title: Ocular Inserts for Sustained Release of the Angiotensin-Converting Enzyme 2 Activator, Diminazene Aceturate, to Treat Glaucoma in Rats.
abstract: The aim of this study was to develop and evaluate the effects of chitosan inserts for sustained release of the angiotensin-converting enzyme 2 (ACE2) activator, diminazene aceturate (DIZE), in experimental glaucoma. Monolayer DIZE loaded inserts (D+I) were prepared and characterized through swelling, attenuated total reflectance Fourier transformed infrared spectroscopy (ATR-FTIR), differential scanning calorimetry (DSC) and in vitro drug release. Functionally, the effects of D+I were tested in glaucomatous rats. Glaucoma was induced by weekly injections of hyaluronic acid (HA) into the anterior chamber and intraocular pressure (IOP) measurements were performed. Retinal ganglion cells (RGC) and optic nerve head cupping were evaluated in histological sections. Biodistribution of the drug was accessed by scintigraphic images and ex vivo radiation counting. We found that DIZE increased the swelling index of the inserts. Also, it was molecularly dispersed and interspersed in the polymeric matrix as a freebase. DIZE did not lose its chemical integrity and activity when loaded in the inserts. The functional evaluation demonstrated that D+I decreased the IOP and maintained the IOP lowered for up to one month (last week: 11.0 ± 0.7 mmHg). This effect of D+I prevented the loss of RGC and degeneration of the optic nerve. No toxic effects in the eyes related to application of the inserts were observed. Moreover, biodistribution studies showed that D+I prolonged the retention of DIZE in the corneal site. We concluded that D+I provided sustained DIZE delivery in vivo, thereby evidencing the potential application of polymeric-based DIZE inserts for glaucoma management.
authors.affiliation: Department of Morphology, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Giselle
authors.initials: G
authors.lastname: Foureaux
authors.affiliation: Department of Pharmaceutical Products, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Juçara Ribeiro
authors.initials: JR
authors.lastname: Franca
authors.affiliation: Department of Morphology, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: José Carlos
authors.initials: JC
authors.lastname: Nogueira
authors.affiliation: Department of Pharmaceutical Products, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Gustavo de Oliveira
authors.initials: Gde O
authors.lastname: Fulgêncio
authors.affiliation: Department of Pharmaceutical Products, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Tatiana Gomes
authors.initials: TG
authors.lastname: Ribeiro
authors.affiliation: Department of Pharmaceutical Products, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Rachel Oliveira
authors.initials: RO
authors.lastname: Castilho
authors.affiliation: Institute of Exact Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Maria Irene
authors.initials: MI
authors.lastname: Yoshida
authors.affiliation: Department of Clinical and Toxicological Analysis, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Leonardo Lima
authors.initials: LL
authors.lastname: Fuscaldi
authors.affiliation: Department of Clinical and Toxicological Analysis, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Simone Odília Antunes
authors.initials: SO
authors.lastname: Fernandes
authors.affiliation: Department of Clinical and Toxicological Analysis, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Valbert Nascimento
authors.initials: VN
authors.lastname: Cardoso
authors.affiliation: Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Sebastião
authors.initials: S
authors.lastname: Cronemberger
authors.affiliation: Department of Pharmaceutical Products, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: André Augusto Gomes
authors.initials: AA
authors.lastname: Faraco
authors.affiliation: Department of Morphology, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Anderson José
authors.initials: AJ
authors.lastname: Ferreira
mesh_terms: D060433:Administration, Ophthalmic; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002152:Calorimetry, Differential Scanning; D048271:Chitosan; D003692:Delayed-Action Preparations; D004133:Diminazene / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D005136:Eye Proteins / Q000819:agonists*; D005901:Glaucoma / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D006820:Hyaluronic Acid / Q000633:toxicity; D007429:Intraocular Pressure / Q000187:drug effects; D008297:Male; D008855:Microscopy, Electron, Scanning; D007703:Peptidyl-Dipeptidase A / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D017550:Spectroscopy, Fourier Transform Infrared; D014018:Tissue Distribution
chemical_list: D003692:Delayed-Action Preparations; D005136:Eye Proteins; D006820:Hyaluronic Acid; D048271:Chitosan; D007703:Peptidyl-Dipeptidase A; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2; C003915:diminazene aceturate; D004133:Diminazene