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2.
Zhonghua Er Ke Za Zhi ; 57(11): 852-856, 2019 Nov 02.
Artigo em Chinês | MEDLINE | ID: mdl-31665839

RESUMO

Objective: To investigate the efficacy and safety of rapamycin in children with tuberous sclerosis complex (TSC) associated renal disease. Methods: A prospective self-control study was conducted. The clinical data of 92 children diagnosed with tuberous sclerosis complex associated kidney disease at the People's Liberation Army General Hospital from January 2011 to January 2019 were collected. The long-term rapamycin treatment for all patients initiated at 1 mg/(m(2)·d), which was gradually adjusted to reach a blood concentration of 5-10 µg/L. The changes of the maximum diameter of renal lesions in children after rapamycin treatment were observed and analyzed with Wilcoxon test. Results: Ninety-two children, including 52 males and 40 females, who met the criteria were analyzed. Sixty patients had only renal angiomyolipoma(RAML), while 24 patients had only multiple renal cysts(MRC), and 8 patients had both lesions. The age of TSC diagnosis was 16.0 (7.0, 42.0) months, and the age of initial treatment with rapamycin was 63.5 (21.0, 103.0) months. The follow-up lasted for 12.0 (4.0, 23.0) months. Sequencing of TSC1 and TSC2 genes was performed in 54 children with TSC, including 3 patients (6%) with mutations in TSC1 gene and 51 patients (94%) with mutations in TSC2 gene. The maximum RAML diameter before treatment was 7.0 (4.0, 9.0) mm. The best effect reached at 3 months of treatment, with the diameter of 4.0 (0,7.0) mm. The maximum diameters at 6 months, 1 year and 1-2 years were 5.0 (0,9.8) mm, 5.0 (1.5, 8.5) mm, 5.5 (3.0, 9.0) mm, respectively, and were significantly different from the baseline (Z=-2.404,-2.350,-2.750,P=0.016,0.019,0.006, respectively). The maximum diameter after 2-3 years, and ≥3 years were 5.0 (3.9,7.0) mm and 6.0 (1.0, 11.0) mm, without significant difference from the baseline (Z=-0.856,-0.102,P=0.393,0.919, respectively).The maximum diameters of MRC after 3 months, 6 months, 1 year,1-2 years, 2-3 years, and ≥3 years were 11.0 (5.0, 14.0) mm,3.0 (0.0,11.0) mm,5.0 (0,21.0) mm,0 (0,14.0) mm,0 (0,10.0) mm, and 0 (0,18.3) mm, respectively, but were not significantly different rom the baseline (7.0 (5.0, 15.7) mm)(Z=-0.944,-1.214,-1.035,-1.896,-1.603,-1.214,P=0.345,0.225,0.301,0.058,0.109,0.225, respectively).Twenty-nine patients (32%) had oral ulcers during the entire treatment period, and no serious adverse reactions were observed. Conclusions: Rapamycin could decrease the diameter of TSC-related RAML, but could not inhibit the growth of cysts. It is well tolerated in the treatment of renal diseases associated with tuberous sclerosis complex.


Assuntos
Angiomiolipoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Sirolimo/uso terapêutico , Esclerose Tuberosa/complicações , Angiomiolipoma/etiologia , Criança , China , Feminino , Humanos , Recém-Nascido , Neoplasias Renais/etiologia , Masculino , Estudos Prospectivos , Sirolimo/administração & dosagem
3.
Vet Parasitol ; 276: 108976, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31739256

RESUMO

Cutaneous leishmaniosis (CL) is a parasitic disease in animals and human with no satisfactory treatments and vaccination. Rapamycin is a potent inhibitor of mammalian target of rapamycin (mTOR) with various applications. Here, the effect of rapamycin alone or in combination with two other drugs, namely amphotericin B (AmB) and glucantime, was investigated against Leishmania tropica infection. In vitro viability and electron microscopy evaluation of the parasites showed detrimental changes in their appearance and viability. Treatment with clinically relevant dose of rapamycin (10.2 µg/dose) is able to control the parasite load in BALB/c mice infected with L. tropica. Furthermore, the cytokine profiles showed significant polarization towards Th1 immune response. Surprisingly, combination therapy with either AmB or glucantime was not efficient. Rapamycin is showed an effective alternative therapy against leishmaniosis caused by L. tropica.


Assuntos
Antiprotozoários/uso terapêutico , Leishmania tropica/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Sirolimo/uso terapêutico , Anfotericina B/farmacologia , Anfotericina B/uso terapêutico , Animais , Antiprotozoários/farmacologia , Linhagem Celular Tumoral , Citocinas/análise , Feminino , Humanos , Concentração Inibidora 50 , Leishmania tropica/crescimento & desenvolvimento , Leishmania tropica/ultraestrutura , Leishmaniose Cutânea/prevenção & controle , Linfonodos/parasitologia , Antimoniato de Meglumina/farmacologia , Antimoniato de Meglumina/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Carga Parasitária , Distribuição Aleatória , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/efeitos dos fármacos
4.
Nat Commun ; 10(1): 4712, 2019 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-31624262

RESUMO

Immune checkpoint inhibitor (ICI) use remains a challenge in patients with solid organ allografts as most would undergo rejection. In a melanoma patient in whom programmed-death 1 (PD-1) blockade resulted in organ rejection and colitis, the addition of the mTOR inhibitor sirolimus resulted in ongoing anti-tumor efficacy while promoting allograft tolerance. Strong granzyme B+, interferon (IFN)-γ+ CD8+ cytotoxic T cell and circulating regulatory T (Treg) cell responses were noted during allograft rejection, along with significant eosinophilia and elevated serum IL-5 and eotaxin levels. Co-treatment with sirolimus abated cytotoxic T cell numbers and eosinophilia, while elevated Treg cell numbers in the peripheral blood were maintained. Interestingly, numbers of IFN-γ+ CD4+ T cells and serum IFN-γ levels increased with the addition of sirolimus treatment likely promoting ongoing anti-PD-1 efficacy. Thus, our results indicate that sirolimus has the potential to uncouple anti-PD-1 therapy toxicity and efficacy.


Assuntos
Transplante de Rim/métodos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Feminino , Rejeição de Enxerto/imunologia , Humanos , Imunossupressores/uso terapêutico , Falência Renal Crônica/imunologia , Falência Renal Crônica/terapia , Melanoma/imunologia , Melanoma/terapia , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Serina-Treonina Quinases TOR/metabolismo , Tolerância ao Transplante/efeitos dos fármacos , Tolerância ao Transplante/imunologia
5.
Transplant Proc ; 51(9): 3072-3073, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31611123

RESUMO

Cutaneous metastases of urological malignancies are a rare phenomenon. We present a case of a renal transplant recipient who presented with skin nodule 12 years posttransplant. Pathohistologic evaluation revealed metastasis from the renal adenocarcinoma. The patient was treated with temsirolimus and later with sorafenib; however, he died 13 months after the initial presentation with a functional renal allograft.


Assuntos
Carcinoma de Células Renais/secundário , Neoplasias Renais/patologia , Transplante de Rim , Neoplasias Cutâneas/secundário , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Humanos , Neoplasias Renais/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Sirolimo/análogos & derivados , Sirolimo/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Transplantados , Transplante Homólogo
6.
Pediatrics ; 144(4)2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31511312

RESUMO

Hepatic hemangioma (HH) is a common asymptomatic, self-limiting benign vascular tumor of the liver in neonates. Although complicated HHs are rare, they have significant risks of morbidity and mortality, especially during the perinatal period. Because of the high risks of complications from surgical interventions, there is an unmet need for effective medical therapy. We report 2 neonates with life-threatening HH who were evaluated for a liver transplant before being treated successfully with combined medical therapy, which included sirolimus, corticosteroids, and propranolol.


Assuntos
Hemangioma/terapia , Neoplasias Hepáticas/terapia , Metilprednisolona/uso terapêutico , Propranolol/uso terapêutico , Sirolimo/uso terapêutico , Quimioterapia Combinada , Embolização Terapêutica , Feminino , Glucocorticoides/uso terapêutico , Hemangioma/diagnóstico por imagem , Artéria Hepática , Humanos , Recém-Nascido , Neoplasias Hepáticas/diagnóstico por imagem , Masculino , Vasodilatadores/uso terapêutico
7.
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
8.
Lancet ; 394(10205): 1243-1253, 2019 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488372

RESUMO

BACKGROUND: Newer-generation drug-eluting stents that combine ultrathin strut metallic platforms with biodegradable polymers might facilitate vascular healing and improve clinical outcomes in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention (PCI) compared with contemporary thin strut second-generation drug-eluting stents. We did a randomised clinical trial to investigate the safety and efficacy of ultrathin strut biodegradable polymer sirolimus-eluting stents versus thin strut durable polymer everolimus-eluting stents in patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing primary PCI. METHODS: The BIOSTEMI trial was an investigator-initiated, multicentre, prospective, single-blind, randomised superiority trial at ten hospitals in Switzerland. Patients aged 18 years or older with acute STEMI who were referred for primary PCI were eligible to participate. Patients were randomly allocated (1:1) to either biodegradable polymer sirolimus-eluting stents or durable polymer everolimus-eluting stents. Central randomisation was done based on a computer-generated allocation sequence with variable block sizes of 2, 4, and 6, which was stratified by centre, diabetes status, and presence or absence of multivessel coronary artery disease, and concealed using a secure web-based system. Patients and treating physicians were aware of group allocations, whereas outcome assessors were masked to the allocated stent. The experimental stent (Orsiro; Biotronik; Bülach, Switzerland) consisted of an ultrathin strut cobalt-chromium metallic stent platform releasing sirolimus from a biodegradable polymer. The control stent (Xience Xpedition/Alpine; Abbott Vascular, Abbott Park, IL, USA) consisted of a thin strut cobalt-chromium stent platform that releases everolimus from a durable polymer. The primary endpoint was target lesion failure, a composite of cardiac death, target vessel myocardial reinfarction (Q-wave and non-Q-wave), and clinically-indicated target lesion revascularisation, within 12 months of the index procedure. All analyses were done with the individual participant as the unit of analysis and according to the intention-to-treat principle. The trial was registered with ClinicalTrials.gov, number NCT02579031. FINDINGS: Between April 26, 2016, and March 9, 2018, we randomly assigned 1300 patients (1623 lesions) with acute myocardial infarction to treatment with biodegradable polymer sirolimus-eluting stents (649 patients and 816 lesions) or durable polymer everolimus-eluting stents (651 patients and 806 lesions). At 12 months, follow-up data were available for 614 (95%) patients treated with biodegradable polymer sirolimus-eluting stents and 626 (96%) patients treated with durable polymer everolimus-eluting stents. The primary composite endpoint of target lesion failure occurred in 25 (4%) of 649 patients treated with biodegradable polymer sirolimus-eluting stents and 36 (6%) of 651 patients treated with durable polymer everolimus-eluting stents (difference -1·6 percentage points; rate ratio 0·59, 95% Bayesian credibility interval 0·37-0·94; posterior probability of superiority 0·986). Cardiac death, target vessel myocardial reinfarction, clinically-indicated target lesion revascularisation, and definite stent thrombosis were similar between the two treatment groups in the 12 months of follow-up. INTERPRETATION: In patients with acute STEMI undergoing primary PCI, biodegradable polymer sirolimus-eluting stents were superior to durable polymer everolimus-eluting stents with respect to target lesion failure at 1 year. This difference was driven by reduced ischaemia-driven target lesion revascularisation in patients treated with biodegradable polymer sirolimus-eluting stents compared with durable polymer everolimus-eluting stents. FUNDING: Biotronik.


Assuntos
Implantes Absorvíveis , Prótese Vascular , Stents Farmacológicos , Everolimo/uso terapêutico , Imunossupressores/uso terapêutico , Intervenção Coronária Percutânea/métodos , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia , Sirolimo/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polímeros , Método Simples-Cego
9.
Transplant Proc ; 51(8): 2731-2734, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31447189

RESUMO

BACKGROUND: There is little evidence about whether mammalian target of rapamycin (mTOR) inhibitor could prevent post-kidney transplant (KT) urothelial carcinoma (UC) or not. The aim of this study is to analyze the role of mTOR inhibitor add-on in tacrolimus-based kidney transplant recipients. METHOD: The data were obtained from the Kaohsiung Chang Gung Memorial Hospital using the Chang Gung Research Database and retrospectively reviewed from January 2000 to December 2015. Patients then were categorized into 2 groups: group FK (more than 2-year tacrolimus [FK] prescription) and group FK + mTOR inhibitor (more than 2-year tacrolimus plus at least 6-month continued sirolimus prescription). The primary end point is post-KT UC development. The secondary end point is mTOR inhibitor add-on effect on renal function deterioration episode. RESULTS: There were 140 patients with tacrolimus-based immunosuppressant (group FK) and 82 patients with tacrolimus-based and add-on mTOR inhibitor regimen (group FK + mTOR inhibitor). The follow-up duration, sex distribution, and combined mycophenolate mofetil rate are similar in both groups. Younger age, lower tacrolimus trough level, lower UC incidence, and longer KT-to-UC interval were observed. Short- to intermediate-term results revealed noninferior graft outcome by creatinine level or creatinine deterioration. CONCLUSIONS: In our preliminary result, mTOR inhibitor add-on in patients with tacrolimus-based regimen revealed less post-KT UC occurrence. In addition, noninferior graft outcome was also observed. In Taiwan, a high UC prevalence area, mTOR inhibitor add-on strategy can be considered as a preventive strategy for UC after KT.


Assuntos
Carcinoma de Células de Transição/epidemiologia , Imunossupressores/uso terapêutico , Transplante de Rim , Complicações Pós-Operatórias/epidemiologia , Sirolimo/uso terapêutico , Adulto , Carcinoma de Células de Transição/etiologia , Carcinoma de Células de Transição/imunologia , Feminino , Rejeição de Enxerto , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Hospedeiro Imunocomprometido , Incidência , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/imunologia , Estudos Retrospectivos , Serina-Treonina Quinases TOR/antagonistas & inibidores , Tacrolimo/uso terapêutico , Taiwan
10.
Pediatrics ; 144(2)2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31366686

RESUMO

Juvenile polyposis syndrome is a rare autosomal dominant condition characterized by multiple hamartomatous polyps throughout the gastrointestinal tract. Juvenile polyposis of infancy is a generalized severe form of juvenile polyposis syndrome associated with a poor prognosis. A 47-month-old female infant presented initially with gastrointestinal bleeding and protein-losing enteropathy at 4 months of age. At the age of 12 months, the condition worsened, requiring albumin infusions every 24 to 48 hours and red blood cell transfusions every 15 days. Upper gastrointestinal endoscopy, colonoscopy, and small-bowel enteroscopy revealed diffuse polyposis that was treated with multiple endoscopic polypectomies. Despite subtotal colectomy with ileorectal anastomosis, protein-losing enteropathy and bleeding persisted, requiring continued blood transfusions and albumin infusions. A chromosomal microarray revealed a single allele deletion in chromosome 10q23, involving both the PTEN and BMPR1A genes. Loss of PTEN function is associated with an increased activation of the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway involved in cell proliferation. Treatment with sirolimus, an mTOR inhibitor, was initiated with the aim of inhibiting polyp growth. Soon after initiation of treatment with sirolimus, blood and albumin infusions were no longer needed and resulted in improved patient growth and quality of life. This case represents the first detailed report of successful drug therapy for life-threatening juvenile polyposis of infancy.


Assuntos
Imunossupressores/uso terapêutico , Polipose Intestinal/congênito , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/tratamento farmacológico , Sirolimo/uso terapêutico , Pré-Escolar , Feminino , Seguimentos , Humanos , Polipose Intestinal/diagnóstico , Polipose Intestinal/tratamento farmacológico , Polipose Intestinal/cirurgia , Síndromes Neoplásicas Hereditárias/cirurgia , Resultado do Tratamento
11.
BMJ Case Rep ; 12(7)2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31300601

RESUMO

This is a rare case of sporadic lymphangioleiomyomatosis (S-LAM) manifesting as refractory chylothorax and chyloperitoneum. A middle-aged woman with unremarkable medical history presented with respiratory failure, abdominal distension and anasarca. She was found to have high-output chylous effusion that required chest tube drainage, as well as chylous ascites. Notably initial chest and abdominal CT did not reveal characteristic pulmonary cysts or the presence of angiomyolipomas suggestive of LAM. An extensive oncologic and infectious work-up was undertaken with negative findings. The chylous effusion was persistent and refractory to thoracic duct embolization, total parenteral nutrition with octreotide, and talc pleurodesis. Diagnosis of S-LAM was confirmed after repeat chest CT showed subtle pulmonary cystic changes, and serum vascular endothelial growth factor-D level was found to be elevated at 834 pg/mL. Patient was started on sirolimus therapy, but lost to follow-up after hospital discharge. Patient died approximately 1 year later.


Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Quilotórax/diagnóstico , Linfangioleiomiomatose/diagnóstico , Insuficiência Respiratória/patologia , Sirolimo/uso terapêutico , Ducto Torácico/patologia , Tubos Torácicos , Quilotórax/fisiopatologia , Quilotórax/terapia , Drenagem , Edema , Evolução Fatal , Feminino , Humanos , Linfangioleiomiomatose/fisiopatologia , Linfangioleiomiomatose/terapia , Pessoa de Meia-Idade , Nutrição Parenteral Total , Insuficiência Respiratória/diagnóstico por imagem
12.
Curr Opin Ophthalmol ; 30(5): 401-406, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31313753

RESUMO

PURPOSE OF REVIEW: To offer an update on advances and controversies in the assessment, investigation and treatment of thyroid eye disease (TED), a disfiguring orbital autoimmune disease, which can manifest with diplopia and threaten not only sight - but also life. RECENT FINDINGS: Developments in biomarkers and imaging are helping to tailor the management of patients. Emerging therapies target different pathways in the disease and are informed by studies into TED pathogenesis: the last 2 years has, for example, seen the culmination of a two-decade long bench-to-bedside story in which an original focus on the IGF1 receptor has translated into an effective treatment for proptosis in thyroid eye disease. Whether this will result in a real-world reduction in TED-related morbidity will depend on access; commercial pricing decisions may preclude widespread adoption of novel therapies. SUMMARY: Thyroid eye disease research is enjoying a renaissance with advances in both monitoring and treatment coupled with a renewed emphasis on a holisitic approach, which includes aesthetic care for patients; this is perhaps the most exciting time to be part of the international thyroid eye disease community in decades - for physicians, surgeons and patients. The commercial window for break-through drugs are narrowing with an array of new therapeutic agents in the pipeline over the coming decade.


Assuntos
Oftalmopatia de Graves/diagnóstico , Oftalmopatia de Graves/terapia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Descompressão Cirúrgica , Humanos , Imunossupressores/uso terapêutico , Metotrexato/uso terapêutico , Ácido Micofenólico/uso terapêutico , Sirolimo/uso terapêutico
13.
EuroIntervention ; 15(12): e1081-e1089, 2019 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-31310239

RESUMO

AIMS: The durable fluoroacrylate polymer-based sirolimus-eluting stent (Angiolite SES) has shown promising preclinical and clinical results regarding inflammatory vascular reaction and neointimal healing. We aimed to compare performance between the Angiolite SES and an everolimus-eluting stent (EES) in patients with coronary artery disease. METHODS AND RESULTS: The ANGIOLITE trial, a prospective, randomised, multicentre trial, compared the restenosis parameters of both stents in de novo coronary lesions. The primary endpoint was late lumen loss at six-month angiographic follow-up. In-stent healing was assessed by optical coherence tomography (OCT). The main clinical endpoint was target lesion failure (TLF) evaluated up to 24 months. A total of 223 patients were randomised 1:1 to EES or SES. At six months, in-stent late lumen loss was 0.08 mm (±0.38) for EES vs 0.04 mm (±0.39) for SES (difference=-0.04 mm, 95% CI: -0.15, 0.07, p for non-inferiority=0.002). By OCT, the rate of uncovered to total number of struts score >30% was comparable between the groups whereas neointimal thickness was reduced in the SES arm (9.0% [7.6, 10.6] vs 9.9% [8.5, 11.3], p=0.41; and 86.4 [81.6, 91.2] µm vs 72.1 [68.2, 76.0] µm, p<0.01, respectively). At 24 months, TLF occurred in eight patients (7.6% [3.3, 14.5]) in the EES arm and in seven patients (7.1% [2.9, 14.0]) in the SES arm (p=0.88). The definite/probable stent thrombosis rate was comparable between the groups (1.9% [0.2, 6.7] vs 1.0% [0.0, 5.5] EES vs SES, respectively; p=0.59). CONCLUSIONS: This trial demonstrates similar antirestenotic efficacy at midterm follow-up of the Angiolite SES vs an EES. Clinical endpoints were comparable between the groups at two-year follow-up. Visual summary. Main results of the ANGIOLITE trial.


Assuntos
Doença da Artéria Coronariana/cirurgia , Stents Farmacológicos , Everolimo/uso terapêutico , Intervenção Coronária Percutânea/métodos , Sirolimo/uso terapêutico , Implantes Absorvíveis , Humanos , Polímeros/uso terapêutico , Estudos Prospectivos , Desenho de Prótese , Resultado do Tratamento
14.
Exp Parasitol ; 204: 107720, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31279929

RESUMO

Parasite life history can be affected by conditions of the host and of the external environment. Rapamycin, a known immunosuppressant of mammals, was fed to laboratory mice that were then infected with the Trichostrongylid nematode Heligmosomoides bakeri to determine if host rapamycin exposure would affect parasite survival, growth, and reproduction. In addition, adult worms from control fed mice were directly exposed to rapamycin to assess if rapamycin would affect worm viability and ex vivo reproduction. We found that host ingestion of rapamycin did not affect H. bakeri survival or growth for male or female worms, but female worms had increased reproduction both in vivo and when removed from the host and cultured ex vivo. After direct rapamycin exposure, motility of female worms was greater at low levels of rapamycin compared to high levels of rapamycin or high levels of DMSO (the vehicle used to solubilize rapamycin) in control media, but was similar to females in low levels of DMSO in control media. Male motility was not affected by the presence of rapamycin or DMSO in the media. Ex vivo egg deposition was higher when exposed to rapamycin than when cultured in control media that contained DMSO, regardless of DMSO dose. Overall, we conclude that host ingestion of rapamycin or direct exposure to rapamycin was generally favorable or neutral for parasite life history traits.


Assuntos
Heligmosomatoidea/efeitos dos fármacos , Imunossupressores/farmacologia , Sirolimo/farmacologia , Análise de Variância , Animais , Dimetil Sulfóxido/administração & dosagem , Dimetil Sulfóxido/farmacologia , Feminino , Heligmosomatoidea/crescimento & desenvolvimento , Heligmosomatoidea/fisiologia , Imunossupressores/uso terapêutico , Intestino Delgado/parasitologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Movimento/efeitos dos fármacos , Oviposição/efeitos dos fármacos , Reprodução/efeitos dos fármacos , Fatores Sexuais , Razão de Masculinidade , Sirolimo/uso terapêutico
16.
Saudi Med J ; 40(7): 669-674, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31287126

RESUMO

OBJECTIVES: To report the genotype-phenotype characteristics, demographic features and clinical outcome of Omani patients with congenital hyperinsulinism (CHI). Methods: We retrospectively analyzed the clinical, biochemical, genotypical, phenotypical characteristics and outcomes of  children with CHI who were presented to the pediatric endocrine team in the Royal Hospital, Muscat, Oman between January 2007 and December 2016. Results: Analysis of 25 patients with CHI genetically revealed homozygous mutation in ABCC8 in 23 (92%) patients and 2 patients (8%) with compound heterozygous mutation in ABCC8. Fifteen (60%) patients underwent subtotal pancreatectomy as medical therapy failed and 2 (8%) patients showed response to medical therapy. Three patients expired during the neonatal period, 2 had cardiomyopathy and sepsis, and one had sepsis and severe metabolic acidosis. Out of the 15 patients who underwent pancreatectomy, 6 developed diabetes mellitus, 6 continued to have hypoglycemia and required medical therapy and one had pancreatic exocrine dysfunction post-pancreatectomy, following up with gastroenterology clinic and was placed on pancreatic enzyme supplements, while 2 patients continued to have hypoglycemia and both had abdominal MRI and 18-F-fluoro-L-DOPA positron emission tomography scan (PET-scan), that showed  persistent of the disease and started on medical therapy. Conclusion:  Mutation in ABCC8 is the most common cause of CHI and reflects the early age of presentation. There is a need for early diagnosis and appropriate therapeutic strategy.


Assuntos
Hiperinsulinismo Congênito/metabolismo , Hipoglicemia/metabolismo , Apneia/etiologia , Apneia/fisiopatologia , Pré-Escolar , Hiperinsulinismo Congênito/genética , Hiperinsulinismo Congênito/fisiopatologia , Hiperinsulinismo Congênito/terapia , Diabetes Mellitus/tratamento farmacológico , Terapia de Reposição de Enzimas , Insuficiência Pancreática Exócrina/tratamento farmacológico , Feminino , Fármacos Gastrointestinais/uso terapêutico , Heterozigoto , Homozigoto , Humanos , Hipoglicemia/complicações , Hipoglicemia/fisiopatologia , Lactente , Recém-Nascido , Letargia/etiologia , Letargia/fisiopatologia , Masculino , Mutação , Octreotida/uso terapêutico , Omã , Pancreatectomia , Peptídeos Cíclicos/uso terapêutico , Complicações Pós-Operatórias/tratamento farmacológico , Estudos Retrospectivos , Convulsões/etiologia , Convulsões/fisiopatologia , Sirolimo/uso terapêutico , Somatostatina/análogos & derivados , Somatostatina/uso terapêutico , Receptores Sulfonilureia/genética , Resultado do Tratamento
17.
Med. clín (Ed. impr.) ; 153(2): 83-87, jul. 2019. ilus, tab
Artigo em Inglês | IBECS | ID: ibc-183370

RESUMO

Antecedents: Perivascular epitheliod cell tumor (PEComa) is a rare mesenchymal tumor. They are rare in the field of gynecology, which makes them difficult to consider as a possible diagnostic. We aim to contribute with our experience to ease clinical practice to others gynecologists. Patients and methods: We contribute to literature with three gynecological cases; uterine, vaginal and retroperitoneal PEComas. Results: The uterine and vaginal PEComa, have required surgical treatment, and are free of disease at 9 and 5 months respectively. The retroperitoneal PEComa has recurred at 72 months of follow-up in form of retroperitoneal mass and pulmonary lymphangioleomyomatosis, continues treatment with sirolimus with good tolerance and partial response. Discussion: Given the scarcity of cases, the literature consists of case reports and mini-reviews. Some authors have categorized the PEComas based on prognostic factors, but there is no agreement regarding the follow-up and treatment. 18F-FDG-PET/CT can help characterize these lesions. The surgery is the standard. In recurrent or malignant cases, there is a lack of evidence regarding chemotherapy and radiotherapy. New therapies with inhibitory m-TOR open a hopeful therapeutic window


Antecedentes: El tumor de célula epitelioide perivascular (PEComa) es un tumor mesenquimal raro. Son entidades ginecológicas extrañas, lo que dificulta su consideración diagnóstica. Contribuimos con nuestra experiencia para facilitar la práctica clínica a otros ginecólogos. Pacientes y métodos: Aportamos 3 casos ginecológicos a la literatura: PEComas uterino, vaginal y retroperitoneal. Resultados: Los PEComas uterino y vaginal requirieron tratamiento quirúrgico y están libres de enfermedad a los 9 y 5 meses, respectivamente. El PEComa retroperitoneal recidivó a los 72 meses de seguimiento en forma de masa retroperitoneal y linfangioleiomiomatosis pulmonar, continuando tratamiento con sirolimus, con buena tolerancia y respuesta parcial. Discusión: Dada la escasez de casos, la literatura consiste en casos clínicos y mini revisiones. Algunos autores han categorizado los PEComas en base a factores pronósticos, pero no hay acuerdo respecto al seguimiento y tratamiento. La 18F-FDG-PET/TC puede ayudar a caracterizar estas lesiones. La cirugía es el tratamiento estándar. En casos de recurrencia o malignidad, hay falta de evidencia respecto a la quimioterapia y radioterapia. Nuevas terapias con inhibidores mTOR abren una ventana terapéutica esperanzadora


Assuntos
Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Neoplasias de Células Epitelioides Perivasculares/diagnóstico por imagem , Neoplasias de Células Epitelioides Perivasculares/cirurgia , Neoplasias Uterinas/diagnóstico por imagem , Neoplasias de Células Epitelioides Perivasculares/patologia , Linfangioleiomiomatose/complicações , Linfangioleiomiomatose/tratamento farmacológico , Sirolimo/uso terapêutico , Neoplasias Uterinas/patologia , Útero/patologia , Neoplasias Retroperitoneais/diagnóstico por imagem , Neoplasias Retroperitoneais/patologia
18.
Ann Acad Med Singapore ; 48(5): 150-155, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31210252

RESUMO

INTRODUCTION: Although drug-eluting stents (DES) have outclassed the use of bare metal stents, the safety and efficacy of DES at long-term follow-up has still been conflicting because of increased occurrence of late or very late restenosis and stent thrombosis after DES implantation. Hence, the present study was aimed to evaluate the 3-year safety and clinical performance of biodegradable polymer-coated ultra-thin (60 µm) sirolimus-eluting stent (SES) in real-world patients with coronary artery disease (CAD). MATERIALS AND METHODS: This was a physician-initiated, retrospective, single-centre, observational study that included 237 consecutive patients who had previously undergone implantation of only Supraflex SES (Sahajanand Medical Technologies Pvt Ltd, Surat, India) for the treatment of CAD. Follow-up was received after 1 year and 3 years of stent implantation. The primary endpoint was major adverse cardiac events (MACE), a composite of cardiac death, myocardial infarction (MI) and target lesion revascularisation (TLR). Stent thrombosis was considered as a safety endpoint. RESULTS: The mean age of patients was 64.1 ± 10.2 years, and 192 (81.0%) patients were male. The average stent length and diameter were 24.4 ± 9.0 mm and 3.1 ± 0.4 mm, respectively. The cumulative MACE rate at 3 years follow-up was 6.5% which included 4 (1.8%) cardiac deaths, 6 (2.8%) MI, and 4 (1.8%) TLR. There were 2 (0.9%) cases of stent thrombosis. CONCLUSION: Treatment of patients with CAD in real-world clinical practice was associated with sustained clinical safety and low rates of restenosis, stent thrombosis and MACE up to 3 years after Supraflex SES implantation.


Assuntos
Plásticos Biodegradáveis/uso terapêutico , Doença da Artéria Coronariana/cirurgia , Reestenose Coronária , Stents Farmacológicos/efeitos adversos , Infarto do Miocárdio , Intervenção Coronária Percutânea , Sirolimo/uso terapêutico , Idoso , Materiais Revestidos Biocompatíveis/uso terapêutico , Doença da Artéria Coronariana/epidemiologia , Reestenose Coronária/epidemiologia , Reestenose Coronária/etiologia , Feminino , Humanos , Imunossupressores/uso terapêutico , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/etiologia , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/instrumentação , Intervenção Coronária Percutânea/métodos , Desenho de Prótese , Estudos Retrospectivos , Análise de Sobrevida
19.
Artigo em Inglês | MEDLINE | ID: mdl-31174699

RESUMO

Sepsis is a life-threatening condition that may develop to multiple organ failure and septic shock. Autophagy is considered to play an important role in the regulation of inflammation. The present study aims to investigate the protective role of mTORC1 inhibitor, rapamycin, on septic death using cecal ligation and puncture (CLP) mice model. Here, results showed that pretreatment with rapamycin reduced the pyroptosis of peritoneal macrophages stimulated by cecal contents and the release of inflammatory factors such as interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α); In septic mice, rapamycin treatment decreased the activation of inflammasome in lung, and alleviated the pathological injuries in lung, liver and spleen tissues during acute stage of sepsis. Treatment of rapamycin rescued animals from septic death significantly. Our results indicated that activation of autophagy is a potential strategy to regulate the excessive inflammation in acute stage of sepsis.


Assuntos
Autofagia/efeitos dos fármacos , Inflamassomos/efeitos dos fármacos , Sepse/tratamento farmacológico , Sirolimo/uso terapêutico , Animais , Ceco , Citocinas/imunologia , Modelos Animais de Doenças , Inflamação/tratamento farmacológico , Ligadura , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Macrófagos Peritoneais/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL
20.
Medicina (Kaunas) ; 55(6)2019 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-31146413

RESUMO

Autophagy is an intracellular process whereby cytoplasmic constituents are degraded within lysosomes. Autophagy functions to eliminate unwanted or damaged materials such as proteins and organelles as their accumulation would be harmful to the cellular system. Autophagy also acts as a defense mechanism against invading pathogens and plays an important role in innate and adaptive immunity. In physiological processes, autophagy is involved in the regulation of tissue development, differentiation and remodeling, which are essential for maintaining cellular homeostasis. Recent studies have demonstrated that autophagy is linked to various diseases and involved in pathophysiological roles, such as adaptation during starvation, anti-aging, antigen presentation, tumor suppression and cell death. The modulation of autophagy has shown greatest promise in Crohn's disease as most of autophagy drugs involved in these diseases are currently under clinical trials and some has been approved by Food and Drug Administration. This review article discusses autophagy and potential drugs that are currently available for its modulation in Crohn's disease.


Assuntos
Autofagia/efeitos dos fármacos , Doença de Crohn/tratamento farmacológico , Adalimumab/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Certolizumab Pegol/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Infliximab/uso terapêutico , Sirolimo/uso terapêutico
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