ABSTRACT
PURPOSE: Glaucoma filtration surgery (GFS) fails due to fibrosis. The α5ß1-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 α5ß1-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 α5ß1-integrin by the novel α5ß1-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.
Subject(s)
Aminoquinolines/pharmacology , Conjunctiva/pathology , Disease Models, Animal , Integrin alpha5beta1/antagonists & inhibitors , Surgical Stomas , Trabeculectomy , Wound Healing/drug effects , Administration, Topical , Alkylating Agents/administration & dosage , Animals , Collagen/metabolism , Conjunctiva/metabolism , Fibrosis/prevention & control , Glaucoma/surgery , Injections, Intraocular , Intraocular Pressure/drug effects , Male , Mitomycin/administration & dosage , Ophthalmic Solutions , RabbitsABSTRACT
Purpose: To evaluate the therapeutic potential of the small molecule integrin α5ß1 inhibitor, CLT-28643, to improve the filtering surgery outcome in a mouse model. Different dose regimens and administration routes of the inhibitor were compared with mitomycin C (MMC), the gold standard in clin ical practice. Methods: The efficacy of CLT-28643 on surgical outcome was studied in a mouse model for filtering surgery (n = 40 eyes from 20 mice per group). Single and repeated subconjunctival (SCJ) injections (1 or 2 µg) and topical eye drops (10 µg) of the integrin inhibitor were compared with 2-minute administration of MMC 0.02%. Bleb size, survival, and signs of toxicity were examined until 28 days after surgery. Immunohistochemical analysis of angiogenesis, inflammation, collagen deposition, and integrin α5ß1 expression were performed on postoperative days 3, 8, 14, and 28. A masked observer performed all the assessments. Results: Immunostaining showed that integrin α5ß1 was highly expressed in the bleb at early time-points after surgery and that CLT-28643 inhibited this upregulation. Efficacy was shown to be dose-dependent for the integrin inhibitor CLT-28643 for bleb area and survival, and the wound healing process. While 2-µg single injection of CLT-28643 improved bleb characteristics in a similar way as 10-µg administered by eye drops and MMC, repeated injections of 2 µg showed superior efficacy compared to MMC, with no corneal toxicity. Conclusions: Administration of the integrin α5ß1 inhibitor CLT-28643 has therapeutic potential as an adjunct to glaucoma surgery, possibly with a superior efficacy and tolerability compared with MMC when used at the optimal dose.
Subject(s)
Aminoquinolines/administration & dosage , Conjunctiva/metabolism , Filtering Surgery , Glaucoma/surgery , Integrin alpha5beta1/antagonists & inhibitors , Wound Healing/drug effects , Animals , Disease Models, Animal , Follow-Up Studies , Glaucoma/metabolism , Glaucoma/physiopathology , Immunohistochemistry , Injections , Integrin alpha5beta1/biosynthesis , Mice , Mice, Inbred C57BL , Ophthalmic Solutions , Postoperative PeriodABSTRACT
The understanding of the physiological role of the G-protein coupled serotonin 5-HT(7) receptor is largely rudimentary. Therefore, selective and potent pharmacological tools will add to the understanding of serotonergic effects mediated through this receptor. In this report, we describe two compound classes, chromans and tetralins, encompassing compounds with nanomolar affinity for the 5-HT(7) receptor and with good selectivity. Within theses classes, we have discovered both agonists and antagonists that can be used for further understanding of the pharmacology of the 5-HT(7) receptor.