Exenatide

The immunosuppressive drugs used in organ transplantation have a narrow therapeutic index, with rejection occurring as a consequence of underdosing and infection, malignancy and a number of drug-specific side effects with excessive dosing. Significant heterogeneity in the dose of drug required to achieve therapeutic blood concentrations adds to the complexity of the problem, which has been partly resolved by therapeutic drug monitoring. Single nucleotide polymorphisms have been identified in genes encoding metabolic enzymes, drug efflux pumps and drug targets for most of the drugs in widespread use. A pharmacogenetic approach to immunosuppressive drug prescribing remains to be tested. Based on current evidence, the most promising strategy would be use of the cytochrome P450 3A5 expresser genotype to guide initial dosing with tacrolimus.     

Does pharmacogenetics have the potential to allow the individualisation of immunosuppressive drug dosing in organ transplantation?

The immunosuppressive drugs used in organ transplantation have a narrow therapeutic index, with rejection occurring as a consequence of underdosing and infection, malignancy and a number of drug-specific side effects with excessive dosing. Significant heterogeneity in the dose of drug required to achieve therapeutic blood concentrations adds to the complexity of the problem, which has been partly resolved by therapeutic drug monitoring. Single nucleotide polymorphisms have been identified in genes encoding metabolic enzymes, drug efflux pumps and drug targets for most of the drugs in widespread use. A pharmacogenetic approach to immunosuppressive drug prescribing remains to be tested. Based on current evidence, the most promising strategy would be use of the cytochrome P450 3A5 expressor genotype to guide initial dosing with tacrolimus.     

The Pharmacogenetics of Immunosuppression for Organ Transplantation

Transplantation has transformed the treatment of patients with organ failure in a number of clinical settings, and immunosuppressive drug therapy is fundamental to its success. However, all the drugs in current use have a narrow therapeutic index. Under-dosing can lead to rejection, while over-dosing increases the risks of infection, malignant disease, and serious drug-specific adverse effects, including diabetes mellitus, nephrotoxicity, hypertension, and hyperlipidemia. Heterogeneity in the pharmacokinetics of these drugs makes initial dose determination difficult, as there is a poor correlation between dose and blood concentration. This results in difficulties in achieving target blood concentrations early after transplantation, which are important for reducing the rate of immunological rejection. This problem is compounded by the observation that neither drug dose nor drug blood concentration accurately predict clinical efficacy or toxicity. The main determinant of heterogeneity in dose requirements is intestinal absorption of the active drug. The oxidative enzymes, cytochrome P450 (CYP) 3A4 and CYP3A5, and the drug efflux pump P-glycoprotein (P-gp) in enterocytes regulate this process. Most substrates for the P-gp pump are also substrates for the CYP3A enzymes. An efficient barrier to xenobiotic absorption is formed by the CYP enzymes and P-gp, and by the two systems working synergistically. Genetic polymorphisms have been reported for the genes associated with the expression of the CYP3A enzymes and P-gp. Genotyping patients for CYP3A genes has the potential to aid the establishment of optimal dosage regimens for transplant patients. Genetic polymorphism of the multiple drug resistance gene-1 (MDR1, also known as ABCB1) [3435C/T] and the CYP3A5 genes (CYP3A5*1, CYP3AP1*1) have the greatest potential to influence the pharmacokinetics of immunosuppressants. Homozygosity of the T allele of the MDR1 3435C/T polymorphism has been associated with reduced enterocyte expression of P-gp resulting in increased drug absorption. The presence of the CYP3A5*1 allele is necessary for the production of a fully catalytic CYP3A5 protein, and also influences the ratio of CYP3A4 : CYP3A5 as well as the overall CYP3A catalytic activity. The CYP3A4 : CYP3A5 ratio may, in turn, influence the pattern of drug metabolites formed. Heterogeneity in the production of active and inactive metabolites has implications for both the pharmacokinetics and pharmacodynamics of these drugs.Gene frequencies and drug dose requirements differ between ethnic groups. Ethnic differences in dose requirements for immunosuppressants have been discussed widely. However, ethnicity is a rather crude marker for genotype. Pharmacogenetic typing offers the possibility of significant improvement in the individualization of immunosuppressive drug prescribing with reduced rates of rejection and toxicity.     

他克莫司免疫抑制方案改善儿童肝移植术后的研究进展

肝移植作为一种有效的治疗手段广泛地应用于儿童终末期肝病的治疗。为了预防可能发生的排斥反应,患儿需要长期服用免疫抑制剂。他克莫司是一种具有强效免疫抑制特性的大环内酯类药物,以他克莫司为主的免疫抑制方案可以减少排斥反应和激素抵抗型排斥反应的发生率。探讨了基因多态性、减少剂量或撤药、不同剂型之间转换以及免疫抑制剂短期、长期生存结果对儿童肝移植术后的影响,以期优化他克莫司的给药方案,为器官移植患儿的他克莫司药物监测和剂量调整提供参考。     

35例肾移植患者他克莫司血药浓度监测分析

目的：分析肾移植患者不同时期他克莫司血药浓度与用药量的关系,为他克莫司的使用提供参考。方法对我院2013年4月～2014年3月35例肾移植患者进行长期血药浓度监测,统计分析术后时间、用药剂量等因素与他克莫司血药浓度的关系。结果35例肾移植患者血药浓度监测共计195次,血药浓度个体差异较大。肾移植手术1个月后,他克莫司用药剂量、血药浓度较高,超过1个月后血药浓度控制在4～8ng/mL较为理想。结论他克莫司治疗窗较窄,建议服药期间进行他克莫司血药浓度监测。     

Pharmacogenetics as a tool for optimising drug therapy in solid-organ transplantation

Existing immunosuppressive therapies used for solid-organ transplantation have narrow therapeutic indices, whereby underdosing is associated with acute immunological rejection of the transplanted organ and overdosing is associated with infections and malignancy, as well as organ-specific toxicities. There is significant inter-individual variation in the pharmacokinetics and pharmacodynamics of these drugs, an issue that has been addressed, in part, by therapeutic drug monitoring. Genetic polymorphisms in drug metabolising enzymes, drug efflux pumps and drug targets which may underly this heterogeneity have been identified and may provide a tool to guide prescribing. There are a number of associations between genotype and pharmacology, but as of now, only thiopurine-S-methyltransferase and cytochrome P450 3A5 have a sufficiently large influence to have potential in guiding therapy. Recent studies have also identified that donor genotype may play a significant role in immunosuppressive drug pharmacokinetics and pharmacodynamics.     

Pharmacogenetics as a tool for optimising drug therapy in solid-organ transplantation

Existing immunosuppressive therapies used for solid-organ transplantation have narrow therapeutic indices, whereby underdosing is associated with acute immunological rejection of the transplanted organ and overdosing is associated with infections and malignancy, as well as organ-specific toxicities. There is significant inter-individual variation in the pharmacokinetics and pharmacodynamics of these drugs, an issue that has been addressed, in part, by therapeutic drug monitoring. Genetic polymorphisms in drug metabolising enzymes, drug efflux pumps and drug targets which may underly this heterogeneity have been identified and may provide a tool to guide prescribing. There are a number of associations between genotype and pharmacology, but as of now, only thiopurine-S-methyltransferase and cytochrome P450 3A5 have a sufficiently large influence to have potential in guiding therapy. Recent studies have also identified that donor genotype may play a significant role in immunosuppressive drug pharmacokinetics and pharmacodynamics.     

Prediction of the possibility of the secondary peaks of iv bolus drug plasma concentration time curve by the model that directly takes into account the transit time through the organ

The article considers the problem of determination of organ clearance and the time course of drug plasma concentration using the model for which the drug transit time through the organ is regarded as one of the parameters. The suggested nonsteady state approach to the determination of organ clearance conceptually corresponds to the parallel tube model, and directly takes into account the delay of drug exit from the organ due to the transit time τ. The considered model is linear, so that the definition of mean organ clearance as D_o/AUC, where D_o is the quantity of drug eliminated by the organ and AUC is the area under drug plasma concentration time curve, is relevant and yields the same value as obtained at steady state. The plasma concentration-time profile for a two-compartmental model (blood–organ) with the account of transit time τ is found. It is a piece-continuous function, which includes exponential and polynomial terms. The considered model provides a better understanding in which situation the account of transit time through the organ may influence pharmacokinetic profiles. The unique feature of the model is that it predicts the possibility of the oscillating drug plasma concentration-time curves following iv bolus dose due to the initial fast distribution of drug into the organs. This could explain the secondary peaks or humps of drug plasma concentration profiles sometimes observed at the early time points after iv bolus injection for compounds that do not undergo hepatic recirculation. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4376–4390, 2009     

New trends in immunosuppression

The goal of immunosuppression in solid organ transplantation is to blunt the immune response of the patient to the allograft, while maintaining sufficient resistance to avoid opportunistic infections and malignancy. Despite progress in this field, rejection processes, particularly of the chronic form, remain an important cause of morbidity and graft loss. This review discusses the advances in drug development and pharmacology as well as in immunobiology, which are likely to lead to more potent, effective and selective regimens to improve the therapeutic efficacy and overcome the range of adverse side effects now plaguing the transplant enterprise. The future era of transplantation is likely to focus on receptor or cytosolic enzyme targets more specifically represented on or in lymphocytes as opposed to other cells or tissues. Four current targets of this strategy are: the chemokine receptor-7 surface marker that mediates lymphocyte affinity for specific types of high endothelial venules; Zap-70, a signaling enzyme associated with T cell antigen receptors (signal 1); plasma membrane proteins mediating costimulation (signal 2); and antagonists of Janus kinase 3 (Jak3), an enzyme transducing cytokine signals from the cell surface to the interior (signal 3).     

万古霉素在我院肝移植患者中的治疗药物监测及临床应用分析

目的:评价万古霉素在我院肝移植患者中的治疗药物监测情况,治疗前、后肾功能变化与影响血药浓度的相关因素。方法:采用回顾性方法,对我院器官移植中心2003年1月-2009年4月肝移植术后应用万古霉素的64例患者的血药浓度监测数据、细菌培养、药敏试验及应用万古霉素前、后的肾功能变化情况进行分析。结果:64例肝移植患者的396例/次血药浓度监测结果显示,平均谷浓度为(16.41±9.20)mg·L-1;谷浓度在5-10mg·L-1的占16.92%,>10mg·L-1的占73.48%,<5mg·L-1的占9.60%。谷浓度>10mg·L-1时,患者的肾功能与应用万古霉素治疗前比较差异有统计学意义(P<0.05)。经回归分析,影响万古霉素血药浓度的相关因素依次为剂量/体重、肌酐、年龄、丙氨酸氨基转移酶(P<0.05)。结论:万古霉素在肝移植患者中的治疗浓度较高;随着血药浓度升高应密切监测肾功能的变化;临床疗效及药物利用指数均表明我院该药的应用是基本合理的。     

成人胰岛细胞肝内移植的临床研究(附1例报告)

目的 评估成人胰岛细胞肝内移植治疗1型糖尿病的临床疗效及价值。方法 2003年间对1例1型糖尿病患者行了3次成人胰岛细胞肝内移植术,术后观察移植前后的血糖、C肽、胰岛素用量和免疫抑制剂的应用等指标．密切观察病情变化,积极防治并发症。结果 移植后患者饮食不受限制,生长发育良好,未发生酮症酸中毒．未发生低血糖反应,血糖平均水平降低了27％,胰岛素用量减少到移植前的40％,C肽水平较移植前有明显的提高。结论 建立了成人胰岛细胞肝内移植的一整套方法,取得了治疗1型糖尿病的临床疗效。     

Metabolism of tacrolimus (FK506) and recent topics in clinical pharmacokinetics

Tacrolimus (FK506), an immunosuppressive drug, is co-medicated with multiple drugs under clinical conditions. Tacrolimus is highly lipophilic and is excreted from the body after receiving extensive metabolism. Due to its narrow therapeutic window following organ transplantation, tacrolimus requires therapeutic drug monitoring by an enzyme immunoassay using the monoclonal antibody raised against tacrolimus. Therefore, metabolism studies including drug-drug interaction and metabolite identification studies are essential for the efficient development and clinically optimal usage of this drug. Tacrolimus was metabolized by the cytochrome P450 (CYP) 3A subfamily. Metabolic drug-drug interaction studies were conducted to provide information regarding the optimal usage of tacrolimus, and its metabolism was inhibited by known CYP3A inhibitors such as ketoconazole, cyclosporine A, and nifedipine. Recent reports on clinical pharmacokinetics indicate that dose levels of tacrolimus need to be adjusted in transplant patients with CYP3A5 polymorphism.     

Thiol proteases: inhibitors and potential therapeutic targets

A better understanding of the biological roles and the pathological consequences of thiol-dependent enzymes has emerged in recent years, and hence considerable progress has been made in identifying and delineating cysteine proteases that can be considered promising drug targets from those involved in housekeeping functions. Cysteine proteases have been implicated in a wide variety of disease processes ranging from cardiovascular, inflammatory, viral and immunological disorders to cancer. The first milestone in drug development of cysteine protease inhibitors has probably been reached, as IDN-6556 (a broad spectrum caspase inhibitor) has recently received Orphan Drug label by the U.S. Food and Drug Administration for use in the treatment of the patients undergoing liver transplantation and other solid organ transplantation. IDN-6556, which blocks apoptosis, is in Phase II human clinical trial in patients undergoing liver transplantation. In addition, more than ten cysteine protease inhibitors are presently at various phases of clinical development/trials for diverse diseases. This review emphasises on the new development from the literature reports since the year 2000 in the exploration of potential cysteine proteases as prospective drug targets, and the investigation of promising inhibitors that can potentially be developed for the treatment of human diseases. Transglutaminases, another class of thiol-dependent enzymes, are not discussed here.     

Population pharmacokinetic analysis of tacrolimus in the first year after pediatric liver transplantation

Purposes

Tacrolimus (TAC) is the most widely used immunosuppressant for the prevention of acute rejection after solid organ transplantation. Its pharmacokinetics (PK) show considerable variability, making TAC a good candidate for therapeutic drug monitoring (TDM). The principal aim of the study was to describe the PK of TAC in pediatric patients during the first year after transplantation.

Methods

Routine TDM trough levels of TAC were obtained from 42 pediatric liver allograft recipients during the first year after transplantation. A population PK model was developed using nonlinear mixed-effects modeling to describe TAC PK during this period and to explain the observed variability by means of patients’ demographics, biochemical test results and physiological characteristics.

Results

The PK of TAC were best described by a two-compartment model with first-order elimination. Apparent volumes of the central compartment, intercomparmental clearance and maximum blood clearance estimates were 253 L, 115 L/day and 314 L/day, respectively. The absorption first-order rate and volume of peripheral compartment were fixed to 4.5 h^-1 and 100 L, respectively. While hematocrit levels, time after transplantation and bodyweight influenced TAC clearance, bodyweight was the only covariate retained on volume of distribution.

Conclusions

We developed a TAC population PK model in pediatrics covering the first year after liver transplantation that may serve as a tool for TAC dose individualization as part of TDM.     

Influence of CYP3A5 Genetic Polymorphism on Tacrolimus Daily Dose Requirements and Acute Rejection in Renal Graft Recipients

Abstract: Tacrolimus is a widely used immunosuppressive drug in organ transplantation. Its oral bioavailability varies greatly between individuals, and it is a substrate of cytochrome P450 3A (CYP3A) and P‐glycoprotein. Our objective was to determine the influence of CYP3A5 and ABCB1 genetic polymorphisms on tacrolimus daily requirements and on transplantation outcome. One hundred and thirty‐six renal graft recipients treated with tacrolimus were genotyped for CYP3A5 (6986A>G), ABCB1 exon26 (3435C>T) and exon21 (2677G>T/A) single nucleotide polymorphisms. Genotypes were correlated to tacrolimus daily dose at 1‐week, 1‐, 6‐ and 12‐month post‐transplantation and with transplantation outcome. At 1‐month post‐transplantation, tacrolimus daily dose was higher for patients with CYP3A5*1/*1 genotype compared to CYP3A5*3/*3 genotype (0.26 ± 0.03 versus 0.16 ± 0.01 mg/kg/day, respectively, P < 0.0001). Similar results were obtained at 6‐ and 12‐month post‐transplantation. Furthermore, CYP3A5*1 homozygotes were associated with increased risk of acute rejection episodes compared to patients with CYP3A5*1/*3 and CYP3A5*3/*3 genotypes (38% versus 10% and 9%, respectively, P = 0.01). CYP3A5 genetic polymorphism was not associated with tacrolimus‐related nephrotoxicity. ABCB1 polymorphisms were not related with transplantation outcome. CYP3A5 genetic polymorphism appeared in our study to affect tacrolimus daily dose requirements and transplantation outcome. Screening for this single nucleotide polymorphism before the transplantation might be helpful for the selection of adequate initial daily dose and to achieve the desired immunosuppression.     

念珠菌生物被膜特性及抗生物被膜治疗

随着广谱抗生素的广泛使用，骨髓实体器官移植与医用材料植入治疗的增加，艾滋病、恶性肿瘤等免疫功能低下的患者增多，耐药念珠菌感染呈逐年上升趋势。耐药念珠菌感染通常与生物被膜的形成有关，生物被膜被认为是念珠菌重要的毒力因子，其形成与耐药性、侵袭力增强以及免疫逃避密切相关。本文从念珠菌生物被膜形成、耐药机制、免疫逃避及抗生物被膜治疗方面进行评述，以期为寻找新的药物靶点、为念珠菌感染的新型治疗策略提供新的思路。     

念珠菌生物被膜特性及抗生物被膜治疗

随着广谱抗生素的广泛使用，骨髓实体器官移植与医用材料植入治疗的增加，艾滋病、恶性肿瘤等免疫功能低下的患者增多，耐药念珠菌感染呈逐年上升趋势。耐药念珠菌感染通常与生物被膜的形成有关，生物被膜被认为是念珠菌重要的毒力因子，其形成与耐药性、侵袭力增强以及免疫逃避密切相关。本文从念珠菌生物被膜形成、耐药机制、免疫逃避及抗生物被膜治疗方面进行评述，以期为寻找新的药物靶点、为念珠菌感染的新型治疗策略提供新的思路。     

MTX药代动力学以及组织与全血浓度相关性研究

目的 研究MTX药代动力学以及组织与全血药物浓度相关性。方法 用30mg/m~2 MTX的给药剂量,在肿瘤病人体内研究其药代动力学过程,并对肿瘤局部血及外周血中的药物浓度进行了相关性比较,同时对该剂量下的药品不良反应作了观察。结果 用同30mg/m~2剂量MTX静脉滴注后,肿瘤病人体内药代动力学为一级动力学三房室模型。肿瘤局部与外周血药浓度有显著相关性。应用本剂量药品不良反应发生率较低。结论 治疗药物浓度监测可为临床治疗提供客观有效的数据,有指导意义,使用30mg/m~2剂量为一安全有效的治疗剂量。     

Therapy for acute rejection in pediatric organ transplant recipients

Despite the availability of potent immunosuppressive drugs, rejection after organ transplantation in children remains a serious concern, and may lead to significant morbidity, graft loss, and death of the patient. Acute graft rejection in pediatric recipients is first treated with methylprednisolone pulses, followed by progressive taper of corticosteroid doses. After control of the rejection episode, baseline immunosuppression has to be adjusted and closely monitored since rejection (especially late episodes, occurring more than 6 months after transplantation) may be due to a lack of compliance or sub-therapeutic drug concentrations. The management of corticosteroid resistant rejection is not standardized, and depends on the transplanted organ and previous immunosuppressive regimen. In patients experiencing corticosteroid resistant acute rejection while on a cyclosporine-based immunosuppressive regimen, cyclosporine is generally changed to tacrolimus. In case of tacrolimus-based immunosuppression, tacrolimus blood levels may be increased, and/or mycophenolate mofetil (which nowadays tends to replace azathioprine) or sirolimus may be added, although pharmacodynamic data and clinical studies with these agents are still scarce in pediatric recipients. The use of antithymocyte globulins or monoclonal anti-CD3 antibodies, muromonab CD3 (OKT3) is hampered by numerous adverse effects, including a significant risk of over-immunosuppression. These therapies are nowadays indicated in very selected cases. Other treatments such as plasmapheresis and high dose immunoglobulins may be useful in difficult cases. In patients with refractory rejection despite therapeutic escalation, the risks of over-immunosuppression, including opportunistic infections and malignancies (especially the Epstein-Barr virus related post-transplant lymphoproliferative disease) have to be balanced with the consequences of graft loss due to rejection. Detransplantation or retransplantation may, in some instances, be preferable to severe infectious or tumoral complications.