Treatment of alkali-injured rabbit corneas with a synthetic inhibitor of matrix metalloproteinases.
Healing of corneal alkali injuries remains a severe clinical challenge. The authors evaluated the effect of a new synthetic inhibitor of matrix metalloproteinases (GM6001 or N-[2(R)-2-(hydroxamido carbonylmethyl)-4-methylpentanoyl]-L-tryptophane methylamide) on preventing ulceration of rabbit corneas after alkali injury. Topical treatment of corneas with severe alkali injuries with 400 micrograms/ml or 40 micrograms/ml GM6001 alone prevented ulceration for 28 days, although 8 of 10 corneas treated with vehicle perforated. Corneas treated with 4 micrograms/ml GM6001 had midstromal depth ulcers. Corneas treated with 400 micrograms/ml of GM6001 contained very few inflammatory cells and had significantly reduced vessel ingrowth compared with vehicle-treated corneas. Epithelial regeneration after moderate alkali injuries also was investigated. Persistent epithelial defects developed 4 days after moderate alkali injury in rabbit corneas treated with vehicle and progressively increased to an average of 20% of the original 6 mm diameter wound by 27 days after moderate alkali injury. By contrast, epithelial regeneration was complete and persisted for 21 days for corneas treated with a formulation containing GM6001 (400 micrograms/ml), epidermal growth factor (10 micrograms/ml), fibronectin (500 micrograms/ml), and aprotinin (400 micrograms/ml). Sporadic punctate staining developed in 20% of the corneas treated with the combination of agents between days 21-28 after moderate alkali injury. These results demonstrate that topical application of GM6001 prevented corneal ulceration after severe alkali injury and that a combination containing GM6001, epidermal growth factor, fibronectin, and aprotinin promoted stable regeneration of corneal epithelium after moderate alkali injury.
Schultz
G S
GS
Department of Obstetrics and Gynecology, University of Florida, Gainesville 32610.
Strelow
S
S
Stern
G A
GA
Chegini
N
N
Grant
M B
MB
Galardy
R E
RE
Grobelny
D
D
Rowsey
J J
JJ
Stonecipher
K
K
Parmley
V
V
D000468:Alkalies; D000818:Animals; D007611:Aprotinin / Q000494:pharmacology; D002057:Burns, Chemical / Q000188:drug therapy* / Q000473:pathology; D003315:Cornea / Q000473:pathology / Q000503:physiopathology; D065306:Corneal Injuries; D003320:Corneal Ulcer / Q000517:prevention & control; D004151:Dipeptides / Q000737:chemistry / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005109:Extracellular Matrix / Q000201:enzymology*; D005126:Eye Burns / Q000139:chemically induced* / Q000188:drug therapy / Q000473:pathology; D005353:Fibronectins / Q000494:pharmacology; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D011817:Rabbits; D012038:Regeneration
D000468:Alkalies; D004151:Dipeptides; D005353:Fibronectins; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D004815:Epidermal Growth Factor; D007611:Aprotinin; D008666:Metalloendopeptidases