DORZOLAMIDE HYDROCHLORIDE - A TOPICALLY ACTIVE, CARBONIC-ANHYDRASE INHIBITOR FOR THE TREATMENT OF GLAUCOMA

Dorzolamide hydrochloride is a water-soluble potent inhibitor of human carbonic anhydrase (CA) isoenzymes II and IV. In contrast to acetazol amide and methazolamide, it is a very weak inhibitor of human CA isoen zyme I. Dorzolamide has been observed to be a very good ocular penetra tor in rabbits following topical dosing. Dorzolamide, alone and in com bination with timolol, was very effective in lowering the intraocular pressure (IOP) of ocular hypertensive animals. This effect of the drug was due to a local action within the eye and was the result of reduce d aqueous humor inflow, Topically applied dorzolamide was well tolerat ed in long-term ocular irritation studies in several animal species an d no microscopic changes in ocular tissues were observed. Dorzolamide is metabolized in the liver by N-deethylation and N-deethyldorzolamide is an inhibitor of CA isoenzymes I, II and IV. Multiple dosing with 2 % dorzolamide resulted in the accumulation of parent drug and metaboli te in human red blood cells. However, the red blood cell content of CA was not saturated and approximately 20% of total CA activity in the r ed blood cell was retained. Furthermore, plasma levels of dorzolamide and N-deethyldorzolamide were lower than the detection limit of the as say (5 ng/ml). These findings are consistent with the inability to det ect biochemical changes indicative of the extraocular inhibition of CA in both plasma and urine of humans following the long-term administra tion of dorzolamide. Experiments have been undertaken in both healthy volunteers and normal-tension glaucoma patients to evaluate the effect of topically applied 2% dorzolamide on retinal blood flow velocity. S canning laser angiography was the technique employed. For the normal s ubjects, 2% dorzolamide hydrochloride ophthalmic solution was administ ered acutely after baseline readings were obtained. Two hours later, a second group of readings was made. Dorzolamide treatment decreased re tinal arteriovenous passage time by 19%, while placebo treatment had n o effect. Both macular capillary transit velocity and optic nerve head capillary transit velocity were also significantly accelerated by the drug. No drug-induced changes were observed in blood velocity in four retrobulbar vessels (nasal and temporal posterior ciliary, central re tinal and ophthalmic arteries), as assessed by color Doppler imaging. Treatment with dorzolamide significantly lowered IOP from 15.7 mmHg to 13.7 mmHg. a pilot study was undertaken in normal-tension glaucoma pa tients who had IOP values of <21 mmHg, glaucomatous optic disc appeara nce and/or visual field loss. Dorzolamide or placebo was administered t.i.d. for 4 weeks. Glaucoma patients demonstrated a significant decre ase of 14% in retinal arteriovenous passage time and their IOP was sig nificantly reduced from 15.8 mmHg to 13.7 mmHg following dosing with t he drug. Dorzolamide hydrochloride ophthalmic solution has been extens ively evaluated in clinical studies and has been found to be highly ef fective both as monotherapy and as adjunctive therapy to beta-blockers . When used as adjunctive therapy, 2.0% dorzolamide b.i.d. has demonst rated a similar IOP-lowering effect to that of 2.0% pilocarpine q.i.d. and approximately 1 mmHg less of an effect than 250 mg acetazolamide p.o. q.i.d. Adjunctive therapy with dorzolamide was greatly preferred by patients over adjunctive therapy with pilocarpine, and was better t olerated than adjunctive therapy with acetazolamide. No significant ch ange in corneal endothelial cell count or corneal thickness was seen a fter 1 year of treatment, thus demonstrating the corneal safety of dor zolamide. Finally, the safety profile of dorzolamide observed in clini cal trials has been supported by market experience in over 1 million p atients worldwide, confirming that dorzolamide is generally well toler ated.