Posterior juxtascleral depot administration of anecortave acetate.

OBJECTIVE: To develop a safe and effective transcleral delivery of anecortave acetate, a novel angiostatic cortisene, in therapeutic concentrations to the choroid and retina in the region of the macula in patients with age related macular degeneration. METHODS: In pre-clinical studies with rabbits and monkeys, several routes of delivery were studied including oral and other systemic routes as well as topical, subconjunctival, intravitreal injections and posterior juxtascleral administration. In addition, posterior juxtascleral depot administration using a specially designed blunt cannula was evaluated in humans. RESULTS: Oral and other systemic routes were not acceptable due to rapid systemic metabolism. Topical and subconjunctival administrations resulted in subtherapeutic concentrations in the macular region (<0.1 microm). Intravitreal injections resulted in adequate drug levels, but the visual axis was obscured due to the opaque nature of the drug, and this method carries risks of endophthalmitis and retinal detachment. Posterior juxtascleral depot administration in rabbits and monkeys resulted in adequate retinal and choroidal drug levels (>or=0.1 microm) up to 6 months after administration. In clinical studies, this administration technique was found to be safe. CONCLUSIONS: Posterior juxtascleral depot administration of anecortave acetate onto the scleral surface near the macula is a safe and effective method for delivering therapeutic concentrations of drug to the macular region of the choroid and retina for up to 6 months.

Identification and characterization of the ocular hypotensive efficacy of travoprost, a potent and selective FP prostaglandin receptor agonist, and AL-6598, a DP prostaglandin receptor agonist.

The structure-activity studies that led to the identification of travoprost, a highly selective and potent FP prostaglandin analog, and AL-6598, a DP prostaglandin analog, are detailed. In both series, the 1-alcohol analogs are very effective and are thought to be acting as prodrugs for the biologically active carboxylic acids. The efficacy of amide prodrugs depends on the degree of substitution and the size of the substituents. Selected compounds are profiled in vitro and in vivo preclinically. Clinical studies show that travoprost 0.004% (isopropyl ester) provided intraocular pressure control superior to timolol 0.5% when used as monotherapy in patients with open-angle glaucoma or ocular hypertension. In clinical studies, AL-6598 0.01% provided a sustained intraocular pressure reduction with q.d. application; b.i.d. provided greater intraocular pressure control. The acute and, apparently, conjunctival hyperemia associated with topical ocular AL-6598 can be attenuated while maintaining intraocular pressure-lowering efficacy by formulating with brimonidine.

Response to travoprost in black and nonblack patients with open-angle glaucoma or ocular hypertension.

Two prospective, controlled, multicenter, double-masked studies--one lasting 6 months (n=594) and the other, 12 months (n=787)--examined the intraocular pressure (IOP)-lowering efficacy of travoprost in 1381 black and nonblack patients with open-angle glaucoma or ocular hypertension. Investigated regimens were travoprost 0.004% once daily, latanoprost 0.005% once daily, and timolol 0:5% twice daily. In both studies, mean IOP was significantly lower in blacks treated with travoprost. The IOP reduction was also significantly greater in blacks after adjustments for age, sex, iris color, diagnosis, and corneal thickness. Timolol lowered mean IOP to a greater extent in nonblack patients. The significantly larger IOP reduction with travoprost compared with timolol in both racial groups was more pronounced in blacks. Travoprost also was superior to latanoprost in blacks. Mean changes from baseline generally were greater for black than for nonblack patients, although the differences did not achieve statistical significance. The response rate to travoprost was higher in blacks. The most common adverse effect was hyperemia.

Comparison of travoprost 0.0015% and 0.004% with timolol 0.5% in patients with elevated intraocular pressure: a 6-month, masked, multicenter trial.

OBJECTIVE: To compare the safety and intraocular pressure (IOP)-lowering efficacy of once-daily travoprost (0.0015% and 0.004%) to twice-daily timolol 0.5%. DESIGN: Prospective, 6-month, randomized, controlled, multicenter, double-masked, phase III study. PARTICIPANTS: Six hundred five patients with open-angle glaucoma or ocular hypertension. METHODS: Patients with an 8 AM IOP between 24 to 36 mmHg in at least one eye (the same eye) at two eligibility visits received either travoprost 0.0015%, travoprost 0.004% (dosed every day), or timolol 0.5% (dosed twice daily). MAIN OUTCOME MEASURES: Mean IOP at 8 AM, 10 AM, and 4 PM in the patient's eye with the higher baseline IOP. RESULTS: The mean IOP was significantly lower for both concentrations of travoprost compared with timolol. Travoprost was statistically superior to timolol at 9 of 13 visits, with differences in IOP reductions ranging from 0.9 to 1.8 mmHg (0.0015%) and 10 of 13 visits with differences in IOP reductions from 0.9 to 2.4 mmHg (0.004%). Mean IOP changes from baseline ranged from -6.0 to -7.5 mmHg (0.0015%), -6.5 to -8.0 mmHg (0.004%), and -5.2 to -7.0 mmHg for timolol. Hyperemia was experienced at rates of 29.2% (59 of 202) for travoprost 0.0015%, 42.8% (86 of 201) for travoprost 0.004%, and 8.9% (18 of 202) for timolol. Iris pigmentation changes were observed in 1.0% (2 of 200) of patients receiving travoprost 0.004% with no changes noted in the travoprost 0.0015% group or the timolol group. A decrease in pulse and systolic blood pressure was observed in the timolol group. There were no other clinically relevant or statistically significant changes from baseline in ocular signs or laboratory values, and no serious, related, unexpected adverse events were reported for any group. CONCLUSIONS: Travoprost (0.0015% and 0.004%), dosed once daily in the evening, is statistically superior or equal to timolol 0.5% dosed twice daily at all treatment visits during this 6-month study. IOP reductions of up to 2.0 mmHg greater than timolol were found in the travoprost 0.004% pooled data group. Travoprost is safe and well tolerated in patients with open-angle glaucoma or ocular hypertension.