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We read with great interest the article by Sherwood and colleagues1 describing the 12-month trial of twice-daily fixed-combination 0.2% brimonidine–0.5% timolol vs monotherapy with the individual components. The authors observed that the rate of allergic conjunctivitis in patients who received the combination product (5.2%) was significantly lower than that seen in patients who received brimonidine alone (9.4%). The authors acknowledge that a partial explanation for the improved tolerability may be related to the fact that the combination product is dosed twice daily while brimonidine was dosed 3 times daily. We would like to postulate that the lower rate of ocular allergy observed in their study may be a direct result of the addition of timolol to brimonidine based on a concept originally described by us a decade ago.2
This concept of ours is based on 2 observations describing the fundamental effect of adrenergic agonists/antagonists on cell volume and the development of ocular allergy in patients using such agents. We have previously shown in experiments using human cultured endothelial cells of the outflow pathways that α-adrenergic agonists reduce cell volume and increase paracellular fluid flow, and that these cell volume effects are effectively abrogated by the addition of the beta blocker, timolol.3 In addition, we have been impressed by the relationship between the concentration of adrenergic agents and the development of the localized inflammatory reactions. For example, Nagasubramanian and colleagues4 reported a 9% rate of ocular allergy with 0.25% apraclonidine and a rate of 36% with the 0.5% preparation. We observed an ocular allergy rate as high as 48% with 1% apraclonidine, although over a longer period.2
Assuming that the adrenergic effects on cell volume and the incidence of untoward effects are related, we propose a sequence of events that might explain such an association. When exposed to α-adrenergic agonists, the conjunctival cells respond by undergoing a reduction in cell volume, as shown for other cell types, with a widening of the intercellular space that facilitates entry into the subconjunctival tissues of several potential proinflammatory agents.2 These include exogenous airborne allergens, endogenous lipid secretions in the tear film, and other potentially toxic agents. We further propose that blocking the adrenergic agonist effect on conjunctival permeability could, in theory, ameliorate some of the recognized untoward inflammatory reactions induced by adrenergic agonists. The advent of fixed-combination therapy with brimonidine and timolol, if proven by other observers to be truly effective in lessening the incidence of allergic responses, may turn out to be the “proof of principle” for this concept of ours and for the benefit of our glaucoma patients.
Correspondence: Dr Alvarado, Department of Ophthalmology, 10 Koret Way, San Francisco, CA 94143 (alvaradoj@vision.ucsf.edu).
Financial Disclosure: None reported.
Funding/Support: This research is supported by Research to Prevent Blindness, Inc.
Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature
Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal
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