title: Polyquad-preserved travoprost/timolol, benzalkonium chloride (BAK)-preserved travoprost/timolol, and latanoprost/timolol in fixed combinations: a rabbit ocular surface study.
abstract: BACKGROUND
  The aim of this study was to use a validated acute rabbit model to test the toxicity of a novel formulation of fixed-combination travoprost 0.004%/timolol 0.5% ophthalmic solution, which contains the antimicrobial preservative polyquaternium-1 (PQ), compared with the commercial formulation of fixed combinations travoprost 0.004%/timolol 0.5% ophthalmic solution and latanoprost 0.005%/timolol 0.5% ophthalmic solution, which both contain the preservative benzalkonium chloride (BAK).
  
  
  METHODS
  Adult male New Zealand albino rabbits (n=24) were randomly divided into four groups. Phosphate-buffered saline (PBS), travoprost/timolol PQ, travoprost/timolol BAK, or latanoprost/timolol BAK were instilled onto rabbit eyes one drop, 15 times at 5 minute intervals. The ocular surface reactions were investigated at hour 4 and day 1 using slit lamp examination; in-vivo confocal microscopy (IVCM) for cornea, limbus, and conjunctiva-associated lymphoid tissue (CALT); conjunctival impression cytology; and standard immunohistology in cryosections for detecting CD45+ infiltrating cells and MUC-5AC-labeled cells.
  
  
  RESULTS
  Travoprost/timolol PQ was better tolerated than travoprost/timolol BAK or latanoprost/timolol BAK. This improved tolerance was evident via clinical observation under slit lamp, IVCM in different layers of the cornea and conjunctiva, conjunctival impression cytology of superficial epithelium aspects, and immunohistochemistry for inflammatory infiltration of CD45+ cells in the cornea and goblet cell distribution. Travoprost/timolol PQ was similar to PBS in regards to in-vivo findings, the Draize test for ocular irritation, and epithelial and limbal aspects as evaluated with IVCM. Treatment with either travoprost/timolol PQ or PBS produced no obvious inflammatory infiltration inside and outside the CALT follicles, yielded similar IVCM toxicity scores and CD45+ cell counts, and eyes treated with either solution had normal goblet cells.
  
  
  CONCLUSIONS
  The fixed combination of travoprost/timolol with 0.001% PQ had decreased ocular surface toxicity relative to the BAK-containing solutions. The potential benefit to the human ocular surface with oncedaily dosing needs to be evaluated clinically.
authors.affiliation: INSERM, UMR_S, Paris, France.
authors.forename: Hong
authors.initials: H
authors.lastname: Liang
authors.forename: Françoise
authors.initials: F
authors.lastname: Brignole-Baudouin
authors.forename: Aude
authors.initials: A
authors.lastname: Pauly
authors.forename: Luisa
authors.initials: L
authors.lastname: Riancho
authors.forename: Christophe
authors.initials: C
authors.lastname: Baudouin
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000009:adverse effects; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000009:adverse effects; D001548:Benzalkonium Compounds / Q000008:administration & dosage / Q000009:adverse effects; D002470:Cell Survival / Q000187:drug effects; D003008:Cloprostenol / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D003228:Conjunctiva / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D004338:Drug Combinations; D019573:Epithelium, Corneal / Q000187:drug effects / Q000473:pathology; D000077338:Latanoprost; D008297:Male; D009798:Ocular Hypertension / Q000188:drug therapy* / Q000473:pathology; D009883:Ophthalmic Solutions; D011108:Polymers / Q000008:administration & dosage / Q000009:adverse effects; D011310:Preservatives, Pharmaceutical / Q000008:administration & dosage / Q000009:adverse effects; D011461:Prostaglandins F, Synthetic / Q000008:administration & dosage / Q000009:adverse effects; D011817:Rabbits; D013999:Timolol / Q000008:administration & dosage / Q000009:adverse effects; D000069557:Travoprost; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D000959:Antihypertensive Agents; D001548:Benzalkonium Compounds; D004338:Drug Combinations; D009883:Ophthalmic Solutions; D011108:Polymers; D011310:Preservatives, Pharmaceutical; D011461:Prostaglandins F, Synthetic; D003008:Cloprostenol; D000077338:Latanoprost; C058655:polyquaternium 1; D013999:Timolol; D000069557:Travoprost