Prostaglandin and thromboxane synthesis by microsomes of rabbit ocular tissues.

Microsomes of albino rabbit ocular tissues were incubated with (1-14C)-arachidonic acid for 15 min at 37 degrees C. Thin-layer chromatography revealed that ciliary body-iris microsomes were capable of synthesizing prostaglandin F2alpha (PGF2alpha), PGE2, PGD2, thromboxane B2(TXB2), and 6-keto-PGF1alpha. Indomethacin 14 micrometer in the incubation medium essentially abolished all prostaglandin synthesis detectable by this method. Imidazole 10 mM in the incubation medium inhibited only TXB2 synthesis. Ciliary body-iris microsomes were incubated for 2 min at 0 degrees C with PGH2. The products of this reaction were superfused over spiral strips of rabbit aorta and produced the strong contractions typical of TXA2. Addition to imidazole to the incubation medium blocked the formation of the contracting substance. Incubation of ciliary body-iris microsomes with (1-14C)--8,11,14-eicosatrienoic acid produced PGF1alpha, PGD1, and PGE1 but no evidence of any thromboxane product or 6-keto-PGF1alpha. Conjunctival and corneal microsomes synthesized prostaglandins, although less effectively than ciliary body-iris microsomes, when incubated with (1-14C)-arachidonic acid. Microsomes of sclera, retina-choroid, and lens synthesized little, if any, prostaglandins.

The ocular anti-inflammatory action of imidazole.

Imidazole administered intraperitoneally to albino rabbits at a dose of 250 mg. per kilogram inhibited the rise of aqueous humor protein concentration by approximately 50 per cent 30 minutes after paracentesis. Systemic imidazole administered daily to albino rabbits injected with intravitreal Shigella endotoxin decreased the conjunctival and iris hyperemia and reduced the anterior chamber cell and flare and the haziness of the optical media. Systemically administered imidazole had no effect on the aqueous humor concentrations of c-AMP or c-GMP in the rabbit. In vitro studies of rabbit ciliary body-iris phosphodiesterase activity indicated no effect of imidazole at a concentration of 10(-3) molar.

The ocular hypotensive effect of epinephrine in high and low corticosteroid responders.

Nonglaucomatous individuals were classified by their intraocular pressure response to 6 weeks of topical dexamethasone, 0.1%, four times daily. Twenty GG responders (over 31 mm. Hg after dexamethasone) and 20 NN responders (below 20 mm. Hg after dexamethasone) of similar age, sex, race, initial intraocular pressure, and facility of outflow were selected. After 24 hr. of treatment (two doses) with 1% epinephrine HCl, the GG subjects demonstrated a mean (+/-sigma) corrected decrease in intraocular pressure of 4.2 mm. Hg (+/- 2.5) as opposed to 1.8 mm. Hg (+/- 2.1) in the NN subjects (p less than 0.005). The relationship between increased responsiveness to corticosteroids, to epinephrine, and to theophylline suggested cyclic nucleotides as a possible common pathway.

Prostaglandin and thromboxane synthesis by microsomes of inflamed rabbit ciliary body--iris.

Microsomes of albino rabbit ciliary body--iris were prepared 6 hr, 24 hr, 3 days, 7 days, and 28 days after intravitreal injection of 10 micrograms of Shigella endotoxin. The microsomal preparations were incubated for 15 min with [1-14C]arachidonic acid. Prostaglandin and thromboxane products (cyclo-oxygenase products) were identified by thin-layer chromatography and quantified by scintillation counting. Synthesis of prostaglandin F2 alpha (PGF2, PGD2, 6-keto-PGF1 alpha (a stable metabolite of PGI2) and thromboxane B2 (TXB2) (a stable metabolite of TXA2) was increased 24 hr, 3 days, and 7 days after endotoxin injection. The greatest increase was in TXB2 synthesis. Cyclo-oxygenase product synthesis returned to normal levels by 28 days. Ciliary body--iris microsomes prepared 15 min after paracentesis synthesized increased amounts of all cyclo-oxygenase products assayed, most notably TXB2 and PGE2. Ciliary body--iris microsomes from albino rabbit treated with topical 1% nitrogen mustard or pigmented rabbits treated with subcutaneous alpha-melanocyte--stimulating hormone (20 micrograms/kg) synthesized normal amounts of cyclo-oxygenase products.

The Ocular Hypertension Treatment Study: design and baseline description of the participants.

BACKGROUND: The Ocular Hypertension Treatment Study (OHTS) seeks to evaluate the safety and efficacy of topical ocular hypotensive medication in preventing or delaying the onset of visual field loss and/or optic nerve damage in subjects with ocular hypertension at moderate risk for developing primary open angle glaucoma. OBJECTIVE: To describe the study protocol, the questions to be answered, and the baseline characteristics of the subjects. DESIGN: Multicenter randomized clinical trial with 2 groups: topical ocular hypotensive medication and close observation. SETTING: Subjects were enrolled and evaluated at 22 participating clinical centers. Visual fields and stereoscopic optic disc photographs were read in masked fashion. METHODS: We determined eligibility from a comprehensive eye examination, medical and ocular history, visual field testing, and stereoscopic optic disc photography. RESULTS: We describe the baseline characteristics of 1637 subjects randomized between February 28, 1994, and October 31, 1996. The mean age was 55 years; 56.9% of the subjects were women; and 25% were African American. The baseline intraocular pressure was 24.9 +/- 2.7 mm Hg (mean +/- SD). Systemic diseases and conditions reported by subjects included previous use of medication for ocular hypertension, 37%; systemic hypertension, 38%; cardiovascular disease, 6%; diabetes mellitus, 12%; and family history of glaucoma, 44%. The mean horizontal cup-disc ratio by contour estimated from stereophotography was 0.36 +/- 0.18. Qualifying Humphrey 30-2 visual fields had to be normal and reliable for entry into the study. Health-related quality of life (36-item short form health survey) scores in the OHTS sample were better than the age- and sex-matched population norms. African American subjects had larger baseline cup-disc ratios and higher reported rates of elevated blood pressure and diabetes than the rest of the subjects. CONCLUSIONS: The intraocular pressure among enrolled subjects was sufficiently high to provide an adequate test of the potential benefit of ocular hypotensive medication in preventing or delaying glaucomatous damage. The large number of African American subjects enrolled should provide a good estimate of the African American response to topical medication.

A simplified test of epinephrine responsiveness.

Forty-three ocular hypertensive and 33 ocular normotensive subjects received two doses of topical 1% epinephrine hydrochloride in one eye. The epinephrine was administered twice, ie, at time "zero" (8 AM) and 12 hours later (at 8 PM). The mean intraocular pressure responses at four hours and at 24 hours (12 hours after the last dose of epinephrine) were significantly correlated, r = 0.59 (P less than .001). This suggested that the simpler four-hour test was an equally accurate measure of the ocular responsiveness to topical epinephrine.

Prognostic factors in glaucomatous visual field loss.

A retrospective review was conducted of 31 patients with bilateral elevations of intraocular pressure and unilateral glaucomatous visual field loss. Nine (29%) of the fellow eyes developed visual field loss during a three- to seven-year follow-up period. Of the 13 fellow eyes that had an initial intraocular pressure greater than 26 mm Hg, eight (62%) developed visual field loss, as opposed to one (6%) of the 18 eyes that had lower intraocular pressures. Of the 11 fellow eyes whose intraocular pressures exceeded 24 mm Hg, either treated or untreated, on more than 50% of the measurements, seven (64%) lost visual field, whereas in the 20 eyes whose intraocular pressures were lower, only two )10%) lost visual field.

A miniature compliance monitor for eyedrop medication.

We developed an eyedrop medication monitor that electronically records the date and time of each medication administration over a six-week period. It records a medication usage in a 15-minute interval when the cap is removed from the bottle and the bottle is inverted. The electronic components housed inside the bottle weigh 7.5 g, including the batteries, and the total volume of the circuit is 7.5 cc. The monitor resembles commercially available 30-mL eyedrop bottles in size, shape, and weight. The monitor is accurate when tested against known patterns of usage. The electronic eyedrop monitor should be useful in assessing compliance with eyedrop medications.

Intraocular pressure response to topical epinephrine and HLA-B12.

Twenty high responders to topical corticosteroids (intraocular pressure greater than 31 mm Hg after six weeks of topical 0.1% dexamethasone, four times daily) and 20 low responders (IOP less than 20 mm Hg) of similar age, sex, race, initial IOP, and facility of outflow were selected. After 24 hours of treatment (two doses) of topical 1% epinephrine hydrochloride, the high corticosteroid responders showed a mean (+/-SD) corrected decrease in IOP of 3.6 +/- 2.0 mm Hg as opposed to 1.8 +/- 2.1 mm Hg in the low corticosteroid responders. Within both corticosteroid groups, individuals with the antigen HLA-B12 showed significantly greater decreases in IOP. This suggested that the presence of HLA-B12 was not only associated with increased responses to corticosteroids but also to epinephrine.

Increased corneal thickness simulating elevated intraocular pressure.

A 17-year-old girl had intraocular pressure readings of 30 to 40 mm Hg in both eyes, with normal visual fields and optic nerve heads. Medical treatment was unsuccessful in lowering the IOP measurements substantially. The central corneal thickness was 0.90 mm in each eye in the absence of corneal edema. Cannulation of the left anterior chamber revealed an IOP of 11 mm Hg, while the Perkins' and Schiotz' tonometers gave readings of 35 and 34 mm Hg, respectively. Previously, elevated tonometry readings had been obtained by Goldmann's, Perkins', Schiotz', MacKay and Marg's, pneumatic tonometer and air puff tonometer. This suggested that measurement of central corneal thickness be performed in cases in which IOP recordings do not correspond to other clinical findings.

Trabeculectomy with releasable sutures.

OBJECTIVE: To determine whether the use of releasable scleral-flap sutures affects the success rate and the incidence of complications following trabeculectomy. DESIGN: A retrospective chart review of a consecutive series of trabeculectomies. SETTING: A university-based referral practice. PATIENTS: Two hundred fifty-eight consecutive patients (274 eyes) undergoing trabeculectomy because of uncontrolled glaucoma. INTERVENTION: During the first year, 124 patients (128 eyes) underwent trabeculectomies with permanent scleral-flap sutures. During the second year, 134 patients (146 eyes) underwent trabeculectomies with releasable scleral-flap sutures. MAIN OUTCOME MEASURES: Incidence of flat and shallow anterior chamber, incidence of operations to drain choroidal detachment and to re-form anterior chamber, and long-term control of intraocular pressure. RESULTS: In the group with permanent sutures, 42 eyes (32.8%) had clinically detectable shallowing of the anterior chamber in the early postoperative period. In contrast, a shallow anterior chamber was noted in 21 eyes (14.4%) in the group with releasable sutures (P = .0003). Flat anterior chamber, defined as iridocorneal apposition to the pupil margin, occurred in 11 eyes with permanent sutures (8.6%) but in only two eyes (1.4%) with releasable sutures (P = .0078). Surgical intervention to drain suprachoroidal fluid and re-form the anterior chamber was required in eight eyes with permanent sutures (6.2%) but in only one eye with releasable sutures (0.7%) (P = .014). At 1-year follow-up, the two groups were similar in terms of intraocular pressure and the need for ocular hypotensive medications. CONCLUSIONS: Releasable scleral-flap sutures reduce the incidence of shallow and flat anterior chamber after trabeculectomy without compromising long-term control of intraocular pressure.

Increased ocular and systemic responsiveness to epinephrine in primary open-angle glaucoma.

Sixteen patients with primary open-angle gaucoma (POAG) were matched as to age, sex, and race with an equal number of patients with secondary glaucoma. Although initial intraocular pressures were comparable, treatment with topical epinephrine hydrochloride, decreased intraocular pressure more than 5 mm Hg in 14 (88%) of the 16 patients with POAG but in only five (31%) of the 16 patients with secondary glaucoma (p less than .005). Eleven (69%) of the 16 patients with POAG demonstrated premature ventricular contractions during tonography as opposed to three (19%) of the 16 patients with secondary glaucoma (p less than .025). These findings suggested greater ocular as well as cardiac responsiveness to epinephrine in patients with POAG.

A computerized glaucoma data base.

The MISAR data base system was modified for ophthalmic use. Approximately 1,165 subject records from the Glaucoma Center of Washington University were entered into this computerized registry. The system has provided a compact, accurate, and well-organized storage of medical data. Searches of the registry for specific diagnoses or for subjects who meet specific criteria have aided the performance of clinical research.

Multivariate analysis of the risk of glaucomatous visual field loss.

In a retrospective study, 92 patients with ocular hypertension, ie, intraocular pressure of 21 mm Hg or higher, and no evidence of glaucomatous visual field defects, were observed for five years. Visual field defects developed in one or both eyes of 33 patients during the five-year follow-up period, while none were detected in the remaining 59. Values for suspected risk factors, determined at the outset of the follow-up period, were subjected to a multivariate analysis with use of linear discriminant analysis and a multiple logistic function. Models of risk providing maximum separation of the two patient groups (visual field loss vs no visual field loss) found that the risk factors having the greatest significance for prediction of visual field loss included vertical estimates of cup/disc ratio, mean IOP during the period of observation, a positive family history of glaucoma, and age. Factors having the lowest predictive values included IOP response to topical dexamethasone, plasma cortisol suppression, and a history of systemic hypertension.

Timolol maleate: efficacy and safety.

A randomized, double-masked trial of various concentrations of timolol maleate ophthalmic solution (0.1%, 0.25%, 0.5%, and 1.0%) vs placebo demonstrated that all concentrations of timolol effectively lowered intraocular pressure (IOP). A 0.5% solution of timolol was as effective in reducing IOP as the 1.0% concentration. Blood pressure, visual acuity, and pupillary diameter were not altered significantly by any concentration of timolol tested during this study. There was a dose-dependent decrease in resting pulse rate with increasing concentrations of timolol. No objective signs of drug intolerance were found on external ocular examination, nor were any subjective symptoms elicited on questioning the subjects. Timolol applied topically twice daily in concentrations of 0.1% to 0.5% appeared to be an effective and safe ocular hypotensive agent.

Histocompatibility antigens and primary open-angle glaucoma. A reassessment.

Histocompatibility (HLA) antigen typing was performed on 306 patients who had been studied and classified carefully. Black individuals with primary open-angle glaucoma (POAG) had no significant differences in HLA antigen prevalences from black control subjects. In one white population with POAG, a significant decrease in HLA-A1, a significant increase in HLA-Aw31, and a significant increase in the antigen combination HLA-B7 and HLA-Bw22 were noted. However, these differences were not confirmed in a second white population with POAG. We concluded that associations between the A and B loci of the HLA antigen system and POAG were not as impressive as has been previously reported.

Quantitative visual field and optic disc correlates early in glaucoma.

A retrospective study was made of persons with ocular hypertension and normal initial visual fields. Seventy eyes were followed, and glaucomatous visual field defects developed in 25 of these eyes. In eyes with ocular hypertensio, the area enclosed by the central visual field isopter (I2e) was significantly smaller than that previously reported for an age-corrected group of eyes with normal intraocular pressure. In the absence of glaucomatous visual field defects, isopter areas were not releated to cup-disc ratios. Coincident with visual field loss, reductions in both peripheral (I4e) and central (I2e) isopter areas correlated linearly with increases in the cup-disc ratio. Prior to visual field loss, the I4e isopter area wassignificantly smaller among those eyes destined to lose visual field.

Timolol and acetazolamide. A study of concurrent administration.

A five-week clinical trial of the concurrent administration of topical timolol maleate and oral acetazolamide was conducted to determine the additivity of the ocular hypotensive effects of the two drugs. One drop of 0.5% timolol maleate, every 12 hours, produced a mean reduction in outflow pressure from baseline of 36.0%. When added to an eye pretreated with oral acetazolamide, timolol caused an additional mean decrease in outflow pressure of 27.6%. Acetazolamide, 500 mg orally every 12 hours, produced a mean reduction in outflow pressure from baseline of 48.6%. When added to an eye receiving topical timolol, oral acetazolamide caused an additional mean decrease in outflow pressure of 43.2%. Concurrent administration of oral acetazolamide and topical timolol reduced outflow pressure only slightly less than the predicted reduction assuming full additivity of the drugs. This study supported the clinical usefulness of concurrent administration of acetazolamide and timolol to lower intraocular pressure.

Dipivefrin and epinephrine treatment of elevated intraocular pressure: a comparative study.

Every 12 hours 0.1% dipivefrin was administered to one eye and 2% epinephrine hydrochloride was administered to the fellow eye of 42 patients with primary open-angle glaucoma or ocular hypertension in a randomized, double-masked study lasting three months. Dipivefrin produced similar percent reductions in intraocular pressure (18.6%) to epinephrine (21.0%), as well as similar increases in outflow facility and pupil diameter. A significantly lower incidence of burning and stinging after drug instillation was noted with dipivefrin therapy. This study supported the contention that dipivefrin is an effective and safe alternative to epinephrine therapy for the reduction of elevated intraocular pressure.

Clinical factors associated with progression of glaucomatous optic disc damage in treated patients.

BACKGROUND: Reducing intraocular pressure (IOP) in glaucomatous eyes does not always prevent disease progression. OBJECTIVE: To determine the clinical factors associated with progressive optic disc damage in glaucomatous eyes receiving treatment to reduce IOP. METHODS: Baseline and follow-up optic disc photographs as well as demographic and clinical data were retrospectively studied in 186 eyes of 93 patients with primary open-angle glaucoma, and in 138 eyes of 69 patients with normal-pressure glaucoma. The patients with primary open-angle glaucoma were included in the study only if their treated IOPs during a follow-up period of 5 years were less than 21 mm Hg. The patients with normal-pressure glaucoma were included only if their IOPs were reduced by at least 20% during the follow-up period. The association of progressive optic disc damage with patient- and eye-specific characteristics was examined using multivariate analysis. RESULTS: During the 5-year study period, 141 (43.5%) of the 324 eyes exhibited progressive optic disc damage defined by at least a 5% decrease in the neural rim area-to-disc area ratio. Using multivariate analysis, the following were found to be strongly associated with progressive neural rim damage: a baseline smaller neural rim area-disc area ratio (P<.001); a baseline larger zone beta area-disc area ratio (P =.04); a baseline larger parapapillary atrophy length-disc circumference ratio (P =.05); a diagnosis of normal-pressure glaucoma (P =.01); and combined medical and surgical treatment prior to the study period (P =.01). CONCLUSIONS: Clinical factors other than IOP may be important indicators of subsequent progression of glaucomatous optic disc damage. Our findings suggest that eyes with advanced glaucomatous optic disc damage and normal-pressure glaucoma are more likely to progress despite receiving treatment to reduce IOP.