Antagonists and inhibitors of lipid mediators in experimental inflammation of the cornea.

In experimental immunogenic keratitis, provoked in rabbits by intracorneal injection of 20 microliters of human serum albumin (HSA), various anti-inflammatory agents were studied in their effects on corneal edema, neovascularisation and leukocyte infiltration. Prophylactic treatment with a corticosteroid completely prevented the occurrence of keratitis. Nonsteroidal anti-inflammatory drugs such as a cyclooxygenase inhibitor partly prevented neovascularisation and corneal edema, a lipoxygenase inhibitor, a leukotriene antagonist or platelet-activating factor (PAF)-antagonist BN 52021 partially prevented mainly leukocyte infiltration. Prophylactic topical treatment with the poly-unsaturated fatty acids eicosapentaenoic acid and columbinic acid or a dietary supplement with fish oil showed less symptoms of keratitis in all respects.

The influence of a fish oil dietary supplement on immunogenic keratitis.

Fish lipids contain large amounts of eicosapentaenoic acid (EPA) and docosahexaenoic acid. These fatty acids are known to have an influence on prostaglandin (PG) and leukotriene (LT) synthesis. We studied the effect of a fish oil dietary supplement on an immune-complex-induced keratitis of the rabbit eye and compared it with the effect of a sunflower seed oil dietary supplement, rich in linoleic acid. Immune complex keratitis induced by intrastromal injection of human serum albumin (HSA) was characterized by leukocyte infiltrate, neovascularization, and corneal edema. Animals given a fish oil diet showed significantly less leukocyte infiltrate, neovascularization, and corneal edema, compared to those given a sunflower seed oil diet.

Platelet-activating factor and laser trauma of the iris.

Local application of platelet-activating factor (PAF) on the rabbit eye caused a dose-dependent significant increase in intraocular pressure (IOP). After laser irradiation of the iris the IOP showed a hypertensive phase of about 3 hr. Prophylactic treatment with the PAF antagonist BN 52021 but not with indomethacin abolished the hypertensive phase. Elevated levels of protein (10.6 +/- 0.9 g/l) and prostaglandin E2 (PGE2, 1.7 +/- 0.2 ng/ml) were measured in the aqueous humor 2 hr after laser irradiation of the iris. Prophylactic treatment with BN 52021 showed lower levels of protein (6.1 +/- 0.7) and PGE2 (1.1 +/- 0.02); with indomethacin pretreatment the level of protein was 3.4 +/- 0.7 g/l and of PGE2 0.10 +/- 0.02 ng/ml. A role of PAF as a mediator in ocular inflammatory response is suggested.

Modulation of immunogenic keratitis in rabbits by topical administration of poly-unsaturated fatty acids.

Several unsaturated fatty acids are precursors of prostaglandins and leukotrienes. Depending on their precursor, these prostaglandins and leukotrienes have different biological characteristics. The effects of topically administered fatty acids on an experimentally provoked inflammatory keratitis were studied in rabbits. Intrastromal injection with human serum albumin induced in the cornea a ring-shaped infiltration with leukocytes, corneal edema and neovascularization. Arachidonic, gamma-linolenic, dihomo-gamma-linolenic (DHGL), eicosapentaenoic (EPA) and columbinic acid were given as eye drops in a suspension in hydroxypropylmethylcellulose 0.5% three times daily during the experiment. EPA, DHGL, columbinic, and gamma-linolenic, but not arachidonic acid, showed a significant inhibition of either leukocyte infiltration, edema or neovascularization. The inhibitory effects of these fatty acids may be caused by topical inhibition of the formation of prostaglandins and leukotrienes in the arachidonic acid cascade in the rabbit cornea.

The effects of 3-isobutyl-methyl-xanthine on experimentally induced ocular inflammation in the rabbit.

The effect of topical administration of 3-isobutyl-methyl-xanthine (IBMX), a potent phosphodiesterase inhibitor, was studied on an experimentally provoked uveitis in rabbits. After presensitization with an intravitreal injection of human serum albumin (HSA), intravenous antigenic challenge induces blood-aqueous barrier breakdown and leukocyte infiltration. The effect of IBMX on the blood-aqueous barrier was determined by scoring the severity of the flare in the anterior chamber and by determination of the levels of ascorbic acid and protein in the aqueous. Treatment with IBMX 1% two times daily, significantly inhibited the breakdown of the blood-aqueous barrier and the increase in PGE2 level of the aqueous humor. There was no effect on leukocyte infiltration. The therapeutic effect of IBMX in blood-aqueous barrier protection is comparable with the effect of topical treatment with the corticosteroid medrysone.

Modulation of immunogenic keratitis in rabbits by topical administration of inhibitors of lipoxygenase and cyclooxygenase.

Intrastromal injection with human serum albumin (HSA) in the rabbit cornea induced edema and a ring-shaped leukocyte infiltrate followed by neovascularization. The effect of topically administered lipoxygenase and cyclooxygenase inhibitors on this inflammatory keratitis was studied. The lipoxygenase inhibitors Bay 08276 and Rev 5901 and the cyclooxygenase inhibitor suprofen were given as 1% eye drops three times daily during the experiment. In eyes treated with lipoxygenase inhibitors leukocyte infiltration, neovascularization and edema formation decreased. In eyes treated with a cyclooxygenase inhibitor the period of neovascularization was slightly shortened and corneal edema decreased. No influence on leukocyte infiltration was seen.

Timolol v guanethidine-epinephrine formulations in the treatment of glaucoma. An open clinical trial.

Patients with glaucoma received either 3% guanethidine-0.5% epinephrine (20 patients) or 1% guanethidine-0.2% epinephrine (20 patients) and then 0.5% timolol maleate. The fall in intraocular pressure during 3% guanethidine-0.5% epinephrine therapy (10.1 mm Hg [34.4%] reduction) was higher than during timolol therapy (7.5 mm Hg [25.5%] reduction) and the response to 1% guanethidine-0.2% epinephrine therapy (7.9 mm Hg [29%] reduction) equaled the response to timolol (7.3 mm Hg [26.8%] reduction). During 3% guanethidine-0.5% epinephrine therapy, 24 (67.7%) of 36 eyes had an average IOP lower than 22 mm Hg, compared with 16 (44.4%) of 36 timolol-treated eyes. With 1% guanethidine-0.2% epinephrine, IOP in 27 (73%) of 37 eyes was less than 22 mm Hg v 23 (62.2%) of 37 timolol-treated eyes. Both guanethidine-epinephrine formulations increased outflow facility. Since timolol produced few side effects, it appears to be the therapy of choice. However, in patients who do not respond sufficiently to timolol, both guanethidine-epinephrine formulations are potent alternatives.