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)

The nephrotoxic potential of ascomycin, the C21-ethyl analogue of FK506, was defined and ways explored to enhance its detection. After 14-day dosing in the Fischer-344 rat, FK506 and ascomycin reduced creatinine clearance by >50% at doses of 1 and 3 mg/kg, i.p., respectively. Ascomycin also had a 3-fold lower immunosuppressive potency in a popliteal lymph node hyperplasia assay, resulting in an equivalent therapeutic index consistent with a common mechanistic dependence on calcineurin inhibition. Renal impairment with different routes of administration was correlated with pharmacokinetics. Sensitivity of detection was not adequate with shorter dosing durations in rats with unilateral nephrectomy or in mice using a cytochrome P-450 inhibitor, SKF-525A. In 14-day studies, nephrotoxicity was not induced by continuous i.p. infusion of ascomycin at 10 mg/kg/day or daily oral administration (up to 50 mg/kg/day) in rats on a normal diet, nor by continuous i.v. infusion (up to 6 mg/kg/day) in rats on a low salt diet to enhance susceptibility. The lack of toxicity at high oral doses of FK506 or ascomycin, and the finding of non-linear oral pharmacokinetics of ascomycin show that this drug class has an oral absorption ceiling. The negative results with continuous infusion suggest that ascomycin nephrotoxicity is governed by peak drug levels. In addition to defining ways to meaningfully compare the nephrotoxic potential of FK506 derivatives, these results have implications for overall safety assessment and improved clinical use.
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PMID:Nephrotoxicity studies of the immunosuppressants tacrolimus (FK506) and ascomycin in rat models. 957 Mar 31

Sirolimus (SRL) provides effective immunosuppression for kidney transplantation and may be useful in patients with delayed allograft function after kidney transplantation. We review our experience with SRL in liver transplant recipients for whom calcineurin inhibitors are undesirable. Fourteen patients with renal insufficiency or acute mental status impairment were administered SRL after liver transplantation (5- to 10-mg load, 1 to 4 mg/d). Immunosuppression also consisted of mycophenolate mofetil and corticosteroids. On resolution of neurological or renal dysfunction (return to baseline mental status or serum creatinine level), tacrolimus (TAC) therapy was initiated. Twelve patients received primary transplants, 1 patient received a combined liver-kidney transplant, and 1 patient received a third transplant. Follow-up was 2 to 7 months. Calcineurin inhibitors were initially withheld in 9 patients, and therapy was aborted because of toxicity in the remaining 5 patients. Mean times to the initiation of SRL and TAC therapy were 5.4 +/- 4.6 and 26.8 +/- 24.4 days, respectively. Serum trough levels of SRL did not correlate with dose or other patient variables. Two patients died after prolonged pretransplantation hospital courses in the intensive care unit. Six patients experienced acute rejection, but only 1 patient required antilymphocyte therapy. Serum creatinine levels at the start of SRL therapy were 2.2 +/- 1.1 and 1.2 +/- 0.6 mg/dL at 3 months. All 3 patients with neurological indications for SRL had a return to their baseline mental status. All patients had improved liver function chemistry test results and prothrombin times. No patients developed leukopenia or thrombocytopenia. SRL is safe after liver transplantation in patients with acute neurological or renal impairment. SRL is an attractive alternative when calcineurin inhibitors are undesirable, but serum trough levels of SRL should be monitored. A prospective randomized study of an SRL-based calcineurin inhibitor-avoiding regimen compared with standard therapy in patients with renal insufficiency will further evaluate the role for SRL in liver transplantation.
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PMID:Experience with the use of sirolimus in liver transplantation--use in patients for whom calcineurin inhibitors are contraindicated. 1108 60

Increased susceptibility to bacterial infection is a recognized side-effect of sirolimus treatment after transplantation, which could be caused by inhibition of neutrophil activation. Blood from 24 healthy subjects was equilibrated with 0 to 50 ng/mL sirolimus or 60 microg/mL propofol. Blood was also collected from 23 transplant recipients (13 kidney, 10 liver) with renal impairment, randomized to remain on calcineurin inhibitors (n=12) or to be switched to sirolimus monotherapy (n=11). Phorbol myristate acetate (PMA)-stimulated oxidative burst was measured by flow cytometry at 0 and 3 months after randomization. There was a linear relationship between inhibition of neutrophil activation in vitro and sirolimus concentrations spanning the therapeutic range (P=0.01). Neutrophil activation was decreased significantly in transplant recipients 3 months after switching from calcineurin inhibitors to sirolimus therapy (mean percentage change -24.4%; 95% confidence interval -7.5, -41.2%, P=0.009), but no changes were observed in patients who remained on calcineurin inhibitors.
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PMID:Sirolimus inhibits oxidative burst activity in transplant recipients. 1468 30

Lung and heart transplantation has become an accepted therapeutic option for patients with end-stage disease. However, the calcineurin-inhibitor-based immunosuppression often causes renal impairment. Therefore, sirolimus, a novel immunosuppressive agent, may serve as an alternative or complementary agent to calcineurin inhibitors. The aim of this review was to summarize the role of sirolimus in lung and heart transplantation. Although only a few, small studies have been conducted so far, the drug's mechanisms of action and low-toxicity profile make it a highly promising option.
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PMID:Role of siroliumus, a novel immunosuppressive drug in heart and lung transplantation. 1533 3

The aim of this pilot study was to investigate whether de novo calcineurin-inhibitor-free immunosuppression after cardiac transplantation is efficacious and can prevent post-operative renal impairment. Eight patients were treated by combining trough level adjusted sirolimus and mycophenolate mofetil; corticosteroids were given for the first 6 post-operative months only. Survival data, acute rejection episodes and adverse events with a special emphasis on renal impairment, myelosuppression, hypercholesterolemia, hypertriglyceridemia and infections, were recorded. With a follow-up of 3-12 months, patient survival was 100% and freedom from rejection 75%. The mean creatinine levels initially decreased and remained stable thereafter. A moderate myelosuppressive effect did not necessitate dose reduction of immunosuppressants, intermittently elevated cholesterol- and triglyceride levels decreased over time. Most frequent adverse events were pericardial effusions and peripheral edema. Complete abandonment of calcineurin inhibitor therapy by de novo use of the combination sirolimus/mycophenolate mofetil resulted in low rejection rate and avoidance of renal impairment, but should not be used without further evaluation of potential complications in a lager setting.
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PMID:First experience with de novo calcineurin-inhibitor-free immunosuppression following cardiac transplantation. 1576 Apr 8

The use of sirolimus as an alternative to calcineurin antagonists has enabled the continuation of immunosuppression in patients with renal impairment with preservation of kidney function. Sirolimus is generally well tolerated, with the main causes of cessation of therapy related to its effect on blood lipid profile as well as leukopenia and thrombocytopenia. We report a case of a debilitating ulcerating maculopapular rash necessitating cessation of the drug in a liver transplantation patient. A 56-year-old Caucasian liver transplantation patient presented with a diffuse, debilitating rash attributed to sirolimus use. This ultimately necessitated cessation of the immunosuppressant with subsequent resolution of her symptoms. From a review of the current literature, this is a highly unusual adverse reaction to sirolimus.
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PMID:Generalized, pruritic, ulcerating maculopapular rash necessitating cessation of sirolimus in a liver transplantation patient. 1603 64

Maintenance immunosuppression with calcineurin inhibitors (CNIs) following renal transplantation is associated with nephrotoxicity and accelerated graft loss. We aimed to assess whether conversion to sirolimus-based immunosuppression would affect the progression of renal impairment. In this single center, randomized controlled trial, 40 renal transplant recipients between 6 months and 8 years post-transplant were randomly assigned to remain on their CNI (cyclosporin or tacrolimus) or to switch to sirolimus. The primary outcome measure was change in glomerular filtration rate (GFR) measurement at 12 months. Analysis was by intention-to-treat. Of the 40 patients randomized, 2 patients never took the study drugs and were excluded, leaving 19 patients per group. There was a significant change in GFR at 12 months following conversion to sirolimus (12.9 mL/min, 95% CI 6.1-19.7; p < 0.001). Following conversion, the principal adverse events were the development of rashes (68%), particularly acne, and mouth ulcers (32%). No patient in either group experienced an acute rejection episode. In renal transplant recipients, a change in maintenance therapy from CNIs to sirolimus is associated with significant improvement in GFR at 12 months.
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PMID:A randomized controlled trial of late conversion from CNI-based to sirolimus-based immunosuppression following renal transplantation. 1616

We report a series of 26 heart transplant recipients with renal impairment in which sirolimus was used as the basic immunosuppresive drug (without associated calcineurin inhibitors) to avoid further nephrotoxicity. Sirolimus (trough levels 10 to 12 ng/mL, average daily dose 3 mg) was used in two settings: de novo in 7 patients with significant preexistent renal impairment and as a chronic conversion in 19 stable patients with established renal failure (creatinine level >2 mg/dL). In all de novo patients (n = 7), the renal function significantly improved. Creatinine fell from 2.95 +/- 0.9 mg/dL to 1.41 +/- 0.4 mg/dL at follow-up (P = .0017). One patient died suddenly of a massive pulmonary embolism. Only one patient experienced histologic but reversible rejection. In one patient, anemia and diarrhea prompted sirolimus withdrawal. Five patients had infectious episodes: three bacterial pneumonias, one mediastinitis, and two CMV infections. In the chronic conversion group (n = 19), the improvement was mostly limited to patients with moderate renal failure (creatinine < or =2.5 mg/dL) in which creatinine fell from 2.24 +/- 0.2 to 1.9 +/- 0.27 mg/dL, P = .009). When basal creatinine was over 2.5 mg/dL, only one third of the patients improved after conversion. Two patients died: terminal renal failure and cerebrovascular accident. There were no clinical episodes of rejection. Secondary effects prompted the discontinuation of sirolimus in five patients: two definite and one possible interstitial pneumonitis and two cases of anemia). The symptoms resolved after sirolimus withdrawal. Six patients had infection: four pneumonias, one sepsis, and one cutaneous abscess. Sirolimus is an interesting alternative to calcineurin inhibitors in selected patients with renal impairment. It prevents renal failure in de novo recipients at high risk of catastrophic renal damage and ameliorates renal dysfunction in chronic patients with moderate renal dysfunction. Given the high incidence of secondary effects, the adequate dosage and the secondary effects profile needs further study.
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PMID:Sirolimus as an alternative to anticalcineurin therapy in heart transplantation: experience of a single center. 1638 15

Sirolimus (SRL) has been proposed to replace calcineurin inhibitors (CNI) in case of CNI-induced toxicity. The aim of this study was to evaluate the efficacy and safety of conversion from CNI to SRL in maintenance liver transplantation (LT) patients. Between 2002 and 2006, conversion was performed in 48 patients (17 female, 31 male; mean age 57 +/- 10 yr) after a median delay of 19.4 months (range 0.2-173 months) after LT. Indication for conversion was renal impairment (RI) (78%), CNI neurotoxicity (13%), or post-LT cancer (9%). Median follow-up was 22.6 +/- 11 months. Median SRL dosage and trough levels were 2.4 +/- 1.3 mg and 8.1 +/- 2.7 microg/L. Immunosuppression consisted of SRL alone (33%), or SRL + mycophenolate mofetil (MMF) (39%), SRL + prednisone (15%), SRL + CNI (4%), or SRL + MMF + prednisone (8%). Mean glomerular filtration rate (GFR) improved from 33 to 48 mL/minute in patients with severe RI (P = 0.022) and from 56 to 74 mL/minute in patients with moderate RI (P = 0.0001). After conversion, main complications were albuminuria (36%), hyperlipidemia (49%), dermatitis (14%), edema (14%), oral ulcers (12%), joint pain (4%), infection (2%), and pneumonia (2%). Acute rejection (AR) occurred in 17% of the patients. SRL was withdrawn in 17% of the patients. In conclusion, conversion from CNI to SRL is safe and is associated with significant renal function improvement.
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PMID:Conversion to sirolimus-based immunosuppression in maintenance liver transplantation patients. 1745 87

Focal and segmental glomerular sclerosis (FSGS) is a heterogeneous disease from a clinical, etiological and clinical point of view. FSGS may be idiopathic, usually associated with nephrotic syndrome, which requires an ''etiological'' treatment approach. In addition, hereditary and secondary forms of FSGS have been described. The response to therapy, including steroids, cytotoxic drugs and calcineurin inhibitors, is considered the best clinical indicator of outcome. Many uncertainties exist regarding the best therapeutic approach to FSGS in patients presenting with chronic renal failure. In this setting, before planning any treatment, the physician should always assess the presence of superimposed functional renal insufficiency and evaluate the severity of the renal impairment, the histological picture, previous immunosuppressive treatments, and the individual patient's risk for side effects. Keeping in mind these considerations and in the absence of appropriate studies, we can formulate the following suggestions: 1. there is no absolute contraindication to the use of full-dose prednisone as initial therapy, although the likelihood of a good response is low; 2. the use of cytotoxic drugs is not recommended unless the patient presents with a steroid-responsive form of the disease; 3. in patients with a glomerular filtration rate of less than 40 mL/min, the use of calcineurin inhibitors should be avoided.
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PMID:[Choosing the right treatment approach in focal and segmental glomerular sclerosis with chronic renal failure]. 1904 92


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