Identification of a major metabolite of danshensu in rat urine and simultaneous determination of danshensu and its metabolite in plasma: application to a pharmacokinetic study in rats

Danshensu, as the effective component of Salvia miltiorrhiza (Danshen), has been widely used in clinical studies for treatment of cardiovascular diseases in China. A new metabolite, 4‐hydroxy‐3‐methoxyphenyllactic acid was isolated from the urine of rats, and its chemical structure was identified by ultraviolet (UV), Infrared Spectroscopy (IR), mass spectrometry (MS) and nuclear magnetic resonance (NMR). Furthermore, a selective and sensitive high performance liquid chromatography‐tandem mass spectrometric (HPLC‐MS/MS) method was developed for the simultaneous quantification of danshensu and its major metabolite, 4‐hydroxy‐3‐methoxyphenyllactic acid, in rat plasma after oral and intravenous administration of danshensu. The separation was performed on a Hypersil Gold C₁₈ column (150 × 2.1 mm i.d., 3.0 µm, Thermo, San jose CA, USA) with gradient elution using a mobile phase composed of methanol and water (containing 0.1% formic acid) at a flow rate of 0.2 mL/min. Linear detection responses were obtained for danshensu and 4‐hydroxy‐3‐methoxyphenyllactic acid ranging from 5 to 10000 ng/mL and 5 to 4000 ng/mL, respectively. The lower limits of quantification (LLOQs) for the two compounds were both 5 ng/mL. The intra‐and inter‐day precision (R.S.D %) were within 5.61% for the two analytes. The average recoveries of the analytes were greater than 72.43%. The method was proved to be stable during all sample storage, preparation and analytic procedures. This method was successfully applied to the pharmacokinetic studies of danshensu and 4‐hydroxy‐3‐methoxyphenyllactic acid after oral and intravenous administration of danshensu in rats.Copyright © 2014 John Wiley & Sons, Ltd.     

生物合成调控的青霉素发酵数学模型与过程优化

青霉素生物合成受溶解氧、溶解二氧化碳、pH、氨氮、碳源(特别是葡萄糖)等的调控，这些调控反应的产生不仅与基础培养基配方有关，更受发酵过程通气、搅拌条件及补料方案的影响。为此，笔者通过把握发酵过程中产生菌生长和青霉素生物合成代谢流的元素平衡、能量平衡以及传递与反应速度平衡的方法，结合生产经验和数据资料，建立了一种能够模拟青霉素发酵过程工艺学参数和经济学参数变化的数学模型。应用这一模型，在充分考虑生物合成代谢调控的基础上，对青霉素发酵过程进行优化，即通过补水维持上述平衡，避免因环境条件、初始条件和约束条件的变化及人为的失误造成的过程波动，使生产不断趋向最优状态。模拟运行表明，这种优化可显著提高发酵生产的经济效益。     

抗炎蛋白肽的分离和性质

猪四肢骨提取物对大白鼠蛋清性关节炎及甲醛性关节炎具有显著抗炎作用,对酒石酸锑钾所引起的疼痛有镇痛作用,现已广泛用于治疗风湿、类风湿关节炎和骨质增生。我们通过葡聚糖凝胶G-25、G-50及羧甲基葡聚糖凝胶C-25等纯化步骤,获得一个蛋白肽组分。此组分经薄层层析鉴定为单一斑点,醋纤电泳为单一区带,凝胶柱等电聚焦为一条强带,一条弱带,分子量为27,000左右,不含糖类及核酸类物质,对大白鼠蛋清性关节炎具有明显的抗炎作用。初步认为此蛋白肽组分可能是猪四肢骨提取物中抗炎作用的有效物质。     

Effects of initial particle size on the tableting properties of L-lysine monohydrochloride dihydrate powder

L-lysine monohydrochloride (LMH) dihydrate was crystallized and the resulting powder was sieved to obtain various size fractions. The influence of other factors, such as crystallinity and crystal shape, was minimized by using the same batch of crystals. Compression of smaller particles at low compaction pressures resulted in tablets of greater porosity. The differences in porosity decreased with increasing compaction pressure. At the same compaction pressure, smaller particles formed tablets of greater tensile strength. However, fragmentation of the larger particles tended to equalize the particle size and reduce its influence. The differences were reduced for particles larger than 710 microm. For crystals of all size fractions, tensile strength increased with increasing compaction pressure. The tensile strength increased more rapidly for smaller crystals. Tensile strength decreased exponentially with increasing porosity for all fractions. The dependence of tensile strength on porosity is explained in term of tablet structure. Yield strength, calculated from 'out-of-die' Heckel analysis, increased with increasing particle size.     

新工艺护肝片的质量标准

目的：制定新工艺护肝片的质量标准,验证新工艺的可行性。方法：对五味子、柴胡、猪胆粉进行薄层鉴别,用高效液相色谱法测定五味子醇甲的含量。结果：在选定的薄层色谱条件下,五味子、柴胡、猪胆粉的特征斑点清晰,五味子醇甲的线性范围为20．5～184．5μg·ml^-1,r=0．9999,平均回收率为99．2％,RSD0．57％,n=9。结论：护肝片的新工艺稳定,其质量标准专属性好。     

Topoisomerase II inhibition by aporphine alkaloids

The aporphine alkaloids (+)-dicentrine and (+)-bulbocapnine are non-planar molecules lacking features normally associated with DNA binding by intercalation or minor groove binding. Surprisingly, dicentrine showed significant activity as a topoisomerase II (EC 5.99.1.3) inhibitor and also was active in a DNA unwinding assay. The DNA unwinding suggests DNA intercalation, which could explain the inhibition of topoisomerase II. Bulbocapnine, which differs from dicentrine only by the presence of a hydroxyl group at position 11 and the absence of a methoxyl group at position 9, was inactive in all assays. Molecular modeling showed that dicentrine can attain a relatively planar conformation, whereas bulbocapnine cannot, due to steric interaction between the 11-hydroxyl group and an oxygen of the methylenedioxy ring. These observations suggest that dicentrine is an "adaptive" DNA intercalator, which can bind DNA only by adopting a somewhat strained planar conformation. The requirement of a suboptimal conformation to achieve DNA binding appears to make dicentrine a weaker topoisomerase II inhibitor than the very planar oxoaporphine alkaloid liriodenine. These results suggest that it may be possible to modulate DNA binding and biologic activity of drugs by modifications affecting their ability to adopt planar conformations.     

Perspectives on developing small molecule inhibitors targeting HIV-1 integrase

HIV-1 integrase (IN) is a crucial enzyme in the life cycle of HIV-1 and also a validated target for developing anti-HIV inhibitors. Recent progress in drug design has significantly accelerated the development of anti-AIDS IN inhibitors. A large amount of novel inhibitors that interact specifically with IN were developed along with the expanding and application of methods to drug design. This article reviewed the anti-HIV IN inhibitors discovered by the rational drug design approaches in the recent 5-year.     

用蒙特卡罗模型探索头孢他美钠的给药方案

目的用蒙特卡罗模型,研究注射用头孢他美钠在犬体内的药效学与药动学的关系,探索合理的给药方案,为临床用药提供参考。方法 6只健康beagle犬(A、B组)交叉静脉注射190mg或264mg头孢他美钠,不同时间点取血,采用HPLC法测定血药浓度,用一室模型计算药动学参数,用蒙特卡罗模型预测头孢他美钠在四种不同给药方案下的治疗效果。结果 190mg组的犬主要药动学参数T1/2,CL,V为(1.21±0.24)h,(115.46±13.02)mL/h/kg,(202.50±50.91)mL/kg。264mg组的犬主要药动学参数T1/2,CL,V为(1.27±0.51)h,(105.75±11.22)mL/h/kg,(189.94±62.23)mL/kg,通过蒙特卡罗模拟,得到头孢他美钠在不同给药方案下的PK-PD曲线及敏感性折点。结论敏感菌感染并以%T>MIC90≥50%为治疗目标时建议选择333mg静脉注射,每8h给药一次(q8h,下同)或500mg,3h静脉滴注,q12h;以%T>MIC90≥65%为治疗目标时建议选择333mg,3h静脉滴注,q8h;耐药菌感染则需要加大剂量或重新选择新的给药方案。     

Synthesis,biological activities,and docking study of novel chalcone‐pleuromutilin derivatives

The issue of antibiotic resistance is becoming progressively serious these days, and the feasible solution to address it is to develop and discover novel antibiotics. The diterpene natural pleuromutilin is a prominent candidate for its special mode of action by inhibiting protein synthesis. In this study, a series of novel pleuromutilin derivatives with chalcone moiety was designed and synthesized, and their antibacterial activities were assessed in vitro. As suggested from the results, most of compounds exhibited potent activities against two methicillin‐resistant Staphylococcus aureus (MRSA) ATCC 33591 and 43300. The further modification of the chalcone structure, aza‐cyclic derivatives were afforded and then assessed, and potent activities against the tested strains were reported. The preliminary docking studies were conducted to explore the interactions between target molecules and binding site.     

试论我国医药价格改革的方向

本文通过对当前我国医药物价方面存在问题的剖析和探讨,提出了全国统一价的药品价格管理体制仍然是适合我国国情和行业实际的好体制。医药价格改革的方向应当是在坚持全国统一价的基础上,通过局部改革、调整,使之进一步完善。