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1. |
Proceedings of the International Consensus Conference on Immunosuppressive Drugs |
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Therapeutic Drug Monitoring,
Volume 17,
Issue 6,
1995,
Page 559-559
Steven Soldin,
Leslie Shaw,
Randall Yatscoff,
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ISSN:0163-4356
出版商:OVID
年代:1995
数据来源: OVID
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2. |
The Evolution of Therapeutic Immunosuppression and the Potential Impact of Drug Concentration Monitoring |
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Therapeutic Drug Monitoring,
Volume 17,
Issue 6,
1995,
Page 560-563
Barry Kahan,
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摘要:
SummaryThe major goal of immunosuppressive development is improved selectivity of the drug's inhibitory action against T and B cell-mediated as opposed to nonspecific granulocyte-, monocyte-, and macrophage-mediated resistance. This enterprise demands increased knowledge of alloantigen-induced stimulation, signal transduction, and/or maturation pathways of T and B cells. A second approach seeks to harness synergistic combinations of existent albeit not entirely specific agents in order to potentiate immunosuppressive and minimize drug-induced toxicity by using subtherapeutic doses of each agent. The development of synergistic regimens demands not only good estimates of drug effects but also precise measures of drug concentrations because therapeutic effects do not reflect administered doses. Therefore, until immunologie assays are available to assess biologic effects and until drug receptor concentrations can be estimated, there is an increasing need for therapeutic drug monitoring (TDM) to afford reliable surrogates that predict the clinical outcomes of therapeutic regimens. The application of mathematical models such as the median effect analysis provides a quantitative tool for this enterprise. Thus, TDM methodologies seem to present the best available approach to develop secure algorithms for clinical immunosuppression.
ISSN:0163-4356
出版商:OVID
年代:1995
数据来源: OVID
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3. |
Mechanisms of Action of New Immunosuppressive Drugs |
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Therapeutic Drug Monitoring,
Volume 17,
Issue 6,
1995,
Page 564-569
Randall Morris,
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摘要:
SummaryMore immunosuppressive drugs than ever have recently graduated from the laboratory to extensive clinical trials of their safety and efficacy in transplant patients. None of these drugs is perfect, but they control different forms of rejection in stringent animal models more effectively than other immunosuppressants, and these novel molecules suppress the immune system far more specifically than steroids and regimens that cause lymphopenia. Cyclosporin A and FK506 are the only drugs that selectively inhibit T-cell proliferation by blocking cytokine synthesis. The primary action of rapamycin appears to be inhibition of the actions of cytokines and growth factors on T, B, and some nonimmune cells. T and B cells are more sensitive than nonimmune cells to the depletion of purines and pyrimidines caused by mizoribine, mycophenolate mofetil, brequinar sodium, and leflunomide. Nucleotide depletion causes interruption of DNA synthesis and glycosylation of adhesion molecules in immune cells. Further differentiation of T and B cells after proliferation into fully functional immune cells is inhibited by unknown mechanisms of brequinar and deoxyspergualin. On the basis of preclinical studies, these drugs may effectively suppress clinical rejection that is acute (all), chronic (rapamycin, leflunomide, mycophenolate mofetil), or antibody mediated (brequinar, deoxyspergualin, mycophenolate mofetil, rapamycin, leflunomide). Some drugs (FK506, deoxyspergualin, mycophenolate mofetil, rapamycin, leflunomide) may reverse acute rejection refractory to conventional immunosuppression. Not only do these new drugs block different biochemical steps that normally lead to fully functional T and B cells after stimulation by alloantigen, but their toxicity profiles also differ. Results from preclinical studies predict that use of selected combinations of these drugs will be more effective, less nephrotoxic, less myelotoxic, and less broadly immunosuppressive than current regimens based on cylcosporine, T-cell depletion, steroids, and azathioprine.
ISSN:0163-4356
出版商:OVID
年代:1995
数据来源: OVID
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4. |
Pharmacokinetics and Therapeutic Drug Monitoring of Immunosuppressants |
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Therapeutic Drug Monitoring,
Volume 17,
Issue 6,
1995,
Page 570-573
Anders Lindholm,
Juliette Säwe,
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摘要:
SummaryImmunosuppressive drug treatment has developed considerably in recent years with new methods describing pharmacokinetic-pharmacodynamic relationships. Using in vitro models it is possible to predict the success of clinical immunosuppressive drug combinations. Furthermore, with the advances of analytical methodology it is now possible to measure minute amounts of potent immunosuppressants and to adjust dosing based on concentration measurements. Concentration control, which first was required for cyclosporine A, is being investigated for most immunosuppressive drugs in development. Characterisation of individual drug pharmacokinetics form the basis for successful immunosuppression. Among possible therapeutic drug monitoring methodologies, trough level monitoring is currently the method of choice.
ISSN:0163-4356
出版商:OVID
年代:1995
数据来源: OVID
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5. |
Receptor (Immunophilin‐Bhiding) Assay for Immunosuppressive Drugs |
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Therapeutic Drug Monitoring,
Volume 17,
Issue 6,
1995,
Page 574-576
Steven Soldin,
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摘要:
SummaryThe major immunophilins that bind cyclosporine (cyclophilin) and FK-506/rapamycin (FK-BP12) have been well characterized. They possess rot-amase activity, which is inhibited by the immunosuppressant that binds to them. The immunosuppressive action does not appear to be coupled to rotamase activity. The literature on some possible mechanisms of immunosuppression is reviewed. Minor immunophilins of 14, 37, and 52 kDa have also been isolated and partially characterized. The 14-kDa immunophilin binds FK-506 and rapamyein whereas the 52-kDa immunophilin binds all three drugs. Neither of these proteins have rotamase activity. Receptor assays employing immunophilins have been developed. Preliminary results are encouraging indicating that they may possess some advantages over current immunoassay procedures.
ISSN:0163-4356
出版商:OVID
年代:1995
数据来源: OVID
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6. |
Analytic Requirements for Immunosuppressive Drugs in Clinical Trials |
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Therapeutic Drug Monitoring,
Volume 17,
Issue 6,
1995,
Page 577-583
Leslie Shaw,
Thomas Annesley,
Bruce Kaplan,
Kenneth Brayman,
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摘要:
SummaryEssential to the evaluation of (1) the pharmacokinetics, (2) concentration-effect relationships, and (3) the application of therapeutic drug monitoring, during new immunosuppressive drug clinical trials, is the development of validated analytical methodology for the measurement of pharmacologically active drug and metabolites in biofluids and tissues. The characteristics of analytical methodology developed for cyclosporines A and G, FK-506, mycophenolate mofetil, and rapamycin during clinical trials will be described. The advantages of establishing validated analytical methodology as early as possible during clinical trials include: (a) early identification of metabolites and their quantitative and pharmacological significance; (b) early development of interpretable PK and PK-PD data; (c) accrual of experience that will be directly useful in patient monitoring after drug approval; (d) optimization of analysis conditions; and (e) early development of reference methodology for therapeutic drug monitoring tests. A suggested set of performance criteria for drug analysis during clinical trials and thereafter will be presented.
ISSN:0163-4356
出版商:OVID
年代:1995
数据来源: OVID
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7. |
Mode of Action of Tacrolimus (FK506): Molecular and Cellular Mechanisms |
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Therapeutic Drug Monitoring,
Volume 17,
Issue 6,
1995,
Page 584-591
A. Thomson,
C. Bonham,
A. Zeevi,
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摘要:
SummaryTacrolimus, formerly known as FK506, is a macrolide antibiotic with immunosuppressive properties. Although structurally unrelated to cyclosporin A (CsA), its mode of action is similar. It exerts its effects principally through impairment of gene expression in target cells. Tacrolimus bonds to an immunophilin, FK506 binding protein (FKBP). This complex inhibits calcineurin phosphatase. The drug inhibits calcium-dependent events, such as interleukin-2 gene transcription, nitric oxide synthase activation, cell degranulation, and apoptosis. Tacrolimus also potentiates the actions of glucocorticoids and progesterone by binding to FKBPs contained within the hormone receptor complex, preventing degradation. The agent may enhance expression of the transforming growth factor beta-1 gene in a fashion analogous to that demonstrated for CsA. T cell proliferation in response to ligation of the T cell receptor is inhibited by tacrolimus. Type 1 T helper cells appear to be preferentially suppressed compared with type 2 T helper cells. T cell-mediated cytotoxicity is impaired. B cell growth and antibody production are affected indirectly by the suppression of T cell-derived growth factors necessary for these functions. Antigen presentation appears to be spared. The molecular events affected by tacrolimus continue to be discovered.
ISSN:0163-4356
出版商:OVID
年代:1995
数据来源: OVID
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8. |
FK506 in Solid Organ Transplantation |
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Therapeutic Drug Monitoring,
Volume 17,
Issue 6,
1995,
Page 592-595
John Fung,
Thomas Starzl,
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摘要:
SummaryFK506 (Prograf) is a new immunosuppressive agent, recently approved for use in solid organ transplants. The first use of FK506 was for the indication of refractory liver allograft rejection. This revealed a marked ability to reverse ongoing rejection, even in cases where chronic changes were observed. Between 50 and 70% of patients converted to FK506 had shown improvement. In long-term follow-up of patients with chronic rejection, 75% of patients were still alive at 3 years following FK506 conversion, and 65% of liver allografts were still functioning. FK506 has been compared to cyclosporine in primary liver transplantation. In the three randomized trials, freedom from rejection was statistically greater in the FK506-treated group, as compared to the cyclosporine-treated group. By intent-to-treat analysis, the patient and graft survival in the FK506 group was the same or better than the cyclosporine group. The good results in the cyclosporine limb was due, in part, to the ability of FK506 to treat rejection in the cyclosporine group. Freedom from steroid use, and the lower incidence of hypertension, were prominent features of FK506 patients. FK506 has been used for rescue of rejecting kidney allografts, with results similar to the liver transplant trials. When used as primary immunosuppression, FK506 was shown to be effective, as measured by graft survival. FK506-based immunosuppression has also been used in primary heart transplantation, as well as for primary adult pulmonary transplantation. Results from these small series of patients are equally encouraging. The results of these studies suggest that FK506 is effective for solid organ transplantation. Both FK506 and cyclosporine administration have been associated with side effects, many of which are similar, and some of which are peculiar to a given organ transplant.
ISSN:0163-4356
出版商:OVID
年代:1995
数据来源: OVID
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9. |
Analysis of Tacrolimus (FK 506) in Relation to Therapeutic Drug Monitoring |
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Therapeutic Drug Monitoring,
Volume 17,
Issue 6,
1995,
Page 596-601
William Jusko,
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摘要:
SummaryTacrolimus (FK506) is a macrolide lactone which is used as an immunosuppressant agent for organ transplantation. Patient monitoring during clinical trials initially involved use of extraction/enzyme immunoassays (ELISA) for plasma and whole blood concentrations of FK506. Therapeutic concentrations of FK506 are 0.4–1.2 ng/ml in plasma and 5–20 ng/ml in whole blood. Blood:plasma ratios are variable among patients and range from 11 to 114. A validation and quality assurance program was established to standardize procedures and assure concordance of ELISA analytic results from clinical sites participating in liver/kidney trials. HPLC/ELISA methods have been used for assessing assay specificity. Comparison of the ELISA method with a HPLC-MS procedure (TexMS) shows good correlation, but indicates metabolite inclusion in the ELISA. This method may be of value in conditions of altered FK-506 metabolism. Commercialization of the immunoassay has been made by Incstar with the ELISA and Abbott Laboratories with an IMxprocedure; the two methods are generally comparable. Additional methods offering clinical promise are radioreceptor and pentamer complex ELISA assays. There are diverse methods offering sensitive quantitation but with varying specificity for tacrolimus in patient plasma and whole blood.
ISSN:0163-4356
出版商:OVID
年代:1995
数据来源: OVID
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10. |
Therapeutic Drug Monitoring of Tacrolimus in Clinical Transplantation |
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Therapeutic Drug Monitoring,
Volume 17,
Issue 6,
1995,
Page 602-605
P. McMaster,
D. Mirza,
T. Ismail,
G. Vennarecci,
P. Patapis,
A. Mayer,
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摘要:
SummaryInitial clinical trials of FK did not incorporate available FK levels, and difficulties were quickly experienced particularly with neurotoxicity and nephrotoxicity. The introduction of routine assay allowed broad parameters to be identified, which assisted in evaluating effective therapeutic parameters. Levels 20 ng/ml were frequently associated with toxicity and the initial therapeutic range between 10–25 ng/ml was probably excessive. Reliable effective assay >5 ng/ml using the Abbott IMxis not available, and many patients will have excellent hepatic or renal function with what are currently undetectable levels of FK. However, IncStar have an ELISA assay with a sensitivity of 0.5 mg/ml. Clinical practice does not, at this time, dictate elevation of FK, although careful monitoring continues. Education of oral administration from 0.15 mg/kg to 0.1 mg/kg in combination therapy with steroids and 0.05 mg/kg with azathioprine and steroids has led to revision of therapeutic parameters, e.g., 5–15 ng/ml is now widely used. Therapeutic drug monitoring is important to avoid unnecessary toxicity, but the lower limit has not been fully defined. Clearly, many patients with <5 ng/ml have excellent hepatic function.
ISSN:0163-4356
出版商:OVID
年代:1995
数据来源: OVID
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