Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 10.717
Filtrar
1.
Expert Opin Drug Metab Toxicol ; 15(10): 779-785, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31593639

RESUMO

Introduction: Interferon (IFN) had both antiviral and immunomodulatory effects, and was one of the approved treatments for hepatitis B virus (HBV). Herein, we reviewed the pharmacokinetics and pharmacodynamics of pegylated IFN-α (PegIFN-α) for the treatment of HBV. Areas covered: The steady-state serum levels of PegIFN-α were reached within 5 to 8 weeks, and the week 48 mean trough concentrations were approximately 2-fold higher than week 1. There was also no difference of the pharmacokinetics in male or female, healthy volunteers or patients with hepatitis B or C infection. PegIFN-α did not affect the metabolism of the cytochrome P450 (CYP) isozymes, except inhibition of CYP1A2. There was also no pharmacokinetic interaction between PegIFN-α and HBV nucleot(s)ide analogues (NUCs). Forty-eight weeks of PegIFN-α achieved 32% of HBeAg seroconversion, 32-43% of HBV DNA suppression, 41-59% of ALT normalization, and 3% of HBsAg seroconversion rate with a post-treatment durable response up to 80% in the initial responders. Expert opinion: On-treatment HBsAg titer guided the treatment of HBV with PegIFN-α. The recommendation of PegIFN-α and NUC combination or switch remained controversial. New immunotherapeutic agents are now in development. Although, PegIFN-α should continue to play a role in the treatment of HBV.


Assuntos
Hepatite B Crônica/tratamento farmacológico , Interferon alfa-2/administração & dosagem , Interferon-alfa/administração & dosagem , Polietilenoglicóis/administração & dosagem , Animais , Antivirais/administração & dosagem , Antivirais/farmacocinética , Antivirais/farmacologia , DNA Viral/efeitos dos fármacos , Interações de Medicamentos , Feminino , Antígenos E da Hepatite B/sangue , Humanos , Interferon alfa-2/farmacocinética , Interferon alfa-2/farmacologia , Interferon-alfa/farmacocinética , Interferon-alfa/farmacologia , Masculino , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/farmacologia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/farmacologia
2.
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
3.
Bratisl Lek Listy ; 120(9): 668-672, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31475551

RESUMO

Restrospective study to evaluate the efficacy of early vs. delayed initiation of G-CSF after autologous hematopoietic stem cell transplantation (AHSCT) in patients with lymphoid malignancies. BACKGROUND: Granulocyte colony stimulating factor (G-CSF) is commonly used after AHSCT to accelerate stem cell engraftment to minimize the morbidity and mortality associated with prolonged neutropenia. However, there is no consensus on the optimal timing of G-CSF after HSCT. METHODS: A total of 117 patients with lymphoid malignancies who underwent AHSCT were included. All patients received G-CSF (filgrastim 5 µg/kg s.c.) daily after AHSCT (43 patients on day 6-8 and 74 patients on day 3 or 4). All patients received standard conditioning regimen for the underlying disease, and standard supportive treatment, including treatment of febrile neutropenia. RESULTS: The incidence of severe neutropenia was 81 % vs 17 %, and very severe neutropenia 61 % vs 4 % in the delayed and early G-CSF groups, respectively (p < 0.0001). The rate of fungal infection was higher in the group of patients who received delayed G-CSF (p < 0.005). CONCLUSION: An early administration of G-CSF after AHSCT (on day 3 or 4) accelerates neutophil engraftment; decreases the incidence of severe neutropenia and the risk of infectious complications (especially fungal infections) (Tab. 1, Fig. 3, Ref. 22).


Assuntos
Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Filgrastim/administração & dosagem , Humanos , Neutropenia/terapia , Neutrófilos/citologia , Proteínas Recombinantes/administração & dosagem , Condicionamento Pré-Transplante , Transplante Autólogo
4.
Life Sci ; 234: 116743, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31408660

RESUMO

AIMS: The present study aimed to investigate the mechanism of bone repair mediated by recombination BMP-2 (rhBMP-2)/recombination CXC chemokine ligand-13 (rhCXCL13)-loaded hollow hydroxyapatite (HA) microspheres/chitosan (CS) composite. MATERIALS AND METHODS: Firstly, the biological activity of rhBMP-2 and rhCXCL13 released from the complex was investigated. Secondly, the effect of rhBMP-2 sustained release solution on ALP activity and rhCXCL13 sustained release solution on cell migration of rat bone marrow mesenchyme stem cells was tested. Thirdly, osteoblasts differentiation test, X-ray scoring and three-point bending test were performed. Finally, the mRNAs expression of osteogenic marker genes and the protein expression of Runx2 was tested by reverse transcription-polymerase chain reaction (RT-PCR) and western blotting (WB), respectively. KEY FINDINGS: RhBMP-2 could significantly promote the proliferation and differentiation, and RhCXCL13 could promote the migration of rat bone marrow MSCs. Detection of ALP activity and calcium salt deposition showed that rhBMP-2 and rhCXCL13 could significantly improve the biological activity and promote cell differentiation ability. X-ray scoring of radius and flexural strength test showed that rhBMP-2 and rhCXCL13 could promote bone healing and improve the bending resistance of bone tissue. The in vitro molecular experiments including RT-PCR and WB further demonstrated the roles of rhBMP-2 and rhCXCL13 in bone formation and bone repair. SIGNIFICANCE: Our results indicated that the hollow HA microspheres/CS composite could be effective as a delivery vehicle for rhBMP-2 and rhCXCL13 in bone regeneration and bone repair. In this process, rhBMP-2 may promote bone regeneration by regulating bone marrow MSCs cells recruited by rhCXCL13.


Assuntos
Proteína Morfogenética Óssea 2/administração & dosagem , Quimiocina CXCL13/administração & dosagem , Quitosana/análogos & derivados , Preparações de Ação Retardada/química , Durapatita/química , Osteogênese/efeitos dos fármacos , Tecidos Suporte/química , Fator de Crescimento Transformador beta/administração & dosagem , Animais , Materiais Biocompatíveis/química , Proteína Morfogenética Óssea 2/farmacologia , Regeneração Óssea/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Quimiocina CXCL13/farmacologia , Humanos , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Coelhos , Ratos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacologia , Fator de Crescimento Transformador beta/farmacologia
5.
Adv Mater ; 31(33): e1902462, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31265196

RESUMO

The controlled presentation of proteins from and within materials remains of significant interest for many bioengineering applications. Though "smart" platforms offer control over protein release in response to a single external cue, no strategy has been developed to trigger delivery in response to user-specified combinations of environmental inputs, nor to independently control the release of multiple species from a homogenous material. Here, a modular semisynthetic scheme is introduced to govern the release of site-specifically modified proteins from hydrogels following Boolean logic. A sortase-mediated transpeptidation reaction is used to generate recombinant proteins C-terminally tethered to gels through environmentally sensitive degradable linkers. By varying the connectivity of multiple stimuli-labile moieties within these customizable linkers, YES/OR/AND control of protein release is exhaustively demonstrated in response to one and two-input combinations involving enzyme, reductant, and light. Tethering of multiple proteins each through a different stimuli-sensitive linker permits their independent and sequential release from a common material. It is expected that these methodologies will enable new opportunities in tissue engineering and therapeutic delivery.


Assuntos
Aminoaciltransferases/química , Proteínas de Bactérias/química , Materiais Biocompatíveis/química , Cisteína Endopeptidases/química , Sistemas de Liberação de Medicamentos/métodos , Hidrogéis/química , Proteínas Recombinantes/química , Aminoaciltransferases/administração & dosagem , Proteínas de Bactérias/administração & dosagem , Cisteína Endopeptidases/administração & dosagem , Dissulfetos/química , Liberação Controlada de Fármacos , Humanos , Luz , Oxirredução , Peptídeos/química , Fotólise , Polietilenoglicóis/química , Proteínas Recombinantes/administração & dosagem , Staphylococcus aureus/enzimologia
6.
J Dairy Sci ; 102(9): 8059-8073, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31326164

RESUMO

Four experiments were conducted to examine the effects of a recombinant bacterial expansin-like protein (BsEXLX1) from Bacillus subtilis and a commercial exogenous fibrolytic enzyme (EFE) preparation for ruminants on hydrolysis of pure substrates (cellulose and xylan) and in vitro digestibility of bermudagrass haylage (BMH). Recombinant Escherichia coli BL21 strain was used to express BsEXLX1; the protein was purified using an affinity column. In experiment 1, carboxymethylcellulose, Whatman #1 filter paper (General Electric, Boston, MA) and oat-spelt xylan substrates were subjected to 4 treatments (1) sodium citrate buffer (control), (2) BsEXLX1 (162 µg/g of substrate), (3) EFE (2.3 mg/g of substrate), and (4) EFE + BsELX1 in 3 independent runs. Samples were incubated at optimal conditions for both additives (pH 5 and 50°C) or at ruminal (pH 6 and 39°C) or ambient (pH 6 and 25°C) conditions for 24 h and sugar release was measured. In experiment 2, digestibility in vitro of BMH was examined after treatment with the following: (1) control (buffer only), (2) BsEXLX1 (162 µg/g of dry matter), (3) EFE (2.2 mg/g of dry matter), and (4) EFE + BsEXLX1 in 3 independent runs at 39°C for 24 h. Experiment 3 examined effects of EFE and BsEXLX1 on simulated preingestive hydrolysis and profile of released sugars from BMH after samples were suspended in deionized water with sodium azide at 25°C for 24 h in 2 independent runs. In experiment 4, the sequence of the BsEXLX1 purified protein was compared with 447 ruminal bacterial genomes to identify similar proteins from the rumen. In experiment 1, compared with EFE alone, EFE and BsEXLX1 synergistically increased sugar release from carboxymethylcellulose and Whatman #1 filter paper under all simulated conditions; however, hydrolysis of xylan was not improved. In experiment 2, compared with EFE alone, treatment with EFE and BsEXLX1 increased neutral detergent fiber and acid detergent fiber digestibility of bermudagrass haylage (by 5.5 and 15%, respectively) and total volatile fatty acid concentrations, and decreased acetate-propionate ratio. In experiment 3, compared with EFE alone. The EFE and BsEXLX1 synergistically reduced concentrations of neutral detergent fiber and acid detergent fiber and increased release of sugars by 9.3%, particularly cellobiose (72.5%). In experiment 4, a similar sequence to that of BsEXLX1 was identified in Bacillus licheniformis, and similar hypothetical protein sequences were identified in Ruminococcus flavefaciens strains along with different protein structures in E. xylanophilum and Lachnospiraceae. This study showed that an expansin-like protein synergistically increased the hydrolysis of pure cellulose substrates and the hydrolysis and digestibility in vitro of BMH.


Assuntos
Ração Animal , Proteínas de Bactérias/administração & dosagem , Bovinos/metabolismo , Cynodon , Proteínas na Dieta/administração & dosagem , Digestão , Xilosidases/administração & dosagem , Animais , Bacillus subtilis , Cynodon/química , Fibras na Dieta/metabolismo , Fermentação , Hidrólise , Distribuição Aleatória , Proteínas Recombinantes/administração & dosagem , Rúmen/metabolismo
7.
Plast Reconstr Surg ; 144(2): 358-370, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31348344

RESUMO

BACKGROUND: Alveolar clefts are traditionally treated with secondary bone grafting, but this is associated with morbidity and graft resorption. Although recombinant human bone morphogenetic protein-2 (rhBMP-2) is under investigation for alveolar cleft repair, safety concerns remain. Dipyridamole is an adenosine receptor indirect agonist with known osteogenic potential. This study compared dipyridamole to rhBMP-2 at alveolar cleft defects delivered using bioceramic scaffolds. METHODS: Skeletally immature New Zealand White rabbits underwent unilateral, 3.5 × 3.5-mm alveolar resection adjacent to the growing suture. Five served as negative controls. The remaining defects were reconstructed with three-dimensionally printed bioceramic scaffolds coated with 1000 µm of dipyridamole (n = 6), 10,000 µm of dipyridamole (n = 7), or 0.2 mg/ml of rhBMP-2 (n = 5). At 8 weeks, new bone was quantified. Nondecalcified histologic evaluation was performed, and new bone was evaluated mechanically. Statistical analysis was performed using a generalized linear mixed model and the Wilcoxon rank sum test. RESULTS: Negative controls did not heal, whereas new bone formation bridged all three-dimensionally printed bioceramic treatment groups. The 1000-µm dipyridamole scaffolds regenerated 28.03 ± 7.38 percent, 10,000-µm dipyridamole scaffolds regenerated 36.18 ± 6.83 percent (1000 µm versus 10,000 µm dipyridamole; p = 0.104), and rhBMP-2-coated scaffolds regenerated 37.17 ± 16.69 percent bone (p = 0.124 versus 1000 µm dipyridamole, and p = 0.938 versus 10,000 µm dipyridamole). On histology/electron microscopy, no changes in suture biology were evident for dipyridamole, whereas rhBMP-2 demonstrated early signs of suture fusion. Healing was highly cellular and vascularized across all groups. No statistical differences in mechanical properties were observed between either dipyridamole or rhBMP-2 compared with native bone. CONCLUSION: Dipyridamole generates new bone without osteolysis and early suture fusion associated with rhBMP-2 in skeletally immature bone defects.


Assuntos
Processo Alveolar/efeitos dos fármacos , Conservadores da Densidade Óssea/farmacologia , Proteína Morfogenética Óssea 2/farmacologia , Regeneração Óssea/efeitos dos fármacos , Dipiridamol/farmacologia , Tecidos Suporte , Fator de Crescimento Transformador beta/farmacologia , Processo Alveolar/lesões , Animais , Conservadores da Densidade Óssea/administração & dosagem , Proteína Morfogenética Óssea 2/administração & dosagem , Transplante Ósseo/métodos , Dipiridamol/administração & dosagem , Modelos Animais de Doenças , Microscopia Eletrônica de Varredura , Modelos Animais , Osteogênese/efeitos dos fármacos , Impressão Tridimensional , Coelhos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacologia , Fator de Crescimento Transformador beta/administração & dosagem , Microtomografia por Raio-X
8.
Medicine (Baltimore) ; 98(27): e16143, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31277114

RESUMO

Ischemia/reperfusion (I/R) injury is associated with primary percutaneous coronary intervention (PPCI). The current study was performed to compare the effect of tirofiban and recombinant human pro-urokinase (rh-proUK) on the improvement of coronary slow blood after PPCI.Sixty-five ST elevation myocardial infarction (STEMI) patients treated with rh-proUK and an equal number treated with tirofiban after PPCI were employed in the current study. The clinicopathological information regarding the biochemical parameters, thrombolysis in myocardial infarction (TIMI) grade, hemodynamics parameters, thrombus core (TS), sum-STR, left ventricular ejection fraction (LVEF), blood routine parameters, high-sensitivity C-reactive protein (CRP) level, uric acid, hepatorenal function, electrocardiogram (ECG), and echocardiography before and after the interventions were collected. The differences in those parameters between the 2 groups then compared with assess the treatment effect and side effects associated with the both therapies.The results showed that the TIMI level post-intervention (P = .03), the proportion of TIMI myocardial perfusion grade level III (P = .04), the changes in thrombus score (P < .001) in rh-proUK group were significantly higher than those in tirofiban group while the corrected TIMI Frame Count (CTFC) (P = .02), the incidence of slow flow (P = .02), the thrombus score post-intervention (P < .001), the stent length (P = .02), and the number of receiving administration of sodium nitroprusside (P = .01) were significantly lower than those in tirofiban group. Moreover, the levels of CK (P < .001), CK-MB (P = .01), and NT-proBNP 24-hour post-intervention (P < .02) were significantly lower in rh-proUK group than those in tirofiban group and the sum-STR right after the intervention (P < .03) of rh-proUK group was significantly higher than that of tirofiban group. No significant difference was detected between the 2 therapies regarding major adverse cardiac events (MACE).The findings outlined in the current study showed that the improvement effect of rh-proUK on blood flow condition was stronger right after the intervention and the therapy had a similar safety when compared with tirofiban during a 30-day follow-up.


Assuntos
Circulação Coronária/efeitos dos fármacos , Intervenção Coronária Percutânea/efeitos adversos , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia , Tirofibana/administração & dosagem , Ativador de Plasminogênio Tipo Uroquinase/administração & dosagem , Função Ventricular Esquerda/efeitos dos fármacos , Idoso , Feminino , Fibrinolíticos , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/administração & dosagem , Estudos Retrospectivos
10.
Pan Afr Med J ; 32: 120, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31223410

RESUMO

Rhesus hemolytic disease of the newborn is rarely found after the implementation of anti-D immunoglobulin prophylaxis. However, it may lead to cholestasis, elevated liver transaminases, iron overload and late hyporegenerative anemia when it occurs. Etiology of this type of anemia is not defined yet and treatment is controversial. It is typically recognized after two weeks of life which is characterized by low hemoglobin and reticulocyte count. We have reported a case of a neonate with Rh hemolytic disease with late hyporegenerative anemia that was noted at day 18 of life. We treated this anemia by erythropoietin (EPO) 250 U/kg three times per week. Two weeks after initiation of erythropoietin treatment, a stable hemoglobin was noted along with an increased reticulocyte count. The patient required one further blood transfusion in the third week of therapy. Other associated findings were self-limited. A year of follow-up showed an appropriate development for age.


Assuntos
Anemia/terapia , Eritroblastose Fetal/terapia , Eritropoetina/administração & dosagem , Isoimunização Rh/complicações , Anemia/etiologia , Transfusão de Sangue/métodos , Hemoglobinas/metabolismo , Humanos , Recém-Nascido , Masculino , Proteínas Recombinantes/administração & dosagem , Fatores de Tempo
11.
Chem Biol Interact ; 309: 108712, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31201777

RESUMO

The recent intentional use of nerve agents and pesticides in Europe and Afghanistan highlights the need for an effective countermeasure against organophosphates (OP) toxins. The most developed pretreatment candidate to date is plasma (native) human butyrylcholinesterase (HuBChE), which is limited in availability and because of its 1:1 stoichiometry with OPs, a large dose will present challenges when delivered parenterally both in terms of pharmacokinetics and manageability in the field. A tetrameric recombinant (r) form of human BChE produced in CHO-K1 cells with similar structure, in vivo stability and antidotal efficacy as the native form, has been developed to deliver rHuBChE as an aerosol (aer) to form a pulmonary bioshield capable of neutralizing inhaled OPs in situ and prevent AChE inhibition in the blood and in the brain; the latter associated with the symptoms of OP toxicity. Previous proof-of-concept macaque studies demonstrated that delivery of 9 mg/kg using a microsprayer inserted down the trachea, resulted in protection against an inhaled dose of 15ug/kg of aer-paraoxon (aer-Px) given 72 h later. In the present studies, pulmonary delivery of rHuBChE in macaques was achieved using Aerogen vibrating mesh nebulizers, similar to that used for human self-administration. The promising findings indicate that despite the poor lung deposition observed in macaques using nebulizers (13-20%), protective levels of RBC-AChE were still present in the blood even when exposure aer-Px (55 µg/kg) was delayed for five days. This long term retention of 5 mg/kg rHuBChE deposited in the lung bodes well for the use of an aer-rHuBChE pretreatment in humans where a user-friendly customized nebulizer with increased lung deposition up to 50% will provide even longer protection at a lower dose.


Assuntos
Aerossóis/química , Butirilcolinesterase/química , Paraoxon/química , Animais , Butirilcolinesterase/genética , Butirilcolinesterase/metabolismo , Células CHO , Cricetinae , Cricetulus , Feminino , Humanos , Pulmão/metabolismo , Macaca , Masculino , Nebulizadores e Vaporizadores , Paraoxon/toxicidade , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/sangue , Proteínas Recombinantes/química
12.
Biomed Res Int ; 2019: 5939372, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31073528

RESUMO

Objective: This study aimed to examine the relationship between serum alanine aminotransferase (ALT) and growth hormone (GH) in children and adolescents with short stature. Methods: In this retrospective cohort study, 670 Chinese children and adolescents with short stature were included, and 253 of them received recombinant human GH (rhGH) therapy. Anthropometric and biochemical indicators were measured. GH peak levels were assessed after provocation tests with L-dopa and insulin. The subjects were divided into 3 groups according to the GH peak level. The association between the GH peak and ALT was analyzed. The change of ALT during rhGH therapy was assessed by a generalized additive mixed model. Results: Serum ALT and incidence of ALT elevation were both decreased across the GH tertiles (P = 0.002, 0.012, respectively). A univariate analysis showed that the GH peak was negatively associated with ALT (ß: -0.12; 95%CI: -0.22, -0.02; P = 0.023). Furthermore, multiple linear stepwise regression analysis demonstrated that the GH peak was independently related to ALT after adjusting for other confounding variables (ß: -0.12; 95%CI: -0.24, -0.00; P = 0.042). Besides, mean values of the change in ALT from baseline displayed that, during the early stages of rhGH treatment, serum ALT level indicated a temporary upward trend, but it subsequently gradually decreased (ß: -0.16; 95%CI: -0.23, -0.09; P < 0.001). Conclusions: GH secretion level was strongly negatively correlated with ALT in short children and adolescents. And rhGH therapy could reduce ALT level over time.


Assuntos
Alanina Transaminase/sangue , Nanismo/sangue , Hormônio do Crescimento/sangue , Proteínas Recombinantes/administração & dosagem , Adolescente , Antropometria , Estatura , Criança , China , Nanismo/tratamento farmacológico , Nanismo/fisiopatologia , Feminino , Hormônio do Crescimento/administração & dosagem , Hormônio do Crescimento/genética , Humanos , Insulina/sangue , Levodopa/sangue , Masculino , Proteínas Recombinantes/genética
13.
Chin J Traumatol ; 22(3): 129-133, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31076162

RESUMO

PURPOSE: To summarize and analyze the early treatment of multiple injuries combined with severe pelvic fractures, especially focus on the hemostasis methods for severe pelvic fractures, so as to improve the successful rate of rescue for the fatal hemorrhagic shock caused by pelvic fractures. METHODS: A retrospective analysis was conducted in 68 cases of multiple trauma combined with severe pelvic fractures in recent 10 years (from Jan. 2006 to Dec. 2015). There were 57 males and 11 females. Their age ranged from 19 to 75 years, averaging 42 years. Causes of injury included traffic accidents in 34 cases (2 cases of truck rolling), high falling injuries in 17 cases, crashing injuries in 15 cases, steel cable wound in 1 case, and seat belt traction injury in 1 case. There were 31 cases of head injury, 11 cases of chest injury, 56 cases of abdominal and pelvic injuries, and 37 cases of spinal and limb injuries. Therapeutic methods included early anti-shock measures, surgical hemostasis based on internal iliac artery devasculization for pelvic hemorrhage, and early treatment for combined organ damage and complications included embolization and repair of the liver, spleen and kidney, splenectomy, nephrectomy, intestinal resection, colostomy, bladder ostomy, and urethral repair, etc. Patients in this series received blood transfusion volume of 1200-10,000 mL, with an average volume of 2850 mL. Postoperative follow-up ranged from 6 months to 1.5 years. RESULTS: The average score of ISS in this series was 38.6 points. 49 cases were successfully treated and the total survival rate was 72.1%. Totally 19 patients died (average ISS score 42.4), including 6 cases of hemorrhagic shock, 8 cases of brain injury, 1 case of cardiac injury, 2 cases of pulmonary infection, 1 case of pulmonary embolism, and 1 case of multiple organ failure. Postoperative complications included 1 case of urethral stricture (after secondary repair), 1 case of sexual dysfunction (combined with urethral rupture), 1 case of lower limb amputation (femoral artery thrombosis), and 18 cases of consumptive coagulopathy. CONCLUSION: The early treatment of multiple injuries combined with severe pelvic fractures should focus on pelvic hemostasis. Massive bleeding-induced hemorrhagic shock is one of the main causes of poor prognosis. The technique of internal iliac artery devasculization including ligation and embolization can be used as an effective measure to stop or reduce bleeding. Consumptive coagulopathy is difficult to deal with, which should be detected and treated as soon as possible after surgical measures have been performed. The effect of using recombinant factor VII in treating consumptive coagulopathy is satisfactory.


Assuntos
Fraturas Ósseas/terapia , Traumatismo Múltiplo/terapia , Ossos Pélvicos/lesões , Adulto , Embolização Terapêutica/métodos , Fator VII/administração & dosagem , Feminino , Fraturas Ósseas/complicações , Hemostasia Cirúrgica , Humanos , Artéria Ilíaca/cirurgia , Escala de Gravidade do Ferimento , Ligadura , Masculino , Pessoa de Meia-Idade , Traumatismo Múltiplo/complicações , Prognóstico , Proteínas Recombinantes/administração & dosagem , Estudos Retrospectivos , Choque Hemorrágico/etiologia , Choque Hemorrágico/prevenção & controle , Adulto Jovem
14.
Korean J Parasitol ; 57(2): 101-115, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31104402

RESUMO

The pathogenesis of cerebral malaria is biologically complex and involves multi-factorial mechanisms such as microvascular congestion, immunopathology by the pro-inflammatory cytokine and endothelial dysfunction. Recent data have suggested that a pleiotropic T-cell immunomodulatory protein (TIP) could effectively mediate inflammatory cytokines of mammalian immune response against acute graft-versus-host disease in animal models. In this study, we identified a conserved homologue of TIP in Plasmodium berghei (PbTIP) as a membrane protein in Plasmodium asexual stage. Compared with PBS control group, the pathology of experimental cerebral malaria (ECM) in rPbTIP intravenous injection (i.v.) group was alleviated by the downregulation of pro-inflammatory responses, and rPbTIP i.v. group elicited an expansion of regulatory T-cell response. Therefore, rPbTIP i.v. group displayed less severe brain pathology and feverish mice in rPbTIP i.v. group died from ECM. This study suggested that PbTIP may be a novel promising target to alleviate the severity of ECM.


Assuntos
Fatores Imunológicos/administração & dosagem , Malária Cerebral/prevenção & controle , Proteínas de Membrana/administração & dosagem , Plasmodium berghei/imunologia , Proteínas de Protozoários/administração & dosagem , Proteínas Recombinantes/administração & dosagem , Administração Intravenosa , Animais , Encéfalo/patologia , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Fatores Imunológicos/isolamento & purificação , Ativação Linfocitária , Malária Cerebral/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/isolamento & purificação , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Plasmodium berghei/genética , Proteínas de Protozoários/genética , Proteínas de Protozoários/isolamento & purificação , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Linfócitos T Reguladores/efeitos dos fármacos , Resultado do Tratamento
15.
Rinsho Shinkeigaku ; 59(6): 335-338, 2019 Jun 22.
Artigo em Japonês | MEDLINE | ID: mdl-31142708

RESUMO

Fabry disease is characterized by deficient activity of α-galactosidase A, which results in accumulation of glycolipids, such as globotriaosylceremide, in various tissue. Clinical symptoms are varied. In childhood, pain in extremities, hypohidrosis, and angiokeratoma are main symptoms, In adulthood, renal, cardiac and cerebrovascular symptoms are occurred In past, only symptomatic treatments were available. In early 2000th, enzyme replacement therapy was developed after positive results of clinical trials. Ten years after approval, the data of long term safety and efficacy of enzyme replacement.


Assuntos
1-Desoxinojirimicina/análogos & derivados , Terapia de Reposição de Enzimas/tendências , Doença de Fabry/tratamento farmacológico , Isoenzimas/administração & dosagem , Chaperonas Moleculares/administração & dosagem , Proteínas Recombinantes/administração & dosagem , alfa-Galactosidase/administração & dosagem , 1-Desoxinojirimicina/administração & dosagem , Animais , Cromossomos Humanos X/enzimologia , Aprovação de Drogas , Terapia de Reposição de Enzimas/métodos , Doença de Fabry/enzimologia , Doença de Fabry/genética , Doença de Fabry/metabolismo , Feminino , Globosídeos/metabolismo , Humanos , Masculino , Camundongos , Mutação , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , alfa-Galactosidase/genética
16.
Int J Oncol ; 54(6): 2237-2249, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31081057

RESUMO

Cytotoxic chemotherapy is the standard treatment for patients with advanced bladder cancer. However, this treatment can cause transient and prolonged neutropenia, which can result in fatal infection. Three recombinant human colony­stimulating factors (CSFs), granulocyte CSF (G­CSF), granulocyte­macrophage CSF (GM­CSF), and macrophage CSF (M­CSF), are currently available to reduce the duration and degree of neutropenia. The present study investigated the pro­ and anti­tumor effects of these three CSFs and the changes in molecular profiles. Xenograft tumors in athymic mice were generated by subcutaneously inoculating the human bladder cancer cell lines MGH­U3 and UM­UC­3. A total of 2 weeks after cell inoculation, mice were randomly divided into four groups (control, G­CSF, GM­CSF and M­CSF) and treated thrice a week for 2 weeks. Tumor growth during monitoring and tumor weight at the time of euthanization were significantly higher in mice treated with G­CSF and lower in mice treated with GM­CSF compared with the control mice. Tumors were examined by immunostaining with antibodies against proteins associated tumor proliferation (Ki­67), angiogenesis [CD31 and vascular endothelial growth factor (VEGF)], anti­immunity (CD204) and epithelial­mesenchymal transition (EMT; E­cadherin). Immunohistochemical staining revealed that tumor proliferation, angiogenesis, recruitment of M2 macrophages and EMT were promoted by G­CSF, whereas lymphangiogenesis and recruitment of M2 macrophages were inhibited by GM­CSF. Treatment­associated changes in serum pro­ and anti­tumoral cytokines and chemokines were evaluated by enzyme­linked immunosorbent assay (ELISA)­based arrays. In the ELISA for serum, the levels of cytokines associated with angiogenesis (interleukin­6 and VEGF), and EMT (transforming growth factor­ß1 and ­ß2) were elevated in mice treated with G­CSF. Treatment with GM­CSF and M­CSF also affected the level of these cytokines characteristically. The current results indicate that administration of exogenous G­CSF to patients with bladder cancer promotes tumor growth through promotion of cell proliferation, angiogenesis, recruitment of M2 macrophages and enhancement of EMT through the modulation of the tumor microenvironment.


Assuntos
Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Fator Estimulador de Colônias de Macrófagos/administração & dosagem , Neoplasias da Bexiga Urinária/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/farmacologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Humanos , Interleucina-6/metabolismo , Fator Estimulador de Colônias de Macrófagos/farmacologia , Camundongos , Distribuição Aleatória , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacologia , Carga Tumoral/efeitos dos fármacos , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
17.
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
18.
Cancer Immunol Immunother ; 68(7): 1211-1222, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31069460

RESUMO

Human tumor cells express antigens that serve as targets for the host cellular immune system. This phase 1 dose-escalating study was conducted to assess safety and tolerability of G305, a recombinant NY-ESO-1 protein vaccine mixed with glucopyranosyl lipid A (GLA), a synthetic TLR4 agonist adjuvant, in a stable emulsion (SE). Twelve patients with solid tumors expressing NY-ESO-1 were treated using a 3 + 3 design. The NY-ESO-1 dose was fixed at 250 µg, while GLA-SE was increased from 2 to 10 µg. Safety, immunogenicity, and clinical responses were assessed prior to, during, and at the end of therapy. G305 was safe and immunogenic at all doses. All related AEs were Grade 1 or 2, with injection site soreness as the most commonly reported event (100%). Overall, 75% of patients developed antibody response to NY-ESO-1, including six patients with increased antibody titer ( ≥ 4-fold rise) and three patients with seroconversion from negative (titer < 100) to positive (titer ≥ 100). CD4 T-cell responses were observed in 44.4% of patients; 33.3% were new responses and 1 was boosted ( ≥ 2-fold rise). Following treatment, 8 of 12 patients had stable disease for 3 months or more; at the end of 1 year, three patients had stable disease and nine patients were alive. G305 is a potent immunotherapeutic agent that can stimulate NY-ESO-1-specific antibody and T-cell responses. The vaccine was safe at all doses of GLA-SE (2-10 µg) and showed potential clinical benefit in this population of patients.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Antígenos de Neoplasias/administração & dosagem , Vacinas Anticâncer/administração & dosagem , Glucosídeos/administração & dosagem , Lipídeo A/administração & dosagem , Proteínas de Membrana/administração & dosagem , Neoplasias/terapia , Adjuvantes Imunológicos/efeitos adversos , Adulto , Idoso , Antígenos de Neoplasias/efeitos adversos , Antígenos de Neoplasias/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Vacinas Anticâncer/efeitos adversos , Vacinas Anticâncer/imunologia , Drogas em Investigação/administração & dosagem , Drogas em Investigação/efeitos adversos , Feminino , Glucosídeos/efeitos adversos , Glucosídeos/imunologia , Humanos , Imunogenicidade da Vacina , Injeções Intramusculares , Lipídeo A/efeitos adversos , Lipídeo A/imunologia , Masculino , Proteínas de Membrana/efeitos adversos , Proteínas de Membrana/imunologia , Pessoa de Meia-Idade , Neoplasias/imunologia , Neoplasias/patologia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/imunologia , Receptor 4 Toll-Like/agonistas , Receptor 4 Toll-Like/imunologia , Resultado do Tratamento , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/efeitos adversos , Vacinas Sintéticas/imunologia , Adulto Jovem
19.
Bull Exp Biol Med ; 166(6): 751-753, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31028578

RESUMO

In vivo experiments showed that antibodies to OmpC and OmpF porins of Yersinia pseudotuberculosis increased thyroxine (T4) level in the blood of experimental animals. The mice were immunized with different antigens: recombinant OmpF porin in a soluble monomeric form, trimers of OmpC and OmpF porins isolated from the outer membrane, or antibodies to them. The level of thyroxine in the blood of mice immunized with OmpF and OmpC porins increased by 5.47 and 22.3 times, respectively; after immunization with antibodies to these proteins, blood thyroxine increased by 9.28 and 14.29 times. Immunization with recombinant OmpF porin induced no reliable increase in thyroxine level. Hence, the serum to recombinant OmpF porin contains no antibodies specific to conformational antigenic determinants that are present in the protein trimer and, according to our previous findings from molecular docking studies, determine cross-reactions between OmpF porin of Y. pseudotuberculosis and thyroidstimulating hormone receptor.


Assuntos
Antígenos de Bactérias/imunologia , Hipertireoidismo/induzido quimicamente , Porinas/imunologia , Yersinia pseudotuberculosis/química , Animais , Anticorpos Antibacterianos/administração & dosagem , Antígenos de Bactérias/administração & dosagem , Antígenos de Bactérias/química , Feminino , Hipertireoidismo/imunologia , Hipertireoidismo/metabolismo , Imunização , Camundongos , Camundongos Endogâmicos BALB C , Porinas/administração & dosagem , Porinas/química , Multimerização Proteica , Receptores da Tireotropina/imunologia , Receptores da Tireotropina/metabolismo , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Tiroxina/biossíntese , Yersinia pseudotuberculosis/imunologia
20.
Int J Oncol ; 54(4): 1209-1220, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30968147

RESUMO

Evaluation of human epidermal growth factor receptor 2 (HER2) expression levels in breast and gastroesophageal cancer is used for the stratification of patients for HER2­targeting therapies. The use of radionuclide molecular imaging may facilitate such evaluation in a non­invasive way. Designed ankyrin repeat proteins (DARPins) are engineered scaffold proteins with high potential as probes for radionuclide molecular imaging. DARPin G3 binds with high affinity to HER2 and may be used to visualize this important therapeutic target. Studies on other engineered scaffold proteins have demonstrated that selection of the optimal labeling approach improves the sensitivity and specificity of radionuclide imaging. The present study compared two methods of labeling G3, direct and indirect radioiodination, to select an approach providing the best imaging contrast. G3­H6 was labeled with iodine­124, iodine­125 and iodine­131 using a direct method. A novel construct bearing a C­terminal cysteine, G3­GGGC, was site­specifically labeled using [125I]I­iodo­[(4­hydroxyphenyl)ethyl]maleimide (HPEM). The two radiolabeled G3 variants preserved binding specificity and high affinity to HER2­expressing cells. The specificity of tumor targeting in vivo was demonstrated. Biodistribution comparison of [131I]I­G3­H6 and [125I]I­HPEM­G3­GGGC in mice, bearing HER2­expressing SKOV3 xenografts, demonstrated an appreciable contribution of hepatobiliary excretion to the clearance of [125I]I­HPEM­G3­GGGC and a decreased tumor uptake compared to [131I]I­G3­H6. The direct label provided higher tumor­to­blood and tumor­to­organ ratios compared with the indirect label at 4 h post­injection. The feasibility of high contrast PET/CT imaging of HER2 expression in SKOV3 xenografts in mice using [124I]I­G3­H6 was demonstrated. In conclusion, direct radioiodination is the preferable approach for labeling DARPin G3 with iodine­123 and iodine­124 for clinical single photon emission computed tomography and positron emission tomography imaging.


Assuntos
Repetição de Anquirina/genética , Radioisótopos do Iodo/administração & dosagem , Imagem Molecular/métodos , Neoplasias/diagnóstico por imagem , Receptor ErbB-2/metabolismo , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Radioisótopos do Iodo/química , Radioisótopos do Iodo/farmacocinética , Marcação por Isótopo/métodos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/patologia , Engenharia de Proteínas , Cintilografia/métodos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/farmacocinética , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA