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1.
N Engl J Med ; 382(2): 140-151, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31914241

RESUMO

BACKGROUND: Patients with anemia and lower-risk myelodysplastic syndromes in whom erythropoiesis-stimulating agent therapy is not effective generally become dependent on red-cell transfusions. Luspatercept, a recombinant fusion protein that binds transforming growth factor ß superfamily ligands to reduce SMAD2 and SMAD3 signaling, showed promising results in a phase 2 study. METHODS: In a double-blind, placebo-controlled, phase 3 trial, we randomly assigned patients with very-low-risk, low-risk, or intermediate-risk myelodysplastic syndromes (defined according to the Revised International Prognostic Scoring System) with ring sideroblasts who had been receiving regular red-cell transfusions to receive either luspatercept (at a dose of 1.0 up to 1.75 mg per kilogram of body weight) or placebo, administered subcutaneously every 3 weeks. The primary end point was transfusion independence for 8 weeks or longer during weeks 1 through 24, and the key secondary end point was transfusion independence for 12 weeks or longer, assessed during both weeks 1 through 24 and weeks 1 through 48. RESULTS: Of the 229 patients enrolled, 153 were randomly assigned to receive luspatercept and 76 to receive placebo; the baseline characteristics of the patients were balanced. Transfusion independence for 8 weeks or longer was observed in 38% of the patients in the luspatercept group, as compared with 13% of those in the placebo group (P<0.001). A higher percentage of patients in the luspatercept group than in the placebo group met the key secondary end point (28% vs. 8% for weeks 1 through 24, and 33% vs. 12% for weeks 1 through 48; P<0.001 for both comparisons). The most common luspatercept-associated adverse events (of any grade) included fatigue, diarrhea, asthenia, nausea, and dizziness. The incidence of adverse events decreased over time. CONCLUSIONS: Luspatercept reduced the severity of anemia in patients with lower-risk myelodysplastic syndromes with ring sideroblasts who had been receiving regular red-cell transfusions and who had disease that was refractory to or unlikely to respond to erythropoiesis-stimulating agents or who had discontinued such agents owing to an adverse event. (Funded by Celgene and Acceleron Pharma; MEDALIST ClinicalTrials.gov number, NCT02631070; EudraCT number, 2015-003454-41.).


Assuntos
Receptores de Activinas Tipo II/uso terapêutico , Anemia Sideroblástica/tratamento farmacológico , Transfusão de Eritrócitos , Hematínicos/uso terapêutico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Síndromes Mielodisplásicas/tratamento farmacológico , Proteínas Recombinantes de Fusão/uso terapêutico , Receptores de Activinas Tipo II/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia Sideroblástica/terapia , Método Duplo-Cego , Feminino , Hematínicos/efeitos adversos , Hemoglobinas/análise , Humanos , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Infusões Subcutâneas , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/terapia , Proteínas Recombinantes de Fusão/efeitos adversos
2.
Int J Radiat Biol ; 96(1): 155-166, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31216213

RESUMO

Purpose: Evaluation of the pharmacodynamics (PD) and pharmacokinetics (PK) of romiplostim alone and in combination with pegfilgrastim in a non-human primate (NHP) model of acute radiation syndrome (ARS).Materials and methods: Male and female rhesus macaques were subjected to Cobalt-60 γ irradiation, at a dose of 550 cGy 24 h prior to subcutaneous administration of either romiplostim alone as a single (2.5 or 5.0 mg/kg on Day 1) or repeat dose (5.0 mg/kg on Days 1 and 8), pegfilgrastim alone as a repeat dose (0.3 µg/kg on Day 1 and 8), or a combination of both agents (romiplostim 5.0 mg/kg on Day 1; pegfilgrastim 0.3 µg/kg on Days 1 and 8). Clinical outcome, hematological parameters and PK were assessed throughout the 45 d study period post-irradiation.Results: Administration of romiplostim, pegfilgrastim or the combination of both resulted in significant improvements in hematological parameters, notably prevention of severe thrombocytopenia, compared with irradiated, vehicle control-treated NHPs. The largest hematologic benefit was observed when romiplostim and pegfilgrastim were administered as a combination therapy with much greater effects on both platelet and neutrophil recovery following irradiation compared to single agents alone.Conclusions: These results indicate that romiplostim alone or in combination with pegfilgrastim is effective at improving hematological parameters in an NHP model of ARS. This study supports further study of romiplostim as a medical countermeasure to improve primary hemostasis and survival in ARS.


Assuntos
Filgrastim/farmacologia , Neutropenia/tratamento farmacológico , Polietilenoglicóis/farmacologia , Lesões Experimentais por Radiação/tratamento farmacológico , Proteínas Recombinantes de Fusão/farmacologia , Trombocitopenia/tratamento farmacológico , Trombopoetina/farmacologia , Animais , Coagulação Sanguínea/efeitos dos fármacos , Coagulação Sanguínea/efeitos da radiação , Relação Dose-Resposta a Droga , Interações de Medicamentos , Feminino , Macaca mulatta , Masculino , Neutropenia/sangue , Neutropenia/metabolismo , Lesões Experimentais por Radiação/sangue , Lesões Experimentais por Radiação/metabolismo , Receptores Fc/uso terapêutico , Proteínas Recombinantes de Fusão/farmacocinética , Proteínas Recombinantes de Fusão/uso terapêutico , Trombocitopenia/sangue , Trombocitopenia/metabolismo , Trombopoetina/farmacocinética , Trombopoetina/uso terapêutico , Fatores de Tempo
3.
Ann Hematol ; 99(1): 7-19, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31650290

RESUMO

Myelodysplastic syndromes (MDS) are hematopoietic stem cell malignancies associated with an erythroid maturation defect, resulting in anemia. Treatments for MDS include erythropoiesis-stimulating agents (ESAs). The identification of prognostic markers is important to help predict response and improve outcomes. Various scoring systems have been developed to help predict response to ESAs. Despite limitations in its assessment, serum erythropoietin (sEPO) level is an important predictor of hematologic response to ESAs in patients with lower-risk MDS. Numerous studies have reported significantly lower sEPO levels among responders versus non-responders. Furthermore, treatment response is significantly more likely among those with sEPO levels below versus those above various cutoffs. Other prognostic indicators for response to ESAs include lower transfusion requirement, fewer bone marrow blasts, higher hemoglobin, lower serum ferritin, lower-risk MDS, and more normal cytogenetics. Studies of other MDS therapies (e.g., lenalidomide and luspatercept) have also reported that lower sEPO levels are indicative of hematologic response. In addition, lower sEPO levels (up to 500 IU/L) have been included in treatment algorithms for patients with lower-risk MDS to define whether ESAs are indicated. Lower sEPO levels are predictive of hematologic response-particularly to ESAs. Further, clinical trials should use sEPO thresholds to ensure more homogeneous cohorts.


Assuntos
Receptores de Activinas Tipo II/uso terapêutico , Eritropoetina/sangue , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Lenalidomida/uso terapêutico , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/tratamento farmacológico , Proteínas Recombinantes de Fusão/uso terapêutico , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Feminino , Ferritinas/sangue , Hemoglobinas/metabolismo , Humanos , Masculino , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/patologia , Prognóstico , Fatores de Risco
4.
Medicine (Baltimore) ; 98(44): e17599, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31689763

RESUMO

This study compares 2 methods of macular function evaluation: the microperimetric examination (mean central retinal sensitivity and fixation stability) and the distance best-corrected visual acuity (BCVA) examination, which is the most frequently used method of assessing macular function in patients with newly diagnosed wet age-related macular degeneration (AMD) who have been treated with anti-vascular endothelial growth factor (VEGF) drug (aflibercept).Prospective analysis was conducted on 44 eyes of 44 patients treated with intravitreal injection of anti-VEGF (aflibercept) because of newly diagnosed neovascular AMD. According to the research protocol, all patients had a 6-month follow-up. The response to treatment was monitored functionallybyMP-1 microperimetry, fixation, and distance BCVA assessment after injection. Improvement of retinal sensitivity and BCVA was found under aflibercept treatment. There was statistically significant improvement in retinal sensitivity in the MP-1 study 3 and 6 months from the beginning of anti-VEGF therapy. Moreover, a significant improvement in retinal sensitivity between 3 and 6 months of observation was demonstrated. At the same time, up to 3 months from the beginning of treatment, BCVA improved significantly compared to the baseline value. In the 6th month of the study BCVA remained stable without further significant improvement.Microperimetric examination with medium sensitivity and fixation stability assessment is a very valuable test determining the retinal function. It is clear that examining the macular morphology itself in modern diagnostics is not enough to assess retinal function. Microperimetry technique is a valuable tool for functional long-term evaluation of retinal function (also for a period of more than 3 months).


Assuntos
Receptores de Fatores de Crescimento do Endotélio Vascular/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Retina/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/uso terapêutico , Degeneração Macular Exsudativa/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Injeções Intravítreas , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Receptores de Fatores de Crescimento do Endotélio Vascular/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/farmacologia , Fator A de Crescimento do Endotélio Vascular/administração & dosagem , Fator A de Crescimento do Endotélio Vascular/farmacologia , Acuidade Visual
5.
Vestn Oftalmol ; 135(5. Vyp. 2): 177-183, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31691657

RESUMO

PURPOSE: To study the effect of ranibizumab and aflibercept on the thickness of retinal nerve fiber layer (RNFL) in patients with neovascular age-related macular degeneration (nAMD) and primary open-angle glaucoma (POAG). MATERIAL AND METHODS: The study included 62 patients (62 eyes) with nAMD and comorbid POAG. Patients were divided into two groups depending on the anti-VEGF treatment. The first group included 42 patients (42 eyes) who received injections of ranibizumab. The second group consisted of 20 patients (20 eyes) who received aflibercept. All patients received three injections of ranibizumab or aflibercept with one-month intervals. In addition to standard ophthalmic examination, patients underwent optical coherence tomography of the macular area and peripapillary RNFL. RESULTS: After anti-VEGF treatment, patients of both groups exhibited improvements expressed in reduced macular edema, increased visual acuity and absence of intraocular pressure (IOP) changes, as well as no statistically significant changes in the width and depth of excavation. There was a statistically significant decrease of peripapillary RNFL thickness in the temporal quadrant after treatment. CONCLUSION: The decrease of peripapillary RNFL thickness in the temporal quadrant occurs due to resorption of macular edema. In the absence of statistically significant changes in IOP, width and depth of excavation, intravitreal injections of ranibizumab and aflibercept can be considered safe treatment options for patients with concomitant nAMD and POAG.


Assuntos
Glaucoma , Degeneração Macular , Ranibizumab/uso terapêutico , Receptores de Fatores de Crescimento do Endotélio Vascular/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Inibidores da Angiogênese , Seguimentos , Glaucoma/tratamento farmacológico , Humanos , Injeções Intravítreas , Fibras Nervosas , Estudos Retrospectivos , Tomografia de Coerência Óptica , Resultado do Tratamento
6.
Cancer Sci ; 110(11): 3565-3572, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31520559

RESUMO

Aflibercept plus 5-fluorouracil/levofolinate/irinotecan (FOLFIRI) is a second-line treatment for metastatic colorectal cancer. This ancillary exploratory analysis of data in Japanese people was aimed at exploring the relationship between a set of potential prognostic biomarkers and efficacy endpoints following aflibercept plus FOLFIRI therapy. Sixty-two patients with metastatic colorectal cancer received aflibercept (4 mg/kg) plus FOLFIRI every 2 weeks. Seventy-eight potential protein biomarkers were chosen for analysis based on their roles in angiogenesis, tumor progression, and tumor-stroma interaction. Plasma levels of biomarkers at baseline and at pre-dose 3 (day 1 of treatment cycle 3) were measured in all patients by ELISA. Relationships between these levels and efficacy endpoints were assessed. Ten potential biomarkers had a ±30% change from baseline to pre-dose 3 (adjusted P < .001), with the greatest changes occurring in placental growth factor (median: +4716%) and vascular endothelial growth factor receptor 1 (+2171%). Baseline levels of eight potential biomarkers correlated with overall survival in a univariate Cox regression analysis: extracellular newly identified receptor for advanced glycation end-products binding protein, insulin-like growth factor-binding protein 1, interleukin-8, kallikrein 5, pulmonary surfactant-associated protein D, tissue inhibitor of metalloproteinases 1, tenascin-C, and tumor necrosis factor receptor 2. None correlated with progression-free survival or maximum tumor shrinkage. Pre-dose 3 levels did not correlate with any efficacy endpoints. Preliminary data show that these eight biomarkers could be associated with overall survival. ClinicalTrials.gov identifier: NCT01882868.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/sangue , Camptotecina/análogos & derivados , Neoplasias do Colo/tratamento farmacológico , Receptores de Fatores de Crescimento do Endotélio Vascular/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Neoplasias Retais/tratamento farmacológico , Grupo com Ancestrais do Continente Asiático , Camptotecina/uso terapêutico , Neoplasias do Colo/sangue , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Fluoruracila/uso terapêutico , Humanos , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Interleucina-8/sangue , Japão , Calicreínas/sangue , Leucovorina/uso terapêutico , Fator de Crescimento Placentário/sangue , Prognóstico , Intervalo Livre de Progressão , Estudos Prospectivos , Proteína D Associada a Surfactante Pulmonar/sangue , Receptor para Produtos Finais de Glicação Avançada/sangue , Receptores Tipo II do Fator de Necrose Tumoral/sangue , Neoplasias Retais/sangue , Neoplasias Retais/mortalidade , Neoplasias Retais/patologia , Análise de Regressão , Tenascina/sangue , Inibidor Tecidual de Metaloproteinase-1/sangue , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue
7.
Cancer Immunol Immunother ; 68(9): 1547-1559, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31482307

RESUMO

Engineered cytokine products represent promising agents for the treatment of immunogenic tumors, such as malignant melanoma, in addition to immune checkpoint inhibitors. Here we describe the results of a controlled, randomized phase II clinical trial, aimed at assessing the therapeutic potential of L19IL2, a fully human fusion protein consisting of the L19 antibody specific to the alternatively spliced extra-domain B of fibronectin, fused to human interleukin-2 in advanced metastatic melanoma. In one arm, patients received dacarbazine (DTIC; 1000 mg/m2 of body surface on day 1 of 21-day cycles) as single agent, while in two other arms L19IL2 (22.5 million international units of IL2 equivalents) was added, based on two different schedules of administration. In total, 69 patients with stage IV melanoma were enrolled (24 in the dacarbazine arm, 23 and 22 in the other combination arms, respectively) and 67 received treatment. Analyses of efficacy results show a statistically significant benefit in terms of overall response rate and median progression-free survival for patients receiving L19IL2 in combination with DTIC, compared to DTIC as single agent. In light of these results, further clinical investigations with L19IL2 (alone or in combination with other agents) are warranted.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dacarbazina/uso terapêutico , Melanoma/terapia , Proteínas Recombinantes de Fusão/uso terapêutico , Neoplasias Cutâneas/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Melanoma/mortalidade , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Cutâneas/mortalidade , Análise de Sobrevida , Adulto Jovem
8.
Lancet Haematol ; 6(11): e562-e572, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31474546

RESUMO

BACKGROUND: Aplastic anaemia is a rare, life-threatening condition, characterised by pancytopenia with hypocellular bone marrow. Haematopoietic stem cells and most progenitor cells express thrombopoietin receptor (c-MPL). Romiplostim is a peptibody with c-MPL agonist activity that stimulates endogenous thrombopoietin production and leads to promoting the proliferation and differentiation of megakaryocytes in the bone marrow. In this phase 2 trial we aimed to assess the activity and safety of romiplostim in patients with aplastic anaemia who were previously treated with immunosuppressive therapy. METHODS: We did an open-label, phase 2 study including a randomised, parallel, dose-finding part followed by an extension part to evaluate long-term treatment at two clinical centres in Seoul, South Korea. Eligible patients were aged 19 years or older, and had aplastic anaemia confirmed by bone marrow and cytogenetic studies and thrombocytopenia (platelet count ≤30 × 109/L), an Eastern Cooperative Oncology Group performance status score of 2 or lower, and were previously treated with immunosuppressive therapy, including at least one course of antithymocyte globulin plus cyclosporin. In the dose-finding part, patients were randomly assigned to fixed dose cohorts (1, 3, 6, or 10 µg/kg) of subcutaneous romiplostim once weekly for 8 weeks, according to a static allocation procedure after stratification by platelet count. In the extension part of the study, patients continued romiplostim titrated every 4 weeks in single steps (1, 3, 6, 10, 13, 16, and 20 µg/kg once weekly), depending on platelet response and safety up to 1 year (weeks 9-52). Patients who had a platelet response during weeks 46-53 continued dose titration in single steps (3, 6, 10, 13, 16, and 20 µg/kg once weekly) for an additional 2 years (weeks 53-156). The primary endpoint was the proportion of patients achieving a platelet response at week 9 (after completion of the dose-finding part). Activity was assessed per-protocol in all patients evaluable for response at week 9 and safety was assessed in all patients who received at least one dose of romiplostim. This trial is registered with ClinicalTrials.gov, NCT02094417. FINDINGS: Between April 14 and Nov 24, 2014, 35 patients were enrolled and randomly assigned to one of four dose cohorts: romiplostim 1 µg/kg (n=7), 3 µg/kg (n=9), 6 µg/kg (n=9), and 10 µg/kg (n=10). Data cutoff for this final analysis was on April 14, 2018. The median duration of treatment for all patients was 53 weeks (IQR 35-155). Ten (30%) of 33 evaluable patients achieved a platelet response at week 9, including seven (70%) of ten patients in the 10 µg/kg cohort, three (33%) of nine patients in the 6 µg/kg cohort, and no patients in both the 3 µg/kg and 1 µg/kg cohorts. During the extension study, 18 (55%) of 33 evaluable patients had a platelet response during weeks 46-53 and were eligible for continued treatment. Ten (30%) patients maintained a platelet response at 2 and 3 years, of whom nine had an erythroid response and five a neutrophil response, and completed protocol treatment. Treatment-related adverse events occurred in three (9%) of 35 patients, including grade 1 or 2 myalgia, fatigue, and dizziness. 17 (49%) of 35 patients had adverse events of grade 3 or higher; seven (20%) had serious adverse events (one event of febrile neutropenia, cataract, retinal detachment, macular fibrosis, inguinal hernia, appendicitis, cellulitis, tendon injury, and transfusion reaction); and one patient died from sepsis during treatment; none of these events were related to treatment. No patients developed clonal evolution. INTERPRETATION: Romiplostim seems to be active and has a favourable safety profile in patients with refractory aplastic anaemia. 10 µg/kg once weekly might be used as a recommended starting dose in future studies. These findings warrant further investigation. FUNDING: Kyowa Hakko Kirin Korea.


Assuntos
Anemia Aplástica/tratamento farmacológico , Receptores Fc/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Trombopoetina/uso terapêutico , Adulto , Plaquetas/citologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Mialgia/etiologia , Neutrófilos/citologia , Proteínas Recombinantes de Fusão/efeitos adversos , Trombopoetina/efeitos adversos , Resultado do Tratamento
9.
Ophthalmic Surg Lasers Imaging Retina ; 50(8): 510-513, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31415698

RESUMO

BACKGROUND AND OBJECTIVE: To describe a novel, simple technique for surgically draining a bullous serous pigment epithelial detachment (PED). PATIENTS AND METHODS: Pars plana vitrectomy was performed with confirmed elevation of the hyaloid face. Proportional diathermy allowed stepwise entry into the PED superotemporally through an initially small, needle-point focus while providing control of any potential bleeding. Thick fluid was aspirated with a soft-tipped cannula, fluid-air exchange was performed, and intravitreal bevacizumab was injected before removing the cannulas. RESULTS: The PED was successfully completely drained intraoperatively and remained flat at 1 week postoperatively. However, the draining site ultimately closed, and continued exudation from choroidal neovascularization led to recurrent PED and eventual nonhemorrhagic retinal pigment epithelial tear despite aggressive treatment with aflibercept and photodynamic therapy. The early visual acuity benefit may relate to resolution of hyperopic shift. CONCLUSION: Serous PED can be surgically reduced without hemorrhagic complications, but long-term success depends upon control of the underlying choroidal neovascularization. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:510-513.].


Assuntos
Descolamento Retiniano/cirurgia , Epitélio Pigmentado da Retina/cirurgia , Vitrectomia/métodos , Idoso , Inibidores da Angiogênese/uso terapêutico , Bevacizumab/uso terapêutico , Neovascularização de Coroide/etiologia , Feminino , Humanos , Fotoquimioterapia/métodos , Receptores de Fatores de Crescimento do Endotélio Vascular/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Descolamento Retiniano/tratamento farmacológico
10.
J Immunol Res ; 2019: 8535273, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31467935

RESUMO

Background: Age-related macular degeneration (AMD), the most common cause of blindness in the developed world, usually affects individuals older than 60 years of age. The majority of visual loss in this disease is attributable to the development of choroidal neovascularization (CNV). Mononuclear phagocytes, including monocytes and their tissue descendants, macrophages, have long been implicated in the pathogenesis of neovascular AMD (nvAMD). Current therapies for nvAMD are based on targeting vascular endothelial growth factor (VEGF). This study is aimed at assessing if perturbation of chemokine signaling and mononuclear cell recruitment may serve as novel complementary therapeutic targets for nvAMD. Methods: A promiscuous chemokine antagonist (BKT130), aflibercept treatment, or combined BKT130+aflibercept treatment was tested in an in vivo laser-induced model of choroidal neovascularization (LI-CNV) and in an ex vivo choroidal sprouting assay (CSA). Quantification of CD11b+ cell in the CNV area was performed, and mRNA levels of genes implicated in CNV growth were measured in the retina and RPE-choroid. Results: BKT130 reduced the CNV area and recruitment of CD11b+ cells by 30-35%. No effect of BKT130 on macrophages' proangiogenic phenotype was demonstrated ex vivo, but a lower VEGFA and CCR2 expression was found in the RPE-choroid and a lower expression of TNFα and NOS1 was found in both RPE-choroid and retinal tissues in the LI-CNV model under treatment with BKT130. Conclusions: Targeting monocyte recruitment via perturbation of chemokine signaling can reduce the size of experimental CNV and should be evaluated as a potential novel therapeutic modality for nvAMD.


Assuntos
Quimiocinas/antagonistas & inibidores , Neovascularização de Coroide/tratamento farmacológico , Monócitos/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Animais , Antígeno CD11b/metabolismo , Movimento Celular/efeitos dos fármacos , Quimiocinas/metabolismo , Neovascularização de Coroide/etiologia , Neovascularização de Coroide/metabolismo , Neovascularização de Coroide/patologia , Feminino , Humanos , Lasers , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Monócitos/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , Ratos , Ratos Long-Evans , Receptores CCR2/metabolismo , Receptores de Fatores de Crescimento do Endotélio Vascular/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Retina/metabolismo , Retina/patologia , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
11.
BMC Ophthalmol ; 19(1): 157, 2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31337360

RESUMO

PURPOSE: To investigate the dynamic changes of hyperreflective foci (HF) in diabetic macular edema (DME) patients during the intravitreal Conbercept treatment in China. METHODS: DME Patients receiving intravitreal Conbercept (IVC) injections during the year 2016-2017 were retrospectively investigated. Thirteen patients (26 eyes) were recruited in this study. They received IVC once a month for 3 consecutive months. The number and location of HFs, the best-corrected visual acuity (BCVA) and central macular thickness (CMT) at each visit were analyzed and compared. RESULTS: After the first injection, BCVA (LogMAR) was increased from 0.75 ± 0.48 to 0.43 ± 0.24 (p < 0.05), CMT improved from 575.9 ± 191.9 to 388.2 ± 198.5 µm (p = 0.014). However, the BCVA and CMT had no statistical difference after the second and third injection as compared with those after the first injection respectively. The baseline number of HFs was 5.39 ± 4.24, 5.15 ± 5.17 and 0.88 ± 1.90 in the inner retinal, outer retinal and subretinal layer respectively. The number of HFs in these three retinal layers decreased significantly after the first injection (p = 0.0045, p < 0.0001 and p = 0.0045, respectively). However, after the second injection, only the number of HFs in the inner retinal layer experienced a further decrease. After the third injection, no statistically significant HFs changes was observed in each retinal layers. Correlation analysis showed that there was a positive significant correlation between the baseline number of HFs in the inner retina, outer retina, subretina and final BCVA (r = 0.571, p = 0.002; r = 0.464, p = 0.017; r = 0.405, p = 0.04 respectively). There was also a significant positive correlation between outer retinal HFs reduction, total retinal HFs reduction and increase of BCVA (r = 0.40, p = 0.043 and r = 0.393, p = 0.04 respectively). There were no severe ocular adverse reactions or systemic adverse events. CONCLUSIONS: Conbercept is effective and safe in the treatment of DME. HFs can act as a biomarker of poor final visual outcome.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Retinopatia Diabética/tratamento farmacológico , Edema Macular/tratamento farmacológico , Proteínas Recombinantes de Fusão/uso terapêutico , Tomografia de Coerência Óptica , Adulto , Idoso , Análise de Variância , Biomarcadores , China , Retinopatia Diabética/diagnóstico por imagem , Retinopatia Diabética/patologia , Feminino , Humanos , Injeções Intravítreas , Macula Lutea/patologia , Edema Macular/diagnóstico por imagem , Edema Macular/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Acuidade Visual
12.
Optom Vis Sci ; 96(7): 531-535, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31274742

RESUMO

SIGNIFICANCE: Perifoveal exudative vascular anomalous complex (PEVAC) is a recently described macular entity, which can be confused with other well-known vascular lesions such as retinal angiomatous proliferation. Perifoveal exudative vascular anomalous complex is more common than previously believed and is usually unresponsive to anti-vascular endothelial growth factor treatment. Clinicians should be aware of this disorder. PURPOSE: The purpose of this study was to report a case of PEVAC using multimodal imaging in a Chinese patient with diabetes mellitus but without diabetic retinopathy, followed by a brief review of the relevant literature. CASE REPORT: A 53-year-old Chinese woman with a 7-year history of diabetes mellitus presented with complaints of a 1-month history of deterioration of visual acuity in her right eye. Complete ophthalmic examination, including fundus examination of the right eye, revealed an isolated lesion immediately temporal to the fovea, accompanied by small hemorrhages and small, hard intraretinal exudates. Fluorescein fundus angiography revealed a well-defined hyperfluorescent lesion in the early phase but with leakage in the late phase. Optical coherence tomography revealed an oval lesion with a hyperreflective wall and relatively dark lumen, intraretinal cystic spaces, and hard exudates. Two intravitreal injections of aflibercept resulted in reduced blood flow in the PEVAC lesion, but with more hemorrhaging and hard exudates and no improvement in visual acuity. CONCLUSIONS: Perifoveal exudative vascular anomalous complex is an isolated, perifoveal, aneurysmal abnormality. It can occur in healthy patients, in addition to those with diabetes mellitus without retinopathy. In contrast to similar macular vascular anomalies, PEVAC does not typically respond to anti-vascular endothelial growth factor therapy.


Assuntos
Diabetes Mellitus/diagnóstico , Doenças Retinianas/diagnóstico , Vasos Retinianos/anormalidades , Malformações Vasculares/diagnóstico , Inibidores da Angiogênese/uso terapêutico , Grupo com Ancestrais do Continente Asiático , Exsudatos e Transudatos , Feminino , Angiofluoresceinografia/métodos , Fóvea Central , Humanos , Injeções Intravítreas , Pessoa de Meia-Idade , Imagem Multimodal , Receptores de Fatores de Crescimento do Endotélio Vascular/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Doenças Retinianas/tratamento farmacológico , Doenças Retinianas/fisiopatologia , Vasos Retinianos/diagnóstico por imagem , Tomografia de Coerência Óptica/métodos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Malformações Vasculares/tratamento farmacológico , Malformações Vasculares/fisiopatologia , Acuidade Visual/fisiologia
13.
Blood Coagul Fibrinolysis ; 30(6): 295-299, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31259778

RESUMO

: Thrombopoietin receptor agonists (TPO-RA) are currently approved to treat chronic immune thrombocytopenia (ITP) but there is increasing interest in considering these drugs earlier during the course of the disease. We present six patients with primary ITP resistant to corticosteroids and intravenous immunoglobulins, who received TPO-RA in the persistent phase and then underwent splenectomy in the chronic phase. Eltrombopag was administered as a second-line therapy in four patients, whereas two patients received romiplostim. Five out of six patients rapidly reached response or complete response (four and one, respectively) and steroid suspension. In one case, remission was obtained with steroid and TPO-RA. No significant side effects were reported. After splenectomy, complete response and response was reached in four and two patients, respectively. One relapse was recorded, rescued by steroid and eltrombopag. Postsplenectomy complication was registered in one patient (grade 4 intra-abdominal bleeding). TPO-RA could be a valuable choice in ITP patients in persistent phase candidates to splenectomy.


Assuntos
Benzoatos/uso terapêutico , Hidrazinas/uso terapêutico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Pirazóis/uso terapêutico , Receptores Fc/uso terapêutico , Receptores de Trombopoetina/agonistas , Proteínas Recombinantes de Fusão/uso terapêutico , Trombopoetina/uso terapêutico , Corticosteroides/farmacologia , Doença Crônica , Resistência a Medicamentos , Feminino , Humanos , Imunoglobulinas Intravenosas/farmacologia , Masculino , Púrpura Trombocitopênica Idiopática/cirurgia , Esplenectomia
14.
BMC Ophthalmol ; 19(1): 123, 2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31151389

RESUMO

BACKGROUNDS: To assess the changes in individual retinal layer thickness and visual function associated with gains in visual acuity after an intravitreal conbercept injection in the diabetic macular edema (DME) on spectral domain optical coherence tomography (SD-OCT) and microperimetry during 1-year follow-up. METHODS: Retrospective observational study. Twenty patients with clinically significant DME in the study eye were imaged by SD-OCT every 3 months and MP1 microperimeter in the third month while receiving anti-vascular endothelial growth factor (VEGF) (conbercept) treatment. In each patient, seven retinal layers were segmented in 98 scans covering a 6 mm × 6 mm area of the macula at baseline and during 1 year of treatment. An automatic, full-threshold microperimetry of the central field (10° × 10°, 40 stimulated points) with the MP1 microperimeter. Thickness and microperimetry changes were quantitatively measured and evaluated for their correlation with increases in visual acuity. RESULTS: Although thicknesses of the inner nuclear layer (INL) and the outer nuclear layer (ONL) were reduced the most after treatment (p < 0.05), decreases of the ganglion cell layer (GCL) (r = 0.591, p = 0.006) and inner plexiform layer (IPL) (r = 0.663, p = 0.001) in central subfield area was associated with best-corrected visual acuity (BCVA) gain, and had the best estimation of BCVA gain (adjust R2 = 0.544). Mean macular sensitivity in the central subfield was also well correlated with BCVA gain (r = 0.531, p = 0.016). CONCLUSIONS: Neural recovery occurred after the resolution of edema during conbercept treatment, due to the decreases in GCL and IPL associating with gains in vision and improved microperimetry.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Retinopatia Diabética/tratamento farmacológico , Edema Macular/tratamento farmacológico , Proteínas Recombinantes de Fusão/uso terapêutico , Retina/patologia , Acuidade Visual/fisiologia , Idoso , Retinopatia Diabética/fisiopatologia , Feminino , Humanos , Macula Lutea/fisiologia , Edema Macular/fisiopatologia , Masculino , Pessoa de Meia-Idade , Células Ganglionares da Retina/patologia , Estudos Retrospectivos
17.
Lancet ; 394(10193): 131-138, 2019 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-31189509

RESUMO

BACKGROUND: Two glucagon-like peptide-1 (GLP-1) receptor agonists reduced renal outcomes in people with type 2 diabetes at risk for cardiovascular disease. We assessed the long-term effect of the GLP-1 receptor agonist dulaglutide on renal outcomes in an exploratory analysis of the REWIND trial of the effect of dulaglutide on cardiovascular disease. METHODS: REWIND was a multicentre, randomised, double-blind, placebo-controlled trial at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo and followed up at least every 6 months for outcomes. Urinary albumin-to-creatinine ratios (UACRs) and estimated glomerular filtration rates (eGFRs) were estimated from urine and serum values measured in local laboratories every 12 months. The primary outcome (first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes), secondary outcomes (including a composite microvascular outcome), and safety outcomes of this trial have been reported elsewhere. In this exploratory analysis, we investigate the renal component of the composite microvascular outcome, defined as the first occurrence of new macroalbuminuria (UACR >33·9 mg/mmol), a sustained decline in eGFR of 30% or more from baseline, or chronic renal replacement therapy. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01394952. FINDINGS: Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). At baseline, 791 (7·9%) had macroalbuminuria and mean eGFR was 76·9 mL/min per 1·73 m2 (SD 22·7). During a median follow-up of 5·4 years (IQR 5·1-5·9) comprising 51 820 person-years, the renal outcome developed in 848 (17·1%) participants at an incidence rate of 3·5 per 100 person-years in the dulaglutide group and in 970 (19·6%) participants at an incidence rate of 4·1 per 100 person-years in the placebo group (hazard ratio [HR] 0·85, 95% CI 0·77-0·93; p=0·0004). The clearest effect was for new macroalbuminuria (HR 0·77, 95% CI 0·68-0·87; p<0·0001), with HRs of 0·89 (0·78-1·01; p=0·066) for sustained decline in eGFR of 30% or more and 0·75 (0·39-1·44; p=0·39) for chronic renal replacement therapy. INTERPRETATION: Long-term use of dulaglutide was associated with reduced composite renal outcomes in people with type 2 diabetes. FUNDING: Eli Lilly and Company.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hipoglicemiantes/uso terapêutico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Idoso , Albuminúria/prevenção & controle , Creatinina/urina , Método Duplo-Cego , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade
18.
Lancet ; 394(10193): 121-130, 2019 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-31189511

RESUMO

BACKGROUND: Three different glucagon-like peptide-1 (GLP-1) receptor agonists reduce cardiovascular outcomes in people with type 2 diabetes at high cardiovascular risk with high glycated haemoglobin A1c (HbA1c) concentrations. We assessed the effect of the GLP-1 receptor agonist dulaglutide on major adverse cardiovascular events when added to the existing antihyperglycaemic regimens of individuals with type 2 diabetes with and without previous cardiovascular disease and a wide range of glycaemic control. METHODS: This multicentre, randomised, double-blind, placebo-controlled trial was done at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo. Randomisation was done by a computer-generated random code with stratification by site. All investigators and participants were masked to treatment assignment. Participants were followed up at least every 6 months for incident cardiovascular and other serious clinical outcomes. The primary outcome was the first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes (including unknown causes), which was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01394952. FINDINGS: Between Aug 18, 2011, and Aug 14, 2013, 9901 participants (mean age 66·2 years [SD 6·5], median HbA1c 7·2% [IQR 6·6-8·1], 4589 [46·3%] women) were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). During a median follow-up of 5·4 years (IQR 5·1-5·9), the primary composite outcome occurred in 594 (12·0%) participants at an incidence rate of 2·4 per 100 person-years in the dulaglutide group and in 663 (13·4%) participants at an incidence rate of 2·7 per 100 person-years in the placebo group (hazard ratio [HR] 0·88, 95% CI 0·79-0·99; p=0·026). All-cause mortality did not differ between groups (536 [10·8%] in the dulaglutide group vs 592 [12·0%] in the placebo group; HR 0·90, 95% CI 0·80-1·01; p=0·067). 2347 (47·4%) participants assigned to dulaglutide reported a gastrointestinal adverse event during follow-up compared with 1687 (34·1%) participants assigned to placebo (p<0·0001). INTERPRETATION: Dulaglutide could be considered for the management of glycaemic control in middle-aged and older people with type 2 diabetes with either previous cardiovascular disease or cardiovascular risk factors. FUNDING: Eli Lilly and Company.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hipoglicemiantes/uso terapêutico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Idoso , Doenças Cardiovasculares/mortalidade , Diabetes Mellitus Tipo 2/complicações , Método Duplo-Cego , Feminino , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/prevenção & controle , Acidente Vascular Cerebral/prevenção & controle
19.
BMJ Case Rep ; 12(6)2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31229978

RESUMO

A rare case of acquired amegakaryocytic thrombocytopenia (AATP) in a 35-year-old woman who presented with anaemia and thrombocytopenia at 22 weeks gestation. The first diagnostic impression was of an evolving aplastic anaemia; however, the patient was simultaneously diagnosed with severe vitamin B12 deficiency in the setting of vegetarianism. Once the cyanocobalamin deficiency was corrected, a repeat bone marrow biopsy revealed an isolated depletion of megakaryocytes, which suggested the diagnosis of AATP. Supportive care was provided for her anaemia and thrombocytopenia and she delivered a healthy baby girl with a normal platelet count. The patient was subsequently started on romiplostim with steady improvement in her platelet counts. This rare AATP case presentation highlights the importance of a well-structured diagnostic approach to thrombocytopenia during pregnancy and supports the successful use of thrombopoietin agonists for the management of AATP.


Assuntos
Doenças da Medula Óssea/complicações , Complicações Hematológicas na Gravidez/fisiopatologia , Púrpura Trombocitopênica/complicações , Receptores Fc/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Trombocitopenia/etiologia , Trombopoetina/uso terapêutico , Adulto , Doenças da Medula Óssea/fisiopatologia , Doenças da Medula Óssea/terapia , Cesárea , Feminino , Humanos , Contagem de Plaquetas , Gravidez , Complicações Hematológicas na Gravidez/terapia , Púrpura Trombocitopênica/fisiopatologia , Púrpura Trombocitopênica/terapia , Trombocitopenia/fisiopatologia , Trombocitopenia/terapia , Resultado do Tratamento
20.
Ophthalmic Surg Lasers Imaging Retina ; 50(6): 398-400, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31233159

RESUMO

Choroidal osteoma is a rare, classically unilateral tumor. Less than half of the cases are complicated by the onset of choroidal neovascularization (CNV). The authors describe a case of bilateral choroidal osteoma in a 10-year-old female patient complicated by the onset of bilateral CNV. The diagnosis was made by multimodal imaging and ultrasonography. Best-corrected visual acuity (BCVA) was 20/63 for the right eye (OD) and 20/25 for the left eye (OS). Interestingly, CNV OD resulted exudative, whereas no signs of fluid were detected OS. OCT angiography (OCTA) clearly detected the presence of CNV in both eyes. The patient underwent a single 1.0 mg/0.025 mL aflibercept injection OD. At follow-up, BCVA improved to 20/32 OD after 1 month and to 20/25 after 3 months, with no exudation recurrence. Both BCVA and imaging findings were unremarkable OS, thus suggesting the possible "quiescent" nature of this CNV. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:398-400.].


Assuntos
Coristoma/complicações , Neoplasias da Coroide/complicações , Neovascularização de Coroide/etiologia , Osteoma/complicações , Inibidores da Angiogênese/uso terapêutico , Criança , Neovascularização de Coroide/tratamento farmacológico , Feminino , Humanos , Receptores de Fatores de Crescimento do Endotélio Vascular/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Resultado do Tratamento
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