title: Effects of anti-glaucoma drugs timolol and GLC756, a novel mixed dopamine D2 receptor agonist and D1 receptor antagonist, on endotoxin-induced-uveitis and -arthritis in rats.
abstract: Anti-glaucoma drugs exhibiting anti-inflammatory properties are desirable for the long-term treatment of glaucoma since they may reduce the risk for treatment-related inflammatory processes in outer compartments of the eye. The purpose of this study was to evaluate potential anti-inflammatory effects of two topically and systemically applied anti-glaucoma drugs i.e. GLC 756, a novel mixed dopamine D2 receptor agonist and D1 receptor antagonist, and timolol a beta-adrenoceptor antagonist using endotoxin-induced uveitis (EIU) and arthritis in rats as an in vivo model. For EIU, 8-week-old Lewis rats were intravenously injected at 160 microg lipopolysaccharide (LPS) from Salmonella typhimurium. GLC756, timolol, or betamethasone, as a positive control, were either topically (0.4%, 0.5%, and 0.1%, respectively, 16-times 20 microL eye drops during 48 h) or systemically (1mg/kg subcutaneous for 5 days) administered. Cell infiltration in tissue of the eye and knee joint were assessed histopathologically and in special compartments of the eye by confocal microscopy 48 h after LPS-induction. Numerous infiltrating cells were detected in the eyes after LPS-induction and half of the animals showed arthritis. Topical and systemic pre-treatment with GLC756 and timolol resulted in reduced cell infiltration in the eye. In addition, GLC756 reduced, whereas timolol increased the incidence of arthritis. Betamethasone suppressed almost completely the cell infiltration in the eye and the incidence of arthritis. In conclusion, the observations that GLC756 reduced cell infiltration in the eye and the incidence of arthritis after LPS-induction is compatible with anti-inflammatory properties of this drug. By contrast, timolol produced no consistent anti-inflammatory effect since both inhibitory as well as stimulatory effects on inflammatory processes were seen.
authors.affiliation: Department of Toxicology/Pathology, Novartis Pharma AG, MUT-2881.133, CH-4002 Basel, Switzerland. Ulrich.Laengle@novartis.com
authors.forename: U W
authors.initials: UW
authors.lastname: Laengle
authors.forename: M
authors.initials: M
authors.lastname: Court
authors.forename: R
authors.initials: R
authors.lastname: Markstein
authors.forename: P G
authors.initials: PG
authors.lastname: Germann
authors.forename: V
authors.initials: V
authors.lastname: Nogues
authors.forename: D
authors.initials: D
authors.lastname: Roman
mesh_terms: D000818:Animals; D001168:Arthritis / Q000188:drug therapy* / Q000473:pathology; D005901:Glaucoma / Q000188:drug therapy*; D008070:Lipopolysaccharides / Q000633:toxicity; D011804:Quinolines / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors*; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D013999:Timolol / Q000627:therapeutic use*; D014605:Uveitis / Q000188:drug therapy* / Q000473:pathology
chemical_list: D008070:Lipopolysaccharides; D011804:Quinolines; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C102871:SDZ GLC 756; D013999:Timolol