Digoxin derivatives with selectivity for the α2ß3 isoform of Na,K-ATPase potently reduce intraocular pressure.

The ciliary epithelium in the eye consists of pigmented epithelial cells that express the α1ß1 isoform of Na,K-ATPase and nonpigmented epithelial cells that express mainly the α2ß3 isoform. In principle, a Na,K-ATPase inhibitor with selectivity for α2ß3 that penetrates the cornea could effectively reduce intraocular pressure, with minimal systemic or local toxicity. We have recently synthesized perhydro-1,4-oxazepine derivatives of digoxin by NaIO4 oxidation of the third digitoxose and reductive amination with various R-NH2 substituents and identified derivatives with significant selectivity for human α2ß1 over α1ß1 (up to 7.5-fold). When applied topically, the most α2-selective derivatives effectively prevented or reversed pharmacologically raised intraocular pressure in rabbits. A recent structure of Na,K-ATPase, with bound digoxin, shows the third digitoxose approaching one residue in the ß1 subunit, Gln84, suggesting a role for ß in digoxin binding. Gln84 in ß1 is replaced by Val88 in ß3. Assuming that alkyl substituents might interact with ß3Val88, we synthesized perhydro-1,4-oxazepine derivatives of digoxin with diverse alkyl substituents. The methylcyclopropyl and cyclobutyl derivatives are strongly selective for α2ß3 over α1ß1 (22-33-fold respectively), as determined either with purified human isoform proteins or intact bovine nonpigmented epithelium cells. When applied topically on rabbit eyes, these derivatives potently reduce both pharmacologically raised and basal intraocular pressure. The cyclobutyl derivative is more efficient than Latanoprost, the most widely used glaucoma drug. Thus, the conclusion is that α2ß3-selective digoxin derivatives effectively penetrate the cornea and inhibit the Na,K-ATPase, hence reducing aqueous humor production. The new digoxin derivatives may have potential for glaucoma drug therapy.

Association between tamsulosin and intraoperative "floppy-iris" syndrome.

Intraoperative "floppy-iris" syndrome is a novel entity that was initially described in 2005 by Chang and Campbell who encountered it during cataract surgery. The manifestations include a triad of the following intraoperative findings: (a) flaccid iris stroma leading to fluttering and bellowing of the iris, (b) prolapse of the iris through the surgical incisions, and (c) progressive pupil constriction. IFIS has been associated with increased surgical difficulty and, as a result, with increased morbidity including retinal detachment and loss of vision. Since the initial publication of IFIS in 2005, there have been several reports of a possible association between the use of tamsulosin for symptomatic prostate hyperplasia and IFIS. Consequently, in 2005 the U.S. Food and Drug Administration issued an alert recommending ophthalmic examination prior to treatment with tamsulosin. In this review we present evidence of the association between tamsulosin and IFIS. We conducted a Medline search using the key words tamsulosin or alpha-blockers and retrieved English written reports and data on the prevalence of treatment with alpha-blockers in general and specifically tamsulosin among patients undergoing cataract surgery, the prevalence of IFIS among treated versus non-treated patients, and the resulting surgical complications. Of the 19 publications on this topic only 7 were patient series providing data on IFIS and treatment with tamsulosin. The prevalence of men receiving tamsulosin for BPH among the patients operated for cataract was 1-3%, the occurrence of IFIS was reported in 2-3% of the patients, and 57-100% of the patients receiving tamsulosin had at least one manifestation of IFIS. The occurrence of IFIS among men receiving other alpha-blockers or in non-treated patients was rare. An association between preoperative treatment with tamsulosin and IFIS is probable. This observation warrants further research to establish causality. Meanwhile, it seems prudent to perform an ophthalmic examination prior to prescribing tamsulosin.