title: Effect of Eye Drops Containing Disulfiram and Low-Substituted Methylcellulose in Reducing Intraocular Pressure in Rabbit Models.
abstract: OBJECTIVE
  We attempted to develop anti-glaucoma eye drops using 0.5% disulfiram (DSF), 5% 2-hydroxypropyl-β-cyclodextrin, 0.1% hydroxypropylmethylcellulose, and 2% methylcellulose (MC) (DSF eye drops with MC), and tested the ability of a DSF eye drops with MC to reduce intraocular pressure (IOP) in rabbit models.
  
  
  METHODS
  Elevated IOP was induced by the rapid infusion of 5% glucose solution (15 ml/kg of body weight) through the marginal ear vein or by keeping rabbits in the dark for 5 h. IOP and the nitric oxide (NO) level in the aqueous humor were measured with an electronic tonometer and by a microdialysis method, respectively. ΔIOP and ΔNO values were analyzed as the differences in IOP and NO in rabbits instilled with saline or eye drops, respectively.
  
  
  RESULTS
  Increased IOP in rabbit models was reduced by the instillation of DSF eye drops with or without MC, and a close relationship was observed between IOP and NO levels in rabbit receiving a rapid infusion of isotonic glucose. We present kinetic parameters [secondary AUC (prolonged drug effect) and secondary MRT (prolonged effective time)] analyzed as the area under the curve (AUC) of ΔIOP or ΔNO versus time using rabbits instilled with eye drops 10, 50, or 90 min prior to the infusion of the isotonic glucose solution. The elevations in IOP and NO level were reduced by the instillation of DSF eye drops with or without MC; the addition of MC increased the secondary AUC and MRT of DSF eye drops.
  
  
  CONCLUSIONS
  The present study demonstrates that 0.5% DSF eye drops suppress increased IOP in rabbit models, probably by inhibiting the elevation in NO levels. In addition, we propose a kinetic analysis method to predict drug effects and effective time. These findings suggest that a low-substituted MC-based drug delivery system promotes drug effectiveness and effective time.
authors.affiliation: a Faculty of Pharmacy , Kinki University , Higashi-Osaka, Osaka , Japan and.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Nagai
authors.affiliation: a Faculty of Pharmacy , Kinki University , Higashi-Osaka, Osaka , Japan and.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Yoshioka
authors.affiliation: a Faculty of Pharmacy , Kinki University , Higashi-Osaka, Osaka , Japan and.
authors.forename: Yu
authors.initials: Y
authors.lastname: Mano
authors.affiliation: a Faculty of Pharmacy , Kinki University , Higashi-Osaka, Osaka , Japan and.
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Ito
authors.affiliation: b Department of Ophthalmology , Kinki University Faculty of Medicine , Osaka-Sayama, Osaka , Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Okamoto
authors.affiliation: b Department of Ophthalmology , Kinki University Faculty of Medicine , Osaka-Sayama, Osaka , Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Shimomura
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000287:Administration, Topical; D000427:Alcohol Deterrents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000818:Animals; D001082:Aqueous Humor / Q000378:metabolism; D004195:Disease Models, Animal; D004221:Disulfiram / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004338:Drug Combinations; D016503:Drug Delivery Systems; D065347:Hypromellose Derivatives / Q000008:administration & dosage* / Q000493:pharmacokinetics; D007429:Intraocular Pressure / Q000187:drug effects*; D008297:Male; D008747:Methylcellulose / Q000008:administration & dosage* / Q000493:pharmacokinetics; D009569:Nitric Oxide / Q000378:metabolism; D009883:Ophthalmic Solutions; D011817:Rabbits; D014065:Tonometry, Ocular; D047392:beta-Cyclodextrins / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D000427:Alcohol Deterrents; D004338:Drug Combinations; D009883:Ophthalmic Solutions; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D009569:Nitric Oxide; D065347:Hypromellose Derivatives; D008747:Methylcellulose; D004221:Disulfiram
keywords: Disulfiram; glaucoma; kinetic analysis; methylcellulose; nitric oxide