Reduction in Intraocular Pressure by the Instillation of Eye Drops Containing Disulfiram Included with 2-Hydroxypropyl-.BETA.-cyclodextrin in Rabbit

Abstract

Glaucoma is characterized by nerve degeneration that causes the disappearance of retinal ganglion cells, visual field loss and excavation of the optic disk, and ophthalmopathy. 1,2) It is one of the most common causes of visual impairment and blindness throughout the world and is more common in the elderly.3) The major risk factor for glaucoma is elevated intraocular pressure (IOP), which leads to apoptosis and loss of retinal ganglion cells. 4) In treating glaucoma, the focus is on reducing IOP, and retinal and optic nerve damage. However, the retinal and optic nerve damage that result from elevated IOP are not satisfactorily controlled by the current therapies. Therefore, the search for successful therapies for glaucoma is a high priority.Nitric oxide (NO) is synthesized from the guanidino-nitrogen of L-arginine and molecular oxygen by nitric oxide synthase (NOS). Endothelial NOS and neuronal NOS are present in most ocular tissues, including those responsible for aqueous dynamics, i.e. the ciliary processes, ciliary muscle and trabecular meshwork.5-7) NO causes relaxation of the ciliary muscle and trabecular meshwork. 8,9) The relaxation of the ciliary muscle tends to decrease trabecular outflow facility and increase uveoscleral outflow, while relaxation of the trabecular meshwork increases trabecular outflow facility. Thus the effects of NO on IOP vary depending upon the site of action. On the other hand, recently, Kiel et al. 10) reported that the systemic inhibition of NOS by N G -nitro-L-arginine methyl ester (L-NAME) causes a large, rapid decrease in IOP by due to ciliary vasoconstriction in rabbits. Therefore, agents that inhibit NOS in the blood vessel of ciliary body might prove useful in the treatment of glaucoma.Diethyldithiocarbamate (DDC) is a potent NOS inhibitor and radical scavenger. 11,12) However, DDC is unstable in neutral solution, and is not able to penetrate through the cornea into the aqueous humor.13) Disulfiram (DSF), a dimer of DDC, has long been used to treat alcoholic syndrome without severe side effects. 14) However, its application in the ophthalmic field is limited due to its poor water solubility.Cyclodextrins are cyclic oligosaccharides comprising R-Dglucose linked by R-(1-4) glucosidic bonds. Natural cyclodextrins and their synthetic derivatives have been studied extensively to improve certain properties such as their solubility, stability, and/or bioavailability.15) 2-Hydroxypropyl-bcyclodextrin (HPbCD) is a cyclic oligosaccharide with a hydrophilic outer surface and a lipophilic cavity that is capable of forming inclusion complexes with many lipophilic drugs by taking up the drug molecule, or part of it, into its lipophilic cavity. 16,17) In aqueous solution, hydroxypropylmethylcellulose (HPMC), a water-soluble polymer, increases the solubilizing effect of cyclodextrins on lipophilic drugs by increasing the stability constants of the drug/cyclodextrin inclusions.18) We previously found that HPbCD and HPMC increase the solubility of DSF, and solve the problem of its poor wat...

Reduction of Enhanced Rabbit Intraocular Pressure by Instillation of Pyroglutamic Acid Eye Drops

“…In addition, it is known that the increase in IOP in rabbits following the rapid infusion of 5% glucose is caused by a rapid production of aqueous humor, 15) and our previously reports showed that enhanced NO in the aqueous humor causes this increase in IOP using NOS inhibitor, disulfiram (DSF) eye drops. 26) In this study, the NO levels in the aqueous humor increased following the rapid infusion of 5% glucose solution, and the instillation of PGA/HPCD eye drops reduced this increase (Fig. 4, Table 4), and the behavior of IOP and NO levels in rabbit instilled PGA/HPCD eye drops was similar to that instilled DSF eye drops.…”

“…4, Table 4), and the behavior of IOP and NO levels in rabbit instilled PGA/HPCD eye drops was similar to that instilled DSF eye drops. 26) The increased IOP and NO levels in rabbits who did receive the 5% glucose infusion were not reduced by instilling the eye drop vehicle (saline containing 0.5% ZnCl 2 and 10% HPCD; data not shown). Thus, we hypothesize that the PGA in the eye drop preparations penetrates the cornea, and may cause a reduction in water production by inhibiting NO production, resulting in a reduction in IOP.…”

Pharmaceutical applications of cyclodextrins: effects on drug permeation through biological membranes

“…Acetazolamide HPbCD [72][73][74] Anandamides HPbCD [75,76] Cannabinoids (various) HPbCD [77] Ciclosporin aCD [78][79][80] Dehydroepiandrosterone HPbCD [81] Dexamethasone HPbCD, gCD [82][83][84][85][86][87][88] Diclofenac HPbCD, RMbCD [89] Dipivefrine SBEbCD [90] Disulfiram HPbCD [91,92] Dorzolamide RMbCD, gCD [88,93] Enalaprilat HPbCD [94] Enalapril maleate HPbCD [94] Ethoxyzolamide HPbCD [72] Fluorometholone HPgCD [95] Hydrocortisone HPbCD [96,97] Ketoconazole HPbCD [98] Loteprednol etabonate HPbCD, DMbCD [99] Pilocarpine aCD, bCD, HEbCD, HPbCD, SBEbCD [100][101][102][103] Prostaglandins HPbCD [104] Rufloxacin HPbCD [105] Thalidomide HPbCD [106] D 9 -Tetrahydrocannobinol aCD [107,108] Nasal drug delivery: Acyclovir HPbCD [115] 17b-Estradiol DMbCD [116] Insulin aCD, DNaCD, HPaCD, bCD, DMbCD, HPbCD [117] Midazolam SBEbCD [118,…”

Study Design and Methodologies for Evaluation of Anti-glaucoma Drugs

“…Rapid administration of 15 ml/kg of 5 % glucose intravenously via the marginal ear vein (usually over 20 s) also gives a transient IOP spike [126,127]. Like oral administration of water, this hypotonic solution reduces blood osmolality which leads to transfer of water into the eye.…”