betadex and tetrahydro-11-deoxycortisol

Folkman and coworkers have described angiostatic steroids that markedly inhibit neovascularization of the rabbit cornea when given topically with beta-cyclodextrin tetradecasulfate (beta-CD), yet have minimal or no glucocorticoid or mineralocorticoid activity. Our objective was to extend these observations to another species, the rat. We induced neovascularization by cauterizing rat corneas with silver nitrate/potassium nitrate; drugs were applied topically four times per day for 4 days in most experiments. Submicron sized emulsions of lipid-soluble dexamethasone and the angiostatic steroids 17 alpha-hydroxyprogesterone (1 or 10 mg ml-1) and cortexolone (1 or 10 mg ml-1) were prepared by lecithin encapsulation of drug microcrystals. The vehicle for water-soluble hydrocortisone 21-phosphate (HCP) +/- beta-CD (Molecusol; Pharmatec, Inc) was 10% Tween 20 in Tris-buffered 0.9% saline. Angiogenesis was significantly inhibited only by 1 mg ml-1 dexamethasone (-63.2% when compared with controls), 0.5 mg ml-1 HCP + 1 mg ml-1 beta-CD (-33.4%), and 1 mg ml-1 HCP (-40.2%). HCP (0.5 mg ml-1) or beta-CD (1 or 2 mg ml-1) alone had no significant effect on neovascularization; the inhibition by 1.0 mg ml-1 HCP was not potentiated by 2 mg ml-1 beta-CD. We also tested HCP and tetrahydro-S (TH-S) using 1.5% hydroxypropyl methylcellulose vehicle and beta-CD from Takeda Chemical Industries, Ltd., to simulate the procedure of Folkman and coworkers.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 17-alpha-Hydroxyprogesterone; Animals; beta-Cyclodextrins; Cornea; Cortodoxone; Cyclodextrins; Dexamethasone; Drug Therapy, Combination; Female; Hydrocortisone; Hydroxyprogesterones; Male; Neovascularization, Pathologic; Nitrates; Potassium Compounds; Rats; Rats, Sprague-Dawley; Silver Nitrate; Steroids

It is known that hydrocortisone can be converted to a potent angiogenesis inhibitor by coadministration with heparin or with a sulfated cyclodextrin. The activity of tetrahydrocortisol-S, a purely angiostatic corticosteroid, can be potentiated by beta-cyclodextrin tetradecasulfate as shown in this study. This drug "pair" and other pairs of corticosteroids and beta-cyclodextrin tetradecasulfate can be applied topically to inhibit corneal neovascularization. Endotoxin-induced corneal neovascularization in rabbits was treated with beta-cyclodextrin tetradecasulfate coadministered with either: hydrocortisone, tetrahydrocortisol-S, or 6-alpha-fluoro-17,21-dihydroxy-16-beta-methyl-pregna-4,9(11),diene,3, 20-dione. When optimal ratios of steroid and cyclodextrin were used, neovascularization was reduced to 13%, 26%, and 28% of untreated controls for the three steroids, respectively. Hydrocortisone-cyclodextrin drug pairs suppressed virtually all inflammatory cell infiltration (induced by endotoxin), whereas tetrahydrocortisol-cyclodextrin pairs only partially reduced inflammation. These results demonstrate that corneal neovascularization and corneal inflammation are separable processes and that the neovascularization may be treated specifically using angiostatic steroids without inflammatory activity.

Topics: Administration, Topical; Angiogenesis Inducing Agents; Animals; beta-Cyclodextrins; Betamethasone; Corneal Neovascularization; Cortodoxone; Cyclodextrins; Disease Models, Animal; Drug Synergism; Hydrocortisone; Male; Rabbits