ER／PgR水平可否预测乳腺癌化疗效果

一国际研究组研究者报道称，乳腺癌患者低雌激素受体（ER）水平和／或孕激素受体（PgR）水平可预测内分泌治疗加化疗的受益情况。 研究者分析了国际乳腺癌研究组试验VIII（绝经前女性）和IX（绝经后女性）结果，以确定雌激素受体和／或孕激素受体水平是否可预测对化疗[环磷酰胺（cyclophosphamide）加甲氨蝶呤（methotrexate）和氟尿嘧啶（fluorouracil）]和／或内分泌治疗（戈舍瑞林（goserelin）（I）或他莫昔芬（tamoxifen））有反应。     

绝经前乳腺癌化疗致闭经的相关研究

绝经前乳腺癌根据患者不同的年龄、化疗方案、是否使用他莫昔芬、卵巢储备功能等可在不同程度上影响卵巢功能。为了准确使用内分泌治疗方案,确定化疗后闭经的绝经前激素受体阳性乳腺癌患者的卵巢功能至关重要。但是化疗后闭经患者的绝经的诊断标准并不统一,以患者的临床特点、雌二醇激素、FSH来判断绝经并不准确。研究证明检测抗穆勒氏管激素对绝经前乳腺癌化疗后的残余卵巢功能评估有所帮助。本研究回顾了绝经前乳腺癌患者化疗致闭经的机制,同时分析了卵巢功能的标志物,以便指导我们更好的选择内分泌治疗药物。     

激素疗法对乳腺癌患者骨骼的影响

最近有研究结果显示,在乳腺癌妇女中使用芳香酶抑制剂（aromataseinhibitors）比使用选择性雌激素受体调节剂他莫昔芬在改善患者的无疾病生存期以及总体存活率方面都有更好的疗效。美国临床肿瘤协会（ASCO）在最近的指南中建议,对雌激素受体阳性乳腺癌妇女在辅助治疗期间可以考虑使用某种芳香酶抑制剂。需要注意的是,芳香酶抑制剂可以阻断雌激素合成,对骨骼产生不良作用,并且很可能会增加骨折的风险。相反,他莫昔芬作为另一种广泛使用的乳腺癌激素疗法,可以在绝经后妇女骨骼中作为部分雌激素激动剂起效。     

乳腺癌内分泌治疗的研究进展

1895年，苏格兰外科医生George Beatso率先给1例33岁晚期乳腺癌妇女实施双侧卵巢切除术，使其生存了4年，揭开了乳腺癌内分泌治疗的序幕。20世纪50年代，相继有肾上腺和垂体切除或放射治疗及放射性卵巢去势（ovarian ablation，OA）治疗问世。1966年，Jensen等在乳腺肿瘤中分离出雌激素受体（estrogen receptor，ER）和孕激素受体（progestin receptor，PR），使乳腺癌的内分泌治疗更具针对性，疗效明显提高。1971年引入临床治疗的雌激素受体拮抗剂他莫昔芬（tamoxifen，TAM），被誉为内分泌治疗的里程碑。20世纪90年代第3代芳香化酶抑制剂（aromatase inhibitors，Ms）和诺雷德（zoladex）等药物性卵巢切除术（medical oophoreetomy）制剂先后研制成功，使乳腺癌内分泌治疗进入一个新的时代，并已成为21世纪各期乳腺癌重要的治疗手段之一。目前认为，只要有10％的肿瘤细胞雌激素受缈孕激素受体阳性，内分泌治疗就可能有效。     

初步证实CYP2D6为他莫昔芬辅助治疗预后预测因素

他莫昔芬国家药物基因组学联盟强调,在他莫昔芬治疗中要考虑到细胞色素P4502D6（CYP2D6）的代谢状态与临床预后之间的矛盾。研究者进行了一项meta分析,数据来自于4973例他莫昔芬治疗的患者（分布在全球12个地方）。采用严格的入组要求（标准1为,雌激素受体阳性的绝经后乳腺癌女性患者,     

他莫昔芬临床研究进展

他莫昔芬是乳腺癌内分泌治疗的首选药物，对雌激素受体阳性的进展期乳腺癌病人的有效率达60％，对早期乳腺癌疗效较好，可降低复发的相对危险性和死亡率。他莫昔芬与化疗联合治疗绝经后早期乳腺癌有协同作用，且可降低对侧乳腺癌和心血管疾病的发病率，并能预防绝经后病人的骨质疏松等。     

他莫昔芬代谢产物endoxifen的研究进展

摘要：他莫昔芬是一种内分泌治疗药物,被批准用于预防和治疗雌激素受体阳性的乳腺癌患者。他莫昔芬的重要次级代谢产物endoxifen,因其比他莫昔芬更强的雌激素受体亲和力,以及更强的抑制雌激素依赖性细胞增殖作用,引起研究人员的重视。Endoxifen的特性,如口服利用度高、不良反应发生率低以及对雌激素受体阳性且内分泌治疗耐药的乳腺癌患者具有抗肿瘤活性,使其成为治疗乳腺癌患者的潜在药物。本文就他莫昔芬转化为endoxifen的代谢过程、药理作用与临床研究进行概述,讨论endoxifen的应用前景。     

他莫昔芬临床研究进展

他莫昔芬是乳腺癌内分泌治疗的首选药物,对雌激素受体阳性的进展期乳腺癌病人的有效率达６０％,对早期乳腺癌疗效较好,可降低复发的相对危险性和死亡率,他莫昔芬与化疗联合治疗绝经后早期乳腺癌有协同作用,且可降低对侧乳腺癌和心血管疾病的发病率,并能预防绝经后病人的骨质疏松等。     

药学资讯

阿那曲唑联合戈舍瑞林可用于绝经前早期乳腺癌新辅助治疗对于绝经前的早期乳腺癌来说,芳香酶抑制剂比他莫昔芬的疗效更好。一项III期随机双盲多中心平行试验,在新辅助化疗期间接受戈舍瑞林的绝经前早期乳腺癌患者中比较了阿那曲唑相比他莫昔芬的疗效和安全性。入组的患者雌激素受体(ER)阳性、HER2阴性、体力状态≤2分且均可手     

唑来膦酸对内分泌治疗绝经前乳腺癌患者所致骨丢失的效果观察

目的：观察唑来膦酸对戈舍瑞林与芳香化酶抑制剂联合治疗绝经前转移性乳腺癌患者所致骨丢失的临床效果和安全性,为临床应用提供参考。方法收集90例在我院乳腺科接受戈舍瑞林联合芳香化酶抑制剂治疗的绝经前转移性乳腺癌患者的临床资料,分为三组,A 组（30例）和 B 组（30例）在戈舍瑞林联合芳香化酶抑制剂治疗的同时使用唑来膦酸,疗程分别为5年和2年;C 组（30例）在戈舍瑞林联合芳香化酶抑制剂治疗期间未使用唑来膦酸。所有患者通过双能 X 线骨密度测量仪检测各时间点各组骨密度值,使用视觉模拟评分法进行肢体骨痛评定,观察记录骨质疏松性骨折的发生率。结果随访60个月,A 组患者各时间点骨密度均较 C 组升高（P ＜0．05）：A组患者在治疗第48,60个月骨密度较 B 组患者升高（P ＜0．05）：四肢疼痛视觉模拟评分 A 组低于 B 组和 C 组（P ＜0．05）：A 组患者骨质疏松性骨折的发生率显著低于 B 组和 C 组（P ＜0．05）。结论绝经前转移性乳腺癌患者行戈舍瑞林联合芳香化酶抑制剂治疗期间,早期足疗程应用唑来膦酸可减少骨量丢失和相关骨折发生,缓解骨痛。     

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.