title: Evaluation of a topical cyclosporine A prodrug on corneal graft rejection in rats.
abstract: OBJECTIVE
  To assess the efficacy of a topical cyclosporine A (CsA), water-soluble prodrug, for promoting the survival of allogenic rat corneal grafts after penetrating keratoplasty (PKP).
  
  
  METHODS
  Corneas of Brown-Norway rats (donors) were transplanted to Lewis rats (recipients). Transplanted rats were divided in three treatment groups: group I (PBS) and group II (0.26% Debio088) received drops five times per day. Group III received a daily intramuscular CsA injection (10 mg/kg/day). Blood CsA concentrations were measured on days 2 and 14. On day 4, 10, 13 after PKP, grafts were scored for corneal transparency, edema and extent of neovascularization. An opacity score of greater than or equal to 3 was considered as a nonreversible graft rejection process. On day 14, the experimental eyes were processed for histology.
  
  
  RESULTS
  On day 13, 12 of the 18 corneal transplants (67%) in group I showed irreversible graft rejection. Three of 18 transplants (19%) in group II and 5 of 16 transplants (28%) in group III showed irreversible graft rejection (p=0.013/p=0.019, OR=0.14/0.06 versus vehicle). Each mean clinical score for edema, opacity, and neovessels in group II were significantly lower than those of the grafts in group I (respectively p=0.010, p=0.013, p=0.024) and III except for neovessels (respectively p=0.002, p=0.001, p=0.057). Histology confirmed the clinical results. The mean CsA blood levels for groups II and III were, respectively 54+/-141 mug/l and 755+/-319 mug/l on day 2 and 14+/-34 mug/l and 1318+/-463 mug/l on day 14.
  
  
  CONCLUSIONS
  Debio088 CsA prodrug drops given five times daily are as effective as intramuscular injection of 10 mg/kg/day for the prevention of acute corneal graft rejection in rats.
authors.affiliation: INSERM, U598, Paris, France. jean-louis.bourges@htd.aphp.fr <jean-louis.bourges@htd.aphp.fr>
authors.forename: J L
authors.initials: JL
authors.lastname: Bourges
authors.forename: F
authors.initials: F
authors.lastname: Lallemand
authors.forename: E
authors.initials: E
authors.lastname: Agla
authors.forename: K
authors.initials: K
authors.lastname: Besseghir
authors.forename: J M
authors.initials: JM
authors.lastname: Dumont
authors.forename: D
authors.initials: D
authors.lastname: BenEzra
authors.forename: R
authors.initials: R
authors.lastname: Gurny
authors.forename: F
authors.initials: F
authors.lastname: Behar-Cohen
mesh_terms: D000287:Administration, Topical; D000818:Animals; D015715:Corneal Edema / Q000209:etiology / Q000473:pathology; D003318:Corneal Opacity / Q000209:etiology / Q000473:pathology; D016572:Cyclosporine / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D003524:Cyclosporins / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D005260:Female; D006084:Graft Rejection / Q000150:complications / Q000453:epidemiology / Q000473:pathology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D015994:Incidence; D007273:Injections, Intramuscular; D015948:Keratoplasty, Penetrating; D011355:Prodrugs / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew
chemical_list: D003524:Cyclosporins; C516789:Debio088; D007166:Immunosuppressive Agents; D011355:Prodrugs; D016572:Cyclosporine