title: Prostaglandin analogues and mouse intraocular pressure: effects of tafluprost, latanoprost, travoprost, and unoprostone, considering 24-hour variation.
abstract: OBJECTIVE
  To establish a mouse model for the pharmacological analysis of antiglaucoma drugs, considering the effect of variations in IOP during 24 hours on the drugs' effects, and to evaluate the effect of a newly developed FP agonist, tafluprost, on mouse IOP, in comparison with three clinically available prostaglandin (PG) analogues.
  
  
  METHODS
  Inbred adult ddY mice were bred and acclimatized under a 12-hour light-dark cycle. With mice under general anesthesia, a microneedle method was used to measure IOP. A single drop of 3 muL of either drug or vehicle solution was topically applied once into one eye in each mouse, in a blinded manner, with the contralateral, untreated eye serving as the control. IOP reduction was evaluated by the difference in IOP between the treated and untreated eyes in the same mouse. First, to determine the period feasible for demonstrating a larger magnitude of ocular hypotensive effect, the 24-hour diurnal variation in mouse IOP was measured, and 0.005% latanoprost was applied at the peak or trough time of variation in 24-hour IOP. The time point of the most hypotensive effect was selected for further studies, to evaluate the effects of PG analogues. Second, mice received tafluprost (0.0003%, 0.0015%, 0.005%, or 0.015%), latanoprost (0.001%, 0.0025%, or 0.005%), travoprost (0.001%, 0.002%, or 0.004%), or isopropyl unoprostone (0.03%, 0.06%, or 0.12%), and each corresponding vehicle solution. IOP was then measured at 1, 2, 3, 6, 9, and 12 hours after drug administration. The ocular hypotensive effects of the other three PG analogues were compared with that of tafluprost. All experiments were conducted in a masked study design.
  
  
  RESULTS
  The IOP in the untreated mouse eye was higher at night than during the day. Latanoprost significantly lowered IOP at night (21.4%), compared with the IOP in the untreated contralateral eye 2 hours after administration. The maximum IOP reduction was 20.2% +/- 2.0%, 18.7% +/- 2.5%, and 11.2% +/- 1.8% of that in the untreated eye 2 hours after administration of 0.005% tafluprost, 0.005% latanoprost, and 0.12% isopropyl unoprostone, respectively, whereas it was 20.8% +/- 4.6% at 6 hours with 0.004% travoprost (n = 7 approximately 17). The order of ocular hypotensive effects of three clinically used PG analogues in mice was comparable to that in humans. Area under the curve (AUC) analysis revealed dose-dependent IOP reductions for each PG analogue. Tafluprost 0.005% decreased IOP more than 0.005% latanoprost at 3, 6, and 9 hours (P = 0.001-0.027) or 0.12% unoprostone at 2, 3, and 6 hours (P = 0.0004-0.01).
  
  
  CONCLUSIONS
  The 24-hour variation in mouse eyes should be taken into consideration when evaluating the reduction of IOP. The mouse model was found to be useful in evaluating the pharmacological response to PG analogues. A newly developed FP agonist, 0.005% tafluprost, lowered normal mouse IOP more effectively than did 0.005% latanoprost.
authors.affiliation: Department of Ophthalmology, University of Tokyo School of Medicine, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ota
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Murata
authors.forename: Ei-ichiro
authors.initials: E
authors.lastname: Sugimoto
authors.forename: Makoto
authors.initials: M
authors.lastname: Aihara
authors.forename: Makoto
authors.initials: M
authors.lastname: Araie
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D002940:Circadian Rhythm / Q000187:drug effects; D003008:Cloprostenol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007429:Intraocular Pressure / Q000187:drug effects*; D000077338:Latanoprost; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009883:Ophthalmic Solutions / Q000494:pharmacology; D011460:Prostaglandins F / Q000494:pharmacology*; D011461:Prostaglandins F, Synthetic / Q000494:pharmacology*; D013997:Time Factors; D000069557:Travoprost
chemical_list: D000959:Antihypertensive Agents; D009883:Ophthalmic Solutions; D011460:Prostaglandins F; D011461:Prostaglandins F, Synthetic; C485333:tafluprost; D003008:Cloprostenol; C072630:isopropyl unoprostone; D000077338:Latanoprost; D015237:Dinoprost; D000069557:Travoprost