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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.
Subject(s)
Humans , Pharmacogenetics , Liver Transplantation , Polymorphism, Single Nucleotide , Organ Transplantation , Tacrolimus , Graft RejectionABSTRACT
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
Subject(s)
Animals , Male , Female , Rats , Pharmaceutical Preparations/analysis , Chemistry, Physical/classification , Tacrolimus/agonists , Ointments/analysis , Disease/classification , Chromatography, High Pressure Liquid/methods , Dermatitis, Atopic/pathology , Absorption, Physiological/drug effectsABSTRACT
OBJECTIVE To provide a reference for the dose adjustment of tacrolimus in patients who underwent lung transplantation after combined use of voriconazole. METHODS The clinical data of lung transplantation patients who used voriconazole and tacrolimus in our hospital from January 2020 to December 2022 were collected retrospectively. The effects of voriconazole on the valley concentration， daily dose and standardized blood concentration of tacrolimus were analyzed by using SPSS 21.0 software； multiple linear regression analysis was conducted for the factors that may affect the standardized blood concentration of tacrolimus. RESULTS A total of 153 lung transplantation patients were included. After the combination of voriconazole， the average daily dose of tacrolimus decreased from 3.37 mg to 0.76 mg， and valley concentration and standardized blood concentration were increased significantly （P＜0.000 1）. The average daily dose of voriconazole was negatively correlated with the standardized blood drug concentration of tacrolimus （P＝0.000 1，r＝－0.224）. The valley concentration of voriconazole was positively correlated with valley concentration （P＜0.000 1，r＝0.316） and standardized blood concentration （P＜0.000 1，r＝ 0.249） of tacrolimus. After combination with voriconazole， the standardized blood drug concentration of patients who underwent single lung transplantation was significantly higher than those who underwent double lung transplantation， and the standardized blood concentration of tacrolimus after oral administration of voriconazole was significantly higher than after intravenous drip of voriconazole （P＜0.05）. Most liver and kidney function indicators showed no significant changes. The results of multiple factor regression analysis showed that the valley concentration of voriconazole had a significant impact on the standardized blood concentration of tacrolimus （P＜0.001）. CONCLUSIONS The valley concentration of voriconazole has greatest influence on the blood concentration and dose adjustment of tacrolimus， which is an independent influencing factor. In clinical practice， the dose of tacrolimus should be reduced in combination with voriconazole， and therapeutic drug monitoring should be conducted for both drugs.
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Objective To investigate the intra-patient variability (IPV) of tacrolimus trough concentrations and its effect on serum creatinine (Scr) level in kidney transplant recipients treated with nematvir/ritonavir. Methods Clinical data of 41 kidney transplant recipients infected by SARS-CoV-2 and treated with nematvir/ritonavir were collected. The usage of nematvir/ritonavir and tacrolimus was summarized. The distribution of tacrolimus trough concentrations and the attainment rate of target concentration were analyzed. The correlation between the IPV distribution of tacrolimus trough concentrations and the changes of Scr level was determined. Results Among 41 kidney transplant recipients, 46%(19/41) were given with full- and low-dose nematvir/ritonavir, and 7%(3/41) were given with high-dose nematvir/ritonavir. Use of tacrolimus was discontinued at 24 h before nematvir/ritonavir treatment in 95%(39/41) patients, and at 24 h after use of nematvir/ritonavir in 5%(2/41) patients. Tacrolimus was given at least 3 d after the 5-d course of nematvir/ritonavir in all patients. The attainment rate of tacrolimus trough concentration was 73%(30/41), 30%(3/10), 48%(15/31), 35%(11/31) and 53%(16/30) before, during, 1 week, 2 weeks and 1 month after use of nematvir/ritonavir, respectively. The median IPV was 35%(23%, 51%). Spearman correlation analysis showed that the increase of Scr level was positively correlated with IPV (rs=0.400 7, P=0.028 2). Conclusions The attainment rate of tacrolimus trough concentration is declined in kidney transplant recipients treated with nematvir/ritonavir. The IPV of tacrolimus trough concentrations is elevated. The recipients with higher IPV are prone to an elevation in Scr level.
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OBJECTIVE To compare the efficacy， safety and economy of tacrolimus （TAC）， cyclosporin A （CsA）， cyclophosphamide （CTX） and rituximab （RTX） in the treatment of membranous nephropathy （MN）. METHODS Retrieved from Pubmed， the Cochrane Library， Wanfang data， CNKI and health technology assessment （HTA） official website， HTA reports， systematic reviews/meta-analysis and pharmacoeconomic studies about TAC， CsA， CTX and RTX combined with glucocorticoid in the treatment of MN were collected during the inception and Mar. 2022. After data extraction and quality evaluation， descriptive analysis was performed on the results of the included studies. RESULTS A total of 15 articles were included， involving 13 systematic reviews/meta-analysis and 2 pharmacoeconomic studies. In terms of efficacy， TAC and CsA showed significant advantages in increasing the response rate， and could improve the levels of urine protein， serum albumin， serum creatinine and serum total cholesterol. In terms of safety， the incidence of adverse reaction induced by TAC， CsA and RTX was low and the symptoms were mild. In terms of economics， CTX cost lower but caused severe adverse reaction； TAC cost higher but showed higher remission rate and good safety. CONCLUSIONS TAC combined with glucocorticoid may be the recommended scheme for MN.
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Objective To identify the risk factors of new-onset hypertriglyceridemia (HTG) in kidney transplant recipients. Methods Clinical data of 149 kidney transplant recipients were retrospectively analyzed. According to serum triglyceride (TG) level after operation, they were divided into the non-HTG group (TG≤1.7 mmol/L, n=60) and new-onset HTG group (TG>1.7 mmol/L, n=89). Baseline data of all recipients were compared between two groups. The risk factors of HTG in kidney transplant recipients were analyzed by generalized estimating equation (GEE), and validated by multiple regression equations. Results No significant differences were observed in baseline data between two groups (all P>0.05). Multivariate analysis showed that the incidence of HTG in the middle and high tacrolimus (Tac) concentration groups was higher than that in the low Tac concentration group [odds ratio (OR) 3.11, 95% confidence interval (CI) 1.22-7.93, P=0.018 in the middle Tac concentration group; OR 5.11, 95%CI 1.31-19.98, P=0.019 in the high Tac concentration group]. Compared with type-A blood recipients, the risk of new-onset HTG was significantly increased in type-O blood counterparts (OR 2.77, 95%CI 1.14-6.71, P=0.024). The risk of new-onset HTG was decreased along with the increase of preoperative globulin level (OR 0.93, 95%CI 0.87-0.99, P=0.043). At postoperative 3 months, Tac blood concentration in the new-onset HTG group was significantly higher compared with that in the non-HTG group, and significant difference was observed (P<0.05). Multiple regression equations confirmed that the risk of new-onset HTG in type-O blood kidney transplant recipients was higher than that in type-A blood counterparts, and the risk of new-onset HTG in the middle and high Tac concentration groups was higher than that in the low Tac concentration group (all P<0.05). Conclusions Type-O blood kidney transplant recipients are more prone to HTG. It is necessary to strengthen postoperative monitoring and control of blood lipids. The blood concentration of Tac probably affects the new-onset HTG in kidney transplant recipients. Maintaining an appropriate blood concentration of Tac may be beneficial to lowering the risk of HTG.
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Objective To study the eye irritation and the pharmacokinetics of tacrolimus-loaded cationic nanoemulsion-based in-situ gel in rabbits. Methods The eye irritation of tacrolimus-loaded cationic nanoemulsion-based in-situ gel in rabbits was observed by histological cross-sections of external ocular tissues stained with HE. The aqueous humor of rabbit eyes was extracted by corneal puncture and analyzed by HPLC-MS for pharmacokinetic study. Results Tacrolimus-loaded cationic nanoemulsion-based in-situ gel had no significant irritation on rabbit eyes. The pharmacokinetic parameter showed that the AUC of tacrolimus-loaded cationic nanoemulsion-based in-situ gel was (128.34±13.09) ng·h/ml, which was 1.13 times of tacrolimus-loaded cationic nanoemulsion (113.61±12.36) ng·h/ml and 1.88 times of Talymus® (68.25±10.82) ng·h /ml. Conclusion Tacrolimus-loaded cationic nanoemulsion-based in-situ gel had the advantages of low irritation, long retention time and high bioavailability in rabbit eyes. It has a good potential for clinical application.
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Objective To evaluate the efficacy and safety of tacrolimus extended-release (Tac-ER) in the early stage after kidney transplantation. Methods Clinical data of 68 recipients undergoing kidney transplantation from 34 pairs of renal allografts were retrospectively analyzed. Two recipients who received bilateral kidneys from the same donor were treated with Tac-ER (Tac-ER group) and tacrolimus immediate-release (Tac-IR) (Tac-IR group) as one of the basic immunosuppressant. The changes of tacrolimus dosage and blood concentration, intra-patient variability (IPV), renal function, incidence of acute rejection, recipient and allograft survival rates and adverse events were statistically compared between two groups. Results The average daily dose of tacrolimus in the Tac-ER group was significantly higher than that in the Tac-IR group (F=8.386, P=0.005). In the Tac-ER group, the mean trough concentration at postoperative 4 d was (6.14±4.04) ng/mL, did not reach the target concentration, significantly lower than (9.41±5.47) ng/mL in the Tac-IR group (F=7.854, P=0.007). In the Tac-ER group, the IPV of trough concentration of tacrolimus within postoperative 1 month was significantly higher than that in the Tac-IR group (0.44±0.15 vs. 0.36±0.12, P=0.032). At postoperative 6 months, there was no significant difference in the renal function between two groups [serum creatinine level was (126±26) μmol/L vs. (120±28) μmol/L, and the estimated glomerular filtration rate was (56±13) mL/(min·1.73 m2) vs. (60±15) mL/(min·1.73 m2), both P > 0.05]. The allograft and recipient survival rates were 100% in both groups. The incidence of acute rejection within postoperative 1 month was 18% in the Tac-ER group and 3% in the Tac-IR group, with no significant difference (P > 0.05). The overall incidence of adverse events was 94% in the Tac-ER group and 97% in the Tac-IR group, with no significant difference (P > 0.05). Conclusions The efficacy and safety of Tac-ER are equivalent to those of Tac-IR, whereas a higher dose of Tac-ER should be orally given to reach the blood concentration similar to that of Tac-IR. During early-stage drug treatment, Tac-ER should be orally given before kidney transplantation or inittally with loading dose, aiming to increase the systemic exposure to tacrolimus early after kidney transplantation and prevent acute rejection caused by insufficient exposure.
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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.
Subject(s)
Animals , Mice , Tacrolimus , Liver , Cholesterol, LDL , Autophagy , Disease Models, AnimalABSTRACT
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.
Subject(s)
Tacrolimus/agonists , Impact Factor , Voriconazole/agonists , Cytochrome P-450 CYP2C19/analysis , In Vitro Techniques/methods , Pharmaceutical Preparations/administration & dosage , Adaptation, Psychological/classificationABSTRACT
Resumen Objetivo: describir un caso de trasplante hepático en un paciente con resultado positivo en la prueba del coronavirus del síndrome respiratorio agudo grave de tipo 2 (SARS-CoV-2) con éxito en el postrasplante temprano, pero que desarrolló complicaciones asociadas a la inmunosupresión y trombosis portal sin una trombofilia identificada en un centro de alta complejidad de un país latinoamericano. Descripción del caso: paciente de 48 años con diagnóstico de cirrosis hepática secundaria a esteatohepatitis no alcohólica (NASH) complicada por varios episodios de ascitis portal hipertensiva y encefalopatía hepática, ingresada para trasplante hepático ortóptico. En los exámenes iniciales tuvo una prueba positiva para SARS-CoV-2 y era asintomático respiratorio. El trasplante se realizó con éxito luego de la autorización del comité de infección. Después del primer mes posoperatorio presentó diarrea, ascitis y daño renal agudo. Los niveles de tacrolimus en el reingreso fueron superiores a 10 ng/mL y hubo una mejoría clínica significativa con la suspensión del fármaco. Finalmente, el paciente requirió retrasplante por trombosis de la vena porta y de las venas suprahepáticas, aunque no se identificó la etiología. Conclusión: se describe uno de los primeros informes de trasplante de hígado en un paciente con recuperación reciente de COVID-19 y pruebas persistentemente positivas. En el postrasplante temprano hubo una buena respuesta; sin embargo, luego del primer mes presentó complicaciones relacionadas con la inmunosupresión. Este caso también plantea la posible asociación entre el SARS-CoV-2 y el desarrollo de trombosis en la circulación portal hepática.
Abstract Objective: To describe a case of liver transplantation in a patient with a positive result in the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) test with success in the early post-transplantation, but who developed complications associated with immunosuppression and portal vein thrombosis without thrombophilia identified at a tertiary referral center in a Latin American country. Case: A 48-year-old patient diagnosed with liver cirrhosis secondary to non-alcoholic steatohepatitis (NASH) complicated by several episodes of portal hypertension ascites and hepatic encephalopathy was admitted for orthoptic liver transplantation. On initial examinations, he had a positive test for SARS-CoV-2 and was asymptomatic in the respiratory tract. The transplant was carried out successfully after the authorization of the infection committee. After the first postoperative month, he presented with diarrhea, ascites, and acute kidney injury. Tacrolimus levels at readmission were more significant than 10 ng/mL, and there was a significant clinical improvement with drug discontinuation. Finally, the patient required re-transplantation due to thrombosis of the portal vein and suprahepatic veins, although the etiology was not identified. Conclusion: One of the first reports of liver transplantation in a patient with recent recovery from COVID-19 and persistently positive tests is described. In the early post-transplant, there was a good response; however, after the first month, he had complications related to immunosuppression. This case also posits the possible association between SARS-CoV-2 and the development of thrombosis in the hepatic portal circulation.
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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.
Subject(s)
Peripheral Nerves/pathology , Tacrolimus/therapeutic use , Cyclosporine/therapeutic use , Immunosuppressive Agents/therapeutic use , Nerve Regeneration/drug effectsABSTRACT
Objective To analyze the incidence and risk factors of colorectal adenomatous polyps (CAP) in recipients after liver transplantation. Methods Seventy-seven liver transplant recipients and 231 individuals undergoing colonoscopy during physical examination were recruited in this study. The incidence of CAP and pathological examination results were analyzed. Clinical data of liver transplant recipients were collected. According to the incidence of CAP, liver transplant recipients were divided into the CAP group (n=28) and non-CAP group (n=49). The risk factors of CAP after liver transplantation were identified. Results The 5-year cumulative incidence rates of colorectal polyps in liver transplant recipients and physical examination individuals were 43% and 34%, and 29% and 23% for the 5-year cumulative incidence rates of CAP, with no significant differences (both P > 0.05). Among all liver transplant recipients, 65 polyps were detected. The quantity of polyps in 1 case was excessively high and not counted. Multiple polyps were identified in certain recipients. Five polyps were not prepared for pathological examination due to small size. Pathological examination of 60 polyps demonstrated 25 inflammatory polyps, 33 CAP (8 complicated with low-grade intraepithelial neoplasia and 3 complicated with high-grade intraepithelial neoplasia), and 2 well-differentiated adenocarcinoma. Cox model analysis prompted that use of ciclosporine after liver transplantation was an independent risk factor for CAP in the recipients. Conclusions The risk of CAP is slightly elevated after liver transplantation. Postoperative use of ciclosporine is an independent risk factor for CAP in recipients after liver transplantation. Colonoscopy should be emphasized in the recipients after liver transplantation.
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Objective To investigate the effect of CYP3A5 and MDR1 gene polymorphisms on blood concentration of tacrolimus and creatinine level in uremic patients during the early phase after kidney transplantation in real clinical practice. Methods 131 patients who underwent kidney transplantation for the first time with triple immunotherapy based on tacrolimus in single-center from 2013 to 2017 were enrolled for retrospective study. Tacrolimus daily dose, blood concentration, blood concentration-to-dose ratio, and serum level were compared according to the various genotypes of CYP3A5 and MDR1 polymorphisms in renal transplantation recipients, respectively. Results The dosage of tacrolimus in CYP3A5*3/*3 (GG) kidney transplantation recipients within 4 weeks after kidney transplantation was lower than those of CYP3A5*1/*1 (AA) and CYP3A5*1/*3 (AG). The serum creatinine levels of patients whose tacrolimus concentration in the range of 10-13 ng/ml were close to the normal value. Conclusion CYP3A5 gene polymorphism affects the blood concentrations of tacrolimus in renal transplant recipients. No association has been found between the blood concentrations of tacrolimus and MDR1 gene polymorphism. Tacrolimus concentration in the range of 10-13 ng/ml might contribute to restore the early kidney graft function.
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Objectives:To establish a candidate reference measurement procedure based on isotope dilution liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS) for cyclosporin A, tacrolimus, sirolimus, and everolimus measurements in human whole blood.Methods:The isotope labeled cyclosporine A, tacrolimus, sirolimus, and everolimus were selected as the internal standards. Samples were accurately weighed while protein precipitation and solid phase extraction were selected for the sample preparation. The standard curve method was applied for quantification. The ultra-high liquid chromatography coupled with triple quadrupole mass spectrometer was used for analysis. The specificity, matrix effect, detection limit, quantification limit, precision, accuracy, and uncertainty of the method were evaluated.Results:The method showed good selectivity and specificity. No apparent interferences or matrix effects were found in the target analyte measurements. The detection limits and quantification limits of cyclosporin A, tacrolimus, sirolimus and everolimus met clinical requirements. Intra-batch coefficients of variation ( CV) were from 1.4% to 1.8% for CSA, from 1.7% to 2.8% for TAC, from 1.3% to 3.7% for SRL and from 2.3% to 3.2% for EVR, and total CVs were from 1.8% to 2.9% for CSA, from 1.7% to 3.8% for TAC, from 2.6% to 4.7% for SRL and from 3.5% to 4.6% for EVR. The relative recoveries were from 97.9% to 100.3% for CSA, from 98.4% to 103.1% for TAC, from 99.4% to 102.0% for SRL and from 98.3% to 99.4% for EVR, and the relative expanded uncertainties at four concentrations were from 4.2% to 4.4% for CSA, from 1.5% to 2.4% for TAC, from 4.4% to 4.9% for SRL and from 2.2% to 2.7% for EVR. Conclusion:A candidate reference measurement procedure for the cyclosporine A, tacrolimus, sirolimus, and everolimus in human whole blood was established by ID-LC-MS/MS.
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Objective:To conduct a retrospective analysis of efficacy and safety of different conversion schemes of tacrolimus to slow-release dosage forms for recipients in stable phase after renal transplantation to provide rationales for the conversion strategy of tacrolimus.Methods:From January 2020 to June 2020, clinical data were reviewed for 101 kidney transplant recipients converting from common tacrolimus dosage form to tacrolimus sustained-release dosage form during postoperative stable period.There were 62 males and 49 females with an age range of 19 to 69 years.They were divided into two groups according to iso-dose and incremental-dose switching schemes.The common dosage form of tacrolimus was converted into a sustained-release dosage form with different conversion doses, They were divided into two groups of 1∶1 conversion( n=55)and >1∶1 conversion( n=46). The clinical parameters of serum creatinine(Scr), blood urea nitrogen(BUN), alanine aminotransferase(ALT)and aspartate aminotransferase(AST), alkaline phosphatase(ALP), serum albumin(ALB), white blood cell count(WBC), urinary white blood cell(UWBC), hemoglobin(Hb)and fasting blood glucose(Glu)were compared between two groups after conversion. Results:Regarding numerical change trend after switching to tacrolimus sustained-release dosage form, drug dose/variation trend was smaller and blood drug concentration more stabilized.In two subgroups converted by 1∶1 and 1>1 initial dose, change trend of dose/blood concentration in 1∶1 conversion group appeared to be more stable.However, no inter-group difference existed in long-term parameters.Scr was lower at 1 week and 3 months after switching to extended-release dosage form( P<0.05)and BUN was lower at 2 weeks( P<0.05). In addition, at 5 months after conversion, ALT and AST significantly improved as compared with common dosage form( P<0.05). Significant differences existed in urinary WBC(UWBC)at 2/3 weeks( P<0.05). After switching for 2 weeks, hemoglobin significantly improved compared with common dosage form( P<0.05). No significant differences existed in ALP, ALB or Glu at other timepoints and pre-conversion( P>0.05). In 1∶1 switch group, renal function tended to improve.At 2 weeks, BUN was lower than pre-conversion; at 1/3 weeks, Scr was lower than pre-conversion( P<0.05). In addition, there was also a trend of improvement in liver function in 1∶1 conversion group.At 1 week and 5 months, ALT was lower than pre-conversion( P<0.05). However, no significant differences existed in AST, ALB, ALP, Glu, UWBC and serum WBC count at each timepoint between two different dose conversion groups( P>0.05). After conversion, intra-individual variability of tacrolimus trough concentration significantly improved( P<0.05). Conclusions:With the same safety and efficacy as common dosage form, sustained-release dosage form of tacrolimus may improve drug variability of individuals.When converting common dosage form into sustained-release dosage form, individual differences should be considered.While monitoring trough concentrations, proper doses should be adjusted on the basis of various clinical parameters.
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Objective:To study the effect of Wuzhi capsules on tacrolimus trough concentration in kidney transplant recipients with different CYP3A5 genotypes.Methods:From June 2015 to October 2019, 162 patients who underwent renal transplantation for the first time were retrospectively analyzed. The patients were divided into two groups, combined and uncombined, according to whether combined with Wuzhi capsules. There were 81 cases in the uncombined group (55 males and 26 females), and 81 in the combined group (62 males and 19 females). There was no significant difference between the two groups( P=0.219). The ages of the uncombined group and the combined group were (39.26±11.91) years old and (37.21±10.88) years old ( P=0.103), the weights were (62.39±11.64) kg and (66.18±13.89)kg ( P=0.298), systolic blood pressure were (147.28±20.24) mmHg and (145.00±16.42) mmHg (1 mmHg=0.133 kPa)( P=0.276), diastolic blood pressure were (92.25±13.87) mmHg and (92.20±12.53) mmHg ( P=0.886), alanine aminotransferase were (12.24±8.59) U/L and (17.06±13.11) U/L ( P=0.015), aspartate aminotransferase were (17.76±9.12) U/L and (16.57±8.37) U/L ( P=0.463), fasting blood glucose were (8.70±3.48) mmol/L and (7.18±2.74)mmol/L ( P=0.006), hemoglobin were (98.96±17.53) g/L and (101.05±18.67) g/L ( P=0.789), creatinine were (665.22±296.55) μmol/L and (797.32±279.32) μmol/L ( P=0.007), estimated glomerular filtration rate were (11.47±14.11) ml/(min·1.73m 2) and (8.85±3.71) ml/(min·1.73m 2) ( P=0.130)in the kidney transplant recipients before surgery. Among the 162 cases in this study, there were 86 cases (53.09%) of CYP3A5*1*3 genotype, 17 cases (10.49%) of CYP3A5*1*1 genotype, 59 cases (36.42%) of CYP3A5*3*3 genotype, and the minimum allele frequency of CYP3A5*1 was 37.04%. In the uncombined group, CYP3A5*1*3 genotype 39 cases (48.15%), CYP3A5*1*1 genotype 5 cases (6.17%), and CYP3A5*3*3 genotype 37 cases (45.68%). In the combined group, CYP3A5*1*3 genotype 47 cases (58.02%), CYP3A5*1*1 genotype 12 cases (14.81%), and CYP3A5*3*3 genotype 22 cases (27.16%), with statistically significant differences in the two groups ( P=0.024). The patients were treated with a triple immunosuppressive regimen (tacrolimus+ mycophenolate mofetil+ glucocorticoid) based on tacrolimus [initial dose: 0.15-0.30 mg/(kg·d)], combination of Wuzhi capsules in the combination group (11.25 mg, twice a day). The trough concentration of tacrolimus was detected by enzyme-linked immunosorbent assay, compare the difference in the trough concentration of tacrolimus between the two groups. The relationship between the effect of Wuzhi capsules and CYP3A5 gene polymorphism was compared, and compare the changes before and after the application of CYP3A5 genotype combined with Wuzhi Capsules. The influencing factors of tacrolimus trough concentration were analyzed by multiple linear regression. Results:In the combined with Wuzhi capsules, the dose corrected trough concentration (C 0/D) of tacrolimus was higher than that in patients without Wuzhi capsules, and the extent of increase was related to genotype. The C 0/D of tacrolimus in patients with CYP3A5*3*3 genotype in the combination and non-combination groups were (12.15±2.95) (ng·ml -1/0.1mg·kg -1·d -1) and (9.99±2.33) (ng·ml -1/0.1mg·kg -1·d -1) ( P=0.004), CYP3A5*1*3 genotype were (11.11±3.20) (ng·ml -1/0.1mg·kg -1·d -1) and (6.86±1.62) (ng·ml -1/0.1mg·kg -1·d -1) ( P<0.001), and there were significant difference. However, CYP3A5*1*1 genotype were(8.29±2.64) (ng·ml -1/0.1mg·kg -1·d -1) and (6.16±2.87) (ng·ml -1/0.1mg·kg -1·d -1) ( P=0.160), there was no significant difference. The tacrolimus C 0/D of the combined group before and after the Wuzhi capsule were as follows: CYP3A5*3*3 genotype: (7.18±2.33)(ng·ml -1/0.1mg·kg -1·d -1) and (13.33±3.09) (ng·ml -1/0.1mg·kg -1·d -1) ( P<0.001); CYP3A5*1*3 genotype: (5.14±2.14) (ng·ml -1/0.1mg·kg -1·d -1) and (10.61±3.20) (ng·ml -1/0.1mg·kg -1·d -1) ( P<0.001); CYP3A5*1*1 genotype: (5.17±3.75) (ng·ml -1/0.1mg·kg -1·d -1) and (8.31±2.74) (ng·ml -1/0.1mg·kg -1·d -1)( P=0.002), and the differences were statistically significant. The results of multiple linear regression showed that the combination of Wuzhi capsules (β=0.508, P<0.001) and CYP3A5 genotype(CYP3A5*1*3 and CYP3A5*3*3: β=-0.361, P<0.001; CYP3A5*1*1 and CYP3A5*3*3: β=-0.425, P<0.001)could influence the trough concentration. The sex (β=-0.100, P=0.124) and age (β=-0.003, P=0.967) of renal transplant recipients had no statistical significance to tacrolimus C 0/D. Conclusions:In the renal transplant patients, CYP3A5 genotype and combined use of Wuzhi capsules are the main factors affecting tacrolimus C 0/D. In order to achieve the expected trough concentration as soon as possible, the interaction between CYP3A5 genotypes and drug combination should be considered.
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Acute severe ulcerative colitis (ASUC) is one emergency in pediatric gastroenterology.The disease is serious, which may even endanger the life of patients.Close monitoring and timely pharmacological and surgical interventions are key measures to improve outcomes.Treatment methods for ASUC include necessary nutritional support, water and electrolyte disturbance correction, and possible concurrent bacterial or viral infection elimination.Patients at high risk require subcutaneous injections of low molecular weight heparin to prevent thrombosis.Intravenous cortico-steroids are the first-line treatment of ASUC.For patients showing insufficient response to corticosteroids after 3-5 days, rescue treatment with immunosuppressants or biological agents is needed.Meanwhile, the clinical symptoms, serum inflammatory indicators and albumin levels of the patients should be closely monitored.Patients who failed medical treatment should undergo timely colectomy to prevent serious complications.In this paper, a systematic review of literature and expert consensus was conducted to summarize the clinical evaluation and treatment methods of ASUC children at different stages, in order to standardize the clinical treatment of pediatric ASUC.
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Aplastic anemia(AA) is a bone marrow failure disease in which peripheral blood is reduced in two or three lines.Clinically, patients are at high risk of bleeding and infection, which may endanger their lives in serious cases.Due to the great differences in economic conditions, medical conditions and AA epidemiology in various regions around the world, there are many treatment methods for newly diagnosed, refractory / relapsed AA patients and their curative effects are different.Haploidentical hematopoietic stem cell transplantation, eltrombopag and tacrolimus are the research focuses in recent years.To facilitate clinicians to choose more appropriate treatments, this paper reviews the progress of hematopoietic stem cell transplantation therapy and non-transplantation therapy in patients with AA.
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ABSTRACT Objective: to evaluate the renal toxicity caused by tacrolimus and mycophenolate mofetil (MMF) in a single kidney ischemia and reperfusion model. Method: experimental study using Wistar rats, submitted to right nephrectomy and left renal ischemia for 20 minutes, separated into groups in the postoperative period (PO): 1) Control (nonoperated); 2) Sham (operated, without PO drug); 3) TAC0.1, TAC1 and TAC10, tacrolimus administered PO at doses of 0.1mg/kg, 1mg/kg and 10mg/kg via gavage, respectively; 4) MMF, administered mycophenolate mofetil 20mg/kg; 5) MMF/TAC1 and MMF/TAC0.5, with an association of mycophenolate mofetil 20mg/kg and tacrolimus 1mg/kg and 0.5mg/kg, respectively. They were killed on the 14th PO and the kidney was removed for tissue oxidative stress analysis, by the dosage of reduced glutathione (GSH), lipoperoxidation (LPO) and protein carbonylation (PCO), and histological analysis by glomerular stereology (Glomerular volume density, Numerical density glomerular and mean glomerular volume). Renal function was evaluated by the measurement of serum creatinine and urea. Results: both drugs caused alterations in renal function, and the toxicity of tacrolimus was dose-dependent. Subacute toxicity did not show significant glomerular histological changes, and there was renal and compensatory glomerular hypertrophy in all groups except TAC10. Conclusion: Both drugs cause changes in renal function. Glomerular morphometry and stereology showed negative interference of immunosuppressants during compensatory glomerular hypertrophy.
RESUMO Objetivo: avaliar a toxicidade renal causada pelo tacrolimus e micofenolato mofetil (MMF) em um modelo de isquemia e reperfusão de rim único. Método: estudo experimental utilizando ratos Wistar, submetidos á nefrectomia direita e isquemia renal esquerda por 20 minutos, separados em grupos no pós- operatório (PO): 1) Controle (não operados); 2) Sham (operados, sem droga PO); 3) TAC0.1, TAC1 e TAC10, administrado tacrolimus no PO nas doses 0,1mg/kg, 1mg/kg e 10mg/kg via gavagem, respectivamentae; 4) MMF, administrado micofenolato mofetil 20mg/kg; 5) MMF/TAC1 e MMF/TAC0.5, com associação de micofenolato mofetil 20mg/kg e tacrolimus 1mg/kg e 0,5mg/kg, respectivamente. Foram mortos no 14º PO e retirado rim para análise do estresse oxidativo tecidual, pela dosagem de glutationa reduzida (GSH), lipoperoxidação (LPO) e carbonilação de proteínas (PCO), e análise histológica por estereologia glomerular (Densidade de volume glomerular, Densidade numérica glomerular e Volume glomerular médio). Foi avaliada função renal pela dosagem de creatinina e uréia séricas. Resultados: ambas drogas provocaram alteração na função renal, sendo a toxicidade do tacrolimus dosedependente. A toxicidade subaguda não mostrou alterações histológicas glomerulares significativas, sendo que houve hipertrofia renal e glomerular compensatória em todos os grupos exceto em TAC10. Conclusão: Ambas drogas provocam alteração na função renal. A morfometria e a estereologia glomerular mostraram interferência negativa dos imunossupressores durante a hipertrofia glomerular compensatória..