Method for treating ocular hypertension

#Glaucoma is a degenerative disease of the eye wherein the intraocular pressure is too high to permit normal eye function. Damage eventually occurs to the optic nerve head, resulting in irreversible loss of visual function. If untreated, glaucoma may eventually lead to blindness. Elevated intraocular pressure or ocular hypertension, is now believed by the majority of ophthalmologists to represent the earliest phase in the onset of glaucoma.

#Many of the drugs formerly used to treat glaucoma proved unsatisfactory. The early methods of treating glaucoma employed pilocarpine and produced undesirable local effects that made this drug, though valuable, unsatisfactory as a first line drug. More recently, clinicians have noted that many β-adrenergic antagonists are effective in reducing intraocular pressure. While many of these agents are effective for this purpose, there exist some patients with whom this treatment is not effective or not sufficiently effective. Many of these agents also have other characteristics, e.g., membrane stabilizing activity, that become more apparent with increased doses and render them unacceptable for chronic ocular use and can also cause cardiovascular effects.

#Although pilocarpine and β-adrenergic antagonists reduce intraocular pressure, none of these drugs manifests its action by inhibiting the enzyme carbonic anhydrase, and thus they do not take advantage of reducing the contribution to aqueous humor formation made by the carbonic anhydrase pathway.

#Production of Compounds A, B, C, D and G

#Step A: Fermentation Conditions for Production of Compounds A-D and G

#Fermentation conditions for the production of Compounds A, B, C, D and G by the microorganism Nalanthamala sp. were as follows: vegetative mycelia of a culture of the above microorganism were prepared by inoculating 54 mL of seed medium (Table 1) in a 250 mL unbaffled Erlenmeyer flask with frozen mycelia of MF5785 (ATCC 74192). Seed flasks were incubated at 25 ° C. and 50% relative humidity on a rotary shaker with a 5-cm throw at 220 rpm in a room with constant fluorescent light, about 400 to 750 nm. Two-mL portions of the resulting 3-day culture were used to inoculate 50 mL portions of Liquid Production Medium (Table 2) in 250 mL unbaffled Erlenmeyer flasks; these cultures were incubated at 25 ° C., 220 rpm with 50% relative humidity in a room with constant fluorescent light. The products appeared in the fermentation as early as 7 days with maximal accumulation observed at day 11. At harvest, the compounds were extracted as described below.