AIM: To describe the long term follow-up of kidney allograft recipients receiving ketoconazole with calcineurin inhibitors(CNI) alone or combined with everolimus. METHODS: This is an open-label, prospective observatio...AIM: To describe the long term follow-up of kidney allograft recipients receiving ketoconazole with calcineurin inhibitors(CNI) alone or combined with everolimus. METHODS: This is an open-label, prospective observational clinical trial in low immunologic risk patients who, after signing an Institutional Review Board approved consent form, were included in one of two groups. The first one(n = 59) received everolimus(target blood level, 3-8 ng/m L) and the other(n = 114) azathioprine 2 mg/kg per day or mycophenolate mofetyl(MMF) 2 g/d. Both groups also received tapering steroids, the cytochrome P-450 3A4(CYP3A4) modulator, ketoconazole 50-100 mg/d, and cyclosporine with C0 targets in the everolimus group of 200-250 ng/mL in 1 mo, 100-125 ng/m L in 2 mo, and 50-65 ng/m L thereafter, and in the azathioprine or MMF group of 250-300 ng/mL in 1 mo, 200-250 ng/mL in 2 mo, 180-200 ng/m L until 3-6 mo, and 100-125 ng/mL thereafter. Clinical visits were performed monthly the first year and quarterly thereafter by treating physicians and all data was extracted by the investigators.RESULTS: The clinical characteristics of these two cohorts were similar. During the follow up(66 + 31 mo), both groups showed comparable clinical courses, but the biopsy proven acute rejection rate during the full follow-up period seemed to be lower in the everolimus group(20% vs 36%; P = 0.04). The everolimus group did not show a higher surgical complication rate thanthe other group. By the end of the follow-up period, the everolimus group tended to show a higher glomerular filtration rate. Nevertheless, we found no evidence of a consistent negative slope of the temporal allograft function estimated by the modification of the diet in renal disease formula in any of both groups. At 6 years of follow-up, the uncensored and death-censored graft survivals were 91% and 93%, and 91% and 83% in the everolimus plus cyclosporine, and cyclosporine alone groups, respectively. The addition of ketoconazole saved 80% of cyclosporine and 56% of everolimus doses. CONCLUSION: Combining CYP3A4 modulators with CNI or mammalian target of rapamycin inhibitor, in low immunological risk kidney transplant recipients is feasible, effective, safe and affordable even in the long term.展开更多
In the study of cyclohexane monoxygenation with PhIO catalyzed by TPPFe( Ⅲ )X, we found the Influence of different axial ionic ligands X (X = F, Cl, Br, I, SCN, OR, R, CH,3, C2H6, (CH3)2CH, (CH2)3C)in TPPFe( Ⅲ )X on...In the study of cyclohexane monoxygenation with PhIO catalyzed by TPPFe( Ⅲ )X, we found the Influence of different axial ionic ligands X (X = F, Cl, Br, I, SCN, OR, R, CH,3, C2H6, (CH3)2CH, (CH2)3C)in TPPFe( Ⅲ )X on the oxidation products distribution and the yields of cyclohexanol. This paper deals with the linear relationship between the catalytic activity of TPPFe(Ⅲ)X and both the electronic or/ and steric effects of the axial ligands OR in TPPFe(Ⅲ)OR on its catalytic activity.展开更多
Monoclonal antibody (MAb) to rat liver cyto-chrome P-450j isozyme, an activating enzyme specific to nitrosamine metabolism, was used coupled with immunoblotting, densitometer scanning of SDS-PAGE gels and immunohistoc...Monoclonal antibody (MAb) to rat liver cyto-chrome P-450j isozyme, an activating enzyme specific to nitrosamine metabolism, was used coupled with immunoblotting, densitometer scanning of SDS-PAGE gels and immunohistochemical technique. The trace P-450HSj isozyme (Mr. 51.5 Kd) was found in human gastric mucosa. It was similar to P-450j in molecular weight, catalytic and immunochemical properties. The concentrations of P-450HSj in mucosa of lesser curvature were higher than those in greater curvature. This might be one of the important reasons that lesser curvature is the commonest area for gastric carcinoma. But there was possibly less P-450HSj in gastric mucosa with cancer. Im-munohistochemically, P-450HSj was discovered in the cytoplasm of some glandular epithelial cells, especially in the glands with hyperplastic and intestinal metaplastic changes adjacent to carcinoma. It was also found in some normal glands and in tumor cells of high-differentiated adenocarcinoma, but not in those of low-differentiated ones. Following subjects are discussed: (1) the method of detecting trace P-450HSj, (2) the rule of distribution of P-450HSj, and (3) the relationship between the isozyme and the occurrence of gastric cancer caused by nitrosa-mines.展开更多
AIM: Genetic polymorphism in enzymes of carcinogen metabolism has been found to have the influence on the susceptibility to cancer. Cytochrome P450 2E1 ( CYP2 E1) is considered to play an important role in the metabol...AIM: Genetic polymorphism in enzymes of carcinogen metabolism has been found to have the influence on the susceptibility to cancer. Cytochrome P450 2E1 ( CYP2 E1) is considered to play an important role in the metabolic activation of procarcinogens such as N-nitroscoamines and Iow molecular weight organic compounds. The purpose of this study is to determine whether CYP450 2Elpolymorphisms are associated with risk s of gastric cancer.METHODS: We conducted a population based case-control study in Changle county, Fujian Province, a high-risk region of gastric cancer in China. Ninety-one incident gastric cancer patients and ninety-four healthy controls were included in our study. Datas including dsmographic characteristcs, diet intake, and alcohol and tobacco consumption of indivduals in our study were completed by a standardized questionnaire. PCR-RFLP revealed three genotypes: heterozygote (C1/C2) and two homozygotes (C1/C1 and C2/C2) in CYP2E1.RESULTS: The frequency of variant genotypes (C1/C2 and C2/C2) in gastric cancer cases and controls was 36.3% and 24.5%, respectively. The rare homozygous C2/C2 genotype was found in 6 indivduals in gastric cancer group(6.6%),whereas there was only one in the control group (1.1%).However, there was no statistically significan difference between the two groups (two-tailed Fisher′s exact test, P =0.066). Indivduals in gastric cancer group were more likely to carry genotype C1/C2 (odds ratio, OR = 1.50) and C2/C2(OR = 7.34) than indivduals in control group (X2 = 4.597, for trend P=0.032). The frequencies of genofypes with the C2allele ( C1/C2 and C2/C2 genotypes) were compared with those of genotypes without C2 allele ( C1/C1 genotype )among indivduals in gastric cancer group and control group according to the pattern of gastric cancer risk factors. The results show that indivduals who exposed to these gastric cancer risk factors and carry the C2 allele seemed to have a higher risk of developing gastric cancer.CONCLUSION: Polymorphism of CYP2E1 gene may have some effct in the development of gastric cancer in Changle county, Fujian Province.展开更多
OBJECTIVE:To investigate the efficacy of Tianma(Rhizoma Gastrodiae)and Gouteng(Ramulus Uncariae Rhynchophyllae cum Uncis)on cytochrome P450(CYP450)enzyme activities in rats.METHODS:A cocktail strategy was followed to ...OBJECTIVE:To investigate the efficacy of Tianma(Rhizoma Gastrodiae)and Gouteng(Ramulus Uncariae Rhynchophyllae cum Uncis)on cytochrome P450(CYP450)enzyme activities in rats.METHODS:A cocktail strategy was followed to evaluate the influence of Tianma(Rhizoma Gastrodiae)and Gouteng(Ramulus Uncariae Rhynchophyllae cum Uncis)on the activities of CYP450 isoforms(CYP1A2,CYP3A4,CYP2E1,CYP2C19,CYP2C9,CYP2D6),which were determined by changes in the pharmacokinetic parameters of six probe drugs,theophylline,dapsone,chlorzoxazone,omeprazole,tolbutamide and dextromethorphan.Study groups included,Control group(CG),Tianma(Rhizoma Gastrodiae)group(TM),Gouteng(Ramulus Uncariae Rhynchophyllae cum Uncis)group(GT)and Tianma Gouteng(Gastrodia Uncaria)group(TMGT).RESULTS:No significant differences between Tianma(Rhizoma Gastrodiae)and control groups were found.Compared with the control group,in the Gouteng(Ramulus Uncariae Rhynchophyllae cum Uncis)group both the AUC and t1/2 of dapsone and tolbutamide were reduced,whereas the CL(clearance rate)of dapsone and tolbutamide were increased.Compared with the control group,in the Tianma Gouteng group,the AUC and t1/2 of dapsone and tolbutamide were reduced,the CL of dapsone and tolbutamide were increased,and the AUC and t1/2 of chlorzoxazone were increased and the CL of chlorzoxazone was reduced.CONCLUSION:Tianma(Rhizoma Gastrodiae)has no significant effect on the six CYP450 subtypes.The activities of CYP3A4 and CYP2C9 were increased by Gouteng(Ramulus Uncariae Rhynchophyllae cum Uncis).The activities of CYP3A4 and CYP2C9 were increased,whereas the activity of CYP32E1 was reduced by combined Tianma(Rhizoma Gastrodiae)and Gouteng(Ramulus Uncariae Rhynchophyllae cum Uncis).展开更多
BACKGROUND Cholangiocarcinoma(CCA)is an intractable cancer,and its incidence in north eastern Thailand is the highest worldwide.Infection with the liver fluke Opisthorchis viverrini(OV)has been associated with CCA ris...BACKGROUND Cholangiocarcinoma(CCA)is an intractable cancer,and its incidence in north eastern Thailand is the highest worldwide.Infection with the liver fluke Opisthorchis viverrini(OV)has been associated with CCA risk.However,animal experiments have suggested that OV alone does not induce CCA,but its combination with a chemical carcinogen like nitrosamine can cause experimentally induced CCA in hamsters.Therefore,in humans,other environmental and genetic factors may also be involved.AIM To examine relations between risk for CCA and genetic polymorphisms in carcinogenmetabolizing and inflammation-related genes.METHODS This hospital-based case-control study enrolled 95 case-control pairs matched by age(±5 years)and sex.We examined relations between risk for CCA and genetic polymorphisms in carcinogenmetabolizing and inflammation-related genes,serum anti-OV,alcohol consumption,and smoking.Polymorphisms of CYP2E1,IL-6(-174 and-634),IL-10(-819),and NF-κB(-94)and their cooccurrence with polymorphisms in the drug-metabolizing enzyme gene GSTT1 or GSTM1 were also analyzed.RESULTS Although CCA risk was not significantly associated with any single polymorphism,persons with the GSTT1 wild-type and CYP2E1 c1/c2+c2/c2 genotype had an increased risk(OR=3.33,95%CI:1.23-9.00)as compared with persons having the GSTT1 wild-type and CYP2E1 c1/c1 wild genotype.The presence of anti-OV in serum was associated with a 7-to 11-fold increased risk,and smoking level was related to an OR of 1.5-1.8 in multivariable analyses adjusted for each of the seven genetic polymorphisms.CONCLUSION In addition to infection with OV,gene-gene interactions may be considered as one of the risk factors for CCA development.展开更多
Objective To localize cytochrome P450 enzymes 4A and 2C in central nervous cells of normal male rats.Methods Eight drug/alcohol untreated normal male rats (150-200 g of body weight) were treated by the optimized perfu...Objective To localize cytochrome P450 enzymes 4A and 2C in central nervous cells of normal male rats.Methods Eight drug/alcohol untreated normal male rats (150-200 g of body weight) were treated by the optimized perfusion technique, then brain tissues were postfixed, paraffin-embedded and cut into series sections, which were labeled by the improved strept-avidin-biotin complex DAB-nickel enhancer (SABC-DAB-Ni) immunohistochemistry and hematoxylin & eosin (H & E) stain techniques.Results The immunohistochemical results indicated that P450 2C-11 enzyme was localized in diverse numbers of neurons as well as some neuroglial cells, with focal or defuse distribution in many brain regions such as cerebrum, thalamus, olfactory bulb, hypothalamus, brain-stem, hippocampus, cerebellum, interpositus nucleus, caudate-putamen, and globus pallidus. In contrast, no positive findings of P450 4A-2, 3 and 8 enzymes were obtained in the same animals. With high magnification, 2C-11 protein was able to be roughly observed on the endoplasmic reticulum of the rat neurons.Conclusions P450 2C-11 protein, rather than P450 4A-2, 3 and 8, may be a candidate of brain P450 enzymes in the normal male rats.展开更多
The present study was designed to alert the public opinion and policy makers on the supposed enhancing effects of exposure to ambient air particulate matter with aerodynamic diameters < 2.5 mm (PM 2.5 ) on non-alco...The present study was designed to alert the public opinion and policy makers on the supposed enhancing effects of exposure to ambient air particulate matter with aerodynamic diameters < 2.5 mm (PM 2.5 ) on non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease in Western countries. For far too long literature data have been fixated on pulmonary diseases and/or cardiovascular disease, as consequence of particulate exposure, ignoring the link between the explosion of obesity with related syndromes such as NAFLD and air pollution, the worst characteristics of nowadays civilization. In order to delineate a clear picture of this major health problem, further studies should investigate whether and at what extent cigarette smoking and exposure to ambient air PM 2.5 impact the natural history of patients with obesity-related NAFLD,i.e. , development of non alcoholic steatohepatitis, disease characterized by a worse prognosis due its progression towards fibrosis and hepatocarcinoma.展开更多
The test organisms (Paralichthys olivaceus) were exposed to CB - 28 with differentspiked concentrations. After 72 h, EROD activities in livers of the test organisms were measured. It was found that EROD activities sig...The test organisms (Paralichthys olivaceus) were exposed to CB - 28 with differentspiked concentrations. After 72 h, EROD activities in livers of the test organisms were measured. It was found that EROD activities significantly mounted up with the increase of spiked quantity. Therefore, there existed a dose-response relationship between EROD activities and specific pollutant concentrations. In the meantime, the optimal conditions for the analysis of EROD activity were discussed. The limitation of EROD activities as a monitoring parameter was also analyzed.展开更多
Peptic ulcer bleeding is a common disease and recurrent bleeding is an independent risk factor of mortality.Infusion with proton pump inhibitors(PPIs) prevents recurrent bleeding after successful endoscopic therapy.A ...Peptic ulcer bleeding is a common disease and recurrent bleeding is an independent risk factor of mortality.Infusion with proton pump inhibitors(PPIs) prevents recurrent bleeding after successful endoscopic therapy.A gastric acidic environment of less than pH 5.4 alters coagulation function and activates pepsin to disaggregate platelet plugs.Gastric acid is secreted by H+,K+-ATPase,naming the proton pump.This update review focuses on the mechanism and the role of PPIs in the clinical management of patients with peptic ulcer bleeding.An intravenous omeprazole bolus followed by high-dose continuous infusion for 72 h after successful endoscopic therapy can prevent the recurrent bleeding.In the Asian,however,the infusion dosage can possibly be diminished whilst preserving favorable control of the intragastric pH and thereby still decreasing rates of recurrent bleeding.Irrespective of the infusion dosage of PPIs,rates of recurrent bleeding remain high in patients with co-morbidities.Because recurrent peptic ulcer bleeding may be prolonged in those with co-morbidities,a lowdose infusion of IV PPIs for up to 7-day may result in better control of recurrent bleeding of peptic ulcers.Due to the inter-patient variability in CYP2C19 genotypes,the infusion form of new generation PPIs,such as esomeprazole,should be promising for the prevention of recurrent bleeding.This article offers a comprehensive review of clinical practice,highlighting the indication,the optimal dosage,the duration,and the potential limitation of PPIs infusion for peptic ulcer bleeding.展开更多
AIM To investigate the contribution of polymorphisms in the CYP1A1, CYP2E1 and EPHX1 genes on sporadic colorectal cancer(SCRC) risk. METHODS Six hundred forty-one individuals(227 patients with SCRC and 400 controls) w...AIM To investigate the contribution of polymorphisms in the CYP1A1, CYP2E1 and EPHX1 genes on sporadic colorectal cancer(SCRC) risk. METHODS Six hundred forty-one individuals(227 patients with SCRC and 400 controls) were enrolled in the study. The variables analyzed were age, gender, tobacco and alcohol consumption, and clinical and histopathological tumor parameters. The CYP1A1 *2A, CYP1A1 *2C CYP2E1 *5B and CYP2E1 *6 polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP). The EPHX1 Tyr113 His, EPHX1 His139 Arg and CYP1A1 *2C polymorphisms were detected by real-time PCR. Chisquared test and binary logistic regression were used in the statistical analysis. Haplotype analysis was conducted using the Haploview program, version 2.05.RESULTS Age over 6 2 years was a risk factor for SCRC development(OR = 7.54, 95%CI: 4.94-11.50, P < 0.01). Male individuals were less susceptible to SCRC(OR = 0.55, 95%CI: 0.35-0.85, P < 0.01). The CYP2E1*5B polymorphism was associated with SCRC in the codominant(heterozygous genotype: OR = 2.66, 95%CI: 1.64-4.32, P < 0.01), dominant(OR = 2.82, 95%CI: 1.74-4.55, P < 0.01), overdominant(OR = 2.58, 95%CI: 1.59-4.19, P < 0.01), and log-additive models(OR = 2.84, 95%CI: 1.78-4.52, P < 0.01). The CYP2E1*6 polymorphism was associated with an increased SCRC risk in codominant(heterozygous genotype: OR = 2.81, 95%CI: 1.84-4.28, P < 0.01; homozygous polymorphic : OR = 7. 3 2, 9 5 % C I : 1.85-28.96, P < 0.01), dominant(OR = 2.97, 95%CI: 1.97-4.50, P < 0.01), recessive(OR = 5.26, 95%CI: 1.35-20.50, P = 0.016), overdominant(OR = 2.64, 95%CI: 1.74-4.01, P < 0.01), and log-additive models(OR = 2.78, 95%CI: 1.91-4.06, P < 0.01). The haplotype formed by the minor alleles of the CYP2E1*5B(C) and CYP2E1*6(A) polymorphisms was associated with SCRC(P = 0.002). However, the CYP1A1 *2A, CYP1A1 *2C, EPHX1 Tyr113 His and EPHX1 His139 Arg polymorphisms were not associated with SCRC.CONCLUSION In conclusion, the results demonstrated that CYP2E1*5B and CYP2E1*6 minor alleles play a role in the development of SCRC.展开更多
Background Variation in prostate cancer incidence between different racial groups has been well documented, for which genetic polymorphisms are hypothesized to be an explanation. We evaluated the association between p...Background Variation in prostate cancer incidence between different racial groups has been well documented, for which genetic polymorphisms are hypothesized to be an explanation. We evaluated the association between polymorphisms in the cytochrome P-450 CYP1A1 (CYP1A1) and glutathione S-transferase M1 (GSTM1) genes and genetic susceptibility to prostate cancer in Chinese men.Methods TWO hundred and eight prostate cancer patients and 230 age matched controls were enrolled in this study. All DNA samples from peripheral blood lymphocytes were genotyped for common genetic polymorphisms of the CYP1A1 and GSTM1 genes using the oligonucleotide microarray (DNA chip) technique and the polymorphism results confirmed by sequencing. The different polymorphisms in prostate cancer patients were also analyzed according to age at diagnosis, prostate specific antigen level, cancer stage and grade (Gleason score).Results The prevalence of the GSTM1 (0/0) genotype was significantly higher in prostate cancer patients (58.2%) than in controls (41.7%, P〈0.05). Further analysis demonstrated that the prostate cancer patients with a GSTM1 (0/0) genotype were younger than those with the GSTM1 (+/+) genotype (P=-0.024). No significant differences in the frequency distributions of CYP1A1 polymorphisms were observed between prostate cancer patients and controls.Conclusion GSTM1 (0/0)-gene polymorphism may be linked to prostate cancer risk and early age of Onset in Chinese.展开更多
Background:The pharmacokinetic and clinical behaviors of many proton pump inhibitors(PPIs)in peptic ulcer treatment are altered by CYP2C19 genetic polymorphisms.This non-inferiority study evaluated the efficacy and sa...Background:The pharmacokinetic and clinical behaviors of many proton pump inhibitors(PPIs)in peptic ulcer treatment are altered by CYP2C19 genetic polymorphisms.This non-inferiority study evaluated the efficacy and safety of the novel PPI anaprazole compared with rabeprazole.We also explored the influence of Helicobacter pylori(H.pylori)infection status and CYP2C19 polymorphism on anaprazole.Methods:In this multicenter,randomized,double-blind,double-dummy,positive-drug parallel-controlled,phase Ⅲ study,Chinese patients with duodenal ulcers were randomized 1:1 to receive rabeprazole 10 mg+anaprazole placebo or rabeprazole placebo+anaprazole 20 mg once daily for 4 weeks.The primary efficacy endpoint was the 4-week ulcer healing rate assessed by blinded independent review.Secondary endpoints were the proportion of patients with improved overall and individual duodenal ulcer symptoms at 4 weeks.Furthermore,exploratory subgroup analysis of the primary endpoint by H.pylori status and CYP2C19 polymorphism was conducted.Adverse events were monitored for safety.Non-inferiority analysis was conducted for the primary endpoint.Results:The study enrolled 448 patients(anaprazole,n=225;rabeprazole,n=223).The 4-week healing rates were 90.9%and 93.7%for anaprazole and rabeprazole,respectively(difference,-2.8%[95%confidence interval,-7.7%,2.2%]),demonstrating non-inferiority of anaprazole to rabeprazole.Overall duodenal ulcer symptoms improved in 90.9%and 92.5%of patients,respectively.Improvement rates of individual symptoms were similar between the groups.Healing rates did not significantly differ by H.pylori status or CYP2C19 genotype for either treatment group.The incidence of treatment-emergent adverse events was similar for anaprazole(72/220,32.7%)and rabeprazole(84/219,38.4%).Conclusions:The efficacy of anaprazole is non-inferior to that of rabeprazole in Chinese patients with duodenal ulcers.Registration:ClinicalTrials.gov,NCT04215653.展开更多
Using guinea pig andrenal microsomes, we studied the inhibitory effects of 20α-hydroxyprogesterone on steroid hydroxylation reactions catalyzed by cytochromes P-450. When 17α-hydroxyprogesterone was used as a substr...Using guinea pig andrenal microsomes, we studied the inhibitory effects of 20α-hydroxyprogesterone on steroid hydroxylation reactions catalyzed by cytochromes P-450. When 17α-hydroxyprogesterone was used as a substrate, 20α-hydroxyprogesterone functioned as a competitive inhibitor on the C<sub>17</sub>—C<sub>20</sub> bond cleavage reaction of P-450<sub>17α lyase</sub>. The inhibition constant, K<sub>i</sub> was 1.37 μmol/L. 20α-hydroxyprogesterone also competitively inhibited the convertion of 17α-bydroxyprogesterone to 11-deoxycortisol by the action of P-450<sub>c21</sub>. The value of K<sub>i</sub> was 1.73μmol/L. When progesterone was used as a substrate, 20α-hydroxyprogesterone inhibited neither the 21-hydroxylation of P-450<sub>c21</sub>. the C<sub>17</sub>—C<sub>20</sub> bond cleavage, nor 17α-hydroxylation of P-450<sub>17α lyase</sub>. Based on the seresults, we can deduce that the production of androstenedione from progesterone by the action of P-450<sub>17α lyase</sub> proceeds through a successive monooxygenase reaction.展开更多
OBJECTIVE: Consuming botanical dietary supplements or herbal drugs along with prescription drugs may lead to potential pharmacokinetic-pharmacodynamic(PK-PD) herb-drug interactions(HDI). The present study focuses...OBJECTIVE: Consuming botanical dietary supplements or herbal drugs along with prescription drugs may lead to potential pharmacokinetic-pharmacodynamic(PK-PD) herb-drug interactions(HDI). The present study focuses on the importance of and novel approach for assessing HDI in integrative medicine with case examples of two frequently-used Ayurvedic Rasayana botanicals.METHODS: The aqueous extracts of Asparagus racemosus(ARE) and Gymnema sylvester(GSE) were prepared as per Ayurvedic Pharmacopoeia of India. Chemoprofiling of these extracts was done using high-performance liquid chromatography(HPLC). Additionally, ARE was characterized for the presence of shatavarins IV and I using HPLC & mass spectroscopy respectively. Effects of ARE and GSE were investigated on rat liver microsome using testosterone probe drug assay. The changes in formation of metabolite(6-β hydroxy testosterone) were monitored on incubation of testosterone alone, testosterone with ketoconazole, ARE and GSE using HPLC. Half inhibitory concentration(IC50) was used to predict plausible HDI.RESULTS: ARE and GSE showed no inhibition with IC50 values 〉1 000 μg/m L while the standard inhibitor ketoconazole completely abolished CYP3A4-dependent activity at 0.531 μg/m L and IC50 was found to be 0.036 μg/m L.CONCLUSION: ARE and GSE prepared as per Ayurvedic Pharmacopoeia of India were found to be safe for CYP3A4-mediated inhibitory HDI in rats. Our in vitro study suggests the need of further in vivo investigation for HDI in order to provide clinical relevance.展开更多
文摘AIM: To describe the long term follow-up of kidney allograft recipients receiving ketoconazole with calcineurin inhibitors(CNI) alone or combined with everolimus. METHODS: This is an open-label, prospective observational clinical trial in low immunologic risk patients who, after signing an Institutional Review Board approved consent form, were included in one of two groups. The first one(n = 59) received everolimus(target blood level, 3-8 ng/m L) and the other(n = 114) azathioprine 2 mg/kg per day or mycophenolate mofetyl(MMF) 2 g/d. Both groups also received tapering steroids, the cytochrome P-450 3A4(CYP3A4) modulator, ketoconazole 50-100 mg/d, and cyclosporine with C0 targets in the everolimus group of 200-250 ng/mL in 1 mo, 100-125 ng/m L in 2 mo, and 50-65 ng/m L thereafter, and in the azathioprine or MMF group of 250-300 ng/mL in 1 mo, 200-250 ng/mL in 2 mo, 180-200 ng/m L until 3-6 mo, and 100-125 ng/mL thereafter. Clinical visits were performed monthly the first year and quarterly thereafter by treating physicians and all data was extracted by the investigators.RESULTS: The clinical characteristics of these two cohorts were similar. During the follow up(66 + 31 mo), both groups showed comparable clinical courses, but the biopsy proven acute rejection rate during the full follow-up period seemed to be lower in the everolimus group(20% vs 36%; P = 0.04). The everolimus group did not show a higher surgical complication rate thanthe other group. By the end of the follow-up period, the everolimus group tended to show a higher glomerular filtration rate. Nevertheless, we found no evidence of a consistent negative slope of the temporal allograft function estimated by the modification of the diet in renal disease formula in any of both groups. At 6 years of follow-up, the uncensored and death-censored graft survivals were 91% and 93%, and 91% and 83% in the everolimus plus cyclosporine, and cyclosporine alone groups, respectively. The addition of ketoconazole saved 80% of cyclosporine and 56% of everolimus doses. CONCLUSION: Combining CYP3A4 modulators with CNI or mammalian target of rapamycin inhibitor, in low immunological risk kidney transplant recipients is feasible, effective, safe and affordable even in the long term.
文摘In the study of cyclohexane monoxygenation with PhIO catalyzed by TPPFe( Ⅲ )X, we found the Influence of different axial ionic ligands X (X = F, Cl, Br, I, SCN, OR, R, CH,3, C2H6, (CH3)2CH, (CH2)3C)in TPPFe( Ⅲ )X on the oxidation products distribution and the yields of cyclohexanol. This paper deals with the linear relationship between the catalytic activity of TPPFe(Ⅲ)X and both the electronic or/ and steric effects of the axial ligands OR in TPPFe(Ⅲ)OR on its catalytic activity.
文摘Monoclonal antibody (MAb) to rat liver cyto-chrome P-450j isozyme, an activating enzyme specific to nitrosamine metabolism, was used coupled with immunoblotting, densitometer scanning of SDS-PAGE gels and immunohistochemical technique. The trace P-450HSj isozyme (Mr. 51.5 Kd) was found in human gastric mucosa. It was similar to P-450j in molecular weight, catalytic and immunochemical properties. The concentrations of P-450HSj in mucosa of lesser curvature were higher than those in greater curvature. This might be one of the important reasons that lesser curvature is the commonest area for gastric carcinoma. But there was possibly less P-450HSj in gastric mucosa with cancer. Im-munohistochemically, P-450HSj was discovered in the cytoplasm of some glandular epithelial cells, especially in the glands with hyperplastic and intestinal metaplastic changes adjacent to carcinoma. It was also found in some normal glands and in tumor cells of high-differentiated adenocarcinoma, but not in those of low-differentiated ones. Following subjects are discussed: (1) the method of detecting trace P-450HSj, (2) the rule of distribution of P-450HSj, and (3) the relationship between the isozyme and the occurrence of gastric cancer caused by nitrosa-mines.
基金Supported by Natural Science Foundation of Fujian Province,China,No.C001009
文摘AIM: Genetic polymorphism in enzymes of carcinogen metabolism has been found to have the influence on the susceptibility to cancer. Cytochrome P450 2E1 ( CYP2 E1) is considered to play an important role in the metabolic activation of procarcinogens such as N-nitroscoamines and Iow molecular weight organic compounds. The purpose of this study is to determine whether CYP450 2Elpolymorphisms are associated with risk s of gastric cancer.METHODS: We conducted a population based case-control study in Changle county, Fujian Province, a high-risk region of gastric cancer in China. Ninety-one incident gastric cancer patients and ninety-four healthy controls were included in our study. Datas including dsmographic characteristcs, diet intake, and alcohol and tobacco consumption of indivduals in our study were completed by a standardized questionnaire. PCR-RFLP revealed three genotypes: heterozygote (C1/C2) and two homozygotes (C1/C1 and C2/C2) in CYP2E1.RESULTS: The frequency of variant genotypes (C1/C2 and C2/C2) in gastric cancer cases and controls was 36.3% and 24.5%, respectively. The rare homozygous C2/C2 genotype was found in 6 indivduals in gastric cancer group(6.6%),whereas there was only one in the control group (1.1%).However, there was no statistically significan difference between the two groups (two-tailed Fisher′s exact test, P =0.066). Indivduals in gastric cancer group were more likely to carry genotype C1/C2 (odds ratio, OR = 1.50) and C2/C2(OR = 7.34) than indivduals in control group (X2 = 4.597, for trend P=0.032). The frequencies of genofypes with the C2allele ( C1/C2 and C2/C2 genotypes) were compared with those of genotypes without C2 allele ( C1/C1 genotype )among indivduals in gastric cancer group and control group according to the pattern of gastric cancer risk factors. The results show that indivduals who exposed to these gastric cancer risk factors and carry the C2 allele seemed to have a higher risk of developing gastric cancer.CONCLUSION: Polymorphism of CYP2E1 gene may have some effct in the development of gastric cancer in Changle county, Fujian Province.
基金Supported by the Science and Technology Department of Sichuan Province[Project Name:Study on the Molecular Pharmacokinetic of Tianma(Rhizoma Gastrodiae)and Gouteng(Ramulus Uncariae Rhynchophyllae cum Uncis)in Liver Uptake and Elimination of Upper Hyperactivity of Liver-yang,No.2018FZ0096]and the Fundamental Research Funds for the Central Universities(Study on Pharmacodynamics and in Vivo Process of Chinese Herbal Compound in Treatment of ARDS Caused by Covid-19 Syndrome)。
文摘OBJECTIVE:To investigate the efficacy of Tianma(Rhizoma Gastrodiae)and Gouteng(Ramulus Uncariae Rhynchophyllae cum Uncis)on cytochrome P450(CYP450)enzyme activities in rats.METHODS:A cocktail strategy was followed to evaluate the influence of Tianma(Rhizoma Gastrodiae)and Gouteng(Ramulus Uncariae Rhynchophyllae cum Uncis)on the activities of CYP450 isoforms(CYP1A2,CYP3A4,CYP2E1,CYP2C19,CYP2C9,CYP2D6),which were determined by changes in the pharmacokinetic parameters of six probe drugs,theophylline,dapsone,chlorzoxazone,omeprazole,tolbutamide and dextromethorphan.Study groups included,Control group(CG),Tianma(Rhizoma Gastrodiae)group(TM),Gouteng(Ramulus Uncariae Rhynchophyllae cum Uncis)group(GT)and Tianma Gouteng(Gastrodia Uncaria)group(TMGT).RESULTS:No significant differences between Tianma(Rhizoma Gastrodiae)and control groups were found.Compared with the control group,in the Gouteng(Ramulus Uncariae Rhynchophyllae cum Uncis)group both the AUC and t1/2 of dapsone and tolbutamide were reduced,whereas the CL(clearance rate)of dapsone and tolbutamide were increased.Compared with the control group,in the Tianma Gouteng group,the AUC and t1/2 of dapsone and tolbutamide were reduced,the CL of dapsone and tolbutamide were increased,and the AUC and t1/2 of chlorzoxazone were increased and the CL of chlorzoxazone was reduced.CONCLUSION:Tianma(Rhizoma Gastrodiae)has no significant effect on the six CYP450 subtypes.The activities of CYP3A4 and CYP2C9 were increased by Gouteng(Ramulus Uncariae Rhynchophyllae cum Uncis).The activities of CYP3A4 and CYP2C9 were increased,whereas the activity of CYP32E1 was reduced by combined Tianma(Rhizoma Gastrodiae)and Gouteng(Ramulus Uncariae Rhynchophyllae cum Uncis).
基金Supported by Japan Society for the Promotion of Science,No.21406011.
文摘BACKGROUND Cholangiocarcinoma(CCA)is an intractable cancer,and its incidence in north eastern Thailand is the highest worldwide.Infection with the liver fluke Opisthorchis viverrini(OV)has been associated with CCA risk.However,animal experiments have suggested that OV alone does not induce CCA,but its combination with a chemical carcinogen like nitrosamine can cause experimentally induced CCA in hamsters.Therefore,in humans,other environmental and genetic factors may also be involved.AIM To examine relations between risk for CCA and genetic polymorphisms in carcinogenmetabolizing and inflammation-related genes.METHODS This hospital-based case-control study enrolled 95 case-control pairs matched by age(±5 years)and sex.We examined relations between risk for CCA and genetic polymorphisms in carcinogenmetabolizing and inflammation-related genes,serum anti-OV,alcohol consumption,and smoking.Polymorphisms of CYP2E1,IL-6(-174 and-634),IL-10(-819),and NF-κB(-94)and their cooccurrence with polymorphisms in the drug-metabolizing enzyme gene GSTT1 or GSTM1 were also analyzed.RESULTS Although CCA risk was not significantly associated with any single polymorphism,persons with the GSTT1 wild-type and CYP2E1 c1/c2+c2/c2 genotype had an increased risk(OR=3.33,95%CI:1.23-9.00)as compared with persons having the GSTT1 wild-type and CYP2E1 c1/c1 wild genotype.The presence of anti-OV in serum was associated with a 7-to 11-fold increased risk,and smoking level was related to an OR of 1.5-1.8 in multivariable analyses adjusted for each of the seven genetic polymorphisms.CONCLUSION In addition to infection with OV,gene-gene interactions may be considered as one of the risk factors for CCA development.
文摘Objective To localize cytochrome P450 enzymes 4A and 2C in central nervous cells of normal male rats.Methods Eight drug/alcohol untreated normal male rats (150-200 g of body weight) were treated by the optimized perfusion technique, then brain tissues were postfixed, paraffin-embedded and cut into series sections, which were labeled by the improved strept-avidin-biotin complex DAB-nickel enhancer (SABC-DAB-Ni) immunohistochemistry and hematoxylin & eosin (H & E) stain techniques.Results The immunohistochemical results indicated that P450 2C-11 enzyme was localized in diverse numbers of neurons as well as some neuroglial cells, with focal or defuse distribution in many brain regions such as cerebrum, thalamus, olfactory bulb, hypothalamus, brain-stem, hippocampus, cerebellum, interpositus nucleus, caudate-putamen, and globus pallidus. In contrast, no positive findings of P450 4A-2, 3 and 8 enzymes were obtained in the same animals. With high magnification, 2C-11 protein was able to be roughly observed on the endoplasmic reticulum of the rat neurons.Conclusions P450 2C-11 protein, rather than P450 4A-2, 3 and 8, may be a candidate of brain P450 enzymes in the normal male rats.
文摘The present study was designed to alert the public opinion and policy makers on the supposed enhancing effects of exposure to ambient air particulate matter with aerodynamic diameters < 2.5 mm (PM 2.5 ) on non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease in Western countries. For far too long literature data have been fixated on pulmonary diseases and/or cardiovascular disease, as consequence of particulate exposure, ignoring the link between the explosion of obesity with related syndromes such as NAFLD and air pollution, the worst characteristics of nowadays civilization. In order to delineate a clear picture of this major health problem, further studies should investigate whether and at what extent cigarette smoking and exposure to ambient air PM 2.5 impact the natural history of patients with obesity-related NAFLD,i.e. , development of non alcoholic steatohepatitis, disease characterized by a worse prognosis due its progression towards fibrosis and hepatocarcinoma.
文摘The test organisms (Paralichthys olivaceus) were exposed to CB - 28 with differentspiked concentrations. After 72 h, EROD activities in livers of the test organisms were measured. It was found that EROD activities significantly mounted up with the increase of spiked quantity. Therefore, there existed a dose-response relationship between EROD activities and specific pollutant concentrations. In the meantime, the optimal conditions for the analysis of EROD activity were discussed. The limitation of EROD activities as a monitoring parameter was also analyzed.
文摘Peptic ulcer bleeding is a common disease and recurrent bleeding is an independent risk factor of mortality.Infusion with proton pump inhibitors(PPIs) prevents recurrent bleeding after successful endoscopic therapy.A gastric acidic environment of less than pH 5.4 alters coagulation function and activates pepsin to disaggregate platelet plugs.Gastric acid is secreted by H+,K+-ATPase,naming the proton pump.This update review focuses on the mechanism and the role of PPIs in the clinical management of patients with peptic ulcer bleeding.An intravenous omeprazole bolus followed by high-dose continuous infusion for 72 h after successful endoscopic therapy can prevent the recurrent bleeding.In the Asian,however,the infusion dosage can possibly be diminished whilst preserving favorable control of the intragastric pH and thereby still decreasing rates of recurrent bleeding.Irrespective of the infusion dosage of PPIs,rates of recurrent bleeding remain high in patients with co-morbidities.Because recurrent peptic ulcer bleeding may be prolonged in those with co-morbidities,a lowdose infusion of IV PPIs for up to 7-day may result in better control of recurrent bleeding of peptic ulcers.Due to the inter-patient variability in CYP2C19 genotypes,the infusion form of new generation PPIs,such as esomeprazole,should be promising for the prevention of recurrent bleeding.This article offers a comprehensive review of clinical practice,highlighting the indication,the optimal dosage,the duration,and the potential limitation of PPIs infusion for peptic ulcer bleeding.
基金Supported by Sao Paulo Research Foundation(FAPESP),No.2011/23969-1 and No.2012/02473-0Coordination for the Improvement of Higher Education Personnel(CAPES)(Master grant)and National Council of Technological and Scientific Development(CNPq),No.310582/2014-8
文摘AIM To investigate the contribution of polymorphisms in the CYP1A1, CYP2E1 and EPHX1 genes on sporadic colorectal cancer(SCRC) risk. METHODS Six hundred forty-one individuals(227 patients with SCRC and 400 controls) were enrolled in the study. The variables analyzed were age, gender, tobacco and alcohol consumption, and clinical and histopathological tumor parameters. The CYP1A1 *2A, CYP1A1 *2C CYP2E1 *5B and CYP2E1 *6 polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP). The EPHX1 Tyr113 His, EPHX1 His139 Arg and CYP1A1 *2C polymorphisms were detected by real-time PCR. Chisquared test and binary logistic regression were used in the statistical analysis. Haplotype analysis was conducted using the Haploview program, version 2.05.RESULTS Age over 6 2 years was a risk factor for SCRC development(OR = 7.54, 95%CI: 4.94-11.50, P < 0.01). Male individuals were less susceptible to SCRC(OR = 0.55, 95%CI: 0.35-0.85, P < 0.01). The CYP2E1*5B polymorphism was associated with SCRC in the codominant(heterozygous genotype: OR = 2.66, 95%CI: 1.64-4.32, P < 0.01), dominant(OR = 2.82, 95%CI: 1.74-4.55, P < 0.01), overdominant(OR = 2.58, 95%CI: 1.59-4.19, P < 0.01), and log-additive models(OR = 2.84, 95%CI: 1.78-4.52, P < 0.01). The CYP2E1*6 polymorphism was associated with an increased SCRC risk in codominant(heterozygous genotype: OR = 2.81, 95%CI: 1.84-4.28, P < 0.01; homozygous polymorphic : OR = 7. 3 2, 9 5 % C I : 1.85-28.96, P < 0.01), dominant(OR = 2.97, 95%CI: 1.97-4.50, P < 0.01), recessive(OR = 5.26, 95%CI: 1.35-20.50, P = 0.016), overdominant(OR = 2.64, 95%CI: 1.74-4.01, P < 0.01), and log-additive models(OR = 2.78, 95%CI: 1.91-4.06, P < 0.01). The haplotype formed by the minor alleles of the CYP2E1*5B(C) and CYP2E1*6(A) polymorphisms was associated with SCRC(P = 0.002). However, the CYP1A1 *2A, CYP1A1 *2C, EPHX1 Tyr113 His and EPHX1 His139 Arg polymorphisms were not associated with SCRC.CONCLUSION In conclusion, the results demonstrated that CYP2E1*5B and CYP2E1*6 minor alleles play a role in the development of SCRC.
文摘Background Variation in prostate cancer incidence between different racial groups has been well documented, for which genetic polymorphisms are hypothesized to be an explanation. We evaluated the association between polymorphisms in the cytochrome P-450 CYP1A1 (CYP1A1) and glutathione S-transferase M1 (GSTM1) genes and genetic susceptibility to prostate cancer in Chinese men.Methods TWO hundred and eight prostate cancer patients and 230 age matched controls were enrolled in this study. All DNA samples from peripheral blood lymphocytes were genotyped for common genetic polymorphisms of the CYP1A1 and GSTM1 genes using the oligonucleotide microarray (DNA chip) technique and the polymorphism results confirmed by sequencing. The different polymorphisms in prostate cancer patients were also analyzed according to age at diagnosis, prostate specific antigen level, cancer stage and grade (Gleason score).Results The prevalence of the GSTM1 (0/0) genotype was significantly higher in prostate cancer patients (58.2%) than in controls (41.7%, P〈0.05). Further analysis demonstrated that the prostate cancer patients with a GSTM1 (0/0) genotype were younger than those with the GSTM1 (+/+) genotype (P=-0.024). No significant differences in the frequency distributions of CYP1A1 polymorphisms were observed between prostate cancer patients and controls.Conclusion GSTM1 (0/0)-gene polymorphism may be linked to prostate cancer risk and early age of Onset in Chinese.
文摘Background:The pharmacokinetic and clinical behaviors of many proton pump inhibitors(PPIs)in peptic ulcer treatment are altered by CYP2C19 genetic polymorphisms.This non-inferiority study evaluated the efficacy and safety of the novel PPI anaprazole compared with rabeprazole.We also explored the influence of Helicobacter pylori(H.pylori)infection status and CYP2C19 polymorphism on anaprazole.Methods:In this multicenter,randomized,double-blind,double-dummy,positive-drug parallel-controlled,phase Ⅲ study,Chinese patients with duodenal ulcers were randomized 1:1 to receive rabeprazole 10 mg+anaprazole placebo or rabeprazole placebo+anaprazole 20 mg once daily for 4 weeks.The primary efficacy endpoint was the 4-week ulcer healing rate assessed by blinded independent review.Secondary endpoints were the proportion of patients with improved overall and individual duodenal ulcer symptoms at 4 weeks.Furthermore,exploratory subgroup analysis of the primary endpoint by H.pylori status and CYP2C19 polymorphism was conducted.Adverse events were monitored for safety.Non-inferiority analysis was conducted for the primary endpoint.Results:The study enrolled 448 patients(anaprazole,n=225;rabeprazole,n=223).The 4-week healing rates were 90.9%and 93.7%for anaprazole and rabeprazole,respectively(difference,-2.8%[95%confidence interval,-7.7%,2.2%]),demonstrating non-inferiority of anaprazole to rabeprazole.Overall duodenal ulcer symptoms improved in 90.9%and 92.5%of patients,respectively.Improvement rates of individual symptoms were similar between the groups.Healing rates did not significantly differ by H.pylori status or CYP2C19 genotype for either treatment group.The incidence of treatment-emergent adverse events was similar for anaprazole(72/220,32.7%)and rabeprazole(84/219,38.4%).Conclusions:The efficacy of anaprazole is non-inferior to that of rabeprazole in Chinese patients with duodenal ulcers.Registration:ClinicalTrials.gov,NCT04215653.
文摘Using guinea pig andrenal microsomes, we studied the inhibitory effects of 20α-hydroxyprogesterone on steroid hydroxylation reactions catalyzed by cytochromes P-450. When 17α-hydroxyprogesterone was used as a substrate, 20α-hydroxyprogesterone functioned as a competitive inhibitor on the C<sub>17</sub>—C<sub>20</sub> bond cleavage reaction of P-450<sub>17α lyase</sub>. The inhibition constant, K<sub>i</sub> was 1.37 μmol/L. 20α-hydroxyprogesterone also competitively inhibited the convertion of 17α-bydroxyprogesterone to 11-deoxycortisol by the action of P-450<sub>c21</sub>. The value of K<sub>i</sub> was 1.73μmol/L. When progesterone was used as a substrate, 20α-hydroxyprogesterone inhibited neither the 21-hydroxylation of P-450<sub>c21</sub>. the C<sub>17</sub>—C<sub>20</sub> bond cleavage, nor 17α-hydroxylation of P-450<sub>17α lyase</sub>. Based on the seresults, we can deduce that the production of androstenedione from progesterone by the action of P-450<sub>17α lyase</sub> proceeds through a successive monooxygenase reaction.
基金BSDT’s Ayurvedic College, Synapse Laboratory Pvt. Ltd., National Toxicology Center, & National Centre for Cell Science, Pune for extending their kind support to carry out this work
文摘OBJECTIVE: Consuming botanical dietary supplements or herbal drugs along with prescription drugs may lead to potential pharmacokinetic-pharmacodynamic(PK-PD) herb-drug interactions(HDI). The present study focuses on the importance of and novel approach for assessing HDI in integrative medicine with case examples of two frequently-used Ayurvedic Rasayana botanicals.METHODS: The aqueous extracts of Asparagus racemosus(ARE) and Gymnema sylvester(GSE) were prepared as per Ayurvedic Pharmacopoeia of India. Chemoprofiling of these extracts was done using high-performance liquid chromatography(HPLC). Additionally, ARE was characterized for the presence of shatavarins IV and I using HPLC & mass spectroscopy respectively. Effects of ARE and GSE were investigated on rat liver microsome using testosterone probe drug assay. The changes in formation of metabolite(6-β hydroxy testosterone) were monitored on incubation of testosterone alone, testosterone with ketoconazole, ARE and GSE using HPLC. Half inhibitory concentration(IC50) was used to predict plausible HDI.RESULTS: ARE and GSE showed no inhibition with IC50 values 〉1 000 μg/m L while the standard inhibitor ketoconazole completely abolished CYP3A4-dependent activity at 0.531 μg/m L and IC50 was found to be 0.036 μg/m L.CONCLUSION: ARE and GSE prepared as per Ayurvedic Pharmacopoeia of India were found to be safe for CYP3A4-mediated inhibitory HDI in rats. Our in vitro study suggests the need of further in vivo investigation for HDI in order to provide clinical relevance.