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Arch Ophthalmol. 2002;120:847-849.

Latanoprost is a prostaglandin F_2aanalogue prodrug that is used in the management of ocular hypertension and glaucoma. Latanoprost is widely prescribed and has displayed ocular hypotensive efficacy greater than that exhibited by timolol maleate in controlled comparative studies.^1-4 The effect on intraocular pressure (IOP) seems to be caused by increased uveoscleral outflow.^5-6

Bimatoprost is a new ocular compound that appears to mimic the prostamides. Prostamides are the most recently described members of the fatty-acid amide family and are potent ocular hypotensive agents. Bimatoprost also has been shown to have superior hypotensive efficacy compared with timolol.^7-8 Bimatoprost seems to work by enhancing pressure-independent aqueous outflow, presumably corresponding to uveoscleral outflow and conventional outflow through the trabecular meshwork. Bimatoprost has also been noted to increase aqueous production.⁹

We have recently noted 3 patients who have demonstrated marked paradoxical IOP elevation after adding bimatoprost to the treatment regimen of an eye already being treated with latanoprost, and we present those cases.

Report of Cases
Case 1

A 61-year-old African American man had been diagnosed as having open-angle glaucoma 6 months previously. When he was first evaluated by one of us (L.W.H.) a month after his diagnosis, he was noted to have a Goldmann applanation IOP of 22 mm Hg OD and 19 mm Hg OS. He had been using timolol 0.5% in both eyes twice daily until discontinuing this medication 1 week before the visit. For compliance reasons and as a trial in 1 eye, he began applying timolol maleate ophthalmic gel-forming solution (Timoptic XE; Merck & Co, Inc, West Point, Pa) 0.5% in the right eye once daily in the morning. A horseshoe retinal tear was incidentally found in the right eye, and the patient underwent prophylactic laser treatment of the tear at the same visit.

At follow-up 3 weeks later, the IOP was 24 mm Hg OD and 21 mm Hg OS. Because he required a lower target IOP, timolol maleate ophthalmic gel-forming solution was replaced with latanoprost in the right eye once daily in the evening. Two months following his initial visit, the IOP was 25 mm Hg OD and 15 mm Hg OS, and bimatoprost was added to the treatment regimen in the right eye once daily in the morning. At follow-up 5 weeks later, the IOP was 48 mm Hg OD and 21 mm Hg OS. Bimatoprost was discontinued, and the IOP 1 week later (following use of latanoprost alone in the right eye) was 33 mm Hg OD and 20 mm Hg OS. The patient reported compliance with therapy at every follow-up visit, and the anterior segment remained stable. The IOP was measured in the early to late afternoon at each visit and by the same person (L.W.H.) each time.

Case 2

A 70-year-old white man was diagnosed as having pigmentary glaucoma, more severe in the right eye than in the left, in 1988. He had undergone trabeculectomy in the right eye and had received an Ahmed valve implantation in the left eye in February 2000. Medications in the right eye had been discontinued since the trabeculectomy. However, the condition of the left eye required that glaucoma medications be resumed. By March 2001, the IOP was 10 mm Hg OU, with the patient applying latanoprost once daily in the evening in the left eye and a combination of dorzolamide hydrochloride and timolol maleate ophthalmic solution (Cosopt; Merck & Co, Inc) twice daily in the left eye, with a stable anterior segment in both eyes. At follow-up in May 2001, the dorzolamide hydrochloride–timolol maleate ophthalmic solution was replaced with dorzolamide hydrochloride twice daily, as the patient was noted to have bradycardia. He continued using latanoprost in the left eye. The IOP at that visit measured 8 mm Hg OD and 20 mm Hg OS. Dorzolamide hydrochloride was replaced with bimatoprost once daily in the morning in the left eye. At the next follow-up visit in 2 weeks, the IOP was 7 mm Hg OD and 35 mm Hg OS. Bimatoprost was discontinued, with resumption of dorzolamide hydrochloride–timolol maleate ophthalmic solution twice daily with the patient applying nasolacrimal duct occlusion. At the follow-up visit 2 weeks later, the IOP was 6 mm Hg OD and 13 mm Hg OS. The IOP was measured in the late morning or early afternoon at each visit and was measured by the same person (L.W.H.) each time. The patient reported compliance with the medical regimen at each visit.

Case 3

A 62-year-old white woman was diagnosed as having acute-angle closure in the left eye in 1974 and underwent surgical peripheral iridectomy. She had laser peripheral iridotomy performed on the right eye in 1982. She had been using treatment drops for glaucomain both eyes since the 1970s, with some recent difficulty in controlling the IOP in the left eye. During the past year, the IOP had remained in the midteens in the right eye, but had ranged between 16 and 23 mm Hg OS. By May 2001, the IOP was 13 mm Hg OD and 19 mm Hg OS using 1 drop of latanoprost daily in both eyes in the evening and 1 drop of brimonidine tartrate twice daily in the left eye. One drop of bimatoprost in the left eye every evening was added to the regimen. Four weeks later, the IOP was 42 mm Hg OS, although the patient had discontinued the bimatoprost 4 days before this visit because of irritation and redness of the left eye. The IOP in the right eye was 16 mm Hg at that visit. Timolol maleate ophthalmic gel-forming solution 0.5% once daily in the morning in the left eye was added to the current regimen of latanoprost and brimonidine, and 3 days later the IOP was 15 mm Hg OU.

Comment
Glaucoma is a chronic, progressive disease characterized by visual field loss and optic nerve damage, often in the presence of elevated IOP.¹⁰ Patients with glaucoma are usually treated initially with monotherapy to reduce their IOP; however, many patients eventually require more than 1 medication.¹¹ Recent studies^12-13 have shown the importance of lowering the IOP in the management of glaucoma, perhaps to lower levels than were thought necessary in the past. With the development of newer glaucoma medications and combinations thereof, lower target IOPs are more readily achieved. Because many patients with glaucoma require combination therapy, the combination of the 2 powerful hypotensive agents latanoprost and bimatoprost may become a popular treatment option. In addition, latanoprost and bimatoprost offer convenient once daily dosing.

Latanoprost and bimatoprost seem to work by increasing uveoscleral outflow, so combining 2 drugs that facilitate outflow may not be the most optimal approach, although these 2 agents presumably work on different receptors. Woodward et al¹⁴ showed that bimatoprost has no significant affinity for prostaglandin receptors or for several other receptors in a feline iris sphincter preparation. This finding, albeit in a feline model, supports the concept that the target receptor for bimatoprost is pharmacologically unique.

It is also known that the use of latanoprost twice daily is less effective than once daily application,^15-18 and an early study⁷ also shows that bimatoprost twice daily is less effective than bimatoprost once daily. In a study of 40 healthy volunteers who received latanoprost once daily in one eye and twice daily in the fellow eye, Linden and Alm¹⁸ showed that once daily dosing resulted in a significantly lower IOP compared with twice daily dosing on day 15, but not on day 2. They believed that a twice daily regimen of latanoprost leads to desensitization at the level of the FP-receptor. In monkeys, treatment with large dosages of prostaglandin F_2afor 4 to 8 days induces loss of extracellular material between the ciliary muscle bundles.^19-20 In their 6-month comparison of the effects of bimatoprost vs timolol, Sherwood et al⁷ reported a 33% reduction of IOP from baseline with bimatoprost once daily, compared with a 26% reduction with bimatoprost twice daily. They speculated that twice daily dosing of bimatoprost may give concentrations that are past the peak of the dose-response curve, resulting in reduced efficacy. Commercially available latanoprost and bimatoprost are near the top of their dose-response curves, so using them together results in excessive dosages (Carl Camras, MD, written communication, March 12, 2001). Brubaker et al⁹ demonstrated that bimatoprost also causes an increase in aqueous production. Perhaps the increased aqueous flow in the face of compromised conventional outflow is the reason for the elevated IOP. Interestingly, the combination of latanoprost and unoprostone isopropyl, another hypotensive lipid, has been reported to have an additive pressure-lowering effect on diurnal curve characteristics.²¹

Each of our patients demonstrated marked IOP elevation within 2 to 5 weeks after adding bimatoprost to the treatment regimen of an eye being treated with latanoprost. There are possible mitigating factors other than the combination therapy that could have contributed to the pressure rises in our patients. Although each patient claimed compliance with medical therapy, missed doses of the eyedrops could have led to rebound elevation in IOP. In case 2, the patient had a diagnosis of pigmentary glaucoma. Wide swings of IOP have been demonstrated with secondary glaucomas, such as pigmentary and pseudoexfoliative glaucoma, although this possibility would be unlikely in this patient, as there was no evidence of active pigment dispersion. In case 3, the patient had a diagnosis of combined mechanism glaucoma after peripheral iridectomy. Certainly, variability of IOP control is notorious in this setting; however, this patient had undergone iridectomy many years previously, and gonioscopic findings were unchanged. Although this patient had discontinued bimatoprost 4 days before the follow-up visit, she had used the medication for 3 weeks before discontinuing it, so it is likely that there was a lingering effect of the bimatoprost. The effect on diurnal IOP of latanoprost applied once daily in the evening has been shown to be superior to that of latanoprost applied once daily in the morning.¹ The IOP-lowering advantage of applying bimatoprost in the evening has not been demonstrated (Achim Krauss, PhD, oral communication, March 24, 2001), so bimatoprost was applied in the morning in 2 of the 3 patients for convenience.

In summary, latanoprost and bimatoprost are powerful ocular hypotensive lipids that have shown efficacy superior to that of timolol in controlled clinical trials. Using these 2 medications together may lead to marked IOP elevation in some patients, and close surveillance is advised whenever combined therapy is prescribed. Further study is indicated to determine more clearly which patients might be at risk for this paradoxical reaction.

AUTHOR INFORMATION

Leon W. Herndon, MD; Sanjay G. Asrani, MD; Gayle H. Williams, MD, PhD; Pratap Challa, MD; Paul P. Lee, MD
Durham, NC

Corresponding author: Leon W. Herndon, MD, Duke University Eye Center, PO Box 3802, Durham, NC 27710 (e-mail: hernd012{at}mc.duke.edu).

REFERENCES
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