摘要:

Transplantation has transformed the treatment of patients with organ failure in a number of clinical settings, and immunosuppressive drug therapy is fundamental to its success. However, all the drugs in current use have a narrow therapeutic index. Under-dosing can lead to rejection, while over-dosing increases the risks of infection, malignant disease, and serious drug-specific adverse effects, including diabetes mellitus, nephrotoxicity, hypertension, and hyperlipidemia.Heterogeneity in the pharmacokinetics of these drugs makes initial dose determination difficult, as there is a poor correlation between dose and blood concentration. This results in difficulties in achieving target blood concentrations early after transplantation, which are important for reducing the rate of immunological rejection. This problem is compounded by the observation that neither drug dose nor drug blood concentration accurately predict clinical efficacy or toxicity.The main determinant of heterogeneity in dose requirements is intestinal absorption of the active drug. The oxidative enzymes, cytochrome P450 (CYP) 3A4 and CYP3A5, and the drug efflux pump P-glycoprotein (P-gp) in enterocytes regulate this process. Most substrates for the P-gp pump are also substrates for the CYP3A enzymes. An efficient barrier to xenobiotic absorption is formed by the CYP enzymes and P-gp, and by the two systems working synergistically. Genetic polymorphisms have been reported for the genes associated with the expression of the CYP3A enzymes and P-gp. Genotyping patients forCYP3Agenes has the potential to aid the establishment of optimal dosage regimens for transplant patients.Genetic polymorphism of the multiple drug resistance gene-1 (MDR1, also known asABCB1) [3435C/T] and theCYP3A5genes (CYP3A5*1,CYP3AP1*1) have the greatest potential to influence the pharmacokinetics of immunosuppressants. Homozygosity of the T allele of theMDR13435C/T polymorphism has been associated with reduced enterocyte expression of P-gp resulting in increased drug absorption. The presence of theCYP3A5*1 allele is necessary for the production of a fully catalytic CYP3A5 protein, and also influences the ratio of CYP3A4 : CYP3A5 as well as the overall CYP3A catalytic activity. The CYP3A4 : CYP3A5 ratio may, in turn, influence the pattern of drug metabolites formed. Heterogeneity in the production of active and inactive metabolites has implications for both the pharmacokinetics and pharmacodynamics of these drugs.Gene frequencies and drug dose requirements differ between ethnic groups. Ethnic differences in dose requirements for immunosuppressants have been discussed widely. However, ethnicity is a rather crude marker for genotype. Pharmacogenetic typing offers the possibility of significant improvement in the individualization of immunosuppressive drug prescribing with reduced rates of rejection and toxicity.

ISSN:1175-2203    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

Proton pump inhibitors (PPIs) are highly effective agents for the treatment of gastric acid-related disorders. They are metabolized by the cytochrome P450 (CYP) system, mainly via the enzyme CYP2C19. A genetically determined defect in this pathway results in impaired metabolism of PPIs, giving rise to three distinct phenotypes: rapid extensive (fast), extensive (medium), and poor (slow) metabolizers. These genetic mutations are more common in certain races, and there is, therefore, considerable inter-individual and -ethnic variation in the capacity to metabolize PPIs.The incidence of mutant alleles in a population treated for acid-related disorders may influence the efficacy of the treatment, with clinical implications for the prescribers of PPIs. Therapeutic failure, such as lack of symptom relief, or ineffectiveHelicobacter pylorieradication, can occur in rapid metabolizers who will have less available drug at a given dose. Conversely, poor metabolizers may be at risk of over-treatment, with increased incidence of adverse effects and unnecessary financial burden.Approaches to this problem include phenotyping or, preferably, genotyping patients prior to treatment with PPIs. This will allow tailoring dose regimens to the individual’s metabolic capacity. An alternative strategy is the development of drugs that are either metabolized by genotype-independent pathways or are less susceptible to inter-individual genetic variation. Non-racemic PPIs fall into the latter category, and the first such agent, esomeprazole, is now commercially available.

ISSN:1175-2203    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

Both inflammation and genetics play an important role in the pathogenesis of atherosclerosis and coronary artery disease. Epidemiological studies have investigated the association between coronary artery disease (CAD) and gene polymorphisms of the inflammatory molecules tumor necrosis factors (TNF) α and β, transforming growth factors (TGF) β-1 and β-2, interleukin (IL)-1 and its receptor antagonist (IL-1ra), CD14 (the receptor for lipopolysaccharide), P- and E-selectins, and platelet endothelial cell adhesion molecule (PECAM)-1.Current evidence suggests that the TNF polymorphisms explored so far are not linked to CAD. The majority of studies conducted showed no significant association between TGFβ-1 and coronary atherosclerosis, but the data currently available are somewhat controversial. Some polymorphisms may increase the risk of myocardial infarction (MI) within specific ethnic groups or in certain populations. The association between the IL-1 system and atherosclerosis is complex and may vary as a result of a number of factors, such as stage of disease, clinical phenotype, and possibly population characteristics.The E-selectin gene (SELE) Arg128, 98T, and Phe554 alleles may increase the risk of atherosclerosis, but not necessarily the risk of MI. This association seems to be more pronounced in younger patients. ThePECAM1Leu125Val and Ser563Asn polymorphisms may increase the risk of atherosclerosis but not necessarily of MI. This association may be especially important in patients with a low risk for developing atherosclerosis.Current data indicate that screening forCD14−260C/T genotypes is unlikely to be a useful tool for risk assessment and it remains unclear whetherCD14polymorphisms significantly increase the risk of MI.The associations between candidate gene polymorphisms and CAD are complex as a consequence of pleiotropy, variations with age, selection due to the high lethality of the disease, and interactions with other genes and environmental factors. Nonetheless, although the current data is preliminary and partly conflicting, it does provide some evidence that alterations in the genetics of the inflammatory system may modify the risk of CAD.

ISSN:1175-2203    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

Migraine is a common complex disorder that affects a large portion of the population and thus incurs a substantial economic burden on society. The disorder is characterized by recurrent headaches that are unilateral and usually accompanied by nausea, vomiting, photophobia, and phonophobia. The range of clinical characteristics is broad and there is evidence of comorbidity with other neurological diseases, complicating both the diagnosis and management of the disorder. Although the class of drugs known as the triptans (serotonin 5-HT1B/1Dagonists) has been shown to be effective in treating a significant number of patients with migraine, treatment may in the future be further enhanced by identifying drugs that selectively target molecular mechanisms causing susceptibility to the disease.Genetically, migraine is a complex familial disorder in which the severity and susceptibility of individuals is most likely governed by several genes that may be different among families. Identification of the genomic variants involved in genetic predisposition to migraine should facilitate the development of more effective diagnostic and therapeutic applications. Genetic profiling, combined with our knowledge of therapeutic response to drugs, should enable the development of specific, individually-tailored treatment.

ISSN:1175-2203    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

The nuclear receptor (NR) superfamily is a large group of related, pharmacologically important receptors, comprising the targets for over 10% of commonly prescribed drugs. Cross-genome analysis of NR sequence, structure, and biological function, provides an important source of information on the function of human NRs and thus plays a role in NR drug discovery. For example, research on the pregnane X receptor (PXR; NR1I2), constitutive androstane receptor (CAR; NR1I3), hepatocyte nuclear factor 4 (HNF4; NR2A1), and farnesoid X receptor (FXR) illustrate how the study of nonhuman orthologs has provided new insights into NR biology and has increased our understanding of human NRs and orphan NR function. Understanding differences between humans and pharmacological model species may provide useful tools for the development of new NR-binding drugs.

ISSN:1175-2203    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

ObjectiveCytochrome P450 (CYP) 2J2 plays an important role in the biosynthesis of the biologically activecis-epoxyeicosatrienoic acids. An allelic variant namedCYP2J2*6, which encodes an enzyme that is almost inactive in the metabolism of arachidonic acid, has recently been described. We investigated the frequency of theCYP2J2*6 variant in a Caucasian population and the relationship between this polymorphism and the development of micro- and macrovascular complications and hypertension in patients with type 1 or type 2 diabetes mellitus.MethodsGenomic DNA was extracted from peripheral blood cells and the fragment containing the A/T single nucleotide polymorphism at position 25 661 in exon 8 of theCYP2J2gene was amplified. The 532 bp amplified product was subsequently digested withTsp509I and analyzed on 12% polyacrylamide gel electrophoresis.ResultsIn the whole population, the frequency of theCYP2J2*6 allele was 0.0064 and the frequency of theCYP2J2*1 allele was 0.9936. Genotype distribution did not show significant differences between controls and patients with type 1 or type 2 diabetes. No homozygotes forCYP2J2*6 allele were found. No association was found between this allele and complications or hypertension in either type of diabetes.ConclusionTheCYP2J2*6 allele is rare in the Caucasian population, and no association is inferred between this allelic variant and diabetic complications.

ISSN:1175-2203    

出版商:ADIS    

年代:2003

数据来源: ADIS