Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 4.674
Filtrar
1.
Anticancer Res ; 39(10): 5417-5425, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570436

RESUMO

BACKGROUND/AIM: Chemotherapy with docetaxel (DTX) is used for castration-resistant prostate cancer (CRPC), but it is inadequate. MATERIALS AND METHODS: We evaluated the effect of the combination treatment DTX and the mTOR inhibitor temsirolimus (TEM) in the PC3 prostate cancer cell line, by focusing on the induction of autophagy and apoptosis. RESULTS: TEM induced autophagy but not apoptosis even at a high dose, whereas DTX induced apoptosis. The combination of low-dose DTX and TEM caused a 34% suppression in cell proliferation compared to monotherapy with a higher dose of DTX. The induction of apoptosis was increased by their combination. The combination with DTX overcame the induction of autophagy by TEM. The combination treatment suppressed tumor growth 72% less than the control group after 14 days of treatment in vivo. CONCLUSION: The combination of TEM and DTX induced apoptosis by overcoming autophagy and enhanced the anticancer effect compared to monotherapy.


Assuntos
Antineoplásicos/administração & dosagem , Autofagia/efeitos dos fármacos , Docetaxel/administração & dosagem , Próstata/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Sirolimo/análogos & derivados , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Terapia Combinada/métodos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células PC-3 , Inibidores de Proteínas Quinases/administração & dosagem , Sirolimo/administração & dosagem
2.
Zhonghua Xin Xue Guan Bing Za Zhi ; 47(10): 784-789, 2019 Oct 24.
Artigo em Chinês | MEDLINE | ID: mdl-31648460

RESUMO

Objective: To evaluate the long-term efficacy of a second generation biodegradable polymer sirolimus-eluting stent (EXCEL2) in treating patients with de novo coronary artery diseases. Methods: CREDIT Ⅱ trial was a prospective, multicenter, randomized, controlled study, conducted at 15 Chinese cardiac centres from November 2013 to December 2014. In this analysis, eligible patients for coronary stenting (n=419) were randomized to receive either the EXCEL2 stent (n=208) or the EXCEL stent (n=211). The primary endpoint was target lesion failure (TLF) at 3 years after PCI defined as a composite endpoints of cardiac death, target vessel myocardial infarction (TVMI), or clinically indicated target lesion revascularization (CI-TLR). Secondary endpoints included patient-oriented composite endpoint (PoCE) including all-cause death, all MI, or any revascularization at 3 years and independent components, and stent thrombosis according to Academic Research Consortium's (ARC) definition. Results: Among 419 enrolled patients, 413 (98.6%) patients completed 3-year clinical follow-up. Compared with the EXCEL group, 3-year TLF (5.4%(11/204) vs. 11.5% (24/209), P=0.025) and PoCE (9.8% (20/204) vs. 20.1% (42/209), P=0.003) were significantly lower in the EXCEL2 group. The cumulative event rate of CI-TLR (2.0% (4/204) vs. 5.7% (12/209), P=0.042) and any revascularization (4.9% (10/204) vs. 14.4% (30/209), P=0.001) were statistically lower in the EXCEL2 group than in the EXCEL group. There were no significant difference between two groups in terms of all-cause death and all MI. Rates of stent thrombosis were low without significant difference between the two groups (EXCEL2 vs. EXCEL, 1.0% (2/204) vs. 2.9% (6/209), P=0.285). Conclusion: 3-year clinical follow-up results demonstrate that EXCEL2 stents are effective and safe in treating CAD patients with de novo coronary lesions.


Assuntos
Fármacos Cardiovasculares/administração & dosagem , Doença da Artéria Coronariana/terapia , Stents Farmacológicos , Sirolimo/administração & dosagem , Implantes Absorvíveis , Humanos , Intervenção Coronária Percutânea , Polímeros , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento
3.
Int J Nanomedicine ; 14: 6249-6268, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496684

RESUMO

Purpose: To develop an intravesical instillation system for the treatment of bladder cancer, rapamycin (Rap) was encapsulated into liposomes and then homogeneously dispersed throughout a poloxamer 407 (P407)-based hydrogel. Methods: Rap-loaded conventional liposomes (R-CL) and folate-modified liposomes (R-FL) were prepared using a film hydration method and pre-loading technique, and characterized by particle size, drug entrapment efficiency, and drug loading. The cellular uptake behavior in folate receptor-expressing bladder cancer cells was observed by flow cytometry and confocal laser scanning microscopy using a fluorescent probe. In vitro cytotoxic effects were evaluated using MTT assay, colony forming assay, and Western blot. For in vivo intravesical instillation, Rap-loaded liposomes were dispersed in P407-gel, generating R-CL/P407 and R-FL/P407. Gel-forming capacities and drug release were evaluated. Using the MBT2/Luc orthotopic bladder cancer mouse model, in vivo antitumor efficacy was evaluated according to regions of interest (ROI) measurement. Results: R-CL and R-FL were successfully prepared, at approximately <160 nm, 42% entrapment efficiency, and 57 µg/mg drug loading. FL cellular uptake was enhanced over 2-fold than that of CL; folate receptor-mediated endocytosis was confirmed using a competitive assay with folic acid pretreatment. In vitro cytotoxic effects increased dose-dependently. Rap-loaded liposomes inhibited mTOR signaling and induced autophagy in urothelial carcinoma cells. With gelation time of <30 seconds and gel duration of >12 hrs, both R-CL/P407 and R-FL/P407 preparations transformed into gel immediately after instillation into the mouse bladder. Drug release from the liposomal gel was erosion controlled. In orthotopic bladder cancer mouse model, statistically significant differences in ROI values were found between R-CL/P407 and R-FL/P407 groups at day 11 (P=0.0273) and day 14 (P=0.0088), indicating the highest tumor growth inhibition by R-FL/P407. Conclusion: Intravesical instillation of R-FL/P407 might represent a good candidate for bladder cancer treatment, owing to its enhanced retention and FR-targeting.


Assuntos
Ácido Fólico/química , Hidrogéis/química , Sirolimo/administração & dosagem , Sirolimo/farmacologia , Temperatura Ambiente , Administração Intravesical , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Coloides , Modelos Animais de Doenças , Liberação Controlada de Fármacos , Feminino , Receptores de Folato com Âncoras de GPI/metabolismo , Humanos , Lipossomos , Camundongos , Tamanho da Partícula , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico
4.
Medicine (Baltimore) ; 98(32): e16767, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31393396

RESUMO

There are limited long-term outcome data comparing BioLinx polymer (B)-zotarolimus-eluting stents (ZES) with phosphorylcholine polymer (P)-ZES. The aim of this study was to compare the efficacy and safety of B-ZES with P-ZES in patients who underwent percutaneous coronary intervention (PCI) during a 3-year follow-up period.One thousand two hundred fifty four patients who underwent PCI with P-ZES (Endeavor [ZES-E] or Endeavor sprint [ZES-S], n = 356) or B-ZES (Endeavor resolute [ZES-R] or Resolute Integrity [ZES-I], n = 889) were enrolled. The primary endpoint was major adverse cardiac events (MACE); the composite of total death, non-fatal myocardial infarction (MI), target lesion revascularization (TLR), target vessel revascularization (TVR), non-target vessel revascularization (Non-TVR), and the secondary endpoint was stent thrombosis (ST).After PSM, 2 propensity-matched (PSM) groups (275 pairs, n = 550, C-statistic = 0.730) were generated. During the 3-year follow-up period, the cumulative incidence of MACE (hazard ratio [HR], 1.525; 95% confidence interval [CI], 0.920-2.526; P = .101) and ST (HR, 1.248; 95% CI, 0.335-4.4649; P = .741) were similar between P-ZES and B-ZES after PSM. However, TLR rate was significantly higher in ZES-S than ZES-I (11.3% vs 3.8%, log rank P = .029) and TVR rate was higher in ZES-S than ZES-R (14.1% vs 4.8%, log rank P = .025).In this single-center, all-comer registry, despite different polymers, P-ZES, and B-ZES showed comparable safety and efficacy during a 3-year follow-up period after PCI.


Assuntos
Doenças Cardiovasculares/epidemiologia , Stents Farmacológicos/efeitos adversos , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/métodos , Fosforilcolina/administração & dosagem , Sirolimo/análogos & derivados , Idoso , Doenças Cardiovasculares/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/mortalidade , Polímeros , Pontuação de Propensão , Desenho de Prótese , Reoperação , Sirolimo/administração & dosagem
5.
Pharm Res ; 36(9): 134, 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31297653

RESUMO

PURPOSE: Despite extensive preclinical investigations, in-vivo properties and formulation characteristics that improve CNS drug delivery following systemic dosing of nanoemulsions remain incompletely understood. METHODS: The CNS targeting potential of systemically administered nanoemulsions was evaluated by formulating rapamycin containing fish oil nanoemulsions, and testing the combined effect of formulation characteristics such as the circulation half-life and particle size distribution, on CNS delivery of rapamycin containing fish oil nanoemulsions in mice. RESULTS: Results generated with rapamycin nanoemulsions suggested that circulation half-life and particle size distribution did not impact the brain targeting efficiency of rapamycin containing fish oil nanoemulsions. Further, in the absence of any improvement in the systemic exposures of rapamycin, nanoemulsions did not outperform their aqueous counterpart with respect to the extent of CNS drug delivery. CONCLUSIONS: Our findings confirm that BBB penetration, which primarily depends on intrinsic drug-related properties, may not be significantly improved following encapsulation of drugs in nanoemulsions. Graphical Abstract The CNS targeting potential of systemically administered nanoemulsions was investigated by formulating various rapamycin containing fish oil nanoemulsions associated with different formulation characteristics such as the circulation half-life and particle size distribution. The targeting efficiency (TE) defined as the ratio of the brain exposures to the accompanying systemic exposures of rapamycin was estimated for each formulation following IV dosing in mice.


Assuntos
Encéfalo/metabolismo , Óleos de Peixe/química , Nanopartículas/química , Sirolimo/administração & dosagem , Animais , Barreira Hematoencefálica/metabolismo , Permeabilidade da Membrana Celular , Emulsões , Camundongos , Tamanho da Partícula , Polietilenoglicóis/química , Sirolimo/farmacocinética , Distribuição Tecidual
6.
EuroIntervention ; 15(7): 607-614, 2019 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-31147308

RESUMO

AIMS: Although the proof of concept of the bioresorbable vascular scaffold (BRS) is well documented, device-related adverse outcomes with first-generation BRS indicate longer-term surveillance. The current study provides insights into the safety and performance of the MeRes100, a novel second-generation sirolimus-eluting BRS, beyond one-year up to three-year follow-up (FU). METHODS AND RESULTS: A total of 108 enrolled patients with de novo coronary artery lesions who underwent implantation of MeRes100 as part of the first-in-human MeRes-1 trial were followed up clinically beyond one year at two and three years and with multiple modality imaging at six months and two years. At three-year FU, the cumulative major adverse cardiac events rate was 1.87%, in the form of two ischaemia-driven target lesion revascularisations. No scaffold thrombosis was reported. Between six months and two years at quantitative coronary angiography, in-segment late lumen loss (LLL) (0.15±0.22 mm vs. 0.23±0.32 mm; p=0.18) and in-scaffold LLL (0.13±0.22 mm vs. 0.24±0.34 mm; p=0.10) changed insignificantly. IVUS subset analysis revealed a non-significant reduction in mean lumen area (6.17±1.28 mm2 vs. 5.47±1.50 mm2; p=0.21) and minimum lumen area (5.14±1.19 mm2 vs. 4.05±1.42 mm2; p=0.10) at two years compared to post-procedural measurements. OCT subset analysis demonstrated 99.24±2.27% neointimal strut coverage. CONCLUSIONS: The extended outcomes of the MeRes-1 trial demonstrated sustained efficacy and safety of the MeRes100 BRS with maintained lumen patency up to two years by multimodality imaging and no very late scaffold thrombosis up to three-year clinical FU.The MeRes-1 trial is registered at the Clinical Trials Registry-India. CTRI Number: CTRI/2015/04/005706.


Assuntos
Implantes Absorvíveis , Fármacos Cardiovasculares/administração & dosagem , Doença da Artéria Coronariana/terapia , Vasos Coronários/efeitos dos fármacos , Stents Farmacológicos , Everolimo/administração & dosagem , Intervenção Coronária Percutânea/instrumentação , Sirolimo/administração & dosagem , Fármacos Cardiovasculares/efeitos adversos , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Vasos Coronários/diagnóstico por imagem , Everolimo/efeitos adversos , Seguimentos , Humanos , Índia , Intervenção Coronária Percutânea/efeitos adversos , Sirolimo/efeitos adversos , Resultado do Tratamento
8.
J Cardiovasc Surg (Torino) ; 60(4): 439-449, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31062571

RESUMO

Drug-eluting stent (DES) are the mainstay therapy for the treatment of coronary artery disease. Stent design and drug-elution strategies have evolved over the years leading to the last generation DES which shows optimal safety and efficacy outcome. Peripheral arteries have different mechanical and biological features and the lessons learned from the coronary field have been difficult to introduce into the development of peripheral vascular technologies. First, due to its complex biomechanical behavior the use of metallic stents is limited in some vascular segments (i.e., distal superficial fermoral artery [SFA]). Also, peripheral vascular atherosclerosis is different containing higher levels of plaque burden and calcium. Finally, peripheral arterial disease tends to be more aggressive including longer lesions and higher incidence of total chronic occlusion. In general terms, restenosis in the peripheral vascular territory is more aggressive and occurs at a later time (~12 months) requiring a different pharmacokinetic profile compared to coronary technologies. Several strategies have been evaluated in the peripheral arteries raging from the bare metal stent to the drug coated balloon and drug eluting stent with outcome varying depending on the different field of application (i.e. SFA and below-the-knee). Results coming from the clinical trial are encouraging but further studies and direct comparison among the different technologies are demanded to determine the best therapy for peripheral vascular disease.


Assuntos
Paclitaxel/administração & dosagem , Doença Arterial Periférica/terapia , Sirolimo/administração & dosagem , Stents , Sistemas de Liberação de Medicamentos , Stents Farmacológicos , Everolimo/administração & dosagem , Artéria Femoral/cirurgia , Humanos , Doença Arterial Periférica/tratamento farmacológico , Polímeros , Prevenção Secundária/métodos , Serina-Treonina Quinases TOR/antagonistas & inibidores
9.
Int Heart J ; 60(3): 521-526, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31105145

RESUMO

Prior research has revealed poorer clinical outcomes after drug-eluting stent (DES) implantation for hemodialysis patients. This study aims to investigate the long-term clinical and angiographic outcomes after new-generation DES implantation for hemodialysis patients.We retrospectively enrolled 91 consecutive patients (118 lesions) who underwent successful new-generation DES (everolimus-, zotarolimus-, and biolimus-eluting stents) implantation for the first time. We measured the serum calcium and phosphorus levels in the blood samples obtained just before hemodialysis. The follow-up period of clinical events was, at least, 1.5 years. In this study, major adverse cardiac and cerebrovascular events (MACCE) and clinically driven target lesion revascularization were reported in 36 (39.6%) and 11 (12.1%) patients, respectively. The prevalence of peripheral artery disease was significantly higher in the MACCE group (41.7% versus 14.5%, P = 0.006). The serum calcium level was significantly higher in the MACCE group (9.34 ± 0.92 mg/dL versus 8.77 ± 0.88 mg/dL; P = 0.004). The multivariate Cox proportional hazards model revealed that the serum calcium level (hazard ratio, 1.86; 95% confidence interval [CI]: 1.26-2.77; P = 0.002), suboptimal (over 55 mg2/dL2) calcium-phosphorus product (hazard ratio, 3.27; 95% CI: 1.41-7.61; P = 0.006) and the coexistence of peripheral artery disease (hazard ratio, 3.15; 95% CI: 1.49-6.65; P = 0.003) were independent predictors of MACCE.For hemodialysis patients, MACCE remains a frequent occurrence after new-generation DES implantation and is associated with calcium-phosphate metabolism and peripheral artery disease.


Assuntos
Angiografia/métodos , Cálcio/sangue , Stents Farmacológicos/efeitos adversos , Doença Arterial Periférica/epidemiologia , Fósforo/sangue , Diálise Renal/instrumentação , Idoso , Everolimo/administração & dosagem , Feminino , Seguimentos , Humanos , Imunossupressores/administração & dosagem , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/etiologia , Doença Arterial Periférica/diagnóstico por imagem , Doença Arterial Periférica/etiologia , Prevalência , Estudos Retrospectivos , Sirolimo/administração & dosagem , Sirolimo/análogos & derivados
10.
Adv Mater ; 31(21): e1808361, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30957932

RESUMO

Reperfusion injury exists as the major obstacle to full recovery of neuron functions after ischemic stroke onset and clinical thrombolytic therapies. Complex cellular cascades including oxidative stress, neuroinflammation, and brain vascular impairment occur within neurovascular units, leading to microthrombus formation and ultimate neuron death. In this work, a multitarget micelle system is developed to simultaneously modulate various cell types involved in these events. Briefly, rapamycin is encapsulated in self-assembled micelles that are consisted of reactive oxygen species (ROS)-responsive and fibrin-binding polymers to achieve micelle retention and controlled drug release within the ischemic lesion. Neuron survival is reinforced by the combination of micelle facilitated ROS elimination and antistress signaling pathway interference under ischemia conditions. In vivo results demonstrate an overall remodeling of neurovascular unit through micelle polarized M2 microglia repair and blood-brain barrier preservation, leading to enhanced neuroprotection and blood perfusion. This strategy gives a proof of concept that neurovascular units can serve as an integrated target for ischemic stroke treatment with nanomedicines.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Circulação Cerebrovascular/efeitos dos fármacos , Microcirculação/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Sirolimo/administração & dosagem , Acidente Vascular Cerebral/tratamento farmacológico , Trombose/metabolismo , Apoptose/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Encéfalo/irrigação sanguínea , Encéfalo/efeitos dos fármacos , Isquemia Encefálica/patologia , Isquemia Encefálica/fisiopatologia , Linhagem Celular , Humanos , Micelas , Microglia/efeitos dos fármacos , Microglia/patologia , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/química , Oligopeptídeos/química , Polietilenoglicóis/química , Espécies Reativas de Oxigênio/metabolismo , Sirolimo/química , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/fisiopatologia
11.
Pharmazie ; 74(4): 221-226, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30940305

RESUMO

The use of sirolimus and its analogs has been evaluated in studies aimed at combating several types of cancer; however, because of the limited bioavailability of the drug, the search for new forms of administration is required. Biodegradable polymeric implants containing sirolimus were developed and assessed as an alternative method of drug administration. Implants containing 25 % (w/w) sirolimus were prepared employing the polymer matrices chitosan, polycaprolactone and poly(lactic-co-glycolic acid) (PLGA) in two proportions: PLGA 50:50 and PLGA 75:25. Thermal analysis techniques such as thermogravimetry and differential scanning calorimetry, combined with x-ray diffraction were used to characterize and evaluate the compatibility of the constituents of the formulation. No incompatibilities were found between the components, but drug amorphization was observed in all samples. Implants made from the polymers chitosan and PCL may accelerate the degradation of SRL when these polymers are dissolved in methanol at 50 °C. HPLC analysis showed that the implant prepared with PLGA 75:25 did not present degradation products and maintained its appropriate drug content, even when dissolved in methanol and heated to 50 °C. Therefore, it represents the most suitable biodegradable polymer for use in implants developed for the treatment of malignant solid tumors. However, it is still necessary to further study the drug effects after amorphization of the crystal and also to perform stability and solubility analysis.


Assuntos
Antineoplásicos/administração & dosagem , Portadores de Fármacos/química , Polímeros/química , Sirolimo/administração & dosagem , Varredura Diferencial de Calorimetria , Química Farmacêutica/métodos , Quitosana/química , Cromatografia Líquida de Alta Pressão/métodos , Implantes de Medicamento , Poliésteres/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Sirolimo/química , Temperatura Ambiente , Termogravimetria , Difração de Raios X
12.
Medicine (Baltimore) ; 98(14): e15106, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30946377

RESUMO

INTRODUCTION: Coronary bifurcations are encountered in about 15% to 20% of percutaneous coronary interventions (PCIs). They are considered technically challenging and associated with worse clinical outcomes than nonbifurcation lesions. The BiOSS LIM C is a dedicated bifurcation balloon expandable stent made of cobalt-chromium alloy (strut thickness 70 µm) releasing sirolimus (1.4 µg/mm) from the surface of a biodegradable coating comprised of a copolymer of lactic and glycolic acids. CONCLUSION: The aim of the randomized, multicenter, open-label, controlled POLBOS III trial is to compare BiOSS LIM C with limus second-generation drug-eluting stents (DES) in the treatment of non-left main stem coronary bifurcations (ClinicalTrials.gov NCT03548272).


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Estenose Coronária/tratamento farmacológico , Stents Farmacológicos , Intervenção Coronária Percutânea/instrumentação , Ensaios Clínicos Controlados Aleatórios como Assunto , Stents Metálicos Autoexpansíveis , Síndrome Coronariana Aguda/terapia , Cromo , Cobalto , Estenose Coronária/terapia , Humanos , Estudos Multicêntricos como Assunto , Projetos de Pesquisa , Sirolimo/administração & dosagem , Resultado do Tratamento
13.
Orv Hetil ; 160(13): 516-520, 2019 Mar.
Artigo em Húngaro | MEDLINE | ID: mdl-30907099

RESUMO

Facial angiofibroma is the characteristic symptom and also a major diagnostic criterion for Bourneville-Pringle disease. The centrofacially localized hamartomatous tumours start to appear in early childhood, and progress over time. Facial angiofibromas represent a significant cosmetological problem for the patients and a therapeutic challenge for the physician. Beside the traditional invasive treating methods, topical sirolimus is a new, promising and well-tolerated treatment modality. Several studies and case reports have been published on this new therapeutic approach, but recommendation for the optimal sirolimus concentration still does not exist. We report here two cases when children were successfully treated with topical sirolimus. Orv Hetil. 2019; 160(13): 516-520.


Assuntos
Angiofibroma/tratamento farmacológico , Neoplasias Faciais/tratamento farmacológico , Sirolimo/administração & dosagem , Esclerose Tuberosa/diagnóstico , Administração Tópica , Criança , Humanos , Resultado do Tratamento
14.
EBioMedicine ; 42: 511-523, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30898651

RESUMO

BACKGROUND: The vast majority of mitochondrial disorders have limited the clinical management to palliative care. Rapamycin has emerged as a potential therapeutic drug for mitochondrial diseases since it has shown therapeutic benefits in a few mouse models of mitochondrial disorders. However, the underlying therapeutic mechanism is unclear, the minimal effective dose needs to be defined and whether this therapy can be generally used is unknown. METHODS: We have evaluated whether low and high doses of rapamycin administration may result in therapeutic effects in a mouse model (Coq9R239X) of mitochondrial encephalopathy due to CoQ deficiency. The evaluation involved phenotypic, molecular, image (histopathology and MRI), metabolomics, transcriptomics and bioenergetics analyses. FINDINGS: Low dose of rapamycin induces metabolic changes in liver and transcriptomics modifications in midbrain. The high dose of rapamycin induces further changes in the transcriptomics profile in midbrain due to the general inhibition of mTORC1. However, neither low nor high dose of rapamycin were able to improve the mitochondrial bioenergetics, the brain injuries and the phenotypic characteristics of Coq9R239X mice, resulting in the lack of efficacy for increasing the survival. INTERPRETATION: These results may be due to the lack of microgliosis-derived neuroinflammation, the limitation to induce autophagy, or the need of a functional CoQ-junction. Therefore, the translation of rapamycin therapy into the clinic for patients with mitochondrial disorders requires, at least, the consideration of the particularities of each mitochondrial disease. FUND: Supported by the grants from "Fundación Isabel Gemio - Federación Española de Enfermedades Neuromusculares - Federación FEDER" (TSR-1), the NIH (P01HD080642) and the ERC (Stg-337327).


Assuntos
Doenças Mitocondriais/tratamento farmacológico , Sirolimo/uso terapêutico , Animais , Autofagia , Respiração Celular/efeitos dos fármacos , Respiração Celular/genética , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Humanos , Metabolômica/métodos , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/etiologia , Encefalomiopatias Mitocondriais/tratamento farmacológico , Encefalomiopatias Mitocondriais/genética , Encefalomiopatias Mitocondriais/metabolismo , Fenótipo , Sirolimo/administração & dosagem , Sirolimo/efeitos adversos , Sirolimo/farmacocinética , Resultado do Tratamento , Ubiquinona/análogos & derivados , Ubiquinona/genética , Ubiquinona/metabolismo
15.
Pharm Res ; 36(5): 70, 2019 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-30888509

RESUMO

PURPOSE: To prepare an oligo(lactic acid)8-rapamycin prodrug (o(LA)8-RAP)-loaded poly(ethylene glycol)-block-poly(lactic acid) (PEG-b-PLA) micelle for injection and characterize its compatibility and performance versus a RAP-loaded PEG-b-PLA micelle for injection in vitro and in vivo. METHODS: Monodisperse o(LA)8 was coupled on RAP at the C-40 via DCC/DMAP chemistry, and conversion of o(LA)8-RAP prodrug into RAP was characterized in vitro. Physicochemical properties of o(LA)8-RAP- and RAP-loaded PEG-b-PLA micelles and their antitumor efficacies in a syngeneic 4 T1 breast tumor model were compared. RESULTS: Synthesis of o(LA)8-RAP prodrug was confirmed by 1H NMR and mass spectroscopy. The o(LA)8-RAP prodrug underwent conversion in PBS and rat plasma by backbiting and esterase-mediated cleavage, respectively. O(LA)8-RAP-loaded PEG-b-PLA micelles increased water solubility of RAP equivalent to 3.3 mg/ml with no signs of precipitation. Further, o(LA)8-RAP was released more slowly than RAP from PEG-b-PLA micelles. With added physical stability, o(LA)8-RAP-loaded PEG-b-PLA micelles significantly inhibited tumor growth relative to RAP-loaded PEG-b-PLA micelles in 4 T1 breast tumor-bearing mice without signs of acute toxicity. CONCLUSIONS: An o(LA)8-RAP-loaded PEG-b-PLA micelle for injection is more stable than a RAP-loaded PEG-b-PLA micelle for injection, and o(LA)8-RAP converts into RAP rapidly in rat plasma (t1/2 = 1 h), resulting in antitumor efficacy in a syngeneic 4 T1 breast tumor model.


Assuntos
Antineoplásicos/administração & dosagem , Portadores de Fármacos/química , Lactatos/química , Polietilenoglicóis/química , Pró-Fármacos/administração & dosagem , Sirolimo/administração & dosagem , Animais , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos/toxicidade , Liberação Controlada de Fármacos , Feminino , Lactatos/toxicidade , Ácido Láctico/química , Camundongos , Micelas , Polietilenoglicóis/toxicidade , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Pró-Fármacos/toxicidade , Ratos , Transdução de Sinais , Sirolimo/química , Sirolimo/farmacologia , Sirolimo/toxicidade , Solubilidade , Serina-Treonina Quinases TOR/metabolismo
16.
Lancet ; 393(10175): 987-997, 2019 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-30827782

RESUMO

BACKGROUND: Supraflex is a sirolimus-eluting stent with a biodegradable polymer coating and ultra-thin struts. We aimed to compare Supraflex with the standard of care, Xience, an everolimus-eluting stent with a durable polymer coating, regarding clinical outcomes with a randomised trial in an all-comer population. METHODS: We did a prospective, randomised, single-blind, multicentre study (TALENT) across 23 centres in Europe (the Netherlands, Poland, the UK, Spain, Bulgaria, Hungary, and Italy). Eligible participants were aged 18 years or older, had one or more coronary artery stenosis of 50% or greater in a native coronary artery, saphenous venous graft, or arterial bypass conduit, and had a reference vessel diameter of 2·25-4·50 mm. Patients underwent percutaneous coronary intervention in an all-comer manner. We randomly assigned patients (1:1) to implantation of either a sirolimus-eluting stent with a biodegradable polymer coating and ultra-thin struts (Supraflex) or an everolimus-eluting stent with a durable polymer coating (Xience). Randomisation was done by local investigators by use of a web-based software with random blocks according to centre. The primary endpoint was a non-inferiority comparison of a device-oriented composite endpoint-cardiac death, target-vessel myocardial infarction, or clinically indicated target lesion revascularisation-between groups at 12 months after the procedure, assessed in an intention-to-treat population. On assumption of 1-year composite endpoint prevalence of 8·3%, a margin of 4·0% was defined for non-inferiority of the Supraflex group compared with the Xience group. This trial is registered with ClinicalTrials.gov, number NCT02870140. FINDINGS: Between Oct 21, 2016, and July 3, 2017, 1435 patients with 1046 lesions were randomly assigned to Supraflex, of whom 720 received the index procedure, and 715 patients with 1030 lesions were assigned to Xience, all receiving the index procedure. At 12 months, the primary endpoint had occurred in 35 patients (4·9 %) in the Supraflex group and in 37 patients (5·3%) in the Xience group (absolute difference -0·3% [one-sided 95% upper confidence bound 1·6%], pnon-inferiority<0·0001). Definite or probable stent thrombosis prevalence, a safety indicator, was low in both groups and did not differ between them. INTERPRETATION: The Supraflex stent was non-inferior to the Xience stent for a device-oriented composite clinical endpoint at 12 months in an all-comer population. Supraflex seems a safe and effective alternative drug-eluting stent to other stents in clinical practice. FUNDING: European Cardiovascular Research Institute.


Assuntos
Aterosclerose/terapia , Stents Farmacológicos , Everolimo/administração & dosagem , Imunossupressores/administração & dosagem , Intervenção Coronária Percutânea/instrumentação , Sirolimo/administração & dosagem , Idoso , Stents Farmacológicos/efeitos adversos , Determinação de Ponto Final , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/etiologia , Intervenção Coronária Percutânea/efeitos adversos , Estudos Prospectivos , Método Simples-Cego , Trombose/etiologia
17.
MBio ; 10(1)2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30782662

RESUMO

Primary effusion lymphoma (PEL) is caused by Kaposi's sarcoma-associated herpesvirus (KSHV). PEL has a highly active mTOR pathway, which makes mTOR a potential therapeutic target. MLN0128 is an ATP-competitive inhibitor of mTOR that has entered clinical trials for solid tumors. Our results demonstrated that MLN0128 has a greater effect on inhibiting proliferation than the allosteric mTOR inhibitor rapamycin. MLN0128 has ∼30 nM 50% inhibitory concentration (IC50) across several PEL cell lines, including PEL that is resistant to conventional chemotherapy. MLN0128 induced apoptosis in PEL, whereas rapamycin induced G1 arrest, consistent with a different mechanism of action. MLN0128 inhibited phosphorylation of mTOR complex 1 and 2 targets, while rapamycin only partially inhibited mTOR complex 1 targets. PEL xenograft mouse models treated with MLN0128 showed reduced effusion volumes in comparison to the vehicle-treated group. Rapamycin-resistant (RR) clones with an IC50 for rapamycin 10 times higher than the parental IC50 emerged consistently after rapamycin exposure as a result of transcriptional adaptation. MLN0128 was nevertheless capable of inducing apoptosis in these RR clones. Our results suggest that MLN0128 might offer a new approach to the treatment of chemotherapy-resistant PEL.IMPORTANCE Primary effusion lymphoma (PEL) is an aggressive and incurable malignancy, which is usually characterized by lymphomatous effusions in body cavities without tumor masses. PEL has no established treatment and a poor prognosis, with a median survival time shorter than 6 months. PEL usually develops in the context of immunosuppression, such as HIV infection or post-organ transplantation. The optimal treatment for PEL has not been established, as PEL is generally resistant to traditional chemotherapy. The molecular drivers for PEL are still unknown; however, PEL displays a constitutively active mammalian target of rapamycin (mTOR) pathway, which is critical for metabolic and cell survival mechanisms. Therefore, the evaluation of novel agents targeting the mTOR pathway could be clinically relevant for the treatment of PEL.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Benzoxazóis/farmacologia , Inibidores Enzimáticos/farmacologia , Linfoma de Efusão Primária/tratamento farmacológico , Pirimidinas/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Antibióticos Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Benzoxazóis/administração & dosagem , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Modelos Animais de Doenças , Inibidores Enzimáticos/administração & dosagem , Xenoenxertos , Humanos , Concentração Inibidora 50 , Linfoma de Efusão Primária/patologia , Camundongos , Transplante de Neoplasias , Pirimidinas/administração & dosagem , Sirolimo/administração & dosagem , Sirolimo/farmacologia , Resultado do Tratamento
18.
J Am Acad Dermatol ; 80(3): 735-742, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30744877

RESUMO

BACKGROUND: Systemic mammalian target of rapamycin (mTOR) inhibitors are currently used in many dermatologic indications. Their topical use is recent and poorly codified. OBJECTIVE: To provide an overview of the topical use of mTOR inhibitors in dermatologic conditions and evaluate their efficacy and safety. METHODS: A literature search was performed in January 2017. Reports of all studies investigating the use of topical mTOR inhibitors in any dermatology diseases were included. The exclusion criteria were systemic use and mucosal administration. RESULTS: We included 40 studies with a total of 262 patients. In all, 11 dermatologic conditions were found, the most frequent being angiofibromas linked to tuberous sclerosis complex (157 patients). Topical mTOR inhibitors were significantly more efficient than placebo for angiofibromas (relative risk, 2.52; 95% confidence interval, 1.27-5.00; I2 = 0%). The median concentration of sirolimus was 0.1%, with a median treatment duration of 12 weeks. Topical mTOR inhibitors were well tolerated, with only mild or moderate local side effects (mostly irritative) reported. Blood level of sirolimus was not detected in 90% of patients. LIMITATIONS: High heterogeneity in most studies. CONCLUSION: This systematic review supports the efficacy of topical sirolimus for angiofibromas linked to tuberous sclerosis complex, with only local side effects reported. Other indications require further research.


Assuntos
Angiofibroma/tratamento farmacológico , Antibióticos Antineoplásicos/uso terapêutico , Sirolimo/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Esclerose Tuberosa/tratamento farmacológico , Administração Cutânea , Angiofibroma/complicações , Antibióticos Antineoplásicos/administração & dosagem , Humanos , Mancha Vinho do Porto/tratamento farmacológico , Psoríase/tratamento farmacológico , Sirolimo/administração & dosagem , Neoplasias Cutâneas/complicações , Esclerose Tuberosa/complicações
19.
PLoS One ; 14(1): e0209841, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30629613

RESUMO

Current drug-eluting stents have abluminal polymer coating; however, thrombus formation in these compared with that in uniformly coated stents remains controversial. We evaluated thrombus formation and early endothelialization after using abluminal biodegradable polymer-coated sirolimus- (BP-SES), and everolimus-eluting stents (BP-EES) versus a durable polymer-coated everolimus-eluting stent (DP-EES) in an in vivo setting. BP-SES, BP-EES, and DP-EES (n = 6 each) were implanted in coronary arteries of 12 mini-pigs that were then sacrificed after 7 and 10 days. Stents were stained with hematoxylin and eosin, and a combined Verhoeff and Masson trichrome stain. Areas of fibrin deposition were digitally detected and measured with off-line morphometric software. Stents were investigated for re-endothelialization by transmission electron microscopy. At 7 days, histological analysis revealed the lowest area of fibrin deposition in BP-SES (BP-SES vs. BP-EES vs. DP-EES; 0.10 ± 0.06 mm2 vs. 0.15 ± 0.07 mm2 vs. 0.19 ± 0.06 mm2, p = 0.0004). At 10 days, the area of fibrin deposition was significantly greater in DP-EES (0.13 ± 0.04 mm2 vs. 0.14 ± 0.05 mm2 vs. 0.19 ± 0.08 mm2, p = 0.007). Endothelial cells in BP-SES demonstrated a significantly greater number of tight junctions than those in DP-EES according to by transmission electron microscopy for both days (p<0.05). Various parameters, including an inflammatory reaction and neointimal formation, were comparable among the groups at 7 and 10 days. An abluminal biodegradable polymer-coated SES showed the least fibrin deposition and greatest endothelial cell recovery at an early stage following implantation in the coronary arteries of mini-pigs.


Assuntos
Implantes Absorvíveis , Vasos Coronários/cirurgia , Stents Farmacológicos , Polímeros/química , Animais , Fármacos Cardiovasculares/administração & dosagem , Materiais Revestidos Biocompatíveis/administração & dosagem , Materiais Revestidos Biocompatíveis/química , Angiografia Coronária/métodos , Doença da Artéria Coronariana/cirurgia , Células Endoteliais/metabolismo , Everolimo/administração & dosagem , Everolimo/química , Fibrina/metabolismo , Modelos Animais , Intervenção Coronária Percutânea , Polímeros/administração & dosagem , Polímeros/efeitos adversos , Desenho de Prótese , Sirolimo/administração & dosagem , Sirolimo/química , Suínos , Porco Miniatura , Trombose/etiologia , Trombose/metabolismo , Resultado do Tratamento
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA