RESUMO
Neovascularization is the pathological driver of blinding eye diseases such as retinopathy of prematurity, proliferative diabetic retinopathy, and wet age-related macular degeneration. The loss of vision resulting from these diseases significantly impacts the productivity and quality of life of patients, and represents a substantial burden on the health care system. Current standard of care includes biologics that target vascular endothelial growth factor (VEGF), a key mediator of neovascularization. While anti-VGEF therapies have been successful, up to 30% of patients are non-responsive. Therefore, there is a need for new therapeutic targets, and small molecule inhibitors of angiogenesis to complement existing treatments. Apelin and its receptor have recently been shown to play a key role in both developmental and pathological angiogenesis in the eye. Through a cell-based high-throughput screen, we identified 4-aminoquinoline antimalarial drugs as potent selective antagonists of APJ. The prototypical 4-aminoquinoline, amodiaquine was found to be a selective, non-competitive APJ antagonist that inhibited apelin signaling in a concentration-dependent manner. Additionally, amodiaquine suppressed both apelin-and VGEF-induced endothelial tube formation. Intravitreal amodaiquine significantly reduced choroidal neovascularization (CNV) lesion volume in the laser-induced CNV mouse model, and showed no signs of ocular toxicity at the highest doses tested. This work firmly establishes APJ as a novel, chemically tractable therapeutic target for the treatment of ocular neovascularization, and that amodiaquine is a potential candidate for repurposing and further toxicological, and pharmacokinetic evaluation in the clinic.
Assuntos
Aminoquinolinas/uso terapêutico , Antimaláricos/uso terapêutico , Reposicionamento de Medicamentos , Neovascularização Retiniana/tratamento farmacológico , Aminoquinolinas/química , Aminoquinolinas/farmacocinética , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Animais , Antimaláricos/química , Antimaláricos/farmacocinética , Apelina/metabolismo , Receptores de Apelina/antagonistas & inibidores , Receptores de Apelina/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Neovascularização de Coroide/tratamento farmacológico , Neovascularização de Coroide/patologia , Modelos Animais de Doenças , Feminino , Humanos , Lasers , Camundongos , Camundongos Endogâmicos C57BL , Neovascularização Retiniana/patologia , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/uso terapêutico , Distribuição Tecidual , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
OBJECTIVE: To implement a service learning program in nutrition and assess its impact on pharmacy students' communication skills and professionalism and elementary school children's knowledge of nutrition concepts. DESIGN: First-year pharmacy students completed 4 nutrition education sessions led by a registered dietitian and then presented the material to pre-selected classes of at-risk elementary school children in kindergarten through third grade. ASSESSMENT: Ninety-six pharmacy students completed the pre- and post-experience survey and more than 90% rated achievement of course objectives as strongly agree or agree. Four hundred sixty-eight elementary students completed a pre- and posttest on nutrition knowledge. Significant improvement was found in all grade levels on the knowledge test. CONCLUSION: This service learning experience was beneficial for the elementary school children and pharmacy students, enhancing the knowledge of both groups and establishing a positive relationship between the pharmacy school and the community.