药用化合物水合物审查标准的探讨

近年来国内关于药用化合物水合物的专利申请量增长迅速,但在审查指南中并没有相关的审查标准。本文从水合物本身的特点及其确认方式出发,并结合具体案例,探讨了药用化合物水合物申请审查过程中的一些问题,以期促进该类化合物审查标准的统一。

羧酸类药用活性化合物在生物碳质上的吸附特性

为研究生物碳质吸附在处理水土环境中羧酸类PhACs(药用活性化合物)的作用,通过比表面积、红外光谱、元素分析及电镜扫描对商业水稻秸秆生物碳质的结构与性质进行了讨论,同时研究了生物碳质对不同初始pH及不同初始质量浓度的五种羧酸类PhACs[KTP(酮洛芬)、IBP(布洛芬)、NPX(萘普生)、ASP(阿司匹林)、SYA(水杨酸)]吸附特征的影响.结果表明:吸附过程包括前期快速吸附和后期缓慢吸附至平衡两个阶段;在第一阶段,外表面吸附与大孔及中孔扩散是控制吸附的机制,在第二阶段,生物碳质内表面吸附及基质在微孔中的扩散是影响吸附的主要机制.初始pH为6.0~7.0时,等温吸附数据符合Freundlich吸附等温方程,反映了非均匀性表面的吸附特性.五种羧酸类PhACs在生物碳质上的吸附能力[通过Kd,0.01(特定液相浓度下的单点分配系数)表达]表现为NPX(24.30 g/L)>IBP(15.82 g/L)>KTP(10.44 g/L)>SYA(2.64 g/L)>ASP(1.24 g/L).溶液初始pH变化对所选PhACs的吸附量有显著影响,初始溶液pH处于p Ka±1.0范围内时,所选吸附质的吸附量达到最大值,随着初始pH的升高,所选PhACs主要以阴离子形式存在,同时生物碳质表面负电性增加,增强的静电斥力减弱了氢键作用.研究显示,氢键作用在生物碳质吸附PhACs过程中起到主要促进作用,除此之外,还受到范德华力及π-π电子供受体等多种作用驱动.

生物技术提高海洋生境药用放线菌代谢产物的研究

海洋生境放线菌可产生较特异的药用化合物,但通常量很少很难满足后续的研究要求,原生质体融合技术是改良放线菌菌株最常用的育种方法之一,本文结合相关研究进展,分析了影响放线菌原生质体制备和融合的因素,介绍了放线菌融合子的筛选方法及应用,并对如何利用融合及基因技术等方法提高放线菌药用抗生素的产量进行了评述。

应用线性自由能关系估算药用活性化合物的生物碳质-水吸附系数

线性自由能关系（LFER）可以用来预测生物碳质对水中药用活性化合物（Ph ACs）的吸附系数,并确定不同分子间作用力对生物碳质吸附性能的相对贡献.利用商业水稻秸秆生物碳质（碳化温度400~500℃,200目）与14种带有不同表面官能团的Ph ACs（羧酸类、羟基类、氮杂环类）进行了吸附等温实验.各物质的等温吸附实验数据均可用Freundlich方程进行很好地拟合.通过建立的LFER模型,可以预测吸附质任一化学饱和水平（CW/SW）下的lg Kd,activity.利用复相关系数（R2=0.93）、回归系数标准偏差（SE=0.23）、F统计量（268）、去一法交叉验证系数（Q2LOO=0.90）以及外部样本交叉验证相关系数（Q2EXT=0.92）等方法对该模型进行验证,结果表明,其显著性与稳健性较好,具有预测能力.模型结果表明在低浓度范围内,空穴作用（V）与氢键碱作用（B）在整个吸附过程中起到主导作用,其中空穴作用为正贡献,氢键碱作用为负贡献.

Chemical constituents of marine medicinal mangrove plant Sonneratia caseolaris

Twenty-four compounds including eight steroids （1-8）, nine triterpenoids （9-16, 24）, three flavonoids （20-22）, and four benzenecarboxylic derivatives （17-19, 23） were isolated and identified from stems and twigs of medicinal mangrove plant Sonneratia caseolaris. The structures of the isolated compounds were determined by extensive analysis of their spectroscopic data. Among these rnetabolites, compounds 1, 4-20 and 22-24 were isolated and identified for the first time from S. caseolaris. In the in vitro cytotoxic assay against SMMC-7721 human hepatoma cells, compound 21 （3＇,4＇,5,7-tetrahydroxyflavone） exhibited significant activity with IC50 2.8 μg/mL, while oleanolic acid （14）, 3,3＇-di-O-methyl ether ellagic acid （18）, and 3,3＇,4-O-tri-O-methyl ether ellagic acid （19） showed weak activity. None of these compounds displayed significant antibacterial activites.

Ribavirin monotherapy increases sustained response rate in relapsers of end treatment virologic responders

AIM: To assess the efficacy of ribavirin monotherapy in patients with biochemical relapse after combination therapy.METHODS: Twenty-four weeks of ribavirin monotherapy was given to biochemical relapsers of end treatment biochemical responders within 6 mo after combination therapy, including non-responders with HCV-RNA level ≤0.2 Meq/mL and end treatment virologic responders (ETVRs) with or without reappearance of HCV-RNA.RESULTS: Sixty-two chronic HCV-infected patients completed 24 wk of interferon-α plus ribavirin combination therapy. Fifty patients (80%) achieved end treatment biochemical response including 16 non-responders and 34 of 36 ETVRs. Twenty-six patients (41.9%) were nonresponders. Ribavirin monotherapy was given to 20biochemical relapsers including 12 non-responders with HCV-RNA levels ≤0.2 Meq/mL, four of eight HCV-RNA reappearing ETVRs, and four HCV-RNA negative ETVRs.After 24 wk of ribavirin monotherapy, one of 12 nonresponders, two of four HCV-RNA reappearing ETVRs and all four RNA-negative biochemical relapsers of ETVRs showed sustained virologic response. Two of 12monotherapy treated non-responders showed persistent normalization of liver function test. In total, 50% (31/62)of patients achieved sustained virologic response.CONCLUSION: Resumption of ribavirin monotherapy in ETVRs at signs of viral rebound and recurrent biochemical abnormalities rather than continuation of monotherapy appears to be the key to success of ribavirin monotherapy after interferon-related combination therapy.

Conservation of Leaves of a Medicinal Plant of Western Algeria （Pistacia atlantica）

In our context, and in the goal to valorize the Pistacia atlantica species Desfthat grows spontaneously in Algeria occidental except the coastline, and that is used by the nomadic populations in their daily consumptions, we are thinking about drying its leaves. Here, the biochemical analysis of dried leaves ofPistacia atlantica is determined, the sorption is other ms are of great importance in the food industry, especially in the drying; the sorption isotherms of pistachio leaves were measured by the gravimetric method at three temperatures 40, 50 and 60 ℃. The equilibrium was achieved after eight days for desorption and seven days for adsorption with water activity ranging from 5% to 90%. Only the GAB and Peleg models were found to be the most suitable for describing the sorption curves. The isosteric heat of sorption of Pistacia atlantica leaves decreases with an increase in moisture content and was found to be an exponential function of moisture content for adsorption and desorption. The pistachio leaves could be considered as a rich natural source of valuable nutriments （carbohydrates, proteins and lipids）; lipid fraction is equal to 2.25%; proteins are the second macronutriment that predominates in these sheets： 4.35%; accordingly carbohydrates content was about 25.77%.

Synthesis and Crystal Structure of 2-Chloromethyl-1H-benzimidazole Nitrate, [ClCH_2(C_7H_6N_2)]NO_3

The title compound [ClCH2(C7H6N2)]NO3 has been prepared and characterized by elemental analysis and X-ray studies. It crystallizes in the monoclinic system, space group P21/n with a = 7.4189(3), b =15.3064(6), c = 9.2657(3) ? b = 102.449(2)? C8H8ClN3O3, Mr = 229.62, V = 1027.44(7) 3, Z = 4, Dc = 1.484 g/cm3, F(000) = 472, = 0.363 mm-1, R = 0.0671 and wR = 0.1546. The crystal structure consists of discrete 2-chloromethyl-1H-benzimidazole cations and NO3- anions. The benzimidazole ring with the conjunction carbon atom C(1) is fairly planar, with the deviation from the least plane through the ring atoms is smaller than 0.010(3) ? The analytical results of crystal structure show that three different non-covalent interactions in the compound, NH…O intermolecular hydrogen bonds, CH…O interaction and p-p stacking interaction, play an important role in the crystal packing.

Scutellaria baicalensis, the golden herb from the garden of Chinese medicinal plants

Scutellaria baicalensis Georgi, or Chinese skullcap, has been widely used as a medicinal plant in China for thousands of years, where the preparation from its roots is called Huang-Qin. It has been applied in the treatment of diarrhea, dysentery, hypertension, hemorrhaging, insomnia,inflammation and respiratory infections. Flavones such as baicalin, wogonoside and their aglycones baicalein wogonin are the major bioactive compounds extracted from the root of S. baicalensis. These flavones have been reported to have various pharmacological functions, including anti-cancer,hepatoprotection, antibacterial and antiviral, antioxidant,anticonvulsant and neuroprotective effects. In this review,we focus on clinical applications and the pharmacological properties of the medicinal plant and the flavones extracted from it. We also describe biotechnological and metabolic methods that have been used to elucidate the biosynthetic pathways of the bioactive compounds in Scutellaria.

Relationship between Temperaments of Medicinal Plants and Their Major Chemical Compounds

Objective: To determine any relationship between temperaments of medicinal plants referred to traditional Iranian manuscripts and their major chemical compounds. Methods: Plants used in traditional Iranian medicine were categorized based on their major chemical compounds including alkaloids, phenolic compounds, and essential oils. Their temperaments were extracted from traditional herbal pharmacopeias of Iran. The possible relationship between major chemical compounds and temperaments of each group were evaluated. Results: Plants containing phenolic compounds as their major constituents are hot and dry temperaments except those contain tannins with cold and dry temperaments. Plants containing essential oils have hot and dry temperaments except those whose major essential oils with alcoholic structure which have cold and dry temperaments. Alkaloid-containing plants have cold and dry or hot and dry temperaments based on their alkaloidal structures. Conclusions: There is a close relationship between major chemical compounds of medicinal plants and their temperaments mentioned in traditional Iranian manuscripts.

Co-delivery of chemotherapeutic drugs and cell cycle regulatory agents using nanocarriers for cancer therapy

Combination chemotherapy is widely exploited to overcome multidrug resistance(MDR) and enhance the therapeutic effect of anti-tumor agents clinically. The traditional combination regimens applied in clinical practice still suffer from various obstacles, such as inevitable side effects.Fortunately, the application of nanotechnology and the proposal of co-delivery systems make the combination therapy more effective. The occurrence, development, and metastasis of tumors are closely related to the cell cycle. The sensitivity of tumor cells to chemotherapeutic drugs can be improved with the cooperation of cell cycle regulators. In this review, the influence of the cell cycle on tumorigenesis and development is introduced briefly. The current strategies of combining chemotherapeutic drugs and cell cycle regulators through codelivery systems are discussed in detail. We also sketch the possibility of treating tumors mildly via artificially controlling the cell cycle and outline the challenges and perspectives about the improvement of co-delivery systems for cancer therapy.

Anti-migratory and increased cytotoxic effects of novel dual drug-loaded complex hybrid micelles in triple negative breast cancer cells

A polymer-based nanocarrier was developed for the co-delivery of epigenetic and chemotherapeutic drugs. The sterically stabilized hybrid micelle system uses micelles composed of D-a-tocopheryl polyethylene glycol 1000 succinate （vitamin E TPGS or TPGS） and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine- N-[methoxy（polyethylene glycol）-2000] （DSPE-PEG2000）. In this study, suberoylanilide hydroxamic acid （SAHA） and paclitaxel were used as model drugs for combination chemotherapy to enhance therapeutic efficiency in targeting mesenchyme-like triple negative breast cancer （TNBC） cells. Combination therapy of paclitaxel and SAHA in a dual drug micelle system, （P ＋ S）mic, exhibited an IC50 value of 0.52 μg/mL, which is about 5.91-fold more cytotoxic than the mere combination of free drugs （P ＋ S）. Furthermore, the （P ＋ S）mic formulation was far more effective at inhibiting cell migration by more than 3.4-fold than the control. Thus, our findings show that the co-delivery of these drugs using the micelle system greatly enhances their therapeutic effect at a lower dosage, thereby minimizing toxicity. In addition, this formulation is proved to be remarkably effective in preventing cell migration at low dosage.