Sequential therapy with saratin, bevacizumab and ilomastat to prolong bleb function following glaucoma filtration surgery in a rabbit model

Gina M. Martorana, Jamie L. Schaefer, Monica A. Levine, Zachary Lee Lukowski, Jeff Min, Craig A. Meyers, Gregory S. Schultz, Mark B. Sherwood

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Abstract

To determine if sequential treatment with Bevacizumab (Avastin), a monoclonal, VEGF antibody that blocks angiogenesis; Saratin, a 12 kD polypeptide with anti-inflammatory and anti-thrombotic properties; and Ilomastat, a matrix metalloproteinase (MMP) inhibitor, prolongs bleb life following glaucoma filtration surgery (GFS) in a rabbit model. Thirty-two New Zealand White rabbits (eight rabbits per group) underwent GFS in the left eye. Group 1 received a perioperative injection of both Saratin and Bevacizumab, and later, subconjuctival injections of Ilomastat on days 8 and 15. Group 2 received only Saratin perioperatively, and also received Ilomastat injections on days 8 and 15. Group 3, the negative control, received a single perioperative injection of Balanced Saline Solution (BSS) along with post-operative BSS injections on days 8 and 15. Group 4, the positive control, received topical treatment with Mitomycin-C (MMC) at the time of surgery with no further treatment. Blebs were evaluated by an observer masked to treatment every third day. Histology was obtained on two eyes in each group on post-op day twelve as well as all eyes following bleb failure. Eyes in group 1 had a mean bleb survival time of 29 ± 2.7 days, whereas those in group 2 that received the experimental treatment without Bevacizumab had a mean survival time of 25.5 ± 2.7 days. An ANOVA test showed that the Saratin/Ilomastat/Bevacizumab group demonstrated a significant prolongation of bleb survival compared to the BSS control -mean survival time of 19.7 ±2.7 days-(p = 0.0252) and was not significantly different from the MMC positive control group (p = 0.4238)-mean survival time of 32.5 ± 3.3. From tissue histology at day 12, the four different groups showed marked differences in the cellularity and capsule fibrosis. The MMC eyes showed minimal cellularity, were avascular and had minimal fibrous tissue. BSS group showed high cellularity, moderate to high fibrosis, and thicker and more defined capsules than either of the treatment groups and the positive control. Both the Saratin/Ilomastat/Bevacizumab and Saratin/Ilomastat only eyes showed moderate cellularity with minimal fibrosis, with less cellularity and fibrosis present in the triple treatment group. Sequential therapy with multiple agents, including Bevacizumab, prolonged bleb function following GFS in the rabbit model and were significantly better than the negative BSS control. The experimental group did not show the same surface tissue histological thinning and side effects associated with MMC treatment.

Original languageEnglish (US)
Article numbere0138054
JournalPLoS One
Volume10
Issue number9
DOIs
StatePublished - Sep 22 2015
Externally publishedYes

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Filtering Surgery
glaucoma
Blister
Glaucoma
Surgery
mitomycin
sodium chloride
surgery
eyes
rabbits
Sodium Chloride
Rabbits
fibrosis
therapeutics
Mitomycin
injection
Fibrosis
Histology
Injections
histology

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Sequential therapy with saratin, bevacizumab and ilomastat to prolong bleb function following glaucoma filtration surgery in a rabbit model. / Martorana, Gina M.; Schaefer, Jamie L.; Levine, Monica A.; Lukowski, Zachary Lee; Min, Jeff; Meyers, Craig A.; Schultz, Gregory S.; Sherwood, Mark B.

In: PLoS One, Vol. 10, No. 9, e0138054, 22.09.2015.

Research output: Contribution to journalArticle

Martorana, Gina M. ; Schaefer, Jamie L. ; Levine, Monica A. ; Lukowski, Zachary Lee ; Min, Jeff ; Meyers, Craig A. ; Schultz, Gregory S. ; Sherwood, Mark B. / Sequential therapy with saratin, bevacizumab and ilomastat to prolong bleb function following glaucoma filtration surgery in a rabbit model. In: PLoS One. 2015 ; Vol. 10, No. 9.
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abstract = "To determine if sequential treatment with Bevacizumab (Avastin), a monoclonal, VEGF antibody that blocks angiogenesis; Saratin, a 12 kD polypeptide with anti-inflammatory and anti-thrombotic properties; and Ilomastat, a matrix metalloproteinase (MMP) inhibitor, prolongs bleb life following glaucoma filtration surgery (GFS) in a rabbit model. Thirty-two New Zealand White rabbits (eight rabbits per group) underwent GFS in the left eye. Group 1 received a perioperative injection of both Saratin and Bevacizumab, and later, subconjuctival injections of Ilomastat on days 8 and 15. Group 2 received only Saratin perioperatively, and also received Ilomastat injections on days 8 and 15. Group 3, the negative control, received a single perioperative injection of Balanced Saline Solution (BSS) along with post-operative BSS injections on days 8 and 15. Group 4, the positive control, received topical treatment with Mitomycin-C (MMC) at the time of surgery with no further treatment. Blebs were evaluated by an observer masked to treatment every third day. Histology was obtained on two eyes in each group on post-op day twelve as well as all eyes following bleb failure. Eyes in group 1 had a mean bleb survival time of 29 ± 2.7 days, whereas those in group 2 that received the experimental treatment without Bevacizumab had a mean survival time of 25.5 ± 2.7 days. An ANOVA test showed that the Saratin/Ilomastat/Bevacizumab group demonstrated a significant prolongation of bleb survival compared to the BSS control -mean survival time of 19.7 ±2.7 days-(p = 0.0252) and was not significantly different from the MMC positive control group (p = 0.4238)-mean survival time of 32.5 ± 3.3. From tissue histology at day 12, the four different groups showed marked differences in the cellularity and capsule fibrosis. The MMC eyes showed minimal cellularity, were avascular and had minimal fibrous tissue. BSS group showed high cellularity, moderate to high fibrosis, and thicker and more defined capsules than either of the treatment groups and the positive control. Both the Saratin/Ilomastat/Bevacizumab and Saratin/Ilomastat only eyes showed moderate cellularity with minimal fibrosis, with less cellularity and fibrosis present in the triple treatment group. Sequential therapy with multiple agents, including Bevacizumab, prolonged bleb function following GFS in the rabbit model and were significantly better than the negative BSS control. The experimental group did not show the same surface tissue histological thinning and side effects associated with MMC treatment.",
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AU - Schaefer, Jamie L.

AU - Levine, Monica A.

AU - Lukowski, Zachary Lee

AU - Min, Jeff

AU - Meyers, Craig A.

AU - Schultz, Gregory S.

AU - Sherwood, Mark B.

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