Effect of Apolipoprotein E ε4 Allele on the Progression of Carotid Atherosclerosis Through Apolipoprotein Levels.

Background: The apolipoprotein E (ApoE) genetic variation may be involved in the development of Carotid Atherosclerosis (CAS) disease. So far, few data are available on the role of ApoE isoforms in CAS. The association between this ApoE genotype and CAS remains controversial. The aim of this study was to investigate ApoE gene polymorphism in relation to CAS and the relationships between ApoE gene polymorphism and plasma lipid levels in the ShaanXi Han populations. Patients and methods: The study group enrolled 399 CAS participants and 399 non-CAS controls. ApoE gene polymorphisms were determined by Polymerase chain reaction and hybridization. Results: The ε3/ε4 genotype and ε4 allele in patients with CAS were significantly higher than control participants. In stratified analyses by age and sex, the elevated risk conferred by ɛ4 allele was evident in adults under 60 years old, but not in adults over 60 years old, females and males. ε4 carriers had significantly elevated ApoB and ApoB/ApoA and decreased ApoE levels than ε2 carriers in CAS patients. After adjusting for confounding factors, hypertension, ApoA-I, low density lipoprotein cholesterol (LDL-C), triglycerides (TG) and ε4 allele were significant independent risk factor for CAS. ApoE-ε4 allele was associated with a nearly 1.5-fold increased risk of CAS. Conclusion: This study provides convincing evidence that ε4 allele, hypertension, ApoA-I, LDL-C and TG levels are independent risk factor for CAS in the ShaanXi Han populations. ApoE polymorphism was associated with CAS and this association was partly mediated through blood lipids. Also, the clinical use of genomic data may become useful in optimizing individual preventative and therapeutic strategies.

Comparison of the Effects of Prophylactic and Therapeutic Administrations on Peripheral Neuropathy in Streptozotocin-Diabetic Rats with Gliclazide or Methylcobalamin.

OBJECTIVE: To observe the differences in curative effects between prophylactic and therapeutic administrations of Gliclazide (GLZ) or Methylcobalamin (MCA) on diabetic peripheral neuropathy in rats. METHODS: GLZ (25 mg/kg/day) or MCA (175 µg/kg/day) was orally administrated prophylactically to streptozotocin-induced diabetic rats for 8 weeks before diabetic peripheral neuropathy developed or administrated therapeutically after diabetic peripheral neuropathy developed, respectively. The motor nerve conduction velocities (MNCV), aldose reductase (AR) activities, the polyol contents and antioxidative enzyme activities in the sciatic never tissues were determined. The morphology of sciatic never tissues was observed. RESULTS: In comparison to vehicle, most of the changes in the sciatic nerves of the diabetic rats (e. g., delayed MNCV, altered/damaged nerve structure, enhanced AR activity, increased polyol contents, altered Cu, Zn-superoxide dismutase, glutathione-peroxidase activities, and elevated malondialdehyde level) were significantly ameliorated by prophylactic administration with either GLZ or MCA. In contrast, only few of above-mentioned parameters were alleviated in DPN rats by therapeutic administration with GLZ or MCA as compared to vehicle. The curative effects of GLZ or MCA prophylactic administration on MNCV, AR activity, polyol contents and antioxidative enzyme activities were markedly stronger than therapeutic administration. CONCLUSION: Prophylactic administration of GLZ or MCA was superior to the therapeutic administration in alleviation of diabetic neuropathy in STZ-rats, suggesting that pharmacotherapy should be initiated at a much earlier stage before diabetic neuropathy developed, but not at a later stage after never damage reached.

Comparative pharmacokinetics of verapamil and norverapamil in normal and ulcerative colitis rats after oral administration of low and high dose verapamil by UPLC-MS/MS.

In this study, UC rat model was established by administration of 5% (w/v) dextran sulfate sodium, and the pharmacokinetics of verapamil and norverapamil were evaluated in normal and UC rats using UPLC-MS/MS after oral administration of 5 mg/kg and 50 mg/kg verapamil.The peak concentration (Cmax) and the area under plasma concentration-time curves (AUC) of verapamil in UC rats after oral administration of 5 mg/kg were significantly greater (2.5 times and 2 times, respectively) than those in normal rats, but the clearance rate (Cl) was significantly lower (by 50%). For norverapamil, Cmax and AUC were significantly greater (2.8 times and 2.5 times, respectively), and Cl was significantly lower (by 45%). But, pharmacokinetic parameters of verapamil and norverapamil after oral administration of 50 mg/kg were no significant differences between UC and normal rats.The better absorption and poor excretion for low-dose verapamil may be attributed to down-regulation of P-gp expression in the intestine and kidney. No significant differences of pharmacokinetic parameters for high-dose verapamil may be explained as the saturation of an efflux mechanism.The findings of this study suggested that in UC patients, doses of verapamil should be decreased when low-dose verapamil was orally administrated.

The quick loss of carbapenem susceptibility in Pseudomonas aeruginosa at intensive care units.

Background Patients colonized with carbapenem-susceptible Pseudomonas aeruginosa (CSPA) strains upon admission to the intensive care unit (ICU) tend to be quickly followed by detected carbapenem-resistant P. aeruginosa strains after admission. Objective To assess the risk factors associated with the quick loss of carbapenem susceptibility and to identify time threshold of prior antimicrobial exposure for the loss during ICU stay. Setting A tertiary-care teaching hospital with 2560 beds located in the northwest region of China. Method A retrospective observational study was conducted between January 2013 and April 2016 at ICUs. Logistic regression analysis was used to assess risk factors, and receiver operating characteristic (ROC) analyses were constructed to identify the time threshold. Main outcome measure The time threshold and risk factors for the quick loss of carbapenem susceptibility. Results Among the 84 patients with CSPA initially, 32 (38.1%) patients were observed to have a loss of carbapenem susceptibility during ICU stay. Logistic regression analyses showed that previous carbapenem exposure was only independently associated with the loss of carbapenem susceptibility (odds ratio 13.16; 95% CI 3.13-55.24; p < 0.001). The optimal cut-off was 3.5 days on ROC curve, indicating the high risk for loss of susceptibility. Conclusion In order to alleviate selective pressure caused by antipseudomonal carbapenems exposure, continued research is needed to determine the most appropriate carbapenems treatment strategies.

The effects of gliclazide, methylcobalamin, and gliclazide+methylcobalamin combination therapy on diabetic peripheral neuropathy in rats.

AIMS: This study investigated the efficacies of gliclazide (GLZ), methylcobalamin (MCA), and GLZ+MCA combination therapy on DPN by evaluating the treatment-related changes in peripheral nerve function, the polyol pathway, and oxidative stress in the sciatic nerve of streptozotocin-induced diabetic rats. MATERIALS AND METHODS: The rat model of streptozotocin-induced diabetes was orally given GLZ (25mg/kg/day), MCA (175µg/kg/day), and GLZ+MCA (25mg/kg/day+175µg/kg/day) combination therapy for 8weeks, in order to observe its effects on the motor nerve conduction velocity (MNCV), on the activities of Na(+), K(+)-ATPase, aldose reductase(AR), AR mRNA expression, on the polyol contents, antioxidative enzyme activities and peroxidation products in the sciatic never tissue. KEY FINDINGS: Most of the indicators of DPN, such as delayed MNCV, altered/damaged nerve structure, inhibited Na(+),K(+)-ATPase activity, enhanced AR activity and AR mRNA expression, increased polyol contents, altered Cu,Zn-superoxide dismutase, catalase, and glutathione-peroxidase activities, and elevated malondialdehyde level in the sciatic nerves of the diabetic rats, were significantly ameliorated by treatment with either GLZ or MCA. Moreover, the combination of GLZ and MCA was found to enhance the curative effect on DPN in parts of above-mentioned parameters as compared to monotherapy. SIGNIFICANCE: Monotherapy with GLZ or MCA, and especially the combined application of GLZ and MCA, could be efficient therapeutic strategies for combating experimental DPN in diabetic rats.

The effect of Astragalus as an adjuvant treatment in type 2 diabetes mellitus: A (preliminary) meta-analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Astragalus is a traditional Chinese medicine that is widely used for tonifying Qi (Qi mainly means life energy) to treat diabetes mellitus and its complications. AIM OF THE STUDY: We performed a meta-analysis to evaluate the effect of Astragalus in adjuvant treatment of type 2 diabetes mellitus (T2DM), and to provide novel information to improve clinical decision-making. MATERIALS AND METHODS: We conducted an exhaustive database search (PubMed, EMbase, Cochrane Library, China Knowledge Resource Integrated Database (CNKI), Wanfang data and SinoMed) of studies associated with "Astragalus" and "type 2 diabetes mellitus" until December 2015. Following quality assessment of study eligibility, the extracted data were statistically analyzed using STATA, ver. 12.0 (Stata Corp.). RESULTS: A total of 13 studies with 1054 participants were included in this meta-analysis. Two subgroups were identified, based on Astragalus dosing regimens: control group vs. Astragalus injection (AI); control group vs. Astragalus aqueous decoction (AAD). The pooled results showed that, in comparison with control group, Astragalus administration significantly reduced fasting plasma glucose (FPG) in both the AI group (WMD=-0.28, 95% CI=-0.46 to -0.10, P=0.002, I(2)=18.5%) and the AAD group (WMD=-0.83, 95% CI=-1.07 to -0.58, P=0.000, I(2)=0.0%); postprandial plasma glucose (PPG) was also significantly reduced in the AI group (WMD=-0.47, 95% CI=-0.77 to -0.17, P=0.002, I(2)=46.8%) and the AAD group (WMD=-1.19, 95% CI=-1.63 to -0.75, P=0.000, I(2)=49.3%). Fasting insulin (Fins) was significantly reduced only in the AAD treatment group (SMD=-0.33, 95% CI=-0.55 to -0.10, P=0.005, I(2)=1.0%) as was the homeostasis model assessment insulin resistance index (HOMA-IRI) levels (SMD=-1.66, 95% CI=-3.24 to -0.09, P=0.038, I(2)=94.0%). Although AAD treatment significantly reduced levels of glycated hemoglobin A1c (HbA1c) (WMD=-1.77, 95% CI=-3.06 to -0.47, P=0.007, I(2)=90.8%), AI treatment failed to show significant efficacy (WMD=-0.28, 95% CI=-0.63 to 0.06, P=0.102, I(2)=83.8%). Sensitivity analysis failed to detect outliers in all studies while Egger's linear regression test revealed a lack of publication bias in this meta-analysis (P=0.771, 95%CI =-3.51 to 4.56). CONCLUSIONS: Astragalus may be beneficial as an adjuvant therapy in the treatment of type 2 diabetes. However, due to the limited quality of existing studies, further high-quality studies are warranted before definitive conclusions may be reached.

Identification of factors influencing the pharmacokinetics of voriconazole and the optimization of dosage regimens based on Monte Carlo simulation in patients with invasive fungal infections.

OBJECTIVES: The objective of this study was to estimate the population pharmacokinetics of voriconazole, to identify the factors influencing voriconazole pharmacokinetics and to identify optimal dosage regimens for attaining target pharmacokinetic/pharmacodynamic indices against Aspergillus and Candida infections in patients with invasive fungal infections (IFIs). METHODS: To prospectively quantify the relationships between the pharmacokinetic parameters of voriconazole and covariates, a population pharmacokinetic analysis was conducted on pooled data from 406 samples taken from 151 patients with IFIs. Voriconazole plasma concentrations were measured by HPLC. The following covariates were tested: demographic factors, laboratory data, concomitant medications and CYP2C19 genotype. Monte Carlo simulation was used to evaluate the effectiveness of the currently recommended dosage regimen and to design an optimized pharmacodynamic dosage strategy for voriconazole. RESULTS: The data were appropriately fit by a one-compartment model with first-order absorption and elimination. The voriconazole clearance (CL) was 6.95 L/h, the volume of distribution (V) was 200 L and the oral bioavailability (F) was 89.5%. CL was significantly associated with age, the serum concentration of alkaline phosphatase and the CYP2C19 genotype. Based on the results of the Monte Carlo stimulation, we concluded that Aspergillus infections could be treated effectively with 200 mg of voriconazole administered intravenously or orally twice daily and that Candida infections could be treated with 300 mg administered orally twice daily or with 200 mg administered intravenously twice daily. CONCLUSIONS: This study showed that optimal voriconazole dosage regimens could be determined successfully with prospective population pharmacokinetic analyses and Monte Carlo simulations.

Drug therapy versus electroconvulsive therapy for refractory schizophrenia: report of a case with 14 years of follow-up.

The long-term efficacy and safety of electroconvulsive therapy (ECT) for refractory schizophrenia is rarely reported. We report the case of a 38-year-old female patient with refractory schizophrenia who was treated with ECT for 14 years (from 24 years of age). Case records of clinical treatment and laboratory tests are described and analyzed. During the first 11 years, the patient was treated with ECT as an adjunct to antipsychotic drugs, but the effectiveness was unstable. For the remaining 3 years she was treated with antipsychotic drugs as an adjunct to ECT and her condition stabilized as she gradually recovered social function. We summarize the clinical characteristics, therapy regimen, long-term effectiveness, and safety of this interesting case.

[Inhibitory effect of ardipusilloside-I on Lewis pulmonary carcinoma and hepatocarcinoma SMMC-7721].

OBJECTIVE: To study the antitumor effect of ardipusilloside-I (ADS-I) on Lewis pulmonary carcinoma and hepatocarcinoma SMMC-7721. METHODS: Lewis pulmonary metastasizing model was made by Sc. diluted 3-time 20 microl cancer cells in the right sole of C57BL/6 mice, after we treated the mice 14 days with ADS-I orally, cut the neoplasia-foot and weighed, we calculated the inhibitory rate in situ, then put the mice to death after being administrated 11 days continuously, counted the lung medtastasis colony and calculated the metastasis inhibitory rate; Human being hepatocarcinoma model was made by sc. in the back 5 x 10(6)/ml SMMC-7721 cells per BALB/c/nu nude mice, after we treated them orally 16 days with ADS-I continuously, measured the volume of tumor growth and body weight, and drew the growth curve, we detached the tumor and calculated the inhibitory rate of tumor growth in the end. RESULTS: Lewis pulmonary carcinoma inhibitory rate in situ and lung transfer inhibitory rate of ADS-I (25 mg/kg - 100 mg/kg) were between 40.5% and 54.0%, 45.4% and 69.1% respectively; Inhibitory rate of hepatocarcinoma SMMC-7721 was between 45.6% and 56.3%. CONCLUSIONS: ADS-I has inhibitory effect on Lewis pulmonary metastasis carcinoma and hepatocarcinoma SMMC-7721 carcinoma.