Efficacy and safety of microspheres of cyclosporin A, a new systemic formulation, to prevent corneal graft rejection in rats.
OBJECTIVE
To evaluate the efficacy and safety of a new systemic formulation of cyclosporin A (CsA)-loaded microspheres in a rat model of penetrating keratoplasty rejection.


METHODS
Female Lewis rats received orthotopic corneal allografts from inbred female Fisher donors. The rats were divided into three groups: 1, untreated controls; 2, daily subcutaneous injection of 10 mg/kg of the commercially intravenous CsA formulation starting after surgery (time 0) and for 15 days; and 3, one subcutaneous injection of 150 mg/kg of CsA microspheres. The grafts were evaluated clinically for 30 days and the rejection index, mean survival time, and rejection rate were calculated. Serum levels of CsA were measured at 5, 10, 15, 20, and 30 days in groups 2 and 3. Eyes, liver, and kidneys were histologically evaluated at the end of the experiment.


RESULTS
Graft rejection was significantly reduced in group 3 at day 30 (P < 0.05) and serum levels of CsA were constant (range, 73.28 +/- 43.93 to 183.33 +/- 83.69 ng/ml). High levels (>3000 ng/ml) were obtained in group 2 as long as CsA was injected. Both formulations delayed rejection onset, but only the microspheres decreased the rate of corneal graft rejection (100% in group 2 and 70% in group 3 at day 30). Histologic examination showed no hepatic lesions with either formulation, but both resulted in deposition of a hemoglobin-like material in the kidneys.


CONCLUSIONS
Although subcutaneous CsA-loaded microspheres delay rejection onset and decrease the rate of corneal graft rejection in an orthotopic keratoplasty rejection model in rats, administration of the microspheres did not prevent acute renal toxicity.
Vallelado
Ana I
AI
Instituto Universitario de Oftalmobiología Aplicada (IOBA), University of Valladolid, Valladolid, Spain. ana@ioba.med.uva.es
López
M Isabel
MI
Calonge
Margarita
M
Sánchez
Alejandro
A
Alonso
M José
MJ
D000818:Animals; D002626:Chemistry, Pharmaceutical; D003315:Cornea / Q000187:drug effects*; D016572:Cyclosporine / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D004337:Drug Carriers; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control*; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D015948:Keratoplasty, Penetrating; D007668:Kidney / Q000187:drug effects; D008863:Microspheres; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D012449:Safety
D004337:Drug Carriers; D007166:Immunosuppressive Agents; D016572:Cyclosporine