Increased susceptibility for intrahepatic cholestasis of pregnancy and contraceptive-induced cholestasis in carriers of the 1331T>C polymorphism in the bile salt export pump

AIM： To study the association of three common ABCB11 and ABCC2 polymorphisms （ABCB11： 1331T〉C→V444A; ABCC2： 3563T〉A → V1188E and 4544G 〉A → C1515Y） with intrahepatic cholestasis of pregnancy （ICP） and contraceptive-induced cholestasis （CIC）. METHODS： ABCB11 and ABCC2 genotyping data were available from four CIC patients and from 42 and 33 ICP patients, respectively. Allele-frequencies of the studied polymorphisms were compared with those in healthy pregnant controls and Caucasian individuals. Furthermore, serum bile acid levels were correlated with the presence or absence of the 1331 C allele. RESULTS： The ABCB11 1331T〉C polymorphism was significantly more frequent in cholestatic patients than in pregnant controls： C allele 76.2% （CI, 58.0-94.4） vs 51.3% （CI 35.8-66.7）, respectively （P = 0.0007）; and CC allele 57.1% （CI 36.0-78.3） vs 20% （CI 7.6-32.4）, respectively （P = 0.0065）. All four CIC patients were homozygous carriers of the C allele. In contrast, none of the studied ABCC2 polymorphism was overrepresented in ICP or CIC patients. Higher serum bile acid levels were found in carriers of the 1331CC genotype compared to carriers of the TT genotype. CONCLUSION： Our data support a role for the ABCB11 1331T〉C polymorphism as a susceptibility factor for the development of estrogen-induced cholestasis, whereas no such association was found for ABCC2. Serum bile acid and 7-glutamyl transferase levels might help to distinguish ABCB4- and ABCB11-related forms of ICP and CIC.

Brain natriuretic peptide and optimal management of heart failure

Aside from the important role of brain natriuretic peptide (BNP) in diagnosis, and differential diagnosis of heart failure, this biological peptide has proved to be an independent surrogate marker of rehospitalization and death of the fatal disease. Several randomized clinical trials demonstrated that drugs such as beta blocker, angiotensin converting enzyme inhibitor, spiro- nolactone and amiodarone have beneficial effects in decreasing circulating BNP level during the management of chronic heart failure. The optimization of clinical decision-making appeals for a representative surrogate marker for heart failure prognosis. The serial point-of-care assessments of BNP concentration provide a therapeutic goal of clinical multi-therapy and an objective guid- ance for optimal treatment of heart failure. Nevertheless new questions and problems in this area remain to be clarified. On the basis of current research advances, this article gives an overview of BNP peptide and its property and role in the management of heart failure.

Smoothelin,a new marker to determine the origin of liver fibrogenic cells

AIM: To explore this hypothesis that smooth muscle cells may be capable of acquiring a myofibroblastic phenotype, we have studied the expression of smoothelin in fibrotic conditions.

Simultaneous determination of acetaminophen and oxycodone in human plasma by LC–MS/MS and its application to a pharmacokinetic study

A simple and rapid liquid chromatography-tandem mass spectrometry （LC-MS/MS） method was de- veloped and validated for simultaneous determination of acetaminophen and oxycodone in human plasma. Acetaminophen-d4 and oxycodone-d3 were used as internal standards. The challenge en- countered in the method development that the high plasma concentration level of acetaminophen made the MS response saturated while the desired lower limit of quantification （LLOQ,） for oxycodone was hard to reach was well solved. The analytes were extracted by protein precipitation using acetonitrile. The matrix effect of the analytes was avoided by chromatographic separation using a hydrophilic C18 column coupled with gradient elution. Multiple reaction monitoring in positive ion mode was performed on tandem mass spectrometer employing electrospray ion source. The calibration curves were linear over the concentration ranges of 40.0-8000 ng/mL and 0.200-40.0 ng/mL for acetaminophen and oxycodone, respectively. This method, which could contribute to high throughput analysis and better clinical drug monitoring, was successfully applied to a pharmacokinetic study in healthy Chinese volunteers.

Science Letters:Brain natriuretic peptide: A potential indicator of cardiomyogenesis after autologous mesenchymal stem cell transplantation?

We observed in a pilot study that there was a transient elevation of brain natriuretic peptide (BNP) level shortly after the transplantation in the patient with ischemic heart failure, which is unexplainable by the simultaneous increase of the cardiac output and six-minute walk distance. Similar findings were observed in the phase I trial. We postulated on the basis of the finding of Fukuda in vitro that this transient elevation of BNP level against the improvement of cardiac function and exercise capacity might indicate cardiomyogenesis in patients after mesenchymal stem cell transplantation. Further study is warranted to verify the hypothesis.

Impact of Pharmaceutical Care on Self-Administration of Outpatient Low-Molecular-Weight Heparin Therapy

Outpatient subcutaneous (s.c.) therapies are becoming more and more common in the treatment of different diseases. The effectiveness of community-pharmacy-based interventions in preventing problems that arise during s.c. self-injections of low-molecular-weight heparins (LMWH) is unknown. Our objective was to provide a standard operating procedure (SOP) for community pharmacists and to compare pharmaceutical vs. standard care in both clinical and daily life settings. We hypothesized that: pharmaceutical care results in improved adherence, safety, and satisfaction, and in fewer complications;the interventions used are feasible in daily life;and the results achieved in clinical and daily life settings are comparable. In the clinical setting (randomized controlled trial), patients were recruited sequentially in hospital wards;in the daily life setting (quasi-experimental design with a comparison group), recruitment took place in community pharmacies by pharmacists and trained master students during their internship. Interventions were offered according to patient needs. Data were collected by means of a monitored self-injection at home and structured questionnaire-based telephone interviews at the beginning and the end of the LMWH treatment. The main outcome measures were: scores to assess patient’s skills;syringe count to assess adherence;and frequency, effectiveness, and patient’s assessment of received interventions. The results show a median age of the 139 patients of 54 years. Interventions resulted in improved application quality (p p = 0.03). Oral instructions were pivotal for improving patients’ application quality. We found no significant score differences between the intervention groups in the clinical and daily life settings. Patients’ baseline skills were high, with the lowest score being 0.86 (score range ?2.00 to +2.00). Adherence rate was high (95.8%). In conclusion, our SOP for pharmacist interventions was of good quality, adequate, appreciated, and feasible in daily life. Patients are capable of managing s.c. injection therapies if adequate assistance is provided.

Are potassium levels in children with hemolytic uremic syndrome predictive of outcome?

Objective: To ascertain the role of serum potassium levels in predicting clinical outcomes in diarrhea-associated hemolytic uremic syndrome (HUS D+). Methods: We reviewed clinical and laboratory data from HUS D+ patients at our tertiary care institution from 2001 to 2008. Serum potassium concentration at presentation and during the acute phase of acute renal failure were recorded and related to laboratory parameters and clinical outcomes. Results: 15 HUS D+ cases were identified. E. coli 0157:H7 was found in 9/15 cases (70%). Potassium levels were not predictive of clinical outcomes. Normal serum potassium levels were found in the majority of patients. Potassium levels <3.6 mmol/L were evident at presentation in 3/15 patients (23%), and no patient manifested hyperkalemia even when creatinine levels were concurrently increase. Conclusions: This study suggests the presence of vigorous compensatory mechanisms in the homoestasis of serum potassium levels during HUS D+ disease since neither the increase stool volumes associated with diarrhea nor the presence of renal failure resulted in clinically significant changes in serum potassium levels.

Validation of a liquid chromatographic method for the pharmaceutical quality control of products containing elacridar

Many anticancer drugs have an impaired bioavailability and poor brain penetration because they are substrates to drug efflux pumps such as P-glycoprotein and Breast Cancer Resistance Protein.Elacridar is a strong inhibitor of these two drug efflux pumps and therefore has great potential to improve oral absorption and brain penetration of many anticancer drugs.Currently,a clinical formulation of elacridar is unavailable and therefore the pharmaceutical development of a drug product is highly warranted.This also necessitates the availability of an analytical method for its quality control.A reverse-phase high-performance liquid chromatographic method with ultraviolet detection was developed for the pharmaceutical quality control of products containing elacridar as the active pharmaceutical ingredient.The analytical method was validated for linearity,accuracy,precision,selectivity,carry-over,stability of stock and reference solutions,stability of the final extract,stability-indicating capability and impurity testing.We found that elacridar is unstable in aqueous solutions that are exposed to light because a hydroxylation product of elacridar is formed.Therefore,sample solutions with elacridar must be protected from light.

Composition of Gentamicin C Components in Gentamicin Sulphate Generics Commonly Used in Small Animal Practice in Nigeria

Gentamicin is one of the commonly used antibiotics in small animal practice in Nigeria. Fake and substandard drugs are responsible for high cost in both economic terms and lives lost. For decades, Nigeria has been flooded by counterfeit and poor-quality medicines. Because of the variations in gentamicin C components in different formulations and the effect of this on its efficacy and toxicity, this study was designed to evaluate the percentage of each of the major components of gentamicin C in some injectable gentamicin sulphate generics commonly used in small animal practice in Nigeria. Of the 22 multisource generics of injectable gentamicin sulphate samples analyzed for percentage content of gentamicin C major components using USP HPLC （United States Pharmacopoeia high performance liquid chromatography） method, 95.5% （21 ） met the USP specification. This suggests that there is a significant improvement in the monitoring of quality of drugs marketed in Nigeria, including gentamicin sulphate. Nevertheless, considering the propensity of the manufacturers adjusting their manufacturing processes following product＇s registration by the regulatory body, there is still the need for regular surveillance of drug products by batches to ensure their efficacy and safety.

关注孕产期用药——加拿大“motherisk”项目简介

孕产期用药的安全性是一个值得关注的课题,因其对儿童健康的影响不可忽视。加拿大多伦多大学附属儿童病院于1985年发起的"Motherisk"研究项目,集临床治疗、研究及教育为一体,旨在为医护人员及患者提供证据充分的怀孕及哺乳期用药安全及风险的信息和指南,并对孕妇提供实用的咨询和帮助。本文结合实际的研究事例,从该项目的基本背景和研究内容及应用情况做一简要介绍。

对儿童用药和临床试验的思考

近年来,有高达79%的儿科药物在没有明确标识或者没有额外获得儿童使用许可的情况下使用[1]。2006年,我国医院对于4亿儿科患者使用的1 103种药品中仅有64种（占5.8%）是按说明书指导使用的[2]。另有数据显示,中国患病儿童占总患病人口的20%左右,但80%以上的已上市药品没有儿童使用标识,90%的药物没有儿童剂型[3]。

Hepatocellular transport proteins and their role in liver disease

MOLECULAR PHYSIOLLGY OF HEPATOCELLULAR TRANSPORT PROTEINS Basolaferal transport systems Na+-dependent bile salt uptake Uptake of bile salts into the liver was first isolated perfused rat liver[1],isolated hepatocyte cultures and basolateral plasma membrane vesicles [2,4].

Glucocorticoid receptor gene haplotype structure and steroid therapy outcome in IBD patients

AIM: To study whether the glucocorticoid receptor (GR/ NR3C1) gene haplotypes influence the steroid therapy outcome in inflammatory bowel disease (IBD). METHODS: We sequenced all coding exons and flanking intronic sequences of the NR3C1 gene in 181 IBD patients, determined the single nucleotide polymorphisms, and predicted the NR3C1 haplotypes. Furthermore, we investigated whether certain NR3C1 haplotypes are significantly associated with steroid therapy outcomes. RESULTS: We detected 13 NR3C1 variants, which led to the formation of 17 different haplotypes with a certainty of > 95% in 173 individuals. The three most commonly occurring haplotypes were included in the association analysis of the influence of haplotype on steroid therapy outcome or IBD activity. None of the NR3C1 haplotypes showed statistically signifi cant association with glucocorticoid therapy success. CONCLUSION: NR3C1 haplotypes are not related to steroid therapy outcome.

Effects of Korean Red Ginseng on Semen Parameters in Male Infertility Patients:A Randomized,Placebo-Controlled,Double-Blind Clinical Study

Objective： To investigate the effects of Korean red ginseng （KRG） on semen parameters in male infertility patients in a randomized, double-blind, placebo-controlled study. Methods： A total of 80 male infertility patients with varicocele were recruited from April 2011 to February 2012. The subjects were then divided into the following four groups： non-varicocelectomy （V）＋placebo （P） group, V＋P group, non-V＋KRG group （1.5-g KRG daily）, and V＋KGR group （1.5-g KRG daily）. Semen analysis was performed and hormonal levels were measured in each treatment arm after 12 weeks. Results： All groups but not the non-V＋P group, showed significant improvements in sperm concentrations, motility, morphology, and viability at the end of the study. However, there were no significant differences in serum follicle-stimulating hormone, luteinizing hormone, and testosterone among groups. The incidence of adverse events was low, and all events were assumed to be unrelated to the treatments administered. Conclusions： Although the exact mechanism by which KRG improves spermatogenesis remains unclear, KRG may be a useful agent for the treatment of male infertility. Nevertheless, additional studies to evaluate the optimal dose and duration of treatment are needed.

Nice new hypertension guidelines

The National Institute for Clinical Excellence in the United Kingdom published a new set of guidelines on the management of primary hypertension in August 2011, reflecting some important changes in the diagnosis and treatment of hypertension. Ambulatory blood pressure measurement is now the new gold standard for diagnosis. Home blood pressure monitoring is a useful alternative for the diagnosis and monitoring of hypertension. Calcium channel blockers(CCB) and blockers of the renin-angiotensin system have surpassed diuretics and β-blockers as first line options. Patients younger than 55 should receive an angiotensin-converting enzyme inhibitor, or an angiotensin receptor blocker if the former is not tolerated. Older patients should be started on a CCB. A thiazide diuretic can be added to these two groups for better blood pressure control, but. chorthalidone and indapamide are the preferred diuretics as they showed favorable outcomes in large clinical trials. Treatment with these three drug classes should be sufficient in the majority of patients, but if triple therapy is still insufficient, referral to a hypertension specialist is recommended. Additional diuretic therapy, spironolactone, or an α or β blocker can be used as the fourth line treatment.

南非成人社区获得性肺炎管理指南

在南非,由于社区获得性肺炎(community-acquired pneumonia,CAP)的疾病负担增加以及抗菌药物耐药率(antimicrobial resistance,AMR)升高,需要规范抗菌药物处方的标准,因而改善CAP患者的管理水平尤其重要。本指南旨在为临床医生提供CAP患者管理的推荐性建议。对临床医生来说,本次更新纳入了CAP患者管理的重要进展和争议。

孕妇接触丁氨苯丙酮的结局:一项前瞻性对照研究

Objective: Bupropion was developed for the treatment of depression, but subsequently was found to be effective for smoking cessation. To date, there are no prospective comparative studies examining its safety in pregnancy. The primary objective was to determine whether bupropion increases the risks for major malformations above baseline. The secondary objective was to examine the rates of live births, stillbirths, spontaneous and therapeutic abortions, mean birth weight, and gestational age at birth. Study design: Women who were pregnant or planning a pregnancy and taking bupropion were enrolled in the study. Follow- up of pregnancy outcome was carried out between 4 months and 1 year after delivery. Three comparisons were carried out: 1) women exposed to bupropion vs a nonteratogen group; 2) those taking for depression vs other antidepressants, vs a nonteratogen group; 3) spontaneous abortions were compared between those taking for depression, vs another antidepressant group vs a nonteratogen group. Results: We completed follow- up on 136 women exposed to bupropion during the first trimester of pregnancy. There were (105) live births, no major malformations, the mean birth weight was (3450g), the mean gestational age at delivery was (40 weeks), the number of spontaneous abortions was 20, there were 10 therapeutic abortions, there was 1 stillbirth, and 1 neonatal death. There were no statistically significant differences between any of the end points we examined between the exposed and comparison groups, with the exception of significantly more spontaneous abortions in the bupropion group (P =. 009). Conclusion: These results suggest that bupropion does not increase the rates of major malformation above baseline. The higher rates of spontaneous abortions are similar to other studies examining the safety of antidepressants during pregnancy.

基于模型指导抗生素给药改善预后

抗生素的传统使用方法正在受到挑战,去年发表在新英格兰医学期刊(NEJM)上的两项重要临床试验研究均表明了口服(或部分口服)药物治疗骨髓炎和左侧心内膜炎的疗效不亚于标准静脉注射[1];也有文献报道在脓毒血症危重患者中应延长抗生素输注时间,而不是经典的一次性大剂量给药。最近的一项荟萃分析则表明,延长输注时间可提高治愈率和降低住院病死率[2]。

Lipolysis supports bone formation by providing osteoblasts with endogenous fatty acid substrates to maintain bioenergetic status

Bone formation is a highly energy-demanding process that can be impacted by metabolic disorders.Glucose has been considered the principal substrate for osteoblasts,although fatty acids are also important for osteoblast function.Here,we report that osteoblasts can derive energy from endogenous fatty acids stored in lipid droplets via lipolysis and that this process is critical for bone formation.As such,we demonstrate that osteoblasts accumulate lipid droplets that are highly dynamic and provide the molecular mechanism by which they serve as a fuel source for energy generation during osteoblast maturation.Inhibiting cytoplasmic lipolysis leads to both an increase in lipid droplet size in osteoblasts and an impairment in osteoblast function.The fatty acids released by lipolysis from these lipid droplets become critical for cellular energy production as cellular energetics shifts towards oxidative phosphorylation during nutrient-depleted conditions.In vivo,conditional deletion of the ATGL-encoding gene Pnpla2 in osteoblast progenitor cells reduces cortical and trabecular bone parameters and alters skeletal lipid metabolism.Collectively,our data demonstrate that osteoblasts store fatty acids in the form of lipid droplets,which are released via lipolysis to support cellular bioenergetic status when nutrients are limited.Perturbations in this process result in impairment of bone formation,specifically reducing ATP production and overall osteoblast function.

第2章 从临床试验到药物利用研究

本章的背景和涉及的挑战可追溯到几年前《英国医学杂志》的一篇编辑部文章。该文呼唤临床医学的大事——“临床自由的终结”。这个有争议的论题不仅扼要地表达了该文的内容,而且贴切地概括了30多年来关于临床诊疗实践基础之争论的答案——临床诊疗实践必须且仅应建立在对照试验,特别是随机对照临床试验结论的基础之上。