Overview of the Safety of Anti-VEGF Drugs: Analysis of the Italian Spontaneous Reporting System

Cutroneo, Paola Maria; Giardina, Claudia; Ientile, Valentina; Potenza, Simona; Sottosanti, Laura; Ferrajolo, Carmen; Trombetta, C. J.; Trifirò, Gianluca

doi:10.1007/s40264-017-0553-y

Cited by 22 publications

(16 citation statements)

References 33 publications

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“…Specifically, ranibizumab binds to the VEGF-A, one of the five isoforms of the VEGF family and one of the strongest inducers of vascular permeability ( Yla-Herttuala et al, 2007 ), which showed neuroprotective effects in several in vitro and in vivo PD models ( Silverman et al, 1999 ; Pitzer et al, 2003 ; Yasuhara et al, 2004 ; Tian et al, 2007 ; Yue et al, 2014 ). A recent study on the Italian ADR Spontaneous Reporting System showed 3 reports of “extrapyramidal syndrome” due to intravitreal bevacizumab and 1 to intravitreal aflibercept ( Cutroneo et al, 2017 ). Similarly, in the Food and Drug Administration’s Adverse Event Reporting System, three cases of neurodegenerative disorders have been reported following bevacizumab use ( Shamloo et al, 2012 ).…”

Section: Discussionmentioning

confidence: 99%

Long-Term Intravitreal Ranibizumab as a Potential Additional Risk Factor for Neurodegeneration in Parkinson’s Disease: A Case Report

et al. 2018

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In November 2012, a 72-year old patient was diagnosed with left eye wet age-related macular degeneration. The patient received three monthly intravitreal injections of ranibizumab, with complete resolution of retinal hemorrhage and edema and reinstatement of visual acuity. In May 2015, symptomatic relapse was detected. The patient was again treated with intravitreal ranibizumab, with overall six injections till the end of February 2016. In May 2016, the patient complained of left hand resting tremor, bradykinesia, and postural rigidity of head and trunk. A diagnosis of clinically established PD was made based on new criteria of the Movement Disorders Society. Single Photon Emission Computerized Tomography of the Dopamine Transporter with (123I) ioflupane documented a low Dopamine Transporter (DAT) uptake mostly in the right striatum. Due to the documented protective role of vascular endothelial growth factor (VEGF) on the dopaminergic neurons, intensive intravitreal injections of the anti-VEGF agent ranibizumab may have played as an additional risk factor accelerating the neurodegeneration process related to PD and the onset of the related clinical signs and symptoms.

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Section: Discussionmentioning

confidence: 99%

Long-Term Intravitreal Ranibizumab as a Potential Additional Risk Factor for Neurodegeneration in Parkinson’s Disease: A Case Report

et al. 2018

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“…The many limitations of RCTs in capturing ADRs (Sultana et al, 2013) highlight the importance of confirming such safety issues using real-world studies. An Italian nationwide pharmacovigilance study confirmed the plausibility of intravitreal anti-VEGF drugs being associated with systemic ADRs, including arterial thromboembolic events, such as stroke and myocardial infarction (Cutroneo et al, 2017). In addition to these ADRs, it has recently come to light that anti-VEGF drugs could be a risk factor for neurodegenerative processes.…”

Section: Introductionmentioning

confidence: 95%

Intravitreal Anti-VEGF Drugs and Signals of Dementia and Parkinson-Like Events: Analysis of the VigiBase Database of Spontaneous Reports

et al. 2020

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Introduction: Since vascular endothelial growth factor (VEGF) regulates several aspects of the central nervous system, particularly in dopaminergic neurons, VEGF inhibitors may be linked to Parkinson-like events and dementia, or variants of these diseases. Two recent case reports have found a potential link between intravitreal anti-VEGF use and Parkinson's disease (PD) and dementia. Aim: To evaluate disproportionality in a large spontaneous reporting database concerning intravitreal anti-VEGF drugs and PD or dementia, and related conditions. Methods: Using VigiBase, individual case safety reports (ICSRs) attributed to intravitreal ranibizumab, aflibercept, pegaptanib, and bevacizumab were identified from 2010 to 2016. Within Standardised Narrow Medical Dictionary for Regulatory Activities (MedDRA ®) Queries (SMQs) for "Parkinson-like events" and "Dementia," suspected events were identified using preferred terms (PTs). The Proportional Reporting Ratio (PRR) was estimated with the lower 95% confidence intervals (CIs) for all drug-event pairs with ≥3 suspected events. The vigiGrade completeness score was reported for the ICSRs. The analyses were repeated, including only persons aged 65 and over. Results: Out of 18.9 million ICSRs, 7,945 (0.004%) concerned intravitreal anti-VEGF drugs. Of these, 27 (0.34%) were identified concerning the SMQs "Dementia" (N = 17, 62.96%) and "Parkinson-like events" (N = 10, 37.94%) in persons of all ages. Among persons age 65 and over, 4,758 (59.88% of relevant ICSRs) ICSRs were identified for anti-VEGF drugs. When restricting disproportionality analysis to persons aged 65 and over, no disproportionality was seen for any of the drug-event pairs at the level of SMQ. However, on analysing disproportionality by PT, a potential signal emerged for intravitreal ranibizumab and Parkinson's disease [N = 6 ICSRs; PRR: 3.05 (95% CI: 1.36-6.81)]. In general, the vigiGrade completeness score was low for all the ICSRs of interest, as no ICSR had a score >0.8.

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“…However, TRPC1 gene knockout in zebrafish and mice showed the opposite results [7,8], which proved that TRPC expression and effect were different in different tissues of different species and genera. Although current antivascular endothelial growth factor (VEGF) drugs cause clinically visible regression of new blood vessels, there is evidence that they can increase the occurrence of retinal traction detachment and other adverse reactions in the treatment of PDR and choroidal neovascularization [9,10]. The specific role of the TRPC family in endothelial cell formation in retinal neovascularization has rarely been reported.…”

Section: Introductionmentioning

confidence: 99%

The Effect and Mechanism of TRPC1, 3, and 6 on the Proliferation, Migration, and Lumen Formation of Retinal Vascular Endothelial Cells Induced by High Glucose

et al. 2020

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Objective: Transient receptor potential canonical (TRPC) channels are involved in neovascularization repairing after vascular injury in many tissues. However, whether TRPCs play a regulatory role in the development of diabetic retinopathy (DR) has rarely been reported. In the present study, we selected TRPC1, 3, and 6 to determine their roles and mechanism in human retina vascular endothelial cells (HREC) under high glucose (HG) conditions. Methods: HRECs were cultured in vitro under HG, hyper osmosis, and normal conditions. The expression of TRPC1, 3, and 6 in the cells at 24 and 48 h were detected by RT-polymerase chain reaction (PCR), Western blot and cell immunohistochemistry (IHC); In various concentrations, SKF96365 acted on HG cultured HRECs, the expression of vascular endothelial growth factor (VEGF) were detected by the same methods above; and the CCK-8, Transwell, cell scratch assay, and Matrigel assay were used to assess cell proliferation, migration, and lumen formation. Results: The RT-PCR, Western blot, and IHC results showed that TRPC1 expression was increased, and TRPC6 mRNA expression was increased under high-glucose conditions. SKF96365 acted on HG cultured HRECs that VEGF expression was significantly decreased. The CCK-8 assay, Transwell assay, cell scratch assay, and Matrigel assay showed that cell proliferation, migration, and lumen formation were downregulated by SKF96365. Conclusion: HG can induce increased expression of TRPC1 and 6 in HRECs. Inhibition of the TRPC pathway not only can decrease VEGF expression but also can prevent proliferation, migration, and lumen formation of HRECs induced by HG. Inhibition of TRPC channels is expected to become a drug target for

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Overview of the Safety of Anti-VEGF Drugs: Analysis of the Italian Spontaneous Reporting System

Cited by 22 publications

References 33 publications

Long-Term Intravitreal Ranibizumab as a Potential Additional Risk Factor for Neurodegeneration in Parkinson’s Disease: A Case Report

Long-Term Intravitreal Ranibizumab as a Potential Additional Risk Factor for Neurodegeneration in Parkinson’s Disease: A Case Report

Intravitreal Anti-VEGF Drugs and Signals of Dementia and Parkinson-Like Events: Analysis of the VigiBase Database of Spontaneous Reports

The Effect and Mechanism of TRPC1, 3, and 6 on the Proliferation, Migration, and Lumen Formation of Retinal Vascular Endothelial Cells Induced by High Glucose

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