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1.
Klin Lab Diagn ; 64(11): 669-672, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31747495

RESUMO

There was reported the results of the use of recombinant interleukin-1ß in basic conservative measures in the surgical treatment of acute gastroduodenal ulcer bleeding. Gastric ulcer were in 20 patients, duodenal ulcer in 84 patients and combined ulcers in 16 patients. According to А.А. Шалимов hospitalized patients with mild blood loss were 27, moderate degree - 62 and severe degree - 31 patients. According to J. Forrest, 29 showed active bleeding (F Ia, F Ib), in 67 - unstable hemostasis (F IIa, F IIb, F IIc) and in 24 - F III. Within the framework of differentiated individual-active tactics, patients were operated in emergency (21), urgent (38), delayed (35), and 26 people underwent early planned operations. Patients in the main group (63) after the operation, was included recombinant interleukin-1ß to the basic therapeutic measures additionally, taking into account the degree of blood loss and immune disorders. Patients of comparison group (57) before and after surgery received standard basic therapy without immunocorrection. In a comparative aspect, it has been proved that in postoperative period on the background of standard conservative measures, the use of recombinant interleukin-1ß positively influences elimination of the secondary immunodeficiency and cytokine imbalance significantly improves the results of surgical treatment.


Assuntos
Úlcera Duodenal/cirurgia , Interleucina-1beta/uso terapêutico , Úlcera Gástrica/cirurgia , Úlcera Duodenal/tratamento farmacológico , Humanos , Período Pós-Operatório , Proteínas Recombinantes/uso terapêutico , Úlcera Gástrica/tratamento farmacológico
2.
J Craniofac Surg ; 30(7): e677-e679, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31574791

RESUMO

INTRODUCTION: Bone morphogenetic protein (BMP) is a signaling protein that has proven efficacy in the setting of bone repair. It has been widely used in orthopedic surgery and is being implemented more in the field of craniofacial surgery, although there is limited report on its use in pediatric patients. CASE: A 6-year-old female with stage IV neuroblastoma with metastasis to the parietal parasagittal calvarium, which had failed to respond to multiple medical therapies, including radiation therapy. The tumor was excised and the defect was replaced with a combination of split calvarial bone graft and rhBMP-2. The patient received post-operative radiation therapy with no reports of complications of the defect site on immediate and long term follow up. CONCLUSION: The use of BMP has the potential to aid in bone generation for high-risk calvarial defects. It can be safe and efficacious to use in the pediatric population; however, future studies should be done to determine the safest and most effective dosing of BMP.


Assuntos
Proteína Morfogenética Óssea 2/uso terapêutico , Crânio/cirurgia , Animais , Transplante Ósseo , Criança , Terapia Combinada , Feminino , Humanos , Período Pós-Operatório , Proteínas Recombinantes/uso terapêutico
3.
Rinsho Ketsueki ; 60(9): 1176-1185, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31597841

RESUMO

Although the Janus kinase (JAK) inhibitor ruxolitinib has long been the only drug licensed for treatment of the classic Philadelphia chromosome negative (Ph-) myeloproliferative neoplasms, years of drug development efforts have begun to bear fruit with the recent approval of a novel monopegylated interferon alfa-2b, ropeginterferon alfa, for patients with polycythemia vera without symptomatic splenomegaly in Europe. Several newer JAK inhibitors (fedratinib, pacritinib, momelotinib) have shown activity in phase 3 trials in patients with myelofibrosis but have, for various reasons, not yet received regulatory approval; all these agents, however, remain in active clinical development. Many other agents with diverse mechanisms of action are being explored in clinical trials in patients with myelofibrosis, both as single agents and in combination with ruxolitinib. Besides splenomegaly and symptoms, improvement of anemia has become a new focus of drug development in myelofibrosis. Ruxolitinib appears promising also in chronic neutrophilic leukemia, where mutations in CSF3R are common. Pemigatinib, a potent and selective inhibitor of fibroblast growth factor receptor (FGFR), has shown impressive efficacy in a small registration-directed trial in patients with FGFR1-rearranged myeloid/lymphoid neoplasms. Finally, avapritinib, a highly potent and selective inhibitor of KITD816V, has demonstrated unprecedented response rates in patients with advanced systemic mastocytosis.


Assuntos
Transtornos Mieloproliferativos/terapia , Mielofibrose Primária/terapia , Ensaios Clínicos Fase III como Assunto , Europa (Continente) , Humanos , Interferon alfa-2/uso terapêutico , Interferon-alfa/uso terapêutico , Policitemia Vera , Polietilenoglicóis/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Esplenomegalia
5.
BMC Infect Dis ; 19(1): 780, 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492102

RESUMO

BACKGROUND: Sepsis is still a common critical disease with high morbidity and mortality in intensive care unit. Despite published guidelines for sepsis, development of antibiotic therapy and advanced organ support technologies, the mortality of sepsis patients is still 25% or more. It is necessary to distinguish the subtypes of sepsis, and the targeted therapy for the patients need to be explored. Platelets have various biological functions in hemostasis and thrombosis, host defense, inflammatory/immune responses and tissue repair/regeneration. Moreover, severe thrombocytopenia or sustained thrombocytopenia was closely associated with multiply organ dysfunction and higher mortality in sepsis patients. The clinical therapies for thrombocytopenia are platelet transfusion and platelet-elevating drugs. However, platelet transfusion has many defects in clinical practice in sepsis patients, and the impact of platelet-elevating drugs for sepsis patients is still unclear. RESCUE trial is aim to explore the effect of a platelet-elevating drug, recombinant human thrombopoietin (rhTPO), as an effective rescue therapy on sepsis patients with acute severe thrombocytopenia. METHODS: It is a randomized, open-label, multi-center, controlled trial in 5 tertiary academic hospitals including medical, surgical or general ICUs. In this study, a total of 200 sepsis patients with severe thrombocytopenia will be randomly assigned in a 1:1 ratio to the control and rhTPO group. The patients will be followed up to 28 days after randomization. All patients in two groups receive the same treatment based on the guideline of Surviving Sepsis Campaign. Primary outcome is 28-day mortality. Secondary outcomes are the changes of PCs, blood transfusion, biomarkers of infection and organ function, days free from advanced organ support, drug-related adverse events, the length of ICU and hospital stay. DISCUSSION: RESCUE trial is the first randomized controlled trial to explore the impact of rhTPO for severe thrombocytopenia in sepsis patients diagnosed by sepsis-3.0 standard. Furthermore, RESCUE trial results will be of significant clinical value on the targeted therapy and add clinical evidence that rhTPO is an effective rescue therapy for these sepsis patients. TRIAL REGISTRATION: ClinicalTrials.gov : NCT02707497. Registered Date: March 3rd, 2016. Protocol Version 3. Protocol Date: January 25th, 2019.


Assuntos
Sepse/complicações , Sepse/tratamento farmacológico , Trombocitopenia/complicações , Trombocitopenia/tratamento farmacológico , Trombopoetina/uso terapêutico , Doença Aguda , Adulto , Idoso , Transfusão de Sangue/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade , Contagem de Plaquetas , Proteínas Recombinantes/uso terapêutico , Terapia de Salvação , Sepse/sangue , Sepse/mortalidade , Índice de Gravidade de Doença , Trombocitopenia/sangue , Trombocitopenia/mortalidade , Resultado do Tratamento , Adulto Jovem
6.
N Engl J Med ; 381(10): 923-932, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31483963

RESUMO

BACKGROUND: Pulmonary alveolar proteinosis is a disease characterized by abnormal accumulation of surfactant in the alveoli. Most cases are autoimmune and are associated with an autoantibody against granulocyte-macrophage colony-stimulating factor (GM-CSF) that prevents clearing of pulmonary surfactant by alveolar macrophages. An open-label, phase 2 study showed some therapeutic efficacy of inhaled recombinant human GM-CSF in patients with severe pulmonary alveolar proteinosis; however, the efficacy in patients with mild-to-moderate disease remains unclear. METHODS: We conducted a double-blind, placebo-controlled trial of daily inhaled recombinant human GM-CSF (sargramostim), at a dose of 125 µg twice daily for 7 days, every other week for 24 weeks, or placebo in 64 patients with autoimmune pulmonary alveolar proteinosis who had a partial pressure of arterial oxygen (Pao2) while breathing ambient air of less than 70 mm Hg (or <75 mm Hg in symptomatic patients). Patients with severe pulmonary alveolar proteinosis (Pao2 <50 mm Hg) were excluded to avoid possible exacerbation of the disease in patients who were assigned to receive placebo. The primary end point was the change in the alveolar-arterial oxygen gradient between baseline and week 25. RESULTS: The change in the mean (±SD) alveolar-arterial oxygen gradient was significantly better in the GM-CSF group (33 patients) than in the placebo group (30 patients) (mean change from baseline, -4.50±9.03 mm Hg vs. 0.17±10.50 mm Hg; P = 0.02). The change between baseline and week 25 in the density of the lung field on computed tomography was also better in the GM-CSF group (between-group difference, -36.08 Hounsfield units; 95% confidence interval, -61.58 to -6.99, calculated with the use of the Mann-Whitney U test and the Hodges-Lehmann estimate of confidence intervals for pseudo-medians). Serious adverse events developed in 6 patients in the GM-CSF group and in 3 patients in the placebo group. CONCLUSIONS: In this randomized, controlled trial, inhaled recombinant human GM-CSF was associated with a modest salutary effect on the laboratory outcome of arterial oxygen tension, and no clinical benefits were noted. (Funded by the Japan Agency for Medical Research and Development and the Ministry of Health, Labor, and Welfare of Japan; PAGE ClinicalTrials.gov number, NCT02835742; Japan Medical Association Center for Clinical Trials number, JMA-IIA00205.).


Assuntos
Doenças Autoimunes/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Fatores Imunológicos/uso terapêutico , Proteinose Alveolar Pulmonar/tratamento farmacológico , Administração por Inalação , Adulto , Idoso , Autoanticorpos/sangue , Doenças Autoimunes/diagnóstico por imagem , Método Duplo-Cego , Esquema de Medicação , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos e Macrófagos/efeitos adversos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/efeitos adversos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Oxigênio/sangue , Proteinose Alveolar Pulmonar/diagnóstico por imagem , Proteinose Alveolar Pulmonar/imunologia , Capacidade de Difusão Pulmonar , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Fumar/efeitos adversos , Tomografia Computadorizada por Raios X , Teste de Caminhada
7.
Cancer Radiother ; 23(5): 449-465, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31400956

RESUMO

Nowadays, ionizing radiations have numerous applications, especially in medicine for diagnosis and therapy. Pharmacological radioprotection aims at increasing detoxification of free radicals. Radiomitigation aims at improving survival and proliferation of damaged cells. Both strategies are essential research area, as non-contained radiation can lead to harmful effects. Some advances allowing the comprehension of normal tissue injury mechanisms, and the discovery of related predictive biomarkers, have led to developing several highly promising radioprotector or radiomitigator drugs. Next to these drugs, a growing interest does exist for biotherapy in this field, including gene therapy and cell therapy through mesenchymal stem cells. In this review article, we provide an overview of the management of radiation damages to healthy tissues via gene or cell therapy in the context of radiotherapy. The early management aims at preventing the occurrence of these damages before exposure or just after exposure. The late management offers promises in the reversion of constituted late damages following irradiation.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos/métodos , Terapia Genética/métodos , Lesões por Radiação/prevenção & controle , Proteção Radiológica/métodos , Amifostina/uso terapêutico , Animais , Antioxidantes/uso terapêutico , Ensaios Clínicos como Assunto , Fracionamento da Dose de Radiação , Edição de Genes , Vetores Genéticos/uso terapêutico , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/uso terapêutico , Transplante de Células-Tronco Mesenquimais , Camundongos , Oxirredutases/genética , Oxirredutases/uso terapêutico , Lesões por Radiação/etiologia , Lesões por Radiação/terapia , Lesões Experimentais por Radiação/prevenção & controle , Lesões Experimentais por Radiação/terapia , Protetores contra Radiação/farmacologia , Protetores contra Radiação/uso terapêutico , Proteínas Recombinantes/genética , Proteínas Recombinantes/uso terapêutico , Fatores de Tempo
8.
Medicine (Baltimore) ; 98(32): e16592, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31393358

RESUMO

RATIONALE: Refractory nasopharyngeal carcinoma is challenging to treat and at present there is no standard treatment or any good choice. PATIENT CONCERNS: Although the three patients in our case reports had already underwent multiple treatments before, they still suffered from disease recurrence of nasopharyngeal carcinoma. DIAGNOSIS: They were diagnosed as refractory nasopharyngeal carcinoma. INTERVENTIONS: A continuous infusion of Endostar, an antiangiogenic agent, combined with chemotherapy and radiation therapy was given to treat the patients. OUTCOMES: Patients showed complete or partial response to the combined therapy as evidenced by regression of tumors and decrease in plasma Epstein-Barr virus (EBV) DNA load. LESSONS: Continuous infusions of Endostar in combination with chemotherapy and/or radiation therapy showed promising efficacy and safety. The combination therapy indicates a new approach to treat refractory nasopharyngeal carcinoma.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Endostatinas/uso terapêutico , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Proteínas Recombinantes/uso terapêutico , Adulto , Quimiorradioterapia/métodos , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/terapia , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/terapia
9.
N Engl J Med ; 381(8): 716-726, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31433919

RESUMO

BACKGROUND: Serelaxin is a recombinant form of human relaxin-2, a vasodilator hormone that contributes to cardiovascular and renal adaptations during pregnancy. Previous studies have suggested that treatment with serelaxin may result in relief of symptoms and in better outcomes in patients with acute heart failure. METHODS: In this multicenter, double-blind, placebo-controlled, event-driven trial, we enrolled patients who were hospitalized for acute heart failure and had dyspnea, vascular congestion on chest radiography, increased plasma concentrations of natriuretic peptides, mild-to-moderate renal insufficiency, and a systolic blood pressure of at least 125 mm Hg, and we randomly assigned them within 16 hours after presentation to receive either a 48-hour intravenous infusion of serelaxin (30 µg per kilogram of body weight per day) or placebo, in addition to standard care. The two primary end points were death from cardiovascular causes at 180 days and worsening heart failure at 5 days. RESULTS: A total of 6545 patients were included in the intention-to-treat analysis. At day 180, death from cardiovascular causes had occurred in 285 of the 3274 patients (8.7%) in the serelaxin group and in 290 of the 3271 patients (8.9%) in the placebo group (hazard ratio, 0.98; 95% confidence interval [CI], 0.83 to 1.15; P = 0.77). At day 5, worsening heart failure had occurred in 227 patients (6.9%) in the serelaxin group and in 252 (7.7%) in the placebo group (hazard ratio, 0.89; 95% CI, 0.75 to 1.07; P = 0.19). There were no significant differences between the groups in the incidence of death from any cause at 180 days, the incidence of death from cardiovascular causes or rehospitalization for heart failure or renal failure at 180 days, or the length of the index hospital stay. The incidence of adverse events was similar in the two groups. CONCLUSIONS: In this trial involving patients who were hospitalized for acute heart failure, an infusion of serelaxin did not result in a lower incidence of death from cardiovascular causes at 180 days or worsening heart failure at 5 days than placebo. (Funded by Novartis Pharma; RELAX-AHF-2 ClinicalTrials.gov number, NCT01870778.).


Assuntos
Doenças Cardiovasculares/mortalidade , Insuficiência Cardíaca/tratamento farmacológico , Relaxina/uso terapêutico , Vasodilatadores/uso terapêutico , Doença Aguda , Idoso , Pressão Sanguínea/efeitos dos fármacos , Progressão da Doença , Método Duplo-Cego , Feminino , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Hospitalização , Humanos , Incidência , Infusões Intravenosas , Masculino , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Relaxina/efeitos adversos , Relaxina/farmacologia , Falha de Tratamento , Vasodilatadores/efeitos adversos
10.
Clin Nucl Med ; 44(9): 714-718, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31162260

RESUMO

PURPOSE: We investigated the risk factors of indeterminate response (IDR) in patients who underwent recombinant human thyroid-stimulating hormone (rhTSH)-aided radioactive iodine therapy (RAIT). METHODS: A total of 128 patients with papillary thyroid cancer were included in this retrospective study. The patients were classified into excellent response and IDR groups based on follow-up diagnostic whole-body scintigraphy (WBS) and TSH-stimulated thyroglobulin (Tg). Indeterminate response was defined as the presence of a faint uptake in the thyroid bed on the diagnostic WBS or a TSH-stimulated Tg detectable, but less than 10 ng/mL. Parameters that act as significant risk factors for IDR, including age, sex, stage, surgeon, time interval between surgery and RAIT, post-treatment WBS finding, urine iodine-to-creatinine ratio, TSH-unstimulated Tg, and rhTSH-stimulated Tg, were analyzed using a Cox proportional hazards regression method. RESULTS: After treatment, 64 patients showed IDR. Recombinant human TSH-stimulated Tg was the only independent risk factor for predicting IDR. Patients with an rhTSH-stimulated Tg greater than 2 ng/mL prior to RAIT were 3.75 times more likely (95% confidence interval, 1.61-8.72) to have an IDR than those with a lower rhTSH-stimulated Tg (≤2 ng/mL). CONCLUSIONS: Pre-RAIT TSH-stimulated Tg levels are a risk factor for IDR after RAIT.


Assuntos
Radioisótopos do Iodo/uso terapêutico , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/radioterapia , Adulto , Terapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/uso terapêutico , Estudos Retrospectivos , Fatores de Risco , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/tratamento farmacológico , Tireotropina/uso terapêutico , Resultado do Tratamento , Imagem Corporal Total
11.
Cell Physiol Biochem ; 53(1): 87-100, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31204440

RESUMO

BACKGROUND/AIMS: Different components of the tumor microenvironment can be either tumor-promoting or tumor-suppressive agents depending on factors which are not fully understood. Fibulins are components of the extracellular matrix from different tissues and constitute a clear example of this dual function. In fact, fibulins may either support tumor growth or abolish progression of malignant cells depending on the crosstalk between tumor cells and their surrounding stroma through mechanisms that remain to be elucidated. Among all fibulins, fibulin-5 contains a particular structural hallmark which consists in the presence of a RGD motif within its architecture. Previous reports have highlighted the importance of the interaction of this motif with integrins, and not only in normal functions but also in a tumor context. METHODS: Site-Directed Mutagenesis technique was employed to introduce the change RGD to RGE (RGD-to-RGE) within Fbln5 cDNA sequence. Cell proliferation was measured using the MTT assay or by counting Ki-67 positive cell nuclei. Cell adhesion was analysed using culture plates coated with different extracellular matrix components. Cell invasion was evaluated using 24-well Matrigel-coated invasion chambers, and mammosphere formation was monitored using ultralow attachment culture plates. BALB/c mice were employed to induce subcutaneous tumors. RESULTS: The RGD-to-RGE change alters the capacity of breast cancer cells to adhere to different extracellular matrix proteins as well as to αvß3 and α5ß1 integrins, and promotes protumor effects using different cell-based assays. Moreover, 4T1 cells, a mouse breast cancer cell line model, shows an increased capacity to generate tumors when exogenously expresses fibulin-5 with a RGD-to-RGE change, and such capacity is similar to that shown for 4T1 cells with an interfered Fbln5 gene. CONCLUSION: These data highlight the importance of the RGD motif of fibulin-5 to induce antitumor effects and provide new insights into the involvement of fibulins in tumor processes.


Assuntos
Adesão Celular/efeitos dos fármacos , Proteínas da Matriz Extracelular/farmacologia , Oligopeptídeos/metabolismo , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células/efeitos dos fármacos , Proteínas da Matriz Extracelular/metabolismo , Proteínas da Matriz Extracelular/uso terapêutico , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Mutagênese Sítio-Dirigida , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Oligopeptídeos/genética , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Transplante Homólogo , Vimentina/metabolismo
12.
Anticancer Res ; 39(5): 2259-2264, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31092417

RESUMO

Disseminated intravascular coagulation (DIC) that occurs during cancer therapy prevents continuation of therapy, contributing to a worse prognosis. While recombinant human-soluble thrombomodulin (rhTM), a new DIC drug, has occasionally shown its efficacy in DIC associated with infection and blood cancer, its efficacy in patients with solid tumors has been unproven. This review presents the results on the efficacy and safety of rhTM as a DIC drug in patients with solid tumors that have been confirmed by the clinical data of three previous reports. The number of cases in each study was 101, 123 and 40. The respective DIC resolution rate was 34.0%, 35.2% and 32.5%, and the 28-day survival rate was 55.4%, 52.0% and 40.0%. Although comparison with other anti-DIC therapies is required, rhTM therapy is considered one of the treatment options of DIC in patients with solid tumors.


Assuntos
Coagulação Intravascular Disseminada/tratamento farmacológico , Neoplasias/tratamento farmacológico , Proteínas Recombinantes/uso terapêutico , Trombomodulina/uso terapêutico , Coagulação Intravascular Disseminada/genética , Coagulação Intravascular Disseminada/patologia , Humanos , Neoplasias/genética , Neoplasias/patologia , Proteínas Recombinantes/genética , Trombomodulina/genética , Resultado do Tratamento
13.
J Craniofac Surg ; 30(7): 1952-1959, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31107382

RESUMO

Large defects of the craniofacial skeleton can be exceedingly difficult to reconstruct since autologous bone grafts are limited by donor site morbidity and alloplastic implants have low biocompatibility. Bone morphogenetic proteins (BMPs) in craniofacial reconstruction have been used with mixed outcomes and complication concerns; however, results for specific indications have been promising.In alveolar clefts, cranial vault defects, mandibular defects, and rare Tessier craniofacial clefts, BMP-2 impregnated in collagen matrix was looked at as an alternative therapy for challenging cases. In cases where structural support was required, BMP-2 was used as part of a construct with bio-resorbable plates. Demineralized bone was added in certain cases.The authors described specific indications, detailed surgical techniques, and a review of the current literature regarding the use of BMP-2 in craniofacial reconstruction. BMP-2 is a viable option for craniofacial reconstruction to decrease donor-site morbidity or when alternatives are contraindicated. It is not recommended for routine use or in the oncologic setting but should currently be reserved as an alternative therapy for complex cases with limited options.Bone morphogenetic proteins are a promising, emerging option for complex craniofacial reconstruction. Future directions of BMP-2 therapies will become apparent as data from prospective randomized trials emerges.


Assuntos
Proteína Morfogenética Óssea 2/uso terapêutico , Terapias Complementares , Fator de Crescimento Transformador beta/uso terapêutico , Transplante Ósseo/métodos , Colágeno/uso terapêutico , Humanos , Mandíbula/cirurgia , Estudos Prospectivos , Proteínas Recombinantes/uso terapêutico , Procedimentos Cirúrgicos Reconstrutivos , Crânio/cirurgia
14.
Cell Mol Life Sci ; 76(18): 3583-3600, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31129856

RESUMO

35 years since identification of HIV as the causative agent of AIDS, and 35 million deaths associated with this disease, significant effort is now directed towards the development of potential cures. Current anti-retroviral (ART) therapies for HIV/AIDS can suppress virus replication to undetectable levels, and infected individuals can live symptom free so long as treatment is maintained. However, removal of therapy allows rapid re-emergence of virus from a highly stable reservoir of latently infected cells that exist as a barrier to elimination of the infection with current ART. Prospects of a cure for HIV infection are significantly encouraged by two serendipitous cases where individuals have entered remission following stem cell transplantation from compatible HIV-resistant donors. However, development of a routine cure that could become available to millions of infected individuals will require a means of specifically purging cells harboring latent HIV, preventing replication of latent provirus, or destruction of provirus genomes by gene editing. Elimination of latently infected cells will require a means of exposing this population, which may involve identification of a natural specific biomarker or therapeutic intervention to force their exposure by reactivation of virus expression. Accordingly, the proposed "Shock and Kill" strategy involves treatment with latency-reversing agents (LRA) to induce HIV provirus expression thus exposing these cells to killing by cellular immunity or apoptosis. Current efforts to enable this strategy are directed at developing improved combinations of LRA to produce broad and robust induction of HIV provirus and enhancing the elimination of cells where replication has been reactivated by targeted immune modulation. Alternative strategies may involve preventing re-emergence virus from latently infected cells by "Lock and Block" intervention, where transcription of provirus is inhibited to prevent virus spread or disruption of the HIV provirus genome by genome editing.


Assuntos
Reservatórios de Doenças/virologia , Infecções por HIV/terapia , HIV-1/fisiologia , Antirretrovirais/uso terapêutico , Edição de Genes , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Humanos , Imunidade Celular , Imunoterapia , Proteínas Recombinantes/uso terapêutico , Latência Viral
15.
Cell Mol Life Sci ; 76(17): 3363-3381, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31101939

RESUMO

Mucopolysaccharidoses (MPSs), which are inherited lysosomal storage disorders caused by the accumulation of undegraded glycosaminoglycans, can affect the central nervous system (CNS) and elicit cognitive and behavioral issues. Currently used enzyme replacement therapy methodologies often fail to adequately treat the manifestations of the disease in the CNS and other organs such as bone, cartilage, cornea, and heart. Targeted enzyme delivery systems (EDSs) can efficiently cross biological barriers such as blood-brain barrier and provide maximal therapeutic effects with minimal side effects, and hence, offer great clinical benefits over the currently used conventional enzyme replacement therapies. In this review, we provide comprehensive insights into MPSs and explore the clinical impacts of multimodal targeted EDSs.


Assuntos
Terapia de Reposição de Enzimas , Doenças por Armazenamento dos Lisossomos/terapia , Mucopolissacaridoses/terapia , Barreira Hematoencefálica/metabolismo , Moléculas de Adesão Celular/metabolismo , Portadores de Fármacos/química , Glucosilceramidase/genética , Glucosilceramidase/metabolismo , Glucosilceramidase/uso terapêutico , Humanos , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/uso terapêutico
16.
JAMA ; 321(20): 1993-2002, 2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-31104069

RESUMO

Importance: Previous research suggested that soluble human recombinant thrombomodulin may reduce mortality among patients with sepsis-associated coagulopathy. Objective: To determine the effect of human recombinant thrombomodulin vs placebo on 28-day all-cause mortality among patients with sepsis-associated coagulopathy. Design, Setting, and Participants: The SCARLET trial was a randomized, double-blind, placebo-controlled, multinational, multicenter phase 3 study conducted in intensive care units at 159 sites in 26 countries. All adult patients admitted to one of the participating intensive care units between October 2012 and March 2018 with sepsis-associated coagulopathy and concomitant cardiovascular and/or respiratory failure, defined as an international normalized ratio greater than 1.40 without other known etiology and a platelet count in the range of 30 to 150 × 109/L or a greater than 30% decrease in platelet count within 24 hours, were considered for inclusion. The final date of follow-up was February 28, 2019. Interventions: Patients with sepsis-associated coagulopathy were randomized and treated with an intravenous bolus or a 15-minute infusion of thrombomodulin (0.06 mg/kg/d [maximum, 6 mg/d]; n = 395) or matching placebo (n = 405) once daily for 6 days. Main Outcome and Measures: The primary end point was 28-day all-cause mortality. Results: Among 816 randomized patients, 800 (mean age, 60.7 years; 437 [54.6%] men) completed the study and were included in the full analysis set. In these patients, the 28-day all-cause mortality rate was not statistically significantly different between the thrombomodulin group and the placebo group (106 of 395 patients [26.8%] vs 119 of 405 patients [29.4%], respectively; P = .32). The absolute risk difference was 2.55% (95% CI, -3.68% to 8.77%). The incidence of serious major bleeding adverse events (defined as any intracranial hemorrhage; life-threatening bleeding; or bleeding event classified as serious by the investigator, with administration of at least 1440 mL [typically 6 units] of packed red blood cells over 2 consecutive days) was 23 of 396 patients (5.8%) in the thrombomodulin group and 16 of 404 (4.0%) in the placebo group. Conclusions and Relevance: Among patients with sepsis-associated coagulopathy, administration of a human recombinant thrombomodulin, compared with placebo, did not significantly reduce 28-day all-cause mortality. Trial Registration: ClinicalTrials.gov Identifier: NCT01598831.


Assuntos
Anticoagulantes/uso terapêutico , Transtornos da Coagulação Sanguínea/tratamento farmacológico , Sepse/complicações , Trombomodulina/uso terapêutico , Idoso , Transtornos da Coagulação Sanguínea/etiologia , Transtornos da Coagulação Sanguínea/mortalidade , Causas de Morte , Feminino , Humanos , Infusões Intravenosas , Injeções Intravenosas , Coeficiente Internacional Normatizado , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/uso terapêutico , Falha de Tratamento
17.
Haemophilia ; 25(3): 398-407, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31066174

RESUMO

INTRODUCTION: Standard treatment of congenital haemophilia A is based on replacement therapy with coagulation factor VIII (FVIII) products. A major complication of FVIII therapy is the occurrence of IgG alloantibodies (inhibitors) that neutralize FVIII activity. AIM: The aim of the analysis was estimating the risk of high-titre inhibitor associated with the second-generation full-length product compared to third-generation full-length product and other recombinant FVIII (rFVIII). METHODS: We conducted a combined analysis of individual patient data from three large studies in previously untreated patients (PUPs) with severe haemophilia A. RESULTS: A total of 1109 PUPs were treated from 1993 to 2013 including 787 PUPs treated from 2004 onwards (primary analysis cohort). A total of 322 patients (29.0%) developed an inhibitor, of which 192 (17.3%) a high-titre inhibitor. In the primary analysis set, 29.9% of patients developed an inhibitor and 17.2% a high-titre inhibitor. The combined analysis indicated a lower risk of high-titre inhibitor development for the third-generation rFVIII product compared to the second-generation rFVIII product (primary analysis: adjusted hazard ratio (HR) = 0.72, 95% CI: 0.49 to 1.06). Adjusted HR for all inhibitor development was significantly lower for the third-generation product compared to the second-generation product. CONCLUSION: The trend of an increased risk of inhibitor development in PUPs for one recombinant product illustrates that extrapolation from one recombinant factor VIII product to other products might not be justified.


Assuntos
Fator VIII/imunologia , Fator VIII/uso terapêutico , Hemofilia A/tratamento farmacológico , Hemofilia A/imunologia , Proteínas Recombinantes/uso terapêutico , Humanos , Fatores de Risco
18.
Virol J ; 16(1): 61, 2019 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-31064399

RESUMO

BACKGROUND: Hepatitis B e antigen (HBeAg) seroconversion represents an endpoint of treatment of chronic hepatitis B virus (HBV) infections. METHODS: We have studied whether levels of serum hepatitis B virus ribonucleic acid (HBV RNA) during pegylated interferon alfa-2a treatment might be helpful for predicting HBeAg seroconversion. 61 HBeAg-positive chronic hepatitis B (CHB) patients treated with pegylated interferon alfa-2a alone or in combination with adefovir (10 mg/day) for 48 weeks were included in this retrospective analysis. Response was defined as HBeAg seroconversion at 24 weeks posttreatment. Receiver operating characteristic analyses were used to identify baseline and on-treatment HBV RNA levels associated with response. RESULTS: Twenty-two of 61 (36.1%) patients achieved a response. Baseline HBV RNA levels were lower in responders than in nonresponders (4.55 ± 1.19 and 5.90 ± 1.13 copies/mL, respectively, P = 0.001). Baseline HBV RNA cut off level (200,000 copies/mL) provided a positive predictive value (PPV) of 56.0% and a negative predictive value (NPV) of 77.8%. HBV RNA level (3000 copies/mL) at week 12 provide a PPV of 75.0% and a NPV of 82.8%. Moreover, HBeAg seroconversion rates at 24 weeks posttreatment were significantly higher in patients with HBV RNA ≤ 200,000 copies/mL at baseline and HBV RNA ≤ 3000 copies/mL at week 12 (92.9%) versus others (12.5%) (All P < 0.05). CONCLUSIONS: In Conclusions, serum HBV RNA levels may serve as a novel tool for prediction of HBeAg seroconversion during therapy with pegylated interferon alfa-2a in HBeAg-positive CHB patients.


Assuntos
Antivirais/uso terapêutico , DNA Viral/sangue , Antígenos E da Hepatite B/sangue , Hepatite B Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Adenina/análogos & derivados , Adenina/uso terapêutico , Adulto , Feminino , Vírus da Hepatite B/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Organofosfonatos/uso terapêutico , Curva ROC , Proteínas Recombinantes/uso terapêutico , Estudos Retrospectivos , Soroconversão , Adulto Jovem
19.
BMC Gastroenterol ; 19(1): 65, 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31046700

RESUMO

BACKGROUND: Pegylated interferon (PEG-IFN) alfa-2b is recommended for chronic hepatitis B (CHB). We aimed to investigate the sustainability of off-treatment responses among Chinese HBeAg-positive CHB patients treated with PEG-IFN alfa-2b from a randomized trial. METHODS: Eligible Chinese patients (n = 322) were followed up by one visit after a median of 6 years (LTFU) following their participation in a randomized trial evaluating the efficacy of three PEG-IFN alfa-2b dosing regimens (1.0 or 1.5 µg/kg/wk. 24 weeks or 1.5 µg/kg/wk. 48 weeks). Primary endpoints at the LTFU were sustained SR and CR (SR/CR at the end of original study [EOS] and at the LTFU). SR was defined as HBeAg loss and seroconversion to anti-HBe and CR as HBeAg loss and seroconversion to anti-HBe and HBV-DNA < 2000 IU/mL. RESULTS: The proportions of patients achieving sustained SR among patients who had SR at EOS were high in three treatment groups (61.9, 65.5, 76.5%, respectively, p = 0.46); treatment with PEG-IFN alfa-2b 1.5 µg/kg/wk. 48 weeks had the highest proportion of a sustained CR among patients who had CR at EOS (75.0%, p = 0.05). A considerable number of patients achieved sustained SR (18.2-29.9%) and sustained CR (14.8-18.3%) after EOS despite no further NA treatment. At the LTFU, rates of SR and CR were less than 70.0 and 50.0%, respectively, among all enrolled patients regardless of additional nucleos(t)ide analogs before the LTFU. CONCLUSIONS: PEG IFN alfa-2b therapy had considerable off-treatment sustainability in Chinese HBeAg positive chronic hepatitis B patients with serological and complete responses.


Assuntos
Antivirais/uso terapêutico , Antígenos E da Hepatite B/sangue , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/virologia , Interferon alfa-2/uso terapêutico , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Resposta Viral Sustentada , Adulto , Antivirais/administração & dosagem , China , Feminino , Seguimentos , Hepatite B Crônica/sangue , Humanos , Interferon alfa-2/administração & dosagem , Interferon-alfa/administração & dosagem , Masculino , Polietilenoglicóis/administração & dosagem , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Adulto Jovem
20.
Nat Commun ; 10(1): 1785, 2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-31040271

RESUMO

Lysosomal replacement enzymes are essential therapeutic options for rare congenital lysosomal enzyme deficiencies, but enzymes in clinical use are only partially effective due to short circulatory half-life and inefficient biodistribution. Replacement enzymes are primarily taken up by cell surface glycan receptors, and glycan structures influence uptake, biodistribution, and circulation time. It has not been possible to design and systematically study effects of different glycan features. Here we present a comprehensive gene engineering screen in Chinese hamster ovary cells that enables production of lysosomal enzymes with N-glycans custom designed to affect key glycan features guiding cellular uptake and circulation. We demonstrate distinct circulation time and organ distribution of selected glycoforms of α-galactosidase A in a Fabry disease mouse model, and find that an α2-3 sialylated glycoform designed to eliminate uptake by the mannose 6-phosphate and mannose receptors exhibits improved circulation time and targeting to hard-to-reach organs such as heart. The developed design matrix and engineered CHO cell lines enables systematic studies towards improving enzyme replacement therapeutics.


Assuntos
Lisossomos/enzimologia , Animais , Células CHO , Cricetinae , Cricetulus , Modelos Animais de Doenças , Doença de Fabry/tratamento farmacológico , Doença de Fabry/enzimologia , Doença de Fabry/metabolismo , Glicosilação , Masculino , Camundongos , Camundongos Knockout , Proteínas Recombinantes/uso terapêutico , alfa-Galactosidase/uso terapêutico
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