双藤巴布剂中青藤碱、雷公藤甲素的体外释放与体外透皮机制研究

目的:研究双藤巴布剂中青藤碱、雷公藤甲素的体外释放与体外透皮机制;比较以化学单体入药(青藤碱雷公藤甲素巴布剂,STP)与浸膏入药(双藤巴布剂,STEP)释放速率与透皮速率的差异。方法:通过释放度测定法测定体外释放度;通过Franze扩散池法测定药物的体外透皮性,皮肤为裸鼠背部皮肤。结果:STP与STEP中青藤碱、雷公藤甲素的体外释放以Higuchi方程拟合度较优(STP:r青=0.9955,r甲=0.9958;STEP:r青=0.9920,r甲=0.9963)。经皮渗透较好地拟合了零级动力学方程,青藤碱在STP、STEP中的r分别为0.9951与0.9926,透皮速率分别为21.729μg.cm-2.h-1与20.063μg.cm-2.h-1;雷公藤甲素在STP、STEP中的r分别为0.9942与0.9902,透皮速率分别为0.4783μg.cm-2.h-1与0.4168μg.cm-2.h-1。结论:青藤碱、雷公藤甲素在STP、STEP中的释放速率大于其经皮渗透速率,属于皮肤限速型经皮给药制剂。     

雷公藤甲素-甘草次酸复方微乳的制备及其理化性质和体外释药特性研究

目的:建立雷公藤甲素-甘草次酸复方微乳的含量测定方法,优化其处方,并考察其理化性质及体外释药特性。方法:采用超高效液相色谱法测定雷公藤甲素-甘草次酸复方微乳的含量,色谱柱为ACQUITY UPLC BEH C_(18),流动相为0.1%甲酸水溶液-乙腈(梯度洗脱),流速为0.4 mL/min,柱温为40℃,检测波长为218 nm,进样量为5μL。采用水滴定法绘制伪三元相图,以油相、表面活性剂、助表面活性剂为指标优化处方;采用体外释放试验考察所制微乳的体外释放特性。结果:雷公藤甲素、甘草次酸的检测质量浓度线性范围分别为1～40μg/m L(r=0.999 7)、10～400μg/m L(r=0.999 8);定量限分别为0.5、0.8μg/m L,检测限分别为0.1、0.2μg/m L;精密度、稳定性、重复性试验的RSD均小于2%;加样回收率分别为100.32%～101.15%(RSD=0.36%,n=6)、99.78%～101.42%(RSD=0.59%,n=6)。最优处方为以中链甘油三酯为油相,聚乙二醇羟基硬脂酸酯为表面活性剂,无水乙醇为助表面活性剂,水为水相,四者质量比为8∶28∶14∶50。所制微乳为水包油型,外观透明澄清,其平均粒径为(62.38±3.44)nm,平均多分散指数为0.096±0.001,平均黏度为(26.84±1.10)m Pa·S。所制微乳在24 h内的雷公藤甲素、甘草次酸累积释放度分别为99.8%、99.7%(pH 2.0的磷酸缓冲盐溶液中),99.3%、99.4%(pH 7.4的磷酸缓冲盐溶液中),98.9%、98.4%(pH 9.0的磷酸缓冲盐溶液中);单方微乳中的雷公藤甲素和甘草次酸释放均快于复方微乳。结论:所建含量测定方法操作简便、准确;所得优化处方稳定、可行;所制雷公藤甲素-甘草次酸复方微乳较单方微乳具有更好的缓释作用。     

甲钴胺缓释片释放度的测定

目的:研究自制甲钴胺缓释片的体外释放度。方法:采用《中国药典》2005年版附录XC第三法,pH 6.8磷酸盐缓冲液为释放介质,转速为50 r·min^-1,HPLC法测定累计释药量。结果:甲钴胺缓释片在2.25～40.50μg·ml^-1范围内线性关系良好（r=0.9998）,平均回收率为99.6%,RSD为0.59%,3批样品在2,4,8 h的平均累计释药量分别为42.9%,64.9%,86.5%。结论:自制甲钴胺缓释片有较好的释药性能,本文建立的释放度检测方法可作为该制剂的质控方法。     

反相高效液相色谱法测定雷公藤口服液中雷公藤甲素含量

目的 建立反相高效液相色谱法测定雷公藤口服液中雷公藤甲素含量的方法.方法 以ODS-BP(4.6 mm×250 mm)为色谱柱,水:甲醇(57:43)为流动相,流速1 mL·min-1,检测波长218 nm,分析时间90 min,测定雷公藤口服液中雷公藤甲素含量;结果 雷公藤甲素进样量在0.0247～0.7904 μg范围内峰面积线性关系良好,r=0.9995,加样回收率为99.56%.结论 该方法简便、准确、稳定性好,线性范围宽,可作为雷公藤甲素含量测定方法.     

HPLC测定不同产地雷公藤中雷公藤甲素含量

目的建立高效液相色谱法测定雷公藤中雷公藤甲素的含量,研究不同产地雷公藤药材中雷公藤甲素含量的差异情况。方法采用外标法,以乙腈-水(30∶70)为流动相;检测波长为220nm;流速为1.0mL·min-1。结果雷公藤甲素进样量在0.04392μg～3.5136μg范围内呈良好的线性关系(r=0.9998),回收率为98.70%,RSD=3.27%(n=9)。其中湖南产(批号:B)的雷公藤含量最高。结论本法简便、准确,适用于雷公藤中雷公藤甲素的含量测定。另外不同产地、来源的雷公藤药材中雷公藤甲素的含量差异较大,在临床用药时应引起重视。     

黄藤素缓释片释放度的测定及其释药特性

目的　进行黄藤素缓释片释放度的测定及释药规律的研究。方法　采用紫外分光光度法测定黄藤素缓释片的释放度,并进行释药规律的研究。结果　测定波长为342nm ,黄藤素在3. 0～1 0 . 0 μg·ml-1 范围内线性关系良好(r =0 . 9999)。其体外释放特性符合Higuchi模式。结论　黄藤素缓释片释药机理是扩散和骨架溶蚀协同作用,而非单纯Fick扩散。     

高效液相色谱法测定雷公藤类药材及其制剂中雷公藤甲素的含量

目的 建立雷公藤药材及其制剂中雷公藤甲素的HPLC测定方法.方法 外标法,色谱柱:Angilent ZORB-AXSC-C18(4.6 mm×25 cm,5 μm);流动相:甲醇-水(40∶60);检测波长:218 nm;柱温:25℃;流速:1.0mL·min-1;进样量:20 μL.结果 雷公藤甲素在0.049 8～0.249 0 mg·mL-1呈良好的线性关系,r=0.999 8(n=5),平均回收率为100.66%,RSD=1.60%(n=9).结论 本方法具有操作简便、准确,回收率好,精密度、重现性高,分析快速的优点.可作为雷公藤药材及其制剂中雷公藤甲素的定量分析和质量控制方法.     

盐酸二甲双胍1000mg缓释片的制备及其体外释药机制考察

目的:制备1000mg规格的盐酸二甲双胍缓释片,考察其体外释药行为并与吡格列酮二甲双胍缓释片(Actoplus MetXR)中的二甲双胍缓释部分比较。方法:用亲水骨架结合缓释膜包衣技术制备盐酸二甲双胍缓释片,以羟丙甲纤维素(HPMC)K100M为片芯缓释材料,以丙烯酸树脂(尤特奇)NE30D为缓释包衣膜,以ActoplusMetXR中的二甲双胍缓释部分(规格:1000mg)为对照药,以两者体外释放曲线比较的相似因子(f2)为考察指标,采用星点设计-效应面法优化处方,同时考察最佳处方的体外释药机制。结果:最佳处方为片芯HPMCK100M/盐酸二甲双胍为0.15(m/m)、缓释膜HPMCE6/尤特奇NE30D为0.18(m/m)、包衣增质量控制在4%～6%;缓释片体外释放行为符合Higuchi方程(r=0.9954),以扩散机制为主,类似骨架系统释药。结论:盐酸二甲双胍1000mg缓释片可以达到与对照药相似的体外释药行为。     

HPLC测定不同采收年限雷公藤根及不同部位雷公藤甲素含量

目的用高效液相色谱法测定雷公藤中雷公藤甲素的含量,研究雷公藤植株不同部位及不同采收年限雷公藤根中雷公藤甲素含量的差异情况。方法采用外标法,以甲醇-水（45：55）为流动相;检测波长为218nm;柱温为28℃;流速为1．0mL·min^-1。结果雷公藤甲素浓度在1．026～10．26μg·mL^-1呈良好的线性关系（r=0．9999）,回收率为95．90％,RSD=3．49％（n=6）。结论本法简便、准确、灵敏、重复性良好,适用于雷公藤甲素的含量测定。在不同采收年限中,3年生雷公藤全根中雷公藤甲素含量最高,1年生最低;在不同部位中,根皮中含量最高,其次是叶片,根木质部最低。     

羧甲司坦缓释片的含量测定及体外释放度研究

目的 测定自制羧甲司坦缓释片的释放度,并与市售羧甲司坦片释放度比较,为处方优选提供实验依据。方法 采用紫外-可见分光光度法(UV)测定羧甲司坦缓释片释放度,检测波长为567 nm。采用桨法,以pH=6.6的磷酸盐缓冲溶液作为释放介质,转速为100 r/min进行药物释放度测定,取样时间点为1 h、2 h、4 h、6 h、8 h、12 h。结果 羧甲司坦缓释片在1.6～14.4μg/mL范围内线性良好,回归方程为：A=0.0695c-0.0898,r=0.9993,平均回收率为99.05%,RSD为1.8%,重现性良好(RSD=0.35%)。羧甲司坦缓释片2 h时累积释放接近30%,8 h时接近90%,0～12 h释药曲线符合一级释药模型。羧甲司坦普通片在1 h时累积释放超过95%。与市售普通片相比,自制羧甲司坦缓释片缓释效果明显。结论 本课题所建立的释放度及含量测定方法操作简单,方便,稳定,可靠,重现性好,可用于羧甲司坦缓释片释放度测定。自制羧甲司坦缓释片释放速度明显低于市售羧甲司坦片,缓释效果明显。     

Efficacy of gut lavage,hemodialysis, and hemoperfusion in the therapy of paraquat or diquat intoxication

Clinical and in vitro investigations were carried out to test the efficacy of gut lavage, hemodialysis, and hemoperfusion in the treatment of poisoning with paraquat or diquat. In a patient suffering from diquat intoxication 130 times more diquat was removed by gut lavage 30 h after ingestion than was removed by complete aspiration of the gastric contents.Determination of in vitro clearances for paraquat and diquat by hemodialysis showed that, at serum concentrations of 1–2 ppm, such as are frequently encountered in poisoning in man, toxicologically relevant quantities of herbicide cannot be removed from the body. At a concentration of 20 ppm, on the other hand, hemodialysis proved to be effective, the clearance being 70 ml/min at a blood flow rate of 100 ml/min. The efficacy of hemoperfusion with coated activated charcoal was on the whole better. Especially at concentrations around 1–2 ppm, the clearance values for hemoperfusion were some 5–7 times higher than those for hemodialysis.In a patient suffering from paraquat poisoning, both hemodialysis as well as hemoperfusion were carried out. The in vitro results could be confirmed: At serum concentrations of paraquat less than 1 ppm no clearance could be obtained by hemodialysis while by hemoperfusion with activated charcoal quite high clearance values were measured and the serum level dropped down to zero.

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Zusammenfassung Klinische Untersuchungen und Laboratoriumsversuche wurden durchgeführt, um die Wirksamkeit von Darmspülung, Hämodialyse und Hämoperfusion bei Paraquat- und Deiquat-Vergiftungen zu prüfen.Bei einem Patienten wurde 30 Std nach Deiquat-Aufnahme durch Darmspülung 130mal mehr Deiquat entfernt als durch vollständige Aspiration des Mageninhaltes. In vitro-Versuche ergaben, daß bei Blutserumkonzentrationen von 1–2 ppm, die bei Vergiftungen oft gemessen werden, durch Hämodialyse keine toxikologisch relevanten Paraquat- oder Deiquat-Mengen entfernt werden können. Dagegen erwies sich die Hämodialyse bei 20 ppm und einer Blutumlaufgeschwindigkeit von 100 ml/min mit einer Clearance von 70 ml/min als wirksam. Die Hämoperfusion mit beschicheter Aktivkohle war in diesen Versuchen aber eindeutig überlegen, denn insbesondere bei Konzentrationen um 1–2 ppm waren die Clearance-Werte 5–7mal höher als bei der Hämodialyse.Die in vitro-Ergebnisse wurden bei einem Patienten mit einer Paraquat-Vergiftung bestätigt: Bei Konzentrationen unter 1 ppm war die Hämodialyse wirkungslos, während durch Hämoperfusion relativ hohe Clearance-Werte erreicht wurden, so daß der Serumspiegel rasch unter die Nachweisgrenze abfiel.

     

In vitro studies on sterically stabilized liposomes (SL) as enzyme carriers in organophosphorus (OP) antagonism

This study describes a new approach for organophosphorous (OP) antidotal treatment by encapsulating an OP hydrolyzing enzyme, OPA anhydrolase (OPAA), within sterically stabilized liposomes. The recombinant OPAA enzyme was derived from Alteromonas strain JD6. It has broad substrate specificity to a wide range of OP compounds: DFP and the nerve agents, soman and sarin. Liposomes encapsulating OPAA (SL)* were made by mechanical dispersion method. Hydrolysis of DFP by (SL)* was measured by following an increase of fluoride ion concentration using a fluoride ion selective electrode. OPAA entrapped in the carrier liposomes rapidly hydrolyze DFP, with the rate of DFP hydrolysis directly proportional to the amount of (SL)* added to the solution. Liposomal carriers containing no enzyme did not hydrolyze DFP. The reaction was linear and the rate of hydrolysis was first order in the substrate. This enzyme carrier system serves as a biodegradable protective environment for the recombinant OP-metabolizing enzyme, OPAA, resulting in prolongation of enzymatic concentration in the body. These studies suggest that the protection of OP intoxication can be strikingly enhanced by adding OPAA encapsulated within (SL)* to pralidoxime and atropine.     

Aquatic Insects and Trace Metals: Bioavailability,Bioaccumulation, and Toxicity

Abstract

The uptake of metals from food and water sources by insects is thought to be additive. For a given metal, the proportions taken up from water and food will depend both on the bioavailable concentration of the metal associated with each source and the mechanism and rate by which the metal enters the insect. Attempts to correlate insect trace metal concentrations with the trophic level of insects should be made with a knowledge of the feeding relationships of the individual taxa concerned. Pathways for the uptake of essential metals, such as copper and zinc, exist at the cellular level, and other nonessential metals, such as cadmium, also appear to enter via these routes. Within cells, trace metals can be bound to proteins or stored in granules. The internal distribution of metals among body tissues is very heterogeneous, and distribution patterns tend to be both metal and taxon specific. Trace metals associated with insects can be both bound on the surface of their chitinous exoskeleton and incorporated into body tissues. The quantities of trace meals accumulated by an individual reflect the net balance between the rate of metal influx from both dissolved and particulate sources and the rate of metal efflux from the organism. The toxicity of metals has been demonstrated at all levels of biological organization: cell, tissue, individual, population, and community. Much of the literature pertaining to the toxic effects of metals on aquatic insects is based on laboratory observations and, as such, it is difficult to extrapolate the data to insects in nature. The few experimental studies in nature suggest that trace metal contaminants can affect both the distribution and the abundance of aquatic insects. Insects have a largely unexploited potential as biomonitors of metal contamination in nature. A better understanding of the physico-chemical and biological mechanisms mediating trace metal bioavailability and exchange will facilitate the development of general predictive models relating trace metal concentrations in insects to those in their environment. Such models will facilitate the use of insects as contaminant biomonitors.     

Pharmacological treatment of COVID-19: an opinion paper

The precocity and efficacy of the vaccines developed so far against COVID-19 has been the most significant and saving advance against the pandemic. The development of vaccines has not prevented, during the whole period of the pandemic, the constant search for therapeutic medicines, both among existing drugs with different indications and in the development of new drugs. The Scientific Committee of the COVID-19 of the Illustrious College of Physicians of Madrid wanted to offer an early, simplified and critical approach to these new drugs, to new developments in immunotherapy and to what has been learned from the immune response modulators already known and which have proven effective against the virus, in order to help understand the current situation.     

Steroidal sapogenin contents in some domestic plants

In order to find out the values of the steroid resources for the future use. the compositions and contents of steroidal sapogenins from 13 domestic plants have been investigated. As a result,Dioscorea nipponica, D. quinqueloba andSmilax china were found to have large amount of diosgenin. And pennogenin inTrillium kamtschaticum andParis verticillata, yuccagenin inAllium fistulosum, hecogenin inAgave americana and neochlorogenin inSolanum nigum were appeared to be major steroidal sapogenins.     

Alzheimer’s disease – current trends in basic and clinical research. Highlights from the 16th ECNP

Advances in the molecular biological knowledge of neuronal nicotinic acetylcholine receptors (nAChRs) have led to a growing interest by the pharmaceutical industry in the development of novel compounds that selectively modulate nAChR function. The ability of (-)-nicotine, an activator of nAChRs, to enhance attentional aspects of cognition in animals and humans, to exert neuroprotective and anxiolytic-like effects, and presumably to mediate the negative correlation between smoking and Alzheimer's (and Parkinson's) Disease, has focused interest on the potential therapeutic utility of modulators of nAChR function for treatment of some of the deficits associated with these progressive, neurodegenerative conditions. Numerous compounds are known which activate nAChRs and which might serve as lead compounds toward the development of such agents. The pharmacologic diversity of neuronal nAChR subtypes suggests the possibility of developing selective compounds which would have more favourable side-effect profiles than existing agents. This broader class of agents, collectively called cholinergic channel modulators (ChCMs), is anticipated to encompass compounds which would have more favourable side-effect profiles than existing agents, which generally exhibit low selectivity. This selectivity may be achieved by preferentially activating some subtypes of nAChRs (i.e., Cholinergic Channel Activators, ChCAs) or inhibiting the function of other subtypes (Cholinergic Channel Inhibitors, ChCIs). An overview of the biology of nAChRs and the rationale for the use of ChCMs for the treatment of dementia related to neurodegenerative diseases are presented, followed by a discussion of lead compounds and compounds under consideration for clinical evaluation.