Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 11.476
Filtrar
1.
Int J Mol Sci ; 22(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209932

RESUMO

Enzymatic transamidation of gliadins by microbial transglutaminase (mTG) inhibits interferon-γ (IFN-γ) secretion by intestinal T cell lines in patients with celiac disease (CD). To gain insight into the cellular mechanisms underlying the down-regulatory effects of transamidation, we tested a single recombinant α-gliadin (r-gliadin) harbouring two immunodominant peptides, p13 (aa. 120-139) and p23 (aa. 220-239), in HLA-DQ8 transgenic mice, a model of gluten sensitivity. Mice were intranasally immunised with r-gliadin or r-gliadin transamidated by mTG (K-r-gliadin) along with cholera toxin, and the response of mesenteric lymph node cells was analysed by cytokine multiplex assay. An in vitro challenge with r-gliadin was characterised by secretion of specific cytokines featuring both innate immunity and the Th1/Th2/Th17 pattern of the adaptive response. Notably, transamidation specifically down-regulated the Th1 response. Structural studies performed on K-r-gliadin confirmed that specific glutamine residues in p13 and p23, previously found to be deamidated by tissue transglutaminase, were also transamidated by mTG. In silico analysis, simulating p13 and p23 peptide binding to HLA-DQ8 showed that these glutamines, in the form of glutamate, could interact by means of salt bridges with peculiar amino acids of the alpha chain of HLA-DQ8, suggesting that their transamidation may influence the HLA-restricted recognition of these peptides. Thus, the structural findings provided a rationale to explain the down-regulation of the r-gliadin-specific Th1 response following transamidation.


Assuntos
Doença Celíaca/tratamento farmacológico , Toxina da Cólera/administração & dosagem , Citocinas/metabolismo , Gliadina/administração & dosagem , Antígenos HLA-DQ/genética , Transglutaminases/metabolismo , Administração Intranasal , Animais , Doença Celíaca/genética , Doença Celíaca/imunologia , Toxina da Cólera/imunologia , Citocinas/efeitos dos fármacos , Modelos Animais de Doenças , Regulação para Baixo , Regulação da Expressão Gênica , Gliadina/química , Gliadina/genética , Gliadina/imunologia , Antígenos HLA-DQ/metabolismo , Imunização , Epitopos Imunodominantes/imunologia , Camundongos , Camundongos Transgênicos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/química , Proteínas Recombinantes/imunologia , Células Th1/imunologia , Células Th17/imunologia , Células Th2/imunologia
2.
Int J Mol Sci ; 22(11)2021 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-34070997

RESUMO

Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disorder based on a mutation in the IDS gene that encodes iduronate 2-sulphatase. As a result, there is an accumulation of glycosaminoglycans-heparan sulphate and dermatan sulphate-in almost all body tissues, which leads to their dysfunction. Currently, the primary treatment is enzyme replacement therapy, which improves the course of the disease by reducing somatic symptoms, including hepatomegaly and splenomegaly. The enzyme, however, does not cross the blood-brain barrier, and no improvement in the function of the central nervous system has been observed in patients with the severe form of the disease. An alternative method of treatment that solves typical problems of enzyme replacement therapy is gene therapy, i.e., delivery of the correct gene to target cells through an appropriate vector. Much progress has been made in applying gene therapy for MPS II, from cellular models to human clinical trials. In this article, we briefly present the history and basics of gene therapy and discuss the current state of knowledge about the methods of this therapy in mucopolysaccharidosis type II.


Assuntos
Glicoproteínas/genética , Mucopolissacaridose II/terapia , Adolescente , Animais , Barreira Hematoencefálica , Sistemas CRISPR-Cas , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Dependovirus/genética , Modelos Animais de Doenças , Portadores de Fármacos , Eletroporação , Terapia de Reposição de Enzimas/métodos , Edição de Genes , Terapia Genética , Vetores Genéticos/efeitos adversos , Vetores Genéticos/uso terapêutico , Glicoproteínas/farmacocinética , Glicoproteínas/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunoconjugados/administração & dosagem , Imunoconjugados/uso terapêutico , Lactente , Injeções Intraventriculares , Injeções Espinhais , Lentivirus/genética , Camundongos , Mucopolissacaridose II/genética , Estudos Multicêntricos como Assunto , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Retroviridae/genética , Nucleases dos Efetores Semelhantes a Ativadores de Transcrição
3.
Int J Mol Sci ; 22(9)2021 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-34066510

RESUMO

Neutrophil extracellular trap (NET) formation, an innate immune system response, is associated with thrombogenesis and vascular endothelial injury. Circulatory disorders due to microvascular thrombogenesis are one of the principal causes of organ damage. NET formation in organs contributes to the exacerbation of sepsis, which is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. We have previously reported that recombinant human soluble thrombomodulin (rTM) reduces lipopolysaccharide (LPS)-induced NET formation in vitro. Here, we aimed to show that thrombomodulin (TM)-mediated suppression of NET formation protects against organ damage in sepsis. Mice were injected intraperitoneally (i.p.) with 10 mg/kg LPS. rTM (6 mg/kg/day) or saline was administered i.p. 1 h after LPS injection. In the LPS-induced murine septic shock model, extracellular histones, which are components of NETs, were observed in the liver and lungs. In addition, the serum cytokine (interleukin-1ß (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), macrophage chemotactic protein-1 (MCP-1), and interleukin-10 (IL-10)) levels were increased. The administration of rTM in this model prevented NET formation in the organs and suppressed the increase in the levels of all cytokines except IL-1ß. Furthermore, the survival rate improved. We provide a novel role of TM in treating inflammation and NETs in organs during sepsis.


Assuntos
Armadilhas Extracelulares/metabolismo , Fígado/patologia , Pulmão/patologia , Choque Séptico/tratamento farmacológico , Trombomodulina/uso terapêutico , Animais , Citocinas/sangue , Modelos Animais de Doenças , Armadilhas Extracelulares/efeitos dos fármacos , Feminino , Humanos , Lipopolissacarídeos , Fígado/ultraestrutura , Camundongos Endogâmicos C57BL , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Choque Séptico/sangue , Choque Séptico/induzido quimicamente , Análise de Sobrevida
4.
AAPS PharmSciTech ; 22(5): 185, 2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34143327

RESUMO

Respiratory diseases are among the leading causes of morbidity and mortality worldwide. Innovations in biochemical engineering and understanding of the pathophysiology of respiratory diseases resulted in the development of many therapeutic proteins and peptide drugs with high specificity and potency. Currently, protein and peptide drugs are mostly administered by injections due to their large molecular size, poor oral absorption, and labile physicochemical properties. However, parenteral administration has several limitations such as frequent dosing due to the short half-life of protein and peptide in blood, pain on administration, sterility requirement, and poor patient compliance. Among various noninvasive routes of administrations, the pulmonary route has received a great deal of attention and is a better alternative to deliver protein and peptide drugs for treating respiratory diseases and systemic diseases. Among the various aerosol dosage forms, dry powder inhaler (DPI) systems appear to be promising for inhalation delivery of proteins and peptides due to their improved stability in solid state. This review focuses on the development of DPI formulations of protein and peptide drugs using advanced spray drying. An overview of the challenges in maintaining protein stability during the drying process and stabilizing excipients used in spray drying of proteins and peptide drugs is discussed. Finally, a summary of spray-dried DPI formulations of protein and peptide drugs, their characterization, various DPI devices used to deliver protein and peptide drugs, and current clinical status are discussed.


Assuntos
Peptídeos Catiônicos Antimicrobianos/síntese química , Composição de Medicamentos/métodos , Inaladores de Pó Seco/métodos , Proteínas Recombinantes/síntese química , Secagem por Atomização , Administração por Inalação , Aerossóis/química , Animais , Peptídeos Catiônicos Antimicrobianos/administração & dosagem , Dessecação/métodos , Excipientes/química , Humanos , Isoleucina/administração & dosagem , Isoleucina/síntese química , Manitol/administração & dosagem , Manitol/síntese química , Tamanho da Partícula , Peptídeos , Pós/química , Proteínas Recombinantes/administração & dosagem
5.
Medicine (Baltimore) ; 100(25): e26453, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34160442

RESUMO

BACKGROUND: Recent observations raised concern that the intravenous recombinant tissue plasminogen activator (rt-PA) may result in damage to stroke patients caused by small artery occlusion (SAO). Thus, we perform a protocol for meta-analysis to investigate the efficacy and safety of intravenous thrombolysis with rt-PA in SAO-patients. METHODS: The search-style electronic libraries, including Pubmed, Embase, the Cochrane Library, Web of Science, Wanfang Data, VIP Chinese Journals, and China Biomedical Literature Service System are used for document retrieval in June 2021 with no restrictions on language. The risk of bias in include articles will be assessed using the Cochrane Risk of Bias Tool. We perform the meta-analysis by Stata version 10.0 software and calculated the statistics using the inverse variance statistical method. Binary outcomes are presented as Mantel-Haenszel-style risk ratios with 95% confidence interval. Continuous outcomes are reported as mean differences. RESULTS: The results of the article will be shown in a peer-reviewed journal. CONCLUSION: Intravenous rt-PA may be effective and safe in SAO-patients.


Assuntos
Arteriopatias Oclusivas/tratamento farmacológico , Fibrinolíticos/administração & dosagem , Hemorragias Intracranianas/epidemiologia , Terapia Trombolítica/métodos , AVC Trombótico/tratamento farmacológico , Ativador de Plasminogênio Tecidual/administração & dosagem , Arteriopatias Oclusivas/complicações , Fibrinolíticos/efeitos adversos , Humanos , Injeções Intravenosas , Hemorragias Intracranianas/induzido quimicamente , Metanálise como Assunto , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Revisões Sistemáticas como Assunto , AVC Trombótico/etiologia , Ativador de Plasminogênio Tecidual/efeitos adversos , Resultado do Tratamento
6.
Curr Top Med Chem ; 21(10): 920-927, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33970846

RESUMO

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), known as Coronavirus disease-2019 (COVID-19), has caused the sixth world's public health emergency. Healthcare staff, as the frontline population fighting the pandemic, are exposed to a high risk of infection. Therefore, developing a protective intervention for medical staff is of significant importance. OBJECTIVE: The aim of the study was to explore the effectiveness and safety of recombinant human interferon alpha (rhIFN-α) nasal drops for the prevention of coronavirus disease 2019 (COVID-19) through administering it to medical staff. METHODS: This was a prospective open-label clinical trial with parallel intervention assignment conducted on 2944 medical staff including both doctors and nurses from Taihe Hospital, Shiyan City, Hubei Province, China from January 21, 2020 to July 30, 2020. The participants were bifurcated into two groups of low risk and high risk groups according to the level of direct exposure to COVID-19 patients. The individuals of the low-risk group received rhIFN-α nasal drops for one month in addition to first level protection, and the high-risk group received a combination of rhIFN-α nasal drops coupled with thymosin-α1 with either second or third-level protection protocol. Moreover, the new-outset of COVID-19 pneumonia diagnosed by chest computed tomography (CT), after thirty days, was the primary outcome. The adverse reactions were recorded in all participants. RESULTS: 2415 of 2944 individuals belonged to the low-risk group, while 529 to the high-risk group. There was no COVID-19 pneumonia in either of the group after thirty days. The pulmonary CT scans were negative for COVID-19 pneumonia in both the groups with no new clinical symptoms. No serious adverse event was observed during the course of the intervention. CONCLUSION: The rhIFN-α nasal drops along with augmented safeguards based on standard physical isolation could effectively protect medical staff against COVID-19 pneumonia.


Assuntos
COVID-19/prevenção & controle , Interferon-alfa/farmacologia , Administração Intranasal , Adulto , Anti-Infecciosos Locais/farmacologia , COVID-19/epidemiologia , China/epidemiologia , Feminino , Humanos , Interferon-alfa/administração & dosagem , Interferon-alfa/efeitos adversos , Masculino , Recursos Humanos em Hospital , Estudos Prospectivos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/farmacologia
7.
Aging (Albany NY) ; 13(9): 12800-12816, 2021 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-33934089

RESUMO

Intracranial aneurysms (IAs) are common cerebrovascular diseases that carry a high mortality rate, and the mechanisms that contribute to IA formation and rupture have not been elucidated. ADAMTS-5 (ADAM Metallopeptidase with Thrombospondin Type 1 Motif 5) is a secreted proteinase involved in matrix degradation and ECM (extracellular matrix) remodeling processes, and we hypothesized that the dysregulation of ADAMTS-5 could play a role in the pathophysiology of IA. Immunofluorescence revealed that the ADAMTS-5 levels were decreased in human and murine IA samples. The administration of recombinant protein ADAMTS-5 significantly reduced the incidence of aneurysm rupture in the experimental model of IA. IA artery tissue was collected and utilized for histology, immunostaining, and specific gene expression analysis. Additionally, the IA arteries in ADAMTS-5-administered mice showed reduced elastic fiber destruction, proteoglycan accumulation, macrophage infiltration, inflammatory response, and apoptosis. To further verify the role of ADAMTS-5 in cerebral vessels, a specific ADAMTS-5 inhibitor was used on another model animal, zebrafish, and intracranial hemorrhage was observed in zebrafish embryos. In conclusion, our findings indicate that ADAMTS-5 is downregulated in human IA, and compensatory ADAMTS-5 administration inhibits IA development and rupture with potentially important implications for treating this cerebrovascular disease.


Assuntos
Proteína ADAMTS5/metabolismo , Matriz Extracelular/patologia , Aneurisma Intracraniano/complicações , Proteína ADAMTS5/administração & dosagem , Proteína ADAMTS5/genética , Adulto , Idoso , Animais , Modelos Animais de Doenças , Embrião não Mamífero , Feminino , Humanos , Injeções Intraperitoneais , Aneurisma Intracraniano/tratamento farmacológico , Aneurisma Intracraniano/patologia , Aneurisma Intracraniano/cirurgia , Masculino , Camundongos , Proteólise , Proteínas Recombinantes/administração & dosagem , Ruptura Espontânea/etiologia , Ruptura Espontânea/patologia , Ruptura Espontânea/prevenção & controle , Remodelação Vascular , Peixe-Zebra , Proteínas de Peixe-Zebra/antagonistas & inibidores , Proteínas de Peixe-Zebra/metabolismo
8.
BMC Pregnancy Childbirth ; 21(1): 348, 2021 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-33934703

RESUMO

BACKGROUND: No previous study directly compares the fixed day-5 initiation versus the flexible initiation of GnRH antagonist administration in IVF/ICSI for those patients who are predicted as high ovarian responders without PCOS. To evaluate whether the number of oocytes retrieved is different by using the two GnRH antagonist protocols in Chinese women with predicted high ovarian response except PCOS. METHODS: A randomized controlled trial of 201 infertile women with predicted high ovarian response except PCOS undergoing in vitro fertilization. Ovary stimulation was performed using recombinant FSH and GnRH antagonists. GnRH antagonist ganirelix (0.25 mg/d) was started either on day 5 of stimulation (fixed group) or when LH was > 10 IU/L, and/or a follicle with mean diameter > 12 mm was present, and/or serum E2 was > 600 pg/ml. Patient monitoring was initiated on day 3 of stimulation in flexible group. RESULT(S): No significant difference was observed between the fixed and flexible groups regarding the number of oocytes retrieved (16.72 ± 7.25 vs. 17.47 ± 5.88, P = 0.421), the Gonadotropin treatment duration (9.53 ± 1.07 vs. 9.67 ± 1.03, P = 0.346) and total Gonadotropin dose (1427.75 ± 210.6 vs. 1455.94 ± 243.44, P = 0.381). GnRH antagonist treatment duration in fixed protocol was statistically longer than the flexible protocol (6.57 ± 1.17 vs 6.04 ± 1.03, P = 0.001). There was no premature LH surge in either protocol. CONCLUSION(S): Fixed GnRH antagonist administration on day 5 of stimulation appear to achieve a comparable oocyte retrieved compared with flexible antagonist administration. TRIAL REGISTRATION: NCT02635607 posted on December 16, 2015 in clinicaltrials.gov.


Assuntos
Infertilidade Feminina/terapia , Ovário/efeitos dos fármacos , Indução da Ovulação/métodos , Síndrome do Ovário Policístico/fisiopatologia , Adulto , Gonadotropina Coriônica/administração & dosagem , Feminino , Fertilização In Vitro/métodos , Hormônio Foliculoestimulante Humano/administração & dosagem , Hormônio Liberador de Gonadotropina/administração & dosagem , Hormônio Liberador de Gonadotropina/análogos & derivados , Humanos , Infertilidade Feminina/fisiopatologia , Ovário/metabolismo , Ovário/fisiopatologia , Síndrome do Ovário Policístico/complicações , Gravidez , Taxa de Gravidez , Proteínas Recombinantes/administração & dosagem , Resultado do Tratamento , Pamoato de Triptorrelina/administração & dosagem , Adulto Jovem
10.
Medicine (Baltimore) ; 100(21): e26077, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34032739

RESUMO

BACKGROUND: Nonacog alfa (recombinant factor IX [FIX]) is approved in China for the control and prevention of bleeding events in patients with hemophilia B. This was the first study to assess prophylaxis and on-demand therapy with recombinant FIX replacement in a real-world setting in China. This study aimed to evaluate the safety and efficacy of nonacog alfa in Chinese patients with hemophilia B. METHODS: In this open-label, multicenter study (clinicaltrials.gov identifier NCT02336178), patients received on-demand or prophylactic treatment with intravenous nonacog alfa for approximately 6 months or 50 exposure days, whichever occurred first. The primary safety outcome was medically important events (i.e., development of FIX inhibitors, allergic reactions, and thrombotic events). Key secondary efficacy outcomes included the annualized bleeding rate for on-demand treatment and prophylaxis, response to on-demand treatment, the number of infusions per bleeding event, and the number of breakthrough bleeding events within 48 hours of prophylaxis. RESULTS: Seventy male patients (mean [standard deviation] age 7.8 [7.2] years) were enrolled (on-demand, n = 37; prophylaxis, n = 57 [24 patients were included in both groups]). Thirty-eight (54%) patients had up to 50 FIX exposure days before the study. The only medically important event was a transient low-titer FIX inhibitor (incidence 1.4%, 95% confidence interval, 0-7.7). The mean annualized bleeding rate was 26.3 for on-demand treatment and 6.5 for prophylaxis. A mean (standard deviation) of 1.5 (1.7) nonacog alfa infusions were given per bleeding episode; 78.8% of episodes resolved with 1 infusion. Response was "excellent" or "good" for 88% of the on-demand infusions. Twenty-three bleeding events (n = 11 patients) occurred within 48 hours of 2032 prophylaxis doses (1.13%). CONCLUSION: In the real-world setting, nonacog alfa is safe and effective for on-demand treatment and for prophylaxis for patients with hemophilia B in China.


Assuntos
Terapia de Reposição de Enzimas/efeitos adversos , Fator IX/efeitos adversos , Hemofilia B/tratamento farmacológico , Hemorragia/epidemiologia , Adolescente , Criança , Pré-Escolar , China , Terapia de Reposição de Enzimas/métodos , Fator IX/administração & dosagem , Hemofilia B/complicações , Hemorragia/etiologia , Hemorragia/prevenção & controle , Humanos , Lactente , Infusões Intravenosas , Masculino , Estudos Prospectivos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Resultado do Tratamento
11.
Medicine (Baltimore) ; 100(18): e25805, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33950982

RESUMO

BACKGROUND: To evaluate the effect of recombinant human erythropoietin (rhEPO) in nervous system of premature infants including different dosage. METHODS: The multiple databases like Pubmed, Embase, Cochrane databases and China National Knowledge Database were used to search for the relevant studies, and full-text articles involved in the evaluation on effect of rhEPO for neurodevelopment among premature infants. Review Manager 5.2 was adopted to estimate the effects of the results among selected articles. Forest plots, sensitivity analysis and bias analysis for the articles included were also conducted. RESULTS: Finally, 10 eligible studies were eventually satisfied the included criteria. The results showed that rhEPO was much higher than placebo group in composite cognitive score (MD = 5.89, 95% confidential interval {CI} [1.95, 9.82], P = .003; I2 = 89%), there was no significant difference between rhEPO and placebo groups (RR = 0.93, 95% CI [0.60, 1.43], P = .74; I2 = 51%) and no difference in neurodevelopmental impairment between rhEPO and placebo was insignificant (RR = 0.55 95% CI [0.30, 1.02], P = .06). Composite cognitive score in high dose rhEPO was much higher than placebo group (MD = 10.39, 95% CI [8.84, 11.93], P < .0001, I2 = 0%) and low dose rhEPO also had higher composite cognitive score than placebo group (MD = 2.58, 95% CI [0.80, 4.37], P = .004, I2 = 11%). Limited publication bias was observed in this study. CONCLUSION: Recombinant human erythropoietin might be a promotor for neurodevelopment among premature infants with limited adverse events.


Assuntos
Desenvolvimento Infantil/efeitos dos fármacos , Eritropoetina/administração & dosagem , Recém-Nascido Prematuro/crescimento & desenvolvimento , Sistema Nervoso/crescimento & desenvolvimento , Transtornos do Neurodesenvolvimento/prevenção & controle , Relação Dose-Resposta a Droga , Eritropoetina/efeitos adversos , Humanos , Recém-Nascido , Sistema Nervoso/efeitos dos fármacos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Resultado do Tratamento
12.
Medicine (Baltimore) ; 100(21): e26086, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34032745

RESUMO

RATIONALE: Dumping syndrome is a frequent and potentially severe complication after gastric surgery. Beinaglutide, a recombinant human glucagon-like peptide-1 (GLP-1) which shares 100% homology with human GLP-1(7-36), has never been reported in the treatment of dumping syndrome before. PATIENT CONCERNS: The patient had undergone distal gastrectomy for gastric signet ring cell carcinoma 16 months ago. He presented with symptoms of paroxysmal palpitation, sweating, and dizziness for 4 months. DIAGNOSIS: He was diagnosed with late dumping syndrome. INTERVENTIONS AND OUTCOMES: The patient was treated with dietary changes and acarbose for 4 months before admitted to our hospital. The treatment with dietary changes and acarbose did not prevent postprandial hyperinsulinemia and hypoglycemia according to the 75 g oral glucose tolerance test (OGTT) and continuous glucose monitoring (CGM) on admission.Therefore, the patient was treated with beinaglutide 0.1 mg before breakfast and lunch instead of acarbose. After the treatment of beinaglutide for 1 month, OGTT showed a reduction in postprandial hyperinsulinemia compared with before starting treatment, and the time in the range of 3.9 to 10 mmol/L became 100% in CGM. No side effect was observed in this patient during beinaglutide treatment. LESSONS: These findings suggest that beinaglutide may be effective for treating post-gastrectomy late dumping syndrome.


Assuntos
Síndrome de Esvaziamento Rápido/tratamento farmacológico , Gastrectomia/efeitos adversos , Peptídeo 1 Semelhante ao Glucagon/administração & dosagem , Hiperinsulinismo/tratamento farmacológico , Hipoglicemia/tratamento farmacológico , Fragmentos de Peptídeos/administração & dosagem , Glicemia/análise , Carcinoma de Células em Anel de Sinete/cirurgia , Síndrome de Esvaziamento Rápido/sangue , Síndrome de Esvaziamento Rápido/diagnóstico , Síndrome de Esvaziamento Rápido/etiologia , Teste de Tolerância a Glucose , Humanos , Hiperinsulinismo/sangue , Hiperinsulinismo/diagnóstico , Hiperinsulinismo/etiologia , Hipoglicemia/sangue , Hipoglicemia/diagnóstico , Hipoglicemia/etiologia , Masculino , Pessoa de Meia-Idade , Período Pós-Prandial , Proteínas Recombinantes/administração & dosagem , Neoplasias Gástricas/cirurgia , Resultado do Tratamento
13.
Anticancer Res ; 41(4): 1745-1751, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33813378

RESUMO

BACKGROUND/AIM: Osteosarcoma is the most frequent malignant bone tumor. Failure of first-line therapy results in poor prognosis of osteosarcoma. In the present report, we examined the efficacy of the combination of oral recombinant methioninase (o-rMETase) and docetaxel (DOC) on an osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model. MATERIALS AND METHODS: Osteosarcoma-PDOX models were established by tumor insertion within the tibia of nude mice. The osteosarcoma PDOX models were randomized into four groups (4-5 mice per group): control; o-rMETae alone; DOC alone; o- rMETase combined with DOC. The treatment period was 3 weeks. RESULTS: The combination of o-rMETase and DOC showed significant efficacy compared to the control group (p=0.03). In contrast, there was no significant efficacy of o-rMETase alone or DOC alone (p=0.65, 0.60, respectively). CONCLUSION: o-rMETase converted an osteosarcoma PDOX from DOC-resistant to -sensitive. This combination therapy may be effective against recalcitrant osteosarcoma and other recalcitrant cancers.


Assuntos
Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Liases de Carbono-Enxofre/administração & dosagem , Docetaxel/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Osteossarcoma/tratamento farmacológico , Tíbia/efeitos dos fármacos , Administração Oral , Adolescente , Animais , Neoplasias Ósseas/patologia , Humanos , Masculino , Camundongos Nus , Osteossarcoma/patologia , Proteínas Recombinantes/administração & dosagem , Tíbia/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Int J Mol Sci ; 22(9)2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33925510

RESUMO

BACKGROUND: Hepatocyte growth factor (HGF) is an endogenously induced bioactive molecule that has strong anti-apoptotic and tissue repair activities. In this research, we identified APOA4 as a novel pharmacodynamic (PD) marker of the recombinant human HGF (rh-HGF), E3112. METHODS: rh-HGF was administered to mice, and their livers were investigated for the PD marker. Candidates were identified from soluble proteins and validated by using human hepatocytes in vitro and an animal disease model in vivo, in which its c-Met dependency was also ensured. RESULTS: Among the genes induced or highly enhanced after rh-HGF exposure in vivo, a soluble apolipoprotein, Apoa4, was found to be induced by rh-HGF in the murine liver. By using primary cultured human hepatocytes, the significant induction of human APOA4 was observed at the mRNA and protein levels, and it was inhibited in the presence of a c-Met inhibitor. Although mice constitutively expressed Apoa4 mRNA in the small intestine and the liver, the liver was the primary organ affected by administered rh-HGF to strongly induce APOA4 in a dose- and c-Met-dependent manner. Serum APOA4 levels were increased after rh-HGF administration, not only in normal mice but also in anti-Fas-induced murine acute liver failure (ALF), which confirmed the pharmacodynamic nature of APOA4. CONCLUSIONS: APOA4 was identified as a soluble PD marker of rh-HGF with c-Met dependency. It should be worthwhile to clinically validate its utility through clinical trials with healthy subjects and ALF patients.


Assuntos
Apolipoproteínas A/sangue , Biomarcadores Farmacológicos/sangue , Fator de Crescimento de Hepatócito/farmacocinética , Hepatócitos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Animais , Apolipoproteínas A/genética , Apolipoproteínas A/metabolismo , Células Cultivadas , Regulação da Expressão Gênica/efeitos dos fármacos , Fator de Crescimento de Hepatócito/administração & dosagem , Hepatócitos/metabolismo , Humanos , Fígado/fisiologia , Falência Hepática Aguda/sangue , Falência Hepática Aguda/etiologia , Masculino , Camundongos Endogâmicos BALB C , Proteínas Proto-Oncogênicas c-met/metabolismo , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacocinética
15.
Anticancer Res ; 41(4): 1921-1926, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33813397

RESUMO

BACKGROUND/AIM: Methionine addiction is a general and fundamental hallmark of cancer due to the excess use of methionine for transmethylation reactions, termed the "Hoffman Effect". Methionine addiction has been shown to be a highly-effective target for cancer therapy by methionine restriction with oral recombinant methioninase (o-rMETase) in preclinical studies, including patient- derived orthotopic xenograft (PDOX) mouse models of cancer. A clinical study of o-rMETase as a supplement showed a 70% reduction of PSA levels in a patient with bone-metastatic prostate cancer. MATERIALS AND METHODS: In the present study, two advanced prostate-cancer patients took o-rMETase as a supplement for approximately one month. RESULTS: One of the patients taking o-rMETase showed a 38% reduction of PSA levels and the second patient showed a 20% PSA reduction. CONCLUSION: o-rMETase shows promise for treating patients with advanced prostate cancer.


Assuntos
Liases de Carbono-Enxofre/administração & dosagem , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/tratamento farmacológico , Administração Oral , Idoso de 80 Anos ou mais , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Progressão da Doença , Regulação para Baixo/efeitos dos fármacos , Terapia de Reposição de Enzimas , Humanos , Masculino , Metionina/sangue , Metionina/efeitos dos fármacos , Pessoa de Meia-Idade , Projetos Piloto , Antígeno Prostático Específico/efeitos dos fármacos , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Proteínas Recombinantes/administração & dosagem
16.
Blood Coagul Fibrinolysis ; 32(5): 349-351, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33878047

RESUMO

Glanzmann thrombasthenia is an inherited disease causing bleeding episodes due to platelet dysfunction. The standard treatment for moderate-severe bleeding is platelet transfusion. Recombinant factor VIIa (rFVIIa) is successfully used in bleeding episodes and invasive procedures. Here, we present a patient with Glanzmann thrombasthenia, whose bleeding episodes could only be controlled by rFVIIa. The patient is a 28 years old male, who has had frequent bleeding episodes unresponsive to local hemostatic agents and tranexamic acid and had an anaphylactoid reaction to platelet transfusion. We started the patient on a low-dose (20 µg/kg) rFVIIa once a week. The patient has no spontaneous bleeding since then. This is the first case report of a Glanzmann thrombasthenia patient on routine prophylaxis with low-dose rFVIIa.


Assuntos
Fator VIIa/uso terapêutico , Hemorragia/etiologia , Hemorragia/prevenção & controle , Trombastenia/complicações , Adulto , Relação Dose-Resposta a Droga , Fator VIIa/administração & dosagem , Humanos , Masculino , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico
17.
Aging (Albany NY) ; 13(8): 12258-12272, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33886503

RESUMO

Growth differentiation factor 11 (GDF11), a member of the transforming growth factor ß superfamily of cytokines, is a critical rejuvenation factor in aging cells. GDF11 improves neurodegenerative and neurovascular disease outcomes, increases skeletal muscle volume, and enhances muscle strength. Its wide-ranging biological effects may include the reversal of senescence in clinical applications, as well as the ability to reverse age-related pathological changes and regulate organ regeneration after injury. Nevertheless, recent data have led to controversy regarding the functional roles of GDF11, because the underlying mechanisms were not clearly established in previous studies. In this review, we examine the literature regarding GDF11 in age-related diseases and discuss potential mechanisms underlying the effects of GDF11 in regulation of age-related diseases.


Assuntos
Envelhecimento/metabolismo , Proteínas Morfogenéticas Ósseas/administração & dosagem , Proteínas Morfogenéticas Ósseas/metabolismo , Fatores de Diferenciação de Crescimento/administração & dosagem , Fatores de Diferenciação de Crescimento/metabolismo , Rejuvenescimento , Envelhecimento/efeitos dos fármacos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Animais , Proteínas Morfogenéticas Ósseas/genética , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , Senescência Celular/efeitos dos fármacos , Senescência Celular/fisiologia , Modelos Animais de Doenças , Fatores de Diferenciação de Crescimento/genética , Humanos , Longevidade/fisiologia , Camundongos , Força Muscular/efeitos dos fármacos , Força Muscular/fisiologia , Músculo Esquelético , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/genética , Sarcopenia/tratamento farmacológico , Sarcopenia/genética , Sarcopenia/patologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/patologia
18.
Medicine (Baltimore) ; 100(9): e25044, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33655983

RESUMO

RATIONALE: Chronic disseminated intravascular coagulation (DIC) associated with thoracic aortic aneurysm is characterized by enhanced fibrinolysis and is thought to be stable in the compensated/asymptomatic stage, with few bleeding symptoms. However, DIC can lead to decompensated/hemorrhagic stage disseminated intravascular coagulation, resulting in severe bleeding diathesis, and there is currently no established strategy for treatment of DIC in aortic aneurysms. PATIENT CONCERNS: A 77-year-old woman underwent angiography and cardiac catheterization, before descending aortic replacement surgery. She developed DIC in postprocedure week 2 with extensive, uncontrollable massive subcutaneous hemorrhage. DIAGNOSES: Her acute-phase DIC score was 7 points, and the risk of mortality within 30 days after surgery according to the JapanSCORE was estimated to be 33.6%. INTERVENTIONS: Therapy was a combination of recombinant human soluble thrombomodulin (rhTM) and an aortic stent-graft treatment. OUTCOMES: Short-term improvements were seen in both DIC and bleeding diathesis. The thoracic aortic aneurysm with severe DIC was eventually corrected by administration of rhTM. LESSONS: We report the use of rhTM as an effective, novel anticoagulant drug with anti-inflammatory activity for treating DIC with suppressed fibrinolysis, which is typically associated with sepsis. In patients with a high hemorrhagic diathesis, in whom preoperative control of DIC cannot be achieved with conventional anticoagulation and radical surgical repair cannot be performed, a combination of rhTM and endovascular therapy may be a powerful new treatment option.


Assuntos
Aneurisma da Aorta Torácica/etiologia , Coagulação Intravascular Disseminada/tratamento farmacológico , Cuidados Pré-Operatórios/métodos , Trombomodulina/administração & dosagem , Procedimentos Cirúrgicos Vasculares , Idoso , Angiografia , Aneurisma da Aorta Torácica/diagnóstico , Aneurisma da Aorta Torácica/cirurgia , Coagulação Intravascular Disseminada/complicações , Relação Dose-Resposta a Droga , Feminino , Humanos , Injeções Intravenosas , Proteínas Recombinantes/administração & dosagem
19.
Medicine (Baltimore) ; 100(10): e25003, 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33725878

RESUMO

ABSTRACT: The efficacy and safety of bivalirudin in percutaneous coronary intervention (PCI) has always been a hot topic in perioperative antithrombotic therapy, but there are still some controversies. So studies are needed to provide more evidence, especially the real world study which includes patients excluded from previous RCT studys. Our study aimed to investigate these information and analyze the independent predictors of postoperative adverse events.A retrospective study enrolled 1416 patients underwent PCI in Tianjin Chest Hospital from May 2016 to October 2017. The incidence of stent-thrombosis and net clinical adverse events, including all-cause death, myocardial infarction, stroke, urgent target-vessel revascularization and bleeding, were followed up for 30 days and 1 year. Logistic regression and COX regression were respectively used to analyze independent predictors of bleeding events within 30-days, and independent predictors of Major adverse cardiovascular and cerebrovascular events (MACCE) in patients with stent implantation within 1-year.Seven hundred six patients were treated with bivalirudin while 710 with unfractionated heparin (UFH). The proportions of diabetes, hypertension, anemia, myocardial-infarction history, PCI history, moderate-to-severe renal-impairment, gastrointestinal-bleeding history in the bivalirudin group were significantly higher (P < .05). Women, anemia were independent risk factors for bleeding within 30-days (P < .05). Among 682 patients with stent implantation in bivalirudin group, anemia, Body Mass Index (BMI) >25 kg/m2, KILLIP ≥2, ejection fraction (EF) <45%, eGFR <60 ml/minutes were independent risk factors for MACCE, while Statins, proton pump inhibitor (PPI) were independent protective factors for MACCE with-in 1-year (P < .05).Bivalirudin have good anticoagulant effect and lower bleeding risk during PCI, especially in patients with higher bleeding risk. In patients treated with bivalirudin, female, anemia were independent predictors of bleeding within 30-days, BMI >25 kg/m2, anemia, KILLIP ≥2, EF <45%, eGFR <60 ml/minutes were independent risk factors and Statins, PPI were independent protective factors of MACCE within 1-year.


Assuntos
Antitrombinas/administração & dosagem , Doença das Coronárias/cirurgia , Hirudinas/administração & dosagem , Fragmentos de Peptídeos/administração & dosagem , Intervenção Coronária Percutânea/efeitos adversos , Hemorragia Pós-Operatória/epidemiologia , Trombose/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Antitrombinas/efeitos adversos , Feminino , Hirudinas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/efeitos adversos , Assistência Perioperatória/efeitos adversos , Assistência Perioperatória/métodos , Hemorragia Pós-Operatória/induzido quimicamente , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais , Stents , Trombose/etiologia , Trombose/prevenção & controle , Resultado do Tratamento
20.
Medicine (Baltimore) ; 100(10): e25004, 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33725879

RESUMO

BACKGROUND: Acute ischemic stroke (AIS) is an important factor leading to adult death and disability globally. For AIS patients who meet certain conditions, recombinant tissue plasminogen activator (rt-PA) intravenous thrombolysis is an important method recommended by national guidelines to achieve vascular recanalization. However, complications such as hemorrhagic transformation and vascular reocclusion after thrombolysis are still unsolved problems in clinical. Several systematic reviews of clinical randomized controlled trials (RCTs) in the past have shown that Chinese herbal injections (CHIs) can improve the neurological function of patients, increase the tolerance of ischemic tissues to hypoxia, and inhibit platelet aggregation. Therefore, this study conducted a meta-analysis of AIS treatment with intravenous thrombolysis alone and compared it with the combined application of CHIs. To evaluate whether CHIs have a synergistic effect on thrombolytic therapy and provide a basis for clinical application. METHODS: The following databases will be searched until September 2020: ①English databases: PubMed, Cochrane Library, Embase; ②Chinese databases: CNKI, Wanfang database, Weipu database, SinoMed. RCTs will be included to compare the efficacy of thrombolysis combined with CHIs and thrombolysis alone in the treatment of AIS. Data extraction and risk of bias assessments will be carried out by 2 verifiers independently. The risk of bias will be evaluated through the Cochrane risk of bias tool. Review Manager software 5.3 will be used for statistical analysis. RESULTS: This study will provide comprehensive evidence for the treatment of AIS by CHIs combined with intravenous thrombolysis from multiple aspects. CONCLUSION: The conclusion of the meta-analysis will provide a basis for judging whether CHIs combined with intravenous thrombolysis is an effective measure for the treatment of AIS. ETHICS AND DISSEMINATION: Ethical approval is not needed because this study will be based on data that already published. We will publish the findings of this study in a peer-reviewed journal and related conferences. PROSPERO REGISTRATION NUMBER: CRD42020215546.


Assuntos
Medicamentos de Ervas Chinesas/administração & dosagem , Fibrinolíticos/administração & dosagem , Hemorragia/epidemiologia , AVC Isquêmico/terapia , Terapia Trombolítica/métodos , Ativador de Plasminogênio Tecidual/administração & dosagem , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Medicamentos de Ervas Chinesas/efeitos adversos , Fibrinolíticos/efeitos adversos , Hemorragia/induzido quimicamente , Hemorragia/prevenção & controle , Humanos , Infusões Intravenosas/efeitos adversos , Infusões Intravenosas/métodos , Metanálise como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Revisões Sistemáticas como Assunto , Terapia Trombolítica/efeitos adversos , Ativador de Plasminogênio Tecidual/efeitos adversos , Resultado do Tratamento
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...