Eyedrops Containing SA9000 Prodrugs Result in Sustained Reductions in Intraocular Pressure in Rabbits

Abstract

Aim: Poor topical bioavailability and ocular irritation have impeded the development of the diuretic, ethacrynic acid (ECA) as a clinically useful ocular hypotensive for the treatment of glaucoma. Thus, the development of analogs and prodrugs of analogs with improved ocular penetration, potency, and tolerability is required. The aim of this work is to evaluate the corneal penetration and ocular distribution of SA9000, an ECA analog. Novel SA9000 prodrugs intended to further improve ocular pharmacodynamic effect were also evaluated. Results: SA9000 penetrated porcine corneas more effectively than ECA in corneal diffusion studies. In vivo studies in Dutch-belted (DB) rabbits indicated that topical application of a single dose (0.3%) of SA9000 could signifi cantly reduce intraocular pressure (IOP) (~25% vs. fellow untreated eye) but caused signifi cant conjunctival hyperemia. Since this hyperemia was likely the result of its inherent thiol reactivity, SA9000 was formulated with equimolar cysteine, an exogenous thiol donor. The administration of increasing SA9000-cysteine adduct concentrations (0.3%, 0.6%, 0.9%) demonstrated that they cause less ocular irritation than unadducted SA9000 but could still signifi cantly reduce IOP (0.3%: 8.7 ± 2%; 0.6%: 14.4 ± 5%; 0.9%: 23.3 ± 4.4%) versus untreated contralateral control eyes. Conclusions: These data suggest that novel thiol donor adduction can improve the ocular bioavailability and tolerability of SA9000. SA9000-cysteine prodrugs may represent a new option for the topical treatment of glaucoma.

In silico analysis of the molecular machinery underlying aqueous humor production: potential implications for glaucoma

“…Digoxin has antiarrhythmic effects via myocytes and some older literature sources describe the lowering effect of digoxin on the IOP in human [ 28 - 30 ] and cats [ 31 ], probably due to blocking of Na + /K + -ATPase in the CBE. Ethacrynic is a diuretic drug and multiple animal studies already showed the IOP lowering effect of intracameral or topical administered ethacrynic acid in the eye, probably through increased AH outflow, but possibly also by decreased AH production [ 32 - 39 ]. The major disadvantage of athacrynic acid is the risk for (severe) corneal edema.…”

Soaring Aspirations: Lessons From My Mentors and Colleagues

“…So, in 1993, I thought I had cured trabecular glaucoma!!!!! Unfortunately, the subsequent decade proved that ECA was very difficult to deliver topically into the eye and, despite many attempts 19,23,24 (still ongoing!) neither ECA nor its direct analogues have proven to be a suitable topical glaucoma drug.…”

The Use of Mucoadhesive Polymers to Enhance the Hypotensive Effect of a Melatonin Analogue, 5-MCA-NAT, in Rabbit Eyes

“…Other options to avoid multiple applications include the use of combinations of already commercialized hypotensive agents [17][18][19][20] or the search for novel active substances with high ocular hypotensive efficacy and low adverse effects on the eye. [21][22][23][24] In addition, several strategies have been developed to increase the bioavailability of topical antiglaucoma drugs by prolonging the contact time of the drug on the ocular surface. [25][26][27] Cellulose polymers are very popular and are used for artificial tear solutions and as enhancers of ophthalmic vehicles' viscosity, in a manner that reduces the drainage rate of the drug from the eye and subsequently improves the therapeutic efficacy.…”