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1.
Chem Biol Interact ; 314: 108849, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31610157

RESUMO

To provide novel insight into approaches designed to combat glioblastoma, the molecular details of the cytotoxicity of gamabufotalin, were investigated in the human glioblastoma cell line U-87. A dose-dependent cytotoxicity was observed in the cells, whereas no detectable toxicity was confirmed in mouse primary astrocytes. LDH leakage was only observed in the cells treated with a relatively high concentration (>80 ng/ml). Downregulation of the expression levels of Aurora B, cdc25A, cdc25C, cdc2, Cyclin B1 and survivin, and upregulation of the expression level of p21 were observed in treated cells and occurred in parallel with G2/M phase arrest. Treatment with gamabufotalin also downregulated the expression level of uPA, CA9, and upregulated the expression level of TIMP3, all of which are closely associated with invasion/metastasis. Autophagy induction was observed in the treated cells and the addition of wortmannin, a potent autophagy inhibitor, significantly rescued U-87 cells. These results indicate that gamabufotalin exhibits cytotoxicity against cancerous glial cells with high potency and selectivity through multiple cytotoxic signaling pathways. The activation of p38 MAPK pathway along with the upregulation of VEGF/VEGFR2 was observed in the treated cells, both of which are likely to be compensatory changes in response to gamabufotalin treatment. Intriguingly, a specific inhibitor of p38 MAPK enhanced the cytotoxicity of the drug, suggesting an important prosurvival role for p38 MAPK. We thus suggest that developing a new combination regimen of gamabufotalin plus a p38 MAPK inhibitor and/or inhibitors for VEGF/VEGFR could improve the efficacy of the drug, and may provide more therapeutic benefits to patients with glioblastoma.


Assuntos
Apoptose/efeitos dos fármacos , Bufanolídeos/farmacologia , Animais , Astrócitos/citologia , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Autofagia/efeitos dos fármacos , Bufanolídeos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Wortmanina/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
2.
Expert Opin Investig Drugs ; 28(10): 851-860, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31554440

RESUMO

Introduction: Renal cell carcinoma (RCC) consists of distinct clinical and biologic entities, with an urgent need for novel therapies targeting histology-specific molecular drivers of cancer growth. The MET pathway is now being targeted by multiple novel agents in clinical development. This review highlights the upcoming role of MET inhibition in the treatment of RCC. Areas covered: The HGF-MET axis is now recognized as playing a vital role in the growth of papillary histology and in driving VEGF inhibitor resistance. The heterogeneity of MET alterations influences sensitivity to MET inhibition and we need predictive biomarkers for improving patient selection. In this review, we highlight the role of the MET pathway in both clear cell and non-clear cell RCC and  provide a comprehensive review of preclinical and early clinical data on multiple drugs targeting the MET pathway. Expert opinion: MET alterations can act as primary or secondary drivers of tumor growth in RCC and represents a viable therapeutic target. Combination strategies of VEGF and MET inhibitors could lead to sustained and deep responses even in non-MET driven RCC by inhibiting pathways of VEGF resistance. Addition of checkpoint inhibitors to MET inhibition has also demonstrated promising signs of early efficacy.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/patologia , Drogas em Investigação/farmacologia , Humanos , Neoplasias Renais/patologia , Terapia de Alvo Molecular , Seleção de Pacientes , Inibidores de Proteínas Quinases/farmacologia , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
3.
Lancet ; 394(10208): 1551-1559, 2019 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-31522845

RESUMO

BACKGROUND: Despite increasing worldwide use of anti-vascular endothelial growth factor agents for treatment of retinopathy of prematurity (ROP), there are few data on their ocular efficacy, the appropriate drug and dose, the need for retreatment, and the possibility of long-term systemic effects. We evaluated the efficacy and safety of intravitreal ranibizumab compared with laser therapy in treatment of ROP. METHODS: This randomised, open-label, superiority multicentre, three-arm, parallel group trial was done in 87 neonatal and ophthalmic centres in 26 countries. We screened infants with birthweight less than 1500 g who met criteria for treatment for retinopathy, and randomised patients equally (1:1:1) to receive a single bilateral intravitreal dose of ranibizumab 0·2 mg or ranibizumab 0·1 mg, or laser therapy. Individuals were stratified by disease zone and geographical region using computer interactive response technology. The primary outcome was survival with no active retinopathy, no unfavourable structural outcomes, or need for a different treatment modality at or before 24 weeks (two-sided α=0·05 for superiority of ranibizumab 0·2 mg against laser therapy). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT02375971. INTERPRETATION: Between Dec 31, 2015, and June 29, 2017, 225 participants (ranibizumab 0·2 mg n=74, ranibizumab 0·1 mg n=77, laser therapy n=74) were randomly assigned. Seven were withdrawn before treatment (n=1, n=1, n=5, respectively) and 17 did not complete follow-up to 24 weeks, including four deaths in each group. 214 infants were assessed for the primary outcome (n=70, n=76, n=68, respectively). Treatment success occurred in 56 (80%) of 70 infants receiving ranibizumab 0·2 mg compared with 57 (75%) of 76 infants receiving ranibizumab 0·1 mg and 45 (66%) of 68 infants after laser therapy. Using a hierarchical testing strategy, compared with laser therapy the odds ratio (OR) of treatment success following ranibizumab 0·2 mg was 2·19 (95% Cl 0·99-4·82, p=0·051), and following ranibizumab 0·1 mg was 1·57 (95% Cl 0·76-3·26); for ranibizumab 0·2 mg compared with 0·1 mg the OR was 1·35 (95% Cl 0·61-2·98). One infant had an unfavourable structural outcome following ranibizumab 0·2 mg, compared with five following ranibizumab 0·1 mg and seven after laser therapy. Death, serious and non-serious systemic adverse events, and ocular adverse events were evenly distributed between the three groups. FINDINGS: In the treatment of ROP, ranibizumab 0·2 mg might be superior to laser therapy, with fewer unfavourable ocular outcomes than laser therapy and with an acceptable 24-week safety profile. FUNDING: Novartis.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Fotocoagulação a Laser , Ranibizumab/administração & dosagem , Retinopatia da Prematuridade/terapia , Inibidores da Angiogênese/efeitos adversos , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Recém-Nascido de muito Baixo Peso , Injeções Intravítreas , Fotocoagulação a Laser/efeitos adversos , Masculino , Ranibizumab/efeitos adversos , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
4.
Middle East Afr J Ophthalmol ; 26(2): 55-59, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31543660

RESUMO

PURPOSE: The aim of this study was to compare the pain scores of the patients during intravitreal injection of ranibizumab and aflibercept based on patient feedback. MATERIALS AND METHODS: Seventy-two eyes of 72 patients, who had not previously undergone any intravitreal injection procedures, were included in this study. Thirty-eight patients received ranibizumab, and 34 patients received aflibercept injections. The pain was measured by visual analog scale (VAS). Patients were asked to rate their pain experienced during the injection between 0 (no pain) and 10 (worst pain ever felt) on VAS just after the injection. RESULTS: VAS pain scores in ranibizumab and aflibercept groups were 3.28 ± 2.45 and 4.20 ± 2.30, respectively. There was a significant difference in average VAS pain scores between groups (P = 0.04). CONCLUSION: VAS pain scores in aflibercept group were found to be significantly higher than the scores in the ranibizumab group.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Dor Ocular/diagnóstico , Injeções Intravítreas/efeitos adversos , Ranibizumab/administração & dosagem , Receptores de Fatores de Crescimento do Endotélio Vascular/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Idoso , Dor Ocular/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor , Estudos Retrospectivos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Degeneração Macular Exsudativa/tratamento farmacológico
5.
Middle East Afr J Ophthalmol ; 26(2): 117-119, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31543672

RESUMO

Vogt-Koyanagi-Harada (VKH) disease is a chronic, bilateral, granulomatous panuveitis associated with cutaneous, neurologic, and auditory manifestations. We report a 4-year-old Saudi boy who developed severe ocular complications by 5 years of age. He presented to King Khalid Eye Specialist Hospital at the age of 4 years and was previously operated on elsewhere for cataract with intraocular lens implantation in his right eye at the age of 3 years. He consecutively had iris capture and membrane formation around the intraocular lens. Examination revealed band keratopathy, posterior synechiae, and fundus depigmentation in both eyes with cataract formation in his left eye. At the age of 5.5 years, he developed subretinal neovascular membrane formation in the left eye. To the best of our knowledge, this patient is youngest VKH case that manifested most of the major complications at a young age as 5 years old.


Assuntos
Síndrome Uveomeningoencefálica/complicações , Inibidores da Angiogênese/uso terapêutico , Catarata/complicações , Extração de Catarata , Pré-Escolar , Neovascularização de Coroide/tratamento farmacológico , Neovascularização de Coroide/etiologia , Distrofias Hereditárias da Córnea/etiologia , Distrofias Hereditárias da Córnea/cirurgia , Angiofluoresceinografia , Hospitais Especializados , Humanos , Injeções Intravítreas , Implante de Lente Intraocular , Lentes Intraoculares , Masculino , Neovascularização Retiniana/diagnóstico , Neovascularização Retiniana/tratamento farmacológico , Neovascularização Retiniana/etiologia , Centros de Atenção Terciária , Síndrome Uveomeningoencefálica/diagnóstico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Adulto Jovem
6.
Asia Pac J Ophthalmol (Phila) ; 8(4): 308-313, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31369406

RESUMO

PURPOSE: The aim of the current study was to compare visco-trabeculotomy (VT) with standard trabeculectomy with mitomycin C (Trab-MMC) in the treatment of quiescent neovascular glaucoma (NVG). METHODS: The study was conducted on 51 eyes of 51 patients presenting with NVG and treated at an Ophthalmic Center in Egypt between March 2014 and April 2017. All study eyes were subjected to a standard protocol of intravitreal injection of ranibizumab followed by panretinal photocoagulation. Eyes were then randomized to either VT or Trab-MMC. Study eyes were followed up for at least 18 months. Success was defined as an intraocular pressure of ≤21 mm Hg and without vision-threatening complications. Complications were noted. RESULTS: The mean ±â€ŠSD (range, median) age of the study patients was 54.1 ±â€Š6.4 (40-67, 54.5) and 52.4 ±â€Š8.8 (38-66, 53) years in the VT (26 eyes) and Trab-MMC (25 eyes) groups, respectively (P = 0.45). The mean ±â€ŠSD (range, median) intraocular pressure (IOP) of the study eyes was 45.19 ±â€Š2.97 (39-52, 45.5) and 45.64 ±â€Š3.56 (3-53, 45) mm Hg on maximal medical therapy in the VT and Trab-MMC groups, respectively (P = 0.61). At 18 months' follow-up, the mean ±â€ŠSD (range, median) IOP of the study eyes was 18.19 ±â€Š2.0 (16-23, 17) and 19.92 ±â€Š2.6 (18-26, 19) mm Hg in the VT and Trab-MMC groups, respectively (P = 0.004). There was no difference in postoperative antiglaucoma medication between the 2 groups (P = 0.62). Complications included hyphema and Descemet split in the VT group and an IOP spike in the Trab-MMC group. Success rates were 84.6% and 80% in the VT and Trab-MMC groups, respectively (P = 0.726). CONCLUSIONS: Both VT and Trab-MMC groups are effective in reducing the IOP in cases of NVG after control of neovascularization with anti-vascular endothelial growth factor and pan retinal photocoagulation.


Assuntos
Glaucoma Neovascular/terapia , Pressão Intraocular/fisiologia , Fotocoagulação/métodos , Ranibizumab/administração & dosagem , Trabeculectomia/métodos , Acuidade Visual , Adulto , Idoso , Inibidores da Angiogênese/administração & dosagem , Feminino , Seguimentos , Glaucoma Neovascular/fisiopatologia , Humanos , Injeções Intravítreas , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
7.
Zhonghua Yan Ke Za Zhi ; 55(8): 565-568, 2019 Aug 11.
Artigo em Chinês | MEDLINE | ID: mdl-31422634

RESUMO

Diabetic retinopathy (DR) is one of the most important etiologies of diabetic blindness. The vascular endothelial growth factor (VEGF) is thought to mediate pathophysiological changes of DR. Anti-VEGF therapy for DRdevelops rapidly. However, there are some misunderstandings about its clinical application, and the strategy is not clear. Sometimes its therapeutic effects are even exaggerated. In this article, by discussing whether anti-VEGF therapy can reverse the course of DR disease, promote the absorption of vitreous hemorrhage, and replace fundus laser therapy, the application strategy of anti-VEGF therapy for DR is proposed. At present, anti-VEGF therapy cannot completely replace retinal photocoagulation therapy, and its clinical application value should not be exaggerated. More innovative drugs and therapies are expected to provide new ways forthe treatment of DR while preserving visual function. (Chin J Ophthalmol, 2019, 55: 565-568).


Assuntos
Inibidores da Angiogênese , Retinopatia Diabética , Fator A de Crescimento do Endotélio Vascular , Inibidores da Angiogênese/uso terapêutico , Retinopatia Diabética/tratamento farmacológico , Humanos , Fotocoagulação a Laser , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
8.
Expert Opin Ther Pat ; 29(10): 749-752, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31456444

RESUMO

Introduction: Age-related macular degeneration (AMD) is the leading cause of central vision loss in developed countries. Effective therapy for AMD is currently limited to the treatment of the patient with intravitreal injections of anti-VEGF drugs. Areas covered: A method for the management of age-related macular degeneration (AMD) is claimed. It consists of the administration of pure botulinum-toxin or a serogroup of recombinant botulinum-toxins or their peptide fragments or neurotoxin associated with accessory proteins in extra-ocular regions of the eye. The toxin modifies the retinal pigment epithelium, maintaining its structure and function, and delaying the various stages of the macular degeneration. Expert opinion: The botulinum-toxin (BT) is administrated as extra-ocular infusions avoiding the risk of direct intraocular injection and the complications associated with the patients. The possibility to administer BT with accessory proteins (hemagglutinin, monoclonal antibody (anti-VEGF)), makes the novel system interesting for developing combined approaches for AMD treatment. The use of BT (alone or conjugated to other agents) as a method for treating or preventing AMD requires necessarily a patient case report study, as well as the in vitro or in vivo data, for supporting all the claims of the present patent.


Assuntos
Toxinas Botulínicas/administração & dosagem , Degeneração Macular/tratamento farmacológico , Epitélio Pigmentado da Retina/efeitos dos fármacos , Humanos , Degeneração Macular/fisiopatologia , Patentes como Assunto , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
9.
Medicine (Baltimore) ; 98(33): e16785, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31415382

RESUMO

Data regarding the safety of anti-vascular endothelial growth factor (anti-VEGF) treatment is limited.To compare the adverse events (AEs) induced by aflibercept and ranibizumab using a spontaneous reporting system and determine the signals.We used data from the Korea Institute of Drug Safety & Risk Management-Korea Adverse Event Reporting System Database (KIDS-KD), collected between 2007 and 2016. Differences in patient demographics, report type, reporter, causality, and serious-AEs between aflibercept and ranibizumab were compared. Metrics including proportional reporting ratio (PRR), reporting odds ratio (ROR), and information component (IC), were used to compare signals with the AEs on the drug labels in the United States of America and Korea. Logistic regression analysis was performed to identify AEs that are more likely to occur with drug use.A total of 32 aflibercept and 103 ranibizumab cases of AEs were identified. The proportion of AEs that were reported voluntarily was higher with aflibercept (50.5%) use than ranibizumab (4.9%), whereas the AEs reported by post-marketing surveillance were higher with ranibizumab (46.6%) use than aflibercept (31.3%). The percentage of AEs in patients >60 years old, reports by consumers, and the ratio of SAEs to AEs associated with aflibercept (84. %, 9.4%, and 75.0%, respectively) were higher than those of ranibizumab (77.7%, 1.9%, and 19.4%, respectively). The number of newly detected AEs after aflibercept and ranibizumab treatment was 3 and 8, respectively. Among these, conjunctivitis and medicine ineffective were not included on the aflibercept and ranibizumab labels, respectively. Endophthalmitis (OR 6.96, 95% CI 2.74-17.73) was more likely to be reported in patients with aflibercept than in patients without aflibercept, whereas medicine ineffective (OR 18.49, 95% CI 2.39-143.29) and retinal disorder (OR 7.03, 95% CI 1.60-30.96) were more likely to be reported in patients with ranibizumab than in patients without ranibizumab.New signals have been identified for aflibercept and ranibizumab. Further research is necessary to evaluate the causality of AEs that were detected as signals in this study.


Assuntos
Inibidores da Angiogênese/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Ranibizumab/efeitos adversos , Proteínas Recombinantes de Fusão/efeitos adversos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Adulto , Sistemas de Notificação de Reações Adversas a Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptores de Fatores de Crescimento do Endotélio Vascular , República da Coreia/epidemiologia , Adulto Jovem
10.
Bone Joint J ; 101-B(7_Supple_C): 108-114, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31256654

RESUMO

AIMS: It is increasingly appreciated that coordinated regulation of angiogenesis and osteogenesis is needed for bone formation. How this regulation is achieved during peri-implant bone healing, such as osseointegration, is largely unclear. This study examined the relationship between angiogenesis and osteogenesis in a unique model of osseointegration of a mouse tibial implant by pharmacologically blocking the vascular endothelial growth factor (VEGF) pathway. MATERIALS AND METHODS: An implant was inserted into the right tibia of 16-week-old female C57BL/6 mice (n = 38). Mice received anti-VEGF receptor-1 (VEGFR-1) antibody (25 mg/kg) and VEGF receptor-2 (VEGFR-2) antibody (25 mg/kg; n = 19) or an isotype control antibody (n = 19). Flow cytometric (n = 4/group) and immunofluorescent (n = 3/group) analyses were performed at two weeks post-implantation to detect the distribution and density of CD31hiEMCNhi endothelium. RNA sequencing analysis was performed using sorted CD31hiEMCNhi endothelial cells (n = 2/group). Osteoblast lineage cells expressing osterix (OSX) and osteopontin (OPN) were also detected with immunofluorescence. Mechanical pull-out testing (n = 12/group) was used at four weeks post-implantation to determine the strength of the bone-implant interface. After pull-out testing, the tissue attached to the implant surface was harvested. Whole mount immunofluorescent staining of OSX and OPN was performed to determine the amount of osteoblast lineage cells. RESULTS: Flow cytometry revealed that anti-VEGFR treatment decreased CD31hiEMCNhi vascular endothelium in the peri-implant bone versus controls at two weeks post-implantation. This was confirmed by the decrease of CD31 and endomucin (EMCN) double-positive cells detected with immunofluorescence. In addition, treated mice had more OPN-positive cells in both peri-implant bone and tissue on the implant surface at two weeks and four weeks, respectively. More OSX-positive cells were present in peri-implant bone at two weeks. More importantly, anti-VEGFR treatment decreased the maximum load of pull-out testing compared with the control. CONCLUSION: VEGF pathway controls the coupling of angiogenesis and osteogenesis in orthopaedic implant osseointegration by affecting the formation of CD31hiEMCNhi endothelium. Cite this article: Bone Joint J 2019;101-B(7 Supple C):108-114.


Assuntos
Inibidores da Angiogênese/farmacologia , Interface Osso-Implante/patologia , Osseointegração/efeitos dos fármacos , Próteses e Implantes , Tíbia/cirurgia , Titânio , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Tíbia/efeitos dos fármacos , Tíbia/metabolismo , Tíbia/patologia
11.
Anticancer Res ; 39(7): 3405-3412, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262862

RESUMO

The prognosis of metastatic pancreatic cancer remains poor despite the recent progress on modern chemotherapeutic regimens, such as FOLFIRINOX, gemcitabine and nab-paclitaxel. A better understanding of the altered signalling pathways and the importance of stroma and the immune environment in pancreatic cancer have led to the development of new clinical trials with promising results. In the present review, a general outline of current first- and second-line therapies is provided. Further, new therapeutic possibilities are reviewed, in particular EGFR and VEGF inhibitors, immunotherapy and PARP inhibitors.


Assuntos
Neoplasias Pancreáticas/terapia , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Receptores ErbB/antagonistas & inibidores , Humanos , Imunoterapia , Neoplasias Pancreáticas/patologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
12.
Bull Cancer ; 106(10): 923-938, 2019 Oct.
Artigo em Francês | MEDLINE | ID: mdl-31324333

RESUMO

INTRODUCTION: Adenoid Cystic Carcinoma is a rare tumor of the head and neck sphere. The purpose of this review is a state of the art of systemic treatments (chemotherapies, targeted therapies, immunotherapies) for locally recurrent or metastatic disease. MATERIAL AND METHODS: Our inclusion criteria included head and neck adult patient, metastatic or locally advanced, treated by a systemic therapy, and with at least 10 or more patients. RESULTS: Forty articles have been selected in this review. The objective response rate under chemotherapy was predominantly<10% (0-70%) with objective responses in monotherapy with cisplatin, mitoxantrone, vinorelbine and eribuline, and with cisplatin-vinorelbine combination. EGFR inhibitors provided 40% objective responses only in combination. Inhibitors of VEGF and histone deacetylase have allowed disease stabilization in progressive patients, with about 10% of objective response. Inhibitors of c-KIT monotherapy yield objective response rates of<5%. Direct inhibitors of the PI3K/AKT/mTOR pathway display 0% objective response rate. CONCLUSION: The best objective response rates were obtained with cisplatin-vinorelbine combination. Many targetable molecular abnormalities have been identified and studies have shown prolonged stabilization with EGFR, VEGF and HDAC inhibitors. Multi-disciplinary collaborative consultation (MCC) meetings such as French network of experts in rare head and neck tumors (REFCOR) or Molecular MCC should be proposed and may allow referral to centers proposing specific therapeutic trials.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Adenoide Cístico/terapia , Imunoterapia , Terapia de Alvo Molecular/métodos , Recidiva Local de Neoplasia/terapia , Neoplasias Otorrinolaringológicas/terapia , Doenças Raras/terapia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Adenoide Cístico/patologia , Carcinoma Adenoide Cístico/secundário , Receptores ErbB/antagonistas & inibidores , Humanos , Neoplasias Otorrinolaringológicas/patologia , Doenças Raras/patologia , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
13.
AAPS PharmSciTech ; 20(7): 254, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31317354

RESUMO

The pathophysiological mechanisms for dry and wet age-related macular degeneration (AMD) involve oxidative stress and increased VEGF release and expression. An ideal drug candidate for both types of AMD is the one which offers significant protection to the retinal cells from oxidative stress and inhibit VEGF release. Curcumin is one such natural product which provides numerous beneficial effects including antioxidant, anti-inflammatory, and anti-VEGF activities and has the potential for the treatment of both types of AMD. The bioavailability of curcumin is negligible due to its poor aqueous solubility. The purpose of this work is to develop an aqueous nanomicellar drop formulation of curcumin (CUR-NMF) for back of the eye delivery utilizing hydrogenated castor oil (HCO-40) and octoxynol-40 (OC-40) to treat AMD. A full factorial design was performed with JMP software analysis to optimize the formulation size, polydispersity index (PDI), entrapment efficiency, loading, and precipitation. MTT and LDH assays on human retinal pigmented epithelial (D407) cells revealed that 5-10 µM CUR-NMF dose is safe for ophthalmic use. Furthermore, CUR-NMF exhibited significant protection of retinal (D407) cells against H2O2-induced oxidative stress. In vitro drug release kinetics suggested a sustained drug release profile indicating a long-term protection ability of CUR-NMF against oxidative stress to retinal cells. In addition, an ELISA suggested that CUR-NMF significantly reduces vascular endothelial growth factor (VEGF) release in D407 cell line, hence diminishes the risk of angiogenesis. Collectively, these results suggest that the proposed CUR-NMF can be tremendously effective in treating both types of AMD.


Assuntos
Curcumina/administração & dosagem , Curcumina/farmacocinética , Olho/metabolismo , Micelas , Nanoestruturas , Administração Oftálmica , Antioxidantes/química , Disponibilidade Biológica , Óleo de Rícino/química , Linhagem Celular , Curcumina/farmacologia , Preparações de Ação Retardada , Humanos , Estresse Oxidativo/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/metabolismo
14.
BMC Ophthalmol ; 19(1): 153, 2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324161

RESUMO

BACKGROUND: There is no consensus on the optimal initial treatment for polypoidal choroidal vasculopathy (PCV). Our study aimed to report the efficacy of repeated injections of intravitreal ranibizumab with or without photodynamic therapy for the treatment of PCV and to determine the possible factors predictive of visual outcomes. METHODS: The results of the initial treatment of 40 patients with PCV with 3 monthly injections of ranibizumab were retrospectively reviewed. We compared the results in terms of the best corrected visual acuity (BCVA), the central retinal thickness (CRT), the number of injections, the regression rates of polyps and the rates of the reduction of subretinal fluid. RESULTS: At the 3-month follow-up, the mean BCVA was significantly increased by 7.3 ± 12.4 letters compared to baseline (p < 0.01). At the 12-month follow-up, the mean BCVA was increased by 3.4 ± 15.4 letters compared to baseline, and there was no significant difference (p > 0.05). The mean CRT at the 12-month follow-up was 593.58 ± 243.64 µm, with an average decrease of 101.55 ± 256.07 µm compared to baseline (p < 0.01). Fifteen eyes (18.8%) showed the complete regression of polyps, and 22 eyes (27.5%) showed a reduction in polyps. The baseline VA, the reduction in subretinal fluids and the greatest lesion diameter were significant independent factors that were predictive of improved VA at the final follow-up. CONCLUSIONS: Three monthly injections of ranibizumab as an initial treatment could significantly improve VA in PCV patients in the short term. At 12 months postinjection, ranibizumab treatment could stabilize VA in most PCV patients. The baseline VA, the reduction in subretinal fluids and the greatest lesion diameter were predictive factors for the relative improvement of VA at the final follow-up.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Neovascularização de Coroide/tratamento farmacológico , Ranibizumab/uso terapêutico , Idoso , Feminino , Humanos , Injeções Intravítreas , Masculino , Pessoa de Meia-Idade , Fotoquimioterapia/métodos , Pólipos/tratamento farmacológico , Estudos Retrospectivos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Acuidade Visual
15.
Expert Opin Drug Saf ; 18(9): 803-815, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31309853

RESUMO

Introduction: Intravitreal anti-VEGF is the most effective therapy for wet AMD, although systemic effects on the endothelium cannot be excluded. Areas covered: The purpose of this review was to evaluate risk of thromboembolic events associated with intravitreal anti-VEGF. Expert opinion: Current data are insufficient to confirm the safety of these compounds, due to the paucity of specific studies. Thus, pharmacovigilance for all anti-VEGF should be improved to verify the true role of anti-VEGF in the occurrence of systemic adverse events.


Assuntos
Inibidores da Angiogênese/efeitos adversos , Tromboembolia/induzido quimicamente , Degeneração Macular Exsudativa/tratamento farmacológico , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/farmacologia , Humanos , Injeções Intravítreas , Farmacovigilância , Tromboembolia/epidemiologia , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
16.
Curr Opin Ophthalmol ; 30(5): 326-330, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31313750

RESUMO

PURPOSE OF REVIEW: To review recent studies on potential neurodevelopmental impacts on the pediatric population through general anesthesia events or intravitreal anti-vascular endothelial growth factor (VEGF) injection. RECENT FINDINGS: Studies on this topic have been extensive with varied reported neurodevelopmental outcomes. Initial investigations in rodents and primates showed negative impact of anesthetics on neurodevelopment. Subsequent retrospective human reviews had mixed results whereas more recent sibling and prospective studies have been published without evidence of clinically significant impact. A similar narrative has more recently come to play regarding the long-term effects of intravitreal injections used in neonates with retinopathy of prematurity. Publications initially indicated a negative correlation whereas later reviews have found no difference between those receiving injections versus laser treatment. SUMMARY: Given that recent data on both general anesthesia events and intravitreal anti-VEGF injections do not show a long-term negative neurodevelopmental impact, ocular procedures needed to improve a pediatric patient's vision or quality of life should not be delayed.


Assuntos
Anestesia Geral/efeitos adversos , Injeções Intravítreas/efeitos adversos , Transtornos do Neurodesenvolvimento/etiologia , Inibidores da Angiogênese/administração & dosagem , Animais , Criança , Humanos , Recém-Nascido , Procedimentos Cirúrgicos Oftalmológicos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
17.
Eur J Ophthalmol ; 29(5): 471-473, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31353948

RESUMO

The authors report a case of a female patient affected by neovascular age-related macular degeneration (AMD). In particular, multiple sub-retinal hyperreflective infiltrates were found on optical coherence tomography. Optical coherence tomography examination of her right eye displayed the presence of sub-retinal pigment epithelium hyporeflective spaces located beneath a hyperreflective fibrotic neovascularization. This case highlights the importance of differentiating choroidal clefts from choroidal caverns.


Assuntos
Doenças da Coroide/diagnóstico , Neovascularização de Coroide/complicações , Degeneração Macular Exsudativa/complicações , Idoso , Inibidores da Angiogênese/uso terapêutico , Lâmina Basilar da Corioide/patologia , Neovascularização de Coroide/tratamento farmacológico , Feminino , Angiofluoresceinografia , Humanos , Epitélio Pigmentado da Retina/patologia , Tomografia de Coerência Óptica/métodos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Acuidade Visual/fisiologia , Degeneração Macular Exsudativa/tratamento farmacológico
19.
BMC Ophthalmol ; 19(1): 129, 2019 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-31208350

RESUMO

BACKGROUND: To evaluate the retinal function before and soon after an intravitreal injection of an anti-vascular endothelial growth factor (anti-VEGF) agents. METHODS: Seventy-nine eyes of 79 patients that were treated by an intravitreal injection of an anti-VEGF agent for age-related macular degeneration (AMD), diabetic macular edema (DME), or retinal vein occlusion (RVO) with macular edema (ME) were studied. The RETeval® system was used to record 28 Hz flicker electroretinograms (ERGs) from the injected and non-injected eyes before (Phase 1, P1), within 2 h after the injection (P2), and 2 to 24 h after the injection (P3). Patients were grouped by disease or by the injected agent and compared. The significance of the changes in the implicit times and amplitudes was determined by t tests. RESULTS: The amplitudes were not significantly different at the three phases. The implicit time of the injected eye was 31.2 ± 3.2 msec at P1, and it was not significantly different at P2 (31.7 ± 3.1 msec) but it was significantly longer at P3 (32.2 ± 3.3 msec, P < 0.01, ANOVA for both). The implicit time in the non-injected fellow eye was 30.5 ± 3.3 msec at P1, and it was significantly longer at P2 (31.1 ± 3.2 msec) and phase 3 (31.3 ± 3.4 msec, P < 0.01, ANOVA for both). CONCLUSIONS: The results indicate that an intravitreal anti-VEGF injection will increase the implicit times not only in the injected eye but also in the non-injected eye soon after the intravitreal injection.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Degeneração Macular/tratamento farmacológico , Edema Macular/tratamento farmacológico , Ranibizumab/administração & dosagem , Retina/fisiopatologia , Oclusão da Veia Retiniana/tratamento farmacológico , Idoso , Análise de Variância , Retinopatia Diabética/tratamento farmacológico , Eletrorretinografia , Feminino , Humanos , Injeções Intravítreas , Degeneração Macular/fisiopatologia , Edema Macular/fisiopatologia , Masculino , Pessoa de Meia-Idade , Oclusão da Veia Retiniana/fisiopatologia , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Acuidade Visual/fisiologia
20.
Asia Pac J Ophthalmol (Phila) ; 8(3): 200-205, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31165603

RESUMO

PURPOSE: To investigate long-term outcomes of pro re nata (PRN) treatment protocol of ranibizumab for diabetic macular edema (DME) adopted from the first month of therapy without 3 loading doses. DESIGN: Retrospective interventional study. METHODS: We analyzed 180 eyes of 144 patients treated with ranibizumab for DME with a minimum follow-up of 1 year during December 2013 to December 2017. Data of all patients with treatment-naive center-involving DME who received at least 1 intravitreal injection of ranibizumab during the study period were drawn from a locally adapted electronic form for DME. The primary outcome measure was change in best-corrected visual acuity (BCVA) from baseline at 1-year follow-up, with intergroup comparisons in BCVA between eyes receiving 1, 2, and 3 injections in the first 3 months of treatment. RESULTS: The mean baseline BCVA was 0.47 ± 0.30 logMAR, which improved to 0.38 ± 0.3 logMAR (P = 0.003) at 3 months and stabilized at 0.35 ± 0.27 logMAR at 1 year (P = 0.46 vs BCVA at 3 months) and 0.34 ± 0.26 logMAR at 2 years of follow-up (P = 0.44 vs BCVA at 3 months). At 3 months, 24 eyes (13%) underwent 1 intravitreal injection, 52 eyes (29%) had 2 injections, and the majority (n = 104 eyes, 58%) had 3 injections on a monthly basis. During the first year, the group that received only 1 injection in the first 3 months also required fewer injections and fewer follow-up visits compared with those receiving 2 or 3 injections in the first 3 months. CONCLUSIONS: One-third of eyes with DME responded well to PRN treatment strategy from the first month without 3 loading doses of ranibizumab. Baseline visual acuity is the best predictor of vision at 1 and 2 years of follow-up.


Assuntos
Retinopatia Diabética/tratamento farmacológico , Macula Lutea/patologia , Edema Macular/tratamento farmacológico , Ranibizumab/administração & dosagem , Acuidade Visual , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/administração & dosagem , Retinopatia Diabética/complicações , Retinopatia Diabética/diagnóstico , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Injeções Intravítreas , Edema Macular/diagnóstico , Edema Macular/etiologia , Masculino , Microscopia Acústica , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Tempo , Tomografia de Coerência Óptica , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
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