title: Toxicity testing of the VEGF inhibitors bevacizumab, ranibizumab and pegaptanib in rats both with and without prior retinal ganglion cell damage.
abstract: OBJECTIVE
  To evaluate the effects of intravitreally introduced vascular endothelial growth factor (VEGF) inhibitors in rat eyes with healthy retinal ganglion cells (RGC) and into others with N-methyl-D-aspartate (NMDA)-induced RGC damage.
  
  
  METHODS
  Bevacizumab, ranibizumab and pegaptanib were intravitreally injected each at two different concentrations. Respective vehicles of the three substances served as controls. In a different group, additionally a rat anti-VEGF antibody was injected after NMDA treatment. Retrogradely labelled RGC were counted on retinal wholemounts 1 week or 2 months after intravitreal introduction of the VEGF inhibitors. Electron microscopy (EM) was performed on normal rat eyes 2 months after introduction of the VEGF inhibitors.
  
  
  RESULTS
  RGC counts in healthy rat eyes were essentially unchanged from those of the control animals after the administration of both low and high concentrations of bevacizumab, ranibizumab or pegaptanib. Compared to the other two substances, however, high doses of pegaptanib and its respective vehicle significantly decreased RGC after 1 week and led to a marked increase of mitochondrial swelling in EM. In eyes with NMDA-induced RGC damage, no changes of RGC numbers were detected after rat anti-VEGF antibody or bevacizumab, ranibizumab and pegaptanib at both tested concentrations.
  
  
  CONCLUSIONS
  Even at higher doses, bevacizumab and ranibizumab showed no toxic effects on RGC in vivo in either untreated rats or in the NMDA-induced RGC damage model. Also a rat anti-VEGF antibody showed no adverse effects after NMDA. Anti-VEGF therapy therefore appears safe even for eyes with additional excitotoxic RGC damage. Potential harm from the pegaptanib carrier solution at very high local concentrations cannot be excluded.
authors.affiliation: Centre for Ophthalmology, University of Tuebingen, Tuebingen, Germany. sebastian.thaler@uni-tuebingen.de
authors.forename: Sebastian
authors.initials: S
authors.lastname: Thaler
authors.forename: Michal
authors.initials: M
authors.lastname: Fiedorowicz
authors.forename: Tomasz J
authors.initials: TJ
authors.lastname: Choragiewicz
authors.forename: Sylvia
authors.initials: S
authors.lastname: Bolz
authors.forename: Ayseguel
authors.initials: A
authors.lastname: Tura
authors.forename: Sigrid
authors.initials: S
authors.lastname: Henke-Fahle
authors.forename: Efdal
authors.initials: E
authors.lastname: Yoeruek
authors.forename: Eberhart
authors.initials: E
authors.lastname: Zrenner
authors.forename: Karl-Ulrich
authors.initials: KU
authors.lastname: Bartz-Schmidt
authors.forename: Focke
authors.initials: F
authors.lastname: Ziemssen
authors.forename: Frank
authors.initials: F
authors.lastname: Schuettauf
mesh_terms: D020533:Angiogenesis Inhibitors / Q000633:toxicity*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000633:toxicity*; D061067:Antibodies, Monoclonal, Humanized; D052157:Aptamers, Nucleotide / Q000633:toxicity*; D000068258:Bevacizumab; D002452:Cell Count; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D005260:Female; D007267:Injections; D008928:Mitochondria / Q000187:drug effects / Q000648:ultrastructure; D016202:N-Methylaspartate / Q000633:toxicity; D000069579:Ranibizumab; D051381:Rats; D011914:Rats, Inbred BN; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000648:ultrastructure; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D014822:Vitreous Body
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D052157:Aptamers, Nucleotide; D018690:Excitatory Amino Acid Agonists; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; C495058:pegaptanib; D000068258:Bevacizumab; D016202:N-Methylaspartate; D000069579:Ranibizumab