RESUMEN
Background: Despite the growing number of elderly kidney transplant (Ktx) recipients, few studies have examined the effects of immunosuppression on their lymphocyte profiles. Methods: We evaluated the early conversion from mycophenolate sodium (MPS) to everolimus (EVL) after rabbit antithymocyte globulin (rATG) 2 mg/kg induction in elderly kidney recipients. Three groups of KTx patients were compared: (a) Young (n=20, 36 ± 7 y) receiving standard immunosuppression (Group A1) (prednisone, tacrolimus, and MPS), (b) Elderly (n=35, 65 ± 3 y) receiving standard immunosuppression (Group B1), and (c) Elderly (n=16, 65 ± 3 y) with early (mean 30 d) conversion from MPS to EVL (Group B2). Naive, memory, and regulatory peripheral blood TCD4+ lymphocytes were quantified at 0, 30, and 365 d. Results: Results are reported as [mean(p25-p75)]. Young recipients had higher lymphocyte counts at baseline [2,100(1,630-2,400) vs. 1,310 (1,000-1,600)/mm3, p<0.0001] maintained higher counts within 365 d [1,850(1,590-2,120) vs. 1,130(460-1,325)/mm3, p=0.018 and vs. 1,410(805-1,895)/mm3, p=0.268]. Elderly recipients showed a decrease in lymphocytes within 30 d [1,310(1,000-1,600) vs. 910(700-1,198)/mm3, p=0.0012] with recovery within 365 d. The same pattern was observed in total lymphocytes and TCD4+ counts. Rabbit antithymocyte globulin induced a reduction in central memory T-cell percentages at 30 d in both young recipients [6.2(3.77-10.8) vs. 5.32(2.49-7.28)% of CD4+, p=0.036] and in elderly recipients [8.17(5.28-12.88) vs. 6.74(4.36-11)% of CD4+, p=0.05] on standard immunosuppression, returning to baseline at 365 d in elderly recipients but not in young recipients. Regulatory T CD39+ cells (Treg) percentages decreased at 30 d in elderly recipients [2.1(1.23-3.51) vs. 1.69(0.8-2.66)% of CD4+, p=0.0028] and in young recipients [1.29(0.45-1.85) vs. 0.84(0.18-1.82)% of CD4+, p=0.0038], returning to baseline at 365 d in elderly recipients [2.1(1.23-3.51) vs. 2.042(0.88-2.42)% of CD4+], but not in young recipients [1.29(0.45-1.85) vs. 0.86(0.7-1.34) % of CD4+]. The elderly everolimus conversion group did not show significant changes in cell profile over time or compared to elderly recipients with standard immunosuppression. Conclusion: Aging favored the maintenance of Treg during the late transplantation period despite ongoing immunosuppression. Lymphocyte depletion due to rATG was more prominent in elderly recipients and affected memory subsets with a temporary reduction in central memory T cells. However, conversion to everolimus did not impact Treg profile. Reducing the dose of rATG in elderly recipients seems necessary for the expected lymphocyte changes with EVL to occur. Clinical trial registration: nEverOld Trial, identifier NTC01631058.
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Inmunosupresores , Trasplante de Riñón , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Edad , Suero Antilinfocítico/uso terapéutico , Everolimus , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Terapia de Inmunosupresión/métodos , Inmunosupresores/uso terapéutico , Recuento de Linfocitos , Ácido Micofenólico/administración & dosificación , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/metabolismo , Tacrolimus/administración & dosificación , Tacrolimus/uso terapéutico , Receptores de TrasplantesAsunto(s)
Everolimus , Inmunosupresores , Trasplante de Riñón , Ácido Micofenólico , Sirolimus , Tacrolimus , Humanos , Everolimus/uso terapéutico , Inmunosupresores/uso terapéutico , Inmunosupresores/efectos adversos , Tacrolimus/uso terapéutico , Ácido Micofenólico/uso terapéutico , Ácido Micofenólico/efectos adversos , Sirolimus/uso terapéutico , Sirolimus/efectos adversos , Rechazo de Injerto/prevención & control , Rechazo de Injerto/inmunología , Resultado del Tratamiento , Persona de Mediana Edad , Femenino , Factores de Tiempo , Masculino , Quimioterapia Combinada , AdultoRESUMEN
BACKGROUND: Mammalian target of rapamycin inhibitors (mTORi), sirolimus (SRL) and everolimus (EVR), have distinct pharmacokinetic/pharmacodynamics properties. There are no studies comparing the efficacy and safety of de novo use of SRL versus EVR in combination with reduced-dose calcineurin inhibitor. METHODS: This single-center prospective, randomized study included first kidney transplant recipients receiving a single 3 mg/kg antithymocyte globulin dose, tacrolimus, and prednisone, without cytomegalovirus (CMV) pharmacological prophylaxis. Patients were randomized into 3 groups: SRL, EVR, or mycophenolate sodium (MPS). Doses of SRL and EVR were adjusted to maintain whole blood concentrations between 4 and 8 ng/mL. The primary endpoint was the 12-mo incidence of the first CMV infection/disease. RESULTS: There were 266 patients (SRL, n = 86; EVR, n = 90; MPS, n = 90). The incidence of the first CMV event was lower in the mTORi versus MPS groups (10.5% versus 7.8% versus 43.3%, P < 0.0001). There were no differences in the incidence of BK polyomavirus viremia (8.2% versus 10.1% versus 15.1%, P = 0.360). There were no differences in survival-free from treatment failure (87.8% versus 88.8% versus 93.3%, P = 0.421) and incidence of donor-specific antibodies. At 12 mo, there were no differences in kidney function (75 ± 23 versus 78 ± 24 versus 77 ± 24 mL/min/1.73 m 2 , P = 0.736), proteinuria, and histology in protocol biopsies. Treatment discontinuation was higher among patients receiving SRL or EVR (18.6% versus 15.6% versus 6.7%, P = 0.054). CONCLUSIONS: De novo use of SRL or EVR, targeting similar therapeutic blood concentrations, shows comparable efficacy and safety. The reduced incidence of CMV infection/disease and distinct safety profile of mTORi versus mycophenolate were confirmed in this study.
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Infecciones por Citomegalovirus , Trasplante de Riñón , Humanos , Everolimus/efectos adversos , Tacrolimus/efectos adversos , Sirolimus/efectos adversos , Trasplante de Riñón/efectos adversos , Trasplante de Riñón/métodos , Estudios Prospectivos , Inmunosupresores/efectos adversos , Ácido Micofenólico/efectos adversos , Infecciones por Citomegalovirus/diagnóstico , Infecciones por Citomegalovirus/prevención & control , Infecciones por Citomegalovirus/tratamiento farmacológico , Citomegalovirus , Rechazo de Injerto/epidemiología , Rechazo de Injerto/prevención & control , Receptores de TrasplantesRESUMEN
BACKGROUND: Drug-eluting stents (DESs) based on biodegradable polymers (BPs) have been introduced to reduce the risk for late and very late stent thrombosis (ST), which were frequently observed with earlier generations of DES designs based on durable polymers (DPs); however, randomized controlled trials on these DES designs are scarce. The meriT-V trial is a randomized, active-controlled, non-inferiority trial with a prospective, multicenter design that evaluated the 2-year efficacy of a novel third-generation, ultra-thin strut, BP-based BioMime sirolimus-eluting stent (SES) versus the DP-based XIENCE everolimus-eluting stent (EES) for the treatment of de novo lesions. METHODS: The meriT-V is a randomized trial that enrolled 256 patients at 15 centers across Europe and Brazil. Here, we report the outcomes of the extended follow-up period of 2 years. The randomization of enrolled patients was in a 2:1 ratio; the enrolled patients received either the BioMime SES (n = 170) or the XIENCE EES (n = 86). The three-point major adverse cardiac event (MACE), defined as a composite of cardiac death, myocardial infarction (MI), or ischemia-driven target vessel revascularization (ID-TVR), was considered as the composite safety and efficacy endpoint. Ischemia-driven target lesion revascularization (ID-TLR) was evaluated as well as the frequency of definite/probable ST, based on the first Academic Research Consortium definitions. RESULTS: The trial had a 2-year follow-up completion rate of 98.44% (n = 252/256 patients), and the clinical outcomes assessment showed a nonsignificant difference in the cumulative rate of three-point MACE between both arms (BioMime vs. XIENCE: 7.74% vs. 9.52%, P = 0.62). Even the MI incidences in the BioMime arm were insignificantly lower than those of the XIENCE arm (1.79% vs.
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Enfermedad de la Arteria Coronaria , Stents Liberadores de Fármacos , Intervención Coronaria Percutánea , Enfermedades Cardiovasculares , EverolimusRESUMEN
BACKGROUND: Trafficking of regulatory T cells (Tregs) modulates the inflammatory response after kidney transplantation (KTx). There is scarce information on whether circulating and intragraft Tregs are similarly affected by immunosuppressive drugs and the type of deceased kidney donor. METHODS: FOXP3 gene expression was measured in the pretransplant kidney biopsies (PIBx) from donors who met extended (ECD) and standard (SCD) criteria donors. In the third month after KTx, the patients were divided according to tacrolimus (Tac) or everolimus (Eve) and the type of kidney they had received. FOXP3 gene expression in the peripheral blood (PB) and kidney biopsies (Bx) was analyzed using real-time polymerase chain reaction. RESULTS: FOXP3 gene expression in the PIBx was higher in ECD kidneys. FOXP3 gene expression in the PB and Bx was greater in Eve- than in Tac-treated patients. However, SCD recipients treated with Eve (SCD/Eve) had higher FOXP3 expression than ECD/Eve. CONCLUSION: Pretransplant kidney biopsies from ECD kidneys had higher FOXP3 gene expression than SCD, and the use of Eve may affect the expression of the FOXP3 gene only in SCD kidneys.
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Supervivencia de Injerto , Sirolimus , Humanos , Sirolimus/uso terapéutico , Estudios Retrospectivos , Tacrolimus/uso terapéutico , Donantes de Tejidos , Everolimus/efectos adversos , Riñón , Factores de Transcripción Forkhead/genética , Serina-Treonina Quinasas TOR , Expresión Génica , BiopsiaRESUMEN
BACKGROUND: Tuberous sclerosis (TS) is a multisystem genetic disease in which epilepsy is a frequent manifestation and is often difficult to control. Everolimus is a drug with proven efficacy in the treatment of other conditions related to TS, and some evidence suggests that its use benefits the treatment of refractory epilepsy in these patients. OBJECTIVE: To evaluate the efficacy of everolimus in controlling refractory epilepsy in children with TS. METHODS: A literature review was conducted in the Pubmed, BVS, and Medline databases, using the descriptors Tuberous sclerosis, Children, Epilepsy, and Everolimus. Original clinical trials and prospective studies published in Portuguese or English in the last decade that evaluated the use of everolimus as an adjuvant therapy in the control of refractory epilepsy in pediatric patients with TS were included. RESULTS: Our search screened 246 articles from electronic databases, 6 of which were chosen for review. Despite the methodological variations between the studies, most patients benefited from the use of everolimus to control refractory epilepsy, with response rates ranging from 28.6 to 100%. Adverse effects were present in all studies leading to dropouts of some patients; however, the majority were of low severity. CONCLUSION: The selected studies suggest a beneficial effect of everolimus in the treatment of refractory epilepsy in children with TS, despite the adverse effects observed. Further studies involving a larger sample in double-blind controlled clinical trials should be performed to provide more information and statistical credibility.
ANTECEDENTES: A esclerose tuberosa (ET) é uma doença genética multissistêmica na qual a epilepsia é a manifestação neurológica mais frequente, sendo muitas vezes de difícil controle. O everolimo é uma droga com eficácia comprovada no tratamento de outras condições relacionadas à ET, e indícios sugerem benefícios de seu uso também no controle da epilepsia refratária nesses pacientes. OBJETIVO: Avaliar a eficácia do everolimo no controle da epilepsia refratária em crianças com ET. MéTODOS: Revisão de literatura nas bases de dados Pubmed, BVS e Medline, utilizando os descritores Tuberous sclerosis, Children, Epilepsy e Everolimus. Incluíram-se ensaios clínicos originais e estudos prospectivos publicados em português ou inglês na última década e que avaliassem o uso do everolimo como terapia adjuvante no controle da epilepsia refratária em pacientes pediátricos com ET. RESULTADOS: Nossa busca rastreou 246 artigos nas bases de dados, dos quais 6 foram escolhidos para a revisão. Apesar das variações metodológicas entre os estudos, a maioria dos pacientes tiveram benefício no uso do everolimo para controle da epilepsia refratária, com taxas de resposta variando entre 28.6 e 100%. Os efeitos adversos estiveram presentes em todos os estudos, levando à desistência de alguns pacientes, contudo a maioria foi de baixa gravidade. CONCLUSãO: Os estudos selecionados sugerem efeito benéfico do everolimo no tratamento da epilepsia refratária em crianças com ET, apesar dos efeitos adversos observados. Novos estudos envolvendo uma amostra maior em ensaios clínicos controlados duplo-cegos devem ser realizados para fornecer mais informações e credibilidade estatística.
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Epilepsia Refractaria , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Esclerosis Tuberosa , Humanos , Niño , Epilepsia Refractaria/tratamiento farmacológico , Epilepsia Refractaria/etiología , Everolimus/uso terapéutico , Estudios Prospectivos , Esclerosis Tuberosa/complicaciones , Esclerosis Tuberosa/tratamiento farmacológico , Terapia Combinada , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Preserving health-related quality of life (HRQOL) is an important goal during renal cell carcinoma treatment. We report HRQOL outcomes from a phase II trial (NCT03173560). PATIENTS AND METHODS: HRQOL data were collected during a multicenter, randomized, open-label phase II study comparing the safety and efficacy of 2 different starting doses of lenvatinib (18 mg vs. 14 mg daily) in combination with everolimus (5 mg daily), following one prior vascular endothelial growth factor-targeted treatment. HRQOL was measured using 3 different instruments-FKSI-DRS, EORTC QLQ-C30, and EQ-5D-3L-which were all secondary endpoints. Change from baseline was assessed using linear mixed-effects models. Deterioration events for time to deterioration (TTD) analyses were defined using established thresholds for minimally important differences in the change from baseline for each scale. TTD for each treatment arm was estimated using the Kaplan-Meier method. RESULTS: Baseline characteristics of the 343 participants randomly assigned to 18 mg lenvatinib (n = 171) and 14 mg lenvatinib (n = 172) were well balanced. Least-squares mean estimates for change from baseline were favorable for the 18 mg group over the 14 mg group for the FKSI-DRS and most EORTC QLQ-C30 scales, but differences between treatments did not exceed the minimally important thresholds. Median TTD was longer among participants in the 18 mg group than those in the 14 mg group for most scales. CONCLUSIONS: Participants who received an 18 mg lenvatinib starting dose had favorable HRQOL scores and longer TTD on most scales compared with those who received a 14 mg starting dose.
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Antineoplásicos , Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Everolimus/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Calidad de Vida , Factor A de Crecimiento Endotelial Vascular , Antineoplásicos/administración & dosificaciónRESUMEN
Introduction: Mutations in the promoter region of telomerase reverse transcriptase occur frequently in meningiomas. Objective: To estimate the prognostic importance of telomerase reverse transcriptase mutations in Colombian patients with grades II and III meningioma. Materials and methods: This was a multicenter retrospective cohort study of patients diagnosed with refractory or recurrent WHO grades II and III meningiomas, recruited between 2011 and 2018, and treated with systemic therapy (sunitinib, everolimus ± octreotide, and bevacizumab). Mutation status of the telomerase reverse transcriptase promoter was established by PCR. Results: Forty patients were included, of which telomerase reverse transcriptase mutations were found in 21 (52.5%), being C228T and C250T the most frequent variants with 87.5 % and 14.3 %, respectively. These were more frequent among patients with anaplastic meningiomas (p=0.18), with more than 2 recurrences (p=0.04); and in patients with parasagittal region and anterior fossa lesions (p=0.05). Subjects characterized as having punctual mutations were more frequently administered with everolimus, sunitinib and bevacizumab drug series (p=0.06). Overall survival was 23.7 months (CI95% 13.1-34.2) and 43.4 months (CI95% 37.5-49.3; p=0.0001) between subjects with and without mutations, respectively. Multivariate analysis showed that the number of recurrences and the presence of telomerase reverse transcriptase mutations were tthe only variables that negatively affected overall survival. Conclusions: Mutations in telomerase reverse transcriptase allows the identification of high-risk patients and could be useful in the selection of the best medical treatment.
Introducción. En los meningiomas, ocurren con frecuencia mutaciones en la región promotora de la transcriptasa inversa de la telomerasa. Objetivo. Estimar la importancia pronóstica de las mutaciones de la transcriptasa inversa de la telomerasa en pacientes colombianos con meningiomas de grados II y III. Materiales y métodos. Es un estudio de cohorte, retrospectivo y multicéntrico, que incluyó pacientes con diagnóstico de meningioma persistente o recidivante, de grados II y III, según la clasificación de la OMS, reclutados entre el 2011 y el 2018, con tratamiento sistémico (sunitinib, everolimus con octreótido o sin él, y bevacizumab). El estado de la mutación del promotor de la transcriptasa inversa de la telomerasa se determinó por medio de la PCR. Resultados. Se incluyeron 40 pacientes, en 21 (52,5 %) de los cuales se encontraron mutaciones en la transcriptasa inversa de la telomerasa, siendo las variantes más frecuentes la C228T (87,5 %) y la C250T (14,3 %). Estas fueron más frecuentes entre los pacientes con meningiomas anaplásicos (p=0,18), en aquellos con más de dos recurrencias (p=0,04), y en los que presentaron lesiones en la región parasagital y la fosa anterior (p=0,05). Los sujetos caracterizados por tener alteraciones puntuales fueron tratados con mayor frecuencia con la serie de medicamentos everolimus, sunitinib y bevacizumab (p=0,06). Tras el inicio del tratamiento médico, la supervivencia global fue de 23,7 meses (IC95% 13,1-34,2) en los pacientes con mutaciones y, de 43,4 meses (IC95% 37,5-49,3), entre aquellos sin mutaciones (p=0,0001). Los resultados del análisis multivariado demostraron que, únicamente, el número de recurrencias y la presencia de mutaciones en el gen de la transcriptasa inversa de la telomerasa, fueron factores que afectaron negativamente la supervivencia global. Conclusiones. Las mutaciones en el gen promotor de la transcriptasa inversa de la telomerasa permiten identificar los pacientes con alto riesgo, cuya detección podría ser de utilidad para seleccionar el mejor esquema terapéutico.
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Neoplasias Meníngeas , Meningioma , Humanos , Meningioma/genética , Bevacizumab , Sunitinib , Everolimus , Estudios Retrospectivos , Neoplasias Meníngeas/genéticaRESUMEN
Objetivo: Avaliar a relação de custo-efetividade dos regimes imunossupressores utilizados em pacientes receptores de transplante renal, no Hospital Santa Casa de Misericórdia de Juiz de Fora, MG, basiliximabe, micofenolato de sódio, tacrolimo e prednisona (Grupo 1 = 93 pacientes), comparados com a associação de timoglobulina, everolimo, tacrolimo e prednisona (Grupo 2 = 91 pacientes). Métodos: Para a análise farmacoeconômica, foi utilizado o modelo de Árvore de Decisão, desenvolvido no software Treeage Suite 2011. Foi considerada uma coorte real de pacientes submetidos ao transplante renal entre janeiro de 2013 e março de 2017, os quais foram acompanhados por um período de um ano, sendo mensurados os benefícios clínicos, bem como os custos associados, na perspectiva do Sistema Único de Saúde. O método de custeio utilizado foi o botton-up. Foram adotados os limiares de custo-efetividade (LCEs) equivalentes a 1 PIB per capita e 1 a 3 PIB, considerando o ano de 2017. Resultados: No que diz respeito à sobrevida, a RCEI foi de cerca de R$ 214.234,12 para 1 ano de vida ganho. Em relação aos eventos adversos, a RCEI foi de cerca de R$ 43.682,98 para 1 ano sem incidência de eventos adversos. Conclusões: Ao avaliar a sobrevida e a incidência de eventos adversos, timoglobulina+everolimo não é considerado custo-efetivo em relação ao esquema contendo basiliximabe+micofenolato de sódio diante do LCE de 1 PIB per capita. No entanto, ao adotarmos o LCE até 3 PIB per capita, o regime contendo moglobulina+everolimo é custo-efetivo, ultrapassando cerca de 38% do PIB per capita.
Objective: Evaluate the cost-effectiveness of immunosuppressive regimens used in kidney transplant recipients at the Santa Casa de Misericórdia, Hospital in Juiz de Fora, MG, compared with basiliximab, mycophenolate sodium, tacrolimus and prednisone (Group 1 = 93 patients) with the association of thymoglobulin, everolimus, tacrolimus and prednisone (Group 2 = 91 patients). Methods: For the pharmacoeconomic analysis, the Decision Tree model was used, developed in the TreeAge Suite 2011 software. A real cohort of patients undergoing kidney transplantation between January 2013 and March 2017 was considered, they were followed up for a period of 1 year, where the clinical benefits were measured, as well as the associated costs, from the perspective
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Trasplante de Riñón , Economía Farmacéutica , Everolimus , Análisis de Costo-Efectividad , Inmunosupresores , Ácido MicofenólicoRESUMEN
Background: EGFR mutations are present in approximately 15−50% of non-small cell lung cancer (NSCLC), which are predictive of anti-EGFR therapies. At variance, NSCLC patients harboring KRAS mutations are resistant to those anti-EGFR approaches. Afatinib and allitinib are second-generation pan-EGFR drugs, yet no predictive biomarkers are known in the NSCLC context. In the present study, we evaluated the efficacy of pan-EGFR inhibitors in a panel of 15 lung cancer cell lines associated with the KRAS mutations phenotype. Methods: KRAS wild-type sensitive NCI-H292 cell line was further transfected with KRAS mutations (p.G12D and p.G12S). The pan-EGFR inhibitors' activity and biologic effect of KRAS mutations were evaluated by cytotoxicity, MAPK phospho-protein array, colony formation, migration, invasion, and adhesion. In addition, in vivo chicken chorioallantoic membrane assay was performed in KRAS mutant cell lines. The gene expression profile was evaluated by NanoString. Lastly, everolimus and pan-EGFR combinations were performed to determine the combination index. Results: The GI50 score classified two cell lines treated with afatinib and seven treated with allitinib as high-sensitive phenotypes. All KRAS mutant cell lines demonstrated a resistant profile for both therapies (GI50 < 30%). The protein array of KRAS edited cells indicated a significant increase in AKT, CREB, HSP27, JNK, and, importantly, mTOR protein levels compared with KRAS wild-type cells. The colony formation, migration, invasion, adhesion, tumor perimeter, and mesenchymal phenotype were increased in the H292 KRAS mutated cells. Gene expression analysis showed 18 dysregulated genes associated with the focal adhesion-PI3K-Akt-mTOR-signaling correlated in KRAS mutant cell lines. Moreover, mTOR overexpression in KRAS mutant H292 cells was inhibited after everolimus exposure, and sensitivity to afatinib and allitinib was restored. Conclusions: Our results indicate that allitinib was more effective than afatinib in NSCLC cell lines. KRAS mutations increased aggressive behavior through upregulation of the focal adhesion-PI3K-Akt-mTOR-signaling in NSCLC cells. Significantly, everolimus restored sensibility and improved cytotoxicity of EGFR inhibitors in the KRAS mutant NSCLC cell lines.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Afatinib/farmacología , Afatinib/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Receptores ErbB/metabolismo , Everolimus/farmacología , Everolimus/uso terapéutico , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mutación , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
End-stage kidney disease is frequently associated with left ventricular hypertrophy (LVH), a condition more prevalent in the elderly, that may increase mortality after renal transplantation (RTx). Previous studies suggested that mTOR inhibitors (mTORi) can improve LVH, but this has never been tested in elderly kidney transplant recipients. In this prospective randomized clinical trial, we analyzed the impact of Everolimus (EVL) on the reversal of LVH after RTx in elderly recipients (≥60 years) submitted to different immunosuppressive regimens: EVL/lowTacrolimus (EVL group, n = 53) or mycophenolate sodium/regularTacrolimus (MPS group, n = 47). Patients performed echocardiograms (Echo) up to 3 months after RTx and then annually. At baseline, mean age was 65±3 years in both groups and LVH was observed in 63.6% of patients in EVL group and in 61.8% of MPS group. Last Echo was performed at mean time of 47 and 49 months after RTx in EVL and MPS groups, respectively (P = .34). LVH regression was observed in 23.8% (EVL group) and 19% (MPS group) of patients (P = 1.00). Mean eGFR, blood pressure, and use of RAS blockers were similar between groups throughout follow-up. EVL did not improve LVH in this cohort, and this lack of benefit may be attributed to concomitant use of TAC, senescence, or both.
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Trasplante de Riñón , Anciano , Everolimus/uso terapéutico , Humanos , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Hipertrofia Ventricular Izquierda/etiología , Inmunosupresores/uso terapéutico , Trasplante de Riñón/efectos adversos , Inhibidores mTOR , Persona de Mediana Edad , Estudios Prospectivos , Sirolimus/uso terapéutico , Serina-Treonina Quinasas TOR , Receptores de TrasplantesRESUMEN
BACKGROUND: Everolimus-induced pneumonitis (EiP) has been poorly studied in patients with neuroendocrine neoplasms (NEN) outside clinical trials. The aim of this study was to evaluate the incidence, risk factors, and outcomes of EiP in patients with NENs using real-world data. METHODS: Retrospective study of everolimus-treated patients with advanced NENs. Imaging reports were systematically reviewed for the presence of pneumonitis. Clinical features and treatment profiles for EiP were summarized. Overall survival (OS) was calculated from the initiation of everolimus to the date of death or last follow-up using the Kaplan-Meier method. RESULTS: A total of 122 patients were included. Median age at start of everolimus was 62 (19-86) years, 62% (76/122) were male, and half were from pancreatic origin (62, 51%). Twenty-eight patients (23%) developed EiP: 82% grade (G)1 or G2, 14% G3 and 4% G4. The median time to EiP was 3.6 (0.8-51) months. Primary tumor site, concurrent lung disease, smoking history, and prior therapies were not associated with the onset of EiP. Patients who developed EiP had longer time on everolimus treatment (median 18 months vs 6 months; P = .0018) and OS (77 months vs 52 months; P = .093). Everolimus-induced pneumonitis was a predictor of improved OS by multivariable analysis (HR 0.39, 95% CI 0.19-0.82; P = .013). CONCLUSION: Everolimus-induced pneumonitis in the real-world clinical setting is present in one quarter of patients with NENs receiving everolimus and often occurs early. While risk factors for EiP were not identified, patients with EiP had improved survival.
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Tumores Neuroendocrinos , Neumonía , Everolimus/efectos adversos , Femenino , Humanos , Masculino , Tumores Neuroendocrinos/patología , Neumonía/inducido químicamente , Neumonía/epidemiología , Estudios Retrospectivos , Factores de RiesgoRESUMEN
BACKGROUND: Children and adolescents undergoing kidney transplantation may present oral conditions after the procedure, but a few studies have recently described them. AIM: To describe the oral conditions of post-renal transplant children and adolescents. DESIGN: Two calibrated dentists examined all the participants by assessing caries experience, enamel defects, periodontal condition and soft tissue lesions. RESULTS: A total of 120 participants were included in the study, in which 63 (52.5%) were male and 57 (47.5%) were female, with a mean age of 12.78 ± 3.9 years. Among the participants, 104 (86.7%) showed at least one oral change directly related to kidney disease. The most frequent oral findings were enamel defect (49/120; 40.8%) and drug-induced gingival overgrowth (DIGO) (20/120; 16.7%). Gingival bleeding was observed on probing in 115 (95.8%) participants, whereas 69 (57.5%) presented dental calculus and 51 (42.5%) had caries experience. CONCLUSION: Gingival bleeding, enamel defects and DIGO were the most frequent oral findings in kidney transplant children and adolescents. The use of amlodipine and anticonvulsants was associated with DIGO, and there was a positive correlation between oral ulcers and use of everolimus.
Asunto(s)
Caries Dental , Sobrecrecimiento Gingival , Trasplante de Riñón , Enfermedades Dentales , Adolescente , Amlodipino/efectos adversos , Anticonvulsivantes/efectos adversos , Niño , Everolimus/efectos adversos , Femenino , Sobrecrecimiento Gingival/inducido químicamente , Sobrecrecimiento Gingival/patología , Humanos , Trasplante de Riñón/efectos adversos , Masculino , Salud BucalRESUMEN
We report a case of disseminated histoplasmosis and COVID-19 infection in a renal transplant recipient in Argentina. The patient exhibited respiratory symptoms, and a chest computed tomography scan (CT) showed multiple bilateral centrilobular opacities with a tree-in-bud pattern in both lobes. The patient was initially treated as having bacterial community-acquired pneumonia, and then tuberculosis. A month later, histoplasmosis was diagnosed, and Histoplasma capsulatum LAmB clade was isolated from sputum, skin and oral lesions. The patient was hospitalized and treatment was started with intravenous liposomal amphotericin B. During the course of the antifungal therapy the respiratory symptoms worsened, a new chest CT showed a unilateral lesion with a ground glass appearance and SARS-CoV-2 was detected in a new nasopharyngeal sample. In addition, plasma therapy was administered, and the immunosuppressive regimen was adjusted (everolimus was interrupted, mycophenolate mofetil reduced, and meprednisone increased). Finally, the patient's progress was favorable and was discharged after five days on oral itraconazole treatment for histoplasmosis.
Asunto(s)
COVID-19 , Histoplasmosis , Trasplante de Riñón , Anfotericina B/uso terapéutico , Antifúngicos/uso terapéutico , COVID-19/complicaciones , Everolimus , Histoplasma , Histoplasmosis/complicaciones , Histoplasmosis/tratamiento farmacológico , Itraconazol/uso terapéutico , Trasplante de Riñón/efectos adversos , Ácido Micofenólico , SARS-CoV-2RESUMEN
As the risk of graft loss due to acute rejection has declined, the goal of post-transplant management has switched to long-term preservation of organ function. Minimizing calcineurin inhibitor (CNI)-related nephrotoxicity is a key component of this objective. Everolimus is a mammalian target of rapamycin inhibitor/proliferation-signal inhibitor with potent immunosuppressive and anti-proliferative effects. It has been widely investigated in large randomized clinical studies that have shown it to have similar anti-rejection efficacy compared with standard-of-care regimens across organ transplant indications. With demonstrated potential to facilitate the reduction of CNI therapy and preserve renal function, everolimus is an alternative to the current standard-of-care CNI-based regimens used in de novo and maintenance solid organ transplantation recipients. Here, we provide an overview of the evidence from the everolimus clinical study program across kidney, liver, heart, and lung transplants, as well as other key data associated with its use in CNI reduction strategies in adult transplant recipients.
Asunto(s)
Everolimus , Trasplante de Órganos , Adulto , Everolimus/efectos adversos , Rechazo de Injerto/prevención & control , Humanos , Inmunosupresores/efectos adversos , Receptores de TrasplantesRESUMEN
BACKGROUND: The short-term efficacy and safety of everolimus in combination with tacrolimus have been described in several clinical trials. Yet, detailed long-term data comparing the use of everolimus or mycophenolate in kidney transplant recipients receiving tacrolimus are lacking. METHODS: This is a 5-y follow-up post hoc analysis of a prospective trial including 288 patients who were randomized to receive a single 3-mg/kg dose of rabbit antithymocyte globulin, tacrolimus, everolimus (EVR), and prednisone (rabbit antithymocyte globulin/EVR, n = 85); basiliximab, tacrolimus, everolimus, and prednisone (basiliximab/EVR, n = 102); or basiliximab, tacrolimus, mycophenolate, and prednisone (basiliximab/mycophenolate, n = 101). RESULTS: There were no differences in the incidence of treatment failure (31.8% versus 40.2% versus 34.7%, P = 0.468), de novo donor-specific HLA antibodies (6.5% versus 11.7% versus 4.0%, P = 0.185), patient (92.9% versus 94.1% versus 92.1%, P = 0.854), and death-censored graft (87.1% versus 90.2% versus 85.1%, P = 0.498) survivals. Using a sensitive analysis, the trajectories of estimated glomerular filtration rate were comparable in the intention-to-treat (P = 0.145) and per protocol (P = 0.354) populations. There were no differences in study drug discontinuation rate (22.4% versus 30.4% versus 17.8%, P = 0.103). CONCLUSIONS: In summary, this analysis in a cohort of de novo low/moderate immunologic risk kidney transplant recipients suggests that the use of a single 3 mg/kg rabbit antithymocyte globulin dose followed by EVR combined with reduced tacrolimus concentrations was associated with similar efficacy and renal function compared with the standard of care immunosuppressive regimen.
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Trasplante de Riñón , Tacrolimus , Quimioterapia Combinada , Everolimus/efectos adversos , Rechazo de Injerto , Supervivencia de Injerto , Humanos , Inmunosupresores/efectos adversos , Trasplante de Riñón/efectos adversos , Ácido Micofenólico/efectos adversos , Estudios Prospectivos , Tacrolimus/efectos adversosRESUMEN
The third generation of antiepileptic drugs that have been approved by international regulatory agencies between 2007 and 2018 include rufinamide, stiripentol, eslicarbazepine acetate, lacosamide, perampanel, brivaracetam and everolimus. As part of demonstrating their safety profile, stability indicating methods are developed to monitor these drugs and their impurities. In this context, this review describe some characteristics, impurities and the stability indicating methods used for the determination of these drugs and the presence of their related substances. Through a search in official compendia and scientific articles, fifty-six analytical methodologies were identified up to October 2020. The methodologies were developed using techniques of HPLC, UPLC, HPTLC, GC and UV/Vis spectrophotometry. A majority of the methods (â¼70%) employed HPLC-UV. A number of these antiepileptic drugs were found to have had a small number of studies related to their stability and for the detection of impurities. The presentation of the current level of research on third generation antiepileptic drugs highlights the need for new stability and safety studies that are necessary to develop new pharmaceutical products containing these drugs.
Asunto(s)
Anticonvulsivantes , Everolimus , Cromatografía Líquida de Alta Presión , Lacosamida , Preparaciones FarmacéuticasAsunto(s)
Humanos , Femenino , Adulto , Trasplante de Órganos/efectos adversos , Rechazo de Injerto/tratamiento farmacológico , Inmunosupresores/análisis , Inmunosupresores/farmacología , Azatioprina/uso terapéutico , Tacrolimus/antagonistas & inhibidores , Ciclosporina/antagonistas & inhibidores , Corticoesteroides/administración & dosificación , Sirolimus/antagonistas & inhibidores , Inhibidores de la Calcineurina/uso terapéutico , Everolimus/antagonistas & inhibidores , Ácido Micofenólico/uso terapéuticoRESUMEN
INTRODUCTION: The association between cardiac rhabdomyoma and intraventricular tumors and/or subcortical nodules is characteristic of tuberous sclerosis complex (TSC). Patients with TSC may have refractory seizures, autistic behavior, and cognitive decline. CASE REPORT: The patient received the fetal diagnosis of TSC at the age of 19 weeks of gestations, where presented at prenatal ultrasound cardiac and brain tumors. Fetal MRI showed a lesion in the right and left lateral ventricles near the foramen of Monro associated with subependymal lesions along the entire ependyma of the lateral ventricles and several subcortical tubercles, and the fetal Doppler echocardiogram revealed three cardiac lesions. The fetus underwent intrauterine treatment with everolimus and presented regression and subsequent stabilization of the cardiac and brain lesions; additionally, the patient did not develop seizures or autism and presented good neuropsychomotor development. CONCLUSION: It is the first evidence that mTOR inhibitors may help to prevent neurological complications associated with TSC.
Asunto(s)
Neoplasias Cardíacas , Rabdomioma , Esclerosis Tuberosa , Everolimus/uso terapéutico , Femenino , Neoplasias Cardíacas/tratamiento farmacológico , Humanos , Lactante , Inhibidores mTOR , Embarazo , Rabdomioma/complicaciones , Rabdomioma/diagnóstico por imagen , Rabdomioma/tratamiento farmacológico , Esclerosis Tuberosa/complicaciones , Esclerosis Tuberosa/diagnóstico por imagen , Esclerosis Tuberosa/tratamiento farmacológicoRESUMEN
Tacrolimus (TAC), a calcineurin inhibitor, and everolimus (EVL), an mTOR inhibitor, have been used as immunosuppressive (ISS) drugs in post-kidney transplantation therapy. The objective of this study was to compare the efficacy of EVL vs TAC in the ISS maintenance triple therapy. Ninety-seven kidney transplant patients, who received triple maintenance therapy with TAC, mycophenolate mofetil (MMF), and methyl prednisone (PRED), were evaluated. After four months of post-kidney transplant therapy, 30 patients enrolled in a randomized controlled clinical trial, in which 16 patients received TAC+MMF+PRED (cohort 1), and 14 patients switched to EVL+MMF+PRED (cohort 2). The patients were followed-up for 36 months. Two patients from cohort 1 lost their grafts after one year due to non-adherence. Two patients from cohort 2 had intolerance to mTOR inhibitors and were switched back to TAC from EVL. One case (6.25%) in cohort 1 and three cases (21.43%) in cohort 2 of acute T-cell-mediated rejection was observed. Antibody-mediated acute rejection (ABMAR) was observed in four patients (25.0%) in cohort 1, and antibody-mediated chronic rejection (ABMCR) was observed in two patients (12.50%). One patient from cohort 2 lost the graft after 15 months due to polyomavirus infection. The graft survival rate was 87.50% in cohort 1 and 92.86% in cohort 2. This clinical trial showed that the EVL+MMF+PRED triple maintenance therapy was efficacious compared with TAC during 32 months of follow-up. However, further studies are needed to confirm the efficacy of this regimen for long-term graft survival.