The complete sequencing of the human genome in 2001 showed that fewer than 3000 genes encode more than a million proteins. One gene can encode not only a single protein but several proteins, depending on the number of transcriptional (mRNA splicing) and post-translational (glycosylation) modifications. Currently the Swiss-Prot protein database contains 276 256 annotated proteins in UniProtKB/Swiss-Prot (release 54.0 of 4 July 2007) and 4 672 908 proteins translated from the European Molecular Biology Laboratory (EMBL) nucleotide sequence in UniProtKB/TrEMBL (release 37.0 of 4 July 2007). These data suggest that the genome does not reflect the organism’s functional complexity, which is inversely correlated with its biological complexity.Classical strategies have measured mRNA transcripts or proteins according to a priori hypothesis based on literature reviews. Because of the need for global approaches without any a priori hypothesis, techniques known as ‘OMICS’ have been developed for use in analysing genes (genomics), mRNA (transcriptomics), proteins (proteomics) and metabolites (metabolomics). These techniques should make it possible to elucidate the functional role of several genes or gene products and thus better understand phenotypes linked to various types of disease status. The importance of measuring proteins has become clear, as mRNA transcripts cannot be directly correlated with protein expression 3 and post-translational modifications, such as phosphorylation and glycosylation are known to produce several proteins with different functions from a single gene. it summarizes the most common of the more than 200 post-translational modifications that have so far been described. These modifications can be seen only at the protein level and they play a role in protein abundance and in cellular localization. The notion of cartography for protein level expression is an old one, dating back to the publication of a technique to separate proteins simultaneously in 2D electrophoresis gel. The term ‘proteome’, however, was first used in 1994 by Wilkins and defined as all proteins expressed by a genome, cell or tissue. Read more…
Menopause is accompanied by accelerated bone loss, and increasing incidence of fractures. Several studies have shown that hormone replacement therapy (HRT) can reduce bone loss, increase bone mineral density, and decrease the risk of fracture. However, the duration of treatment needed and of the protective effect after treatment is stopped, and the influence of age at which treatment is initiated, are still controversial. We carried out a large, population based, nested case-control study to investigate these issues.
The data used for this study were obtained from the health services database of Lombardia. Lombardia is one of 20 Regions in Italy, with a population of about 9 million inhabitants (about 16% of the population of Italy). The population is entirely covered by the National Health Service (NHS), which has administered this program since 1997. It utilizes an automated system of databases on the use of health services including demographic and administrative data, hospital discharge and outpatient prescription drug benefits. Information is recorded for the NHS and can be linked for each individual using a unique personal identification code. Read more…
Carbamazepine (CBZ) is considered as the primary drug for the treatment of partial and tonic-clonic seizures. It is also the drug of choice for trigeminal neuralgia and frequently used for treating bipolar depression. The originator patent expired long ago (in 1986) and there are now several generic alternatives. However, after the introduction of the generic competitors concerns have arisen about the safety and therapeutic equivalence of generic CBZ tablets.
Several cases have been published about the occurrence of adverse effects after switching from one CBZ product to another. Crawford et al. have reported that approximately 10% of patients complained especially about central nervous system (CNS)-related adverse effects when they were switched to one of the generic products. Read more…
The cytochrome P450 3A enzymes (CYP3A4 and CYP3A5) participate in the biotransformation of approximately half of the drugs that undergo metabolic clearance in human adults. CYP3A4 is highly expressed in the liver and the epithelium of the small intestine and represents on average 30% of total hepatic CYP protein and 33â87% of intestinal CYP. CYP3A5 exhibits a polymorphic expression pattern with high expression in 10â30% of Whites and is clinically important in the disposition of some CYP3A substrates such as tacrolimus and sirolimus. CYP3A enzymes metabolize a broad array of structurally diverse compounds, including macrolide antibiotics, benzodiazepines, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors, calcium channel blockers and human immunodeficiency virus protease inhibitors, and consequently are at the centre of many clinically significant drug interactions. Clarithromycin is a widely used macrolide antibiotic that is a potent inhibitor of CYP3A4 in vitro and in vivo and appears to exert inhibition by an irreversible mechanism. We have previously shown that clarithromycin irreversibly inhibits midazolam hydroxylation in intestinal biopsy tissue obtained from pretreated, young, healthy subjects. An important consequence of this irreversible mechanism is that the inhibition remains for up to 10 days after discontinuation of the inhibitor; this time delay is determined by the elimination half-life of CYP3A4. We have used the simultaneous intravenous (i.v.)/oral (p.o.) midazolam dosing paradigm to demonstrate that clarithromycin exerts a sex-dependent inhibition of intestinal and hepatic CYP3A in young, healthy subjects. Clinically important consequences of CYP3A inhibition by clarithromycin include excessive sedation following benzodiazepine administration, increased concentrations of ciclosporin A and increased risk of nifedipine-induced vasodilatory shock. However the extent of inhibition of CYP3A at hepatic and intestinal sites by potent inhibitors has not previously been examined in the elderly. Read more…
Despite many decades of clinical utilization, the drug interaction potential of tricyclic antidepressants (TCAs), particularity inhibition of drugs eliminated by cytochromes P450 (CYP), is not completely understood. Desipramine is known to cause modest increases in the plasma concentrations of paroxetine and nefazodone whereas imipramine and nortriptyline may precipitate phenytoin toxicity. Amitriptyline increases the metabolic ratio of dextromethorphan/dextrorphan (an in vivo marker for CYP2D6), but has no effect on the metabolism of mephenytoin, a known CYP2C19 substrate. Furthermore, coadministration of amitriptyline or desipramine with moclobemide, another CYP2C19 substrate, is well tolerated. Consistent with these observations, in vitro data confirm TCAs as potent competitive inhibitors of human liver microsomal CYP2D6 CYP2C19 is weakly inhibited and the activities of CYP1A2 and CYP2C9 appear to be unaffected . In vitro data for CYP3A are conflicting. Some authors report inhibition of CYP3A-catalysed reactions by TCAs, whereas others do not. Read more…
The thiazolidinediones rosiglitazone and pioglitazone are peroxisome proliferator-activated receptor-γ agonists, with insulin-sensitizing properties, used in the treatment of Type 2 diabetes. The oral bioavailability of rosiglitazone is nearly 100% and that of pioglitazone >80%. Both drugs are extensively metabolized in the liver. Rosiglitazone is mainly biotransformed by N-demethylation and pyridine ring hydroxylation and pioglitazone by hydroxylation and oxidation. In vitro studies suggest that these reactions are catalysed mainly by CYP2C8, with minor contributions from CYP2C9 for rosiglitazone and CYP3A4 for pioglitazone. All circulating metabolites of rosiglitazone are less potent than the parent drug and are not thought to have substantial effects on blood glucose concentrations, whereas the main metabolites of pioglitazone (M3 and M4) are pharmacologically active, and their plasma concentrations are equal to or greater than those of the parent pioglitazone. The elimination half-life of rosiglitazone is about 3â6 h and that of pioglitazone is about 4â9 h. Read more…
Treatment of inflammatory bowel disease (IBD) is currently based on aminosalicylates, corticosteroids, immunosuppressives, biologicals, antibiotics, nutritional support and surgery. These therapies are limited by side-effects and may be inefficient in up to 30% of patients. Steroid-refractory and steroid-dependent patients are at great risk of extensive bowel resections, even though surgery cannot cure IBD. These patients are qualified for more extensive immunosuppression and the most successful treatment so far has been thiopurine treatment with azathioprine (AZA) or 6-mercaptopurine (6-MP).
The thiopurines are subject to extensive metabolism with both activating and inactivating pathways. The drugs are activated intracellularly by hypoxanthine guanine phosphoribosyltransferase (HPRT1, EC 2.4.2.8). Phosphorylation to thioguanine nucleotides (6-TGN) and incorporation of 6-TGN in DNA has traditionally been regarded as the most important immunosuppressive mechanism. Competing pathways to 6-TGN formation are methylation regulated by the polymorphic enzyme thiopurine S-methyltransferase (TPMT, EC 2.1.1.67), and oxidation to thiouric acid by xanthine oxidase (EC 1.1.3.22). Both 6-MP and AZA also mediate their effects through inhibition of de novo purine biosynthesis by methylated metabolites (6-methylthioinsoine 5′-monophosphate, meTIMP). Recently, it has also been suggested that thioguanine-triphosphate (thio-GTP) interferes with the Rac1-Vav activation of guanosine 5′-diphosphate (GDP), promoting apoptosis, and that the drugs selectively inhibit the expression of inflammatory genes in activated T lymphocytes. Studies have implicated the inosine triphosphate pyrophosphatase (ITPA, EC 3.6.1.19) 94CâA polymorphism in the development of adverse events of thiopurine drugs, such as rash, flu-like symptoms, pancreatitis and also leukopenia, but with divergent results.
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Antilymphocyte globulins (ALGs) are polyclonal antibodies used in organ transplantation to prevent or treat acute allograft rejection. ALGs are obtained by immunizing animals (rabbits or horses) with human lymphoid cells (lymphoblasts, lymphocytes or thymocytes). Although ALGs have been in use for several decades, the interindividual variability in patient response remains poorly understood. Monitoring of drug effect is based on lymphocyte numeration, because ALG doses may be decreased when lymphopenia is obtained or the drug readministered to maintain it. Although lymphocyte count is an established biomarker of ALG therapeutic effect, the study of its quantitative relationship with ALG concentrations has not been reported. Read more…