Refractory pyoderma gangrenosum of the orbit and the lacrimal sac

Pyoderma gangrenosum (PG) is a rare, idiopathic, necrotizing, and non-infectious ulcerating skin disease included among the neutrophilic dermatoses. It rarely affects the eye, orbit, and/or ocular adnexa. We describe one case of PG affecting both orbits and the lacrimal sac in a patient with Crohn's disease.     

Prostaglandin analogues and mouse intraocular pressure: effects of tafluprost, latanoprost, travoprost, and unoprostone, considering 24-hour variation

PURPOSE: To establish a mouse model for the pharmacological analysis of antiglaucoma drugs, considering the effect of variations in IOP during 24 hours on the drugs' effects, and to evaluate the effect of a newly developed FP agonist, tafluprost, on mouse IOP, in comparison with three clinically available prostaglandin (PG) analogues. METHODS: Inbred adult ddY mice were bred and acclimatized under a 12-hour light-dark cycle. With mice under general anesthesia, a microneedle method was used to measure IOP. A single drop of 3 muL of either drug or vehicle solution was topically applied once into one eye in each mouse, in a blinded manner, with the contralateral, untreated eye serving as the control. IOP reduction was evaluated by the difference in IOP between the treated and untreated eyes in the same mouse. First, to determine the period feasible for demonstrating a larger magnitude of ocular hypotensive effect, the 24-hour diurnal variation in mouse IOP was measured, and 0.005% latanoprost was applied at the peak or trough time of variation in 24-hour IOP. The time point of the most hypotensive effect was selected for further studies, to evaluate the effects of PG analogues. Second, mice received tafluprost (0.0003%, 0.0015%, 0.005%, or 0.015%), latanoprost (0.001%, 0.0025%, or 0.005%), travoprost (0.001%, 0.002%, or 0.004%), or isopropyl unoprostone (0.03%, 0.06%, or 0.12%), and each corresponding vehicle solution. IOP was then measured at 1, 2, 3, 6, 9, and 12 hours after drug administration. The ocular hypotensive effects of the other three PG analogues were compared with that of tafluprost. All experiments were conducted in a masked study design. RESULTS: The IOP in the untreated mouse eye was higher at night than during the day. Latanoprost significantly lowered IOP at night (21.4%), compared with the IOP in the untreated contralateral eye 2 hours after administration. The maximum IOP reduction was 20.2% +/- 2.0%, 18.7% +/- 2.5%, and 11.2% +/- 1.8% of that in the untreated eye 2 hours after administration of 0.005% tafluprost, 0.005% latanoprost, and 0.12% isopropyl unoprostone, respectively, whereas it was 20.8% +/- 4.6% at 6 hours with 0.004% travoprost (n = 7 approximately 17). The order of ocular hypotensive effects of three clinically used PG analogues in mice was comparable to that in humans. Area under the curve (AUC) analysis revealed dose-dependent IOP reductions for each PG analogue. Tafluprost 0.005% decreased IOP more than 0.005% latanoprost at 3, 6, and 9 hours (P = 0.001-0.027) or 0.12% unoprostone at 2, 3, and 6 hours (P = 0.0004-0.01). CONCLUSIONS: The 24-hour variation in mouse eyes should be taken into consideration when evaluating the reduction of IOP. The mouse model was found to be useful in evaluating the pharmacological response to PG analogues. A newly developed FP agonist, 0.005% tafluprost, lowered normal mouse IOP more effectively than did 0.005% latanoprost.     

Alpha 1-adrenergic receptor induced subsensitivity and supersensitivity in rabbit iris-ciliary body. Effects on myo-inositol trisphosphate accumulation, arachidonate release, and prostaglandin synthesis

Topical treatment of the rabbit eye with three successive doses of 2% epinephrine resulted in attenuation of the in vitro drug response of the alpha 1-adrenoceptor-mediated phosphoinositide hydrolysis system and of alpha 1-adrenergic receptor-mediated contraction in the iris. In contrast, sympathetic denervation of the eye resulted in potentiation of these responses. Desensitized tissues showed a significant decrease in epinephrine-induced myo-inositol trisphosphate (IP3) accumulation, 1,2-diacylglycerol (DG) formation, measured as phosphatidate, arachidonic acid (AA) liberation, measured by radiochromatography, prostaglandin (PG) E2 release, measured by radiochromatography and radioimmunoassay, and muscle contraction. Adrenergic desensitization of the eye resulted in attenuation of: The polyphosphoinositide response in the iris, measured both as loss of 32P-radioactivity from phosphatidylinositol 4,5-bisphosphate (PIP2) and as IP3 accumulation; the epinephrine-stimulated liberation of AA, from membrane phosphoinositides and other phospholipids, and PGE2 release in the iris; and the epinephrine-induced muscle contraction in the iris dilator. This adrenergic desensitization of the eye is reversible. Surgical sympathetic denervation, previously found to increase alpha 1-adrenoceptor mediated accumulation of IP3 and contraction, increased AA liberation. Dexamethasone blocked the epinephrine-induced liberation of AA and PG release, both in vivo and in vitro. These data support the hypothesis that changes in the activity of the alpha 1-adrenergic receptor-mediated phosphoinositide hydrolysis system and its derived second messengers may underlie the mechanism of adrenergic subsensitivity and supersensitivity in the iris-ciliary body. How much the desensitization of alpha 1-adrenergic receptor-mediated responses contribute to the therapeutic action of epinephrine in the eye remains to be determined.     

The ocular pharmacokinetics of eicosanoids and their derivatives. 1. Comparison of ocular eicosanoid penetration and distribution following the topical application of PGF2 alpha, PGF2 alpha-1-methyl ester, and PGF2 alpha-1-isopropyl ester

These experiments were undertaken to determine whether the increased ocular hypotensive potency of topically applied prostaglandin (PG) PGF2 alpha esters, as compared with that of PGF2 alpha free acid, can be accounted for by increased penetration of the eicosanoid moiety of the esterified PG into the eye. One hour after the topical application of [3H]PGF2 alpha-1-methyl ester (ME) in peanut oil, the 3H activities in the cornea, aqueous humor, and ciliary body of the rabbit eye were 32-, 22-, and 8-fold higher, respectively, than they were following the topical application of [3H]PGF2 alpha free acid. 3H activity during the first 3 hr declined rapidly in the cornea and more slowly in the aqueous humor, but remained essentially constant in the ciliary body for up to 6 hr, declining rapidly only between 6- and 24 hr. 3H activity in eyes that received [3H]PGF2 alpha ME was also several-fold higher in the anterior sclera and iris than in eyes that were treated with [3H]PGF2 alpha free acid, but this difference was much smaller in the conjunctiva. At 1 hr, most of the 3H activity in the aqueous humor was associated with PGF2 alpha, as determined by chromatography, but at 2- and 3 hr other peaks, presumably reflecting metabolites of PGF2 alpha, became apparent. The penetration and intraocular distribution of 3H activity was similar when [3H]PGF2 alpha ME was applied to the eye in normal saline rather than in peanut oil or when the isopropyl rather than the methyl ester of PGF2 alpha was used. These studies indicate that esterification of the carboxyl group of PGF2 alpha greatly enhances the penetration of the PGF2 alpha moiety into the eye and suggests that effective de-esterification of the PGF2 alpha ester occurs in the cornea, resulting in the delivery of PGF2 alpha free acid into the aqueous humor. It is concluded that topically applied PG esters act as pro-drugs and that the increased ocular penetration of these esters may account for the previously reported increase in their ocular hypotensive potency as compared to that of PG free acid or salts.     

Absorptive transport of prostaglandins from intraocular fluids to blood: a review of recent findings

Some, but not all, vertebrate tissues including the anterior uvea and the choroid plexuses, concentratively accumulate ³H-activity when incubated in tissue culture medium containing ³H-labeled prostaglandins ([³H]PGs). Studies on some tissues indicate that this in vitro [³H]PG accumulation is temperature-dependent, saturable, and the accumulated activity is readily elutable. These and other findings indicate that PGs can be actively accumulated by some tissues and transported across some biological membranes. In the case of the ciliary process the apparent direction of transport is from intraocular fluids to blood. This is indicated by the fact that the loss of intravitreally injected PG from the eye is much more rapid than the rate of loss of simultaneously injected sucrose. Since PGs are normally produced by intraocular tissues and can have a profound effect on the eye, such an active process for the efficient removal of PGs from the intraocular fluids could have a great physiological significance. Interference with such absorptive PG transport could contribute to accumulation of PG in the aqueous humor, a phenomenon which has been observed under pathological conditions.     

Combined exfoliation and pigment dispersion: paradigm of an overlap syndrome

OBJECTIVE: To describe a series of patients with combined pigment dispersion syndrome (PDS) and exfoliation syndrome (XFS) and to introduce a concept, the overlap syndrome, to aid in assessing multiple risk factors for glaucomatous damage. DESIGN: Clinic-based, cross-sectional study. SETTING: New York Eye and Ear Infirmary. PARTICIPANTS: Twenty-six patients identified from the glaucoma database as having combined pigment dispersion syndrome-glaucoma and exfoliation syndrome-glaucoma. MAIN OUTCOME MEASURES: Quantification of patients with both pigment dispersion syndrome-glaucoma (PDS/PG) and exfoliation syndrome-glaucoma (XFS/XFG) and its clinical implications. RESULTS: Among the 26 patients (all white) having both XFS/XFG and PDS/PG, the average age was 64.3 +/- 9.8 years and 19 of 26 were men. All patients had bilateral PDS/PG. Bilateral XFS/XFG was present in 9 of 26 patients and, of the 17 patients with unilateral involvement, the left eye was affected in 13. CONCLUSIONS: Both XFS and PDS are common. Middle-aged patients with known PDS/PG should be suspected of having the onset of XFS if one eye escapes intraocular pressure control. Patients with unilateral XFG at presentation may also have signs of PDS/PG, often remitted. We define the term overlap syndrome to describe the sequential appearance over time of two or more risk factors for glaucomatous damage. The appearance of a new risk factor in a patient whose condition has been stable can alter the course and prognosis of the disease. This concept should prove useful in dealing with secondary and normal-tension glaucomas.     

Evaluation of the efficacy of the Allegretto Wave and the Wavefront‐optimized ablation profile in non‐anterior astigmatisms

Purpose: To assess the efficacy of the Allegretto Wave and the wavefront‐optimized ablation profile (WFO) in non‐anterior astigmatism correction, in both LASIK and photorefractive keratectomy (PRK) treatments. Methods: Seventy‐four refractive surgery candidates were recruited prospectively in a non‐randomized trial. Only one eye from each candidate was randomly enrolled in the study. Of them, 40 eyes underwent LASIK treatment (LG group), while 34 eyes underwent PRK treatment (PG group). Preoperatively, the ocular residual astigmatism (ORA) was calculated for each eye, according to which each astigmatism fault was characterized as primarily anterior or non‐anterior. Twenty LG eyes and 16 PG eyes presented primarily anterior astigmatism (LG‐A and PG‐A subgroups, respectively), while 20 LG eyes and 18 PG eyes demonstrated primarily non‐anterior astigmatism (LG‐NA and PG‐NA subgroups, respectively). Postoperatively, vector analysis of astigmatism correction was conducted. The following indexes were calculated: (i) correction index (CI), (ii) difference vector (DV) and (iii) index of success (IOS). Results: Preoperatively, mean differences between manifest and topographic astigmatisms for the LG and the PG subgroups were significant (p:0.006 and p < 0.001, respectively), while postoperatively, aforementioned differences were non‐significant (p:0.18 and p:0.09, respectively). Regarding vector analysis in the LG group, mean CI, IOS and DV were 1.39 ± 1.26, 0.37 ± 1.06 and 0.30 ± 0.51, respectively. Differences in CI, IOS and DV between LG‐A and LG‐NA subgroups were non‐significant. Regarding vector analysis in the PG group, mean CI, IOS and DV were 1.22 ± 0.33, 0.47 ± 0.46 and 0.27 ± 0.25, respectively. Differences in CI, IOS and DV between PG‐A and PG‐NA subgroups were non‐significant. Conclusions: Our results suggest that the Allegretto Wave and WFO profile seem to be equally effective in both anterior and non‐anterior astigmatism correction, regardless of treatment type.     

Degree of degraded proteoglycan in human vitreous and the influence of peroxidation

PURPOSE: The degradation of hyaluronic acid induced by reactive oxygen species has been reported in vitro as a cause of vitreous liquefaction. In this study on in vivo human vitreous liquefaction, we examined the degree of degraded proteoglycan (PG) in human vitreous and the influence of peroxidation. SUBJECTS AND METHODS: In this study we examined the vitreous of 5 eyes with diabetic retinopathy, 12 eyes with retinal detachment, 2 eyes with retinal vein occlusion, and one eye with macular hole. The degree of degraded PG was determined by cellulose acetate membrane electrophoresis. To evaluate the influence of oxidation, copper ions, iron ions, hydrogen peroxide, lipid peroxide, L-ascorbic acid concentrations, and superoxide scavenging activity were measured. RESULTS: The electrophoretic patterns of PG were classified into the origin type (non-fragmented PG) in which only the origin was stained, and the mobile type (fragmented PG) showed other patterns. In the mobile type, the copper ion and hydrogen peroxide concentrations were higher, and the lipid peroxide concentrations were significantly higher, while the superoxide scavenging activity was lower. CONCLUSION: These results indicated that the degradation of PG and dissociation of glycosaminoglycan in human vitreous were associated with peroxidation.     

Topical timolol 0.5% as the primary treatment of ophthalmic pyogenic granuloma: A prospective,single-arm study

Purpose:To study topical timolol (0.5%) as a first-line treatment in ophthalmic pyogenic granuloma (PG) in terms of safety and efficacy.Methods:This was a prospective, interventional, single-arm study conducted at a tertiary eye care hospital in central India. Only new cases of PG were counseled to get enrolled in the study. A total of 40 patients were analyzed in the study. Topical timolol eye drop (0.5%) was started in each patient twice daily for 4–6 weeks duration. The patients were divided into five categories according to the percentage reduction in the size of PG as follows: i) 80–100% reduction - excellent responders, ii) 60–80% – good, iii) 40–60% – satisfactory, iv) 20–40% – poor, and v) <20% – very poor/nonresponder. After 6 months of starting treatment final evaluation was done.Results:The mean age of the patients was 23.5 ± 13.3 years. Etiology of the disease included chalazion (n = 11, 27.5%), trauma (n = 2, 5%), surgery (n = 7, 17.5%), foreign body (n = 2, 5%), and idiopathic (n = 18, 45%). An excellent response was achieved in 31 (77.5%) patients. Twenty-seven (67.5%) patients had complete resolution of lesions within 6 weeks. Recurrence of the lesion was not noticed in any patients.Conclusion:Timolol 0.5% in topical form is a good treatment option for ophthalmic PG in all age groups. The treatment has no adverse effects when given to suitable individuals for a limited period.     

Studies on the mechanism of action of timolol and on the effects of suppression and redirection of aqueous flow on outflow facility

Long-term use of drugs that suppress aqueous humor formation, such as timolol and dorzolamide, or that redirect aqueous humor outflow from the trabecular meshwork, such as prostaglandin F2alpha analogues, could cause underperfusion of the trabecular meshwork and a secondary decrease in outflow facility. We investigated the mechanism of suppression of aqueous humor formation by timolol in monkey eyes by measuring aqueous humor ascorbate levels. We also determined whether suppression of aqueous humor formation with and without redirection of aqueous humor away from the trabecular meshwork could lead to a subsequent reduction in outflow facility, and whether this reduction was correlated with increased fibronectin levels in anterior chamber aqueous humor. In cynomolgus monkeys, unilateral dose/aqueous humor formation response curves were generated for timolol, dorzolamide, and a combination of timolol + dorzolamide. Aqueous humor formation and/or outflow facility were measured in both eyes after approximately four days, four weeks and seven weeks of twice daily treatment with 3.5 microg timolol + 1.0 mg dorzolamide to one eye and 30% DMSO to the other. In some monkeys, 5 microg prostaglandin F2alpha-isopropyl ester (PG) was added to timolol + dorzolamide for 4-week treatments. Intraocular pressure and corneal endothelial transfer coefficients (k(a)) were also measured at four weeks. Aqueous humor fibronectin levels were determined in four monkeys after approximately 9.5 weeks of timolol + dorzolamide treatment. Aqueous humor formation, intraocular pressure, and aqueous humor ascorbate levels were also determined in rhesus monkeys at baseline and after a single unilateral topical administration of 25 microg timolol. Compared to baseline for the same eye, aqueous humor formation was significantly decreased in treated eyes at all doses of timolol and at 1.8 and 4 mg dorzolamide. Compared to the opposite control eye, aqueous humor formation was lower in treated eyes after 3.5 and 5 microg timolol and after all doses of dorzolamide. Aqueous humor formation after treatment with 3.5 microg timolol + 1.0 mg dorzolamide was decreased in treated vs. control eyes, after four days and was suppressed in both treated and control eyes after four weeks of treatment, but not when PG was added. There was no difference in k(a) values with or without the addition of PG. Intraocular pressure was significantly lower in both treated and control eyes vs. baseline after approximately 6.5 weeks treatment with timolol + dorzolamide when taken 2 hr after the last dose and after approximately 3.5 weeks treatment with timolol + dorzolamide + PG when measured 6 hr after the last dose. Outflow facility after treatment with timolol + dorzolamide was unchanged after four days, tended to be lower in the treated vs. control eyes after four and seven weeks, and was significantly lower in treated vs. control eyes after four weeks treatment with timolol + dorzolamide + PG (0.352 +/- 0.052 vs. 0.515 +/- 0.096 microl min(-1) mmHg(-1), p < or = 0.02). Both treated vs. control eye aqueous humor fibronectin levels were below the level of detection for our assay (0.01 microg ml(-1)). The 25 microg timolol dose decreased ipsilateral, but not contralateral intraocular pressure (12.6 +/- 1.7 vs. 15.2 +/- 0.9; p < 0.05) and aqueous humor formation (1.40 +/- 0.08 vs. 2.03 +/- 0.09 microg ml(-1), p < or = 0.01). There was no difference in anterior chamber ascorbate levels in treated vs. control eyes or compared to their respective baselines. Our findings indicate that timolol affects neither ciliary epithelial transport of ascorbate nor aqueous fibronectin levels. Our data also indicate that decreasing aqueous humor formation over a period of time can lead to reduction in outflow facility, particularly when combined with therapy that redirects aqueous from the trabecular meshwork. Future intraocular pressure-lowering therapies for glaucoma may better be directed at enhancing flow through the trabecular pathway as opposed to decreasing aqueous humor formation or rerouting aqueous humor away from the trabecular meshwork.