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1.
Sheng Li Xue Bao ; 74(2): 225-236, 2022 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-35503070

RESUMO

This study was to investigate the changes of autophagy in pancreatic tissue cells from hyperlipidemic acute pancreatitis (HLAP) rats and the molecular mechanism of autophagy to induce inflammatory injury in pancreatic tissue cells. Male Sprague Dawley (SD) rats were intraperitoneally injected with caerulein to establish acute pancreatitis (AP) model and then given a high fat diet to further prepare HLAP model. The HLAP rats were treated with autophagy inducer rapamycin or inhibitor 3-methyladenine. Pancreatic acinar (AR42J) cells were treated with caerulein to establish HLAP cell model. The HLAP cell model were treated with rapamycin or transfected with vascular endothelial growth factor (VEGF) siRNA. The inflammatory factors in serum and cell culture supernatant were detected by ELISA method. The histopathological changes of pancreatic tissue were observed by HE staining. The changes of ultrastructure and autophagy in pancreatic tissue were observed by electron microscopy. The expression levels of Beclin-1, microtubule- associated protein light chain 3-II (LC3-II), mammalian target of rapamycin complex 1 (mTORC1), and VEGF were measured by immunohistochemistry and Western blot. The results showed that, compared with control group, the autophagy levels and inflammatory injury of pancreatic tissue cells from HLAP model rats were obviously increased, and these changes were aggravated by rapamycin treatment, but alleviated by 3-methyladenine treatment. In HLAP cell model, rapamycin aggravated the autophagy levels and inflammatory injury, whereas VEGF siRNA transfection increased mTORC1 protein expression, thus alleviating the autophagy and inflammatory injury of HLAP cell model. These results suggest that VEGF-induced autophagy plays a key role in HLAP pancreatic tissue cell injury, and interference with VEGF-mTORC1 pathway can reduce the autophagy levels and alleviate the inflammatory injury. The present study provides a new target for prevention and treatment of HLAP.


Assuntos
Pancreatite , Doença Aguda , Animais , Autofagia , Ceruletídeo/efeitos adversos , Masculino , Mamíferos/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina , Proteínas Associadas aos Microtúbulos/metabolismo , RNA Interferente Pequeno/genética , Ratos , Ratos Sprague-Dawley , Sirolimo/efeitos adversos , Fator A de Crescimento do Endotélio Vascular/genética
2.
Exp Clin Transplant ; 20(Suppl 1): 145-148, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35384826

RESUMO

OBJECTIVES: We investigated patients with genitourinary cancer after kidney transplant and the effects of immunosuppression reduction and switching to mechanistic target of rapamycin inhibitors. MATERIALS AND METHODS: We retrospectively evaluated kidney transplant recipients seen at our center between January 2000 and January 2020. Patients with <1 year of follow-up were excluded. RESULTS: Of 827 patients, genitourinary cancer was detected in 11 (1.3%): prostate cancer in 5 patients (45%), renal cell carcinoma in native kidney in 3 (27%), renal cell carcinoma in allograft kidney in 2 (18%), and transitional cell carcinoma of the bladder in 1 (9%). All patients had surgery. Two patients had bone metastasis due to prostate cancer at diagnosis. Two patients had allograft nephrectomy due to de novo renal cell carcinoma. Mean follow-up and age were 97 ± 45 months (range, 26-189) and 50 ± 10.2 years (19% female). After cancer diagnosis, excluding the 2 patients with allograft nephrectomy, immunosuppression was changed in 8 patients (88.8%) (1 patient received the same treatment before and after cancer diagnosis). Six patients received double-drug and 3 received triple-drug protocols. Of 9 patients, 2 were already using mechanistic target of rapamycin inhibitors before cancer diagnosis and 7 were switched: 4 to double-based and 3 to triple-based regimens. Six were switched from tacrolimus. With new treatments, patients showed no progressive kidney failure or rejection (38 ± 40 mo average follow-up). At last follow-up, mean glomerular filtration rate was 62.8 ± 34 mL/min/1.72 m2, which was similar to rate at cancer diagnosis (58.9 ± 24 mL/ min/1.72 m2; P = .78). During follow-up, no patients developed local recurrence of primary tumor or new metastasis, and none showed adverse effects after switch to mechanistic target of rapamycin inhibitors. Three patients died of malignancy-unrelated reasons (ileus, urinary sepsis, heart failure). CONCLUSIONS: Mechanistic target of rapamycin inhibitor-based drugs can be an important maintenance immunosuppressive treatment option for kidney transplant recipients with genitourinary cancers.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Transplante de Rim , Neoplasias da Próstata , Neoplasias Urogenitais , Carcinoma de Células Renais/induzido quimicamente , Rejeição de Enxerto , Humanos , Imunossupressores/efeitos adversos , Neoplasias Renais/etiologia , Transplante de Rim/efeitos adversos , Masculino , Estudos Retrospectivos , Sirolimo/efeitos adversos , Resultado do Tratamento , Neoplasias Urogenitais/induzido quimicamente , Neoplasias Urogenitais/tratamento farmacológico
3.
Trials ; 23(1): 334, 2022 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-35449070

RESUMO

BACKGROUND: Peripheral arterial disease is a progressive atherosclerotic disease with symptoms ranging from an intermittent claudication to acute critical limb ischemia and amputations. Drug-coated balloons and stents were developed to prevent neo-intimal proliferation and restenosis after percutaneous transluminal angioplasty. Randomized controlled trials showed that drug-coated, notably paclitaxel-coated, devices reduce restenosis, late lumen loss, and the need for target lesion re-vascularization compared with uncoated ones. However, the size of these trials was too small to prove superiority for "hard" clinical outcomes. Moreover, available studies were characterized by too restrictive eligibility criteria. Finally, it remains unclear whether paclitaxel-coated balloons may impair long-term survival. Alternative drug-coated balloons, the so-called limus-based analogs, have been approved for clinical use in patients with peripheral arterial disease. By encapsulating sirolimus in phospholipid drug nanocarriers, they optimize adhesion properties of sirolimus and provide better bioavailability. METHODS: In this investigator-initiated all-comer open-label phase III randomized controlled trial, we will evaluate whether sirolimus-coated balloon angioplasty is non-inferior and eventually superior, according to a predefined hierarchical analysis, to uncoated balloon angioplasty in adults with infra-inguinal peripheral arterial disease requiring endovascular angioplasty. Key exclusion criteria are pregnancy or breastfeeding, known intolerance or allergy to sirolimus, and participation in a clinical trial during the previous 3 months. The primary efficacy outcome is the composite of two clinically relevant non-subjective "hard" outcomes: unplanned major amputation of the target limb and endovascular or surgical target lesion re-vascularization for critical limb ischemia occurring within 1 year of randomization. The primary safety outcome includes death from all causes. DISCUSSION: By focusing on clinically relevant outcomes, this study will provide useful information on the efficacy and safety of sirolimus-coated balloon catheters for infra-inguinal peripheral arterial disease in a representative ("all-comer") population of unselected patients. As regulatory agencies had raised safety concerns in patients exposed to paclitaxel-coated devices (versus uncoated ones), collect mortality data up to 5 years after randomization will be collected. TRIAL REGISTRATION: ClinicalTrials.gov NCT04238546.


Assuntos
Angioplastia com Balão , Paclitaxel , Doença Arterial Periférica , Sirolimo , Angioplastia com Balão/efeitos adversos , Angioplastia com Balão/métodos , Ensaios Clínicos Fase III como Assunto , Materiais Revestidos Biocompatíveis , Constrição Patológica , Artéria Femoral , Humanos , Paclitaxel/efeitos adversos , Doença Arterial Periférica/terapia , Artéria Poplítea , Ensaios Clínicos Controlados Aleatórios como Assunto , Sirolimo/efeitos adversos , Resultado do Tratamento , Grau de Desobstrução Vascular
4.
J Invasive Cardiol ; 34(5): E363-E368, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35451995

RESUMO

BACKGROUND: Dual-antiplatelet treatment (DAPT) has conventionally been prescribed for 1 year after percutaneous coronary intervention (PCI) with drug-eluting stent (DES) implantation. Recent evidence suggests that a duration of only 6 months may be equally safe and effective when using contemporary DES options. OBJECTIVE: The aim of this study was to assess clinical outcomes in patients treated with the BioMatrix biodegradable-polymer coated biolimus-eluting stent (BP-BES; Biosensors International) who received only 6 months of DAPT. METHODS: This prospective "all-comers" registry enrolled 2038 patients in France. Following PCI, DAPT was started for a recommended period of 6 months. Patients were followed up at 6 and 24 months. The primary endpoint of major adverse cardiac and cerebrovascular event (MACCE) was a composite of all-cause death, cerebrovascular accidents, non-fatal myocardial infarction, or clinically driven target-vessel revascularization. Secondary endpoints included stent thrombosis (ST) and major bleeding (MB). RESULTS: The mean age of the study population was 67 ± 10.5 years and 77% of patients were male. Follow-up data were available in 96.9% and 95.3% of patients at 6 and 24 months, respectively. At 6 months, the incidences of MACCE, ST, and MB were 3.1%, 0.3%, and 0.4%, respectively. At 24 months, 21.2% of patients were still on DAPT and the cumulative incidences of MACCE, ST, and MB were 9.7%, 0.54%, and 0.79%, respectively. CONCLUSIONS: In this unselected population of patients undergoing PCI with a BP-BES, a 6-month duration of DAPT after implantation is safe and effective.


Assuntos
Doença da Artéria Coronariana , Stents Farmacológicos , Intervenção Coronária Percutânea , Idoso , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/cirurgia , Stents Farmacológicos/efeitos adversos , Feminino , Hemorragia/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/efeitos adversos , Inibidores da Agregação Plaquetária/uso terapêutico , Polímeros , Estudos Prospectivos , Sistema de Registros , Sirolimo/efeitos adversos , Resultado do Tratamento
5.
Front Immunol ; 13: 857424, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35401500

RESUMO

Background: Thrombocytopenia (TP) is considered as a warning sign of high-risk antiphospholipid syndrome (APS) and sometimes a paradoxical sign of anti-thrombosis treatment. Currently, there is an extreme paucity of effective and safe drugs for long-term management of TP in primary APS patients; therefore, we explored the efficacy and safety of sirolimus monotherapy. Methods: In this real-world study, we included 7 consecutive patients with primary APS who received sirolimus monotherapy for TP. Oral sirolimus was initiated at a dose of 1-2 mg once daily and then adjusted primarily based on clinical efficacy and tolerance, with consideration of the sirolimus trough concentration of ≤15 ng/ml. Results: Of included patients, the median age was 58 years with a median disease course of 1.5 years and 4 patients were treatment-naïve. All patients completed 6 months of sirolimus therapy with a median follow-up of 6 months (range: 6-15). All patients received sirolimus monotherapy for TP during the entire follow-up, without any additional agents. Overall, the platelet count exhibited a substantially increasing trend after sirolimus administration during the first 6 months (p < 0.001) and stability later. Specifically, the median platelet count was significantly increased from 59 × 109/l before sirolimus to 90 × 109/l at month 1 (p = 0.028), 131 × 109/l at 3 months (p = 0.028), and 178 × 109/l at 6 months (p = 0.018). Overall and complete responses were respectively achieved in 6 (85.7%) and 5 (71.4%) patients at month 6. Importantly, overall response was achieved in all 4 treatment-naïve patients. Additionally, there were different extents of decline in the titers of antiphospholipid antibodies after sirolimus treatment. Regarding safety, only one patient experienced an elevated cholesterol level with recovery after atorvastatin treatment. Conclusion: Sirolimus monotherapy confers good efficacy and tolerance for TP in primary APS patients and therefore may be considered as a first-line therapy.


Assuntos
Síndrome Antifosfolipídica , Leucopenia , Trombocitopenia , Síndrome Antifosfolipídica/complicações , Síndrome Antifosfolipídica/diagnóstico , Síndrome Antifosfolipídica/tratamento farmacológico , Humanos , Pessoa de Meia-Idade , Projetos Piloto , Sirolimo/efeitos adversos , Centros de Atenção Terciária , Trombocitopenia/tratamento farmacológico , Trombocitopenia/etiologia
6.
Proc Natl Acad Sci U S A ; 119(10): e2107357119, 2022 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-35238644

RESUMO

Significance The mechanistic target of rapamycin (mTOR) plays a central role in growth, metabolism, and aging. It is assembled into two multiprotein complexes, namely, mTORC1 and mTORC2. We previously demonstrated the efficacy of sirolimus in ARHL in mice by decreasing mTORC1. However, the aspect of mTORC2 regulation in the cochlea is poorly characterized. Herein, based on pharmacological and genetic interventions, we found that a high dose of sirolimus resulted in severe hearing loss by reducing the mTORC2/AKT signaling pathway in the cochlea. Furthermore, selective activation of mTORC2 could protect against hearing loss induced by acoustic trauma and cisplatin-induced ototoxicity. Hence, the therapeutic activation of mTORC2 in conjunction with decreasing mTORC1 might represent a promising and effective strategy in preventing hearing loss.


Assuntos
Perda Auditiva Neurossensorial/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Proteína Companheira de mTOR Insensível à Rapamicina/metabolismo , Transdução de Sinais , Animais , Modelos Animais de Doenças , Perda Auditiva Neurossensorial/induzido quimicamente , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/prevenção & controle , Alvo Mecanístico do Complexo 2 de Rapamicina/genética , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína Companheira de mTOR Insensível à Rapamicina/genética , Sirolimo/efeitos adversos , Sirolimo/farmacologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
8.
JACC Cardiovasc Interv ; 15(7): 770-779, 2022 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-35305906

RESUMO

OBJECTIVES: The aim of this randomized controlled trial was to investigate a novel sirolimus-coated balloon (SCB) compared with the best investigated paclitaxel-coated balloon (PCB). BACKGROUND: There is increasing clinical evidence for the treatment of coronary de novo disease using drug-coated balloons. However, it is unclear whether paclitaxel remains the drug of choice or if sirolimus is an alternative, in analogy to drug-eluting stents. METHODS: Seventy patients with coronary de novo lesions were enrolled in a randomized, multicenter trial to compare a novel SCB (SeQuent SCB, B. Braun Melsungen; 4 µg/mm2) with a PCB (SeQuent Please, B. Braun Melsungen; 3 µg/mm2). The primary endpoint was angiographic late lumen loss (LLL) at 6 months. Secondary endpoints included major adverse cardiovascular events and individual clinical endpoints such as cardiac death, target lesion myocardial infarction, clinically driven target lesion revascularization, and binary restenosis. RESULTS: Quantitative coronary angiography revealed no differences in baseline parameters. After 6 months, in-segment LLL was 0.01 ± 0.33 mm in the PCB group versus 0.10 ± 0.32 mm in the SCB group. The mean difference between SCB and PCB was 0.08 (95% CI: -0.07 to 0.24). Noninferiority at a predefined margin of 0.35 was shown. However, negative LLL was more frequent in the PCB group (60% of lesions vs 32% in the SCB group; P = 0.019). Major adverse cardiovascular events up to 12 months also did not differ between the groups. CONCLUSIONS: This first-in-human comparison of a novel SCB with a crystalline coating showed similar angiographic outcomes in the treatment of coronary de novo disease compared with a clinically proven PCB. However, late luminal enlargement was more frequently observed after PCB treatment. (Treatment of Coronary De-Novo Stenosis by a Sirolimus Coated Balloon or a Paclitaxel Coated Balloon Catheter Malaysia [SCBDNMAL]; NCT04017364).


Assuntos
Angioplastia Coronária com Balão , Fármacos Cardiovasculares , Doença da Artéria Coronariana , Reestenose Coronária , Angioplastia Coronária com Balão/efeitos adversos , Fármacos Cardiovasculares/efeitos adversos , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/terapia , Reestenose Coronária/diagnóstico por imagem , Reestenose Coronária/etiologia , Humanos , Paclitaxel/efeitos adversos , Estudos Prospectivos , Sirolimo/efeitos adversos , Resultado do Tratamento
9.
J Affect Disord ; 303: 91-97, 2022 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-35101523

RESUMO

Suicide is a public health crisis with limited treatment options. Ketamine has demonstrated rapid and robust improvements in suicidal ideation (SI). The parent study for the secondary pilot analyses presented here was a double-blind, cross-over trial that found pretreatment with the mechanistic target of rapamycin complex 1 (mTORC1) prolonged the antidepressant effects of ketamine. Here we examined the effect of mTORC1 inhibition on ketamine's antisuicidal effects. Twenty patients in a major depressive episode were randomized to pretreatment with oral rapamycin (6 mg) or placebo prior to IV ketamine (0.5 mg/kg). We found ketamine administration resulted in significant improvements across all measures with the largest effect at 24 h with only the Beck Scale for Suicide remaining significant at the two-week follow-up. There were no significant main effects of pretreatment. While these analyses are pilot in nature and overall severity of SI was relatively low, the antisuicidal findings (no effect of rapamycin) being in contrast to the antidepressant effects (prolonged effect with rapamycin), suggest the rapid-acting antisuicidal and antidepressant effects of ketamine may be mechanistically distinct and the trajectories of response, recovery, and relapse may be independent. These findings provide additional evidence of ketamine's antisuicidal effects and highlight the importance of future studies that continue to examine potential differences in mechanisms and trajectory of outcomes.


Assuntos
Transtorno Depressivo Maior , Ketamina , Antidepressivos/efeitos adversos , Depressão/tratamento farmacológico , Transtorno Depressivo Maior/tratamento farmacológico , Humanos , Ketamina/efeitos adversos , Alvo Mecanístico do Complexo 1 de Rapamicina , Sirolimo/efeitos adversos , Ideação Suicida
11.
JACC Cardiovasc Interv ; 15(6): 618-626, 2022 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-35219622

RESUMO

OBJECTIVES: The aim of the study was to assess 24-month efficacy and safety of a novel drug-eluting stent (DES) for femoropopliteal interventions with an innovative stent design and abluminal reservoir technology releasing the amphilimus formulation (sirolimus plus fatty acid) for efficient drug transfer and optimized release kinetics. BACKGROUND: DES releasing paclitaxel exhibited good patency rates after femoropopliteal interventions. No benefit has been reported when sirolimus or everolimus were used for antiproliferative stent coating. METHODS: Within a multicenter, first-in-man, single-arm study, 100 patients with symptomatic femoropopliteal disease (Rutherford category 2-4, mean lesion length 5.8 ± 3.9 cm, 35.0% total occlusions) were treated with the NiTiDES stent (Alvimedica). Two-year follow-up included assessment of primary patency (defined as absence of clinically driven target lesion revascularization or binary restenosis with a peak systolic velocity ratio >2.4 by duplex ultrasound), safety, functional, and clinical outcomes. RESULTS: At 24 months, Kaplan-Meier estimates of primary patency and freedom from clinically driven target lesion revascularization were 83.4% (95% CI: 73.9%-89.6%) and 93.1% (95% CI: 85.3%-96.9%), respectively. Over the study period, 3 deaths were reported with no major limb amputation. Functional and clinical benefits were sustained, as 82.1% of patients fell into Rutherford category 0 or 1 at 24 months, which was associated with preserved improvements in all walking disability questionnaire scores. CONCLUSIONS: The 2-year results of the ILLUMINA (Innovative siroLimus seLf expanding drUg-eluting stent for the treatMent of perIpheral disease: evaluation of safety aNd efficAcy) study demonstrate a sustained treatment benefit with a novel sirolimus-eluting stent that also compares favorably to other femoropopliteal intervention trials. Head-to-head comparisons of NiTiDES with a paclitaxel-based DES are warranted. (The ILLUMINA Study [ILLUMINA]; NCT03510676).


Assuntos
Fármacos Cardiovasculares , Stents Farmacológicos , Doença Arterial Periférica , Fármacos Cardiovasculares/efeitos adversos , Artéria Femoral/diagnóstico por imagem , Humanos , Paclitaxel/efeitos adversos , Doença Arterial Periférica/diagnóstico por imagem , Doença Arterial Periférica/terapia , Artéria Poplítea/diagnóstico por imagem , Sirolimo/efeitos adversos , Stents , Resultado do Tratamento , Grau de Desobstrução Vascular
12.
J Cardiovasc Surg (Torino) ; 63(1): 8-12, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35179337

RESUMO

BACKGROUND: There appears to be an association between paclitaxel-coated devices and increased 5-year all-cause mortality. METHODS: We are conducting a prospective, randomized, controlled, single-center, noninferiority study. All consecutive patients with femoropopliteal arterial disease who fulfilled the inclusion/exclusion criteria are sequentially and consecutively assigned to either paclitaxel (Ranger, Boston Scientific) or sirolimus (MagicTouch, Concept Medical) coated balloon angioplasty treatment. The primary outcome are procedural success and primary vessel patency at index procedure. The secondary outcomes are 30-day and 12-month freedom from MAEs (amputation, death, TLR/TVR, MI, distal embolization that requires a separate intervention or hospitalization), procedural success (≤30% residual diameter stenosis or occlusion after the procedure), Rutherford category improvement (reduction ≤1 category) and ABI improvement (increase ≥0.10 from baseline). RESULTS: A total of six patients have been enrolled in the present study up to now. The mean age was 72.6 years old and five were male. All patients had angiographic evidence of isolated occlusion in the transition segment of the distal femoral superficial artery in the popliteal artery. The mean length was 109 mm. Three patients were treated by sirolimus-coated (group A) and three by paclitaxel coated balloon angioplasty (group B). The primary patency and procedural success was in two of three and three of three patients, for group A and B, respectively. CONCLUSIONS: Preliminary results show safety and feasibility of the Sirolimus-coated balloon angioplasty. Further investigation and increase of sample size will allow for more sustained conclusions regarding patency and procedural success of this type of balloons for the endovascular treatment of peripheral arterial disease.


Assuntos
Angioplastia com Balão/instrumentação , Fármacos Cardiovasculares/administração & dosagem , Materiais Revestidos Biocompatíveis , Artéria Femoral , Paclitaxel/administração & dosagem , Doença Arterial Periférica/terapia , Artéria Poplítea , Sirolimo/administração & dosagem , Idoso , Amputação , Angioplastia com Balão/efeitos adversos , Angioplastia com Balão/mortalidade , Fármacos Cardiovasculares/efeitos adversos , Feminino , Artéria Femoral/diagnóstico por imagem , Artéria Femoral/fisiopatologia , Humanos , Salvamento de Membro , Masculino , Paclitaxel/efeitos adversos , Doença Arterial Periférica/diagnóstico por imagem , Doença Arterial Periférica/mortalidade , Doença Arterial Periférica/fisiopatologia , Placa Aterosclerótica , Artéria Poplítea/diagnóstico por imagem , Artéria Poplítea/fisiopatologia , Intervalo Livre de Progressão , Sirolimo/efeitos adversos , Fatores de Tempo , Grau de Desobstrução Vascular
13.
Transplant Cell Ther ; 28(4): 185.e1-185.e7, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35017119

RESUMO

Although tacrolimus and sirolimus (TAC/SIR) is an accepted graft-versus-host disease (GVHD) prophylaxis regimen following allogeneic hematopoietic cell transplantation (HCT), toxicity from this regimen can lead to premature discontinuation of immunosuppression. There are limited studies reporting outcomes and subsequent treatment of patients with TAC/SIR intolerance. This study was conducted to assess the outcomes of patients with TAC/SIR intolerance and guide their subsequent management. We retrospectively analyzed transplantation outcomes of consecutive adult patients at Moffitt Cancer Center who underwent allogeneic HCT with TAC/SIR as GVHD prophylaxis between 2009 and 2018. TAC/SIR intolerance was defined as discontinuation of either TAC or SIR due to toxicity before post-transplantation day +100. A total of 777 patients met the inclusion criteria. The median duration of follow-up was 22 months (range, 0.2 to 125 months). Intolerance occurred in 13% (n = 104) of the patients at a median of 30 days (range, 5 to 90 days). The most common causes of intolerance were acute kidney injury (n = 53; 51%), thrombotic microangiopathy (n = 31; 28%), and veno-occlusive disease (n = 23; 22%). The cumulative incidence of grade II-IV acute GVHD at 100 days was 50% (95% CI, 39% to 64%) in the TAC/SIR-intolerant patients and 25% (95% CI, 22% to 29%) in patients tolerant to this regimen (P < .0001). In multivariate analyses, the incidence of grade II-IV 4 acute GVHD was significantly higher in the TAC/SIR-intolerant patients (hazard ratio [HR], 2.40; 95% CI, 1.59 to 3.61; P < .0001). Similarly, in multivariate analyses, the TAC/SIR-intolerant patients had a higher incidence of chronic GVHD (HR, 1.48; 95% CI, 1.03 to 2.12; P = .03). The nonrelapse mortality (NRM) at 1 year was 47% (95% CI, 38% to 59%) in the TAC/SIR-intolerant patients and 12% (95% CI, 10% to 15%) in those tolerant to the regimen (P < .0001). The 2-year relapse-free survival was 35% (95% CI, 25% to 44%) in the TAC/SIR-intolerant patients and 60% (95% CI, 57% to 65%) in the TAC/SIR-tolerant patients (HR, 2.30; 95% CI, 1.61 to 3.28; P < .0001). Intolerance stratified by early (≤30 days) versus late (31 to 100 days) significantly affected the cumulative incidence of acute GVHD at 75% (early; 95% CI, 59% to 94%) versus 33% (late; 95% CI, 21% to 50%) (P = .001), as well as the cumulative incidence of NRM at 61% (early; 95% CI, 48% to 77%) versus 35% (late; 95% CI, 24% to 51%) (P = .006). Most patients who developed TAC/SIR intolerance were switched to an alternative 2-drug regimen (71 of 104; 68%), most commonly mycophenolate mofetil in addition to continuing TAC or SIR (68 of 71; 96%). Overall, TAC/SIR intolerance was associated with poorer outcomes. Early intolerance contributed to a higher risk of acute GVHD, increased NRM, and inferior survival. Patients with early intolerance were often switched to an alternative agent, and patients with late intolerance tended to be continued on single-drug therapy without substitution. The use of single-drug versus 2-drug regimens after intolerance did not appear to affect outcomes. Management strategies to mitigate the risks of intolerance are warranted.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Adulto , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Estudos Retrospectivos , Sirolimo/efeitos adversos , Tacrolimo/efeitos adversos
14.
Childs Nerv Syst ; 38(5): 947-952, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35083513

RESUMO

PURPOSE: There was no evidence whether the mammalian/mechanistic target of rapamycin pathway hyperactivation and long-term use of mTOR inhibitors have any effects on the physical development of children. The aim was to evaluate these effects by comparing the physical development of children with TSC and normal children. METHODS: A total of 120 eligible children were enrolled. They were administered sirolimus and followed for at least 12 months. Height, weight, BMI and lipid metabolism index were collected during treatment. Pearson's chi-square and Fisher's exact test were used for comparison of proportions of patients exhibiting normal and abnormal physical growth before and after 1 year of treatment. Logistic regression was used to evaluate the influence of age, sex and abnormal lipid metabolism on the increased BMIs of TSC patients after treatment. RESULTS: Most of the enrolled TSC children were in the normal height, weight and BMI ranges at baseline (91.7%, 95.8% and 78.3%, respectively). Most remained in the normal height, weight and BMI ranges after 1 year of sirolimus treatment (94.2%, 95% and 76.7%, respectively). There was no significant difference in the proportion of physical development before and after treatment (p > 0.05). Thirty-eight (38/106, 35.8%) patients had increased BMIs after 1 year of treatment, but there was no significant correlation between age, sex and lipid metabolism and increased BMI. CONCLUSIONS: Overactivation of the mTOR pathway and long-term administration of sirolimus does not affect the physical development of children with TSC.


Assuntos
Esclerose Tuberosa , Animais , Criança , Humanos , Mamíferos , Sirolimo/efeitos adversos , Esclerose Tuberosa/tratamento farmacológico
15.
Ann Clin Transl Neurol ; 9(2): 181-192, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35040598

RESUMO

OBJECTIVE: To determine whether sirolimus, a mechanistic target of rapamycin (mTOR) inhibitor, reduces epileptic seizures associated with focal cortical dysplasia (FCD) type II. METHODS: Sixteen patients (aged 6-57 years) with FCD type II received sirolimus at an initial dose of 1 or 2 mg/day based on body weight (FCDS-01). In 15 patients, the dose was adjusted to achieve target trough ranges of 5-15 ng/mL, followed by a 12-week maintenance therapy period. The primary endpoint was a lower focal seizure frequency during the maintenance therapy period. Further, we also conducted a prospective cohort study (RES-FCD) in which 60 patients with FCD type II were included as an external control group. RESULTS: The focal seizure frequency reduced by 25% in all patients during the maintenance therapy period and by a median value of 17%, 28%, and 23% during the 1-4-, 5-8-, and 9-12-week periods. The response rate was 33%. The focal seizure frequency in the external control group reduced by 0.5%. However, the background characteristics of external and sirolimus-treated groups differed. Adverse events were consistent with those of mTOR inhibitors reported previously. The blood KL-6 level was elevated over time. INTERPRETATION: The reduction of focal seizures did not meet the predetermined level of statistical significance. The safety profile of the drug was tolerable. The potential for a reduction of focal seizures over time merit further investigations.


Assuntos
Epilepsia/complicações , Malformações do Desenvolvimento Cortical do Grupo I/complicações , Inibidores de Proteínas Quinases/farmacologia , Convulsões/tratamento farmacológico , Convulsões/etiologia , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Adolescente , Adulto , Criança , Humanos , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Sirolimo/administração & dosagem , Sirolimo/efeitos adversos , Adulto Jovem
16.
Lupus Sci Med ; 9(1)2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34980680

RESUMO

OBJECTIVE: The effectiveness and safety of sirolimus for SLE treatment have been shown in some uncontrolled studies. However, a comparison of sirolimus with other classic immunosuppressants has not been reported. We conducted the study to compare the effectiveness and safety of sirolimus versus tacrolimus for SLE treatment. METHODS: A real-world cohort study was conducted. Patients with clinically active SLE who were prescribed sirolimus or tacrolimus were enrolled. Propensity score matching was used to ensure equivalent disease conditions and background medications. SLE disease activity indices, serological parameters, steroid doses, modification of other immunosuppressants, renal effectiveness and adverse events were compared between the two groups at 3-month, 6-month, 9-month and 12-month follow-up visits. RESULTS: Data from 52 patients in each of the sirolimus and tacrolimus groups were analysed. Indices regarding the effectiveness of sirolimus, including Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) scores, physician's global assessment (PhGA) scores, and proportion of patients with SLEDAI-2K reduction of ≥4 and PhGA increase of <0.3, were equivalent to those of tacrolimus at all follow-up timepoints (all p≥0.05). Greater improvements in complement levels were observed in the sirolimus group at 3 and 6 months. Higher percentages of patients with prednisone doses ≤7.5 mg/day were observed in the sirolimus group at all timepoints. Seventeen adverse events in the sirolimus group were recorded. None was severe or led to drug discontinuation. CONCLUSIONS: Overall, sirolimus was as effective as tacrolimus in the treatment of SLE. Sirolimus had better effects on serological improvement and glucocorticoid tapering. Sirolimus was well tolerated in patients with SLE.


Assuntos
Lúpus Eritematoso Sistêmico , Tacrolimo , Estudos de Coortes , Humanos , Imunossupressores/efeitos adversos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Sirolimo/efeitos adversos , Tacrolimo/efeitos adversos
17.
Transplant Proc ; 54(1): 180-184, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35000775

RESUMO

Pulmonary alveolar proteinosis (PAP) is a rare parenchymal pulmonary disease, characterized by the accumulation of surfactant material in alveoli. Rare cases of pulmonary alveolar proteinosis have been reported following the use of sirolimus. All published cases have been described following solid organ transplantation, and symptoms improved quickly after treatment's cessation. We describe a case of PAP secondary to sirolimus treating graft-versus-host reaction in a patient who received a stem cell transplant for chronic lymphocytic leukemia. Pulmonary alveolar proteinosis was cured after stopping sirolimus without any other therapeutic management. PAP can be a rare but serious side effect of sirolimus. It is important to rule out other causes of primary or secondary PAP before suggesting a toxic drug cause. The main challenge is to quickly diagnose this side effect to stop exposure to the toxic agent.


Assuntos
Proteinose Alveolar Pulmonar , Rejeição de Enxerto , Células-Tronco Hematopoéticas , Humanos , Pulmão , Proteinose Alveolar Pulmonar/induzido quimicamente , Proteinose Alveolar Pulmonar/diagnóstico , Proteinose Alveolar Pulmonar/terapia , Sirolimo/efeitos adversos
18.
Leuk Res ; 112: 106749, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34839054

RESUMO

A phase II study was conducted to ascertain whether sequential exposure to decitabine followed by rapamycin, an mTOR (mechanistic target of rapamycin) inhibitor would result in better responses than decitabine alone. Newly diagnosed acute myelogenous leukemia (AML) patients who were >65 years old and not eligible for intensive induction regimens or patients with relapsed or refractory AML received 10 days of decitabine followed by 12 days of rapamycin in cycle 1 and 5 days of decitabine followed by 17 days of rapamycin in subsequent cycles. The composite complete remission rate (CR) was 33 % (CR plus CR with incomplete count recovery). Median overall survival was 7.7 months in newly diagnosed elderly AML patients and 6.6 months in relapsed/refractory AML patients. Twenty-four evaluable patients were enrolled, and the study did not meet its primary endpoint of demonstrating a significant improvement in composite CR rate with the combination as compared to an established historical CR rate of 25 % with decitabine alone. Despite that, the survival rates in relapsed/refractory cases appear comparable to what is reported with other salvage regimens, and no significant patterns of non-hematologic toxicity were noted. 50 % of subjects in the de novo group achieved a composite CR which is significantly higher (p = 0.02) than the rate of 25 % with decitabine alone. This trial is registered at clinical trials.gov as NCT02109744.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide/tratamento farmacológico , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Decitabina/administração & dosagem , Decitabina/efeitos adversos , Intervalo Livre de Doença , Fadiga/induzido quimicamente , Neutropenia Febril/induzido quimicamente , Feminino , Humanos , Leucopenia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Sirolimo/administração & dosagem , Sirolimo/efeitos adversos , Resultado do Tratamento
19.
J Cardiovasc Pharmacol ; 79(3): 355-367, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-34840266

RESUMO

ABSTRACT: The present study aimed to explore the contribution of mammalian target of rapamycin (mTOR) in deoxycorticosterone acetate (DOCA) salt-induced hypertension and related pathophysiological changes in cardiovascular and renal tissues. DOCA salt loading resulted in an increase in systolic blood pressure, diastolic blood pressure, and mean blood pressure along with the activity of ribosomal protein S6, the effector protein of mTOR. Treatment with rapamycin, the selective inhibitor of mTOR, initiated at the fourth week of DOCA- salt administration normalized the systolic blood pressure and attenuated ribosomal protein S6 activity in the heart, aorta, and kidney. Cardiac and vascular hypertrophy, oxidative stress, and infiltration of macrophages (CD68+), the marker of inflammation, were also reduced in rapamycin-treated, DOCA-salt, hypertensive rats. In addition, renal hypertrophy and dysfunction were also reduced with rapamycin-treated hypertensive rats. Moreover, these pathophysiological changes in DOCA-salt hypertensive rats were associated with increased NADPH oxidase (NOX) activity, gp91phox (formerly NOX2) expression, ERK1/2, and p38 MAPK activities in the heart, aorta, and kidney were minimized by rapamycin. These data indicate that mTOR plays an important role in regulating blood pressure and the development of cardiovascular and renal pathophysiological changes, most likely due to increased NOX expression/activity, ERK1/2, and p38 MAPK activity with macrophages infiltration in the heart, kidney, and aorta. Pharmacological inhibition of mTOR and related signaling pathways could serve as a novel target for the treatment of hypertension.


Assuntos
Acetato de Desoxicorticosterona , Hipertensão , Acetatos/efeitos adversos , Animais , Pressão Sanguínea , Acetato de Desoxicorticosterona/efeitos adversos , Hipertensão/induzido quimicamente , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Hipertrofia , Inflamação , Masculino , Mamíferos/metabolismo , Estresse Oxidativo , Ratos , Proteína S6 Ribossômica/metabolismo , Sirolimo/efeitos adversos , Serina-Treonina Quinases TOR/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
20.
Hepatobiliary Pancreat Dis Int ; 21(2): 106-112, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34583911

RESUMO

Mammalian target of rapamycin (mTOR) inhibitor as an attractive drug target with promising antitumor effects has been widely investigated. High quality clinical trial has been conducted in liver transplant (LT) recipients in Western countries. However, the pertinent studies in Eastern world are paucity. Therefore, we designed a clinical trial to test whether sirolimus can improve recurrence-free survival (RFS) in hepatocellular carcinoma (HCC) patients beyond the Milan criteria after LT. This is an open-labeled, single-arm, prospective, multicenter, and real-world study aiming to evaluate the clinical outcomes of early switch to sirolimus-based regimens in HCC patients after LT. Patients with a histologically proven HCC and beyond the Milan criteria will be enrolled. The initial immunosuppressant regimens are center-specific for the first 4-6 weeks. The following regimens integrated sirolimus into the regimens as a combination therapy with reduced calcineurin inhibitors based on the condition of patients and centers. The study is planned for 4 years in total with a 2-year enrollment period and a 2-year follow-up. We predict that sirolimus conversion regimen will provide survival benefits for patients particular in the key indicator RFS as well as better quality of life. If the trial is conducted successfully, we will have a continued monitoring over a longer follow-up time to estimate indicator of overall survival. We hope that the outcome will provide better evidence for clinical decision-making and revising treatment guidelines based on Chinese population data. Trial register: Trial registered at http://www.chictr.org.cn: ChiCTR2100042869.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Transplante de Fígado , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/cirurgia , Humanos , Imunossupressores/efeitos adversos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/cirurgia , Transplante de Fígado/métodos , Estudos Multicêntricos como Assunto , Recidiva Local de Neoplasia/tratamento farmacológico , Estudos Prospectivos , Qualidade de Vida , Sirolimo/efeitos adversos , Resultado do Tratamento
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