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排序方式: 共有859条查询结果,搜索用时 15 毫秒
81.
Azathioprine and 6-mercaptopurine pharmacogenetics and metabolite monitoring in inflammatory bowel disease 总被引:4,自引:0,他引:4
The thiopurine drugs azathioprine and 6-mercaptopurine (6-MP) are well-established in the treatment of inflammatory bowel disease (IBD). However, there is a wide inter- and intra-patient variation in the concentrations of active and toxic metabolites due to their complex metabolism and genetic polymorphisms in metabolizing enzymes. Serious drug toxicity leads to cessation of therapy in 9-25% of patients, and there is failure to achieve efficacy in approximately 15% of cases. Advances in the understanding of thiopurine drug metabolism have led to new genetic and metabolite tests to help clinicians optimize thiopurine use. Thiopurine methyltransferase (TPMT) enzyme activity can predict life-threatening myelotoxicity in the one in 300 patients who are TPMT-deficient. However, myelotoxicity can also occur in the presence of normal TPMT activity so blood count monitoring should remain standard practice. TPMT testing may also aid in dose individualization. 6-Thioguanine nucleotides (6-TGN) are thought to be the predominant active metabolites of the thiopurines. 6-thioguanine nucleotide concentration is correlated with bone marrow toxicity and may also correlate with efficacy in IBD. Measurement of 6-TGN and 6-methylmercaptopurine (6-MMP) concentration is most useful in determining why a patient is not responding to a standard dose of a thiopurine drug and may help in avoiding myelosuppression. The ratio of these metabolites can help distinguish non-compliance, under-dosing, thiopurine-resistant and thiopurine-refractory disease. Some of these investigations are entering routine clinical practice but more research is required to determine their optimal use in patients with IBD. 相似文献
82.
Gusella M Pasini F Bolzonella C Meneghetti S Barile C Bononi A Toso S Menon D Crepaldi G Modena Y Stievano L Padrini R 《British journal of clinical pharmacology》2011,71(3):437-444
AIM
Gemcitabine (GEM) enters normal and tumour cells via concentrative (CNT) and equilibrative nucleoside transporters (ENT) and is subsequently deaminated to the inactive difluorodeoxyurine (dFdU) by cytidine deaminase (CDA). The aim of our study was to ascertain whether the nucleoside transporter genotype and the CDA activity phenotype can predict total GEM plasma clearance.METHODS
Forty-seven patients received GEM 1000–1250 mg m−2 i.v. over 30 min. Plasma concentrations of GEM and dFdU were measured and individual pharmacokinetic profiles were determined. CDA activity was measured ex vivo in plasma samples. The two most common hENT1 and hCNT1 polymorphisms were determined from genomic DNA.RESULTS
Multivariate analysis revealed that GEM plasma clearance (CL) was positively correlated with the end of infusion dFdU : GEM ratio (P < 0.0001), which is a marker of in vivo CDA activity. The ENT1 genotype characterized by high transport capacity (G/G) and age were inversely correlated with CL (P= 0.027 and 0.048, respectively). A strong correlation was found between end of infusion GEM concentration and area under the concentration–time curve from time 0 to infinity (AUC(0,∞)) (r2= 0.77).CONCLUSIONS
Our results confirm the role of CDA and age on the interindividual variability of GEM CL and show the contribution of the hENT1 genotype for the first time. 相似文献83.
Recent clinical and laboratory studies have shown that the effects of naltrexone for alcoholism may be moderated by the Asn40Asp single-nucleotide polymorphism (SNP) of the μ-opioid receptor gene (OPRM1). Allele frequencies for this polymorphism, however, have been shown to vary substantially as a function of ethnic background, such that individuals of Asian descent are more likely to carry the minor (Asp40) allele. The objective of this study is to test the naltrexone pharmacogenetic effects of the Asn40Asp SNP in a sample of Asian Americans. This study consists of a double-blinded, randomized, placebo-controlled laboratory trial of naltrexone. Participants (n=35, 10 females; 13 Asn40Asn and 22 Asp40 carriers) were non-treatment-seeking heavy drinkers recruited from the community. After taking naltrexone or placebo, participants completed an intravenous alcohol administration session. The primary outcome measures were subjective intoxication and alcohol craving. Results suggested that Asp40 carriers experienced greater alcohol-induced sedation, subjective intoxication, and lower alcohol craving on naltrexone, as compared to placebo, and to Asn40 homozygotes. There results were maintained when controlling for ALDH2 (rs671) and ADH1B (rs1229984) markers and when examining the three levels of OPRM1 genotype, thereby supporting an OPRM1 gene dose response. These findings provide a much-needed extension of previous studies of naltrexone pharmacogenetics to individuals of Asian descent, an ethnic group more likely to express the minor allele putatively associated with improved biobehavioral and clinical response to this medication. These findings help further delineate the biobehavioral mechanisms of naltrexone and its pharmacogenetics. 相似文献
84.
Lane S Al-Zubiedi S Hatch E Matthews I Jorgensen AL Deloukas P Daly AK Park BK Aarons L Ogungbenro K Kamali F Hughes D Pirmohamed M 《British journal of clinical pharmacology》2012,73(1):66-76
BACKGROUND
Warfarin is a drug with a narrow therapeutic index and large interindividual variability in daily dosing requirements. Patients commencing warfarin treatment are at risk of bleeding due to excessive anticoagulation caused by overdosing. The interindividual variability in dose requirements is influenced by a number of factors, including polymorphisms in genes mediating warfarin pharmacology, co-medication, age, sex, body size and diet.AIMS
To develop population pharmacokinetic models of both R- and S-warfarin using clinical and genetic factors and to identify the covariates which influence the interindividual variability in the pharmacokinetic parameters of clearance and volume of distribution in patients on long-term warfarin therapy.METHODS
Patients commencing warfarin therapy were followed up for 26 weeks. Plasma warfarin enantiomer concentrations were determined in 306 patients for S-warfarin and in 309 patients for R-warfarin at 1, 8 and 26 weeks. Patients were also genotyped for CYP2C9 variants (CYP2C9*1,*2 and *3), two single-nucleotide polymorphisms (SNPs) in CYP1A2, one SNP in CYP3A4 and six SNPs in CYP2C19. A base pharmacokinetic model was developed using NONMEM software to determine the warfarin clearance and volume of distribution. The model was extended to include covariates that influenced the between-subject variability.RESULTS
Bodyweight, age, sex and CYP2C9 genotype significantly influenced S-warfarin clearance. The S-warfarin clearance was estimated to be 0.144 l h−1 (95% confidence interval 0.131, 0.157) in a 70 kg woman aged 69.8 years with the wild-type CYP2C9 genotype, and the volume of distribution was 16.6 l (95% confidence interval 13.5, 19.7). Bodyweight and age, along with the SNPs rs3814637 (in CYP2C19) and rs2242480 (in CYP3A4), significantly influenced R-warfarin clearance. The R-warfarin clearance was estimated to be 0.125 l h−1 (95% confidence interval 0.115, 0.135) in a 70 kg individual aged 69.8 years with the wild-type CYP2C19 and CYP3A4 genotypes, and the volume of distribution was 10.9 l (95% confidence interval 8.63, 13.2).CONCLUSIONS
Our analysis, based on exposure rather than dose, provides quantitative estimates of the clinical and genetic factors impacting on the clearance of both the S- and R-enantiomers of warfarin, which can be used in developing improved dosing algorithms. 相似文献85.
Tybura P Samochowiec A Beszlej A Grzywacz A Mak M Frydecka D Bieńkowski P Mierzejewski P Potemkowski A Samochowiec J 《Pharmacological reports : PR》2012,64(3):528-535
BackgroundTherapeutic effects of all clinically used antipsychotics are related to the reduction of dopaminergic transmission in the limbic system. The aim of present study was two-fold. First, efficacy of atypical drugs (ziprasidone and olanzapine) against schizophrenia symptoms was compared to that offered by a typical antipsychotic medication, perazine. Second, associations between some dopaminergic genes polymorphisms and therapeutic response to antipsychotics were assessed in the same group of schizophrenia patients.MethodsOne hundred ninety one Caucasian patients admitted with exacerbation of paranoid schizophrenia were genotyped for polymorphisms of the DRD2 [the ins/del -141C (rs1799732) and exon 8 (rs 71653615)], DRD2/ANKK1 Taq IA (rs 1800497), DAT1 (the 40 bp VNTR), COMT (rs 4680), and MAOA gene (the 30 bp VNTR in promoter). The patients were randomly assigned to the treatment with perazine, olanzapine or ziprasidone givenasmonotherapy for 3 months. Treatment efficacy was measured from baseline (T0) to T1 (14 days) and T2 (3 months). A retention rate was also assessed at T1 and T2.ResultsThe three antipsychotics did not differ in terms of reduction of the PANSS score or retention rate at the follow-up. There was no interaction between the investigated polymorphisms and response to the antipsychotic treatment.ConclusionsThe present results suggest that: i) there are no major differences in short-term efficacy or effectiveness of atypical (olanzapine, ziprasidone) and typical (perazine) antipsychotic drugs; ii) the studied polymorphisms are not primarily involved in treatment response to antipsychotics in schizophrenia patients. 相似文献
86.
87.
Droney J Riley J Ross JR 《Clinical oncology (Royal College of Radiologists (Great Britain))》2011,23(6):418-428
Inter-individual variation in response to opioids for cancer pain is a well-established phenomenon. Variation occurs in the dose of opioid required, the analgesic efficacy of the opioid and also in the side-effects experienced by the individual taking the drug. To date, no clinical factor has been identified that can reliably explain or predict such variation. In recent years there has been growing interest in the possibility that genetic factors may play a role in the variability in opioid response. The aims of this review are to present the evidence supporting pharmacogenetic research in this area, to evaluate some of the studies and results that have been published to date and to present some of the challenges for future research in this area. 相似文献
88.
Metharom E Galettis P Manners S Jelinek M Liauw W de Souza PL Hoskins JM Links M 《Asia-Pacific Journal of Clinical Oncology》2011,7(1):65-74
Aim: Controversy exists over the optimal dosing for the nucleoside analogue gemcitabine. A pharmacological advantage is achieved by prolonging infusion times but evidence for a clinical benefit has been conflicting. We hypothesized that polymorphisms in genes involved in gemcitabine accumulation, particularly the cytidine deaminase CDA c.79A>C, may influence the optimal dosing regimen in individual patients. Methods: DNA was collected from 32 patients participating in a randomized crossover study comparing 30‐min with 100‐min infusions of gemcitabine. The relationships between seven polymorphisms among three genes (CDA, RRM1 and DCK) and (i) gemcitabine triphosphate accumulation; (ii) gemcitabine‐induced toxicity; and (iii) dose delivery were examined for each infusion time and week of administration. Results: There were trends for increased accumulation of gemcitabine‐triphosphate (GEM‐TP) with the variant alleles of CDA c.79A>C, and RRM1‐37C>A and ‐524T>C but none of these reached statistical significance in a univariate analysis. In a multivariable model there were significant effects of infusion duration and week of administration on GEM‐TP accumulation. There were significant interactions between CDA c.79A>C (P = 0.01) and RRM1‐37C>A (P = 0.019) genotypes, infusion time, and arm. More patients with one or two CDA c.79 variant alleles had doses delays (57 vs 13 %, P = 0.03) and a pharmacological advantage for prolonged infusion after week 1. Conclusion: It is important to consider both pharmacokinetics and pharmacogenetics in optimizing gemcitabine accumulation. This represents a classical interaction between genes and environment and provides support for the consideration of both CDA genotype and infusion duration in development of an individualized dosing strategy. 相似文献
89.
90.
I Sayers J Hawley CE Stewart CK Billington A Henry JR Leighton-Davies SJ Charlton IP Hall 《British journal of pharmacology》2009,158(1):277-286