There is, I think, something ethereal about i —the square root of minus one. I remember first hearing about it at school. It seemed an odd beast at that time—an intruder hovering on the edge of reality.

Usually familiarity dulls this sense of the bizarre, but in the case of i it was the reverse: over the years the sense of its surreal nature intensified. It seemed that it was impossible to write mathematics that described the real world in …

I and i

Appendix I: List of Statistical Fact Sheets. URL: http://www.americanheart.org/presenter.jhtml?identifier=2007

We wish to thank Drs Brian Eigel and Michael Wolz for their valuable comments and contributions. We would like to acknowledge Tim Anderson and Tom Schneider for their editorial contributions and Karen Modesitt for her administrative assistance.

Disclosures 



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# Summary {#article-title-2}

Each year, the American Heart Association, in conjunction with the Centers for Disease Control and Prevention, the National Institutes of Health, and other government agencies, brings together the most up-to-date statistics on heart disease, stroke, other vascular diseases, and their risk factors and presents them in its Heart Disease and Stroke Statistical Update. The Statistical Update is a valuable resource for researchers, clinicians, healthcare policy makers, media professionals, the lay public, and many others who seek the best national data available on disease …

Heart Disease and Stroke Statistics—2010 Update A Report From the American Heart Association

Rosamond, Paul D. Sorlie, Randall S. Stafford, Tanya N. Turan, Melanie B. Turner, Nathan D. Dariush Mozaffarian, Michael E. Mussolino, Graham Nichol, Nina P. Paynter, Wayne D. Ariane Marelli, David B. Matchar, Mary M. McDermott, James B. Meigs, Claudia S. Moy, Lackland, Judith H. Lichtman, Lynda D. Lisabeth, Diane M. Makuc, Gregory M. Marcus, John A. Heit, P. Michael Ho, Virginia J. Howard, Brett M. Kissela, Steven J. Kittner, Daniel T. Caroline S. Fox, Heather J. Fullerton, Cathleen Gillespie, Kurt J. Greenlund, Susan M. Hailpern, Todd M. Brown, Mercedes R. Carnethon, Shifan Dai, Giovanni de Simone, Earl S. Ford, Véronique L. Roger, Alan S. Go, Donald M. Lloyd-Jones, Robert J. Adams, Jarett D. Berry, Association 2011 Update : A Report From the American Heart −− Heart Disease and Stroke Statistics

Heart Disease and Stroke Statistics—2011 Update A Report From the American Heart Association

We thank Drs Sean Coady, Eric L. Ding, Brian Eigel, Gregg C. Fonarow, Linda Geiss, Cherie James, Michael Mussolino, and Michael Wolz for their valuable comments and contributions. We acknowledge Tim Anderson and Tom Schneider for their editorial contributions, and Karen Modesitt for her administrative assistance.

Disclosures 

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Writing Group Disclosures, Continued 



# Summary {#article-title-2}

Each year, the American Heart Association, in conjunction with the Centers for Disease Control and Prevention, the National Institutes of Health, and other government agencies, brings together the most up-to-date statistics on heart disease, stroke, other vascular diseases, and their risk factors and presents them in its Heart Disease and Stroke Statistical Update. The Statistical Update is a valuable resource for researchers, clinicians, healthcare policy makers, media professionals, the lay …

Heart Disease and Stroke Statistics—2009 Update

Heart disease and stroke statistics--2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee.

Accumulating evidence indicates that CYP2C9 ranks amongst the most important drug metabolizing enzymes in humans. Substrates for CYP2C9 include fluoxetine, losartan, phenytoin, tolbutamide, torsemide, S-warfarin, and numerous NSAIDs. CYP2C9 activity in vivo is inducible by rifampicin. Evidence suggests that CYP2C9 substrates may also be induced variably by carbamazepine, ethanol and phenobarbitone. Apart from the mutual competitive inhibition which may occur between alternate substrates, numerous other drugs have been shown to inhibit CYP2C9 activity in vivo and/or in vitro. Clinically significant inhibition may occur with coadministration of amiodarone, fluconazole, phenylbutazone, sulphinpyrazone, sulphaphenazole and certain other sulphonamides. Polymorphisms in the coding region of the CYP2C9 gene produce variants at amino acid residues 144 (Arg144Cys) and 359 (Ile359Leu) of the CYP2C9 protein. Individuals homozygous for Leu359 have markedly diminished metabolic capacities for most CYP2C9 substrates, although the frequency of this allele is relatively low. Consistent with the modulation of enzyme activity by genetic and other factors, wide interindividual variability occurs in the elimination and/or dosage requirements of prototypic CYP2C9 substrates. Individualisation of dose is essential for those CYP2C9 substrates with a narrow therapeutic index.

/pdf/cytochrome-p4502c9-an-enzyme-of-major-importance-in-human-2jk2wltlsu.pdf

Cytochrome P4502C9: an enzyme of major importance in human drug metabolism.

Several novel UDP glycosyltransferase (UGT) genes, mainly UDP glucuronosyltransferases, have been identified in the human, mouse and rat genomes and in other mammalian species. This review provides an update of the UGT nomenclature to include these new genes and prevent the confusion that arises when the same gene is given different names. The new genes are named following previously established recommendations, taking into consideration evolutionary relatedness and the names already in general usage in the literature. The mammalian UGT gene superfamily currently has 117 members that can be divided into four families, UGT1, UGT2, UGT3 and UGT8. The 5-exon genes of the UGT1 family each contain a unique first exon, plus four exons that are shared between the genes; the exons 1 appear to have evolved by a process of duplication, leading to the synthesis of proteins with identical carboxyl-terminal and variable amino-terminal domains. Exon-sharing is also seen with the 6-exon UGT2A1 and UGT2A2 genes. However, UGT2A3 and those of the UGT2B (six exons), UGT3 (seven exons) and UGT8 gene families (five or six exons) do not share exons and most likely were derived by a process of duplication of all exons in the gene. Most UGT1 and UGT8 enzymes have been characterized in detail; however, the catalytic functions of the UGT3A enzymes and several UGT2 enzymes remain to be characterized.

Nomenclature update for the mammalian UDP glycosyltransferase (UGT) gene superfamily.

Tolbutamide undergoes hydroxylation in humans via a cytochrome P450-mediated pathway. The primary P450 isozyme responsible for this metabolism is thought to be CYP2C9. Population studies have indicated the existence of slow metabolizers of tolbutamide (approximately 1 in 500) suggesting a rare polymorphism associated with 2C9. Several allelic variants of 2C9 have been identified; however, the effect of these allelic variations on metabolism in vivo is not established. In the present study, the coding regions, intron-exon junctions, and upstream region of CYP2C9 were amplified by PCR and sequenced in two slow metabolizers. One individual was homozygous for Leu359/Leu359 and the other individual was heterozygous for Arg144/Cys144 and for Ile359/Leu359. No other genetic variations in 2C9 were detected in these individuals. PCR-RFLP tests showed that Arg144 Tyr358 Ile359 Gly417 is the principle CYP2C9 allele. Frequencies of the rarer Leu359 and Cys144 alleles were 0.06 and 0.08, respectively, in a Caucasian-American population and 0.005 and 0.01 respectively in African-Americans. The frequency of the Leu359 allele was 0.026 in Chinese-Taiwanese, but the Cys144 allele was not detected in this population. Studies in a recombinant yeast expression system showed that the Leu359 variant had the highest Km and the lowest Vmac for hydroxylation of tolbutamide of all the CYP2C9 allelic variants. This allelic variant also had the highest Km for the 7-hydroxylation of S-warfarin. The present data suggest that the incidence of the Leu359 allelic variant of CYP2C9 may account for the occurrence of poor metabolizers of tolbutamide.

John O. Miners

Papers

Cytochrome P4502C9: an enzyme of major importance in human drug metabolism.

Nomenclature update for the mammalian UDP glycosyltransferase (UGT) gene superfamily.

The role of the CYP2C9-Leu359 allelic variant in the tolbutamide polymorphism.

The UDP-glucuronosyltransferases: their role in drug metabolism and detoxification.

Drug glucuronidation in humans.