DEVELOPMENT OF D-TIMOLOL FOR THE TREATMENT OF GLAUCOMA AND OCULAR HYPERTENSION

It has been found that D-timolol is equipotent or slightly less potent than L-timolol to lower the intraocular pressure (IOP) in normotensive rabbits, water loaded ocular hypertensive rabbits, α-chymotrypsin induced glaucoma rabbits, hypertonic saline infused IOP recovery model of rabbits, normotensive human volunteers, glaucoma patients and ocular hypertensive human individuals. Although L-timolol has been used widely for the treatment of glaucoma and ocular hypertension, it produces numerous side effects including cardiovascular disturbances, asthmatic attack, psychological depression, etc. Since D-timolol has much weaker affinity toward β-adrenergic receptors, it was found to have 1/80-1/300 the β-adrenergic blocking potency of L-timolol to block β-adrenergic receptors in guinea pig tracheal preparations and 1/90 of L-timolol to block β-adrenergic receptors in guinea pig atrial preparations. As a result, D-timolol showed no subjective nor objective side effects on pupil size, conjunctiva, cornea, blood pressure and pulse rate. Further, D-timolol was reported to increase retinal and choroid blood flow in rabbits without affecting overall ocular blood flow. On the contrary, L-timolol was found to significantly reduce the overall ocular blood flow and retinal and choroid blood flows in rabbits, although it might slightly increase the retinal blood flow in normotensive individuals. D-Timolol was well absorbed across the cornea as L-timolol and produced the duration of action as long as L-timolol. These results indicate that D-timolol could be a better agent than L-timolol for the treatment of glaucoma and ocular hypertension. © 1990, Mary Ann Liebert, Inc. All rights reserved.