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1.
Zhonghua Xin Xue Guan Bing Za Zhi ; 49(2): 121-127, 2021 Feb 24.
Artigo em Chinês | MEDLINE | ID: mdl-33611897

RESUMO

Objective: To evaluate the five-year safety and efficacy of the second generation biodegradable polymer sirolimus-eluting stent (EXCROSSAL) in treating patients with de novo coronary artery diseases. Methods: Patients with coronary artery disease (CAD)who were implanted with EXTROSSAL stents in CREDIT Ⅱ and CREDIT Ⅲ study were included. CREDIT Ⅱ was a randomized trial, and CREDIT Ⅲ was a single-arm study. From November 2013 to December 2014, 833 CAD patients with de novo coronary lesions implanted with EXTROSSAL stents were selected from 33 centers in China. The primary outcome was 5-year target lesion failure (TLF), a composite of cardiac death, target vessel myocardial infarction and clinically indicated target lesion revascularization. Secondary endpoints was patient-oriented composite endpoint (PoCE), including all-cause death, all myocardial infarction, or any revascularization within 5 years post stenting and stent thrombosis according to Academic Research Consortium's (ARC) definition. Kaplan Meier method was used to calculate the incidence of TLF and PoCE within 5 years after operation. Univariate Cox regression analysis was used to analyze the impacts of diabetes, small vessel disease (vessel diameter ≤ 2.74 mm), lesion length ≥ 16.7 mm and multivessel disease on the incidence of TLF within 5 years after operation. Results: A total of 833 patients were included in this study including 579 males (69.5%), the age was (59.3±9.1) years. And 832 (99.9%) patients completed 5-year clinical follow-up. The incidence of TLF and PoCE in the 5-year follow-up were 10.6%(86/811) and 15.5%(126/811), respectively. Stent thrombosis occurred in 1.0%(8/811) of patients. Univariate Cox regression analysis showed that vessel diameter ≤ 2.74 mm (HR=3.20,95%CI 1.90-5.39,P<0.001), lesion length ≥ 16.7 mm (HR=1.88,95%CI 1.18-2.99,P=0.007) and multivessel disease (HR=2.44,95%CI 1.60-3.72,P<0.001) were related factors of TLF within 5 years after operation. Conclusion: EXCROSSAL stent is effective and safe in treating CAD patients with de novo coronary lesions, with low incidence of TLF and PoCE within 5 years after operation.


Assuntos
Fármacos Cardiovasculares , Doença da Artéria Coronariana , Stents Farmacológicos , Intervenção Coronária Percutânea , Idoso , China , Doença da Artéria Coronariana/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Polímeros , Fatores de Risco , Sirolimo/uso terapêutico , Fatores de Tempo , Resultado do Tratamento
2.
Int J Nanomedicine ; 16: 269-281, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33469286

RESUMO

Background: Rapamycin is a promising agent for treating tumors, but clinical applications of rapamycin are limited due to its poor water solubility and low bioavailability. This paper constructs a liposome delivery system for rapamycin to improve the effect in treating colorectal cancer. Methods: We prepared the rapamycin liposomes using the ethanol injection method. The cellular uptake and biodistribution were detected by LC-MS and in vivo imaging system. MTT assay, transwell migration experiment, flow cytometry, and Western blot analysis evaluated the antitumor effect of rapamycin liposomes in vitro. Furthermore, HCT-116 tumor-bearing mice were used to assess the therapeutic efficacy of rapamycin liposomes in vivo. Results: The prepared rapamycin liposomes had a particle size of 100±5.5 nm and with a narrow size distribution. In vitro cellular uptake experiments showed that the uptake of rapamycin liposomes by colorectal cells was higher than that of free rapamycin. Subsequently, in vivo imaging experiments also demonstrated that rapamycin liposomes exhibited higher tumor accumulation. Therefore, the ability of rapamycin liposomes to inhibit tumor proliferation, migration and to induce tumor apoptosis is superior to that of free rapamycin. We also demonstrated in vivo good antitumor efficacy of the rapamycin liposomes in HCT-116 xenograft mice. In addition, rapamycin liposomes and 5-FU can synergistically improve the efficacy of colorectal cancer via the Akt/mTOR and P53 pathways. Conclusion: Collectively, rapamycin liposomes are a potential treatment for colorectal cancer, as it not only improves rapamycin's antitumor effect but also synergistically enhances 5-FU's chemotherapy effect.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/uso terapêutico , Sirolimo/administração & dosagem , Sirolimo/uso terapêutico , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/patologia , Sinergismo Farmacológico , Fluoruracila/administração & dosagem , Fluoruracila/farmacologia , Humanos , Concentração Inibidora 50 , Lipossomos , Camundongos , Tamanho da Partícula , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia , Distribuição Tecidual , Ensaio Tumoral de Célula-Tronco , Ensaios Antitumorais Modelo de Xenoenxerto
3.
N Engl J Med ; 384(1): 11-19, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33406328

RESUMO

BACKGROUND: Dipeptidyl peptidase 4 (DPP-4; also known as CD26), a transmembrane receptor expressed on T cells, has a costimulatory function in activating T cells. In a mouse model, down-regulation of CD26 prevented graft-versus-host disease (GVHD) but preserved graft-versus-tumor effects. Whether inhibition of DPP-4 with sitagliptin may prevent acute GVHD after allogeneic stem-cell transplantation is not known. METHODS: We conducted a two-stage, phase 2 clinical trial to test whether sitagliptin plus tacrolimus and sirolimus would reduce the incidence of grade II to IV acute GVHD from 30% to no more than 15% by day 100. Patients received myeloablative conditioning followed by mobilized peripheral-blood stem-cell transplants. Sitagliptin was given orally at a dose of 600 mg every 12 hours starting the day before transplantation until day 14 after transplantation. RESULTS: A total of 36 patients who could be evaluated, with a median age of 46 years (range, 20 to 59), received transplants from matched related or unrelated donors. Acute GVHD occurred in 2 of 36 patients by day 100; the incidence of grade II to IV GVHD was 5% (95% confidence interval [CI], 1 to 16), and the incidence of grade III or IV GVHD was 3% (95% CI, 0 to 12). Nonrelapse mortality was zero at 1 year. The 1-year cumulative incidences of relapse and chronic GVHD were 26% (95% CI, 13 to 41) and 37% (95% CI, 22 to 53), respectively. GVHD-free, relapse-free survival was 46% (95% CI, 29 to 62) at 1 year. Toxic effects were similar to those seen in patients undergoing allogeneic stem-cell transplantation. CONCLUSIONS: In this nonrandomized trial, sitagliptin in combination with tacrolimus and sirolimus resulted in a low incidence of grade II to IV acute GVHD by day 100 after myeloablative allogeneic hematopoietic stem-cell transplantation. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT02683525.).


Assuntos
Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Fosfato de Sitagliptina/uso terapêutico , Adulto , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Quimioterapia Combinada , Feminino , Humanos , Imunossupressores/uso terapêutico , Leucemia Mieloide/terapia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Recidiva , Sirolimo/uso terapêutico , Fosfato de Sitagliptina/administração & dosagem , Fosfato de Sitagliptina/efeitos adversos , Análise de Sobrevida , Tacrolimo/uso terapêutico , Transplante Homólogo , Adulto Jovem
4.
Medicine (Baltimore) ; 99(50): e23291, 2020 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-33327255

RESUMO

BACKGROUND: Interleukin 6 (IL-6) inhibitors are the first-line treatment for idiopathic multicentric Castleman disease (iMCD); however, there is no established treatment for cases that are resistant to IL-6 inhibitors. Although sirolimus, a mammalian target of rapamycin inhibitor, has been suggested to be effective in patients with iMCD, the long-term safety and efficacy of sirolimus on individuals with IL-6 inhibitor-resistant iMCD have not been evaluated. METHODS/DESIGN: In this investigator-initiated, multicenter, open-label trial, the long-term safety of sirolimus will be evaluated in patients participating in a placebo-controlled, randomized, double-blind, parallel-group trial on tocilizumab (TCZ)-resistant iMCD. The study will be conducted in 7 centers in Japan. This trial will be promptly started after the evaluation and examination for 16 weeks in the preceding study. The trial will be completed by the time the drug is approved for iMCD treatment in Japan. The primary endpoint is the incidence of adverse events. The secondary endpoints include the following: the levels of hemoglobin, albumin, and C-reactive protein; change in CHAP score; physician global assessment (100-mm visual analog scale); patient global assessment (100-mm visual analog scale); and lymph node changes in subjects with lymphadenopathy. DISCUSSION: This clinical trial will provide evidence regarding the long-term safety of sirolimus as a potential novel therapeutic agent for patients with tocilizumab-resistant iMCD. TRIAL REGISTRATION NUMBER: jRCT2051200050.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Hiperplasia do Linfonodo Gigante/tratamento farmacológico , Imunossupressores/uso terapêutico , Sirolimo/uso terapêutico , Método Duplo-Cego , Humanos , Imunossupressores/efeitos adversos , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Sirolimo/efeitos adversos , Falha de Tratamento , Resultado do Tratamento
5.
Nat Metab ; 2(12): 1472-1481, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33324011

RESUMO

Leigh syndrome is a fatal neurometabolic disorder caused by defects in mitochondrial function. Mechanistic target of rapamycin (mTOR) inhibition with rapamycin attenuates disease progression in a mouse model of Leigh syndrome (Ndufs4 knock-out (KO) mouse); however, the mechanism of rescue is unknown. Here we identify protein kinase C (PKC) downregulation as a key event mediating the beneficial effects of rapamycin treatment of Ndufs4 KO mice. Assessing the impact of rapamycin on the brain proteome and phosphoproteome of Ndufs4 KO mice, we find that rapamycin restores mitochondrial protein levels, inhibits signalling through both mTOR complexes and reduces the abundance and activity of multiple PKC isoforms. Administration of PKC inhibitors increases survival, delays neurological deficits, prevents hair loss and decreases inflammation in Ndufs4 KO mice. Thus, PKC may be a viable therapeutic target for treating severe mitochondrial disease.


Assuntos
Doenças Mitocondriais/tratamento farmacológico , Proteína Quinase C/biossíntese , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Animais , Química Encefálica/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Complexo I de Transporte de Elétrons/biossíntese , Complexo I de Transporte de Elétrons/genética , Doença de Leigh/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Quinase C/genética , Proteoma/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/antagonistas & inibidores
6.
Chem Biol Interact ; 331: 109282, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33031791

RESUMO

The novel human coronavirus-2 (HCoV-2), called SARS-CoV-2, is the causative agent of Coronavirus Induced Disease (COVID-19) and has spread causing a global pandemic. Currently, there is no vaccine to prevent infection nor any approved drug for the treatment. The development of a new drug is time-consuming and cannot be relied on as a solution in combatting the immediate global challenge. In such a situation, the drug repurposing becomes an attractive solution to identify the potential of COVID-19 treatment by existing drugs, which are approved for other indications. Here, we review the potential use of rapamycin, an mTOR (Mammalian Target of Rapamycin) inhibitor that can be repurposed at low dosages for the treatment of COVID-19. Rapamycin inhibits protein synthesis, delays aging, reduces obesity in animal models, and inhibits activities or expression of pro-inflammatory cytokines such as IL-2, IL-6 and, IL-10. Overall, the use of rapamycin can help to control viral particle synthesis, cytokine storms and contributes to fight the disease by its anti-aging and anti-obesity effects. Since, rapamycin targets the host factors and not viral machinery, it represents a potent candidate for the treatment of COVID-19 than antiviral drugs as its efficacy is less likely to be dampened with high mutation rate of viral RNA. Additionally, the inhibitory effect of rapamycin on cell proliferation may aid in reducing viral replication. Therefore, by drug repurposing, low dosages of rapamycin can be tested for the potential treatment of COVID-19/SARS-CoV-2 infection.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos , Pneumonia Viral/tratamento farmacológico , Sirolimo/uso terapêutico , Betacoronavirus/isolamento & purificação , Betacoronavirus/fisiologia , Proliferação de Células/efeitos dos fármacos , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Citocinas/metabolismo , Expressão Gênica/efeitos dos fármacos , Humanos , Pandemias , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Replicação Viral/efeitos dos fármacos
8.
Cochrane Database Syst Rev ; 10: CD012796, 2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-33058158

RESUMO

BACKGROUND: Several comparative randomised controlled trials (RCTs) have been performed including combinations of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors since the publication of a Cochrane Review on targeted therapy for metastatic renal cell carcinoma (mRCC) in 2008. This review represents an update of that original review. OBJECTIVES: To assess the effects of targeted therapies for clear cell mRCC in patients naïve to systemic therapy. SEARCH METHODS: We performed a comprehensive search with no restrictions on language or publication status. The date of the latest search was 18 June 2020. SELECTION CRITERIA: We included randomised controlled trials, recruiting patients with clear cell mRCC naïve to previous systemic treatment. The index intervention was any TKI-based targeted therapy. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the included studies and extracted data for the primary outcomes: progression-free survival (PFS), overall survival (OS) and serious adverse events (SAEs); and the secondary outcomes: health-related quality of life (QoL), response rate and minor adverse events (AEs). We performed statistical analyses using a random-effects model and rated the certainty of evidence according to the GRADE approach. MAIN RESULTS: We included 18 RCTs reporting on 11,590 participants randomised across 18 comparisons. This abstract focuses on the primary outcomes of select comparisons. 1. Pazopanib versus sunitinib Pazopanib may result in little to no difference in PFS as compared to sunitinib (hazard ratio (HR) 1.05, 95% confidence interval (CI) 0.90 to 1.23; 1 study, 1110 participants; low-certainty evidence). Based on the control event risk of 420 per 1000 in this trial at 12 months, this corresponds to 18 fewer participants experiencing PFS (95% CI 76 fewer to 38 more) per 1000 participants. Pazopanib may result in little to no difference in OS compared to sunitinib (HR 0.92, 95% CI 0.80 to 1.06; 1 study, 1110 participants; low-certainty evidence). Based on the control event risk of 550 per 1000 in this trial at 12 months, this corresponds to 27 more OSs (95% CI 19 fewer to 70 more) per 1000 participants. Pazopanib may result in little to no difference in SAEs as compared to sunitinib (risk ratio (RR) 1.01, 95% CI 0.94 to 1.09; 1 study, 1102 participants; low-certainty evidence). Based on the control event risk of 734 per 1000 in this trial, this corresponds to 7 more participants experiencing SAEs (95% CI 44 fewer to 66 more) per 1000 participants. 2. Sunitinib versus avelumab and axitinib Sunitinib probably reduces PFS as compared to avelumab plus axitinib (HR 1.45, 95% CI 1.17 to 1.80; 1 study, 886 participants; moderate-certainty evidence). Based on the control event risk of 550 per 1000 in this trial at 12 months, this corresponds to 130 fewer participants experiencing PFS (95% CI 209 fewer to 53 fewer) per 1000 participants. Sunitinib may result in little to no difference in OS (HR 1.28, 95% CI 0.92 to 1.79; 1 study, 886 participants; low-certainty evidence). Based on the control event risk of 890 per 1000 in this trial at 12 months, this would result in 29 fewer OSs (95% CI 78 fewer to 8 more) per 1000 participants. Sunitinib may result in little to no difference in SAEs (RR 1.01, 95% CI 0.93 to 1.10; 1 study, 873 participants; low-certainty evidence). Based on the control event risk of 705 per 1000 in this trial, this corresponds to 7 more SAEs (95% CI 49 fewer to 71 more) per 1000 participants.  3. Sunitinib versus pembrolizumab and axitinib Sunitinib probably reduces PFS as compared to pembrolizumab plus axitinib (HR 1.45, 95% CI 1.19 to 1.76; 1 study, 861 participants; moderate-certainty evidence). Based on the control event risk of 590 per 1000 in this trial at 12 months, this corresponds to 125 fewer participants experiencing PFS (95% CI 195 fewer to 56 fewer) per 1000 participants. Sunitinib probably reduces OS (HR 1.90, 95% CI 1.36 to 2.65; 1 study, 861 participants; moderate-certainty evidence). Based on the control event risk of 880 per 1000 in this trial at 12 months, this would result in 96 fewer OSs (95% CI 167 fewer to 40 fewer) per 1000 participants. Sunitinib may reduce SAEs as compared to pembrolizumab plus axitinib (RR 0.90, 95% CI 0.81 to 1.02; 1 study, 854 participants; low-certainty evidence) although the CI includes the possibility of no effect. Based on the control event risk of 604 per 1000 in this trial, this corresponds to 60 fewer SAEs (95% CI 115 fewer to 12 more) per 1000 participants.  4. Sunitinib versus nivolumab and ipilimumab Sunitinib may reduce PFS as compared to nivolumab plus ipilimumab (HR 1.30, 95% CI 1.11 to 1.52; 1 study, 847 participants; low-certainty evidence). Based on the control event risk of 280 per 1000 in this trial at 30 months' follow-up, this corresponds to 89 fewer PFSs (95% CI 136 fewer to 37 fewer) per 1000 participants. Sunitinib reduces OS (HR 1.52, 95% CI 1.23 to 1.89; 1 study, 847 participants; high-certainty evidence). Based on the control event risk 600 per 1000 in this trial at 30 months, this would result in 140 fewer OSs (95% CI 219 fewer to 67 fewer) per 1000 participants. Sunitinib probably increases SAEs (RR 1.37, 95% CI 1.22 to 1.53; 1 study, 1082 participants; moderate-certainty evidence). Based on the control event risk of 457 per 1000 in this trial, this corresponds to 169 more SAEs (95% CI 101 more to 242 more) per 1000 participants. AUTHORS' CONCLUSIONS: Based on the low to high certainty of evidence, several combinations of immune checkpoint inhibitors appear to be superior to single-agent targeted therapy in terms of PFS and OS, and with a favourable AE profile. Some single-agent targeted therapies demonstrated a similar or improved oncological outcome compared to others; minor differences were observed for AE within this group. The certainty of evidence was variable ranging from high to very low and all comparisons were based on single trials.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Axitinibe/efeitos adversos , Axitinibe/uso terapêutico , Bevacizumab/efeitos adversos , Bevacizumab/uso terapêutico , Viés , Carcinoma de Células Renais/mortalidade , Everolimo/efeitos adversos , Everolimo/uso terapêutico , Humanos , Ipilimumab/efeitos adversos , Ipilimumab/uso terapêutico , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/uso terapêutico , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Qualidade de Vida , Quinolinas/efeitos adversos , Quinolinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Sirolimo/efeitos adversos , Sirolimo/análogos & derivados , Sirolimo/uso terapêutico , Sorafenibe/efeitos adversos , Sorafenibe/uso terapêutico , Sulfonamidas/efeitos adversos , Sulfonamidas/uso terapêutico , Sunitinibe/efeitos adversos , Sunitinibe/uso terapêutico
9.
Medicine (Baltimore) ; 99(40): e22596, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33019479

RESUMO

BACKGROUND: The pathophysiologic of vascular malformations is still unclear, and the treatment of vascular malformations is a challenge. With improvement in the understanding of pathogenesis of vascular malformations, sirolimus has been a promising and effective treatment. As so far, there is absent convincing evidence to confirm the efficacy of sirolimus for vascular malformations. The purpose of this study was to evaluate the effectiveness and safety of sirolimus in the treatment of vascular malformations. METHODS: The literatures about the management of vascular malformations with sirolimus would be searched from databases of MEDLINE, EMBASE, PubMed, Web of Science, Clinicaltrials.org., Cochrane Library, China Biology Medicine Database (CBM), Wan Fang Database, China National Knowledge Infrastructure Database (CNKI), and VIP Science Technology Periodical Database. We will search each database from inception or 1995 to August 20, 2020. Two researchers worked independently on literature selection, data extraction and quality assessment. The efficacy and safety of sirolimus in the treatment of vascular malformations were the main outcomes. Adverse events after sirolimus were evaluated as the secondary outcomes. The included studies will be analyzed by Review Manager 5.3. If the results are applicable, meta-analysis would also be performed. RESULTS: The study will evaluate the efficacy and safety of sirolimus in the treatment of vascular malformations based on current evidence. CONCLUSION: The conclusion of this study will provide more reliable, evidence-based data for the use of sirolimus in the treatment of vascular malformations. PROSPERO REGISTRATION NUMBER: CRD42020167881.


Assuntos
Imunossupressores/uso terapêutico , Sirolimo/uso terapêutico , Malformações Vasculares/tratamento farmacológico , Gerenciamento de Dados , Feminino , Humanos , Imunossupressores/efeitos adversos , Masculino , Projetos de Pesquisa , Segurança , Sirolimo/efeitos adversos , Serina-Treonina Quinases TOR/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Resultado do Tratamento , Malformações Vasculares/fisiopatologia
10.
Ann Surg ; 272(5): 855-862, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32889867

RESUMO

OBJECTIVE: The aim of this study was to evaluate the survival benefit of sirolimus in patients undergoing liver transplantation (LT) for hepatocellular carcinoma (HCC) (exploratory analysis of the SiLVER-trial). SUMMARY AND BACKGROUND DATA: Patients receiving LT) for HCC are at a high risk for tumor recurrence. Calcineurin inhibitors have shown evidence to promote cancer growth, whereas mammalian target of rapamycin (mTOR) inhibitors like sirolimus have anticancer effects. In the SiLVER-trial (Clinicaltrials.gov: NCT00355862), the effect of sirolimus on the recurrence of HCC after LT was investigated in a prospective randomized trial. Although the primary endpoint of improved disease-free survival (DFS) with sirolimus was not met, outcomes were improved for patients in the sirolimus-treatment arm in the first 3 to 5 years. To learn more about the key variables, a multivariate analysis was performed on the SiLVER-trial data. PATIENTS AND METHODS: Data from 508 patients of the intention-to-treat analysis were included in exploratory univariate and multivariate models for overall survival (OS), DFS and a competing risk analysis for HCC recurrence. RESULTS: Sirolimus use for ≥3 months after LT for HCC independently reduced the hazard for death in the multivariate analysis [hazard ratio (HR): 0.7 (95% confidence interval, CI: 0.52-0.96, P = 0.02). Most strikingly, patients with an alpha-fetoprotein (AFP) ≥10 ng/mL and having used sirolimus for ≥3 months, benefited most with regard to OS, DFS, and HCC-recurrence (HR: 0.49-0.59, P = 0.0079-0.0245). CONCLUSIONS: mTOR-inhibitor treatment with sirolimus for ≥3 months improves outcomes in LT for HCC, especially in patients with AFP-evidence of higher tumor activity, advocating particularly for mTOR inhibitor use in this subgroup of patients. CLINICAL TRIAL REGISTRATION: EudraCT: 2005-005362-36 CLINICALTRIALS.GOV:: NCT00355862.


Assuntos
Carcinoma Hepatocelular/cirurgia , Imunossupressores/uso terapêutico , Neoplasias Hepáticas/cirurgia , Transplante de Fígado , Recidiva Local de Neoplasia/prevenção & controle , Sirolimo/uso terapêutico , Idoso , Carcinoma Hepatocelular/mortalidade , Feminino , Humanos , Análise de Intenção de Tratamento , Neoplasias Hepáticas/mortalidade , Transplante de Fígado/mortalidade , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida
11.
Zhongguo Dang Dai Er Ke Za Zhi ; 22(9): 1011-1016, 2020 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-32933636

RESUMO

To study the clinical effect of oral sirolimus in the treatment of children with blue rubber bleb nevus syndrome (BRBNS) in the gastrointestinal tract, a retrospective analysis was performed on the clinical data and follow-up results of two children with BRBNS treated by sirolimus. The two children with BRBNS had gastrointestinal bleeding and anemia and were treated with sirolimus at a dose of 1 mg/day as part of treatment. The plasma concentration of the drug was maintained between 2.5-12.0 ng/mL. The children showed disappearance of gastrointestinal bleeding and improvements in anemia and coagulation function, and blood transfusion could be stopped during treatment, with no obvious adverse drug reactions. PubMed, Wanfang Data, and CNKI were searched for related articles on sirolimus in the treatment of BRBNS. A total of 26 cases of children with BRBNS, aged 0-18 years, were obtained. With the addition of the 2 cases in this study, sirolimus treatment achieved a satisfactory clinical effect in all 28 cases. Sirolimus may be effective and safe in the treatment of children with BRBNS, and further prospective studies are needed to evaluate the long-term efficacy of this drug.


Assuntos
Neoplasias Gastrointestinais , Nevo Azul , Sirolimo/uso terapêutico , Neoplasias Cutâneas , Adolescente , Criança , Pré-Escolar , Neoplasias Gastrointestinais/tratamento farmacológico , Humanos , Lactente , Recém-Nascido , Nevo Azul/tratamento farmacológico , Estudos Prospectivos , Estudos Retrospectivos , Neoplasias Cutâneas/tratamento farmacológico
12.
Medicine (Baltimore) ; 99(30): e20710, 2020 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-32791665

RESUMO

BACKGROUND: Idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder of unknown etiology with systemic symptoms that include fever, night sweats, weight loss, and fatigue. Although tocilizumab (TCZ), which is a recombinant, humanized, anti-human interleukin 6 receptor monoclonal antibody, has been recommended to treat patients with iMCD, 40% of patients with iMCD do not achieve complete remission with TCZ treatment. METHODS/DESIGN: In this phase II, investigator-initiated, multicenter, double-blind, randomized, parallel-group trial, the efficacy and safety of sirolimus will be compared with placebo in patients with TCZ-resistant iMCD. The study will be conducted in 8 centers in Japan. Participants (n = 20) will be randomly assigned to receive 2 mg of oral sirolimus (n = 10) or placebo (n = 10) once daily for 16 weeks. The primary endpoint is a decrease in CHAP score by ≥1 from baseline at 16 weeks. Secondary endpoints include levels of hemoglobin, albumin, and C-reactive protein; change in CHAP score; SF-36 Health Survey Questionnaire; physician global assessment (100 mm visual analog scale); patient global assessment (100 mm visual analog scale) at 2, 4, 8, 12, and 16 weeks; change in lymphadenopathy at 16 weeks; and pharmacodynamic assessment, including the measurement of whole blood sirolimus level. DISCUSSION: This clinical trial will provide evidence of efficacy and safety of sirolimus as a potential new therapeutic agent for patients with TCZ-resistant iMCD. TRIAL REGISTRATION: This study was registered with the Japan Registry of Clinical Trials as jRCT2071190029 on October 8, 2019.


Assuntos
Hiperplasia do Linfonodo Gigante/tratamento farmacológico , Imunossupressores/uso terapêutico , Sirolimo/uso terapêutico , Anticorpos Monoclonais Humanizados , Método Duplo-Cego , Resistência a Medicamentos , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
13.
Gene ; 759: 144987, 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-32712065

RESUMO

BACKGROUND: The immune response is influenced by the administration of omega-3 polyunsaturated fatty acids (PUFA). Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE) are affected by PUFA. The combination of evening primrose/hemp seed oil (EPO/HSO) has essential fatty acids (EFAs) for human optimal health due to the favorable ratio of omega-6/omega-3 and antioxidantal properties. The study was conducted to evaluate the effects of EPO/HSO on improving the membrane fatty acids composition of spleen and blood cells and immunologic factors in compared to rapamycin (RAPA) in the EAE model. METHODS AND MATERIALS: Chronic-EAE was induced by induction of MOG in C57BL/6J mice (female, age: 6-8 weeks, weight 18-21). Mice were assigned to 5 groups (6/group) to evaluate the therapeutic effects of EPO/HSO supplement in comparison with rapamycin: A group; EPO/HSO + RAPA, B group; RAPA, C group; EPO/HSO. Results were compared to two control groups (EAE and naive). The fatty acid profile of the spleen and blood cell membrane was evaluated. Real-time-polymerase chain reaction was used for the evaluate the genes expression levels of interleukin (IL) -4, IL-5, and IL-13 in lymphocytes. Also, IL-4 of serum was evaluated by enzyme-linked immunosorbent assay (ELISA). RESULTS: Our findings indicated that EPO/HSO therapy significantly increased the percentage of essential fatty acids in cell membrane of the spleen and blood. The relative expression of IL-4, IL-5, and IL-13 genes in lymphocytes and serum level of IL-4 was significantly increased in the HSO/EPO treated group versus other groups. CONCLUSION: These results point to potential therapeutic effects on the repair of the structure of cell membranes and suppression of inflammation by EPO/HSO in EAE.


Assuntos
Antioxidantes/uso terapêutico , Encefalomielite Autoimune Experimental/tratamento farmacológico , Ácidos Graxos Essenciais/metabolismo , Fatores Imunológicos/uso terapêutico , Interleucinas/metabolismo , Óleos Vegetais/uso terapêutico , Sirolimo/uso terapêutico , Animais , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Cannabis/química , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Suplementos Nutricionais , Combinação de Medicamentos , Feminino , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/farmacologia , Lipídeos de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Óleos Vegetais/administração & dosagem , Primula/química , Sirolimo/administração & dosagem
15.
Gastroenterol Hepatol ; 43(8): 457-463, 2020 Oct.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-32646657

RESUMO

SARS-CoV-2 infection has produced a pandemic with serious consequences for our health care system. Although liver transplant patients represent only a minority of the population, the hepatologists who follow these patients have tried to coordinate efforts to produce a protocol the management of immunosuppression during SARS-CoV-2 infection. Although there are no solid studies to support general recommendations, experiences with other viral infections (hepatitis C, cytomegalovirus) suggest that management of immunosuppression without mycophenolate mofetil or m-Tor inhibitors (drugs that are also associated with leukopenia and lymphopenia) may be beneficial. It is also important to pay attention to possible drug interactions, especially in the case of tacrolimus, with some of the treatments with antiviral effect given in the context of COVID 19 (lopinavir/ritonavir, azithromycin). Finally, the immunosuppressive effect of immunomodulating drugs (tocilizumab and similar) administered to patients with severe lung disease should be taken into account. The mechanisms of action of the different immunosuppressive drugs are reviewed in this article, as well as their potential effect on SARS-CoV-2 infection, and suggests guidelines for the management of immunosuppression.


Assuntos
Betacoronavirus , Infecções por Coronavirus/epidemiologia , Imunossupressão/efeitos adversos , Imunossupressores/efeitos adversos , Transplante de Fígado , Pandemias , Pneumonia Viral/epidemiologia , Imunidade Adaptativa , Antivirais/farmacologia , Betacoronavirus/imunologia , Betacoronavirus/fisiologia , Inibidores de Calcineurina/efeitos adversos , Inibidores de Calcineurina/farmacologia , Inibidores de Calcineurina/uso terapêutico , Contraindicações de Medicamentos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Suscetibilidade a Doenças , Interações Medicamentosas , Everolimo/efeitos adversos , Everolimo/farmacologia , Everolimo/uso terapêutico , Glucocorticoides/efeitos adversos , Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , Humanos , Imunidade Inata , Hospedeiro Imunocomprometido , Imunossupressão/métodos , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Ácido Micofenólico/efeitos adversos , Ácido Micofenólico/farmacologia , Ácido Micofenólico/uso terapêutico , Pneumonia Viral/imunologia , Complicações Pós-Operatórias/imunologia , Complicações Pós-Operatórias/prevenção & controle , Sirolimo/efeitos adversos , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores
16.
Transplant Proc ; 52(5): 1617-1618, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32505499

RESUMO

T-cell large granular lymphocytic (T-LGL) leukemia is a rare clonal proliferation presenting with cytopenia, splenomegaly, and autoimmune manifestations. It has rarely been described in recipients of solid organ transplants. We report the clinical case of a young kidney transplant recipient that developed T-LGL leukemia 3 years after kidney transplantation. The disorder manifested with a severe form of autoimmune hemolytic anemia in the absence of other laboratory abnormalities. The anemia was successfully treated with an intense course of corticosteroids ands witch of immunosuppressive therapy from a calcineurin inhibitor to sirolimus, a mammalian target of rapamycin inhibitor. Our case shows that autoimmune hemolytic anemia can be a life-threatening manifestation of T-LGL disease. The antiproliferative effects of sirolimus may be useful in the treatment of symptoms of T-LGL leukemia in kidney transplantation.


Assuntos
Anemia Hemolítica/etiologia , Falência Renal Crônica/cirurgia , Transplante de Rim/efeitos adversos , Leucemia Linfocítica Granular Grande/etiologia , Humanos , Imunossupressores/uso terapêutico , Leucemia Linfocítica Granular Grande/diagnóstico , Masculino , Sirolimo/uso terapêutico , Adulto Jovem
17.
PLoS One ; 15(6): e0233887, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32492043

RESUMO

Increased cytoplasmic lipid droplets (LDs) and elevated AKT/mTOR signaling are characteristics of clear cell renal cell carcinoma (ccRCC). Lysophosphatidic acid (LPA), a potent lipid mitogen generated via autotaxin (elevated in ccRCC), can modulate tumor progression but its role in altering chemotherapeutic sensitivity to mTOR inhibitors is unclear and thus is the focus of the studies presented herein. Using malignant (A-498, 769-P and 786-O) and normal immortalized kidney (HK-2) cell lines, we investigated their cellular responsiveness to Temsirolimus (TEMS, mTOR inhibitor) in the absence or presence of LPA by monitoring alterations in AKT/mTOR pathway mediators (via western blotting), LDs (using LipidTOX and real-time PCR to assess transcript changes in modulators of LD biogenesis/turnover), mitochondrial networks (via immunofluorescence staining for TOM20 and TOM70), as well as cellular viability. We identified that TEMS reduced cellular viability in all renal cell lines, with increased sensitivity in the presence of an autophagy inhibitor. TEMS also altered activation of AKT/mTOR pathway mediators, abundance of LDs, and fragmentation of mitochondrial networks. We observed that these effects were antagonized by LPA. In HK-2 cells, LPA markedly increased LD size and abundance, coinciding with phospho-MAPK and phospho-S6 activation, increased diacylglycerol O-acetyltransferase 2 (DGAT2) mRNA (which produces triacylglycerides), and survival. Inhibiting MAPK partially antagonized LPA-induced LD changes. Collectively, we have identified that LPA can reverse the effects of TEMS by increasing LDs in a MAPK-dependent manner; these results suggest that LPA may contribute to the pathogenesis and chemotherapeutic resistance of ccRCC.


Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Lisofosfolipídeos/metabolismo , Sirolimo/análogos & derivados , Antineoplásicos/uso terapêutico , Autofagia/efeitos dos fármacos , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Humanos , Hidroxicloroquina/farmacologia , Hidroxicloroquina/uso terapêutico , Neoplasias Renais/patologia , Gotículas Lipídicas/efeitos dos fármacos , Gotículas Lipídicas/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo
18.
Pediatr Cardiol ; 41(7): 1354-1362, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32474740

RESUMO

Ductal stenting (DS) palliates duct-dependent lesions using coronary stents. Sirolimus-eluting stents have replaced bare-metal stents in coronary interventions. Concerns exist about sirolimus levels in neonates. Therapeutic immunosuppressive sirolimus level is 5-15 ng/ml. After neonatal DS, drug levels were assessed at 24 h, 7 days and monthly thereafter till they were undetectable. Clinical course, ductal patency till their final corrective surgery was analyzed. The exact quantity of sirolimus in each stent was known. Twelve neonates with median age of 5.5 days received sirolimus-eluting stents, one stent in nine and two in the rest. The lesions were pulmonary atresia intact ventricular septum(PAIVS) in four, univentricular lesions with pulmonary atresia in four, biventricular lesions with pulmonary atresia in three and right ventricular rhabdomyoma in one neonate. If single stents up to 22 mm length, 24-h drug levels were less than 5 ng/ml. Even though 24-h levels were above 5 ng/ml in patients with single longer stent or two stents, it reduced to very low levels by seventh day. Two hospital deaths included rhabdomyoma with complete heart block and post-valvotomy cardiac failure for PAIVS. Stent patency after valvotomy for PAIVS exceeded three years. Patency was retained for 8-27 months till their elective corrective surgery in others. Sirolimus levels were acceptable at 24 h in all neonates receiving single stent under 22 mm length. In patients needing two stents, drug levels were in immunosuppressive range at 24 h but reduced rapidly within 7 days. The palliation provided by sirolimus-eluting DS was sufficiently long to provide clinical benefit.


Assuntos
Stents Farmacológicos , Permeabilidade do Canal Arterial/tratamento farmacológico , Circulação Pulmonar/efeitos dos fármacos , Sirolimo/sangue , Sirolimo/uso terapêutico , Cromo , Cobalto , Permeabilidade do Canal Arterial/cirurgia , Feminino , Ventrículos do Coração/fisiopatologia , Humanos , Imunossupressores , Recém-Nascido , Masculino , Estudos Prospectivos , Implantação de Prótese , Atresia Pulmonar/cirurgia , Resultado do Tratamento , Septo Interventricular
19.
Aging (Albany NY) ; 12(11): 10004-10021, 2020 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-32534452

RESUMO

COVID-19 is not deadly early in life, but mortality increases exponentially with age, which is the strongest predictor of mortality. Mortality is higher in men than in women, because men age faster, and it is especially high in patients with age-related diseases, such as diabetes and hypertension, because these diseases are manifestations of aging and a measure of biological age. At its deepest level, aging (a program-like continuation of developmental growth) is driven by inappropriately high cellular functioning. The hyperfunction theory of quasi-programmed aging explains why COVID-19 vulnerability (lethality) is an age-dependent syndrome, linking it to other age-related diseases. It also explains inflammaging and immunosenescence, hyperinflammation, hyperthrombosis, and cytokine storms, all of which are associated with COVID-19 vulnerability. Anti-aging interventions, such as rapamycin, may slow aging and age-related diseases, potentially decreasing COVID-19 vulnerability.


Assuntos
Envelhecimento , Infecções por Coronavirus/mortalidade , Pneumonia Viral/mortalidade , Animais , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Senescência Celular , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/metabolismo , Citocinas/metabolismo , Suscetibilidade a Doenças , Humanos , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/metabolismo , Sirolimo/farmacologia , Sirolimo/uso terapêutico
20.
Arch Biochem Biophys ; 689: 108461, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32531316

RESUMO

The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway plays an important role in the development of papillary thyroid cancer. While rapamycin has been shown to exhibit anti-tumor effects, it may also activate AKT, resulting in increased cell survival and drug resistance, thereby limiting its anti-tumor effects. Resveratrol can also inhibit tumor growth by regulating the PI3K/AKT/mTOR signaling pathway. The present study investigated the anti-tumor effects of the combined use of rapamycin and resveratrol in papillary thyroid cancer. We first treated two human papillary thyroid cancer cell lines (KTC-1 and TPC-1) with single or combined administration, and examined the effects on proliferation, the cell cycle, apoptosis, and invasion/migration of papillary thyroid cancer cells. A mouse xenograft model was induced with KTC-1 and TPC-1 cells followed by treatment with single or combined administration. Body weight and tumor size were monitored to assess the toxicity of each compound. The phosphorylation of AKT and the mTORC1 target p70S6 kinase (p70S6K) in tumors was also examined. Both rapamycin and resveratrol inhibited proliferation, altered the cell cycle, and induced apoptosis of papillary thyroid cancer cells. Invasion and migration were also reduced, as was the tumor growth rate in the xenograft model. Co-administration significantly enhanced the anti-tumor effects than use of any one drug, and significantly reduced the phosphorylation of AKT and p70S6K compared to treatment with rapamycin alone. Overall, compared to single use of rapamycin or resveratrol, co-administration had a synergistic effect in inhibiting proliferation and invasion/migration of papillary thyroid cancer cells and inducing apoptosis. Resveratrol is sensitizing the anti-tumor effects of rapamycin and the PI3K/AKT/mTOR signaling is involved. Although further animal and clinical studies are needed to clarify the mechanism and assess drug safety, the present study suggests that the combination of rapamycin and resveratrol may be a promising strategy for the treatment of papillary thyroid cancer.


Assuntos
Antineoplásicos/uso terapêutico , Resveratrol/uso terapêutico , Sirolimo/uso terapêutico , Câncer Papilífero da Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Resveratrol/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Câncer Papilífero da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/metabolismo
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