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)

Over the last few years, improved knowledge of the immunological mechanisms underlying transplant rejection have resulted in the development of new immunosuppressive agents capable of selectively blocking various steps of the immune response. It is anticipated that these agents will prove useful in the treatment of autoimmune disease and graft-versus-host disease. Neoral is a cyclosporin microemulsion characterized by better and more consistent absorption as compared to the conventional galenic form. Tacrolimus shares with cyclosporin an ability to inhibit calcineurin and may have similar indications. Rapamycin and RAD are two related molecules that inhibit signal transduction by cytokines to T-cells, although they have not yet been proved clinically effective in large studies of solid organ transplant recipients. Mycophenolate mofetil selectively inhibits purine synthesis and lymphocyte proliferation; it is easy to use and has been found effective in a number of autoimmune disorders. Further clinical work is needed to determine the therapeutic indications for each of these new drugs. Elucidation of their mechanisms of action may help to identify drug combinations providing both enhanced efficacy and improved safety.
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PMID:[New immunosuppressive agents]. 1057 3

Post-transplant diabetes mellitus, a complication due to corticosteroids and the calcineurin inhibitors, cyclosporine and tacrolimus (FK506), is commonly regarded as a form of type-2 (adult-onset) diabetes mellitus. Diabetic ketoacidosis, which requires relative insulin deficiency to impair fatty acid metabolism, is a complication of type-1 diabetes mellitus. We report three patients who presented with diabetic ketoacidosis post-transplant. All three patients presented with severe hyperglycemia, significant ketosis and metabolic acidosis of variable severity. One patient was a renal transplant recipient on a cyclosporine-based regimen. The other two patients were liver transplant recipients receiving either cyclosporine or tacrolimus-based immunosuppression. Both of the liver transplant recipients were found to have moderate to high serum levels of calcineurin inhibitors on presentation. The liver recipient on cyclosporine (Neoral) had a 4 hour post-dose level of 388 ng/ml and the patient on tacrolimus was found to have a trough level of 21.2 ng/ml. Our experience suggests that post-transplant diabetes mellitus, in association with calcineurin inhibition, may result in ketoacidosis either secondary to relative beta cell dysfunction, peripheral insulin resistance, or a combination of the two effects. Post-transplant diabetes mellitus can be an atypical form of adult-onset diabetes with features of both type I and type II diabetes mellitus.
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PMID:Post-transplant diabetic ketoacidosis--a possible consequence of immunosuppression with calcineurin inhibiting agents: a case series. 1074 93

The calcineurin inhibitors cyclosporine and tacrolimus form the cornerstones of most immunosuppression protocols. Because of their variable pharmacokinetics, and their narrow therapeutic indices, post-transplant immunosuppressive drug monitoring is an essential part of patient care to minimize the risks of toxicity or acute rejection. Furthermore, a reduction in the rate of acute rejection has been shown to result in a lower rate of graft loss due to chronic rejection. The introduction of the microemulsion formulation of cyclosporine with its more consistent bioavailability has renewed interest in the use of alternative sampling strategies to the trough cyclosporine concentration. Both pharmacokinetic and pharmacodynamic considerations support the concept that determination of cyclosporine during the absorption phase (0-4 h) might offer a better prediction of cyclosporine immunosuppressive efficacy. Initial investigations suggest that monitoring a 2-h postdose concentration C(2) may provide a more efficacious alternative to trough monitoring for optimizing therapy with Neoral. Tacrolimus has a 10- to 100-fold greater in vitro immunosuppressive activity compared with cyclosporine. Consistent with its greater potency, therapeutic whole blood trough concentrations for tacrolimus are around 20-fold lower than the corresponding cyclosporine concentrations. The correlation between toxicity and tacrolimus trough concentrations appears to be stronger than that for acute rejection. The results from a concentration-ranging trial in primary kidney-transplantation and liver-transplantation trials all found a significant relationship between toxicity and tacrolimus trough levels. Azathioprine is converted in vivo to 6-mercaptopurine, which is subsequently metabolized to the pharmacologically active 6-thioguanine nucleotides. The latter are also responsible for the cytotoxic side effects. Reliance on blood counts to monitor azathioprine therapy can be misleading, and they do not provide information on immunosuppresive efficacy. More pertinent information can be obtained through the measurement of thiopurine S-methyltransferase activity and the quantification of intracellular 6-thioguanine nucleotides concentrations in red blood cells. Prospective studies have demonstrated the clinical utility of determining 6-thioguanine nucleotides to individualise immunosuppressive therapy with azathioprine not only in the field of transplantation, but also in inflammatory bowel disease.
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PMID:New developments in the immunosuppressive drug monitoring of cyclosporine, tacrolimus, and azathioprine. 1123 9

Forty percent of patients with severe ulcerative colitis will fail to respond to intravenous corticosteroids. Cyclosporine and other calcineurin inhibitors offer an alternative to colectomy for these patients. Intravenous cyclosporine will induce remission within 14 days in 50-80% of patients who fail intravenous corticosteroids. The long-term response rates for responding patients are 40-60%. Subsequent maintenance therapy with azathioprine or 6-mercaptopurine is recommended at the present time, although the uncontrolled studies underlying this observation have yielded variable results. Toxicity occurs frequently in patients treated with high dose cyclosporine, and there is a small risk of opportunistic infection and death. Pilot studies have suggested that the microemulsion cyclosporine formulation Neoral and tacrolimus may also be of benefit in this patient population. Additional studies to determine the dose response of intravenous cyclosporine, to determine the role of azathioprine for maintenance, and to determine the efficacy of Neoral and tacrolimus are needed.
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PMID:Cyclosporine in ulcerative colitis: state of the art. 1147 36

1. The increased utilization of Neoral, Tacrolimus and mycophenolate mofetil correlated with the dramatic decrease in rejection rates in the 1990s. 2. The 4% difference in the incidence of rejection noted for recipients treated with Tacrolimus (20%) compared with Neoral (16%) corresponded to a 34% increased odds ratio in the multivariate analysis. The risk of graft loss and patient death were similar for the 2 calcineurin inhibitors. 3. Almost every renal transplant recipient received mycophenolate mofetil in 1999. This agent reduced the risk of 3-year graft loss by 60% and halved the risk of death compared with azathioprine. 4. Use of solumedrol as a corticosteriod increased from 26-67% in the 1990s, but this change in practice did not significantly impact outcome. 5. Although recipients given induction ATG or OKT3 had increased risk of graft failure, these recipients more likely were sensitized or required early dialysis. 6. The risk of rejection was 90% higher for recipients with 5-6 HLA mismatches than those with 0 A,B,DR mismatches. Recipients with a poorly HLA-matched kidney had 50% increased risk of graft loss within 3 years compared with HLA-matched transplants.
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PMID:Maintenance immunosuppression. 1151 60

Sandimmun displays considerable inter- and intra-patient variability because its absorption is bile-dependent and affected by concomitant intake of food. Neoral is a microemulsion preconcentrate; a microemulsion is a mixture of the lipophilic active substance with accurately balanced amounts of lipophilic solvent, hydrophilic solvent and surfactant. As the result of advanced microemulsion technique, Neoral has more consistent and improved absorption characteristics. Cyclosporin (cyclosporin A) has been used as an immunosuppressive agent. The major pharmacodynamic action of cyclosporin within T cells is calcineurin inhibition. The complex cyclophilin-cyclosporin competitively binds to the Ca(2+)- and calmodulin-dependent phosphatase calcineurin which then inhibits downstream dephosphorylation and activation of NFAT(transcription factor). The greatest calcineurin inhibition is seen 1-2 h after administration of Neoral in parallel to the highest blood concentration. Variability in cyclosporin exposure was also identified as a risk factor for acute rejection in organ transplant recipients. "Absorption profiling" provides a more accurate prediction of drug exposure and leads to less acute rejection and toxicity. The evolution of Neoral monitoring strategies from trough level to absorption profile will raise the standard of performance of Neoral, resulting in clinical benefits for transplant patients.
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PMID:[Neoral (Cyclosporin microemulsion preconcentrate): pharmacokinetics, pharmacodynamics and its improved clinical outcome]. 1153 Jun 80

Mycophenolic acid (MPA), the active compound of mycophenolate mofetil (MMF), shows substantial interindividual and intraindividual variability. It was recently shown that in vitro calcineurin inhibitors alter the bioavailability of MPA by dose-dependent inhibition of MPA glucuronidation. The authors retrospectively analyzed full 10-point profiles for both MPA and cyclosporine (CyA) in 23 pediatric patients receiving MMF and cyclosporine microemulsion (Neoral; Novartis Pharmaceuticals Canada; Dorval, Quebec, Canada). Mycophenolic acid was measured using a commercially available EMIT (Novartis Pharmaceuticals, Canada) assay. As the majority of patients were treated with low doses of cyclosporine after adding MMF, the area under the concentration-time curve (AUC) for cyclosporine showed a wide scatter ranging from 296 to 6400 ng x h/mL. The mean cyclosporine dose was 100 +/- 76 mg/m2 per day (range: 28 to 331). There was no correlation between MPA AUC and MPA dose, and there was substantial interindividual variation. However, there was a significant negative correlation between dose-normalized MPA AUC and cyclosporine AUC ( r2 = 0.23, p < 0.0220). When dividing the MPA profiles into two groups (11 and 12 patients) with a CyA AUC less than or greater than 1600 ng x h/mL, there was a significantly higher 8-hour concentration in the patients with the lower CyA AUC, secondary to a higher second peak. The data demonstrate that the cyclosporine AUC is a determining factor for the MPA AUC and that MPA dose should be reduced when cyclosporine dose is reduced to achieve the same MPA AUC. The significantly higher peak in the group with a lower CyA profile supports the concept of a dose-dependent cyclosporine-induced inhibition of MPA glucuronidation.
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PMID:Effect of cyclosporine on mycophenolic acid area under the concentration-time curve in pediatric kidney transplant recipients. 1159 96

SDZ RAD (everolimus, Certican is a novel macrolide immunosuppressant that blocks growth factor-driven transduction signals in the T-cell response to alloantigen. After stimulation of the IL-2 receptor on the activated T-cell, SDZ RAD inhibits p70S6 kinase, acting at a later stage in the T-cell mediated response than do cyclosporine and other calcineurin inhibitors (CNIs). Unlike the CNIs, SDZ RAD is a proliferation signal inhibitor, blocking growth factor-driven proliferation of both hematopoietic and nonhematopoietic cells. These activities are complementary to those of cyclosporine and provide a rationale for the addition of SDZ RAD to cyclosporine-based immunosuppression, with the potential for minimizing CNI nephrotoxicity, reducing the incidence of acute rejection, and favoring long-term graft survival. Potential also exists for beneficial effects on other factors that may influence the development of chronic rejection. These factors include comorbid diseases such as hypertension, which may affect transplant vasculopathy, and opportunistic infection with cytomegalovirus (CMV) and other viruses, which may increase the risk of chronic rejection. The synergistic effect of SDZ RAD and cyclosporine has been confirmed in preclinical models, with graft survival being significantly prolonged in rat models of kidney and heart allotransplantation. Clinical experience with SDZ RAD in cyclosporine-based immunosuppression, including low-dose cyclosporine regimens, has also resulted in predictable and favorable clinical outcomes. Low rates of acute rejection, excellent rates of patient and graft survival, lower incidence of CMV infections, better cholesterol, triglyceride and creatinine profiles, and better renal function have been demonstrated with SDZ RAD and lower doses of cyclosporine (Neoral; Novartis) in recipients of renal transplants. These findings, combined with good tolerability rates and an acceptable side-effect profile, indicate that the synergistic profile of SDZ RAD in combination with nontoxic dosages of CNI's and IL2 inhibitors will further improve longterm results in renal transplantation.
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PMID:Early clinical experience with a novel rapamycin derivative. 1180 23

NEW KNOWLEDGE: Over the last few years, improved knowledge of the immunological mechanisms underlying transplant rejection have resulted in the development of new immunosuppressive agents capable of selectively blocking various steps of the immune response. NEW MOLECULES: The review focuses on new immunosuppressive drugs that have been developed for clinical use in renal transplantation and mechanism of action, advantages and side effects will be discussed for each of them. Neoral is a cyclosporin microemulsion, characterized by more consistent absorption. Tacrolimus shares with cyclosporin an ability to inhibit calcineurin but presents some differences. Mycophenolate mofetyl selectively inhibits purine synthesis and lymphocyte proliferation; it is easy to use and has been found effective in large clinical trials. Rapamycin and RAD are two related molecules that inhibit signal transduction by cytokines to T-cells, their use in transplant therapy remains to be determined. Anti-interleukin-2 receptor antibodies are also reviewed; they are easy to use and have been found effective. NEW STRATEGIES: These new immunosuppressive drugs provide new approaches in transplant therapy to improve their efficacy and safety.
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PMID:[The benefits of new immunosuppressive treatments in adult kidney transplantation]. 1193 40

Tacrolimus (Tac), which blocks T- and B-cell proliferation by inhibiting calcineurin, was first used for immunosuppression following heart transplant (HT) in 1989. Two multicenter randomized trials have compared Tac to the oil-based cyclosporine (CsA) formulation (both combined with azathioprine and steroids) in HT patients. The two drugs displayed similar patient survival rates and incidences of rejection, nephrotoxicity, diabetes, and infections. The Tac group however, showed a lower incidence of arterial hypertension (and, in one study, of dyslipidemia). A pilot study of Tac in combination with mycophenolate mofetil (MMF) and steroids suggested that maintenance of serum mycophenolic acid levels at 2.5 to 4.5 microg/mL yields lower rejection rates without greater toxicity than previous regimens. Currently, a European multicenter randomized trial is comparing Tac with Neoral CsA, both used in combination with MMF, steroids, and induction antibodies. For patients undergoing primary immunosuppression with CsA, Tac has proved effective for rescue from steroid-resistant acute rejection. It also has tentatively been used without other drugs in selected patients. It is a valid alternative to CsA in current immunosuppressive regimens, because it does not cause gingival hyperplasia or hirsutism and, thus, may improve the quality of life and treatment compliance of female and pediatric patients. It may be preferable to CsA for patients with arterial hypertension or intractable dyslipidemia. Current and future studies will clarify the efficacy and safety of regimens combining Tac with MMF or rapamycin.
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PMID:Tacrolimus in heart transplantation. 1296 69


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