基于马来酰亚胺基团的肠道黏附纳米粒对改善药物口服生物利用度的研究

目的 探索基于马来酰亚胺与肠道黏蛋白共价结合的肠道黏附纳米粒对药物口服生物利用度的影响,构建新型纳米载体用于增强药物口服吸收.方法 通过乳化溶剂挥发法制备包载荧光剂香豆素6的马来酰亚胺肠道黏附纳米粒,对制备的黏附纳米粒与非黏附聚乳酸-羟基乙酸共聚物[poly(lactic-co-glycolic acid),PLGA]...     

Modulation of gastrointestinal function by MuDelta,a mixed μ opioid receptor agonist/ μ opioid receptor antagonist

BACKGROUND & PURPOSE

Loperamide is a selective µ opioid receptor agonist acting locally in the gastrointestinal (GI) tract as an effective anti-diarrhoeal but can cause constipation. We tested whether modulating µ opioid receptor agonism with δ opioid receptor antagonism, by combining reference compounds or using a novel compound (‘MuDelta’), could normalize GI motility without constipation.

EXPERIMENTAL APPROACH

MuDelta was characterized in vitro as a potent µ opioid receptor agonist and high-affinity δ opioid receptor antagonist. Reference compounds, MuDelta and loperamide were assessed in the following ex vivo and in vivo experiments: guinea pig intestinal smooth muscle contractility, mouse intestinal epithelial ion transport and upper GI tract transit, entire GI transit or faecal output in novel environment stressed mice, or four weeks after intracolonic mustard oil (post-inflammatory). Colonic δ opioid receptor immunoreactivity was quantified.

KEY RESULTS

δ Opioid receptor antagonism opposed µ opioid receptor agonist inhibition of intestinal contractility and motility. MuDelta reduced intestinal contractility and inhibited neurogenically-mediated secretion. Very low plasma levels of MuDelta were detected after oral administration. Stress up-regulated δ opioid receptor expression in colonic epithelial cells. In stressed mice, MuDelta normalized GI transit and faecal output to control levels over a wide dose range, whereas loperamide had a narrow dose range. MuDelta and loperamide reduced upper GI transit in the post-inflammatory model.

CONCLUSIONS AND IMPLICATIONS

MuDelta normalizes, but does not prevent, perturbed GI transit over a wide dose-range in mice. These data support the subsequent assessment of MuDelta in a clinical phase II trial in patients with diarrhoea-predominant irritable bowel syndrome.     

Shoulder strain in keyboard workers and its alleviation by arm supports

Summary Keyboard work consists mostly of dynamic contractions of the small muscles of the forearms and hands. This is accompanied by continuous activity in the arm, shoulder and neck muscles keeping the head and hand in the correct position. Eliminating the weight from the arm by means of support and the position of the arms influences the electrical activity of shoulder muscles when working at a keyboard. We studied the influence of elbow angle, as well as that of different arm supports, on electrical activity of upper trapezius muscle during keyboard work in healthy workers and persons suffering from shoulder pains. The measurements were carried out in the laboratory. EMG activities, which where measured as mean square root (RMS)-values at every 100-millisecond period in trapezius muscle when working, were lower, the greater the elbow angle. Furthermore electrical activity decreased when subjects used arm supports while working. It is evident that the static load to shoulder muscles can be lowered significantly in keyboard work, when the forearms are at an angle of at least 100 degrees and by using arm supports. The most convienient and ergonomic working position can also be found individually be the method used here.     

Population pharmacokinetics analysis of intravenous busulfan in Chinese patients undergoing hematopoietic stem cell transplantation

There are several reports describing population pharmacokinetic (popPK) models of busulfan (BU). However, limited information is available in Chinese hematopoietic stem cell transplantation (HSCT) patients. The present study aimed to establish a popPK model of intravenous BU in Chinese HSCT patients for individualized drug therapy. The popPK model of BU was developed from a total of 284 concentration–time points from 53 patients. The effects of demographic and biochemical covariates were investigated by nonlinear mixed effect model (NONMEM) software. Plots, visual predictive check (VPC), bootstrap and normalized prediction distribution error (NPDE) were performed to determine the stability and the reliability of the final model. A one‐compartment model with first‐order elimination process was confirmed as the final structural model for BU. For a typical patient whose body surface area (BSA) is 1.7 m², the population typical values of CL and Vd were 11.86 L/h, and 48.2 L, respectively. The result suggested BSA showed significant influence on CL and Vd (P<.001). Plots revealed the final model was performing a goodness fit. The steady rate verified by bootstrap was 100%, relative deviation was less than 4.00%, estimated value of final model was in the 95% confidence interval (CI). The VPC results showed the observed values were almost all positioned within the 5th and 95th CIs. The mean and variance of the NPDE were 0.0363 (Wilcoxon signed‐rank test, 0.298) and 0.877 (Fisher variance test, 0.134; SW test of normality, 0.108), respectively. The global adjusted P value was 0.305, which indicated that the prediction of the BU popPK model was adequate. A physician‐friendly Microsoft Excel‐base tool was implemented using the final popPK model for designing individualized dosing regimens.     

基于Nrf2/HO-1通路探讨二十五味鬼臼丸对宫颈炎大鼠的治疗作用及机制

目的 研究藏药二十五味鬼臼丸对苯酚胶浆致宫颈炎模型大鼠的治疗作用及机制。方法 将雌性SD大鼠48只随机分为对照组、模型组及二十五味鬼臼丸低、中、高剂量（0.2、0.4、0.8 g·^kg-1）组和抗宫炎片（0.47 g·^kg-1）组,每组8只。除对照组外,其余5组建立25%苯酚胶浆致宫颈炎大鼠模型,各药物组分别以相应药物ig给药,每日1次,连续给药12 d后取材。观察大鼠外阴炎症程度评分、子宫指数、子宫解剖形态学改变;采用苏木精-伊红（HE）染色观察大鼠子宫组织病理学改变;采用酶联免疫吸附测定（ELISA）法检测子宫组织中超氧化物歧化酶（SOD）、丙二醛（MDA）含量变化;采用实时荧光定量PCR（qRT-PCR）法和蛋白免疫印迹（Western blotting）法检测子宫组织中核因子E2相关因子（Nrf2）、血红素氧合酶-1（HO-1）、NADPH氧化酶4（Nox4）的mRNA和蛋白表达情况。结果 与对照组比较,模型组大鼠外阴炎症评分、子宫指数、子宫组织中MDA水平、Nox4的mRNA和蛋白表达均显著升高（P＜0.01）,体质量、SOD活性、Nrf2、HO-1的mRNA和蛋白表达均显著降低（P＜0.01）,子宫组织出现不同程度的病理变化;与模型组比较,二十五味鬼臼丸能明显降低外阴炎症评分、子宫指数、子宫组织中MDA水平、Nox4的mRNA和蛋白表达（P＜0.05、0.01）,升高体质量及子宫组织中SOD活性和Nrf2、HO-1的mRNA和蛋白表达（P＜0.05、0.01）,减轻子宫颈炎症损伤程度。结论 二十五味鬼臼丸可能通过抑制Nox4的表达,激活Nrf2/HO-1通路,发挥抗氧化作用,减轻炎症反应,从而抑制宫颈炎发展。     

带锁髓内钉与微创经皮钢板治疗胫腓骨骨折的临床比较研究

目的通过对微创经皮钢板与带锁髓内钉治疗胫腓骨骨折的回顾性随访分析,比较两者的特点及临床适应证的选择。方法采用回顾性对比分析,比较胫腓骨骨折中使用带锁髓内钉组与微创经皮钢板组术中及术后的一般情况。结果两组患者在手术时间、出血量、切口大小、完全负重时间等方面差异显著（P〈0．05）,但是在骨折愈合时间、X线暴露时间、Johner-Wruhs评价、并发症的发生等方面差异并无显著性。结论两者都具有手术不剥离骨膜、创伤小等优点,带锁髓内钉适合胫骨骨干及胫骨多段骨折,微创经皮钢板对胫骨骨干或干骺端的骨折都适合。     

Association of Family Background with Adolescent Smoking and Regular Use of Illicit Substances Among Underage Psychiatric In-Patients

ABSTRACT

This study investigated whether adolescent's family type was associated with regular smoking or the use of illicit substances (cannabis or hard drugs) among underage adolescent psychiatric in-patients. The sample consisted of 471 adolescents aged 12–17 years admitted to psychiatric hospital between April 2001 and March 2006 at Oulu University Hospital, Finland. The information on family factors and substance use was based on the Schedule for Affective Disorder and Schizophrenia for School-Age Children, Present and Lifetime interview and the European modification of the Addiction Severity Index questionnaire. Compared to adolescent boys from two-parent families, those from child welfare placement were more likely to regularly use both cannabis (odds ratio [OR] = 4.4; 95% confidence interval [CI] = 1.4–13.7; P = .012) and hard drugs (OR = 8.4; 95% CI = 1.7–42.1; P = .01). Among girls, no association was found between family type and the use of illicit substances. Two-parent or foster family units may protect adolescents from involvement with illicit substances. In clinical adolescent psychiatric practice more attention should be paid to family interventions and parental support.     

Nicotine use and dependence and their association to psychiatric disorders in a large sample of adolescent psychiatric inpatients

The purpose of this research was to evaluate the level of nicotine dependence (ND) and to examine its association to psychiatric disorders in a representative clinical sample of adolescent psychiatric inpatients. The modified Fagerstrom Tolerance Questionnaire (mFTQ) was used to assess the level of ND. Psychiatric DSM-IV diagnoses were obtained by using the Schedule for affective disorder and schizophrenia for school-age children (K-SADS-PL). Of the total of 342 inpatients in the study sample, 259 (75.7%) reported to be current smokers. A sum score 6 or higher in the mFTQ, indicating a high level of ND, was found in 37.9% of all smokers. An increased likelihood for high level of ND was associated with substance related disorders (OR 5.1, 95% CI 2.8-9.3), conduct disorder and oppositional defiant disorders (OR 2.4, 95% CI 1.4-4.4). The usefulness of mFTQ in measuring ND among adolescent inpatients is apparent. Therefore, it can be recommended to be used as a routine screening instrument for ND among adolescents hospitalized due to psychiatric disorders.     

纵隔神经源性肿瘤临床病理特征和外科治疗

目的　探讨原发性纵隔神经源性肿瘤的临床病理特征和外科治疗原则。方法　总结125 例纵隔神经源性肿瘤的诊治经验。所有病例均经手术和病理证实。结果　神经源性肿瘤占同期原发性纵隔肿瘤及囊肿的22 .0 % (125/568) 。其中神经鞘瘤48 .9 % (61/125) ,神经纤维瘤27 .2 % (34/125) ,节细胞神经瘤13 .6 % (17/125) ,其他少见肿瘤10 .4 % (13/125) 。无临床症状而于查体时发现78例,占62 .4 % 。肿瘤位于后纵隔117 例。手术切除率98 .4 % (123/125) ,术后并发症发生率4 .0 % (5/125) ,手术死亡率0 .8 % 。恶性肿瘤的3 年生存率18 .2 % 。结论　纵隔神经源性肿瘤的临床特征与病理类型相关,无论良恶性均首选手术治疗,不同的病理类型有不同的预后。