Structure and tumor-promoting activity of analogues of anthralin (1,8-dihydroxy-9-anthrone)

Seventeen analogues of the tumor-promoting agent anthralin were tested for the same biological property by repeated skin application on mouse skin using female ICR/Ha Swiss mice, after a single application of a subcarcinogenic dose of 7,12-dimethylbenz[a]anthracene. Seven of the compounds tested are new compounds. They are 1,8-diacetoxy-9-anthrone, 1,8-dimyristoyloxy-9-anthrone, 1,8-dihydroxy-10-acetyl-9-anthrone, 1,8-dihydroxy-10-myristoyl-9-anthrone, 1,8,10-trihydroxy-9-anthrone, 1,8-dihydroxy-9,10-dihydroanthracene, and myristoyljuglone. All compounds were used in pure form for the bioassays. Of the 17 test compounds four showed notable tumor-promoting activity. They are 1,8-dihydroxy-10-acetyl-9-anthrone, 1,8-dihydroxy-10-myristoyl-9-anthrone, 1-hydroxy-9-anthrone, and juglone. In order to determine whether there is any relationship between tumor-promoting activity and metal chelation in this series, the chelating abilities of anthralin and of its inactive analogue 1,8-dihydroxyanthraquinone were examined using the bivalent metal ions Cu(II), Zn(II), Mn(II), Mg(II), and Ca(II). No relationship between chelation and tumor-promoting ability was found.     

Synergistic and antagonistic interactions of anticholinesterase terpenoids in Salvia lavandulaefolia essential oil

In vitro anticholinesterase activities of eight commercially available terpenoid constituents of Salvia lavandulaefolia have been investigated. These included 1,8-cineole, camphor, alpha-pinene, beta-pinene, borneol, caryophyllene oxide, linalool and bornyl acetate. Dose-dependent inhibition of acetylcholinesterase (AChE) by these chemical constituents was determined using the method of Ellman [Biochem. Pharmacol. 7 (1961) 88]. The IC50 value of 1,8-cineole was 0.06+/-0.01 mg/ml similar to that of the essential oil (0.05+/-0.01 mg/ml). Analyses of the expected inhibitions based on the prediction of a zero interactive response of a combination at its naturally occurring ratios were carried out in comparison with observed inhibition. Minor synergy was apparent in 1,8-cineole/alpha-pinene and 1,8-cineole/caryophyllene oxide combinations, with interaction indexes not exceeding 0.5. In contrast, a combination of camphor and 1,8-cineole was antagonistic with an interaction index of 2. A combination of all eight compounds was zero interactive. A combination of six constituents, excluding 1,8-cineole and camphor, was used to compare the method of expected response of a combination with a method of summation. These findings reveal that the inhibitory activity of the oil results from a complex interaction between its constituents, which produce both synergistic and antagonistic responses between the component terpenes. Understanding such interactions is important in comparing species on the basis of chemical composition.     

FEMA expert panel review of p-mentha-1,8-dien-7-al genotoxicity testing results

p-Mentha-1,8-dien-7-al is a naturally occurring cyclic alpha,beta-unsaturated aldehyde that is used as a flavoring substance throughout the world. Due to the chemical structure and the potential DNA reactivity of the alpha,beta-unsaturated carbonyl moiety, a battery of genotoxicity assays was requested by the European Food Safety Authority. Previous genotoxicity studies on the substance gave mixed results, but both positive and negative results were hampered by not always being performed to any standard guideline. The new test battery data indicated some evidence of mutagenicity in vitro, but an in vivo comet/micronucleus combination assay performed in rats was concluded by the study directors to not result in any biologically relevant positive responses. However, EFSA concluded that the in vivo assay gave evidence that p-mentha-1,8-dien-7-al was of potential genotoxic concern. The Expert Panel of the Flavor and Extract Manufacturers Association (FEMA) has reviewed the newly available data and considered its interpretation relative to standard guidelines such as that established by the Organization for Economic Cooperation and Development, and has concluded that the results in the comet/micronucleus combination assay are consistent with the interpretation by the study directors; namely, that p-mentha-1,8-dien-7-al does not appear to have any in vivo genotoxic potential.     

桉油精的药理作用研究进展

桉油精是许多芳香植物精油的主要有效成分,在医药、化妆品和香料工业领域广泛应用。大量研究证明桉油精具有抑菌、抗炎、抗氧化、抗肿瘤、镇痛、神经保护等多种药理作用,具有较高的药用价值和开发前景。本文通过查阅国内外近10年的文献,对桉油精药理作用研究新进展进行梳理和总结,为桉油精的进一步开发和临床应用提供参考。     

The Role of Impulsivity and Expectancies in Predicting Marijuana Use: An Application of the Acquired Preparedness Model

ABSTRACT

Impulsivity and substance use covary. Smith and Anderson’s acquired preparedness model proposes that impulsivity predicts substance use through a mediational model such that substance use expectancies mediate the relation between impulsivity and drug use. The present study seeks to examine the relation between positive urgency, an important component of impulsivity with specific relations to substance use behavior, marijuana expectancies, and marijuana use patterns. The study focused on a sample of frequent marijuana users (n = 3,616) and assessed positive urgency using the UPPS-P, expectancies using the Biphasic Marijuana Effects Scale, an adapted form of the Biphasic Alcohol Effects Scale to measure the sedative and stimulant properties of marijuana, and also assessed use patterns. Findings suggest that stimulant expectancies predict heavier, more frequent marijuana use than sedative expectancies and that marijuana expectancies vary based on the limb of marijuana intoxication. Examination of the acquired preparedness model revealed that positive urgency’s link to marijuana use was fully mediated by expectancies.     

Statistical approaches to determine analytical variability and specifications: application of experimental design and variance component analysis

Assessment of analytical variability is recognized as an important factor for the establishment of specifications. Estimation of the variance for an analytical procedure can be accomplished using a variety of approaches. The approach of variance component analysis was applied retrospectively, as well as prospectively, to estimate analytical variance. The prospective approach also included the use of experimental design. Recent new drug substance examples illustrating these approaches are presented. In these examples, the analytical property of potency was evaluated. Factors examined in the experimental design include laboratory, day, analyst, instrument and column. Process variability can also be determined by variance component analysis. For a stable drug substance, combining the analytical and process variances provides an estimate on the total variance for the analytical property of potency. With the total variability statistically derived, an appropriate specification that is consistent with process and analytical capability can be established.     

The application of 1,8-cineole,a terpenoid oxide present in medicinal plants,inhibits castor oil-induced diarrhea in rats

Abstract

Context: 1,8-Cineole, a terpene, characterized as a major constituent occurring in the essential oils of several aromatic plants. It is widely used in pharmaceutical industry, as a food additive and for culinary purposes.

Objective: This study investigates the inhibitory effect of 1,8-cineole on transit time and diarrhea in animal models.

Materials and methods: Acute toxicity and lethality of 1-8-cineole was determined by Lork’s guidelines. The antidiarrheal effect of 1,8-cineole was investigated by determining the intestinal transit and enterpooling in rats. In all experiments, different doses of 1,8-cineole (20–120?mg/kg), atropine, and loperamide were administered orally.

Results: The LD₅₀ of 1,8-cineole for oral administration was estimated to be 1280?mg/kg. 1,8-Cineole (20–120?mg/kg) did not show a significant decrease in small intestine transit (p?>?0.05); however, the highest dose displayed a significant decrease in comparison with atropine (p?<?0.05). This substance decreased the peristaltic index value to 68?±?0.36% at a dose of 120?mg/kg compared with the control group (85.22?±?4.31%) in the castor oil transit test. 1,8-Cineole significantly delayed the onset of diarrhea to ?142.33?±?6.08?min at 120?mg/kg, while the time was 103.66?±?20.73?min for the control and >240?min for the loperamide. Moreover, 1,8-cineole significantly decreased intestinal fluid accumulation (p?<?0.05).

Conclusions: This study demonstrated antispasmodic and antisecretory activities of 1,8-cineole and rationalized the traditional use of the plant containing various levels of this terpene in the treatment of gastrointestinal complains such as diarrhea.     

Impact of different tissue-simulating hydrogel compartments on in vitro release and distribution from drug-eluting stents

In vitro drug release testing is an appropriate approach to identify critical parameters helping to predict drug release from drug-eluting stents (DES) prior to studying drug release behavior under in vivo conditions. Drug release and distribution from DES coated with a fluorescent model substance were studied in vitro using the vessel-simulating flow-through cell equipped with different long-term stable hydrogel compartments composed of agarose, polyacrylamide or poly(vinyl alcohol). The obtained experimental results were compared with the results of finite-element modeling obtained using experimentally determined diffusion coefficients and partition coefficients. In spite of differences regarding these parameters, experimental and mathematical data yielded only minor differences between the different gels regarding the release and distribution behavior and reasonable agreement between the modeling and the experiment was obtained. In an attempt to further elucidate the dosage form behavior, the diffusion coefficients in the gel as well as in the stent coating were systematically varied in the finite-element model. Changes in the diffusivity in the stent coating mainly impacted on the initial concentrations. Slower diffusion inside the hydrogel yielded a retarded elution from the stent coating and a higher model substance accumulation in the gel compartment at late time points.     

1,8-桉油精对卵白蛋白致哮喘豚鼠的气道高反应性和炎症的抑制作用

目的探讨1,8-桉油精(1,8-cineol)对哮喘豚鼠肺功能的改善作用及其机制。方法豚鼠第0天和第7天ip给予0.5ml含卵白蛋白(OVA)20μg的氢氧化铝凝胶致敏,28d后OVA攻击制备哮喘模型。观察豚鼠OVA攻击后1h,1,8-桉油精10,30和100mg.kg-1对豚鼠吸入OVA后1,2,3,4,10,20和30min时气道阻力(Raw)和肺顺应性(Cdyn)变化及支气管肺泡灌洗液(BALF)中白细胞数和细胞分类的影响,并测量豚鼠肺组织中嗜酸细胞阳离子蛋白(ECP)、白细胞介素4(IL-4)、IL-8和肿瘤坏死因子α(TNF-α)的含量。观察豚鼠OVA攻击后17h再吸入乙酰甲胆碱(MCh)后,1,8-桉油精10,30和100mg.kg-1对Raw和Cdyn及BALF中白细胞数和细胞分类的影响,并测量豚鼠肺组织中ECP,IL-4,IL-8和TNF-α的含量。结果与正常对照组比较,豚鼠OVA攻击后1h,在4min时模型组Raw达到高峰;与模型组比较,1,8-桉油精30和100mg.kg-1明显抑制Raw增加(P<0.05);在3min时模型组Cdyn达到高峰,与模型组比较,1,8-桉油精10,30和100mg.kg-1均能明显抑制Cdyn降低(P<0.05);模型组豚鼠肺组织ECP,IL-4和TNF-α含量明显高于正常对照组(P<0.05);1,8-桉油精100mg.kg-1组ECP,IL-4和TNF-α含量均明显低于模型组(P<0.05),模型组与正常对照组豚鼠肺组织IL-8含量无明显差异。与模型组比较,1,8-桉油精100mg.kg-1能明显减少BALF中白细胞数和嗜酸性粒细胞比例(P<0.05)。致敏豚鼠OVA攻击17h后,模型组豚鼠Raw与正常对照组比较显著升高(P<0.05),模型组豚鼠Cdyn与正常对照组比较有显著性差异(P<0.01),1,8-桉油精100mg.kg-1对MCh引起的Raw的增加有明显的抑制作用,1,8-桉油精10,30和100mg.kg-1对MCh引起的Cdyn降低有明显的改善作用;与模型组相比,1,8-桉油精100mg.kg-1能明显减少BALF中白细胞数和中性粒细胞比例,降低肺组织ECP,IL-8和TNF-α含量(P<0.01);模型组与正常对照组豚鼠肺组织IL-4含量无明显差异;1,8-桉油精30mg.kg-1也能降低哮喘豚鼠肺组织中ECP和TNF-α含量(P<0.01)。结论在哮喘急性发作时,1,8-桉油精通过减少嗜酸性粒细胞,下调嗜酸性粒细胞的活性,从而抑制了哮喘的急性发作。在哮喘迟发相阶段,1,8-桉油精可通过下调IL-8水平,降低TNF-α活性,从而抑制或改善由IL-8水平升高导致的中性粒细胞聚集于支气管肺泡而直接引起的哮喘加重和持续状态。     

白刺链霉菌(Streptomyces albospinus)CT205次生代谢产生活性物质的分离纯化及结构鉴定

目的 为了确定白刺链霉菌(S. albospinus)CT205次生代谢产生抗菌活性物质的结构。方法 S. albospinus CT205进行液体摇瓶发酵，对发酵上清液进行溶媒萃取、减压浓缩、薄板检测Rf值，采用制备型薄板分离获得单体化合物。紫外扫描检测吸收峰的波长范围，以HPLC-TOF-HR-MS检测物质分子量，并检测其核磁共振波谱(1H NMR、13C NMR)及红外光谱。结果 GF254薄板在氯仿:乙酸乙酯:甲醇:甲酸(16:1:2:0.04)的层析系统展层时，Rf 值为0.68的组分具有抗菌活性。紫外扫描显示在λ=215nm处有最大吸收峰，HPLC-TOF-HR-MS检测分析一级质谱、二级质谱表明活性物质分子量为282.2，该物质与放线酮分子量相同，1H NMR、13C NMR检测其骨架结构，红外光谱佐证活性物质各功能基团(羰基，羟基，氨基等)的存在。结论 确定活性物质成分为放线酮，又名环己酰亚胺(cycloheximide)。     

beta-Pyridylcarbinol (Ronicol) releases a prostacyclin-like substance into arterial blood of patients with arteriosclerosis obliterans

Beta-pyridylcarbinol (Ronicol) when injected (1,2-1,4 mg/kg i.v.) into four patients with arteriosclerosis obliterans caused a release of an unstable disaggregatory substance into arterial blood of those patients. This release was not observed in other two patients who had been pretreated with aspirin (1,8 g p.o.daily). It is postulated that some of pharmacological properties of nicotinic acid derivatives are mediated through the release of endogenous PGI2-like substance.     

雄土鳖虫活性物质分离工艺考察

目的：采用不同方法对雄土鳖虫虫活性物质进行分离,得到活性组分。方法：比较SephadexG15、SephadexG25对样品的分离情况,需用最佳的物质对雄土鳖虫虫活性物质进行分离,然后再采用高效液相仪对分离后的组分进行鉴别,同时采用半制备液相柱对物质进行分离,获得活性单体。并对活性单体进行体外溶栓和抗凝验证。结果：实验得出SephadexG25对雄土鳖虫虫活性物质分离效果比较好。而后采用高效液相仪对分离后的活性组分进行分析,图谱出现五个含量较大的组分。并采用半制备液相柱进行分别收集后,验证得到第二个组分和第三个组分活性较强。结论：采用不同方法对雄土鳖虫虫活性物质进行系统分离后,得到纯度较高的活性组分,为后期研发和应用奠定基础。     

Circadian-induced change in the pharmacokinetic pattern exemplified on hexobarbital/Retrospective analysis of experimental data (author's transl)

The present study dealt with data from a study to evaluate circadian influences on the pharmacokinetics of hexobarbital. It could be seen that the pharmacokinetic model changes from an open one-compartment model to an open two-compartment model in dependence of the time of application. The curve fitting to an open two-compartment model reached high correlations when the test substance was applied at 18 h. The pharmacokinetic parameters to be evaluated did not fit to literature data. After application of the substance at 10 h in the morning the curve fitting to an open one-compartment model correlated highly. The pharmacokinetic parameters at this time comparable with the known literature.     

采用HPLC法测定左氧氟沙星杂质A含量的不确定度分析

目的:建立HPLC法标定左氧氟沙星杂质A对照品含量的不确定度评定方法。方法:建立数学模型,对含量测定过程中各影响因素进行分析评估。结果:通过计算各变量的不确定度,合成不确定度,最终得出测定结果的扩展不确定度。结论:该评定方法适用于HPLC法标定左氧氟沙星杂质A对照品含量的不确定度评定。     

Evidence that the contractile response of the guinea-pig ileum to capsaicin is due to substance P release

Summary The mechanism of action of capsaicin on the guinea-pig isolated ileum was studied. Capsaicin (1.5×10^–6mol l^–1) produced a large contractile response of the ileum which exhibited marked tachyphylaxis. The response was reduced by treatment of preparations with atropine, 5×10^–6mol l^–1, and by substance P-autodesensitization, and was abolished by a combination of these treatments. It was concluded that capsaicin released both substance P and acetylcholine from the guinea-pig ileum. Evidence for a cholinergic component in the action of high concentrations of substance P was also obtained and therefore it is proposed that capsaicin releases substance P from neurones in the ileum, and the released substance P in turn stimulates cholinergic neurones to release acetylcholine, as well as producing direct muscle contraction.     

Validation of the Co-occurring Disorder Quadrant Model

Abstract

The co-occurring disorders quadrant model has been used as a framework for characterizing the heterogeneity in persons with low- and high-severity substance use and psychiatric disorders. This study investigated the validity and stability of the quadrant model in 155 adults who presented to one county hospital with psychiatric, substance use, or medical complaints. Quadrant placement was defined using data that is routinely gathered in clinical care or available in administrative data sets (i.e., substance dependence diagnosis, Global Assessment of Functioning scores). Fifty-four percent (n = 84) of study participants were categorized into quadrant IV (high-severity psychiatric/substance use), followed by quadrant I (low-severity psychiatric/substance use) (n = 32, 21%), quadrant II (high-severity psychiatric & low-severity substance use) (n = 25, 16%), and quadrant III (low-severity psychiatric & high-severity substance use) (n = 14, 9%). Quadrant placement was correlated with psychiatric and/or substance use diagnoses, psychiatric symptom severity, drug/alcohol toxicology and psychiatric and substance use health utilization, supporting the concurrent validity of the model. Initial quadrant placement was correlated with validity measures administered at three-month follow-up supporting predictive validity of the model. Initial and follow-up quadrant placement was significantly correlated suggesting stability of the quadrant model. Data support the validity of the quadrant model for application in clinical and administrative purposes.     

Application of the quality by design approach to the drug substance manufacturing process of an Fc fusion protein: Towards a global multi-step design space

The article describes how Quality by Design principles can be applied to the drug substance manufacturing process of an Fc fusion protein. First, the quality attributes of the product were evaluated for their potential impact on safety and efficacy using risk management tools. Similarly, process parameters that have a potential impact on critical quality attributes (CQAs) were also identified through a risk assessment. Critical process parameters were then evaluated for their impact on CQAs, individually and in interaction with each other, using multivariate design of experiment techniques during the process characterisation phase. The global multi‐step Design Space, defining operational limits for the entire drug substance manufacturing process so as to ensure that the drug substance quality targets are met, was devised using predictive statistical models developed during the characterisation study. The validity of the global multi‐step Design Space was then confirmed by performing the entire process, from cell bank thawing to final drug substance, at its limits during the robustness study: the quality of the final drug substance produced under different conditions was verified against predefined targets. An adaptive strategy was devised whereby the Design Space can be adjusted to the quality of the input material to ensure reliable drug substance quality. Finally, all the data obtained during the process described above, together with data generated during additional validation studies as well as manufacturing data, were used to define the control strategy for the drug substance manufacturing process using a risk assessment methodology.     

Substance P as a transmitter in the human ciliary muscle

The present experiments, carried out on the human fresh ciliary muscle, were undertaken to define whether substance P is involved as an excitatory transmitter in the contractile response evoked by electrical stimulation. Our results show that, following cholinergic and adrenergic blockade, the resistant component of contraction was completely abolished by (D-Pro2-D-Trp7,9)-SP, a synthetic analogue of substance P with antagonistic activity. Moreover the effects of exogenous substance P were investigated.     

妇科再造胶囊联合地屈孕酮治疗月经不调的临床研究

目的 优化1,8-桉叶油素（1,8-cineole,1,8-Cin）自微乳给药系统（1,8-cineole self-microemulsion drug delivery system,1,8-Cin-SMEDDS）处方,对其进行表征并进行细胞摄取考察。方法 通过绘制伪三元相图,确定1,8-Cin-SMEDDS有效自乳化区域,进行初步处方筛选。以粒径和载药量为指标,采用星点设计-效应面法对1,8-Cin-SMEDDS处方进行优化并验证。荧光显微镜观察高糖损伤的人脐静脉内皮细胞（HUVEC）对1,8-Cin-SMEDDS的摄取情况。结果 1,8-Cin-SMEDDS的最佳处方是大豆油（7.5%）与1,8-Cin（22.5%）为混合油相,HS15（56%）为乳化剂,乙醇（14%）为助乳化剂,滴加纯水至8 mL得半透明略带蓝色乳光液体。透射电镜观察其外观呈球形液滴,激光粒度Zeta电位测定仪测得平均粒径为（131.68±1.44）nm,Zeta电位为（-10.03±1.63）mV;HPLC法测得包封率为（99.890±0.012）%,载药量为（224.750±0.028）mg/g。HUVEC细胞摄取实验结果表明,细胞对1,8-Cin-SMEDDS的摄取高于游离1,8-Cin。结论 1,8-Cin-SMEDDS制备方法简便,重复性好,所得1,8-Cin-SMEDDS外观良好,包封率高,理化性质稳定,且能促进细胞摄取。     

Skin penetration enhancement of mefenamic acid by ethanol and 1,8-cineole can be explained by the 'pull' effect

The simultaneous skin permeation of drug and penetration enhancer have been studied in vitro. Simple formulations of mefenamic acid in PEG400 incorporating various proportions of ethanol or 1,8-cineole were prepared and applied to porcine ear skin in diffusion cells under infinite conditions. Receptor phases were assayed for mefenamic acid by HPLC and ethanol or 1,8-cineole by GC. Concentration-dependent permeation profiles were obtained for both ethanol or 1,8-cineole, in addition to concentration-dependent enhancement of mefenamic acid. When the steady state flux of mefenamic acid was plotted against ethanol or 1,8-cineole, linear relationships were observed with r2 values of 0.988 and 0.999, respectively. The close connection between rates of excipient and solute permeation is generally referred to as the 'pull' (or 'drag') effect, where in this case permeation of the enhancer facilitated permeation of the solute. This appears to be sufficient to account for the enhancing activity of ethanol and 1,8-cineole, notwithstanding initial modulations that may occur within the stratum corneum.