title: Muscarinic receptor antagonist-induced lenticular opacity in rats.
abstract: Investigations on compound A, an M2-sparing M3 muscarinic receptor antagonist, showed that focal polar anterior subcapsular lenticular opacities, characterized by focal epithelial proliferation, developed in Sprague-Dawley rats. The incidence and bilateral localization of this change increased generally with dose and time, though plateauing after 8 months of treatment; however the severity progressed very slightly. Over a 1-year period, no anterior cortical lens fiber changes or other histological ocular changes developed. A decreased severity of the change and apoptosis suggested some regression after a 26-week recovery period. Two nonselective muscarinic receptor antagonists, atropine and tolterodine, induced similar lenticular changes in rats. A hypothesis in relation to an indirect effect of the drug, such as increased illumination of the lens due to mydriasis observed with all these compounds, was investigated and disproven. Because these opacities are induced by structurally unrelated muscarinic receptor antagonists (atropine and tolterodine), it is likely that these lenticular changes are the result of muscarinic receptor inhibition. However, hypotheses regarding a direct effect of the drug on muscarinic receptors in the lens epithelium, possibly mediated by drug and/or metabolite(s) in the aqueous humor and/or lens epithelium, remain to be investigated. This lenticular opacity is similar to that observed spontaneously in Sprague-Dawley rats, although the latter occur at a lower incidence. No such lenticular opacities have been reported in other animal species, including man, after treatment with muscarinic receptor antagonists.
authors.affiliation: Laboratoires Merck Sharp and Dohme-Chibret, Route de Marsat, Riom, 63963 Clermont-Ferrand Cedex 9, France. genevieve_durand@merck.com
authors.forename: Geneviève
authors.initials: G
authors.lastname: Durand
authors.forename: Marie-Françoise
authors.initials: MF
authors.lastname: Hubert
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kuno
authors.forename: William O
authors.initials: WO
authors.lastname: Cook
authors.forename: Christine
authors.initials: C
authors.lastname: Boussiquet-Leroux
authors.forename: Roger
authors.initials: R
authors.lastname: Owen
authors.forename: Yukio
authors.initials: Y
authors.lastname: Fujimaki
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kemi
authors.forename: Michel
authors.initials: M
authors.lastname: Virat
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: van Zwieten
mesh_terms: D000818:Animals; D001285:Atropine / Q000633:toxicity; D044482:Benzeneacetamides; D001559:Benzhydryl Compounds / Q000633:toxicity; D002386:Cataract / Q000139:chemically induced / Q000473:pathology*; D003408:Cresols / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004848:Epithelium / Q000187:drug effects / Q000473:pathology; D005260:Female; D007908:Lens, Crystalline / Q000187:drug effects / Q000473:pathology; D008297:Male; D018727:Muscarinic Antagonists / Q000633:toxicity*; D010665:Phenylpropanolamine; D010880:Piperidines / Q000633:toxicity; D011725:Pyridines / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000187:drug effects*; D000068737:Tolterodine Tartrate
chemical_list: C425905:(2R)-N-(1-(6-aminopyridin-2-ylmethyl)piperidin-4-yl)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylacetamide; D044482:Benzeneacetamides; D001559:Benzhydryl Compounds; D003408:Cresols; D018727:Muscarinic Antagonists; D010880:Piperidines; D011725:Pyridines; D011976:Receptors, Muscarinic; D010665:Phenylpropanolamine; D000068737:Tolterodine Tartrate; D001285:Atropine