Patent Update: Antibacterial Patents Appearing in the Third Quarter of 1991

The sulfonamides constitute an important class of drugs, with several types of clinically used agents, possessing antibacterial, anticarbonic anhydrase (CA), diuretic, hypoglycaemic, anti-thyroid, protease inhibitory, anticancer and cyclooxygenase (COX) inhibitory activities, among others. A recently developed class of such pharmacological agents, incorporating primary sulfamoyl moieties in their molecule, is constituted by the COX-2 selective inhibitors, with at least two clinically used drugs, celecoxib and valdecoxib, discovered by Pharmacia Corp. It was recently shown that the sulfonamide COX-2-selective inhibitors (but not the methylsulfone ones, such as rofecoxib developed by Merck and Co.) also act as nanomolar inhibitors of CAs, some of which are strongly involved in tumorigenesis. In consequence, the potent anticancer effects of the sulfonamide COX-2-selective inhibitors and the much weaker effects of rofecoxib, reported ultimately by many researchers, may be explained by the contribution of CA inhibition to such processes in addition to COX-2 inhibition. In these two patents, Pharmacia Corp. claim the use of their sulfonamide COX-2 inhibitory compounds (celecoxib, valdecoxib and their many congeners), alone or in combination with classical sulfonamide CA inhibitors (acetazolamide, methazolamide, dichlorophenamide, dorzolamide, brinzolamide and their congeners, as well as structurally-related derivatives) for the treatment of CA-mediated disorders, including glaucoma and neoplasia. The patents do not contain any experimental evidence for the potential use of such compounds/combinations for the management of these pathologies, but are based on literature data from other laboratories.     

Fixed topical combinations in glaucomatous patients and ocular discomfort

Objective: The purpose of this study was to verify the ocular comfort of a fixed topical combination of brinzolamide 1% plus timolol 0.5% suspension vs. dorzolamide 2% plus timolol 0.5% solution, both preserved with benzalkonium chloride (BAK), in patients with primary open-angle glaucoma (POAG) through subjective and objective methods. BAK is the most commonly used preservative in topical glaucoma medications.

Methods: 62 subjects were examined and included in the analysis. Each patient was asked to complete a questionnaire on symptoms (Ocular Surface Disease Index) and then underwent a series of examinations. The Ocular Protection Index evaluated the risk of damage to the ocular surface, and was expressed as the ratio between fluorescein breakup time and blinking interval. These and other analyses were repeated 30 days after instillation of the new eye drop treatment.

Results: The results demonstrated that patients enrolled with the preserved fixed combination of dorzolamide or brinzolamide represented a subgroup of patients in which the discomfort symptoms were supposedly justified by the presence of BAK used chronically in antihypertensive drops. Ocular discomfort scores were significantly higher with dorzolamide/timolol than brinzolamide/timolol (p < 0.0001).

Conclusions: This work shows the better tolerability of brinzolamide 1% plus timolol 0.5% suspension, compared with dorzolamide 2% plus timolol 0.5% solution. Fortunately, some of the adverse reactions induced by preserved eye drop glaucoma medication are reversible after removing the preservatives. Both the potential for added benefit and patient compliance should be considered when selecting ocular hypotensive therapy.     

Comparison of brimonidine-timolol and dorzolamide-timolol in the management of intraocular pressure increase after phacoemulsification

AIM: To compare the effectiveness of brimonidine/timolol fixed combination (BTFC) and dorzolamide/timolol fixed combination (DTFC) in the management of short-term intraocular pressure (IOP) increase after phacoemulsi?cation surgery.METHODS: Eighty eyes of 80 patients undergoing phacoemulsi?cation and intraocular lens (IOL) implantation were randomly assigned into three groups. Group 1 consisted of 28 eyes and represented the control group. Group 2 consisted of 25 eyes undergoing phacoemulsi?cation surgery and BTFC was instilled at the end of surgery. Group 3 consisted of 27 eyes undergoing phacoemulsi?cation surgery and DTFC was instilled at the end of surgery. IOP was measured preoperatively and 6, 24h and 1wk postoperatively.RESULTS: There was no statistically signi?cant difference in preoperative baseline IOP among the three groups (P=0.84). However, IOP was significantly lower in groups 2 and 3 compared to the control group (P<0.05 for all comparisons) at all postoperative visits. There was no significant difference between groups 2 and 3 at any visit. Eight eyes (28.6%) in the control group, two (8%) in Group 2 and one (3.7%) in Group 3 had IOP >25 mm Hg at 6h after surgery (P=0.008). However, IOP decreased and was >25 mm Hg in only one eye in each group at 24h after surgery.CONCLUSION: BTFC and DTFC have similar effects in reducing increases in IOP after phacoemulsification surgery and can both be recommended for preventing IOP spikes after such surgery.     

Comparison of the safety and efficacy of the fixed combination of dorzolamide/timolol and the concomitant administration of dorzolamide and timolol: a clinical equivalence study

AIMS—To compare the tolerability and efficacy of a fixed combination solution of dorzolamide/timolol (Cosopt), administered twice daily with the concomitant administration of its components, dorzolamide (Trusopt) twice daily and timolol (Timoptic) twice daily.
METHODS—After a 2 week timolol run in, patients with open angle glaucoma or ocular hypertension were randomised (1:1) to receive treatment with either the dorzolamide/timolol combination solution twice daily (combination) or the dorzolamide solution twice daily plus timolol maleate solution twice daily (concomitant) for 3 months.
RESULTS—299 patients were entered and 290 patients completed the study. Compared with the timolol baseline, additional IOP lowering of 16% was observed at trough (hour 0) and 22% at peak (hour 2) at month 3 in both the concomitant and combination groups. The IOP lowering effects of the two treatment groups were clinically and statistically equivalent as demonstrated by the extremely small point differences (concomitant − combination) observed in this study−0.01 mm Hg at trough and 0.08 mm Hg at peak. The safety variables of the concomitant and combination groups were very similar. Both combination and concomitant therapy were well tolerated and few patients discontinued due to adverse effects.
CONCLUSIONS—The dorzolamide/timolol combination solution administered twice daily is equivalent in efficacy and has a similar safety profile to the concomitant administration of the components administered twice daily.

Keywords: dorzolamide; timolol; intraocular pressure; glaucoma; ocular hypertension