药学英语第五版原文翻译

Introduction to Physiology

Introduction

Physiology is the study of the functions of living matter. It is concerned with how an organism performs its varied activities: how it feeds, how it moves, how it adapts to changing circumstances, how it spawns new generations. The subject is vast and embraces the whole of life. The success of physiology in explaining how organisms perform their daily tasks is based on the notion that they are intricate and exquisite machines whose operation is governed by the laws of physics and chemistry.

Although some processes are similar across the whole spectrum of biology—the replication of the genetic code for or example—many are specific to particular groups of organisms. For this reason it is necessary to divide the subject into various parts such as bacterial physiology, plant physiology, and animal physiology.

To study how an animal works it is first necessary to know how it is built. A full appreciation of the physiology of an organism must therefore be based on a sound knowledge of its anatomy. Experiments can then be carried out to establish how particular parts perform their functions. Although there have been many important physiological investigations on human volunteers, the need for precise control over the experimental conditions has meant that much of our present physiological knowledge has been derived from studies on other animals such as frogs, rabbits, cats, and dogs. When it is clear that a specific physiological process has a common basis in a wide variety of animal species, it is reasonable to assume that the same principles will apply to humans. The knowledge gained from this approach has given us a great insight into human physiology and endowed us with a solid foundation for the effective treatment of many diseases.

The building blocks of the body are the cells, which are grouped together to form tissues. The principal types of tissue are epithelial, connective, nervous, and muscular, each with its own characteristics. Many connective tissues have relatively few cells but have an extensive extracellular matrix. In contrast, smooth muscle consists of densely packed layers of muscle cells linked together via specific cell junctions. Organs such as the brain, the heart, the lungs, the intestines, and the liver are formed by the aggregation of different kinds of tissues. The organs are themselves parts of distinct physiological systems. The heart and blood vessels form the cardiovascular system; the lungs, trachea, and bronchi together with the chest wall and diaphragm form the respiratory system; the skeleton and skeletal muscles form the musculoskeletal system; the brain, spinal cord, autonomic nerves and ganglia, and peripheral somatic nerves form the nervous system, and so on.

Cells differ widely in form and function but they all have certain

生理学简介

介绍

生理学是研究生物体功能的科学。它研究生物体如何进行各种活动，如何饮食，如何运动，如何适应不断改变的环境，如何繁殖后代。这门学科包罗万象，涵盖了生物体整个生命过程。生理学成功地解释了生物体如何进行日常活动，基于的观点是生物体好比是结构复杂而灵巧的机器，其操作受物理和化学规律控制。

尽管从生物学整个范畴看，生物体某些活动过程是相似的——如基因编码的复制——但许多过程还是某些生物体群组特有的。鉴于此有必要将这门学科分成不同部分研究，如细菌生理学、植物生理学和动物生理学。

要研究一种动物如何活动，首先需要了解它的构成。要充分了解一个生物体的生理学活动就必须掌握全面的解剖学知识。一个生物体的各部分起着什么作用可通过实验观察得知。尽管我们对志愿者进行了许多重要的生理调查，但是实验条件需要精确控制，所以我们当前大多生理知识还是源于对其它动物如青蛙，兔子，猫和狗等的研究。当我们明确大多数动物物种的特定生理过程存在共同之处时，相同的生理原理适用于人类也是合理的。通过这种方法，我们获得了大量的知识，从而让我们对人类生理学有了更深入的了解，为我们有效治疗许多疾病提供了一个坚实的基础。

机体的基本组成物质是细胞，细胞结合在一起形成组织。组织的基本类型有上皮组织，结缔组织，神经组织和肌组织，每类组织都有各自的特征。许多结缔组织中细胞量相对较少，但是有大量的细胞外基质。相比而言，光滑的肌组织由大量密密麻麻的肌细胞通过特定的细胞连接组成。各种器官如脑，心脏，肺，小肠和肝等由不同种类的组织聚集而成。这些器官是不同生理系统的组成部分。心脏和血管组成心血管系统；肺，器官，支气管，胸壁和膈肌组成呼吸系统；骨骼和骨骼肌组成骨骼肌系统；大脑，脊髓，自主神经和神经中枢以及周围躯体神经组成神经系统等等。

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common characteristics. Firstly, they are bounded by a limiting membrane, the plasma membrane. Secondly, they have the ability to break down large molecules to smaller ones to liberate energy for their activities. Thirdly, at some point in their life history, they possess a nucleus which contains genetic information in the form of deoxyribonucleic acid (DNA).

Living cells continually transform materials. They break down glucose and fats to provide energy for other activities such as motility and the synthesis of proteins for growth and repair. These chemical changes are collectively called metabolism. The breakdown of large molecules to smaller ones is called catabolism and the synthesis of large molecules from smaller ones anabolism.

In the course of evolution, cells began to differentiate to serve different functions. Some developed the ability to contract (muscle cells), others to conduct electrical signals (nerve cells). A further group developed the ability to secrete different substances such as hormones or enzymes. During embryological development, this process of differentiation is re-enacted as many different types of cell are formed from the fertilized egg.

Most tissues contain a mixture of cell types. For example, blood consists of red cells, white cells, and platelets. Red cells transport oxygen around the body. The white cells play an important role in defense against infection and the platelets are vital components in the process of blood clotting. There are a number of different types of connective tissue but all are characterized by having cells distributed within an extensive noncellular matrix. Nerve tissue contains nerve cells and glial cells.

The Principal Organ Systems

The cardiovascular system

The cells of large multicellular animals cannot derive the oxygen and nutrients they need directly from the external environment. The oxygen and nutrients must be transported to the cells. This is one of the principal functions of the blood, which circulates within blood vessels by virtue of the pumping action of the heart. The heart, blood vessels, and associated tissues form the cardiovascular system.

The heart consists of four chambers, two atria and two ventricles, which form a pair of pumps arranged side by side. The right ventricle pumps deoxygenated blood to the lungs where it absorbs oxygen from the air, while the left ventricle pumps oxygenated blood returning from the lungs to the rest of body to supply the tissues. Physiologists are concerned with establishing the factors responsible for the heartbeat, how the heart pumps the blood around the circulation, and how it is distributed to perfuse the tissues according to their needs. Fluid exchanged between the blood plasma and the tissues passes into the lymphatic system, which eventually drains back into the blood.

The respiratory system

细胞在形体和功能上差异很大，但是它们有某些共同的特征。第一，它们由限制膜包被，即细胞质膜；第二，细胞有把大分子分解为小分子来释放活动所需能量的能力；第三，在生命过程中某个阶段，细胞体内存在一个以脱氧核糖核酸(DNA)形式包含基因信息的细胞核。

活体细胞不断转化物质。它们为其它活动提供能量分解葡萄糖和脂肪，比如自身生长和修复所需的蛋白质运动和合成。这些化学变化统称为新陈代谢。把大分子分解为小分子的过程称为分解代谢，小分子合成大分子的过程称为合成代谢。

细胞在进化过程中不断分化进行不同的功能活动。有些细胞具有收缩能力（如肌细胞），有些可以传导电信号（如神经细胞）。进一步进化的细胞能够分泌不同物质如荷尔蒙（如内分泌细胞）或酶。胚胎发育过程中，分化的过程由于很多不同细胞来源于受精卵而再次发生。

大多数组织包含有不同的细胞类型。比如，血液中含红细胞，白细胞和血小板。红细胞运输全身的氧气。白细胞在抵御感染时起重要作用，血小板是血液凝集过程中重要的成分。结缔组织有多种不同类型，但有一个共同特征，即细胞分布在丰富的细胞外基质中。神经组织含神经细胞和神经胶质细胞。

主要的器官系统

心血管系统

大型多细胞动物体的细胞不能从外界环境中获取直接所需的氧气和营养物质。这些氧气和营养物质必须转运到细胞。这是血液的主要功能之一，血液凭借心脏的泵血作用在血管内流动循环。心脏、血管和结缔组织组成了心血管系统。

心脏包括四个腔，两个心房和两个心室构成了一对并排存在的泵。右心室将脱氧的血液泵至肺中，肺中的血液吸收空气中的氧气，而左心室把从肺回流来的有氧血液泵出至身体其它部位，供应给各组织。生理学家研究促使心脏跳动的因素，心脏如何泵送血液使其循环，心脏如何根据各组织所需分配血液。血浆和组织间的流动液体交换流入淋巴系统，最终回流到血液中。

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The energy required for performing the various activities of the body is ultimately derived from respiration. This process involves the oxidation of foodstuffs to release the energy they contain. The oxygen needed for this process is absorbed from the air in the lungs and carried to the tissues by the blood. The carbon dioxide produced by the respiratory activity of the tissues is carried to the lungs by the blood in the pulmonary artery where it is excreted in the expired air. The basic questions to be answered include the following: How is the air moved in and out of the lungs? How is the volume of air breathed adjusted to meet the requirements of the body? What limits the rate of oxygen uptake in the lungs?

The digestive system

The nutrients needed by the body are derived from the diet. Food is taken in by the mouth and broken down into its component parts by enzymes in the gastrointestinal tract. The digestive products are then absorbed into the blood across the wall of the intestine and pass to the liver via the portal vein. The liver makes nutrients available to the tissues both for their growth and repair and for the production of energy. In the case of the digestive system, key physiological questions are: How is food ingested? How is it broken down and digested? How are the individual nutrients absorbed? How is the food moved through the gut? How are the indigestible remains eliminated from the body?

The kidneys and urinary tract

The chief function of the kidneys is to control the composition of the extracellular fluid. In the course of this process, they also eliminate non-volatile waste products from the blood. To perform these functions, the kidneys produce urine of variable composition which is temporarily stored in the bladder before voiding. The key physiological questions in this case are: how do the kidneys regulate the composition of the blood? How do they eliminate toxic waste? How do they respond to stresses such as dehydration? What mechanisms allow the storage and elimination of the urine?

The reproductive system

Reproduction is one of the fundamental characteristics of living organisms. The gonads produce specialized sex cells known as gametes. At the core of sexual reproduction is the creation and fusion of the male and female gametes, the sperm and ova (eggs), with the result that the genetic characteristics of two separate individuals are mixed to produce offspring that differ genetically from their parents.

The musculoskeletal system

This consists of the bones of the skeleton, skeletal muscles, joints, and their associated tissues. Its primary function is to provide a means of movement, which is required for locomotion, for the maintenance of 呼吸系统

机体进行各项活动所需的能量最终来源于呼吸。这一过程包括食物（主要是糖类和脂肪）的氧化，释放它们所含的能量。这一过程中，氧气来自于肺中的空气，经由血液到达全身各组织。组织呼吸活动中释放的二氧化碳由肺动脉中的血液运送至肺，然后呼气排出体外。需回答的基本问题如下：空气是如何进出肺的？呼吸的空气量如何适应机体所需？限制肺吸收氧气频率的因素是什么？

消化系统

机体所需营养物质来源于饮食。食物经口腔进入体内，在胃肠道内经酶将其分解成小分子物质。这些消化物通过肠壁吸收入血液，通过门静脉进入肝脏。经肝脏作用后，这些营养物质能够满足组织生长修复及能量需求。在消化系统部分，重要的生理学问题是：食物是如何消化的？食物如何被个体分解消化？个体营养物质如何吸收？食物如何在肠内转运的？未消化的残留如何从体内排出？

泌尿系统

肾脏主要功能是控制细胞外液体的形成。在这一过程中，肾脏也会把不可挥发的废物排出去。为行使这一功能，在排出之前，肾脏产生含有各种成分的尿液并将其暂时储存在膀胱中。这一部分主要的生理学问题是：肾脏如何调节血液中的成分？如何排出有毒废物？如何应对像脱水这样的应激反应？以及尿液可以存储和排出体外的机制是什么？

生殖系统

生殖是活生物体的一个基本特征。生殖腺产生专门的性细胞，被称为配子。性生殖的核心是雌雄配子即精子和卵子的产生和融合，因此两个独立个体的基因特征融合而产生一个基因上与双亲不同的后代。

运动系统

这一系统由骨、骨骼肌、关节和它们的相关组织组成。其主要功能是提供运动需

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posture, and for breathing. It also provides physical support for the internal organs. Here the mechanism of muscle contraction is a central issue. The endocrine and nervous systems.

The endocrine and nervous systems

The activities of the different organ systems need to be coordinated and regulated so that they act together to meet the needs of the body. Two coordinating systems have evolved: the nervous system and the endocrine system. The nervous system uses electrical signals to transmit information very rapidly to specific cells. Thus the nerves pass electrical signals to the skeletal muscles to control their contraction. The endocrine system secretes chemical agents, hormones, which travel in the bloodstream to the cells upon which they exert a regulatory effect. Hormones play a major role in the regulation of many different organs and are particularly important in the regulation of the menstrual cycle and other aspects of reproduction.

The immune system provides the body’s defenses against infection both by killing invading organisms and by eliminating diseased or damaged cells.

Although it is helpful to study how each organ performs its functions, it is essential to recognize that the activity of the body as a whole is dependent on the intricate interactions between the various organ systems. If one part fails, the consequences are found in other organ systems throughout the whole body. For example, if the kidneys begin to fail, the regulation of the internal environment is impaired which in turn leads to disorders of function elsewhere.

Homeostasis

Complex mechanisms are at work to regulate the composition of the extracellular fluid and individual cells have their own mechanisms for regulating their internal composition. The regulatory mechanisms stabilize the internal environment despite variations in both the external world and the activity of the animal. The process of stabilization of the internal environment is called homeostasis and is essential if the cells of the body are to function normally.

Taking one example, the beating of the heart depends on the rhythmical contractions of cardiac muscle cells. This activity depends on electrical signals which, in turn, depend on the concentration of sodium and potassium ions in the extracellular and intracellular fluids. If there is an excess of potassium in the extracellular fluid, the cardiac muscle cells become too excitable and may contract at inappropriate times rather than in a coordinated manner. Consequently, the concentration of potassium in the extracellular fluid must be kept within a narrow range if the heart is to beat normally.

How Does The Body Regulate Its Own Composition? 要，维持姿势及呼吸运动。它也为内脏器官提供物理支持。这一部分，肌肉收缩机制是主要问题。

内分泌系统和神经系统

不同器官系统的活动需要协作和调节，以便共同作用满足机体需要。人体有两大调节系统：神经系统和内分泌系统。神经系统通过电信号迅速将信息传导给特定细胞。这样神经将电信号传递给骨骼肌以控制收缩。内分泌系统分泌化学物质―激素。激素通过血流到达施与调节作用的细胞。激素在许多不同器官中起着重要作用，在月经期调节和其它生殖方面尤其重要。

免疫系统通过杀死入侵的有机体，清除致病或损伤细胞为机体提供防御功能。

虽然研究各器官如何行使功能很有益处，但我们必须认识到机体作为一个整体所做的活动依赖于各器官系统间错综复杂的相互作用。如果一部分无法正常工作，全身其它器官系统也会受到影响。例如，如果肾脏出现问题，内部环境的调节受损，结果导致其它器官系统功能紊乱。

稳态

各种复杂机制共同作用调节细胞外液的形成，不同个体细胞有自身机制调节内在组成成分。尽管外界环境和动物活动不停变化，调节机制维持着体内环境的稳定。内部环境的稳定被称为稳态，它是机体能够正常发挥作用所必须的。

例如，心脏的跳动依赖于心肌细胞有节律的收缩。这一活动依赖于电信号，而电信号反过来依赖存在于细胞外和细胞内液体中钠和钾离子的浓度。如果细胞外液中钾离子过多，心肌细胞兴奋性增强，可能出现不规律的收缩。因此，要维持心脏正常跳动，细胞外液中钾离子的浓度就必须控制在一定范围内。

机体如何调节物质成分

平衡的概念

一天中，一个成人需要消耗约1千克食物，2~3升液体。以一个月计算，这相当于约30千克食物，60~90升液体。然而，一般来说，机体体重是基本不变的。这类个体可

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The concept of balance

In the course of a day, an adult consumes approximately 1 kg of food and drinks 2~3 liters of fluid. In a month, this is equivalent to around 30 kg of food and 60~90 liters of fluid. Yet, in general, body weight remains remarkably constant. Such individuals are said to be in balance; the intake of food and drink matches the amounts used to generate energy for normal bodily activities plus the losses in urine and feces. In some circumstances, such as starvation, intake does not match the needs of the body and muscle tissue is broken down to provide glucose for the generation of energy. Here, the intake of protein is less than the rate of breakdown and the individual is said to have a negative nitrogen balance. Equally, if the body tissues are being built up, as is the case for growing children, pregnant women and athletes in the early stages of training, the daily intake of protein is greater than the normal body turnover and the individual is in positive nitrogen balance.

This concept of balance can be applied to any of the body constituents including water and salt and is important in considering how the body regulates its own composition. Intake must match requirements and any excess must be excreted for balance to be maintained. Additionally, for each chemical constituent of the body there is a desirable concentration range, which the control mechanisms are adapted to maintain. For example, the concentration of glucose in the plasma is about 4~5mmol/L between meals. Shortly after a meal, plasma glucose rises above this level and this stimulates the secretion of the hormone insulin by the pancreas, which acts to bring the concentration down. As the concentration of glucose falls, so does the secretion of insulin. In each case, the changes in the circulating level of insulin act to maintain the plasma glucose at an appropriate level. This type of regulation is known as negative feedback. During the period of insulin secretion, the glucose is being stored as either glycogen or fat.

A negative feedback loop is a control system that acts to maintain the level of some variable within a given range following a disturbance. Although the example given above refers to plasma glucose, the basic principle can be applied to other physiological variables such as body temperature, blood pressure, and the osmolality of the plasma. A negative feedback loop requires a sensor of some kind that responds to the variable in question but not to other physiological variables. Thus an osmoreceptor should respond to changes in osmolality of the body fluids but not to changes in body temperature or blood pressure. the information from the sensor must be compared in some way with the desired level by some form of comparator. if the two do not match ,an error signal is transmitted to an effector, a system that can act to restore the variable to its desired level .these features of negative feedback can be appreciated by examining a simple heating system .the controlled variable is room temperature, which is sensed by a thermostat. the effector is a heater of some kind .when the room temperature falls below the set point, the temperature 以说处于平衡状态。食物和液体的摄入量相当于正常机体活动消耗的能量加上尿液和粪便中丢失的能量。在一些情况下，如饥饿状态，摄入量与机体所需量并不相当，肌组织断裂，提供葡萄糖产生能量。蛋白质的摄入低于肌组织断裂的速度，机体处于负氮平衡。同样地，如果机体组织正处于生长期，如生长期的儿童，孕妇和早期训练阶段的运动员，那么蛋白质的日常摄入量比正常机体所需要的多。相反，此时个体处于正氮平衡。

平衡的概念可以应用到机体的任何构成成分上，包括水和盐，而且平衡在机体调节其自身成分上是非常重要的。摄入必须等于所需，为维持机体平衡，任何多余的能量都必须排出。此外，因为机体的每种化学成分都有一个可取的浓度范围，控制机制维持这个范围。例如，两餐间血糖浓度大约为4~5mmol/L。进食后不久，血糖含量超过这一范围，刺激胰腺分泌胰岛素，降低浓度。随着葡萄糖浓度的下降，胰岛素分泌减少。在此情况下，循环胰岛素水平的改变都是为了使血浆中的葡萄糖维持在一个合适的范围内。这种调节称为负反馈机制。在胰岛素分泌期间，葡萄糖像肝糖原或脂肪一样被储存。

负反馈调节是在机体出现紊乱时，将一些变量控制在限定范围内的一个控制系统。虽然上面的例子讲到血糖，但这一基本原则可以应用到其它生理变量中如体温、血压和血浆的渗透浓度。负反馈调节需要一种能对不确定的变量做出反应而对其它生理变量不应答的传感器。因此，渗透压感受器应该能对机体体液渗透的变化而不是体温和血压的变化产生应答。感受器传递的信息必须和理想水平（系统的调定点）以比较者的身份，以某种方式进行比较。如果两者不相符，一个错误信号就会传递给效应器，效应器是一种能使变量保持在理想水平的系统。负反馈的这些特点可以通过检测一种简单的加热系统来理解。被控制的变量是室温，它可以由一个温度计检测到，效应器是一种加热器。当室温降低到调定点以下时，温度计就可以监测到温度的变化而开启加热器，对室内进行加温，直到室温升高到先前调好的调定点，加热器关闭。

总而言之，机体实际上是由100万亿细

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difference is detected by the thermostat which switches on the heater .this heats the room until the temperature reaches the per set level whereupon the heater is switched off.

To summarize, the body is actually a social order of about 100 trillion cells organized into different functional structures, some of which are called organs. each functional structures its share to the maintenance of homeostatic conditions in the extracellular fluid, which is called the internal environment.as long as normal conditions are maintained in this internal environment ,the cells of the body continue to live and function properly. Each cell benefits from homeostasis, and in turn, each cell contributes its share toward the maintenance of homeostasis. This reciprocal interplay provides continuous automaticity of the body until one or more functional systems lose their ability to contribute their share of function. When this happens, all the cells of the body suffer. Extreme dysfunction leads to death; moderate dysfunction leads to sickness. 胞有序组成了不同的功能结构，其中一些被称为器官。每个功能结构都在维持细胞外液稳态方面发挥其作用，这称之为内环境。只要内部环境处于正常状态，机体细胞继续生存并正常运行。每个细胞都从稳态中获益，反过来，每个细胞都为稳态做出贡献。这种相互作用促使机体持续自主运行，直至一个或多个功能系统不能正常运转。此时，机体所有细胞都会受损。功能极度异常会导致死亡，轻微的功能异常导致疾病的发生。

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The Other Side of Antibiotics

Antibiotics have eliminated or controlled so many infectious diseases that virtually everyone has benefited from their use at one time or another. Even without such personal experience, however, one would have to be isolated indeed to be unaware of the virtues, real and speculative, of these “miracle” drugs. The American press, radio, and television have done a good job of reporting the truly remarkable story of successes in the chemical war on germs. What’s more, any shortcomings on their part have been more than made up for by the aggressive public relations activity of the pharmaceutical companies which manufacture and sell antibiotics.

In comparison, the inadequacies and potential dangers of these remarkable drugs are much less widely known. And the lack of such knowledge can be bad, especially if it leads patients to pressure their doctors into prescribing antibiotics when such medication isn’t really needed, or leads them to switch doctors until they find one who is, so to speak, antibiotics-minded.

Because the good side of the antibiotics story is so very well-known, there seems more point here to a review of some of the immediate and long-range problems that can come from today’s casual use of these drugs. It should be made clear in advance that calamities from the use of antibiotics are rare in relation to the enormous amounts of the drugs administered. But the potential hazards, so little touched on generally, do need a clear statement. The antibiotics are not, strictly speaking, exclusively prescription drugs. A number of them are permitted in such over-the-counter products as nasal sprays, lozenges, troches, creams, and ointments. Even if these products do no harm, there is no point whatsoever in using them. If you have an infection serious enough to warrant the launching of chemical warfare, you need much bigger doses of the antibiotics than any of the non-prescription products are allowed to contain.

Over-the-counter products, however, account for only a small percentage of total antibiotics production. It is the prescription dosages that give people trouble. These drugs—even allowing for the diverse abilities of the many narrow-spectrum ones and the versatility of the broad-spectrum ones—are not the cure-alls, they often are billed as being. There are wide gaps in their ability to master contagious diseases. Such important infections as mumps, measles, common colds, influenza, and infectious hepatitis still await conquest. All are virus infections and despite intense efforts, very little progress has been made in chemotherapy against viruses. Only small progress has been achieved against fungi. Many strains of bacteria and fungi are naturally resistant to all currently available antibiotics and other chemotherapeutic drugs. Some microorganisms originally sensitive to the action of antibiotics, especially staphylococcus, have developed resistant strains. This

抗生素的另一面

抗生素已经消除或控制了很多传染病，实际上每个人都从这种或那种使用中受益。即使没有这样的个人经验，人们也不得不孤立地认识到这些“奇迹”药物的优点，真实性和推测性。美国新闻界，广播电台和电视台在报道有关细菌化学战争成功的真实故事方面做得很好。更重要的是，制造和销售抗生素的制药公司的积极的公共关系活动已经弥补了他们的缺点。

相比之下，这些显着的药物的不足之处和潜在的危险是广为人知的。缺乏这样的知识可能是不好的，特别是如果它导致病人迫使他们的医生处方抗生素，当这种药物是不是真的需要，或导致他们切换到医生，直到他们找到一个谁可以说，抗生素- 头脑。

因为抗生素故事的好处是如此众所周知，在这里似乎更重要的是要回顾一下当今随便使用这些药物可能产生的一些近期和远期问题。应该预先说明，使用抗生素造成的灾难与所投入的大量药物有关。但是一般来说很少涉及的潜在危害确实需要一个明确的说法。严格来说，抗生素不是完全处方药。它们中的一些允许用于鼻腔喷雾剂，锭剂，锭剂，霜剂和软膏等非处方产品。即使这些产品没有坏处，使用它们也没有任何意义。如果感染的严重程度足以保证发动化学战争，则需要比任何非处方产品所含的抗生素剂量大得多的抗生素。

然而，非处方药产品仅占抗生素总产量的很小比例。这是给人们麻烦的处方剂量。这些药物，即使考虑到许多窄谱药物的多样性和广谱药物的多样性，也不是治愈所有的药物，他们往往被称为“药物”。掌握传染病的能力差距很大。像腮腺炎，麻疹，感冒，流行性感冒和传染性肝炎等重要感染仍在等待征服。所有这些都是病毒感染，尽管付出了巨大的努力，但在化学疗法方面进展甚微。真菌只取得小的进展。许多细菌和真菌菌株对所有目前可用的抗生素和其他化学治疗药物都具有天然的抗性。一些原本对抗生素作用敏感的微生物，特别是葡萄球菌，已经产生了耐药菌株。

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acquired resistance imposes on the long range value of the drugs a very important limitation, which is not adequately met by the frequent introduction of new antimicrobial agents to combat the problem.

It has been pretty well established that the increase in strains of bacteria resistant to an antibiotic correlates directly with the duration and extent of use of that antibiotic in a given location. In one hospital a survey showed that, before erythromycin had been widely used there, all strains of staphylococci taken from patients and personnel were sensitive to its action. When the hospital started extensive use of erythromycin, however, resistant staphylococcus strains began to appear.

The development of bacterial resistance can be minimized by a more discriminating use of antibiotics, and the person taking the drug can help here. When an antibiotic must be used, the best way to prevent the development of resistance is to wipe out the infection as rapidly and thoroughly as possible. Ideally, this requires a bactericidal drug, which destroys, rather than a bacteriostatic drug, which inhibits. And the drug must be taken in adequate dosage for as long as it is necessary to eradicate the infection completely. The doctor, of course, must choose the drug, but patients can help by being sure to take the full course of treatment recommended by the doctor, even though symptoms seem to disappear before all the pills are gone. In rare instances the emergence of resistance can be delayed or reduced by combinations of antibiotics. Treatment of tuberculosis with streptomycin alone results in a high degree of resistance, but if para-aminosalicylic acid or isoniazid is used with streptomycin the possibility that this complication will arise is greatly reduced.

In hospital treatment of severe infections, the sensitivity of the infecting organism to appropriate antibiotics is determined in the laboratory before treatment is started. This enables the doctor to select the most effective drug or drugs; it determines whether the antibiotic is bactericidal or bacteriostatic for the germs at hand; and it suggests the amount needed to destroy the growth of the bacteria completely. In either hospital or home, aseptic measures can help to reduce the prevalence of resistant strains of germs by preventing cross infection and the resultant spreading of organisms.

Every one of the antibiotics is potentially dangerous for some people. Several serious reactions may result from their use. One is a severe, sometimes fatal, shock-like anaphylactic action, which may strike people who have become sensitized to penicillin. Anaphylactic reaction happens less frequently and is less severe when the antibiotic is given by mouth. It is most apt to occur in people with a history of allergy, or a record of sensitivity to penicillin. Very small amounts of penicillin, even the traces which get into the milk of cows for a few days after they are treated with the antibiotic for mastitis, may be sufficient to sensitize; hence, the strong campaign by food and drug officials keeps such milk off the market. 这种获得的耐药性对药物的远距离价值提出了一个非常重要的限制，而这种限制并不能通过频繁引入新的抗菌剂来解决这个问题。

已经确定的是，对抗生素耐药的细菌菌株的增加直接与在给定位置使用抗生素的持续时间和程度相关。在一家医院进行的一项调查显示，在红霉素被广泛使用之前，所有从患者和人员中获得的葡萄球菌菌株对其作用敏感。当医院开始广泛使用红霉素时，耐药葡萄球菌菌株开始出现。

细菌耐药性的发展可以通过更加区分使用抗生素来最小化，服用这种药物的人可以在这里帮助。当必须使用抗生素时，防止抗药性发展的最好方法是尽可能迅速彻底地消灭感染。理想情况下，这需要一种杀菌药物，而不是一种抑制抑制药物的杀菌药物。只要有必要彻底根除感染，必须服用足够的药物。当然，医生必须选择药物，但即使在所有药丸消失之前症状似乎消失，患者仍然可以通过确保服用医生推荐的整个治疗过程来提供帮助。在极少数情况下，抵抗的出现可以通过抗生素的组合来延迟或减少。单独使用链霉素治疗结核病会导致高度的耐药性，但是如果对氨基水杨酸或异烟肼与链霉素一起使用，则会出现这种并发症的可能性大大降低。

在医院治疗严重感染时，在开始治疗之前，在实验室中确定感染生物对适当抗生素的敏感性。这使医生能够选择最有效的药物或药物;它决定了抗生素是否对手边的细菌具有杀菌或抑菌作用;它提示了完全消灭细菌生长所需的量。在医院或家中，无菌措施可以通过预防交叉感染和生物体的扩散来帮助减少耐药菌株的流行。

每一种抗生素都对某些人有潜在危险。他们的使用可能会导致一些严重的反应。一种是严重的，有时是致命的，类似休克的过敏反应，可能会引起对青霉素敏感的人。口服抗生素时，过敏反应发生频率较低，严重程度较轻。最容易发生在有过敏史或对青霉素有敏感记录的人群中。非常少量的青霉素，甚至在用抗生素治疗乳腺炎之后进入母牛乳中几天的痕迹可能足以致敏。因此，食品和药物官员的强力运动使这种牛奶不在市场上。

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To minimize the risk of anaphylactic shock in illnesses where injections of penicillin are the preferred treatment, a careful doctor will question the patient carefully about allergies and previous reactions. In case of doubt another antibiotic will be substituted if feasible, or other precautionary measures will be taken before the injection is given.

Other untoward reactions to antibiotics are gastrointestinal disorders—such as sore mouth, cramps, diarrhea, or anal itch—which occur most frequently after use of the tetracycline group but have also been encountered after use of penicillin and streptomycin. These reactions may result from suppression by the antibiotic of bacteria normally found in the gastrointestinal tract. With their competition removed, antibiotic-resistant staphylococci or fungi, which are also normally present, are free to flourish and cause what is called a super-infection. Such infections can be extremely difficult to cure.

A few antibiotics have such toxic effects that their usefulness is strictly limited. They include streptomycin and dihydrostreptomycin, which sometimes cause deafness, and chloramphenicol, which may injure the bone marrow. Drugs with such serious potential dangers as these should be used only if life is threatened and nothing else will work. All the possible troubles that can result from antibiotic treatment should not keep anyone from using one of these drugs when it is clearly indicated. Nor should they discourage certain preventive uses of antibiotics which have proved extremely valuable.

为了尽量减少注射青霉素是首选治疗的疾病过敏性休克的风险，谨慎的医生会仔细询问病人有关过敏和以前的反应。如果有疑问，如果可行，另一种抗生素将被替代，或在注射前采取其他预防措施。

对抗生素的其他不良反应是使用四环素组后最频繁出现的胃肠疾病- 例如口疮，痉挛，腹泻或肛门瘙痒，但在使用青霉素和链霉素后也遇到过。这些反应可能是由抗生素抑制胃肠道中正常发现的细菌引起的。通过消除竞争，抗生素抗性葡萄球菌或真菌（通常也存在）可以自由繁殖并引起所谓的超感染。这种感染可能极难治愈。

一些抗生素有这样的毒性作用，它们的用途是严格限制的。它们包括有时引起耳聋的链霉素和二氢链霉素，以及可能伤害骨髓的氯霉素。只有在生命受到威胁的情况下才能使用这类具有如此严重潜在危险的药物，否则就不能起作用。在抗生素治疗中可能产生的所有可能的麻烦都不应该使任何人在使用这些药物时明确指出。他们也不应该阻止某些已被证明非常有价值的抗生素的预防性用途。

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Discovery of Insulin, and the Making of a

Medical Miracle

Background

Insulin is a hormone that regulates the amount of glucose (sugar) in the blood and is required for the body to function normally. Insulin is produced by β-cells in the pancreas, also called the islets of Langerhans. These cells continuously release a small amount of insulin into the body, but release surges of the hormone in response to a rise in the blood glucose level.

Certain cells in the body change the food ingested into energy, or blood glucose, that cells can use. Every time a person eats, the blood glucose rises. Raised blood glucose triggers the cells in the islets of Langerhans to release the necessary amount of insulin. Insulin allows the blood glucose to be transported from the blood into the cells. Cells have an outer wall, called a membrane, which controls what enters and exits the cell. Researchers do not yet know exactly how insulin works, but they do know insulin binds to receptors on the cell membrane. This activates a set of transport molecules so that glucose and proteins can enter the cell. The cells can then use the glucose as energy to carry out its functions. Once transported into the cell, the blood glucose level is returned to normal within hours.

Without insulin, the blood glucose builds up in the blood and the cells are starved of their energy source. Some of the symptoms that may occur include fatigue, constant infections, blurred eye sight, numbness, tingling in the hands or legs, increased thirst, and slowed healing of bruises or cuts. The cells will begin to use fat, the energy source stored for emergencies. When this lasts for too long a time the body produces ketones, chemicals produced by the liver. Ketones can poison and kill cells if they build up in the body over an extended period of time. This can lead to serious illness and coma.

People who do not produce the necessary amount of insulin have diabetes. There are two general types of diabetes. The most severe type, known as Type or juvenile-onset diabetes, is when the body does not produce any insulin, Type I diabetics usually inject themselves with different types of insulin three to four times daily. Dosage is taken based on the person's blood glucose reading, taken from a glucose meter. Type n diabetics produce some insulin, but it is either not enough or their cells do not respond normally to insulin. This usually occurs in obese or middle aged and older people. Type II diabetics do not necessarily need to take insulin, but they may inject insulin once or twice a day.

How Insulin Almost Wasn't Discovered

胰岛素的发现和医学奇迹的建立

背景

胰岛素是一种调节血液中葡萄糖（糖）含量的激素，是人体正常功能所必需的。胰岛素由胰腺中的β细胞产生，也称为朗格罕氏胰岛。这些细胞不断释放少量的胰岛素进入人体，但随着血糖水平的升高而释放激素的激增。

体内的某些细胞会将摄入的食物转化为细胞可以利用的能量或血糖。每人一吃，血糖就会升高。升高的血糖引发朗格汉斯胰岛中的细胞释放必要量的胰岛素。胰岛素允许血液从血液运输到细胞。细胞有一个外壁，称为膜，它控制着什么进入和离开细胞。研究人员尚不清楚胰岛素是如何工作的，但他们知道胰岛素与细胞膜上的受体结合。这激活了一组转运分子，使葡萄糖和蛋白质可以进入细胞。然后细胞可以使用葡萄糖作为能量来执行其功能。一旦运送到细胞中，血糖水平在数小时内恢复正常。

如果没有胰岛素，血液中的血糖会积聚在血液中，细胞就会缺乏能量来源。可能发生的一些症状包括疲劳，感染持续，视力模糊，手脚麻木，手脚刺痛，口渴增加，伤口愈合减慢。细胞将开始使用脂肪，紧急情况下储存的能源。当这种持续时间太长时，身体会产生酮，肝脏产生的化学物质。如果酮在体内长时间累积，酮可以毒杀细胞。这可能导致严重的疾病和昏迷。

不产生必需量的胰岛素的人患有糖尿病。有两种一般类型的糖尿病。最严重的类型，即类型或青少年型糖尿病，是当身体不产生任何胰岛素时，I型糖尿病患者通常每天注射不同类型的胰岛素三至四次。根据从葡萄糖计取得的人的血糖读数来服用剂量。n型糖尿病患者会产生一些胰岛素，但这或者是不够的，或者他们的细胞对胰岛素没有正常的反应。这通常发生在肥胖或中年人和老年人。II型糖尿病患者不一定需要服用胰岛素，但可以每天注射一次或两次胰岛素。

胰岛素几乎没有被发现

在发现胰岛素之前，糖尿病是一种可怕的疾病，最可能导致死亡。病人浪费了，变得虚弱，在不可避免的死亡之前难以形容。他们渴

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Before the discovery of insulin, diabetes was a feared disease that most certainly led to death. Patients wasted away, grew weak, and suffered indescribably before their inevitable death. They had insatiable thirst and hunger, but trying to satisfy their hunger only made things worse, and they continued to lose weight. Doctors knew that sugar worsened the condition of diabetic patients and that the most effective treatment was to put the patients on very strict diets where sugar intake was kept to a minimum. At best, this treatment could buy patients a few extra years, but it never saved them. In some cases, the harsh diets even caused patients to die of starvation.

During the nineteenth century, observations of patients who died of diabetes often showed that the pancreas was damaged. In 1869, a German medical student, Paul Langerhans, found that within the pancreatic tissue that produces digestive juices there were clusters of cells whose function was unknown. Some of these cells were eventually shown to be the insulin-producing beta cells. Later, in honor of the person who discovered them, the cell clusters were named the islets of Langerhans.

In 1889 in Germany, physiologist Oskar Minkowski and physician Joseph von Mering, showed that if the pancreas was removed from a dog, the animal got diabetes. But if the duct through which the pancreatic juices flow to the intestine was ligated-surgically tied off so the juices couldn't reach the intestine-the dog developed minor digestive problems but no diabetes. So it seemed that the pancreas must have at least two functions:

●To produce digestive juices

●To produce a substance that regulates the sugar glucose.

This hypothetical internal secretion was the key. If a substance could actually be isolated, the mystery of diabetes would be solved. Progress, however, was slow.

In 1920, an unknown Canadian surgeon named Frederick Banting approached Professor John Macleod, the head of the University of Toronto's physiology department, with an idea about finding that secret. He theorized that the pancreatic digestive juices could be harmful to the secretion of the Pancreas produced by the islets of Langerhans. He therefore wanted to ligate the pancreatic ducts in order to stop the flow of nourishment to the pancreas. This would cause the pancreas to degenerate, making it shrink and lose its ability to secrete the digestive juices. The cells thought to produce an antidiabetic secretion could then be extracted from the pancreas without being harmed. Unfortunately, Macleod, a leading figure in the study of diabetes in Canada, didn't think much of Banting's theories and rebuffed his suggestion. Despite this, Banting managed to convince Macleod that his idea was worth trying. Macleod gave Banting a laboratory with a minimum of equipment and ten dogs. Banting also got an assistant, a medical student by the name of 望饥渴，但饥饿只是让事情变得更糟，继续减肥。医生知道，糖会加重糖尿病患者的病情，最有效的治疗方法是将病人的糖摄入量控制在非常严格的水平。充其量，这种治疗可以多买几年的病人，但从来没有挽救过。在某些情况下，严酷的饮食甚至导致病人死于饥饿。

在十九世纪期间，死于糖尿病的病人的观察结果常常表明胰脏已经受损。1869年，一位德国医学学生Paul Langerhans发现，在产生消化液的胰腺组织内，有功能未知的细胞簇。其中一些细胞最终被证明是产生胰岛素的β细胞。后来，为了纪念发现他们的人，细胞群被命名为朗格汉斯岛。

1889年在德国，生理学家奥斯卡·闵可夫斯基（Oskar Minkowski）和医师约瑟夫·冯·梅林（Joseph von Mering）发现，如果将胰脏从狗身上取下，动物就会患上糖尿病。但是，如果将胰液流入肠道的导管结扎在外科手术中，使得汁液不能到达肠道，那么狗就会产生轻微的消化问题，但不会产生糖尿病。所以胰腺似乎至少有两个功能：

●产生消化液

●生产调节糖分的物质。

这个假设的内分泌是关键。如果一个物质实际上可以孤立，糖尿病的奥秘将被解决。但进展缓慢。

1920年，一位名叫弗雷德里克·班廷（Frederick Banting）的未知加拿大外科医生向多伦多大学生理学系主任约翰·麦克劳德（John Macleod）教授提供了一个关于如何找到这个秘密的想法。他推论胰腺消化液可能对朗格汉斯胰岛产生的胰腺分泌有害。因此，他想结扎胰管，以阻止营养物流向胰腺。这会导致胰腺退化，使其萎缩，失去分泌消化液的能力。认为产生抗糖尿病分泌物的细胞然后可以从胰腺中提取而不受伤害。不幸的是，加拿大糖尿病研究领域的领军人物麦克劳德（Macleod）对班廷的理论并没有太多的想法，并且拒绝了他的建议。尽管如此，万津设法说服了麦克劳德，他的想法值得尝试。麦克劳德给班廷一个实验室，配备了最少的设备和十只狗。班廷还找到了一位名叫查尔斯·贝斯特的医学助理。实验定于1921年夏天开始。

万津和最好的开始他们的实验，从狗取出胰腺。这导致了以下结果：

●血糖升高

Charles Best. The experiment was set to start in the summer of 1921.

Banting and Best began their experiments by removing the pancreas from a dog. This resulted in the following:

●It's blood sugar rose.

●It became thirsty drank lots of water, and urinated more often. ●It became weaker and weaker Experimenting on another dog,

Banting and Best surgically ligated the pancreas, stopping the flow of nourishment, so that the pancreas degenerated. After a while, they removed the pancreas, sliced it up and froze the pieces in a mixture of water and salts. When the pieces were half frozen, they were ground up and filtered. The isolated substance was name d “isletin”.

The extract was injected into the diabetic dog. Its blood glucose level dropped, and it seemed healthier and stronger. By giving the diabetic dog a few injections a day, Banting and Best could keep it healthy and free of symptoms. Banting and Best showed their result to Macleod, who was impressed but he wanted more tests to prove that their pancreatic extract really worked. For the increased testing, Banting and Best realized that they required a larger supply of organs than their dogs could provide, and they starred using pancreases from cattle. with this new source, they managed to produce enough extract to keep several diabetic dogs alive. The new results convinced Macleod that they were onto something big. He gave them more funds and moved them to a better laboratory with proper working conditions. He also suggested that they should call their extract "insulin". Now, the work proceeded rapidly. In late1921, a third person biochemist Bertram Collip, joined the team. Collip was given the task of trying topuri4 the insulin so that it would be clean enough for testing on humans. During the intensified testing, the team also realized that the process of shrinking the pancreases had been unnecessary. Using whole fresh pancreases from adult animals worked just as well.

In 1922 the insulin was tested on Leonard Thompson, a 14-year-old diabetes patient who lay dying at the Toronto General Hospital. He was given an insulin injection. At first he suffered a severe, allergic reaction and further injections were cancelled. The scientists worked hard on improving/ the extract and then a second dose of injections were administered on Thompson. The results were spectacular. The scientists went to the other wards with diabetic children, most of them comatose and dying from diabetic keto-acidosis. They reacted just as positively as Leonard to the insulin extract.

Banting and Macleod were awarded the Nobel Prize in 1923 for the practical extraction of insulin. They were incensed that the other members of their team were not included, and they immediately shared their prize money with Best and Collip. They sold the original ●口渴，多喝水，多喝水。

●变得越来越弱对另一只狗进行试验，万津

和贝佳手术结扎胰腺，停止营养的流动，使胰腺退化。过了一段时间，他们将胰脏

切除，将其切片并冻结在水和盐的混合物

中。当冰块半冻时，将其磨碎并过滤。分

离的物质被命名为“通报”。

将提取物注射到糖尿病狗中。其血糖水平下降，似乎更健康和更强。通过给糖尿病狗每天注射几次，Banting和Best可以保持健康和没有症状。Banting和Best向麦克劳德展示了他们的成果，他对此印象深刻，但他想要进行更多的测试来证明他们的胰脏提取物确实有效。为了增加测试，Banting和Best认识到他们需要比他们的狗能够提供更多的器官供应，并且他们使用来自牛的胰脏来主演。有了这个新的来源，他们设法产生足够的提取物，让几只糖尿病的狗保持活着。新的结果使麦克劳德相信他们正在做一些大事。他给了他们更多的资金，把他们搬到了一个有适当工作条件的更好的实验室。他还建议，他们应该叫他们的提取物“胰岛素”。现在，工作进展迅速。在1921年底，第三人称生物化学家Bertram Collip加入了队伍。Collip被赋予尝试topuri4胰岛素的任务，以便它足够干净，可以在人体上进行测试。在加强检测过程中，团队也意识到缩小胰腺的过程是不必要的。使用来自成年动物的全新鲜的胰腺也同样如此。

1922年，在14岁的多伦多综合医院死亡的糖尿病患者伦纳德·汤普森（Leonard Thompson）身上测试了胰岛素。他被给了胰岛素注射。起初，他遭受了严重的过敏反应，取消了进一步的注射。科学家努力改善/提取物，然后在汤普森进行第二次注射。结果是壮观的。科学家去了另一个病房与糖尿病的孩子，他们大多是昏迷和死于糖尿病酮酸中毒。他们的反应和Leonard一样积极。

万津和麦克劳德在1923年被授予诺贝尔奖，用于实际提取胰岛素。他们被激怒，其他队员不包括在内，他们立即用Best和Collip 分享他们的奖金。他们把原来的专利卖给了多伦多大学半美元。他们不是为了名利，他们想让生病的孩子免于死亡。他们最终在经济上受益，但这是他们心中的最后一件事。

在发现胰岛素后不久，医药公司Eli Lilly 就开始大规模生产提取物。早在1923年，该

patent to the University of Toronto for one half dollar. They were not looking for fame or fortune; they wanted to keep sick children from dying. They did eventually benefit financially, but that was the last thing on their minds.

Very soon after the discovery of insulin, the medical firm Eli Lilly started large-scale production of the extract. As early as in 1923, the firm was producing enough insulin to supply the entire North American continent. Although insulin doesn't cure diabetes, it's one of the biggest discoveries in medicine. When it came, it was like a miracle. People with severe diabetes and only days left to live were saved. And as long as they kept getting their insulin, they could live an almost normal life.

Working with human insulin

In 1982, the Eli Lilly Corporation produced a human insulin (Humulin®) that became the first approved genetically engineered pharmaceutical product. This important achievement was the result of a vast network of basic and applied scientific advances that began in the 1950s with the classic structural studies on DNA by Watson and Crick and on insulin by Sanger.' Without needing to depend on animals, researchers could produce genetically engineered insulin in unlimited supplies. It also did not contain any of the animal contaminants. Using human insulin also took away any concerns about transferring any potential animal diseases into the insulin. While companies still sell a small amount of insulin produced from animals—mostly porcine—from the 1980s onwards, insulin users increasingly moved to a form of human insulin created through recombinant DNA technology.

Insulin is a protein consisting of two separate chains of amino acids, an A above a B chain, that are held together with disulfide bonds. The insulin A chain consists of 21 amino acids and the B chain has 30. Before becoming an active insulin protein, insulin is first produced as preproinsulin. This is one single long protein chain with the A and B chains not yet separated, a section in the middle linking the chains together and a signal sequence at one end telling the protein when to start secreting outside the cell. After preproinsulin, the chain evolves into proinsulin, still a single chain but without the signaling sequence. Then comes the active protein insulin, the protein without the section linking the A and B chains. At each step, the protein needs specific enzymes to produce the next form of insulin.

Lilly has prepared human insulin by two different means'"-initially, by a chain combination procedure and, since 1986, by transforming human proinsulin into human insulin. In the first method, the two insulin chains are produced separately. Manufacturers need the two mini-genes: one that produces the A 公司就生产出足够的胰岛素供应整个北美大陆。虽然胰岛素不能治愈糖尿病，但这是医学界最大的发现之一。一旦到来，就像是一个奇迹。患有严重糖尿病，只剩下几天生活的人得救了。只要不断得到胰岛素，他们就能过上几乎正常的生活。

使用人胰岛素

1982年，礼来公司生产了一种人胰岛素（Humulin®），成为首个获得批准的基因工程药物产品。这一重要成就是20世纪50年代由沃森和克里克对DNA进行的经典结构研究以及由桑格公司提供的胰岛素开始的一个广泛的基础和应用科学进展网络的结果。研究人员不需要依赖动物，就可以生产出无限制供应的基因工程胰岛素。它也没有包含任何动物污染物。使用人体胰岛素也消除了将任何潜在动物疾病转移到胰岛素中的担忧。尽管从20世纪80年代开始，公司仍然出售少量由动物产生的胰岛素（主要是猪），但是胰岛素使用者越来越多地转向通过重组DNA技术形成的人胰岛素形式。

胰岛素是一种蛋白质，由两条独立的氨基酸链组成，一条B链以上的A链与二硫键结合在一起。胰岛素A链由21个氨基酸组成，B链有30个。在成为活性胰岛素蛋白质之前，胰岛素首先作为前胰岛素原产生。这是一个单链长的蛋白质链，A链和B链还没有分开，中间的一段链接在一起，信号序列的一端告诉蛋白质何时开始在细胞外分泌。前胰岛素原后，链发展成胰岛素原，仍然是单链，但没有信号序列。然后是活性蛋白质胰岛素，不含连接A 和B链的部分的蛋白质。在每个步骤中，蛋白质都需要特定的酶来产生下一种形式的胰岛素。

礼来公司通过两种不同的方式来制备人胰岛素- 最初是通过链式结合的方法，自1986年以来，通过将人胰岛素原转化成人胰岛素，第一种方法是分别生产两种胰岛素链，基因：一个产生A链和一个B链，由于每条链的确切的DNA序列是已知的，他们合成每个小基因的DNA并将它们插入到质粒中，然后转化新形成的重组质粒在发酵过程中，携带重组质粒的数百万个细菌通过细胞分裂大约每隔20分钟复制一次，每个细胞表达胰岛素基因; 倍增后，将细胞从发酵罐中取出，打开提

chain and one for the B chain. Since the exact DNA sequence of each chain is known, they synthesize each mini-gene's DNA and insert them into plasmids. The recombinant, newly formed, plasmids are then transformed into bacterial cells. During a fermentation process, the millions of bacteria harboring the recombinant plasmid replicate roughly every 20 minutes through cell division, and each expresses the insulin gene. After multiplying, the cells are taken out of the fermentation tanks and broken open to extract the protein chains. The two chains are then mixed together and joined by disulfide bonds through the reduction-reoxidation reaction. Although the chain combination procedure worked quite well, the proinsulin approach required fewer processing steps and, consequently, superseded the chain method in 1986. The sequence that codes for proinsulin is inserted into the non-pathogenic E.coli bacteria. The bacteria go through the fermentation process where they reproduce and produce proinsulin. Then the connecting sequence between the A and B chains is spliced away with an enzyme and the resulting insulin is purified.

The Future

The future of insulin holds many possibilities. Since insulin was first synthesized, diabetics needed to regularly inject the liquid insulin with a syringe directly into their bloodstream. This allows the insulin to enter the blood immediately. For many years it was the only way known to move the intact insulin protein into the body. In the 1990s, researchers began to make inroads in synthesizing various devices and forms of insulin that diabetics can use in an alternate drug delivery system.

Manufacturers are currently producing several relatively new drug delivery devices. Insulin pens look like a writing pen. A cartridge holds the insulin and the tip is the needle. The user set a dose, inserts the needle into the skin, and presses a button to inject the insulin. With pens there is no need to use a vial of insulin. However, pens require inserting separate tips before each injection. Another downside is that the pen does not allow users to mix insulin types, and not all insulin is available.

The insulin pump allows a controlled release in the body. This is a computerized pump about the size of a beeper, that diabetics can wear on their belt or in their pocket. The pump has a small flexible tube that is inserted just under the surface of the diabetic's skin. The diabetic sets the Pump to deliver a steady, measured dose of insulin throughout the day, increasing the amount right before eating. This mimics the body's normal release of insulin. Manufacturers have produced insulin pumps since the 1980s but advances in the late 1990s and early twenty-first century have made them increasingly easier to use and more popular. Researchers are exploring the possibility of implantable insulin pumps. Diabetics would control 取蛋白质链，然后将两条链混合在一起，通过还原- 再氧化反应通过二硫键连接，尽管链组合过程起作用胰岛素原方法需要较少的处理步骤，因此在1986年取代了链式方法。将编码胰岛素原的序列插入到非致病性大肠杆菌细菌中。细菌经过发酵过程，再生产胰岛素原。然后用酶将A链和B链之间的连接顺序剪切掉，得到的胰岛素被纯化。

未来

胰岛素的未来有很多可能性。由于胰岛素首先被合成，糖尿病患者需要定期用注射器将液体胰岛素直接注入他们的血液中。这使胰岛素立即进入血液。多年来，这是将完整的胰岛素蛋白质移入体内的唯一方式。在二十世纪九十年代，研究人员开始着手合成糖尿病患者可用于替代药物输送系统的各种装置和形式的胰岛素。

制造商目前正在生产几种较新的药物输送装置。胰岛素笔看起来像写字笔。一个墨盒容纳胰岛素，尖端是针。用户设定剂量，将针插入皮肤，并按下按钮以注射胰岛素。用钢笔不需要使用一小瓶胰岛素。但是，笔需要在每次注射之前插入单独的提示。另一个缺点是，笔不允许用户混合胰岛素类型，并不是所有的胰岛素都可用。

胰岛素泵可以在体内控制释放。这是一个关于蜂鸣器大小的电脑泵，糖尿病患者可以穿在腰带上或口袋里。该泵具有插入糖尿病皮肤表面下方的小柔性管。糖尿病患者将泵设置为在一整天内提供稳定的测量剂量的胰岛素，在进食之前增加量。这模仿人体正常的胰岛素释放。自20世纪80年代以来，制造商已经生产了胰岛素泵，但是在20世纪90年代末和21世纪初的发展使得它们越来越易于使用和更受欢迎。研究人员正在探索植入式胰岛素泵的可能性。糖尿病患者将通过外部遥控器控制这些设备。

研究人员正在探索其他的药物输送选择。通过药片摄取胰岛素是一种可能性。食用胰岛素的挑战在于，胃的高酸性环境会破坏蛋白质进入血液之前。研究人员正在研究用特殊材料涂覆胰岛素，以保护药物不受胃酸的影响。

在2001年，有希望的测试发生在吸入式胰岛素装置和制造商汀可能在未来几年内开始生产的产品。由于胰岛素是一个相对较大的

these devices through an external remote control.

Researchers are exploring other drug-delivery options. Ingesting insulin through pills is one Possibility. The challenge with edible insulin is that the stomach's high acidic environment destroys the protein before it can move into the blood. Researchers are working on coating insulin with special materials that would protect the drugs from the stomach's acid.

In 2001 promising tests are occur Ting on inhaled insulin devices and manufacturers could begin producing the products within the next few years. Since insulin is a relatively large protein, it does not permeate into the lungs. Researchers of inhaled insulin are working to create insulin particles that are small enough to reach the deep lung. The particles can then pass into the bloodstream. Researchers are testing several inhalation devices much like that of an asthma inhaler.

Insulin patches are another drug delivery system in development. Patches would release insulin continuously into the bloodstream. The challenge is finding a way to have insulin pass through the skin. Ultrasound is one method researchers are investigating. These low frequency sound waves could change the skin's permeability and allow insulin to pass.

Other research has the potential to discontinue the need for manufacturers to synthesize insulin. Researchers are working on creating the cells that produce insulin in the laboratory. The thought is that physicians can someday replace the non-working pancreatic cells with insulin-producing cells. Another hope for diabetics is gene therapy. Scientists are working on correcting the insulin gene's mutation so that diabetics would be able to produce insulin on their own. 蛋白质，它不会渗透到肺部。吸入式胰岛素的研究人员正在努力创造足够小的胰岛素颗粒，以达到深肺。颗粒然后可以进入血流。研究人员正在测试几种吸入装置，就像哮喘吸入器一样。

胰岛素贴剂是另一种正在开发的药物输送系统。补丁会不断释放胰岛素进入血液。挑战是找到一种方法让胰岛素通过皮肤。超声波是研究人员正在研究的一种方法。这些低频声波可以改变皮肤的渗透性，使胰岛素通过。

其他研究有可能不再需要制造商合成胰岛素。研究人员正在研究在实验室中制造产生胰岛素的细胞。这个想法是，医生有一天可以用胰岛素生产细胞取代非工作的胰腺细胞。糖尿病患者的另一个希望是基因治疗。科学家正在努力纠正胰岛素基因的突变，使糖尿病患者能够自行产生胰岛素。

Adverse Drug Reactions

Adverse drug reactions are unwanted effects caused by normal therapeutic doses .Drugs are great mimics of diseases, and adverse drug reactions present with diverse clinical signs and symptoms. The classification proposed by Rawlins and Thompson divides reactions into type A and type B.

Type A reactions ,which constitute the great majority of adverse drug reactions, are usually a consequence of the drug’s main pharmacological effect (bleeding from warfarin) or a low therapeutic index (nausea from digoxin), and they are therefore predictable. They are dose-related and usually mild, although they may be serious or even fatal (intracranial bleeding from warfarin). Such reactions are usually due to incorrect dosage (too much or too long), for the individual patient or to disordered pharmacokinetics, usually impaired drug elimination. The term “side-effects” is often applied to minor type A reactions.

Type B (idiosyncratic) reactions are not predictable from the drug’s main pharmacological action, are not dose-related and are severe, with a considerable mortality. The underlying pathophysiology of type B reactions is poorly if at all understood, and often has a genetic or immunological basis. Type B reactions occur infrequently (1:1000-1:1000 treated subjects being typical).

Three further minor categories of adverse drug reactions have been proposed.

1.Type C: continuous reactions due to long-term drug use

(neuroleptic-related tardive dyskinesia or analgesic nephropathy);

2.Type D: delayed reactions (alkylating agents leading to

carcinogenesis, or retinoid-associated teratogenesis);

3.Type E: end-of-use reactions such as adrenocortical insufficiency

following withdrawal of corticosteroids, or withdrawal syndromes following discontinuation of treatment with clonidine, benzodiazepines, tricyclic antidepressants or beta-adrenoreceptor antagonists.

There are between 30000 and 40000 medicinal products available directly or on prescription in the UK, A recent survey suggested that approximately 80% of adults take some kind of medication during any 2-week period, Exposure to drugs in the population is thus substantial, and the incidence of adverse reactions must be viewed in this context. Type A reactions are believed to be responsible for up to 3%of acute hospital admissions and 2%~3%of consultations in general practice. In hospital, clinically significant adverse reactions are estimated to complicate10%~20% of all admissions, prolonging hospital stay and causing suffering and an appreciable number of fatalities, as well as wasting resources, They are the most frequent and severe in neonates, the elderly, women, patients with hepatic or renal disease, and

药物不良反应

药物不良反应是正常治疗剂量引起的不良反应。药物是疾病的很好的模拟药物，不良的药物反应表现出不同的临床症状和体征。罗林斯和汤普森提出的分类将反应分为A型和B型。

A型反应占绝大多数不良反应，通常是药物主要药理作用（华法林出血）或低治疗指数（地高辛引起的恶心）的结果，因此可预测。他们是剂量相关的，通常是轻微的，尽管他们可能是严重的甚至是致命的（华法林的颅内出血）。这种反应通常是由于不正确的剂量（太多或太长），对于个别患者或药代动力学紊乱，通常是药物消除受损。术语“副作用”通常适用于轻微的A型反应。

B型（特异性）反应不能从药物的主要药理作用预测，与剂量无关并且是严重的，具有相当大的死亡率。B型反应的潜在病理生理学如果根本理解的话是很差的，并且通常具有遗传或免疫学基础。B型反应发生率很低（典型情况下为1：1000-1：1000）。

已经提出了另外三个小的不良药物反应。

1.C型：由于长期使用药物引起的持续反

应（与神经阻滞剂有关的迟发性运动障

碍或镇痛性肾病）;

2.D型：延迟反应（烷化剂导致致癌，或

维甲酸相关致畸形）;

3.E型：停用反应如停用皮质类固醇后肾

上腺皮质功能不全，停用可乐定，苯二

氮卓类，三环类抗抑郁药或β-肾上腺素

受体拮抗剂终止使用后的综合征。

在英国，直接或处方药品有30000到40000种之间。最近的一项调查显示，大约80％的成年人在任何2周的时间内服用某种药物。因此，人群中的药物暴露量很大，必须从这个角度来看待不良反应的发生率。A 型反应被认为是造成急性住院的高达3％，在一般实践中占2％~3％。在医院中，临床上显着的不良反应估计使全部住院病人的10％~20％复杂化，延长住院时间，造成痛苦和可观的死亡人数以及浪费资源，是新生儿/老年人中最常见和最严重的，女性，肝脏或肾脏疾病患者，以及有既往药物不良反应史的患者。药物不良反应经常发生在治疗的早

individuals with a history of previous adverse drug reactions, Adverse drug reactions often occur early in therapy (during the first 1~10day).

The drugs most commonly implicated are digoxin, antimicrobials, diurectics, potassium salt replacements, analgesics, sedatives and major tranquillizers, insulin, aspirin, glucocorticosteroids, antihypertensives and warfarin

Factors involved in the etiology of adverse drug reactions can be classified as follows

1.patient factors

Intrinsic:

Age: neonatal, infant and elderly

Sex: hormonal environment

Genetic abnormalities (e.g. enzyme or receptor polymorphisms)

Previous adverse drug reactions, allergy, atopy

Presence of organ dysfunction: disease

Personality and habits: alcoholic, drug addict, nicotine, compliance

Extrinsic:

Environment-sun

Xenobiotics (e.g. drugs, herbicides)

Malnutrition

2.Prescriber factors

Incorrect drug or drug combination

Incorrect route of administration

Incorrect dose

Incorrect duration of therapy

3.Drug factors

Drug-drug interactions

Pharmaceutical-batch problems, shelf-life, incorrect dispensing

Adverse Drug Reaction Monitoring/Surveillance

Pharmacovigilance

The evaluation of drug safety is complex, and there are many methods for monitoring adverse drug reactions. Each of these has its own advantages and shortcomings, and no single system can offer the absolute security that public opinion expects. The ideal method would identify adverse drug reactions with a high degree of sensitivity and specificity and respond rapidly.

It would detect rare but severe adverse drug reactions, but would not be overwhelmed by common ones, the incidence of which would quantify together with predisposing factors, Continued surveillance is mandatory after a new drug has been marketed, as it is inevitable that the preliminary testing of medicines in humans during drug development, although excluding many ill effects, cannot identify uncommon adverse effects. A variety of early detection methods have been introduced to identify adverse drug reactions as swiftly as 期（第1~10天）。

最常涉及的药物是地高辛、抗菌剂、利尿剂、钾盐替代品、镇痛剂、镇静剂和主要镇定剂、胰岛素、阿司匹林，糖皮质激素、抗高血压药和华法林

涉及药物不良反应病因的因素可以分类如下

1.患者因素

固有：

年龄：新生儿，婴幼儿和老年人

性别：荷尔蒙环境

遗传异常（例如酶或受体多态性）

以前的药物不良反应，过敏，特应性

器官功能障碍的存在：疾病

个性和习惯：酒精，吸毒者，尼古丁，依从性

外在：

环境：光照

异生素（如药物，除草剂）

营养不良

2.处方因素

不正确的药物或药物配伍

不正确的管理路线

不正确的剂量

不正确的治疗持续时间

3.药物因素

药物相互作用

药品批次问题，保质期，错误配药

药物不良反应监测/监测药物警戒

药物安全性的评估是复杂的，监测药物不良反应的方法有很多。每一个都有自己的优点和缺点，没有一个单一的制度可以提供舆论期望的绝对安全。理想的方法是以高度的敏感性和特异性鉴别药物不良反应，并迅速做出反应。

它可以检测罕见但严重的药物不良反应，但不会被普通药物所淹没，其发生率将与易感因素一起量化。新药上市后必须持续监测，因为初步检测是不可避免的药物在人体内的药物开发虽然排除了许多不良影响，但不能识别不寻常的副作用。已经引入了多种早期检测方法来尽可能迅速地识别药物不良反应。

I / II / III期试验

possible.

Phase I/II/III Trials

Early (Phase I/II) trials are important for assessing the tolerability and dose-response relationship of new therapeutic agents, However, these studies are very insensitive at detecting adverse reactions because they are performed on relatively few subjects (perhaps 200~300).This is illustrated by the failure to detect the serious toxicity of several drugs (practolol, benoxaprofen, temafloxacin ,felbamate, dexfenfluramine and fenfluramin, troglitazone) before marketing. However, phase III clinical trials can establish the incidence of common adverse reactions and relate this to therapeutic benefit. Analysis of the reasons given for dropping out of phase III trials is particularly valuable in establishing whether common events such as headache, constipation, lethargy or male sexual dysfunction are truly drug related. The Medical Research Council Mild Hypertension Study unexpectedly identified impotence as being more commonly associated with thiazide diuretics than with placebo or beta-adrenoreceptor antagonist therapy in this way.

The problem of adverse drug reaction recognition is much greater if the reaction resembles spontaneous disease in the population, such that physicians are unlikely to attribute the reaction to drug exposure, The numbers of patients that must be exposed to enable such reactions to be detected are probably greater than those quoted by more than one or two orders of magnitude.

早期（I / II期）试验对于评估新型治疗药物的耐受性和剂量反应关系是重要的。然而，这些研究对于检测不良反应非常不敏感，因为它们是在相对较少的受试者（可能为200-300）下进行的。这可以通过在销售前未检测到几种药物（普罗洛尔，苯氧丙酸，替马沙星，非氨酯，右芬氟拉明和芬氟拉明，曲格列酮）的严重毒性来说明。然而，III期临床试验可以确定常见不良反应的发生率，并将其与治疗益处联系起来。对于剔除III 期临床试验的原因的分析，对于确定头痛，便秘，嗜睡或男性性功能障碍等常见事件是否真正与药物有关是特别有价值的。医学研究委员会轻度高血压研究出乎意料地发现，与安慰剂或β-肾上腺素受体拮抗剂治疗相比，噻嗪类利尿剂更通常与阳痿相关。

如果反应类似于人群中的自发性疾病，则药物不良反应识别的问题更为严重，因此医生不太可能将反应归因于药物暴露。必须暴露以使得能够检测到这种反应的患者的数目可能大于那些超过一个或两个数量级的引用。

Lead compounds

Before any medicinal chemistry project can get underway, a lead compound is required. A lead compound will have some property considered therapeutically useful. The property sought will depend on the tests used to detect the lead compound, which in turn depends on the drug’s target. The level of biological acti vity may not be particularly high, but that does not matter. The lead compound is not intended to be used as a clinical agent. It is the starting point from which a clinically useful can be developed. Similarly, it does not matter whether the lead compound is toxic or has undesirable side effects. Again, drug design aims to improve the desirable effects of the lead compound and to remove the undesirable effects.

Lead compounds can be obtained from a variety of different sources such as the flora and fauna of the natural world, or synthetic compounds made in the laboratory. There is also the potential of designing lead compounds using computer modeling or NMR spectroscopic studies.

In order to search for lead compounds, a suitable test is required. This could be a test that reveals a physiological effect in a tissue preparation, organ or test animal. Alternatively, it could be a cellular effect, resulting from the interaction of a lead compound with a particular target, such as a receptor or an enzyme; or a molecular effect, such as the binding of a compound with a receptor. In the last two situations, the molecular target is considered important to a particular disease state, and in such cases, the lead compound may not have the desired physiological activity at all. For example, there have been several examples where the natural agonist for a receptor was used as the lead compound in order to design a receptor antagonist. Here, the crucial property for the lead compound was that it should be recognized and bound to the binding site of the target receptor. The lead compound was then modified to bind as an antagonist rather than as an agonist. For example, the chemical messenger histamine was used as the lead compound in developing the anti-ulcer agent, cimetidine. Histamine is an agonist that activates histamine receptors in the stomach wall to increase the gastric acid of release. Cimetidine acts as an antagonist at these receptors, thus reducing the levels of gastric acid release and allowing the body to heal the ulcer.

The natural world is particularly rich in potential lead compounds. For example, plants, trees, snakes, lizards, frogs, fungi, corals and fish have all yielded potent lead compounds which have either resulted in clinically useful drugs or have the potential to do so. There is a good reason why nature should be so rich in potential lead compounds, Years of evolution have resulted in the “selection” of biologically potent natural compounds that have proved useful to the natural host for a variety of reasons. For example, a fungus that produces a toxin can kill off its microbiological competitors and take advantage of available

先导化合物

在任何药物化学项目开始之前，都需要先导化合物。先导化合物将具有被认为治疗有用的一些性质。所寻求的财产将取决于用于检测先导化合物的测试，而这又取决于药物的目标。生物活性水平可能不是特别高，但这并不重要。先导化合物不打算用作临床药物。这是开发临床有用的起点。同样，先导化合物是否有毒或有不良副作用并不重要。同样，药物设计旨在改善先导化合物的理想效果并消除不良影响。

先导化合物可以从各种不同的来源获得，例如自然界的动植物，或者在实验室中制造的合成化合物。使用计算机建模或核磁共振氢谱研究还有设计先导化合物的潜力。

为了寻找先导化合物，需要进行适当的测试。这可能是揭示在组织准备，器官或测试动物中的生理效应的测试。或者，它可以是细胞效应，由先导化合物与特定靶标例如受体或酶的相互作用产生;或分子效应，例如化合物与受体的结合。在最后两种情况下，分子靶标被认为对于特定疾病状态是重要的，在这种情况下，先导化合物可能根本不具有所需的生理活性。例如，为了设计受体拮抗剂，已经有几个实例将受体的天然激动剂用作先导化合物。在这里，先导化合物的关键性质是它应该被识别并与目标受体的结合位点结合。然后将先导化合物修饰成结合拮抗剂而不是激动剂。例如，化学信使组胺被用作开发抗溃疡剂西咪替丁的先导化合物。组胺是激活胃壁组胺受体以增加胃酸释放的激动剂。西咪替丁作为这些受体的拮抗剂，从而降低了胃酸释放的水平并使身体能够治愈溃疡。

自然界在先导化合物方面尤为丰富。例如，植物，树木，蛇，蜥蜴，青蛙，真菌，珊瑚和鱼都已经产生了有效的先导化合物，这些化合物或者导致了临床上有用的药物或者有可能这样做。为什么大自然应该如此丰富潜在的先导化合物有一个很好的理由。多年的进化已经导致生物有效天然化合物的“选择”，由于各种原因已经证

nutrients.

Large numbers of novel structures are synthesized in research laboratories across the world for a diverse range of synthetic projects. These are a potential source of lead compounds, and pharmaceutical companies will often enter into arguments with research teams in order to test their compounds. Many of these structures may have been synthesized in research topics unrelated to medicinal chemistry, but are still potential lead compounds. The history of medicinal chemistry has many examples of lead compounds that were discovered from synthetic projects that had no medicinal objective in mind, for example, prontosil was manufactured as a dye, but was the lead compound for the development of the sulfonamides.

Strategies in the Search for New Lead Compounds

A retrospective analysis of the ways leading to discovery of new drugs suggests that there are four types of successful strategies leading to new lead compounds.

The first strategy consists of systematic screening of sets of compounds arbitrarily chosen for their diversity, by selected biological assays. This approach was useful in the past for the discovery of new antibiotics such as streptomycin and for the identification of compactin as an HMG-CoA reductase inhibitor. Presently, as high-throughput screening (HTS), it is applied in a very general manner to synthetic as well as to natural compounds. Experience gathered has confirmed that high-throughput screening allows for the rapid identification of numerous hits, and the literature is full of success stories obtained with that approach. Among them, one could mention the discovery of insulin mimetics, of ORL1 receptor agonists, of protein tyrosine phosphatase-1 B inhibitors, of selective neuropeptide Y5 receptor antagonists, of selective COX-2 inhibitors, of corticotropin releasing factor (CRF) receptor modulators, and of CXCR2 receptor antagonists. Yet the HTS strategy for drug discovery has several limitations. It suffers from inadequate diversity, has low Mt rate and often leads to compounds with poor bioavailability or toxicity profiles.

The second strategy is based on the modification and improvement of existing active molecules. The objective is to start with known active principles and, by various chemical transformations, prepare new molecules, (sometimes referred to as "me-too compounds") for which an increase. In potency, a better specific activity profile, improved safety, and a formulation that is easier to handle by physicians and nurses or more acceptable to the patient are claimed. A typical illustration of this approach is found in the series of lovastatin analogues (lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, etc.). In the pharmaceutical industry, motivations for this kind of research are often driven by competitive and economic factors. Indeed, if the sales of a given medicine are high and if a company is in a monopolistic situation 明对天然宿主有用。例如，产生毒素的真菌可以杀死其微生物竞争者，并利用可用的营养物质。

世界各地的研究实验室合成了大量的新型结构，用于各种合成项目。这些是先导化合物的潜在来源，制药公司通常会与研究团队进行争论，以测试其化合物。这些结构中的许多可能是在与药物化学无关的研究课题中合成的，但仍然是潜在的先导化合物。药物化学的历史有许多先导化合物的例子，这些例子是从没有药用目的的合成项目中发现的，例如，百浪多息是作为染料生产的，但是是磺胺类药物开发的先导化合物。

寻找新先导化合物的策略

对导致发现新药的方式的回顾分析表明，有四种类型的成功策略导致新的先导化合物。

第一种策略包括通过选择的生物测定系统筛选任意选择其多样性的化合物组。在过去，这种方法对于发现新的抗生素如链霉素和鉴定康帕丁作为HMG-CoA还原酶抑制剂是有用的。目前，作为高通量筛选（HTS），其以非常一般的方式应用于合成以及天然化合物。收集到的经验证实，高通量筛选可以快速鉴定大量的命中，而文献是用这种方法获得的11个成功案例。其中，可以提及胰岛素模拟物，ORL1受体激动剂，蛋白酪氨酸磷酸酶-1B抑制剂，选择性神经肽Y5受体拮抗剂，选择性COX-2抑制剂，促肾上腺皮质素释放因子（CRF）受体调节剂，和CXCR2受体拮抗剂。然而，HTS药物发现策略有一些局限性。它的多样性不足，Mt值低，常常导致生物利用度或毒性差的化合物。

第二个策略是基于对现有活性分子的修改和改进。目标是从已知的有效成分开始，通过各种化学转化，制备新的分子（有时称为“派生化合物”），其效力增加，更好的比活性，改善的安全性和制剂要求医生和护士更容易处理，或更容易接受的病人。在洛伐他汀类似物（洛伐他汀，辛伐他汀，普伐他汀，氟伐他汀，阿托伐他汀，罗苏伐他汀等）系列中发现了这种方法的典型例子。在制药行业，这类研究的