Cellular cytotoxicity of antiglaucoma drugs in cultured corneal endothelial cells.

In this study, the various antiglaucoma drugs including betaxolol, timolol, levobunolol, carteolol, brimonidine, dipivefrin, dorzolamide, brinzolamide, latanoprost, unoprostone, and pilocarpine were used to investigate the effects of cellular cytotoxicity in cultured bovine corneal endothelial cells. After exposure to the drugs in three dilutions, 1/100, 1/1,000, and 1/10,000, for 100 minutes, cells were estimated based on the release assay of lactate dehydrogenase (LDH) enzyme. It was found that cellular LDH was significantly released in the medium only at 1/100th dilution of betaxolol, brimonidine, dorzolamide, dipivefrin, latanoprost and unoprostone to 130%, 123%, 145%, 157%, 128% and 237%, respectively, compared with controls upon exposure to drugs for 100 minutes. Moreover, benzalkonium chloride preservative at the concentrations ranging from 0.001 to 0.00001 mg/mL did not affect cellular LDH release in bovine corneal endothelial cells. These results indicate that high concentrations of antiglaucoma drugs may induce cytotoxicity in corneal endothelial cells.

A multiattribute-utility-function approach to weighing the risks and benefits of pharmaceutical agents.

Both the selection of doses of pharmaceutical agents and comparisons between pharmaceutical agents have long been based on the nonquantified concept of the risk-benefit ratio. Though useful, this concept implies a data comparison that is difficult to make: the toxicity versus the efficacy of a drug compound. This research demonstrates an approach for weighing risks and benefits by combining utility functions for human efficacy and toxicity with animal and laboratory toxicity information to develop an overall multiattribute utility function for an ophthalmic pharmaceutical agent, I-bunolol, intended for the treatment of glaucoma. With this multiattribute function and a small portion of the published data available for this drug, the expected utilities for six doses (including a control) could be compared and the value of this approach in drug-dosage selection demonstrated.

Chronic toxicity and carcinogenicity studies with the beta-adrenoceptor antagonist levobunolol.

The chronic toxicity and carcinogenicity of levobunolol, a nonselective beta-adrenoceptor antagonist, was evaluated in Swiss mice and Wistar rats. The drug was administered in the diet to mice at 0, 12, 50, and 200 mg/kg/day for 80 weeks and to rats at 0, 0.5, 2, 5, 30, and 180 mg/kg/day for 2 years. In mice, uterine leiomyomas were present in 4 of 50 females at 200 mg/kg but not in any other group. The incidences of other tumor types, as well as pathologic findings, were comparable among groups. In rats, significant body weight gain suppression occurred at 5, 30, and 180 mg/kg. Brown discoloration of perianal fur and steel-gray discoloration of hairless skin were evident in high-dose rats. A generalized steel-gray discoloration of internal organs and tissues occurred in the 30 and 180 mg/kg groups. No other differences between treated and control groups were evident. The clinical relevance of the increased incidence of uterine leiomyoma in mice is questionable because it occurred only in one species at more than 200 times the projected therapeutic dose.

Levobunolol for the long-term treatment of glaucoma.

Systemically, levobunolol is as effective as propranolol for cardiovascular indications, with a greater potency and greater duration of action. Ocularly, levobunolol is as effective and as safe as topical timolol for the long-term treatment of elevated IOP. The utility of topical levobunolol as an additional, effective beta-blocker for the treatment of glaucoma will be determined by additional research and use by ophthalmologists in countries where levobunolol is approved.