Bone mass and mineral metabolism in liver transplant patients treated with FK506 or cyclosporine A

The purpose of this study was to compare the effects of Cyclosporine A (CyA) and FK506 on bone mass and mineral metabolism in liver transplantation (LT) patients. A prospective study was performed on 18 male patients who underwent LT treated with CyA, and 7 LT patients who received FK506. Bone mineral density (BMD) of the lumbar spine and proximal femur (DPX-L) was measured before and at 6, 12, and 24 months after transplantation. Moreover, intact parathyroid hormone (PTH) and 25-hydroxyvitamin D (25OHD) levels were determined at the same time. The cumulative dose of glucocorticoids was calculated in all patients. At 6 months, lumbar BMD decreased 5.2 ± 1.2 % (P=0.0005) and 2.9 ± 2.1 % (p=ns) in CyA and FK506 groups, respectively. Lumbar BMD reached baseline values at 1 year in the FK506 group and 2 years after LT in the CyA group. Moreover, significant intergroup differences in femoral neck BMD changes after 2 years of transplant were observed (CyA: −5.2 ± 1.97 versus FK506: +1.55 ± 2.2 %;P=0.039). In the first year posttransplant both groups showed a marked increase in PTH and 25OHD levels. The mean cumulative dose of glucocorticoids was higher in the CyA group (CyA group 11.06 ± 0.46 g versus FK 506 group 6.71 ± 0.42 g;P<0.001), and multiple linear regression analysis showed a negative correlation between BMD changes at the lumbar spine and mean cumulative dose of glucocorticoids (P=0.022). In conclusion, our data suggest that after liver transplantation treatment with FK506 shows a more favorable long-term effect on bone mass evolution than CyA therapy. These differences seem to be associated with the lower dose of glucocorticoids used in the FK506 group.     

Pharmacokinetics of cyclosporine in monkeys after oral and intramuscular administration: relation to efficacy in kidney allografting

In cynomolgus and rhesus monkeys, the dose-normalized exposure of cyclosporine administered orally as microemulsion preconcentrate (Neoral) was lower than that upon intramuscular administration. For oral administration, mean values ( ± SD) of C_max, 24-h area-under-the curve (AUC) and 24-h trough level, all normalized for a 1 mg/kg dose, were 20 ± 9 ng kg/mg ml, 210 ± 70 ng h kg/mg ml and 2.6 ± 0.9 ng kg/mg ml, respectively. For intramuscular administration, levels were about 5.5-fold, 9-fold and 22-fold higher. Based on pharmacokinetic data, the efficacy of oral cyclosporine treatment (without any other immunosuppressant) was evaluated in life-supporting cynomolgus monkey kidney allotransplantation. Rejection-free kidney allograft survival could be achieved using oral cyclosporine monotherapy with average 24-h trough concentrations above 100 ng/ml during maintenance treatment. Typically, daily oral doses of 100 mg/kg–150 mg/kg during the first two weeks post-transplantation, followed by daily 30 mg/kg–100 mg/kg dose levels during subsequent maintenance can result in long-term allograft survival, with 24-h average trough levels in individual animals during maintenance between 110 ng/ml and 700 ng/ml. Received: 1 October 1997 Revised: 20 April 2001 Accepted: 7 June 2001     

A favourable response to surgical intervention and hyperbaric oxygen therapy in pyoderma gangrenosum

Pyoderma gangrenosum (PG) is a neutrophilic dermatosis characterised with ulcerations. Inflammatory bowel diseases (ulcerative colitis and Crohn's disease) and haematologic diseases (leukaemia, preleukaemia and monoclonal gammopathy) have been reported in about 40–50% of PG patients in whom the treatment of the underlying disease is important for the improvement of the lesions. We herein report a colorectal adenocarcinoma patient with PG, who responded partially to topical treatments and systemic immunosuppressants and healed completely with the aid of surgical wound repair and hyperbaric oxygen therapy.     

Renoprotective effect of N-acetylcysteine on chronic cyclosporine A nephrotoxicity

Objective To explore the renoprotective effect of N-acetylcysteine (NAC) on chronic cyclosporine A (CsA) nephrotoxicity in mice model. Methods ICR mice were randomly divided into 4 groups: normal control group [olive oil, 1 ml/kg subcutaneous injection (s.c)], NAC control group (olive oil, 1 ml/kg s.c plus NAC 150 mg•kg-1•d-1 in drinking water), model group [ICR mice maintained on a salt-depleted diet (0.05% sodium) plus CsA (30 mg•kg-1•d-1) for four weeks]; Treatment group [ICR mice maintained on a salt-depleted diet (0.05% sodium) plus CsA (30 mg•kg-1•d-1 s.c) and NAC (150 mg•kg-1•d-1 in drinking water). Basic parameters, histopathology, 8-hydroxydeoxyguanosine (8-OHdG), the expression of Klotho and AKT-FoxO1 were studied. Results Compared with the normal control group, mice in model group showed deterioration in renal function [Scr (27.8±1.2) μmol/L vs (19.0±2.2) μmol/L, P＜0.01], development of tubulointerstitial fibrosis, increased urinary 8-OHdG output [(41.2±16.8) ng/d vs (28.7±7.4) ng/d, P＜0.05], and decreased Klotho expression [(17.8±4.5)% vs (100.0±4.0)%, P＜0.01]. Concomitant administration of NAC significantly improved all above parameters (all P＜0.05). Correlation analysis revealed that Klotho expression was negatively correlated with urinary 8-OHdG excretion (r＝-0.934, P＜0.01) and AKT-FoxO1 expression （AKT: r＝-0.939, P＜0.01; FoxO1: r＝-0.919, P＜0.01). Conclusion NAC can attenuate tubulointerstitial fibrosis in chronic CsA nephrotoxicity mice, which may be associated with the up-regulation of Klotho expression and the inhibition of AKT-FoxO1 signaling pathway.     

环孢素A短期替代他克莫司对肾移植后新发糖尿病的改善作用

目的 初步探讨环孢素A(CsA)短期替代他克莫司(Tac)对移植后新发糖尿病( NODAT)的改善作用.方法 前瞻性分析19例以Tac为基础免疫抑制剂的NODAT患者的资料.其中7例NODAT诊断明确后将Tac转换为CsA,6个月后再次转换回Tac(转换组);12例诊断为NODAT后继续应用Tac(对照组).结果 转换组空腹血糖(FPG)由人组时的(8.3±3.9)mmol/L降至转换12个月时的(5.6±1.8)mmol/L(P＜0.01),对照组入组时和12个月时的FPG分别为(8.1±3.5) mmol/L和(8.0±3.0)mmol/L(P＞0.05),组间12个月时相比较,差异有统计学意义(P＜0.05).转换组糖化血红蛋白(HbA1c)由入组时的(6.8±0.8)％降至12个月时的(6.1±0.4)％(P＜0.05),对照组入组时和12个月时的HbA1c分别为(6.9±0.7)％和(6.8±1.5)％(P＞0.05),两组间12个月时相比较,差异有统计学意义(P＜0.05).随访结束时,转换组中4例(57.1％,4/7)NODAT完全缓解,而对照组中无NODAT缓解病例(P＜0.01).转换组血压和血脂水平在转换之后维持稳定.两组间移植物功能以及急性排斥反应发生率的差异无统计学意义(P＞0.05).两组随访结束时移植物和受者存活率均为100％.结论 发生NODAT的肾移植受者将Tac短期(6个月)转换为CsA,可明显改善糖代谢异常.     

环孢素预处理对同种带瓣主动脉移植的保护作用

目的 观察环孢素预处理在同种带瓣管道移植的作用.方法 将1个月龄的中国白兔50只(取其带瓣主动脉)作为供体,体质量0.25 ～0.35 kg;将成年中国白兔50只,体质量2.50～3.50 kg,随机分2组作为受体,25只(移植时供体带瓣主动脉接受环孢素预处理)为实验组,25只(移植时供体带瓣主动脉不接受环孢素预处理)为对照组,移植前后应用葡萄糖代谢法检测带瓣血管的代谢,分别于第2、4周取出移植主动脉,观察血管是否通畅,苏木素-伊红(HE)染色组织病理图片观察,普通聚合酶链反应(PCR)鉴定MGP基因,荧光定量PCR 2-△△Cr方法检测实验组4周、8周时血管平滑肌细胞中的MGP mRNA的相对表达量.结果 (1)实验组通畅率为86.96％,明显高于对照组通畅率(59.09％),两组均数比较差异有统计学意义(P＜0.05);实验组(25例)葡萄糖代谢率均数±标准差值为(4.3950 ±0.5642) mmol/(L·24 h),对照组(25例)葡萄糖代谢为(4.4720±0 7213) mmol/(L·24 h),两组均数比较差异无统计学意义(P＞0.05).(2)组织病理学观察,对照组明显出现内膜增生、中膜坏死和外膜浸润,随时间推移细胞成分明显减少,瓣膜正常分层状结构和结缔组织不断丧失;(3)MGP基因在实验组中表达,而在对照组中不表达;实验组中术后4周的MGP mRNA表达量(14.564±0.243)明显高于术后8周的表达量(6.492±0.962).结论 环孢素预处理的同种带瓣主动脉可提高移植血管通畅率,降低血栓形成,血管内皮细胞改变较轻;MGP mRNA水平的动态变化可能与环孢素抑制血管平滑肌细胞的表型转化及增殖有关.     

不同剂量环孢素A对肾移植病人精液质量的影响

目的 :探讨不同治疗剂量环孢素A(CsA)对肾移植病人精液主要参数和精子形态学的影响。　方法 :对 18例应用不同治疗剂量CsA的肾移植病人的精液进行主要参数和精子形态学分析 ,并与 12例正常男性精液进行比较。　结果 :CsA剂量在 1.5～ 3.0mg·Kg-1·d-1及 3.1～ 5 .5mg·Kg-1·d-1时 ,病人精液的主要参数与正常男性精液比较差异无显著性 (P >0 .0 5 ) ,但病人正常形态精子百分率与正常男性相比差异有显著性 (P <0 .0 5 )。结论 :不同治疗剂量的CsA对肾移植病人的精液主要参数无明显影响 ,但对精子形态可能有一定的影响。     

尼卡地平对肾移植受者环孢素A血浓度的影响

目的：研究尼卡地平对肾移植受者血压和环孢素A（CaA)全血谷值浓度的影响。方法：试验组62例肾移植术后肾功能恢复正常的受者服用尼卡地平，服药前后作自身对照；23例受者服用硝苯地平作为对照组，以CsA全血谷值浓度、CsA剂量、肌酐、血压作为临床评价指标。结果：试验组受者服用尼卡地平后CsA血药浓度显著升高、血压下降并维持在正常范围，与服用尼卡地平前比较，差异均有显著性意义（P＜0．01），6个月后环孢素剂量A减少达34．2％，对血肌酐无明显影响。结论：尼卡地平用于肾移植术后能有效治疗和预防高血压，并可提高CsA血药浓度，减少CsA用量和费用，并不增加CsA的毒性反应。尼卡地平与CsA合用可节省费用。     

Differential Effect of Diarrhea on FK506 Versus Cyclosporine A Trough Levels and Resultant Prevention of Allograft Rejection in Renal Transplant Recipients

Diarrhea is the most frequently reported adverse event in patients treated with mycophenolate mofetil. Twenty-six renal transplant patients on a mycophenolate mofetil-based immunosuppressive regime with persistent afebrile diarrhea were examined. Diarrhea caused a significant rise in FK-506 trough levels despite intake of stable doses, necessitating FK-506 dose reductions of 30% to obtain pre-diarrhea trough levels. In contrast, trough levels of cyclosporine A remained stable without dose adjustments. This suggests that absorption and/or metabolism is differentially altered for FK506 compared with cyclosporine A in patients with diarrhea. In nine patients mycophenolate mofetil was reduced or stopped because of persistent diarrhea without identifiable cause. This resulted in end-stage renal disease because of chronic rejection in two patients, and in acute rejection in two patients, all taking FK506 and steroids. Therefore, dose adjustments of FK506 in patients with diarrhea must be carefully monitored, especially when doses of mycophenolate mofetil are also reduced.     

氟伐他汀对环孢素A所致大鼠成纤维细胞肾毒性的保护作用

目的 观察免疫抑制剂环孢素Ａ（CsA）对大鼠肾脏成纤维细胞增殖及细胞因子表达的影响以及氟伐他汀的干预作用，探讨氟伐他汀对CsA肾毒性的保护作用。 方法 体外培养大鼠肾脏成纤维细胞，四甲基偶氮唑盐（MTT）比色法测定CsA及氟伐他汀对细胞增殖的影响。RT-PCR方法检测转化生长因子β1（TGF-β1）、结缔组织生长因子（CTGF）及c-fos mRNA水平。Western印迹检测纤连蛋白(FN)的表达。 结果 CsA可明显抑制成纤维细胞增殖，且呈剂量和时间依赖效应（P < 0.05）。氟伐他汀与CsA合用后，对细胞增殖有明显的抑制作用（P < 0.01）。CsA刺激成纤维细胞TGF-β1、CTGF、c-fos及FN的产生（P < 0.05），氟伐他汀可下调这些改变（P < 0.05）。 结论 氟伐他汀可减轻CsA所致的大鼠肾脏成纤维细胞毒性