Albert Alm

Phase III latanoprost studies in Scandinavia, the United Kingdom and the United States

Three large, masked, multicenter studies are reviewed comparing the safety and efficacy of 0.005% latanoprost eyedrops given once daily to 0.5% timolol eyedrops given twice daily for six months in patients with elevated intraocular pressure (IOP). A total of 829 patients were recruited from centers in Scandinavia, the United Kingdom (UK) and the United States of America (USA). In addition, data are reviewed from the first 198 of these patients to complete an additional six months of latanoprost treatment in an openlabel study. In all centers, both latanoprost and timolol were very effective in reducing the diurnal IOP. In the UK, both drugs reduced the IOP by 34%. In the USA, latanoprost was more effective than timolol, reducing IOP by 27% compared to 20%. In Scandinavia, latanoprost was given for three months in the evening and for three months in the morning while timolol was given twice daily for six months. Latanoprost given in the evening reduced IOP (35% reduction) significantly (p < 0.001) more than latanoprost given in the morning (31% reduction) and timolol given twice daily (27% reduction). Darkening of the iris color occurred in 7% of eyes treated with latanoprost for six months. A clinical evaluation of eyes with increased pigmentation, as well as preclinical studies; suggest that this side effect is a cosmetic problem in patients treated unilaterally. Other side effects were slight and not clinically significant. After one year of treatment with latanoprost in 198 patients, the IOP reduction of 32% was maintained. There was no loss of efficacy and no significant increase in the incidence of side effects or adverse events other than iris color darkening, which occurred or was suspected in 12%. These results demonstrate that latanoprost is a valuable drug for the treatment of chronic open angle glaucoma.

Initial clinical studies with prostaglandins and their analogues

Several prostaglandins (PGs), their prodrugs, and their analogues have been shown to reduce intraocular pressure (IOP) in normotensive volunteers and in patients with elevated IOP. Initial clinical trials demonstrated efficacy with most of these agents, but a PGE2 analogue, PGD2, and BW245C (an analogue selective for the DP-receptor) cause an initial rise in IOP with a minimal subsequent reduction. Although PGF2 alpha tromethamine salt, PGF2 alpha-isopropyl ester (PGF2 alpha-IE), and 15-propionate-PGF2 alpha-IE are all very effective in reducing IOP, they produce unacceptable side effects, including conjunctival hyperemia and ocular irritation. Isopropyl unoprostone, a 22-carbon chain PGF2 alpha metabolite, produces a 10-25% reduction in IOP lasting approximately 2-5 hours, is well tolerated, and is commercially available for use in Japan. 17-phenyl substituted PGF2 alpha-IE analogues, such as PhXA34 or latanoprost, effectively reduce IOP by 30-40% for at least 24 hours, and are very well tolerated with minimal conjunctival hyperemia and without irritation. Latanoprost is the more potent 15R-epimer of PhXA34, and has become a useful agent in glaucoma therapy.

The additive intraocular pressure-lowering effect of latanoprost in combined therapy with other ocular hypotensive agents

Latanoprost, a prostaglandin F2 alpha analogue prodrug, has been shown to be an effective ocular hypotensive agent when used alone on ocular hypertensive or open angle glaucoma patients. In various studies, the ocular hypotensive effects of latanoprost have also been evaluated when used in addition to, or in combination with, other ocular hypotensive agents. Latanoprost produces an additional reduction of intraocular pressure (IOP) when used in combination with timolol, pilocarpine, acetazolamide and dipivefrin. These represent four different classes of glaucoma drugs-beta-adrenergic antagonists, cholinergic agonists, carbonic anhydrase inhibitors, and adrenergic agonists-all of which reduce the IOP by different mechanisms (reduction of aqueous humor production, increased outflow facility, or by a mixed effect on aqueous humor dynamics). All the available evidence shows that latanoprost produces a clinically significant additive ocular hypotensive effect when used in combination with any currently available ocular hypotensive agent.

A population‐based study of macular thickness in full‐term children assessed with Stratus OCT: normative data and repeatability

Purpose:  We aimed to determine normal macular thickness values, assessed with optical coherence tomography (OCT), in a population of full‐term children of normal birthweight.

The effect of latanoprost on intraocular pressure during 2 years of treatment.

Our objective was to study the intraocular pressure (IOP) in open-angle glaucoma or ocular hypertensive patients during long-term treatment with latanoprost. A total of 532 patients treated with 0.005% latanoprost were enrolled, including 493 and 113 patients treated for 6 and 24 months, respectively. Mean IOP was analyzed with the analysis of variance technique. The risk of treatment failure was analyzed with survival analysis technique. After 2 weeks of latanoprost treatment, the mean IOP was reduced 8.2 (32%) and 8.9 (34%) mm Hg in the subgroups of patients treated for 6 and 24 months, respectively. The change in mean IOP during 2 years of latanoprost treatment was not statistically significant (p = 0.15). Patients with primary open-angle glaucoma or ocular hypertension showed an 86% and 97% chance of receiving a sufficient IOP reduction with latanoprost (p < 0.01), repectively. The initial mean IOP reduction was maintained throughout the 2 years of treatment.

Measurement of ocular blood flow.

Many of these techniques have been adapted to investigate hemodynamic alterations, not only in glaucoma, but in diverse disorders such as diabetic retinopathy, macular degeneration, retinal dystrophies, and nonglaucomatous optic neuropathies. However, each of these techniques has limitations and there is not a single methods that provides comprehensive measurements for all the ocular tissues. Our enhanced understanding of ocular vascular anatomy has helped to direct our hemodynamic investigations of the various vascular beds within the eye. However, many of the techniques have lacked validation (reproducibility and accuracy) prior to clinical implementation. Understanding the limitations and the theoretical assumptions of each of these techniques will allow more prudent application in the clinical arena in the future.

Pseudoexfoliation as a risk factor for prevalent open-angle glaucoma

Purpose:  To estimate the risk of open‐angle glaucoma (OAG) associated with exposure to pseudoexfoliation (PEX) and increased intraocular pressure (IOP).

Pooled-data analysis of three randomized, double-masked, six-month studies comparing intraocular pressure-reducing effects of latanoprost and timolol in patients with ocular hypertension.

PurposeTo assess retrospectively the intraocular pressure (IOP)-reducing effect of latanoprost compared with timolol in the subset of patients with ocular hypertension (OH). MethodsThree randomized, double-masked, multicenter, parallel group, 6-month studies conducted in the United States, United Kingdom, and Scandinavia compared the efficacy and safety of latanoprost and timolol. The present study represents an analysis of the pooled data for the subset of OH patients. Intent-to-treat analyses were based on all randomized OH patients. ResultsOf the 441 patients with OH, 247 were treated with latanoprost and 194 were treated with timolol. Baseline mean diurnal IOP levels were 24.4 ± 0.2 mm Hg (mean ± standard error of the mean) in the latanoprost group and 24.2 ± 0.2 mm Hg in the timolol group. Overall, latanoprost lowered mean diurnal IOP by 1.1 ± 0.2 mm Hg (95% CI: 1.6 to 0.7 mm Hg, P < 0.001) more than timolol. The difference in IOP-lowering ability between the two drugs was not shown to be related to patient sex, age, race, presence or absence of previous treatment of OH, time elapsed since ocular diagnosis, or family history of glaucoma/OH. Percentage reductions from baseline in diurnal IOP levels of at least 20% were achieved by 83% of patients treated with latanoprost versus 62% of those receiving timolol. ConclusionLatanoprost provides superior IOP reduction compared with timolol in patients with OH.

Latanoprost and Cholinergic Agonists in Combination

Latanoprost, a prodrug of a prostaglandin F(2alpha) analog, is a potent ocular hypotensive agent, reducing intraocular pressure (IOP) primarily by increasing aqueous humor drainage through the uveoscleral outflow pathway. Initial assessments in animals found that high concentrations of cholinergic agonists reduced drainage through this pathway and attenuated the effects of a PGF(2alpha) analog. This raised the question of whether latanoprost would be effective when added to the treatment regimen of patients on pilocarpine or strong miotics. In published clinical studies, latanoprost was additive to the maximally tolerated medical therapy (which included cholinergic agonists) of glaucoma patients. Multiple doses of physostigmine in healthy volunteers did not block the effect of a single drop of latanoprost during a 1-day study. One study attempting to find the optimal timing of administration of latanoprost and pilocarpine claimed to show that additivity was best when pilocarpine was given one hour after latanoprost in the evening. Two other studies found that the timing of the doses was not important. To explain the additivity of latanoprost and pilocarpine, aqueous humor dynamics were assessed in ocular hypertensive patients treated for 1 week with each drug alone and then for one week in combination. The results showed that latanoprost increased uveoscleral outflow, pilocarpine increased outflow facility, and pilocarpine did not block or attenuate the uveoscleral outflow effect of latanoprost. The result was greater IOP reduction when these drugs were used in combination than when either drug was used alone. All available evidence demonstrates that addition of latanoprost to the treatment regime of patients already taking cholinergic agonists is an effective, although not necessarily the preferred, combination of medications for the treatment of elevated IOP.

Retinal nerve fibre layer thickness in full‐term children assessed with Heidelberg retinal tomography and optical coherence tomography: normal values and interocular asymmetry

Purpose:  This study aimed to investigate normal values and interocular differences in retinal nerve fibre layer (RNFL) thickness, using optical coherence tomography (OCT) and Heidelberg retinal tomography (HRT), in 5–16‐year‐old children born at full‐term with normal birthweights.