ISSN:0960-314X    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Oral contraceptives are currently used by more than 100 million women in developed countries and are a highly efficacious method to prevent undesired pregnancies. However, oral contraceptives are associated with an increased risk of venous and arterial thrombosis, through changes in blood coagulation and fibrinolysis. In order to reduce such complications, the composition of oral contraceptives has changed over the past decades, both for the dose of oestrogen and the type of progestagen. However, the risk for venous thromboembolism remains, particularly for women who are carriers of inherited thrombophilia. In these women, prescription of oral contraceptives should be carried out on an individual basis. This review illustrates the risk of thrombosis, particularly venous thromboembolism, associated with the use of oral contraceptives, underlines the crucial role of the interaction of these drugs with other risk factors for the disease, and gives suggestions on the utility of thrombophilia screening before prescription.

ISSN:0960-314X    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

CYP3A activity in adults varies between individuals and it has been suggested that this has a genetic basis, possibly related to variant alleles inCYP3A4andCYP3A5genes. Accordingly, genotype–phenotype associations were investigated under constitutive and induced conditions. Midazolam's systemic and oral clearances, and the erythromycin breath test (ERBT) were determined in 57 healthy subjects: 23 (11 men, 12 women) European- and 34 (14 men, 20 women) African-Americans. Studies were undertaken in the basal state and after 14–15 days pretreatment with rifampin. DNA was characterized for the common polymorphismsCYP3A4*1B,CYP3A5*3,CYP3A5*6andCYP3A5*7by direct sequencing, and for exon 21 and exon 26 variants ofMDR1by allele-specific, real-time polymerase chain reaction. In 95% of subjects, the basal systemic clearance of midazolam was unimodally distributed and variability was less than four-fold whereas, in 98% of the study population, oral clearance varied five-fold. No population or sex-related differences were apparent. Similar findings were observed with the ERBT. Rifampin pretreatment markedly increased the systemic (two-fold) and oral clearance (16-fold) of midazolam, and the ERBT (two-fold) but the variabilities were unchanged. No associations were noted between these phenotypic measures and any of the studied genotypes, except for oral clearance and its fold-increase after rifampin. These were related to the presence ofCYP3A4*1Band the inversely linkedCYP3A5*3polymorphism, with the extent of induction being approximately 50% greater inCYP3A5*3homozygotes compared to wild-type subjects. In most healthy subjects, variability in intestinal and hepatic CYP3A activity, using midazolam as an in-vivo probe, is modest and common polymorphisms inCYP3A4andCYP3A5do not appear to have important functional significance.

ISSN:0960-314X    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

CYP3Aisozymes are involved in tobacco carcinogen- and steroid-metabolism, and are expressed in human lung tissue showing interindividual variation in expression and activity. TheCYP3A4*1Ballele has been associated with a two-fold higher promoter activity and with high-grade prostate cancers. The very frequent intron 3 polymorphism in theCYP3A5gene (CYP3A5*3)results in decreased CYP3A5 protein levels. A case–control study was conducted in 801 Caucasian lung cancer patients that included 330 adenocarcinomas, 260 squamous cell carcinomas, 171 small cell lung cancers (SCLC) and 432 Caucasian hospital-based controls.CYP3A-genotyping was performed by capillary polymerase chain reaction followed by fluorescence-based melting curve analysis. A significantly increased SCLC risk forCYP3A4*1Ballele carriers [odds ratio (OR) 2.25, 95% confidence interval (CI) 1.11–4.55,P= 0.02] was found. After dividing cases and controls by gender, an increased lung cancer risk forCYP3A4*1Bcarriers (OR 3.04, 95% CI 0.94–9.90,P= 0.06) for women but not for men (OR 1.00, 95% CI 0.56–1.81) was revealed. Heavier smoking men (⩾ 20 pack-years) with theCYP3A4*1Ballele had a significant OR for lung cancer of 3.42 (95% CI 1.65–7.14,P= 0.001) compared to *1A/*1Acarriers with lower tobacco exposure (<20 pack-years). For women, the respective OR was 8.00 (95% CI 2.12–30.30,P= 0.005). Genotype frequencies were generally in Hardy–Weinberg equilibrium, except for CYP3A5 where a greater than expected number ofCYP3A5*1homozygotes was observed among cases (P= 0.006). In addition, we observed linkage disequilibrium ofCYP3A4andCYP3A5(P<0.00001), but a non-significantly increased lung cancer risk was only found for homozygousCYP3A5*1allele carriers (OR 5.24, 95% CI 0.85–102.28,P= 0.14) but not for heterozygotes. To confirm our observation that theCYP3A4*1Ballele increases SCLC risk and modifies the smoking-related lung cancer risk in a gender-specific manner, further studies, includingCYP3Ahaplotype analysis, will be necessary.

ISSN:0960-314X    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Bupropion is applied in depression and smoking cessation. Genetic polymorphisms in cytochrome P450 2B6 (CYP2B6) may cause variability in bupropion pharmacokinetics since hydroxylation is known to be mediated by CYP2B6. Bupropion may be a probe drug for CYP2B6 activity in humans. Bupropion pharmacokinetics were studied after a single oral dose of 150 mg in 121 healthy male volunteers. The amino acid polymorphisms R22C, Q172H, S259R, K262R and R487C were analysed by polymerase chain reaction and restriction fragment length polymorphism and plasma concentrations were measured by high-performance liquid chromatography. Pharmacokinetic analysis was performed by non-parametric methods and by population pharmacokinetic modelling. A unimodal distribution of bupropion and hydroxybupropion kinetic parameters was detected with a mean (range) area under the curve (AUC) of 3.64 (0.89–8.14) μmol⋅h/l for bupropion and 25.5 (6.72–75.3) μmol⋅h/l for hydroxybupropion. Population kinetic analysis revealed that bupropion total clearance viaCYP2B6alleles*1,*2,*5and*6did not differ, but clearance via allele*4was 1.66-fold higher compared to wild-type allele*1(P= 0.001). Corresponding to the high clearance of bupropion, carriers of theCYP2B6genotype*1/*4had significantly higherCmaxof hydroxybupropion compared to all other genotypes (P= 0.03). Only a minor fraction of the variability in bupropion and hydroxybupropion kinetics could be explained by the known CYP2B6 amino acid variants, in particular by theCYP2B6*4allele. The role of this allele should also be studied in other CYP2B6 substrates, including cyclophosphamide, halothane, mianserin, promethazine and propofol.

ISSN:0960-314X    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Perhexiline is metabolized by CYP2D6 and has concentration-related hepatoxicity and peripheral neuropathy. The risk of toxicity is reduced using therapeutic drug monitoring.CYP2D6genotyping before therapy may allow earlier appropriate dosing. This study aimed to determine whether assessment ofCYP2D6genotype in patients on perhexiline could predict accurately metabolizer status as determined by the perhexiline metabolic ratio (MR). Blood samples from patients stabilized on perhexiline were analysed forCYP2D6genotype and for concentrations of perhexiline and its hydroxy metabolite. The MR was determined. Of 74 patients, five were poor metabolizers (PM) defined by a MR < 0.4, and the remainder were extensive metabolizers (EM). The genotypes were:*1/*1(n= 21),*1/*4(n= 18),*1/*2(n= 12),*1/*3(n= 2),*1/*5(n= 1),*1/*9(n= 2),*1/*10(n= 2),*2/*4(n= 4),*2/*2(n= 3),*4/*41(n= 3),*2/*41(n= 1),*41/*41(n= 1),*4/*9(n= 1),*4/*5(n= 1),*5/*6(n= 1) and*4/*6(n= 1). Allele frequencies were consistent with those reported in population studies. The 3 PMs with the lowest MR were predicted by genotype (*4/*5,*5/*6,*4/*6). The other 2 PMs had intermediate metabolizer genotypes and were on CYP2D6 inhibiting drugs. Amongst the EMs, the highest MR was associated with *1and *2allele combinations and the MR was progressively lower with the presence of alleles with intermediate function (*9,*10,*41) followed by alleles with no functional product (*3,*4,*5,*6). Thus, a gene–dose effect was observed. Genotype predicted PM phenotype and also intermediate metabolizers. Determination ofCYP2D6genotype before therapy with perhexiline may help predict perhexiline dose requirements and reduce the risk of perhexiline concentration-related toxicity.

ISSN:0960-314X    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

A polymorphism at position −511 of interleukin-1B (IL-1B) gene promoter regulates IL-1B levels, immune and inflammatory responses and possible atherogenesis. We used positron emission tomography (PET) to study whether coronary reactivity or its response to pravastatin is related to this IL-1B polymorphism. The study comprised a randomized, double-blind, placebo-controlled trial with two treatment groups: (i) pravastatin (40 mg/day,n= 14) and (ii) placebo (n= 20) for 6 months (baseline mean cholesterol 5.5 ± 0.8 mmol/l; age 35 ± 4 years). Myocardial blood flow was measured by PET at rest and during adenosine infusion using15O-labelled water. PET studies, lipid, IL-1β and C-reactive protein analyses were performed at baseline and after 6 months of therapy. IL-1B genotype was determined by polymerase chain reaction. There were no differences between IL-1B allele 2 carriers (A2+) and non-carriers (A2−) in basal or adenosine-stimulated myocardial flow (ASMF), at baseline. Regarding the change in ASMF and coronary flow reserve, there was a significant IL-1B genotype-by-treatment group interaction (analysis of covariance,P= 0.028 andP= 0.002, respectively) during follow-up. In the pravastatin group, the ASMF increased by 18.0% in subjects with IL-1B A2− (n= 7), but decreased by 2% in subjects with IL-1B A2+ (n= 7). There were no significant changes from the baseline values in placebo recipients. After treatment, both genotype groups showed a similar decrease in serum total and low density lipoprotein cholesterol (P<0.0001 for both). In conclusion, coronary function improves after 6 months of pravastatin therapy in subjects with the IL-1B A2− allele but not in those with the IL-1B A2+ allele.

ISSN:0960-314X    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

The clinical heterogeneity of asthma suggests that the contribution of genetic variability in candidate gene loci to well-defined phenotypes, such as atopy, may be examined to identify appropriate genetic risk factors for asthma. The gene encoding the cysteinyl leukotriene 2 (CysLT2) receptor has been implicated in atopy since it is localized to a region of chromosome 13q14 that has been linked to atopy in several populations and the cysteinyl leukotrienes are known to activate eosinophils and mast cells in atopy. Accordingly, we analysed the contribution of CysLT2receptor gene variation to atopy in the inhabitants of Tristan da Cunha, a population characterized by both a founder effect and a 47% prevalence of atopy. Single-stranded conformational polymorphism analysis revealed four variants. Among these, the M202V variant was activated with four-fold less potency by leukotriene D4(LTD4) in a calcium flux assay. The CysLT2receptor partial agonist, BAY u9773, also showed four-fold lower potency on the M202V variant. The M202V mutation is located within the extracellular region of the fifth transmembrane spanning domain of CysLT2receptor, a position that may alter ligand binding and effector signalling. The novel M202V CysLT2receptor variant was associated with atopy (21%) on Tristan da Cunha compared with those who were non-atopic (7%) (Fisher's exact test,P= 0.0016) in a manner that was independent of asthma (two-way ANOVA,P= 0.0015). This represents the first association of a coding mutation in the CysLT2receptor gene, located on chromosome 13q14, with the atopic phenotype found in the Tristan da Cunha population.

ISSN:0960-314X    

出版商:OVID    

年代:2003

数据来源: OVID