Descripción de polimorfismos genéticos en CYP3A5 y MDR-1 y su impacto en el rechazo agudo clínico de pacientes trasplantados de hígado del Hospital San Vicente Fundación Rionegro / Description of genetic polymorphisms in CYP3A5 and MDR-1 and their impact on clinical acute rejection in liver transplant patients at Hospital San Vicente Fundación Rionegro

Introducción. El tacrolimus es un medicamento inmunosupresor ampliamente usado en trasplante hepático, que presenta una gran variabilidad interindividual la cual se considera asociada a la frecuencia de polimorfismos de CYP3A5 y MDR-1. El objetivo de este estudio fue evaluar la frecuencia de los polimorfismos rs776746, rs2032582 y rs1045642 y su asociación con rechazo clínico y toxicidad farmacológica. Métodos. Se incluyeron pacientes inmunosuprimidos con tacrolimus a quienes se les realizó trasplante hepático en el Hospital San Vicente Fundación Rionegro entre 2020 y 2022, con supervivencia mayor a un mes. Se evaluaron las variables clínicas, rechazo agudo y toxicidad farmacológica. Se secuenciaron los genes de estudio mediante PCR, comparando la expresión o no en cada uno de los pacientes. Resultados. Se identificaron 17 pacientes. El 43 % de los pacientes se clasificaron como CYP3A5*1/*1 y CYP3A5*1/*3, entre los cuales se encontró asociación con aumento en la tasa de rechazo agudo clínico, al comparar con los pacientes no expresivos (100 % vs. 44 %, p=0,05); no hubo diferencias en cuanto a la toxicidad farmacológica u otros desenlaces. Se encontró el polimorfismo rs2032582 en un 50 % y el rs1045642 en un 23,5 % de los pacientes, sin embargo, no se identificó asociación con rechazo u otros eventos clínicos. Conclusiones. Se encontró una asociación entre el genotipo CYP3A5*1/*1 y CYP3A5*1/*3 y la tasa de rechazo clínico. Sin embargo, se requiere una muestra más amplia para validar estos datos y plantear modelos de medicina personalizada.

Introduction. Tacrolimus is an immunosuppressive drug widely used in liver transplantation, which presents great interindividual variability which is considered associated with the frequency of CYP3A5 and MDR-1 polymorphisms. The objective of this study was to evaluate the frequency of the rs776746, rs2032582 and rs1045642 polymorphisms and their association with clinical rejection and drug toxicity. Methods. Immunosuppressed patients with tacrolimus who underwent a liver transplant at the Hospital San Vicente Fundación Rionegro between 2020 and 2022 were included, with survival of more than one month. Clinical variables, acute rejection and pharmacological toxicity were evaluated. The study genes were sequenced by PCR, comparing their expression or not in each of the patients. Results. Seventeen patients were identified. 43% of the patients were classified as CYP3A5*1/*1 and CYP3A5*1/*3, among which an association was found with increased rates of clinical acute rejection when compared with non-expressive patients (100% vs. 44%, p=0.05). There were no differences in drug toxicity or other outcomes. The rs2032582 polymorphism was found in 50% and rs1045642 in 23.5% of patients; however, no association with rejection or other clinical events was identified. Conclusions. An association was found between the CYP3A5*1/*1 and CYP3A5*1/*3 genotype and the clinical rejection rate. However, a larger sample is required to validate these data and propose models of personalized medicine.

Pharmacogenetic testing improves treatment responses in patients with PLA2R-related membranous nephropathy / 南方医科大学学报

OBJECTIVE@#To evaluate the value of pharmacogenetic testing for improving the efficacy and safety of treatment with cyclosporine, tacrolimus, and cyclophosphamide (CTX) for PLA2R-related membranous nephropathy and for determing individualized and precise treatment plans for the patients.@*METHODS@#A total of 63 patients with PLA2R-related membranous nephropathy hospitalized in the Department of Nephrology at our hospital from January, 2019 to October, 2021 were enrolled in this study. Thirty-three of the patients underwent pharmacogenetic testing before taking the immunosuppressive drugs selected based on the results of genetic screening for sensitive targets, and the other 30 patients were empirically given immunosuppressive drugs according to the guidelines (control group). The clinical efficacy and adverse effects of the immunosuppressive drugs were analyzed for all the patients. The two groups of patients were compared for demographic and biochemical parameters including 24-h urine protein, serum albumin, renal function, and serum anti-phospholipase A2 receptor antibody both before and at 3 months after the beginning of the treatment.@*RESULTS@#Among the 33 patients undergoing pharmacogenetic testing, 51.5% showed a GG genotype for cyclosporine, and 61.6% had an AG genotype for tacrolimus; for CTX, 51.5% of the patients showed a homozygous deletion and 63.6% had an AA genotype. After treatment for 3 months, serum anti-phospholipase A2 receptor antibody, 24-h urine protein, and serum albumin levels were significantly improved in pharmacogenetic testing group as compared with the control group (P < 0.05).@*CONCLUSION@#Individualized and precise administration of immunosuppressive drugs based on pharmacogenetic testing better controls proteinuria and serum antiphospholipase A2 receptor antibodies and increases serum albumin level in patients with PLA2R-related membranous nephropathy.

Fibroblast growth factor 21 (FGF21) attenuates tacrolimus-induced hepatic lipid accumulation through transcription factor EB (TFEB)-regulated lipophagy / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Tacrolimus (TAC), also called FK506, is one of the classical immunosuppressants to prevent allograft rejection after liver transplantation. However, it has been proved to be associated with post-transplant hyperlipemia. The mechanism behind this is unknown, and it is urgent to explore preventive strategies for hyperlipemia after transplantation. Therefore, we established a hyperlipemia mouse model to investigate the mechanism, by injecting TAC intraperitoneally for eight weeks. After TAC treatment, the mice developed hyperlipemia (manifested as elevated triglyceride (TG) and low-density lipoprotein cholesterol (LDL-c), as well as decreased high-density lipoprotein cholesterol (HDL-c)). Accumulation of lipid droplets was observed in the liver. In addition to lipid accumulation, TAC induced inhibition of the autophagy-lysosome pathway (microtubule-associated protein 1 light chain 3β (LC3B) II/I and LC3B II/actin ratios, transcription factor EB (TFEB), protein 62 (P62), and lysosomal-associated membrane protein 1 (LAMP1)) and downregulation of fibroblast growth factor 21 (FGF21) in vivo. Overexpression of FGF21 may reverse TAC-induced TG accumulation. In this mouse model, the recombinant FGF21 protein ameliorated hepatic lipid accumulation and hyperlipemia through repair of the autophagy-lysosome pathway. We conclude that TAC downregulates FGF21 and thus exacerbates lipid accumulation by impairing the autophagy-lysosome pathway. Recombinant FGF21 protein treatment could therefore reverse TAC-caused lipid accumulation and hypertriglyceridemia by enhancing autophagy.

Plasma cell cheilitis in an elderly female: A case report

Introduction@#Plasma cell cheilitis (PCC) is a rare, chronic inflammatory dermatitis of unknown etiology. Due to the limited number of cases reported, no guidelines have been established for its treatment. We present a case of PCC clinically similar to actinic cheilitis or mucosal lichen planus, and squamous cell carcinoma but showed response to topical tacrolimus 0.1% ointment. @*Case Report@#A 62-year-old female with extreme fondness to piping hot food presented with a solitary painful ulceration with some pustules and bleeding on the lower lip with three (3) months duration. Skin punch biopsy revealed a dense band-like infiltrate of plasma cells which is consistent with Plasma cell cheilitis. The patient was given tacrolimus 0.1% ointment and showed significant improvement after a month of treatment.@*Conclusion@#PCC is a rare condition that should still be considered in patients presenting with persistent cheilitis. Clinical and histological correlation is advised for proper management and prognostication.

Prediction of the Impact of CYP2C19 Polymorphism on Drug-Drug Interaction between Voriconazole and Tacrolimus Using Physiologically-Based Pharmacokinetic Modelling

Abstract Voriconazole increases tacrolimus blood concentration significantly when coadministrated. The recommendation of reducing tacrolimus to 1/3 in voriconazole package insert seems not to be satisfactory in clinical practice. In vitro studies demonstrated that the magnitude of inhibition depends on the concentration of voriconazole, while voriconazole exposure is determined by the genotype status of CYP2C19. CYP2C19 gene polymorphism challenges the management of drug-drug interactions(DDIs) between voriconazole and tacrolimus. This work aimed to predict the impact of CYP2C19 polymorphism on the DDIs by using physiologically based pharmacokinetics (PBPK) models. The precision of the developed voriconazole and tacrolimus models was reasonable by evaluating the pharmacokinetic parameters fold error, such as AUC0-24, Cmax and tmax. Voriconazole increased tacrolimus concentration immediately in all population. The simulated duration of DDIs disappearance after voriconazole withdrawal were 146h, 90h and 66h in poor metabolizers (PMs), intermediate metabolizers (IMs) and extensive metabolizers(EMs), respectively. The developed and optimized PBPK models in this study can be applied to assit the dose adjustment for tacrolimus with and without voriconazole.

Development, physicochemical evaluation, and in vivo permeation studies of topical formulations containing 0.1% tacrolimus

Abstract The objective of this paper was to develop and evaluate two semi-solid pharmaceutical forms containing 0.1% tacrolimus: cream (CRT01) and gel (GLT01). For the evaluation of physicochemical stability, at times 0, 30, 60 and 90 days, at 23°C and at 40°C, High Performance Liquid Chromatography coupled with a Diode Array Detector (HPLC-DAD) was employed. This method was developed and validated for tacrolimus quantification. The occlusivity test and skin permeation assay were also performed, using an animal model (Wistar rats), and the CRT01 and GLT01 were compared to the 0.1% tacrolimus ointment (PFU01) obtained from the University Pharmacy, Federal University of Rio de Janeiro, Brazil. CRT01 and GLT01 presented a homogeneous aspect and consistency adequate for topical products, along with sensory characteristics above PFU01. They also presented adequate physicochemical stability for 90 days and a lower occlusive effect than PFU01 (p<0.05). CRT01 showed greater affinity for the skin when compared to PFU01 and GLT01, with low systemic absorption. The CRT01 semi-solid formulation was considered the most adequate one to treat patients with atopic dermatitis or other dermatologic inflammatory diseases, promoting rational use of tacrolimus

Fenómeno infrecuente la co-localización de alopecia frontal fibrosante y vitiligo en un varón: informe de un caso / Infrequent phenomenon the co-localization of fibrosing frontal alopecia and vitiligo in a male: case repor

La alopecia frontal fibrosante es una alopecia cicatricial que se caracteriza por la recesión de la línea de implantación frontotemporal que afecta principalmente a mujeres caucásicas en edad posmenopáusica y rara vez a hombres. Actualmente los mecanismos específicos de desarrollo continúan en estudio; sin embargo hay varias hipótesis sobre la asociación de la alopecia frontal fibrosante con otros trastornos autoinmunitarios. Se comunica el caso de un paciente masculino de 58 años con alopecia frontal fibrosante en áreas comprometidas por vitiligo. (AU)

Frontal fibrosing alopecia is a cicatricial alopecic characterized by progressive regression of the frontotemporal hairline. It usually affects postmenopausal caucasian women, and rarely men. Currently the specific mechanisms of development remain unknown, however there are several hypotheses about the association of frontal fibrosing alopecia with other autoimmune disorders. The case of a 58-year-old male patient with frontal fibrosing alopecia in areas affected by vitiligo. (AU)

Effect of Tacrolimus and Cyclosporine Immunosuppressants on Peripheral Nerve Regeneration: Systematic Review and Meta-analysis / Efeito dos imunossupressores tacrolimus e ciclosporina na regeneração de nervos periféricos: Revisão sistemática e metanálises

Abstract Peripheral nerve damage is an important cause of seeking medical attention. It occurs when the continuity of structures is interrupted and the propagation of nervous impulses is blocked, affecting the functional capacity of individuals. To assess the effects of the immunosuppressants tacrolimus and cyclosporine on the regeneration of peripheral nerves, a systematic review of the literature was carried out. The articles included were published until September 2018 and proposed to evaluate the effects of the immunosuppressants tacrolimus and cyclosporine on nerve regeneration and neuroprotection, available in the MEDLINE, EMBASE, Cochrane Library, Web of Science, Oxford Pain Relief Database, and LILACS databases. The research analysed a total of 56 articles, of which 22 were included in the meta-analysis. Statistical analysis suggests the protective effect of tacrolimus in the regeneration of the number of myelinated axons (95% confidence interval [CI]: 0.93-2.39; p< 0.01); however, such effect was not observed in relation to cyclosporine (95%CI: - 0.38-1.18; p» 0.08) It also suggests that there is a significant relationship between the use of tacrolimus and myelin thickness (95%CI» 2.00-5.71; p< 0. 01). The use of immunosuppressants in the regeneration of peripheral nerve damage promotes an increase in the number of myelinated axons in general, regardless of the administered dose. In addition, it ensures greater myelin thickness, muscle weight and recovery of the sciatic functional index. However, heterogeneity was high in most analyses performed.

Resumo As lesões nervosas periféricas são uma causa importante de busca por atendimento médico. Elas ocorrem quando há a interrupção da continuidade das estruturas e do bloqueio da propagação dos impulsos nervosos, afetando a capacidade funcional dos indivíduos. Para avaliar os efeitos dos imunossupressores tacrolimus e ciclosporina na regeneração de nervos periféricos, foi realizada uma revisão sistemática da literatura. Foram incluídos artigos publicados até setembro de 2018, que se propunham avaliar os efeitos dos imunossupressores tacrolimus e ciclosporina na regeneração nervosa e neuroproteção, disponíveis nas bases de dados MEDLINE, EMBASE, Cochrane Library, Web of Science, Oxford Pain Relief Database e LILACS. A pesquisa analisou um total de 56 artigos, dos quais 22 foram para metanálise. A análise estatística sugere o efeito protetor do tacrolimus na regeneração do número de axônios mielinizados (intervalo de confiança [IC] 95%: 0,93-2,39; p< 0,01); todavia tal efeito não foi observado em relação à ciclosporina (IC95%: - 0,38-1,18; p» 0,08). Ela também sugere haver uma relação significativa entre o uso do tacrolimus e a espessura da mielina (IC95%: 2,00-5,71; p< 0,01). O uso de imunossupressores na regeneração de lesão nervosa periférica promove um aumento no número de axônios mielinizados de forma geral, independentemente da dose administrada. Além disso, garante uma maior espessura da mielina, um maior peso muscular e restabelecimento do índice da função do nervo ciático. Todavia, a heterogeneidade foi alta na maioria das análises realizadas.

Lesiones ampollares en una paciente con morfea panesclerótica discapacitante de la infancia / Bullous lesions in a patient with panesclerotic morphea of the childhood

La morfea ampollar es un tipo enfrecente de esclerodermia localizada que se caracteriza por presentar ampollas sobre placas escleróticas. La presencia de este tipo de lesiones obliga a descartar la variante extraenital de liquen esclerodemias localizadas, es posible hallar ambas afecciones. Se describe el caso de una paciente de 19 años con diagnóstico de morfea panesclerótica y liquen escleroso ampollar.

Bollous morphea is an infreqent type of morphea characterized for developing bullae on sclerodermiformic plaques. The presence of bullae forces to discard lichen sclerosus, a disease that usually develops in the genital zone, the extragenital variant could belong to the same spectrum that localized sclerodermiformic diseases. We present a 19 year old female patient with the diagnosis of panesclerotic morphea and bullous lichen sclerosus.

Transplante hepático: variação dos níveis sanguíneos de tacrolimo e desfechos de sobrevida, rejeição e óbito / Liver transplantation: tacrolimus blood levels variation and survival, rejection and death outcomes

ABSTRACT BACKGROUND: Immunosuppressive drugs have important role in transplant of solid grafts, it aim avoid episodes of acute and chronic rejection and improving graft survival and patient survival. In Brazil, in 2016, liver transplantation was the third most frequent, with 1,880 transplants performed, of which 150 in Rio Grande do Sul. Several studies evaluated the association between variability in blood levels of immunosuppressive tacrolimus and late acute cellular graft rejection. OBJECTIVE: To investigate the association of tacrolimus blood levels with clinical outcomes late acute cellular rejection, death, patient survival and graft survival in patients undergoing liver transplantation. METHODS: This is a retrospective longitudinal study including patients submitted to adult liver transplantation by the Liver Transplantation Group in the Santa Casa de Misericórdia Hospital of Porto Alegre, from January 2006 to January 2013, and who used tacrolimus as immunosuppressive therapy. RESULTS: Of the 127 patients included in the study, the majority were male (70.1%), 52-60 years old (33.9%) at the transplant. The most frequent causes of liver transplantation in this series were hepatitis C virus and hepatocellular carcinoma (24.4%) and alcohol (15.7%). Thirteen patients had late acute cellular rejection (10.2%); of these, three had two episodes. Regarding severity classification, seven patients had mild late acute cellular rejection. The mean time of rejection after liver transplantation was 14 months (ranging from 8 to 33 months). Overall survival was 8.98 years. Regarding tacrolimus blood levels, 52 patients with a variation ≥2 standard deviations were identified. Of these patients, eight had rejection; however, the association was not significant (P=0.146). A significant association was found between variation ≥2 standard deviations in tacrolimus blood levels and death (P=0.023) and survival (P=0.019). Regarding 5-year follow-up of graft survival, being two standard deviations above increases by 2.26 times the risk of transplanted graft loss, and for each unit of increase of standard deviation of tacrolimus blood levels there is a two-fold increase in the risk of graft loss in 5 years. CONCLUSION: Increased risk of graft loss associated with increased standard deviations of tacrolimus blood levels may indicate the need for more rigorous and prospective monitoring of tacrolimus blood levels.

RESUMO CONTEXTO: Os imunossupressores desempenham importante papel no transplante de órgãos sólidos, com o objetivo de evitar a rejeição aguda e crônica, aumentando o tempo de sobrevida do órgão e do paciente. No Brasil, em 2016, o transplante de fígado foi o 3° mais frequente, com um número de 1.880 transplantes, sendo 150 realizados no Rio Grande do Sul. OBJETIVO: Investigar a associação da variação dos níveis sanguíneos de tacrolimo com os desfechos clínicos, rejeição celular aguda tardia, óbito, sobrevida de paciente e enxerto em pacientes submetidos ao transplante hepático. MÉTODOS: Trata-se de um estudo longitudinal retrospectivo, no qual foram incluídos os pacientes submetidos ao transplante hepático adulto pelo grupo de transplante hepático na Irmandade Santa Casa de Misericórdia de Porto Alegre, no período de janeiro de 2006 a janeiro de 2013, e que fizeram o uso de tacrolimo como terapia imunossupressora. RESULTADOS: Dos 127 pacientes incluídos no estudo, a maioria era do gênero masculino (70,1%), caucasiana (86,4%), com idade entre 52 e 60 anos (33,9%). As associações de causas mais frequentes para transplante hepático foram vírus da hepatite C, carcinoma hepatocelular (24,4%) e álcool (15,7%). Um total de treze pacientes apresentaram rejeição celular aguda tardia (10,2%); destes, três tiveram dois episódios. O tempo médio de rejeição após o transplante hepático foi de 14 meses, variando de 8 a 33 meses. A sobrevida global foi de 8,98 anos. Em relação aos níveis sanguíneos de tacrolimo, foram identificados 52 pacientes com uma variação maior ou igual a dois desvios-padrão. Destes pacientes, oito tiveram rejeição, contudo, a associação não foi significativa (P=0,146). Foi encontrada uma associação significativa entre a variação maior ou igual a dois desvios-padrão nos níveis sanguíneos de tacrolimo com óbito (P=0,023) e sobrevida (P=0,019). Em relação ao acompanhamento de sobrevida do enxerto em cinco anos, estar dois desvios-padrão acima aumenta em 2,26 vezes o risco de perda do enxerto transplantado, e a cada unidade de aumento de desvio-padrão dos níveis sanguíneos de tacrolimo há um aumento de duas vezes no risco de perda do enxerto transplantado em 5 anos. CONCLUSÃO: O aumento do risco da perda do enxerto associado ao aumento da variação dos níveis sanguíneos de tacrolimo pode indicar a necessidade do acompanhamento mais rigoroso e prospectivo dos níveis sanguíneos de tacrolimo.

Tacrolimus action pathways in an ointment base for hypertrophic scar prevention in a rabbit ear model

Abstract Background: Tacrolimus is used to prevent unaesthetic scars due to its action on fibroblast activity and collagen production modulation. Objectives: To evaluate the action pathways, from the histopathological point of view and in cytokine control, of tacrolimus ointment in the prevention of hypertrophic scars. Methods: Twenty-two rabbits were submitted to the excision of two 1-cm fragments in each ear, including the perichondrium. The right ear received 0.1% and 0.03% tacrolimus in ointment base twice a day in the upper wound and in the lower wound respectively. The left ear, used as the control, was treated with petrolatum. After 30 days, collagen fibers were evaluated using special staining, and immunohistochemistry analyses for smooth muscle actin, TGF-β and VEGF were performed. Results: The wounds treated with 0.1% tacrolimus showed weak labeling and a lower percentage of labeling for smooth muscle actin, a higher proportion of mucin absence, weak staining, fine and organized fibers for Gomori's Trichrome, strong staining and organized fibers for Verhoeff when compared to controls. The wounds treated with 0.03% tacrolimus showed weak labeling for smooth muscle actin, a higher proportion of mucin absence, strong staining for Verhoeff when compared to the controls. There was absence of TGF-β and low VEGF expression. Study limitations: The analysis was performed by a single pathologist. Second-harmonic imaging microscopy was performed in 2 sample areas of the scar. Conclusions: Both drug concentrations were effective in suppressing TGF-β and smooth muscle actin, reducing mucin, improving the quality of collagen fibers, and the density of elastic fibers, but only the higher concentration influenced elastic fiber organization.

Prevalência e tempo de desenvolvimento da hipertensão arterial sistêmica em pacientes após transplante de fígado / Prevalence and time of development of systemic arterial hypertension in patients after liver transplantation

ABSTRACT BACKGROUND: The use of immunosuppressive drugs after liver transplantation (LT) is associated with the development of systemic arterial hypertension (SAH), in addition to other comorbidities of metabolic syndrome. OBJECTIVE: Therefore, the purpose of this study was to analyze the time after use immunosuppressive drugs the patient progresses to SAH, as well as to identify its prevalence and the factors that may be correlated to it. METHODS: A retrospective and longitudinal study was conducted, based on the analysis of medical records of 72 normotensive patients, attended in the transplant unit of a university hospital, between 2016 and 2019. RESULTS: It was observed, on average, 9±6.98 months after immunosuppressive use, the patients were diagnosed with hypertension, and the prevalence of transplanted patients who evolved to SAH in this study was 59.64% (41 patients). In addition, there was a correlation between serum dosage of tacrolimus and the development of SAH (P=0.0067), which shows that tacrolimus has a significant role in the development of SAH. Finally, it was noticed that the development of post-transplantation hypertension indicates a higher risk of the patient presenting the other parameters of metabolic syndrome, as well as a higher impairment in its renal function (P=0.0061). CONCLUSION: This study shows that the patients evolved to SAH in an average of 9±6.98 months after immunosuppressive drug use. We have also found high prevalence of systemic arterial hypertension (59.64%) in patients after liver transplantation, who used calcineurin inhibitors, especially when associated with the use of tacrolimus.

RESUMO CONTEXTO: O uso de imunossupressores pós-transplante de fígado (TF) está associado ao desenvolvimento de hipertensão arterial sistêmica (HAS), além de outras alterações da síndrome metabólica. OBJETIVO: Sendo assim, o objetivo deste estudo foi analisar a partir de quando tempo após o uso do imunossupressor o paciente evolui para HAS, assim como, identificar a sua prevalência e outros fatores que podem estar relacionados, como injuria renal. MÉTODOS: Realizou-se um estudo retrospectivo, longitudinal, baseado em análise de 72 prontuários de pacientes, atendidos na unidade de transplante de um hospital universitário, que não apresentavam hipertensão arterial prévia, entre período de 2016 a 2019. RESULTADOS: Observou-se que, em média, 9±6,98 meses após uso do imunossupressor, os pacientes foram diagnosticados com hipertensão arterial sistêmica, sendo que a prevalência de pacientes transplantados que evoluíram para HAS, neste estudo, foi de 59,64% (41 pacientes). Além disso, verificou-se uma correlação entre a dosagem sérica de tacrolimus e o desenvolvimento de HAS (P=0,0067), o que evidencia que o tacrolimus tem uma atuação significativa no desenvolvimento da hipertensão arterial sistêmica. Por fim, percebeu-se que o desenvolvimento de HAS pós-transplante indica um maior risco de paciente apresentar os outros parâmetros da síndrome metabólica, como também maior prejuízo na sua função renal (P=0,0061). CONCLUSÃO: Este estudo mostra que os pacientes evoluíram para HAS em média 9±6,98 meses após o início do uso do imunossupressor. Verificou-se também alta prevalência de hipertensão arterial sistêmica (59,64%) em pacientes pós-transplante de fígado, que usavam inibidores de calcineurina, principalmente, quando associado ao uso de tacrolimus.

Influencia del polimorfismo de CYP3A4 y CYP3A5 en la farmacocinética de tacrolimus en receptores de trasplante renal. Revisión narrativa / Influence of CYP3A4 and CYP3A5 polymorphism of the pharmacokinetics of tacrolimus in renal transplant recipients. Narrative review

El uso de inhibidores de calcineurina, en particular de tacrolimus como terapia inmunosupresora se ha generalizado a nivel mundial, permitiendo mejorar la tasa de sobrevida del injerto y la calidad de vida del paciente trasplantado. Con el acceso a los estudios de farmacogenética, los grupos de trasplante a nivel mundial se han visto motivados a realizar estudios genéticos que permitan interpretar la influencia de polimorfismos de genes como mTOR, PPP3CA, FK BP1A, FKBP2, y FOXP3, sin embargo, los más estudiados en la población trasplantada para optimizar la dosis de tacrolimus y ciclosporina son los polimorfismos del citocromo p450, CYP3A4 y CYP3A5.El objetivo de la presente revisión narrativa es examinar publicaciones recientes que estudien la relación entre el polimorfismo de CYP3A4/5 y el metabolismo de tacrolimus en pacientes trasplantados renales.Se revisó literatura reciente extraída de los sitios NCBI PubMed y PharmGKB.org en la que se hubiera investigado la influencia de los polimorfismos de CYP3A4/5 en el metabolismo de tacrolimus en trasplantados renales. Se identificó variaciones genéticas de CYP3A4/5 en pacientes trasplantados tratados con tacrolimus que permitirán a los médicos trasplantólogos dosificar de manera precisa el inmunosupresor. El uso de análisis farmacogenéticos permite determinar las variables genéticas del CYP3A4/5, y por lo tanto la toma de decisiones personalizadas en la dosis de inicio y de mantenimiento del inmunosupresor tacrolimus para alcanzar los niveles óptimos y con ello disminuir el riesgo de rechazo, de infecciones asociadas a inmunosupresión, y de toxicidad por el medicamento.

The use of the calcineurin inhibitor tacrolimus as immunosuppressive therapy, has become widespread world-wide, improving the graft's survival rate and the quality of life of the transplanted patient. With access to pharmacogenetic studies, transplant groups worldwide have been motivated to conduct genetic studies to inter-pret the influence of polymorphisms of genes such asmTOR, PPP3CA, FK BP1A, FKBP2, and FOXP3, however the most studied in the transplanted population to optimize the dose of tacrolimus and cyclosporine are those of cytochrome p450,CYP3A4 and CYP3A5. The objective of this narrative review is to examine recent publications studying the relationship betweenCYP3A4/5polymorphism, and tacrolimus metabolism in renal transplant patients. Literature extracted from the NCBI PubMed site and PharmGKB.org, from the past five years, which investigated the influence ofCYP3A4/5polymorphism on tacrolimus metabolism in renal transplants had been reviewed. Genetic variations ofCYP3A4/5 were identified in transplant patients treated with tacrolimus that will allow transplant physicians to dose the immunosuppressant accurately. The use of pharmacogenetic analyses makes it possible to determine the genetic polymorphisms ofCYP3A4/5, and therefore the decision-making cus-tomized at the starting and maintenance dose of the tacrolimus immunosuppressant to achieve optimal levels and thereby reduce the risk of rejection, immunosuppression-associated infections, and drug toxicity.

Treatment of oral chronic graft-versus-host disease: a retrospective cohort study / Tratamento da doença do enxerto contra hospedeiro crônica oral: um estudo de coorte retrospectivo

ABSTRACT Objective The aim of this study was to evaluate patients with complete response of oral chronic graft-versus-host disease to immunosuppressive treatment. Methods A total of 29 patients submitted to allogeneic hematopoietic stem cell transplantation, with oral chronic graft-versus-host disease, were enrolled in this retrospective study, from September 2012 to February 2018. Patients were treated with combined topical dexamethasone solution and topical tacrolimus ointment, combined topical dexamethasone and topical tacrolimus, systemic immunosuppressive medication, and topical dexamethasone only. Results The mean time of complete response of lichenoid lesions, erythema, and ulcers using dexamethasone and systemic immunosuppressive medication was of 105, 42 and 42 days, respectively (p=0.013).When we associated dexamethasone, tacrolimus and systemic immunosuppressive medication, the mean time of complete response of lichenoid lesions, erythema and ulcers was of 91,84 and 77 days (p=0.011). When dexamethasone was used alone, the mean time of complete response of lichenoid lesions, erythema and ulcers was 182, 140, 21 days, respectively (p=0.042). Conclusion Our study shows that lichenoid lesions require more time to heal. Notably, lichenoid lesions tend to respond better to dexamethasone combined with tacrolimus and systemic immunosuppressive medication, whereas erythema and ulcers respond better to dexamethasone combined with systemic immunosuppressive medication and dexamethasone only, respectively.

RESUMO Objetivo Avaliar os pacientes com resposta completa da doença do enxerto contra hospedeiro crônica oral ao tratamento com imunossupressor. Métodos Vinte e nove pacientes submetidos ao transplante alogênico de células tronco hematopoiéticas, com doença do enxerto contra hospedeiro crônica oral, foram incluídos neste estudo retrospectivo, de setembro de 2012 a fevereiro de 2018. Os pacientes foram tratados com dexametasona para bochecho associada ao tacrolimo pomada, dexametasona para bochecho associada ao tacrolimo tópico, tratamento imunossupressor sistêmico, e dexametasona tópica apenas. Resultados O tempo médio para resposta completa das lesões liquenoides, eritema e ulcerações usando dexametasona e imunossupressor sistêmico foi de 105, 42 e 42 dias, respectivamente (p=0,013). Quando a dexametasona estava associada ao tacrolimo e a medicação imunossupressora sistêmica, o tempo médio para resposta completa das lesões liquenóides, eritema e ulcerações foi de 91, 84 e 77 dias (p=0,011). Quando foi utilizada apenas dexametasona, o tempo médio para resposta completa das lesões liquenoides, eritema e ulcerações foi de 182, 140 e 21 dias, respectivamente (p=0,042). Conclusão Nosso estudo mostra que as lesões liquenoides requerem mais tempo para cicatrização completa. É notável que as lesões liquenoides tendem a responder melhor ao tratamento da dexametasona combinada com o tacrolimo e o imunossupressor sistêmico. Já o eritema e as ulcerações respondem melhor à dexametasona combinada com medicação imunossupressora sistêmica, e dexametasona apenas, respectivamente.

Lupus miliaris disseminatus faciei: when a rare skin disease involves the eyelid / Lupus miliaris disseminatus faciei: quando uma rara dermatose acomete a pálpebra

ABSTRACT The authors present a case of lupus miliaris disseminatus faciei , a rare skin disease of unknown etiology, which may cause unaesthetic scarring due to its difficult treatment. The histopathological examination of epithelioid granulomas with caseating necrosis, together with the clinical features, are important for diagnosis and early treatment with better results. Despite difficult and unsatisfactory treatment, there are ongoing studies on therapy to improve aesthetic and social impairment. This case report describes an initial misdiagnosis delaying appropriate treatment, and highlights the value of physical examination and clinical judgment for another pathological examination, whenever necessary, aiming at better treatment outcomes in daily practice.

RESUMO Os autores apresentam um caso de lupus miliaris disseminatus faciei , uma dermatose rara, de etiologia desconhecida, que pode deixar cicatrizes não estéticas, pela dificuldade de tratamento. O exame histopatológico de granulomas compostos por células epitelioides, com necrose caseosa, e as características clínicas, são importantes para o diagnóstico e tratamento precoce, com melhores resultados. Apesar do tratamento difícil e insatisfatório, há estudos em andamento sobre terapias para melhorar o comprometimento estético e social. Este relato de caso descreve um diagnóstico inicial errôneo, que atrasou o tratamento adequado, e destaca o valor do exame físico e raciocínio clínico para solicitar outro exame anatomopatológico, quando necessário, de forma a obter melhores desfechos com o tratamento, na prática diária.

An open-label randomized clinical trial to evaluate the efficacy of everolimus versus tacrolimus in triple maintenance immunosuppressive therapy for kidney transplant patients

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.

Safety and effectiveness of mycophenolate mofetil associated with tacrolimus for liver transplantation immunosuppression: a systematic review and meta-analysis of randomized controlled trials

A combination of immunosuppressants may improve outcomes due to the synergistic effect of their different action mechanisms. Currently, there is no consensus regarding the best immunosuppressive protocol after liver transplantation. This review aimed to evaluate the effectiveness and safety of tacrolimus associated with mycophenolate mofetil (MMF) in patients undergoing liver transplantation. We performed a systematic review and meta-analysis of randomized clinical trials. Eight randomized trials were included. The proportion of patients with at least one adverse event related to the immunosuppression scheme with tacrolimus associated with MMF was 39.9%. The tacrolimus with MMF immunosuppression regimen was superior in preventing acute cellular rejection compared with that of tacrolimus alone (risk difference [RD]=-0.11; p =0.001). The tacrolimus plus MMF regimen showed no difference in the risk of adverse events compared to that of tacrolimus alone (RD=0.7; p=0.66) and cyclosporine plus MMF (RD=-0.7; p=0.37). Patients undergoing liver transplantation who received tacrolimus plus MMF had similar adverse events when compared to patients receiving other evaluated immunosuppressive regimens and had a lower risk of acute rejection than those receiving in the monodrug tacrolimus regimen.

Postoperative serum triglyceride levels in predicting risk of new-onset diabetes mellitus in patients following liver transplantation / 浙江大学学报·医学版

To investigate the postoperative serum triglyceride (TG) levels in predicting the risk of new-onset diabetes mellitus (NODM) in patients following allogeneic liver transplantation. One hundred and forty three patients undergoing allogeneic liver transplantation in Shanghai General Hospital from July 2007 to July 2014 were enrolled in this study. The NODM developed in 33 patients after liver transplantation. The curve of dynamic TG levels in the early period after liver transplantation was generated. Independent risk factors of NODM were determined by univariate and multivariant logistic regression analyses. The clinical value of TG in predicting NODM was analyzed by area under the ROC curve (AUC). Serum TG levels were gradually rising in the first week and then reached the plateau phase (stable TG, sTG) in patients after surgery. The sTG in NODM group were significantly higher than that in non-NODM group (=-2.31, <0.05). Glucocorticoid therapy (=4.054, <0.01), FK506 drug concentration in the first week after operation (=3.482, <0.05) and sTG (=3.156, <0.05) were independent risk factors of NODM. ROC curve analysis showed that the AUC of sTG in predicting NODM was 0.72. TG shows a gradual recovery process in the early period after liver transplantation, and the higher TG level in stable phase may significantly increase the risk of NODM in patients.

Informe diário de evidências COVID-19: busca realizada em 11 de agosto de 2020 / COVID-19 daily evidence report: search conducted on August 11, 2020

O Informe Diário de Evidências é uma produção do Ministério da Saúde que tem como objetivo acompanhar diariamente as publicações científicas sobre tratamento farmacológico e vacinas para a COVID-19. Dessa forma, são realizadas buscas estruturadas em bases de dados biomédicas, referentes ao dia anterior desse informe. Não são incluídos estudos pré-clínicos (in vitro, in vivo, in silico). A frequência dos estudos é demonstrada de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, coortes, entre outros). Para cada estudo é apresentado um resumo com avaliação da qualidade metodológica. Essa avaliação tem por finalidade identificar o grau de certeza/confiança ou o risco de viés de cada estudo. Para tal, são utilizadas ferramentas já validadas e consagradas na literatura científica, na área de saúde baseada em evidências. Cabe ressaltar que o documento tem caráter informativo e não representa uma recomendação oficial do Ministério da Saúde sobre a temática. Foram encontrados 14 artigos e 5 protocolos.