Academic Press is an imprint of Elsevier 30 Corporate Drive, Suite 400, Burlington, MA 01803, USA 525 B Street, Suite 1900, San Diego, California 92101-4495, USA 84 Theobald’s Road, London WC1X 8RR, UK Copyright # 2009, Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher. Permissions may be sought directly from Elsevier’s Science & Technology Rights Department in Oxford, UK: phone: (þ44) 1865 843830, fax: (þ44) 1865 853333, E-mail: Dedica t ion This textbook is dedicated to the memory of three of our close colleagues and friends, Gerald Sherman, Timothy Sullivan, and James Byers, and their efforts to help students understand and appreciate pharmacology and pharmacokinetics. Contr ibutor s Kenneth Alexander (Ch. 2) John S. Lazo (Ch. 21) University of Toledo College of Pharmacy, Toledo, OH Allegheny Foundation Professor, Department of Kenneth Bachmann (Ch. 8, 12) Pharmacology & Chemical Biology, Drug Discovery Institute, CeutiCare, LLC and University of Toledo College of The University of Pittsburgh, Pittsburgh, PA Pharmacy (Emeritus), Toledo, OH Markos Leggas (Ch. 7) James Bigelow (Ch. 11) Department of Pharmaceutical Sciences, College of Department of Biomedical and Pharmaceutical Sciences, Pharmacy, University of Kentucky, Lexington, KY Idaho State University, Pocatello, ID Karen Lounsbury (Ch. 6) William Bress (Ch. 14) University of Vermont, Burlington, VT Vermont Department of Health, Burlington, Vermont Patrick J. McNamara (Ch. 7) James P. Byers (Ch. 10) Department of Pharmaceutical Sciences, College of University of Toledo College of Pharmacy, Toledo, OH Pharmacy, University of Kentucky, Lexington, KY Edward Calabrese (Ch. 5) Georgi V. Petkov (Ch. 16) Environmental Health Sciences Division, School of Public Department of Pharmaceutical and Biomedical Sciences, Health, University of Massachusetts, Amherst, MA South Carolina College of Pharmacy, University of South Carolina, Columbia, SC Jen-Fu Chiu (Ch. 20) Open Laboratory for Molecular Biology, Shantou University George S. Robertson (Ch. 18) Medical College, Shantou, China Dalhousie University, Halifax, NS, Canada Paul Erhardt (Ch. 19) Jeffrey G. Sarver (Ch. 10) University of Toledo College of Pharmacy, Toledo, OH University of Toledo College of Pharmacy, Toledo, OH Aaron Grabovich (Ch. 17) David R. Taft (Ch. 9) University of Toledo, Toledo, OH Long Island University, Brooklyn, NY Martin Holcik (Ch. 18) Pei Tang (Ch. 3) Children’s Hospital of Eastern Ontario Research Institute, University of Pittsburg School of Medicine, Pittsburgh, PA Ottawa, ON, Canada William R. Taylor (Ch. 17) University of Toledo, Toledo, OH Miles Hacker (Ch. 1, 13, 15) University of Toledo College of Pharmacy, Toledo, OH Tommy S. Tillman (Ch. 3) University of Pittsburg School of Medicine, Pittsburgh, PA Lori Hazlehurst (Ch. 15) H. Lee Moffitt Cancer Center & Research Institute Ying Wang (Ch. 20) University of Hong Kong, Hong Kong, SAR, China Qing-Yu He (Ch. 20) University of Hong Kong, Hong Kong, SAR, China Yan Xu (Ch. 3) University of Pittsburg School of Medicine, Pittsburgh, PA Terry Kenakin (Ch. 4) GlaxoSmithKline Research and Development, Research Triangle Park, NC Eric C. LaCasse (Ch. 18) Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada ix Pre face Several years ago we noted a paucity of textbooks chapters dealing with each level of biological organiza- that dealt with the principles of pharmacology as a sci- tion, both biology and chemistry which has been ence rather than pharmacology as a therapeutic entity. included in discussion of each chapter and how they In an attempt to remedy this we organized a textbook related to one another. The material in this textbook designed to meet the needs of students interested in will provide the student and the practicing pharmacol- pharmacology at the advanced undergraduate and ogy scientist excellent education and reference materi- early graduate level. This text addresses the many als. Each chapter is written in a matter similar to facets that form the foundation of pharmacology. Scientific American where the text is not interrupted Students will find extensive discussions by leaders in by referencing but an extensive bibliography is the field are written in clear and straightforward man- provided for the reader at the end of each chapter. ner. Illustrations are included to help further the read- The editors are grateful the for the dedication and er’s understanding of the material covered in each cooperation of the authors and recognize the efforts chapter. The editors and authors have focused on put forth by each to create a textbook that is not only the science of pharmacology and use drugs for illustra- first rate but a useful resource to students and tive purposes only. researchers alike. The editors are also deeply grateful As pharmacology is a field of science that encom- for the assistance that we received from the high tal- passes science from various arrays, we have included ented and professional staff of the publisher, Elsevier. xiii C h a p t e r 1 History of Pharmacology— From Antiquity to the Twentieth Century Miles Hacker 2. Drug’s effects: the effects that a drug has when OUTLINE taken by somebody, especially as a medical treatment Yet another source defines pharmacology in this way: 1.1 What Is Pharmacology? 1 1.2 What Is the Position of Pharmacology in the Field Branch of medicine dealing with the actions of drugs of Therapeutics? 2 in the body—both therapeutic and toxic effects—and 1.3 The Beginnings of Pharmacology 2 development and testing of new drugs and new uses 1.4 Pharmacology of the Greco-Roman Era 3 of existing ones. 1.5 Pharmacology and the Middle Ages 3 Though the first Western pharmacological treatise 1.6 Pharmacology and the Renaissance 4 (a listing of herbal plants) was compiled in the first 1.7 Pharmacology and the Baroque Period 5 century AD, scientific pharmacology was possible only 1.8 The Birth of Modern Pharmacology 5 from the eighteenth century on, when drugs could be purified and standardized. Pharmacologists develop drugs from plant and animal sources and create syn- thetic versions of these, along with new drugs based 1.1 WHAT IS PHARMACOLOGY? on them or their chemical structure. They also test drugs, first in vitro for biochemical activity and then Obviously, a discussion of all the ancient remedies in vivo for safety, effectiveness, side effects, and inter- would require more space than possibly could be allot- actions with other drugs and to find the best dose, ted for one chapter in a textbook. In this chapter we timing, and route. will discuss a few of the more fascinating examples of When reading textbooks, we find such definitions as: how ancient civilization was able to treat disease with available natural products. We will then discuss the Pharmacology is the science of drugs, their chemical progression of pharmacology from the science of test- composition, their biological action and their thera- peutic application to man and animal. It includes toxi- ing crude extracts of plants, animals, and minerals cology, which encompasses the harmful effects of for their medicinal properties, to the science it is chemicals, whether it is used therapeutically or not. today, in which isolated chemicals are examined for Pharmacology is the study of the interaction of their effects on live tissue. This begs the question, what chemicals with biological entities. is a good working definition for modern pharmacol- Pharmacology is the study of substances that interact ogy? On the surface, this seems like an easy task, but with living systems through chemical processes, espe- as we peruse the textbooks and articles pertaining to cially by binding to regulatory molecules and thereby pharmacology we rapidly realize that the definition of activate or inhibit biological activities in the body. pharmacology varies greatly, depending on who is There are as many definitions of pharmacology as defining the discipline. there are those defining the science. Given the A dictionary defines pharmacology as: breadth and scope of the discipline it is hardly 1. Study of drugs: the science or study of drugs, espe- surprising that there is such a variance in definitions. cially of the ways in which they react biologically at For the purposes of this chapter we will define the receptor sites in the body field in as simple yet inclusive terms as possible: 1 C h a p t e r 1 History of Pharmacology—From Antiquity to the Twentieth Century Pharmacology is the study of the effects of chemi- 1.3 THE BEGINNINGS OF cals and the mechanism of these effects on living organisms (pharmacodynamics), and the effects of PHARMACOLOGY the living organisms on the chemicals including Pharmacology is both an ancient science and a rela- absorption, distribution, metabolism, and excretion tively new science. Since the beginning of mankind (pharmacokinetics). there has been a search for ways to alleviate the pain and suffering associated with life. To the ancient phar- macologist this meant painstaking observations and experimentation with natural products such as plants, 1.2 WHAT IS THE POSITION OF animals, and minerals. Substances like fruits, leaves, PHARMACOLOGY IN THE FIELD bark, roots, dirt, and animal parts were rubbed on to the human body, boiled in hot water and drunk, OF THERAPEUTICS? smelled, or consumed in the physical state that they Briefly, the medicinal chemist works in concert with were gathered. The effects of these preparations on the pharmacologist in determining the efficacy of the human were noted and discussed and thus tribal the chosen target molecule. The lead molecule then folklore evolved. Slowly a knowledge base developed is identified following a series of chemical modifica- regarding what to use for a given malady. tions of the target molecule (structure activity rela- As different tribes comingled, exchange of tribal tionship, or SAR). The analytical chemist works with folklore more than likely occurred and an ever-increas- both the medicinal chemist and the pharmacologist ing compendium of useful, not so useful, and even to assure the chemical structure and purity of the horribly dangerous remedies developed. A good exam- chemical product. The pharmacodynamics group ple of how these ideas and concepts grew into under- works closely with pharmacology while performing standing the need of specific items in our diet and the SAR studies. The pharmacokinetics group works health was common salt. Long before recorded time, with pharmacology and analytical chemistry to assess salt trade routes were established between the hot dry how the body affects a chemical once administered. climates near the sea where salt deposits flourished, The pharmaceutics group works with the pharmacoki- and the areas where salt was scarce. Why did salt netics/pharmacodynamics groups and the pharma- become an essential ingredient in the lives of the cologist to determine how best to formulate the ancients? Perhaps by ancients observing animal behav- drug for maximum efficacy. Once the lead com- ior and dietary activities in and around natural salt pound, formulation, and route(s) of administration flats. The practice of mimicking animal behavior aided have been selected, the toxicology group works with in the evolution of both foodstuffs and potential reme- the pharmacologist to determine potential sites of dies for disease. toxicity in experimental animals. Diet was then and remains today a vital component Once preclinical toxicology studies have been of maintaining good health and battling disease. Var- completed, an application is submitted to the FDA ious foods were scrutinized for their possible health for approval to perform clinical trials for efficacy values and were passed from culture to culture and and toxicity in human subjects. Finally, if efficacy generation to generation. Those who were charged and toxicology warrant it, another application is sub- with maintaining the health of a given tribe or popu- mitted to the FDA for drug marketing approval. lation were expected to know the values of different As we can see from the brief description, the phar- foods, medicinal plants, minerals, and even such eso- macologist plays a pivotal role in every aspect of the teric things as the healing properties of smoke and drug discovery and development process. A thor- chants. Equally importantly these individuals had to ough discussion of this process can be found in know how and when to administer these healing Chapter 15 of this textbook. agents. Records from ancient China, India, Sumeria, Egypt, and Greece are full of suggestions, often in great detail, of the health benefits of every known fruit, grain, tuber, berry, or vegetable. Other records Medicinal Analytical describe different soil and mineral preparations, as Toxicology Chemistry Chemistry well as animal parts, for medicinal properties. In cer- tain cultures, many of these preparations remain in vogue and are still used. Consider one example and how important itmay have Pharmaco Pharmacology Clinical Trials been inmaintaining the health of early hunter/gatherer dynamics societies, especially nomadic tribes constantly moving into new uncharted territories. Having no extensive knowledge of the new area these people relied heavily Pharmaco Pharmaceutics FDA Approval on trial and error when it came to gathering plants for kinetics food. Using observational information obtained by watching what the indigenous animal ate helped some- Figure 1.1 Pharmacology: A multifacted discipline. what. Given what we now know about species variation 2 1.5 Pharmacology and the Middle Ages among animals, plants that are edible for a given animal With the growth of knowledge of the medicinal could prove to be a devastating poison to the humans properties associated with plants came the fear of acci- who recently moved into the new region. From careful dental or intentional poisoning. Rulers of Rome were observations the ancients also knew that certain plants especially fearful as it was clearly established that ascen- or parts of plants could induce vomiting. If the consump- sion along the political ranks was best accomplished by tion of an unknown foreign plant resulted in unpleasant assassination of those above you. An interesting under- sensations in the GI tract they knew to consume taking was that of Mithridates, King of Pontus, in a medicinal plant to rid themselves of the new plant. In which he described a “universal antidote” called mithri- fact, one of the most widely described medicinal pur- datium, a concoction of 35 different ingredients. An poses of plants was that of a purgative. interesting myth associated with this universal antidote One of the oldest medicinal preparations made by is that a ruler taking mithridatium was given the oppor- man was alcohol. Here again careful observations tunity to kill himself rather than suffer the embarrass- provided the basis for the development of this ancient ment of being killed by his captors. To do this he had and important drug. Recipes for beer, wine, and mead to use his sword because none of the available poisons are found in the oldest of recorded literature from cul- were effective against mithridatium. tures worldwide. Not only were these liquids used in An important physician during the second century ceremonial practices, their medicinal properties of AD was Galen, who solidified the concept of the four decreasing pain sensation and the ability to induce humors first championed by Hippocrates into the work- sleep were greatly appreciated. As the cultures became ings of the healthcare providers. These humors were more sophisticated these alcoholic beverages were blood, phlegm, yellow bile, and black bile. So powerful used as tinctures of herbs to enhance the medicinal was the influence of Galen, that Galenic principles of effectiveness of herbs and plants. medicine were practiced to the eighteenth century, much to the detriment of medical evolution. It must be noted however that Galen was an excellent experi- mentalist and observationalist. Galen first described 1.4 PHARMACOLOGY OF THE that blood occupied the arterial system, that the heart GRECO-ROMAN ERA provided the power to move blood, and that the heart isolated from the body continued to beat. Probably the best recognized of all the ancient Greek As time progressed, the Byzantine and Muslim physicians is Hippocrates. It is likely that much of the worlds added to the base of knowledge concerning writings attributed to this man came from a group of drugs. Most of the information gained during this health professionals of whom Hippocrates was the period was a continuation of the efforts started in most prominent member. During this time rationality Greece and Rome, that being the production of fur- was introduced in the healing process as they began ther compendia of medicinal plants. The Muslims to understand the importance of careful descriptions provided such contributions as the development of syr- of diseases, symptoms, and geographical locations. In ups for respiratory ailments, the use of mercurial spite of the importance of this group in the field of formulations for skin diseases and the process of distil- medicine they really had little to do with drugs. lation to obtain concentrates of beer and wine. In Rather, Hippocrates and his followers relied much addition, important refinements were made in the more on the healing power of nature, known as Vis record keeping and organization of medical plants. medicatrix naturae. It is of interest that even today there However during this time the alchemists came into is evidence of the placebo effect in which the patient fashion and worked diligently on such projects as turn- cures him- or herself though the belief in the curing ing lead into gold and the search for the universal effects of the drug even though no drug is present in “elixir of life” to cure all diseases and prolong a their medicine. Is this not an example of the healing healthy life. The concept behind the elixir arose from power of nature? the observations that wine made the ill feel better, The evolution of the healing practices was trans- brought on a feeling of euphoria, and made the elders ferred to the Roman empire as Greek doctors came feel young again. Thus, it was believed that with proper to Rome, many times as slaves. It is here where inter- distillation techniques the important elixir or spirit est in medicines grew rapidly. Celsus wrote eight could be isolated and used. Unfortunately for all, this books on disease, containing significant references was never accomplished. to the use of drugs in the treatment of disease. As in Greece, the health professionals of Rome felt it neces- sary to maintain excellent records and perform care- ful observations. One of the most important records 1.5 PHARMACOLOGY AND THE of that time was kept by Dioscorides, a Roman sur- MIDDLE AGES geon, who traveled with Nero’s armies compiling all the information on drugs that he could. This com- The middle ages of Europe (ca 10–15 centuries AD) pendium, entitled Materia Medica, included some were a time of feudalism, authoritarianism, and dog- 600 plants, also including illustrations, how to find matic religious leaders. During this period intellectual the plant, where to find the plant, and how and when thought and discovery were hampered terribly by the to use the plant. intellectual complexity of the times. The Roman era 3 C h a p t e r 1 History of Pharmacology—From Antiquity to the Twentieth Century of peace and security was gone and was replaced by time glorious new geographical explorations were leav- epidemics, squalor, poverty, and ignorance through- ing from Europe to the far reaches of the Earth. The out Europe. All teachings revolved around salvation adventurers returned with exotic plants and stories through the church. The health professional virtually on how these plants were used medically. Finally, the disappeared and the use and understanding of drugs mind of the European was now open after centuries fell back to pre-Greco-Roman times. Civilization and of religious constraints and new ideas and concepts learning were almost the exclusive provenance of the began to evolve. monasteries, monks skillfully copying manuscripts for Herbalists in every country were gathering plants dispersal to other monasteries. Monks maintained and knowledge in attempts to develop new medicines drug-herbal gardens to assure at least a semblance of to treat disease. With the gain of medical knowledge plant drug supply. came the birth of a formalized botany. German herbal- If one city can be highlighted as the most important ists are considered to be the fathers of botany. One in bringing Greco-Roman medicine back to Europe German physician condemned his fellow German it must be Salerno, an important trading center on herbalists for using names on their drug receptacles the southwest coast of Italy. Here traders from all over with Greek names that were no longer applicable. He the world came to trade their goods and bring infor- authored a short poetic piece that expressed the feel- mation and knowledge back to Europe. It is here ings of society of that day toward the healers (come where a hospital not under the thumb of the church to think of it, many today still hold this belief): sprang up. The caretakers of the sick sought refer- Three faces has the doctor: ence works from the foreign traders and back came A god’s when first he’s sought the drug information that had been all but lost dur- And then an angel’s, cures half wrought: ing the middle ages. The task of converting these But when comes due the doctor’s fee, compendia from their native languages of Greek Then Satan looks less terrible than he! and Arabic to Latin fell onto the shoulders of a few, What was the crowning achievement of this with one of the most notable being Constantinus enlightened period? Probably a continuation of what Africanus. Born in Carthage and widely traveled, Con- had preceded this era—care in cataloguing plant med- stantinus took on the onerous responsibility of manu- icines, how to prepare them, and how to use them. script translation including a major compendium on The printing press enabled these cataloguers to widely Greco-Roman and Muslim plant- and animal-based disperse their work. Two important names are asso- drugs. So influential was his work that he was asked ciated with this period, Cordus and Vesalius. Valerius to translate classical literature, which may have played Cordus, during his relatively short life, edited and a role in the recovery of universities in Europe. expanded the pivotal work of Dioscorides. His work The medical school in Salerno slowly became quite marked the transition from magic, spells, and alchemy successful. Members of the school were allowed to to a rational approach to chemical experimentation. think freely and question authority, providing an intel- In addition, Cordus developed the first true pharmaco- lectual atmosphere for growth. During this time a peia, the Dispesatorium pharmacopolarum, which received rebirth in codifying medical plants occurred. New wide use and served as the format for plethora of phar- approaches to treating disease were developed such macopeias that arose following the publication of his as the use of seaweed (high in iodine) to treat goiter, work. Vesalius’s major contribution was the standardi- cleaning a wound using alcohol distillates, and the zation of drug preparation in order to assure to some rediscovery of mercurial ointments to treat skin sores degree a uniformity in expected results following the and lice. So successful was this school of medicine that use of any given drug. the churches began to build medical schools modeled One of the most important experimentalists of the after that in Salerno. Toward the end of the middle time was a Swiss named Auerrolus Theophrastus Bom- ages drug use and drug trade were firmly reestab- bastus von Hohenheim, or Paracelsus as he called him- lished, thus paving the way for growth during the self. His father was a physician and he, too, became a Renaissance. trained physician. After earning his degree he traveled extensively, learning the art of medicine from a num- ber of different sources. An interesting character, he 1.6 PHARMACOLOGY AND THE was appointed professor of medicine at Basel and shortly thereafter was erroneously thought to have RENAISSANCE been killed in a tavern brawl in Salzburg. A gruff, bom- Several important events occurred during the Renais- bastic, but brilliant individual, he first described the sance that drove the growth of pharmacology. First concept of dose response relationship when he said was the development of the movable type printing (paraphrased), “Everything is a poison and nothing is press. With this machine came the availability of books a poison, it is only the dose that counts.” As an experi- that could be dispersed and read. Knowledge could be mentalist he noted a correlation between exposure to obtained and spread with relative ease, enabling those dust in mines and lung damage, he studied the effect interested to learn about medicinal plants and ani- of mineral baths on skin disorders, and the role of mals. Further, new knowledge could be dispersed far heavy metals in the treatment of disease. He may well more easily and rapidly than ever before. At the same have been the first to use pure chemicals as drugs. 4 1.8 The Birth of Modern Pharmacology Along with the growing appreciation for careful source of the bark was lost, which necessitated the observations and record keeping came the increa- development of alternative medicines to treat this hor- sed interest in and the use of poisons. The most rid disease. fascinating family of the era was the Borgias, an Italian In addition to the introduction of many new med- family who manipulated the papacy and the empire in icines, many important discoveries were made by large part through their expertise in poisoning. An scientists of the time. For example, William interesting aspect of this was the fact that they used Withering, a British physician, first described the arsenic trioxide, a water-soluble white powder without effects of an extract of the leaves of the purple fox- taste or aroma. The compound often was mixed with glove on cardiac dropsy (congestive heart failure). wine and was virtually nondetectable. It is often said From his careful experimentation, the dose-related that the Borgias gave rise to experimental toxicology. difference in the effects of digitalis on the human Although arsenic trioxide was used during the Renais- body were first described and still remain pertinent sance, just recently the drug has been approved by the today. Edward Jenner noted that milkmaids seldom FDA for the treatment of cancer! got small pox but instead suffered a far less severe form of the disease known as cow pox. From this observation, soon he was inoculating an individual with the pus from a cow pox pustule and then later 1.7 PHARMACOLOGY AND THE challenged that individual with small pox. Cow pox protected the person from small pox! William Harvey BAROQUE PERIOD first reported that the circulatory system was a closed The next two centuries brought about changes in med- system using the heart to pump blood through the icine and the developing field of pharmacology too vasculature system. He also suggested that drugs numerous to discuss in detail. An attempt will be made taken orally entered the body through the gastroin- to select some of the more important highlights of this testinal tract and were distributed throughout the interesting era. This period can be considered a body via the blood. groundbreaking time with respect to experimentalism. Work done during this period was severely ham- A motivating factor in drug discovery during this pered by the lack of chemical isolation and characteri- period was the introduction of new plants (and drugs) zation techniques. However, it was during this time from places far away for this was the time of extended that the foundations for such approaches were devel- geographical exploration. The Spaniards brought back oped. Individuals such as Robert Boyle, Joseph Priestly, a variety of plant samples from South America, and the and Antoine-Laurent Lavoisier were actively investigat- Portuguese discovered a trade route to the Far East ing the principles of physics, gasses, and chemical iso- and brought back many medicinal plants and spices. lation. This time period provided the basis for the The introduction of these highly acclaimed and explosion of scientific investigation and the birth of important new sources of drugs to European medicine modern pharmacology that occurred during the next was slow because each country carefully guarded their century. findings. However, two of the most important drugs had to be ipecacuanha and cinchona bark. The former was shown to have significant but relatively safe emetic properties. The drug became an important treatment 1.8 THE BIRTH OF MODERN for diarrhea and dysentery. In the decoction was a PHARMACOLOGY drug emetine that became the treatment of choice for amebic dysentery and amebic abscess. It wasn’t The basics of analytical chemistry had been intro- until the twentieth century that newer drugs to treat duced in the late eighteenth century and were rapidly amebiasis were introduced. The cinchona bark was applied to pharmacology. The seminal work in the important in treating fevers as an extract of the bark; field of active ingredient isolation was that of Frie- often referred to simply as The Bark, it seemed to treat drich Wilhelm Serturner, a German pharmacist with all fevers regardless of origin. The use of The Bark a deep interest in opium. Extracting opium with an became so widespread throughout Europe that the acid, he isolated a water soluble compound that cinchona tree became scarce. It is of interest that a induced sleep in dogs and himself. He called the similar situation occurred quite recently when the bark chemical morphine, in honor of the god of sleep. of old-growth Yew trees was shown to contain taxanes, Within a relatively short period of time a variety of which proved effective in treating cancer. So effective chemicals were isolated from crude plant sources in fact that there was a very real fear that there were and the beginnings of testing isolated chemicals, insufficient trees to support the production of the rather than a crude extract of a plant, for pharmaco- drug. We encourage you to read the story of taxol logical activities began in earnest. and how this problem was overcome. Francois Magendie studied a variety of chemical Cinchona remained a very valuable medicine even extracts of plants, focusing primarily on the newly up to WWII, when Allied soldiers in the South Pacific defined class of chemicals called the alkaloids. He were exposed to malaria. Cinchona bark (quinine) became so impressed with the chemicals that he devel- was used extensively to treat the disease. After the oped a compendium of alkaloids that described the Japanese invaded and controlled Java, an important actions and indications of a variety alkaloids recently 5