Generic tacrolimus in solid organ transplantation

The availability of a wide range of immunosuppressive therapies has revolutionized the management of patients who have undergone solid organ transplantation (SOT). However, the cost of immunosuppressive drugs remains high. This situation has led to the development of generic equivalents, which are similar in quality, safety, and efficacy to their approved innovator drugs. There are data available for three generic brands, tacrolimus (Intas), tacrolimus (PharOS), and tacrolimus (Sandoz). Bioequivalence has been demonstrated for generic tacrolimus (Sandoz) within a narrow therapeutic range to its innovator tacrolimus drug (Prograf) in both healthy volunteers and kidney transplant patients. Clinical experience with this generic tacrolimus formulation has also been established in both de novo and conversion patients who have undergone kidney and liver transplantation, as well as in conversion of other SOT patients, including lung and heart recipients.     

Generic immunosuppression in solid organ transplantation: a Canadian perspective

The introduction of generic immunosuppressant medications may present an opportunity for cost savings in solid organ transplantation if equivalent clinical outcomes to the branded counterparts can be achieved. An interprofessional working group of the Canadian Society of Transplantation was established to develop recommendations on the use of generic immunosuppression in solid organ transplant recipients (SOTR) based on a review of the available data. Under current Health Canada licensing requirements, a demonstration of bioequivalence with the branded formulation in healthy volunteers allows for bridging of clinical data. Cyclosporine, tacrolimus, and sirolimus are designated as "critical dose drugs" and are held to stricter criteria. However, whether this provides sufficient guarantee of therapeutic equivalence in SOTR remains controversial, and failure to maintain an appropriate balance of immunosuppression may have serious consequences, including rejection, graft loss, and death. Published evidence supporting therapeutic equivalence of generic formulations in SOTR is lacking. Moreover, in the setting of multiple generic formulations the potential for uncontrolled product switching is a major concern, since generic preparations are not required to demonstrate bioequivalence with each other. Although close monitoring is recommended with any change in formulation, drug product switches are likely to occur without prescriber knowledge and may pose a significant patient safety risk. The advent of generic immunosuppression will require new practices including more frequent therapeutic drug and clinical monitoring, and increased patient education. The additional workload placed on transplant centers without additional funding will create challenges and could ultimately jeopardize patient outcomes. Until more robust clinical data are available and adequate regulatory safeguards are instituted, caution in the use of generic immunosuppressive drugs in solid organ transplantation is warranted.     

Meeting report: Consensus recommendations for a research agenda to address immunosuppressant nonadherence in organ transplantation

Despite advances in the field of transplantation, immunosuppressant medication nonadherence (NA) remains a primary contributor to suboptimal long‐term outcomes. Due to the multidimensional and multifactorial causes of medication NA, studies to date have focused on individual differing facets or single point barriers of NA with relative success. However, these successes have not proven to be sustainable, partly due to the intense resources needed for continued viability. This article provides a summary of a 2‐day meeting held in April 2017 (Chicago, IL) prior to the American Transplant Congress in which a multidisciplinary group convened to identify the unmet research needs related to medication NA in transplantation. Thought leaders in the field presented the past, present, and future directions of medication NA with the primary outcome of designing, developing, and ranking targeted interventions into a dynamic research agenda to identify which interventions maintained effects over time. Break‐out sessions were created based on the five World Health Organization (WHO) dimensions of adherence. Participants were then organized into the newly formed AST Transplant Pharmacy Adherence Consortium (AST TPAC) research group. This meeting report summarizes the content of the symposium, and the development, background, and future directions of the AST TPAC.     

局部应用缓释免疫抑制剂对胰岛细胞移植的影响

Objective To explore the local application of immunosuppressant in improving the survival rate of the transplanted islet cells and systemic side effects.Methods The streptozocin of 200 ms/kg was injected into the abdominal cavity of the Wistar rats,the blood sugar was tested after 48,and 72 hours,and the rats with two consecutive measurements ≥20 mol/L were taken as the experimental animal model.The dose of pancreatic islet cells transplanted into the abdominal cavity was 8 000 IE,/kg,and that of cyclosporine dosage was 1.5 mg/(100 g·d).The pancreatic islet cells were divided into three groups：(1)systemic immunosuppressive agents through stomach lavage with the intraperitoneal injection of microencapsulated islet cells;(2)pure intraperitoneal injection of microencapsulated islet cells;(3)intraperitoneal injection microencapsulated activated carbon particles loaded with immunosuppressants,and mieroencapsulated islet cells.Changes of blood glucose and pathological in rats after transplantation were detected.Results The blood glucose of group 3 and group 1 showed no significant difference(P＞0.05),as well as compared with group 2(P＞0.05).But the local application of immune agents could prolong the effective time of the islet cells and attenuate the fibrotic extent of the surrounding islets when compared with the control group,the C peptide level in applicating immunosuppressive agents group was significantly hisher in the immunosuppressive group than the pure transplantation group.Conclusion Compared with the systemic immune suppression via stomach lavage,local application of slow-release immunosuppressive agents showed the same effects of activated carbon particles,with a prolonged the effective time of islet cell and reduced topical side effects in the latter.     

局部应用缓释免疫抑制剂对胰岛细胞移植的影响

目的 探索局部应用免疫抑制剂对提高移植胰岛细胞的存活率及改善全身不良反应的影响.方法 造模:将链脲霉素按200 mg/kg注射到昆明小鼠腹腔内,48、72 h后测血糖,连续测两次≥20 mol/L作为实验动物糖尿病型.腹腔内移植入胰岛细胞的量为8 000 IE/kg,环孢素用量为1.5 mg/(100 g·d).实验分...     

肾移植术后肺部感染状态下免疫抑制剂的调整

目的 探讨肾移植术后肺部感染患者免疫抑制剂的应用与预后的关系.方法 对肾移植术后合并肺部感染的98例患者临床资料进行回顾性分析.将患者分为维持应用免疫抑制剂组(维持剂量组,45例)与免疫抑制剂减量或停用组(调整剂量组,53例).按与感染相关的器官衰竭估计评分(SOFA)标准,在肾移植术后肺部感染较重(SOFA≥12分)和感染较轻(SOFA＜12分)的情况下,分别分析两组患者的死亡率、感染恢复时间和排斥反应发生率的差异.结果 当SOFA≥12分时,调整剂量组死亡率和感染恢复时间明显低于维持剂量组(P＜0.05),而排斥反应发生率在两组之间的差异则无统计学意义(P＞0.05);当SOFA＜12分时,死亡率和感染恢复时间在两组之间差异无统计学意义(P＞0.05),但调整剂量组患者排斥反应发生率明显高于维持剂量组(P＜0.05).结论 在肾移植术后肺部感染较重(SOFA≥12分)时,减量和停用免疫抑制剂有利于降低患者的死亡率和缩短抗感染疗程;但感染较轻(SOFA＜12分)时,建议维持免疫抑制剂原剂量不变.     

Reduction of immunosuppressant therapy requirement in heart transplantation by calcitriol

Calcitriol has been shown to have immunomodulatory effects. We examined whether heart transplant recipients, randomly assigned to receive calcitriol to reduce bone loss, required less immunosuppressive therapy or demonstrated different rejection and survival outcomes. Patients receiving low-dose calcitriol required substantially lower cumulative doses of cyclosporin (29% [95% confidence interval; 8%-50%] and 28% [7%-50%] for 1 and 2 years, respectively) for organ rejection without any detectable change in episodes of rejection, infection, or deaths. This major reduction of oral cyclosporine requirement, in addition to the skeletal benefits of calcitriol in those receiving immunosuppressive therapy, indicates a potential role for co-therapy with calcitriol or its analogues in the management of patients with solid-organ transplantation.     

Hyperhomocysteinemia in organ transplantation

An elevated total homocysteine plasma concentration is associated with an increased morbidity and mortality due to cardiovascular disease in the general population, in patients with renal failure and in recipients of kidney or heart transplants. The fasting or post-methionine loading plasma concentration of total homocysteine is elevated in 50-60% of renal transplant recipients with stable graft function and in the majority of heart transplant recipients. Fasting and post-methionine loading hyperhomocysteinemia can be normalized in virtually all renal transplant patients by a combination of folic acid (5 mg/d), vitamin B6 (50 mg/d) and vitamin B12 (0.4 mg/d). In individuals without renal failure much lower doses of folate and vitamin B12 are able to correct hyperhomocysteinemia. Currently, prospective studies are under way to clarify whether folate and vitamin therapy improves cardiovascular disease morbidity and mortality in the general population and in organ transplant recipients. While population wide screening for and treatment of hyperhomocysteinemia is generally not recommended, treatment of high risk patients, including renal failure patients and kidney and heart transplant recipients, can be considered but still represents an experimental therapy.     

Biologics in organ transplantation

The last two decades have witnessed a pandemic in antibody development, with over 600 entering clinical studies and a total of 28 approved by the FDA and European Union. The incorporation of biologics in transplantation has made a significant impact on allograft survival. Herein, we review the armamentarium of clinical and preclinical biologics used for organ transplantation--with the exception of belatacept--from depleting and IL-2R targeting induction agents to costimulation blockade, B-cell therapeutics, BAFF and complement inhibition, anti-adhesion, and anti-cytokine approaches. While individual agents may be insufficient for tolerance induction, they provide possibilities for reduction of steroid or calcineurin inhibitor use, alternatives to rejection episodes refractory to conventional therapies, and specialized immunosuppression for highly sensitized patients.     

代谢组学在器官移植中的应用

代谢组学是继基因组学、转录组学和蛋白组学后出现的一种新的生物组学。代谢组学关注的是整个代谢过程中所有小分子代谢物的整体轮廓。与其他组学不同,代谢组学研究的是生物事件的终点,这一技术也许会对临床有深远的影响。尽管代谢组学尚不成熟,但在发现疾病的生物标志物研究中已经展现出巨大的潜力。本文主要从临床角度阐述代谢组学在肝移植、心脏移植和肾移植后移植器官功能和排斥反应监测中的应用。     

Alemtuzumab在器官移植中的应用

近年来,诱导免疫耐受治疗成为器官移植研究热点.自1998年Calne等[1]首次报道alemtuzumab诱导免疫耐受治疗用于肾移植后,alemtuzumab诱导免疫耐受治疗在器官移植领域逐步引起广泛关注.     

中国人体器官分配与共享基本原则和肝脏与肾脏移植核心政策

一、人体器官分配与共享基本原则 （一）总则。申请人体器官移植手术患者的排序,应当符合医疗需要,遵循公平、公正和公开的原则。（二）基本原则。1．人体器官分配与共享应当符合医疗的需要。2．移植医院根据合理的医学判断,有权为其移植等待者拒绝接受不合适的器官。