口服降糖药的遗传药理学研究进展

糖尿病是一种受多基因和环境因素共同影响的代谢性疾病。药物代谢酶、受体和转运体的遗传多态性对口服降糖药的体内代谢和降糖疗效有重要作用。本文从细胞色素P450酶、转运体和受体多态性方面对5种主要口服降糖药（磺脲类、噻唑烷二酮类、氯茴苯酸类、双胍类、α-葡萄糖甙酶抑制剂）的体内代谢和药物效应的影响作一综述。     

阿托伐他汀的药物基因组学研究进展

阿托伐他汀是目前临床上广泛使用的口服降脂药,其对冠心病的一级和二级预防具有重要作用;但其疗效以及不良反应存在显著的个体差异,这与药物相关基因的多态性有关。本文主要介绍了基因多态性在阿托伐他汀的代谢、转运以及不良反应等方面的作用。     

CYP2C9、CYP2C19、CYP3A4基因多态性对磺脲类降糖药代谢的影响

磺脲类口服降糖药在人体内主要经过肝脏代谢。肝脏中的细胞色素氧化酶P450是一种重要的药物代谢酶系统,在人群中存在基因多态性,导致药物疗效和不良反应在个体间存在着较大的差异。本文将对CYP450中的几种重要的代谢酶亚型CYP2C9、CYP2C19、CYP3A4的基本结构、基因多态性、种族差异及其对磺脲类降糖药代谢的影响作一综述。     

6-巯基嘌呤治疗儿童急性淋巴细胞白血病个体化用药的研究进展

目的:了解6-巯基嘌呤(6-MP)治疗急性淋巴细胞白血病(ALL)个体化用药的研究进展,以期为6-MP治疗ALL个体化用药提供依据。方法:查阅近年来国内外相关文献,就6-MP治疗ALL时与代谢有关的代谢酶基因的多态性和转运体酶基因的多态性的研究进行归纳和总结。结果:6-MP代谢酶和转运体酶的基因多态性是影响6-MP个体化治疗ALL患儿疗效和不良反应的重要因素。其中,代谢酶基因硫嘌呤甲基转移酶、亚甲基四氢叶酸还原酶、重组人肌苷三磷酸酶和转运体酶基因多药耐药相关蛋白5的多态性影响6-MP个体化治疗的疗效和不良反应;转运体基因多药耐药1、溶质运载蛋白(SLC)28A3和SLC29A2的多态性仅在体外研究中显示出对6-MP转运和耐药性等的影响。结论:关于6-MP治疗ALL的代谢和转运的相关基因多态性的研究尚存在样本量偏小、研究群体局限于某一种族、转运体相关基因多态性的研究不够充分和药物受体基因多态性的研究匮乏等不足,有待将与6-MP相关的代谢酶、转运体和受体的单核苷酸多态性进行扩大样本量的综合研究,归纳出给药剂量的综合预测方程,以为6-MP在临床的个体化给药提供参考。     

瑞格列奈药物基因组学的研究进展

目的:了解瑞格列奈药物基因组学的研究进展,为瑞格列奈的临床个体化给药提供参考。方法:查阅近年来国内外相关文献,就瑞格列奈的药物基因组学的研究进行归纳和总结。结果:瑞格列奈相关的药物基因组学研究主要集中于药物代谢和转运相关基因、药物作用靶点和受体的编码基因、2型糖尿病(T2DM)易感基因等方面,其中KCNQ1、Neuro D1/BETA2、PAX4、NOS1AP、SLC30A8、IGF2BP2、UCP2、NAMPT为代表的T2DM易感基因对瑞格列奈药效学的影响是目前研究的重点。T2DM易感基因可能通过影响胰岛B细胞的增殖、腺苷三磷酸敏感性钾通道(KATP)和电压门控Ca~(2+)通道的表达和活性以及胰岛素分泌,从而增加T2DM的易感性并影响药物治疗反应性。CYP2C8、CYP3A4、SLCO1B1和MDR1等与药物代谢和转运有关的基因多态性可能影响瑞格列奈的药-时曲线下面积、峰浓度、半衰期和清除率等,间接影响药物疗效和安全性。在开展药物基因组学研究时,还应根据不同种族的等位基因频率来选择基因多态性位点,以期获得更大的临床应用价值。结论:基因多态性是瑞格列奈治疗反应性个体差异的部分原因,有望通过基因导向的个体化治疗提高疗效、减少不良反应。     

基因多态性对阿片类药物疼痛治疗影响的研究进展

目的:综述阿片类药物镇痛治疗相关基因组学的研究现状,为临床疼痛治疗提供参考。方法:查阅近年国内外有关文献,对已报道的有关阿片类药物镇痛治疗的基因组学及其相关研究进行总结和归纳。结果:阿片类药物镇痛治疗基因组学研究取得很大进展。因受药物代谢酶基因(如CYP3A4、CYP2D6、UGT、COMT)、药物作用靶点或受体基因(如OPRM1)、转运蛋白基因(如ABCB1)多态性的影响,阿片类药物镇痛治疗疗效和不良反应存在很大个体差异。以上相关基因的多态性与阿片类药物用于患者疼痛治疗的有效剂量、治疗效果以及不良反应的发生有密切关系。结论:开展相关基因检测,有助于提高阿片类药物疼痛治疗的精准性。     

消化系统疾病药物基因组学的临床研究进展

药物基因组学涉及所有编码与药物代谢、处置、转运蛋白、靶蛋白等相关的基因。从基因水平研究基因多态性与药物疗效关系以及预测不良反应发生将成为消化系统疾病临床治疗新的切入点。药物基因组学将成为传统方法选药及给药方案制定的重要补充。     

2型糖尿病口服降糖药处方分析

目的：对2型糖尿病口服降糖药进行处方分析,探讨此类药物的疗效以及用药合理性。方法60例2型糖尿病患者,随机分为研究组(30例)和对照组(30例)。研究组采取联合应用口服降糖药治疗方案,对照组采取单一口服降糖药治疗方案,并且将两组患者临床治疗糖尿病处方进行用药分析。结果研究组2型糖尿病患者口服降糖药处方联合用药,使用磺酰脲类和双胍类量大,并且逐年增加胰岛素增敏剂,联合用药的情况比较普遍,患者临床病情得到明显改善,治疗效果明显,显著高于对照组(P<0.05)。结论2型糖尿病治疗中,联合用药疗效确切,安全有效,不良反应小,用药合理。     

基因多态性与奥氮平临床疗效相关性的研究进展

目的:了解基因多态性与奥氮平(OLA)临床疗效的相关性,为OLA个体化给药方案的制订提供参考。方法:查阅近年来国内外相关文献,就OLA代谢酶和作用靶点编码基因的多态性与其疗效相关性的研究进行归纳和总结。结果:参与OLA代谢的各个酶系编码基因的多态性均可影响药物在体内的代谢及药物浓度,从而进一步影响疗效,但相关结论仍然存在争议。这可能因为基因多态性对OLA疗效的影响由多个基因或某些基因之间的连锁平衡所决定,因此代谢酶的基因多态性与OLA临床疗效的关系仍需进一步研究探讨。而OLA作用靶点多巴胺受体(DR)基因多态性则影响OLA的应答时间以及体内的催乳素水平,五羟色胺受体(5-HTR)基因多态性与OLA改善精神分裂症致体质量增加存在相关性。结论:DR、5-HTR相关基因的多态性对OLA临床疗效及不良反应的存在不可忽视的影响。临床制订OLA治疗方案时需要考虑代谢酶和作用靶点基因多态性对其疗效的影响。     

遗传药理学:个体化用药的科学依据

遗传药理学的研究进展为基因导向性个体化用药提供了理论依据遗传药理学主要在基因水平研究药物反应相关蛋白的多态性等,来揭示药物治疗中疗效和不良反应差异的遗传特征,鉴别基因序列中的差异。遗传药理学是以药物效应及安全性为目标,研究药物代谢酶(影响药物的代谢,如细胞色素P450)、药物转运蛋白(影响药物的吸收、分布和排泄,如P-糖蛋白)以及药物作用受体或靶位(影响药物反应的敏感性,如β肾上腺素受体)等药物反应相关蛋白基因突变与药效及安全性之间的关系,而这些基因突变是不同个体产生不同药物效应的根本原因。1.药物代谢酶关于药物代…     

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.     

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.     

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.