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A Pharmacodynamic Analysis of Choroidal Neovascularization in a Porcine Model Using Three Targeted Drugs.

Abstract To compare the efficacy of microneedle-delivered suprachoroidal (SC) pazopanib to intravitreal (Ivit) delivery of pazopanib, bevacizumab, or a fusion protein hI-con1 versus vehicle controls on choroidal neovascularization (CNV) growth in a pig model.
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Authors

Mayor MeshTerms

Disease Models, Animal

Keywords
Journal Title investigative ophthalmology & visual science
Publication Year Start




PMID- 28738417
OWN - NLM
STAT- MEDLINE
DA  - 20170724
DCOM- 20170728
LR  - 20170728
IS  - 1552-5783 (Electronic)
IS  - 0146-0404 (Linking)
VI  - 58
IP  - 9
DP  - 2017 Jul 01
TI  - A Pharmacodynamic Analysis of Choroidal Neovascularization in a Porcine Model
      Using Three Targeted Drugs.
PG  - 3732-3740
LID - 10.1167/iovs.16-21230 [doi]
AB  - Purpose: To compare the efficacy of microneedle-delivered suprachoroidal (SC)
      pazopanib to intravitreal (Ivit) delivery of pazopanib, bevacizumab, or a fusion 
      protein hI-con1 versus vehicle controls on choroidal neovascularization (CNV)
      growth in a pig model. Methods: Forty-one pigs were injected on the day of CNV
      induction (hI-con1 on postinduction day 14) with either 2.5 mg Ivit bevacizumab
      (n = 9), 1 mg Ivit pazopanib (n = 9), 300 Ivit mug hI-con1 (n = 4), or 1 mg SC
      pazopanib (n = 9), vs. 10 vehicle controls (3 SC + 7 Ivit = 10). Pigs were
      euthanized at week 2 (11), 3 (8), 4 (11), and 8 (11), and eyes were fixed for
      histology. The size of the CNV was determined from histology, and CNV height was 
      the primary outcome measure. Immunostaining for cytotoxic T-cells was performed
      in the hI-con1 study. Results: In 39 of 41 (95%) eyes, type 2 CNV lesions were
      identified. One CNV lesion was lost during dissection. One animal was euthanized 
      due to surgical complications. For mean CNV size comparisons, Ivit pazopanib had 
      smaller mean height measurements (90 +/- 20 mum) versus controls (180 +/- 20 mum;
      P = 0.009), and Ivit pazopanib had smaller maximum CNV height (173 +/- 43 mum)
      compared to SC pazopanib (478 +/- 105 mum; P = 0.018). The mean lesion size in
      hI-con1-treated animals trended smaller than in controls (P = 0.11).
      Immunostaining did not detect cytotoxic T-cells. Conclusions: Intravitreal
      pazopanib and to a lesser extent hI-con1 reduced the size of CNV lesions. The pig
      model has nearly a 100% rate of type 2 CNV induction and is a reliable
      preclinical model with pharmacodynamics similar to humans.
FAU - Tran, Jeffrey
AU  - Tran J
AD  - Emory Eye Center, Emory University Department of Ophthalmology, Atlanta, Georgia,
      United States.
FAU - Craven, Caroline
AU  - Craven C
AD  - Emory Eye Center, Emory University Department of Ophthalmology, Atlanta, Georgia,
      United States.
FAU - Wabner, Kathy
AU  - Wabner K
AD  - Emory Eye Center, Emory University Department of Ophthalmology, Atlanta, Georgia,
      United States 2The University of Minnesota, Department of Civil, Environmental,
      and Geo-Engineering, Minneapolis, Minnesota, United States.
FAU - Schmit, Jenn
AU  - Schmit J
AD  - Emory Eye Center, Emory University Department of Ophthalmology, Atlanta, Georgia,
      United States 2The University of Minnesota, Department of Civil, Environmental,
      and Geo-Engineering, Minneapolis, Minnesota, United States.
FAU - Matter, Brock
AU  - Matter B
AD  - The University of Colorado, Department of Pharmaceutical Sciences, University of 
      Colorado School of Pharmacy, Aurora, Colorado, United States.
FAU - Kompella, Uday
AU  - Kompella U
AD  - The University of Colorado, Department of Pharmaceutical Sciences, University of 
      Colorado School of Pharmacy, Aurora, Colorado, United States.
FAU - Grossniklaus, Hans E
AU  - Grossniklaus HE
AD  - Emory Eye Center, Emory University Department of Ophthalmology, Atlanta, Georgia,
      United States.
FAU - Olsen, Timothy W
AU  - Olsen TW
AD  - Emory Eye Center, Emory University Department of Ophthalmology, Atlanta, Georgia,
      United States.
LA  - eng
GR  - P30 EY006360/EY/NEI NIH HHS/United States
GR  - R01 EY022097/EY/NEI NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PL  - United States
TA  - Invest Ophthalmol Vis Sci
JT  - Investigative ophthalmology & visual science
JID - 7703701
RN  - 0 (Angiogenesis Inhibitors)
RN  - 0 (Immunoconjugates)
RN  - 0 (Pyrimidines)
RN  - 0 (Sulfonamides)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (hI-con1)
RN  - 2S9ZZM9Q9V (Bevacizumab)
RN  - 7RN5DR86CK (pazopanib)
SB  - IM
MH  - Angiogenesis Inhibitors/*pharmacology
MH  - Animals
MH  - Bevacizumab/*pharmacology
MH  - Choroidal Neovascularization/*drug therapy/pathology
MH  - *Disease Models, Animal
MH  - Fluorescein Angiography
MH  - Immunoconjugates/*pharmacology
MH  - Intravitreal Injections
MH  - Pyrimidines/*pharmacology
MH  - Sulfonamides/*pharmacology
MH  - Swine
MH  - T-Lymphocytes, Cytotoxic/immunology
MH  - Vascular Endothelial Growth Factor A/antagonists & inhibitors
PMC - PMC5525553
EDAT- 2017/07/25 06:00
MHDA- 2017/07/29 06:00
CRDT- 2017/07/25 06:00
AID - 2645903 [pii]
AID - 10.1167/iovs.16-21230 [doi]
PST - ppublish
SO  - Invest Ophthalmol Vis Sci. 2017 Jul 1;58(9):3732-3740. doi:
      10.1167/iovs.16-21230.