RESUMO
SUMMARY: Although tacrolimus (TAC) significantly reduces allograft rejection incidence in solid-organ transplantation, its long-term use is associated with an increased risk of TAC-induced nephrotoxicity. In this study, we investigated the renoprotective effects of green tea extract (GTE) with or without the dipeptidyl peptidase 4 inhibitor, gemigliptin, by assessing serum creatinine levels, the amount of proteinuria, and histopathology in TAC-induced nephrotoxicity. TAC-induced nephrotoxicity was induced by intraperitoneal TAC injection, GTE was administered via subcutaneous injection, and gemigliptin was administered orally. Mice with TAC-induced nephrotoxicity exhibited a significant increase in both serum creatinine levels and 24-hour urine protein. However, when treated with GTE via subcutaneous injection, mice showed a decrease in serum creatinine levels and the amount of proteinuria. When GTE was combined with gemigliptin, further renoprotective effects were observed in biochemical assessments, consistent with the attenuation of TAC-induced nephrotoxicity in histopathology. The expression of p53 protein was lower in the mice treated with the combination of GTE and gemigliptin compared to mice with TAC-induced nephrotoxicity. Our results demonstrate that the combination of GTE and gemigliptin treatment reveals synergistic renoprotective effects by decreasing the expression of p53 protein. These findings suggest that the combination of GTE and gemigliptin could potentially be used as a prophylactic or therapeutic strategy for TAC-induced nephrotoxicity.
Aunque tacrolimus (TAC) reduce significativamente la incidencia de rechazo de aloinjertos en trasplantes de órganos sólidos, su uso a largo plazo se asocia con un mayor riesgo de nefrotoxicidad inducida por TAC. En este estudio, investigamos los efectos renoprotectores del extracto de té verde (GTE) con o sin el inhibidor de la dipeptidil peptidasa 4, gemigliptina, mediante la evaluación de los niveles de creatinina sérica, la cantidad de proteinuria y la histopatología en la nefrotoxicidad inducida por TAC. La nefrotoxicidad inducida por TAC se indujo mediante inyección intraperitoneal de TAC, el GTE se administró mediante inyección subcutánea y la gemigliptina se administró por vía oral. Los ratones con nefrotoxicidad inducida por TAC mostraron un aumento significativo tanto en los niveles de creatinina sérica como en la proteína en orina de 24 horas. Sin embargo, cuando se trataron con GTE mediante inyección subcutánea, los ratones mostraron una disminución en los niveles de creatinina sérica y en la cantidad de proteinuria. Cuando se combinó GTE con gemigliptina, se observaron efectos renoprotectores adicionales en las evaluaciones bioquímicas, lo que concuerda con la atenuación de la nefrotoxicidad inducida por TAC en histopatología. La expresión de la proteína p53 fue menor en los ratones tratados con la combinación de GTE y gemigliptina en comparación con los ratones con nefrotoxicidad inducida por TAC. Nuestros resultados demuestran que la combinación de tratamiento con GTE y gemigliptina revela efectos renoprotectores sinérgicos al disminuir la expresión de la proteína p53. Estos hallazgos sugieren que la combinación de GTE y gemigliptina podría usarse potencialmente como estrategia profiláctica o terapéutica para la nefrotoxicidad inducida por TAC.
Assuntos
Animais , Camundongos , Piperidonas/administração & dosagem , Pirimidinas/administração & dosagem , Chá , Extratos Vegetais/administração & dosagem , Tacrolimo/toxicidade , Nefropatias/tratamento farmacológico , Piperidonas/farmacologia , Pirimidinas/farmacologia , Extratos Vegetais/farmacologia , Substâncias Protetoras , Sinergismo Farmacológico , Imunossupressores/toxicidade , Rim/efeitos dos fármacos , Nefropatias/induzido quimicamenteRESUMO
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.
Assuntos
Ácido Micofenólico , Tacrolimo , Animais , Hipertrofia/complicações , Hipertrofia/metabolismo , Imunossupressores/toxicidade , Isquemia/induzido quimicamente , Isquemia/complicações , Rim , Ácido Micofenólico/metabolismo , Ratos , Ratos Wistar , Reperfusão , Tacrolimo/toxicidadeRESUMO
PURPOSE: To evaluate the in vivo release and ocular toxicity of a tacrolimus-loaded PLGA intravitreal implant. METHODS: Tacrolimus-loaded PLGA implants were inserted into the vitreous cavity of rabbits' eye. At different time points, the vitreous was retrieved and the concentration of tacrolimus released from the implants was determined. Clinical examination was performed to evaluate the implant tolerance. RESULTS: PLGA implants provided controlled and prolonged release of tacrolimus. Approximately 99.97% of the drug was released from the devices at 6 weeks. Ophthalmic examination revealed no evidence of toxic effects of implants. CONCLUSIONS: Tolerance and feasibility of the tacrolimus-loaded PLGA implants, as sustained intraocular drug delivery systems, were demonstrated.
Assuntos
Ácido Láctico/toxicidade , Ácido Poliglicólico/toxicidade , Próteses e Implantes/efeitos adversos , Tacrolimo/toxicidade , Uveíte/tratamento farmacológico , Animais , Materiais Biocompatíveis/farmacologia , Materiais Biocompatíveis/toxicidade , Corioide/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/efeitos adversos , Estudos de Viabilidade , Feminino , Imunossupressores/farmacologia , Imunossupressores/toxicidade , Injeções Intravítreas , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Coelhos , Retina/efeitos dos fármacos , Esclera/efeitos dos fármacos , Tacrolimo/farmacologia , Corpo Vítreo/efeitos dos fármacosRESUMO
PURPOSE: Tacrolimus is a potent immunosuppressive agent with limited corneal penetration. Microemulsions can increase the drug solubility and enhance drug absorption in the eye. This work aimed to develop a tacrolimus microemulsion as well as to characterize and to evaluate its ocular tolerance and pharmacokinetics after topical application in rabbits. METHODS: The microemulsion was prepared by the titration with the cosurfactant technique and its physical-chemical parameters and stability were determined. The cytotoxicity was evaluated using the corneal epithelium and conjunctiva cell lines. The ocular pharmacokinetic parameters in rabbits were determined and compared with that obtained after instillation of tacrolimus suspension. RESULTS: The microemulsion containing tacrolimus was successfully developed. It was nonirritating to rabbits' eyes and it was also not toxic to the corneal and conjunctival cells. When compared to the suspension, the microemulsion containing tacrolimus presented higher values of AUC (2,912.5±245.4 min.ng/mL vs. 1,669.8±93 min.ng/mL) and Cmax (26.8±2.3 ng/mL vs. 20.7±2.8 ng/mL). On the other hand, the Cl/F value was smaller when compared to the suspension that may decrease the number of applications of eye drops. CONCLUSION: The developed microemulsion could be an alternative to reduce the systemic adverse effects of tacrolimus and, consequently, increase the patient compliance to the treatment.
Assuntos
Túnica Conjuntiva/metabolismo , Córnea/metabolismo , Imunossupressores/administração & dosagem , Tacrolimo/administração & dosagem , Administração Oftálmica , Animais , Área Sob a Curva , Linhagem Celular , Estabilidade de Medicamentos , Emulsões , Feminino , Humanos , Imunossupressores/farmacocinética , Imunossupressores/toxicidade , Tamanho da Partícula , Coelhos , Suspensões , Tacrolimo/farmacocinética , Tacrolimo/toxicidadeRESUMO
La inmunosupresión en niños con trasplante hepático, ha evolucionado con dos momentos clave: la disponibilidad de los inhibidores de calcineurina ciclosporina y tacrolimus. La inmunosupresión primaria se diseña sobre la base de un inhibidor de calcineurina como fármaco principal. Los esteroides se incluyen en la pauta de inmunosupresión primaria en la mayoría de los centros. Las pautas habituales a largo plazo consisten en ciclosporina o tacrolimus, en monoterapia a niveles inferiores a los deseados en el periodo precoz postrasplante, o en combinación con dosis bajas de esteroide. Los inhibidor e s de c a l c ineur ina induc en vasoconstricción arterial aguda y crónica que causa nefrotoxicidad, con disminución del filtrado glomerular y tubulopatía. Los niveles ensangre de ciclosporina o de tacrolimus se determinan para evaluar el estado de inmunosupresión. La edad de adolescente y adulto joven es una etapa de riesgo para el injerto por ser frecuente la omisión accidental de dosis de medicación inmunosupresora, una irregularidad que es difícil de evaluar en su extensión a pesar de una buena relación médicopaciente y frecuentes chequeos. El rechazo tiene una incidencia entre el 30 y 50% de los pacientes, entre los días 5 y 30 postrasplante.
Immunosuppression in children with liver transplantation has evolved with two key moments: the availability of calcineurin inhibitors, cyclosporine and tacrolimus. The primary immunosuppression is designed on the basis of a calcineurin inhibitor as primary drug. Steroids are included in the pr imary immunosuppression regimen in most schools. The long-term normal patterns consist of cyclosporine or tacrolimus as monotherapy to lower than desired levels in the early period aftertransplantation, or in combination with low dose steroid. Calcineurin inhibitors induce arterial vasoconstriction causing acute and chronic nephrotoxicity, with reduced glomerular filtration and tubular. Blood levels of cyclosporine or tacrolimus are determined to assess the state of immunosuppression. The age of adolescence and young adulthood is a time of risk to the graft by the accidental omission to be frequent doses ofimmunosuppressive medication, an irregularitywhich is difficult to assess its extent in spite of a good doctor-patient relationship and frequentcheckups. The rejection has an incidence between 30 and 50% of patients, between 5 and 30 aftertransplantation.
Assuntos
Humanos , Masculino , Feminino , Criança , Calcineurina/administração & dosagem , Calcineurina/análise , Calcineurina , Calcineurina/farmacologia , Calcineurina , Calcineurina/uso terapêutico , Terapia de Imunossupressão/métodos , Terapia de Imunossupressão , Transplante de Fígado/classificação , Transplante de Fígado , Ciclosporina/administração & dosagem , Ciclosporina/farmacologia , Ciclosporina/toxicidade , Ciclosporina , Ciclosporina/uso terapêutico , Tacrolimo/administração & dosagem , Tacrolimo , Tacrolimo/farmacologia , Tacrolimo/toxicidade , Tacrolimo/uso terapêuticoRESUMO
BACKGROUND: Tacrolimus (FK) is currently widely used in transplant immunosuppression and the treatment of autoimmune diseases. However, FK induces nephrotoxicity which is characterized by functional and structural renal injury. The ubiquitous protein annexin A1 (ANXA1) has potent anti-inflammatory effects and protects against ischemia/reperfusion injury. We investigated the effects of exogenous ANXA1 treatment in an experimental model of acute FK nephrotoxicity. METHODS: Munich-Wistar rats received a low-salt diet for 1 week and were randomized to treatment with ANXA1 (Ac2-26 peptide 0.5 mg/kg/day s.c.), FK (6 mg/kg/day p.o.), association (FK+ANXA1) and vehicles (1 ml/kg/day) for 7 days. RESULTS: FK induced a significant decrease in glomerular filtration rate and renal blood flow, and a significant increase in renal vascular resistance. In addition, FK caused extensive acute tubule-interstitial damage and an increase in anti-inflammatory ANXA1 expression in renal tissue. Exogenous ANXA1 treatment reduced FK-induced tubular dilatation and macrophage infiltration. For the first time, we observed that FK augmented ANXA1 expression in renal tissue. CONCLUSION: Exogenous ANXA1 treatment partially protected against FK-induced tubular injury and macrophage infiltration, and may be targeted in renal intervention strategies.
Assuntos
Anexina A1/farmacologia , Anti-Inflamatórios/farmacologia , Imunossupressores/toxicidade , Nefropatias/induzido quimicamente , Tacrolimo/toxicidade , Animais , Modelos Animais de Doenças , Taxa de Filtração Glomerular , Nefropatias/tratamento farmacológico , Masculino , Ratos , Ratos WistarRESUMO
Las blaschkitis pueden definirse como procesos adquiridos inflamatorios cutáneos que asientan en las líneas de Blaschko y pueden tener diversas características clínicas e histopatológicas. Cuando éstas se localizan en la cara se mencionan el liquen estriado, el liquen plano lineal y el lupus eritematoso lineal. Se presenta el caso de una mujer de 42 años de edad con una blaschkitis de 4 meses de evolución localizada en frente cuya histopatología evidenció un ataque centrofolicular inflamatorio y destructivo. Se plantean diagnósticos diferenciales y se comunica la exitosa respuesta terapéutica al tacrolimus tópico.
Assuntos
Humanos , Adulto , Feminino , Dermatopatias Papuloescamosas/diagnóstico , Dermatopatias Papuloescamosas/patologia , Diagnóstico Diferencial , Eritema/patologia , Pele/patologia , Tacrolimo/administração & dosagem , Tacrolimo/toxicidadeRESUMO
BACKGROUND: Tacrolimus (FK-506) is an immunosuppressant that binds to a specific immunophilin, resulting in the suppression of the cellular immune response during transplant rejection. Except for some alterations in the spermatozoa, testicular morphological alterations have not been described in rats treated with tacrolimus. In the present study, we purpose to evaluate if the treatment with tacrolimus at long term of follow-up interferes in the integrity of the seminiferous tubules. METHODS: Rats aging 42-day-old received daily subcutaneous injections of 1 mg/kg/day of tacrolimus during 30 (T-30) and 60 (T-60) days; the rats from control groups (C-30 and C-60) received saline solution. The left testes were fixed in 4% formaldehyde and embedded in glycol methacrylate for morphological and morphometric analyses while right testes were fixed in Bouin's liquid and embedded in paraffin for detection of cell death by the TUNEL method. The epithelial and total tubular areas as well as the stages of the seminiferous epithelium and the number of spermatocytes, spermatids and Sertoli cells (SC) per tubule were obtained. RESULTS: In the treated groups, seminiferous tubules irregularly outlined showed disarranged cellular layers and loss of germ cells probably due to cell death, which was revealed by TUNEL method. In addition to germ cells, structural alterations in the SC and folding of the peritubular tissue were usually observed. The morphometric results revealed significant decrease in the number of SC, spermatocytes, spermatids and significant reduction in the epithelial and total tubular areas. CONCLUSION: Tacrolimus induces significant histopathological disorders in the seminiferous tubules, resulting in spermatogenic damage and reduction in the number of Sertoli cells. A careful evaluation of the peritubular components will be necessary to clarify if these alterations are related to the effect of FK-506 on the peritubular tissue.
Assuntos
Imunossupressores/toxicidade , Túbulos Seminíferos/efeitos dos fármacos , Tacrolimo/toxicidade , Animais , Peso Corporal , Marcação In Situ das Extremidades Cortadas , Masculino , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Túbulos Seminíferos/patologia , Testículo/efeitos dos fármacos , Testículo/patologiaRESUMO
OBJETIVO: avaliar a toxicidade do tacrolimus sobre o desenvolvimento embrionário em ratas tratadas durante o período de trânsito tubário. MÉTODOS: sessenta ratas Wistar foram distribuídas em quatro grupos (15 animais cada), que receberam diferentes doses de tacrolimus por via intragástrica: (T1) 1,0 mg/kg/dia, (T2) 2,0 mg/kg/dia e (T3) 4,0 mg/kg/dia. O grupo controle (C) recebeu água destilada. As ratas foram observadas diariamente para detectar sinais clínicos de toxicidade. O tratamento foi realizado do primeiro ao quinto dia de gestação. As seguintes variáveis maternas foram analisadas: peso corporal, de ovários, fígados e rins, consumo de alimento, número de corpos lúteos, implantes, fetos vivos e mortos e índice de implantação. Os fetos e placentas foram pesados e os primeiros foram observados para detectar malformações externas. Estatística: análise de variância (ANOVA), uma via, seguida de teste de Dunnett (alfa=0,05). RESULTADOS: não ocorreram indícios clínicos de toxicidade materna, tais como perda de peso, redução do consumo de alimento ou do peso de órgãos (p>0,05). Também não houve diferença significativa no peso corporal dos fetos (C: 1,8±0,6; T1: 2,2±0,5; T2: 1,9±0,5 e T3: 2,0±0,5 g) e de placentas (C: 1,6±0,4; T1: 1,5±0,4; T2: 1,8±0,4 e T3: 1,6±0,4 g), com p>0,05. Nenhuma malformação externa foi detectada. CONCLUSÕES: a administração de tacrolimus a ratas prenhes durante o período de trânsito tubário não parece ter qualquer efeito tóxico e materno ou embrionário.
PURPOSE: to evaluate the toxicity of tacrolimus on embryonic development in rats treated during the tubal transit period. METHODS: sixty Wistar rats were distributed into four groups (15 animals each), which received different doses of tacrolimus through intragastric administration: (T1) 1.0 mg/kg/day, (T2) 2.0 mg/kg/day and (T3) 4.0 mg/kg/day. The control group (C) received distilled water. The rats were observed daily to detect clinical signs of toxicity. The treatments were performed from the first to the fifth day of pregnancy. The following maternal variables were analyzed: body, ovary, liver, and kidney weights, food intake, number of corpora lutea, implants, alive and dead fetuses, and implantation rates. The fetuses and placentae were weighed and the former were observed in order to detect external malformation. Statistical analysis was performed by one way: analysis of variance (ANOVA), folowed by the Dunnet test (alpha=0.05). RESULTS: there were no signs of maternal toxicity, such as body weight loss, decrease in food intake or in organ weights (p>0.05). There was also no significant difference among weights of fetuses (C: 1.8±0.6; T1: 2.2±0.5; T2: 1.9±0.5 and T3: 2.0±0.5 g) and placentae (C: 1,6±0.4; T1: 1.5±0.4; T2: 1.8±0.4 e T3: 1.6±0.4 g), with p>0.05; no external malformation was detected in the fetuses. CONCLUSIONS: the administration of tacrolimus to pregnant rats during the tubal transit period does not seem to generate any toxic effect to mother or embryo.
Assuntos
Animais , Feminino , Gravidez , Ratos , Desenvolvimento Embrionário/efeitos dos fármacos , Imunossupressores/toxicidade , Tacrolimo/toxicidade , Ratos WistarRESUMO
PURPOSE: to evaluate the toxicity of tacrolimus on embryonic development in rats treated during the tubal transit period. METHODS: sixty Wistar rats were distributed into four groups (15 animals each), which received different doses of tacrolimus through intragastric administration: (T1) 1.0 mg/kg/day, (T2) 2.0 mg/kg/day and (T3) 4.0 mg/kg/day. The control group (C) received distilled water. The rats were observed daily to detect clinical signs of toxicity. The treatments were performed from the first to the fifth day of pregnancy. The following maternal variables were analyzed: body, ovary, liver, and kidney weights, food intake, number of corpora lutea, implants, alive and dead fetuses, and implantation rates. The fetuses and placentae were weighed and the former were observed in order to detect external malformation. Statistical analysis was performed by one way: analysis of variance (ANOVA), followed by the Dunnet test (alpha=0.05). RESULTS: there were no signs of maternal toxicity, such as body weight loss, decrease in food intake or in organ weights (p>0.05). There was also no significant difference among weights of fetuses (C: 1.8+/-0.6; T1: 2.2+/-0.5; T2: 1.9+/-0.5 and T3: 2.0+/-0.5 g) and placentae (C: 1,6+/-0.4; T1: 1.5+/-0.4; T2: 1.8+/-0.4 e T3: 1.6+/-0.4 g), with p>0.05; no external malformation was detected in the fetuses. CONCLUSIONS: the administration of tacrolimus to pregnant rats during the tubal transit period does not seem to generate any toxic effect to mother or embryo.