LABORATORY SCIENCES Effect of Latanoprost or 8-iso Prostaglandin E2 Alone and in Combination on Intraocular Pressure in Glaucomatous Monkey Eyes Rong-Fang Wang, MD; Steven M. Podos, MD; Janet B. Serle, MD; Thomas W. Mittag, PhD; F. Ventosa, MD; Bernard Becker, MD Objective: To evaluate the possible additivity of the ef- duction of IOP of 4.0 ± 0.6 mm Hg was produced when fects of latanoprost and 8-iso prostaglandin E2 (8-iso PGE2) 8-iso PGE2 was added to latanoprost and of 3.0 ± 0.7 on intraocular pressure (IOP) in monkey eyes with laser- mm Hg was produced when latanoprost was added to 8-iso induced glaucoma. PGE2 on day 13 before the morning dosing. Combina- tion therapy with both agents caused maximum IOP re- Methods: The IOP was measured hourly for 6 hours be- ductions from baseline of 11.3 ± 3.0 mm Hg (33%) (P,.05) ginning at 9:30 AM on day 1 (baseline day), days 6 and 7 (latanoprost with 8-iso PGE2 added) and of 9.8 ± 1.3 , (single-agent therapy), and days 13 and 14 (combination mm Hg (31%) (P .01) (8-iso PGE2 with latanoprost added) therapy with both agents). Following 1 day of baseline mea- on day 14. surement, 4 monkeys with unilateral glaucoma received monotherapy twice daily with either 1 drop of 0.005% la- Conclusion: Latanoprost and 8-iso PGE2 have an addi- tanoprost, or 0.1% 8-iso PGE2, 25 µL, at 9:30 AM and 3:30 tive effect on IOP in glaucomatous monkey eyes. PM from days 2 through 7. From days 8 through 14, both agents were applied twice daily 5 minutes apart. Clinical Relevance: At least 50% of patients are treated with more than 1 ocular hypotensive medication. Thus, the Results: The maximum reduction of IOP (mean ± SEM) determinationoftheadditiveeffectsonIOPofglaucomamedi- was 8.8 ± 1.9 mm Hg (26%) (P,.05) with latanoprost alone cations will help to define optimum treatment regimens. , and 6.5 ± 1.0 mm Hg (21%) (P .01) with 8-iso PGE2 alone, 2 hours after the morning dosing on day 7. A further re- Arch Ophthalmol. 2000;118:74-77 ATANOPROST, a new prosta- appear to reduce IOP by 2 different mecha- glandin F2a analogue, has nisms have additive effects on IOP when been shown to be an effec- used in combination. tive ocular hypotensive agent 1,2 in patients with glaucoma RESULTS and in monkey eyes with laser-induced L3 glaucoma. The mechanism by which la- Latanoprost and 8-iso PGE2, when applied tanoprost reduces intraocular pressure as single agents, significantly (P,.05) re- From the Department of (IOP) is primarily by increasing uveo- duced the IOP for at least 18 hours after the Ophthalmology, Mount Sinai scleral outflow without notably affecting eighth dose, which was measured at the 0 School of Medicine of New York aqueous humor flow rates or tonographi- hour(trough)onstudyday6(Table).Maxi- University, New York cally measured outflow facility.4 mum reductions of IOP with single-agent (Drs Wang, Podos, Serle, and 8-iso Prostaglandin E (8-iso PGE ), Mittag); La Asociacion Para 2 2 therapy (peak) occurred 2 hours after the Evitar La Ceguera En Mexico, a novel bioactive prostaglandinlike com- morning dosing on day 7 and were 8.8 ± 1.9 IAP, Hospital Dr Luis Sanchez pound that is structurally different from la- mm Hg (26%) (P,.05) with latanoprost and Bulens, San Lucas Coyoacan, tanoprost, reduces IOP in normal and glau- 6.5 ± 1.0 mm Hg (21%) (P,.01) with 8-iso 5 Mexico, DF (Dr Ventosa); comatous monkey eyes. A substantial PGE2 (Table). Intraocular pressure reduc- and the Department of increase in outflow facility appears to ac- tions were similar comparing study day 6 Ophthalmology and Visual count for most of the IOP reduction in nor- withstudyday7oftreatmentwith8-isoPGE2 Science, Washington University mal monkey eyes.5 This implies that there (P..70)orcomparingstudyday6withstudy Medical School, St Louis, Mo are different mechanisms by which pros- day 7 of treatment with latanoprost (P..60). (Dr Becker). Dr Podos is a taglandins with different stereochemical or Intraocular pressure reductions were simi- consultant to Alcon Laboratories, Inc, Ft Worth, geometric configurations can affect aque- lar comparing study day 13 with study day Tex. Drs Podos, Mittag, and ous humor dynamics and lower IOP. 14 of treatment with latanoprost added to . Becker have a proprietary Thus, this study was designed to de- 8-iso PGE2 (P .40) or comparing study day interest in the drug evaluated in termine if 2 different prostaglandin de- 13 with study day 14 of treatment with 8-iso . this article. rivatives, latanoprost and 8-iso PGE2, that PGE2 added to latanoprost (P .80). The ARCH OPHTHALMOL / VOL 118, JAN 2000 WWW.ARCHOPHTHALMOL.COM 74 ©2000 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 Effects of Single-Agent Therapy Followed by Combination Therapy on Intraocular Pressure MATERIALS AND METHODS in 4 Monkeys With Unilateral Glaucoma* Eight adult female cynomolgus monkeys (each weigh- Latanoprost + 8-iso Prostaglandin E2 + ing 3-5 kg), in which glaucoma had been induced uni- 8-iso Prostaglandin E2† Latanoprost‡ laterally by repeated argon or diode laser photoco- Trough (0 h) agulation of the midtrabecular meshwork, were used Baseline (day 1) 32.5 ± 1.9 33.3 ± 2.5 6 in this study. First drug The IOP was measured hourly, beginning at 9:30 Day 6 28.3 ± 1.3 (13)§ 29.5 ± 1.8 (11)§ AM, for a total of 6 hours on day 1 (baseline day), days Day 7 27.5 ± 1.9 (15)§ 29.0 ± 2.0 (13)§ 6and7(single-agenttherapy),anddays13and14(com- Both drugs bination therapy with both agents) using a calibrated Day 13 24.3 ± 1.3 (25)§\ 26.5 ± 2.1 (20)§\ pneumatonometer (model 30 classic; Mentor Inc, Nor- Day 14 24.0 ± 1.4 (26)§ 26.0 ± 1.6 (22)§\ well, Mass). Five minutes before tonometry, 1 drop of Peak (2 h) 0.5% proparacaine hydrochloride was topically applied, Baseline (day 1) 33.8 ± 3.5 31.5 ± 2.0 and ketamine hydrochloride, 1 to 5 mg/kg, was admin- First drug istered intramuscularly for adequate sedation. Day 6 25.5 ± 2.5 (24)§ 25.3 ± 1.5 (20)§ Day 7 25.0 ± 1.7 (26)§ 25.0 ± 1.7 (21)§ On each day of the study, 8-iso PGE2 (Cayman Chemical Co Inc, Ann Arbor, Mich) was freshly pre- Both drugs pared by dissolving in dimethyl sulfoxide, 100 g/L, and Day 13 22.0 ± 1.6 (35)§ 22.5 ± 1.3 (29)§ Day 14 22.5 ± 0.9 (33)§ 21.8 ± 1.0 (31)§\ diluting with 0.9% sodium chloride to a 0.1% solu- tion, a concentration that produces the greatest effect 5 *Data are given as the mean ± SEM (percentage reduction from baseline) on IOP. The commercially available preparation of la- intraocular pressure, measured in millimeters of mercury. Single-agent tanoprost, 0.005% (Pharmacia and Upjohn, Kalama- therapy and combination therapy were given twice daily. zoo, Mich), was used, which is also at the top of the †Treatment was started with 0.005% latanoprost, and 0.1% 8-iso dose-response relation. On the drug treatment days, prostaglandin E2 was added. days 2 through 14, the first IOP measurement was taken ‡Treatment was started with 0.1% 8-iso prostaglandin E2, and 0.005% latanoprost was added. just before the 9:30 AM dosing. On days 2 through 7, §Significant intraocular pressure reduction compared with baseline monkeys were treated twice daily with 1 drop of la- measurements (2-tailed paired t test, P,.05). tanoprost, or with 0.1% 8-iso PGE2, 25 µL, at 9:30 AM \Significant intraocular pressure reduction for combination therapy and 3:30 PM. On days 8 through 14, both 8-iso PGE2 compared with single-agent therapy (day 13 vs day 6 and day 14 vs day 7; and latanoprost were applied twice daily at 9:30 AM 2-tailed paired t test; P,.05). and 3:30 PM, 5 minutes apart. The monkeys were treated unilaterally, in the glaucomatous eye only. IOP reductions of up to 12% (3.8 ± 1.2 mm Hg) were noted The following statistical analyses were per- when 8-iso PGE was added to latanoprost and of up to 11% formed using the 2-tailed paired t test: the change in 2 IOP between baseline and single-agent therapy with (3.6 ± 0.8 mm Hg) were noted when latanoprost was added to 8-iso PGE 1 hour following morning dosing (Figure). latanoprost or 8-iso PGE2, the change in IOP be- 2 tween single-agent therapy and combination therapy, MaximumreductionsofIOPwithcombinationtherapycom- the change in IOP with single-agent therapy on days pared with baseline on day 14 were 11.3 ± 3.0 mm Hg (33%) , 6 and 7, the change in IOP with combination therapy (P .05) when 8-iso PGE2 was added to latanoprost and on days 13 and 14, and the change in IOP between 9.8 ± 1.3mmHg(31%)(P,.01)whenlatanoprostwasadded , combination therapy and baseline. A value of P .05 to 8-iso PGE2 (Table). was considered statistically significant. Data were cal- culated as the mean ± SEM. All experimental stud- ies complied with the Association for Research in Vi- COMMENT sion and Ophthalmology Resolution on the Use of Animals in Research and were approved by the Mount 8-iso Prostaglandin E2 is an isoprostane derivative. The iso- Sinai School of Medicine, New York, NY, Institu- prostanesareauniqueseriesofprostaglandinlikecompounds tional Animal Care and Utilization Committee.