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Glaucoma A New Option for Glaucoma PatientsClinical trials have shown that Rescula is a safe and effective new drug for glaucoma patients.Peter Netland, MD, PhD
 The product has been in clinical use since 1994 in Japan, as well as
Latin America and South America. In the United States and Europe, late-phase
randomized clinical trials in patients with primary open-angle glaucoma and
ocular hypertension show the drug to be safe and effective, both as monotherapy
and adjunctive therapy. This article will review how Rescula works, its performance in preclinical and clinical trials and how you can best incorporate the drug into your prescribing regimen for glaucoma patients. Pharmacology and Mechanism of Action As a member of the newly discovered family of metabolites known as docosanoids, unoprostone isopropyl has a unique molecular structure that gives it desirable pharmacologic properties (See Figure 1). It does not cause the smooth muscle contraction typical of primary prostaglandins. Nor does it demonstrate effects on the cardiovascular, central nervous, digestive, respiratory or hematologic systems, or on the metabolism or body temperature.5 It has no affinity for prostaglandin receptors, including the FP and EP receptors antagonized by latanoprost, nor for the other receptors traditionally involved in the pharmacologic treatment of glaucoma, including the alpha and beta adrenergic receptors (brimonidine and timolol, respectively) and muscarinic receptors (pilocarpine).6 The drug does not affect aqueous humor production7 and appears to lower IOP by increasing aqueous humor outflow as a result of an increase in conventional trabecular outflow, uveoscleral outflow or both.8-10 Unoprostone isopropyl has a constant diurnal effect that mimics the natural circadian rhythm of the IOP.3,11 In preclinical and clinical studies, unoprostone isopropyl improved ocular blood flow.12-15 It dilated in vitro pig retinal arteries that had been preconstricted with endothelin (ET)-1.6 It abolished ET-1-induced vasoconstriction in bovine trabecular meshwork and ciliary muscle strips.6 In the choroidal vessels of monkeys in vivo, a single instillation abolished the ET-1-induced decrease in choroidal blood flow.15 There is evidence that topical administration of the drug improves blood flow to the optic nerve in humans.12 Animal studies also demonstrate evidence of a neuroprotective effect. For example, a single intraperitoneal dose of unoprostone isopropyl improved retinal ganglion cell survival in rats after ischemia was induced by ligation of the ophthalmic vessels.16 Together these findings support the potential for unoprostone isopropyl to improve ocular blood flow and promote neuronal survival in the retina, thereby protecting against visual field loss from ischemic damage. Efficacy and Safety of Monotherapy Several studies have evaluated the efficacy and safety of unoprostone isopropyl1-3 (See Figure 2). In addition, a recent Phase III U.S. study compared the IOP-lowering effects of unoprostone isopropyl (0.15%, instilled b.i.d.) and timolol maleate (0.5% b.i.d.) as monotherapies for 12 months.6 While timolol maleate was more effective in reducing IOP, unoprostone isopropyl lowered IOP in a clinically and statistically significant manner, with reductions from 12-15 percent, and was considered safe in terms of ocular and systemic adverse effects. Another recent Phase III study in Europe compared unoprostone, timolol maleate and betaxolol as monotherapies for 12 months.6 Unoprostone isopropyl (0.15% b.i.d.) was as effective as betaxolol (0.5% b.i.d.) in terms of IOP reduction, but it was not equivalent to timolol (0.5% b.i.d.). Again, the local and systemic safety profiles of unoprostone isopropyl were favorable. There were no reported cases of uveitis, iritis, cystoid macular edema (CME), eyelash changes or endothelial cell toxicity. A change in iris pigmentation occurred in one case after nine months of therapy. Other recent trials have further documented the absence of beta-blocking effects with unoprostone isopropyl as monotherapy. An exercise study compared the effects of chronic unoprostone isopropyl (0.15%), timolol maleate (0.5%) and placebo on heart rates in healthy patients.6 After 15 minutes of exercise, changes in heart rate were the same with unoprostone isopropyl and placebo, whereas timolol demonstrated a beta-blockade effect by significantly slowing the heart rate. A study assessing the effect of a single 0.15% instillation of unoprostone isopropyl on pulmonary function in patients with stable-to-moderate asthma found similar effects in unoprostone isopropyl and a placebo, suggesting that unoprostone isopropyl is safe to use in patients for whom beta-blockers are contraindicated. Efficacy and Safety of Adjunctive Therapy Studies in Japan have documented the effectiveness of unoprostone isopropyl as adjunctive therapy in the treatment of patients with glaucoma, resulting in additional decreases in IOP.4,17-18 A recent additivity study in Europe evaluated the safety and efficacy of unoprostone isopropyl (0.15% b.i.d.) as an adjunct to timolol maleate (0.5% b.i.d.).6 Patients with glaucoma (IOP = 22 mgHg on beta-blocker therapy) or ocular hypertension were randomized to this combination or to dorzolamide plus timolol maleate or brimonidine plus timolol maleate. Mean changes in diurnal IOP from baseline to week 12 showed that the effectiveness of unoprostone isopropyl plus timolol did not differ statistically from that of the other combinations. However, systemic side effects were reported more often with the other combinations. In an additivity study in the United States, patients received adjunctive therapy with placebo or unoprostone isopropyl (0.12% b.i.d.) if latanoprost alone (0.005% qpm) had inadequately lowered IOP.6 The addition of unoprostone isopropyl resulted in further IOP reductions at trough and in diurnal pressure. The combination was safe, with no associated uveitis or CME and no increase in hyperemia over latanoprost alone. Prescribing Information Unoprostone isopropyl 0.15% (1.5 mg/mL) is a clear, isotonic, buffered, preserved colorless solution. It is packaged as 5 mL solution in a 7.5 mL natural polypropylene bottle with a dropper tip and a turquoise closure with a white, tamper-evident overcap. It does not require refrigeration, and it should be stored between 2°-25° C (36°-77° F). The recommended dosing is one drop (0.15%) in the affected eye(s) twice daily. Unoprostone isopropyl may be used in conjunction with other topical ophthalmic drugs to lower IOP; if two agents are used, they should be administered at least five minutes apart. There are 251 drops per bottle. The approximate cost per day (b.i.d) is $0.75, and the cost per 90-day therapy is $67.50. Unoprostone isopropyl has been found effective as monotherapy for patients with mild to moderate elevations of IOP, and it has been a successful adjunct to other therapeutic regimens for glaucoma. It exhibits excellent safety both locally and systemically. It has a continuous diurnal effect for constant IOP control. In addition, it has the potential to enhance ocular blood flow and provide neuroprotection. Dr. Netland is the director of the Glaucoma Service at the University of Tennessee, Memphis, Department of Ophthalmology. Contact him at 956 Court Avenue, Memphis, TN 38163. Tel: (901) 448-5833. He has no proprietary interest in the product described.
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