【注：这类讲的 药物分子之间的相互作用 主要是指病人同时服用两种（AB）或多种药物的时候，由于其中某个药物分子A对肝脏中的某些代谢酶起到抑制作用，使得那些酶不能正常地代谢药物分子B，这样一来B分子就容易在体内累积，相当于服用大剂量的药物，从而产生毒副作用。还有其它类的相互作用。与此相关的还有食物与药物的相互作用，这里的化学本质是一样的，也就是食物中的分子干扰另一个药物的效果，影响了体内相关的大小分子间的平衡。下面这篇文章很有意思，感兴趣的读者如果有时间的话，可以给一个翻译。】 Dangerous Liaisons From The Scientist ： http://www.the-scientist.com/2010/5/1/38/1/ Volume 24 | Issue 5 | Page 38 Date: 2010-05-01 By Chris Bode （ All illustrations raquel aparicio） With a large portion of the US population taking multiple prescription drugs and supplements, the increased risk of drug interactions and side effects drives the need for better testing before the medicines reach patients. My mother-in-law moved in with us when she was 82. As her physical condition gradually deteriorated, the number of medications she was taking for various ailments increased: two for high blood pressure, two to promote gastric motility, one for congestive heart failure, one synthetic thyroid hormone, an expectorant, and two inhalers for chronic obstructive pulmonary disease (COPD). In addition, there was the occasional antibiotic for recurrent pneumonia. The drugs were prescribed by at least three different groups of doctors, none of whom communicated with the others. It soon became difficult to tell a new malady from a side effect of one of the drugs, or a potentially harmful interaction between the combinations of chemicals in her system. A year or two into her time with us, she started to have an irregular heartbeat, an arrhythmia. After EKGs, a Holter monitor, and stress tests, the arrhythmia was diagnosed as a side effect of the cisapride that she was taking for gastric reflux. When her doctors replaced the cisapride with another gastric reflux medication, the drug caused a tremor so pronounced that her primary physician thought she had Parkinsons disease. Shortly after she stopped taking cisapride, it was removed from the US market for causing cardiac arrhythmia in a number of patients. But the situation was a little more complicated; the serious, potentially fatal arrhythmia that led to the withdrawal of the drug (following at least 80 reported deaths) was more likely to occur in patients who also took another drug that blocked a liver enzyme that eliminates cisapride from the body. With the natural elimination of cisapride blocked, the body would accumulate the drug to dangerous levels. The problem was that this liver enzyme wasnt just inhibited by one drug. A wide variety of therapeutics could block it, including common antibiotics such as erythromycin and HIV antiretroviral drugs such as ritonavir. If my mother-in-law had been prescribed erythromycin while she was still taking cisapride, it is likely that she could have died from a stroke or from a fall after fainting. Physicians have hundreds of drugdrug interactions (DDIs) to keep track of, and even that long list is not complete, generally covering interactions that have been experienced by patients, reported, and recognized for what they were. As more drugs become available for various ailments, the potential for drug interactions increases, especially in retirement-age adults who are the highest consumers of prescription medications per capita. According to a recent study, about 2.2 million adults in the United States between the ages of 57 and 85 take multiple medications, and could be at risk for drugdrug interactions. 1 A patients thin line of defense consists of the pharmaceutical companies requirement to test for dangerous combinations of drugs before they reach the market. But the tests are limited. For example, there are no methods for testing the interaction of 10 drugs concurrently. Instead, we test specific types of interactions that are the most common and harmful. With prescription patterns becoming more complex, many companies, including ours, have started developing new tests to try to capture other types of interactions before new drugs reach the clinical trial stage of development. Every drug that makes it to the pharmacists shelf has been tested and dosed based on how rapidly and extensively it is absorbed, how quickly it gets to its site of action at an effective concentration, and how long it stays active before being cleared by the liver or kidneysmeasures that are collectively called a drugs pharmacokinetics. So far, so good for individual drugs. But detecting DDIs is not so straightforward. It is rarely a simple matter of one chemical interfering directly with another; the link between drugs is often indirect and complicated by cellular and biochemical compartmentalization. Before the 1990s, the only way to spot a DDI was in a patient. 2 The enzyme involved in the DDI between cisapride and erythromycin was discovered back in the 1980s, when the first nonsedating antihistamine, terfenadine, came on the market. Over the course of several years, clinicians realized that the sudden death of some patients taking terfenadine was associated with the drugs combination with antibiotics as well as other drugs. Eventually, researchers realized that the antibiotics and other drugs were inhibiting cytochrome P450 (CYP) 3A4, a liver enzyme that oxidizes and inactivates terfenadine as part of the bodys normal metabolism of the antihistamine. The CYP family is a hugely important group of metabolic enzymes involved in the synthesis of hormones, membrane lipids, bile acids, and vitamins. It also eliminates cellular toxins and drugs. With CYP3A4 blocked, the terfenadine build-up resulted in a severe cardiac arrhythmia in many patients. According to a recent study, about 2.2 million adults in the United States between the ages of 57 and 85 take multiple medications, and could be at risk for drug-drug interactions. In the 1990s, when researchers realized that CYP inhibition was a property of multiple existing drugs, the FDA responded by requiring a series of preclinical in vitro tests for all investigational new drugs. 3,4 One of the most effective testing mechanisms that came out of that guidance was the requirement to use human in vitro systems such as human liver microsomes to test for CYP inhibition. Microsomes are prepared by homogenizing human liver tissue and separating out the subcellular components via high-speed differential centrifugation. The pellet contains the endoplasmic reticulum membranesthe site of CYP-mediated metabolism of drugs. This organelle suspension provides a sensitive and effective system for detecting inhibition of CYPs by a drug, as researchers can readily tell when the concentration of a probe substrate diminishes (with active CYP) or remains constant (with CYP blocked). Such interactions didnt preclude drugs from being prescribed together; clinical pharmacologists could develop dosing schemes that took those interactions into account. For example, inhibitors could be classified by the strength of their inhibition of different CYPs, and appropriate dose adjustments could be made to other drugs that were administered at the same time. Today we know that we also have to take the inhibiting drugs mechanism of action into account: is it a reversible vs. irreversible inhibitior? Reversible inhibitors block CYP function only as long as the inhibitor is present in the bloodstream, whereas irreversible inhibitors inactivate an enzyme permanently, knocking out its function until the cell produces more enzyme, which could take hours or days. The FDA relied on these and other in vitro tests, saying that results indicating no interaction are sufficient to rule out the need for a clinical DDI study. Positive or borderline in vitro results, on the other hand, indicate the need for such a clinical study in healthy human volunteers. While these assays, which remain the industry standard today, were certainly an improvement over discovering DDIs in patients, they still fall short of catching all of the clinically observed interactions. By the year 2000, researchers thought they had a pretty good handle on which metabolizing enzymes had to be tested for DDIs. The FDA required in vitro data on the interactions with human drug-metabolizing enzymes, with the understanding that members of the CYP superfamily were involved in most cases. But metabolizing enzymes were not the only mechanism for eliminating drugs from the body. One clue, although nobody knew it at the time, was the discovery in 1976 that drug-resistant mutants of a mammalian cell line expressed more of a membrane-bound protein called P-glycoprotein (P-gp) than wild-type cells. Before long, it became clear that P-gp was an efflux transporter that ejected drugs from a cell and played a role in the resistance of cancer cells to chemotherapeutic drugs. The human gene encoding that protein was named MDR1 in recognition of its role in multidrug resistance in cancer. 5 A number of other mammalian efflux transporters, or pumps, have since been discovered, first in cancer cells and eventually in normal cells. These pumps are important for drug uptake, distribution, and clearance (collectively called a drugs disposition), specifically in pharmacologically crucial organs such as the small intestine, bloodbrain barrier, liver, and kidneys. Once researchers appreciated the central role played by overexpression of P-gp and other transporters in drug-resistant tumors, they turned a spotlight on this class of proteins. Soon drug companies were looking for ways to block the activities of the efflux pumps in order to retain the chemotherapeutic agents in the tumor cells longerthus improving the efficacy of the drug. In a sense, they were trying to create an intentional drugdrug interaction. The problem was that, due to the fact that P-gp is expressed in multiple pharmacokinetically important locations, the concentration of the chemotherapeutic agent increased everywhere in the body, leading to side effects so intolerable that an increase in therapeutic efficacy became a moot point. To this day, no company has successfully developed a P-gp inhibitor that achieves the desired effect on tumors without the undesirable systemic effects. It gradually became clear that these proteins played a role in the disposition of many types of drugs by the bodynot just chemotherapieswhich meant that they could also play a role in unintentional drugdrug interactions, and might be a way to explain interactions that had to date gone unidentified. Drug Metabolizing Enzymes Researchers first learned the role of metabolizing enzymes in drug-drug interactions when some patients died from the combined administration of an antihistamine and an antibiotic. The antihistamine terfenadine was normally metabolized by the enzyme cytochrome P 450 (CYP) 3A4a fact taken into account to establish a safe dose. But when certain antibioticsor other drugswere administered at the same time, they blocked CYP3A4 activity, which caused a dangerous buildup of terfenadine. Surprisingly, its often difficult to tell whether a transporter is involved in a DDI and, if so, to what degree. The few examples of a purely transporter-mediated DDI have involved drugs with a narrow therapeutic range (NTR) that are not metabolized by CYP3A4. NTR drugs have a very small window of efficacyif the dose is too low, there is no effect and if the dose is even slightly beyond a threshold level, serious side effects can result. In these cases, inhibition of a transporter, resulting in even a slight alteration of the circulating concentration of the drug, could have severe consequences. The best example is digoxin, a drug taken for heart failure and atrial fibrillation. If exposure to the drug is increased by as little as 25% to 50%, side effects including cardiac arrest, nausea, vomiting and diarrhea can occur (with other drugs, increases in exposure of less than 100% arent generally considered significant to the patient). When digoxin is taken with a drug such as quinidine (an anti-arrhythmic), which inhibits P-glycoprotein, plasma concentrations of the drug increase on the order of 150%, enough to cause a digoxin overdose in some patients. 6 But there may be other transporter-mediated interactions we havent pinned down yet. One example is the interaction that occurs in organ transplant recipients. In these patients, cyclosporine is given to prevent immune rejection in combination with statin drugs, which are administered to combat the hypercholesterolemia that is a frequent consequence of organ transplantation. Cyclosporine inhibits both CYP3A4, which metabolizes some statins, and multiple uptake transporters that some statins rely on for entry into liver cells. When taken together, the exposure to the statin can increase as much as 20-fold, with the consequences ranging from muscle discomfort to the potentially fatal condition, rhabdomyolysisthe rapid breakdown of muscle fiber. One of the reasons that so few DDIs have been confirmed to be transporter mediated is that the in vitro tools available to study them have been less than definitive. A limited number of assay systems and cell lines exist, but each is problematic. For example, human cell lines contain multiple transporters, making it impossible to pinpoint a single receptor. Nonhuman cell lines that overexpress a single human transporter, on the other hand, function on a backdrop of animal transporters, which can also obscure findings, as animal and human transporters interact differently with some substrates and inhibitors. Another problem is that when one transporter is knocked out in a cell, another will often take over its function. In fact, because of the redundant function of many transporters, there may never be a toolbox of specific probe substrates and inhibitors of transporters, comparable to those available for drug-metabolizing enzymes. Without information about which specific transporter is responsible for a given DDI, drug developers cant design a definitive clinical trial to assess the implications of co-administration of drugs in a human. This is very different from the situation with drug-metabolizing enzymes of the CYP superfamily, where many drugs and other chemicals act as highly specific probe substrates or inhibitors to isolate the offending CYP enzyme. Drug Transporters Rather than metabolize drugs, transporter proteins simply shuttle them either into (uptake) or out of (efflux) a cell. For example, the efflux transporter P-gp shuttles digoxina drug given to patients with heart failurefrom kidney cells into urine at a particular rate. When the transporter is blocked by the anti-arrhythmic quinidine, the renal clearance of digoxin is reduced, potentially resulting in an overdose. In recognition of its clinical importance, the FDA has announced that it expects in vitro P-gp interaction data as part of any new drug application filed as of September 2006. 4 Not that P-gp is the only important transporter; in fact, a new white paper from an international panel of experts, including some from the FDA, indicates the importance of a number of other key transporters. 7 This is the next step in the evolution and eventual finalization of the FDAs guidance on this topic, which has been in draft form since 2006. In response, a number of companiesincluding our own, Absorption Systemsare developing better ways to define the role played by transporters in DDIs. Our approach tackles the problem of trying to identify the most important efflux transporter in a particular interaction by multiple-choice elimination. We start with a human intestinal cell line, in this case one called Caco-2, in which the expression and function of multiple efflux transporters is well characterized. When cultured under appropriate conditions, the cells differentiate into a polarized monolayer that mimics the epithelial cells lining the human small intestine. On the apical surface (i.e., the surface that would be facing the intestinal lumen in vivo), three efflux transporters are expressed: P-gp, BCRP and MRP2. By means of RNA gene silencing, we have knocked down the expression of one efflux transporter at a time. 8 Unlike typical in vitro RNA interference, the transporter knockdown phenotype is long-lasting and stable. As a result, we now have a panel of cell lines, in each of which the expression of one efflux transporter is reduced. The utility of this system, which we call CellPort Technologies, was demonstrated recently to help explain a clinical DDI that was partially responsible for the decision to withdraw ximelagatran, an anticoagulant, from the market. The study identified P-gp as the efflux transporter responsible for pumping ximelagatran and its active metabolite, melagatran, into bile. 9 Co-administration of the common antibiotic erythromycin inhibited the transporter, leading to elevated levels of ximelagatran and melagatran, which was associated with liver damage. While these assays were certainly an improvement over discovering DDIs in patients, they still fall short of catching all of the clinically observed interactions. By knocking down one transporter at a time, we can test a new drug candidate in the parental cell line and each of the knockdown lines in turn, and by process of elimination see which of the three targeted transporters is responsible for efflux of the drug. Another advantage is that the results dont rely on the available toolbox of transporter inhibitors, which are nondefinitive. Furthermore, it is an all-human system, unlike several other commonly used cell lines in which a given human transporter is overexpressed in a nonhuman cell line. CellPort Technologies, as it currently stands, is not perfect. It wont necessarily enable us to test for interactions among multiple drugs at one time (a feat no current assay system achieves), but it does offer the opportunity to screen for another class of interactions. As the number of drugs that the elderly take inevitably increases, and the more tools we have to interrogate potential drug interactions, the more capable well be to catch interactions before they occur in patients. It was frustrating to watch my once-vibrant mother-in-law decline, to watch as she was shuttled from one doctor to the next for test after test. By the time we reach our 80s, it is practically inevitable that we will be taking multiple drugs for what ails us. The more we know about how each of those drugs interacts with the transporters and enzymes that process drugs and toxins, the less likely it is well be treating the side effect rather than the disease. Chris Bode is a pharmacologist and the vice president of Corporate Development at Absorption Systems. He has been associated with the pharmaceutical industry for more than 20 years. References 1. D.M. Qato et al., Use of prescription and over-the-counter medications and dietary supplements among older adults in the United States, JAMA , 300:286778, 2008. 2. B.P. Monahan et al., Torsades de pointes occurring in association with terfenadine use, JAMA, 264:278890, 1990. 3. U.S. Department of Health and Human Services, Food and Drug Administration, 1997. Guidance for Industry, Drug metabolism/drug interaction studies in the drug development process: studies in vitro; available online at http://www.fda.gov... 4. U.S. Department of Health and Human Services, Food and Drug Administration, 2006. Guidance for Industry, Drug interaction studiesStudy design, data analysis, and implications for dosing and labeling; available online at http://www.fda.gov... 5. R.L. Juliano and V. Ling, A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants, Biochim Biophys Acta, 455:15262, 1976. 6. W. Doering, Quinidine-digoxin interaction: Pharmacokinetics, underlying mechanism and clinical implications, N Engl J Med, 301:4004, 1979. 7. K. Giacomini et al., Membrane transporters in drug development, Nature Rev Drug Disc, 9:21536, 2010. 8. W. Zhang et al., Silencing the breast cancer resistance protein expression and function in Caco-2 cells using lentiviral vector-based short hairpin RNA, Drug Metab Disp, 37:73744, 2009. 9. M. Darnell et al., Investigation of the involvement of P-gp and MRP2 in the efflux of ximelagatran and its metabolites by using short hairpin RNA knockdown in Caco-2 cells, Drug Metab Dispos, 38:49197, 2010. Related Articles Diverting a Diet Drug Selling Systems Biology Proteomic profiling
2009 年创刊的Drug Testing and Analysis《药品测试与分析》，ISSN: 1942-7603，月刊，英国（JOHN WILEY SONS LTD, THE ATRIUM, SOUTHERN GATE, CHICHESTER, ENGLAND, W SUSSEX, PO19 8SQ）出版，2010年入选 Web of Science的Science Citation Index Expanded，目前在SCI数据库可以检索到该期刊2009年的第1卷1-12期到2010年第2卷第1-4期共101篇论文。 101 篇文章包括学术论文79篇、评论13篇、社论8篇、通讯1篇。 101 篇文章的主要国家分布：德国22篇，埃及17篇，美国、英国各15篇，印度9篇， 瑞士6篇，比利时5篇，奥地利4篇，中国、芬兰各3篇，澳大利亚、加拿大、希腊、葡萄牙、伊朗、罗马尼亚、沙特阿拉伯各2篇等。 中国学者以通讯作者单位在该期刊发表论文的是泰山学院（Taishan Univ）2篇，河北大学（Hebei Univ）1篇。 101篇文章共被引用59次，其中2009年被引用11次，2010年被引用48次，平均引用0. 58次， H指数为3（有3篇文章每篇最少被引用3次）。 Drug Testing and Analysis 《药品测试与分析》投稿指南： 该刊主要刊登研究论文、评论、案例报告和通讯，重点在下面六个重点课题： l Sports doping l Illicit/recreational drugs use e.g. drug-testing methods by employers l Pharmaceuticals e.g. pharmacokinetics, metabolism studies, characterization and detection of new therapeutics, natural products, biosimilars and generics l Toxico-pathology e.g. determining posthumous drug presence l Forensics/homeland security e.g. determining the presence of controlled substances at a crime scene or use by perpetrators, analysis of compounds with potential use as biological or chemical warfare agents l Environment e.g. wastewater analysis, determination of pollutants/contaminants, etc. 网址： http://www3.interscience.wiley.com/journal/121408477/home 编委会： http://www3.interscience.wiley.com/journal/121408477/home/EditorialBoard.html 作者指南： http://www3.interscience.wiley.com/journal/121408477/home/ForAuthors.html 在线投稿： http://mc.manuscriptcentral.com/dta Drug Testing and Analysis 《药品测试与分析》热点论文： 1.标题: SDS-PAGE of recombinant and endogenous erythropoietins: benefits and limitations of the method for application in doping control 作者: Reichel C, Kulovics R, Jordan V, et al. 来源出版物: DRUG TESTING AND ANALYSIS 卷: 1 期: 1-2 页: 43-50 出版年: JAN-FEB 2009 被引频次: 7 2.标题: Annual banned-substance review: the Prohibited List 2008-analytical approaches in human sports drug testing 作者: Thevis M, Kuuranne T, Geyer H, et al. 来源出版物: DRUG TESTING AND ANALYSIS 卷: 1 期: 1-2 页: 4-13 出版年: JAN-FEB 2009 被引频次: 4 3.标题: C-13/C-12 Ratios of endogenous urinary steroids investigated for doping control purposes 作者: Piper T, Flenker U, Mareck U, et al. 来源出版物: DRUG TESTING AND ANALYSIS 卷: 1 期: 1-2 页: 65-72 出版年: JAN-FEB 2009 被引频次: 4 4.标题: Screening for the calstabin-ryanodine receptor complex stabilizers JTV-519 and S-107 in doping control analysis 作者: Thevis M, Beuck S, Thomas A, et al. 来源出版物: DRUG TESTING AND ANALYSIS 卷: 1 期: 1-2 页: 32-42 出版年: JAN-FEB 2009 被引频次: 3 5.标题: Proteolysis and autolysis of proteases and the detection of degradation products in doping control 作者: Thomas A, Kohler M, Walpurgis K, et al. 来源出版物: DRUG TESTING AND ANALYSIS 卷: 1 期: 1-2 页: 81-86 出版年: JAN-FEB 2009 被引频次: 3
http://www.gopubmed.org/web/gopubmed/1?WEB014f5ur0ash4dI37I1I00f01000j10040001rl Abnormalities, Drug-Induced 25,211 documents semantically analyzed 1 2 3 Top Years Publications 1970 319 1964 290 1967 265 1969 260 1965 242 1966 220 1963 150 2010 88 1962 3 1955 2 1958 1 1957 1 1953 1 1 2 3 1 2 3 ... 6 Top Countries Publications USA 5,256 Japan 1,282 Italy 740 United Kingdom 732 Canada 702 France 651 Germany 589 Spain 327 India 323 China 288 Netherlands 283 Australia 267 Sweden 223 Brazil 195 Israel 174 Turkey 167 Belgium 144 Hungary 128 Switzerland 125 South Korea 122 1 2 3 ... 6 1 2 3 ... 64 Top Cities Publications Boston 284 London 258 New York 249 Toronto 212 Tokyo 209 Paris 193 Philadelphia 172 Milan 144 Baltimore 130 Houston 130 Berlin 130 Seattle 120 Montreal 118 Chicago 118 Osaka 117 Bethesda 116 Los Angeles 111 Cincinnati 107 Budapest 107 Rome 105 1 2 3 ... 64 1 2 3 ... 180 Top Journals Publications Teratology 1,050 Lancet 344 Reprod Toxicol 333 Toxicol Appl Pharm 279 Mutat Res-fund Mol M 174 Am J Obstet Gynecol 167 Toxicology 144 Epilepsia 137 Environ Health Persp 134 Arzneimittel-forsch 132 New Engl J Med 127 Food Chem Toxicol 123 Teratogen Carcin Mut 120 Fundam Appl Toxicol 116 Toxicol Sci 115 Jama-j Am Med Assoc 115 Toxicol Lett 110 Obstet Gynecol 108 J Pediatr 108 Neurology 107 1 2 3 ... 180 1 2 3 ... 1220 Top Terms Publications Humans 14,253 Animals 12,913 Abnormalities, Drug-Induced 12,852 Pregnancy 11,455 Patients 5,868 Rats 5,822 Adult 5,507 Teratogens 5,032 Pharmaceutical Preparations 4,997 Infant, Newborn 3,947 Mice 3,810 Fetus 3,728 Evaluation Studies as Topic 3,351 Middle Aged 2,711 female pregnancy 2,621 Dose-Response Relationship, Drug 2,421 Child 2,214 Women 2,201 Syndrome 2,165 Incidence 2,163 1 2 3 ... 1220 主题词： 畸形, 药物性 英文名称： Abnormalities, Drug-Induced 树状结构号： C16.131.042 相关参见： Teratogens(致畸剂) 标引注释： IM; do not use /chem ind /compl /congen do not coord with INFANT, NEWBORN, DISEASES; coord IM with specific chem /adv eff-pois-tox (IM) + specific organ /abnorm or specific abnorm /chem ind (IM); Manual 23.20.3 历史注释： 64 主题词详解： Congenital abnormalities caused by medicinal substances or drugs of abuse given to or taken by the mother, or to which she is inadvertently exposed during the manufacture of such substances. The concept excludes abnormalities resulting from exposure to non-medicinal chemicals in the environment. 树形结构1 先天性遗传性新生儿疾病和畸形 先天畸形 畸形, 药物性
药物的多晶型现象， 即同一物质具有两种或两种以上的空间排列和晶胞参数， 生成完全不同类型的晶体。 制备并测量了呋喃苯胺酸 五种不同的 同质多晶变体在 0.2-1.6 THz 频率范围内的吸收系数和折射指数的信息，并同直接购买的未处理的呋喃苯胺酸进行比较。 研究发现太赫兹光谱 技术具有鉴定 药物不同晶型的可能性，并且 在制药工业和质量控制领域的有潜在的应用前景。 Bull Korean Chem Soc 30 (10), (2009), 2265-2268 Cited by: 1, Conformational and Synthon Polymorphism in Furosemide (Lasix), CRYSTAL GROWTH DESIGN 10 (4): 1979-1989 APR 2010 2, Terahertz pulsed spectroscopy and imaging for pharmaceutical applications: A review INTERNATIONAL JOURNAL OF PHARMACEUTICS2011,417(1-2):48-60 3, Novel furosemide cocrystals and selection of high solubility drug forms JOURNAL OF PHARMACEUTICAL SCIENCES2012,101(2),664-680
我目前的文章中引用率(57次， July 2010) 最高的是这一篇早期的论文。此文阐述了同一个分子但不同晶型可展示完全不同的机械性能。这个工作显示了在发展新药的过程中控制晶型的重要性。 一个较熟悉的类比是碳元素的两个晶型：石墨和钻石。 石墨很软可做很好的润滑剂。 钻石却是自然界中我们所知道的最硬的物质。同样的，若晶型不对，药品的物理性能可能会大大不同，甚至如同两个不同的药物分子一样。一般讲， 若晶体里有滑层 (slip planes) ， 晶体会较软更有可塑性，易变形， 易压片。 目前，我的研究小组正继续测试和发展这个概念。这是我晶体工程学研究的一部分。盼望和有兴趣的学者共同探讨。 Influence of crystal structure on the tableting properties of sulfamerazine polymorphs C. C. Sun and D. J.W. Grant Purpose . To understand the influence of polymorphic structure on the tableting properties of sulfamerazine. Methods . Bulk powders of sulfamerazine polymorph I and of two batches, II(A) and II(B) of different particle size, of polymorph II were crystallized. The powders were compressed to form tablets whose porosity and tensile strength were measured. The relationships between tensile strength, porosity and compaction pressure were analyzed by the method developed by Joiris, E., et al. Pharm. Res. 15:11221130 (1998). Results . The sensitivity of tensile strength to compaction pressure, known as the tabletability, follows the order, I II(A) II(B) and the porosity at the same compaction pressure, which measures the compressibility, follows the order, I II(A) II(B). Therefore, the superior tabletability of I over II(A) or II(B) is attributed to its greater compressibility. Molecular simulation reveals slip planes in crystals of I but not in II. Slip planes provide I crystals greater plasticity and therefore greater compressibility and tabletability. Larger crystal size of II(B) than of II(A) leads to fewer contact points between crystals in the tablets and results in a slightly lower tabletability. Conclusions . Slip planes confer greater plasticity to crystals of I than II and therefore greater tabletability.
后基因时代药物筛选策略与传统中药学理论 王晓明 湖北中医学院药学院，湖北武汉（ 430065 ） E-mail ： shermanwang@yahoo.com.cn , 摘要： 本文作者首次明确给出了生命的定义，一个生命有五个最基本的特征：生长、繁殖、自我调节和修复、可以被杀死和老死。解释了地球上的各种生命如何进化和发展，指出了生命发展的三个发展方向：生命种类的不断演变而进化，生命的类型不断分化而专业化，生命的层次不断的增加而多重化。 分析了疾病发生的原因和特点以及药物的特征，诠释了传统中药配伍理论的哲学本质，指出了未来人类药物筛选研究的战略策略。 关键词： 生命的定义，健康；药物；中药配伍理论 ； 中图分类号 N02 1． 引言 药物是人类在地球上生存的重要物质，人类有长期使用药物治疗和预防疾病的历史。十九世纪以前，药物治疗作用的发现完全是依靠长期的生活经验积累。目前，全世界大约 6000 个化合物和 15000 种天然产物曾经被作为药物使用来治疗疾病。今天，发现疗效好的药物依然是一项具有巨大挑战性的工作，特别是对于某些疾病，如抗肿瘤药物，治疗艾滋病药物等。药物的研究是一项耗资巨大而又十分艰巨的工作，大约从 50000 个新化合物中才有可能筛选到一个可用于临床使用的新药，需要投入 5 亿美元的研究经费，耗时 5 至 8 年时间。随着科学技术的不断发展，人类已经积累了大量的人体自生和其它生物相关的生物科学知识。我们现在已经知道人体的全部 DNA 序列，了解了很多人体的生物代谢途径，科学家正在研究人体 DNA 的每个片段功能与生物代谢调控之间的关系。这对于从分子水平认识和理解人体的生理功能以及病理过程都十分重要。我们说现在是后基因时代，是因为人类已经完全知道了人体的全部 DNA 序列的分子结构顺序。在我们积累了大量的分子生物学的知识与技术的今天，我们应该有更好的思想和方法来研究药物。发现新药不仅仅需要发明新的技术得到大量的新结构的化合物以及建立高通量低成本生物活性筛选技术。更重要而更关键的问题是哪些类型的化合物生物活性可以更快更有效的治疗疾病，并且如何更加安全、更加合理的使用这些化合物生物活性。 2 ．生命的定义 药物治疗疾病不同于修理汽车，药物治疗疾病是为了拯救病人的生命或减轻病人的痛苦。但是，什么是生命？这个问题看起来十分难以回答。人们数千年来一直在寻找这个问题的答案。亚里斯多德和薛定格都对这个问题有着浓厚的兴趣。这也是认知地球上我们周围各种生命现象的一个基本问题，包括认识人体自身的生物机能以及病理过程。如果我们能给生命一个正确的定义，这有利于我们认识生命现象存在的过去，也可指导我们可以预计生命现象发展的未来。同时帮助我们理解我们周围的生命的各种现象，在分子水平理解我们人体的各种生理结构和功能以及疾病的发生过程。帮助我们了解和推测可能的物种生物进化的化学分子过程，认识生物物种生态的结构功能关系以及人类社会的结构功能关系的发展。同时，可以指导药物研究的发展方向。 人们可能会依据不同的目的，以不同的方式定义生命。但是，我们是为了认识所有生命体中最本质的的根本共性，这种共性存在于所有生命体中，有这种共性的物体一定有生命。我们将归纳总结什么是一个生命的概念。 人类已经积累了地球上各种生物体大量的知识和信息，如何确定何种物体拥有生命，何种物体没有生命是十分重要的事情。因此，明确的定义什么是生命十分重要。生命的定义必须具有充分必要性、简明性、客观性、广泛性、延伸性。所谓充分必要性，也就是说给生命定义的条件一定是既充分又必要，即这些条件对所有有生命的物体都存在，同时，具备这些条件的物体一定有生命。简明性是指这些条件简单明了，任何十岁以上的儿童都可能理解。客观性是指生命定义的条件具有广泛的客观识别标准，不会因为不同的人理解上产生差异。广泛性是指生命的定义适用于所有的有生命的物体，无论过去的、还是现在的、以及将来的生命体，无论是地球上的生物体还是其它星球上生物体。延伸性是指生命的定义不仅可以帮助人们认识已经明确的拥有生命的体系，还能促进人们认识过去不曾认识或不完全认识的生命现象和规律。虽然人类积累了大量的生物学知识，但是至今为止还没有一个被普遍接受的生命的定义。有生命物体具有的很多特性明显不同意非生命体物质。地球上的生物体主要由四种元素组成：碳、氢、氧、氮。在每个生物体中有许多生化反应。哪些特征是一个有生命的生物体拥有，而死亡的生物体和无生命的物体一定不拥有呢？这对于我们认识什么是一个生命非常重要。我们说生命体中有一系列生物化学反应，但是一系列的生物化学反应可能没有生命。让我们来分析生命体的共性特征。 第一点， 所有拥有生命的生物体都能生长，也就是说有生命的物体能够从小变大，体积变大和质量变大。变大意味着生命体都能不断从外界获得物质和能量。地球上所有的生物都是从小物体变成大物体。有人认为病毒不能生长，其实病毒感染寄主，从寄主细胞获得活性能量物质开始复制。但是，一个物体能够从小变大不一定有生命，例如，气球从小变大，晶体的生长。 第二点， 所有生命体都能自我繁殖，也就是说每一个有生命的物体可以从一个生命体变成两个生命体，一个变两个也可认为从一代生物到第二代生物。许多科学家被生命的多种复杂自我繁殖现象困惑。一个男人能自我繁殖吗？骡子能自我繁殖吗？我们知道每一个人体细胞能够自我繁殖，为何一个男人不能自我繁殖？只是由于很多学者不明白一个男人和一个细胞是在生命的不同层次，一个人身上的无数细胞都能自我繁殖，但是有繁殖一个人体需要组织更高级的生命层次：一个男女组成的家庭生命层次。同样，能够自我繁殖的物体不一定都有生命， DNA 可以复制，计算机病毒也可以自我复制，他们都没有生命。 第三点， 所有的有生命的生物体能够自我调节和修复，也就是说所有的生命物体，当有外界的刺激条件下，或受到外界的损伤，都能一定程度的自我调节和自我修复。然而，在外界的刺激条件下能自我调节的物体不一定是生命体。例如，机器人具有在外界刺激条件下自动调节的功能。我们知道它没有生命。 第四点， 许都生物体都会随着年龄增加而老死，这是生命的一个基本特征码？实际上我们说所有的生物体都会随年龄老死。什么是一个生命的死亡呢？所谓死亡就是这个生命不能生长，不能繁殖，不能自我调节和修复。老死意味着当一个生命存在了一段时间以后，它会自动的失去生命。有人说细菌可以不断的繁殖分裂下去，但不会老死。实际上一个细菌细胞繁殖很多代以后，会失去繁殖分裂能力，最终会死去。如果没有老的生命死去，地球上的生命就不能进化。然而，很多非生命的物体和现象看起来很像老死过程，例如，木头燃尽，铁器锈蚀，鞋子穿破等等。 第五点， 所有的生命物体都可以被杀死。也就是说有很多物质、方法、或因素可以使得有生命的物体失去生命，不能生长、繁殖。许多科学家和哲学家没有注意到这是生命的最基本特性之一。一个很小的因素可以使一个庞大的生命体死去。只有理解这一点才能理解我们周围的各种生命现象。然而，一个很小的因素也可使一台复杂机器停止运转。 分析思考一个有生命的物体，我们知道每一个生命体都同时具有以上五个特征。我们是否可以说任何一个物体同时具有以上五个特征就一定是一个生命呢？答案是肯定的。一个细胞是一个生命，一棵树是一个生命，一个人是一个生命，一个家庭也是一个生命，一个公司是一个生命，一个城市也是一个生命，一个民族是一个生命，一个国家也是一个生命。一个生态流域是一个生命，地球上所有的生命物质在一起组成地球生物圈，地球生物圈也是一个生命。这就是英国环境学家 James Lovelock 提出的著名 Gaia 假说。 这些生命是不同层次的生命，所有这些不同层次的生命都具有以上我们所说的五个特征。一个生命只能存在一次。所以我们可以得出结论：任何一个物体，如果它具有以上我们所说的五个特征，它就具有一个生命。在宇宙之中，或者在其它星球之上，任何一个物体，无论它是何种元素组成，只有具有这五种特征，一定是一个有生命的物体。 3 生命的发展 一个生物体拥有生命，这意味着这个生物体能够生长，繁殖和老死。任何一个新的生命都有这样的生命过程：出生、生长、繁殖、老死。我们称这个过程为一个生命周期。每一种类的生命都由自己的生命周期。为何我们说生命可以被许多因素杀死是它的最基本特征之一？因为每一个生命体都可以尽可能调节和修复自己以避免被某种因素杀死。这就是为何我们这个地球上的生命体不断发展成为许多种类、许多类型和许多层次。我们知道细胞是地球上很多生命体最基本的生命单元，许多生命体都是由细胞组成，每一个细胞具有一个生命，当环境变化时，每个细胞的新陈代谢都需要调整变化以适应环境的变化来维持细胞的生命。一个生命个体可以有许多细胞组成，当整个个体的生存环境变化时，整个个体的生命就需要调节所有的细胞来适应生命环境的变化。每个生命都是不断的生长繁殖的，它们从小变大，从一个变成多个。这造成了空间的拥挤，物质的短缺，和能源的减少，因而改变了其它生命的生存环境。这使得生命不断调节改变自己，产生生命种类的不断进化，不同种类的生命都在竞争中不断变化，在其生命周期中使用不同的空间、物质和能源。另外一些生命体生存于同一空间，但是他们竞争更加高效的利用物质和能源，它们分化成不同的生命类型，每一种不同类型的生命就有不同的功能，这些不同功能的生命类型组织在一起，形成一个更高一层次的生命体。生命可以像这样不断分化，同时又不断组织成更高层次的生命。地球上所有生命的存在和发展，使得地球上的生命生存的环境更加稳定，同时更加有效地利用太阳传递给地球的能量。当太阳的能量发生变化时，所有的生命都为生命环境的稳定而调节。 让我们来分析一下我们人类，人类相对于其它动物在使用不同的物质和能源。我们人体的细胞分化成为不同类型的细胞，每一类型的细胞都有各自不同的特殊功能，所有这些不同功能的细胞组成了一个人体生命。男人和女人组成了一个家庭的生命；人们分化从事不同的工作，不同工作的人组成了一个社会群体的生命，例如，一个公司的生命；许多不同的社会群体生命组成了一个民族的生命；许多民族生命组成了一个国家的生命。清楚定义什么是一个生命，对于我们认识人体不同细胞的生理功能，认识整个人体的生理过程，疾病发生的过程都有非常重大的意义。同时，对于我们认识其它不同种类的生物体的生理结构，地球上的生态平衡都有很大的帮助。我们可以较容易的推测当生命的环境发生变化是，哪种类型的细胞，或者哪种生化途径可能发生，以及哪种蛋白质可能会产生以利于整个生命体来适应环境的变化。并且，从人类社会的角度，可以预测社会结构的变化方向，每一个社会生命的命运方向和可能。 总之，生命的发展方向主要是三个方面：生命的种类的不断演变而进化，生命的类型的不断分化而专业化，生命的层次不断的增加而多重化 4 ．疾病与药物 我们知道人体有两个层次的生命组成，一个是细胞层次，一个是整体层次。每个层次的生命都有生命周期，都有生命共有的五个基本特征：生长、繁殖、自我调整和修复、被杀死和老死。我们的身体中每一个细胞中有许多新陈代谢反应，并且有许多细胞间的调节。不同的细胞有不同的功能，它们工作在一起来维持整个生命体的功能，使得整个生命体能够适应地球一年四季的环境变化。对于一个健康的生命体来说，所有的新陈代谢反应和细胞间的生理调节都是平衡的。这种平衡使得我们身体中的每个器官工作正常，整个生命在一年四季的环境变化中生命生长繁殖。在整体生命的生长过程中，有许多因素可以引起细胞的新陈代谢和细胞间的生理调节不平衡，例如，营养的缺乏，气温的突然变化，某些化学物质，或者某些物理因素，以及其它种类的生命入侵，都可能引起这些不平衡的发生。如果有某种因素引起细胞内新陈代谢不平衡，整个生命体就有两个层次的调整和修复，一个是细胞水平，一个是整体水平。一个不平衡可能会触发一系列的生化反应，这一系列的反应可能会导致人体的细胞和器官的某些功能损坏，如是这个人就不健康了。如果这种不平衡可以被自身的细胞水平和整体水平来调节和修复，这个人只需要休息就可以康复。如果这种不平衡不能被细胞和整体水平调整和修复，这个人就得了疾病，需要药物来治疗。药物是一些化学物质能够帮助恢复这些细胞水平和细胞间调节平衡。药物对生化代谢反应可能有三种作用方式：一是激动生化反应，二是抑制生化反应，三是终止生化反应。所有的药物都是从病人身体的外面进入到生病的部位发生作用。我们的身体有很多的不同种类的细胞，如何让药物从体外进入体内到达不平衡的生病部位而不伤害其它健康的细胞呢？于是我们至少需要从 50000 个化合物中筛选，才有可能得到一个可能满足条件的化学结构。如何发现以及发现何种药物生物活性可以最好的治疗疾病同时又最小的损伤其它细胞就是我们的艰巨工作。 5 ．药物筛选策略与中药配伍理论 中华民族拥有长期使用天然药物治疗疾病的历史，长期以来积累了大量的药学经验和知识，《神农本草经》明确指出用药物治病宜君臣佐使用药。这就是中药的配伍理论。长期以来，很多学者并没有完全正确的理解君臣佐使的用药原理，甚至某些人将此观点认为是封建迷信。中药就是在这个理论指导下的复方用药，西方学者也对中药复方十分不理解。我在这里给出君臣佐使中药配伍理论的现代概念诠释，君药是用于 治疗最主要的疾病问题，也就是身体内造成疾病的最关键的细胞生化代谢不平衡或细胞间调控不平衡，这种不平衡会导致疾病生命体死亡；臣药是帮助君药到达疾病发生的细胞和组织部位，因为君药从人体外部进入到疾病发生部位，必须通过很多的组织和细胞，这些组织和细胞可以使君药失去生理活性，所以需要臣药来保护君药，使其在药物输送过程中不被其它组织和细胞破坏；佐药用于保护其它生命的健康组织和细胞不被君药、臣药、使药伤害，尽可能减轻药物的毒副作用；使药用于治疗引起疾病的原因，也就是说治疗外界因素引起的人体细胞内部或细胞间的调节的第一个不平衡。由于这个不平衡触发一系列的生化反应的不平衡，最终导致某些重要而关键的细胞内部或细胞间的调节不平衡发生，引起细胞和器官功能损坏而产生疾病，进一步的发展会导致整个生命的死亡。因此，治疗疾病既要指标，又要治本。所以，中药配伍理论是人类最伟大的哲学智慧，只有依据中药配伍理论才可能最有效的治疗疾病，而同时毒副作用最小，对其它组织和细胞损伤最小。我们现代进行药学研究，筛选具有何种生物活性的化合物分子可以用与治疗疾病呢？答案就是具有君臣佐使功能的的生物活性的化学分子。中药君臣佐使配伍理论不仅可以用于用药治病，也可以用于指导药物筛选。在人类未来的药物研究和使用中一定会发挥巨大的影响。 参考文献 Joseph Morales. The Definition of Life Psychozoan: A Journal of Culture Copyright 1998 http://www.baharna.com/philos/life.htm Daniel E. Koshland Jr . The seven pillars of life . Science , 2002 . Vol. 295, 2215-17 Encyclopedia Britannica . Definition of life. 2007 Ultimate Reference Suite Drug screening strategy at post-genome era with Chinese traditional theory of materia medica Xiao Ming Wang Hubei College of Traditional Chinese Medicine, wuhan (430065) E-mail: shermanwang@yahoo.com.cn , Abstract: The author first gives the definition of a life. A life has five characteristics: grow, reproduce itself, adjust and repair itself, can be killed, age to die. He first explained why and how development of life. He concluded: life development consist s three aspects: life species evolution, life type specialization, life level multiplication. He proposed a strategy to screen drug bioactivity and give an explanation of Chinese Traditional theory of Materia medica in modern concept. The best drug to treat a disease life consists of the component s or function s of Monarch drug, minister drug, assistant drug and guide drug. Keywords: definition of life; life development; drug; Chinese traditional theory of materia medica 作者联系： 电话： 02763940732 E-mail: shermanwang@yahoo.com.cn 湖北中医学院药学院 湖北省武汉市洪山区黄家湖西路 1 号 邮编： 430065
标签: 药物
