title: Preclinical overview of brinzolamide.
abstract: The development of topically active carbonic anhydrase inhibitors (CAIs) is a significant recent achievement in glaucoma medical treatment. Brinzolamide, the newest topical CAI, exhibits selectivity, high affinity, and potent inhibitory activity for the carbonic anhydrase type II isozyme (CA-II), which is involved in aqueous humor secretion. These characteristics, along with good ocular bioavailability, make brinzolamide maximally effective in lowering intraocular pressure (IOP) by locally inhibiting CA-II in the ciliary processes and suppressing aqueous humor secretion. Notable among its attributes as a safe and efficacious glaucoma drug is brinzolamide's superior ocular comfort profile because of its optimized suspension formulation at physiologic pH. The degree of tolerability in the eye is considered an important determinant of a patient's willingness to comply with the dosing regimen for a long-term glaucoma medication. Results from the preclinical pharmacologic evaluation of brinzolamide indicated that it acts specifically to inhibit CA without significant other pharmacologic actions that could introduce undesired side effects. Moreover, the typical side effects associated with systemically administered CAIs are expected to occur at a lower incidence or not occur at all with brinzolamide, as its therapeutic dose and low systemic absorption do not produce a problematic level of systemic CA inhibition. Brinzolamide's long tissue half-life in the eye, particularly in the iris-ciliary body, favors a prolonged duration of IOP lowering. This was substantiated in clinical trials, which showed that twice-daily brinzolamide provides as significant an IOP reduction as three-times-daily brinzolamide or dorzolamide in a relatively high percentage of patients. Brinzolamide has been shown by the laser Doppler flowmetry technique to improve blood flow to the optic nerve head in pigmented rabbits after topical administration, without producing an increase of blood pCO2, indicating a potential for a local vasodilatory effect involving the optic nerve head circulation. The mean concentration of brinzolamide found in the retina of pigmented rabbits (0.338 microg equivalents/g) after a single dose of 14C-brinzolamide is sufficient to inhibit CA-II. These data suggest that topical brinzolamide could improve the blood flow in the optic nerve head in humans should it inhibit carbonic anhydrase in that vascular bed. Brinzolamide is a new topically active CAI that is safe and efficacious for reducing intraocular pressure. It offers the convenience of topical dose administration and greater freedom from side effects related to the inhibition of CA seen with the systemic administration of CAIs. Its formulation has been optimized to provide greater comfort upon instillation, and this can result in a higher compliance rate by the patient. Results of studies in animals show that brinzolamide has promise for increasing blood flow to the optic nerve head; however, this requires further assessment in the clinic. Brinzolamide represents a significant technical achievement and an important addition to the medical treatment of glaucoma as both a primary and an adjunctive drug.
authors.affiliation: Alcon Research, Ltd., Fort Worth, Texas 76134, USA.
authors.forename: L
authors.initials: L
authors.lastname: DeSantis
mesh_terms: D000042:Absorption; D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D002257:Carbonic Anhydrase Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D005123:Eye / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D007429:Intraocular Pressure / Q000187:drug effects; D009883:Ophthalmic Solutions / Q000493:pharmacokinetics / Q000494:pharmacology; D011817:Rabbits; D013449:Sulfonamides / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D013843:Thiazines / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D014018:Tissue Distribution
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D009883:Ophthalmic Solutions; D013449:Sulfonamides; D013843:Thiazines; C111827:brinzolamide