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Purpose To evaluate the therapeutic potential of the small molecule integrin α5β1 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 α5β1 expression were performed on postoperative days 3, 8, 14, and 28. A masked observer performed all the assessments. Results Immunostaining showed that integrin α5β1 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 α5β1 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.

Purpose To evaluate prior studies including a glaucoma drainage device and to describe the timing and incidence of conjunctival exposure. A meta-analysis of previously published articles. Methods Articles included were prospective, single cohort, or comparative parallel design, with a mean treatment period of at least 3 months and at least 30 patients per treatment arm. We limited our analysis to studies that evaluated the most common devices, including Ahmed, Baerveldt, and Molteno. Results We included 38 studies containing 45 treatment arms (16 Ahmed, 12 Baerveldt, and 17 Molteno). These studies included 3,105 patients and 3,255 eyes with an average follow-up of 26.1±3.3 months. The overall incidence of exposure was 2.0±2.6% (n=64) of eyes with an average exposure/month of 0.09±0.14%. There was no significant correlation between study length and incidence of exposure (p=0.11), although multivariate regression analysis identified length of follow-up as a risk factor for exposure (p=0.001). Among individual drainage devices, there was no significant difference in the incidence of exposure (p=0.22) or percent exposure per month (p=0.18). In addition, no difference existed in the incidence of exposure between sizes for the Baerveldt 250, 350 or 500 mm (p=0.7), number of plates for the Molteno Single or Double (p=0.3), nor between the composition of the Ahmed Silicone or Polypropylene (p=0.7). Conclusions This study suggests that tube exposure of glaucoma implants is unusual and the incidence does not differ between the Ahmed, Baerveldt, and Molteno implants. However, exposure appears to occur at any time within the first 5 years following implantation.

Purpose 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.

Purpose The aim of this study was to evaluate the therapeutic potential of α5β1-integrin inhibitor (CLT-28643) to improve the outcome of filtering surgery in a mouse model. Different dose regimen and administration routes of the inhibitor were compared to mitomycin C (MMC), the gold standard in clinical 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). Group 1 received a single subconjunctival (SC) injection of 2 µg of the integrin inhibitor immediately after surgery, whereas repeated SC injections were administered on day 0, 3, 7, 14 and 21 in groups 2 and 3 (2 and 1 µg, respectively). Group 4 received topical eye drops containing 10 µg of the compound 3 times daily. MMC 0.02% was applied for 2 minutes in group 5 and repeated SC injections of NaCl were given in the last group. Treatment outcome was studied by a masked observer every other day by clinical investigation of the bleb until postoperative day 28. Results Surgical outcome was improved in all treatment groups compared to NaCl treated eyes (P