dorzolamide and brinzolamide

Carbonic anhydrase (CA, EC 4.2.1.1) is an enzyme and a very omnipresent zinc metalloenzyme which catalyzed the reversible hydration and dehydration of carbon dioxide and bicarbonate; a reaction which plays a crucial role in many physiological and pathological processes. Carbonic anhydrase is present in human (h) with sixteen different isoforms ranging from hCA I-hCA XV. All these isoforms are widely distributed in different tissues/organs and are associated with a range of pivotal physiological activities. Due to their involvement in various physiological roles, inhibitors of different human isoforms of carbonic anhydrase have found clinical applications for the treatment of various diseases including glaucoma, retinopathy, hemolytic anemia, epilepsy, obesity, and cancer. However, clinically used inhibitors of CA (acetazolamide, brinzolamide, dorzolamide, etc.) are not selective causing the undesirable side effects. One of the major hurdles in the design and development of carbonic anhydrase inhibitors is the lack of balanced isoform selectivity which thrived to new chemotypes. In this review, we have compiled the recent strategies of various researchers related to the development of carbonic anhydrase inhibitors belonging to different structural classes like pyrimidine, pyrazoline, selenourea, isatin, indole, etc. This review also summarizes the structure-activity relationships, analysis of isoform selectivity including mechanistic and in silico studies to afford ideas and to provide focused direction for the design and development of novel isoform-selective carbonic anhydrase inhibitors with therapeutic implications.

Topics: Acetazolamide; Animals; Antineoplastic Agents; Antioxidants; Benzenesulfonamides; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Humans; Indoles; Isatin; Molecular Docking Simulation; Organoselenium Compounds; Oxadiazoles; Protein Binding; Protein Isoforms; Pyrimidines; Structure-Activity Relationship; Sulfonamides; Thiazines; Thiophenes; Urea

Carbonic anhydrase inhibitors (CAIs) of the sulfonamide and sulfamate type are clinically used drugs as diuretics, antiglaucoma, antiepileptic, antiobesity and anti-high altitude disease agents. Anticancer agents based on CAIs are also in clinical development for the management of hypoxic, metastatic tumors. Acetazolamide, methazolamide, dichlorophenamide, dorzolamide and brinzolamide are mainly used as antiglaucoma drugs, sulthiame, topiramate and zonisamide as antiepileptic/antiobesity agents, celecoxib and polmacoxib are dual carbonic anhydrase/cycloxygenase inhibitors. Girentuximab, a monoclonal antibody and SLC-0111, a sulfonamide inhibitor, are in clinical trials as anticancer agents.. The drug interactions with many classes of pharmacological agents are reviewed. Some of these drugs, such as acetazolamide, topiramate and celecoxib show a large number of interactions with non-steroidal anti-inflammatory drugs (NSAIDs), diuretics, antiepileptics, immunosupressants, anticholinesterase drugs, β-blockers, anesthetics, oral contraceptives, anticancer agents, antifungals, anti-mycobacterials, lithium, metformin and clopidogrel.. The multiple drug interactions in which CAIs are involved should be carefully considered when such drugs are used in combination with the drug classes mentioned above, as the risks of developing toxicity and serious side effects if the dosages are not adjusted are high. There are also synergistic effects between CAIs and some NSAIDs, anticancer agents and benzodiazepines for the management of cystoid macular edema, some tumor types and neuropathic pain, respectively.

Topics: Acetazolamide; Anti-Inflammatory Agents, Non-Steroidal; Anti-Obesity Agents; Antibodies, Monoclonal; Anticonvulsants; Antineoplastic Agents; Benzodiazepines; Carbonic Anhydrase Inhibitors; Celecoxib; Clinical Trials as Topic; Contraindications; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Fructose; Humans; Isoxazoles; Methazolamide; Phenobarbital; Sulfanilamide; Sulfanilamides; Sulfonamides; Sulfonic Acids; Thiazines; Thiophenes; Topiramate; Zonisamide

Since their introduction the local carbonic anhydrase inhibitors (CAH) dorzolamide and brinzolamide have become well established in the drug therapy of glaucoma. They lower intraocular pressure (IOP) by blocking specifically carbonic anhydrase in the ciliary epithelium and thereby the secretion of aqueous humor. The IOP lowering effect is comparable with that of beta-blockers, but less than that of prostaglandin agonists. Because of their specific mode of action they produce an additive pressure lowering effect with any other glaucoma drug. Therefore they are ideal for being combined with other drugs. In addition, CAH may improve perfusion of the posterior eye. Preliminary results in glaucoma patients under dorzolamide therapy suggesting a reduction in the risk of progression due to enhanced blood flow need further confirmation.

Topics: Animals; Antihypertensive Agents; Aqueous Humor; Carbonic Anhydrase Inhibitors; Ciliary Body; Drug Combinations; Glaucoma; Humans; Intraocular Pressure; Ophthalmic Solutions; Retinal Vessels; Sulfonamides; Thiazines; Thiophenes

To evaluate the efficacy of α2-adrenergic agonist (AA) brimonidine and topical carbonic anhydrase inhibitors (CAIs) dorzolamide and brinzolamide in reducing intraocular pressure (IOP) when used as adjunctive therapy to β-blockers (BBs) or prostaglandin analogs (PGAs).. Pertinent publications were identified through systematic searches of PubMed, EMBASE, and the Cochrane Controlled Trials Register. Randomized controlled trials comparing AA with CAIs in patients with primary open-angle glaucoma (POAG) or ocular hypertension (OHT) who had inadequate IOP control with monotherapy of a BB or PGA. The weighted mean differences (WMD) of IOP-lowering efficacy were calculated by performing meta-analysis.. The main efficacy measures were the reduction from baseline to end of treatment in IOP at peak, trough, and diurnal curve.. Eleven published randomized clinical trials involving 1493 patients were included in the meta-analysis. As adjunctive therapy, the IOP reduction was greater in the brimonidine group than in the CAI group at peak (WMD: 0.99 mmHg [95% confidence interval, 0.45 to 1.53]) and diurnal curve (WMD: 0.62 mmHg [0.07 to 1.18]). As adjunctive therapy to BBs, brimonidine was more effective than CAIs in reducing IOP at peak (WMD: 0.85 mmHg [0.42 to 1.29]) and trough (WMD: 0.47 mmHg [0.12 to 0.83]). As adjunctive therapy to PGAs, brimonidine resulted greater reduction in peak IOP than CAIs (WMD: 1.04 mmHg [0.08 to 2.00]).. Brimonidine provides greater IOP-lowering efficacy than topical carbonic anhydrase inhibitors as adjunctive therapy to BBs or PGAs.

Topics: Adrenergic alpha-2 Receptor Agonists; Carbonic Anhydrase Inhibitors; Databases, Factual; Female; Humans; Intraocular Pressure; Male; Randomized Controlled Trials as Topic; Sulfonamides; Thiazines; Thiophenes

Dorzolamide and brinzolamide are topical carbonic anhydrase inhibitors (CAI) indicated for patients with glaucoma and ocular hypertension.. An evidence-based review of clinical trials of dorzolamide and brinzolamide was undertaken to determine an effect of these medications on visual function (primarily visual field) in open-angle glaucoma and ocular hypertension. Using the keywords 'dorzolamide' and 'brinzolamide', all articles describing trials of these medications reporting on visual acuity, contrast sensitivity and visual field from September 1966 to July 2009 were found in MEDLINE and EMBASE databases. No information from other sources was included in this review.. A relatively modest number of trials was identified, where impact of therapy on one or more of the visual function modes was reported. In the studies of less than 1 year duration (3 days to 1 year, 23 studies) in all but three studies treatment with topical CAIs did not influence visual function, in two studies with dorzolamide some improvement in the contrast sensitivity was observed and in one open-label retrospective no-control-group study with dorzolamide visual field indices improved significantly. A different picture was seen in long-term studies, which were designed and powered to detect changes in visual field. One large study (European Glaucoma Prevention Study) with dorzolamide versus placebo failed to detect significant protective effect of the drug on glaucoma occurrence in ocular hypertensives. Several interesting aspects of this study are discussed in detail. The other two long-term studies reported on the superiority of adding dorzolamide over timolol therapy alone, and the superiority of the combination of dorzolamide and timolol over brinzolamide and timolol in terms of improving ocular blood flow (retrobulbar Color Doppler Imaging--CDI parameters) as well as in terms of visual field preservation in glaucoma patients over 4 to 5 years.. For the first time one study could demonstrate that an improvement in ocular blood flow in the long run results in preservation of visual field in glaucoma patients. Dorzolamide, combined with the beta-blocker timolol, seems to be superior in this regard to brinzolamide plus timolol.

Topics: Administration, Topical; Carbonic Anhydrase Inhibitors; Glaucoma; Humans; Ocular Hypertension; Sulfonamides; Thiazines; Thiophenes; Visual Fields

To evaluate the intraocular pressure (IOP) reduction achieved by the most frequently prescribed antiglaucoma drugs in patients with normal tension glaucoma (NTG).. Systematic review and meta-analysis.. Fifteen randomized clinical trials reported 25 arms for peak IOP reduction, 16 arms for trough IOP reduction, and 13 arms for diurnal curve IOP reduction.. Pertinent publications were identified through systematic searches of PubMed, EMBASE, and the Cochrane Controlled Trials Register. The patients had to be diagnosed as having NTG. Methodological quality was assessed by the Delphi list on a scale from 0 to 18. The pooled 1-month IOP-lowering effects were calculated using the 2-step DerSimonian and Laird estimate method of the random effects model.. Absolute and relative reductions in IOP from baseline for peak and trough moments.. Quality scores of included studies were generally high, with a mean quality score of 12.7 (range, 9-16). Relative IOP reductions were peak, 15% (12%-18%), and trough, 18% (8%-27%) for timolol; peak, 14% (8%-19%), and trough, 12% (-7% to 31%) for dorzolamide; peak, 24% (17%-31%), and trough, 11% (7%-14%) for brimonidine; peak, 20% (17%-24%), and trough, 20% (18%-23%) for latanoprost; peak, 21% (16%-25%), and trough, 18% (14%-22%) for bimatoprost. The differences in absolute IOP reductions between prostaglandin analogues and timolol varied from 0.9 to 1.0 mmHg at peak and -0.1 to 0.2 mmHg at trough.. Latanoprost, bimatoprost, and timolol are the most effective IOP-lowering agents in patients with NTG.

Topics: Aged; Amides; Antihypertensive Agents; Betaxolol; Bimatoprost; Brimonidine Tartrate; Cloprostenol; Female; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Latanoprost; Male; Middle Aged; Prostaglandins F, Synthetic; Quinoxalines; Randomized Controlled Trials as Topic; Sulfonamides; Thiazines; Thiophenes; Timolol; Tonometry, Ocular; Travoprost

To evaluate the intraocular pressure (IOP)-lowering effects of adjunctive medications when added to 0.005% latanoprost taken once daily.. Pertinent publications were identified through systematic searches of PubMed, Embase, and the Cochrane Controlled Trials Register. Randomized clinical trials with over 85% of patients presenting with primary open-angle glaucoma or ocular hypertension who were treated with the combination treatment of latanoprost were selected. The pooled additional IOP-lowering effects at 1-3 months after a run-in phase of at least 2 weeks on 0.005% latanoprost once daily were calculated using the random effects model.. Nine randomized clinical trials were included. The mean pooled IOP reductions were 3.3 mm Hg (95% CI: 2.1-4.5) at trough and 4.4 mm Hg (95% CI: 3.4-5.4) at peak when adding 0.5% timolol once daily, 2.6 mm Hg (95% CI: 1.9-3.3) at trough and 3.8 mm Hg (95% CI: 2.5-5.2) at peak when adding 0.1/0.15% brimonidine twice daily, 2.6 mm Hg (95% CI: 1.7-3.4) at trough and 3.1 mm Hg (95% CI: 2.6-3.6) at peak when adding 2% dorzolamide twice daily, 2.4 mm Hg (95% CI: 2.0 -2.8) at trough and 2.7 mm Hg (95% CI: 2.2-3.2) at peak when adding 0.5% timolol twice daily, and 2.8 mm Hg (95% CI: 1.5-4.1) at trough and 1.8 mm Hg (95% CI: 1.2-2.3) at peak when adding 1% brinzolamide twice daily.. The addition of brimonidine, dorzolamide, timolol, or brinzolamide can further lower IOP in eyes being treated with latanoprost. Timolol 0.5% once daily might be the most effective adjunctive medication.

Topics: Aged; Antihypertensive Agents; Brimonidine Tartrate; Databases, Factual; Drug Therapy, Combination; Female; Glaucoma; Humans; Intraocular Pressure; Latanoprost; Male; Middle Aged; Optic Nerve Diseases; Prostaglandins F, Synthetic; Quinoxalines; Sulfonamides; Thiazines; Thiophenes; Timolol

Significant advances have recently been achieved in the development of topical glaucoma medications. The primary advantage of a topical preparation is the reduced incidence of adverse systemic effects attributable to a given drug compared to its systemically administered counterpart. However, the strong protective barrier of the eye forces topical ophthalmic preparations to be highly concentrated and in some cases, they have the potential to produce unwanted systemic effects, particularly in smaller animals. Oral carbonic anhydrase inhibitors are commonly associated with adverse effects in both humans and animals. Two recently developed topical carbonic anhydrase inhibitors, dorzolamide and brinzolamide, have shown promise in reducing intraocular pressure in animals and systemic side effects are apparently limited with their use. The topical alpha2-agonist apraclonidine, on the other hand, effectively reduces intraocular pressure in cats and dogs, but in its currently available form is likely to induce unwanted systemic effects. Latanoprost is a topical prostaglandin F2alpha analog that has proven effective in reducing intraocular pressure in dogs and horses, but while systemic side effects have not yet been reported, this topical preparation may exacerbate pre-existing or concurrent ocular inflammatory disease.

Topics: Administration, Topical; Animals; Cat Diseases; Cats; Clonidine; Dog Diseases; Dogs; Glaucoma; Humans; Latanoprost; Ophthalmic Solutions; Prostaglandins F, Synthetic; Sulfonamides; Thiazines; Thiophenes

Topical carbonic anhydrase inhibitors are a novel addition to the armamentarium of medical glaucoma treatment; dorzolamide has been available since 1995 and brinzolamide since 1998. They lower intraocular pressure by inhibiting carbonic anhydrase, a key enzyme for aqueous humor formation. Intraocular pressure-lowering activity of the substances appears to be the same and is similar to that of most other agents, but it does not reach the activity of the unselective beta-blocker timolol or the prostaglandin latanoprost. On concomitant treatment, additivity is reached with all other topical agents. A possible improvement of blood flow may offer an additional benefit, but its significance for the long-term outcome for human glaucoma remains to be shown. Side effects are mostly local. A more physiologic pH of brinzolamide appears to be advantageous.

Topics: Antihypertensive Agents; Aqueous Humor; Blood Flow Velocity; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Dose-Response Relationship, Drug; Eye; Glaucoma; Humans; Intraocular Pressure; Latanoprost; Ophthalmic Solutions; Prostaglandins F, Synthetic; Sulfonamides; Thiazines; Thiophenes

There was a time gap of over 40 years between the demonstrated oral effectiveness of acetazolamide in lowering the intraocular pressure (IOP) of glaucoma patients and the introduction of a topical carbonic anhydrase (CA) inhibitor. This is due to the fact that CA-II, the isoenzyme which most likely plays an important role in the production of aqueous humor in humans, must be essentially inhibited by 100% to elicit a pharmacological response. The lack of success with earlier attempts to obtain a topical agent stems from an inability to attain and maintain a sufficiently high intraocular concentration of drug to achieve the required inhibition of CA. Dorzolamide and brinzolamide are two topical CA inhibitors which are currently available to treat ocular hypertension and/or glaucoma. Dorzolamide is a very potent inhibitor of CA-II and its site of action is local within the eye. Like oral CA inhibitors, topically applied dorzolamide lowers IOP by decreasing the production of aqueous humor. The drug is used in monotherapy as a 2% solution administered three times daily. Its ocular hypotensive effect is comparable to that of timolol at peak but is somewhat less at trough. The IOP lowering effect of timolol is enhanced by the twice daily administration of 2% dorzolamide either concomitantly or in combination. Topically applied dorzolamide is generally well tolerated and had a low drop-out rate in clinical studies. The most frequent ocular adverse experience is burning and/or stinging. Corneal and lenticular problems have generally not been encountered with long-term therapy with dorzolamide. Topically applied dorzolamide penetrates directly to the posterior segment of the eye and its presence is consistent with the initial report that dorzolamide increases retinal blood flow velocity in patients with normal tension glaucoma. The most frequent systemic adverse experience is a transient bitter taste. Biochemical changes indicative of the systemic inhibition of CA have not been observed in monotherapy studies lasting up to 2 years. This is in harmony with the inability of dorzolamide at steady-state to saturate CA in the red blood cell and the failure to detect its presence in plasma. A 1% suspension of brinzolamide is comparable to 2% dorzolamide in lowering IOP, both drugs being administered three times daily. Although brinzolamide has a lower incidence of burning/ stinging, it elicits more blurred vision.

Topics: Administration, Topical; Animals; Carbonic Anhydrase Inhibitors; Clinical Trials as Topic; Forecasting; Glaucoma; Humans; In Vitro Techniques; Sulfonamides; Thiazines; Thiophenes

To investigate the effects of topical dorzolamide 2% q8h and brinzolamide 1% q8h, administered either alone (A and B, respectively) or in combination with topical timolol 0.5% q12h (C and D, respectively), on the circadian pattern of intraocular pressure (IOP), the pupil size, and heart rate in healthy cats.. In this prospective, randomized, double-blinded study, 10 healthy, adult cats were randomly assigned to one of four groups and the eye to be medicated was randomly assigned. IOP, pupil diameter, and heart rate were measured at 3-hour intervals. A 5 days' adjustment period was followed by a 5 days' placebo (baseline) period. Then, all groups of cats received all four treatments (A-D) according to a Latin square-based rotating schedule. Five days' medication periods were alternated with 3 days' washout periods.. Mean baseline IOP was 13.6 ± 2.7 mm Hg. All treatments resulted in a statistically significant decrease in mean IOP in the treated eye: A: -2.33 mm Hg (95% CI: -2.71, -1.94), B: -1.91 mm Hg (95% CI: -2.30, -1.53), C: -2.36 mm Hg (95% CI: -2.74, -1.97), and D: -2.37 mm Hg (95% CI: -2.76, -1.98) and the nontreated eye: A: -0.19 mm Hg (95% CI: -0.28, -0.11), B: -0.18 mm Hg (95% CI: -0.27, -0.10), C -0.31 mm Hg (95% CI: -0.40, -0.23), and D: -0.24 mm Hg (95% CI: -0.32, -0.15). Timolol resulted in an additional, significant decrease in IOP of 4% and 5%, respectively, compared to A and B, and in mild bradycardia and miosis.. Topical administration of dorzolamide 2% and brinzolamide 1% q8h significantly decreased IOP in healthy cats. Supplemental timolol 0.5% eye drops q12h resulted in an additional, statistically significant reduction of IOP.

Topics: Animals; Cats; Cross-Over Studies; Double-Blind Method; Drug Combinations; Drug Interactions; Drug Therapy, Combination; Female; Heart Rate; Intraocular Pressure; Male; Ophthalmic Solutions; Pupil; Sulfonamides; Thiazines; Thiophenes; Timolol

To compare the efficiency of brinzolamide/brimonidine fixed combination vs the dorzolamide/timolol fixed combination.. Forty-four eyes of 44 patients were divided in 2 groups treated either with dorzolamide/timolol twice a day (group A) or with brinzolamide/brimonidine twice a day (group B). Complete ophthalmic examination including Goldmann applanation tonometry was performed before treatment administration and 1, 4, 8, and 12 weeks afterwards. The intraocular pressure (IOP) was measured twice a day (morning at 9 AM and afternoon at 4 PM).. At the end of the follow-up period (12 weeks), mean morning IOP reduction was 7.0 ± 2.8 mm Hg in group A and 8.4 ± 1.9 mm Hg in group B. A significant difference was found (p = 0.0343). In contrast, mean afternoon IOP reduction was 8.6 ± 2.7 mm Hg in group A and 7.9 ± 1.6 mm Hg in group B and no significant difference was found (p = 0.3413). No significant adverse effects were observed in either group.. Brinzolamide/brimonidine seems to be an effective and safe alternative β-blocker free fixed combination, especially for patients with comorbidities, having its own antihypertensive profile.

Topics: Aged; Antihypertensive Agents; Double-Blind Method; Drug Combinations; Female; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Male; Middle Aged; Ocular Hypertension; Ophthalmic Solutions; Prospective Studies; Sulfonamides; Thiazines; Thiophenes; Timolol; Tonometry, Ocular; Treatment Outcome

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.. 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.. 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).. 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.

Topics: Administration, Ophthalmic; Aged; Antihypertensive Agents; Benzalkonium Compounds; Carbonic Anhydrase Inhibitors; Drug Combinations; Female; Glaucoma, Open-Angle; Humans; Male; Middle Aged; Preservatives, Pharmaceutical; Prospective Studies; Single-Blind Method; Sulfonamides; Suspensions; Thiazines; Thiophenes; Time Factors; Timolol

To determine possible differences in the intraocular pressure (IOP) and ocular pulse amplitude (OPA) lowering capacity of the fixed drug combinations dorzolamide/timolol and brinzolamide/timolol.. In this cross-sectional study, one of the eyes of 25 healthy subjects was randomly assigned to treatment with dorzolamide/timolol and the other eye with brinzolamide/timolol. After instilling the drops, possible adverse effects (e.g., blurred vision, itching) were assessed in each eye. This assessment was repeated 30 minutes later. IOP and OPA were determined In each eye by dynamic contour tonometry at baseline and two hours following treatment.. Both fixed drug combinations significantly reduced IOP and OPA with no differences detected between treatment groups. Among the adverse effects recorded, itching was significantly greater in the first assessment in the eyes treated with dorzolamide/timolol (P = .011). This difference was no longer apparent in the second assessment.. Both fixed combinations were similarly effective in reducing intraocular pressure and ocular pulse amplitude. Adverse effects related to both treatments were mild and well-tolerated, though itching occurred most frequently in the eyes treated with dorzolamide/timolol.

Topics: Adult; Antihypertensive Agents; Carbonic Anhydrase Inhibitors; Cross-Sectional Studies; Drug Combinations; Female; Humans; Intraocular Pressure; Male; Pulse; Sulfonamides; Thiazines; Thiophenes; Timolol; Young Adult

To assess ocular surface status and tolerability after switching glaucoma patients from dorzolamide/timolol to brinzolamide/timolol fixed combination (FC).. Six-month, multicenter, open-label, prospective study that switched 72 patients from dorzolamide/timolol to brinzolamide/timolol FC. Intraocular pressure (IOP), tear film break-up-time (TF-BUT), fluorescein staining and Glaucoma Symptom Scale (GSS) questionnaire were recorded at baseline and after 6 months.. Median interquartile range (IQR) IOP was 16 (IQR 15 - 18) mmHg at baseline and 16 (15 - 17) mmHg and 6 months. TF-BUT significantly improved (p < 0.0001); the regression analysis found a negative association between TF-BUT changes and age at baseline and at month 6 (r = -0.32; p = 0.0082 and r = -0.31; p = 0.0085). Patients with no corneal fluorescein staining statistically increased after substitution (p = 0.04). Quality of life - as examined by the GSS symptoms (SYMP) score - statistically improved (p < 0.0001), revealing an association between GSS SYMP score and age [coefficient -0.67, 95% confidence interval (CI) -1.13 to -0.21, p = 0.0005), superficial keratitis (coefficient -8.26, 95% CI -15.73 to -0.80, p = 0.031) and TF-BUT (coefficient 4.94, 95% CI 1.71 to 8.17, p = 0.003).. Brinzolamide/timolol FC is associated with reduced topical discomfort and improved signs of ocular surface disease. The good tolerability and comfort of this FC might contribute to good patient adherence.

Topics: Aged; Antihypertensive Agents; Diagnostic Techniques, Ophthalmological; Drug Combinations; Female; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Male; Quality of Life; Sulfonamides; Surveys and Questionnaires; Thiazines; Thiophenes; Timolol

This study aims to identify progression factors in patients with primary open-angle glaucoma (POAG), including the effects of treatment with dorzolamide 2% or brinzolamide 1%, each added to timolol 0.5%.. A sample of 161 POAG patients were prospectively randomized to receive either dorzolamide 2% (DT) or brinzolamide 1% (BT) b.i.d., each added to timolol 0.5%, during a 60-month, evaluator-masked study. Progression was determined by perimetric criteria. Factors associated with visual field progression were estimated using a conditional Cox hazard model with patient intraclass correlation and were expressed as hazard ratios (HRs) with 95% confidence intervals (95% CIs).. Predictive baseline factors were lower diastolic blood pressure (DBP), lower mean arterial pressure (MAP), antihypertensive treatment, lower end-diastolic velocity (EDV) in the ophthalmic artery (OA) and short posterior ciliary artery (SPCA), and a higher resistivity index (RI) in the OA and SPCA. Progression risk decreased by approximately 30% and 20% with each centimetre per second increase of EDV in the OA and SPCA, respectively, from baseline to the last follow-up visit. Each RI decrease (or increase) of 0.01 unit in the OA or SPCA was associated with an approximate 20% decrease (or increase) in risk for progression. In a multivariate analysis, progression risk was significantly lower in eyes treated with DT (HR=0.65, 95% CI 0.41-0.90) compared with those treated with BT.. Progression increased with lower DBP, lower MAP, antihypertensive medication, lower EDV in the OA and SPCA, and higher RI in the OA and SPCA. The risk for progression in patients treated with DT was half that in patients treated with BT.

Topics: Aged; Antihypertensive Agents; Blood Flow Velocity; Blood Pressure; Carbonic Anhydrase Inhibitors; Ciliary Arteries; Disease Progression; Drug Therapy, Combination; Female; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Male; Middle Aged; Ophthalmic Artery; Proportional Hazards Models; Prospective Studies; Retinal Artery; Risk Factors; Sulfonamides; Thiazines; Thiophenes; Timolol; Tonometry, Ocular; Ultrasonography, Doppler, Color; Vision Disorders; Visual Fields

To compare the effect on the retrobulbar hemodynamics and intraocular pressure (IOP) of dorzolamide 2% and brinzolamide 1%, each added to timolol 0.5% in patients with primary open-angle glaucoma (POAG).. 146 POAG patients were prospectively randomized to receive either dorzolamide 2% or brinzolamide 1% BID, each added to timolol 0.5%, during a 60-month evaluator-masked study. At baseline and every 6 months for 60 months, we measured the retrobulbar hemodynamic parameters in the ophthalmic artery (OA), central retinal artery (CRA), and short posterior ciliary arteries (SPCA) using color Doppler imaging (CDI), intraocular pressure (IOP), and blood pressure measurements.. Dorzolamide significantly increased the end-diastolic velocity (EDV) in the OA in 1.22 cm/s, 95% confidence interval (95% CI) 0.90-1.56 cm/s, P < 0.001 and reduced the resistivity index (RI) in the OA in 0.04 units, 95% CI 0.03-0.05, P < 0.001. None of the retrobulbar parameters changed significantly on therapy with brinzolamide when the results were analyzed at month 60. Both dorzolamide and brinzolamide significantly decreased IOP (-4.3, 95% CI -4.5 to -4.2 mmHg and -4.3, 95% CI -4.4 to -4.2 mmHg, respectively). Dorzolamide significantly reduced the RI in the OA from 0.74 (0.02) to 0.70 (0.02), CRA from 0.66 (0.02) to 0.62 (0.02), and SPCA from 0.66 (0.02) to 0.62 (0.02), P < 0.001, respectively.. Our results suggest augmented retrobulbar blood flow after 5 years of treatment with dorzolamide but not with brinzolamide, each added to timolol, in POAG patients.

Topics: Administration, Topical; Aged; Antihypertensive Agents; Blood Pressure; Carbonic Anhydrase Inhibitors; Drug Administration Schedule; Drug Combinations; Female; Glaucoma, Open-Angle; Hemodynamics; Humans; Intraocular Pressure; Male; Middle Aged; Ophthalmic Solutions; Prospective Studies; Regional Blood Flow; Sulfonamides; Thiazines; Thiophenes; Timolol; Ultrasonography, Doppler, Color

To compare the efficacy of brimonidine, dorzolamide, and brinzolamide in reducing intraocular pressure (IOP) when used as adjunctive therapy to a prostaglandin analog (PGA).. Randomized, controlled, investigator-masked, single-site, parallel-group clinical trial.. One hundred twenty eyes of 120 patients with open-angle glaucoma or ocular hypertension who had inadequate IOP control after at least 6 weeks of monotherapy with a once-daily PGA (bimatoprost, latanoprost, or travoprost).. Study eyes were assigned randomly to adjunctive treatment with thrice-daily brimonidine tartrate 0.15% (n = 41), dorzolamide hydrochloride 2% (n = 40), or brinzolamide 1% (n = 39) for 4 months.. Efficacy was evaluated by IOP measured at 10 am and 4 pm at baseline, month 1, and month 4.. The mean IOP at each hour at PGA-treated baseline was comparable among treatment groups. After initiation of adjunctive therapy, the mean IOP was lower and the mean change from baseline IOP was greater in the brimonidine group than in either the dorzolamide group or the brinzolamide group at 10 am and 4 pm at months 1 and 4 (P<0.001). After 4 months of adjunctive treatment, the mean IOP reduction from baseline at 10 am and 4 pm was 4.8 mmHg (21%) and 3.8 mmHg (19%) with brimonidine, 3.4 mmHg (16%) and 2.8 mmHg (14%) with dorzolamide, and 3.4 mmHg (16%) and 2.6 mmHg (13%) with brinzolamide (P<0.001 for brimonidine vs. dorzolamide and brinzolamide at each time point). Each of the study drugs was well tolerated, and all patients completed the study.. The addition of brimonidine to a PGA provided greater IOP lowering than the addition of either dorzolamide or brinzolamide. Further studies are needed to evaluate the relative long-term efficacy and tolerability of these medications as adjunctive therapy to a PGA.. Proprietary or commercial disclosure may be found after the references.

Topics: Aged; Aged, 80 and over; Amides; Antihypertensive Agents; Bimatoprost; Brimonidine Tartrate; Cloprostenol; Drug Therapy, Combination; Female; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Latanoprost; Male; Middle Aged; Ocular Hypertension; Prospective Studies; Prostaglandins F, Synthetic; Quinoxalines; Single-Blind Method; Sulfonamides; Thiazines; Thiophenes; Tonometry, Ocular; Travoprost; Treatment Outcome

The aim of this study was to evaluate the ocular discomfort of brinzolamide 1%/timolol 0.5% ophthalmic suspension fixed combination dosed twice-daily compared to dorzolamide 2%/timolol 0.5% ophthalmic solution fixed combination dosed twice-daily.. This was a prospective, double-masked, parallel-group, randomized, clinical trial. Patients had open-angle glaucoma or ocular hypertension and were randomized to twice-daily therapy with either brinzolamide 1%/timolol 0.5% or dorzolamide 2%/timolol 0.5%. Patients completed ocular discomfort assessments (based on burning, stinging, a feeling of heat or warmth, sharp pain, or smarting pain) on their current intraocular pressure-lowering therapy at baseline and on study medication after 1 week of dosing.. In the intent-to-treat analyses, mean ocular discomfort scores at 1 week were significantly lower in eyes receiving brinzolamide 1%/timolol 0.5% than dorzolamide 2%/timolol 0.5% (0.77 vs. 1.53; P = 0.0003). Mean increases from baseline in ocular discomfort scores were statistically significant in both groups but were smaller in eyes receiving brinzolamide 1%/timolol 0.5% (0.49; P = 0.0028) than dorzolamide 2%/timolol 0.5% (1.32; P < 0.0001). Over threefold more patients on brinzolamide 1%/timolol 0.5% (23/47, 49%) than dorzolamide 2%/timolol 0.5% (7/47, 15%) reported no ocular discomfort after 1 week of therapy (P = 0.0004).. Brinzolamide 1%/timolol 0.5% ophthalmic suspension is associated with a statistically significantly less ocular discomfort profile than dorzolamide 2%/timolol 0.5% ophthalmic solution.

Topics: Adult; Aged; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Female; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Male; Middle Aged; Ocular Hypertension; Prospective Studies; Sulfonamides; Thiazines; Thiophenes; Timolol

To assess the effects of brinzolamide and dorzolamide on ocular haemodynamics and retinal oxygen saturation in patients with primary open-angle glaucoma (OAG).. Fifteen patients with OAG were evaluated in a randomised, cross-over, double-blind study. They were treated with either brinzolamide or dorzolamide for 3 months and then crossed-over after a 4-week washout period. They were given timolol during a 4-week run-in period and during washout. The following were performed after run-in, after washout and after each treatment period: adverse events check, measurement of visual acuity, contrast sensitivity, blood pressure, heart rate, and intraocular pressure, and fundus examination. Ocular blood flow was assessed using confocal scanning laser Doppler flowmetry (HRF) and colour Doppler imaging (CDI). Retinal oxygenation levels were determined using a non-invasive measurement of haemoglobin oxygen saturation by digital photographic fundus oximetry.. Both brinzolamide and dorzolamide reduced the number of zero-flow pixels in the retina as measured by HRF, suggesting an increase in retinal blood flow (-6.86 and -0.452 respectively) with brinzolamide treatment resulting in fewer zero-flow pixels than dorzolamide (-6.41) (p = 0.024). Both brinzolamide and dorzolamide increased oxygen saturation in the retina as measured by photographic retinal oximetry in the superior (0.82 (p = 0.002) and 0.87 (p = 0.005)) and inferior (0.88 (p = 0.035) and 0.82 (p = 0.002)) retinal veins. No significant changes were found in CDI measurements of the retrobulbar blood supply during either treatment.. This pilot study suggests that brinzolamide and dorzolamide may increase retinal oxygen saturation in patients with OAG.

Topics: Aged; Antihypertensive Agents; Blood Pressure; Carbonic Anhydrase Inhibitors; Contrast Sensitivity; Cross-Over Studies; Double-Blind Method; Female; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Laser-Doppler Flowmetry; Male; Microcirculation; Middle Aged; Oxygen; Pilot Projects; Retinal Vessels; Sulfonamides; Thiazines; Thiophenes; Visual Acuity

Inhibitors of carboanhydrase (ICA) in the form of dorzolamide 2% drops and brinzolamide 1% drops are in use for 8-10 years, with a significant intraocular pressure (IOP) lowering effect. The goal of the present study was to obtain precise data on the efficacy of local ICA in conjunction with timolol 0.5% drops, and to evaluate the incidence of side effects. This was a prospective study that lasted 2 years and included 110 patients. Initial IOP values, before therapy with ICA, amounted to 19 +/- 8.4 mm Hg in group A and 20.5 +/- mm Hg in group B. Although the results obtained demonstrated statistically significant lowering of IOP (in group A by 4.5 +/- 2.4 mm Hg, and in group B by 4.6 +/- 2.1 mm Hg) after therapy with ICA, the difference between the groups was not found. Dorzolamide more frequently caused local side effects like aching, itching and pain in the eye. Aditional lowering of lOP in our patients was somewhat greater than reported before (4.6:4.3). Side effects (itching, aching, pain) were three times more frequent in the group treated with dorzolamide than reported by other authors; this difference could be due to patient age, as our patients were mostly elderly people and the data are subjective. The results of this study suggested the effectiveness of additional local therapy with ICA in patients with open angle glaucoma.

Topics: Carbonic Anhydrase Inhibitors; Drug Therapy, Combination; Female; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Male; Middle Aged; Sulfonamides; Thiazines; Thiophenes; Timolol

Brinzolamide and dorzolamide are often used as adjunctive therapy to other antiglaucoma agents. The purpose of this study was to compare the efficacy and safety of brinzolamide 1% versus dorzolamide 1% when added to the combination therapy of latanoprost and a beta-blocker in patients with glaucoma.. An 8-week, randomized, open-label comparative study was performed in 52 patients with glaucoma. Brinzolamide 1% (twice a day) or dorzolamide 1% (3 times a day) was randomly administered to the patients who had been treated with both latanoprost and a betablocker.. Intraocular pressure (IOP) were both decreased significantly (P < 0.0001) from 18.6 +/- 2.3 mmHg to 16.7 +/- 2.3 mmHg and from 18.4 +/- 2.6 mmHg to 16.6 +/- 2.5 mmHg, respectively, 8 weeks after the addition of brinzolamide or dorzolamide. However, the difference between the groups was not significant (P = 0.86). The incidence of ocular irritation was significantly higher (P < 0.0001) in the dorzolamide group (74%) than the brinzolamide group (16%), but there was no significant difference in blurred vision between the groups (dorzolamide 37% versus brinzolamide 52%, P = 0.40).. We concluded that the efficacy of brinzolamide 1% was equivalent to dorzolamide 1%; however, the safety of brinzolamide 1% was superior to dorzolamide 1% as adjunctive therapy to the combination with latanoprost and a beta-blocker.

Topics: Adrenergic beta-Antagonists; Aged; Drug Therapy, Combination; Female; Glaucoma, Open-Angle; Humans; Instillation, Drug; Intraocular Pressure; Latanoprost; Male; Ophthalmic Solutions; Prostaglandins F, Synthetic; Sulfonamides; Thiazines; Thiophenes; Treatment Outcome

The aim of this study was evaluate the efficacy and ocular discomfort of substituting brinzolamide for dorzolamide in patients with glaucoma treated by latanoprost, timolol, and dorzolamide.. An 8-week, prospective, randomized, open-label, comparative study was performed in 58 patients with primary open-angle glaucoma treated by latanoprost, timolol, and dorzolamide. These patients were randomly enrolled into two groups: (1) dorzolamide three times daily was substituted with brinzolamide twice-daily (substituting group); and (2) dorzolamide three times daily was continued (control group). Intraocular pressure (IOP) was measured at baseline, 4, and 8 weeks after the enrollment. Subjective ocular discomfort (irritation and blurred vision) at the time of the instillation of the patient was noted with interview.. The IOPs at baseline, 4 and 8 weeks after the enrollment were 17.7 +/- 2.7 mmHg, 17.5 +/- 2.6 mmHg, and 17.4 +/- 2.9 mmHg in the substituting group, and 18.0 +/- 2.5 mmHg, 17.8 +/- 2.5 mmHg, and 17.9 +/- 2.6 mmHg in the control group, respectively. There were no significant differences in IOP changes between the two groups (P = 0.74). In the substituting group, ocular irritation was decreased significantly (P = 0.0014) from 63% to 20%. The slight increase of blurred vision from 27% to 37% that occurred in the substituting group was not significant (P = 0.58). In the control group, neither ocular irritation (P = 0.58, from 68% to 57%) nor blurred vision (P = 0.99, from 25% to 21%) was changed.. Substituting brinzolamide for dorzolamide maintained stable IOP with improvement in ocular comfort in patients with glaucoma.

Topics: Aged; Drug Therapy, Combination; Female; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Latanoprost; Male; Middle Aged; Prostaglandins F, Synthetic; Sulfonamides; Thiazines; Thiophenes; Timolol; Vision, Ocular

To compare ocular tolerability of dorzolamide 2%, brinzolamide 1%, and placebo given three times daily.. A prospective, double-masked, three-centre, crossover comparison in which 25 ocular hypertensive or primary-open angle glaucoma subjects were randomized to receive dorzolamide, brinzolamide, or placebo three times daily for 3 days. Intraocular pressure, visual acuity, a visual analogue scale, and ocular and systemic symptom queries were completed at the end of each period.. After chronic dosing, there was a significant difference in ocular pain on the visual analogue scale among the groups at the 10-s postinstillation time point with dorzolamide having the highest level (22.5+/-28.9) compared to brinzolamide (5.0+/-8.7) or placebo (3.2+/-10.4) (P=0.0006). No differences between groups were observed preinstillation nor following dosing at 3 or 10-min postinstillation. On the initial instillation, the 10-s postinstillation pain was rated as 43.3+/-77.1, which was significantly higher than after chronic dosing (P=0.017). On the ocular symptom query, dorzolamide had the highest incidence of burning/stinging and redness compared to the other groups, but was generally characterized as mild. There were no significant differences in the visual acuity at any time point.. This study suggests that subjects treated with dorzolamide suffer more ocular pain upon instillation compared to brinzolamide or placebo. However, pain symptoms are fewer following chronic dosing and are generally characterized as mild.

Topics: Adult; Aged; Antihypertensive Agents; Carbonic Anhydrase Inhibitors; Cross-Over Studies; Double-Blind Method; Drug Administration Schedule; Female; Glaucoma, Open-Angle; Humans; Male; Middle Aged; Ocular Hypertension; Ophthalmic Solutions; Pain; Pain Measurement; Prospective Studies; Severity of Illness Index; Sulfonamides; Thiazines; Thiophenes

Cost is an issue when prescribing two drugs with equivalent efficacy. We compared the direct medical costs of topical brinzolamide 1% (twice a day or three times daily) with topical dorzolamide 2% (twice a day or three times daily) in France, Italy, Portugal and Spain in patients with ocular hypertension or primary open-angle glaucoma.. Three double-blind, controlled, randomised trials (with a study duration of 3 months) compared the response rate of brinzolamide twice a day or three times daily versus dorzolamide three times daily, and the response rate of brinzolamide-timolol twice a day versus a dorzolamide-timolol combination twice a day. A fourth double-blind randomised trial (with a duration of 12 months) compared brinzolamide twice a day and three times daily with timolol monotherapy. Local tolerance was compared in two dedicated studies. Rates of switching to a new medication regimen were evaluated through a US health maintenance organisation database. In case of treatment failure, the patients were treated with latanoprost. A model was developed to value direct medical costs over 3 months. The economic perspective was that of the third-party payer and the patient, and included direct medical costs (reimbursed part plus co-payment).. Patients with ocular hypertension and/or primary open-angle glaucoma who had not responded to or could not tolerate beta-blocker therapy.. The daily direct medical costs of therapy with the two drugs.. As monotherapy, brinzolamide twice daily and three times daily was found to be as efficacious as dorzolamide three times a day. Brinzolamide twice daily plus timolol was also as efficacious as a combination of dorzolamide and timolol twice a day. Stinging of the eye upon instillation with brinzolamide was experienced by fewer patients than with dorzolamide (p < 0.0001). The likelihood of patients treated with dorzolamide changing therapy was 1.28 times greater than that for those treated with brinzolamide. The size of the brinzolamide drop is 18.7% smaller than that of dorzolamide allowing seven more therapy days per bottle with brinzolamide twice daily than with dorzolamide monotherapy, and five more days when brinzolamide is used three times a day. The direct medical costs for patients treated with brinzolamide were lower in all four European countries when drop size was taken into account than for those treated with dorzolamide. Sensitivity analyses confirmed the robustness of our findings.. Because brinzolamide can be prescribed twice daily in monotherapy and because fewer patients treated with brinzolamide switch therapy due to local intolerance, our model suggests that brinzolamide is a cost-saving alternative to dorzolamide.

Topics: Administration, Topical; Carbonic Anhydrase Inhibitors; Drug Administration Schedule; Economics, Pharmaceutical; Europe; Glaucoma, Open-Angle; Humans; Ocular Hypertension; Randomized Controlled Trials as Topic; Sulfonamides; Thiazines; Thiophenes

The aim was to compare topical brinzolamide 1% twice daily with dorzolamide 2% twice daily, each given with timolol 0.5% twice daily, for safety and effects on intraocular pressure in patients with primary open-angle glaucoma or ocular hypertension.. This double-blind, randomized, active controlled, parallel group study was conducted multinationally at 31 sites, in 241 patients as above, with assessments at baseline and monthly during 3 months of treatment. The primary end point was a diurnal reduction of trough/peak intraocular pressure from a timolol 0.5% twice daily baseline.. Both treatment regimens reduced intraocular pressure significantly at all time points (P <.001): brinzolamide plus timolol by -3.6 to -5.3 mm Hg (-14.2 to -21.9%), dorzolamide plus timolol by -3.6 mm Hg to -5.1 mm Hg (-14.1 to -21.2%). Clinically relevant intraocular pressure reductions (decreases 5 mm Hg or greater or absolute intraocular pressure values 21 mm Hg or less) were manifested by 50.0% to 89.3% of patients under brinzolamide plus timolol and by 43.9% to 85.4% under dorzolamide plus timolol. The treatments were equivalent in mean intraocular pressure-lowering. In general, both regimens were well tolerated. However, more patients (P =.001) experienced at least one adverse event with dorzolamide plus timolol (32.8%) as compared with brinzolamide plus timolol (14.7%); also, more patients (P =.001) experienced ocular discomfort (stinging and burning) after dorzolamide plus timolol (13.1%) than after brinzolamide plus timolol (1.7%).. In terms of intraocular pressure reduction, brinzolamide 1% twice daily was equivalent to dorzolamide 2% twice daily, each added to timolol 0.5% twice daily, but brinzolamide produced significantly less ocular burning and stinging.

Topics: Administration, Topical; Adrenergic beta-Antagonists; Aged; Carbonic Anhydrase Inhibitors; Double-Blind Method; Drug Therapy, Combination; Female; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Male; Middle Aged; Ocular Hypertension; Ophthalmic Solutions; Safety; Sulfonamides; Thiazines; Thiophenes; Timolol; Treatment Outcome

A randomized, multicenter, double-masked, prospective, parallel study was designed to establish the intraocular pressure (IOP)-lowering efficacy, safety, and tolerability of brinzolamide 1.0% (Azopt) as a primary therapy compared with dorzolamide 2.0% (Trusopt) and placebo in patients diagnosed with open-angle glaucoma (with or without a pseudoexfoliative or a pigmentary dispersion component) or ocular hypertension. Brinzolamide 1.0%, dosed two times (b.i.d.) and three times (t.i.d.) a day, dorzolamide 2.0% (t.i.d.), and placebo (t.i.d) were administered to patients during a 3-month treatment period. Diurnally corrected IOP reduction from baseline, including peak and trough times, was the primary end point. Sample sizes were chosen to establish statistical equivalence between treatments. Mean IOP changes observed on treatment were as follows: -3.4 mm Hg (-13.2%) to -4.1 mm Hg (-16.7%) with brinzolamide 1.0% b.i.d.; -4.1 mm Hg (-16.6%) to -4.8 mm Hg (-19.1%) with brinzolamide 1% t.i.d.; and -4.3 mm Hg (-16.9%) to -4.9 mm Hg (-20.1%) with dorzolamide 2.0%. IOP reductions after administration of brinzolamide 1.0% b.i.d. and t.i.d. were equivalent to each other and also clinically and statistically equivalent to those with dorzolamide 2.0% t.i.d. The incidence of ocular discomfort (burning and stinging) upon instillation was significantly higher for dorzolamide (10.7%) than brinzolamide (b.i.d. or t.i.d., 3.0% each). The most frequent non-ocular event reported was taste perversion, which was less (3.7%) with brinzolamide 1.0% b.i.d., but brinzolamide t.i.d. was similar to dorzolamide t.i.d. (6.8% vs. 5.3%). Brinzolamide 1.0% b.i.d., brinzolamide 1.0% t.i.d., and dorzolamide 2.0% t.i.d. equaled each other in IOP-lowering efficacy, and brinzolamide was significantly more comfortable than dorzolamide upon instillation.

Topics: Adult; Aged; Carbonic Anhydrase Inhibitors; Double-Blind Method; Drug Hypersensitivity; Female; Glaucoma, Open-Angle; Humans; Incidence; Intraocular Pressure; Male; Middle Aged; Ocular Hypertension; Prospective Studies; Safety; Sulfonamides; Suspensions; Thiazines; Thiophenes; Treatment Outcome

Two independent, prospective, multicenter, double-masked, parallel group trials were conducted to compare the ocular comfort of brinzolamide 1.0% administered three times daily (t.i.d.) with t.i.d.-dosed dorzolamide 2.0% in patients with primary open-angle glaucoma or ocular hypertension. Patients were randomized to one of two treatment groups, receiving either brinzolamide 1.0% t.i.d. or dorzolamide 2.0% t.i.d. for 1 week. On the last day of dosing, patients received one drop of masked medication in both eyes, and ocular discomfort (burning or stinging) was evaluated by means of a 4-unit ocular discomfort scale. The incidence and extent of ocular discomfort across both treatment groups were analyzed. The results from both studies were confirmatory and demonstrated that the ocular discomfort score for brinzolamide 1.0% was 1.3 units lower than the score for dorzolamide 2.0%, which was both statistically significant and clinically relevant. In addition, a statistically significantly greater percentage of patients reported no ocular discomfort with brinzolamide 1.0% compared with dorzolamide. A greater percentage of patients receiving dorzolamide 2.0% also reported mild, moderate, severe, and very severe ocular discomfort compared with those treated with brinzolamide 1.0%. The most frequent ocular adverse event reported in the brinzolamide group was transient blurred vision, which ranged from 20% to 25%. Overall, adverse events associated with brinzolamide 1.0% and dorzolamide 2.0% were nonserious, were usually mild, and resolved without treatment. The findings of each study independently demonstrated that brinzolamide 1.0% was significantly more comfortable than dorzolamide 2.0% when instilled in the eye.

Topics: Adult; Carbonic Anhydrase Inhibitors; Double-Blind Method; Female; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Male; Middle Aged; Ocular Hypertension; Ophthalmic Solutions; Patient Satisfaction; Prospective Studies; Sulfonamides; Suspensions; Thiazines; Thiophenes; Treatment Outcome

To compare the efficacy of combinations of betaxolol-brinzolamide and timolol-dorzolamide as suppressors of aqueous humor flow and ocular hypotensive agents.. Placebo-controlled, masked comparison of the two drug combinations.. Twenty-five normal human volunteers with the fellow eye serving as control. METHODS OR TESTING: Fluorophotometric measurement of aqueous humor flow and pneumatonometric measurement of intraocular pressure.. Aqueous humor flow and intraocular pressure.. The betaxolol-brinzolamide combination lowered aqueous flow 39% to 44%, and the timololdorzolamide combination lowered aqueous flow 51%. The betaxolol-brinzolamide combination lowered intraocular pressure 14% to 19%, and the timolol-dorzolamide combination lowered it 18% to 24%.. Both drug combinations were effective; the timolol-dorzolamide combination appeared to be the more effective of the two after short-term exposure (24 hours).

Topics: Adrenergic beta-Antagonists; Adult; Aged; Aqueous Humor; Betaxolol; Carbonic Anhydrase Inhibitors; Drug Therapy, Combination; Female; Fluorophotometry; Humans; Intraocular Pressure; Male; Middle Aged; Ophthalmic Solutions; Safety; Sulfonamides; Thiazines; Thiophenes; Timolol; Tonometry, Ocular

The first topically active carbonic anhydrase inhibitor, dorzolamide, was developed to circumvent the adverse systemic effects of oral carbonic anhydrase inhibitors. However, its use has been associated with ocular discomfort.. The present study examined the acceptability of brinzolamide, as measured by patients' ratings and stated preferences, in patients with glaucoma previously treated with dorzolamide in the clinical practice setting.. This was a prospective, open-label, noncomparative study conducted shortly after the approval of brinzolamide. Ophthalmologists in private practice in the continental United States were asked to select patients currently using dorzolamide as their sole or combination therapy for glaucoma. Patients underwent a screening assessment in which they were asked to rate their ocular comfort with dorzolamide on a scale from 1 to 6. Brinzolamide was then substituted for dorzolamide, and patients returned for a follow-up visit approximately 1 to 3 months later. At this visit, patients were asked about ocular comfort, their preferred medication, and whether they thought ocular comfort influenced their adherence to treatment. Intraocular pressure (IOP) was measured at both visits.. Valid visit dates (ie, both baseline and follow-up dates) were available for 447 of 501 patients from 68 of 73 sites (range, 1-40 patients per site). Because not all measurements were available for all patients at each visit, the sample size varied for each measurement. Demographic data were not available. The switch to brinzolamide resulted in a mean decrease in IOP of approximately 0.8 mm Hg (P < 0.001, paired t test). Sixty-nine percent of patients (274/397) reported an improvement of > or =1 grade in their comfort rating with brinzolamide versus dorzolamide. The mean (+/- SD) improvement in comfort rating was 1.43 +/- 1.48 grades (P < 0.001, Wilcoxon rank sum test). When patients were asked whether their adherence to treatment was affected by the occurrence of burning and stinging, 43% (173/399) answered affirmatively. Fifty-nine percent (251/424) preferred brinzolamide to dorzolamide. At the end of the study, based on patient preference, physician judgment, and other factors, 73% of responding patients (301/410) continued with brinzolamide therapy.. In this study, the switch from dorzolamide to brinzolamide resulted in overall improvements in comfort and ocular hypotensive efficacy. However, studies using a more rigorous randomized, controlled, crossover design are needed to support these observations.

Topics: Carbonic Anhydrase Inhibitors; Glaucoma; Humans; Intraocular Pressure; Patient Satisfaction; Prospective Studies; Sulfonamides; Thiazines; Thiophenes

To measure the relative efficacy of brinzolamide hydrochloride 1% ophthalmic suspension, a new carbonic anhydrase inhibitor, compared with the currently used dorzolamide hydrochloride 2% ophthalmic solution as suppressors of aqueous humor flow in human eyes, and to study the difference of effect during the day and at night.. A randomized, double-masked, placebo-controlled study of 25 normal human subjects was carried out at Mayo Clinic. The daytime rate of aqueous humor flow was measured every 2 hours from 8 AM to 4 PM by means of fluorophotometry. Likewise, the night-time rate of aqueous humor flow was measured every 2 hours from 12 AM to 6 AM. Intraocular pressure was measured at 4 PM and 6 AM.. Brinzolamide reduced aqueous flow by 0.47+/-0.20 microl per min (mean+/-SD) during the day, whereas dorzolamide reduced flow by 0.34+/-0.20 microl per min. Brinzolamide reduced aqueous flow by 0.16+/-0.12 microl per min during the night, whereas dorzolamide reduced flow by 0.10+/-0.13 microl per min. Brinzolamide reduced afternoon intraocular pressure by 1.5+/-1.1 mm Hg, and dorzolamide reduced afternoon intraocular pressure by 1.1+/-1.0 mm Hg. Brinzolamide reduced the morning awakening intraocular pressure by 0.3+/-1.6 mm Hg, and dorzolamide reduced it by 0.8+/-1.0 mm Hg.. Our data support the idea that brinzolamide is at least as efficacious as dorzolamide as a suppressor of aqueous humor flow in normal human eyes and that there is probably not a clinically significant difference between the two drugs in this efficacy. Clinicians who prescribe brinzolamide should expect similar ocular hypotensive responses from brinzolamide and dorzolamide.

Topics: Adult; Aqueous Humor; Carbonic Anhydrase Inhibitors; Double-Blind Method; Drug Evaluation; Female; Fluorescein; Fluorophotometry; Humans; Intraocular Pressure; Male; Ophthalmic Solutions; Sulfonamides; Thiazines; Thiophenes

To determine the intraocular pressure-lowering efficacy and safety of brinzolamide 1.0%, compared with dorzolamide 2.0% and timolol 0.5%.. A multicenter, double-masked, prospective, parallel-group study was conducted to compare brinzolamide 1.0%, administered two and three times a day, dorzolamide 2.0% three times a day, and timolol 0.5% twice a day in 572 patients with primary open-angle glaucoma or ocular hypertension. The primary end point was diurnally corrected intraocular pressure reduction from baseline, evaluated at both peak and trough times during a 3-month period.. Mean intraocular pressure changes after twice daily (-3.8 to -5.7 mm Hg) and three times daily (-4.2 to -5.6 mm Hg) dosing with brinzolamide 1.0% were statistically equivalent (confidence limit < or = 1.5 mm Hg) to each other and also to dorzolamide 2.0% three times a day (-4.3 to -5.9 mm Hg). The range of intraocular pressure change with timolol 0.5% twice daily was -5.2 to -6.3 mm Hg. Clinically relevant intraocular pressure changes (reduction > or = 5 mm Hg or intraocular pressure < or = 21 mm Hg) were observed in up to 75.7% of patients taking brinzolamide twice daily and in up to 80.1% taking brinzolamide three times daily. Treatment with brinzolamide 1.0% was safe, comfortable, and well tolerated. The incidence of ocular discomfort (burning and stinging) on instillation of brinzolamide (twice daily, 1.8%; three times daily, 3.0%) was significantly less (P = .000) compared with treatment with dorzolamide (16.4%).. Brinzolamide 1.0% produced clinically relevant intraocular pressure reductions in substantial numbers of patients. Brinzolamide's effectiveness equaled that of dorzolamide 2.0% and it produced less ocular discomfort (burning and stinging) on instillation.

Topics: Administration, Topical; Adrenergic beta-Antagonists; Aged; Carbonic Anhydrase Inhibitors; Double-Blind Method; Female; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Male; Middle Aged; Ocular Hypertension; Ophthalmic Solutions; Prospective Studies; Safety; Sulfonamides; Thiazines; Thiophenes; Timolol; Treatment Outcome

Long-term use of topical, especially benzalkonium chloride (BAC)-preserved, antiglaucoma medications can cause a negative impact on the ocular surface. The aim of the study was to assess the effect of topical carbonic anhydrase inhibitors (CAIs) on selected oxidative stress biomarkers in the tear film.. The patients were divided into four sex-matched groups: group C (n = 25) - control group - subjects who did not use topical antiglaucoma medications, group DL (n = 14) - patients using preservative-free dorzolamide, group DL + BAC (n = 16) - patients using topical BAC-preserved dorzolamide, group BL + BAC (n = 17) - patients using BAC-preserved brinzolamide. Subjects in all the study groups have been using the eye drops two times daily for 6-12 months. The oxidative stress biomarkers in the tear film samples were measured: total protein (TP) concentration, advanced oxidation protein products (AOPP) content, total sulfhydryl (-SH) groups content, the activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), as well as Total Oxidant Status (TOS), Total Antioxidant Response (TAR), and Oxidative Stress Index (OSI).. The advanced oxidation protein products content, Total Oxidant Status as well as superoxide dismutase and catalase activities in the group DL + BAC and BL + BAC were higher in comparison with the group C. The total sulfhydryl groups content was lower in the group DL + BAC and BL + BAC when compared to group C. Oxidative Stress Index was higher in the groups DL + BAC and BL + BAC in comparison with the groups DL and C.. Use of topical benzalkonium chloride-preserved carbonic anhydrase inhibitors increases oxidative stress in the tear film.

Topics: Benzalkonium Compounds; Biomarkers; Carbonic Anhydrase Inhibitors; Humans; Ophthalmic Solutions; Oxidative Stress; Sulfonamides; Thiazines; Thiophenes

To report two cases with corneal sterile infiltration presumably due to topical ocular hypotensive agent.. Case report.. Case 1: A 65-year-old man presented with corneal opacity and neovascularization in his left eye. A diagnosis of glaucoma was made 2 years previously, and anti-glaucoma agents were prescribed (brimonidine tartrate, ripasudil hydrochloride hydrate, and brinzolamide) for both eyes. Case 2: A 75-year-old woman noticed corneal opacity in the left eye. A diagnosis of glaucoma was made 35 years previously, and anti-glaucoma agents were prescribed (brimonidine tartrate, 1% dorzolamide, and bimatoprost) for both eyes. In both cases, ocular examination revealed follicular conjunctivitis and blepharitis in both eyes, and corneal sterile infiltration with neovascularization in the left eyes. The three topical drugs were discontinued and replaced with 0.1% fluorometholone. Both the blepharitis and corneal sterile infiltration improved thereafter, although corneal opacity remained across the stromal layer.. We encountered two cases of corneal and conjunctival complications that were suspected as side effects after brimonidine eye drop use. Special care should be taken to observe the condition of ocular surface when topical brimonidine is administered.

Topics: Aged; Antihypertensive Agents; Bimatoprost; Blepharitis; Brimonidine Tartrate; Conjunctivitis; Corneal Neovascularization; Corneal Opacity; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Low Tension Glaucoma; Male; Ophthalmic Solutions; Sulfonamides; Thiazines; Thiophenes

Carbonic anhydrase inhibitors (CAIs) are frequently used as an initial step to treat retinitis pigmentosa-associated cystoid macular oedema (RP-CMO). Interestingly, it has been postulated that CAIs might reduce outer nuclear layer (ONL) fluid more effectively than inner nuclear layer (INL) fluid due to better access to retinal pigment epithelium basolateral membrane than neurosensory retina. This retrospective cohort study explores if an association between spatial distribution of cystoid spaces in RP-CMO and CAI response exists.. Two independent graders reviewed pretreatment and post-treatment optical coherence tomography (OCT) images of 25 patients (43 eyes) initiated on topical and/or oral CAIs between January 2013 and December 2014. Documentation included the presence/absence of fluid (and layer(s) involved), external limiting membrane, epiretinal membrane (ERM), vitreomacular adhesion/traction, lamellar/full-thickness macular hole and central macular thickness (CMT)/volume.. INL fluid was found in all study eyes. All 13 'responders' (at least 11% reduction of CMT after treatment) demonstrated pretreatment ONL fluid. In seven patients (four responders and three non-responders), complete clearance of ONL fluid was achieved despite persistence of INL fluid. ERM presence was similar in responders and non-responders.. In this study, INL fluid was found to be the most common spatial distribution of RP-CMO. However, patients who were classed as a 'responder' to CAI treatment all demonstrated coexisting ONL fluid on their pretreatment OCT scans. This may be explained by CAIs having better access to retinal pigment epithelium basolateral membrane than neurosensory retina. Our study also suggests a minimal impact on response to CAIs by ERM.

Topics: Acetazolamide; Adolescent; Adult; Aged; Carbonic Anhydrase Inhibitors; Female; Humans; Macular Edema; Male; Middle Aged; Retinitis Pigmentosa; Retrospective Studies; Sulfonamides; Thiazines; Thiophenes; Tomography, Optical Coherence; Visual Acuity; Visual Field Tests; Young Adult

Timolol is a non-cardioselective beta blocker and has different combined ophthalmic dosage forms for treatment of glaucoma. This research introduce an HPLC method for the separation of three drugs used in combination with timolol simultaneously by applying isocratic mobile phase system in a single run and the same detection wavelength with short time. The drugs included in the separation procedures are; dorzolamide, brinzolamide, and brimonidine. The HPLC method was carried out through a single mobile phase system, which contains acetonitrile: 0.05M phosphate buffer at the ratio of 30:70, respectively at pH 3.5 and wavelength of 220nm. The method, regarding its simplicity allows determination of the studied drugs simultaneously using single run in about 8minutes. The method was rectilinear in the ranges of concentration: 1.25-25μg/mL for timolol, 4-80μg/mL for dorzolamide, 5-50μg/mL for brinzolamide and 2-20μg/mL for brimonidine. Different factors affecting the separation are thoroughly studied. The developed method was validated based on the official guidelines and the results were compared statistically with previously published methods and showed non-significant difference.

Topics: Adrenergic beta-Antagonists; Brimonidine Tartrate; Chromatography, High Pressure Liquid; Drug Combinations; Drug Compounding; Glaucoma; Limit of Detection; Ophthalmic Solutions; Reference Standards; Reproducibility of Results; Sulfonamides; Thiazines; Thiophenes; Timolol

To examine the relevance of concentration of benzalkonium chloride (BAK) on the cornea, we investigated the effects of latanoprost containing BAK alone and in combination with other antiglaucoma drug classes on corneal epithelium in vitro in a cultured rabbit corneal cell line (SIRC) and in vivo, using a corneal resistance device (CRD). [In vitro] staten's seruminstitut rabbit corneal cells were exposed to 0.005% latanoprost for 30s, followed by either phosphate buffered saline (control), 0.1% brimonidine, 0.5% timolol, 1% dorzolamide, or 1% brinzolamide. The number of viable cells was counted at 8, 15, and 30min. [In vivo] Albino rabbits were administered one drop of 0.005% latanoprost, followed 5min later by one drop of an agent from the in vitro trial. This was repeated every 15min for a total of three times. The change in corneal barrier function was assessed by measuring the corneal resistance at 2 and 30min after the final administration. [In vitro] At 8min, the viable cell count in the latanoprost+dorzolamide group was significantly lower than in the control group. At 15 and 30min, all treatment groups, except the latanoprost+brimonidine group, demonstrated significantly lower viable cell counts than the control group. [In vivo] At 2min after the final eye drop, the latanoprost+timolol group and the latanoprost+brinzolamide group demonstrated significantly lower corneal resistance than did the latanoprost+brimonidine group. No significant difference was observed between the agents at 30min. In conclusion, when combining latanoprost containing benzalkonium chloride with other classes of antiglaucoma drugs, brimonidine may cause the least corneal damage, and the number of drug administrations may be an important factor.

Topics: Animals; Brimonidine Tartrate; Cell Survival; Electric Impedance; Epithelium, Corneal; Intraocular Pressure; Latanoprost; Male; Ophthalmic Solutions; Prostaglandins F, Synthetic; Rabbits; Safety; Sulfonamides; Thiazines; Thiophenes; Timolol

The antiglaucoma drugs dorzolamide (1) and brinzolamide (2) lower intraocular pressure (IOP) by inhibiting the carbonic anhydrase (CA) enzyme to reduce aqueous humor production. The introduction of a nitric oxide (NO) donor into the alkyl side chain of dorzolamide (1) and brinzolamide (2) has led to the discovery of NO-dorzolamide 3a and NO-brinzolamide 4a, which could lower IOP through two mechanisms: CA inhibition to decrease aqueous humor secretion (reduce inflow) and NO release to increase aqueous humor drainage (increase outflow). Compounds 3a and 4a have shown improved efficacy of lowering IOP in both rabbits and monkeys compared to brinzolamide (2).

Topics: Animals; Carbonic Anhydrase Inhibitors; Drug Design; Glaucoma; Intraocular Pressure; Male; Nitric Oxide Donors; Rabbits; Sulfonamides; Thiazines; Thiophenes

A carbonic anhydrase (CA, EC 4.2.1.1) belonging to the γ-class has been cloned, purified and characterized from the Antarctic cyanobacterium Nostoc commune. The enzyme showed a good catalytic activity for the physiologic reaction (hydration of carbon dioxide to bicarbonate and a proton) with the following kinetic parameters, kcat of 9.5×10(5)s(-1) and kcat/KM of 8.3×10(7)M(-1)s(-1), being the γ-CA with the highest catalytic activity described so far. A range of aromatic/heterocyclic sulfonamides and one sulfamate were investigated as inhibitors of the new enzyme, denominated here NcoCA. The best NcoCA inhibitors were some sulfonylated sulfanilamide derivatives possessing elongated molecules, aminobenzolamide, acetazolamide, benzolamide, dorzolamide, brinzolamide and topiramate, which showed inhibition constants in the range of 40.3-92.3nM. As 1,5-bisphosphate carboxylase/oxygenase (RubisCO) and γ-CAs are closely associated in carboxysomes of cyanobacteria for enhancing the affinity of RubisCO for CO2 and the efficiency of photosynthesis, investigation of this new enzyme and its affinity for modulators of its activity may bring new insights in these crucial processes.

Topics: Amino Acid Sequence; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Molecular Sequence Data; Nostoc commune; Sequence Alignment; Sulfanilamide; Sulfanilamides; Sulfonamides; Thiazines; Thiophenes

To determine the effect of 1% brinzolamide, 2% dorzolamide hydrochloride or combination 2% dorzolamide hydrochloride/0 · 5% timolol to delay the elevation of the intraocular pressure in second eyes of dogs with primary closed-angle glaucoma.. Analysis of retrospectively collated data from 40 dogs with primary closed-angle glaucoma, where the non-affected eye was treated prophylactically with brinzolamide (n = 10), dorzolamide (n = 18) or combination dorzolamide/timolol therapy (n = 12).. The 40 treated dogs (median age of 76 · 2 months) comprised 25 females/15 males, 19 entire/21 neutered. Twenty dogs developed glaucoma in the contralateral eye (median time of 9 · 2 months). No statistically significant difference was identified during treatment failure between the treatment groups (P = 0 · 66). The second eye remained normotensive in 20 dogs; four dogs until the conclusion of the study (median: 27 · 0 months), three dogs until death (median: 15 · 4 months), seven dogs until lost to follow-up (median: 11 · 6 months). Out of these 20 dogs, treatment was discontinued because of lack of owner compliance in two dogs and following a local drug reaction in four dogs (median: 8 · 9 months).. There was no evidence that the tested drugs delayed elevation of intraocular pressure in contralateral eyes of dogs with primary closed-angle glaucoma.

Topics: Administration, Ophthalmic; Animals; Carbonic Anhydrase Inhibitors; Dog Diseases; Dogs; Drug Therapy, Combination; Female; Glaucoma, Angle-Closure; Intraocular Pressure; Male; Retrospective Studies; Sulfonamides; Thiazines; Thiophenes; Timolol

6 dogs (10 eyes) with keratitis following long-term topical treatment with a carbonic anhydrase inhibitor (CAI) were evaluated. In 4 dogs (6 eyes), CAI treatment was discontinued. Three dogs (4 eyes) underwent enucleation because of end-stage corneal disease. One dog was treated differently in each eye and thus was represented in both aforementioned groups.. Following initiation of treatment with a CAI (ie, brinzolamide or dorzolamide), the median time to development of severe ocular signs was 266 days (range, 133 to 679 days). Clinically severe ocular signs included ulcerative and nonulcerative perilimbal keratitis or severe diffuse keratitis with marked vascularization. The keratitis was refractory to treatment with anti-inflammatory medications. Histologic and immunohistochemical examination of enucleated globes was performed in 3 affected dogs and in 1 dog with keratitis that recovered. Corneal lesions included 2 distinct inflammatory infiltrates with plasma cells predominating in the anterior stroma and both T cells and neutrophils in the epithelium. Stromal plasma cells and overlying epithelium exhibited strong positive immunoreactivity for IgG.. Topical CAI treatment was discontinued in 4 dogs after a median of 209 days (range, 44 to 433 days), and in these dogs, clinical improvement was evident within 2 to 4 days of CAI treatment cessation. Signs of keratitis resolved in 12 to 25 days in these 4 dogs, and median follow-up time after CAI discontinuation was 25.5 months (range, 6 to 42 months), during which time signs of corneal disease did not recur.. On the basis of this small series, presumed topical CAI-associated keratitis in dogs appeared to be an uncommon immune-mediated disease that was not responsive to corticosteroid treatment. Affected patients improved rapidly, but only after discontinuation of CAI treatment. In dogs with glaucoma, clinicians should consider the development of punctate keratopathy and severe diffuse keratitis as potential adverse effects related to topical administration of CAIs, even after previously uneventful long-term use.

Topics: Animals; Carbonic Anhydrase Inhibitors; Dog Diseases; Dogs; Female; Glaucoma; Keratitis; Male; Sulfonamides; Thiazines; Thiophenes

Carbonic anhydrases (CAs, EC 4.2.1.1) are metalloenzymes that catalyze the reversible hydration of carbon dioxide and bicarbonate. Their pivotal role in metabolism, ubiquitous nature, and multiple isoforms (CA I-XIV) has made CAs an attractive drug target in clinical applications. The usefulness of CA inhibitors (CAIs) in the treatment of glaucoma and epilepsy are well documented. In addition several isoforms of CAs (namely, CA IX) also serve as biological markers for certain tumors, and therefore they have the potential for useful applications in the treatment of cancer. This is a structural study on the binding interactions of the widely used CA inhibitory drugs brinzolamide (marketed as Azopt®) and dorzolamide (marketed as Trusopt®) with CA II and a CA IX-mimic, which was created via site-directed mutagenesis of CA II cDNA such that the active site resembles that of CA IX. Also the inhibition of CA II and CA IX and molecular docking reveal brinzolamide to be a more potent inhibitor among the other catalytically active CA isoforms compared to dorzolamide. The structures show that the tail end of the sulfonamide inhibitor is critical in forming stabilizing interactions that influence tight binding; therefore, for future drug design it is the tail moiety that will ultimately determine isoform specificity.

Topics: Antigens, Neoplasm; Binding Sites; Carbonic Anhydrase II; Carbonic Anhydrase Inhibitors; Carbonic Anhydrase IX; Carbonic Anhydrases; Catalytic Domain; Crystallography, X-Ray; Humans; Kinetics; Molecular Docking Simulation; Mutagenesis, Site-Directed; Protein Binding; Structure-Activity Relationship; Sulfonamides; Thermodynamics; Thiazines; Thiophenes

To investigate whether a self-reported history of allergy to sulfa-based drugs is a predictor for subsequent adverse reactions to topical carbonic anhydrase inhibitors (CAIs).. A retrospective case-controlled cohort study via chart review was performed on 1,287 patients with a diagnosis of glaucoma. The outcome measure was the development of an adverse reaction (either ocular, systemic, or both) within at least 30 days after receipt of 1 of 4 classes of topical glaucoma medications: CAIs (dorzolamide and brinzolamide), prostaglandin analogues, beta-adrenergic blockers, and alpha2-adrenergic agonists.. Patients with a self-reported history of sulfa allergy had significantly more ocular adverse reactions after the initiation of any of the topical antiglaucoma medications when compared to those patients with no reported allergies. Patients with a self-reported sulfa allergy and patients who self-reported other, nonsulfa-related allergies had similar rates of adverse reactions to most of the topical medications. The patients reporting a sulfa allergy who used topical CAIs did not have more adverse reactions compared with patients who reported having other, nonsulfa-related allergies who used topical CAIs. Self-reported sulfa-allergic patients had similar rates of adverse reactions to topical CAIs compared with topical prostaglandin analogues.. It may be safe to use a topical CAI in patients who report a history of a sulfa allergy. Patients with medication allergies of any kind may be more likely to develop allergic reactions to other, unrelated drug classes.

Topics: Administration, Ophthalmic; Adrenergic alpha-2 Receptor Agonists; Adrenergic beta-Antagonists; Aged; Aged, 80 and over; Carbonic Anhydrase Inhibitors; Case-Control Studies; Cohort Studies; Drug Hypersensitivity; Female; Glaucoma; Humans; Male; Middle Aged; Prostaglandins; Retrospective Studies; Sulfonamides; Thiazines; Thiophenes

To evaluate prospectively whether anti-glaucomatic drugs administered prior to intravitreal anti-vascular endothelial growth factor (VEGF) injection bevacizumab (Avastin,® Roche) or ranibizumab (Lucentis,® Novartis) prevents intraocular hypertension after the injection.. In total, 166 patients (175 eyes) scheduled for intravitreal anti-VEGF injection treatment were prophylactically treated 1 hour before the procedure with Dorzolamide/Timolol (Cosopt,® MSD) (Group 1, 53 eyes) or Brinzolamide/Timolol (Elazop,® Alcon) (Group 2, 84 eyes) or left untreated (Group 3, 29 eyes). Intraocular pressure was analyzed 5 minutes prior to the injection, every 5 minutes for 30 minutes after the procedure, and 1 hour, 1 day, 7 days, and 1 month after the procedure.. The intraocular pressures 5 minutes before the procedure (baseline) for Groups 1, 2, and 3 were 12.06 ± 1.85, 13.98 ± 2.68, and 13.81 ± 2.24 mmHg, respectively. Five and 30 minutes after the procedure, the intraocular pressures of the three groups were 14.12 ± 4.18, 14.87 ± 3.35, and 28.21 ± 3.16 mmHg, respectively, and 10.87 ± 1.58, 14.25 ± 2.43, and 17.48 ± 2.34 mmHg, respectively. For all three groups, the changes relative to baseline 5 and 30 minutes after injection were significant. When the three groups were divided according to whether they received bevacizumab or ranibizumab and the changes in intraocular pressure relative to baseline were analyzed, all six subgroups exhibited significant changes in intraocular pressure 5 and 30 minutes after the procedure.. The prophylactic administration of anti-glaucomatic drugs prior to intravitreal anti-VEGF injection effectively reduced the early intraocular pressure elevation. This approach was also safe and could be performed accurately.

Topics: Administration, Topical; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antihypertensive Agents; Bevacizumab; Drug Therapy, Combination; Female; Humans; Intraocular Pressure; Intravitreal Injections; Male; Middle Aged; Ocular Hypertension; Ophthalmic Solutions; Prospective Studies; Ranibizumab; Retinal Diseases; Sulfonamides; Thiazines; Thiophenes; Timolol; Tonometry, Ocular; Vascular Endothelial Growth Factor A

Carbonic anhydrase inhibitors (CAIs) are used to reduce aqueous production in glaucoma, which includes a direct effect on the ciliary body. However, CAIs also affect ciliary blood flow, but the mechanisms of action of CAIs on the tone of intraocular ciliary arteries supplying the ciliary body have not been studied in detail.. The intraocular part of porcine ciliary arteries was isolated and mounted in a wire myograph system for isometric tension recordings. After contraction with the thromboxane analogue U46619, the vasorelaxing effect of the CAIs acetazolamide, brinzolamide and dorzolamide was studied. Subsequently, the involvement of the carbonic anhydrase reaction and nitric oxide (NO) in dorzolamide-induced vasorelaxation was characterized.. All CAIs induced relaxation of contracted ciliary arteries, but the effect of dorzolamide was most pronounced. Dorzolamide-induced relaxation was unaffected by changes in pH and CO(2), and by removal of substrates to the carbonic anhydrase enzyme, but was abolished after inhibition of NO synthase and guanylyl cyclase and after removal of the vascular endothelium.. Dorzolamide-induced vasorelaxation of ciliary arteries is independent of changes in the substances involved in the carbonic anhydrase reaction, but depends on NO and the vascular endothelium. The mechanism of action of dorzolamide in ocular disease may involve an effect on vascular tone mediated by NO.

Topics: Acetazolamide; Animals; Carbon Dioxide; Carbonic Anhydrase Inhibitors; Ciliary Arteries; Dose-Response Relationship, Drug; Endothelium, Vascular; Enzyme Inhibitors; Hydrogen-Ion Concentration; Isometric Contraction; Muscle, Smooth, Vascular; Nitric Oxide; Oxadiazoles; Quinoxalines; S-Nitroso-N-Acetylpenicillamine; Sulfonamides; Swine; Thiazines; Thiophenes; Vasodilation; Vasodilator Agents

Ophthalmic carbonic anhydrase inhibitors have been shown to improve retinal and optic nerve blood flow. However, the relative tissue distributions of commercially available carbonic anhydrase inhibitors to the optic nerve are not known. The objective of this study was to compare the ocular pharmacokinetics and tissue distribution profiles of dorzolamide and brinzolamide after single and multiple topical applications. Pigmented rabbits were treated with single or multiple topical administrations of 30 μl of Trusopt (dorzolamide hydrochloride ophthalmic solution, 2%) to one eye and 30 μl of Azopt (brinzolamide ophthalmic suspension, 1%) to the other eye. Rabbits were euthanized at 10 predetermined time intervals over a period of 24 h, and ocular tissues and plasma samples were collected. For multiple dosing, rabbits were dosed twice per day with an 8-h interval between two doses, groups of rabbits were euthanized at 7, 14, and 21 days at 1 h after the last dose, and ocular tissues and plasma samples were collected. Drug levels in tissue samples were measured using liquid chromatography/tandem mass spectrometry. Pharmacokinetic parameters (C(max), T(max), and AUC(0-24)) were estimated by noncompartmental analysis. After a single dose, dorzolamide delivery (AUC(0-24)) to the aqueous humor, anterior sclera, posterior sclera, anterior retina, posterior retina, anterior vitreous, and optic nerve was 2-, 7-, 2.6-, 1.4-, 1.9-, 1.2-, and 9-fold higher than those of brinzolamide. C(max) was 2- to 5-fold higher for dorzolamide than that of brinzolamide in all of the ocular tissue. After multiple dosing, dorzolamide levels in the aqueous humor, sclera, retina, vitreous humor, and optic nerve were higher than those of brinzolamide, but statistical significance was achieved only with aqueous humor, vitreous humor, and optic nerve. Dorzolamide levels in the aqueous humor, anterior vitreous, posterior vitreous, and optic nerve were 1.4- to 3.2-, 2.4- to 2.7-, 2.2- to 4.5-, and 2.4- to 5.2-fold higher than those of brinzolamide. Upon multiple dosing, both drugs accumulated in all of the tissues except the conjunctiva, where the drug levels were lower than those observed with single dosing. No significant differences were found in the AUC values of these two drugs in the cornea and conjunctiva after single and multiple dosing. Drug levels were significantly higher in anterior regions than posterior regions in the sclera, retina, and vitreous for both drugs.

Topics: Administration, Topical; Animals; Carbonic Anhydrase Inhibitors; Chromatography, Liquid; Drug Administration Schedule; Eye; Male; Optic Nerve; Rabbits; Regional Blood Flow; Sulfonamides; Tandem Mass Spectrometry; Thiazines; Thiophenes

Topically applied carbonic anhydrase inhibitors (CAIs) are commonly used to treat glaucoma. However, their short duration of action requiring multiple daily dosing can hamper patient compliance. The aim of this study was to develop novel aqueous CAI eye drop formulation containing self-assembled drug/cyclodextrin (D/CD) microparticles that enhance and prolong drug delivery to the eye. Phase-solubility of each drug tested (i.e. methazolamide, brinzolamide and dorzolamide HCl) was determined in either pure water or an aqueous eye drop medium. The pH was adjusted to maximize the fraction of unionized drug. Dorzolamide had the highest affinity for γ-cyclodextrin (γCD) and, thus, was selected for further investigation. Hydroxypropyl methylcellulose (HPMC) was the most effective polymer tested for stabilization of the dorzolamide/γCD complexes and gave the highest mucoadhesion at 0.5% w/v concentration. Thus, the dorzolamide eye drop vehicle containing γCD (18% w/v) and HPMC (0.5% w/v) was developed. The physicochemical properties of this formulation complied with the specifications of the eye drop suspension monograph of the European Pharmacopoeia. The in vivo testing of the formulation showed that the drug was delivered to the aqueous humor in rabbits for at least 24h with the maximum drug concentration at 4h. Furthermore, this formulation delivered the drug to the posterior segment of the eye after topical administration. These results indicate that this CAI eye drop formulation has the potential of being developed into a once-a-day product.

Topics: Administration, Topical; Animals; Carbonic Anhydrase Inhibitors; Delayed-Action Preparations; Drug Stability; Excipients; gamma-Cyclodextrins; Hydrogen-Ion Concentration; Hypromellose Derivatives; Methazolamide; Methylcellulose; Polymers; Rabbits; Solubility; Sulfonamides; Suspensions; Thiazines; Thiophenes; Time Factors; Tissue Distribution

Topics: Antihypertensive Agents; Blood Flow Velocity; Disease Progression; Drug Therapy, Combination; Glaucoma, Open-Angle; Humans; Optic Disk; Regional Blood Flow; Sulfonamides; Thiazines; Thiophenes; Timolol; Vision Disorders; Visual Fields

Systemic carbonic anhydrase (CA) inhibitors are among the most powerful agents to lower intraocular pressure. Unfortunately, their use is frequently accompanied by undesired side effects. Some are due to the relatively large amounts of drug that have to be systematically administered to inhibit the CA in the ciliary processes. The aim of the present work was to study in vitro effects of some pesticides on CA enzyme obtained from blood of fish, which play a key role in salt- and osmoregulation and acid-base balance in the fish, Oncorhynchus mykiss and Cyprinus carpio carpio living in freshwaters, and compared with CA inhibitors. CA activities were significantly inhibited by pesticides and inhibitors. I(50) values of O. mykiss CA enzyme inhibited by lambda-cyhalothrin, deltametrin, diozinon, dorzolamide and brinzolamide were 6.05 x 10(-4), 1.48 x 10(-5), 6.84 x 10(-3), 3.82 x 10(-5) and 1.80 x 10(-6) mol/l, and that for C. c. carpio 6.86 x 10(-4), 4.70 x 10(-4), 3.92 x 10(-3), 8.34 x 10(-6) and 1.42 x 10(-6) mol/l, respectively. The pesticides used in this study inhibited the CA activity from different fish species to various degrees. It was found that the most effective inhibitor of CA enzyme within pesticides used was detrametrin. These findings observed in vitro could be useful in the understanding of the toxic effects that pesticides elicit on aquatic organisms in vivo.

Topics: Animals; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Carps; Diazinon; In Vitro Techniques; Insecticides; Nitriles; Oncorhynchus mykiss; Pyrethrins; Sulfonamides; Thiazines; Thiophenes; Water Pollutants, Chemical

The aim of this study was to compare brinzolamide with dorzolamide in regard to blurred vision after instillation. We also compared saline with two topical carbonic anhydrase inhibitor drugs.. The study population comprised 21 healthy volunteers whose best corrected visual acuity was 1.0 or better. Brinzolamide 1% or dorzolamide 1% was applied to one eye the contralateral eye was exposed to the other drug. At 30 sec after instillation, visual acuity was measured every 30 sec until best visual acuity was recovered. Because visual acuity can fluctuate widely with blinking, subjects blinked for 5 sec before visual acuity measurement. As control, we applied saline alone to both eyes of 14 subjects and measured the change in visual acuity in the same way. Subjective sensations in each eye were recorded after measurement.. Average visual acuity every 30 sec for 5 min was 0.41, 0.56, 0.68, 0.86, 0.87, 0.96, 1.04, 1.08, 1.11, and 1.12 after dorzolamide instillation, and 0.28, 0.42, 0.60, 0.69, 0.81, 0.91, 0.93, 0.99, 1.06, and 1.10 after brinzolamide instillation. In contrast, the average visual acuity after saline instillation for 2 min was 1.09, 1.13, 1.16 and 1.16. Of the 21 subjects, 15 (71.4%) felt moderate or severe irritation when dorzolamide was instilled; 2 (9.5%) felt moderate or severe irritation when brinzolamide was instilled.. Both brinzolamide and dorzolamide caused significantly prolonged blurring of vision, from 30 sec to 2 or 3 min after instillation, as compared with saline only. The average visual acuity after brinzolamide instillation was lower than after dorzolamide for 5 min after instillation, although there was no significant difference. Judging from the subjects' sensations, it is suggested that with dorzolamide the prolonged blurred vision was due to reflex tearing from irritation, as explained above, whereas with brinzolamide it was due to opaque tears on the ocular surface.

Topics: Administration, Topical; Adult; Carbonic Anhydrase Inhibitors; Female; Humans; Male; Middle Aged; Sulfonamides; Tears; Thiazines; Thiophenes; Time Factors; Visual Acuity

Reaction of 3- and 4-carboxybenzenesulfonyl chloride with 5-amino-1,3,4-thiadiazole-2-sulfonamide/5-imino-4-methyl-delta(2)-1,3,4-thiadiazoline-2-sulfonamide afforded two series of benzolamide analogues to which the carboxyl moiety has been derivatized as esters or amides, in order to reduce their very polar character. The new derivatives showed low nanomolar affinity for three carbonic anhydrase (CA) isozymes, CA I, II and IV, and were effective as topical antiglaucoma agents in normotensive rabbits. Efficacy of several of the new sulfonamides reported was better than that of the standard drugs dorzolamide and brinzolamide, whereas their duration of action was prolonged as compared to that of the clinically used drugs.

Topics: Administration, Topical; Animals; Benzolamide; Carbonic Anhydrase I; Carbonic Anhydrase II; Carbonic Anhydrase Inhibitors; Carbonic Anhydrase IV; Cattle; Esters; Glaucoma; Humans; Intraocular Pressure; Rabbits; Structure-Activity Relationship; Sulfonamides; Thiazines; Thiophenes

Over releasing of glutamate and cellular calcium influx always results in neuronal death. In the present study, we investigated various commercial antiglaucoma drugs including timolol (0.58 microM to 58 microM), betaxolol (1.62 microM to 162 microM), carteolol (6.8 microM to 680 microM), pilocarpine (4.08 microM to 408 microM), latanoprost (0.01 microM to 1.1 microM), dorzolamide (6.16 microM to 616 microM), brinzolamide (2.6 microM to 260 microM), brimonidine (0.68 microM to 68 microM), dipivefrin (0.28 microM to 28 microM) and preservative benzalkonium chloride on their effects to inhibit glutamate-induced intracellular free Ca(2+) ([Ca(2+)](i)) increase in cultured N1E-115 neuroblastoma cells. These drugs were diluted from original concentrations to 1/100, 1/1000 and 1/10000. The [Ca(2+)](i) mobility was studied after loading with fura-2-AM and analyzed by spectrofluorometry. It was found that betaxolol, dipivefrin and brimonidine have remarkable effects not only to inhibit the glutamate-induced [Ca(2+)](i) increase but also to decrease the basal [Ca(2+)](i). In the case of other drugs, only high concentration of timolol (58 microM) exhibited significant effect to completely prevent glutamate-induced [Ca(2+)](i) increase. Moreover, benzalkonium chloride did not exhibit any inhibitive effect. These results indicate that betaxolol, dipivefrin and brimonidine may have neuroprotective effects to inhibit the glutamate-induced over Ca(2+) influx damage.

Topics: Animals; Antihypertensive Agents; Betaxolol; Brimonidine Tartrate; Calcium; Carteolol; Cell Death; Dose-Response Relationship, Drug; Epinephrine; Glaucoma; Glutamic Acid; Latanoprost; Mice; Neuroblastoma; Neurons; Neuroprotective Agents; Pilocarpine; Prostaglandins F, Synthetic; Quinoxalines; Sulfonamides; Thiazines; Thiophenes; Timolol; Tumor Cells, Cultured

Sulfonamides incorporating cis-5-norbornene-endo-3-carboxy-2-carboxamido moieties in their molecules were prepared by reaction of cis-5-norbornene-endo-2,3-dicarboxylic anhydride with aromatic/heterocyclic sulfonamides possessing free amino, hydrazino, or imino groups. Some of these compounds showed very good CA II and CA IV inhibitory properties, with affinities for the enzymes in the low nanomolar range. Some of the most active CA II inhibitors reported here have been formulated as aqueous solutions for topical administration as antiglaucoma agents in normotensive rabbits. Some of the derivatives incorporating cis-5-norbornene-endo-3-carboxy-2-carboxamido and aromatic sulfonamide moieties (as sodium salts) showed effective and longer lasting intraocular pressure (IOP) lowering as compared to dorzolamide, a widely used topical antiglaucoma drug. Compounds incorporating cis-5-norbornene-endo-2,3-carboximido moieties, although stronger in vitro CA inhibitors as compared to the corresponding cis-5-norbornene-endo-3-carboxy-2-carboxamido-;derivatives, showed no topical IOP lowering properties, probably due to their very poor water solubility.

Topics: Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Cloning, Molecular; Escherichia coli; Glaucoma; Humans; Indicators and Reagents; Isoenzymes; Kinetics; Norbornanes; Recombinant Proteins; Structure-Activity Relationship; Sulfonamides; Thiazines; Thiophenes

Topical carbonic anhydrase inhibitors have been used since 1995 for medical glaucoma therapy, when dorzolamide was approved. In 2000, a second carbonic anhydrase inhibitor, brinzolamide, has become available in most of Europe. Both substances exhibit a comparable intraocular pressure-lowering activity, however, the side-effects are somewhat different. In the five years since its introduction, dorzolamide has had a positive risk-benefit-profile. In combination with any other topical agent, carbonic anhydrase inhibitors have an additive effect on the reduction of the intraocular pressure. Animal studies suggest that dorzolamide may improve ocular blood flow independent of the intraocular pressure; however, the significance for human glaucoma remains to be established.

Topics: Administration, Topical; Adrenergic beta-Antagonists; Animals; Antihypertensive Agents; Carbonic Anhydrase Inhibitors; Glaucoma; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Rabbits; Sulfonamides; Thiazines; Thiophenes; Time Factors; Timolol

Using a three-way crossover study design, we compared the effects of brinzolamide 2%, dorzolamide 2%, and placebo (vehicle) on microvascular optic nerve head (ONH) blood flow, intraocular pressure (IOP), blood pressure, heart rate, and acid-base balance in nine acepromazine-tranquilized Dutch-belted rabbits.. Baseline measurements were taken before treatment and after drug-free washout periods of 7-14 days. Microvascular ONH blood flow was measured with a fundus camera-based laser Doppler flowmeter (LDF). Intraocular pressure was measured with a Tono-Pen XL. One drop of brinzolamide, dorzolamide, or vehicle was administered twice daily (9 A.M. and 5 P.M.) in right eyes only for 7 days. Experimental measurements were made 90 minutes after the 9 A.M. topical dose was administered on day 8.. ONH blood flow was significantly increased (P< or =0.05) in carbonic anhydrase inhibitor (CAI)-treated rabbits, as compared with vehicle-treated controls. The percent increase from baseline was 11.2+/-1.8% in brinzolamide-treated animals and 8.4+/-4.3% in dorzolamide-treated animals. Compared with controls, IOP in the brinzolamide- and dorzolamide-treated groups was significantly decreased (P< or =0.05). The changes in ONH blood flow and IOP were not significantly different between the CAI treatment groups. Small but significant changes in systemic blood gas tensions and pH were present in both CAI treatment groups, as compared with the vehicle group. Systemic blood pressure and heart rate were not significantly changed.. Topical ocular CAI treatment for 1 week with either brinzolamide or dorzolamide significantly reduced IOP and significantly increased ONH blood flow in tranquilized Dutch-belted rabbits, while eliciting minimal systemic acid-base balance disturbances.

Topics: Animals; Blood Flow Velocity; Carbonic Anhydrase Inhibitors; Cross-Over Studies; Hemodynamics; Intraocular Pressure; Laser-Doppler Flowmetry; Male; Ophthalmic Solutions; Optic Disk; Rabbits; Sulfonamides; Thiazines; Thiophenes