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Drug-induced hyperglycemia/diabetes is a global issue. Some drugs induce hyperglycemia by activating the pregnane X receptor (PXR), but the mechanism is unclear. Here, we report that PXR activation induces hyperglycemia by impairing hepatic glucose metabolism due to inhibition of the hepatocyte nuclear factor 4-alpha (HNF4α)‒glucose transporter 2 (GLUT2) pathway. The PXR agonists atorvastatin and rifampicin significantly downregulated GLUT2 and HNF4α expression, and impaired glucose uptake and utilization in HepG2 cells. Overexpression of PXR downregulated GLUT2 and HNF4α expression, while silencing PXR upregulated HNF4α and GLUT2 expression. Silencing HNF4α decreased GLUT2 expression, while overexpressing HNF4α increased GLUT2 expression and glucose uptake. Silencing PXR or overexpressing HNF4α reversed the atorvastatin-induced decrease in GLUT2 expression and glucose uptake. In human primary hepatocytes, atorvastatin downregulated GLUT2 and HNF4α mRNA expression, which could be attenuated by silencing PXR. Silencing HNF4α downregulated GLUT2 mRNA expression. These findings were reproduced with mouse primary hepatocytes. Hnf4α plasmid increased Slc2a2 promoter activity. Hnf4α silencing or pregnenolone-16α-carbonitrile (PCN) suppressed the Slc2a2 promoter activity by decreasing HNF4α recruitment to the Slc2a2 promoter. Liver-specific Hnf4α deletion and PCN impaired glucose tolerance and hepatic glucose uptake, and decreased the expression of hepatic HNF4α and GLUT2. In conclusion, PXR activation impaired hepatic glucose metabolism partly by inhibiting the HNF4α‒GLUT2 pathway. These results highlight the molecular mechanisms by which PXR activators induce hyperglycemia/diabetes.
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Objective:To establish the population pharmacokinetics model of mitiglinide given by oral route in Chinese healthy volunteers using nonlinear mixed effect model (NONMEM), investigate the pharmacokinetic characteristics of mitiglinide in Chinese healthy people to evaluate the factors that can influence the clinical pharmacokinetics of mitiglinide .Methods: Clinical data from 22 healthy volunteers were collected and the experiment was with single-dose administration.The volunteers were given 10 mg mitiglinide calcium orally and mitiglinide plasma concentration was determined by LC-MS/MS.The data was analyzed by the first order conditional estimation, and the influences of fixed effect factors such as demographic index and biochemical index were quantitatively evaluated . The population pharmacokinetics model of mitiglinide was established , and the result was verified by using the VPC and self-test meth-od.Results:The result showed that mitiglinide pharmacokinetics was fit single-compartment model .The inter-individual variability could be described by an exponential model .The typical values including central volume of distribution , clearance and absorption con-stant was 2.4 L· h-1(24％), 9.82 L(4％) and 6.46 h-1(14％), respectively.The clearance was influenced by creatinine clear-ance rate , and the absorption constant was influenced by ALT .Conclusion:The population pharmacokinetic parameters were mainly influenced by creatinine clearance rate and ALT .The established population pharmacokinetics model can explain the reasons for the in -dividual variation in the plasma concentration of mitiglinide , which can be used to guide the clinical administration of Chinese people .
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Objective Laryngeal and upper esophageal foreign bodies are common diseases, we explored a new and simple method to remove these foreign bodies. Methods The clinical data of 177 patients with laryngeal and upper esophageal foreign bodies from June 2008 to January 2016 were analyzed retrospectively. We used two methods to treat these foreign bodies:130 foreign bodies were directly removed under video endoscopy;47 foreign bodies were removed with suspension laryngoscopy, and video endoscopy was used meanwhile. Result 177 laryngeal and upper esophageal foreign bodies were removed well, without severe complications like esophageal perforation or phyryngeal fistula. Conclusion Removing esophageal and laryngeal foreign bodies with video endoscopy is simple, safe and effective.
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Objective:To develop a chemiluminescent microparticle immunoassay ( CMIA) method for the determination of meco-balamin in human serum to investigate the pharmacokinetics and bioequivalence of mecobalamin. Methods:A single oral dose of two kinds of mecobalamin was given to 19 healthy volunteers in a randomized three-period crossover study. The concentrations of mecobal-amin in serum were assayed by CMIA, the main pharmacokinetic parameters were analyzed by DAS 3. 0 software, and the bioequiva-lence was evaluated. Results: The main pharmacokinetic parameters of test and reference mecobalamin tablets were as follows: tmax were (4.2 ±1.9)h and (4.4 ±2.4)h,Cmax were (322.0 ±145.4) ng·L-1 and (282.2 ±108.1) ng·L-1,t1/2 were (19.2 ±5.3) h and (20.0 ±6.3)h,AUC0-72 were (6 769.1 ±2 169.4) ng·h·L-1 and (6 400.6 ±1 921.5) ng·h·L-1. F(0-72) and F(0-∞) of the test tablets was 105. 9% ± 13. 2% and 104. 9% ± 12. 6%,respectively. Conclusion:The method is simple and precise. The two tablets are bioequivalent.
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Objective To investigate the related factors of percutaneous balloon compression (PBC) for the treatment of trigeminal neuralgia complicating cerebrovascular disease in order to reduce the incidence of surgical complications. Methods The clinical data in patients with trigeminal neuralgia complicating cerebrovascular disease treated with PBC in the People's Hospital of Liaoning Province from December 2000 to December 2010 were analyzed retrospectively. The reasons for its occurrence were investigated. Results Of the 6 759 patients with trigeminal neuralgia who received PBC treatment, 10 (0. 15％ ) developed cerebrovascular disease,and 2 of them had arteriovenous fistula; 5 patients developed intracranial hemorrhage: 2 acute subdural hemorrhage, 2 intraventricular hemorrhage with subarachnoid hemorrhage, and 1 small amount of bleeding in brain stem; 1 patient developed internal carotid hemorrhage during the intraoperative puncture and the operation was stopped temporarily, and he was reoperated successfully after 2 weeks; 2 patients had cerebral infarction, they were all in the risk population of cerebrovascular disease, and 3 weeks after treatment, their disease conditions were improved. One of them left severe paralysis of limbs at discharge. Condusions The treatment of trigeminal neuralgia with PBC is safe and the incidence of cerebrovascular complications is lower. The surgical operations and blood pressure changes are the important causes of cerebrovascular complications.
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Objective To investigate the apoptotic effect of the transmembrane form vaccine of human blood group A mimotope on malignant melanoma cell line B16. Methods B16 cells were transfected with different recombinant plasmid through Lipofectamine 2000 and incubated with different concentration of monoclonal anti-A antibody at 2.5 μg/ml, 5 μg/ml,10 μg/ml and 20 μg/ml. Apoptosis rate of cells was determined with Annexin Ⅴ/PI double staining by flow cytometry. Results Apoptosis rate to P/F-M-pIRES group B16 cells was 74.74% when anti-A monoclonal antibody concentration was 10 μg/ml; apoptosis rate of plasmids carrying peptide/Fas fusion gene such as P/F-M-pIRES group and P/F-pIRES group were significantly higher than M-pIRES group and pIRES group. The apoptosis rate was statistically significantly different between different recombinated plasmid groups (F＝669.707,P＜0.01). The apoptosis rate was statistically significantly different between different antibody groups (F＝106.596,P＜0.01). The interaction between recombinated plasmid groups and antibody groups was statistically significant (F＝34.806,P＜0.01). Conclusions The transmembrane form vaccine of human blood group A mimotope could induce B16 cell apoptosis in vitro. This vaccine may be a promising candidate for potential malignant melanoma therapy.
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AIM: A new HPLC-MS method was developed to determine finasteride in human plasma. METHODS: Two formulations of finasteride tablets were given to 20 healthy male volunteers according to a randomized 2-way cross-over design. The samples were extracted by ethyl acetate under basic conditions, then were separated by C18 column and determined by mass detector. RESULTS: The calibration curve of finasteride was linear and intra-day and inter-day RSD were less than 10 %. The pharmacokinetics parameters of the two formulations (4.5 ± 0.5) h for t1/2; (3.0 ± 0.7) and (2.8 ± 0.9) h for tmax, respectively. The results indicated that there was no significant difference on cmax, A UC0-24, t1/2 or tmax values between the two formulations. CONCLUTION: The relative bioavailability of tablets I with respect to tablets Ⅱ is (99.3 ± 9.2) % by the A UC0-24 measurement, and bioe quivalence is observed between the two tablets.
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AIM: To compare the pharmacokinetics and relative bioavailability of the domestic and imported sustained-release tablets of gliclazide in healthy volunteers. METHODS:The study was performed by an four-period crossover design with singledose and multiple-dose administration. The plasmadrug concentrations of twenty male healthy volunteers were determined by liquid chromatography with mass spectrum detector method (LC-MS). RESULTS:The pharmacokinetic parameters after a single oral dose of the domestic and imported gliclazide tablets were (7.2+s 1.5) h and (6.9 +1.4) h for tmax, (13.4 ±1.2) h and (13.7 +1.3) h for t1/2, (2.4 +0.8) mg ·L-1and (2.3 ±0.6) mg· L-1 forcmax, (48 ±14)mg · h · L-1 and (48 +14) mg· h · L-1 forAUC0-60,(51+15) mg· h· L-1 and (50±14) mg· h· L-1for AUC0-∞, (22.4 ± 1.9 ) h and (22.8 ± 1.9 ) h for MRT, respectively. The steady state pharmacokinetic parameters after multiple doses of the domestic and imported gliclazide tablets were (6. 1 ± 1.4) h and (6.5+1.4) h for tmax, (4.6±0.9) mg· L-1 and (4.7±1.1) mg· L-1 for cmax, (0.23 ±0.08) mg ·L-1and (0.26±0.08) mg· L-1 forcmin, (1.6±0.3) mg·L-1 and (1.6±0.3) mg · L-1 for mean value of steady plasma-drug concentration (cav),(94±19) mg· h · L-1 and (95 ±20) mg · h · L-1forAUCss, (282 ±33)% and (283 ±43)% for degree of fluctuation DF ), respectively. The relative bioavailability of the domestic gliclazide tablet to the imported gliclazide tablet following a single and multiple dose were ( 102 ± 9) % and (99 ± 10 ) %, respectively. Main pharmacokinetic parameters between the two formulations in both single and multiples dose studies showed no statistical difference ( P >0.05 ). CONCLUSION: The result of two one side t-test shows that the two formulations are bioequivalent.
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OBJECTIVE:To study the bioequiavailability of domestic roxithromycin tablets and imported ones.METH?ODS:20male healthy volunteers took single dose of150mg roxithromycin tablet orally in a random crossover design,blood concentrations were determined by LC-MS.RESULTS:The main pharmacokinetic parameters of domestic and imported tablets were determined respectively as follows,AUC 0～72 were(72.81?23.85)(mg?n)/L and(72.63?20.86)(mg?h)/L,AUC 0～∞ were(74.41?24.45)(mg?h)/L and(74.42?24.45)(mg?h)/L,C max were(6.46?1.51)mg/L and(6.58?1.55)mg/L,t max were(1.9?0.5)h and(1.8?0.5)h,t 1/2 were(13.56?1.35)h and(14.18?1.50)h,the relative bioavailability of the homemade tablet to imported one was(99.8?11.2)%.CONCLUSIONS:Domestic and imported roxithromycin are bioequivalent.