The retinal tolerance to bevacizumab in co-application with a recombinant tissue plasminogen activator.
OBJECTIVE
To investigate the retinal toxicity of bevacizumab in co-application with a commercially available recombinant tissue plasminogen activator (rt-PA), and to facilitate a new therapeutic concept in the treatment of massive subretinal haemorrhage caused by neovascular age-related macular degeneration (AMD).


METHODS
Isolated bovine retinas were perfused with an oxygen-preincubated nutrient solution. The electroretinogram (ERG) was recorded as a transretinal potential using Ag/AgCl electrodes. Bevacizumab (0.25 mg/ml) and rt-PA (20 microg/ml) were added to the nutrient solution for 45 min. Thereafter, the retina was reperfused for 60 min with normal nutrient solution. Similarly, the effects of rt-PA (20 microg/ml, 60 microg/ml and 200 mug/ml) on the a- and b-wave amplitudes were investigated. The percentages of a- and b-wave reduction during application and at washout were calculated.


RESULTS
During application of bevacizumab (0.25 mg/ml) in co-application with 20 microg/ml (rt-PA), the ERG amplitudes remained stable. The concentrations of rt-PA alone (20 microg/ml and 60 microg/ml) did not induce significant reduction of the b-wave amplitude. In addition, 20 microg/ml rt-PA did not alter the a-wave amplitude. However, 60 microg/ml rt-PA caused a slight but significant reduction of the a-wave amplitude. A full recovery was detected for both concentrations during the washout. At the highest tested concentration of 200 microg/ml rt-PA, a significant reduction of the a- and b-wave amplitudes was provoked during the exposure. The reduction of ERG amplitudes remained irreversible during the washout.


CONCLUSIONS
The present study suggests that a subretinal injection of 20 microg/ml rt-PA in co-application with bevacizumab (0.25 mg/ml) for the treatment of massive subretinal haemorrhage seems possible. This is a safety study. Therefore, we did not test the clinical effectiveness of this combined treatment.
Lüke
Matthias
M
Department of Ophthalmology, University of Tuebingen, Schleichstr. 12-16, D-72076 Tuebingen, Germany. matthias.lueke@med.uni-tuebingen.de
Januschowski
Kai
K
Warga
Max
M
Beutel
Julia
J
Leitritz
Martin
M
Gelisken
Faik
F
Grisanti
Salvatore
S
Schneider
Toni
T
Lüke
Christoph
C
Bartz-Schmidt
Karl Ulrich
KU
Szurman
Peter
P
D020533:Angiogenesis Inhibitors / Q000009:adverse effects*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects*; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D002417:Cattle; D004338:Drug Combinations; D005343:Fibrinolytic Agents / Q000009:adverse effects*; D011994:Recombinant Proteins / Q000009:adverse effects; D012160:Retina / Q000187:drug effects*; D012166:Retinal Hemorrhage / Q000139:chemically induced*; D046509:Tissue Culture Techniques; D010959:Tissue Plasminogen Activator / Q000009:adverse effects*
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D004338:Drug Combinations; D005343:Fibrinolytic Agents; D011994:Recombinant Proteins; D000068258:Bevacizumab; D010959:Tissue Plasminogen Activator