AIM:To investigate the neuroprotective potential of ciclosporin during acute liver failure. We evaluated the effect of intrathecally administered ciclosporin on intracranial pressure, brain water content and aquaporin...AIM:To investigate the neuroprotective potential of ciclosporin during acute liver failure. We evaluated the effect of intrathecally administered ciclosporin on intracranial pressure, brain water content and aquaporin-4 expression in a rat model with acute hyperammonaemia.METHODS:Twenty-four male Wistar rats with portacaval anastomosis were randomised into four groups receiving ciclosporin or vehicle and ammonia or saline infusion. Ciclosporin or vehicle was given intrathecally prior to the ammonia or saline infusion. The ammonia or saline infusion was given intravenously for 4 h,while intracranial pressure and arterial pressure was recorded. At the end of the experiment, cerebral cortex and cerebellar brain tissue was analysed for water and aquaporin-4 content.RESULTS:The following intracranial pressures were found at the end of the experiment:ammonia + ciclosporin:10.0±1.7 mmHg, ammonia + vehicle:6.8±1.0mmHg, saline + ciclosporin:3.1±0.5 mmHg, saline +vehicle:3.3 ± 0.6 mmHg. Ammonia infusion had a significant effect on intracranial pressure and brain water content, which both were higher in the groups receiving ammonia(P<0.001, two-way analysis of variance). Treatment with ciclosporin resulted in relevant tissue concentrations of ciclosporin(>0.2 micromolar)but did not reduce intracranial pressure after 4 h. Furthermore, ciclosporin did not attenuate the increase in cerebral water content, and did not affect aquaporin-4expression.CONCLUSION:Intrathecal administration of ciclosporin does not attenuate intracranial hypertension or brain oedema in rats with portacaval anastomosis and 4 h of ammonia infusion.展开更多
Background and Aims:Previous trials comparing cyclosporine and tacrolimus after liver transplantation(LT)showed conflicting results.Most used trough monitoring for cyclosporine(C0),leading to less accurate dosing than...Background and Aims:Previous trials comparing cyclosporine and tacrolimus after liver transplantation(LT)showed conflicting results.Most used trough monitoring for cyclosporine(C0),leading to less accurate dosing than with 2-h monitoring(C2).Only one larger trial compared C2 with tacrolimus based on trough level(T0)after LT,with similar treated biopsy-proven acute rejection(tBPAR)and graft loss,while a smaller trial had less tBPAR with C2 compared to T0.Therefore,it is still unclear which calcineurin inhibitor is preferred after LT.We aimed to demonstrate superior efficacy(tBPAR),tolerability,and safety of C2 or T0 after first LT.Methods:Patients after first LT were randomized to C2 or T0.tBPAR,patient-and graft survival,safety and tolerability were the main endpoints,with analysis by Fisher test,Kaplan-Meier survival analysis and log-rank test.Results:In intention-totreat analysis 84 patients on C2 and 85 on T0 were included.Cumulative incidence of tBPAR C2 vs.T0 was 17.7%vs.8.4%at 3 months(p=0.104),and 21.9%vs.9.7%at 6 and 12 months(p=0.049).One-year cumulative mortality C2 vs.T0 was 15.5%vs.5.9%(p=0.049)and graft loss 23.8%vs.9.4%(p=0.015).Serum triglyceride and LDL-cholesterol was lower with T0 than with C2.Incidence of diarrhea in T0 vs,C2 was 64%vs.31%(p≤0.001),with no other differences in safety and tolerability.Conclusions:In the first year after LT immunosuppression with T0 leads to less tBPAR and better patient-/re-transplant-free survival as compared to C2.展开更多
建立了液相色谱-串联质谱同时测定人全血中他克莫司、雷帕霉素、环孢素A与霉酚酸4种免疫抑制剂药物浓度的检测方法。全血样品经蛋白沉淀后,通过Waters XBridge C18色谱柱(100 mm×2.1 mm,5μm),以甲醇-水(含0.1%甲酸和5 mmol/L乙酸...建立了液相色谱-串联质谱同时测定人全血中他克莫司、雷帕霉素、环孢素A与霉酚酸4种免疫抑制剂药物浓度的检测方法。全血样品经蛋白沉淀后,通过Waters XBridge C18色谱柱(100 mm×2.1 mm,5μm),以甲醇-水(含0.1%甲酸和5 mmol/L乙酸铵)为流动相梯度洗脱,采用电喷雾电离源,正离子化多反应监测模式定量检测。结果表明,4种免疫抑制剂在各自检测浓度范围内线性良好,相关系数均大于0.99。基质效应相对标准偏差(RSD)在9.4%以内。加标回收率在94.2%~104.3%之间,日内日间精密度RSD<5.49%。参加英国Laboratory of the Government Chemist(LGC)室间质评的偏差均在12.50%以内,正确度良好。该方法操作简单、准确度好、灵敏度高,适用于血液中免疫抑制剂治疗药物浓度监测。展开更多
文摘AIM:To investigate the neuroprotective potential of ciclosporin during acute liver failure. We evaluated the effect of intrathecally administered ciclosporin on intracranial pressure, brain water content and aquaporin-4 expression in a rat model with acute hyperammonaemia.METHODS:Twenty-four male Wistar rats with portacaval anastomosis were randomised into four groups receiving ciclosporin or vehicle and ammonia or saline infusion. Ciclosporin or vehicle was given intrathecally prior to the ammonia or saline infusion. The ammonia or saline infusion was given intravenously for 4 h,while intracranial pressure and arterial pressure was recorded. At the end of the experiment, cerebral cortex and cerebellar brain tissue was analysed for water and aquaporin-4 content.RESULTS:The following intracranial pressures were found at the end of the experiment:ammonia + ciclosporin:10.0±1.7 mmHg, ammonia + vehicle:6.8±1.0mmHg, saline + ciclosporin:3.1±0.5 mmHg, saline +vehicle:3.3 ± 0.6 mmHg. Ammonia infusion had a significant effect on intracranial pressure and brain water content, which both were higher in the groups receiving ammonia(P<0.001, two-way analysis of variance). Treatment with ciclosporin resulted in relevant tissue concentrations of ciclosporin(>0.2 micromolar)but did not reduce intracranial pressure after 4 h. Furthermore, ciclosporin did not attenuate the increase in cerebral water content, and did not affect aquaporin-4expression.CONCLUSION:Intrathecal administration of ciclosporin does not attenuate intracranial hypertension or brain oedema in rats with portacaval anastomosis and 4 h of ammonia infusion.
基金This study was funded by Novartis Pharma,producer of Neoral ciclosporin.
文摘Background and Aims:Previous trials comparing cyclosporine and tacrolimus after liver transplantation(LT)showed conflicting results.Most used trough monitoring for cyclosporine(C0),leading to less accurate dosing than with 2-h monitoring(C2).Only one larger trial compared C2 with tacrolimus based on trough level(T0)after LT,with similar treated biopsy-proven acute rejection(tBPAR)and graft loss,while a smaller trial had less tBPAR with C2 compared to T0.Therefore,it is still unclear which calcineurin inhibitor is preferred after LT.We aimed to demonstrate superior efficacy(tBPAR),tolerability,and safety of C2 or T0 after first LT.Methods:Patients after first LT were randomized to C2 or T0.tBPAR,patient-and graft survival,safety and tolerability were the main endpoints,with analysis by Fisher test,Kaplan-Meier survival analysis and log-rank test.Results:In intention-totreat analysis 84 patients on C2 and 85 on T0 were included.Cumulative incidence of tBPAR C2 vs.T0 was 17.7%vs.8.4%at 3 months(p=0.104),and 21.9%vs.9.7%at 6 and 12 months(p=0.049).One-year cumulative mortality C2 vs.T0 was 15.5%vs.5.9%(p=0.049)and graft loss 23.8%vs.9.4%(p=0.015).Serum triglyceride and LDL-cholesterol was lower with T0 than with C2.Incidence of diarrhea in T0 vs,C2 was 64%vs.31%(p≤0.001),with no other differences in safety and tolerability.Conclusions:In the first year after LT immunosuppression with T0 leads to less tBPAR and better patient-/re-transplant-free survival as compared to C2.
文摘建立了液相色谱-串联质谱同时测定人全血中他克莫司、雷帕霉素、环孢素A与霉酚酸4种免疫抑制剂药物浓度的检测方法。全血样品经蛋白沉淀后,通过Waters XBridge C18色谱柱(100 mm×2.1 mm,5μm),以甲醇-水(含0.1%甲酸和5 mmol/L乙酸铵)为流动相梯度洗脱,采用电喷雾电离源,正离子化多反应监测模式定量检测。结果表明,4种免疫抑制剂在各自检测浓度范围内线性良好,相关系数均大于0.99。基质效应相对标准偏差(RSD)在9.4%以内。加标回收率在94.2%~104.3%之间,日内日间精密度RSD<5.49%。参加英国Laboratory of the Government Chemist(LGC)室间质评的偏差均在12.50%以内,正确度良好。该方法操作简单、准确度好、灵敏度高,适用于血液中免疫抑制剂治疗药物浓度监测。
