Lipopolysaccharide (LPS) from Brucella abortus is less toxic than that from Escherichia coli, suggesting the possible use of B. abortus or LPS from B. abortus as a carrier in vaccines.

Brucella abortus may be useful as a component of vaccines. This is because it possesses several unique properties as a carrier that enable it to stimulate human B cells even in the relative absence of T cells. Human immunodeficiency virus type 1 proteins conjugated to B. abortus could induce neutralizing antibodies against human immunodeficiency virus type 1. Recently we showed that the characteristics of lipopolysaccharide (LPS) derived from B. abortus are similar to those of the whole bacterium in that the LPS acts as a T-independent type 1 carrier in mice. In this study we wanted to determine whether LPS derived from B. abortus is associated with the adverse effects seen with other bacterial endotoxins. LPS purified from B. abortus by butanol extraction was shown to have less than 2% (wt/wt) contamination by protein and less than 1% (wt/wt) contamination by nucleic acids and to contain 1% (wt/wt) ketodeoxyoctanic acid. Compared with LPS derived from Escherichia coli, B. abortus LPS was 10,000-fold less potent in eliciting fever in rabbits, 268-fold less potent in killing D-galactosamine-sensitized mice, and 1,400-fold and 400-fold less potent in inducing interleukin-1 beta and tumor necrosis factor alpha production, respectively. These results suggest that B. abortus LPS is much less likely than the LPS from E. coli to evoke endotoxic shock; therefore, it may be feasible to incorporate B. abortus as a component of vaccines.     

Acute toxicity is a dose-limiting factor for intravenous polymyxin B: A safety and pharmacokinetic study in healthy Chinese subjects

ObjectivesPolymyxin B is a last-line antibiotic for multidrug-resistant gram-negative bacterial infections. However, limited safety and pharmacokinetic information is available. We investigated the safety and pharmacokinetics of intravenous polymyxin B in healthy subjects.MethodsAn open-label, single-dose clinical trial was conducted in healthy Chinese subjects. Polymyxin B (sulphate) was administered intravenously at 0.75 or 1.5 mg/kg (n = 10 per dose, 5 males and 5 females) to examine the safety and pharmacokinetics.ResultsOne female subject in the 1.5-mg/kg group discontinued due to abdominal pain during administration. The most frequently reported adverse events were perioral paraesthesia, dizziness, and numbness of extremities (7/10 subjects in the 0.75-mg/kg group, all subjects in the 1.5-mg/kg group). All neurotoxicity-related events dissipated without treatment within a maximum of 23 h. Notably, abdominal pain (3/5) and vulvar pruritus (2/5), colpitis (2/5) or abnormal uterine bleeding (1/5) were reported in female subjects receiving the 1.5-mg/kg dose. In the 0.75-mg/kg group, the total clearance, volume of distribution and half-life of polymyxin B were 0.028±0.002 L/h/kg, 0.219±0.023 L/kg and 5.44±0.741 h, respectively; similar values were observed in the 1.5-mg/kg group. Urinary recovery was 3.7 ± 1.1% and 8.1 ± 1.3% in the 0.75- and 1.5-mg/kg groups, respectively. Population pharmacokinetics of polymyxin B was consistent with a three-compartment model. The clearance and distribution of the central compartment were 0.027 L/h/kg and 0.071 L/kg, respectively.ConclusionsThis study is the first to examine the safety and pharmacokinetics of polymyxin B in healthy subjects. Our results highlight that acute toxicity is a dose-limiting factor for intravenous polymyxin B.     

P2Y12 receptor as a new target for electroacupuncture relieving comorbidity of visceral pain and depression of inflammatory bowel disease

Dried fruits of Psoralea corylifolia L. (Psoraleae Fructus) is one of the most popular traditional Chinese medicine with treatment for nephritis, spermatorrhea, pollakiuria, asthma, and various inflammatory diseases. Bakuchiol is main meroterpenoid with bioactive diversity from Psoraleae Fructus. This study was designed to seek structural diverse bakuchiol derivants with anti-inflammatory activities from this plant. Various column chromatography methods were used for isolation experiment. Structures and configurations of these compounds were determined by spectroscopic methods and single-crystal X-ray diffraction. Their inhibition on nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages were evaluated by the Griess reaction. Twelve unpresented bakuchiol dimmers, bisbakuchiols M–U (1–9) and bisbakuchiol ethers A–C (10–12), along with five known compounds (13–17), were isolated from the fruits of Psoralea corylifolia L. Compounds 1–3, 10–12, 16 and 17 exhibited inhibitory activities against LPS-induced NO production in RAW264.7 macrophages, and the inhibition of compound 1 (half maximal inhibitory concentration (IC50) value = 11.47 ± 1.57 μM) was equal to that of L-N(6)-(1-iminoethyl)-lysine (IC50 = 10.29 ± 1.10 μM) as a positive control. Some compounds exhibited inhibitory activities against NO production, and the study of structure–activity relationship suggested that uncyclized compounds with oxygen substitution at C-12/12′ showed strong inhibitory activities, and carbonyl units contributed to enhanced activities.     

甲状腺滤泡细胞的自噬活性参与慢性淋巴细胞性甲状腺炎的发病机制

目的探讨甲状腺滤泡细胞自噬对慢性淋巴细胞性甲状腺炎( CLT)的影响及炎性因子干扰素 ?γ(IFN?γ)对甲状腺滤泡细胞自噬参与 CLT的作用。方法 2018年 1—7月,选取新疆喀什地区第二人民医院 24例 CLT甲状腺切除的病人作为 CLT组,并选择同期入院的 24例单纯甲状腺肿( SG)甲状腺切除病人作为 SG组;对人甲状腺滤泡细胞分离、培养、鉴定;流式细胞技术检测甲状腺组织中 CD3+T细胞占比;放射性免疫法检测甲状腺滤泡细胞三碘甲状腺原氨酸( T3)、甲状腺素( T4)、甲状腺球蛋白(Tg)的水平,酶联免疫吸附试验( ELISA)试剂盒检测 IFN?γ、环磷酸腺苷( cAMP)水平;蛋白质印迹法检测自噬相关蛋白 Be? cline、微管相关蛋白 1轻链 3?Ⅱ(LC3B?Ⅱ)、哺乳动物雷帕霉素靶蛋白( mTOR)及不同浓度 IFN?γ对 Becline、LC3B?Ⅱ、mTOR蛋白的影响。结果成功分离出人甲状腺滤泡上皮细胞,倒置显微镜下观察,可见人甲状腺滤泡细胞在贴壁之前呈圆形或椭圆形或不规则形状, CLT病人组织切片可见多个淋巴生发中心,大量淋巴细胞浸润,甲状腺滤泡细胞萎缩。 SG病人甲状腺组织甲状腺滤泡细胞未见明显炎症浸润。流式细胞分析结果显示, CLT组甲状腺滤泡上皮细胞内浸润的 CD3+淋巴细胞数所占百分比( 25.76±4.05)%明显高于 SG组( 10.35±4.21)%,两组间比较差异有统计学意义( n＝24,P＜0.001)。与 SG组比较, CLT组中 T3、T4、Tg、INF?γ及 cAMP水平［甲状腺组织:(6.70±0.32)nmol/L,(44.05±0.39)nmol/L,(0.65±0.01)μg/L,(15.84±1.43)μg/L,(3.680±0.046)μmol/L;血清:(9.89±0.32)nmol/L,(39.25±0.27)nmol/L,(1.86±0.42)μg/L,(16.32±0.31)μg/L,(4.325±0.012)μmol/L］均升高,差异有统计学意义。 CLT组织与 SG组织相比自噬水平低下,表现为 Becline,LC3B?Ⅱ蛋白低表达［Becline蛋白:(7.16±0.15); LC3B?Ⅱ蛋白:(0.82±0.01)］,mTOR蛋白高表达( 12.26±0.16)。 IFN?γ干预后,甲状腺滤泡细胞中自噬蛋白 Be? cline,mTOR,LC3B?Ⅱ被诱导,表现为 Becline,LC3B?Ⅱ水平高表达［250 U/mL组:(7.80±0.07),(1.51±0.05); 500 U/mL组:(8.50±0.10),(1.82±0.04); 1 000 U/mL:(9.16±0.14)(2.47±0.09)］mTOR水平低表达［250 U/mL组:(12.26±0.16); 500 U/mL组:(0.84±0.13); 1 000 U/mL组:(9.66±0.07)］N?γ浓度的诱导作用愈明显。结论甲状腺滤泡细胞自噬参与 CLT的发展,且作用机制可能与炎性因子 IFN?γ关。     

Pathogenic implication of a fibrinogen-binding protein of Staphylococcus epidermidis in a rat model of intravascular-catheter-associated infection

The involvement of Fbe, a fibrinogen-binding protein of Staphylococcus epidermidis, in the pathogenesis of catheter-associated infection was investigated. An fbe (gene encoding Fbe protein) mutant was constructed by allelic replacement, wherein an erythromycin resistance gene replaced a portion of the A region of fbe. Meanwhile, a rat central venous catheter (CVC) infection model was established to assess the importance of Fbe in the pathogenesis of CVC-associated infection due to S. epidermidis. Fbe-positive S. epidermidis strain HB was significantly more likely to cause a CVC-associated infection resulting in bacteremia and metastatic disease than its isogenic Fbe-deficient mutant (100% versus 20%, P < 0.01). These results confirm the importance of adherence associated with Fbe in the pathogenesis of CVC-associated infection caused by S. epidermidis.     

一种简便快速的液相色谱串联质谱法用于人体内血尿样品中奈诺沙星浓度的测定

目的建立一种简便快速高效液相色谱串联质谱(LC-MS/MS)的方法用于测定人血浆和尿液中奈诺沙星药物浓度。方法色谱柱为Waters Symmetry RP1 8柱(50mm×2.1 mmm,5μm),以加替沙星为内标,血浆和尿液样品测定采用0.1%甲酸乙腈混合溶液为流动相,比例分别为82:1 8和85:1 5,流速均为0.2 mL/min。采用蛋白沉淀法处理血浆样品,以液液萃取法清除尿液样品中杂质。ESI源正离子选择性反应临测(SRM),奈诺沙星检测通道:m/z 372.4→m/z354.1,内标检测通道:m/z376.1→m/z 332.2。结果本方法测定血浆和尿液中的奈诺沙星的线性范围均为5～100ng/mL,最低检测浓度均为5ng/mL血浆和尿液的奈诺沙星提取回收率分别为(98.49±4.69)%和(84.92±6.81)%,且血浆和尿液的RSD)分别小于或等于4.31%和9.76%。奈诺沙星血浆样品的方法日内、日间准确度分别为(99.27～103.75)%和(100.40～106.36)%;而尿液样品的方法日内、日间准确度依次为(103.52～11 5.94)%和(9 9.50～1 10.96)%,且基质效应、精密度、稳定性等均通过方法学验证。并已用于该药的人体药动学研究中药物浓度的测定。结论本方法操作简便、迅速,特异性强,灵敏度高,准确性好,符合奈诺沙星人体药物动力学研究中血尿样测定的方法学要求。     

支气管哮喘吸入糖皮质激素治疗前后嗜酸细胞阳离子蛋白对比分析

目的:探讨支气管哮喘血清嗜酸细胞阳离子蛋白(ECP)与吸入糖皮质激素疗效关系。方法:采用荧光酶标法pharmacia CAP检测系统测定支气管哮喘患者血清ECP及其肺功能FEV1。结果:支气管哮喘舒利迭组与辅舒酮组治疗前后血清ECP值差异非常显著,肺功能显著改善。结论:血清ECP可作为临床观察支气管哮喘疗效指标之一,以指导临床使用吸入糖皮质激素治疗支气管哮喘。     

盐酸克林霉素胶囊剂人体生物等效性研究

目的 :研究盐酸克林霉素胶囊剂的生物等效性。方法 :2 0名男性健康志愿者随机交叉空腹口服普强苏州制药有限公司研制的盐酸克林霉素胶囊剂 (试验品 )和苏州第四制药厂生产的盐酸克林霉素胶囊剂 (对照品 )各 6 0 0mg ,其血浆药物浓度以高效液相色谱法测定。结果 :受试者单剂空腹口服试验品和对照品 6 0 0mg后 ,其平均实测血药高峰浓度分别为 (4 .6 7± 0 .86 )mg/L和 (4 .5 7± 0 .98)mg/L ,实测平均达峰时间分别为 (0 .5 3± 0 .11)h和 (0 .5 5± 0 .15 )h ,平均消除半衰期分别为 (3.12± 1.0 1)h和 (3.2 0± 1.2 6 )h ,实测平均药时曲线下面积分别为 (14.92± 3.2 9)h·mg/L和 (14.41± 3.94)h·mg/L。两制剂的药代动力学参数经方差分析差异均无显著性 (P >0 .0 5 )。试验品与对照品相比 ,其相对生物利用度为 (110 .5 2± 37.2 1) %。对两药品的cmax和AUC等参数以双向单侧t检验法和 (1～ 2α)置信区间法分析 ,结果均表明两药具生物等效性。结论 :盐酸克林霉素胶囊剂体内过程符合血管外二室模型 ,口服后吸收迅速。试验品与对照品具有生物等效性。     

Population Pharmacokinetics Study of Nemonoxacin Among Chinese Patients With Moderate Hepatic Impairment

Purpose

Nemonoxacin is a novel C-8-methoxy nonfluorinated quinolone that has been approved for the treatment of community-acquired pneumonia (CAP) in adults. The goals of this study were to evaluate the pharmacokinetic (PK) and population PK parameters of nemonoxacin and to provide the appropriate dose adjustment recommendations for patients with hepatic impairment.