A closed chest catheter technique was used in dogs to examine the potential cardiac effects of alprenoxime, a potent new ocular antihypertensive agent. Alprenoxime was designed to undergo metabolic activation to the beta-blocker, alprenolol, specifically within the eye using hydrolase and reductase enzymes that reside in the iris-ciliary body. Previous studies in rabbits confirmed that intraocular pressure (IOP) significantly decreased after topically instilling ophthalmic drops of alprenoxime, while heart rates remained essentially unchanged after intravenous dosing. To further explore the safety and ocular specificity of this potential antiglaucoma drug, several cardiac electrophysiologic parameters were monitored during alprenoxime infusion in anesthetized dogs. In contrast to the pharmacologically significant increases (33-144%) measured after alprenolol or other previously tested beta antagonist infusion, the identical dose of alprenoxime had no effect on sinus cycle length (SCL), conduction times through the bundle of His and atrium (H and AH), or any other monitored cardiac electrophysiologic parameter. No changes greater than 6% from baseline were detected with alprenoxime infusion. Similarly, no beta-antagonist cardiac activity could be detected in isoproterenol stimulated dogs after alprenoxime. The results demonstrate that alprenoxime has no significant cardiac activity at doses much greater than potential therapeutic levels. The study provides further support that the new agent could be safely used in treating glaucoma.

01 Jan 1995·Journal of Ocular Pharmacology and TherapeuticsQ4 · MEDICINE

Sequential Bioactivation of Methoxime Analogs of β-Adrenergic Antagonists in the Eye

Q4 · MEDICINE

Article

Author: Whei-Mei Wu ; Nicholas Bodor ; Gabor Somogyi ; Laszlo Prokai ; Hassan Farag

Selected beta-adrenoreceptor antagonists are the antiglaucoma drugs of first choice in most cases. However, a number of significant central nervous system (CNS), cardiovascular and respiratory side-effects following topical ocular installation of beta-blockers have also been reported. Site- and stereo-specific delivery to the eye of beta-blockers was achieved by application of a sequential bioactivation of the chemical delivery system (CDS) analogs of these drugs, which are converted to the active beta-blockers only in the eye, thus systemic side effects are avoided. The corresponding ketoxime analogs of the various beta-blockers were successfully applied and one of them, Alprenoxime, was tested in humans. The main problem with these compounds, however, is formulation stability: Alprenoxime has a t90 of only 2-3 months. Thus, alternate structures were searched. Methoxime analogs of selected beta-blockers were synthesized and their chemical stability established at different pH's. Subsequently, their in vivo sequential enzymatic conversion was confirmed using HPLC. Comparative intraocular pressure (IOP) reducing activity of the methoximes were then studied using normotensive rabbits. The methoxime analogs showed significantly improved hydrolytic stability at pH approximately 7.0, the t90 is over 1 year. The in vivo sequential bioactivation, however, proceeds similarly to the oximes. The intermediate ketones and the active beta-blockers can be detected in the various eye compartments at different time intervals following topical administration of the methoximes. The mechanism of the eye-selective bioactivation and the results of the IOP reducing activity studies will be discussed.

01 Jan 1991·Pharmaceutical ResearchQ3 · MEDICINE

Improved delivery through biological membranes. LVI. Pharmacological evaluation of alprenoxime--a new potential antiglaucoma agent.

Q3 · MEDICINE

Article

Author: Nicholas Bodor ; Alaaeldin Elkoussi

A new site-specific chemical delivery system (CDS) for alprenolol was designed and investigated as a potential novel antiglaucoma agent. The effect of this compound, alprenoxime (AO), on the intraocular pressure (IOP) of rabbits was evaluated after its uni- and bilateral administration. AO produced significant reduction of the IOP starting at 30 min and lasting for more than 6 hr after its topical administration. Both in rats and in rabbits the i.v. bolus injection of AO (6 mg/kg) led to insignificant transient bradycardia, while no activity was found after oral or topical administration. Alprenolol (ALP) in a similar dose produced a sustained and significant bradycardia for more than 30 min. When the beta-adrenergic blocking activity was assessed against isoprenaline-tachycardia, the same results were obtained, i.e., AO led to a transient brief activity, whereas ALP produced a significant long-lasting beta blockade. These results support the potent ocular hypotensive action and the weak systemic beta-adrenergic blocking and cardiovascular activity of AO: a significant improvement in the therapeutic index. This finding recommends alprenoxime as a potent site-specific antiglaucoma agent with minimal systemic side effects.

100 Deals associated with Alprenoxime Hydrochloride

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Indication	Highest Phase	Country/Location	Organization	Date
Glaucoma	Phase 2	US	W World Corp.	-

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