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2.
Brasília; s.n; 19 jun. 2020.
Não convencional em Português | LILACS, BRISA/RedTESA, PIE | ID: biblio-1100432

RESUMO

O Informe Diário de Evidências é uma produção do Ministério da Saúde que tem como objetivo acompanhar diariamente as publicações científicas sobre tratamento farmacológico e vacinas para a COVID-19. Dessa forma, são realizadas buscas estruturadas em bases de dados biomédicas, referente ao dia anterior desse informe. Não são incluídos estudos pré-clínicos (in vitro, in vivo, in silico). A frequência dos estudos é demonstrada de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, coortes, entre outros). Para cada estudo é apresentado um resumo com avaliação da qualidade metodológica. Essa avaliação tem por finalidade identificar o grau de certeza/confiança ou o risco de viés de cada estudo. Para tal, são utilizadas ferramentas já validadas e consagradas na literatura científica, na área de saúde baseada em evidências. Cabe ressaltar que o documento tem caráter informativo e não representa uma recomendação oficial do Ministério da Saúde sobre a temática. Foram encontrados 9 artigos e 6 protocolos.


Assuntos
Humanos , Pneumonia Viral/tratamento farmacológico , Infecções por Coronavirus/tratamento farmacológico , Betacoronavirus/efeitos dos fármacos , Avaliação da Tecnologia Biomédica , Imunoglobulinas/uso terapêutico , Metilprednisolona/uso terapêutico , Heparina/uso terapêutico , Cefoperazona/uso terapêutico , Cloroquina/uso terapêutico , Ritonavir/uso terapêutico , Oseltamivir/uso terapêutico , Lopinavir/uso terapêutico , Moxifloxacina/uso terapêutico , Timalfasina/uso terapêutico , Hidroxicloroquina/uso terapêutico
3.
s.l; s.n; ene. 2020. ilus, tab.
Não convencional em Espanhol | LILACS, BRISA/RedTESA | ID: biblio-1095041

RESUMO

OBJETIVO: Se sugiere no utilizar Timosina alfa-1 como terapia adyuvante en el tratamiento del câncer. TECNOLOGÍA EVALUADA: El sistema inmunitario juega un rol fundamental en las propias defensas del organismo contra las células cancerosas. El timo juega un papel central en esta situación y modifica los linfocitos T, una clase de linfocitos. Los estudios de péptidos tímicos hallaron numerosos efectos sobre el sistema inmunitario. Existen dos grupos de péptidos tímicos disponibles para el tratamiento, a saber: los extractos purificados de timo animal (mayormente de terneros) y los péptidos de timo producidos de forma sintética. Se cree que los extractos de timo purificados (pTE, por sus siglas en inglés) y los péptidos tímicos sintéticos (sTP, por sus siglas en inglés) mejoran el sistema inmunitario de los pacientes con cáncer para poder luchar contra el crecimiento de células tumorales y resistir las infecciones por la inmunodepresión inducida por la enfermedad y el tratamiento antineoplásico. METODOLOGÍA: Este estudio incluyó 26 ensayos (2736 pacientes). Veinte ensayos investigaron los Pte (timoestimulina o timosina fracción 5) y seis ensayos investigaron los sTP (timopentina o timosina α1). 4 estudios evaluaron el uso de Timosina alfa-1 en pacientes con cáncer Cheng 2004; Gish 2009; Maio 2010; Schulof 1985. Veintiún ensayos informaron los resultados de la SG, seis los de la SLE, 14 los de la RT, nueve los de los EA y diez los de seguridade de los pTE y los sTP. El agregado de pTE no produjo beneficios en la SG (CR 1,00; IC del 95%: 0,79 a 1,25); la SLE (CR 0,97; IC del 95%: 0,82 a 1,16); ni en la RT (CR 1,07; IC del 95%: 0,92 a 1,25). La heterogeneidad de estos resultados fue de moderada a alta. Para la timosina α1el CR agrupado de la SG fue de 1,21 (IC del 95%: 0,94 a 1,56; p = 0,14), con una baja heterogeneidad; y de 3,37 (IC del 95%: 0,66 a 17,30; p = 0,15) para la SLE, con heterogeneidad moderada. Los pTE redujeron el riesgo de complicaciones infecciosas graves (CR 0,54; IC del 95%: 0,38 a 0,78; p = 0,0008; I2 = 0%). El CR de la neutropenia grave en los pacientes tratados con timoestimulina fue de 0,55 (IC del 95%: 0,25 a 1,23; p = 0,15). La tolerabilidad de los pTE y los sTP fue adecuada. La mayoría de ensayos tenían al menos un riesgo de sesgo moderado. RECOMENDACIONES Y JUICIOS: En general, no se hallaron pruebas de que el agregado de pTE al tratamento antineoplásico reduzca el riesgo de mortalidad o la progresión de la enfermedad, ni que mejore la tasa de respuestas tumorales al tratamiento antineoplásico. Se sugiere no utilizar Timosina alfa-1 como terapia adyuvante en el tratamiento del câncer.


Assuntos
Humanos , Timalfasina/uso terapêutico , Neoplasias/tratamento farmacológico , Avaliação da Tecnologia Biomédica , Análise Custo-Eficiência
4.
Prep Biochem Biotechnol ; 50(3): 281-291, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31718419

RESUMO

The use of interferon α-2 in combination with thymosin α-1 shows higher anti-cancer effect in comparison when both are used individually because of their synergistic effects. In this study we produced an important human interferon α-2-thymosin α-1 (IFNα2-Tα1) fusion protein with probable pharmaceutical properties coupled to its high-level expression, characterization, and study of its biological activity. The IFNα2-Tα1 fusion gene was constructed by over-lap extension PCR and expressed in Escherichia coli expression system. The expression of IFNα2-Tα1 fusion protein was optimized to higher level and its maximum expression was obtained in modified terrific broth medium when lactose was used as inducer. The fusion protein was refolded into its native biologically active form with maximum yield of 83.14% followed by purification with ∼98% purity and 69% final yield. A band of purified IFNα2-Tα1 fusion protein equal to ∼23 kDa was observed on 12 % SDS-PAGE gel. The integrity of IFNα2-Tα1 fusion protein was confirmed by western blot analysis and secondary structure was assessed by CD spectroscopy. When IFNα2-Tα1 fusion protein was subjected to its biological activity analysis it was observed that it exhibits both IFNα2 & Tα1 activities as well as significantly higher anticancer activity as compared to IFNα-2 alone.


Assuntos
Interferon-alfa , Proteínas Recombinantes de Fusão , Timalfasina , Escherichia coli/química , Escherichia coli/genética , Escherichia coli/metabolismo , Humanos , Interferon-alfa/química , Interferon-alfa/genética , Interferon-alfa/isolamento & purificação , Interferon-alfa/farmacologia , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/isolamento & purificação , Proteínas Recombinantes de Fusão/farmacologia , Timalfasina/química , Timalfasina/genética , Timalfasina/isolamento & purificação , Timalfasina/farmacologia
5.
Ann Clin Lab Sci ; 49(3): 368-371, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31308037

RESUMO

OBJECTIVE: This study aims to investigate the changes in CD3+, CD4+ and CD8+ expression in cells in peripheral blood of silicosis patients, and observe the immunoregulatory effect of thymalfasin. METHODS: A total of 80 silicosis patients were enrolled in the study, randomly divided into two groups: treatment group and control group (n=40, each group). In addition, 40 healthy adults, who underwent physical examinations in our hospital, were enrolled into the health examination group. Patients in the control group and treatment group were given anti-infection treatment, according to their conditions. Patients in the treatment group additionally received thymalfasin. Then, the number of peripheral blood T lymphocyte subsets in subjects in all three groups before and after treatment was measured. RESULTS: (1) Before treatment, CD3+, CD4+ and CD8+ levels in cells were significantly lower in the treatment group and control group than in the health examination group, and the differences were statistically significant (P<0.05). (2) In the treatment group, the number of CD4+ cells in peripheral blood was significantly higher after one week of treatment, when compared to that before treatment, and the difference was statistically significant (P<0.05). CONCLUSION: In silicosis patients, CD3+, CD4+ and CD8+ cells in peripheral blood are decreased, and thymalfasin can significantly increase CD4+ cells in peripheral blood of silicosis patients.


Assuntos
Antígenos CD/metabolismo , Silicose/sangue , Silicose/tratamento farmacológico , Timalfasina/uso terapêutico , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Silicose/imunologia , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Timalfasina/farmacologia
6.
Int Immunopharmacol ; 74: 105662, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31220695

RESUMO

Thymosin alpha 1 (Tα1) is an immunomodulatory polypeptide secreted from the thymus. Tα1 has a wide range of biological functions, such as immunomodulation and endocrine regulation. Tα1 also displays antiviral and antitumor activities. Tα1 has been successfully used in clinical adjuvant therapy for solid tumors to improve the immune response of patients undergoing chemotherapy and radiotherapy. However, the half-life of Tα1 in the body is short, so frequent administration is required to maintain efficacy. In order to improve the pharmacokinetic profile of Tα1, we linked the mutated CH3 (mCH3) fragment of IgG1 (human) to the C-terminus of Tα1 to produce a long-acting fusion protein, Tα1-mCH3. The half-life of Tα1-mCH3 (47 h) was substantially increased compared with that of the parent molecule Tα1 (3 h). In vivo studies indicated that mCH3 fusion retained the original biological activity of Tα1, and Tα1-mCH3 showed slightly better immunomodulatory effect than Ta1. In the 4 T1 and B16F10 tumor xenograft models, Tα1-mCH3 induced a greater abundance of CD4+ and CD8+ T-cells in tumor tissues compared with Ta1. Tα1-mCH3 exhibited better effect in promoting the production of IL-2 and IFN-γ compared with Tα1. Therefore, Tα1-mCH3 more efficiently inhibited the growth of 4 T1 and B16F10 tumors than Tα1. In conclusion, fusion with mCH3 is an attractive strategy to lengthen the half-life and increase the activity of Tα1.


Assuntos
Antineoplásicos , Fragmentos de Imunoglobulinas , Imunoglobulina G , Neoplasias/tratamento farmacológico , Proteínas Recombinantes de Fusão , Timalfasina , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Citocinas/imunologia , Feminino , Meia-Vida , Fragmentos de Imunoglobulinas/genética , Fragmentos de Imunoglobulinas/uso terapêutico , Imunoglobulina G/genética , Imunoglobulina G/uso terapêutico , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Mutação , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/patologia , Ratos Sprague-Dawley , Proteínas Recombinantes de Fusão/farmacocinética , Proteínas Recombinantes de Fusão/uso terapêutico , Timalfasina/farmacocinética , Timalfasina/uso terapêutico
7.
Environ Toxicol ; 34(8): 941-949, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31067016

RESUMO

This research was conducted to investigate the biochemical effects of thymosin alpha-1 using human lung cancer cells (A549). The A549 cells were treated with different concentrations of Thα1 for 24 h and the growth, inhibition of cells was determined. Thα1 revealed anti-proliferative effect at 24 and 48 µg/ml after 24 h. Furthermore, it indicated antioxidant properties by significantly enhancing the activity of catalase (12 µg/ml), superoxide dismutase (6 and 12 µg/ml), and glutathione peroxidase (3, 6 and 12 µg/ml) and reducing the production of cellular ROS. Our results showed that Thα1 inhibits the migration of A549 cells in a concentration-dependent manner after 24 and 48 h. Moreover, the effect of Thα1 on apoptosis was investigated by Hoechst 33342 staining and cell cycle analysis. Results demonstrated no significant effect on the induction of apoptosis in A549 cells. In conclusion, our results showed the antioxidant properties of Thα1 on A549 cancer cells.


Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Timalfasina/farmacologia , Células A549 , Apoptose/efeitos dos fármacos , Catalase/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Glutationa Peroxidase/metabolismo , Humanos , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo
8.
Transplant Proc ; 51(2): 556-560, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30879589

RESUMO

Mucormycosis is an uncommonly encountered fungal infection in solid-organ transplantation, occurring most often gastrointestinally. The most common and fatal infectious disease is cytomegalovirus (CMV) pneumonia, which may result in acute respiratory distress syndrome (ARDS), with rapid onset. Early diagnosis, active treatment, and rational reduction of immunosuppressants are crucial for successful kidney transplantation. We performed successful treatment for both mucormycosis and CMV pneumonia and adjusted the tacrolimus dose accordingly. The case we describe was that of a 47-year-old woman with history of renal transplantation 1 month earlier. She presented with chest pain and gastrointestinal bleeding and was diagnosed with gastric mucormycosis and a secondary episode of hospital-acquired pneumonia. Preemptive therapy, which included liposomal amphotericin B and posaconazole, was adminstered when voriconazole proved to be unhelpful and before histologic reports of gastric mucormycosis. Moreover, CMV re-activation was confirmed by CMV antibody detection, and we administered gancyclovir and thymosin α1 but reduced the strength of the immunosuppressive drugs. Fourteen days after the aforementioned therapy, the patient began to recover and she was discharged on day 81 postoperatively. We conclude that preemptive treatment is critical for severe infection in renal transplant recipients, especially with the rarely seen gastric mucormycosis and with ARDS. In addition, immunoregulated agents, such as asthymosin α1, are also of great value in renal transplant recipients in the setting of opportunistic pathogen infections.


Assuntos
Infecções por Citomegalovirus/imunologia , Hospedeiro Imunocomprometido , Transplante de Rim/efeitos adversos , Mucormicose/imunologia , Infecções Oportunistas/imunologia , Anti-Infecciosos/uso terapêutico , Citomegalovirus , Feminino , Ganciclovir/uso terapêutico , Humanos , Imunossupressores/efeitos adversos , Pessoa de Meia-Idade , Pneumonia/imunologia , Pneumonia/microbiologia , Gastropatias/imunologia , Gastropatias/microbiologia , Timalfasina/uso terapêutico
9.
J Pharm Biomed Anal ; 170: 16-21, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-30903925

RESUMO

Thymosin α1 (Thymalfasin, Tα1) is a naturally occurring polypeptide widely used as an immune system enhancer for the treatment of HIV/AIDS, hepatitis B and C, and cancer. Recombinant human Tα1 (rh-Tα1) lacking N-terminal acetylation (NTA) displays similar biological activity to Tα1 and has completed phase III clinical trials in China. To compare the pharmacokinetics of rh-Tα1 and Tα1 and establish whether they undergo mutual transmutation in vivo, we developed a novel bioassay based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the simultaneous determination of the two peptides in human plasma and urine. Sample preparation by protein precipitation using a mixture of methanol and perchloric acid was followed by HPLC on a Zorbax 300SB-C18 column (150 × 4.6 mm, 5 µm) maintained at 40 °C. Detection was by multiple reaction monitoring (MRM) of the precursor-to-product ion transitions at m/z 778.0→316.0 for Tα1, m/z 767.3→955.0 for rh-Tα1 and m/z 832.3→159.2 for the internal standard, eptifibatide. The method was linear in the range 2-100 ng/mL for both analytes with good accuracy and precision. High sample throughput was facilitated by inclusion of a parallel two-column chromatographic system. The method was successfully applied to a comparative pharmacokinetic study involving single subcutaneous injections of either Tα1 or rh-Tα1 to two groups of healthy male volunteers. The results indicate that rh-Tα1 undergoes NTA in vivo to form Tα1 but that Tα1 is not deacetylated to rh-Tα1.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Plasma/química , Espectrometria de Massas em Tandem/métodos , Timalfasina/sangue , Timalfasina/urina , Adulto , China , Humanos , Masculino , Reprodutibilidade dos Testes , Adulto Jovem
10.
Neurosci Bull ; 35(4): 637-648, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30790216

RESUMO

Activation of inflammatory responses regulates the transmission of pain pathways through an integrated network in the peripheral and central nervous systems. The immunopotentiator thymosin alpha-1 (Tα1) has recently been reported to have anti-inflammatory and neuroprotective functions in rodents. However, how Tα1 affects inflammatory pain remains unclear. In the present study, intraperitoneal injection of Tα1 attenuated complete Freund's adjuvant (CFA)-induced pain hypersensitivity, and decreased the up-regulation of pro-inflammatory cytokines (TNF-α, IL-1ß, and IL-6) in inflamed skin and the spinal cord. We found that CFA-induced peripheral inflammation evoked strong microglial activation, but the effect was reversed by Tα1. Notably, Tα1 reversed the CFA-induced up-regulation of vesicular glutamate transporter (VGLUT) and down-regulated the vesicular γ-aminobutyric acid transporter (VGAT) in the spinal cord. Taken together, these results suggest that Tα1 plays a therapeutic role in inflammatory pain and in the modulation of microglia-induced pro-inflammatory cytokine production in addition to mediation of VGLUT and VGAT expression in the spinal cord.


Assuntos
Citocinas/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Dor/tratamento farmacológico , Dor/metabolismo , Timalfasina/farmacologia , Sistema X-AG de Transporte de Aminoácidos/metabolismo , Animais , Adjuvante de Freund , Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
11.
Front Immunol ; 9: 2449, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30405635

RESUMO

Autocrine activation of the complement receptors C3aR and CD46 by complement activation components C3a and C3b produced through C3 cleavage by the protease cathepsin L (CTSL) during T cell stimulation is a requirement for IFN-γ production and Th1 induction in human CD4+ T cells. Thus, lack of autocrine CD46 activation, such as in CD46-deficient patients, is associated with defective Th1 responses and recurrent infections. We have identified LGMN [the gene coding for legumain, also known as asparaginyl endopeptidase (AEP)] as one of the key genes induced by CD46 co-stimulation during human CD4+ T cell activation. AEP processes and activates a range of proteins, among those α1-thymosin and CTSL, which both drive intrinsically Th1 activity-but has so far not been described to be functionally active in human T cells. Here we found that pharmacological inhibition of AEP during activation of human CD4+ T cells reduced CTSL activation and the CTSL-mediated generation of intracellular C3a. This translated into a specific reduction of IFN-γ production without affecting cell proliferation or survival. In line with these findings, CD4+ T cells isolated from Lgmn -/- mice also displayed a specific defect in IFN-γ secretion and Th1 induction. Furthermore, we did not observe a role for AEP-driven autocrine α1-thymosin activation in T cell-derived IFN-γ production. These data suggest that AEP is an "upstream" activator of the CTSL-C3-IFN-γ axis in human CD4+ T cells and hence an important supporter of human Th1 induction.


Assuntos
Catepsina L/metabolismo , Complemento C3a/imunologia , Complemento C3b/imunologia , Cisteína Endopeptidases/metabolismo , Interferon gama/metabolismo , Células Th1/imunologia , Animais , Proliferação de Células , Cisteína Endopeptidases/genética , Humanos , Interferon gama/biossíntese , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Proteína Cofatora de Membrana/metabolismo , Camundongos , Camundongos Knockout , Receptores de Complemento/metabolismo , Timalfasina/metabolismo
12.
Biomed Pharmacother ; 108: 610-617, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30243095

RESUMO

Thymosin alpha1 (Tα1) is a multifunctional polypeptide involved in immunoregulation, which universally exists in various organs. The clinical application, however, is limited because of its short half-life. The Fc domain of human IgG has functional properties, improving the affinity and serum half-life. In this study, we fused Tα1 to Fc domain of human IgG1 for generation of a novel long-acting fusion protein, termed Tα1-Fc. Tα1-Fc was expressed, purified, and identified. The results showed that Tα1-Fc was more potent than Tα1 in inhibiting the growth of 4T1 and MCF-7 breast cancer cells in vivo. Furthermore, in the 4T1 tumor model the mice treated with Tα1-Fc exhibited higher level of CD4 and CD8 cells compared with that of the mice Tα1 treated. The interferon-γ and interleukin-2 level in the Tα1-Fc-treated mice was higher than that in the Tα1-treated mice. Tα1-Fc could also alleviate immunosuppression induced by hydrocortisone. In summary, Tα1-Fc provides a novel potent strategy to recruit immune cells against tumors and enhance the antitumor activity of Tα1.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Fragmentos Fc das Imunoglobulinas/farmacologia , Timalfasina/farmacologia , Animais , Antineoplásicos/farmacologia , Neoplasias da Mama/metabolismo , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Humanos , Imunoglobulina G/metabolismo , Interferon gama/metabolismo , Interleucina-2/metabolismo , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Camundongos Nus , Ratos , Ratos Wistar
13.
Sci Rep ; 8(1): 12351, 2018 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-30120362

RESUMO

Thymosin alpha 1 (Tα1) is a biological response modifier that has been introduced into markets for treating several diseases. Given the short serum half-life of Tα1 and the rapid development of Fc fusion proteins, we used genetic engineering method to construct the recombinant plasmid to express Tα1-Fc (Fc domain of human IgG4) fusion protein. A single-factor experiment was performed with different inducers of varying concentrations for different times to get the optimal condition of induced expression. Pure proteins higher than 90.3% were obtained by using 5 mM lactose for 4 h with a final production about 160.4 mg/L. The in vivo serum half-life of Tα1-Fc is 25 h, almost 13 times longer than Tα1 in mice models. Also, the long-acting protein has a stronger activity in repairing immune injury through increasing number of lymphocytes. Tα1-Fc displayed a more effective antitumor activity in the 4T1 and B16F10 tumor xenograft models by upregulating CD86 expression, secreting IFN-γ and IL-2, and increasing the number of tumor-infiltrating CD4+ T and CD8+ T cells. Our study on the novel modified Tα1 with the Fc segment provides valuable information for the development of new immunotherapy in cancer.


Assuntos
Neoplasias da Mama/etiologia , Neoplasias da Mama/metabolismo , Fragmentos Fc das Imunoglobulinas/imunologia , Melanoma/etiologia , Melanoma/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Timalfasina/metabolismo , Animais , Biomarcadores Tumorais , Neoplasias da Mama/patologia , Modelos Animais de Doenças , Progressão da Doença , Feminino , Meia-Vida , Humanos , Hidrocortisona/sangue , Hidrocortisona/metabolismo , Hospedeiro Imunocomprometido , Fragmentos Fc das Imunoglobulinas/genética , Fragmentos Fc das Imunoglobulinas/farmacologia , Imunomodulação/efeitos dos fármacos , Masculino , Melanoma/patologia , Melanoma Experimental , Camundongos , Prognóstico , Ratos , Proteínas Recombinantes de Fusão/sangue , Timalfasina/genética , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Biochimie ; 154: 99-106, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30096371

RESUMO

Thymosin α1 (Tα1), a hormone containing 28 amino acids, has been approved in several cancer therapies, but the lack of tumor-targeting hinders its full use in tumor treatment. We designed a new peptide by connecting Tα1 and RGDR, generating a product, Tα1-RGDR, where RGDR is located in the C-end with both tumor-homing and cell internalizing properties (C-end rule peptides, a consensus R/KXXR/K motif). This work aimed to study the antitumor and immunological activities of Tα1-RGDR, and its differences compared with the wild-type Tα1. The antitumor and immunological activities of Tα1-RGDR were measured using the B16F10 tumor and immunologic suppression models. Tα1-RGDR treatment led to significant inhibition of tumor growth at a dose at which Tα1 showed a slight effect in the B16F10 tumor growth model. In the immunologic suppression model, Tα1-RGDR shared almost equivalent immunomodulatory effect with Tα1. These results demonstrated the better therapeutic effects after treatment with Tα1-RGDR compared with Tα1. Moreover, both Tα1-RGDR and Tα1 shared a helical conformation in the presence of trifluoroethanol based on CD spectroscopy. Our dock information of Tα1-RGDR when combined with integrin αvß3 or neuropilin-1 further confirmed previous experimental results. All these findings suggest that Tα1-RGDR might be a useful therapy for tumors by overcoming its wild type limitation of tumor homing.


Assuntos
Antineoplásicos/química , Melanoma/metabolismo , Timosina/análogos & derivados , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Melanoma/tratamento farmacológico , Melanoma/patologia , Camundongos , Timalfasina , Timosina/química , Timosina/farmacologia
15.
Expert Opin Biol Ther ; 18(sup1): 77-83, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-30063847

RESUMO

BACKGROUND: Immune checkpoint blockade antibodies (imAbs), such as the anti Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) ipilimumab (IPI) raised overall survival (OS) in metastatic melanoma (MM). Further, long-term OS is a crucial endpoint in MM. Thymosin alpha-1 (Tα1) with dacarbazine (DTIC) showed activity in a phase II trial and a compassionate use program (EAP). We report on long-term follow-up of patients treated with Tα1 to investigate the preconditioning role of Tα1 in imAbs-treated patients. METHODS: Records of patients with melanoma treated with Tα1 within a phase II trial and EAP program were reviewed comparing median OS among patients that sequentially received anti-CTLA-4 imAb and Tα1. Further, the effect of Tα1 on IPI long-term survivor patients was investigated. RESULTS: Among patients treated with Tα1, 21/61 patients received sequentially even anti CTLA-4 imAbs. Median OS at the data cut-off was 57.8 and 7.4 months in patients treated sequentially with anti-CTLA-4 imAbs or not, respectively. Moreover, pretreatment with Tα1 in all (95) IPI-evaluable patients confirmed a significant increase in long-term OS. CONCLUSION: This is the first report on long-term follow-up of Tα1-treated patients. Moreover, an advantage in OS in patients sequentially treated with Tα1 and IPI was seen that suggests a synergistic effect.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ipilimumab/administração & dosagem , Melanoma/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Neoplasias Cutâneas/tratamento farmacológico , Timalfasina/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/imunologia , Ensaios Clínicos Fase II como Assunto , Dacarbazina/administração & dosagem , Dacarbazina/efeitos adversos , Sinergismo Farmacológico , Feminino , Seguimentos , Humanos , Ipilimumab/efeitos adversos , Masculino , Melanoma/mortalidade , Melanoma/patologia , Pessoa de Meia-Idade , Metástase Neoplásica , Inibidores de Proteínas Quinases/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Análise de Sobrevida , Timalfasina/efeitos adversos , Fatores de Tempo , Adulto Jovem
16.
Expert Opin Biol Ther ; 18(sup1): 53-60, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-30063854

RESUMO

INTRODUCTION: Severe acute pancreatitis (SAP) is an acute inflammatory disease with prolonged clinical course, which is complicated by the presence of persistent organ failure and severe infection. Infection mainly occurs in the late phase of SAP and it is found to be the main cause of death. Therefore, developing strategies for the prevention of SAP-related infection has been a crucial approach to improve patients' outcomes. Due to remarkable immune-cells-regulating properties, thymosin α1 has been recognized as a promising immune therapy, especially in several infectious diseases. Recently, thymosin α1 has been given high expectations to exert clinical benefits in the prevention of SAP-related infection. AREAS COVERED: The review of currently available strategies for SAP-related infection prevention and the use of thymosin α1 in SAP patients. EXPERT OPINION: The current available strategies achieve limited success for preventing SAP-related infection. A possible explanation is that the trigger of infection, immunosuppression has not been concurrently resolved. The application of thymosin α1 in a clinical study showed a prophylactic effect against SAP-related infection. However, the use of thymosin α1 in SAP patients is still at an early stage of clinical investigation and requires high-quality and large sample size evidences.


Assuntos
Quimioprevenção/métodos , Infecções/tratamento farmacológico , Pancreatite/tratamento farmacológico , Sepse/prevenção & controle , Timalfasina/uso terapêutico , Doença Aguda , Humanos , Pancreatite/patologia , Índice de Gravidade de Doença
17.
Expert Opin Biol Ther ; 18(sup1): 33-42, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-30063856

RESUMO

INTRODUCTION: Thymosins have been extracted, characterized, and identified from Thymus. The Thymosins are hormones whose therapeuric applications have seen a recent increase. The action of Thymosin α1 is based on the stimulation of the immune response with a large number of results in a variety of pathologies. The absence of a specific receptor prompted us to investigate the direct interaction with membranes, particularly those exposing phosphatidylserine thus contributing to assess the Thymosin α1's pleiotropy. AREAS COVERED: The interaction with membranes has been studied with a number of models indicating that Thymosin α1 interacts preferentially with negative regions of the membrane (SDS mixed with dodecylphosphocholine) or, better, with vesicles of dipalmitoylphosphatidylcholine with exposed phosphatidylserine. EXPERT OPINION: The study of the role of the membrane in the mechanism of action of Thymosin α1 indicated that probably the first interaction occurs at the membrane level with recognition of negative surface due to the phosphatidylserine exposure. Upon assuming a conformation, with two helices with a disordered tract in between, it diffuses on the membrane surface by lateral diffusion. Then the interaction with membrane receptor(s) causes a membrane complex to be formed, with an activation of a signalling cascade. This can be considered the basis of its pleiotropy. Differences in structuration mechamism of Thymosin ß4 was outlined.


Assuntos
Membrana Celular/metabolismo , Timalfasina/química , Timalfasina/metabolismo , Animais , Humanos , Ligação Proteica , Estrutura Secundária de Proteína , Especificidade por Substrato , Timalfasina/genética
18.
Expert Opin Biol Ther ; 18(sup1): 61-69, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-30063860

RESUMO

ABSTRACT Background: Thymosin alpha-1 (Ta-1) suppresses HBV viral replication, while the evidence of combination effect with nucleoide is still limited. We aimed to investigate the efficacy and safety of combination therapy of Ta-1 with entecavir (ETV) in patients with compensated liver cirrhosis. RESEARCH DESIGN AND METHODS: A total of 690 patients were randomized to receive Ta-1 plus ETV (n = 351) or ETV monotherapy (n = 339) for 52 weeks after 26 weeks of ETV treatment, followed by continued entecavir therapy. The primary endpoint was defined as liver decompensation, hepatocellular carcinoma (HCC) or death. RESULTS: The median followed up was 38.2 months. The cumulative incidence of liver decompensation, HCC, or death were similar between two groups. During the Ta-1 combination treatment, the HCC incidence was 1.7% in combination group and 2.1% in ETV group, without new HCC cases developed during week 39 to week 77 in combination group. The virologic response, serologic response, biochemical response was similar between two groups at week 104. Both therapies were well-tolerated. CONCLUSION: There was no significant difference between two groups in endpoint events, while combination therapy with Ta-1 has a tendency to inhibit the development of HCC.


Assuntos
Guanina/análogos & derivados , Hepatite B Crônica/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , Falência Hepática/tratamento farmacológico , Timalfasina/administração & dosagem , Adulto , Antivirais/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/virologia , Quimioterapia Combinada , Feminino , Guanina/administração & dosagem , Guanina/efeitos adversos , Hepatite B Crônica/complicações , Hepatite B Crônica/epidemiologia , Humanos , Incidência , Cirrose Hepática/epidemiologia , Cirrose Hepática/virologia , Falência Hepática/epidemiologia , Falência Hepática/virologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Timalfasina/efeitos adversos , Resultado do Tratamento
19.
Expert Opin Biol Ther ; 18(sup1): 23-31, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-30063863

RESUMO

BACKGROUND: Thymosin alpha 1 (Tα1) is a well-recognized immune response modulator in a wide range of disorders, particularly infections and cancer. The bioinformatic analysis of public databases allows drug repositioning, predicting a new potential area of clinical intervention. We aimed to decipher the cellular network induced by Tα1 treatment to confirm present use and identify new potential clinical applications. RESEARCH DESIGN AND METHODS: We used the transcriptional profile of human peripheral blood mononuclear cells treated in vitro with Tα1 to perform the enrichment network analysis by the Metascape online tools and the disease enrichment analysis by the DAVID online tool. RESULTS: Networked cellular responses reflected Tα1 regulated biological processes including immune and metabolic responses, response to compounds and oxidative stress, ion homeostasis, peroxisome biogenesis and drug metabolic process. Beyond cancer and infections, the analysis evidenced the association with disorders such as kidney chronic failure, diabetes, cardiovascular, chronic respiratory, neuropsychiatric, neurodegenerative and autoimmune diseases. CONCLUSIONS: In addition to the known ability to promote immune response pathways, the network enrichment analysis demonstrated that Tα1 regulates cellular metabolic processes and oxidative stress response. Notable, the analysis highlighted the association with several diseases, suggesting new translational implication of Tα1 treatment in pathological conditions unexpected until now.


Assuntos
Infecções/tratamento farmacológico , Leucócitos Mononucleares/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Timalfasina/uso terapêutico , Transcriptoma/efeitos dos fármacos , Doenças Autoimunes/tratamento farmacológico , Fenômenos Biológicos/efeitos dos fármacos , Fenômenos Biológicos/genética , Perfilação da Expressão Gênica , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Infecções/sangue , Infecções/genética , Leucócitos Mononucleares/metabolismo , Análise em Microsséries , Neoplasias/sangue , Neoplasias/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
20.
Expert Opin Biol Ther ; 18(sup1): 13-21, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-30063864

RESUMO

INTRODUCTION: Thymosin alpha 1 (Ta1) is a natural occurring peptide hormone that is crucial for the maintenance of the organism homeostasis. It has been chemically synthesized and used in diseases where the immune system is hindered or malfunctioning. AREAS COVERED: Many clinical trials investigate the Ta1 effects in patients with cancer, infectious diseases and as a vaccine enhancer. The number of diseases that could benefit from Ta1 treatment is increasing. To date, questions remain about the physiological basal levels of Ta1 and the most effective dose and schedule of treatment. Evidence is growing that diseases characterized by deregulation of immune and/or inflammatory responses are associated with serum levels of Ta1 significantly lower than those of healthy individuals: to date, B hepatitis, psoriatic arthritis, multiple sclerosis and sepsis. The sputum of cystic fibrosis patients contains lower levels of Ta1 than healthy controls. These data are consistent with the role of Ta1 as a regulator of immunity, tolerance and inflammation. EXPERT OPINION: Low serum Ta1 levels are predictive and/or associated with different pathological conditions. In case of Ta1 treatment, it is crucial to know the patient's baseline serum Ta1 level to establish effective treatment protocols and monitor their effectiveness over time.


Assuntos
Doença , Homeostase/fisiologia , Timalfasina/sangue , Adjuvantes Imunológicos/sangue , Adjuvantes Imunológicos/uso terapêutico , Doenças Transmissíveis/sangue , Doenças Transmissíveis/tratamento farmacológico , Doença/etiologia , Hepatite B/sangue , Hepatite B/tratamento farmacológico , Humanos , Neoplasias/sangue , Neoplasias/imunologia , Neoplasias/terapia , Sepse/sangue , Sepse/tratamento farmacológico , Timalfasina/fisiologia , Timalfasina/uso terapêutico , Vacinas/uso terapêutico
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