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Noël Knops, Elena Levtchenko, Bert van den Heuvel, Dirk Kuypers
Since their introduction circa 35 years ago, calcineurin-inhibitors (CNI) have become the cornerstone of immunosuppressive therapy in solid organ transplantation. However, CNI's possess a narrow therapeutic index with potential severe consequences of drug under- or overexposure. This demands a meticulous policy of Therapeutic Drug Monitoring (TDM) to optimize outcome. In clinical practice optimal dosing is difficult to achieve due to important inter- and intraindividual variation in CNI pharmacokinetics. A complex and often interdependent set of factors appears relevant in determining drug exposure...
August 16, 2013: International Journal of Pharmaceutics
Pamala A Jacobson, David Schladt, Ajay Israni, William S Oetting, Yi Cheng Lin, Robert Leduc, Weihau Guan, Vishal Lamba, Arthur J Matas
BACKGROUND: Calcineurin inhibitor (CNI)-related acute nephrotoxicity is a common complication of transplantation. Clinical factors and elevated CNI levels are associated with nephrotoxicity; however, they do not fully explain the risk. Genetic factors may also predispose individuals to nephrotoxicity. METHODS: We enrolled 945 kidney recipients into a multicenter, prospective study. DNA was genotyped for 2724 single-nucleotide polymorphisms (SNPs) using a customized chip...
March 27, 2012: Transplantation
Yan Chen, Marcelo S Sampaio, Jae Wook Yang, David Min, Ian V Hutchinson
Transcription factors of the nuclear factor of activated T cells (NFAT) family regulate both immune activation and insulin production. Calcineurin inhibitors (CNIs) target NFAT activation. Hence, CNIs not only prevent organ transplant rejection but also contribute to the development of new-onset diabetes after transplantation (NODAT). Given individual variation in the susceptibility to NODAT, we hypothesized that polymorphisms in the cytoplasmic NFAT (NFATc)4 gene, which is expressed in pancreatic islets, may be associated with NODAT...
February 15, 2012: Transplantation
Laure Elens, Ron H van Schaik, Nadtha Panin, Martine de Meyer, Pierre Wallemacq, Dominique Lison, Michel Mourad, Vincent Haufroid
AIMS: CYP3A4 is involved in the oxidative metabolism of many drugs and xenobiotics including the immunosuppressants tacrolimus (Tac) and cyclosporine (CsA). The objective of the study was to assess the potential influence of a new functional SNP in CYP3A4 on the pharmacokinetic parameters assessed by dose requirements and trough blood levels of both calcineurin inhibitors (CNI) in stable renal transplant patients. PATIENTS & METHODS: A total of 99 stable renal transplant patients receiving either Tac (n = 49) or CsA (n = 50) were genotyped for the CYP3A4 intron 6 C>T (rs35599367) and CYP3A5*3 SNPs...
October 2011: Pharmacogenomics
T Ashavaid, H Raje, K Shalia, B Shah
The outcome of renal transplantation is improved by cyclosporine and tacrolimus. However, its success is limited by drug-induced nephrotoxicity. Therefore, monitoring their levels is important. These levels are influenced mainly by CYP3A4, CYP3A5 and MDR- 1 genes. These levels also affect target molecules of CNIs, mainly IL-2. Inter-individual differences in these levels have been attributed to SNPs in these genes and hence study of these SNPs assumes significance. So far no study has been carried out on Indian renal transplant recipients covering the SNPs of the genes involved in metabolism, efflux and drug target of CNIs, hence the data is lacking for Indian population...
July 2010: Indian Journal of Nephrology
P T Loh, H X Lou, Y Zhao, Y M Chin, A Vathsala
Calcineurin inhibitors (CNI) are metabolized by cytochrome-P4503A (CYP3A) enzymes and extruded into the intestinal lumen by the drug efflux pump, P-glycoprotein (P-gp). The impact of single nucleotide polymorphisms (SNPs) of genes encoding CYP3A5 and P-gp on CNI dosing was examined among Asian renal transplant recipients. Frequencies of CYP3A5*1 versus *3 and MDR1-C3435T were correlated with tacrolimus (TAC) and cyclosporine (CSA) concentration-to-dose (C/D) ratios. Among 82 recipients (49% male; 88% Chinese), the majority were CYP3A5 expressors (*1*1 and *1*3, 11% and 40%, respectively) and 49% were nonexpressors (*3/*3)...
June 2008: Transplantation Proceedings
Luigi Scotto, Gopeshwar Narayan, Subhadra V Nandula, Shivakumar Subramaniyam, Andreas M Kaufmann, Jason D Wright, Bhavana Pothuri, Mahesh Mansukhani, Achim Schneider, Hugo Arias-Pulido, Vundavalli V Murty
BACKGROUND: Copy number gains and amplifications are characteristic feature of cervical cancer (CC) genomes for which the underlying mechanisms are unclear. These changes may possess oncogenic properties by deregulating tumor-related genes. Gain of short arm of chromosome 5 (5p) is the most frequent karyotypic change in CC. METHODS: To examine the role of 5p gain, we performed a combination of single nucleotide polymorphism (SNP) array, fluorescence in situ hybridization (FISH), and gene expression analyses on invasive cancer and in various stages of CC progression...
June 17, 2008: Molecular Cancer
Luigi Scotto, Gopeshwar Narayan, Subhadra V Nandula, Hugo Arias-Pulido, Shivakumar Subramaniyam, Achim Schneider, Andreas M Kaufmann, Jason D Wright, Bhavana Pothuri, Mahesh Mansukhani, Vundavalli V Murty
Recurrent karyotypic abnormalities are a characteristic feature of cervical cancer (CC) cells, which may result in deregulated expression of important genes that contribute to tumor initiation and progression. To examine the role of gain of the long arm of chromosome 20 (20q), one of the common chromosomal gains in CC, we evaluated CC at various stages of progression using single nucleotide polymorphism (SNP) array, gene expression profiling, and fluorescence in situ hybridization (FISH) analyses. This analysis revealed copy number increase (CNI) of 20q in >50% of invasive CC and identified two focal amplicons at 20q11...
September 2008: Genes, Chromosomes & Cancer
David G Ingram, Sean C Newcomer, Elmer M Price, Kevin E Eklund, Richard M McAllister, M Harold Laughlin
Current literature suggests that chronic nitric oxide synthase (NOS) inhibition has differential effects on endothelium-dependent dilation (EDD) of conduit arteries vs. arterioles. Therefore, we hypothesized that chronic inhibition of NOS would impair EDD of porcine left anterior descending (LAD) coronary arteries but not coronary arterioles. Thirty-nine female Yucatan miniature swine were included in the study. Animals drank either tap water or water with N(G)-nitro-L-arginine methyl ester (L-NAME; 100 mg/l), resulting in control and chronic NOS inhibition (CNI) groups, respectively...
June 2007: American Journal of Physiology. Heart and Circulatory Physiology
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