Evaluation of the inhibitory effects of antigout drugs on human carboxylesterases in vitro.

Gout is an immune-metabolic disease that frequently coexists with multiple comorbidities such as chronic kidney disease, cardiovascular disease and metabolic syndrome, therefore, it is often treated in combination with these complications. The present study aimed to evaluate the inhibitory effect of antigout drugs (allopurinol, febuxostat, topiroxostat, benzbromarone, lesinurad and probenecid) on the activity of the crucial phase I drug-metabolizing enzymes, carboxylesterases (CESs). 2-(2-benzoyl-3-methoxyphenyl) benzothiazole (BMBT) and fluorescein diacetate (FD) were utilized as the probe reactions to determine the activity of CES1 and CES2, respectively, through in vitro culturing with human liver microsomes. Benzbromarone and lesinurad exhibited strong inhibition towards CESs with Ki values of 2.16 and 5.15 µM for benzbromarone towards CES1 and CES2, respectively, and 2.94 µM for lesinurad towards CES2. In vitro-in vivo extrapolation (IVIVE) indicated that benzbromarone and lesinurad might disturb the metabolic hydrolysis of clinical drugs in vivo by inhibiting CESs. In silico docking showed that hydrogen bonds and hydrophobic interactions contributed to the intermolecular interactions of antigout drugs on CESs. Therefore, vigilant monitoring of potential drug-drug interactions (DDIs) is imperative when co-administering antigout drugs in clinical practice.

Inhibitory effects of phthalate esters (PAEs) and phthalate monoesters towards human carboxylesterases (CESs).

Phthalate esters (PAEs), accompanied by phthalate monoesters as hydrolysis metabolites in humans, have been widely used as plasticizers and exhibited disruptive effects on the endocrine and metabolic systems. The present study aims to investigate the inhibition behavior of PAEs and phthalate monoesters on the activity of the important hydrolytic enzymes, carboxylesterases (CESs), to elucidate the toxicity mechanism from a new perspective. The results showed significant inhibition on CES1 and CES2 by most PAEs, but not by phthalate monoesters, above which the activity of CES1 was strongly inhibited by DCHP, DEHP, DiOP, DiPP, DNP, DPP and BBZP, with inhibition ratios exceeding 80%. Kinetic analyses and in vitro-in vivo extrapolation were conducted, revealing that PAEs have the potential to disrupt the metabolism of endogenous substances catalyzed by CES1 in vivo. Molecular docking results revealed that hydrogen bonds and hydrophobic contacts formed by ester bonds contributed to the interaction of PAEs towards CES1. These findings will be beneficial for understanding the adverse effect of PAEs and phthalate monoesters.

Efficacy of ezetimibe combined with atorvastatin in the treatment of carotid artery plaque in patients with type 2 diabetes mellitus complicated with coronary heart disease.

BACKGROUND: The aim of this study was to evaluate the efficacy of ezetimibe combined with atorvastatin in treatment of carotid artery plaque in patients with type 2 diabetes mellitus complicated with coronary heart disease (CHD). METHODS: A total of 100 patients with carotid atherosclerosis (CAS) confirmed by ultrasound and diagnosed with type 2 diabetes mellitus and CHD were randomly assigned to atorvastatin group (atorvastatin 20 mg/day) or combined treatment group (ezetimibe 10 mg/day and atorvastatin 20 mg/day). All those patients were followed for 12 months. Serum lipid, ALT, AST, and CK were measured before and after treatment. Ultrasonography was used to evaluate the stability of carotid artery plaques. RESULTS: After 12 months of treatment, the level of TC, TG, LDL-C, hs-CRP, FPG and HbA1c decreased in both groups compared with before treatment. TC, TG, LDL-C and hs-CRP in the combined treatment group were much lower than that in the atorvastatin group (P<0.05). The IMT and plaque area in the two groups were lower than that before the treatment (P<0.05). IMT and plaques area in the combined treatment group is much lower than that in the atorvastatin group after treatment. There was no significant difference in two groups on the level of ALT, AST, CK compared with baseline after treatment. CONCLUSIONS: The effect of combined use of atorvastatin and ezetimibe was better than atorvastatin alone, which can effectively reduce the blood lipid levels in diabetic patients with CHD and improve plaque stability. Both treatment regimens were safe and well tolerated.

3-Tesla magnetic resonance imaging improves the prostate cancer detection rate in transrectral ultrasound-guided biopsy.

The detection rate of prostate cancer (PCa) using traditional biopsy guided by transrectal ultrasound (TRUS) is not satisfactory. The aim of this study was to determine the utility of 3-Tesla (3-T) magnetic resonance imaging (MRI) prior to TRUS-guided prostate biopsy and to investigate which subgroup of patients had the most evident improvement in PCa detection rate. A total of 420 patients underwent 3-T MRI examination prior to the first prostate biopsy and the positions of suspicious areas were recorded respectively. TRUS-guided biopsy regimes included systematic 12-core biopsy and targeted biopsy identified by MRI. Patients were divided into subgroups according to their serum prostate-specific antigen (PSA) levels, PSA density (PSAD), prostate volume, TRUS findings and digital rectal examination (DRE) findings. The ability of MRI to improve the cancer detection rate was evaluated. The biopsy positive rate of PCa was 41.2% (173/420), and 41 of the 173 (23.7%) patients were detected only by targeted biopsy in the MRI-suspicious area. Compared with the systematic biopsy, the positive rate was significantly improved by the additional targeted biopsy (P=0.0033). The highest improvement of detection rate was observed in patients with a PSA level of 4-10 ng/ml, PSAD of 0.12-0.20 ng/ml2, prostate volume >50 ml, negative TRUS findings and negative DRE findings (P<0.05). Therefore, it is considered that 3-T MRI examination could improve the PCa detection rate on first biopsy, particularly in patients with a PSA level of 4-10 ng/ml, PSAD of 0.12-0.20 ng/ml2, prostate volume of >50 ml, negative TRUS findings and negative DRE findings.

Risk factors associated with PICC-related upper extremity venous thrombosis in cancer patients.

AIMS AND OBJECTIVES: To investigate the incidence and risk factors for peripherally inserted central venous catheters-related upper extremity venous thrombosis in patients with cancer. BACKGROUND: With the widespread use of peripherally inserted central venous catheters, peripherally inserted central venous catheters-related upper extremity venous thrombosis in patients with cancer leads to increasing morbidity and mortality. It is very important to further explore the incidence and risk factors for peripherally inserted central venous catheters-related venous thrombosis. DESIGN AND METHODS: Consecutive patients with cancer who were scheduled to receive peripherally inserted central venous catheters, between September 2009 and May 2012, were prospectively studied in our centre. They were investigated for venous thrombosis by Doppler sonography three times a day within 30 days after catheter insertion. Univariable and multivariable logistic regressions' analyses were performed to identify the risk factors for peripherally inserted central venous catheters-related thrombosis. RESULTS: A total of 89 patients with cancer were studied in our research. Of these, 81 patients were followed up within one month. The mean interval between catheter insertion and the onset of thrombosis was 12.45 ± 6.17 days. The multivariable analyses showed that chemotherapy history, less activities and diabetes were the key risk factors for thrombosis. CONCLUSIONS: Peripherally inserted central venous catheters-related upper extremity venous thrombosis had high incidence rate, and most cases had no significant symptoms. The history of chemotherapy, less activities and diabetes were found to be the key risk factors. It should be routinely scanned in high-risk patients every 3-5 days after catheter insertion, which would then find blood clots in time and reduce the incidence of pulmonary embolism. RELEVANCE TO CLINICAL PRACTICE: Risk factors associated with peripherally inserted central venous catheters-related upper extremity venous thrombosis are of critical importance in improving the quality of patients' life. It is very important to grasp the indications to reduce the incidence rate of peripherally inserted central venous catheters-related upper extremity venous thrombosis.

Doppler myocardial performance index in assessment of ventricular function in children with single ventricles.

BACKGROUND: Quantitative assessment of ventricular function in children with single ventricles is both difficult and subjective because of asymmetric ventricular geometry. The Doppler myocardial performance index (MPI) allows the assessment regardless of ventricular shape. This study was designed to evaluate the feasibility of MPI in assessing ventricular function in children with single ventricles before and after total cavopulmonary connection (TCPC). METHODS: Subjects consisted of 161 pediatric patients with single ventricles and 80 normal children without heart disease. The maximum positive rate of ventricular pressure change (Max dp/dt) was obtained in 58 patients by cardiac catheterization. Sixty-eight children with single ventricles received TCPC. MPI was calculated from Doppler tracings of ventricular inflow and outflow, then MPI of single ventricles before and after surgery and normal heart were compared. RESULTS: Normal MPI value was 0.30+/-0.08 in the left ventricle and 0.26+/-0.08 in the right ventricle. Compared to normal children, MPI was significantly higher in 161 children with single ventricles (0.54+/-0.11, P<0.001). MPI correlated inversely with Max (dp/dt) (r=-0.77, P<0.01), and was positively related to age (r=0.54, P<0.01) in patients with single ventricles. MPI did not differ significantly before and after surgery in 68 patients with single ventricles (0.55+/-0.21 vs 0.51+/-0.20, P>0.05). However, MPI in 48 patients of <6 years old decreased significantly (0.55+/-0.21 vs 0.48+/-0.18, P<0.05), suggesting improved ventricular function. CONCLUSIONS: Compared to normal children, ventricular function is impaired in patients with single ventricles and may worsen with age. MPI provides an accurate method for assessing ventricular function in children with single ventricles before and after TCPC.