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)

Neurological complications post transplant have been described with the use of calcineurin inhibitors. Although tacrolimus may be a better immunosuppressant than cyclosporine, its neurological side effects may be worse. Two children, living-related kidney transplant recipients, were treated with antibody induction, mycophenolate mofetil, prednisone, and tacrolimus. Soon after transplant, they each developed an encephalopathy, which when visualized by magnetic resonance imaging showed that it affected both white and grey matter of the brain. Although the encephalopathy was associated with the use of tacrolimus, there was a complete neurological recovery without cessation of the drug.
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PMID:Reversible encephalopathy associated with tacrolimus in pediatric renal transplants. 1146 99

Recently, new calcineurin inhibitors, such as tacrolimus (FK-506) and microemulsion cyclosporin, have been approved for maintenance immunosuppression in renal transplant recipients and short-term outcomes have been accumulating. In the majority of patients, these calcineurin inhibitors have been used in combination with new immunosuppressive drugs, such as mycophenolate mofetil (MMF) or sirolimus. Under these circumstances, a comparison of cyclosporin and tacrolimus provides the answer to a very important controversial issue. Which drug should we choose in individual patients? In an attempt to answer this question, this review compared the use of tacrolimus and cyclosporin in modern immunosuppressive regimens, which have already been published in well designed clinical studies, and discusses how immunosuppression should be individualised in renal transplant patients.Overall, short-term patient and graft survival with cyclosporin microemulsion and tacrolimus is almost identical. The incidence of acute rejection is generally lower in tacrolimus/azathioprine- than in cyclosporin/azathioprine-treated patients. However, in conjunction with MMF, the difference in the incidence of acute rejection between tacrolimus- and cyclosporin-treated patients became smaller. Adverse events, such as hypertension, hyperlipidaemia and cosmetic changes (gum hypertrophy, hirsutism) seem to be less frequent in tacrolimus-treated than in cyclosporin-treated patients. Recent randomised studies showed that the incidence of post-transplant diabetes mellitus was almost identical between low-dose tacrolimus- and cyclosporin-treated patients. According to the data discussed in this review, the recommendation on the choice of calcineurin inhibitors at this moment is that either cyclosporin or tacrolimus can be used safely and effectively for patients without any risk factors. However, at our centre, we prefer tacrolimus to cyclosporin in patients with a high risk for rejection, such as those with ABO-incompatibility, delayed graft function, sensitisation, and African American race and some other risk factors, such as hypertension and hyperlipidaemia. Moreover, tacrolimus may be preferable to cyclosporin for women because of hirsutism and for children because of the steroid-sparing effect. We consider that cyclosporin should be chosen when patients experience tacrolimus-related adverse events, such as severe chest pain, tremor, gastrointestinal symptoms and encephalopathy. In conclusion, well tolerated and effective immunosuppression is feasible with both cyclosporin and tacrolimus. In the current immunosuppressive regimens, a calcineurin inhibitor, either tacrolimus or cyclosporin, is the essential basic standard immunosuppressant. Clinicians need to decide the best means of optimising therapy for individual patients, based on various risk factors, such as risk of rejection, i.e. sensitisation, delayed graft function and ABO-incompatibility, and some adverse events, such as hypertension, hyperlipidaemia and cosmetic changes.
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PMID:Calcineurin inhibitors in renal transplantation: what is the best option? 1288 61

Voriconazole (VRC) is a broad-spectrum antifungal triazole with nonlinear pharmacokinetics. The utility of measurement of voriconazole blood levels for optimizing therapy is a matter of debate. Available high-performance liquid chromatography (HPLC) and bioassay methods are technically complex, time-consuming, or have a narrow analytical range. Objectives of the present study were to develop new, simple analytical methods and to assess variability of voriconazole blood levels in patients with invasive mycoses. Acetonitrile precipitation, reverse-phase separation, and UV detection were used for HPLC. A voriconazole-hypersusceptible Candida albicans mutant lacking multidrug efflux transporters (cdr1Delta/cdr1Delta, cdr2Delta/cdr2Delta, flu1Delta/flu1Delta, and mdr1Delta/mdr1Delta) and calcineurin subunit A (cnaDelta/cnaDelta) was used for bioassay. Mean intra-/interrun accuracies over the VRC concentration range from 0.25 to 16 mg/liter were 93.7% +/- 5.0%/96.5% +/- 2.4% (HPLC) and 94.9% +/- 6.1%/94.7% +/- 3.3% (bioassay). Mean intra-/interrun coefficients of variation were 5.2% +/- 1.5%/5.4% +/- 0.9% and 6.5% +/- 2.5%/4.0% +/- 1.6% for HPLC and bioassay, respectively. The coefficient of concordance between HPLC and bioassay was 0.96. Sequential measurements in 10 patients with invasive mycoses showed important inter- and intraindividual variations of estimated voriconazole area under the concentration-time curve (AUC): median, 43.9 mg x h/liter (range, 12.9 to 71.1) on the first and 27.4 mg x h/liter (range, 2.9 to 93.1) on the last day of therapy. During therapy, AUC decreased in five patients, increased in three, and remained unchanged in two. A toxic encephalopathy probably related to the increase of the VRC AUC (from 71.1 to 93.1 mg x h/liter) was observed. The VRC AUC decreased (from 12.9 to 2.9 mg x h/liter) in a patient with persistent signs of invasive aspergillosis. These preliminary observations suggest that voriconazole over- or underexposure resulting from variability of blood levels might have clinical implications. Simple HPLC and bioassay methods offer new tools for monitoring voriconazole therapy.
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PMID:Variability of voriconazole plasma levels measured by new high-performance liquid chromatography and bioassay methods. 1708 83

Transplant-associated microangiopathy (TAM) is a life-threatening complication after allogeneic HSCT, particularly with the use of calcineurin inhibitors as post-transplantation immunosuppressive therapy. We report our experience with TAM after HSCT with tacrolimus-based GVHD prophylaxis in a single-center study. Sixty-six of 1219 transplant recipients developed TAM with a cumulative incidence of 5.9%. Risk factors for TAM were female gender, lymphoid malignancy, receipt of a matched unrelated donor, and grade II-IV aGVHD. Most patients had infection and/or active GVHD at the diagnosis of TAM (82%). In the absence of renal dysfunction or encephalopathy, tacrolimus was generally continued, maintaining blood levels within the lower therapeutic range. Sixty-three patients were treated with plasma exchange. The cumulative incidence of response of TAM was 60%. Only 1 patient had a response of TAM without resolution of concomitant infections or GVHD. Six-month survivals were 0% and 50% for TAM nonresponders and responders, respectively. In conclusion, TAM is a common, life-threatening complication of allogeneic hematopoietic transplantation using tacrolimus prophylaxis. Control of TAM generally requires response of associated infections and GVHD. TMA response may occur despite continuation of tacrolimus treatment.
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PMID:Transplant-associated microangiopathy in patients receiving tacrolimus following allogeneic stem cell transplantation: risk factors and response to treatment. 1738 53

There has been no reported case of Hashimoto's encephalopathy (HE) ('steroid-responsive encephalopathy associated with autoimmune thyroiditis', 'SREAT'), in the renal transplant recipient population. We describe the case of a 55-year-old female with Type-1 diabetes who presented 2 years posttransplantation in a comatose state that had developed over the preceding 24 h. The patient had received a short, intensive course of rATG induction at the time of transplantation and early steroid withdrawal. After 6 months she had been withdrawn from calcineurin inhibitors and was maintained on mycophenolate mofetil and sirolimus. Systematic workup determined the cause of her coma to be HE. High-dose steroid therapy resulted in complete resolution of the patient's symptoms. The literature regarding the diagnosis, course and treatment of HE is reviewed and the possibility that increased use of steroid-free immunosuppression and intensive lymphocyte depletion regimens may increase the prevalence of de novo autoimmune disease is discussed.
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PMID:Hashimoto's encephalopathy after intensive lymphocyte depletion with rabbit anti-thymocyte globulin in a renal transplant patient. 1809 72

Neurologic complications are common after solid organ transplantation and are associated with significant morbidity. Approximately one-third of transplant recipients experiences neurologic alterations with incidence ranging from 10% to 59%. The complications can be divided into such of those common to all types of transplant and others of those specific to transplanted organ. The most common complication seen with all types of transplanted organ is neurotoxicity attributable to immunosuppressive drugs, followed by seizures, opportunistic central nervous system (CNS) infections, cardiovascular events, encephalopathy and de novo CNS neoplasms. Amongst immunosuppressants, calcineurin inhibitors are the main drugs involved in neurotoxicity, leading to complications which ranges from mild symptoms, such as tremors and paresthesia to severe symptoms, such as disabling pain syndrome and leukoencephalopathy. Neurologic complications of liver transplantation are more common than that of other solid organ transplants (13-47%); encephalopathy is the most common CNS complication, followed by seizures; however, central pontine myelinolysis can appear in 1-8% of the patients leading to permanent disabilities or death. In kidney transplanted patients, stroke is the most common neurologic complication, whereas cerebral infarction and bleeding are more typical after heart transplantation. Metabolic, electrolyte and infectious anomalies represent common risk factors; however, identification of specific causes and early diagnosis are still difficult, because of patient's poor clinical status and concomitant systemic and metabolic disorders, which may obscure symptoms.
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PMID:Neurologic complications after solid organ transplantation. 1907 32

Posterior reversible encephalopathy syndrome (PRES) is one of the serious adverse side effects of calcineurin inhibitors, which are used for the prophylaxis of graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (allo-SCT). We retrospectively analyzed 12 patients who developed PRES after allo-SCT aiming to clarify the clinical features, risk factors, and prognosis of PRES. Median onset of PRES is 17 days after allo-SCT. The most frequent primary symptom was high blood pressure, followed by headache and visual disturbance. Nine of our patients subsequently developed systemic seizure. Sites of PRES by MRI were detected in the frontal, temporal, and parietal lobes, basal ganglia, and brain stem in addition to occipital lobe. Serum creatinine that had increased two-fold from the baseline value was identified as the only risk factor for developing PRES after allo-SCT. The incidence of acute GVHD (grade II-IV) in patients with PRES and those without were 88.9% and 48.7%; respectively (P<0.001), and most of these patients died of GVHD or GVHD-related causes. The 2-year overall survival of patients with PRES and those without were 16.7% and 72.4%, respectively (P<0.001). These data suggested the importance of early intervention for PRES and exploitation of optimal GVHD prophylaxis after developing PRES.
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PMID:[Retrospective analysis of posterior reversible encephalopathy syndrome after allogeneic stem cell transplantation]. 1922 23

Reversible posterior leukoencephalopathy (RPLS), also known as posterior reversible encephalopathy syndrome, is characterized by magnetic resonance imaging (MRI) findings of reversible vasogenic subcortical edema without infarction. The clinical presentation is usually nonspecific and typically involves global encephalopathy, seizures, headache, or visual symptoms. MRI of the brain is essential to the diagnosis of RPLS. Typical findings of RPLS include high-intensity signal on T2-weighted images predominantly in the posterior lobes of the brain that is caused by subcortical white matter vasogenic edema. Fluid-attenuated inversion recovery (FLAIR) sequences on MRI improve sensitivity and detect subtle peripheral lesions. This clinical radiographic syndrome has been described in a number of medical conditions, with hypertensive encephalopathy, eclampsia, and the use of immunosuppressant drugs (most notably calcineurin inhibitors) being the most common. It has occasionally been reported with cisplatin and rarely with carboplatin. Its occurrence with oxaliplatin is very unusual. An extensive literature search including PUBMED and direct contact with the drug manufacturer yielded only 2 known case reports. Herein, we describe a case that had classic clinical and radiologic features of RPLS. We also briefly describe 2 other patients who have been described to have RPLS with oxaliplatin in the literature.
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PMID:Delayed reversible posterior encephalopathy syndrome following chemotherapy with oxaliplatin. 1963 31

Tacrolimus (TAC) is an immunosuppressant drug discovered in 1984 by Fujisawa Pharmaceutical Co., Ltd. This drug belongs to the group of calcineurin inhibitors, which has been proven highly effective in preventing acute rejection after transplantation of solid organs. However, neurotoxicity and nephrotoxicity are its major adverse effects. Posterior reversible encephalopathy syndrome (PRES) is the most severe and dramatic consequence of calcineurin inhibitor neurotoxicity. It was initially described by Hinchey et al. in 1996 [N Engl J Med 1996;334:494-450]. Patients typically present with altered mental status, headache, focal neurological deficits, visual disturbances, and seizures. Magnetic resonance imaging is the most sensitive imaging test to detect this. With the more deep-going studies done recently, we have learnt more about this entity. It was noted that this syndrome is frequently reversible, rarely limited to the posterior regions of the brain, and often located in gray matter and cortex as well as in white matter. Therefore, in this review, the focus is on the current understanding of clinical recognition, pathogenesis, neuroimaging and management of TAC-associated PRES after solid organ transplantation.
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PMID:Tacrolimus-associated posterior reversible encephalopathy syndrome after solid organ transplantation. 2069 17

Posterior reversible encephalopathy syndrome (PRES) was originally used to describe a reversible, predominantly posterior leukoencephalopathy in patients who had renal insufficiency, hypertension, or who received immunosuppressive therapy. Since PRES is prevalent in children with kidney diseases, awareness and understanding of it is important for practicing pediatric nephrologists. A comprehensive approach to the diagnosis of PRES includes thorough determination of predisposing factors, clinical symptoms, and mandatory appropriate imaging. Unfortunately, the pathophysiology of PRES is still obscure and specificity of radiological examination has not yet been established. Two major predisposing factors, namely hypertension and calcineurin inhibitors, are well recognized. In addition, nephrotic syndrome is a common underlying condition for development of PRES. Frequent symptoms include altered consciousness (coma, stupor, lethargy, confusion), seizure, headache, and visual disturbance. Most of these symptoms usually develop abruptly and resolve within a few weeks after proper management. Cranial magnetic resonance (MR) imaging is the first-line modality of imaging studies for detecting PRES. Diffusion-weighted imaging with quantification of apparent diffusion coefficient (ADC) values by ADC mapping may provide more accurate and specific images in the future.
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PMID:Posterior reversible encephalopathy syndrome in children with kidney diseases. 2155 18


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