Investigation of Drug Interactions among Ophthalmic Solutions for Treating Glaucoma and Establishment of Rational Choice on Pharmacotherapy for Cost-Minimization

Abstract

Latanoprost, a prostaglandin F2alpha analog (PG), has been shown to be an effective ocular hypotensive agent for treating glaucoma. Carbonic anhydrase (CA) inhibitors are also used to reduce ocular hypertension by decreasing aqueous humor secretion, and are given in combination with PG. Timolol malate has been shown to be an effective ocular hypotensive agent when used alone or with CA inhibitor on glaucoma patients. However, the effects of latanoprost and timolol malate on CA have not been clarified. Therefore, we studied the effects of latanoprost free acid and timolol hemihydrate on human CA (hCA)-I and hCA-II using stopped flow method. Latanoprost free acid inhibited the hydration activity of hCA-I or hCA-II by a noncompetitive mechanism. Timolol hemihydrate activates the enzyme activities of hCA-I and hCA-II. In hCA-I and hCA-II, the enzyme kinetic results clearly showed that timolol hemihydrate increases the value of Vmax but does not influence the value of Km. The noncompetitive inhibition mechanism and the binding mode of latanoprost free acid indicate that the behavior of latanoprost free acid is similar to that of simple anions. Timolol hemihydrate has a heterocyclic moiety and secondary amino group, which are typical structures in efficient activators of carbonic anhydrase. Moreover, we compared the cost of lowering intraocular pressure (IOP) by 1 mmHg in the treatment of glaucoma. Latanoprost is less expensive for lowering IOP by 1 mmHg than other products. These data should be helpful in selecting topical ophthalmic solutions from the viewpoint of cost-minimization.