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The aims of the current studies were to determine the in vitro and in vivo ocular and non-ocular pharmacological properties of cabergoline using well documented receptor binding, cell-based functional assays, and in vivo models. Cabergoline bound to native and/or human cloned serotonin-2A/B/C (5HT(2A/B/C)), 5HT(1A), 5HT(7), alpha(2B), and dopamine-2/3 (D(2/3)) receptor subtypes with nanomolar affinity. Cabergoline was an agonist at human recombinant 5HT(2), 5HT(1A) and D(2/3) receptors but an antagonist at 5HT(7) and alpha(2) receptors. In primary human ciliary muscle (h-CM) and trabecular meshwork (h-TM) cells, cabergoline stimulated phosphoinositide (PI) hydrolysis (EC(50)=19+/-7 nM in TM; 76 nM in h-CM) and intracellular Ca(2+) ([Ca(2+)](i)) mobilization (EC(50)=570+/-83 nM in h-TM; EC(50)=900+/-320 nM in h-CM). Cabergoline-induced [Ca(2+)](i) mobilization in h-TM and h-CM cells was potently antagonized by a 5HT(2A)-selective antagonist (M-100907, K(i)=0.29-0.53 nM). Cabergoline also stimulated [Ca(2+)](i) mobilization more potently via human cloned 5HT(2A) (EC(50)=63.4+/-10.3 nM) than via 5HT(2B) and 5HT(2C) receptors. In h-CM cells, cabergoline (1 microM) stimulated production of pro-matrix metalloproteinases-1 and -3 and synergized with forskolin to enhance cAMP production. Cabergoline (1 microM) perfused through anterior segments of porcine eyes caused a significant (27%) increase in outflow facility. Topically administered cabergoline (300-500 microg) in Dutch-belted rabbit eyes yielded 4.5 microMM and 1.97 microM levels in the aqueous humor 30 min and 90 min post-dose but failed to modulate intraocular pressure (IOP). However, cabergoline was an efficacious IOP-lowering agent in normotensive Brown Norway rats (25% IOP decrease with 6 microg at 4h post-dose) and in conscious ocular hypertensive cynomolgus monkeys (peak reduction of 30.6+/-3.6% with 50 microg at 3h post-dose; 30.4+/-4.5% with 500 microg at 7h post-dose). In ketamine-sedated monkeys, IOP was significantly lowered at 2.5h after the second topical ocular dose (300 microg) of cabergoline by 23% (p<0.02) and 35% (p<0.004) in normotensive and ocular hypertensive eyes, respectively. In normotensive eyes, cabergoline increased uveoscleral outflow (0.69+/-0.7 microL/min-1.61+/-0.97 microL/min, n=13; p<0.01). However, only seven of the eleven ocular hypertensive monkeys showed significantly increased uveoscleral outflow. These data indicate that cabergoline's most prominent agonist activity involves activation of 5HT(2), 5HT(1A), and D(2/3) receptors. Since 5HT(1A) agonists, 5HT(7) antagonists, and alpha(2) antagonists do not lower IOP in conscious ocular hypertensive monkeys, the 5HT(2) and dopaminergic agonist activities of cabergoline probably mediated the IOP reduction observed with this compound in this species.

Purpose: To determine the effect on aqueous flow of topical dorzolamide 2%, topical timolol 0.5%, or oral acetazolamide 250 mg when used alone or when dorzolamide is combined with either timolol or acetazolamide., Methods: In 30 patients with ocular hypertension, aqueous flow and intraocular pressure (IOP) were determined at baseline and on the following combinations of drugs in a crossover design: (1) vehicle alone, (2) dorzolamide alone, (3) acetazolamide alone, (4) timolol alone, (5) dorzolamide + acetazolamide, and (6) dorzolamide + timolol. Treated eyes were compared with control eyes and comparisons were made between treatments., Results: Compared with baseline, significant (P < 0.04) IOP reductions in the order of efficacy were: dorzolamide + timolol > dorzolamide + acetazolamide = acetazolamide = timolol > dorzolamide. Aqueous flow was reduced more by dorzolamide + timolol than by each drug alone (P < 0.04) and more by dorzolamide + acetazolamide than by dorzolamide alone (P < 0.04)., Conclusion: The combination of dorzolamide and timolol demonstrated significant aqueous flow additivity and had greater IOP efficacy than the combination of dorzolamide and acetazolamide.

Purpose: To determine the ocular hypotensive mechanism underlying the additivity of latanoprost and pilocarpine., Methods: This randomized, double-masked study included 30 patients with ocular hypertension on no ocular medications for at least 3 weeks. On each of six visits to the clinic, measurements were taken of aqueous flow and outflow facility by fluorophotometry, intraocular pressure by tonometry, and episcleral venous pressure by venomanometry. Uveoscleral outflow was calculated. Clinic visits were scheduled on baseline day; on day 8 of four times daily pilocarpine (2%) to one eye and vehicle to the other; on day 8 of continued pilocarpine/vehicle treatment plus latanoprost (0.005%) once daily to both eyes; after a 3-week washout period; on day 8 of once-daily latanoprost to one eye and vehicle to the other; and on day 8 of continued latanoprost/vehicle treatment plus pilocarpine four times a day to both eyes. Drug-treated eyes were compared with contralateral vehicle-treated eyes and with baseline day by paired t tests. Combined pilocarpine and latanoprost-treated eyes were compared with individual drug-treated eyes and with baseline day using the Bonferroni test., Results: Compared with baseline, pilocarpine reduced intraocular pressure from 18.9 to 16.2 mm Hg (P =.001) and increased outflow facility from 0.18 to 0.23 microl per minute per mm Hg (P =.03). No other parameters were affected. Adding latanoprost further reduced intraocular pressure to 13.7 mm Hg (P <.001) and increased uveoscleral outflow from 0.82 to 1.36 microl per minute (P =.02). Latanoprost alone reduced intraocular pressure from 17.6 to 14.3 mm Hg (P <.0001) and increased uveoscleral outflow from 0.89 to 1.25 microl per minute (P =.05). Adding pilocarpine to the latanoprost treatment further reduced intraocular pressure to 12.7 mm Hg (P <.001) and increased outflow facility from 0.21 to 0.30 microl per minute per mm Hg (P =.03)., Conclusions: Latanoprost and pilocarpine predominantly increase uveoscleral outflow and outflow facility, respectively, when given alone. These drugs are additive because pilocarpine does not inhibit the uveoscleral outflow increase induced by latanoprost.

This study determines the effects of laser-induced glaucoma on aqueous humor dynamics of 18 cynomolgus monkeys. Baseline measurements of 12 monkeys included intraocular pressure (IOP) by pneumatonometry, aqueous flow by fluorophotometry and outflow facility by tonography. Beginning 4 to 14 days later, the trabecular meshwork of one eye was treated repeatedly with laser photocoagulation until elevated IOP was induced. Thirty-six to 75 days after the last laser treatment, all measurements were repeated. Between 1.7 and 11.4 years after laser treatment, the same 12 monkeys plus 6 additional monkeys underwent IOP and aqueous flow measurements. In addition, outflow facility was determined with fluorophotometry, and uveoscleral outflow was both calculated (n=18) and measured with an intracameral tracer (n=7). In glaucoma eyes compared to control eyes (n=12), IOP was increased (p<0.04) by at least 8 mmHg at Time 1 (1 to 3 months) or Time 2 (3 to 4 years) after laser treatment; aqueous flow was reduced (p=0.0007) by 46% at Time 1 but returned to baseline levels at Time 2; tonographic outflow facility was reduced (p=0.0008) by 71% at Time 1. In lasered eyes compared to control eyes, fluorophotometric outflow facility was reduced (p=0.0008; n=18) by 63%, and uveoscleral outflow was increased (p<0.05), whether calculated or measured with tracers at least 1 year after laser treatment. The increased IOP in monkeys with laser-induced glaucoma was caused by a sustained reduction in outflow facility. The uveoscleral outflow increase was not enough to prevent the rise in IOP.

This study was undertaken to develop a feline model of corticosteroid-induced ocular hypertension. In the first experiment, eight cats were selected whose intraocular pressure (17 +/- 0.4 mmHg) was consistently below the mean baseline intraocular pressure of our colony (24 +/- 0.5) during the preceding 2 months. Unilateral twice or thrice daily topical application of 10 microliters 1% dexamethasone sodium phosphate caused a gradual intraocular pressure increase that became significant (P less than 0.05) within 2-3 weeks. There was no significant change in body weight, but several eyes developed cataracts. Similar results were obtained with treatment of normotensive cat eyes with dexamethasone, or with 1.0% prednisolone acetate (PredForte) twice a day. Topical application of PGF2 alpha-1-isopropyl ester (0.1 or 0.25 microgram PG equivalent) to such steroid-treated eyes yielded significant intraocular pressure reduction and pupillary miosis, similar in magnitude to those exhibited by normal eyes. When dexamethasone treatment was reduced to once daily, after prolonged twice daily treatment, intraocular pressure decreased only slightly within 10 days. When dexamethasone treatment was stopped, intraocular pressure declined to normal levels within 6-7 days. These findings show that adult cat eyes develop steroid-induced ocular hypertension that is maintained and reversible. As opposed to previous findings on rabbits, steroid-induced feline ocular hypertension appears to be a good model for this clinical condition and may be suitable for the testing of potential glaucoma drugs.