ObjectiveTo evaluate the possible additivity of the effects of latanoprost and 8-iso prostaglandin E2(8-iso PGE2) on intraocular pressure (IOP) in monkey eyes with laser-induced glaucoma.MethodsThe IOP was measured hourly for 6 hours beginning at 9:30 AM on day 1 (baseline day), days 6 and 7 (single-agent therapy), and days 13 and 14 (combination therapy with both agents). Following 1 day of baseline measurement, 4 monkeys with unilateral glaucoma received monotherapy twice daily with either 1 drop of 0.005% latanoprost, or 0.1% 8-iso PGE2, 25 µL, at 9:30 AM and 3:30 PM from days 2 through 7. From days 8 through 14, both agents were applied twice daily 5 minutes apart.ResultsThe maximum reduction of IOP (mean ± SEM) was 8.8 ± 1.9 mm Hg (26%) (P<.05) with latanoprost alone and 6.5 ± 1.0 mm Hg (21%) (P<.01) with 8-iso PGE2alone, 2 hours after the morning dosing on day 7. A further reduction of IOP of 4.0 ± 0.6 mm Hg was produced when 8-iso PGE2was added to latanoprost and of 3.0 ± 0.7 mm Hg was produced when latanoprost was added to 8-iso PGE2on day 13 before the morning dosing. Combination therapy with both agents caused maximum IOP reductions from baseline of 11.3 ± 3.0 mm Hg (33%) (P<.05) (latanoprost with 8-iso PGE2added) and of 9.8 ± 1.3 mm Hg (31%) (P<.01) (8-iso PGE2with latanoprost added) on day 14.ConclusionLatanoprost and 8-iso PGE2have an additive effect on IOP in glaucomatous monkey eyes.Clinical RelevanceAt least 50% of patients are treated with more than 1 ocular hypotensive medication. Thus, the determination of the additive effects on IOP of glaucoma medications will help to define optimum treatment regimens.LATANOPROST, a new prostaglandin F2αanalogue, has been shown to be an effective ocular hypotensive agent in patients with glaucomaand in monkey eyes with laser-induced glaucoma.The mechanism by which latanoprost reduces intraocular pressure (IOP) is primarily by increasing uveoscleral outflow without notably affecting aqueous humor flow rates or tonographically measured outflow facility.8-iso Prostaglandin E2(8-iso PGE2), a novel bioactive prostaglandinlike compound that is structurally different from latanoprost, reduces IOP in normal and glaucomatous monkey eyes.A substantial increase in outflow facility appears to account for most of the IOP reduction in normal monkey eyes.This implies that there are different mechanisms by which prostaglandins with different stereochemical or geometric configurations can affect aqueous humor dynamics and lower IOP.Thus, this study was designed to determine if 2 different prostaglandin derivatives, latanoprost and 8-iso PGE2, that appear to reduce IOP by 2 different mechanisms have additive effects on IOP when used in combination.MATERIALS AND METHODSEight adult female cynomolgus monkeys (each weighing 3-5 kg), in which glaucoma had been induced unilaterally by repeated argon or diode laser photocoagulation of the midtrabecular meshwork, were used in this study.The IOP was measured hourly, beginning at 9:30 AM, for a total of 6 hours on day 1 (baseline day), days 6 and 7 (single-agent therapy), and days 13 and 14 (combination therapy with both agents) using a calibrated pneumatonometer (model 30 classic; Mentor Inc, Norwell, Mass). Five minutes before tonometry, 1 drop of 0.5% proparacaine hydrochloride was topically applied, and ketamine hydrochloride, 1 to 5 mg/kg, was administered intramuscularly for adequate sedation.On each day of the study, 8-iso PGE2(Cayman Chemical Co Inc, Ann Arbor, Mich) was freshly prepared by dissolving in dimethyl sulfoxide, 100 g/L, and diluting with 0.9% sodium chloride to a 0.1% solution, a concentration that produces the greatest effect on IOP.The commercially available preparation of latanoprost, 0.005% (Pharmacia and Upjohn, Kalamazoo, Mich), was used, which is also at the top of the dose-response relation. On the drug treatment days, days 2 through 14, the first IOP measurement was taken just before the 9:30 AM dosing. On days 2 through 7, monkeys were treated twice daily with 1 drop of latanoprost, or with 0.1% 8-iso PGE2, 25 µL, at 9:30 AM and 3:30 PM. On days 8 through 14, both 8-iso PGE2and latanoprost were applied twice daily at 9:30 AM and 3:30 PM, 5 minutes apart. The monkeys were treated unilaterally, in the glaucomatous eye only.The following statistical analyses were performed using the 2-tailed paired ttest: the change in IOP between baseline and single-agent therapy with latanoprost or 8-iso PGE2, the change in IOP between single-agent therapy and combination therapy, the change in IOP with single-agent therapy on days 6 and 7, the change in IOP with combination therapy on days 13 and 14, and the change in IOP between combination therapy and baseline. A value of P<.05 was considered statistically significant. Data were calculated as the mean ± SEM. All experimental studies complied with the Association for Research in Vision and Ophthalmology Resolution on the Use of Animals in Research and were approved by the Mount Sinai School of Medicine, New York, NY, Institutional Animal Care and Utilization Committee.RESULTSLatanoprost and 8-iso PGE2, when applied as single agents, significantly (P<.05) reduced the IOP for at least 18 hours after the eighth dose, which was measured at the 0 hour (trough) on study day 6 (Table 1). Maximum reductions of IOP with single-agent therapy (peak) occurred 2 hours after the morning dosing on day 7 and were 8.8 ± 1.9 mm Hg (26%) (P<.05) with latanoprost and 6.5 ± 1.0 mm Hg (21%) (P<.01) with 8-iso PGE2(Table 1). Intraocular pressure reductions were similar comparing study day 6 with study day 7 of treatment with 8-iso PGE2(P>.70) or comparing study day 6 with study day 7 of treatment with latanoprost (P>.60). Intraocular pressure reductions were similar comparing study day 13 with study day 14 of treatment with latanoprost added to 8-iso PGE2(P>.40) or comparing study day 13 with study day 14 of treatment with 8-iso PGE2added to latanoprost (P>.80). The maximum effect on IOP had been obtained by study day 6 for single-agent therapy and by study day 13 for combined therapy. Combination therapy resulted in additional IOP reductions at all measurement times on study day 13 compared with study day 6 and on study day 14 compared with study day 7. The average IOP on days 6 and 7 (single-agent therapy) was compared with the average IOP on days 13 and 14 (combination therapy) in each of the 2 treatment groups. The additional reductions in IOP were statistically significant (P<.05) at 0, 1, 5, and 6 hours when 8-iso PGE2was added to latanoprost, and from 0 through 4 hours when latanoprost was added to 8-iso PGE2(Figure 1). Additional IOP reductions of up to 12% (3.8 ± 1.2 mm Hg) were noted when 8-iso PGE2was added to latanoprost and of up to 11% (3.6 ± 0.8 mm Hg) were noted when latanoprost was added to 8-iso PGE21 hour following morning dosing (Figure 1). Maximum reductions of IOP with combination therapy compared with baseline on day 14 were 11.3 ± 3.0 mm Hg (33%) (P<.05) when 8-iso PGE2was added to latanoprost and 9.8 ± 1.3 mm Hg (31%) (P<.01) when latanoprost was added to 8-iso PGE2(Table 1).Effects of Single-Agent Therapy Followed by Combination Therapy on Intraocular Pressure in 4 Monkeys With Unilateral Glaucoma*Latanoprost + 8-iso Prostaglandin E2†8-iso Prostaglandin E2+ Latanoprost‡Trough (0 h)Baseline (day 1)32.5 ± 1.933.3 ± 2.5First drugDay 628.3 ± 1.3 (13)§29.5 ± 1.8 (11)§Day 727.5 ± 1.9 (15)§29.0 ± 2.0 (13)§Both drugsDay 1324.3 ± 1.3 (25)§∥26.5 ± 2.1 (20)§∥Day 1424.0 ± 1.4 (26)§26.0 ± 1.6 (22)§∥Peak (2 h)Baseline (day 1)33.8 ± 3.531.5 ± 2.0First drugDay 625.5 ± 2.5 (24)§25.3 ± 1.5 (20)§Day 725.0 ± 1.7 (26)§25.0 ± 1.7 (21)§Both drugsDay 1322.0 ± 1.6 (35)§22.5 ± 1.3 (29)§Day 1422.5 ± 0.9 (33)§21.8 ± 1.0 (31)§∥*Data are given as the mean ± SEM (percentage reduction from baseline) intraocular pressure, measured in millimeters of mercury. Single-agent therapy and combination therapy were given twice daily.†Treatment was started with 0.005% latanoprost, and 0.1% 8-iso prostaglandin E2was added.‡Treatment was started with 0.1% 8-iso prostaglandin E2, and 0.005% latanoprost was added.§Significant intraocular pressure reduction compared with baseline measurements (2-tailed paired ttest, P<.05).∥Significant intraocular pressure reduction for combination therapy compared with single-agent therapy (day 13 vs day 6 and day 14 vs day 7; 2-tailed paired ttest; P<.05).Percentage reduction of intraocular pressure (IOP) compared with baseline in 4 glaucomatous monkeys for latanoprost or 8-iso prostaglandin E2therapy followed by combined therapy. The asterisk indicates a significant change in reduction of IOP between days 13 plus 14 and days 6 plus 7 (2-tailed paired ttest, P<.05).COMMENT8-iso Prostaglandin E2is an isoprostane derivative. The isoprostanes are a unique series of prostaglandinlike compounds that have potential biological activity and take part in mediating the detrimental effects of oxidative stress in association with several human diseases. The biological effects of these compounds may be mediated through a unique isoprostane receptor.Latanoprost is not an isoprostane derivative. Thus, although latanoprost and 8-iso PGE2are prostaglandinlike compounds, they differ considerably.Latanoprost reduces IOP by increasing non–pressure-dependent uveoscleral outflow.8-iso Prostaglandin E2reduces IOP by increasing traditional, tonographically measured, pressure-dependent outflow facility.Although both of these agents are prostaglandin derivatives, they reduce IOP through different mechanisms. The different effects of these 2 agents on IOP may be due to activity at different receptors, due to the fact that 8-iso PGE2is an isoprostane derivative and latanoprost is not, or due to other as yet undetermined factors. The additivity of these 2 agents, for lowering IOP, as demonstrated in this study, is not unexpected. It occurs at concentrations that produce maximum effects on IOP. Clinical trials demonstrate that in some patients the effect of latanoprost is additive to cholinergic agents,which also reduce IOP by enhancing traditional tonographically measured outflow facility.In the present study, latanoprost and 8-iso PGE2, when applied as single agents, each reduced the IOP in glaucomatous monkey eyes. Peak IOP reductions were similar (P>.30) when comparing the effects of the 2 drugs, 26% after 6 days of dosing with latanoprost and 21% after 6 days of dosing with 8-iso PGE2. Studiespreviously conducted in glaucomatous monkeys demonstrated comparable magnitudes of IOP reduction, up to 29% after 5 days of twice-daily dosing with latanoprostand up to 24% after 5 days of twice-daily dosing with 8-iso PGE2. For either drug, reductions of IOP were similar on days 6 and 7, somewhat less than on day 5, suggesting that a longer duration of treatment would not produce an enhanced effect. In this monkey model, using latanoprost and 8-iso PGE2in combination resulted in additional IOP reductions of up to 12%. The small number of eyes in each treatment group, only 4, and the large fluctuations in IOP characteristically observed in the eyes of monkeys with laser-induced glaucoma explain why the additive effects on IOP that were observed at each point were not always statistically significant.There has been considerable debate as to what is measured when using a tonographic technique. Tonographically measured outflow facility represents the sum of trabecular outflow facility, pseudofacility, and uveoscleral facility. Under normal circumstances, pseudofacility and uveoscleral facility in monkeys are each less than 0.02 µL/min per millimeter of mercury.Thus, it is most probable that increases in tonographically measured outflow facility following application of 8-iso PGE2to monkeys primarily represent an increase in trabecular outflow facility. The mechanism by which IOP was reduced with combination therapy with latanoprost and 8-iso PGE2was not measured in this study. The additive effect of the 2 drugs on IOP suggests that both uveoscleral outflow and traditional outflow facility are enhanced.CONCLUSIONSProstaglandins are the newest class of compounds for managing glaucoma. Latanoprost or 8-iso PGE2when used alone lowers IOP less than when these agents are used in combination in glaucomatous monkey eyes. Tachyphylaxis does not occur. Thus, 8-iso PGE2, a new prostaglandin compound that substantially differs from latanoprost, may have potential as a new agent for treating glaucoma.CBCamrasComparison of latanoprost and timolol in patients with ocular hypertension and glaucoma.Ophthalmology.1996;103:138-147.AAlmCBCamrasPGWatsonPhase III latanoprost studies in Scandinavia, the United Kingdom and the United States.Surv Ophthalmol.1997;41(suppl 2):S105-S110.JBSerleSMPodosYKitazawaRFWangA comparative study of latanoprost (Xalatan) and isopropy unoprostone (Rescula) in normal and glaucomatous monkey eyes.Jpn J Ophthalmol.1998;42:95-100.CBTorisCBCamrasMEYablonskiEffects of PhXA41, a new prostaglandin F2αanalog on aqueous humor dynamics in human eyes.Ophthalmology.1993;100:1297-1304.RFWangPYLeeTWMittagSMPodosJBSerleBBeckerEffect of 8-iso prostaglandin E2on aqueous humor dynamics in monkeys.Arch Ophthalmol.1998;116:1213-1216.RFWangRASchumerJBSerleSMPodosA comparison of argon and diode laser photocoagulation of the trabecular meshwork to produce the glaucoma monkey model.J Glaucoma.1998;7:45-49.JDMorrowLJRobertsThe isoprostanes: current knowledge and directions for future research.Biochem Pharmacol.1996;51:1-9.PHoyngARuloEGrevePWatsonAAlmThe additive intraocular pressure-lowering effect of latanoprost in combined therapy with other ocular hypotensive agents.Surv Ophthalmol.1997;41(suppl 2):S93-S98.PLKaufmanKCrawfordAqueous humor dynamics: how PGF2αlowers intraocular pressure.In: Bito LZ, Stjernschantz J, eds. The Ocular Effects of Prostaglandins and Other Eicosanoids.New York, NY: Alan R Liss Inc; 1989:387-416.PLKaufmanAqueous humor dynamics.In: Durance TD, ed. Clinical Ophthalmology.Philadelphia, Pa: Harper & Row; 1985:1-24.Accepted for publication July 17, 1999.This study was supported in part by grant EY01867 from the National Eye Institutes, National Institutes of Health, Bethesda, Md, and an unrestricted grant from Research to Prevent Blindness Inc, New York, NY.Reprints: Steven M. Podos, MD, Campus Box 1183, Mount Sinai School of Medicine of New York University, One Gustave L. Levy Place, New York, NY 10029 (e-mail: Steven117@aol.com).
JAMA Ophthalmology – American Medical Association
Published: Jan 1, 2000
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