In vivo ocular efficacy profile of mapracorat, a novel selective glucocorticoid receptor agonist, in rabbit models of ocular disease.
OBJECTIVE
To compare the efficacy of mapracorat (formerly ZK-245186, and subsequently BOL-303242-X), a novel selective glucocorticoid receptor agonist (SEGRA), with that of dexamethasone (DEX) in rabbit models of ocular disease. The effects of topical BOL-303242-X and DEX on intraocular pressure (IOP) and body weight changes were also evaluated.


METHODS
Dry eye was induced by atropine sulfate administration and was treated with saline, BOL-303242-X (0.1%-1.0%), DEX (0.1%), Restasis 0.05% (Allergan, Inc., Irvine, CA), or Refresh Endura (Allergan, Inc.) three times per day for 7 to 8 days. For paracentesis studies, vehicle, BOL-303242-X (0.1%, 0.5%, and 1.0%), or DEX (0.1%) were repeatedly administered topically 3 hours before paracentesis and continued for 90 minutes afterward. For IOP and body weight measurements, right eyes of rabbits were topically treated with vehicle, BOL-303242-X (1.0% or 0.1%), or DEX (0.1%) four times per day for 6 weeks.


RESULTS
In the dry eye model, BOL-303242-X and DEX were fully efficacious, maintaining tear volume and tear breakup time (TBUT) at baseline levels. Although Restasis improved tear volume compared with vehicle, no changes were observed in TBUT. In the paracentesis study, BOL-303242-X and DEX improved ocular inflammation. BOL-303242-X reduced protein and PGE(2) levels. Finally, BOL-303242-X showed no effects on integrated IOP or body weight, whereas DEX significantly increased integrated IOP and prevented the increase of body weight observed in the vehicle-treated animals.


CONCLUSIONS
BOL-303242-X shows full anti-inflammatory efficacy (similar to DEX) in experimental models of dry eye and postoperative inflammation while demonstrating reduced effects in IOP and body weight. These data indicate that mapracorat, a SEGRA, shows efficacy similar to that of traditional steroids while exhibiting an improved side effect profile in IOP and muscle wasting.
Shafiee
Afshin
A
Department of Preclinical Pharmacology, Pharmaceutical R&D, Bausch & Lomb, Inc., Rochester, New York, USA.
Bucolo
Claudio
C
Budzynski
Ewa
E
Ward
Keith W
KW
López
Francisco J
FJ
D000287:Administration, Topical; D000818:Animals; D001082:Aqueous Humor / Q000378:metabolism; D001572:Benzofurans / Q000008:administration & dosage* / Q000009:adverse effects; D001835:Body Weight / Q000187:drug effects; D003907:Dexamethasone / Q000008:administration & dosage / Q000009:adverse effects; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015352:Dry Eye Syndromes / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage / Q000009:adverse effects; D007429:Intraocular Pressure / Q000187:drug effects; D000439:Pentanols / Q000008:administration & dosage* / Q000009:adverse effects; D011804:Quinolines / Q000008:administration & dosage* / Q000009:adverse effects; D011817:Rabbits; D011965:Receptors, Glucocorticoid / Q000819:agonists*; D013666:Tears / Q000378:metabolism; D016896:Treatment Outcome
D001572:Benzofurans; D005938:Glucocorticoids; D000439:Pentanols; D011804:Quinolines; C546413:R-1,1,1-trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-4-methyl-2-(((2-methyl-5-quinolyl)amino)methyl)pentan-2-ol; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D015232:Dinoprostone