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Ricardo Japiassu, Maria Alice Fusco, Silvana Allodi; VEGF OVEREXPRESSION AS A POSSIBLE MOLECULAR MECHANISM OF TACHYPHYLAXIS INDUCTION AFTER TREATMENT WITH INTRAVITREAL BEVACIZUMAB AND RANIBIZUMAB. Invest. Ophthalmol. Vis. Sci. 2014;55(13):615.
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The tachyphylaxis, defined as a decreased therapeutic response after repeated administrations of a medication, is a phenomenon often seen in patients with age-related Macular Degeneration (AMD) treated with bevacizumab (Avastin) and ranibizumab (Lucentis). These are antibodies intravitreally applied whose action mechanism is based on the neutralization of Vascular endothelial growth factor (VEGF), which is the main cytokine responsible for the abnormal growth of blood vessels with subsequent vascular extravasation and vitreous hemorrhage. The mechanisms related to the phenomenon may involve metabolic tolerance (with consequent reduction of the effective concentration of drug) or mobile (cellular mechanisms of tolerance adaptation to the constant presence of medications with consequent decrease in response to the same. In order to evaluate the expression of VEGF after treatment with anti-VEGF medications bevacizumab and ranibizumab was performed the experiment described below.
New Zealand adult albino rabbits were treated once with bevacizumab or ranibizumab at the dosage of 0.03 mL intravitreally on left eye, or water for injection in the same dosage (sham). The right eyes did not receive any treatment and served as control of the eyes treated. After seven days, the animals underwent euthanasia. The retinas were collected and analyzed by western blotting for verification of the expression of VEGF. For viewing of the cell type responsible for expression of VEGF, protein research GFAP (glial fibrilar aminoacid protein), specific antibody for glial cells in the histological sections by immunohistochemical technique.
The results showed statistically higher expression of VEGF in the group treated with bevacizumab (p < 0.03) when compared to the control group of sham, followed by a trend in the increase of the expression of VEGF in the ranibizumab group. For qualitative analysis there has been greater for GFAP immunoreactive cell markup in the same groups (bevacizumab and ranibizumab), which features reactive gliosis.
The decrease in VEGF available to the retina to neuronal maintenance after use of anti-VEGF medications leads to overexpression of this neurotrophic factor in retina of healthy rabbits, which would explain the tachyphylaxis observed with the use of these medications.
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