Ethacrynic Acid Increases Facility of Outflow in the Human Eye In Vitro

Liang, Lu-Lan; Epstein, David L.; Kater, A W de; Shahsafaei, Aliakbar; Erickson-Lamy, Kristine

doi:10.1001/archopht.1992.01080130108036

Cited by 45 publications

(18 citation statements)

References 6 publications

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“…On the other hand, the diuretic etha crynic acid inhibits the N a/2C I /K cotransporter in TM cells and has a significant facility-enhancing effect in calf and monkey [15] and in human eyes [16]. It has been postu lated that the effect of ethacrynic acid on outflow facility might be the consequence of ethacrynic acid on the cytoskeletal and junctional proteins (probably [3-tubulin) in TM cells and the inner wall o f Schlemm's canal [17].…”

Section: Diureticsmentioning

confidence: 99%

“…Thus, diuretics which interfere with the Na 7 2 0 /K co transporter such as bumetanide and furosemide do not influ ence contractility of the TM and thus have no effect on the regulation o f aqueous humor outflow [14], On the other hand, a diuretic substance like ethacrynic acid which also interferes with the Na 7 2 0 /K cotransporter in TM cells relaxes the TM and thus increases aqueous humor outflow in the calf, monkey and human eye [15,16]. However, this effect on contractility and outflow regulation is probably based on a direct effect of ethacrynic acid on the influx of calcium and on intracellular filaments which are also mod ified by cytochalasin [17,18].…”

Section: Diureticsmentioning

confidence: 99%

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Effect of Diuretics, Channel Modulators and Signal Interceptors on Contractility of the Trabecular Meshwork

Wiederholt

Dörschner²,

Groth³

1997

Ophthalmologica

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Measurements of isometric tension were performed on isolated trabecular meshwork (TM) and ciliary muscle (CM) strips of the bovine eye. Anterior segments of bovine eyes with well-preserved TM were perfused to measure outflow rate. (1) Bumetanide (10^––4 mol/l) and hydrochlorothiazide (10^––4 mol/l) did not change the contractility of TM and CM strips in the presence or absence of carbachol. Ethacrynic acid dose-dependently relaxed TM and CM strips precontracted either by carbachol or endothelin. (2) Cytochalasin D totally relaxed TM and CM strips precontracted by carbachol. The outflow rate almost doubled after application of cytochalasin D. (3) The effects of various modulators of K⁺ and Ca²⁺ channels are summarized. Carbachol and endothelin are postulated to modify nonselective cation channels. An effective blocker of nonselective cation channels (flufenamic acid) relaxed TM and CM precontracted by carbachol or endothelin. These relaxing effects were independent of the relaxing effects of ethacrynic acid and isosorbide dinitrate. (4) Evidence for the presence of various transporters and receptors in TM cells is summarized. (5) The TM per se is a contractile element which is involved in the regulation of aqueous humor outflow. The contractility of TM and CM cells is differently modulated.

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Section: Diureticsmentioning

confidence: 99%

Section: Diureticsmentioning

confidence: 99%

Effect of Diuretics, Channel Modulators and Signal Interceptors on Contractility of the Trabecular Meshwork

Wiederholt

Dörschner²,

Groth³

1997

Ophthalmologica

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“…The dotted line shown in Fig. 6 indicates the minimum effective C TM , which was chosen to be 10 lM because Liang et al have shown that TM outflow facility in excised human eyes is increased by 28% after the eyes are perfused with ECA solution at 10 lM for 1 h. 21 When t 1/2 was infinite, C TM increased with time in a biphasic manner. The increase was rapid initially and then became gradual, presumably due to the reduction in the concentration gradient across the cornea.…”

Section: Resultsmentioning

confidence: 99%

“…7,30 Different routes and methods have been considered for ECA administration. They include (i) direct infusion of ECA into the anterior chamber of living monkey's eyes, 31 enucleated human, 21 calf eyes, 6 and the eyes of patients with advanced open-angle glaucoma 24 ; (ii) implantation of a polymeric film into the sclera to locally release ECA 33 ; and (iii) topical application of ECA solutions onto the corneas of rabbits and monkeys. 32 In the study of topical application of ECA, corneal edema was observed in some animals at the precorneal concentration of 100 mM, which was required for lowering IOP in these animals.…”

Section: Introductionmentioning

confidence: 99%

Numerical Simulations of Ethacrynic Acid Transport from Precorneal Region to Trabecular Meshwork

Lin

Yuan

2010

Ann Biomed Eng

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Topical application of drugs for treatment of intraocular diseases is often limited by inadequate transport and induced toxicity in corneal tissues. To improve the drug delivery, a mathematical model was developed to numerically simulate the transport process of ethacrynic acid (ECA), a potential drug for glaucoma treatment, in the anterior segment of a typical human eye. The model considered diffusion of ECA in all tissues and the aqueous humor (AH) as well as convection of ECA in the AH. The simulation results showed that ECA concentration in the eye depended on the rate of AH production, the half-life of ECA in the precorneal tear film, and the transport parameters in the model. In addition, the main pathway for ECA clearance from the eye was the trabecular meshwork (TM) and the rate of clearance was approximately proportional to the AH production rate. The model predicted that the most effective approach to improving topical drug delivery was to prolong its half-life in the precorneal tear film. These simulation results and model prediction, which could be verified experimentally, might be useful for improving delivery of ECA and other therapeutic agents to the TM as well as other tissues in the anterior segment of the eye.

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“…1), a commercially marketed diuretic, has previously been demonstrated to increase anterior chamber outfl ow facility in vitro and reduce IOP in vivo. [7][8][9][10][11][12][13] The mechanism of action of ECA appears to involve cytoskeletal modulation and relaxation of TM/SC cells.…”

Section: Introductionmentioning

confidence: 99%

Eyedrops Containing SA9000 Prodrugs Result in Sustained Reductions in Intraocular Pressure in Rabbits

Arnold

Choksi²,

Chen³

et al. 2009

Journal of Ocular Pharmacology and Therapeutics

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Aim: Poor topical bioavailability and ocular irritation have impeded the development of the diuretic, ethacrynic acid (ECA) as a clinically useful ocular hypotensive for the treatment of glaucoma. Thus, the development of analogs and prodrugs of analogs with improved ocular penetration, potency, and tolerability is required. The aim of this work is to evaluate the corneal penetration and ocular distribution of SA9000, an ECA analog. Novel SA9000 prodrugs intended to further improve ocular pharmacodynamic effect were also evaluated. Results: SA9000 penetrated porcine corneas more effectively than ECA in corneal diffusion studies. In vivo studies in Dutch-belted (DB) rabbits indicated that topical application of a single dose (0.3%) of SA9000 could signifi cantly reduce intraocular pressure (IOP) (~25% vs. fellow untreated eye) but caused signifi cant conjunctival hyperemia. Since this hyperemia was likely the result of its inherent thiol reactivity, SA9000 was formulated with equimolar cysteine, an exogenous thiol donor. The administration of increasing SA9000-cysteine adduct concentrations (0.3%, 0.6%, 0.9%) demonstrated that they cause less ocular irritation than unadducted SA9000 but could still signifi cantly reduce IOP (0.3%: 8.7 ± 2%; 0.6%: 14.4 ± 5%; 0.9%: 23.3 ± 4.4%) versus untreated contralateral control eyes. Conclusions: These data suggest that novel thiol donor adduction can improve the ocular bioavailability and tolerability of SA9000. SA9000-cysteine prodrugs may represent a new option for the topical treatment of glaucoma.

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Ethacrynic Acid Increases Facility of Outflow in the Human Eye In Vitro

Cited by 45 publications

References 6 publications

Effect of Diuretics, Channel Modulators and Signal Interceptors on Contractility of the Trabecular Meshwork

Effect of Diuretics, Channel Modulators and Signal Interceptors on Contractility of the Trabecular Meshwork

Numerical Simulations of Ethacrynic Acid Transport from Precorneal Region to Trabecular Meshwork

Eyedrops Containing SA9000 Prodrugs Result in Sustained Reductions in Intraocular Pressure in Rabbits

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