Therapeutic and toxicological evaluations of cyclosporine a microspheres as a treatment vehicle for uveitis in rabbits.
OBJECTIVE
This study was undertaken to investigate the therapeutic efficacy and the toxicity of the intravitreal biodegradable poly(dl-lactide-co-glycolide)co-polymer microspheres containing cyclosporin A (CsA-PLGA-MS) on experimental uveitis in rabbits.


METHODS
CsA-PLGA-MS that had been prepared by a solvent evaporation approach were characterized for morphology, particle size, entrapment efficiency, and in vitro release profile of CsA-PLGA-MS. Therapeutic efficacy of the CsA-PLGA-MS was evaluated by scoring of the inflammation, aqueous leukocyte counting, aqueous protein determination, and histological examination in the experimental rabbits with artificial uveitis induced by the injection of lipopolysaccharide. The toxicity was investigated by slit-lamp examination, indirect ophthalmoscopy, and electroretinography (ERG) in the noninflamed rabbit eye.


RESULTS
The CsA-PLGA-MS were spherical in shape, with an average particle size of nearly 50 microm and an entrapment efficiency of more than 80%. The compositions of the formulation that was most effective in the in vivo studies included CsA, PLGA, and 3% Pluronic F68. In vitro released cyclosporine A from the optimized microspheres was approximately 25% during the 60-day incubation at 37 degrees C. It was demonstrated that the intravitreal injection of the optimized CsA-PLGA-MS decreased significantly the severity of the inflammatory signs, cellular infiltrate, aqueous leukocyte counts, and protein levels in the eyes of experimental rabbits with uveitis, compared to other formulations. Also, the preparation did not cause obvious toxicity in the noninflamed eyes of rabbits, except that the ERG b-wave amplitude for the test eyes was reversibly depressed, compared to those of the control eyes at 2 weeks, which almost recovered at the end of 6 weeks.


CONCLUSIONS
The CsA-PLGA-MS preparation might be useful in the treatment of patients with severe chronic posterior uveitis who cannot tolerate systemic or periocular therapy.
He
Yuan
Y
Department of Ophthalmology, Peking University Third Hospital, Beijing, People's Republic of China.
Wang
Jian-Cheng
JC
Liu
Yu-Ling
YL
Ma
Zhi-Zhong
ZZ
Zhu
Xiu-An
XA
Zhang
Qiang
Q
D000818:Animals; D001082:Aqueous Humor / Q000166:cytology; D001672:Biocompatible Materials; D016572:Cyclosporine / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000737:chemistry*; D004596:Electroretinography; D005123:Eye / Q000187:drug effects* / Q000473:pathology; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D007267:Injections; D019344:Lactic Acid / Q000737:chemistry*; D007958:Leukocyte Count; D007962:Leukocytes / Q000166:cytology; D008863:Microspheres; D010316:Particle Size; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry*; D011817:Rabbits; D012995:Solubility; D014605:Uveitis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology
D001672:Biocompatible Materials; D004337:Drug Carriers; D007166:Immunosuppressive Agents; D011108:Polymers; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D016572:Cyclosporine