Original article
Topical Mecamylamine for Diabetic Macular Edema

https://doi.org/10.1016/j.ajo.2009.12.005Get rights and content

Purpose

Stimulation of nicotinic acetylcholine (nACh) receptors on vascular endothelial cells promotes angiogenesis and vascular permeability in animal models. The safety and bioactivity of topical mecamylamine, an antagonist of nACh receptors, was tested in patients with diabetic macular edema.

Design

A multicenter phase I/II clinical trial.

Methods

Twenty-three patients with chronic diabetic macular edema received 1% mecamylamine topically twice daily for 12 weeks, the primary end point. Patients underwent safety assessments, measurement of best-corrected visual acuity (BCVA), and measurement of foveal thickness using optical coherence tomography at baseline, 1, 4, 8, 12, and 16 weeks.

Results

Mecamylamine drops were well tolerated and there were no drug-related safety problems. Mean improvement in BCVA at 1, 4, 8, 12, and 16 weeks was 2.8, 1.9, 2.4, 0.8, and 3.1 letters, respectively. There was little change in mean excess foveal thickness. There was substantial heterogeneity in response, because 8 patients showed convincing improvement in BCVA, foveal thickness, or both, 9 patients showed equivocal or no substantial changes, and 4 patients showed worsening. Five patients showed a substantial improvement in BCVA, foveal thickness, or both between their last visit while receiving mecamylamine and 1 month after stopping mecamylamine.

Conclusions

This study suggested that administration of topical mecamylamine, a nonspecific nACh receptor blocker, may have heterogeneous effects in patients with diabetic macular edema. Variable expression of nACh receptor subtypes on endothelial cells that have different effects on permeability would provide an explanation for these results and should be investigated, because more specific nACh receptor blockers may dissociate antipermeability and propermeability effects.

Section snippets

Methods

This was a phase I/II, open-label clinical trial conducted at 3 sites in the United States through an Investigational New Drug application granted by the Food and Drug Administration.

Results

The primary objective of this study was to evaluate the safety of topical mecamylamine in patients with DME. A few patients reported transient stinging after application, but in general the drops were well tolerated. Twenty-three patients were enrolled in the study, and 19 completed all study visits. Two patients withdrew consent before the week 1 visit and no data are available for those patients; 1 patient decided that the time commitment was too great and the other decided that an eye drop

Discussion

This was the first study investigating the use of topical mecamylamine for an ocular disease, and the formulation was found to be safe and well tolerated. Although the study was not powered to assess the efficacy of topical mecamylamine in patients with DME, there were several findings that suggest that mecamylamine gained access to the retina and had biological effects. Eight of the 21 patients for whom data were available showed evidence of improvement. Although patients with DME occasionally

Peter A. Campochiaro, MD, is the Eccles Professor of Ophthalmology and Neuroscience at the Wilmer Eye Institute of the Johns Hopkins University School of Medicine, Baltimore, Maryland. Dr. Campochiaro is a clinician-scientist who investigates molecular mechanisms involved in retinal diseases in both laboratory and clinical research. He has directed preclinical and early phase clinical studies for several new therapies for ocular neovascularization and macular edema.

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    Peter A. Campochiaro, MD, is the Eccles Professor of Ophthalmology and Neuroscience at the Wilmer Eye Institute of the Johns Hopkins University School of Medicine, Baltimore, Maryland. Dr. Campochiaro is a clinician-scientist who investigates molecular mechanisms involved in retinal diseases in both laboratory and clinical research. He has directed preclinical and early phase clinical studies for several new therapies for ocular neovascularization and macular edema.

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