prostaglandin-f2-isopropyl-ester and Glaucoma

Topics: Animals; Antihypertensive Agents; Awards and Prizes; Dinoprost; Glaucoma; Humans; Intraocular Pressure; Latanoprost; Melanosis; Molecular Structure; Ophthalmology; Prostaglandins F, Synthetic; Respiratory System; Societies, Scientific

A need exists for new ocular hypotensive agents that are more efficacious and that have fewer side effects than those now clinically used. Laser-induced glaucoma in monkeys is an excellent model to test potential new drugs that lower intraocular pressure (IOP). A variety of agents that act through secondary messenger systems or via enzymes to lower IOP are being investigated in primates. Several alpha-adrenergic agonists and antagonists are effective ocular hypotensive agents in monkeys and humans. Para-aminoclonidine, an alpha2 agonist, inhibits the transient post-laser rise of IOP in humans. Prostaglandin F2 alpha-1-isopropyl ester significantly reduces IOP when tested in multiple dose fashion in glaucomatous monkey eyes and glaucoma patients. Modified carbonic anhydrase inhibitors, designed to enhance intraocular penetration, reduce IOP in the monkey model and in ocular hypertensive patients in single-dose studies when given topically. Studies show that forskolin and vanadate are less promising agents for glaucoma therapy.

Topics: Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Animals; Carbonic Anhydrase Inhibitors; Clinical Trials as Topic; Colforsin; Dinoprost; Drug Evaluation; Glaucoma; Haplorhini; Intraocular Pressure; Vanadates

A lipid-soluble PG ester such as PGF2 alpha-IE reduces IOP in the human eye when given in considerably lower doses than are needed for the tromethamine salt of this PG to do so. However, with the pharmaceutical composition now used, the concomitant and dose-related side effects, both objective and subjective, are clearly clinically unacceptable at doses corresponding to the upper part of the dose-response curve for IOP reductions. Moderate side effects were observed after twice-daily treatment with the 0.5 microgram dose for up to two weeks. The pressure reduction obtained in healthy eyes with this dose of PGF2 alpha-IE was less than one would expect with conventional glaucoma drugs. However, the pressure reduction in response to this dose of PGF2 alpha-IE among glaucoma patients who had moderately increased IOP was adequate for clinical use. A useful approach to the development of PGs as potential drugs for the treatment of glaucoma would clearly be the identification of an alternative PG or PG formulation that will permit the use of doses at the upper portion of the IOP dose-response curve without unacceptable side effects. Long-term studies on glaucoma patients, using an appropriate PG formulation, remain to be done before we can evaluate the true clinical usefulness of this new class of ocular hypotensive drugs.

Topics: Administration, Topical; Dinoprost; Dose-Response Relationship, Drug; Evaluation Studies as Topic; Glaucoma; Humans; Intraocular Pressure; Male; Time Factors

Four clinical studies were performed in 54 healthy Japanese volunteers to assess the efficacy and the safety of two phenyl-substituted PGF2 alpha-isopropyl ester analogues, PhXA34 and PhXA41 after both single and repeated administrations. PhXA34 and PhXA41 reduced intraocular pressure (IOP) significantly in a dose-dependent way. The maximum IOP reductions were 14.5% to 17.5% with baseline adjustment at 10 to 12 hours after a single administration. No transient early elevation in IOP after treatment was observed. Based on the maximum IOP reducing effect of 1 microgram of PhXA34 and PhXA41, PhXA41 appeared to be at least 1.5 times more active than PhXA34. Tachyphylaxis of the ocular hypotensive effect did not develop during repeated administration for 5 days. A mild conjunctival hyperemia occurred in some subjects at high doses; it tended to diminish with time during the repeated administration of both drugs. Neither PhXA34 nor PhXA41 caused any change at any time in the aqueous flare intensity measured with a laser flare-cell meter. There were no changes in pupillary diameter after treatment. Each drug was well tolerated and caused no other ocular or systemic side effects.

Topics: Adolescent; Adult; Aqueous Humor; Dinoprost; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Tolerance; Evaluation Studies as Topic; Glaucoma; Humans; Hyperemia; Intraocular Pressure; Latanoprost; Male; Ophthalmic Solutions; Prostaglandins F, Synthetic

A need exists for new ocular hypotensive agents that are more efficacious and that have fewer side effects than those now clinically used. Laser-induced glaucoma in monkeys is an excellent model to test potential new drugs that lower intraocular pressure (IOP). A variety of agents that act through secondary messenger systems or via enzymes to lower IOP are being investigated in primates. Several alpha-adrenergic agonists and antagonists are effective ocular hypotensive agents in monkeys and humans. Para-aminoclonidine, an alpha2 agonist, inhibits the transient post-laser rise of IOP in humans. Prostaglandin F2 alpha-1-isopropyl ester significantly reduces IOP when tested in multiple dose fashion in glaucomatous monkey eyes and glaucoma patients. Modified carbonic anhydrase inhibitors, designed to enhance intraocular penetration, reduce IOP in the monkey model and in ocular hypertensive patients in single-dose studies when given topically. Studies show that forskolin and vanadate are less promising agents for glaucoma therapy.

Topics: Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Animals; Carbonic Anhydrase Inhibitors; Clinical Trials as Topic; Colforsin; Dinoprost; Drug Evaluation; Glaucoma; Haplorhini; Intraocular Pressure; Vanadates

Topics: Animals; Dinoprost; Glaucoma; Haplorhini; Humans; Intraocular Pressure; Latanoprost; Prostaglandins F, Synthetic; Prostaglandins, Synthetic; Rabbits

The ophthalmic solution of UF-021, a novel prostaglandin (PG) related compound, was investigated for its intraocular pressure (IOP) reducing activity and local ocular side effects in different species of animals. UF-021 ophthalmic solution (0.03 to 0.24%), when topically applied to the eyes of rabbits, caused dose-dependent IOP reduction (2.8 to 5.2 mmHg), without transient IOP rise. Both in cats and monkeys, UF-021 ophthalmic solution (0.12%) elicited rapid, significant IOP reduction (ca. 9 mmHg and 2 mmHg, respectively), without any controversial, local ocular side effects being revealed. On the other hand, PGE2, PGF2 alpha-isopropyl ester all brought about marked increases in IOP prior to development of their IOP reducing activities. In addition, these primary PGs showed intense local ocular irritation, which presented a striking contrast with UF-021. Enhancement of IOP reducing activity, coupled with freedom from any significant ocular side effects, as described above, suggests that UF-021 ophthalmic solution could be promising as a new anti-glaucoma agent.

Topics: Animals; Cats; Dinoprost; Dinoprostone; Female; Glaucoma; Intraocular Pressure; Macaca; Male; Rabbits

Topical instillations of 1.0, 10, and 20 micrograms/50 microliters of prostaglandin PGA2, 0.5 and 1.0 microgram/50 microliters of PGA2 isopropyl ester, and 0.5, 1.0, 5.0 and 10.0 micrograms/50 microliters of PGF2 alpha isopropyl ester were evaluated in the normal dogs and glaucomatous beagles eyes. Each concentration of drug was evaluated for a seven day period. On Day 1 baseline values were obtained, days 2-4, the drug was instilled (once a day) and on days 5-7 post-treatment values were measured. All concentrations of PGA2 failed to lower intraocular pressure (IOP) in the normal and the glaucomatous (P greater than 0.72) dogs. PGA2 isopropyl ester decreased IOP in the normal dogs and in the glaucomatous beagles (P less than 0.01). The declines in IOP were significant at 1/2 to 1 hour and continued for up to 5 hours. No significant change in IOP occurred in the non-treated fellow eye of the normotensive dog (P less than 0.54) and the glaucomatous beagle (P less than 0.29). All concentrations of PGF2 alpha isopropyl ester significantly decreased IOP in the treated eyes of the normotensive dog (P less than 0.05) and the glaucomatous beagle (P less than 0.01). The significant change in IOP occurred within one hour after the instillation of PGF2 alpha isopropyl ester. The IOP remained lower than the baseline pressures 24 hours post-treatment for both the normotensive and glaucomatous dogs. Maximal change in IOP for normal dogs was a decrease of 9 mm Hg while the glaucomatous beagle had a decrease of 19 mm Hg. No significant change in IOP occurred in the non-treated fellow eye of the normotensive animal (P less than 0.16) and the glaucomatous beagle (P less than 0.40). The side effects of PGF2 alpha isopropyl ester were miosis and mild conjunctival irritation.

Topics: Administration, Topical; Animals; Antihypertensive Agents; Conjunctival Diseases; Dinoprost; Dogs; Female; Glaucoma; Intraocular Pressure; Male; Miosis; Prostaglandins A

The effect of prostaglandin (PG) F2 alpha-isopropyl ester (IE), PGA2, or PGA2-IE on intraocular pressure (IOP) was tested in eight cynomolgus monkey eyes with argon laser-induced glaucoma. Dose-response testing and baseline IOP measurements were done. For multiple dose testing, 5 micrograms in 25 microliters (0.02%) of each PG was topically applied twice daily for 5 days. The IOP was measured at 30- or 60-minute intervals for 6 hours after the morning dose each day. A significant (P less than 0.05) reduction of IOP peaked at 5-9 mm Hg below baseline values on the 5th day of treatment for each PG. The ocular hypotensive effect of these PGs progressively became more pronounced during the course of twice-daily dosing, with a significant reduction maintained at least 17 hours after some doses. No more than trace aqueous flare and no cells were observed in any eye during the course of treatment. These findings demonstrate that PGs other than F2 alpha are potent ocular hypotensive agents in primates.

Topics: Administration, Topical; Animals; Dinoprost; Disease Models, Animal; Dose-Response Relationship, Drug; Glaucoma; Intraocular Pressure; Macaca fascicularis; Prostaglandins A