抗结核分枝杆菌化合物结构特征及体外活性的研究进展

目的:综述抗结核分枝杆菌化合物的结构特征及体外活性,为抗结核分枝杆菌的新药设计提供参考。方法:以"抗结核""结核分枝杆菌""化合物""Antituberculosis""Mycobacterium tuberculosis""Compounds"等为关键词,组合查询2008年1月-2019年1月在中国知网、万方数据、Science Direct、ACS、Wiley、Springer Link等数据库中的相关文献,对文献中具有抗结核分枝杆菌活性的化合物结构特征及体外活性[以最低抑菌浓度(MIC)评价]进行归纳总结。结果与结论:共检索到相关文献188篇,其中有效文献47篇。目前,抗结核分枝杆菌的化合物有喹啉类化合物、吲哚类化合物、三唑类化合物、苯并噻吩类化合物(MIC为0.91μg/mL)、嘧啶类化合物和金属配合物。喹啉类化合物中具有抗结核分枝杆菌活性的有喹唑啉酮苯甲酸酯衍生物(MIC均为2.5μg/mL)、唑并喹啉衍生物(MIC均为1.0μg/mL)、唑酯类喹啉衍生物(MIC均<5.0μg/mL)、碳酰腙类喹啉衍生物(MIC均为1.0μg/mL);吲哚类化合物中具有抗结核分枝杆菌活性的有酰胺吲哚类化合物(MIC均≤0.25μg/mL)、氮杂吲哚类化合物(MIC均≤1.03μg/mL);三唑类化合物中具有抗结核分枝杆菌活性的有苯并咪唑类三唑衍生物(MIC均≤0.58μg/mL)、羰基三唑类衍生物(MIC均为2.5μg/mL);嘧啶类化合物中具有抗结核分枝杆菌活性的有氟苯嘧啶类衍生物(MIC为3.58μg/mL)、吡咯三唑嘧啶衍生物(MIC均为0.78μg/mL);金属配合物中具有抗结核分枝杆菌活性的有芳香类金属配合物(MIC均≤1.25μg/mL)、氟喹诺酮类金属配合物(MIC为0.31μg/mL)等。上述化合物可通过抑制ATP合成酶、乙酰羧酸合成酶、十聚异戊烯磷酰基-β-D-核糖氧化酶或烯酯酰基载体蛋白还原酶等活性发挥抗结核分枝杆菌活性。这些化合物的发现可为研发新型抗结核分枝药物奠定基础,但由于并未进行体内活性评价,因此,在后续研究中还需通过动物实验进一步评价其体内活性。     

鲍曼不动杆菌对米诺环素等抗菌药物的耐药性研究

目的 初步探讨米诺环素等16种临床常用抗菌药物对鲍曼不动杆菌的体外抗菌活性,为临床合理用药提供实验依据.方法 四川大学华西医院抗感染药物研究室分离自临床感染患者的115株非重复多重耐药鲍曼不动杆菌菌株,采用琼脂二倍稀释法进行16种临床常用抗菌药物体外抗菌活性测定.结果 米诺环素和多黏菌素B对鲍曼不动杆菌有很好的抗菌活性,MIC50分别为4μg/mL与0.25μg/mL,MIC90分别为16μg/mL与4μg/mL,亚胺培南等碳青霉烯类抗生素对多重耐药的鲍曼不动杆菌也有较强的抗菌活性,MIC50为2μg/mL,MIC90为32μg/mL.结论 米诺环素、多黏菌素B、亚胺培南对临床分离鲍曼不动杆菌具有良好的抗菌活性,可作为治疗选择药物.     

抗结核化合物9005B的分离纯化、结构解析及生物活性研究

为研究放线菌9005发酵液中的抗结核活性成分,采用活性追踪的方法 ,用多种色谱技术进行分离纯化,得到活性化合物9005B.通过理化性质和波谱学数据的分析,确定化合物9005B的结构为放线菌素X2.采用定量微孔板快速显色法(MABA)定出化合物9005B对结核分枝杆菌H37Rv的MIC为64μg/ml,具有较强的抗结核活性,属首次报道.     

头孢曲松-川参通注射液配伍液抗菌活性的观察

目的观察川参通注射液与头孢曲松配伍的抗菌活性及稳定性.方法将川参通注射液与头孢曲松钠注射液混合,以分光光度仪检测其吸光度值并以最低抑菌浓度(MIC)和最低杀菌浓度(MBC)试验检测其对粪链球菌、淋病奈瑟菌、大肠埃希菌及普通变形杆菌的抑菌与杀菌活性.结果头孢曲松-川参通配伍液外观为棕色澄清液体,无沉淀、浑浊或絮状物形成,405nm波长处的吸光度值小于川参通注射液的吸光度值.头孢曲松-川参通注射液配伍液对粪链球菌的MIC为200μg/mL/0.8μL/mL,MBC为500μg/mL/2μL/mL;对淋病奈瑟菌的MIC为0.1μg/mL/0.0004μL/mL,MBC为0.1μg/mL/0.0004μL/mL;对大肠埃希菌的MIC为0.005μg/mL/0.00002μL/mL,MBC为0.5μg/mL/0.002μL/mL;对变形杆菌的MIC为0.01μg/mL/}μL/mL,MBC为0.01μg/mL/0.00004μL/mL,较配伍前降低或不变.结论川参通注射液与头孢曲松配伍后未见浑浊或沉淀,对淋病奈瑟菌与大肠埃希菌的抗菌活性增高,对粪链球菌与普通变形杆菌的抗菌活性不变.     

不同浓度盐酸罗哌卡因复合芬太尼用于硬膜外镇痛对尿潴留的影响

目的:比较不同浓度的盐酸罗哌卡因复合芬太尼用于术后硬膜外镇痛对尿潴留的影响.方法:选择择期行腹股沟区手术患者90例,ASAⅠ~Ⅱ级,其中无张力斜疝修补术62例,鞘膜翻转术28例.行持续硬膜外麻醉,术毕开始PCEA,镇痛时间为48h.根据PCEA配药方案不同,随机分为三组,每组30例:A组0.075%罗哌卡因+2μg/mL芬太尼;B组0.113%罗哌卡因+2μg/mL芬太尼;C组0.150%罗哌卡因+2μg/mL芬太尼.PCEA设置:负荷量5mL,维持量2mL/h,bolus 4mL/次,锁定时间为15min,极限量12mL/h.镇痛开始后4h、8h、24h、36h随访,观察36h累计用药量,各时间点VAS评分、运动阻滞改良Bromage评分、心率(HR)、血压(MBP)、氧饱和度(SpO2)、发生尿潴留安置尿管例数以及其他不良反应.结果:A组36h用药量显著大于B组和C组,P<0.05,B组与C组比较,P>0.05;VAS评分,A组显著高于B组和C组,P<0.05,B组与C组比较,P>0.05;改良Bromage评分,C组显著高于A组和B组,P<0.05,B组与A组比较,P>0.05;尿潴留安置尿管例数,分别为0、1、5例,C组显著高于A组和B组,P<0.05,B组与A组比较,P>0.05;HR、MBP、SpO2及其他副反应无显著差异,P>0.05.结论:0.113%盐酸罗哌卡因+2μg/mL芬太尼硬膜外镇痛止痛效果确切,不产生明显运动阻滞,几乎无尿潴留发生.     

亚胺培南对携带blaNDM-1耐药基因的Escherichia coli耐药性及内膜secY、secE和secG转录水平的影响

目的 探讨亚胺培南(IPM)对bla_NDM-1阳性Escherichia coli耐药性及其内膜secY、secE和secG转录水平的影响。方法以重组质粒pET28a(+)-bla_NDM-1转化菌株E. coli DH5α-bla_NDM-1和E. coli BL21(DE3)-bla_NDM-1为研究对象，在梯度浓度增加或撤消IPM暴露下传代培养菌株，检测17种抗生素对IPM暴露菌株的MIC值；SDS-PAGE凝胶电泳检测NDM-1表达；蛋白活性实验检测NDM-1活性；qRT-PCR检测bla_NDM-1及内膜secY、secE和secG转录水平。结果 12μg/mL和020μg/mL IPM暴露的E. coli DH5α-bla_NDM-1菌株CFZ、CXM、FOX、CRO、CAZ、FEP等头孢类药物的MIC值(≥8μg/mL/≥8μg/mL、≥32μg/mL/≥32μg/mL、≥32μg/mL/≥32μg/mL、≥64μg/mL/=32μg/mL、≥32μg...     

硬膜外罗哌卡因复合芬太尼用于小儿术后镇痛的临床观察

目的比较硬膜外应用0.1%罗哌卡因＋芬太尼1μg/mL与硬膜外应用0.2%罗哌卡因＋芬太尼1μg/mL,及单纯硬膜外应用0.2%罗哌卡因用于小儿先天性巨结肠根治术术后镇痛效果,以探讨小儿安全有效的术后镇痛方式。方法选取我院2012年1月至2013年12月择期行先天性巨结肠根治术的患儿60例,随机分为A、B、C 3组,每组20例。3组均行硬膜外镇痛,A组所用药物为0.1%罗哌卡因＋芬太尼1μg/mL,B组用0.2%罗哌卡因,C组用0.2%罗哌卡因＋芬太尼1μg/mL。观察镇痛治疗后的1、6、12h的SpO2、脉搏、平均动脉压（MAP）、客观疼痛评分、镇痛泵按压次数。结果镇痛治疗后的1、6、12h,C组SpO2、脉搏、MAP与术前无差别,A、B组脉搏、MAP比术前明显增高;C组的镇痛泵按压次数少于A组和B组,C组的客观疼痛评分低于A组和B组。结论用0.2%罗哌卡因＋芬太尼1μg/mL行硬膜外镇痛比单纯应用0.2%罗哌卡因及用0.1%罗哌卡因＋芬太尼1μg/mL进行术后硬膜外镇痛效果更好。     

植物内生阿维链霉菌I06A-01716次生代谢产物的研究

目的 分离鉴定阿维链霉菌106A-01716发酵液中抗植物病原真菌活性成分,并进行抗真菌、抗肿瘤和免疫抑制活性研究.方法 在抗真菌活性指导下,采用硅胶柱层析、凝胶柱层析、HPLC等分离手段对活性组分进行分离:通过高分辨质谱,ID-NMR和2D-NMR对其结构进行鉴定;采用琼脂平板纸片法,进行抗植物病原真菌的最低抑制浓度测定;采用MTT法检测其对肿瘤细胞生长的抑制作用;采用流式细胞仪测定其对细胞周期的影响.结果 分离得到2个活性组分:1716-1和1716-2.1716-1和1716-2对人肝癌细胞HepG2的IC_(50)值分别为2.42μg/mL和3.42μg/mL～对人口腔上皮癌细胞KB的IC_(50)值分别为1.64μg/mL和6.73μg/mL. 细胞周期研究表明,随着1716-2的浓度增加,在KB细胞中,G_2/M期比例由对照组的15.23%逐步升高到36.53%;在HepG2细胞中,G_2/M期比例由对照组的4.39%升高到35.78%.结论 1716-1和1716-2结构分别与寡霉素B和寡霉素A一致.1716-1和1716-2有抗多种植物病原真菌活性.1716-1和1716-2在较低浓度下能够抑制人肝癌细胞HepG2和人口腔上皮癌细胞KB生长.1716-2使HepG2细胞和KB细胞阻滞在G2/M期.     

高效液相色谱法检测尿毒清颗粒(无糖型)中芍药苷、大车前苷和丹参酮 ⅡA成分的含量

目的 建立检测尿毒清颗粒(无糖型)中芍药苷、大车前苷和丹参酮ⅡA成分含量的方法.方法 取尿毒清颗粒(无糖型)适量,研细,取约1.0 g,精密称定,置50 mL棕色容量瓶中,加90％甲醇溶液超声处理30 min后,放冷定容,0.45μm滤膜滤过,Waters Spherisorb ODS1液相色谱柱分离.检测波长为芍药苷(230 nm)、大车前苷(330 nm)、丹参酮ⅡA(270 nm);流动相为乙腈(A)-0.2％磷酸溶液(B),梯度洗脱;流速为1.0 mL/min,柱温为25℃,进样量为10μL,二极管阵列检测器定量检测.结果 芍药苷、大车前苷和丹参酮ⅡA线性范围分别为1.427～57.06μg/mL、2.255～90.2μg/mL和0.498～19.9μg/mL(R2为0.992～0.996);平均加样回收率分别为99.39％,97.99％和98.41％;重复性RSD分别为3.16％、3.38％和2.69％;样品稳定性良好.结论 HPLC法重复性好、操作简单,弥补了单一指标成分含量测定作为质控手段的不足,为提高该产品的质量控制提供技术依据.     

HPLC法测定委陵菜中黄酮类成分的含量

目的:建立HPLC法测定委陵菜中槲皮素、翻白叶苷A和芹菜素含量的方法.方法:色谱柱为ZORB-AXSB.C18色谱柱(4.6 mm×150 mm,5μm);流动相为甲醇-0.3%磷酸水溶液(51:49);检测波长为360 nm;流速为0.9 mL/min.结果:槲皮素、翻白叶苷A和芹菜素的进样量分别在0.72～10.08μg/mL、0.86～12.04μg/mL和0.54～7.56 μg/mL范围内与其峰面积呈良好的线性关系,线性系数均为0.999 9,平均回收率分别为95.37%、96.87%、97.66%,RqD分别为1.79%、1.63%、2.08%,药材中三中黄酮的含量分别为100.0μg/g、323.0μg/g和55.0μg/g;结论:该方法快速、简便、可靠,适用于委陵莱中黄酮类成分的含量测定.     

Affective and Anxiety Disorders and Alcohol and Drug Dependence:

Depression and anxiety frequently coexist in patients with substance use disorders. This clinically-oriented article examiens the relationship between these conditions and emphasizes data showing that substances of abuse can cause signs and symptoms of both depression and anxiety. These substance-related syndromes appear to have a different course and prognosis than uncomplicated, independent anxiety and major depressive disorders, and clinicians should consider the role of alcohol and other drugs in all patients presenting with these complaints. The authors will also outline an approach for diagnosing and managing patients with the combination of a substance use and depressive or anxiety disorder.     

Synthesis and anti-nociceptive and anti-inflammatory effects of gaultherin and its analogs

The synthesis of gaultherin (1) and its analogs was carried out to provide 11 glycosides under phase-transfer catalytic conditions. The activities of all synthesized compounds were evaluated by nitric oxide production inhibitory assay in vitro. Methyl 2-O-(4-O-β-d-galactopyranosyl)-β-d-glucopyranosylbenzoate (5f) showed significantly anti-nociceptive and anti-inflammatory effects by the evaluation in vivo. Structure–activity relationships within these compounds were discussed.     

Modelling and simulation of variability and uncertainty in toxicokinetics and pharmacokinetics

Two important methodological issues within the framework of the variability and uncertainty analysis of toxicokinetic and pharmacokinetic systems are discussed: (i) modelling and simulation of the existing physiologic variability in a population; and (ii) modelling and simulation of variability and uncertainty when there is insufficient or not well defined (e.g. small sample, semiquantitative, qualitative and vague) information available. Physiologically based pharmacokinetic models are especially suited for separating and characterising the physiologic variability from the overall variability and uncertainty in the system. Monte Carlo sampling should draw from multivariate distributions, which reflect all levels of existing dependencies in the intact organism. The population characteristics should be taken into account. A fuzzy simulation approach is proposed to model variability and uncertainty when there is semiquantitative, qualitative and vague information about the model parameters and their statistical distributions cannot be defined reliably.     

成骨细胞的功能与损伤和骨质疏松的防治

骨质疏松是一种全身性骨骼疾病,导致骨折风险增加。成人的骨量通过破骨细胞的骨吸收和成骨细胞的骨形成作用来维持动态平衡,治疗骨质疏松症的理想策略是抑制破骨细胞的骨吸收和/或增强成骨细胞的骨形成功能。目前针对保护成骨细胞及增强其功能的骨质疏松疗法相对较少。因此,本文针对成骨细胞相关功能蛋白、各种细胞损伤机制（内质网应激、氧化应激、机械过载、微小RNA和长链非编码RNA的影响等）及骨质疏松的治疗与预防作一综述,以期为针对增强成骨细胞功能的骨质疏松治疗策略提供新思路。     

Self-stimulation and amphetamine: Tolerance to d and l isomers and cross tolerance to cocaine and methylphenidate

The effects of the d and l isomers of amphetamine on self-stimulation responding were tested following acute and chronic administration. Tolerance and post-drug depression of responding occurred in tests with both isomers, indicating no role for p-hydroxynorephedrine (PHN) which is one of the metabolites of d-amphetamine. In the second experiment, d-amphetamine, methylphenidate and cocaine all produced quantitatively and qualitatively similar effects on self-stimulation responding following acute administration. Following chronic administration of d-amphetamine, animals showed tolerance to all three drugs, indicating cross-tolerance among them. These data are consistent with an hypothesis that tolerance and post-drug depression following chronic amphetamine treatment are the result of decreases in postsynaptic receptor sensitivity, which would lead to a decreased effectiveness of all three drugs, regardless of their pre-synaptic mechanisms.     

益生菌与肿瘤防治

益生菌广泛存在于自然界中,通过维持宿主体内菌群平衡、影响肠屏障功能和调节免疫应答等作用,提高宿主健康水平,被公认为"肠道健康卫士".一些益生菌可以增强机体的免疫功能,抑制致癌物质,影响肿瘤细胞的基因表达,对肿瘤具有拮抗作用.大量研究表明,益生菌在未来的肿瘤防治中有很好的应用和发展前景.     

Acamprosate and naltrexone treatment effects on ethanol and sucrose seeking and intake in ethanol-dependent and nondependent rats

Rationale  Two pharmacotherapies are approved for treating alcohol craving (acamprosate and naltrexone), but both have shown mixed findings in animals and humans. Objectives  The present experiments utilized a “reinforcer blocking” approach (i.e., rats were able to consume ethanol during treatment) to better understand the efficacy of these treatments for ethanol seeking and drinking using ethanol-dependent and nondependent rats. Materials and methods  In “nondependent” experiments, drugs (acamprosate 50, 100, and 200 mg/kg; naltrexone 0.1, 0.3, and 1.0 mg/kg) were administered over 3-week periods prior to operant sessions with a low response requirement to gain access to reinforcers for 20 min. For “dependent” experiments, rats were made dependent in vapor/inhalation chambers. Results  Acamprosate and naltrexone had similar effects on intake in nondependent and dependent rats; neither drug was selective for ethanol over sucrose drinking. In nondependent animals, naltrexone was more efficacious at more doses than acamprosate, and acamprosate’s effects were limited to a dose that also had adverse effects on body weight. Both pharmacotherapies showed more selectivity when examining reinforcer seeking. In nondependent rats, acamprosate and naltrexone had response-attenuating effects in ethanol, but not sucrose, groups. In dependent animals, acamprosate had selective effects limited to a decrease in sucrose seeking. Naltrexone, however, selectively decreased ethanol-seeking in nondependent rats. Conclusions  The naltrexone-induced decreases in seeking suggested a change in incentive motivation which was selective for ethanol in nondependent rats. The “nondependent” paradigm may model early stages of “problem drinking” in humans, and the findings suggest that naltrexone could be a good intervention for this level of alcohol abuse and relapse prevention.     

Antiinfective and encrustation-inhibiting materials--myth and facts

Catheters, urethral and ureteral stents and other urological implants are frequently affected by encrustration and infection due to their permanent contact with urine. Indwelling urinary catheters provide a haven for microorganisms and thus require extensive monitoring. Several surface modification techniques have been proposed to improve the performance of devices including the immobilization of biomolecules, the incorporation of hydrophilic grafts to reduce protein adsorption, the creation of hydrophobic surfaces, the creation of microdomains to regulate cellular and protein adhesion, new polymers and antimicrobial coatings. Physico-chemical explanation to elucidate the mechanism of such encrustation or infection inhibiting materials is still not available. Our series of experiments showed a marked decrease of silver-activity in biological fluids which corresponds with the controversial clinical results obtained with silver coated urinary catheters. Rifampicin/minocycline coated catheters had very low activity against Gram-negative rods, enterococci and Candida spp., the main causing organisms of urinary catheter infection. Surface engineered materials and antimicrobial drug delivery systems will be the next generation of sophisticated urinary catheters and stents, if both efficacy as well as efficiency has been proved clinically.     

Alprazolam and lorazepam single and multiple-dose effects on psychomotor skills and sleep

Summary The effects of alprazolam 0.5 mg and lorazepam 2 mg on cognitive and psychomotor skills were assessed in twelve normal volunteer subjects in a randomised, double-blind, crossover design. Single and multiple dose effects were monitored using a battery of tests comprising critical flicker fusion threshold (CFFT), choice reaction time (CRT), simulated car tracking, and subjective ratings of perceived sedation (LARS) and of sleep behaviour (LSEQ). Compared with placebo baseline scores, treatment with lorazepam 2 mg (both single and multiple doses) resulted in a widespread impairment of CRT, tracking accuracy, and CFFT. Single doses of alprazolam 0.5 mg reduced CFFT with respect to the placebo baseline. Single and multiple dose treatment with both drugs resulted in subjective reports of sedation, a reduction of sleep onset latency, and improved sleep quality. Only lorazepam 2 mg significantly disrupted the integrity of behaviour on waking from sleep. These results suggest important pharmacodynamic differences between the two drugs in the doses used.