Shan Cao

Plant polyphenol curcumin significantly affects CYP1A2 and CYP2A6 activity in healthy, male Chinese volunteers.

Background: Curcumin is a kind of plant polyphenol that is extracted from the rhizome of Curcuma longa. Studies about the effect of curcumin on the activity of drug-metabolizing enzymes in humans are lacking. Objective: To investigate the effect of curcumin on the activities of CYP1A2, CYP2A6, N-acetyltransferase (NAT2), and xanthine oxidase (XO) in vivo, using caffeine as a probe drug. Method: Sixteen unrelated, healthy Chinese men were recruited for the study. There were 2 phases in the study. In the first phase, volunteers orally received 100 mg caffeine and 0- to 12-hour blood and urine samples were collected. In the second phase, volunteers received 1000 mg curcumin once daily for 14 continuous days, and blood and urine samples were collected on day 15, following the same procedure used on the first day. Urinary caffeine metabolite ratios were used as the indicators of the activities of CYP1A2, CYP2A6, NAT2, and XO. The pharmacokinetics of caffeine and its metabolites were determined by high-performance liquid chromatography. Results: In the curcumin-treated group, CYP1A2 activity was decreased by 28.6% (95% CI 15.6 to 41.B; p < 0.000), while increases were observed in CYP2A6 (by 48.9%; 95% CI 25.3 to 72.4; p < 0.000). Plasma area under the curve from zero to 12 hours of 1,7-dimethylxanthine (17X) was decreased by 27.2% (95% CI 6.1 to 48.3; p = 0.014). The urinary excretion of 17X and 1-methylxanthine was significantly decreased by 36.4% (95% C119.4 to 53.6; p < 0.000) and 31.2% (95% CI 8.5 to 54.1; p = 0.010), respectively. The excretion of 1,7-dimethylurate (17U) was significantly increased by 77.3% (95% CI 5.6 to 148.8; p = 0.036). No significant changes were observed for caffeine, 1-methylurate, and 5-acetyiamino-6-formylamino-3-methyluracil between the 2 study phases. Conclusions: The results indicated that curcumin inhibits CYP1A2 function but enhances CYP2A6 activity. Simultaneously, some pharmacokinetic parameters relating lo 17X were affected by curcumin. If this finding is confirmed by other studies, the possibility of herb-drug interactions associated with curcumin should be considered in clinical practice,

Long non-coding RNA GAS5 polymorphism predicts a poor prognosis of acute myeloid leukemia in Chinese patients via affecting hematopoietic reconstitution.

Abstract Whether long non-coding RNA (lncRNA) single-nucleotide polymorphisms (SNPs) affect prognosis of acute myeloid leukemia (AML) remains unknown. To search the association between lncRNA SNPs and AML outcomes, thirty tagSNPs in five lncRNAs were genotyped in 313 AML patients. Survival analysis indicated that GAS5 rs55829688 (T > C) was significantly associated with prognosis of AML (p = 0.018). Patients with rs55829688 CC genotype showed higher GAS5 expression in peripheral blood mononuclear cells (PBMCs) (p = 0.025) and harbored a longer platelets recovery (p = 0.040) than carriers of rs55829688T allele. In vitro study indicated that GAS5 promoter harboring the rs55829688C allele showed marginally increased reporter gene activity (p = 0.019), and the promoter activity was increased by TP63 in a dose-dependent manner (P = 0.001). Moreover, GAS5 higher expression predict shorter AML overall survival (OS), which validated in GEO GSE12417 dataset (p = 0.011). In conclusion, rs55829688 polymorphism could increase GAS5 expression by interacting with TP63, which might aggravate the myelosuppression and in turn lead to poor prognosis in AML. Trail registration number: ChiCTR-PPC-14005297.

Pharmacokinetic interactions between ilaprazole and clarithromycin following ilaprazole, clarithromycin and amoxicillin triple therapy

Aim:To investigate the drug interactions between ilaprazole, a new proton pump inhibitor, and clarithromycin following ilaprazole, clarithromycin and amoxicillin combination therapy.Methods:Twelve healthy Chinese volunteers were recruited in a randomized, open-label, 3-period crossover study. All subjects were administered ilaprazole (5 mg), clarithromycin (500 mg) or a triple therapy, including ilaprazole (5 mg), clarithromycin (500 mg) and amoxicillin (1 g), twice daily for 6 consecutive days. On the 7th day, the drugs were given once, and blood samples were collected and analyzed using a well-validated HPLC/MS/MS method.Results:Following the triple therapy, the peak concentration (Cmax) and the area under the concentration-time curve from 0 h to 12 h (AUC0→12) of ilaprazole were significantly decreased, as compared with the single medication group (Cmax:1025.0±319.6 vs 1452.3±324.6 ng/mL; AUC0→12: 9777.7±3789.8 vs 11363.1±3442.0 ng·h/mL). Similar changes were found for ilaprazole sulfone (Cmax: 5.9±0.5 vs 9.3±1.7 ng/mL; AUC0→12: 201.4±32.1 vs 277.1±66.2 ng·h/mL). The triple therapy significantly elevated the Cmax of clarithromycin (3161.5±702.2 vs 2541.9±476.2 ng/mL).Conclusion:The H pylori eradication therapy with clarithromycin, amoxicillin and ilaprazole may cause pharmacokinetic interactions that decrease the amount of ilaprazole and its metabolites and elevate that of clarithromycin.

Association between DCK 35708 T>C variation and clinical outcomes of acute myeloid leukemia in South Chinese patients.

AIM DCK is a rate-limiting enzyme in cytarabine activation. rs4643786 and rs67437265 (P122S) variants are reported to affect DCK activity. PATIENTS & METHODS A total of 282 newly diagnosed acute myeloid leukemia (AML) patients were treated with cytarabine combined chemotherapy and genotyped for rs4643786 and rs67437265. Prognosis data were obtained through regular follow-up. DCK mRNA expression was detected in pretreatment blood or bone marrow mononuclear cells. RESULTS rs4643786 showed strong linkage disequilibrium with rs67437265. rs4643786 CT heterozygotes showed significantly higher complete remission rate (p = 0.028), superior overall survival (p = 0.006) and relapse-free survival (p = 0.020) than wild-type TT homozygotes. rs4643786 polymorphism was an independent predictor for AML prognosis. CONCLUSION DCK rs4643786 may serve as an independent predictor of drug response and AML outcome.

Effect of carboxylesterase 1 S75N on clopidogrel therapy among acute coronary syndrome patients

Carboxylesterase 1 (CES1) hydrolyzes the prodrug clopidogrel to an inactive carboxylic acid metabolite. The effects of CES1 S75N (rs2307240,C>T) on clopidogrel response among 851 acute coronary syndrome patients who came from the north, central and south of China were studied. The occurrence ratios of each endpoint in the CC group were significantly higher than in the CT + TT group for cerebrovascular events (14% vs 4.8%, p < 0.001, OR = 0.31), acute myocardial infarction (15.1% vs 6.1%, p < 0.001, OR = 0.37) and unstable angina (62.8% vs 37.7%, p < 0.001, OR = 0.36). The results showed that there was a significant association between CES1 S75N (rs2307240) and the outcome of clopidogrel therapy. Moreover, the frequency of the T allele of rs2307240 in acute coronary syndrome patients (MAF = 0.22) was more than four times higher than that in the general public (MAF = 0.05).

Effects of four novel genetic polymorphisms on clopidogrel efficacy in Chinese acute coronary syndromes patients

Dual antiplatelet therapy is the gold standard for the clinical treatment of coronary artery disease, especially for acute coronary syndromes patients. However, a substantial number of patients do not respond to clopidogrel despite a standardized dosage regimen, and this is directly associated with poor prognosis. Genetic polymorphisms may be one of the most important factors that contribute to this phenomenon. In this study, we aimed to detect new single nucleotide polymorphisms that can influence the efficacy of clopidogrel in 851 acute coronary syndromes (ACS) patients. Four outcomes (cerebrovascular event, Acute Myocardium Infarction, unstable angina and death) were used as endpoints among three cohorts (northern, central and southern China) of acute coronary syndromes patients. Three SNPs (rs2244923, rs2773341 and rs34428341) were significantly associated with at least one outcome in all subjects. One SNP rs16863352, may play a role in predicting unstable angina in acute coronary syndrome patients ≥75years of age.

Development and validation of a LC–MS/MS method for the determination of clebopride and its application to a pharmacokinetics study in healthy Chinese volunteers

A sensitive and specific liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS/MS) method has been developed and validated for the identification and quantification of clebopride in human plasma using itopride as an internal standard. The method involves a simple liquid-liquid extraction. The analytes were separated by isocratic gradient elution on a CAPCELL MG-III C(18) (5 microm, 150 mm x 2.1 mm i.d.) column and analyzed in multiple reaction monitoring (MRM) mode with positive electrospray ionization (ESI) interface using the respective [M+H](+) ions, m/z 373.9-->m/z184.0 for clebopride, m/z 359.9-->m/z71.5 for itopride. The method was validated over the concentration range of 69.530-4450.0 pg/ml for clebopride. Within- and between-batch precision (RSD%) was all within 6.83% and accuracy ranged from -8.16 to 1.88%. The LLOQ was 69.530 pg/ml. The extraction recovery was on an average 77% for clebopride. The validated method was used to study the pharmacokinetics profile of clebopride in human plasma after oral administration of clebopride.

Influence of UGT1A1 polymorphisms on the outcome of acute myeloid leukemia patients treated with cytarabine-base regimens

BackgroundsUDP-glucuronosyltransferase 1A subfamily (UGT1A) enzymes can inactivate cytarabine (Ara-C) by glucuronidation, and thus serves as candidate genes for interindividual difference in Ara-C response. UGT1A1 is a major UGT1A isoform expressed in human liver.MethodsUGT1A1*6 and *28 polymorphisms resulting in reduced UGT1A1 activity were genotyped in 726 adult acute myeloid leukemia (AML) patients treated with Ara-C based regimens. Influences of both polymorphisms on chemosensitivity and disease prognosis of the patients were evaluated.ResultsAfter one or two courses of Ara-C based induction chemotherapy, the complete remission (CR) rate was significantly higher in patients carrying the UGT1A1*6 (77.0%) or the UGT1A1*28 (76.4%) alleles as compared with corresponding wild-type homozygotes (66.9 and 68.5%, respectively). Carriers of the UGT1A1*6 or *28 alleles showed significantly decreased risk of non-CR (OR = 0.528, 95% CI 0.379–0.737, P = 1.7 × 10−4) and better overall survival (HR = 0.787, 95% CI 0.627–0.990, P = 0.040) as compared with homozygotes for both polymorphisms.ConclusionOur results suggest that UGT1A1*28 and UGT1A1*6 are associated with improved clinical outcomes in Chinese AML patients treated with Ara-C.