Emerging perspectives on glaucoma: highlights of a roundtable discussion.

PURPOSE: To present emerging perspectives on open-angle glaucoma related to patient compliance, current drug therapy, and treatment options. METHODS: Roundtable discussion. RESULTS: The panel discussion identified the following issues about patient compliance:1. It is a common problem in clinical practice and is often underappreciated by physicians.2. It is difficult for clinicians to detect.3. There are several risk factors that increase the probability of noncompliance. 4. Compliance can be improved through education, communication, improvement of the doctor-patient relationship, compliance aids, and simplifying the treatment regimen. CONCLUSION: Patients' compliance with the therapeutic regimen for open-angle glaucoma is very important to the eventual outcome of their disease treatment. Physicians can improve their patients' compliance by a few simple, cost-effective interventions in the clinical setting. When considering different agents as first-line therapies, once-a-day dosing would be optimal for enhancing compliance.

A new look at dry eye disease and its treatment.

This review examines the impact of moderate to severe dry eye disease on daily life and medical-resource utilization. The results suggest that current treatment paradigms can lead to unacceptable costs in both quality of life and progressive use of healthcare resources. Evidence linking this disease to T-cell-mediated inflammatory processes lays the foundation for understanding the clinical benefits of topical cyclosporine, an immunomodulatory and anti-inflammatory agent.

Tissue plasminogen activator to treat impending pupillary block glaucoma in patients with acute fibrinous HLA-B27 positive iridocyclitis.

PURPOSE: To report the use of intracameral tissue plasminogen activator to dissolve fibrinous membranes and break posterior synechiae in patients with acute HLA-B27-positive iridocyclitis with impending pupillary block. METHODS: Two patients with severe acute fibrinous iridocyclitis and seclusio pupillae were identified. Because of the concern of impending pupillary block, intracameral tissue plasminogen activator (12.5 microg in 0.1 ml, Activase; Genentech, Inc, South San Francisco, California) was injected with a 25-gauge needle through the corneal limbus. RESULTS: Both patients showed complete dissolution of fibrin with disruption of posterior synechiae. There were no adverse events after injection. Neither patient required further invasive intervention, and both fully recovered with medical management. CONCLUSIONS: Intracameral tissue plasminogen activator is a safe and effective agent for patients with severe acute iridocyclitis and pupillary seclusion. Patients with clinical signs suggestive of impending pupillary block glaucoma may be considered for tissue plasminogen activator injection to avoid the possible need for emergency surgical iridectomy and synechiolysis.

Aqueous and vitreous penetration of levofloxacin after oral administration.

OBJECTIVE: To investigate the penetration of levofloxacin, an optical S-(-)isomer of ofloxacin, into the aqueous and vitreous humor after oral administration. DESIGN: Randomized, clinical trial comparing tissue levels of levofloxacin after one or two doses 12 hours apart. PARTICIPANTS: Forty-five patients undergoing initial vitrectomy between February 1997 and June 1997 at the UIC Eye Center. METHODS: Aqueous, vitreous, and serum samples were obtained and later analyzed from 45 patients after oral administration of 1 500-mg tablet (group 1, 22 patients) or 2 500-mg tablets (group 2, 23 patients) 12 hours apart before surgery. MAIN OUTCOME MEASURES: Aqueous, vitreous, and serum concentrations of levofloxacin (micrograms/milliliter). RESULTS: Group 1 achieved mean aqueous, vitreous, and serum levels of 0.59 +/- 0.48 microg/ml, 0.32 +/- 0.34 microg/ml, and 4.34 +/- 3.59 microg/ml, respectively. Group 2 achieved mean aqueous, vitreous, and serum levels of 1.90 +/- 0.97 microg/ml, 2.39 +/- 0.70 microg/ml, and 8.02 +/- 3.14 microg/ml. CONCLUSIONS: Mean inhibitory aqueous and vitreous MIC90 levels were achieved against a majority of ocular pathogens, including Staphylococcus aureus and Staphylococcus epidermidis, Streptococcus pneumoniae (vitreous), Bacillus cereus (vitreous), Haemophilus influenzae, Moraxella catarrhalis, and most gram-negative aerobic organisms except Pseudomonas aeruginosa after two doses given 12 hours apart. Mean MIC90 levels were obtained in the vitreous for a majority of pathogens responsible for traumatic, postoperative, or bleb-related endophthalmitis.

Cost considerations of medical therapy for glaucoma.

PURPOSE: To determine the calculated daily patient cost (cost minimization) of medical glaucoma therapy. METHODS: The actual volume of various glaucoma medications was determined for all commercially available sizes of the tested products. The drops per ml on the basis of the actual volume and the daily costs of the dosage schedules recommended by the manufacturers were compared. The cost of each bottle of medication was determined from the average wholesale price in the United States. RESULTS: The generic timolol products dosed twice daily and the once-daily gel-forming solutions (range, $0.30 to $0.46/day) were similar on a cost-per-day basis compared with the brand name metipranolol (Optipranolol; Bausch & Lomb Pharmaceuticals, Tampa, Florida, at $0.43/day) and timolol (Timoptic; Merck, West Point, Pennsylvania, at $0.46/day and Timoptic XE at $0.38/ day). Betaxolol (Betoptic S; Alcon Laboratories, Fort Worth, Texas, at $0.65/day), carteolol (Ocupress; CibaVision, Duluth, Georgia, at $0.57/day), levobunolol ($0.61/day), and brand name levobunolol (Betagan; Allergan, Irvine, California, at $0.81/day) all were dosed twice daily and were more costly on a per-day basis. The topical carbonic anhydrase inhibitors brinzolamide (Azopt; Alcon, at $0.96/day) and dorzolamide (Trusopt; Merck, at $1.02/day) were dosed three times daily and were similar on a cost-per-day basis. The combination product Cosopt (timolol 0.5% + dorzolamide 2.0%, Merck, at $1.12/day) was less costly than separate bottles of a topical carbonic anhydrase inhibitor (three times daily dosing) and a beta-blocker ($1.26 to $1.83/day), often even if the topical carbonic anhydrase inhibitor was dosed two times daily ($0.94 to $1.49). The selective alpha2-agonist brimonidine (Alphagan; Allergan, at $0.90/day) twice daily and the prostaglandin analog latanoprost (Xalatan; Pharmacia & Upjohn, Kalamazoo, Michigan, at $0.92/day) once daily were similarly priced. CONCLUSIONS: All generic timolol, Optipranolol, Timoptic, and Timoptic XE ranged between $0.30 and $0.46 per day. Betaxolol, Ocupress, generic levobunolol, and Betagan were more costly, ranging between $0.57 and $0.81 per day. Cosopt ($1.12/day) was less costly than separate bottles of a topical beta-blocker and a topical carbonic anhydrase inhibitor dosed three times daily ($1.26 to $1.83/day) and often twice daily ($0.94 to $1.49). Alphagan and Xalatan were similarly priced ($0.90/day and $0.92/day, respectively). This study is based on a best-case scenario for all medicines and does not account for wasted doses, the frequency of refills, or a medication's success or failure rate. New adjunctive glaucoma regimens exhibit similar costs per day compared with more traditional regimens.

Intraocular penetration of gentamicin after once-daily aminoglycoside dosing.

BACKGROUND: Intraocular concentrations-particularly intravitreal concentrations-after systemic administration of gentamicin are poor. Once-daily aminoglycoside dosing of intravenous gentamicin achieves peak serum levels up to five times higher than conventional dosing. Whether these increased serum levels of gentamicin improve the aqueous or vitreous concentrations in humans has not been determined. The authors sought to determine if the intraocular penetration of gentamicin would be improved using this method. METHODS: Patients undergoing vitrectomy procedures were administered intravenous gentamicin in a dose of 7 mg/kg approximately 1 hour before surgery. An adjustment in dosing was made for anyone more than 20% over his or her ideal body weight. Aqueous, vitreous, and serum samples were collected before any intraocular surgical manipulation. The samples were analyzed by fluorescence polarization immunoassay (TDx system). RESULTS: The average single gentamicin dose was 498 mg (range, 360-700 mg). The aqueous, vitreous, and serum levels averaged 1.14 microg/mL, 0.41 microg/mL, and 22.07 microg/mL, respectively. No correlation between serum level concentrations and time of administration was found for the aqueous and vitreous levels in this study. CONCLUSION: Although the average peak serum level of gentamicin was five times higher than previously reported, the vitreous levels averaged only 1.5 times higher. The blood-retinal barrier is difficult to penetrate even when higher serum levels are achieved. Due to its poor ocular penetration, gentamicin may not be among the best drugs for prophylaxis of penetrating eye injuries, surgical prophylaxis, or treatment of endophthalmitis.

The effect of minoxidil on keratocyte proliferation in cell culture.

PURPOSE: To determine if minoxidil inhibits keratocyte proliferation in a nontoxic manner. METHODS: Rabbit keratocytes were cultured in Eagle's minimum essential medium supplemented with fetal bovine serum. Minoxidil varying in concentration from 10(0) to 10(3) micrograms/ml was added to the culture medium and incubated for 7 days. The cultures were inspected for morphologic appearance and the cell number was determined at 1, 3 and 7 days after the addition of minoxidil. After 7 days of incubation, minoxidil was withdrawn from the cell culture medium and the cells were examined 3 and 7 days thereafter. In addition, a nonradioactive cytotoxic assay was performed to determine if toxicity is associated with the presence of minoxidil. RESULTS: Minoxidil inhibited keratocyte proliferation in a dose-dependent fashion. 29% of control growth was achieved when keratocytes were cultured for 7 days in 10(3) micrograms/ml, whereas 82% control growth was achieved when keratocytes were cultured in 10(2) micrograms/ml of minoxidil. Intermediate concentrations between 10(2) and 10(3) micrograms/ml produced a linear decline in cell counts in a dose-dependent fashion. The concentration of minoxidil required for 50% control growth at 7 days extrapolated from the dose-response curve was 600 micrograms/ml. Upon withdrawal of minoxidil, cell counts returned to baseline for concentrations of 10(2) micrograms/ml or less. Phase contrast microscopy revealed that the presence of minoxidil was associated with intercellular separation, enlargement of cell bodies and elongated processes. After the withdrawal of minoxidil, the cells in all media reassumed the morphological features of normal keratocytes which included a regular fusiform shape and extensive intercellular contact. The nonradioactive cytotoxic assay revealed the lack of cytotoxicity at all concentrations of minoxidil based on a lack of lactate dehydrogenase release. CONCLUSIONS: Minoxidil inhibits keratocyte proliferation by a nontoxic mechanism. It might be particularly useful for modulating corneal wound healing following excimer laser photorefractive keratectomy.

The effect of propranolol versus placebo on resident surgical performance.

PURPOSE: To determine whether propranolol can decrease surgical tremor and anxiety in residents performing ocular microsurgery without impairing patient or physician safety. METHODS: In this randomized, double-masked, crossover study, 5 third-year ophthalmology residents ingested a capsule containing either propranolol, 40 mg, or placebo 1 hour prior to performing ophthalmic microsurgery. All residents were healthy men under age 30 years. Prior to commencement of the study, all participants had successfully been administered a test dose of propranolol without side effects. The study took place over a 10-week period. At the conclusion of each case, both the resident and attending surgeon observer independently completed a form grading, on a sliding scale: (1) amount of overall tremor; (2) amount of tremor during placement of the first 3 sutures after lens or nucleus extraction; (3) anticipated difficulty of the case; (4) actual difficulty with the case; and (5) anxiety (surgeon only). In addition, the type of procedure performed, complications encountered, and surgeon side effects were recorded. The data were analyzed with a 2-way analysis of variance for unbalanced data. RESULTS: A total of 73 surgical cases were performed; the surgeons were administered propranolol for 40 cases and placebo for 33. As judged by the resident surgeon, there was a highly significant effect of propranolol in decreasing anxiety (P = .0058), reducing surgical tremor overall (P < .0001), and reducing tremor while placing the first 3 sutures following lens extraction (P < .0001). There was no treatment-by-surgeon interaction for any of the measures. Complications and difficulty of the case, as judged by both the resident and attending surgeons, were not significantly different in the propranolol versus placebo groups (P > .05). There were no side effects reported or observed in any of the surgeons. CONCLUSIONS: Propranolol, 40 mg, administered 1 hour prior to surgery, significantly decreases tremor and anxiety in the surgeon without untoward effects to the surgeon and the patient. However, it is unknown whether decreased tremor and anxiety improved surgical outcome.

Polyhexamethylene biguanide (PHMB) in the treatment of experimental Fusarium keratomycosis.

PURPOSE: We wanted to determine whether topical polyhexamethylene biguanide (PHMB) 0.02% was effective in the treatment of experimental Fusarium keratomycosis in rabbits. METHODS: Fusarium solani keratomycosis was induced in the eyes of 12 New Zealand white rabbits. The rabbits were treated with PHMB 0.02% in one eye and placebo in the other eye for 6 days. The rabbits were evaluated in a masked fashion using a standardized system for clinical progression of the disease. Then the corneas were trephined and growth of F. solani in colony-forming units per milliliter (CFU/ml) determined. RESULTS: Clinical evaluation demonstrated no significant mean difference (p > 0.10) in clinical scores between treated and control eyes on day 6 (0.583 +/- 2.503). There was a significant mean CFU difference (p = 0.06) between treated eyes and control eyes (182.5 +/- 314.44). Seven of 12 eyes (58%) in the PHMB group exhibited no growth, whereas two of 12 (17%) eyes reported no growth in the control group. One of 12 eyes (8%) reported > 100 CFU in the PHMB group, whereas seven of 12 eyes (58%) reported > 100 CFU in the control group. CONCLUSIONS: PHMB 0.02% was effective in significantly reducing the fungal growth in our rabbit model of Fusarium keratomycosis. The future role of PHMB in the treatment of Fusarium keratitis needs to be further evaluated.

Efficacy of dorzolamide hydrochloride in the management of chronic cystoid macular edema in patients with retinitis pigmentosa.

PURPOSE: To compare the effectiveness of topical dorzolamide hydrochloride (Trusopt, Merck and Co., Inc., West Point, PA), a carbonic anhydrase inhibitor, with that of oral acetazolamide (Diamox; Lederle Laboratories, Pearl River, NY) for the management of chronic cystoid macular edema in patients with retinitis pigmentosa. METHODS: A prospective, double-masked, crossover study was conducted in five patients with retinitis pigmentosa who had chronic cystoid macular edema. After baseline visual acuity was measured and a fluorescein angiogram was obtained, each patient was randomly assigned to receive either topical dorzolamide or a placebo for 4 weeks, followed by a crossover for the same period. Oral acetazolamide then was given separately to each patient for 2 weeks. Each phase of the study was followed by a washout period of 4 weeks, during which the patient was taken off all medications. At each visit, best corrected visual acuity was measured, a fluorescein angiogram was obtained, a subjective assessment of the effects on visual function, and any side effects of the medication or placebo were recorded in the form of a questionnaire by an independent observer. RESULTS: Compared with baseline or placebo values, there was no measurable improvement in visual acuity on the Early Treatment Diabetic Retinopathy Study charts with dorzolamide in any of the patients. The visual acuity in three of five patients, however, improved by seven letters or more with acetazolamide. Compared again with baseline or placebo values, fluorescein angiograms of two of five patients showed improvement in macular edema in both eyes with the use of dorzolamide, whereas all five showed improvement with acetazolamide. The improvement in macular edema was more marked with acetazolamide than with dorzolamide. The effect of dorzolamide given three times a day was the same as that when it was given five times a day. One patient indicated that dorzolamide was more effective than acetazolamide in improving visual function, three of five patients believed that acetazolamide was more effective, and one felt that both were equally effective. CONCLUSION: Dorzolamide provided improvement in cases of macular edema on fluorescein angiograms and subjective improvement of visual function in some patients with retinitis pigmentosa with cystoid macular edema. However, there was no measurable improvement in visual acuity with the topical use of this drug. Oral acetazolamide was found to be more effective than dorzolamide in managing macular edema and improving visual acuity.

Ofloxacin penetration into the eye after intravenous and topical administration.

PURPOSE: To determine the aqueous and vitreous fluid penetration of ofloxacin after a combined topical and single intravenous dose protocol before vitrectomy surgery. MATERIALS AND METHODS: Before undergoing vitrectomy surgery, patients were given two drops of ofloxacin 0.3% topically and a single intravenous dose of ofloxacin 400 mg. Aqueous (mean, 43 minutes) and vitreous (mean, 53 minutes) fluid samples were collected at the start of the surgical procedure. The samples were analyzed for ofloxacin penetration. RESULTS: The mean aqueous fluid concentration was 1.083 micrograms/mL +/- 0.406. The mean +/- SD vitreous fluid concentration in nondiabetic patients with intact vitreous was 0.352 microgram/mL +/- 0.301. Vitreous levels obtained more than 50 minutes after administration (0.414 microgram/mL +/- 0.336) were generally higher than those obtained after less than 50 minutes (P = 0.12). Eyes with prior vitrectomies achieved better ofloxacin penetration (0.984 microgram/mL +/- 0.680) than did nonvitrectomized eyes. CONCLUSION: Ofloxacin achieved measurable aqueous fluid penetration after topical and intravenous administration. Aqueous levels were above the minimum inhibitory concentration for most ocular pathogens. Vitreous levels were adequate in vitrectomized eyes to achieve inhibitory concentrations against many common ocular pathogens. Combined preoperative topical and a single dose of intravenous ofloxacin may provide inhibitory aqueous and vitreous antibiotic levels in vitrectomized eyes in cases where intravitreal antibiotics are not considered and oral administration is not practical.

Intraocular penetration of periocular ketorolac and efficacy in experimental uveitis.

PURPOSE: To determine in rabbits whether periocular injection of ketorolac tromethamine effectively delivers the drug to the eye and, if so, whether this is efficacious in the treatment of experimental uveitis. METHODS: Ketorolac was administered by anterior subconjunctival injection, posterior periocular injection, intramuscular injection, or topical eye drops. The aqueous and vitreous were assayed for ketorolac. Anterior subconjunctival and topical ketorolac were compared to control as well as topical and anterior subconjunctival steroid treatments in uveitis induced by the intravitreal injection of tumor necrosis factor. RESULTS: Anterior subconjunctival injection led to high, though short-lived, levels of drug in the aqueous and vitreous. Posterior periocular injection led to much lower levels. Topical dosing led to relatively low aqueous and undetectable vitreous levels. No ocular levels were detected after intramuscular dosing. All tested antiinflammatory treatments were similarly effective in controlling uveitis. CONCLUSIONS: Anterior subconjunctival injection of ketorolac produced high intraocular concentrations of drug and was beneficial in controlling the inflammation in this animal model of uveitis.

Biotransformation in review: applications in ocular disease and drug design.

The purpose of this paper is to review the biochemical processes of systemic biotransformation and describe their relevance to ocular disease and drug metabolism. The diverse nature of the biochemical pathways, commonly found in enzyme metabolism, is discussed. The occurrence of these processes in the eye has significance in that the products of metabolism may accumulate locally and exert deterimental effects, presumably by altering the cellular structure and/or function of crucial visual elements. The manipulation of these metabolic pathways within the eye has ramifications in the development of novel drug design for both ocular disease treatment and, perhaps more importantly, disease prevention.

Stability of cyclosporine 1% in artificial tears.

We wished to determine the stability of frozen, refrigerated, and room temperature topical cyclosporine 1% in artificial tears (Tears Plus). Cyclosporine 1% eye drops were made in artificial tears prior to the manufacturers recommendations of using a lipid soluble vehicle, such as olive oil. Patients preferred the artificial tears preparation over the oil based cyclosporine product. Because of the good clinical response and the reluctance of patients to change to the oil vehicle product, we determined the stability of cyclosporine 1% in artificial tears. Cyclosporine 1% was prepared in artificial tears (polyvinyl alcohol 1.4% and povidone 0.6%) by adding 1 ml of the injectable (50 mg/ml) cyclosporine into 4 ml of the artificial tears solution. Each bottle was frozen at -20 degrees C for one month and then the cyclosporine concentration was determined after thawing and refrigeration or storage at room temperature. Refrigerated stability was determined after thawing for up to 28 days and room temperature stability was determined for up to 1 week after thawing. Cyclosporine concentration was determined by HPLC analysis. None of the samples exhibited any significant loss of cyclosporine at any time period. Frozen cyclosporine appears stable when frozen in a 1% solution for one month. Cyclosporine 1% in artificial tears is stable for up to 28 days in the refrigerator or at least 7 days at room temperature. Because of the ease of preparation, the proven clinical effectiveness of the product and better patient acceptance, we continue to make this product.