BACKGROUND & AIMS: :Cytochrome P450 3A4 (CYP3A4) is a major drug-metabolizing enzyme that is widely investigated. So far, no homozygous inactive variant has been described. We report on a 19-year-old kidney transplant patient suffering from Alport syndrome, who experienced unexpected high tacrolimus plasma trough levels during immunosuppressant therapy. Because nonadherence, liver failure, or drug-drug interactions could be excluded, we hypothesized a diminished metabolism of the drug caused by mutations in the main detoxification enzyme, CYP3A4. Exome sequencing revealed a novel single-nucleotide polymorphism (c.802C>T) resulting in a premature stop codon in CYP3A4 exon 5. Accordingly, no CYP3A4 protein could be detected in kidney biopsy tissue, and there was lack of expression in HepG2 cells transiently transfected with the mutated CYP3A4. In addition, the patient harbored inactive CYP3A5*3, resulting in loss of function of the entire CYP3A locus, explaining the deteriorated tacrolimus clearance. This is, to our knowledge, the first case of a complete failure of CYP3A4 in humans.

背景与目标： : 细胞色素P450 3A4 (CYP3A4) 是广泛研究的主要药物代谢酶。到目前为止，还没有描述纯合的无活性变体。我们报道了一名患有Alport综合征的19岁肾脏移植患者，他在免疫抑制剂治疗期间经历了意想不到的他克莫司血浆谷水平升高。由于不依从性，肝衰竭或药物相互作用可以排除，因此我们假设主要解毒酶CYP3A4突变导致药物代谢减少。外显子组测序揭示了一种新的单核苷酸多态性 (c.802C>T)，导致CYP3A4外显子5过早终止密码子。因此，在肾脏活检组织中未检测到CYP3A4蛋白，并且在突变的CYP3A4瞬时转染的HepG2细胞中缺乏表达。此外，患者携带无活性的CYP3A5 * 3，导致整个CYP3A基因座功能丧失，解释了他克莫司清除率恶化。据我们所知，这是CYP3A4在人类中完全失败的第一例。

BACKGROUND & AIMS: :Following organ engraftment, initial dosing of tacrolimus is based on recipient weight and adjusted by measured C(0) concentrations. The bioavailability and elimination of tacrolimus are affected by the patients CYP3A5 genotype. Prospective data of the clinical advantage of knowing patient's CYP3A5 genotype prior to transplantation are lacking. A nonparametric population model was developed for tacrolimus in renal transplant recipients. Data from 99 patients were used for model development and validation. A three-compartment model with first-order absorption and lag time from the dosing compartment described the data well. Clearances and volumes of distribution were allometrically scaled to body size. The final model included fat-free mass, body mass index, hematocrit, time after transplantation, and CYP3A5 genotype as covariates. The bias and imprecision were 0.35 and 1.38, respectively, in the external data set. Patients with functional CYP3A5 had 26% higher clearance and 37% lower bioavailability. Knowledge of CYP3A5 genotype provided an initial advantage, but only until 3-4 tacrolimus concentrations were known. After this, a model without CYP3A5 genotype predicted just as well. The present models seem applicable for clinical individual dose predictions but need a prospective evaluation.

背景与目标： : 器官植入后，他克莫司的初始剂量基于接受者的体重，并通过测量的C(0) 浓度进行调整。他克莫司的生物利用度和消除受患者CYP3A5基因型的影响。缺乏在移植前了解患者CYP3A5基因型的临床优势的前瞻性数据。针对肾移植受者的他克莫司建立了非参数种群模型。来自99名患者的数据用于模型开发和验证。具有一阶吸收和来自给药室的滞后时间的三室模型很好地描述了数据。间隙和分布量按体型大小进行了异同比例缩放。最终模型包括无脂肪质量，体重指数，血细胞比容，移植后时间和CYP3A5基因型作为协变量。在外部数据集中分别0.35和1.38偏差和不精确性。具有功能性CYP3A5的患者26% 更高的清除率和37% 更低的生物利用度。对CYP3A5基因型的了解提供了最初的优势，但直到已知3-4他克莫司浓度为止。此后，也可以预测没有CYP3A5基因型的模型。目前的模型似乎适用于临床个体剂量预测，但需要前瞻性评估。

BACKGROUND & AIMS: :Transformations of the macrocyclic lactone tacrolimus (1), an important immunosuppressive drug produced by Streptomyces species, are described. These transformation products are primarily of interest as reference substances for drug impurity analyses. Upon action of acid (p-toluenesulfonic acid in toluene), tacrolimus is dehydrated by loss of water from the β-hydroxyketone moiety with partial inversion of configuration at C-8, resulting in formation of 5-deoxy-Δ(5,6)-tacrolimus and 5-deoxy-Δ(5,6)-8-epitacrolimus. The structure of the latter was determined by single-crystal X-ray crystallography. The same products are formed upon action of free radicals (iodine in boiling toluene), along with formation of 8-epitacrolimus. The latter is converted by p-toluenesulfonic acid to 5-deoxy-Δ(5,6)-8-epitacrolimus. Treatment of tacrolimus with weak base (1,5-diazabicyclo[4.3.0]nonene) gives, in addition to 8-epitacrolimus, the open-chain acid corresponding to 5-deoxy-Δ(5,6)-tacrolimus, a rare non-cyclic derivative of tacrolimus. Strong base (t-butoxide) causes pronounced degradation of the molecule. Thermolysis of tacrolimus leads to ring expansion by an apparent [3,3]-sigmatropic rearrangement of the allylic ester moiety with subsequent loss of water from the β-hydroxyketone moiety. ¹H and ¹³C NMR spectra of the obtained compounds, complicated by the presence of amide bond rotamers and ketal moiety tautomers, were assigned by extensive use of 2D NMR techniques.

背景与目标： : 描述了由链霉菌种产生的重要免疫抑制药物大环内酯他克莫司 (1) 的转化。这些转化产物主要是作为药物杂质分析的参考物质。在酸 (对甲苯磺酸在甲苯中的作用) 的作用下，他克莫司通过从 β-羟基酮部分失水而脱水，并在C-8处部分反转构型，导致形成5-脱氧-Δ(5,6)-他克莫司和5-脱氧-Δ(5,6)-8-表阿莫司。后者的结构是通过单晶x射线晶体学确定的。在自由基 (沸腾的甲苯中的碘) 的作用下，形成了相同的产物，并形成了8-依地莫司。后者被对甲苯磺酸转化为5-脱氧-Δ(5,6)-8-依他克莫司。用弱碱 (1,5-二氮杂双环 [4.3.0] 壬烯) 处理他克莫司，除了8-表位莫司外，还得到与5-脱氧-Δ(5,6)-他克莫司相对应的开链酸，他克莫司的一种罕见的非环衍生物。强碱 (叔丁醇) 导致分子明显降解。他克莫司的热解通过烯丙基酯部分的明显的 [3,3]-sigmatropic重排导致环膨胀，随后从 β-羟基酮部分失去水。通过广泛使用2D NMR技术，分配了获得的化合物的h和c NMR光谱，其中酰胺键旋转异构体和缩酮部分互变异构体的存在。

BACKGROUND & AIMS: :The cutaneous manifestations of autoimmune diseases, including systemic lupus erythematosus, are common and often recalcitrant to treatment. Unfortunately, therapy for lupus and other autoimmune skin diseases has not advanced and relies heavily on the use of oral and topical corticosteroids. Frequently, treatments prove less than ideal, either from toxicity or lack of efficacy. A topical form of the immunomodulating transplant medication, tacrolimus (FK-506, Protopic), has recently been developed and approved for use in treating atopic dermatitis. Its mechanism of action and local route of administration render tacrolimus a potentially attractive novel therapeutic alternative for the treatment of various autoimmune dermatologic conditions. We report our successful experience using this drug in 3 patients with autoimmune dermatologic disease who were referred to a tertiary care subspecialty clinic.

背景与目标： : 自身免疫性疾病 (包括系统性红斑狼疮) 的皮肤表现是常见的，并且经常难以治疗。不幸的是，狼疮和其他自身免疫性皮肤病的治疗尚未进展，严重依赖于口服和局部皮质类固醇的使用。通常，无论是毒性还是缺乏疗效，治疗都不理想。最近开发了一种局部形式的免疫调节移植药物他克莫司 (FK-506，Protopic)，并批准用于治疗特应性皮炎。他克莫司的作用机制和局部给药途径使他克莫司成为治疗各种自身免疫性皮肤病的潜在有吸引力的新型治疗选择。我们报告了我们在3例自身免疫性皮肤病患者中使用这种药物的成功经验，这些患者被转诊到三级护理亚专科诊所。

BACKGROUND & AIMS: BACKGROUND:Recent studies in murine models of allergic contact dermatitis have shown that systemic treatment with pimecrolimus in contrast to tacrolimus did not inhibit the sensitization phase, whereas both compounds equivalently suppressed the inflammatory response in sensitized animals. This finding indicated a differential sensitivity of antigen-naïve and primed T cells towards pimecrolimus and tacrolimus. METHODS:T cells obtained from healthy and allergic donors were subjected to primary and secondary stimulation by allogeneic or staphylococcal superantigen-presenting dendritic cells (DC). Human skin-derived, allergen-specific T cell clones from an atopic dermatitis patient were activated by anti-CD3 antibodies or by specific allergen-presenting DC. The inhibition of T cell proliferation and cytokine release by graded doses of calcineurin inhibitors was evaluated. RESULTS:Primary stimulation of T cells was inhibited by pimecrolimus with an approximately 8-fold lower potency as compared with tacrolimus. In contrast, the secondary response of ex vivo expanded T cells activated by allogeneic or staphylococcal superantigen-presenting DC was inhibited by both compounds with equivalent potency. Likewise, both drugs showed very similar potency to inhibit the proliferation and cytokine synthesis from antigen- stimulated T cell clones and the induction of cytokines in Jurkat T cells. CONCLUSION:These data indicate that pimecrolimus has a selectivity for antigen-primed memory T cells not seen with tacrolimus.

背景与目标：

BACKGROUND & AIMS: BACKGROUND:Corticosteroids have long been a cornerstone of orthotopic liver transplant (OLTx) immunosuppression. Newer, more potent, agents have successfully allowed for more rapid tapering and discontinuation of corticosteroids in OLTx recipients. We hypothesize that corticosteroids can be safely avoided after the first postoperative day (POD) using these newer agents.

METHODS:Thirty adult OLTx recipients were prospectively enrolled in a randomized open-label, institutional review board-approved protocol. Fifteen patients (group A) received our standard regimen of tacrolimus, mycophenolate mofetil, and corticosteroids, and 15 patients (group B) received daclizumab, 2 mg/kg on POD 0 and 14, with tacrolimus, mycophenolate mofetil, and corticosteroids on POD 0 and 1 and then discontinuation. In both groups, mycophenolate mofetil was tapered off between 3 and 4 months after OLTx. Bone mineral densitometry was performed at 1, 3, and 6 months after OLTx. Quantitative hepatitis C virus (HCV) polymerase chain reaction was obtained at days 0, 7, 14, 21, and 28. Retransplant recipients, patients with autoimmune hepatitis, or status 1 or 2A patients were excluded.

RESULTS:Patient and graft survival rates were 93% (group A) and 100% (group B) with mean follow-up of 18 months. Patients in group B had more rejection diagnosed (25%) compared with group A (6.7%). Yet, the incidence of biopsy-proven acute rejection requiring steroid therapy was 6.7% in both groups. Hispanic race was common in groups A and B (87% and 74%). A total of six biopsies were performed in group B, with three patients having mild rejection responding to an increase in tacrolimus without the need for corticosteroids. One patient in group B was switched to cyclosporine for severe neurotoxicity and remains on monotherapy with normal graft function. No patient in either group developed a requirement for additional antihypertensive medication. Likewise, there were no patients with new-onset diabetes. The bone mineral densitometry was higher in group B at every time point but did not reach statistical significance. Serum cholesterol level was significantly (P=0.03) lower in group B at 6 months after OLTx. Serum triglycerides were also lower, but the difference was not significant. Quantitative polymerase chain reaction for HCV-positive patients (group A, n=7; group B, n=8) frequently increased after OLTx. There was no correlative decrease associated with daclizumab. At present, two patients in group A have documented HCV recurrence.

CONCLUSION:Corticosteroids can be safely avoided after POD 1 with the current regimen. With early follow-up, there is no difference in hypertension or diabetes or bone density. Lipid panels tended to be lower in patients who were not on corticosteroids. Longer term follow-up will be needed to demonstrate the potential advantage of corticosteroid avoidance in regard to hypertension, diabetes, and possibly HCV recurrence.

背景与目标： 背景 : 皮质类固醇长期以来一直是原位肝移植 (OLTx) 免疫抑制的基石。更新，更有效的药物已成功地使OLTx接受者的皮质类固醇激素更快速地逐渐减少和停用。我们假设使用这些新型药物可以在术后第一天 (POD) 安全避免使用皮质类固醇。
方法 : 30名成年OLTx接受者被前瞻性纳入了随机开放标签，机构审查委员会批准的方案。15例患者 (A组) 接受了他克莫司，霉酚酸酯和皮质类固醇的标准方案，15例患者 (B组) 在POD 0和14上接受了2 mg/kg的达珠单抗，在POD 0和1上接受他克莫司，霉酚酸酯和皮质类固醇，然后停用。在两组中，霉酚酸酯在OLTx后3至4个月之间逐渐减少。在OLTx后1、3和6个月进行骨矿物质密度测定。在第0、7、14、21和28天获得了定量的丙型肝炎病毒 (HCV) 聚合酶链反应。排除了再移植受者，自身免疫性肝炎患者或状态1或2A患者。
结果 : 患者和移植物存活率分别为93% (A组) 和100% (B组)，平均随访18个月。与A组 (25%) 相比，B组患者的排斥反应更多 (6.7%)。然而，在两组中，经活检证实的需要类固醇治疗的急性排斥反应的发生率均6.7%。西班牙裔种族在A组和B组 (87% 和74%) 中很常见。B组共进行了6次活检，其中3例患者对他克莫司的增加有轻度排斥反应，而无需使用皮质类固醇。B组的一名患者因严重的神经毒性而改用环孢素，并继续接受移植功能正常的单药治疗。两组都没有患者需要额外的抗高血压药物。同样，也没有新发糖尿病患者。B组的骨矿物质密度在每个时间点均较高，但未达到统计学意义。在OLTx后6个月，B组的血清胆固醇水平显着降低 (P = 0.03)。血清甘油三酯也较低，但差异不显著。HCV阳性患者 (A组，n = 7; B组，n = 8) 的定量聚合酶链反应在OLTx后频繁增加。没有与达珠单抗相关的减少。目前，A组中有两名患者已记录了HCV复发。
结论 : 使用当前方案的POD 1后，可以安全地避免皮质类固醇。随着早期随访，高血压，糖尿病或骨密度没有差异。未使用皮质类固醇的患者的脂质组趋于降低。需要进行长期随访，以证明避免使用皮质类固醇激素在高血压，糖尿病和可能的HCV复发方面的潜在优势。

BACKGROUND & AIMS: The effects of renal failure on the hepatic and intestinal extraction of tacrolimus were evaluated to examine the mechanisms for the increased bioavailability of this drug in cisplatin-induced renal failure model rats. Tacrolimus extractions in the liver and intestine were evaluated by intravenous, intraportal and intraintestinal infusion. The intestinal metabolism and absorption rate were estimated by incubating the isolated intestine with drug solution and by an in situ loop method, respectively. Blood concentrations of tacrolimus following the intraintestinal infusion were significantly increased in rats with renal failure compared with those in normal rats. The blood concentration of tacrolimus during intraportal infusion in rats with renal failure showed non-linearity against dose, and was increased as compared with that in normal rats. The intestinal metabolism was not altered, but the absorption rate was significantly increased in the intestine from rats with renal dysfunction. These results suggest that the hepatic metabolism of tacrolimus is impaired in rats with renal failure, and that the accelerated absorption rate in the intestine in renal dysfunction is followed by partial saturation of hepatic extraction, which may be one of the mechanisms of increased bioavailability of tacrolimus.

背景与目标： 评估了肾衰竭对他克莫司肝和肠提取的影响，以研究该药物在顺铂诱导的肾衰竭模型大鼠中生物利用度增加的机制。通过静脉内，静脉内和肠内输注评估他克莫司在肝脏和肠道中的提取液。分别通过将分离的肠与药物溶液一起孵育和通过原位循环方法来估算肠的代谢和吸收率。与正常大鼠相比，肾衰竭大鼠在肠内输注后他克莫司的血药浓度显着增加。肾衰竭大鼠在静脉内输注过程中他克莫司的血药浓度显示出对剂量的非线性，并且与正常大鼠相比有所增加。肠道代谢没有改变，但肾功能不全大鼠的肠道吸收率显着增加。这些结果表明，他克莫司的肝代谢在肾功能衰竭大鼠中受损，肾功能不全时肠道吸收速度加快，肝提取部分饱和，这可能是他克莫司生物利用度增加的机制之一。

BACKGROUND & AIMS: BACKGROUND:Wide variation in tacrolimus concentrations and low tacrolimus exposure have been reported to be associated with poor renal graft outcomes in non-Asians. The CYP3A5 polymorphism is a representative genetic factor that might affect this association, together with environmental factors. We investigated whether tacrolimus variability or the mean tacrolimus trough concentration can influence kidney allograft outcomes in Asians and whether the CYP3A5 polymorphism (rs776746) can affect this relationship. METHODS:Data from renal transplant patients between 2000 and 2010 were analyzed retrospectively. The tacrolimus intraindividual variability (IIV) and the mean tacrolimus trough concentration were calculated from the tacrolimus concentrations between 6 and 12 months after transplantation. RESULTS:A total of 249 renal transplant patients were enrolled. The patients with higher tacrolimus IIV had shorter rejection-free survival (P = 0.002). However, there was no difference in rejection-free survival between CYP3A5 expressers and nonexpressers. The tacrolimus IIV was not associated with the CYP3A5 polymorphism. High IIV of tacrolimus was an independent risk factor of biopsy-proven acute rejection after adjusting for mean tacrolimus concentration, HLA mismatch, induction therapy, donor type, and CYP3A5 polymorphism (hazard ratio 2.655, 95% confidence interval 1.394-5.056). Interestingly, the impact of tacrolimus IIV on acute rejection was significant in CYP3A5 expressers, whereas it was not in CYP3A5 nonexpressers. CONCLUSIONS:The IIV of tacrolimus trough concentrations had a significant impact on rejection-free survival. The effect was influenced by CYP3A5 polymorphism, although the tacrolimus variability itself was not determined by the CYP3A5 polymorphism.

背景与目标：

BACKGROUND & AIMS: :Autoimmune hemolytic anemia (AIHA) has been reported to occur after renal transplantation, and typically does so in the first few weeks post-transplant. We report on a 3-yr-old child who developed cold AIHA nearly 1 yr after an ABO identical, living donor renal transplant from his mother. Numerous transfusions, pulse steroids, repeat plasma exchange treatments, and IVIG were unsuccessful. Nearly 3 wk into his illness, tacrolimus was changed to cyclosporine, and then to sirolimus, and resulted in a prompt response. He currently has a normal renal function and a normal hemoglobin level on sirolimus monotherapy.

背景与目标： : 据报道，肾移植后发生自身免疫性溶血性贫血 (AIHA)，通常在移植后的最初几周内发生。我们报告了一个3岁的孩子，该孩子在母亲进行ABO相同的活体供体肾移植后近1年出现了冷AIHA。大量输血，脉冲类固醇，重复血浆交换治疗和IVIG均未成功。近3周，他克莫司被改为环孢素，然后改为西罗莫司，并导致迅速反应。他目前在西罗莫司单药治疗中肾功能正常，血红蛋白水平正常。

BACKGROUND & AIMS: :Psoriasis is a common skin condition affecting approximately 2.6% of the population in the US. The most effective current therapies for psoriasis have suppressive activity against T lymphocytes directly or by modulating the biologic effects of inflammatory cytokines. Tacrolimus has been used successfully to treat a number of T cell-mediated diseases. UVA1 has been shown to induce T lymphocyte apoptosis. Combination treatment is commonly used in the management of psoriasis. Therefore, this pilot study was performed to evaluate if the combination of medium-dose UVA1 (50 J/cm2) and tacrolimus ointment is effective for the treatment of palmar plantar psoriasis. A total of 5 patients completed the study of 30 UVA1 treatments, and another patient completed half of the treatments. No dramatic changes in plaque thickness or scaling were seen with either tacrolimus alone or with the combination of tacrolimus and medium dose UVA1 on palmar or plantar psoriasis.

背景与目标： : 牛皮癣是一种常见的皮肤病，影响了美国大约2.6% 的人口。目前最有效的银屑病疗法具有直接或通过调节炎性细胞因子的生物学作用对T淋巴细胞的抑制活性。他克莫司已成功用于治疗许多T细胞介导的疾病。已显示UVA1可诱导T淋巴细胞凋亡。银屑病的治疗常用联合治疗。因此，进行了这项初步研究，以评估中剂量UVA1 (50 J/cm2) 和他克莫司软膏的组合是否可有效治疗掌足底牛皮癣。共有5名患者完成了30种UVA1治疗的研究，另一名患者完成了一半的治疗。单独使用他克莫司或他克莫司与中剂量UVA1联合治疗掌上或足底银屑病均未观察到斑块厚度或鳞屑的显着变化。

BACKGROUND & AIMS: BACKGROUND:In nonprimates, organ allografts are often not rejected after withdrawal of immunosuppression. In this study, we examined whether such a phenomenon also occurs in primates.

METHODS:Vervet monkeys were transplanted with renal allografts and treated for 60 days with tacrolimus, or tacrolimus plus sirolimus. The drugs were totally withdrawn on day 61. The survival of the monkeys was monitored, and their response to donor- or third party-derived alloantigens was examined in vivo and in vitro.

RESULTS:The majority (80-100%) of the grafts survived for at least additional 30 days with no signs of acute rejection. The compromised rejection is donor-specific, because recipient monkeys failed to reject a donor-derived skin graft, but a third-party skin graft was rejected. In vitro mixed lymphocyte reaction and interleukin-2 production in the mixed lymphocyte reaction between the recipients and their donors or between the recipients and a third party had no discernable patterns, and thus did not reflect the in vivo status of the immune system. Although the recipients could not reject the graft acutely after drug withdrawal, the kidney grafts and the donor-derived skin grafts had pathological findings of chronic rejection.

CONCLUSIONS:The rejection response of the monkeys to an established graft after withdrawal of immunosuppression is compromised. The compromised rejection is specific and is not due to a permanent alteration of the immune system by the initial drug treatment. The allografts are not inert but have low levels of interaction with the recipient immune system.

背景与目标： 背景 : 在非灵长类动物中，器官同种异体移植通常在免疫抑制退出后不被排斥。在这项研究中，我们检查了灵长类动物是否也发生了这种现象。
方法 : 将长尾猴移植了同种异体肾，并用他克莫司或他克莫司加西罗莫司治疗60天。药物在第61天被完全撤回。监测猴子的存活，并在体内和体外检查它们对供体或第三方来源的同种异体抗原的反应。
结果 : 大多数移植物 (80-100%) 存活至少另外30天，没有急性排斥反应的迹象。受损的排斥是特定于供体的，因为受体猴未能拒绝供体衍生的皮肤移植物，但第三方皮肤移植物被拒绝。在受体与其供体之间或受体与第三方之间的混合淋巴细胞反应中，体外混合淋巴细胞反应和interleukin-2产生没有可辨别的模式，因此不能反映免疫系统的体内状态。尽管停药后接受者不能急性排斥移植物，但肾脏移植物和供体来源的皮肤移植物具有慢性排斥的病理学发现。
结论 : 取消免疫抑制后，猴子对已建立的移植物的排斥反应受到损害。受损的排斥是特定的，不是由于最初的药物治疗对免疫系统的永久性改变。同种异体移植物不是惰性的，但与受体免疫系统的相互作用水平较低。

BACKGROUND & AIMS: BACKGROUND:Our previous studies confirmed that tacrolimus (FK506) and sirolimus [rapamycin (RAPA)], in combination, are not antagonistic but are synergistic in the prolongation of heart and small bowel grafts in the rodent. The aim of this study was to confirm further the synergistic effect of combined FK506 and RAPA in the more clinically relevant model, kidney transplantation in monkeys.

METHODS:A total of 60 male Vervet monkeys were randomly assigned to 10 groups (n> or =5). Monkeys with renal allografts were treated with different doses of FK506 and/or RAPA orally for 60 days. Graft survival, body weight, clinical biochemistry determinations, oral glucose tolerance test, trough levels of the two drugs, and histopathology were investigated.

RESULTS:Low doses of FK506 (1 or 4 mg/kg) combined with RAPA (0.5 mg/kg) produced synergistic effect in the prolongation of renal graft survival [combination index (CI) = 0.292, 0.565]. There were no additive or synergistic drug-associated toxicities such as hyperglycemia, nephrotoxicity, and hyperlipidemia. There also was no pharmacological antagonism.

CONCLUSION:Concomitant therapy of low-dose (drug-optimal) FK506 and RAPA produced a synergistic effect in the prolongation of kidney allograft survival in Vervet monkeys without additive drug-associated toxicities.

背景与目标： 背景 : 我们以前的研究证实，他克莫司 (FK506) 和西罗莫司 [雷帕霉素 (RAPA)] 的组合不是拮抗的，但在延长啮齿动物的心脏和小肠移植物方面具有协同作用。这项研究的目的是进一步证实FK506和RAPA联合在更临床相关的模型 (猴子的肾脏移植) 中的协同作用。
方法 : 将60只雄性长尾猴随机分为10组 (n> 或 = 5)。用不同剂量的FK506和/或RAPA口服治疗肾脏同种异体移植的猴子60天。研究了移植物存活率，体重，临床生化测定，口服葡萄糖耐量试验，两种药物的谷水平以及组织病理学。
结果 : 低剂量的FK506 (1或4 mg/kg) 联合RAPA (0.5 mg/kg) 在延长肾移植物存活方面产生协同作用 [组合指数 (CI) = 0.292，0.565]。没有与药物相关的累加或协同毒性，例如高血糖，肾毒性和高脂血症。也没有药理拮抗作用。
结论 : 低剂量 (药物最佳) FK506和RAPA的合并治疗在延长长尾猴的肾脏同种异体移植存活率方面产生了协同作用，而没有与药物相关的额外毒性。

BACKGROUND & AIMS: :Calcineurin inhibitors (CNIs) are routinely used in immunosuppressive therapy and both Cyclosporine (CsA) and Tacrolimus (FK506) show similar efficacies to prevent rejection and death within the first year after organ transplantation. However, their use is limited by side effects such as kidney damage, hypertension, onset of diabetes and hyperlipidemia. It is a consensus that compared with CsA, FK506 causes less changes in blood pressures, serum lipids and renal function. Nevertheless, FK506 use is associated with a higher incidence of post-transplant diabetes mellitus (PTDM). FTY720 is a new compound that has shown a protective effect in animal models with respect to rejection in transplantation, ischemia-reperfusion injury, autoimmune diseases and tumor development. FTY720 acts by altering lymphocytes homing from blood to peripheral lymphoid organs. In mice, FTY720 administered in combination with CsA during 21 days has prolonged skin allograft survival without causing significant renal changes. In a model of CsA-induced chronic nephropathy in rats, FTY720 administration prevented renal injury suggesting benefit from using a combination of these drugs. In a canine kidney allograft model, FTY720 in combination with low doses of CsA or FK506 showed an addictive anti-rejection effect without causing critical adverse effects. We therefore, investigated whether 21 days of FTY720 administration in association with FK506 could prevent renal damage and development of diabetes in mice. Mice receiving FK506 alone or FTY720 + FK506 during 21 days showed changes in kidney function and structure besides an increase in blood glucose and lymphopenia. The FTY720 + FK506 combination requires further investigation with an aim toward understanding the mechanisms involved with respect to side effects.

背景与目标： : 钙调神经磷酸酶抑制剂 (CNIs) 通常用于免疫抑制治疗，环孢素 (CsA) 和他克莫司 (FK506) 在器官移植后第一年内显示出相似的预防排斥反应和死亡的功效。但是，它们的使用受到诸如肾脏损害，高血压，糖尿病和高脂血症等副作用的限制。共识是，与CsA相比，FK506引起的血压，血脂和肾功能变化较小。然而，FK506的使用与移植后糖尿病 (PTDM) 的较高发生率相关。FTY720是一种新化合物，已在动物模型中显示出对移植排斥，缺血再灌注损伤，自身免疫性疾病和肿瘤发展的保护作用。FTY720通过改变从血液到周围淋巴器官的淋巴细胞归巢而起作用。在小鼠中，在21天内与CsA联合施用FTY720可延长皮肤同种异体移植的存活时间，而不会引起明显的肾脏变化。在CsA诱导的大鼠慢性肾病模型中，FTY720的给药可预防肾损伤，表明使用这些药物的组合可带来益处。在犬肾脏同种异体移植模型中，FTY720与低剂量的CsA或FK506组合显示出成瘾性抗排斥作用，而不会引起严重的不良反应。因此，我们研究了与FK506联合使用FTY720的21天是否可以预防小鼠的肾脏损害和糖尿病的发展。在21天内单独接受FK506或FTY720 FK506的小鼠显示出肾脏功能和结构的变化，以及血糖和淋巴细胞减少的增加。FTY720 + FK506组合需要进一步研究，目的是了解副作用相关的机制。

BACKGROUND & AIMS: BACKGROUND:The aim of this study is to evaluate the efficacy of topical tacrolimus in treating perianal Crohn's disease. METHODS:Nineteen patients, stratified into 7 with ulcerating, and 12 with fistulizing, perianal Crohn's disease were randomized to topical tacrolimus 1 mg/g (1 g ointment twice a day [bid]) or placebo for 12 weeks. Sixteen patients had been on, or were currently taking, azathioprine/6-MP, and 6 had received infliximab. The primary outcome in ulcerating disease was global improvement in perianal/anal lesions, as assessed by the attending physician; for fistulas, it was reduction of > or =50% of actively draining fistulas on 2 consecutive visits. Blood tacrolimus levels and adverse events were assessed. RESULTS:Three of 4 patients treated with topical tacrolimus for ulcerating disease improved compared with none of 3 in the placebo group. Complete healing was not achieved. In fistulizing disease, topical tacrolimus was not beneficial. Two tacrolimus-treated patients developed perianal abscesses, 1 after improvement in fistula drainage. Adverse events were otherwise infrequent and mild. Whole blood tacrolimus levels were detectable in only 2 patients and were low. CONCLUSIONS:These preliminary data suggest that topical tacrolimus is effective and safe in the treatment of perianal or anal ulcerating Crohn's disease. This therapy is unlikely to be beneficial in fistulizing perianal Crohn's disease, although a larger study is required to confirm this.

背景与目标：

BACKGROUND & AIMS: OBJECTIVE:To assess the efficacy of clobetasol propionate 0.05% cream in male patients suffering from genital lichen sclerosus (GLS), as well as the efficacy of methylprednisolone aceponate 0.1% cream and tacrolimus 0.1% ointment as maintenance therapy. METHODS:The study was conducted retrospectively. At baseline, male patients with GLS (n = 41) were treated with clobetasol propionate 0.05% cream applied twice daily for 8 weeks. Visual Analog Scale (VAS) score for pruritus, Investigator's Global Assessment (IGA) score and Dermatology Life Quality Index (DLQI) were recorded at baseline, week 8 and week 20. At week 8, patients responsive to treatment (n = 37) were further treated with methylprednisolone aceponate 0.1% cream twice weekly (n = 17) or tacrolimus 0.1% ointment once daily (n = 20), as maintenance therapy until week 20. RESULTS:VAS, IGA and DLQI median scores were significantly decreased from baseline to week 8 (p < 0.001). At week 20, patients treated with methylprednisolone aceponate 0.1% cream presented no significant difference in median IGA score (p = 0.865), median DLQI score (p = 0.853) or median VAS score (p = 0.474) compared with patients treated with tacrolimus 0.1% ointment. CONCLUSIONS:Clobetasol propionate 0.05% cream is effective as first-line treatment in male GLS. The data suggest that there is no difference between methylprednisolone aceponate 0.1% cream and tacrolimus 0.1% ointment in preventing the relapses.

背景与目标：