甲巯咪唑乳膏透皮吸收的体内动力学

目的:研究甲巯咪唑乳膏经皮给药体内动力学及血清药物含量测定。方法:兔颈前甲状腺局部经皮给药,以高效液相色谱法测定血清中甲巯咪唑浓度,以3P87药动学软件计算药物体内动力学参数。结果:药时曲线符合一室模型,药物吸收速率常数(Ka)为2.590h-1;消除半衰期(T1/2β)为2.258h;峰浓度(Cmax)为1.480μg·ml-1;达峰时间(Tmax)为0.934h;曲线下积分面积(AUC)为6.230μg·ml-1·h。结论:甲巯咪唑乳膏局部给药有良好的透皮吸收性。     

恩洛地平的临床应用

<正> 恩洛地平(Amlodipine)是一种新的二氢吡啶类钙拮抗剂。虽然与硝苯吡啶有类似的药理作用,但由于结构的差别,恩洛地平有别于其它二氢吡啶类钙拮抗剂,其药动学和药效学有十分重要的特点。与其它二氢吡啶类钙拮抗剂相比,恩洛地平生物利用度高(64%),分布容积大(21 L/kg),清除率低(7ml/min/kg)以及消除半衰期长(45h)。每d仅给药一次。恩洛地平吸收较慢,起效平缓。口服后6～8h达峰浓度,7～9d达稳态浓度,稳态浓度峰谷变化较小。这些特点使恩洛地平具有给药次数少,长效,副作用轻的优点。     

抗高血压新药—拉西地平

<正> 拉西地平(Lacidipine)是一种新型的1,4-二氢吡啶类钙拮抗剂。其特点是起效缓慢,作用持久,可每天给药一次及对血管平滑肌的相对选择性,适于高血压的治疗。其化学结构如下: 药物动力学拉西地平口服吸收迅速完全,经过“首过代谢”绝对生物利用度较低(<10%),生物转化后的代谢物经粪便排出。两种主要代谢物是吡啶和羧酸衍生物,均不具药理活性。拉西地平和其他二氢吡啶类钙拮抗剂药动学参数比较详见表1。     

二氢吡啶类钙拮抗剂的体内测定方法和药代动力学研究进展

二氢吡啶类钙拮抗剂的体内测定方法和药代动力学研究进展马骏，中国人民解放军兰州军区总医院药材科兰州７３００５０）赵德化，许顺尧第四军医大学药理教研室西安７１００３２二氢吡啶类（ＤＨＰｓ）钙拮抗剂是近２０年来广泛用于治疗心血管疾病如高血压、心绞痛、心律失...     

钙拮抗剂对高血压患者心-肾危险性的影响

Nathan等报道，钙拮抗剂包括2个主要亚类，二氢吡啶类和非二氢吡啶类，并且已在高血压患者中进行大量研究。早期荟萃分析提示，短效钙拮抗剂与心血管事件和其他病因所致的死亡率高有关连。最近的荟萃分析未显示长效钙拮抗剂和其他抗高血压药类在2或3期无蛋白尿的肾脏疾病伴有低度至中度心血管危险性或肾脏疾病有进展者的心血管后果无明显差别。钙拮抗剂的试验资料一致表明，该药可降低脑卒中的发生率而不能阻止新发生的心力衰竭，在有蛋白尿的肾脏疾病者中（即蛋白，肌酐〉300mg／g），应用二氢吡啶钙拮抗剂可降低血压并且不合用阻滞肾素血管紧张素醛固酮系统的药物不会很理想地减缓肾病的进展。此种情况与此类药无抗蛋白尿作用有直接关系，并且不见于比二氢吡啶类降低蛋白尿的程度较大的非二氢吡啶类药。因此，用钙拮抗剂对降低心血管的危险性是安全的，并且与其他抗高血压药的效果相同。此类药应避免用于有收缩功能障碍者，但是可用于降低保持收缩功能者的血压。在有蛋白尿的肾脏疾病中．二氢吡啶类钙拮抗剂必须与血管紧张素转移酶抑制剂或血管紧张素受体阻滞剂联合使用。     

诺模图法预测口服给药的吸收速率常数

目的：用已知的达峰时间(tpeak)和消除速率常数(ke)建立诺模法，估算口服给药的吸收速率常数(ka)。方法：根据口服给药的血药浓度—时间曲线曲线方程和tpeak,ka和ke的函数关系，进行数学推导建立诺模图。应用诺模图分析46个药物的ka与数学解析法计算的ka，比较评价诺模图的准确度。用高效液相色谱荧光法检测18位健康志愿者羧甲司坦的血药浓度，将羧甲司坦实测血药浓度与由ka结合其他药代动力学参数的估计血药浓度比较，评估诺模图执行误差。结果：诺模图估算的ka值与解析法计算的ka值接近；MDPE和MDAPE执行误差分别为1．32％，18．15％。结论：本文设计的诺模图准确可靠，执行误差符合临床药代动力学要求。可为制定合理的个体化给药方案提供一个方便快捷的方法。     

新型钙拮抗剂拉西地平的药理与临床应用

拉西地平是治疗高血压的新型长效二氢吡啶类钙拮抗剂，本文综述其药代动力学，药理作用，临床应用及不良反应。     

用荧光偏振免疫分析法监测庆大霉素

本文选用荧光偏振免疫分析方法,测试了8名健康志愿受试者,单剂量肌注庆大霉素80mg 后的血药浓度经时过程,用微机MCPKP 药物动力学程序处理并求得庆大霉素的药物动力学参数、吸收速率常数(Ka)、消除速率常数(K)、消除半衰期(T_(1/2)k)、表观分布容积(Vd)、达峰时间(Tp)等,与文献报告值接近,可作给药剂量估算的依据.     

二氢吡啶类钙拮抗剂药物基因组学的研究进展

二氢吡啶类钙拮抗剂是临床常用的一类降压药。临床使用过程中,疗效受到患者基因组学特征的影响。细胞色素P450(CYP3A)酶、P-糖蛋白(P-gp)和乳腺癌耐药蛋白(BCRP)转运体参与了药物体内处置过程,而CACNA1C受体是发挥药效的关键。大量临床研究结果表明,它们的基因多态性对该类药物的药动学和药效学会产生较大影响。本文在查阅近年来国内外文献基础上,就酶、转运体和受体的基因多态性对二氢吡啶类钙拮抗剂药动和药效的影响研究进展进行了综述,为临床用药提供参考。     

甲巯咪唑灌服用外用给药对比观察及体内药动学

目的：研究甲巯咪唑不同给药途径的血及甲状腺组织中药物含量。方法：用HPLC法测定大鼠在同剂量下,灌服甲巯硫唑与颈部外涂甲巯咪唑乳膏后的不同时间血及甲状腺组织中甲巯咪唑的含量,以3P87药动学软件计算动力学参数。结果：灌服给药与颈部外用给药,血清药时曲线均符合一室模型。甲巯咪唑透皮吸收乳膏单剂量给药后,甲状腺组织中药物浓度明显高于灌服给药组（P＜0．05）;血中药物峰浓度（Cmax)和曲线下面积（AUC）均显著高于灌服给药组（P＜0．01）;药物消除半衰期（T1／2）灌服组为2．486h ,外用组为2．645h;达峰时间（Tmax)灌服组为1．894h,外用组为1．784h,两种方法无明显差异。结论：甲巯咪唑经皮给药可提高靶组织浓度,延长药物作用时间。     

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.     

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.