LABORATORY SCIENCES

Effect of or 8-iso E2 Alone and in Combination on 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 (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 . 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%) (PϽ.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 Ͻ (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 . Thus, the Results: The maximum reduction of IOP (mean ± SEM) determinationoftheadditiveeffectsonIOPofglaucomamedi- was 8.8 ± 1.9 mm Hg (26%) (PϽ.05) with latanoprost alone cations will help to define optimum treatment regimens. Ͻ 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 F2␣ 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 (PϽ.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 (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%) (PϽ.05) with latanoprost and Bulens, San Lucas Coyoacan, tanoprost, reduces IOP in normal and glau- 6.5 ± 1.0 mm Hg (21%) (PϽ.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 (PϾ.70)orcomparingstudyday6withstudy Medical School, St Louis, Mo are different mechanisms by which pros- day 7 of treatment with latanoprost (PϾ.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 Ͼ 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 Ͼ this article. rivatives, latanoprost and 8-iso PGE2, that PGE2 added to latanoprost (P .80). The

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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 , 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, PϽ.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; PϽ.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%) Ͻ 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%)(PϽ.01)whenlatanoprostwasadded Ͻ 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 derivative. The iso- Sinai School of Medicine, New York, NY, Institu- prostanesareauniqueseriesofprostaglandinlikecompounds tional Animal Care and Utilization Committee. that have potential biological activity and take part in me- diating the detrimental effects of oxidative stress in asso- ciation with several human diseases. The biological effects of these compounds may be mediated through a unique maximum effect on IOP had been obtained by study day 6 isoprostane .7 Latanoprost is not an isoprostane for single-agent therapy and by study day 13 for combined derivative. Thus, although latanoprost and 8-iso PGE2 are therapy. Combination therapy resulted in additional IOP prostaglandinlike compounds, they differ considerably. reductions at all measurement times on study day 13 com- Latanoprost reduces IOP by increasing non–pressure- 4 pared with study day 6 and on study day 14 compared with dependent uveoscleral outflow. 8-iso Prostaglandin E2 re- study day 7. The average IOP on days 6 and 7 (single-agent duces IOP by increasing traditional, tonographically mea- therapy) was compared with the average IOP on days 13 sured, pressure-dependent outflow facility.5 Although both and 14 (combination therapy) in each of the 2 treatment of these agents are prostaglandin derivatives, they reduce groups. The additional reductions in IOP were statistically IOP through different mechanisms. The different effects Ͻ significant (P .05) at 0, 1, 5, and 6 hours when 8-iso PGE2 of these 2 agents on IOP may be due to activity at differ- was added to latanoprost, and from 0 through 4 hours when ent receptors, due to the fact that 8-iso PGE2 is an iso- latanoprost was added to 8-iso PGE2 (Figure). Additional prostane derivative and latanoprost is not, or due to other

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–20 ∗ ∗ ∗ ∗ ∗ ∗ ∗ ∗ Reduction in IOP, % Reduction in IOP, –30 ∗

Latanoprost Therapy Only 8-iso Prostaglandin E2 (Days 6 and 7) Therapy Only (Days 6 and 7) –40 Latanoprost Therapy Plus 8-iso Prostaglandin E2 8-iso Prostaglandin E2 Therapy Plus Latanoprost Therapy (Days 13 and 14) Therapy (Days 13 and 14)

0123456 0123456 Time, h Time, h

Percentage reduction of intraocular pressure (IOP) compared with baseline in 4 glaucomatous monkeys for latanoprost or 8-iso prostaglandin E2 therapy 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 t test, PϽ.05).

as yet undetermined factors. The additivity of these 2 agents, cility. The mechanism by which IOP was reduced with for lowering IOP, as demonstrated in this study, is not un- combination therapy with latanoprost and 8-iso PGE2 was expected. It occurs at concentrations that produce maxi- not measured in this study. The additive effect of the 2 mum effects on IOP. Clinical trials demonstrate that in drugs on IOP suggests that both uveoscleral outflow and some patients the effect of latanoprost is additive to cho- traditional outflow facility are enhanced. linergic agents,8 which also reduce IOP by enhancing tra- ditional tonographically measured outflow facility. CONCLUSIONS In the present study, latanoprost and 8-iso PGE2, when applied as single agents, each reduced the IOP in glauco- are the newest class of compounds for man- matous monkey eyes. Peak IOP reductions were similar aging glaucoma. Latanoprost or 8-iso PGE2 when used alone (PϾ.30) when comparing the effects of the 2 drugs, 26% lowers IOP less than when these agents are used in com- after 6 days of dosing with latanoprost and 21% after 6 days bination in glaucomatous monkey eyes. Tachyphylaxis does 5 of dosing with 8-iso PGE2. Studies previously conducted not occur. Thus, 8-iso PGE2, a new prostaglandin compound in glaucomatous monkeys demonstrated comparable mag- that substantially differs from latanoprost, may have poten- nitudes of IOP reduction, up to 29% after 5 days of twice- tial as a new agent for treating glaucoma. daily dosing with latanoprost3 and up to 24% after 5 days of twice-daily dosing with 8-iso PGE2. For either drug, re- Accepted for publication July 17, 1999. ductions of IOP were similar on days 6 and 7, somewhat This study was supported in part by grant EY01867 less than on day 5, suggesting that a longer duration of treat- from the National Eye Institutes, National Institutes of Health, ment would not produce an enhanced effect. In this mon- Bethesda, Md, and an unrestricted grant from Research to key model, using latanoprost and 8-iso PGE2 in combi- Prevent Blindness Inc, New York, NY. nation resulted in additional IOP reductions of up to 12%. Reprints: Steven M. Podos, MD, Campus Box 1183, The small number of eyes in each treatment group, only Mount Sinai School of Medicine of New York University, 4, and the large fluctuations in IOP characteristically ob- One Gustave L. Levy Place, New York, NY 10029 (e-mail: served in the eyes of monkeys with laser-induced glaucoma [email protected]). 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 mea- REFERENCES sured when using a tonographic technique. Tonographi- cally measured outflow facility represents the sum of tra- 1. Camras CB. Comparison of latanoprost and in patients with ocular hy- pertension and glaucoma. Ophthalmology. 1996;103:138-147. becular outflow facility, pseudofacility, and uveoscleral 2. AlmA,CamrasCB,WatsonPG.PhaseIIIlatanoproststudiesinScandinavia,theUnited facility. Under normal circumstances, pseudofacility and Kingdom and the United States. Surv Ophthalmol. 1997;41(suppl 2):S105-S110. 3. Serle JB, Podos SM, Kitazawa Y, Wang RF. A comparative study of latanoprost uveoscleral facility in monkeys are each less than 0.02 (Xalatan) and isopropy (Rescula) in normal and glaucomatous mon- 9,10 µL/min per millimeter of mercury. Thus, it is most prob- key eyes. Jpn J Ophthalmol. 1998;42:95-100. able that increases in tonographically measured outflow 4. Toris CB, Camras CB, Yablonski ME. Effects of PhXA41, a new prostaglandin F2␣ analog on aqueous humor dynamics in human eyes. Ophthalmology. 1993;100: facility following application of 8-iso PGE2 to monkeys 1297-1304. primarily represent an increase in trabecular outflow fa- 5. Wang RF, Lee PY, Mittag TW, Podos SM, Serle JB, Becker B. Effect of 8-iso pros-

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50 Years Ago in the ARCHIVES

A look at the past...

he colossal growth of all phases of ophthalmology during the last 20 years in both the clinical and the experimental field makes it impos- Tsible for the reader to keep abreast of the times without some process of condensation.

Reference: Adler F. Editorial. Arch Ophthalmol. 1950;43:967.

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