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M. Sharir; Succinimides as Topical Ocular Hypotensive Agents. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4811.
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To evaluate the anti-Petit Mal epilepsy succinimides as potential topical ocular hypotensive agnets. The hypothesis is that Absence epilepsy and glaucoma share similar pathophysiology, reflecting change in secretion and/or defective outflow facility (of CSF and aqueous humor, respectively). Succinimides modulate chloride secretion in the choroidal plexus, and thus will be able to exert their effect at the posterior chamber of the eye.
Ocular pharmacodynamic studies were conducted at the Tel-Aviv University animal facility. Six Dark Agauti (DA) pigmented rats (250-300g in weight) were slightly sedated with 1.5-2mg intraperitoneal xylazine. One eye was randomly selected to receive 50 microliters of gelatinous topical 250mg/0.2ml ethosuximide (Petnidan, Desitin, Germany), while the control-eye received a viscoelastic tear substitute (Viscotears, Novartis, Switzerland). At t=o and at 1/2, 1, 2, 4 and 6 hours post administration, intraocular pressure (IOP) was measured repeatedly by Tonopen XL tonometer (Medtronics, USA) and eyes assessed for local toxicity. In a second experiment, using the same protocol, the topical compund was tested on five awake albino rabbits (3 kg in weight). Results were recorded and analyzed, using two-tailed Student's t-test for paired data as well as analysis of variance.
In the DA rats the IOP showed a biphasic response, with an increase of 0.5 mmHg at 1/2 and 1 hour post instillation, followed by a significant 2.6 mmHg decrease in the treated eyes versus control (or 18% from baseline, p<0.005) at 2 hours. In the rabbits the effect was even more impressive, with a decrease of 4.8 mmHg (or 25%) vs. control at 4-5 hours (p<0.005). Two of the rat treated eyes, three of the rabbit treated eyes and one control eye showed mild conjunctival injection, which subsided an hour after the instillation of the drops.
Ethosuximide, an effective anti-epileptic medication, can be efficacious as a topical ocular hypotensive agent. The effect measured in the studies is comparable to that of beta-adrenoreceptor antagonists and prostaglandins. Ethosuximide's topical effect should be due to its low molecular weight and favorable physicochemical properties, being both lipid (alcohol or ether) and water soluble.
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