河南大学12年药学英语.docVIP

n Drug development aims to produce a novel therapeutic agent which is superior in efficacy to existing remedies and which causes less frequent or less severe adverse effects.n 药物研制旨在生产出在疗效上优于现存药品，且副作用发生率减少、程度降低的新型治疗药物。n The development of a new therapeutic agent involves a multidisciplinary group in many years of work. Formerly, drugs were extracted from natural plant and animal sources. Therapeutic use was empirical and based on traditional experience.n 新药研制涉及到多学科研究人员多年的共同研究成果。以前药物是由天然植物和动物体提取的，其治疗作用全凭经验和传统做法来确定的n Over the last 80 years an impressive number of drugs have been synthesized chemically. With the development of genetic engineering and the production of monoclonal antibodies it is likely that even more agents will be produced artificially.n 在过去的80年中，人们通过化学合成，研制出大量药物。随着遗传工程学和单克隆抗体技术的发展，人们必将研制出更多新药。n Synthetic techniques have produced pure substances. This has led to increased specificity of action and, in some cases, greater efficacy and reduced toxicity. Unfortunately new drug development is expensive, and only a few substances (less than 1%) of those developed are actually marketed and used in practice.n 合成技术已研制出高纯度药物，这不仅提高了治疗的专一性，有时还提高了疗效，减少了毒副作用。遗憾的是，新药研制的费用太高，只有少量已研制出的药物（不到1%）被实际推向市场，投入使用。n The range of novel chemical entities developed has occasionally led to unexpected toxicity. As a consequence, most governments have established bodies to regulate drug marketing, e.g. the committee on Safety of Medicines in Britain, and the Food and Drug Administration in the USA. These agencies supervise clinical research on new drugs and license new products.n 在研制出的新型化学制品中，有些会产生意想不到的毒副作用。因此，大多数政府都设有药品发行的调节机构，例如：英国的药品安全委员会和美国的食品药品管理局。这些机构负责管理新药的临床研究和审批发行事宜。Although they serve to protect the public and are seen to do so, the statutory procedures that must be followed in applying for a license for a new drug add greatly to the costs and time of development. n 尽管他们的职责是保护公众,他们也确实这么做了,但申报新药必须遵循的诸多法定程序却大大增加了研制的成本和时间There is some evidence that the rate of introduction of entirely novel agents is slowing down. Whether this reflects economic pressures or diminished novel synthetic capacity or ability is not clear 有迹象显示，全新药物投入使用的速率正在下降。这一现象或许反应了生产成本过高,或者是新药数量的减少或研制能力的下降,具体情况尚不清楚.Drug development strategies 新药开发策略 Several strategies have been used in the development of new drugs. Over the years all have had success but no single approach has been consistently successful几种策略已用于开发新的药物。多年来都取得了成功，但没有一个单一的方法一贯成功Serendipity, luck and intuition运气和直觉This approach has been applied less frequently in recent years. The discovery ofpenicillin by Fleming was in this category.这种方法已应用于近年来较少。发现弗莱明的青霉素在此类别。Molecular roulette 分子轮盘n Random chemical synthesis of new structures and pharmacological screening. This approach is wasteful and depends on the availability of sensitive animal or in vitro models of human disease, which often do not exist.n 对新结构的随机化学合成和药理学筛选。此法不经济（耗费巨大），且依赖于得到往往很难的到的人类疾病的活体标本或试管标本。n Minor structural changes in existing agentsn 对现有药物结构的修饰n Occasionally this leads to compounds of greater efficacy and rarely to drugs with novel actions detected in pharmacological screening or clinical practice.n 此法偶尔可产生功效更高的化合物，但罕有可能产生药理学筛选和临床实践中被检测出具有新功效的药物。n Programmed basic research with synthesis of specific chemical n 程序与特定的化学合成的基础研究Intellectually this approach is the most satisfying. There have been spectacular results, e.g. levodopa and dopamine agonists in the treatment of Parkinsonism; beta-receptor blockers for angina; histamine (H2) antagonists in peptic ulcer disease; converting enzyme inhibitors in hypertension. However, this approach is expensive and there is no guarantee of success理性地说，该途径是最令人满意的。已经有一些引人注目的例子。比如左旋多巴及多巴胺受体激动剂治疗帕金森。b-受体阻断剂治疗心绞痛。组胺受体阻断剂治疗消化道溃疡。ACEI （血管紧张素转化酶抑制剂angiotensin converting enzyme inhibitor，ACEI）治疗高血压。但是该途径成本高，而且并不能保证是成功的。n Clinical observation of drug action in practice 在实践中的作用药物的临床观察n This is the traditional means of drug assessment. New applications arise from measurement of drug action in man in disease states. The antihypertensive effects of thiazide diuretics and beta-blockers were not predicted from animal screening tests. They were only identified after the drugs were available and were being used in practice.n 这是药物评估的传统方法。通过对人体处于疾患状态中药物作用的评估，人们发现其有新的应用价值。噻嗪类利尿剂的抗高血压作用在动物检测试验中没有发现，只是在这些药物投放市场并被实际应用后，其上述作用才被发现。n 3实验药理 以下几段为谷歌翻译不太准确n These studies determine whether the drug has the desired profile of action in model systems. The models are selected to provide as reliable an index of efficacy in man as possible. 这些研究确定该药物是否有行动所需的模型系统中的个人资料。该机型被选中，以提供作为可靠的在尽可能的男子的疗效的索引。n 通常采用的几种模式。模型可能是简单或复杂的，包括n 1细胞培养或细菌n 2部分纯化的酶或亚颗粒n 3孤立的组织n 4灌注器官n 5从老鼠到灵长类动物完整n 对象是，以确定治疗有用的药理活性，并利用建立的模型和药物已知的行动来表征这些行动n 121页Page 121, line 1n When drugs with specific actions on enzymes or receptors are being studied, relatively simple cell-free systems or isolated tissue preparations can be used.n 在研制药物对酶或受体的特异性功效时，可选择相对简单的、较为独立的系统或组织施药。n When poorly characterized subjective actions are sought, particularly involving behavioral effects, it may be necessary to perform tests in conscious intact animals.n 当探索缺乏表征的主观的作用，尤其是涉及行为效应，使用清醒的完整动物进行试验也许是必须的。n In parallel with pharmacological experiments on efficacy, the toxic effects of acute and chronic dosing are determined. Acute toxicity is less important as long as LD50 (the dose that kills 50% of animals) is not close to the ED50 (the dose causing 50% of maximum pharmacological response).n 与药物功效的药理学实验类似，其用药的急慢性毒副作用须被确定。只要LD50（导致50%实验动物死亡的剂量）未接近ED50(引起50%实验动物最大药理学反应的剂量)，急性毒性便不甚重要。n Chronic toxicity testing is more relevant to clinical applications and should take place along the following lines:n 慢性毒性测试与临床应用关系更为密切，须按下列规则进行：The route of administration, dose range, dose frequency and plasma levels should be appropriate to likely clinical indications. 给药途径，剂量范围，给药次数，及血浆药物浓度尽量与临床适应症相一致n (2) At least two species should be studied, usually dog and rat or mouse. If possible a species should be selected with a similar profile of metabolism to man.n 至少应检测两种动物，通常为狗和鼠。有可能的话，其中一种动物的代谢状况应与人相似。n （3）The duration of treatment should be consistent with the likely duration of use in man and the relative life expectancy of the animal species. Usually toxicity studies are undertaken over a period of 4 weeks to at least 1 year.n 治疗期限应与用于人类和具有相关预期寿命的动物的可能治疗期限相一致。通常毒性研究所花时为四周至一年n (4) Haematological and biochemical measurements should be made serially. All tissues should be examined histologically at death or on sacrifice of the experimental group. An untreated control group of littermates should be maintained for comparison.n 应不断地进行血液学测定和生化测定。对实验组中的死亡对象的所有组织都要进行组织学检查。应设定同胎仔畜的非治疗用对照组以便比较。n Depending on the proposed patient group and disease indication, attention must be paid to:(a) Effects on fertility in both males and females.根据拟议的病人组和疾病的征兆，必须注意到：对男性和女性的生育能力。Teratogenic effects on development of the embryo. The vulnerable period in very early in development, during organogenesis.对发育胚胎的致畸性。易感期是胚胎发育的最早期，在器官发生期。Mutagenicity or an increased rate of mutation in germ cell lines or nonreproductive cells, e.g. bone marrow. 致突变性，即生殖细胞系或非生殖性细胞如骨髓细胞系突变率上升。 Carcinogenicity or the induction or promotion of malignant tumor致癌性，即诱导或促进恶性肿瘤的产生 n There is disagreement over the relevance of some animal carcinogenicity studies to man.= Some researchers think tha