Does it add up?
Does it add up?
复制标题
加起来吗？
DOI：
--
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发表时间：
2008
影响因子：
5.7
通讯作者：
R. Eckenhoff
中科院分区：
文献类型：
--
作者：
M. Kelz;R. Eckenhoff
罗德里克湾几年前，我们提出了一个不受欢迎的概念，即麻醉状态可能是由麻醉剂对许多分子靶点的微小影响来传达的。虽然不完全是新的，（雷·芬克在他的比喻中引用了这样一个概念“润滑良好的机器中的砂砾”），但它不受欢迎，主要是因为它很难测试，因此在这个假设驱动的时代被认为是不科学的，还原主义生物学。本期《麻醉与镇痛》的一组手稿现在解决了这个问题，从合理的假设开始，即当不同的药物组合时，多靶点机制应该产生除累加效应之外的其他效应。这些论文的方法、假设、药物、模型和数据集各不相同，因此缺乏一个统一的答案也就不足为奇了。尽管如此，这种追求是崇高的，有价值的，当然也是发人深省的。如果一个多目标模型应该产生非加和性，那么一个单一目标应该产生加和性吗？Jenkins等人研究了假定通过配体门控离子通道家族起作用的麻醉剂的这个问题。他们的结论是，麻醉剂对这些通道的变构调节完全是相加的，即使是强烈怀疑在单个受体中使用不同结合位点的药物。尽管没有提到，但激动剂（氨基丁酸、甘氨酸、乙酰胆碱）和麻醉剂对这些受体的非加性行为的明显情况确实增加了同一受体上不同位点之间变构协同作用的可能性。也许他们研究中使用的“麻醉剂”在物理化学上太相似，无法产生必要的位点选择。无论如何，这项研究是重要的支持的想法，添加剂的行为意味着单一的目标。但是单个受体并不能很好地代表细胞的行为，更不用说网络或有机体了。因此，为了适应额外的复杂性，埃格等人将问题扩展到完整的动物。在这里，吸入麻醉药组在最小肺泡麻醉药浓度（MAC）反应中表现出相加性，但一氧化二氮除外，其表现出较小程度的拮抗作用。有趣的是，可以容忍与严格可加性线10%的偏差，大概是因为这是MAC研究中的典型置信水平。当然，替代的任意值或改善的信噪比可能会改变结论，正如Shafer等人所说明的那样。然而，这些作者将这项研究解释为与单一靶标相互作用产生的固定一致，但应该记住，从行为测量中提取分子机制的先例很少。Hendrickx等人更进一步，将任何可以产生催眠或不动的药物包括在内，并使用文献回顾作为体内数据的来源。从某种意义上说，这是“积极控制”的假设，协同作用产生于对多个目标的行动。正如对于这样的化合物的多样化集合所预期的那样（例如，神经递质，阿片类药物和吸入麻醉剂），结果存在差异。与上述研究一致，吸入麻醉剂通常彼此相加，但与其他类别的药物协同。其他药物相互之间有协同作用。虽然乍一看，药物的选择似乎是任意和无纪律的，这里的观点是很好的，如果吸入麻醉剂真正使用不同的网站，从麻醉学和重症监护系，宾夕法尼亚大学医学院，费城，宾夕法尼亚州。2008年4月25日接受出版。重印本：不详。与Roderic G的通信地址。埃肯霍夫，医学博士，311 A约翰摩根大厦，3620汉密尔顿步行，费城，宾夕法尼亚州19104-6112。给罗德里克发邮件。eckenhoff@uphs.upenn.edu.版权所有© 2008国际麻醉研究学会
Roderic G. Eckenhoff, MD A few years ago, we raised the unpopular notion that the state of anesthesia might be conveyed by small effects of anesthetics on many molecular targets. Although not entirely novel, (Ray Fink invoked such a concept in his metaphor “grit in well-oiled machinery”), it was unpopular primarily because it is so difficult to test, and was therefore considered unscientific in this era of hypothesis-driven, reductionist biology. A group of manuscripts in this issue of Anesthesia & Analgesia now tackles this question, starting with the reasonable assumption that a multiple target mechanism should produce other than additive effects when disparate drugs are combined. The approaches, assumptions, drugs, models, and datasets differ among the papers, and thus it should not be surprising that a single harmonious answer was lacking. Nonetheless, the quest is lofty, worthwhile, and certainly thought-provoking. If a multiple target model should produce non-additivity, should a single target produce additivity? Jenkins et al. examine this question for anesthetics presumed to act via the family of ligand-gated ion channels. They conclude that allosteric modulation of these channels by anesthetics is entirely additive, even for drugs strongly suspected as using different binding sites within the single receptor. Although not mentioned, the obvious case of nonadditive behavior between agonist ( aminobutyric acid, glycine, acetylcholine) and anesthetics on these receptors certainly raises the possibility of allosteric synergy between divergent sites on the same receptor. Perhaps the “anesthetics” used in their study are physicochemically too similar to produce the necessary site selection. Regardless, this study is important support for the idea that additive behavior implies single targets. But single receptors do not well represent the behavior of a cell, let alone a network or an organism. Thus, to accommodate the additional complexity, Eger et al. extend the question to intact animals. Here again, the group of inhaled anesthetics demonstrate additivity in the minimum alveolar anesthetic concentration (MAC) response, with the exception of nitrous oxide, which showed a small degree of antagonism. It is of interest that a 10% degree of deviation from the line of strict additivity was tolerated, presumably because this is the typical level of confidence in MAC studies. Of course, an alternate arbitrary value or improved signal-to-noise ratio could change the conclusions, as well illustrated by Shafer et al. Nevertheless, this study was interpreted by these authors as being consistent with immobilization arising from interactions with a single target, but one should keep in mind that there is little precedent for the extraction of molecular mechanisms from behavioral measurements. Hendrickx et al. open things even further, by including any drug that can produce hypnosis or immobility, and using a retrospective review of the literature as the source of in vivo data. In a sense, this is the “positive control” for the assumption that synergy arises from actions on multiple targets. As might be expected for such a diverse collection of compounds (e.g., neurotransmitters, opioids, and inhaled anesthetics), there is diversity in the results. Consistent with the above studies, the inhaled anesthetics are generally additive with each other, but synergistic with other classes of drugs. Other drugs are synergistic with each other. Although at first glance the choice of drugs seems arbitrary and undisciplined, the point here is well taken, if the inhaled anesthetics truly use diverse sites to From the Department of Anesthesiology and Critical Care, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania. Accepted for publication April 25, 2008. Reprints: Not available. Address correspondence to Roderic G. Eckenhoff, MD, 311A John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA 19104-6112. Address e-mail to roderic. eckenhoff@uphs.upenn.edu. Copyright © 2008 International Anesthesia Research Society
蛋白质中挥发性麻醉剂结合位点的预测。
影响因子：
3.4
作者：
Streiff,JohnH;Allen,ThomasW;Atanasova,Elena;Juranic,Nenad;Macura,Slobodan;Penheiter,AlanR;Jones,KeithA
通讯作者：
Jones,KeithA
挥发性麻醉剂与烟碱乙酰胆碱受体结合的核磁共振研究。
影响因子：
3.4
作者：
Xu,Y;Seto,T;Tang,P;Firestone,L
通讯作者：
Firestone,L