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1.
Int J Nanomedicine ; 15: 5279-5288, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801691

RESUMO

Introduction: Today, a new paradigm has emerged for cancer treatment introducing combination therapies. Doxil, a liposomal doxorubicin serving as a chemotherapeutic agent, is an effective immunogenic killer of cancer cells. Anti-CTLA-4 has been approved for the treatment of some cancers, including melanoma, but side effects have limited its therapeutic potential. Methods: In this study, two approaches were utilized to increase treatment efficiency and decrease the side effects of anti-CTLA-4, combining it with chemotherapy and encapsulation in a PEGylated liposome. A different sequence of anti-CTLA-4 and Doxil was assessed in combination therapy using non-liposomal and liposomal anti-CTLA-4. Results: Our results showed that liposomal anti-CTLA-4 reduced the size of established tumors and increased survival in comparison with non-liposomal anti-CTLA-4 in a well-established B16 mouse melanoma model. In combination therapy with Doxil, only the administration of anti-CTLA-4 before Doxil showed synergism in both non-liposomal and liposomal form and increased the CD8+/regulatory T cell ratio. Discussion: In summary, our results demonstrate the potential of utilizing a nanocarrier system for the delivery of checkpoint blockers, such as anti-CTLA-4 which further showed potential in a combination therapy, especially when administered before chemotherapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Antígeno CTLA-4/antagonistas & inibidores , Melanoma Experimental/tratamento farmacológico , Animais , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Antígeno CTLA-4/imunologia , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Feminino , Lipossomos/química , Camundongos Endogâmicos C57BL , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/química , Linfócitos T Reguladores/efeitos dos fármacos
2.
Anticancer Res ; 40(7): 3939-3945, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620635

RESUMO

BACKGROUND: Trabectedin and pegylated liposomal doxorubicin (PLD) is an effective combination therapy for platinum-sensitive recurrent ovarian cancer (ROC), particularly for disease relapsing within 6-12 months of platinum therapy. The non-interventional PROSPECTYON study evaluated trabectedin/PLD in French clinical practice. PATIENTS AND METHODS: Patients with ROC after at least one platinum-based regimen received 1.1 mg/m2 trabectedin plus 30 mg/m2 PLD every 3 weeks. Efficacy and safety were evaluated in subgroups according to platinum-free interval [6-12 versus ≥12 months (partially or fully platinum sensitive, respectively)]. RESULTS: Recurrent disease was partially platinum-sensitive in 58 patients and fully sensitive in 33 patients treated between July 2014 and June 2016. Patients in both subgroups received a median of six cycles of trabectedin and PLD. The most common grade 3 or more toxicities were haematological. Median progression-free survival was 6 months for both subgroups. CONCLUSION: Trabectedin/PLD is a valuable treatment option for partially or fully platinum-sensitive ROC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Feminino , Humanos , Pessoa de Meia-Idade , Compostos Organoplatínicos/farmacologia , Polietilenoglicóis/administração & dosagem , Estudos Prospectivos , Trabectedina/administração & dosagem
3.
Int J Infect Dis ; 96: 562-566, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32474201

RESUMO

OBJECTIVES: The purpose of this study was to analyze the clinical characteristics of chronic hepatitis B (CHB) cured by antiviral therapy. METHODS: Forty-two patients with CHB were enrolled. All patients had been treated with peginterferon (Peg-IFN) in combination with nucleoside analogue (NA) therapy for variable amounts of time, and all had been successfully cured of the disease. RESULTS: The combined treatment time for all participants was 124.7 ± 58.8 weeks, and the average Peg-IFN treatment time was 102.6 ± 56.1 weeks. At 24 weeks, Hepatitis B surface antigen (HBsAg) and Hepatitis B e antigen (HBeAg) had decreased more than 50% from baseline. Multivariate logistic regression analysis of the week 96 HBsAg-clearing group and the non-HBsAg-clearing group showed a statistically significant difference in baseline HBV DNA levels and week 48 HBsAg levels. Those which baseline HBV DNA was < 2.75 log10 IU/mL, and week 48 HBsAg levels were < 0.88 log10 IU/mL were more likely to achieve rapid HBsAg clearance at 96 weeks. This suggests that low levels of baseline HBV DNA and week 48 HBsAg are a predictor of rapid HBsAg clearance at 96 weeks. CONCLUSIONS: Individualized extension of combination therapy to more than 96 weeks depending on the patient's response and adverse reaction conditions can help achieve a clinical cure. Patients with low baseline HBV DNA and low HBsAg levels at 48 weeks achieve HBsAg clearance more quickly than other populations.


Assuntos
Antivirais/administração & dosagem , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Interferon-alfa/administração & dosagem , Nucleosídeos/administração & dosagem , Polietilenoglicóis/administração & dosagem , Adulto , Quimioterapia Combinada , Feminino , Antígenos de Superfície da Hepatite B/genética , Antígenos de Superfície da Hepatite B/metabolismo , Antígenos E da Hepatite B/genética , Antígenos E da Hepatite B/metabolismo , Vírus da Hepatite B/genética , Vírus da Hepatite B/metabolismo , Hepatite B Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/administração & dosagem , Estudos Retrospectivos , Resultado do Tratamento
4.
Thromb Haemost ; 120(5): 737-746, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32369845

RESUMO

Long-term safety and efficacy data of extended half-life factor IX (FIX) prophylaxis in children with hemophilia B (HB) are sparse. paradigm 5 is a multinational, open-label, single-arm, phase III trial assessing once-weekly (40 IU/kg) prophylactic nonacog beta pegol (N9-GP) in previously treated patients (PTPs) aged ≤ 12 years with HB (FIX activity ≤ 2%). Primary endpoint: incidence of anti-FIX inhibitory antibodies (≥ 0.6 Bethesda Units). We present a 5-year analysis (N = 25, including remaining patients with ≥ 5 years' follow-up) and compare with a 1-year analysis (≥ 52 weeks' exposure). The main phase enrolled 25 children; 22 entered the extension phase; 17 remained in trial at data cutoff. Median treatment period: 5.6 years/patient; median total number of N9-GP exposure days: 290.0/patient. No patients developed anti-FIX inhibitory antibodies. No other safety concerns, including thromboembolic events, were reported. Neurological examinations have not revealed any new abnormal findings. Sixteen (64.0%) patients remained free from spontaneous bleeds; all bleeds were mild/moderate in severity; 93.0% were controlled with 1 to 2 N9-GP injections. No intracranial hemorrhages were reported. Annualized bleeding rates (ABRs) were very low at 5 years (median/Poisson-estimated mean overall ABR: 0.66/0.99), having decreased from the 1-year analysis (1.00/1.44). Median/Poisson-estimated mean spontaneous ABRs for the 1- and 5-year analyses: 0.00/0.45 and 0.00/0.33. Mean FIX trough activity at 5 years: 17.9%. Mean polyethylene glycol plasma concentration reached steady state at 6 months, increasing slightly over time, in line with increased FIX trough activity. N9-GP administered for ≥ 5 years shows favorable long-term safety and efficacy in PTPs with HB (FIX activity ≤ 2%).


Assuntos
Fator IX/administração & dosagem , Hemofilia B/tratamento farmacológico , Hemostáticos/administração & dosagem , Polietilenoglicóis/administração & dosagem , Adolescente , Fatores Etários , Ásia , Criança , Pré-Escolar , Esquema de Medicação , Europa (Continente) , Fator IX/efeitos adversos , Fator IX/farmacocinética , Hemofilia B/sangue , Hemofilia B/diagnóstico , Hemorragia/sangue , Hemorragia/diagnóstico , Hemorragia/prevenção & controle , Hemostáticos/efeitos adversos , Hemostáticos/sangue , Hemostáticos/farmacocinética , Humanos , Lactente , América do Norte , Segurança do Paciente , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/farmacocinética , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/sangue , Proteínas Recombinantes/farmacocinética , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
6.
Life Sci ; 252: 117646, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32272178

RESUMO

Myeloid-derived suppressor cells (MDSCs) are immunosuppressive cells causing resistance to immunotherapies in cancer tumors. In the current study, various immunogenic and therapeutic features of the combination therapies with non-liposomal Doxorubicin (Dox) and the E75 immunogenic peptide (Pep), derived from the human epidermal receptor-2 (HER-2), are investigated in parallel with their liposomal formulations (Lip-Dox (Doxil®) and Lip-Pep). Therefore, triple injection doses of Lip-Pep were preceded with Dox and Lip-Dox injections in TUBO/breast tumor-bearing BALB/c mice. Chemotherapy with either Dox or Lip-Dox reduced the frequency of MDSCs, the level of reactive oxygen species (ROS), and MDSCs-associated genes of Arg1, iNOS, S100A8, S100A9. Whereas Lip-Pep + Dox and Lip-Pep + Lip-Dox treatments synergistically potentiated the immunized splenocytes to produce INF-γ and enhanced the frequency of the anti-tumor CD8+ and CD4+ T cells as opposed to both chemotherapy and immunotherapy regimens. Chemo-immunotherapy increased the number of tumor-infiltrating lymphocytes (TILs) and reduced the level of CD25+ FoxP3+ T regulatory cells. Taken together, chemo-immunotherapy was the optimum treatment for the limitation of tumor progression as they targeted more cancer-related immune players.


Assuntos
Neoplasias da Mama/terapia , Vacinas Anticâncer/administração & dosagem , Doxorrubicina/análogos & derivados , Receptor ErbB-2/imunologia , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/farmacologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Vacinas Anticâncer/imunologia , Terapia Combinada , Progressão da Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacologia , Feminino , Imunoterapia/métodos , Lipossomos , Camundongos , Camundongos Endogâmicos BALB C , Células Supressoras Mieloides/metabolismo , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/farmacologia
7.
Lancet Oncol ; 21(5): 699-709, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32305099

RESUMO

BACKGROUND: State-of-the art therapy for recurrent ovarian cancer suitable for platinum-based re-treatment includes bevacizumab-containing combinations (eg, bevacizumab combined with carboplatin-paclitaxel or carboplatin-gemcitabine) or the most active non-bevacizumab regimen: carboplatin-pegylated liposomal doxorubicin. The aim of this head-to-head trial was to compare a standard bevacizumab-containing regimen versus carboplatin-pegylated liposomal doxorubicin combined with bevacizumab. METHODS: This multicentre, open-label, randomised, phase 3 trial, was done in 159 academic centres in Germany, France, Australia, Austria, and the UK. Eligible patients (aged ≥18 years) had histologically confirmed epithelial ovarian, primary peritoneal, or fallopian tube carcinoma with first disease recurrence more than 6 months after first-line platinum-based chemotherapy, and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were stratified by platinum-free interval, residual tumour, previous antiangiogenic therapy, and study group language, and were centrally randomly assigned 1:1 using randomly permuted blocks of size two, four, or six to receive six intravenous cycles of bevacizumab (15 mg/kg, day 1) plus carboplatin (area under the concentration curve [AUC] 4, day 1) plus gemcitabine (1000 mg/m2, days 1 and 8) every 3 weeks or six cycles of bevacizumab (10 mg/kg, days 1 and 15) plus carboplatin (AUC 5, day 1) plus pegylated liposomal doxorubicin (30 mg/m2, day 1) every 4 weeks, both followed by maintenance bevacizumab (15 mg/kg every 3 weeks in both groups) until disease progression or unacceptable toxicity. There was no masking in this open-label trial. The primary endpoint was investigator-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1. Efficacy data were analysed in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug. This completed study is registered with ClinicalTrials.gov, NCT01837251. FINDINGS: Between Aug 1, 2013, and July 31, 2015, 682 eligible patients were enrolled, of whom 345 were randomly assigned to receive carboplatin-pegylated liposomal doxorubicin-bevacizumab (experimental group) and 337 were randomly assigned to receive carboplatin-gemcitabine-bevacizumab (standard group). Median follow-up for progression-free survival at data cutoff (July 10, 2018) was 12·4 months (IQR 8·3-21·7) in the experimental group and 11·3 months (8·0-18·4) in the standard group. Median progression-free survival was 13·3 months (95% CI 11·7-14·2) in the experimental group versus 11·6 months (11·0-12·7) in the standard group (hazard ratio 0·81, 95% CI 0·68-0·96; p=0·012). The most common grade 3 or 4 adverse events were hypertension (88 [27%] of 332 patients in the experimental group vs 67 [20%] of 329 patients in the standard group) and neutropenia (40 [12%] vs 73 [22%]). Serious adverse events occurred in 33 (10%) of 332 patients in the experimental group and 28 (9%) of 329 in the standard group. Treatment-related deaths occurred in one patient in the experimental group (<1%; large intestine perforation) and two patients in the standard group (1%; one case each of osmotic demyelination syndrome and intracranial haemorrhage). INTERPRETATION: Carboplatin-pegylated liposomal doxorubicin-bevacizumab is a new standard treatment option for platinum-eligible recurrent ovarian cancer. FUNDING: F Hoffmann-La Roche.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bevacizumab/administração & dosagem , Neoplasias das Tubas Uterinas/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Austrália/epidemiologia , Áustria/epidemiologia , Bevacizumab/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Neoplasias das Tubas Uterinas/patologia , Feminino , França/epidemiologia , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Neoplasias Ovarianas/patologia , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Platina/administração & dosagem , Platina/efeitos adversos , Polietilenoglicóis/administração & dosagem
8.
PLoS One ; 15(4): e0231888, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32343708

RESUMO

BACKGROUND AND AIMS: Inadequate bowel preparation (BP) is an unfavorable factor that influence the success of colonoscopy. Although standard education (SE) given to patients are proved useful to avoid inadequate BP. Studies concerning the effects of reinforced education (RE) on the quality of BP were inconsistent. The aim of this updated meta-analysis of randomized controlled trial was to compare the quality of BP between patients receiving RE in addition to SE and those receiving SE alone. METHODS: MEDLINE, EMBASE, Web of Science and the Cochrane Library were systemically searched to identify the relevant studies published through April 2019. The primary outcome was the rate of adequate BP. Subgroup analyses were conducted. Secondary outcomes included BP score, adenoma detection rate (ADR), polyp detection rate (PDR), insertion time, withdrawal time, adverse events, >80% purgative intake and diet compliance. Dichotomous variables were reported as odds ratio (OR) with 95% confidence interval (CI). Continuous data were reported as mean difference (MD) with 95%CI. Pooled estimates of OR or MD were calculated using a random-effects model. Statistical heterogeneity was accessed by calculating the I2 value. A P value less than 0.05 was considered significant. RESULTS: A total of 18 randomized controlled trails (N = 6536) were included in this meta-analysis. Patients who received RE had a better BP quality than those only receiving SE (OR 2.59, 95%CI: 2.09-3.19; P<0.001). A higher ADR (OR 1.35; 95%CI: 1.06-1.72; P = 0.020) and PDR (OR 1.24, 95%CI: 1.02-1.50; P = 0.030), shorter insertion (MD -0.76; 95%CI: -1.48-(-0.04); P = 0.040) and withdrawal time (MD -0.83; 95%CI: -1.83-(-0.28); P = 0.003), less nausea/vomiting (OR 0.78; 95%CI: 0.64-0.97; P = 0.020) and abdominal distension (OR 0.72; 95%CI: 0.68-0.92; P = 0.020) were achieved in the RE group. More patients had >80% purgative intake (OR 2.17; 95%CI, 1.09-4.32; P = 0.030) and were compliant with diet restriction (OR 2.38; 95%CI: 1.79-3.17; P<0.001) in the RE group. CONCLUSION: RE significantly improved BP quality, increased ADR and PDR, decreased insertion and withdrawal time and adverse events.


Assuntos
Colonoscopia , Educação de Pacientes como Assunto , Adenoma/patologia , Humanos , Laxantes/administração & dosagem , Laxantes/efeitos adversos , Náusea/etiologia , Razão de Chances , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Pólipos/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto
9.
Am J Physiol Renal Physiol ; 318(5): F1271-F1283, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32281418

RESUMO

PEGylated carboxyhemoglobin (PEGHbCO), which has carbon monoxide-releasing properties and plasma expansion and oxygen-carrying properties, may improve both skeletal microcirculatory flow and renal cortical microcirculatory Po2 (CµPo2) and, subsequently, limit endotoxemia-induced acute kidney injury. Anesthetized, ventilated Wistar albino rats (n = 44) underwent endotoxemic shock. CµPo2 was measured in exposed kidneys using a phosphorescence-quenching method. Rats were randomly assigned to the following five groups: 1) unresuscitated lipopolysaccharide (LPS), 2) LPS + Ringer's acetate (RA), 3) LPS + RA + 0.5 µg·kg·-1min-1 norepinephrine (NE), 4) LPS + RA + 320 mg/kg PEGHbCO, and 5) LPS + RA + PEGHbCO + NE. The total volume was 30 mL/kg in each group. A time control animal group was used. Skeletal muscle microcirculation was assessed by handheld intravital microscopy. Kidney immunohistochemistry and myeloperoxidase-stained leukocytes in glomerular and peritubular areas were analyzed. Endotoxemia-induced histological damage was assessed. Plasma levels of IL-6, heme oxygenase-1, malondialdehyde, and syndecan-1 were assessed by ELISA. CµPo2 was higher in the LPS + RA + PEGHbCO-resuscitated group, at 35 ± 6mmHg compared with 21 ± 12 mmHg for the LPS+RA group [mean difference: -13.53, 95% confidence interval: (-26.35; -0.7156), P = 0.035]. The number of nonflowing, intermittent, or sluggish capillaries was smaller in groups infused with PEGHbCO compared with RA alone (P < 0.05), while the number of normally perfused vessels was greater (P < 0.05). The addition of NE did not further improve CµPo2 or microcirculatory parameters. Endotoxemia-induced kidney immunohistochemistry and histological alterations were not mitigated by PEGHbCO 1 h after resuscitation. Renal leukocyte infiltration and plasma levels of biomarkers were similar across groups. PEGHbCO enhanced CµPo2 while restoring skeletal muscle microcirculatory flow in previously nonflowing capillaries. PEGHbCO should be further evaluated as a resuscitation fluid in mid- to long-term models of sepsis-induced acute kidney injury.


Assuntos
Lesão Renal Aguda/prevenção & controle , Substitutos Sanguíneos/administração & dosagem , Carboxihemoglobina/administração & dosagem , Endotoxemia/terapia , Hidratação , Córtex Renal/irrigação sanguínea , Microcirculação/efeitos dos fármacos , Músculo Esquelético/irrigação sanguínea , Consumo de Oxigênio/efeitos dos fármacos , Polietilenoglicóis/administração & dosagem , Circulação Renal/efeitos dos fármacos , Ressuscitação , Lesão Renal Aguda/sangue , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/fisiopatologia , Animais , Biomarcadores/sangue , Modelos Animais de Doenças , Endotoxemia/sangue , Endotoxemia/induzido quimicamente , Endotoxemia/fisiopatologia , Córtex Renal/metabolismo , Lipopolissacarídeos , Masculino , Ratos Wistar , Fatores de Tempo
10.
Drugs Today (Barc) ; 56(3): 195-202, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32282866

RESUMO

Ropeginterferon alfa-2b is a novel mono-PEGylated alfa interferon. It is the first interferon approved for the treatment of patients with polycythemia vera (PV) and the first and only approved treatment for PV independent of previous hydroxyurea exposure. In contrast to other interferons, the drug has to be subcutaneously injected every 2 weeks only, with intervals of 4 weeks being possible after prolonged use. It is generally well tolerated and can lead to deep molecular responses. In this article, we provide a review of available preclinical and clinical data of ropeginterferon alfa-2b leading to its E.U. approval and give an outlook on future clinical trials involving this drug.


Assuntos
Interferon alfa-2/uso terapêutico , Interferon-alfa/uso terapêutico , Policitemia Vera/tratamento farmacológico , Polietilenoglicóis/uso terapêutico , Humanos , Hidroxiureia , Interferon alfa-2/administração & dosagem , Interferon-alfa/administração & dosagem , Polietilenoglicóis/administração & dosagem , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico
11.
AAPS PharmSciTech ; 21(4): 124, 2020 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-32342227

RESUMO

To achieve improved drug delivery efficiency to hepatocellular carcinoma (HCC), biodegradable poly (ethylene glycol)-poly (lactic-co-glycolic acid) (PEG-PLGA) nanoparticles (NP), surface-modified with SP94 peptide, were designed for the efficient delivery of cryptotanshinone to the tumor for the treatment of HCC. Cryptotanshinone NP and SP94-NP were prepared by using nanoprecipitation. The physicochemical and pharmaceutical properties of the NP and SP94-NP were characterized, and the release kinetics suggested that both NP and SP94-NP provided continuous, slow release of cryptotanshinone for 48 h. The in vitro cellular experiment demonstrated that SP94-NP significantly enhanced the cellular uptake of cryptotanshinone and induced high cytotoxicity and cellular apoptosis of hepatocellular carcinoma (HepG2) cells. The in vivo detecting results of targeting effect using the Cy5.5 probe evidenced that SP94-NP showed an accumulation in tumor more efficiently than that of unconjugated ones. Meanwhile, SP94-NP exhibited the smallest tumor size than other groups and showed no toxicity to body. The results of this study provide a promising nanoplatform for the targeting of HCC.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Nanopartículas/administração & dosagem , Fragmentos de Peptídeos/administração & dosagem , Fenantrenos/administração & dosagem , Poliésteres/administração & dosagem , Polietilenoglicóis/administração & dosagem , Animais , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Sistemas de Liberação de Medicamentos/métodos , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/síntese química , Medicamentos de Ervas Chinesas/metabolismo , Feminino , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/química , Nanopartículas/metabolismo , Fragmentos de Peptídeos/síntese química , Fragmentos de Peptídeos/metabolismo , Fenantrenos/síntese química , Fenantrenos/metabolismo , Poliésteres/síntese química , Poliésteres/metabolismo , Polietilenoglicóis/síntese química , Polietilenoglicóis/metabolismo
12.
Cir. pediátr ; 33(2): 55-60, abr. 2020. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-190841

RESUMO

Objetivo: Comparar la eficacia de la preparación intestinal para colonoscopia con 1 día de preparación con PEG 3350 (polietilenglicol) (4 g/kg/día) + bisacodilo en comparación con 2 días de preparación con PEG 3350 (2 g/kg/día) + bisacodilo en pacientes pediátricos. Material y métodos: Se realizó un ensayo clínico, aleatorizado y cegado para los médicos endoscopistas que evaluaron la limpieza del colon. Se incluyeron pacientes de 2 a 18 años, que ameritaban colonoscopia en forma programada. Se aleatorizaron a los pacientes en dos grupos: 1 día de preparación con PEG 3350 (4 g/kg/día) + bisacodilo y 2 días de preparación con PEG 3350 (2 g/kg/día) + bisacodilo. Por medio de valoración endoscópica (escala de Boston) se determinó la eficacia de las dos preparaciones a evaluar. Análisis estadístico: T de student para cuantitativas y Chi2 para cualitativas. Resultados: Se incluyeron 72 pacientes con edad promedio de 94 ± 49 meses. No hubo diferencia significativa entre los grupos con respecto a la dificultad y seguridad de la preparación. La eficacia, evaluada por el puntaje de la escala de Boston y la proporción de calificación excelente o buena, fue mejor en el grupo de un 1 día, el colon izquierdo y el puntaje total fue mejor en comparación al grupo de 2 días (colon izquierdo 2,20 vs. 1,89 p = 0,03 y total 7,28 vs. 6,76 p = 0,01) (colon izquierdo 94,4 vs. 83,4% p = 0,034). Conclusiones: La eficacia de la calidad en la preparación intestinal para colonoscopia fue mejor entre el grupo de 1 día con PEG 3350 + bisacodilo vía oral en comparación a la preparación de 2 días


Objective: The objective was to compare the efficacy of 1-day intestinal preparation for colonoscopy using PEG 3350 (polyethylene glycol) (4 g/kg/day) + bisacodyl vs. 2-day intestinal preparation using PEG 3350 (2 g/kg/day) + bisacodyl in pediatric patients. Materials and methods: A blind, randomized clinical trial was car-ried out with endoscopists who assessed colon cleansing. Patients aged 2-18 years old undergoing scheduled colonoscopy were included. They were randomized into 2 groups: 1-day preparation using PEG 3350 (4 g/kg/day) + bisacodyl, and 2-day preparation using PEG 3350 (2 g/kg/day) + bisacodyl. Endoscopic evaluation (Boston Scale) allowed the efficacy of both preparations to be assessed. Statistical analysis: T of Student for quantitative variables, and Chi square for qualitative variables. Results: 72 patients with a mean age of 94 ± 49 months were included. No significant difference was found between groups regarding preparation difficulty and safety. Efficacy, assessed using the Boston Scale score and the proportion of excellent and good grades achieved, was higher in the 1-day group. Left colon score and total score were higher than in the 2-day group (left colon: 2.20 vs. 1.89, p = 0.03; total score: 7.28 vs. 6.76, p = 0.01) (left colon: 94.4% vs. 83.4%, p = 0.034). Conclusions: Efficacy in the quality of intestinal preparation for colonoscopy was higher in the 1-day group using PEG 3350 + oral bisacodyl than in the 2-day group


Assuntos
Humanos , Masculino , Feminino , Pré-Escolar , Criança , Adolescente , Bisacodil/administração & dosagem , Catárticos/administração & dosagem , Colonoscopia/métodos , Polietilenoglicóis/administração & dosagem
13.
Expert Opin Pharmacother ; 21(8): 883-891, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32129103

RESUMO

INTRODUCTION: Due to the increased use of opioids for pain and their abuse globally, the rate of restrictive side effects is elevating. Opioid-induced constipation (OIC) is probably the most widespread, underdiagnosed, and yet common adverse effect. Naloxegol, as an opioid antagonist, is associated with beneficial impacts in OIC. Indeed, blocking mu (µ)-opioid receptors in the gastrointestinal tract (GI) may lead to neutralization of the GI adverse events of opioids. AREAS COVERED: This review is based on a PubMed and Clinicaltrials.gov search for studies undertaken over the past 20 years (2000-2020) using the following keywords: Movantik®, Moventig®, Naloxegol, Opioids, Opioid-induced constipation and Opioid antagonists. EXPERT OPINION: Similar to the management of functional constipation, non-pharmacological therapies are applied as the first step of the procedure. However, in most cases, laxative therpaies with or without stool softeners, which may not result in satisfactory relief are applied. In these instances, administration of prokinetic agents is recommended. Furthermore, studies have shown that the best second-line therapy option is a peripherally acting µ-opioid receptor antagonist (PAMORA), which antagonizes GI adverse events.


Assuntos
Analgésicos Opioides/efeitos adversos , Morfinanos/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Constipação Induzida por Opioides/tratamento farmacológico , Polietilenoglicóis/uso terapêutico , Receptores Opioides mu/antagonistas & inibidores , Analgésicos Opioides/uso terapêutico , Humanos , Laxantes/uso terapêutico , Morfinanos/administração & dosagem , Antagonistas de Entorpecentes/administração & dosagem , Constipação Induzida por Opioides/metabolismo , Dor/tratamento farmacológico , Polietilenoglicóis/administração & dosagem
14.
Cochrane Database Syst Rev ; 3: CD000475, 2020 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-32199406

RESUMO

BACKGROUND: Pelvic adhesions can form secondary to inflammation, endometriosis, or surgical trauma. Strategies to reduce pelvic adhesion formation include placing barrier agents such as oxidised regenerated cellulose, polytetrafluoroethylene, and fibrin or collagen sheets between pelvic structures. OBJECTIVES: To evaluate the effects of barrier agents used during pelvic surgery on rates of pain, live birth, and postoperative adhesions in women of reproductive age. SEARCH METHODS: We searched the following databases in August 2019: the Cochrane Gynaecology and Fertility (CGF) Specialised Register of Controlled Trials, MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO, the Cochrane Central Register of Controlled Trials (CENTRAL), Epistemonikos, and trial registries. We searched reference lists of relevant papers, conference proceedings, and grey literature sources. We contacted pharmaceutical companies for information and handsearched relevant journals and conference abstracts. SELECTION CRITERIA: Randomised controlled trials (RCTs) on the use of barrier agents compared with other barrier agents, placebo, or no treatment for prevention of adhesions in women undergoing gynaecological surgery. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed trials for eligibility and risk of bias and extracted data. We calculated odds ratios (ORs) or mean differences (MDs) with 95% confidence intervals (CIs) using a fixed-effect model. We assessed the overall quality of the evidence using GRADE (Grades of Recommendation, Assessment, Development and Evaluation) methods. MAIN RESULTS: We included 19 RCTs (1316 women). Seven RCTs randomised women; the remainder randomised pelvic organs. Laparoscopy (eight RCTs) and laparotomy (11 RCTs) were the primary surgical techniques. Indications for surgery included myomectomy (seven RCTs), ovarian surgery (five RCTs), pelvic adhesions (five RCTs), endometriosis (one RCT), and mixed gynaecological surgery (one RCT). The sole indication for surgery in three of the RCTs was infertility. Thirteen RCTs reported commercial funding; the rest did not state their source of funding. No studies reported our primary outcomes of pelvic pain and live birth rate. Oxidised regenerated cellulose versus no treatment at laparoscopy or laparotomy (13 RCTs) At second-look laparoscopy, we are uncertain whether oxidised regenerated cellulose at laparoscopy reduced the incidence of de novo adhesions (OR 0.50, 95% CI 0.30 to 0.83, 3 RCTs, 360 participants; I² = 75%; very low-quality evidence) or of re-formed adhesions (OR 0.17, 95% CI 0.07 to 0.41, 3 RCTs, 100 participants; I² = 36%; very low-quality evidence). At second-look laparoscopy, we are uncertain whether oxidised regenerated cellulose affected the incidence of de novo adhesions after laparotomy (OR 0.72, 95% CI 0.42 to 1.25, 1 RCT, 271 participants; very low-quality evidence). However, the incidence of re-formed adhesions may have been reduced in the intervention group (OR 0.38, 95% CI 0.27 to 0.55, 6 RCTs, 554 participants; I² = 41%; low-quality evidence). No studies reported results on pelvic pain, live birth rate, adhesion score, or clinical pregnancy rate. Expanded polytetrafluoroethylene versus oxidised regenerated cellulose at gynaecological surgery (two RCTs) We are uncertain whether expanded polytetrafluoroethylene reduced the incidence of de novo adhesions at second-look laparoscopy (OR 0.93, 95% CI 0.26 to 3.41, 38 participants; very low-quality evidence). We are also uncertain whether expanded polytetrafluoroethylene resulted in a lower adhesion score (out of 11) (MD -3.79, 95% CI -5.12 to -2.46, 62 participants; very low-quality evidence) or a lower risk of re-formed adhesions (OR 0.13, 95% CI 0.02 to 0.80, 23 participants; very low-quality evidence) when compared with oxidised regenerated cellulose. No studies reported results regarding pelvic pain, live birth rate, or clinical pregnancy rate. Collagen membrane with polyethylene glycol and glycerol versus no treatment at gynaecological surgery (one RCT) Evidence suggests that collagen membrane with polyethylene glycol and glycerol may reduce the incidence of adhesions at second-look laparoscopy (OR 0.04, 95% CI 0.00 to 0.77, 47 participants; low-quality evidence). We are uncertain whether collagen membrane with polyethylene glycol and glycerol improved clinical pregnancy rate (OR 5.69, 95% CI 1.38 to 23.48, 39 participants; very low-quality evidence). One study reported adhesion scores but reported them as median scores rather than mean scores (median score 0.8 in the treatment group vs median score 1.2 in the control group) and therefore could not be included in the meta-analysis. The reported P value was 0.230, and no evidence suggests a difference between treatment and control groups. No studies reported results regarding pelvic pain or live birth rate. In total, 15 of the 19 RCTs included in this review reported adverse events. No events directly attributed to adhesion agents were reported. AUTHORS' CONCLUSIONS: We found no evidence on the effects of barrier agents used during pelvic surgery on pelvic pain or live birth rate in women of reproductive age because no trial reported these outcomes. It is difficult to draw credible conclusions due to lack of evidence and the low quality of included studies. Given this caveat, low-quality evidence suggests that collagen membrane with polyethylene glycol plus glycerol may be more effective than no treatment in reducing the incidence of adhesion formation following pelvic surgery. Low-quality evidence also shows that oxidised regenerated cellulose may reduce the incidence of re-formation of adhesions when compared with no treatment at laparotomy. It is not possible to draw conclusions on the relative effectiveness of these interventions due to lack of evidence. No adverse events directly attributed to the adhesion agents were reported. The quality of the evidence ranged from very low to moderate. Common limitations were imprecision and poor reporting of study methods. Most studies were commercially funded, and publication bias could not be ruled out.


Assuntos
Celulose Oxidada/uso terapêutico , Infertilidade Feminina/cirurgia , Politetrafluoretileno/administração & dosagem , Complicações Pós-Operatórias/prevenção & controle , Colo do Útero/cirurgia , Colágeno/administração & dosagem , Feminino , Fibrina/administração & dosagem , Glicerol/administração & dosagem , Humanos , Ácido Hialurônico/administração & dosagem , Incidência , Laparoscopia/efeitos adversos , Laparotomia/efeitos adversos , Membranas Artificiais , Dor Pós-Operatória/prevenção & controle , Pelve/cirurgia , Polietilenoglicóis/administração & dosagem , Complicações Pós-Operatórias/epidemiologia , Gravidez , Taxa de Gravidez , Ensaios Clínicos Controlados Aleatórios como Assunto , Cirurgia de Second-Look , Aderências Teciduais/epidemiologia , Aderências Teciduais/prevenção & controle , Viscossuplementos/administração & dosagem
15.
Geriatr Gerontol Int ; 20(6): 559-563, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32207216

RESUMO

AIMS: Colon preparation is vital yet more difficult in elderly patients with severe lower gastrointestinal bleeding (LGIB). The aim of this study is to show the efficacy, safety and outcomes of unprepared polyethylene glycol (PEG)-flush retrograde colon cleansing in the diagnosis and treatment of elderly home care patients with LGIB. METHODS: A single-center study was performed between January 2014 and June 2018. Elderly home healthcare patients presenting with hematochezia were enrolled, and an unprepared retrograde bowel cleansing colonoscopy was performed within the first 8 h after admission to the emergency department. PEG solution (2 L) was added to the water jet tank, and jet pump injection was started from the left side of the colon to the right segment of the colon and ended up at the cecum. RESULTS: In total, 33 elderly patients presenting with hematochezia were evaluated. Mean inward and outward procedure times were 17.06 ± 4.92 (8-33 min) and 28.66 ± 6.88 (10-30 min), respectively. Most of the bleeding was localized in the right colon at 22 patients (66.3%). Endoscopic treatment was performed in 87.9% of patients. The average length of stay in hospital was 44.70 ± 42.81 (range 18.00-240.00 h). CONCLUSIONS: Immediate unprepared PEG-flush colonoscopy in elderly home care patients with acute LGIB is a safe and effective method, which detects bleeding sources and provides endoscopic therapy. With this procedure, the time of hospital stay is reduced. This approach may be used for the initial intervention in patients admitted to emergency departments or intensive care unit with severe acute LGIB. Geriatr Gerontol Int 2020; ••: ••-••.


Assuntos
Colonoscopia/métodos , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/terapia , Polietilenoglicóis/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Catárticos/administração & dosagem , Feminino , Hospitalização , Humanos , Masculino
16.
Nat Commun ; 11(1): 661, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005826

RESUMO

High dose interleukin-2 (IL-2) is active against metastatic melanoma and renal cell carcinoma, but treatment-associated toxicity and expansion of suppressive regulatory T cells (Tregs) limit its use in patients with cancer. Bempegaldesleukin (NKTR-214) is an engineered IL-2 cytokine prodrug that provides sustained activation of the IL-2 pathway with a bias to the IL-2 receptor CD122 (IL-2Rß). Here we assess the therapeutic impact and mechanism of action of NKTR-214 in combination with anti-PD-1 and anti-CTLA-4 checkpoint blockade therapy or peptide-based vaccination in mice. NKTR-214 shows superior anti-tumor activity over native IL-2 and systemically expands anti-tumor CD8+ T cells while inducing Treg depletion in tumor tissue but not in the periphery. Similar trends of intratumoral Treg dynamics are observed in a small cohort of patients treated with NKTR-214. Mechanistically, intratumoral Treg depletion is mediated by CD8+ Teff-associated cytokines IFN-γ and TNF-α. These findings demonstrate that NKTR-214 synergizes with T cell-mediated anti-cancer therapies.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Interleucina-2/análogos & derivados , Melanoma/tratamento farmacológico , Polietilenoglicóis/administração & dosagem , Pró-Fármacos/administração & dosagem , Linfócitos T Reguladores/imunologia , Animais , Anticorpos Monoclonais Humanizados/administração & dosagem , Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/imunologia , Estudos de Coortes , Quimioterapia Combinada , Feminino , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-2/administração & dosagem , Interleucina-2/agonistas , Interleucina-2/imunologia , Ipilimumab/administração & dosagem , Ativação Linfocitária/efeitos dos fármacos , Melanoma/genética , Melanoma/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Interleucina-2/genética , Receptores de Interleucina-2/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
17.
PLoS One ; 15(2): e0229517, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32106270

RESUMO

AIMS: To analyze the efficacy and safety of sofosbuvir (SOF)-based regimens in Thai patients with chronic hepatitis C virus infection who had pre-existing significant liver fibrosis. PATIENTS AND METHODS: This was a retrospective cohort study, conducted between 1 June 2018 and 31 May 2019 at Rajavithi Hospital, Bangkok, Thailand. All patients completed 12 weeks of SOF-based regimens and had follow-up for at least 12 weeks after therapy discontinuation. The primary outcome was sustained virological response (SVR) 12 weeks after the end of therapy. RESULT: A total of 185 patients were included, with 52, 63 and 70 taking SOF+Ledipasvir (SOF+LDV), SOF+LDV+ribavirin (RBV) and SOF+Pegylated interferon (Peg-IFN)+RBV (SOF+Peg-IFN+RBV) respectively. Genotype (GT) 1 was predominant at 40.0%, followed by GT3 at 37.8%, and GT6 at 22.2%. Overall 95.1% of patients in this study achieved SVR (n = 176/185), and the only factor associated with SVR was HCV genotype (p = 0.001). GT6 patients had lower SVR rates compared to GT1 and GT3 patients (82.9%, 98.6%, and 98.6% respectively) while there was no association between SVR and other factors (p >0.05) such as gender, age, BMI, underlying cirrhosis, baseline HCV viral load, or prior treatment history. No serious adverse events were reported in the present study. CONCLUSION: Sofosbuvir-based regimens in the treatment of patients with chronic HCV infection were highly efficacious with excellent safety and tolerability profiles in a real-world setting; however, further research is required to establish whether or not such a regimen is an adequate treatment for all genotype 6 patients.


Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Sofosbuvir/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Estudos de Coortes , Quimioterapia Combinada , Feminino , Fluorenos/administração & dosagem , Fluorenos/efeitos adversos , Genótipo , Hepacivirus/genética , Hepatite C Crônica/patologia , Hepatite C Crônica/virologia , Humanos , Interferon alfa-2/administração & dosagem , Interferon alfa-2/efeitos adversos , Interferon-alfa/administração & dosagem , Interferon-alfa/efeitos adversos , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Estudos Retrospectivos , Ribavirina/administração & dosagem , Ribavirina/efeitos adversos , Sofosbuvir/administração & dosagem , Sofosbuvir/efeitos adversos , Resposta Viral Sustentada , Tailândia , Fatores de Tempo , Resultado do Tratamento , Uridina Monofosfato/administração & dosagem , Uridina Monofosfato/efeitos adversos , Uridina Monofosfato/análogos & derivados
18.
Anticancer Res ; 40(2): 689-694, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32014909

RESUMO

BACKGROUND/AIM: Piperine, a major alkaloid of the fruit of black pepper plants, selectively inhibits the growth of triple-negative breast cancer cells but its lipophilicity restricts possible clinical application. This study therefore determined the feasibility of encapsulating piperine in nanoparticles (NPs) to increase its solubility in an aqueous environment. MATERIALS AND METHODS: Piperine-loaded biodegradable methoxy poly(ethylene glycol)-poly(lactic-co-glycolic) acid copolymer-based NPs were produced by single emulsion solvent extraction and thin-film hydration. Growth and viability of triple-negative breast cancer (TNBC) cells were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and Annexin-V-FLUOS/propidium iodide staining, respectively. RESULTS: Thin-film hydration was superior to single emulsion solvent extraction, yielding piperine-loaded NPs with an average size of 50 nm. Piperine-loaded NPs inhibited TNBC cell growth and induced apoptosis while sparing normal fibroblasts. CONCLUSION: It is feasible to deliver a cytotoxic concentration of piperine to TNBC cells via NPs with the potential for improved bioavailability and solubility in biological fluids.


Assuntos
Alcaloides/administração & dosagem , Benzodioxóis/administração & dosagem , Nanopartículas/administração & dosagem , Piperidinas/administração & dosagem , Alcamidas Poli-Insaturadas/administração & dosagem , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Alcaloides/química , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Apoptose/efeitos dos fármacos , Benzodioxóis/química , Linhagem Celular Tumoral , Emulsões/administração & dosagem , Emulsões/química , Feminino , Humanos , Nanopartículas/química , Piperidinas/química , Poliésteres/administração & dosagem , Poliésteres/química , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/química , Alcamidas Poli-Insaturadas/química , Neoplasias de Mama Triplo Negativas/patologia
19.
Medicine (Baltimore) ; 99(8): e19208, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32080109

RESUMO

AIM: Adequate bowel preparation is essential to the quality of colonoscopy. We performed a meta-analysis to determine the efficacy and safety of the addition of lubiprostone to the bowel preparation process prior to colonoscopy. METHODS: Online databases, namely, PubMed, MEDLINE and Cochrane Library, were searched for randomized controlled trials that assessed the additive effect of lubiprostone on the quality of colon preparation in patients undergoing colonoscopy. Each included study was evaluated by the Jadad score to assess the quality of the study. The primary outcome was bowel preparation efficacy, defined as the proportion of patients with an excellent or poor preparation. The secondary outcomes included the length of the colonoscopy, polyp detection, and any adverse effects. RESULTS: In total, 5 articles published between 2008 and 2016 fulfilled the selection criteria. The addition of lubiprostone to the bowel cleansing process significantly increased the proportion of patients with an excellent preparation (risk ratio [RR] = 1.68, 95% confidence interval (CI): 1.40-2.02, P < .00001) but did not decrease the procedural time or increase the polyp detection rate (mean difference = -0.52, 95% CI: -3.74-2.69, P = .75; RR = 1.16, 95% CI: 0.96-1.42, P = .13, respectively). There was no significant difference in the proportion of patients with any adverse events. CONCLUSION: The addition of lubiprostone to the bowel preparation regimen prior to colonoscopy is effective and safe.


Assuntos
Colonoscopia/métodos , Lubiprostona/administração & dosagem , Catárticos , Quimioterapia Combinada , Humanos , Duração da Cirurgia , Polietilenoglicóis/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto
20.
Nat Commun ; 11(1): 660, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005809

RESUMO

Interleukin-2 (IL-2) is a component of most protocols of adoptive cell transfer (ACT) therapy for cancer, but is limited by short exposure and high toxicities. NKTR-214 is a kinetically-engineered IL-2 receptor ßγ (IL-2Rßγ)-biased agonist consisting of IL-2 conjugated to multiple releasable polyethylene glycol chains resulting in sustained signaling through IL-2Rßγ. We report that ACT supported by NKTR-214 increases the proliferation, homing and persistence of anti-tumor T cells compared to ACT with IL-2, resulting in superior antitumor activity in a B16-F10 murine melanoma model. The use of NKTR-214 increases the number of polyfunctional T cells in murine spleens and tumors compared to IL-2, and enhances the polyfunctionality of T and NK cells in the peripheral blood of patients receiving NKTR-214 in a phase 1 trial. In conclusion, NKTR-214 may have the potential to improve the antitumor activity of ACT in humans through increased in vivo expansion and polyfunctionality of the adoptively transferred T cells.


Assuntos
Transferência Adotiva , Interleucina-2/análogos & derivados , Interleucina-2/agonistas , Melanoma/tratamento farmacológico , Polietilenoglicóis/administração & dosagem , Receptores de Interleucina-2/imunologia , Linfócitos T/imunologia , Animais , Humanos , Interleucina-2/administração & dosagem , Interleucina-2/imunologia , Ativação Linfocitária/efeitos dos fármacos , Melanoma/genética , Melanoma/imunologia , Melanoma Experimental , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Interleucina-2/genética
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