Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Maintenance immunosuppressive drugs act by partially blocking rate-limiting steps in the immune response. The new maintenance immunosuppressive drugs are either inhibitors of de novo synthesis of nucleotides (purines or pyrimidines), or are immunophilin-binding drugs that inhibit signal transduction in lymphocytes. The new inhibitors of de novo nucleotide synthesis include mycophenolate mofetil (MMF), mizoribine (MZ), brequinar (BQR), and leflunomide (LEF). MMF and MZ act to inhibit de novo purine synthesis, by inhibition of inosine monophosphate dehydrogenase (IMPDH). They create a selective immunodeficiency in T and B lymphocytes. MMF is hydrolyzed to mycophenolic acid (MPA), an uncompetitive inhibitor of IMPDH. MPA reduces the pools of guanine nucleotides, and increases some adenine nucleotides, inhibiting the cell cycle. Thus the number of specific effector T and B lymphocytes is reduced by limiting clonal expansion. MZ is a competitive inhibitor of IMPDH, which creates a similar defect. The relative clinical effectiveness of MMF versus MZ is not known. MMF has been approved in a number of countries; MZ has been approved in Japan. The inhibitors of de novo pyrimidine synthesis (BQR, LEF) act on the enzyme dehydroorotate dehydrogenase. Neither is currently in clinical trials in transplantation. The new immunophilin-binding drugs inhibit either the calcium-dependent phosphatase calcineurin (CN) [tacrolimus (or FK-506) and the microemulsion form of cyclosporine (CsA)] or signaling from growth factor receptors [rapamycin (sirolimus)]. Tacrolimus binds to FK binding protein-12 (FKBP-12) to create a complex that inhibits CN. CsA binds to cyclophilin to create a complex that inhibits CN. Inhibition of CN prevents activation of cytokine genes in T cells. The relative clinic effectiveness of tacrolimus versus microemulsion CsA is unknown. Rapamycin inhibits signaling from growth factor receptors, such as IL-2R. Rapamycin binds to FKBP to create a complex that engages proteins called TOR (target of rapamycin), or RAFT (rapamycin and FKBP target), which may be kinases. The result is a block in the ability of cytokine receptors to activate cell cycling, interfering with clonal expression. Deoxyspergualin, a parenteral drug in development for induction or antirejection therapy, may inhibit intracellular chaperoning by Hsc70, a member of the heat shock protein family. It may have its principal effect by inhibiting the activation of transcription factor NF-kappa B in antigen-presenting cells and monocytes.
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PMID:Molecular mechanisms of new immunosuppressants. 868 47

Recently, two structures of the Ser/Thr phosphorylase calcineurin in complex with FK506 and its cognate immunophilin, FKBP12, have been reported, both solved by small pharmaceutical companies focused on structure-based drug design. A realization, however, that the toxicities associated with calcineurin-mediated immunosuppressants might be mechanism based has driven the current interest in alternative approaches to autoimmunity prophylaxis and preventing transplant rejection. Regulatory approval in 1995 of the immunosuppressant prodrug mycophenolate mofetil, whose active metabolite, mycophenolic acid, inhibits inosine monophosphate dehydrogenase, has focused attention on the potential significance of the de novo purine-biosynthesis pathway as a target for immunosuppressive drugs, leading ultimately to the solution of enzyme structure as a drug design target. As this and other clinically relevant targets are discovered, elaborated and refined via the activity of their cognate agents (as was the case for the phosphatase calcineurin via the activity of cyclosporin), a critical opportunity should ensue for structural biology to exert a profound effect on the future development of these therapies.
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PMID:Protein-drug complexes important for immunoregulation and organ transplantation. 899 85

Many new agents are in or near clinical trials in organ transplantation. The small molecule antibioticlike drugs are inhibitors of key enzymes in T-cell signal transduction (calcineurin target of rapamycin [TOR], and inosine monophosphate dehydrogenase). Calcineurin inhibitors include cyclosporine microemulsion formulation generic cyclosporine preparations, and tacrolimus. Rapamycin (also known as sirolimus) acts on target of rapamycin to abrogate signals necessary for clonal expansion and is now in phase III. Recent trials of mycophenolate mofetil, an inhibitor of inosine monophosphate dehydrogenase, have shown that it reduces acute renal graft rejection when used with steroids and cyclosporine. New protein reagents in trials include polyclonal antilymphocyte antibodies, mouse monoclonal antibodies, "humanized" mouse monoclonals, and engineered proteins based on naturally occurring signalling molecules. Humanized antibodies against the interleukin-2 receptor are promising because humanized antibodies should combine low toxicity with the potential for long-term use. Engineered human proteins designed to block costimulatory molecules on antigen-presenting cells could have similar potential for low toxicity and extended use. These agents are designed to reduce acute rejection and the toxicity of the existing drugs and eventually improve long-term patient and graft survival. Organ transplant practice will probably change considerably as these agents become available.
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PMID:Immunosuppressive agents in clinical trials in transplantation. 914 38

Pharmacodynamic (PD) monitoring measures the biological response to a drug, which alone--or coupled with pharmacokinetics--provides a novel method for optimization of drug dosing. PD monitoring has been investigated by us and other investigators primarily for four immunosuppressive drugs: cyclosporine (CsA), azathioprine (AZA), mycophenolate mofetil (MMF), and rapamycin (RAPA). PD monitoring of CsA and MMF involves measuring the activity of the enzymes calcineurin and inosine monophosphate dehydrogenase, respectively. The PD of AZA is assessed by measuring the activity of thiopurine methyltransferase, which is induced by a metabolite of AZA, 6-mercaptopurine. The PD for RAPA involves measuring the activity of a P70 S6 kinase in lymphocytes. To date, the most detailed studies have been performed with PD monitoring of CsA and MMF. Similarities exist in the PD responses to CsA and MMF in renal-transplant patients. At trough concentrations in blood, both drugs reduce the activity of their target enzymes by only 50%; however, considerable interpatient variability is evident. Throughout the dosing interval, the enzyme activities parallel the respective drug concentrations. AZA treatment of renal-transplant patients who exhibited an increase in thiopurine methyltransferase activity from time of transplantation resulted in fewer episodes of active rejection. Additional clinical trials are currently underway to relate various pharmacokinetics and PD parameters to clinical response, to ascertain which provides the best guide for dosing. PD monitoring may provide an alternative approach to additional measurements of drug concentrations.
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PMID:Pharmacodynamic monitoring of immunosuppressive drugs. 947 55

Pharmacodynamic monitoring measures biologic response to a drug, which, alone or coupled with pharmacokinetics, provides a novel method for the optimization of drug dosing. Pharmacodynamic monitoring has been investigated by us and other investigators on primarily five immunosuppressive drugs: cyclosporine (CsA), mycophenolate mofetil (MMF), rapamycin (RAPA), azathioprine (AZA), and methylprednisolone (MP). The pharmacodynamic monitoring of CsA and MMF involves measurement of the activity of the enzymes calcineurin and inosine monophosphate dehydrogenase, respectively. The pharmacodynamics of AZA are assessed by measurement of the activity of thiopurine methyl transferase (TPMT), which is induced by a metabolite of AZA, 6-mercaptopurine. The pharmacodyamics for RAPA involve the measurement of a P70 S6 kinase activity within lymphocytes, whereas that for MP involves the measurement of the endogenous synthesis of cortisol by the suppression of the hypothalamic pituitary axis. To date, the most detailed studies have been performed involving pharmacodynamic monitoring of CsA and MMF. Similarities exist in the pharmacodynamic response to CsA and MMF in patients who undergo renal transplantation. At trough concentrations in blood, both drugs result in only a 50% reduction in activity of their target enzymes; however, there is considerable interpatient variability. Throughout the dosing interval, enzyme activity parallels that of drug concentrations. Renal transplant recipients who are treated with AZA and who exhibit an increase in TPMT activity from the time of transplantation experience fewer episodes of active rejection. Renal transplant recipients who are administered MP and in whom suppression of endogenous synthesis of cortisol is greatest exhibit the least incidence of steroid-induced side effects. Additional clinical trials relating pharmacokinetics and pharmacodynamic parameters to clinical response are under way to ascertain which provides the best guide for dosing. Pharmacodynamic monitoring may provide an alternative approach to traditional drug level measurement.
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PMID:The monitoring of immunosuppressive drugs: a pharmacodynamic approach. 978 Jan 18

During the past 50 years, many immunosuppressive drugs have been described. Often their mechanisms of action were established long after their discovery. Eventually these mechanisms were found to fall into five groups: (i) regulators of gene expression; (ii) alkylating agents; (iii) inhibitors of de novo purine synthesis; (iv) inhibitors of de novo pyrimidine synthesis; and (v) inhibitors of kinases and phosphatases. Glucocorticoids exert immunosuppressive and anti-inflammatory activity mainly by inhibiting the expression of genes for interleukin-2 and other mediators. Cyclophosphamide metabolites alkylate DNA bases and preferentially suppress immune responses mediated by B-lymphocytes. Methotrexate and its polyglutamate derivatives suppress inflammatory responses through release of adenosine; they suppress immune responses by inducing the apoptosis of activated T-lymphocytes and inhibiting the synthesis of both purines and pyrimidines. Azathioprine metabolites inhibit several enzymes of purine synthesis. Mycophenolic acid and mizoribine inhibit inosine monophosphate dehydrogenase, thereby depleting guanosine nucleotides. Mycophenolic acid induces apoptosis of activated T-lymphocytes. A leflunomide metabolite and Brequinar inhibit dihydroorotate dehydrogenase, thereby suppressing pyrimidine nucleotide synthesis. Cyclosporine and FK-506 (Tacrolimus) inhibit the phosphatase activity of calcineurin, thereby suppressing the production of IL-2 and other cytokines. In addition, these compounds have recently been found to block the JNK and p38 signaling pathways triggered by antigen recognition in T-cells. In contrast, rapamycin inhibits kinases required for cell cycling and responses to IL-2. Rapamycin also induces apoptosis of activated T-lymphocytes. Immunosuppressive and anti-inflammatory compounds in development include inhibitors of p38 kinase and of the type IV isoform of cyclic AMP phosphodiesterase which is expressed in lymphocytes and monocytes.A promising future application of immunosuppressive drugs is their use in a regime to induce tolerance to allografts. The role of leukocytes in grafts, and the induction of apoptosis of clones of responding T-lymphocytes, is discussed.
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PMID:Immunosuppressive drugs: the first 50 years and a glance forward. 1087 84

Although considerable progress has been achieved using immunosuppressive drugs that inhibit lymphocyte activation and T-cell cytokine signal transduction pathways, the widespread tissue distribution of the molecular targets exploited to date, calcineurin, mammalian target of rapamycin, and inosine monophosphate dehydrogenase, engenders a constellation of collateral toxicities. One strategy to develop new immunosuppressants seeks to identify targets that are critical for and specific to the adaptive immune response. Three approaches have been used to guide this enterprise; molecular design based on steric resemblance of the antagonist to the natural ligand; construction of complementary DNA oligonucleotides that hybridize with the leader sequence of messenger RNA encoding the synthesis of the specific target, thereby preventing production of that protein; and functional comparisons based on similar inhibitory profiles of candidate compounds and a probe that blocks the target nonselectively. Use of these 3 technologies has led to identification of antagonists blocking selectins, intercellular adhesion molecule-1, or Janus kinase 3, respectively. These lead compounds have been tested for their effects on the alloimmune response and/or the ischemia-reperfusion injuries.
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PMID:New approaches to transplant immunosuppression. 1296 33

In recent years, significant milestones have been reached in the field of transplantation through the development of immunosuppressive drugs that inhibit lymphocyte activation, cytokine signal transduction, and cellular proliferation. However, the widespread tissue distribution of the molecular targets exploited to date-calcineurin, mammalian target of rapamycin (mTOR), and inosine monophosphate dehydrogenase-produces an array of collateral toxicities. Avoiding these side effects requires new strategies that selectively block destructive immune responses: a fifth generation of immunosuppressants. These agents must target molecules that are critical for and specific to the adaptive immune response.
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PMID:The emerging matrix of immunosuppressive agents. 1452 43

In the last few years, novel immunosuppressive agents and new formulations, including sirolimus, mycophenolic acid (the active metabolite of mycophenolate mofetil), tacrolimus, and microemulsion cyclosporine, have significantly improved the clinical outcome of transplant recipients. However, the majority of immunosuppressive agents need a constant monitoring of drug levels to reduce the risk of graft rejection as well as drug-induced toxicities. Many factors may affect the pharmacokinetic characteristics of immunosuppressive agents, potentially reducing treatment effectiveness. Absorption and metabolism of immunosuppressive drugs are influenced by patient genotype and comedications, while comorbidities (ie, diabetes and cystic fibrosis) are responsible for altered pharmacokinetics. Dose individualization in transplant recipients is performed according to their health status, graft function, and drug therapeutic range. With respect to the last issue, therapeutic drug monitoring (TDM) plays a crucial role in achieving optimal immunosuppression, improving the efficacy of drugs, and lowering toxic effects. Pharmacokinetic analysis allowed the identification of specific parameters, such as plasma or blood levels, immediately before dosing (C(min) or trough levels) or 2 hours after administration (C(2)), which are significantly related to tissue exposure to the drug. More recently, studies have investigated treatment individualization by evaluating drug pharmacogenetics based on the expression level or mutations of their molecular targets, including calcineurin for cyclosporine and tacrolimus, and inosine monophosphate dehydrogenase for mycophenolic acid. Although no conclusive data may be drawn from these preliminary trials, further studies are underway to address the role of pharmacogenetics in clinical decision making.
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PMID:Prospects for personalized immunosuppression: pharmacologic tools--a review. 1511 Jun 31

Biomarkers are characteristics that are objectively measured and evaluated as indicators of normal biological processes, pathogenic processes, or pharmacological responses to a therapeutic intervention. Biomarkers of pharmacological responses allow pharmacokinetic-pharmacodynamic modelling based on what is known of the mechanism of action of the drug. Characteristics predictive of the pharmacological response, such as a genotype, constitute a specific category of biomarkers and can be used as covariates in the model. In the case of "classical" immunosuppressive agents, the biomarkers of response most studied are lymphocyte calcineurin activity for ciclosporin and tacrolimus, and inosine monophosphate dehydrogenase activity for mycophenolate. Pharmacokinetic-pharmacodynamic analysis of monoclonal antibodies with immunosuppressive properties requires complex models and immunological biomarkers such as, for example, the number of circulating lymphocytes with a given surface antigen. Pharmacodynamic indirect response models are particularly relevant in this instance.
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PMID:[Biomarkers and pharmacokinetic-pharmacodynamic studies of immunosuppressive agents]. 1535 9


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