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)

Kidney transplantation therapy can be divided into two periods: the induction periods during which immunosuppressants are aggressively administered, and the maintenance periods during which treatment is continued at a maintenance dosage. During the induction periods, which usually lasts for several months after surgery, the host defense mechanism in the patient is so profoundly impaired that major infections, including deep-seated mycosis, occur in most cases. The incidence of mycosis as a result of superinfection was quite high in the l960s and l970s, when steroids and antimetabolites were the mainstay immunosuppressants, and antibacterial agents were used without any specific purpose for fear of post-transplantation infections. The new calcineurin inhibitor ciclosporin was developed around 1980 and has since become the primary immunosuppressant used to prevent graft dysfunction after transplantation. As a result of its advent, use of steroids and antimetabolites has declined. Later studies have shown that ciclosporin selectively inhibits lymphocytes and provides more information on the pattern of bacterial infections after transplantation, making it possible to optimize the use of antibacterial agents. As a result, the incidence of bacterial infections and mycosis has dramatically declined. Candida and Aspergillus are most frequently detected in post-transplantation mycosis. But Cryptococcus is also occasionally seen. Antifungal agents such as flucytosine (5-FC) and ketoconazole are effective for deep-seated mycosis such as pulmonary infections which, occurring at a relatively early stage after transplantation, threaten a patients life. However, the coadministration of ketoconazole must be carefully done because it increases blood concentrations of calcineurin inhibitors such as ciclosporin and tacrolimus by inhibiting the production of cytochrome P-450. Amphotericin B, which is effective but is associated with nephrotoxicity, is usually used in a mouthwash or inhalation therapy. Dermatomycosis such as tinea versicolor due to fragility of the skin structure is not necessarily rare even in patients with a quasi-normal host defense mechanism and good renal function at a late stage in the maintenance phase. This paper outlines change in post-transplantation mycosis in recent years and presents some case reports.
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PMID:[Mycosis in kidney transplant patients]. 1170 45

Rapamycin is an immunosuppressive drug with a distinct and unique mode of action and a specific side effect profile. We report here briefly on our personal clinical experience using this immunosuppressive drug in different combinations and settings. Rapamycin is without any doubt an efficient drug capable of preventing acute allograft rejection in a variety of immunosuppressive combinations. It is also a very potent drug that is not devoid of serious side effects. Infectious complications as a result of strong inhibition of the immune system are a frequent cause of hospitalization with severe morbidity and even mortality. Fungal infections and pneumonia are among the most devastating complications. As clinical experience with rapamycin grows and the therapeutic window of the drug can be further narrowed, these infectious complications will improve. Wound healing problems and lymphocoeles form another frequent surgical dilemma and are related to the antiproliferative properties of rapamycin. Last, hyperlipidemia warrants the use of statins in the majority of rapamycin-treated patients and whether this unfavorable side effect will offset the theoretically beneficial cardiovascular effects of the drug remains to be determined in controlled trials with long-term follow-up. Finally, the specific antiproliferative properties of rapamycin and the fact that it exerts no nephrotoxicity make this drug an alternative for calcineurin inhibitors and could make it an ideal candidate for treating chronic allograft dysfunction.
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PMID:Clinical use of rapamycin in renal allograft recipients identifies its relevant toxicity profile and raises unsolved questions: a single-center experience. 1274 86

Invasive mycoses are associated with a high mortality rate, and their incidence is increased in immunologically deficient patients. From a diagnostic and therapeutic perspective, these infections represent a significant challenge to medicine. In addition to new antifungal agents, drug combinations are an important therapeutic resource, which might be exploited clinically, owing to the multiplicity of fungal targets against which currently available agents are active. In this review, we examine the experimental data regarding the combination of conventional antifungal agents with cytokines, antibacterial agents, calcineurin inhibitors and drugs under development characterized by novel mechanisms of action.
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PMID:Molecular targeted treatments for fungal infections: the role of drug combinations. 1282 16

Recently, we have used an anti-T-cell agent, alemtuzumab, as induction or conversion therapy to achieve a calcineurin (CNI) and steroid-free immunosuppressive regimen. We identified recipients who developed systemic fungal infections after the initiation of alemtuzumab and looked at their outcomes. The study population consisted of all pancreas transplant recipients who received alemtuzumab. Only invasive fungal infections were included in the analysis (eg, fungemia, meningitis, or pneumonia; fungal urinary tract infections were excluded). The organism was confirmed by culture, histopathology, or latex antigen test. Between February 2003 and February 2004, a total of 121 pancreas transplant recipients received alemtuzumab-56 as part of induction, and 65 as part of conversion. Of these, 8 (6.6%) developed an invasive fungal infection; 2 (3.6%) recipients as part of induction therapy and 6 (9.2%) as part of conversion therapy. Mean recipient age was 42.1 years. The mean length of time from alemtuzumab administration (first dose) to the diagnosis of the fungal infection was 115.9 days (range 5 to 318). The organisms identified initially were: Cryptococcus, Histoplasma, Aspergillus, and Candida. Overall, 3 (38%) of the eight patients died during ongoing treatment of their fungal infection: two from sepsis, one due to myocardial infarction. The other five recipients were treated successfully and have functioning grafts. The initial therapeutic agents used included: amphotericin B/liposomal AMB (n = 6), voriconazole (n = 3), capsofungin (n = 2), and fluconazole (n = 1). The use of alemtuzumab as induction or conversion therapy in pancreas transplant recipients may predispose patients to the development of systemic fungal infections. It would be important to determine what the most appropriate prophylaxis regimen would be for these patients.
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PMID:Fungal infections in transplant recipients receiving alemtuzumab. 1584 79

Changing transplantation practices, novel immunosuppressive protocols, and evolving recipient characteristics have led to notable changes in the epidemiology of invasive aspergillosis in transplant recipients. The frequency of disseminated infection and of central nervous system involvement has declined significantly in organ transplant recipients in the recent years. Amongst variables that may have contributed to these trends is an overall lesser severity of illness of transplant recipients in the current era. Calcineurin-inhibitor immunosuppressive agents may also have had a role in altering the disease course and the risk of dissemination. A new paradigm in the management of post-transplant immunosuppression is the use of calcineurin-inhibitor and corticosteroid sparing regimens by pretreatment of the recipient with T-cell depleting agents (Campath 1-H or thymoglobulin) and utilization of minimal post-transplant immunosuppression. The impact of these potent lymphoablative regimens on opportunistic mycoses in organ transplant recipients remains to be fully discerned. Although still unacceptably high, the mortality rate in organ transplant recipients with invasive aspergillosis in the current era appears to have declined. A focus of a great interest and controversy is the use of combination therapy for invasive aspergillosis in transplant recipients.
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PMID:Invasive aspergillosis in organ transplant recipients: new issues in epidemiologic characteristics, diagnosis, and management. 1611 Aug 19

Lung transplant recipients have one of the highest rates of invasive aspergillosis (IA) in solid organ transplantation. We used a single center, nonrandomized, retrospective, sequential study design to evaluate fungal infection rates in lung transplant recipients who were managed with either universal prophylaxis with voriconazole (n = 65) or targeted prophylaxis (n = 30) with itraconazole +/- inhaled amphotericin in patients at high risk (pre- or posttransplant Aspergillus colonization [except Aspergillus niger]). The rate of IA at 1 year was better in lung transplant recipients receiving voriconazole prophylaxis as compared to the cohort managed with targeted prophylaxis (1.5% vs. 23%; p = 0.001). Twenty-nine percent of cases in the targeted prophylaxis group were in patients colonized with A. niger who did not receive itraconazole. A three-fold or higher increase in liver enzymes was noted in 37-60% of patients receiving voriconazole prophylaxis as compared to 15-41% of patients in the targeted prophylaxis cohort. Fourteen percent in the voriconazole group as compared to 8% in the targeted prophylaxis group had to discontinue antifungal medications due to side effects. Voriconazole prophylaxis can be used in preventing IA in lung transplant recipients. Regular monitoring of liver enzymes and serum concentrations of calcineurin inhibitors are required to avoid hepatotoxicity and nephrotoxicity.
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PMID:Voriconazole prophylaxis in lung transplant recipients. 1706 3

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

Paracoccidioides brasiliensis is a dimorphic fungus that causes paracoccidioidomycosis, the most prevalent human deep mycosis in Latin America. The dimorphic transition from mycelium to yeast (M-Y) is triggered by a temperature shift from 25 degrees C to 37 degrees C and is critical for pathogenicity. Intracellular Ca(2+) levels increased in hyphae immediately after temperature-induced dimorphism. The chelation of Ca(2+) with extracellular (EGTA) or intracellular (BAPTA) calcium chelators inhibited temperature-induced dimorphism, whereas the addition of extracellular Ca(2+) accelerated dimorphism. The calcineurin inhibitor cyclosporine A (CsA), but not tacrolimus (FK506), effectively decreased cell growth, halted the M-Y transition that is associated with virulence, and caused aberrant growth morphologies for all forms of P. brasiliensis. The difference between CsA and FK506 was ascribed by the higher levels of cyclophilins contrasted to FKBPs, the intracellular drug targets required for calcineurin suppression. Chronic exposure to CsA abolished intracellular Ca(2+) homeostasis and decreased mRNA transcription of the CCH1 gene for the plasma membrane Ca(2+) channel in yeast-form cells. CsA had no detectable effect on multidrug resistance efflux pumps, while the effect of FK506 on rhodamine excretion was not correlated with the transition to yeast form. In this study, we present evidence that Ca(2+)/calmodulin-dependent phosphatase calcineurin controls hyphal and yeast morphology, M-Y dimorphism, growth, and Ca(2+) homeostasis in P. brasiliensis and that CsA is an effective chemical block for thermodimorphism in this organism. The effects of calcineurin inhibitors on P. brasiliensis reinforce the therapeutic potential of these drugs in a combinatory approach with antifungal drugs to treat endemic paracoccidioidomycosis.
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PMID:Evidence for the role of calcineurin in morphogenesis and calcium homeostasis during mycelium-to-yeast dimorphism of Paracoccidioides brasiliensis. 1877 37

Plant PR10 is one of the pathogenesis related proteins, induced upon exposure to different stress conditions including fungal infection. PR10 proteins have been implicated in fungal disease resistance in some species; however its transcriptional regulation is not well understood. In the present work we cloned a PR10 gene from European plums (Prunus domestica L.) and monitored the quantitative changes in its transcript levels as a result of fungal infection in two varieties. We also studied the possible involvement of the membrane degrading enzyme phospholipase D-alpha (PLDalpha). In the susceptible variety, 'Veeblue', infection with the brown rot fungus Monilinia fructicola induced PLDalpha and PR10 expression, while in the resistant variety, 'Violette', a constitutive expression of PLDalpha and PR10 transcripts levels were observed. Resistance to M. fructicola also coincides with a sharp decrease in the expression of ABI1, a protein phosphatase and elevated hydrogen peroxide content after infection. Further, inhibition of PLDalpha by hexanal treatment, up-regulated ABI1 and decreased PR10 expression, suggesting a possible relationship between the two. We further confirm these results in Arabidopsis abi1 mutant that shows a higher level of PR10 transcripts.
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PMID:Expression analysis of a plum pathogenesis related 10 (PR10) protein during brown rot infection. 1881 87

ABSTRACT In the present study, in a candidate gene approach, a class IV chitinase gene (PmCh4A) of pathogenesis-related family three was cloned and characterized in western white pine (Pinus monticola). PmCh4A chitinase expression in the different organs of healthy seedlings was below levels detectable by western immunoblot analysis using an antibody raised against PmCh4A protein. However, a 27-kDa isozyme of PmCh4A accu mulated in both susceptible and slow-canker-growth (SCG) resistant seedlings after infection by Cronartium ribicola. As with fungal infection, the application of a signal chemical (methyl jasmonate) and a protein phosphatase 1 and 2A inhibitor (okadaic acid) increased the PmCh4A protein accumulation. Furthermore, another 26-kDa isozyme was expressed specifically in SCG resistant seedlings, providing a potential tool for marker-assisted selection in forest breeding. Wounding treatment also induced expression of the protein. These data suggest that the class IV chitinase PmCh4A is involved in the defense response of western white pine to infection and abiotic stresses.
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PMID:A Class IV Chitinase Is Up-Regulated by Fungal Infection and Abiotic Stresses and Associated with Slow-Canker-Growth Resistance to Cronartium ribicola in Western White Pine (Pinus monticola). 1894 22


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