Physiologically based pharmacokinetic modeling to assess the drug-drug interactions of anaprazole with clarithromycin and amoxicillin in patients undergoing eradication therapy of H. pylori infection.

OBJECTIVE: This study aimed to assess the pharmacokinetic (PK) interactions of anaprazole, clarithromycin, and amoxicillin using physiologically based pharmacokinetic (PBPK) models. METHODS: The PBPK models for anaprazole, clarithromycin, and amoxicillin were constructed using the GastroPlus™ software (Version 9.7) based on the physicochemical data and PK parameters obtained from literature, then were optimized and validated in healthy subjects to predict the plasma concentration-time profiles of these three drugs and assess the predictive performance of each model. According to the analysis of the properties of each drug, the developed and validated models were applied to evaluate potential drug-drug interactions (DDIs) of anaprazole, clarithromycin, and amoxicillin. RESULTS: The developed PBPK models properly described the pharmacokinetics of anaprazole, clarithromycin, and amoxicillin well, and all predicted PK parameters (Cmax,ss, AUC0-τ,ss) ratios were within 2.0-fold of the observed values. Furthermore, the application of these models to predict the anaprazole-clarithromycin and anaprazole-amoxicillin DDIs demonstrates their good performance, with the predicted DDI Cmax,ss ratios and DDI AUC0-τ,ss ratios within 1.25-fold of the observed values, and all predicted DDI Cmax,ss, and AUC0-τ,ss ratios within 2.0-fold. The simulated results show no need to adjust the dosage when co-administered with anaprazole in patients undergoing eradication therapy of H. pylori infection since the dose remained in the therapeutic range. CONCLUSION: The whole-body PBPK models of anaprazole, clarithromycin, and amoxicillin were built and qualified, which can predict DDIs that are mediated by gastric pH change and inhibition of metabolic enzymes, providing a mechanistic understanding of the DDIs observed in the clinic of clarithromycin, amoxicillin with anaprazole.

Therapeutic effects and mechanism of human amnion-derived mesenchymal stem cells on hypercoagulability in a uremic calciphylaxis patient.

Calciphylaxis is a rare cutaneous vascular disease that manifests with intolerable pains, non-healing skin wounds, histologically characterized by calcification, fibrointimal hyperplasia, and microvessel thrombosis. Currently, there are no standardized guidelines for this disease. Recent studies have recognized a high prevalence of thrombophilias and hypercoagulable conditions in calciphylaxis patients. Here, we report a case of uremic calciphylaxis patient whom was refractory to conventional treatments and then received a salvage strategy with intravenous and local hAMSC application. In order to investigate the therapeutic mechanism of hAMSCs from the novel perspective of hypercoagulability, coagulation-related indicators, wound status, quality of life and skin biopsy were followed up. Polymerase chain reaction (PCR) was performed to determine the distribution of hAMSCs in multiple tissues including lung, kidney and muscle after infusion of hAMSCs for 24 h, 1 week and 1 month in mice aiming to investigate whether hAMSCs retain locally active roles after intravenous administration. Improvement of hypercoagulable condition involving correction of platelet, D-dimer and plasminogen levels, skin regeneration and pain alleviation were revealed after hAMSC administration over one-year period. Skin biopsy pathology suggested regenerative tissues after 1 month hAMSC application and full epidermal regeneration after 20 months hAMSC treatment. PCR analysis indicated that hAMSCs were homing in lung, kidney and muscle tissues of mice even until tail vein injection of hAMSCs for 1 month. We propose that hypercoagulability is a promising therapeutic target of calciphylaxis patients, which can be effectively improved by hAMSC treatment.

Pharmacokinetic and pharmacodynamic studies of CD19 CAR T cell in human leukaemic xenograft models with dual-modality imaging.

In recent years, chimeric antigen receptor T (CAR T)-cell therapy has shown great potential in treating haematologic disease, but no breakthrough has been achieved in solid tumours. In order to clarify the antitumour mechanism of CAR T cell in solid tumours, the pharmacokinetic (PK) and pharmacodynamic (PD) investigations of CD19 CAR T cell were performed in human leukaemic xenograft mouse models. For PK investigation, we radiolabelled CD19 CAR T cell with 89 Zr and used PET imaging in the CD19-positive and the CD19-negative K562-luc animal models. For PD evaluation, optical imaging, tumour volume measurement and DNA copy-number detection were performed. Unfortunately, the qPCR results of the DNA copy number in the blood were below the detection limit. The tumour-specific uptake was higher in the CD19-positive model than in the CD19-negative model, and this was consistent with the PD results. The preliminary PK and PD studies of CD19 CAR T cell in solid tumours are instructive. Considering the less efficiency of CAR T-cell therapy of solid tumours with the limited number of CAR T cells entering the interior of solid tumours, this study is suggestive for the subsequent CAR T-cell design and evaluation of solid tumour therapy.

Utilization of Mobile Application for Better Implementation of Good Clinical Practice in a Biorepository Sample Collection Process: Functions of PancMoBio in Biobanking.

Preanalytical variables of biospecimens play a vital role in biobanking. Currently, there is a lack of a convenient and precise methods to document these variables. Paper documentation and computer-based Lab Information Management System software are the most common solutions, but both have clear disadvantages. An application named PancMoBio was newly developed in our pancreas biobank, with the guidance of good clinical practice principles as well as the incorporation of technical support from professional software companies. With portable electronic devices running this application, all data can be precisely collected in a synchronous manner during sample collection and processing. PancMoBio comprises two major modules-recording and searching-and five submodules in the recording module: blood sample collection, solid tumor tissue sample collection, cystic tumor sample collection, plasma sample separation, and serum sample separation. Compared with other methods, our application was found to be more convenient and accurate in recording preanalytical variables and demonstrated improved capability in facilitating real-time quality control and quality assurance. It was apparent that PancMoBio could improve the integrity of biospecimen and biobank quality management. Thus, it should be considered for further utilization in biobanking.

Prevalence and associated factors of knee osteoarthritis in a rural Chinese adult population: an epidemiological survey.

BACKGROUND: The exact pathogenic mechanism of knee osteoarthritis (OA) is still unknown. With the exception of clinical treatment to alleviate symptoms, or total knee replacement, there is currently no effective treatment method. Consequently, an in-depth etiological and epidemiological study of knee OA can provide clues for diagnosis, treatment and scientific research, and will ultimately have a beneficial effect on public health. METHODS: A cross-sectional community study in the rural village of Gaoyou was conducted in 3428 Chinese adults (aged ≥ 40 years). Subjects completed an interviewer-administered questionnaire, evaluating knee pain and associated disability, analgesia, use of health services, past medical history, walking, income, smoking, and use of oral contraceptives, and standardized weight-bearing knee radiographs were obtained. Patient demographic characteristics and biochemical parameters were recorded. RESULTS: Single-factor regression analysis indicated that age, overweight, central adiposity, high low-density lipoprotein cholesterol (LDLC), high total cholesterol (TC), high triglycerides (TG), dyslipidemia, hypertension and low income were the associated factors for knee OA in females; age, high LDLC, hypertension, low income and frequent walking were the associated factors for knee OA in males. Interestingly, male heavy smokers were less likely to develop severe knee OA compared with non-smokers. Stepwise logistic regression analysis indicated that age and overweight were the associated factors for knee OA for all individuals. Although central adiposity, high LDLC, high TC, high TG, dyslipidemia, hypertension and low income appeared to be related to knee OA in females according to univariate analysis, these factors were not identified in stepwise logistic regression analysis. In addition although age, high LDLC, hypertension and frequent walking were also the associated factors for knee OA in males by stepwise logistic regression analysis, smoking as a protective factor was not identified in this analysis. CONCLUSIONS: In this study, aging, obesity, frequent walking, low income and relevant multiple metabolic disorders were the associated factors for knee OA. Smoking might be associated with a lower prevalence of OA in male smokers according to univariate analysis. A retrospective association of smoking with OA may constitute an important etiologic clue, but further well-designed, large-scale prospective controlled trials are required to confirm these findings.

[Analysis on current laws and regulations of medical device clinical trial in China].

A series of laws and regulations are the essential legal requirement in the field of clinical trial of medical device currently in China, especially the Provision for Clinical Trial of Medical Device. On the basis of current situation of medical device clinical trial, systemic analysis on the hot spot topics in the regulations was conducted to explore the way of improving the control system of clinical trial of medical device in China, which will provide the reference for medical device industry and the investigators of the clinical trial of medical device.

Association of CYBA rs7195830 polymorphism with estimated glomerular filtration rate in an adult Han sample from Jiangsu province, China.

BACKGROUND: Reactive oxygen species are thought to contribute to the development of renal damage. The P22phox subunit of nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase, encoded by the cytochrome b245a polypeptide gene, CYBA, plays a key role in superoxide anion production. We investigated the association of CYBA rs7195830 polymorphism with estimated glomerular filtration rate (eGFR) and the role it plays in the pathogenesis of chronic kidney disease (CKD) in a Han Chinese sample. METHODS: The Gaoyou study enrolled 4473 participants. Serum levels of creatinine were measured and eGFR was estimated using the Chronic Kidney Disease Epidemiology Collaboration equations. The CYBA polymorphisms were genotyped. Then we investigated the association between eGFR and the rs7195830 polymorphism in the recessive model. RESULTS: The AA genotype of rs7195830 was associated with significantly lower values of eGFR compared with the GG and AG genotypes ((102.76 ± 17.07) ml×min(-1)×1.73 m(-2) vs. (105.08 ± 16.30) ml×min(-1)± 1.73 m(-2)). The association remained significant in the recessive model after adjusting for age, gender, body mass index, smoking, hypertension, diabetes mellitus, uric acid, triglyceride, low density lipoprotein cholesterol and high density lipoprotein cholesterol (ß=1.666, P=0.031). The rs7195832 AA genotype was an independent risk factor for CKD: eGFR <60 ml×min(-1)×1.73 m(-2) (odds ratio=3.32; 95% CI=1.21-9.13). CONCLUSION: The AA genotype of rs7195830 is independently associated with lower estimated glomerular filtration rate and is significantly associated with CKD.

Physical activity modifies the association between CYBA gene polymorphisms and small artery elasticity in a Chinese population.

Emerging evidence suggests that increased superoxide production is responsible for a significant proportion of endothelial dysfunction. The relationship between variants of the CYBA gene and cardiovascular diseases is currently debated. In the present study, we investigated the influence of CYBA polymorphisms (rs1049255 and rs7195830) on arterial elasticity in a Chinese population. In the 2178 participants enrolled in the GaoYou study, we measured large artery elasticity (C1) and small artery elasticity (C2) non-invasively, genotyped the CYBA polymorphisms and calculated energy expenditure. The AA genotype of the rs1049255 polymorphism was associated with a lower C2 than were the GG/AG genotypes (5.31±0.11 vs. 5.52±0.06 ml mm Hg(-1) × 100; P=0.01). Further analyses revealed an interaction between CYBA polymorphisms and physical activity with respect to C2 (P=0.007 for rs1049255 and P=0.038 for rs7195830). In less physically active participants, the AA genotype of the rs1049255 polymorphism was associated with a significantly lower C2 than the GG/AG genotypes (4.69±0.16 vs. 5.26±0.19 ml mm Hg(-1) × 100; P=0.008). In physically active participants, the GG/AG genotypes of rs7195830 polymorphism were correlated with higher C2 values than the AA genotype (5.84±0.08 vs. 5.08±0.32 ml mm Hg(-1) × 100; P=0.049). Haplotype analyses revealed higher C2 values in rs1049255G-rs7195830G carriers (P=0.0015). In conclusion, the rs1049255 and rs7195830 polymorphisms of the CYBA gene were associated with C2 in a Chinese population; physical activity could modify this genetic effect.

[Relationship between high-sensitive c-reactive and blood pressure].

OBJECTIVE: To investigate the relationship between c-reactive protein (CRP) and blood pressure in a general population. METHODS: We randomly selected 3889 subjects aged 18 - 74 years stratified by gender and age in Baqiao, a rural area of Jiangsu Province. A standardized questionnaire was used to collect information on medical history, smoking, alcohol intake and use of medications. Blood pressure was measured by mercury sphygmomanometer. Serum CRP (hCRP) concentration was measured using a high sensitivity BNprosec immunonephelometric assay. Subjects were divided into 4 groups according to their interquartile range of CRP levers: group Q1 (men hCRP < 2.04 mg/L; women hCRP < 1.80 mg/L); group Q2 (men 2.04 mg/L ≤ hCRP < 3.01 mg/L; women 1.80 mg/L ≤ hCRP < 2.76 mg/L); group Q3 (men 3.01 mg/L ≤ hCRP < 4.14 mg/L; women 2.76 mg/L ≤ hCRP < 3.84 mg/L); and group Q4 (men 4.14 mg/L ≤ hCRP; women 3.84 mg/L ≤ hCRP). RESULTS: Systolic blood pressure (SBP, adjusted P = 0.016) and pulse pressure (PP, adjusted P = 0.003) of men and PP (adjusted P = 0.002) of women were increased in proportion to increased CRP levels. Diastolic blood pressure was not associated with CRP levels. Multiple stepwise regression analysis showed that logCRP was independently associated with SBP and PP in men and PP in women. hCRP was independently associated with hypertension in men. Compared with group Q1, male people in group Q4 faced a 40.4% (95% confidence interval: 4.9% - 87.9%) higher risk of hypertension. CONCLUSIONS: hCRP was independently associated with PP in men and women, and SBP in men. hCRP was independently associated with hypertension in men but not in women in this study population.