TY - JOUR
T1 - Topical Mecamylamine for Diabetic Macular Edema
AU - Campochiaro, Peter A.
AU - Shah, Syed Mahmood
AU - Hafiz, Gulnar
AU - Heier, Jeffery S.
AU - Lit, Eugene S.
AU - Zimmer-Galler, Ingrid
AU - Channa, Roomasa
AU - Nguyen, Quan Dong
AU - Syed, Beena
AU - Do, Diana V.
AU - Lu, Lili
AU - Monk, James
AU - Cooke, John P.
AU - Kengatharan, M. Ken
AU - Hsu, Henry H.
N1 - Funding Information:
Sponsored by the Juvenile Diabetes Research Foundation (New York, New York), CoMentis, Inc (South San Francisco, California), Grants R01 EY012609 (P.A.C.) and R01 CA098303 (J.P.C.) from the National Institutes of Health , Bethesda, Maryland; and the California Tobacco Related Disease Research Program of the University of California, Oakland, California (18XT-0098). Dr Campochiaro is the George S. and Dolores Doré Eccles Professor of Ophthalmology and Neuroscience. Drs Campochiaro, Nguyen, and Do receive research support and have an institutional consulting agreement through which Johns Hopkins University receives compensation with Genentech, Inc. Dr Campochiaro has an institutional consulting agreement with GlaxoSmithKline. Dr Nguyen is a consultant for Bausch & Lomb and receives research support from Genentech, Inc , and Regeneron, Inc. Dr Campochiaro serves on the data and safety monitoring committee for a phase III trial sponsored by Regeneron, Inc , and receives research support from Alimera and CoMentis for diabetic macular edema trials. These activities are being managed by the Conflict of Interest Committee of the Johns Hopkins University School of Medicine. Dr Cooke is a scientific advisor and holds equity in Comentis and receives royalties as an inventor on Stanford patents licensed to Comentis. Dr Heier is a consultant for Genentech, Alcon, Allergan, Bausch & Lomb, Eyemaginations, Fovea, Genzyme, Heidelburg, IScience, ISTA, Jerini, LPath, NeoVista, Nodal Vision, Novagali, Novartis, Optherion, Oxigene, Paloma, Pfizer, Regeneron, Resolvyx, Schering Plough, Scyfix, and VisionCare and has received honoraria from Genentech, Heidelberg, Jerini, NeoVista, Optimedica, and Regeneron. Involved in Conception and design (P.A.C.; M.K.K., H.H.H.); Analysis and interpretation of data (P.A.C., S.M.S., G.H., R.C.); Data collection (P.A.C., S.M.S., G.H., J.S.H., E.S.L., I.Z.-G., R.C., Q.D.N., B.S., D.V.D., L.L., J.M.); Statistical expertise (S.M.S.); Provision of materials, patients, or resources (P.A.C., J.S.H., E.S.L., I.Z.-G., Q.D.N., D.V.D., M.K.K., H.H.H.); Literature search (P.A.C.); Administrative and technical support (G.H.); Logistical support (J.M.); Writing the article (P.A.C., S.M.S., R.C., J.P.C.); Critical revision of the article (P.A.C., S.M.S., J.S.H., E.S.L., I.Z.-G., Q.D.N., B.S., D.V.D., L.L., J.P.C.); and Final approval of the article (P.A.C., S.M.S., G.H., J.S.H., E.S.L., I.Z.-G., Q.D.N., B.S., D.V.D., L.L., J.M., J.P.C., M.K.K., H.H.H.). The study adhered to the guidelines of the Declaration of Helsinki, and the protocol and consent form were approved by a local investigational review board (IRB) or by Western IRB. Each subject provided written informed consent. The study is registered at www.clinicaltrials.gov under the identifier NCT00536692 .
PY - 2010/5
Y1 - 2010/5
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ajo.2009.12.005
DO - 10.1016/j.ajo.2009.12.005
M3 - Article
C2 - 20189159
AN - SCOPUS:77950863290
SN - 0002-9394
VL - 149
SP - 839-851.e1
JO - American journal of ophthalmology
JF - American journal of ophthalmology
IS - 5
ER -