title: α5β1-Integrin inhibitor (CLT-28643) effective in rabbit trabeculectomy model.
abstract: OBJECTIVE
  Glaucoma filtration surgery (GFS) fails due to fibrosis. The α5β1-integrin plays a pivotal role in fibrosis, angiogenesis and inflammation. This is the first experiment evaluating the prevention of fibrosis after GFS by a specific small molecule α5β1-integrin inhibitor (CLT-28643).
  
  
  METHODS
  Twenty-four rabbits received trabeculectomy on their right eyes. The rabbits were randomized into three groups of eight eyes each. CLT-28643 was given as a single subconjunctival injection intraoperatively to two of the right eye groups followed by postoperative vehicle eye drops (CLT+ group) or CLT-28643 eye drops 4 times daily (CLT++ group). A third group received mitomycin-C (MMC) intraoperatively (sponge application, 0.04%, 2 min) followed by vehicle eye drops postoperatively. The control-surgery group consisted of 12 left eyes having trabeculectomy with no adjunctive therapy. The remaining 12 left eyes formed the untreated group. Clinical assessment included intraocular pressure (IOP) measurement, slit-lamp examination (including bleb survival and morphology) and bleb photography. The rabbits were killed after four weeks for histology.
  
  
  RESULTS
  Both CLT-28643-treated groups showed significantly prolonged bleb survival, and better bleb score compared to the control-surgery group. At end of the study, most functioning blebs were found in the MMC group (MMC group 75%; CLT+ group 12.5%, CLT++ group 25%; CLT+ group 12.5%, control-surgery group 0%). CLT-28643 was non-toxic and well tolerated.
  
  
  CONCLUSIONS
  This rabbit GFS study indicates that inhibition of α5β1-integrin by the novel α5β1-integrin antagonist CLT-28643 significantly improved the outcome. The effect of a single intro-operative application of CLT-28643 seems to be inferior to 0.04% MMC.
authors: Centre of Ophthalmology, University Eye Hospital Tübingen, Tübingen, Germany.
authors: Maximilian
authors: http://orcid.org/0000-0002-6537-3153
authors: M
authors: Schultheiss
authors: Centre of Ophthalmology, University Eye Hospital Tübingen, Tübingen, Germany.
authors: Sven
authors: S
authors: Schnichels
authors: Centre of Ophthalmology, University Eye Hospital Tübingen, Tübingen, Germany.
authors: Eva-Maria
authors: EM
authors: Konrad
authors: Centre of Ophthalmology, University Eye Hospital Tübingen, Tübingen, Germany.
authors: Karl U
authors: KU
authors: Bartz-Schmidt
authors: Clanotech AB, Stockholm, Sweden.
authors: Grit
authors: G
authors: Zahn
authors: Clanotech AB, Stockholm, Sweden.
authors: Patrizia
authors: P
authors: Caldirola
authors: Clanotech AB, Stockholm, Sweden.|International Pharm-Med Ltd, St. Albans, UK.
authors: Mario G
authors: MG
authors: Fsadni
authors: Clanotech AB, Stockholm, Sweden.|Encecor, Uppsala, Sweden.
authors: Ninus
authors: N
authors: Caram-Lelham
authors: Centre of Ophthalmology, University Eye Hospital Tübingen, Tübingen, Germany.
authors: Martin S
authors: MS
authors: Spitzer
mesh_terms: D000287:Administration, Topical; D000477:Alkylating Agents / Q000008:administration & dosage; D000634:Aminoquinolines / Q000494:pharmacology*; D000818:Animals; D003094:Collagen / Q000378:metabolism; D003228:Conjunctiva / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D005355:Fibrosis / Q000517:prevention & control; D005901:Glaucoma / Q000601:surgery; D056965:Injections, Intraocular; D039081:Integrin alpha5beta1 / Q000037:antagonists & inhibitors*; D007429:Intraocular Pressure / Q000187:drug effects; D008297:Male; D016685:Mitomycin / Q000008:administration & dosage; D009883:Ophthalmic Solutions; D011817:Rabbits; D054047:Surgical Stomas; D014130:Trabeculectomy; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D000477:Alkylating Agents; D000634:Aminoquinolines; C000613971:CLT-28643; D039081:Integrin alpha5beta1; D009883:Ophthalmic Solutions; D016685:Mitomycin; D003094:Collagen
keywords: CLT-28643; bleb; glaucoma surgery; intraocular pressure; mitomycin; trabeculectomy; α5β1-integrin