Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Because virtually all of the currently available oral immunosuppressive agents show significant inter- and/or intrapatient variability, drug doses do not predict patient exposure, which is the critical parameter of efficacy versus toxicity. Therefore, at least for the critical-dose baseline immunosuppressive agents CsA and tacrolimus, all transplant centers use some sort of therapeutic drug monitoring. However, for CsA, Cminss values show a poor correlation with exposure and therefore are of limited use. Reliable therapeutic drug monitoring demands some measure of CsA absorption profiles with or without an estimate of clearance rates. The suggested methods include full AUC, limited sampling AUC, and a single 2- or 3-hour post-dose blood concentration. For tacrolimus, Cminss displays a reasonable correlation with systemic drug exposure as measured by AUC, however, there is little correlation between Cminss and clinical events within recommended therapeutic ranges. Sirolimus, which has been recently approved for use in kidney transplant recipients by the Food and Drug Administration in 2 or 5 mg doses, also shows the behavior of a critical-dose drug and that therapeutic monitoring using trough levels correlate strongly with drug exposure and the occurrence of adverse events. However, there is no approved automated assay and thus LC estimates must be utilized to estimate exposure. Pharmacodynamic drug monitoring opportunities are available for calcineurin inhibitors, MMF and sirolimus, but none is currently available for clinical use; however, the field of transplant pharmacodynamics is progressing rapidly. In the coming decade it is likely that an array of pharmacodynamic tools will be developed to complement the available pharmacokinetic information and lead to the development of models that predict optimal concentrations at the target sites in order to maximize immunosuppression and minimize toxic effects.
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PMID:Pharmacological surrogates of allograft outcome. 1121 2

Cyclosporin and tacrolimus have improved survival figures in organ transplantation. However, both drugs are potentially nephrotoxic. The immunosuppressive and nephrotoxic effects of both drugs appear to depend on the inhibition of calcineurin. Cyclosporin and tacrolimus cause acute (functional changes) and chronic nephrotoxicity (structural lesions in the kidney). These last important lesions include arteriolar hyalinosis, stripped interstitial fibrosis and tubular atrophy. It is possible that repeated episodes of renal ischaemia contribute to the development of chronic nephrotoxicity and then chronic allograft nephropathy. Cyclosporin and tacrolimus also induce arterial hypertension. Therefore, the beneficial effects of immunosuppression have been limited due to nephrotoxicity and arterial hypertension. Rapamycin, a novel immunosuppressive agent, that does not inhibit calcineurin, provides immunosuppression without nephrotoxicity. In fact, in the trials performed in Europe, sirolimus-treated immunosuppression patients exhibited a much better renal function than cyclosporin-treated patients. However, sirolimus can potentiate the nephrotoxic effect of cyclosporin. Therefore, when cyclosporin and sirolimus are used in combination, a reduction of the cyclosporin dose is desirable.
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PMID:Influence of cyclosporin, tacrolimus and rapamycin on renal function and arterial hypertension after renal transplantation. 1136 39

FK506 (tacrolimus)-binding protein (FKBP) is associated with intracellular Ca2+ release channel and modulates its function. To elucidate the effect of FK506 on Ca2+ dynamics and Ca2+-mediated Cl- secretion in airway epithelium, we studied intracellular Ca2+ ([Ca2+]i) concentration and Cl(-)-dependent short-circuit current (Isc), in cultured bovine tracheal epithelial cells. Addition of ATP induced an increase in [Ca2+]i, and this response was dose dependently inhibited by FK506. Rapamycin, which binds FKBP with high affinity, likewise inhibited the [Ca2+]i rise, but cyclosporin A, a specific calcineurin inhibitor, did not. In Cl- secretion studies using Ussing chamber, ATP increased Ca2+-mediated Isc in amiloride-treated cells, an effect that was inhibited by FK506 and rapamycin but not by cyclosporin A. Therefore, FK506 inhibits Ca2+ mobilization in airway epithelium via FKBP but not calcineurin-dependent mechanism, which may result in the suppression of Ca2+-activated Cl- secretion.
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PMID:FK506 inhibits Cl- secretion in airway epithelium via calcineurin-independent mechanism. 1142 33

DE NOVO DIABETES AND CARDIOVASCULAR RISK: Certain kidney transplant recipients who develop de novo diabetes have an unfavorable cardiovascular risk profile, comparable to patients with type 2 diabetes mellitus, with advanced age, dyslipidemia, obesity and high blood pressure. MYOCARDIAL INFARCTION IN THE PERIOPERATIVE PERIOD: Among kidney transplant recipients, those whose risk factors include male gender diabetes, age over 50 years and prior revascularization procedure for coronary artery disease have a higher risk for myocardial infarction in the perioperative period. The usefulness of anticoagulant or beta-blockers as preventive treatment for these high-risk patients remains to be determined. HYPERLIPIDEMIA: A retrospective analysis of 530 kidney transplant recipients demonstrated that a very significant proportion of those with dyslipidemia are not receiving appropriate care although their lipid profile is indicative of a high or very high cardiovascular risk. MASSIVE PROTEINURIA: An angiotensin II inhibitor, losartan, has been found to be effective against massive proteinuria (> 3.5 g/l) occurring after kidney transplantation. CALCINEURIN-INHIBITOR-INDUCED HEMOLYTIC UREMIA SYNDROME: Five to ten percent of patients given calcineurin inhibitors develop a hemolytic uremia syndrome. Sirolimus appears to be a very interesting alternative for immunoprophylaxys against acute rejection.
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PMID:[Complications in kidney transplantation]. 1157 77

The immunosuppressive benefits of cyclosporine and tacrolimus in short-term and medium-term renal allograft survival are well documented. It is becoming increasingly clear that the basis of this immunosuppression, the inhibition of calcineurin, may be linked with nephrotoxicity, hypertension, hyperlipidemia, and new-onset diabetes mellitus, side effects that may lead to CRAD, death due to CVD, and late renal allograft loss. This clinical picture presents a clear need for new strategies that produce adequate immunosuppression to prevent acute rejection while simultaneously reducing the side effects associated with CNI-related therapies. Sirolimus combined with cyclosporine and tacrolimus has demonstrated an ability to reduce incidences of early acute rejection and, used as base therapy, has provided protection against acute rejection equivalent to that of cyclosporine, without the consequent nephrotoxicity associated with CNIs. In preliminary results from an ongoing clinical trial, sirolimus has been used to eliminate cyclosporine during maintenance immunosuppression, with subsequent improvements in measures of blood pressure and renal function. In addition, the antiproliferative properties of sirolimus and its ability to prevent graft vascular disease in animal studies make sirolimus a promising agent to decrease incidences of CRAD and improve long-term renal allograft survival. These findings point to a clear need to further explore both the efficacy of sirolimus immunotherapy and its long-term effects.
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PMID:Exploring treatment options in renal transplantation: the problems of chronic allograft dysfunction and drug-related nephrotoxicity. 1158 88

Rapamycin binds and inhibits the Tor protein kinases, which function in a nutrient-sensing signal transduction pathway that has been conserved from the yeast Saccharomyces cerevisiae to humans. In yeast cells, the Tor pathway has been implicated in regulating cellular responses to nutrients, including proliferation, translation, transcription, autophagy, and ribosome biogenesis. We report here that rapamycin inhibits pseudohyphal filamentous differentiation of S. cerevisiae in response to nitrogen limitation. Overexpression of Tap42, a protein phosphatase regulatory subunit, restored pseudohyphal growth in cells exposed to rapamycin. The tap42-11 mutation compromised pseudohyphal differentiation and rendered it resistant to rapamycin. Cells lacking the Tap42-regulated protein phosphatase Sit4 exhibited a pseudohyphal growth defect and were markedly hypersensitive to rapamycin. Mutations in other Tap42-regulated phosphatases had no effect on pseudohyphal differentiation. Our findings support a model in which pseudohyphal differentiation is controlled by a nutrient-sensing pathway involving the Tor protein kinases and the Tap42-Sit4 protein phosphatase. Activation of the MAP kinase or cAMP pathways, or mutation of the Sok2 repressor, restored filamentation in rapamycin treated cells, supporting models in which the Tor pathway acts in parallel with these known pathways. Filamentous differentiation of diverse fungi was also blocked by rapamycin, demonstrating that the Tor signaling cascade plays a conserved role in regulating filamentous differentiation in response to nutrients.
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PMID:The TOR signal transduction cascade controls cellular differentiation in response to nutrients. 1173 4

Few studies have used a pharmaco-behavioural methodology to directly investigate roles for the calcium-dependent protein phosphatase calcineurin (CaN) in memory formation, due partly to the absence of specific inhibitory agents. A number of drugs with different inhibitory profiles were used to examine this issue in groups of chicks trained on a single-trial, passive-avoidance task. Bilateral intracranial administration of the immunosuppressants FK506 and cyclosporin A (CyA) led to two temporally distinct effects, distinguished by the concentration of drug required and the effective time of administration relative to training. In addition to inhibiting CaN, CyA and FK506 inhibit distinct classes of peptidyl prolyl-cis/trans-isomerases (PPIases). Other agents known to inhibit these enzymes, including the Map kinase inhibitor Rapamycin, also induced memory deficits in a complex, dose- and time-of-administration-dependent, manner. The data fail to conclusively implicate CaN in memory formation, but are consistent with proposals that a phosphatase cascade may participate in an early stage of information storage. PPIases may be required at a later stage to catalyse the folding of new or translocated proteins, the synthesis of which is required for formation of long-term memory, although other possible explanations for the data remain to be investigated.
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PMID:Cyclosporin A, FK506 and rapamycin produce multiple, temporally distinct, effects on memory following single-trial, passive avoidance training in the chick. 1182 Oct 11

A highly effective immunosuppressive therapy with as few side effects as possible can only be achieved by a reliable drug monitoring. For neoral monitoring of the C2 level is essential while for tacrolimus measuring of the trough level is sufficient. Due to the different immunogenicity of the organ transplants the type and intensity of the immunosuppressive therapy should be organ-specific. Sirolimus is highly effective in combination with calcineurin antagonists in immunologically high-risk patients. In addition in case of severe side effects sirolimus can substitute for the calcineurin antagonists. Il-2 receptor antibodies are characterized by minimal side effects and have been shown to be a highly effective new therapeutic principle for immunosuppressive induction therapy.
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PMID:[New developments in immunosuppressive therapy]. 1182 27

Sirolimus (Rapamune), Wyeth-Ayerst, Madison, NJ) is a new, potent, immunosuppressant that is emerging as a foundation for long-term immunosuppressive therapy in renal transplantation. The drug acts during both co-stimulatory activation and cytokine-driven pathways via a unique mechanism: inhibition of a multifunctional serine-threonine kinase, mammalian target of rapamycin (mTOR). Although there is no a priori reason to assume it, sirolimus displays a synergistic interaction to enhance the efficacy of cyclosporin A (CsA). In trials wherein the concentrations of CsA and sirolimus were tightly controlled, rates of acute rejection episodes were < 10%, despite markedly reduced exposures to each agent. In pivotal multi-centre blinded dose-controlled trials, the rates of acute rejection episodes within 12 months following administration of 2 or 5 mg/day sirolimus in combination with CsA and steroids were reduced to 19 and 14%, respectively. Since the inhibitory effect of sirolimus disables virtually all responses to cytokine mediators due to the widespread involvement of mTOR in multiple signalling pathways, the agent is likely also to retard proliferation of endothelial and vascular smooth muscle cells, an important component of the immuno-obliterative processes associated with chronic rejection. The advantages of this unique therapeutic action combined with an intrinsic lack of nephrotoxicity are counterbalanced by myelosuppressive and hyperlipidaemic side effects. Ongoing studies are assessing whether the long-term benefits of sirolimus to permit reduction in exposure to or elimination of calcineurin inhibitors ameliorate the progression of chronic nephropathy, the condition that erodes long-term renal transplant survival.
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PMID:Sirolimus: a comprehensive review. 1182 25

FK506 (Tacrolimus) and cyclosporin A exert their immunosuppressive effects via a common mechanism, calcineurin inhibition, after binding to intracellular proteins termed immunophilins: FK506-binding protein (FKBP) and cyclophilin. In this study, FK506 was found to induce chondrogenic differentiation of ATDC5 cells (clonal mouse embryonal carcinoma cells) in a concentration-dependent manner (0.1-1000 ng/ml). Immunohistochemical staining showed that ATDC5 cells induced to differentiate by FK506 produced proteoglycan and type II collagen, main components of the extracellular matrix of cartilage. Rapamycin, an immunosuppressant that binds to FKBP, antagonized the effect of FK506. Cyclosporin A did not induce chondrogenesis at concentrations up to 1000 ng/ml. Taken together, these results suggest that FK506 induces chondrogenic differentiation of ATDC5 cells via a calcineurin-independent mechanism, after binding to FKBP.
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PMID:FK506 induces chondrogenic differentiation of clonal mouse embryonic carcinoma cells, ATDC5. 1189 Aug 99


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