Pharmacological testing in the laser-induced monkey glaucoma model

Lee, Ping-Yu; Podos, Steven M.; Howard-Williams, J.; Severin, C; Rose, Aron D.; Siegel, Marc J.

doi:10.3109/02713688509020033

Cited by 53 publications

(24 citation statements)

References 13 publications

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“…Various experi¬ mental drugs effectively reduce IOP in this model after single-dose admin¬ istration. 6 Multiple-dose administra¬ tion on a twice-daily basis of the investigational compounds PGF2a and vanadate have a persistent hypoten¬ sive effect on IOP. Forskolin, on the other hand, does not reduce IOP in this model after the second day of treatment, indicating rapid develop¬ ment of tolerance and/or tachyphy¬ laxis.…”

Section: Resultsmentioning

confidence: 99%

Intraocular Pressure Effects of Multiple Doses of Drugs Applied to Glaucomatous Monkey Eyes

Lee¹,

Podos²,

Serle³

et al. 1987

Archives of Ophthalmology

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Section: Resultsmentioning

confidence: 99%

Intraocular Pressure Effects of Multiple Doses of Drugs Applied to Glaucomatous Monkey Eyes

Lee¹,

Podos²,

Serle³

et al. 1987

Archives of Ophthalmology

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“…Ocular hypertension was produced by partial circumferential laser photocoagulation of the trabecular meshwork, which is recognized as a model for ocular hypertension and glaucoma (Gaasterland and Kupfer, 1974;Lee et al, 1985). In the glaucomatous monkey model the animals are rendered unilaterally hypertensive and consequently, there is no contralateral eye that can be used to assess procedural influences on intraocular pressure.…”

Section: Resultsmentioning

confidence: 99%

“…Intraocular pressure studies were conducted in female cynomolgus monkeys (2-4 kg). Studies were performed in bilaterally ocular normotensive monkeys and in animals rendered unilaterally ocular hypertensive by circumferential laser treatment (Gaasterland and Kupfer, 1974;Lee et al, 1985). Intraocular pressure studies were performed in conscious animals trained to accept pneumatonometry.…”

Section: ϫ5mentioning

confidence: 99%

Pharmacological Characterization of a Novel Antiglaucoma Agent, Bimatoprost (AGN 192024)

Woodward¹,

Krauss²,

Chen³

et al. 2003

J Pharmacol Exp Ther

141

143

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Replacement of the carboxylic acid group of prostaglandin (PG) F 2␣ with a nonacidic moiety, such as hydroxyl, methoxy, or amido, results in compounds with unique pharmacology. Bimatoprost (AGN 192024) is also a pharmacologically novel PGF 2␣ analog, where the carboxylic acid is replaced by a neutral ethylamide substituent. Bimatoprost potently contracted the feline lung parenchymal preparation (EC 50 value of 35-55 nM) but exhibited no meaningful activity in a variety of PG-sensitive tissue and cell preparations. Its activity seemed unrelated to FP receptor stimulation according to the following evidence. 1) Bimatoprost exhibited no meaningful activity in tissues and cells containing functional FP receptors. 2) Bimatoprost activity in the cat lung parenchyma is not species-specific because its potent activity in this preparation could not be reproduced in cells stably expressing the feline FP receptor. 3) Radioligand binding studies using feline and human recombinant FP receptors exhibited minimal competition versus [3 H]17-phenyl PGF 2a for Bimatoprost. 4) Bimatoprost pretreatment did not attenuate PGF 2␣ -induced Ca 2ϩ signals in Swiss 3T3 cells. 5) Regional differences were apparent for Bimatoprost but not FP agonist effects in the cat lung. Bimatoprost reduced intraocular pressure in ocular normotensive and hypertensive monkeys over a 0.001 to 0.1% dose range. A single-dose and multiple-dose ocular distribution/metabolism studies using [ 3 H]Bimatoprost (0.1%) were performed. Within the globe, bimatoprost concentrations were 10-to 100-fold higher in anterior segment tissues compared with the aqueous humor. Bimatoprost was overwhelmingly the predominant molecular species identified at all time points in ocular tissues, indicating that the intact molecule reduces intraocular pressure.Eicosanoids and related fatty acids have long been the subject of extensive investigation. More recently, it has become apparent that the corresponding neutral lipids exist for several fatty acids (Devane et al

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“…The intraocular pressure of the right eye of sedated cynomolgus monkeys was experimentally elevated by photocoagulating the trabecular meshwork with an argon laser (Coherent model 920) as described elsewhere (Lee et al, 1985). For measurements of intraocular pressure, the monkeys were kept in a sitting position in restraint chairs throughout the experiment.…”

Section: Methodsmentioning

confidence: 99%

“…The intraocular pressure of unilateral, ocular hypertensive, cynomolgus monkeys is decreased by the acute (Lee et al, 1985) and repeated instillation (Lee et al, 1987) of a range of clinically used ocular hypotensive agents. Moreover, the doses shown to be active are the same as those used to treat glaucoma patients.…”

Section: Intraocular Pressure Studiesmentioning

confidence: 99%

L‐662,583 is a topically effective ocular hypotensive carbonic anhydrase inhibitor in experimental animals

Sugrue

Gautheron²,

Mallorga

et al. 1990

British J Pharmacology

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1 L-662,583 was a potent inhibitor in vitro of purified, human erythrocyte carbonic anhydrase II, pos-sessing an IC50 of 0.7 nm. The IC50 values for MK-927, acetazolamide and methazolamide were 13.0 nm, 10.8 nm and 21.2 nm, respectively. 2 A 1 h pretreatment with one 50 u1 drop of a 0.1% solution of L-662,583 blocked carbonic anhydrase activity in a homogenate of the iris + ciliary body of albino rabbits by 63%. Similar treatment with 0.1% suspensions of acetazolamide and methazolamide elicited inhibitions of 30% and 20%, respectively. This ex vivo model indirectly assesses the ability of an agent to enter the rabbit eye. 3 Concentrations of L-662,583 in the cornea, aqueous humour and iris + ciliary body of albino rabbits were determined by h.p.l.c. at predetermined times after the instillation (one drop of 50pl) of a 2% solution of L-662,583. Peak levels for cornea (47.4pgg-1), aqueous humour (4.51 ygml-1) and iris + ciliary body (9.61 pgg 1-) occurred at 0.5, 2 and 1 h after instillation, respectively. 4 The experimentally elevated intraocular pressure of the right eye of rabbits, induced by prior intraocular injection of a-chymotrypsin, was maximally decreased by 4.5 mmHg, 6.2 mmHg and 9.8 mmHg after the instillation (one drop of 50pl) of 0.01%, 0.1% and 0.5% solutions of L-662,583, respectively. All three concentrations lowered intraocular pressure at all time points from 1 h up to and including 5 h, the last recorded time point. The unilateral instillation of L-662,583 (0.5%) into the contralateral, left eye failed to lower the elevated intraocular pressure of the untreated, right eye. This finding indicates that the site of action of topically applied L-662,583 in this paradigm is local. The ocular normotensive, albino rabbit was much less susceptible than the ocular hypertensive rabbit to the intraocular pressure lowering effect of topically applied L-662,583, with a 2% solution maximally decreasing intraocular pressure by 2.3 mmHg. 5 Unilateral ocular hypertension was elicited in the right eye of sedated, cynomolgus monkeys by argon laser-induced photocoagulation of the trabecular meshwork. The instillation (one drop of 50p1) of L-662, 583 (2%) significantly lowered the elevated intraocular pressure of the right eye at all time points from 1 h up to and including 5 h. The maximum decline was 8.3 mmHg at 3 h and this represented a reduction of 23% from the corresponding baseline value of 36.8 mmHg. The intraocular pressure of the hypertensive, right eye was maximally decreased by 4.1 mmHg and 4.8 mmHg after the instillation of 0.5% and 1% solutions of L-662,583, respectively. Like the rabbit, the normotensive eye of cynomolgus monkeys was more resistant than the hypertensive eye to the ocular hypotensive action of L-662, 583, as indicated by the inability of 0.5% and 1% solutions of the agent to lower intraocular pressure. L-662,583 (2%) maximally reduced the intraocular pressure of normotensive monkey eyes by 2.4 mmHg at 2 h. 6 L-662,583 is structurally different from MK-927, a carbonic anhydrase inhibit...

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Pharmacological testing in the laser-induced monkey glaucoma model

Cited by 53 publications

References 13 publications

Intraocular Pressure Effects of Multiple Doses of Drugs Applied to Glaucomatous Monkey Eyes

Intraocular Pressure Effects of Multiple Doses of Drugs Applied to Glaucomatous Monkey Eyes

Pharmacological Characterization of a Novel Antiglaucoma Agent, Bimatoprost (AGN 192024)

L‐662,583 is a topically effective ocular hypotensive carbonic anhydrase inhibitor in experimental animals

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