J
authors.lastname: Arezzo
authors.forename: Doyle
authors.initials: D
authors.lastname: Frank
authors.forename: Mona
authors.initials: M
authors.lastname: Litwak
authors.forename: Richard E
authors.initials: RE
authors.lastname: Morrissey
authors.forename: James
authors.initials: J
authors.lastname: MacDonald
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Davis
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry / Q000633:toxicity*; D004285:Dogs; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008064:Lipidoses / Q000139:chemically induced*; D008526:Medulla Oblongata / Q000187:drug effects / Q000648:ultrastructure; D009197:Myenteric Plexus / Q000187:drug effects / Q000378:metabolism; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000648:ultrastructure; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism*; D013788:Thalamus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D036401:Toxicity Tests, Chronic; D014230:Triazoles / Q000737:chemistry / Q000633:toxicity*
chemical_list: D000935:Antifungal Agents; D010743:Phospholipids; D014230:Triazoles; C101425:posaconazole