摘要:

Summary:The current health care environment of cost-cutting highlights the need to reinforce the contribution of laboratory medicine to improvement in health care. This must be a patient-focused activity using continuous quality improvement, a familiar concept in laboratory practice. Involvement in the creation of clinical practice guidelines, care maps, and outcome measures will place laboratory medicine in the circle of continuous quality improvement. The laboratory must provide strong evidence that tests contribute to better overall resource utilization. Laboratory Information Systems can be used to better integrate laboratory data with clinical, diagnostic, pharmaceutic, statistical, and financial information. Improving laboratory utilization requires clear demonstrations of appropriate versus inappropriate laboratory use, and instructions on implementing appropriate use. The education of laboratory professionals should include search strategies, understanding the diagnostic accuracy of medical tests, and the application of systematic reviews and meta-analysis. With the rapid increase in the data base supporting evidence-based laboratory medicine, there is a significant challenge in translating the existing knowledge into practice. There is also a need for a cooperative strategy between the diagnostics industry and the laboratory medicine profession to provide evidence of the added value of laboratory testing. There is a significant role in developing the academic basis of the unique aspects of evidence-based laboratory medicine.

ISSN:0163-4356    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Summary:Mycophenolic acid, the active metabolite of the immunosuppressant and antiproliferative agent, mycophenolate mofetil, is primarily metabolized by glucuronidation to the inactive 7-O-glucuronide. Although the uridine diphosphate (UDP) 7-0-glucuronide is the principal excretion product of this drug, carboxyl-linked glucuronides have also been detected in vitro and in vivo. To identify human UDP glucuronosyltransferases that are active in the glucuronidation of mycophenolic acid, cDNAs encoding individual UDP glucuronosyltransferase forms have been expressed in cell culture, and the capacity of the expressed enzymes to use mycophenolic acid as a substrate has been assessed. Two UDP glucuronosyltransferase forms, UGT1A8 and UGT1A10, were active in the glucuronidation of mycophenolic acid. Both enzymes are predominantly expressed in the gastrointestinal tract and hence, may play a role in the metabolism of mycophenolic acid in the gastrointestinal tract and in the acquisition of resistance to the mito-inhibitory effects of this drug in cultured human colorectal carcinoma cell lines. The identities of the UDP glucuronosyltransferase forms that are mainly responsible for the glucuronidation of mycophenolic acid in the liver and kidney remain unknown; however, UGT1A9 may be important in this respect as the cDNA-expressed enzyme has some capacity to glucuronidate mycophenolic acid. Other UGT1A forms in the liver and kidney (UGT1A1, UGT1A3, UGT1A4, and UGT1A6) were inactive toward mycophenolic acid.

ISSN:0163-4356    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Summary:Data have emerged that provide the scientific basis for therapeutic drug monitoring of mycophenolic acid (MPA) in transplant patients receiving mycophenolate mofetil (MMF), the parent drug, in combination with other immunosuppressive agents. There is a significant relationship between the dose-interval MPA AUC and risk for acute rejection based on retrospective investigations in renal and heart transplant patients and on prospective investigations in renal transplant patients. The MPA dose-interval AUC varies naturally by more than 10-fold in renal and heart transplant patients. Other significant sources of pharmacokinetic variability for MPA include the effects of concomitant medications, and the effects of disease states such as renal dysfunction and liver disease on the steady state MPA AUC. Individualized MMF dose evaluation, guided by MPA plasma concentrations, is becoming the standard of practice at a growing number of transplant centers worldwide because of these factors and because of the need to closely evaluate the immunosuppression afforded by MPA when a change in the immunosuppression regimen in stable transplant patients is planned. Investigations of therapeutic drug monitoring strategies with an emphasis on identifying an optimal abbreviated sampling strategy for MPA AUC estimation are ongoing. Based on the concentration-outcome studies and experience at the authors' institutions and other centers, the authors propose a set of therapeutic drug monitoring guidelines for MPA in stable renal and heart transplant patients for the immediate (first 3 months posttransplant) and maintenance (>3 months) periods. When MPA binding to human serum albumin is altered, as occurs in patients with significant renal dysfunction, liver disease, or a substantial reduction in human serum albumin concentration, the possibility of increased MPA free fraction and free concentration will need to be taken into account in the interpretation of MPA total concentrations.

ISSN:0163-4356    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Summary:The need for mycophenolic acid (MPA) monitoring is still under discussion. Key issues for the PK/PD relationships of this drug are: the role of metabolites, the usefulness of AUC versus predose levels, and the need to monitor the free concentration of MPA (f-MPA). Recent advances have revealed that, in addition to 7-O-MPAG, three additional MPA metabolites are present in the plasma of transplant recipients. One of these metabolites (M-2), identified as an acyl glucuronide of MPA, was found to inhibit IMPDH-II in vitro. This active metabolite was also found to cross-react in the Emit assay for MPA. In an ongoing multicenter study, the authors are evaluating the relevance of monitoring total (t-MPA) and free mycophenolic acid (f-MPA) in pediatric renal transplant recipients. As in adults, a time-dependent increase of t-MPA-AUC0–12hwithin the first 3 months posttransplant (35 versus 64 mg × L/h, 3 weeks versus 3 months respectively; daily dosage: 0.6 g/m2bid) was seen. Receiver operating characteristics curve analyses were used to test the ability of predose levels or AUC0–12hto discriminate between cases with no complications and those with acute rejection, adverse events (severe infections, leukopenia), or gastrointestinal disorders observed during the early posttransplant course. In agreement with observations in adults, a significant (p = 0.001) association was observed between AUC0–12hand acute rejection. A t-MPA-AUC0–12hof approximately 30–60 mg × L/h, as determined by HPLC, seems to be a reasonable target for the early posttransplant period. It remains to be elucidated whether regular predose level monitoring may be of more practical value. A higher incidence of rejection was observed at predose MPA concentrations ≤1mg/L, as measured by HPLC. In contrast to t-MPA, f-MPAAUC0–12hwas significantly related to severe infections and leukopenia. The risk for severe adverse events was increased at f-MPA-AUC0–12hvalues ≥600 &mgr;g × L/h. On the basis of these data and the observed variability in the pharmacokinetics of MPA, the development of monitoring strategies for this drug appears to be promising.

ISSN:0163-4356    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Summary:Mycophenolate mofetil (MMF) is now widely used in solid organ transplantation. MMF is rapidly converted to its active form, mycophenolic acid (MPA), upon reaching the systemic circulation. MPA is metabolized to its glucuronide metabolite, mycophenolic acid glucuronide (MPAG), by glucoronyl transferases in the liver and possibly elsewhere. MPAG is then excreted by the kidney. MPA is extensively and avidly bound to serum albumin. Previous studies have demonstrated that it is only the free (non–protein-bound) fraction of MPA that is available to exert its action. In vivo and in vitro studies demonstrate that renal insufficiency decreases the protein binding of MPA and increases free MPA concentrations. This decrease in protein binding seems to be caused both by the uremic state itself and by competition with the retained metabolite MPAG. The disposition of MPA in patients with severe renal impairment may be significantly affected by this change in protein binding.

ISSN:0163-4356    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Summary:Sirolimus (rapamycin, Rapamune) is a potent immunosuppressive drug that received marketing approval from the US Food and Drug Administration on September 15, 1999. Research into defining its pharmacokinetic (PK) behavior, interaction with other agents, and metabolism is ongoing. It has been established that oral doses of both liquid and solid formulation are rapidly, though incompletely and variably, absorbed. Metabolism by the intestinal and hepatic CYP3A family of enzymes likely contributes to variability in absorption and low bioavailability. Sirolimus has a long terminal half-life, the AUC correlates well with trough and peak concentrations, and it exhibits a moderate degree of dose proportionality. There is significant interpatient variability in PK parameters of sirolimus, though it exhibits predictable PK behavior when used with prednisone and cyclosporine neoral. There is a decreased rejection risk with higher doses and target level attainment. Several species of sirolimus metabolites have been characterized, and are measurable in whole blood and tissue specimens. Many more species of sirolimus metabolites are detectable, but they are not quantifiable at this time. The total concentration of metabolites appears to be less than that of the parent drug when examined through the PK profile. A reference method for the quantitation of metabolites remains elusive because of a lack of proper standardization. The clinical significance of sirolimus metabolites remains to be proven.

ISSN:0163-4356    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Summary:Immunosuppressive drugs have contributed significantly to the success of organ transplantation. Therapeutic drug monitoring is an integral part of transplant protocols. However, there is little information concerning its positive contribution to pharmacoeconomics. Before developing studies to demonstrate the potential benefits of TDM, consideration must be given to the type of TDM to be evaluated. It is argued that, given that the lymphocyte in the central compartment is the target for immunosuppressants, Area-Under-the-Curve monitoring may be a better reflection of control and toxicity than traditional trough monitoring.

ISSN:0163-4356    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Summary:Cytokines participate in the induction and effector phases of all immune and inflammatory responses. They are therefore obvious candidates for exploitation as drugs or drug targets to promote, limit, or alter these responses in infection, allergy, autoimmunity, and other disease states. Although some cytokines and related molecules are already in clinical use, the full therapeutic potential of this class of hormones has yet to be realized, and this will depend in part on understanding their normal functions and regulation in health and disease. An overview is given of the cytokines and their receptors, their genetic and structural relationships, and the regulation of their activities by naturally occurring antagonists and other physiologic mechanisms. Some of the ways in which new therapeutic strategies are being developed from knowledge of the structure, function, and regulation of these various components of the cytokine network are outlined.

ISSN:0163-4356    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Summary:This article reviews recent developments in the immunophilin arena and the current state of knowledge about the biochemical properties of immunophilins. The role of immunophilin-binding assays is also explored with the conclusion that some of these immunosuppressive-drug–binding proteins may provide better assays for sirolimus and tacrolimus than current immunoassays.

ISSN:0163-4356    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Summary:The chemical 2-amino-2[2-(4-octylphenyl)ethyl]-1,3,propane diol is one of a class of small-molecule immunosuppressive agents. Better known as FTY720, this compound was chemically synthesized in an effort to minimize the toxic in vivo properties of a structurally related and highly potent immunosuppressive agent, myriocin. FTY720's mechanism of action, although not fully characterized, appears to be unique among immunosuppressants. Whereas the most well known biochemical characteristic of myriocin is its ability to inhibit serine palmitoyl transferase, the enzyme that initiates the biosynthetic pathway that leads to sphingosine, FTY720 is ineffective in this regard. In vivo, FTY720 induces a significant reduction in the number of circulating lymphocytes. It is thought to act by altering lymphocyte trafficking/homing patterns through modulation of cell surface adhesion receptors and ligands in a manner that has yet to be elucidated. Although much research has yet to be done to unravel the nature of the mechanism of action of FTY720, its efficacy has been sufficiently proven in numerous animal models, especially when administered in combination with cyclosporine. The agent is now progressing through human clinical trials, with the results of phase 1 clinical trials showing safety and tolerability in adult recipients of renal transplants. It is hoped that FTY720 will eventually prove to be an efficacious new weapon in the immunosuppressive armamentarium.

ISSN:0163-4356    

出版商:OVID    

年代:2000

数据来源: OVID