与药效有关的小蘗碱物理化学性质的研究 Ⅰ.小蘗碱的酸解常数问题

用光谱法测定了氯化小蘖碱的酸解常数(K_a),在pH 14-15水中pK_a为15.23,在pH 12-13乙醇中pK_2为13.05,和文献所载相差很大.此外并以中性硫酸小蘖碱在氢氧化钡水溶液中,用光谱法测定其季胺离子浓度,未见变化,故可以说明小蘖碱为-强电解质.     

莲子心总碱缓释片体外释放度试验

目的 考察莲子心总碱缓释片体外释放度。方法 模拟人体体内环境,用紫外分光光度法测定莲子心总碱的体外释放度。结果 莲子心总碱释药方程:log(100-R_n)=2.112-0.128t(F=219.310,P<0.001),r=-0.982(P<0.001),T₅₀=3.233h,T_d=4.274h,K_r=0.128h^-1。结论 莲子心总碱缓释片体外释药符合一级释药模式,具有缓释特点。     

溶液中药物稳定性的研究 Ⅲ.苯甲異噁唑青霉素纳水溶液的化学动力学研究

苯甲异噁唑青霉素钠在水溶液中的降解为伪一级反应,受H⁺,OH^-的催化,HPO₄^-的催化也相当剧烈.20℃时最稳定的pH值为6.54.在35℃,pH 1.5时,水溶液较青霉素G稳定9-10倍.37℃时在pH 6.5的一倍稀释的McIlvaine缓冲溶液中较青霉素G稳定1.5倍.0℃储藏十分稳定.文中给出了各种速度常数如K_{H^A-,KOH^A-,Ko,KHPO4^-的Arrhenius公式和稳定性的预测数值.}     

独活有效成分大鼠在体单向灌流肠吸收

为了考察独活提取物中二氢欧山芹醇乙酸酯、蛇床子素、二氢欧山芹醇当归酸酯等3种主要有效成分在大鼠的肠吸收性质,了解中药提纯后对大鼠肠吸收的影响，本文运用单向灌流模型并采用HPLC法测定独活提取物I(总香豆素含量＜10%)灌流液中3种成分在体肠灌流的浓度变化，并与独活提取物II(总香豆素含量≥60%)进行比较。结果表明二氢欧山芹醇乙酸酯、蛇床子素及二氢欧山芹醇当归酸酯的质量浓度分别为62～555 μg·mL^-1、101～887 μg·mL^-1和19～186 μg·mL^-1，吸收量与浓度呈线性关系,无高浓度饱和现象，吸收速率常数(K_a)、吸收渗透系数(P_app)值基本保持不变。3种成分在大鼠小肠主要以被动扩散方式吸收；在各肠段均有吸收，其中结肠吸收最好，各肠段的K_a、 P_app是结肠＞十二指肠＞空肠＞回肠，且结肠的K_a、 P_app值显著大于其他肠段；独活提取物II中3种成分的K_a、 P_app值显著小于独活提取物I中相应成分。     

异三尖杉酯碱的合成及其异构体的分离

本文报道对实验动物肿瘤有抑制作用的异三尖杉酯碱的合成。以天然的三尖杉碱为原料,经过三尖杉碱-5-甲基-2-氧己酸酯与α-苄氧溴乙酸酯和活化锌进行Reformatsky反应,产品为苄氧异三尖杉酯碱及其三个立体异构体的混合物(8),收率51%。所含四个异构体的量相近。经旋转薄层层析分离为(8 a)和(8 b)两部分。分别以10%钯炭氢解生成(9 a)和(9 b),氢解产物再分别分离为(9 a₁),(9 a₂)和(9 b₁),(9 b₂)。(9 b₁)的物理常数和各种光谱均与天然异三尖杉酯碱一致。根据核磁共振光谱推测了其它三个立体异构体的绝对构型。     

白头翁皂苷B3的溶解度及油水分配系数与大鼠在体肠吸收研究

目的 测定白头翁皂苷B3的表观溶解度及油水分配系数,并研究其大鼠在体肠吸收机制。方法 HPLC-ELSD法测定B3的表观溶解度和油水分配系数,重量法计算大鼠在体单向肠灌流实验中吸收速率常数(K_a)和表观吸收系数(P_app)。结果 白头翁皂苷B3在37℃有机溶剂中的表观溶解度较低,在碱性磷酸盐缓冲液中的表观溶解度较高;白头翁皂苷B3在不同磷酸盐缓冲液中的油水分配系数相差不大;白头翁皂苷B3在大鼠十二指肠、空肠、回肠和结肠的K_a和P_app没有显著性差异(P > 0.05);白头翁皂苷B3在0.05~2.5 mg/mL随着浓度提高出现过饱和现象;加入P-糖蛋白抑制剂维拉帕米和P-糖蛋白底物地高辛后,都能显著提高白头翁皂苷B3的K_a值。结论 在实验浓度范围内,溶解度和油水分配系数能够较好地预测肠吸收情况;白头翁皂苷B3不完全依赖浓度梯度转运,细胞膜上的载体蛋白参与了药物的转运过程,其小肠吸收机制并不完全为被动转运;受吸收部位影响较小,无特殊的吸收窗;P-糖蛋白介导了白头翁皂苷B3的小肠吸收。     

蝙蝠葛酚性碱对离体大鼠心肌顿抑的保护作用

目的　探讨蝙蝠葛酚性碱(PAMD)对离体大鼠心肌顿抑的作用。方法　采用缺血10min后再灌注30min造成心肌顿抑模型(S) ,灌流液中加0.5mg·mL^-1 PAMD(P)组同样缺血再灌注。结果　灌注末S组LVSP ,+dp/dt_max和-dp/dt_max分别降至预灌末的49% ,53%和58% ,LVEDP则增至422% ;心肌钙含量为(514±142 ) μg·g^-1 (干重) ;出现可逆性心肌超微结构损伤。而P组再灌注末LVSP ,LVEDP ,+dp/dt_max和-dp/dt_max恢复为预灌末值的70% ,205% ,78%和79% ;心肌钙为(316±84) μg·g^-1 (干重) ;以上变化均有显著差异。结论　PAMD对离体大鼠顿抑心肌有保护作用     

生物碱的安培滴定 Ⅰ.黄连中生物碱含量测定

本文报告了黄连中生物碱的安培滴定测定方法,将生药样品用pH2.6缓冲液浸泡后,过滤,滤液加NaOH碱化,再用乙醚提取,然后在-0.4伏特外加电位,0.05-0.2M K₂SO₄中,用硅钨酸进行滴定.本法结果与文献方法一致,平均偏差低于2%.     

马钱子碱与β-环糊精聚合物的包合平衡常数及热力学研究

摘 要 目的： 研究马钱子碱与β-环糊精聚合物(β-CDP)在不同温度,pH溶液中的包合作用及包合过程中的热力学参数变化。方法: 采用相溶解度法测定β-CDP对马钱子碱溶解度的影响,计算包合平衡常数(K_c)和包合热力学参数。结果: 在25℃,37℃,45℃时,包合平衡常数(K_c)分别为88.38,349.29,641.79 L·moL^-1,在pH为4,6.8,10时,K_c分别为490.66,111.85,58.86 L·moL^-1。马钱子碱的溶解度随β-环糊精聚合物浓度的增加呈线性增加,其相溶解度曲线均为AL型,在酸性条件下β-CDP包合常数及增溶作用较大。结论: β-CDP对马钱子碱有较好地增溶作用,可形成摩尔比为1∶1的稳定包合物,包合过程可自发进行(ΔG<0) ,温度的升高,pH的降低有利于包合物的形成。     

响应面法优化西罗莫司胶束及其促小肠吸收作用

目的 制备和优化西罗莫司（sirolimus，SRL）聚合物胶束，考察其对大鼠在体肠吸收动力学的影响。方法 以去氧胆酸修饰的壳聚糖（deoxycholic acid grafted chitosan，CS-DCA）为载体，采用溶剂蒸发法制备SRL CS-DCA胶束。以包封率、载药量、粒径和电位作为考察指标，结合星点设计-效应面法优化处方。建立大鼠在体单向肠灌流模型，并通过肠腔有效吸收系数（P_eff）、吸收速率常数（K_a）和药物吸收剂量分数（f_a）研究不同浓度SRL CS-DCA的肠吸收特性。结果 SRL CS-DCA最优处方：载体浓度（CS-DCA）为10 mg·mL^-1，药物与载体质量比为20%，该条件下制备得到的SRL CS-DCA带正电荷（37.0±2.7）mV，粒径（182.2±5.7）nm，包封率>90%，载药量（15.8±0.5）%。SRL CS-DCA经大鼠全肠后，反映药物肠吸收程度的评价指标P_eff、K_a和f_a均较SRL有显著提高（P<0.05）；不同浓度的SRL CS-DCA在大鼠全肠段的P_eff、K_a、f_a值无显著性差异，提示胶束在10~100 μg·mL^-1吸收无浓度抑制，吸收特征为被动转运的线性动力学过程，推测其可能的吸收机制为被动扩散。结论 SRL制备成聚合物胶束后，对其在大鼠小肠的吸收具有明显的促进作用，从侧面证明SRL CS-DCA能有效改善SRL口服生物利用度。     

Determination of dissociation constants of aminomethyl phenols with UV spectrometric titration

Dissociation constants of phenoles aminomethylated once or twice were determined using UV spectrometric titration. Pka values were computed by non linear regression; correlation coefficients show that experimental data and calculated curves fit well.     

Modifications of clonidine binding to rabbit liver protein under the influence of non-steroid-anti-inflammatory drugs in vitro.

This study was designed to investigate the binding of clonidine to liver protein as well as the possible interactions with non-steroid anti-inflammatory drugs (NSAIDs) during the binding process in the rabbit. The binding of clonidine to slices (S) and homogenized slices (H) was estimated by a radioisotopic method following incubation with a mixture of cold and 3H-labelled clonidine in Ringer solution at 37 degrees C for 360 min. The binding of clonidine was assessed in the absence and presence of the following NSAIDs: flurbiprofen, ketoprofen, ibuprofen and acetylsalicylic acid. The results showed that the percentage of clonidine binding did not differ between intact and homogenized slices. The addition of all NSAIDs but ibuprofen, significantly decreased the protein binding of clonidine both in intact and homogenized liver slices. This finding could be attributed to the different affinity of ibuprofen for liver protein compared to the remaining NSAID's which may arise from a number of chemical properties including its dual Pka values.     

The use of outdoor freshwater pond microcosms. III. Responses of phytoplankton and periphyton to pyridaben

An outdoor freshwater microcosm study was conducted in which pyridaben, an insecticide-miticide, was directly applied to water to determine its biological effects on phytoplankton and periphyton. Twenty-four microcosms (24 m3 each) were monitored for 11 months, then four treatments of pyridaben were applied two times at three concentrations (0.34, 3.4, 34.0 micrograms/L), including an untreated control. The succession of algal groups observed and the major genera found in microcosms during the baseline phase of the study were typical of oligo-mesotrophic systems in Florida. Following application of pyridaben, the most remarkable effect was a positive correlation of phytoplankton abundance with pyridaben concentrations in water; indicating increased abundance as a result of exposure. Both Chlorophyta and Pyrrophyta exhibited a significant increase (p = 0.05) in population abundance at 3.4 and 34.0 micrograms/L pyridaben. Chrysophyta also elicited a trend of increased abundance at 34.0 micrograms/L, although the effect was not significant. The effects on phytoplankton populations were associated with the decline of zooplankton populations as a result of a direct effect of pyridaben exposure. There were no effects of pyridaben on periphyton communities or on functional endpoints.     

Hepatic gene expression analysis of mice exposed to raw water from Meiliang Bay,Lake Taihu,China

Lake water is a micro‐polluted water system, and characterization of its toxicity remains difficult. Microarray‐based determination of altered gene expression might be an alterative approach. We chose raw water from Meiliang Bay, Lake Taihu, China as the target water. Male mice were exposed to the lake water for 90 days. Total hepatic RNA was applied to interrogate the Affymetrix Mouse Genome 430A 2.0 array. Gene ontology analysis, pathway analysis and gene network analysis were used to identify biological effects of differently expressed genes. The results showed that the expressions of 170 genes were altered. Nine biological processes and nine biological pathways were significantly perturbed (P ≤ 0.01), mainly linked to the regulation of cell processes, DNA repair, chromatin modification, oxidative reduction and carbohydrate metabolism. Important genes, such as Prkca, Pik3r1, Fgfr1 and Zbtb16, were identified by gene network analysis. This study provided excellent insights into early toxicological effects related to raw Lake Taihu water, and illustrated that the toxicogenomic approach might be a useful tool to evaluate potential environmental health effects of raw lake water. Copyright © 2012 John Wiley & Sons, Ltd.     

In vitro hepatotoxicity of the cyanobacterial alkaloid cylindrospermopsin and related synthetic analogues.

Cylindrospermopsin (CY), a sulfate ester of a tricyclic guanidine substituted with a hydroxymethyluracil, is a cyanobacterial toxin of increasing environmental import as it frequently occurs in drinking water reservoirs. As a toxin, CY mainly targets the liver but also involves other organs. In hepatocytes CY inhibits the synthesis of protein and of glutathione, leading to cell death. The total chemical synthesis of CY has recently been reported (Xie et al., 2000, J. Am. Chem. Soc. 22, 5017-5024). The synthesis has provided analogues of CY to study aspects of the relationship between chemical structure and activity that contribute to toxicity. Protein synthesis inhibition was measured in vitro using a rabbit reticulocyte system. Primary cultures of rat hepatocytes were used to determine the biological activity of CY and analogues in intact cells. Protein synthesis and cell glutathione levels were measured. We could distinguish between CY transport and biological activity by comparing the results in vitro to those in intact cells. The role of the sulfate group in CY toxicity was examined by comparing biological effects of CY with that of CY-DIOL (synthetic CY lacking the sulfate group). The sulfate group was found not to play a role in CY activity or in its uptake into cells, since there was no significant difference in biological activity in vitro or in cells between natural CY and CY-DIOL. The orientation of the hydroxyl group at C7 also had no impact on biological activity or transport of CY, since the C7 epimer of CY (EPI-CY) and the corresponding diol (EPI-DIOL) had activity similar to RAC-CY in vitro and in intact cells. AB-MODEL, the analogue lacking an intact C ring, and the methyl and hydroxyl groups of ring A could inhibit protein synthesis (but at concentrations 500-1000-fold higher than natural CY). Other structurally simpler synthetic analogues lacked biological activity.     

Hormesis [biological effects of low-level exposure (B.E.L.L.E.)] and dermatology

Hormesis is characterized by nonmonotonic dose response that is biphasic, displaying opposite effects at low and high doses. Its occurrence has been documented across a broad range of biological models and diverse types of exposure. The effects of hormesis at various points can be beneficial or detrimental, depending on the context in which they occur. Because hormesis appears to be a relatively common phenomenon in many areas, the objective of this review is to explore its occurrence related to dermatology and its public health and risk assessment implication. Hormesis appears to be a common phenomenon in dermatology. Better understanding of this phenomenon will likely lead to different strategies for risk assessment process employed in the fields of dermatologic toxicology and pharmacology. More focus should be redirect from looking only at adverse effects at high levels of exposure to characterizing the complex biological effects, both adverse and beneficial, at low levels of exposure. Low-dose toxicology and pharmacology will not only provide a significant research challenge but also should contribute to better methods for low-dose risk assessment for complex mixtures of chemical compounds. This refocusing from high- to low-dose effects will shift the focus in the field of toxicology from emphasizing on adverse effects into studying the biological effects of chemical compounds on living organisms, taking into account the realization that the ultimate biological effect of a chemical may vary with its dose, the endpoint, the target organ considered, the interaction with other cell types/systems, and/or the combined exposure with other chemicals. The skin, with its ready accessibility, and its own areas of non-invasive technology, should provide fertile options to not only understand skin, but further explore practical implications in human and animal. We believe that hormesis is a common phenomenon and should be given detailed consideration to its concept and its risk assessment implications, and how these may be incorporated into the experimental and regulatory processes in dermatology. The skin, with its unique characteristics, its accessibility, and the availability of non-invasive bioengineering and DNA microarray technology, will be a good candidate to extend the biology of hormesis.     

Anti-tumoral and anti-inflammatory effects of biological stains.

The biological stains, methylene blue and its metabolite azure B, were evaluated as anti-tumor and anti-inflammatory agents. Azur B, administered in drinking water to tumor-bearing mice, inhibited the growth of transplanted tumors and the growth of primary tumors induced by methylcholanthrene. Inhibition of growth of primary tumors was observed only in female mice. Azure B also reduced the wet weight of carrageenin-induced granulomas in rats. Azure B, given intravenously to BCG-sensitized mice 15 minutes prior to challenge with lipopolysaccharide, decreased TNF production (to 10% of control values) and prevented death from endotoxic shock. Methylene blue decreased TNF production (to 50% of control values) but did not protect the animals from endotoxic shock. Our results suggest that some of the effects previously ascribed to methylene blue are probably mediated via its metabolite, i.e. azure B. Low toxicity and easy administration of the dyes explain their use in clinical settings.     

Solvent constraints on the property space of acetylcholine. I. Isotropic solvents

The objective of this study was, first, to examine the property space of a test molecule and, second, to assess solvent constraints. Acetylcholine was chosen as the object of study given its interesting molecular structure and major biological significance. Molecular dynamics simulations of long duration (30 ns) were carried out with acetylcholine in a vacuum or in a box of solvent (chloroform, water, water plus one chloride counterion). For each of the 6000 conformers stored during each run, various geometric and physicochemical properties were calculated, namely, N(+)-C8 distance, solvent-accessible surface area (SAS), polar surface area (PSA), dipole moment, and lipophilicity (virtual log P). The variations of these properties as a function of the dihedral angles tau(2) and tau(3) were unexpectedly broad for such a small molecule. Dipole moment and virtual log P were well correlated, and they varied in a complex manner with the dihedral angles. For example, each of the seven conformational clusters was able to access much of the lipophilicity space of acetylcholine. Solvent constraints on the property space clearly indicate that a polar medium tends to favor polar conformers, whereas the opposite is true for a solvent of low polarity.     

Localization and health effects of lanthanum chloride instilled intratracheally into rats.

Lanthanum (La) is one of the rare earths used in diverse high technology fields for which sufficient data for assessing its health effects have been lacking. The biological effects and metabolic behaviors of La were studied by instilling lanthanum chloride intratracheally into male Wistar rats. The distribution of La among tissues revealed that the metal remains mostly in the lung with a biological half-time of 244 days. The subcellular localization by transmission electron microscopy with an X-ray microanalyzer indicated that La localizes in macrophages as high electron-dense granular inclusions in lysosomes and on the cell surface and basement membranes of type I pneumocytes among lung cells. The pulmonary health effects were examined by biological indices of the bronchoalveolar lavage fluid (BALF) and lung tissue. The acute toxicity estimated by lactate dehydrogenase activity in BALF was comparable to those of yttrium and copper that had been determined under the same protocol. Microscopic examination of the lung indicated a characteristic increase in the number of eosinophils.     

Monitoring the rivers rhine and meuse in the Netherlands for toxicity

Organic concentrates of water of the rivers Rhine and Meuse were tested for toxicity with a 48-h mortality test on fish (Poecilia reticulata) at 3-mth intervals for 1 yr. The river samples were concentrated by adsorption on XAD followed by elution with acetone. This method proved to be at least as effective in concentrating organic toxicants from river water as liquid-liquid extraction or freeze-drying. Generally, Rhine water samples were found to be more toxic than those of Meuse water. On examining one Rhine location on a weekly basis, toxicity was found to vary with the seasons more than a factor 12. It is recommended to incorporate such toxicity screening tests next to chemical analyses in surveillance programmes of water quality. Additionally, the biological significance of the mutagenic activity previously observed in Rhine water concentrates was studied in a 6-mth test on P. reticulata. No effects were found at concentration factors ?10. In a 33 × concentrate partial effects were observed (impaired swimming performance, hypertrophy of the liver, mortality). At concentration factors ?100 mortality occurred rapidly. No tumours were observed. The ecological significance of chemical mutagens in the river Rhine is briefly discussed.