Effect of selected antihypertensives, antidiabetics, statins and diuretics on adjunctive medical treatment of glaucoma: a population based study.

BACKGROUND: The prevalence of open angle glaucoma increases with age, with many patients also receiving medications for non-ocular systemic diseases. Little is known about how systemic medications impact on the need for adjunctive therapy with prostaglandin analogues (PGA). OBJECTIVES: To evaluate whether systemic medications for hypertension, cholesterol, or glucose influence the need for adjunctive intraocular pressure (IOP) lowering medications in patients using PGAs. METHODS: Pharmaceutical records from the Québec prescription database provided a sample of patients receiving prescriptions for bimatoprost, latanoprost, or travoprost, from which subjects receiving > or =1 prescription for antihypertensives, antidiabetics. diuretics, and statins were identified. Chi-square tests compared proportions using PGAs to those using PGAs + adjunctive therapy, based on the use or non-use of systemic medications; a logistic regression was performed post hoc to adjust for gender and age. RESULTS: Of the 8548 evaluated patients (all using PGAs); 2934 (34.3%) took none of the studied systemic drugs. For the 5614 patients taking systemic medications, significantly fewer (p < 0.001) required an additional IOP lowering medication if taking a systemic antihypertensive medication. The use of a statin or a diabetic medication, alone or in combination, in addition to a PGA, made no significant difference in the need for adjunct glaucoma therapy. Individual drugs associated with significantly less utilization of adjunctive glaucoma medications were calcium-channel blockers, angiotensin-converting enzyme (ACE), and combination antihypertensive therapies. DISCUSSION: A profound association between systemic antihypertensive use and a reduced need for adjunct topical IOP lowering medications in patients using the same prostaglandin analogue for at least one year was found. LIMITATIONS: The use of a prescription claims database without patient compliance or patient outcomes may not reflect actual patient medication use. In addition, these findings may not be applicable to all patients initiating prostaglandin analogues. CONCLUSIONS: In this real-world population-based evaluation, a significant association exists between using systemic antihypertensive medications and reduced use of adjunctive IOP lowering therapies. These results confirm findings from previous studies suggesting an IOP lowering effect with systemic agents or some synergy with topical therapies.

Travoprost compared with latanoprost and timolol in patients with open-angle glaucoma or ocular hypertension.

PURPOSE: This study evaluated the safety and intraocular pressure-lowering efficacy of two concentrations of travoprost (0.0015% and 0.004%) compared with latanoprost 0.005% and timolol 0.5% in patients with open-angle glaucoma or ocular hypertension. METHODS: Eight hundred one patients with open-angle glaucoma or ocular hypertension were randomly assigned to travoprost 0.0015%, travoprost 0.004%, latanoprost 0.005%, or timolol 0.5%. The efficacy and safety of travoprost (0.0015% and 0.004%) daily was compared with latanoprost daily and timolol twice daily for a period of 12 months. RESULTS: Travoprost was equal or superior to latanoprost and superior to timolol with mean intraocular pressure over visits and time of day ranging from 17.9 to 19.1 mm Hg (travoprost 0.0015%), 17.7 to 19.1 mm Hg (travoprost 0.004%), 18.5 to 19.2 mm Hg (latanoprost), and 19.4 to 20.3 mm Hg (timolol). For all visits pooled, the mean intraocular pressure at 4 PM for travoprost was 0.7 mm Hg (0.0015%, P =.0502) and 0.8 mm Hg (0.004%, P =.0191) lower than for latanoprost. Travoprost 0.004% was more effective than latanoprost and timolol in reducing intraocular pressure in black patients by up to 2.4 mm Hg (versus latanoprost) and 4.6 mm Hg (versus timolol). Based on a criterion of 30% or greater intraocular pressure reduction from diurnal baseline or intraocular pressure 17 mm Hg or less, travoprost 0.0015% and 0.004% had an overall response to treatment of 49.3% and 54.7%, respectively, compared with 49.6% for latanoprost and 39.0% for timolol. Iris pigmentation change was observed in 10 of 201 of patients (5.0%) receiving travoprost 0.0015%, six of 196 of patients (3.1%) receiving travoprost 0.004%, 10 of 194 of patients (5.2%) receiving latanoprost, and none of the patients receiving timolol (0 of 196). The average ocular hyperemia score was less than 1 on a scale of 0 to 3, indicating that on average patients experienced between none/trace and mild for all treatment groups. There were no serious, unexpected, related adverse events reported for any therapy. CONCLUSIONS: Travoprost (0.0015% and 0.004%), a highly selective, potent prostaglandin F (FP) receptor agonist, is equal or superior to latanoprost and superior to timolol in lowering intraocular pressure in patients with open-angle glaucoma or ocular hypertension. In addition, travoprost 0.004% is significantly better than either latanoprost or timolol in lowering intraocular pressure in black patients. Travoprost is safe and generally well tolerated in the studied patient population.

Effects of time of storage, albumin, and osmolality changes on outflow facility (C) of bovine anterior segment in vitro.

PURPOSE: To analyze the influence of time of storage, the presence of albumin at physiological concentrations, and the perfusion with anisosmotic media on the aqueous humor outflow facility (C) of isolated bovine anterior segments (AS). METHODS: Anterior segments dissected from cow eyes were perfused at a constant pressure of 10 mm Hg with Dulbecco's modified Eagle's medium (DMEM; osmolality 300 mOsm/kg), with hyposmotic media (150, 210, and 270 mOsm/kg), or with hyperosmotic media (360, 420, and 480 mOsm/kg). Outflow facility was calculated every 5 seconds as the ratio between average inflow from the reservoir (in microliters per minute) and the perfusion pressure (in millimeters of mercury). Three groups were studied: a 0-hour group, with AS perfused with DMEM 1 to 3 hours after enucleation; a 0-hour alb-group, with AS perfused with DMEM plus 0.1 mg/ml albumin 1 to 3 hours after enucleation; and a 24-hour group, with AS perfused after storage for 24 hours in DMEM. In the 0-hour groups, perfusion with increasingly hyposmotic or hyperosmotic media was also made in 30-minute steps, followed by a return to isosmotic medium for 90 minutes. RESULTS: Perfusion of AS with DMEM for 9 hours caused a progressive increase in C that was statistically significant at 225 minutes in the 0-hour group perfused with DMEM and at 195 minutes in the 24-hour group perfused with DMEM. The 0-hour alb-group perfused with DMEM did not show changes in C throughout the 9-hour perfusion period. Perfusion with increasingly hyposmotic media induced a progressive decrease in C that did not recover on return to isotonic medium. Hyperosmotic media caused a progressive increase in C that returned to control values when isotonic medium was again perfused. CONCLUSIONS: Preservation of tissue for C measurements is best achieved with short storage time (1 to 3 hours). Physiological concentrations of albumin (0.1 mg/ml) prevent development of washout, suggesting that albumin or an albumin-bound factor in aqueous humor may play a role in the maintenance of outflow resistance. Outflow facility also may be influenced by volume changes in the trabecular meshwork.

Facility changes mediated by cAMP in the bovine anterior segment in vitro.

The aim of this study was to investigate the influence of substances that increase intracellular cAMP levels on the aqueous humor outflow facility (C) of isolated bovine anterior segments. Anterior segments were perfused in vitro at a constant pressure of 10 mmHg for 270 min with a general protocol as follows: 90 min control perfusion with DMEM, 90 min of experimental perfusion with DMEM containing the test drug(s), and 90 min of postdrug-perfusion with DMEM. C was calculated as the ratio between the rate of medium inflow (microliter/min) and the perfusion pressure (mmHg). Anterior segments can be perfused in vitro for up to 5 hr without significantly modifying their C. The addition of epinephrine, forskolin, dibutyryl-cAMP or isobutylmethylxanthine to the control perfusion medium elicited a significant increase of C. If, during isobutylmethylxanthine perfusion, forskolin or epinephrine was added, C increased significantly. Finally, perfusion with indomethacin prior to addition of epinephrine prevented the increase of C induced by epinephrine. Epinephrine, the adenylate cyclase activator forskolin, the cAMP analog dibutyryl-cAMP, and the phosphodiesterase inhibitor isobutylmethylxanthine all increase aqueous facility. It seems reasonable to suspect that the cAMP system is involved in epinephrine's effects on bovine trabecular meshwork cells. Moreover, the complete inhibition by indomethacin of the outflow facility increase induced by epinephrine suggests that prostaglandins may be involved in the outflow facility mechanisms related to adrenoreceptor stimulation of trabecular meshwork cells.

Treatment of chronic nonbacterial conjunctivitis with a cyclo-oxygenase inhibitor or a corticosteroid. Pranoprofen Study Group.

A multicenter, double-masked, parallel-group clinical trial was carried out in 151 patients with moderate to severe chronic conjunctivitis. The study compared the antiinflammatory efficacy and safety of pranoprofen 0.1%, a new cyclo-oxygenase inhibitor, with fluorometholone 0.1%, after topical doses four times a day for 15 days. The basal mean score for the signs and symptoms of inflammation, was significantly reduced (P < .001), with no significant difference between the two groups, at days 8 and 15. There was a statistically significant difference of approximately 1.0 mm Hg (P < .05) in the mean intraocular pressure between treatment, which was a decrease of 0.3 mm Hg with pranoprofen and an increase of 0.8 mm Hg with fluorometholone. One patient in the pranoprofen group had an adverse experience, compared to nine patients in the fluorometholone group (P < .03). Our data suggest that pranoprofen has efficacy equivalent to a moderate-potency corticosteroid with a better safety profile. It should be considered for the treatment of chronic conjunctivitis of presumed nonbacterial origin.

Disinfecting activities of non-peroxide soft contact lens cold disinfection solutions.

The antimicrobial activities of three non-peroxide soft contact lens chemical disinfection systems--ReNu Multi-Purpose Solution (0.00005% polyaminopropyl biguanide), Opti-Soft Disinfecting Solution (0.001% polyquaternium-1), and Opti-Free Rinsing, Disinfecting & Storage Solution (0.001% polyquaternium-1)--were compared to Soft Mate Disinfecting Solution (0.005% chlorhexidine digluconate). Each product was separately inoculated with each of five microorganisms at approximately 10(6) microorganisms per mL. All of the solutions demonstrated excellent disinfecting activity against Pseudomonas aeruginosa and Staphylococcus epidermidis, with complete disinfection occurring within 4 hours. Only Soft Mate disinfected Serratia marcescens within 4 hours. ReNu reduced the microorganisms to 10-100 cells/mL and Opti-Soft and Opti-Free reduced the number to 10(2)-10(3) cells/mL. For the fungal species, Soft Mate showed excellent activity against Candida albicans (disinfection in 4 hours) and reduced Aspergillus fumigatus to 10(3) spores/mL in 4 hours. After 4 hours ReNu, Opti-Soft, and Opti-Free had reduced C. albicans only slightly, to 10(5) cells/mL and displayed virtually no disinfecting activity against A. fumigatus. For these newer chemical disinfection systems, diligent cleaning and rinsing of the soft contact lenses are the most important steps in the patient care regimen.

The ocular hypotensive action of SK&F 86466 in the conscious rabbit.

SK&F 86466, 6-chloro-3-methyl-2, 3, 4, 5-tetrahydro-1H-3-benzazepine, a potent and selective competitive antagonist of the alpha 2-adrenoceptor is of interest as a potential antiglaucoma agent. Following instillation into the rabbit eye, SK&F 86466 produced concentration (0.25 to 10%) dependent reductions in intraocular pressure (IOP). The ocular hypotensive effect of SK&F 86466 was maximal 30-60 minutes post treatment and persisted for at least 90 minutes. The IOP of the contralateral (untreated) eye was significantly decreased only at the 10% concentration. A 10% solution of SK&F 86466 had no significant effect on mean arterial blood pressure (MAP) of rabbits during the time of maximal bilateral ocular hypotensive activity. These results suggest: (1) a selective alpha 2-adrenoceptor antagonist can reduce IOP when applied topically to rabbit eyes and (2) the ocular hypotensive effect of SK&F 86466 is not secondary to a reduction in systemic blood pressure.

Suppression of adrenergic adaptation in the eye with a prostaglandin synthesis inhibitor.

The treatment of glaucoma patients with a topical medication is sometimes associated with adaptation (the development of subsensitivity) to the effect of the medication. In the rabbit eye, adaptation develops when norepinephrine is administered topically on a daily basis. A marked decrease in the intraocular pressure is observed the first day, but diminishing responses are observed on subsequent days. Since prostaglandins may be released in response to catecholamines and have been found to inhibit adrenergic neurotransmission, we treated rabbits with topical flurbiprofen, a potent cyclooxygenase (prostaglandin synthesis) inhibitor, to suppress adaptation to norepinephrine. The results demonstrate a significant suppression of adaptation in the concentration range of 0.001% flurbiprofen (p less then 0.0005). This finding supports the theory that cyclooxygenase products mediate the development of adaptation to exogenous norepinephrine in the rabbit eye.

Topical flurbiprofen or prednisolone. Effect on corneal wound healing in rabbits.

Flurbiprofen is a nonsteroidal anti-inflammatory (NSAI) agent currently undergoing clinical investigation. Anti-inflammatory steroids have long been known to delay the healing of corneal stromal wounds. This was designed to compare the effects of equipotent anti-inflammatory doses of flurbiprofen and of prednisolone acetate on the inflammation and the healing (as measured by the wound bursting pressure) or 4-mm through-and-through incisions treated four times a day for ten postoperative days. The results suggest that flurbiprofen and prednisolone are not different in their effect on both postoperative inflammation and postoperative wound healing. Since NSAI agents and steroids inhibit prostaglandin formation at different enzymatic steps, it is possible that prostaglandins not only are responsible for postoperative inflammation but also are required for postoperative wound healing.

Use of flurbiprofen to inhibit corneal neovascularization.

Following the suggestion that prostaglandins are involved in corneal neovascularization, two inhibitors of prostaglandin formation, prednisolone acetate and flurbiprofen sodium, have been evaluated in two experimental models of corneal neovascularization. The fatty acid cyclooxygenase inhibitor, flurbiprofen, at concentrations of 0.01% and 0.1%, significantly decreased the rate of vessel growth compared with vehicle controls in both silver nitrate cauterization and anterior chamber alloxan models of corneal neovascularization. Prednisolone, at a concentration of 1%, was used as a positive control. It did inhibit neovascularization in the latter model, but was ineffective in the former. It is concluded that 0.1% flurbiprofen is equipotent to 1% prednisolone as an inhibitor of corneal neovascularization. The mechanism is unknown but is likely to be via inhibition of prostaglandin formation and/or inhibition of leukocytic infiltration.

Kinetic studies of sheep kidney gamma-glutamyl transpeptidase.

The kinetics of sheep kidney gamma-glutamyl transpeptidase was studied using a novel substrate L-alpha-methyl-gamma-glutamyl-L-alpha-aminobutyrate. When the substrate was incubated with the enzyme in the presence of an amino acid or peptide acceptor, the corresponding L-alpha-methyl-gamma-glutamyl derivatives of the acceptors were formed. In the absence of acceptor only hydrolysis occurred, and no transpeptidation products were detected. The presence of the methyl group on the alpha-carbon apparently prevents enzymatic transfer of the L-alpha-methyl-gamma-glutamyl residue to the amino group of the substrate itself (autotranspeptidation). When the enzyme was incubated with conventional substrates, such as glutathione or gamma-glutamyl-p-nitroanilide and an amino acid acceptor, hydrolysis, autotranspeptidation, and transpeptidation to the acceptor occurred concurrently. Initial velocity measurements in which the concentration of L-alpha-methyl-gamma-glutamyl-L-alpha-aminobutyrate was varied at several fixed acceptor concentrations, and either the release of alpha-aminobutyrate or the formation of the transpeptidation products was determined, yielded results which are consistent with a ping-pong mechanism modified by a hydrolytic shunt. A scheme of such a mechanism is presented. This mechanism predicts the formation of an alpha-methyl-gamma-glutamyl-enzyme intermediate, which can react with an amino acid to form the transpeptidation product; or in the absence of, or in the presence of low concentrations of amino acids, can react with water to form the hydrolytic products. Kinetic derivations for the reaction of the enzyme with the conventional substrate gamma-glutamyl-p-nitroanilide predict either linear or nonlinear double-reciprocal plots, depending on the prevalence of the hydrolytic, autotranspeptidation, or transpeptidation reactions. The results of kinetic experiments confirmed these predictions.