高效液相色谱法测定利福布汀的含量

目的 建立测定利福布汀的HPLC方法,并测定市售胶囊制剂中利福布汀的含量.方法 以Lichrospher100(RP-85.0μm×250mm)为分析柱,乙腈-甲醇-0.04mol/LKH2PO4(54:10:36,v/v)为流动相,流速1ml/min,柱温:40℃,进样量:5.0μl,254nm处紫外检测;对硝基苯酚为内标.结果 利福布汀在3.75～150.00μg/ml范围内,峰面积对浓度呈良好的线性关系(r=0.99987),平均回收率为100.24%,RSD为0.90%(n=6).结论 本法简便、快速、准确、灵敏度高、重现性好,适用于利福布汀的质量控制和临床血药浓度的监测.     

氨酚伪麻片Ⅱ溶出度测定方法研究

目的 建立测定氨酚伪麻片Ⅱ溶出度的高效液相色谱方法.方法 以2.4％的盐酸溶液(24→1 000)为溶出介质,转速为100 r/min,取样时间为45 min.结果 线性范围为10.4～52.0 μg/ml,r=0.999 9;平均回收率为99.8％.结论 建立的测定氨酚伪麻片Ⅱ溶出度的高效液湘色谱方法操作简便,结果准确可靠.     

HPLC法测定利福布汀原料药及胶囊中有关物质

目的:建立利福布汀原料药及胶囊中有关物质检查的方法。方法:采用高效液相色谱法。色谱柱为Agilent XDB-C_8,流动相为乙腈-0.1 mol/L磷酸二氢钾溶液(pH 6.5±0.1)(50:50,V/V),流速为1.0 mL/min,检测波长为254 nm,柱温为30℃,进样量为20μL,供试品以流动相为溶剂制备成质量浓度为1.0 mg/mL的溶液。采用此新建立的方法与利福布汀原料药及胶囊质量标准中的现行方法(供试品溶液质量浓度为0.5 mg/mL,色谱柱为C_18)分别进行系统适用性试验,并对利福布汀原料药及胶囊共6批样品进行有关物质检查(峰面积归一化法)。结果:利福布汀的检测质量浓度线性范围为0.8～16μg/mL(r=1.000 0),精密度、重复性和稳定性试验(12 h)的RSD均小于2.0%(n=6),检测限和定量限分别为0.025 4、0.085 2μg/mL。在系统适用性试验中,采用改进方法与现行方法,利福布汀峰与其前降解产物峰的分离度分别为7.50、3.47;在测定6批样品时,采用新方法检出的杂质个数较现行方法多1～5个,杂质总量高出0.19%～0.55%。结论:建立的新方法分离效果好,灵敏度高,可用于利福布汀原料药和胶囊有关物质的检查,更有助于控制药品质量。     

卡维地洛胶囊溶出度的测定方法研究

目的 建立卡维地洛胶囊中卡维地洛溶出度的测定方法.方法 采用溶出度测定第一法,以盐酸溶液(9→1000)900 mL为溶出介质,转速为100 r/min,经30 min时取样用紫外-可见分光光度法在240 nm波长测定.结果 卡维地洛在1.003—8.024 μg/mL范围内,浓度与吸光度呈良好线性关系(r=0.999 9);平均回收率99.99％,相时标准偏差(RSD)为1.41％:溶出均一性好,RSD为3.61％;样品供试液在24h内稳定.结论 该法简便、稳定可靠、专属性强,可有效测定卡维地洛胶囊溶出度,为控制卡维地洛胶囊质量提供了依据.     

维生素BT片溶出度检测的方法建立

目的 建立维生素BT片溶出度的检测方法 .方法 溶出度采用桨法,以0.1 mol/L盐酸1 000 ml作为溶出介质,转速为50 r/min;含量测定采用高效液相色谱法(HPLC),采用phenomenex Luna C18 (250×4.6 mm,5 m)色谱柱;流动相:磷酸盐缓冲液[取11.5 ml磷酸加入1 900 ml水中,再加入100 ml氢氧化钠(1 mol/L)溶液,调pH值为2.4]-甲醇(95∶5),每1 000 ml加入555 mg庚烷磺酸钠;检测波长:215 nm;流速:1.0 ml/min.结果 维生素BT线性范围为 10～1 000 μg/ml(r=1.0000),平均回收率100.56％,溶出曲线表明45 min内维生素BT片可溶出85％以上.结论 所建方法 操作简便,结果 准确可靠,可用于维生素BT片的溶出度测定.     

复方利福平片溶出度测定方法的研究

目的 建立复方利福平片的溶出度测定方法。方法 采用溶出度测定法第二法，以水为溶剂，转速为50r／min，经45min取样，紫外分光光度法在474nm处测定利福平的溶出量，溶出限度为标示量的75％。结果利福平在10．3—36．1μg／ml范围内线性关系良好(r＝1．0000)，平均回收率99．8％。结论 本方法准确、快速、简便。通过测定复方利福平片的溶出度可有效检测其制剂工艺水平。     

含利福布汀的三联或四联疗法在幽门螺杆菌根除失败后的应用

根除幽门螺杆菌(Hp)是防治消化性溃疡、慢性活动性胃炎等疾病的主要措施,作为一线治疗的三联或四联方案的根除率逐年降低。抗分枝杆菌药物利福布汀有较强的抗Hp活性,国内外陆续有将含利福布汀方案作为Hp感染一线治疗失败后的补救或三/四线方案的报道。本文对利福布汀的作用机制、药动学特点及含利福布汀方案的疗效和安全性作一综述。     

利福布汀的合成工艺改进

目的:探索利福布汀的最佳合成工艺。方法:以利福霉素S为起始原料,经溴代、硝基化、还原、亚氨基化,最后与侧链环合得到利福布汀;并对合成3-氨基利福霉素S的反应溶剂二氯甲烷的前处理方法(未处理、常压蒸馏、氢化钙干燥、分子筛干燥、氢氧化钾干燥)、合成3-氨基-4-亚氨基利福霉素S的反应温度(25³0、2030、20²5、1525、15²0、1020、10¹5℃)以及侧链N-异丁基哌啶酮的制备工艺进行改进。结果:利福布汀的收率为16.44%,高效液相色谱法检测纯度为99.17%。二氯甲烷的前处理选用氢氧化钾进行干燥;合成3-氨基-4-亚氨基利福霉素S反应温度控制为1515℃)以及侧链N-异丁基哌啶酮的制备工艺进行改进。结果:利福布汀的收率为16.44%,高效液相色谱法检测纯度为99.17%。二氯甲烷的前处理选用氢氧化钾进行干燥;合成3-氨基-4-亚氨基利福霉素S反应温度控制为15²0℃;侧链N-异丁基哌啶酮合成改为以异丁胺和丙烯酸乙酯为原料,其收率为85.2%、气相色谱法检测纯度为98.5%。结论:该改进工艺合成收率和纯度较高,原料易得、反应条件温和、操作简单。     

利福布汀的药效学和药物动力学特点

虽然利福布汀的抗菌谱和抗菌机制与利福平相似,但在药效学和药物动力学特点上却显著优于利福平．利福布汀在药效学方面,它对大多数革兰氏阳性和阴性菌有活性,特别是对结核分枝杆菌和胞内分枝杆菌有活性;对非典型分枝杆菌鸟分枝杆菌一胞内分枝杆菌复合体（ＭＡＣ）的活性超过利福平;利福平耐药性分枝杆菌对利福布汀无完全交叉耐药性,３０％以上菌株对利福布汀仍然敏感．利福布汀与许多抗菌药物包括抗结核药物联用具有累加或协同作用。在治疗结核（包括耐药性分枝杆菌所致）和防治ＭＡＣ 感染上的卓起效果已彼动物实验和临床观察所证实。利福布汀在药物动力学方面,具有良好的脂溶性,易于透人组织和体液．可迅速透人多型核白细胞,并在其中较长时间保持较高浓度,分布广,半衰期长而具有长效作用．细胞内浓度与细胞外浓度的比值为９～１５（利福平为５）．利福布汀的血浆蛋白结合率为７１％～９４％。基于利福布汀的上述特点,可以认为其应用前景看好。     

利禄布汀的药效学和药物动力学特点

虽然利福布汀的抗菌谱和抗菌机制与利福平相似，但在药效学和药物动力学特点上却显著优于利禄平，利福布汀在药效学方面，它对大多数革兰氏阳性和阴性菌有活性，特别是对结核分枝杆菌和胞内分枝杆菌有活性，对非典型分枝杆菌鸟分枝杆菌一胞内分枝杆菌复合体（ＭＡＣ）的活性超过利福平；利福平耐药性分枝杆菌对利福平汀无完全交叉耐药性，３０％以上菌株对利禄布汀仍然敏感。利禄布汀与许多抗菌药物包括抗结核药物联用具有累加或协同     

Synthesis,Cytotoxicity and Antileishmanial Activity of Some N-(2-(indol-3-yl)ethyl)-7-chloroquinolin-4-amines

We report herein the condensation of 4,7-dichloroquinoline (1) with tryptamine (2) and D-tryptophan methyl ester (3) . Hydrolysis of the methyl ester adduct (5) yielded the free acid (6) . The compounds were evaluated in vitro for activity against four different species of Leishmania promastigote forms and for cytotoxic activity against Kb and Vero cells. Compound (5) showed good activity against the Leishmania species tested, while all three compounds displayed moderate activity in both Kb and Vero cells.     

Lung disease and PKCs

The lung offers a rich opportunity for development of therapeutic strategies focused on isozymes of protein kinase C (PKCs). PKCs are important in many cellular responses in the lung, and existing therapies for pulmonary disorders are inadequate. The lung poses unique challenges as it interfaces with air and blood, contains a pulmonary and systemic circulation, and consists of many cell types. Key structures are bronchial and pulmonary vessels, branching airways, and distal air sacs defined by alveolar walls containing capillaries and interstitial space. The cellular composition of each vessel, airway, and alveolar wall is heterogeneous. Injurious environmental stimuli signal through PKCs and cause a variety of disorders. Edema formation and pulmonary hypertension (PHTN) result from derangements in endothelial, smooth muscle (SM), and/or adventitial fibroblast cell phenotype. Asthma, chronic obstructive pulmonary disease (COPD), and lung cancer are characterized by distinctive pathological changes in airway epithelial, SM, and mucous-generating cells. Acute and chronic pneumonitis and fibrosis occur in the alveolar space and interstitium with type 2 pneumocytes and interstitial fibroblasts/myofibroblasts playing a prominent role. At each site, inflammatory, immune, and vascular progenitor cells contribute to the injury and repair process. Many strategies have been used to investigate PKCs in lung injury. Isolated organ preparations and whole animal studies are powerful approaches especially when genetically engineered mice are used. More analysis of PKC isozymes in normal and diseased human lung tissue and cells is needed to complement this work. Since opposing or counter-regulatory effects of selected PKCs in the same cell or tissue have been found, it may be desirable to target more than one PKC isozyme and potentially in different directions. Because multiple signaling pathways contribute to the key cellular responses important in lung biology, therapeutic strategies targeting PKCs may be more effective if combined with inhibitors of other pathways for additive or synergistic effect. Mechanisms that regulate PKC activity, including phosphorylation and interaction with isozyme-specific binding proteins, are also potential therapeutic targets. Key isotypes of PKC involved in lung pathophysiology are summarized and current and evolving therapeutic approaches to target them are identified.     

Gender-related symptoms and correlates of alcohol dependence among men and women with a lifetime diagnosis of alcohol use disorders

This study explored gender-related symptoms and correlates of alcohol dependence in a crosssectional study of 150 men and 150 women with a lifetime diagnosis of alcohol use disorders (AUD). Participants were recruited in equal numbers from treatment settings, correctional centres and the general community. Standardized measures were used to determine participants' use of substances, history of psychiatric disorders and psychosocial stress, their sensation seeking and family history of substance use and mental health disorders. Multivariate analyses were used to detect patterns of variables associated with gender and the lifetime severity of AUD. Men had a longer history of severe AUD than women. Women had similar levels of alcohol dependence and medical and psychological sequelae as men, despite 6 fewer years of AUD. More women than men had a history of severe psychosocial stress, severe dependence on other substances and antecedent mental health problems, especially mood and anxiety disorders. There were differences in family history of alcohol-related problems approximating same-gender aggregation. The severity of a lifetime AUD was predicted by its earlier age at onset and the occurrence of other disorders, especially anxiety, among both men and women. The limitations in the generalizability of these findings due to sample idiosyncrasies are discussed.     

Biochemical and molecular characterisation of cubozoan protein toxins

Class Cubozoa includes several species of box jellyfish that are harmful to humans. The venoms of box jellyfish are stored and discharged by nematocysts and contain a variety of bioactive proteins that are cytolytic, cytotoxic, inflammatory or lethal. Although cubozoan venoms generally share similar biological activities, the diverse range and severity of effects caused by different species indicate that their venoms vary in protein composition, activity and potency. To date, few individual venom proteins have been thoroughly characterised, however, accumulating evidence suggests that cubozoan jellyfish produce at least one group of homologous bioactive proteins that are labile, basic, haemolytic and similar in molecular mass (42-46 kDa). The novel box jellyfish toxins are also potentially lethal and the cause of cutaneous pain, inflammation and necrosis, similar to that observed in envenomed humans. Secondary structure analysis and remote protein homology predictions suggest that the box jellyfish toxins may act as α-pore-forming toxins. However, more research is required to elucidate their structures and investigate their mechanism(s) of action. The biological, biochemical and molecular characteristics of cubozoan venoms and their bioactive protein components are reviewed, with particular focus on cubozoan cytolysins and the newly emerging family of box jellyfish toxins.     

Dose tolerability of chronically inhaled voriconazole solution in rodents

Invasive pulmonary aspergillosis (IPA) is a fungal disease of the lung associated with high mortality rates in immunosuppressed patients despite treatment. Targeted drug delivery of aqueous voriconazole solutions has been shown in previous studies to produce high tissue and plasma drug concentrations as well as improved survival in a murine model of IPA. In the present study, rats were exposed to 20 min nebulizations of normal saline (control group) or aerosolized aqueous solutions of voriconazole at 15.625 mg (low dose group) or 31.25 mg (high dose group). Peak voriconazole concentrations in rat lung tissue and plasma after 3 days of twice daily dosing in the high dose group were 0.85 ± 0.63 μg/g wet lung weight and 0.58 ± 0.30 μg/mL, with low dose group lung and plasma concentrations of 0.38 ± 0.01 μg/g wet lung weight and 0.09 ± 0.06 μg/mL, respectively. Trough plasma concentrations were low but demonstrated some drug accumulation over 21 days of inhaled voriconazole administered twice daily. Following multiple inhaled doses, statistically significant but clinically irrelevant abnormalities in laboratory values were observed. Histopathology also revealed an increase in the number of alveolar macrophages but without inflammation or ulceration of the airway, interstitial changes, or edema. Inhaled voriconazole was well tolerated in a rat model of drug inhalation.