The Endothelin-A Receptor Antagonist Zibotentan Induces Damage to the Nasal Olfactory Epithelium Possibly Mediated in Part through Type 2 Innate Lymphoid Cells

Abstract

Zibotentan, an endothelin-A receptor antagonist, has been used in the treatment of various cardiovascular disorders and neoplasia. Castrated athymic nude mice receiving zibotentan for a preclinical xenograft efficacy study experienced weight loss, gastrointestinal bloat, and the presence of an audible respiratory click. Human side effects have been reported in the nasal cavity, so we hypothesized that the nasal cavity is a target for toxicity in mice receiving zibotentan. Lesions in the nasal cavity predominantly targeted olfactory epithelium in treated mice and were more pronounced in castrated animals. Minimal lesions were present in vehicle control animals, which suggested possible gavage-related reflux injury. The incidence, distribution, and morphology of lesions suggested direct exposure to the nasal mucosa and a possible systemic effect targeting the olfactory epithelium, driven by a type 2 immune response, with group 2 innate lymphoid cell involvement. Severe nasal lesions may have resulted in recurrent upper airway obstruction, leading to aerophagia and associated clinical morbidity. These data show the nasal cavity is a target of zibotentan when given by gavage in athymic nude mice, and such unanticipated and off-target effects could impact interpretation of research results and animal health in preclinical studies.

Synthesis, characterization, biological evaluation, and molecular docking studies of new 1,3,4-oxadiazole-thioether derivative as antioxidants and cytotoxic agents

“…Furthermiles, the 1,3,4-oxadiazole nucleus has attracted the attention of synthetic organic and medicinal chemists as a bioisosteric replacement for carbonyl-containing compounds such as carboxylic acids, esters, and amides in the development of new drugs with anticancer activities [ 4 ]. There are different commercially available drugs that contain the 1,3,4-oxadiazole ring, such as the antiviral medication raltegravir [ 5 ], the hypnotic drug fenadiazole [ 6 ], the anticancer agent zibotentan [ 7 ], a medication for the treatment of Duchenne muscular dystrophy, ataluren [ 8 ], and an alpha-1 adrenergic receptor, tiodazosin [ 9 ]. As shown their structure in Fig.…”