Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 105.317
Filtrar
1.
RMD Open ; 9(1)2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36593080

RESUMO

Anti-melanoma differentiation-associated protein 5 (MDA5) antibody-positive dermatomyositis (MDA5-DM) is frequently complicated with rapidly progressive-interstitial lung disease (RP-ILD). The prognosis of MDA5-DM with RP-ILD is mostly poor despite intensive treatment with a combination of high-dose glucocorticoids and single conventional immunosuppressants. It was reported that the triple therapy (high-dose glucocorticoids, cyclophosphamide and tacrolimus) was more effective than a combination of high-dose glucocorticoids and stepwise addition of immunosuppressants. In addition, the efficacy of tofacitinib 10 mg/day for MDA5-DM with RP-ILD refractory to the triple therapy was suggested. However, the effect of those therapies was evaluated only in comparison to the historical control. Moreover, more importantly, there are still refractory patients even if treated with those therapies. In this case series, we report six MDA5-DM cases with RP-ILD in which the dose of tofacitinib was increased from 10 mg to 20 mg/day due to poor response to the triple therapy, followed by tofacitinib 10 mg/day. Four of six patients improved after dose escalation of tofacitinib, while two non-responders died. All six patients developed at least one infection including five cases of cytomegalovirus reactivation, one pulmonary aspergillosis, one herpes zoster and one herpes simplex keratitis. These cases suggest that the dose escalation of tofacitinib can be an option for MDA5-DM patients refractory to 10 mg/day of tofacitinib and other immunosuppressants although the risk of infection is a concern. The risk-benefit balance of the dose escalation of tofacitinib should be carefully assessed in each case.


Assuntos
Dermatomiosite , Imunossupressores , Humanos , Dermatomiosite/complicações , Dermatomiosite/tratamento farmacológico , Glucocorticoides/uso terapêutico , Imunossupressores/efeitos adversos , Doenças Pulmonares Intersticiais/epidemiologia
3.
Respir Res ; 24(1): 6, 2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36624431

RESUMO

BACKGROUND: Systemic sclerosis (SSc) is a rare, complex, connective tissue disorder. Interstitial lung disease (ILD) is common in SSc, occurring in 35-52% of patients and accounting for 20-40% of mortality. Evolution of therapeutic options has resulted in a lack of consensus on how to manage this condition. This Delphi study was initiated to develop consensus recommendations based on expert physician insights regarding screening, progression, treatment criteria, monitoring of response, and the role of recent therapeutic advances with antifibrotics and immunosuppressants in patients with SSc-ILD. METHODS: A modified Delphi process was completed by pulmonologists (n = 13) and rheumatologists (n = 12) with expertise in the management of patients with SSc-ILD. Panelists rated their agreement with each statement on a Likert scale from - 5 (complete disagreement) to + 5 (complete agreement). Consensus was predefined as a mean Likert scale score of ≤ - 2.5 or ≥ + 2.5 with a standard deviation not crossing zero. RESULTS: Panelists recommended that all patients with SSc be screened for ILD by chest auscultation, spirometry with diffusing capacity of the lungs for carbon monoxide, high-resolution computed tomography (HRCT), and/or autoantibody testing. Treatment decisions were influenced by baseline and changes in pulmonary function tests, extent of ILD on HRCT, duration and degree of dyspnea, presence of pulmonary hypertension, and potential contribution of reflux. Treatment success was defined as stabilization or improvement of signs or symptoms of ILD and functional status. Mycophenolate mofetil was identified as the initial treatment of choice. Experts considered nintedanib a therapeutic option in patients with progressive fibrotic ILD despite immunosuppressive therapy or patients contraindicated/unable to tolerate immunotherapy. Concomitant use of nintedanib with MMF/cyclophosphamide can be considered in patients with advanced disease at initial presentation, aggressive ILD, or significant disease progression. Although limited consensus was achieved on the use of tocilizumab, the experts considered it a therapeutic option for patients with early SSc and ILD with elevated acute-phase reactants. CONCLUSIONS: This modified Delphi study generated consensus recommendations for management of patients with SSc-ILD in a real-world setting. Findings from this study provide a management algorithm that will be helpful for treating patients with SSc-ILD and addresses a significant unmet need.


Assuntos
Doenças Pulmonares Intersticiais , Escleroderma Sistêmico , Humanos , Consenso , Imunossupressores/uso terapêutico , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/etiologia , Pulmão , Ácido Micofenólico/uso terapêutico , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/terapia
5.
Lupus Sci Med ; 10(1)2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36631164

RESUMO

BACKGROUND: Recent guidelines for SLE recommend using a hydroxychloroquine (HCQ) dose less than 5.0 mg/kg/day to reduce the risk of retinopathy. To determine if this dose reduction would have an impact on the clinical course of SLE, we compared flare incidence in a cohort of patients with SLE treated with two different oral HCQ dosages (≤5 mg/kg/day or >5 mg/kg/day). As a secondary analysis, we compared HCQ blood levels between the two different oral dosages, and evaluated the frequency of non-adherence in patients with SLE treated with HCQ. METHODS: We identified a cohort of patients with SLE taking HCQ for at least 6 months and followed for 24 months. At study entry and 6 months later, a blood venous sample was taken to measure HCQ blood levels by liquid chromatography. Incidence of new SLE flares after recruitment was put in relation to daily HCQ dose and mean HCQ blood levels. Cox regression analysis served to identify factors associated with SLE flares. RESULTS: 83 patients were enrolled. We observed 11 (16%) flares that developed in mean 14.8 months of follow-up. The difference in terms of flare rate and mean HCQ blood levels between the two oral dosages was not statistically significant. There was a trend (p=0.08) for high HCQ dose being associated with a lower flare rate. At Cox analysis, higher HCQ blood levels and older age at baseline were protective against flare occurrence, while concomitant immunosuppressant therapy showed significant positive association. HCQ blood levels did not correlate with prescribed HCQ dose. CONCLUSION: Patients with low oral HCQ dosage tend to have more flares, although the difference was not statistically significant. Higher HCQ blood levels were protective against flare occurrence. The risks and benefits must be balanced in choosing HCQ dose.


Assuntos
Antirreumáticos , Lúpus Eritematoso Sistêmico , Doenças Retinianas , Humanos , Hidroxicloroquina/efeitos adversos , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Antirreumáticos/efeitos adversos , Imunossupressores/efeitos adversos , Doenças Retinianas/induzido quimicamente
6.
Int J Mol Sci ; 24(2)2023 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-36674739

RESUMO

Sirolimus (SRL) is widely used as an immunosuppressant to prevent graft rejection, despite the risk of impairing glucose metabolism. Metformin (MET) can reduce the detrimental effects of SRL in many patients, including diabetes and renal transplant recipients. Limited in vivo studies have reported on SRL and MET therapy, particularly in relation to cellular bioenergetics, glucose metabolism, and insulin resistance. Herein, we investigated the efficacy of SRL and MET co-treatment in BALB/c mice over 4 weeks. Balb/c mice (4-6 weeks old) were divided into four groups and injected intraperitoneally (i.p.) with water (control, CTRL), MET (200 µg/g), SRL (5 µg/g), or MET (200 µg/g) +SRL (5 µg/g) over a period of one month. We evaluated the body weight, food consumption rate, random blood glucose (BG), insulin levels, serum biochemistry parameters (ALT, Albumin, BUN, Creatinine), and histomorphology in all groups using standardized techniques and assays. All drug-treated groups showed a statistically significant decrease in weight gain compared to the CTRL group, despite normal food intake. Treatment with SRL caused elevated BG and insulin levels, which were restored with SRL + MET combination. Serum biochemical parameters were within the normal range in all the studied groups. SRL+ MET co-treatment decreased liver cellular respiration and increased cellular ATP levels in the liver. In the pancreas, co-treatment resulted in increased cellular respiration and decreased cellular ATP levels. Liver and pancreatic histology were unchanged in all groups. This study showed that co-treatment of SRL with MET alleviates hyperglycemia induced by SRL without any deleterious effects. These results provide initial insights into the potential use of SRL + MET therapy in various settings.


Assuntos
Hiperglicemia , Insulinas , Metformina , Animais , Camundongos , Sirolimo/farmacologia , Metformina/farmacologia , Camundongos Endogâmicos BALB C , Imunossupressores , Hiperglicemia/tratamento farmacológico , Hiperglicemia/induzido quimicamente , Respiração Celular , Glucose , Trifosfato de Adenosina , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/prevenção & controle
7.
J Chromatogr A ; 1689: 463724, 2023 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-36592482

RESUMO

In the field of solid organ transplantation, chemotherapy and autoimmune disorders, treatment with immunosuppressant drugs requires intensive follow-up of the blood concentrations via therapeutic drug monitoring (TDM) because of their narrow therapeutic window and high intra- and inter-subject variability. This requires frequent hospital visits and venepunctures to allow the determination of these analytes, putting a high burden on the patients. In the context of patient-centric thinking, it is becoming increasingly established that at least part of these conventional blood draws could be replaced by microsampling, allowing home-sampling and increasing the quality of life for these patients. In this review we discuss the published methods - mostly using liquid chromatography coupled to tandem mass spectrometry - that have utilized (volumetric) dried blood samples as an alternative for conventional liquid whole blood for the TDM of immunosuppressant drugs. Furthermore, some pre-analytical considerations using DBS or volumetric alternatives are considered, as well as the applicability on clinical samples. The implementation status in clinical practice is also discussed, including (1) the cost-effectiveness of this approach compared to venepuncture, (2) the availability of multiplexed methods, (3) the status of harmonization and (4) patient perception. A brief perspective on potential future developments for the dried blood-based TDM of immunosuppressant drugs is provided, by considering how obstacles for the implementation of these strategies into clinical practice might be overcome.


Assuntos
Monitoramento de Medicamentos , Imunossupressores , Humanos , Imunossupressores/uso terapêutico , Monitoramento de Medicamentos/métodos , Qualidade de Vida , Cromatografia Líquida/métodos , Manejo de Espécimes/métodos , Teste em Amostras de Sangue Seco/métodos
8.
Int J Mol Sci ; 24(1)2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36614214

RESUMO

Fruiting bodies of Cordyceps cicadae (CC) have been reported to have a therapeutic effect in chronic kidney disease. Due to the rare and expensive resources from natural habitats, artificially cultivated mycelia using submerged liquid cultivation of CC (CCM) have been recently developed as an alternative to scarce sources of CC. However, little is known regarding potential protective effects of CCM against cyclosporine A (CsA)-induced acute nephrotoxicity in vivo and in vitro. In this study, male Sprague-Dawley rats were divided into six groups: control, CCM (40 mg and 400 mg/kg, orally), CsA (10 mg/kg, oral gavage), and CsA + CCM (40 mg and 400 mg/kg, orally). At the end of the study on day 8, all rats were sacrificed, and the blood and kidneys retrieved. CsA-induced acute nephrotoxicity was evident by increased levels of blood urea nitrogen (BUN). Levels of the endoplasmic reticulum (ER) resident chaperone glucose regulated protein 78 (GRP 78) were increased significantly in rats with acute nephrotoxicity. BUN and GRP 78 were significantly ameliorated in synchronous oral groups of CCM (40 or 400 mg/kg) plus CsA. Examination of hematoxylin and eosin stained kidney tissues revealed that the combined treatment of CCM slightly improved vacuolization in renal tubules upon CsA-induced damage. CsA-induced down-regulation of protein expression of magnesium ion channel proteins and transient receptor potential melastatin 6 and 7 were abolished by the combined treatment of CCM. CCM has the potential to protect the kidney against CsA-induced nephrotoxicity by reducing magnesium ion wasting, tubular cell damage, and ER stress demonstrated further by human renal proximal tubular epithelial cell line HK-2. Our results contribute to the in-depth understanding of the role of polysaccharides and nucleobases as the main secondary metabolites of CCM in the defense system of renal functions in CsA-induced acute nephrotoxicity.


Assuntos
Ciclosporina , Nefropatias , Animais , Masculino , Ratos , Ciclosporina/toxicidade , Chaperona BiP do Retículo Endoplasmático , Imunossupressores/uso terapêutico , Rim/metabolismo , Nefropatias/induzido quimicamente , Nefropatias/tratamento farmacológico , Nefropatias/metabolismo , Magnésio/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Ratos Sprague-Dawley
9.
J Immunother Cancer ; 11(1)2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36650020

RESUMO

BACKGROUND: Immunotherapy emerged as a promising treatment option for multiple myeloma (MM) patients. However, therapeutic efficacy can be hampered by the presence of an immunosuppressive bone marrow microenvironment including myeloid cells. S100A9 was previously identified as a key regulator of myeloid cell accumulation and suppressive activity. Tasquinimod, a small molecule inhibitor of S100A9, is currently in a phase Ib/IIa clinical trial in MM patients (NCT04405167). We aimed to gain more insights into its mechanisms of action both on the myeloma cells and the immune microenvironment. METHODS: We analyzed the effects of tasquinimod on MM cell viability, cell proliferation and downstream signaling pathways in vitro using RNA sequencing, real-time PCR, western blot analysis and multiparameter flow cytometry. Myeloid cells and T cells were cocultured at different ratios to assess tasquinimod-mediated immunomodulatory effects. The in vivo impact on immune cells (myeloid cell subsets, macrophages, dendritic cells), tumor load, survival and bone disease were elucidated using immunocompetent 5TMM models. RESULTS: Tasquinimod treatment significantly decreased myeloma cell proliferation and colony formation in vitro, associated with an inhibition of c-MYC and increased p27 expression. Tasquinimod-mediated targeting of the myeloid cell population resulted in increased T cell proliferation and functionality in vitro. Notably, short-term tasquinimod therapy of 5TMM mice significantly increased the total CD11b+ cells and shifted this population toward a more immunostimulatory state, which resulted in less myeloid-mediated immunosuppression and increased T cell activation ex vivo. Tasquinimod significantly reduced the tumor load and increased the trabecular bone volume, which resulted in prolonged overall survival of MM-bearing mice in vivo. CONCLUSION: Our study provides novel insights in the dual therapeutic effects of the immunomodulator tasquinimod and fosters its evaluation in combination therapy trials for MM patients.


Assuntos
Reabsorção Óssea , Mieloma Múltiplo , Quinolonas , Animais , Camundongos , Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Proliferação de Células , Imunossupressores/farmacologia , Mieloma Múltiplo/patologia , Células Mieloides/metabolismo , Quinolonas/farmacologia , Quinolonas/uso terapêutico , Quinolonas/metabolismo , Microambiente Tumoral , Humanos
11.
Int J Mol Sci ; 24(2)2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36674775

RESUMO

The intestinal microflora is extremely important, not only in the processes of absorption, digestion and biosynthesis of vitamins, but also in shaping the immune and cognitive functions of the human body. Several studies demonstrate a correlation between microbiota composition and such events as graft rejection, kidney interstitial fibrosis, urinary tract infections, and diarrhoea or graft tolerance. Some of those changes might be directly linked with pathologies such as colonization with pathogenic bacterial strains. Gut microbiota composition also plays an important role in metabolic complications and viral infections after transplantation. From the other side, gut microbiota might induce graft tolerance by promotion of T and B regulatory cells. Graft tolerance induction is still an extremely important issue regarding transplantology and might allow the reduction or even avoidance of immunosuppressive treatment. Although there is a rising evidence of the pivotal role of gut microbiota in aspects of kidney transplantation there is still a lack of knowledge on the direct mechanisms of microbiota action. Furthermore, some of those negative effects could be reversed by probiotics of faecal microbiota trapoinsplantation. While diabetes and hypertension as well as BKV and CMV viremia are common and important complications of transplantation, both worsening the graft function and causing systemic injuries, it opens up potential clinical treatment options. As has been also suggested in the current review, some bacterial subsets exhibit protective properties. However, currently, there is a lack of evidence on pro- and prebiotic supplementation in kidney transplant patients. In the current review, we describe the effect of the microbiota on the transplanted kidney in renal transplant recipients.


Assuntos
Microbioma Gastrointestinal , Transplante de Rim , Viroses , Humanos , Rim , Transplante de Rim/efeitos adversos , Imunossupressores , Bactérias
12.
BMJ Open ; 13(1): e064220, 2023 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-36657752

RESUMO

INTRODUCTION: Primary membranous nephropathy (PMN) is a major cause of nephrotic syndrome in adults. Rituximab has been recommended in the treatment of PMN by the updated Kidney Disease Improved Outcome guideline. However, the optimal dosing regimen of rituximab for the initial treatment of patients with PMN is unclear. METHODS AND ANALYSIS: A comprehensive screening will be performed by searching PubMed, Embase and the CENTRAL (Cochrane Central Register of Controlled Trials) without language restriction. Studies evaluating the efficacy of rituximab monotherapy using the following types of dosing regimens will be included: high-dose regimen; standard regimen and low-dose regimen. Studies with less than 10 participants will be excluded. The primary outcome is the remission rate at 12 months. The secondary outcomes are remission rate at 6 and 24 months, complete remission rate at 6, 12 and 24 months, relapse at 6, 12 and 24 months, and side effects. Risk of Bias In Non-randomised Studies of Interventions tool will be used to assess the risk of bias for non-randomised studies and the Cochrane risk of bias assessment tool will be used for randomised controlled trials. The pooled remission rate, complete remission rate, relapse rate and side effects will be estimated using the metaprop command. All analyses will be calculated using Stata software (V.15.0; StataCorp). ETHICS AND DISSEMINATION: Ethics approval is not required. The results of our study will be submitted to a peer-review journal. PROSPERO REGISTRATION NUMBER: CRD42022319401.


Assuntos
Glomerulonefrite Membranosa , Nefropatias , Síndrome Nefrótica , Adulto , Humanos , Glomerulonefrite Membranosa/tratamento farmacológico , Imunossupressores/uso terapêutico , Nefropatias/induzido quimicamente , Recidiva Local de Neoplasia/tratamento farmacológico , Síndrome Nefrótica/tratamento farmacológico , Rituximab/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Ensaios Clínicos Controlados não Aleatórios como Assunto
13.
Int J Mol Sci ; 24(2)2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36675265

RESUMO

The clinical success of solid organ transplantation is still limited by the insufficiency of immunosuppressive regimens to control chronic rejection and late graft loss. Moreover, serious side effects caused by chronic immunosuppressive treatment increase morbidity and mortality in transplant patients. Regulatory T cells (Tregs) have proven to be efficient in the induction of allograft tolerance and prolongation of graft survival in numerous preclinical models, and treatment has now moved to the clinics. The results of the first Treg-based clinical trials seem promising, proving the feasibility and safety of Treg therapy in clinical organ transplantation. However, many questions regarding Treg phenotype, optimum dosage, antigen-specificity, adjunct immunosuppressants and efficacy remain open. This review summarizes the results of the first Treg-based clinical trials for tolerance induction in solid organ transplantation and recapitulates what we have learnt so far and which questions need to be resolved before Treg therapy can become part of daily clinical practice. In addition, we discuss new strategies being developed for induction of donor-specific tolerance in solid organ transplantation with the clinical aims of prolonged graft survival and minimization of immunosuppression.


Assuntos
Transplante de Órgãos , Linfócitos T Reguladores , Rejeição de Enxerto , Tolerância Imunológica , Transplante de Órgãos/efeitos adversos , Terapia de Imunossupressão/métodos , Tolerância ao Transplante , Imunossupressores/uso terapêutico
14.
Ther Drug Monit ; 45(1): 102-109, 2023 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-36624577

RESUMO

PURPOSE: Tacrolimus is an immunosuppressant widely used in transplantations requiring mandatory concentration-controlled dosing to prevent acute rejection or adverse effects, including new-onset diabetes mellitus (NODM). However, no relationship between NODM and tacrolimus exposure has been established. This study aimed to evaluate the relationship between cumulative tacrolimus exposure and NODM occurrence. METHODS: A total of 452 kidney transplant patients were included in this study. Sixteen patients developed NODM during the first 3 months after transplant. We considered all tacrolimus concentration (C0) values collected until the diagnosis of NODM in these patients and until 3 months after transplant in the others. New tacrolimus cumulative exposure metrics were derived from the time profile of the tacrolimus morning predose concentration, C0: the percentage of C0 values > cutoff, the average of C0 values above the cutoff, and the percentage of the area under C0 versus time curve, AUCC0, above the cutoff. The cutoff chosen was 15 ng/mL, corresponding to the higher end of the therapeutic range for the early post-transplant period. The influence of these metrics on NODM and other clinical and biological characteristics was investigated using the Cox models. RESULTS: The percentage of C0 > 15 mcg/L was statistically different between patients with and without NODM (P = 0.01). Only these tacrolimus C0-derived metrics were significantly associated with an increased risk of NODM [HR: 1.73 (1.43-2.10, P < 0.001)]. CONCLUSION: This study shows that tacrolimus concentrations >15 mcg/L affect the incidence of NODM.


Assuntos
Diabetes Mellitus , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Transplante de Rim , Humanos , Transplante de Rim/efeitos adversos , Tacrolimo/efeitos adversos , Imunossupressores/efeitos adversos , Diabetes Mellitus/induzido quimicamente
15.
Ther Drug Monit ; 45(1): 35-44, 2023 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-36624575

RESUMO

BACKGROUND: The general population widely uses herbal medicines, as they are regarded as effective and safe. St. John's wort, which is an effective herbal antidepressant, exhibits both pharmacokinetic and pharmacodynamic interactions with several drugs. The aim of this review was to highlight the clinically significant interactions of St. John's wort with drugs that require to be monitored to assess their therapeutic effect. METHODS: Published literature was searched using electronic databases, such as MEDLINE, PubMed, and Elsevier ScienceDirect using terms such as "herbal medicine," "herbal toxicity," "legislation herbal medicine," "drug-herb interactions," "St. John's wort," and "St. John's wort-drug interactions." Searches were limited to the English language, and there was no restriction on the date of publication. RESULTS: St. John's wort exhibits a number of pharmacokinetic and pharmacodynamic interactions with drugs. The most dangerous interactions occurred when used concurrently with the immunosuppressants, cyclosporine, and tacrolimus (treatment failure or organ rejection) or warfarin (treatment failure resulting in thromboembolic events) or antiretroviral agents (treatment failure and the emergence of new viral variants that are resistant to conventional drugs). CONCLUSIONS: Patients should consult their health care providers before consuming herbal supplements, especially St. John's wort, to avoid potentially dangerous drug-herb interactions.


Assuntos
Hypericum , Medicamentos sob Prescrição , Humanos , Monitoramento de Medicamentos , Imunossupressores , Antirretrovirais , Interações Medicamentosas , Extratos Vegetais , Interações Ervas-Drogas
16.
Ther Drug Monit ; 45(1): 95-101, 2023 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-36624576

RESUMO

BACKGROUND: Transplant recipients require individualized tacrolimus doses to maximize graft survival. Multiple pediatric tacrolimus population pharmacokinetic (PopPK) models incorporating CYP3A5 genotype and other covariates have been developed. Identifying the optimal popPK model is necessary for clinical implementation in pediatric solid organ transplant. The primary objective was to compare the dose prediction capabilities of the developed models in pediatric kidney and heart transplant recipients. METHODS: Pediatric kidney or heart transplant recipients treated with tacrolimus and available CYP3A5 genotype data were identified. The initial weight-based tacrolimus dose and first therapeutic tacrolimus dose were collected retrospectively. Three published popPK models were used to predict the tacrolimus dose required to achieve a tacrolimus trough concentration of 10 ng/mL. Model dose predictions were compared with the initial and first therapeutic doses using Friedman test. The first therapeutic dose was plotted against the model-predicted dose. RESULTS: The median initial dose approximately 2-fold lower than the first therapeutic dose for CYP3A5 expressers. The Chen et al model provided the closest estimates to the first therapeutic dose for kidney transplant recipients; however, all 3 models tended to underpredict the observed therapeutic dose. For heart transplant recipients, Andrews et al model predicted doses that were higher than the initial dose but similar to the actual therapeutic dose. CONCLUSIONS: Weight-based tacrolimus dosing appears to underestimate the tacrolimus dose requirements. The development of a separate popPK model is necessary for heart transplant recipients. A genotype-guided strategy based on the Chen et al model provided the best estimates for doses in kidney transplant recipients and should be prospectively evaluated.


Assuntos
Citocromo P-450 CYP3A , Transplante de Órgãos , Humanos , Criança , Citocromo P-450 CYP3A/genética , Estudos Retrospectivos , Tacrolimo/uso terapêutico , Transplantados , Genótipo , Imunossupressores/uso terapêutico
17.
Transpl Int ; 36: 11045, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36713116
18.
Am J Transplant ; 23(1): 84-92, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36695625

RESUMO

Reducing the recipient's T cell repertoire is considered to increase the efficacy of regulatory T cell (Treg) therapy. This necessitates timing the administration of antithymocyte globulin (ATG) early enough before adoptive cell therapy (ACT) so that residual serum ATG does not deplete the transferred Tregs. The optimum time point in this regard has not been defined. Herein, we report the effects of residual serum ATG on the viability of an in vitro expanded Treg cell product used in a clinical trial of ACT in kidney transplant recipients (NCT03867617). Patients received ATG monotherapy (either 6 or 3 mg/kg body weight) without concomitant immunosuppression 2 to 3 weeks before transplantation and Treg transfer. An anti-ATG immunoglobulin G (IgG) immune response was elicited in all patients within 14 days. In turn, the elimination of total and Treg-specific ATG was accelerated substantially over control patients receiving the same dose of ATG with concomitant immunosuppression. However, ATG serum concentrations of <1 µg/mL, which had previously been reported as subtherapeutic threshold, triggered apoptosis of Tregs in vitro. Therefore, ATG levels need to decline to lower levels than those previously thought for efficacious Treg transfer. In 5 of 6 patients, such low levels of serum ATG considered safe for Treg transfer were reached within 2 weeks after ATG administration.


Assuntos
Soro Antilinfocitário , Transplante de Rim , Humanos , Rejeição de Enxerto , Terapia de Imunossupressão , Imunossupressores/uso terapêutico , Linfócitos T Reguladores , Ensaios Clínicos como Assunto
19.
PLoS One ; 18(1): e0278894, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36662740

RESUMO

INTRODUCTION: Calcineurin inhibitors constitute a cornerstone of immunosuppressive therapy in kidney transplant recipients. There are two main formulations of tacrolimus (Tac) which exhibit a prolonged-release mode of action: Advagraf® (MR-4) and Envarsus® (LCPT). However, they are not bioequivalent. Data comparing both once-daily prolonged-release formulations of Tac are insufficient. OBJECTIVE: The aim of the study was to compare safety and efficacy profiles of once-daily LCPT and MR-4 formulations of tacrolimus in adult kidney transplant recipients. PATIENTS AND METHODS: An observational, cohort single-center study was performed. One hundred fifteen kidney transplant recipients transplanted between 2016 and 2019 were enrolled to the study (59 vs 56, Envarsus® vs Advagraf®, respectively). Safety and efficacy profiles were assessed. RESULTS: Patient and graft survival at 12 and 24 months did not differ between the groups. There were no significant differences in serum creatinine at any timepoint. C/D ratio in the LCPT group was significantly higher at 12 and 24 months. Sepsis occurrence was more frequent in MR-4 group at 12 months. CONCLUSION: Both prolonged-release formulations of tacrolimus are safe and effective in immunosuppressive therapy in kidney transplant recipients.


Assuntos
Transplante de Rim , Tacrolimo , Adulto , Humanos , Tacrolimo/efeitos adversos , Imunossupressores/efeitos adversos , Seguimentos , Rejeição de Enxerto , Transplantados , Preparações de Ação Retardada
20.
Liver Transpl ; 29(2): 184-195, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36668691

RESUMO

The aim of this study was to investigate whether the combination of low-dose sirolimus (SRL) and low-dose extended-release tacrolimus (TAC) compared to normal-dose extended-release TAC results in a difference in the renal function and comparable rates of rejection, graft and patient survival at 36 months after transplantation. This study was an open-label, multicenter randomized, controlled trial. Patients were randomized to once-daily normal-dose extended-release TAC (control group) or once-daily combination therapy of SRL and low-dose extended-release TAC (interventional group). The primary endpoint was the cumulative incidence of chronic kidney disease (CKD) defined as grade ≥3 (estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2) at 36 months after transplantation. In total, 196 patients were included. CKD at 36 months was not different between the control and interventional group (50.8%, 95% CI: 39.7%-59.9%) vs. 43.7%, 95% CI: 32.8%-52.8%). Only at 6 months after transplantation, the eGFR was higher in the interventional group compared to the control group (mean eGFR 73.1±15 vs. 67.6±16 mL/min/1.73 m2, p=0.02) in the intention-to-treat population. No differences in the secondary endpoints and the number of serious adverse events were found between the groups. Once daily low-dose SRL combined with low-dose extended-release TAC does ultimately not provide less CKD grade ≥3 at 36 months compared to normal-dose extended-release TAC.


Assuntos
Transplante de Rim , Transplante de Fígado , Insuficiência Renal Crônica , Humanos , Tacrolimo/uso terapêutico , Sirolimo/efeitos adversos , Imunossupressores/uso terapêutico , Transplante de Fígado/efeitos adversos , Transplante de Rim/efeitos adversos , Rim/fisiologia , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/induzido quimicamente , Rejeição de Enxerto/epidemiologia , Rejeição de Enxerto/prevenção & controle , Rejeição de Enxerto/tratamento farmacológico , Sobrevivência de Enxerto
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...