Population pharmacokinetics and Bayesian estimation of mycophenolic acid concentrations in stable renal transplant patients

BACKGROUND: Therapeutic drug monitoring of mycophenolic acid (MPA) may minimise the risk of acute rejection after transplantation. Area under the curve (AUC) rather than trough concentration-based monitoring is recommended and models for AUC estimation are needed. OBJECTIVES: To develop a population pharmacokinetic model suitable for Bayesian estimation of individual AUC in stable renal transplant patients. PATIENTS AND METHODS: The population pharmacokinetics of MPA were studied using nonlinear mixed effects modelling (NONMEM) in 60 patients (index group) receiving MPA on a twice-daily basis. Ten blood samples were collected at fixed timepoints from ten patients and four blood samples were collected at sparse timepoints from 50 patients. Bayesian estimation of individual AUC was made on the basis of three blood concentration measurements and covariates. The predictive performances of the Bayesian procedure were evaluated in an independent group of patients (test group) comprising ten subjects in whom ten blood samples were collected at fixed timepoints. RESULTS: A two-compartment model with zero-order absorption best fitted the data. Covariate analysis showed that bodyweight was positively correlated with oral clearance. However, the weak magnitude of the reduction in variability (from 34.8 to 28.2%) indicates that administration on a per kilogram basis would be of limited value in decreasing interindividual variability in MPA exposure. Bayesian estimation of pharmacokinetic parameters using samples drawn at 20 minutes and 1 and 3 hours enabled estimation of individual AUC with satisfactory accuracy (bias 7.7%, range of prediction errors 0.43-15.1%) and precision (root mean squared error 12.4%) as compared with the reference value obtained using the trapezoidal method. CONCLUSION: This paper reports for the first time population pharmacokinetic data for MPA in stable renal transplant patients, and shows that Bayesian estimation can allow accurate prediction of AUC with only three samples. This method provides a tool for therapeutic drug monitoring of MPA or for concentration-effect studies. Its application to MPA monitoring in the early period post-transplantation needs to be evaluated.     

Polyploidisation of metastatic colon carcinoma cells by microtubule and tubulin interacting drugs: effect on proteolytic activity and invasiveness

When SW620 colon cancer-derived metastatic cells were exposed to nanomolar concentrations of Taxol, colchicine or (Z)-3,5,4'-trimethoxystilbene (R3), huge aneuploid, polynuclear cells survived the treatment. These cells released considerable amounts of the matrix metalloproteinase matrilysin (MMP-7), and tissue-type plasminogen activator (tPA) into the surrounding culture medium. MMP-7, and other proteolytic enzymes were highly expressed by these cells. In spite of their enormous size, the polyploid cells exhibited a considerable migratory capacity, as was demonstrated by their migration through an artificial basement membrane. While colchicine and R3-treated cells showed an inverse relationship between drug concentration and invasiveness, treatment with Taxol increased the capacity of the SW620 cells to penetrate through the membrane. The invasive capacity was not correlated with the induction and release of proteolytic enzymes. The idea that expression and release of proteolytic enzymes is a fundamental prerequisite of tumour cell invasiveness is generally accepted. The ability of the cells to respond to chemotactic signalling, and the filamentous structures of the cells, together with several cell adhesion factors, which are the basis of cell migration, are prerequisites of invasiveness. These factors are presumably different in the aneuploid cells produced by Taxol, colchicine and R3, and await scrutiny.     

Intestinal transplantation

Advances in immunosuppressive treatment as well as better monitoring and control of acute rejection have brought intestinal transplantation (ITx) into the realm of standard treatment for permanent intestinal failure. The results from the intestinal Transplant International Registry (www.intestinaltransplant.org) indicate that ITx is currently an acceptable clinical modality for selected patients with permanent intestinal failure¹. The goal of this short review is to deal with indications, clinical results and complications of ITx. Although it has been used in humans for the past two decades, very few data are available regarding graft function and its monitoring.     

Genetic information and life insurance: a 'real' risk?

Public concern about genetic discrimination, particularly access to insurance following genetic testing, has been reported in the literature. This paper aims to separate myths from realities regarding genetic discrimination in life insurance and to underline the positive aspects of allowing insurers access to relevant genetic information for underwriting purposes. We present a review of the literature pertinent to discrimination in life insurance and a comparative analysis of industries guidelines. There are few reported cases in the literature of validated genetic discrimination. However, the benefits to be gained by allowing insurers access to relevant genetic data could justify fostering a more active role in the use of genetic information by insurance companies.     

Contribution of magnetic resonance spectrometry to the diagnosis of intracranial tumors

Magnetic resonance spectroscopy (MRS) is a method enabling the analysis of the tissue metabolic content. It may offer a more accurate diagnosis of the intracranial tumors than conventional MRI sequences. MRS of normal brain parenchyma displays 4 main metabolites: N-acetyl aspartate (neuronal marker), creatine (cellular density marker), choline (membrane activity marker) and myoinositol (glial marker); pathological processes lead to variations of the level of these metabolites and/or the appearance of abnormal metabolites (lactate), following different patterns according to pathological process involved: glioma, meningioma, metastasis, bacterial or toxoplasmic abscess, radionecrosis. The potential clinical use of this method includes positive, differential and etiological diagnosis of tumors, determination of the level of malignancy of gliomas, screening for tumor recurrence following treatment. Our laboratory has been performing MR spectroscopic explorations of brain tumors for many years. Based on this experience, we show how MRS can be routinely performed in the clinical setting, what are its limitations and potential, and what kind of information can be supplied to the clinician.     

北京市40家基层医院高血压防治硬件条件的现状调查

目的 了解北京市基层一、二级医院高血压诊断治疗相关辅助检查设备以及抗高血压药物的拥有和使用现状,评估基层医院开展高血压防治工作的能力。从医院硬件条件(辅助检查设备、药物等)的角度分析基层医院实施《中国高血压防治指南》(以下简称《指南》)的过程中可能存在的障碍和问题。方法 采用面访和问卷调查的方式,访问北京市部分基层医院主管业务的院长以及检验科、药房、影像科的相关业务主管,了解医院高血压相关辅助检查设备及用药情况。结果 (1)被调查的二级医院现有的设备条件基本能够满足《指南》提出的对高血压患者进行临床评估的要求;(2)64．5％的一级医院具有开展高血压防治所需要的最基本的设备和检查项目,35．5％的一级医院检查项目不全(缺少血离子、尿蛋白、血浆肌酐浓度等检测);(3)71．0％的一级医院无法独立完成患者靶器官损害的评估工作;(4)一、二级医院抗高血压药物的种类比较齐全,可以满足患者治疗的需要。结论 只要相关实验室检查项目配备齐全,基层医院完全有能力按照《指南》的要求开展高血压的治疗和疗效监测工作,但一级医院需要和上级医院配合才能完成对高血压患者全面的临床评估。     

The reversed Delta shoulder prosthesis in reconstruction of the proximal humerus after tumour resection

The authors present two series of six and seven patients respectively, with a tumour of the proximal humerus, who were treated at two different institutions with a Delta type inverted shoulder prosthesis (DePuy International Ltd) after a Malawer type Ia or Ib resection. The rationale of using an inverted shoulder prosthesis is the aim to improve the functional outcome in rotator cuff deficient shoulders. This type of prosthesis medializes and lowers the centre of rotation, lengthens the lever arm of the deltoid muscle and improves its function. At one institution the resected part of the humerus was re-implanted after extracorporeal irradiation. It was fixed intramedullarly by cementation of the humeral prosthetic component to facilitate restoration of humeral height. This graft allowed reinsertion of muscles (deltoid, pectoralis, biceps) thus improving power generation postoperatively. The largest glenosphere, size 42, was routinely used to reconstruct the glenoid; this theoretically improves the functional outcome (increased external rotation) and stability. At the other institution no graft augmentation was used except in one patient. The height of the humeral prosthetic component was assessed after resection of the tumour by measurement of the resected part. The prosthetic stem was fitted in the remaining part of the humeral diaphysis, in three cases by cementation and in three cases by press-fit (hydroxyapatite coating). Muscle balance was appreciated intra-operatively. Stability of the prosthesis was directly related to the level of resection. Both techniques resulted in a minimum active abduction of 60 degrees, reaching 90 degrees or more in most patients. When compared to other results in the literature, this is a major functional improvement. The mean adjusted postoperative Constant score was 72.5% (range: 30-90%), and the mean MSTS score was 75.8% (range 36.7-96.7%).     

Resveratrol analog (Z)-3,5,4'-trimethoxystilbene is a potent anti-mitotic drug inhibiting tubulin polymerization

Resveratrol (3,5,4'-trihydroxystilbene) a natural polyphenol present in medicinal plants, grapes and wines, has potent chemopreventive properties on intestinal carcinogenesis. A methylated derivative (Z-3,5,4'-trimethoxystilbene: R3) was synthesized. R3 at 0.3 microM exerted a 80% growth inhibition of human colon cancer Caco-2 cells and arrested growth completely at 0.4 microM (R3 was 100-fold more active than resveratrol). The cis conformation of R3 was also 100-fold more potent than the trans isomer. R3 (0.3 microM) caused cell cycle arrest at the G2/M phase transition. The drug inhibited tubulin polymerization in a dose-dependent manner (IC50=4 microM), and it reduced also by 2-fold ornithine decarboxylase and s-adenosylmethionine decarboxylase activities. This caused the depletion of the polyamines, putrescine and spermidine, which are growth factors for cancer cells. R3 inhibited partially colchicine binding to its binding site on tubulin, indicating that R3 either partially overlaps with colchicine binding or that R3 binds to a specific site of tubulin that is not identical with the colchicine binding site modifying colchicine binding by allosteric influences. The resveratrol derivative (Z)-3,5,4'-trimethoxystilbene (R3) is an interesting anti-mitotic drug that exerts cytotoxic effects by depleting the intracellular pool of polyamines and by altering microtubule polymerization. Such a drug may be useful for the treatment of neoplastic diseases.