Drugs That Changed the World Drugs That Changed the World How Therapeutic Agents Shaped Our Lives Irwin W. Sherman CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 © 2017 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, an Informa business No claim to original U.S. Government works Printed on acid-free paper Version Date: 20160922 International Standard Book Number-13: 978-1-4987-9649-1 (Hardback) This book contains information obtained from authentic and highly regarded sources. While all reasonable efforts have been made to publish reliable data and information, neither the author[s] nor the publisher can accept any legal respon- sibility or liability for any errors or omissions that may be made. 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Identifiers: LCCN 2016022679 | ISBN 9781498796491 (hardback : alk. paper) Subjects: | MESH: Pharmaceutical Preparations--history | Drug Therapy--history | Drug Discovery--history | Social Change--history Classification: LCC RM300 | NLM QV 11.1 | DDC 615.1--dc23 LC record available at https://lccn.loc.gov/2016022679 Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the CRC Press Web site at http://www.crcpress.com Contents List of Figures ............................................................ .vii Preface ................................................................... ix A Note to the Reader ........................................................ xi Chapter 1 Malaria and Antimalarials .......................................... 3 Chapter 2 The Painkiller, Aspirin............................................. 31 Chapter 3 Ether, Chloroform, Cocaine, Morphine, Heroin, and Anesthesia ........... 39 Chapter 4 The Pill......................................................... 53 Chapter 5 Diabetes and Insulin.............................................. 65 Chapter 6 Smallpox and Vaccination .......................................... 75 Chapter 7 Vaccines to Combat Infectious Diseases .............................. 87 Chapter 8 The Great Pox Syphilis and Salvarsan................................ 115 Chapter 9 Prontosil, Pyrimethamine, and Penicillin ............................. 125 v vi Contents Chapter 10 AIDS, HIV, and Antiretrovirals .................................... 147 Chapter 11 Organ Transplantation and Cyclosporine ............................. 159 Chapter 12 Malaria, Madness, and Chlorpromazine ............................. 171 Epilogue ................................................................. 181 Notes ���������������������������������������������������������������������������������������������������������������������������������������185 Index ................................................................... 191 List of Figures Figure 1.1 A comparison of the structures of quinoline, acridine, methylene blue, and the derivative of methylene blue, atabrine. .......................14 Figure 1.2 A sign from the South Pacific theater of operations. ...................17 Figure 1.3 A comparison of the structure of chloroquine with quinine and atabrine. ....18 Figure 1.4 A comparison of the structure of mefloquine with quinine. 22 Figure 1.5 A comparison of the structures of artemisinin, artemether, and artesunate. ...27 Figure 2.1 Formation of acetylsalicylic acid (aspirin) by treatment of salicylic acid with acetic anhydride. ...........................................34 Figure 4.1 Russell Marker with the yam “cabeza de negro.”.......................55 Figure 4.2 A comparison of the structure of diosgenin with progesterone and norethindrone. ..............................................56 Figure 9.1 The relationship of prontosil with sulfanilamide and that of pABA. ......129 Figure 9.2 (a) The folate pathway and (b) the thymidylate cycle. ..................132 Figure 12.1 A comparison of the structure of methylene blue with phenothiazine and chlorpromazine. ...........................................176 vii Preface he dictionary defines drug as a therapeutic agent. Through the ages, drugs—natural or Tsynthetic—have been used in the diagnosis, alleviation, treatment, prevention, or cure of disease. These drugs are based on thousands of years of knowledge accumulated from folklore, serendipity, and scientific discovery. This is a book about drugs that have changed the world in which we live, how they were developed, and the manner in which they exert their “magic.” In telling the fascinating history of the findings and use of drugs, there is drama of triumphs and failures filled with colorful personalities—the selfless and the selfish, the competitor and the cooperator, the hero and the villain, those with unbridled ambition, those seeking fortune, and the bold as well as the timid. Today, there are drugs to protect against infectious diseases, to alleviate aches and pains, to allow new organs to replace old ones, and to modify brain function. Yet, for the most part, the manner by which drugs are developed and by whom remains a mystery. For many of us, a drug is a pill or a liquid, prescribed by a physician, found in the medicine cabinet. Drugs are more than this, and although only several dozen or so drugs have markedly affected our lives and altered the path of civilization, to simply catalog these would be too numbing to read. Instead, I have selected a sampling—drugs that represent milestones in affecting our well-being and that have influenced social change. Quinine, the first antimalarial to cure the disease malaria (Chapter 1), illustrates how a natu- ral product enabled armies to triumph in the tropics. This chapter also deals with synthetic anti- malarials (atabrine, chloroquine, and mefloquine) and the newest natural product, artemisinin. It provides the reader with an appreciation of what goes into drug testing, the role of animal models, the need for clinical trials, and the problems associated with drug resistance. In the sec- ond two chapters, Chapter 2—on aspirin, the first drug to treat simple pain; and Chapter 3— on anesthesia, the power of making a person insensible to surgical operation, are described. Hormones, too, are drugs; their role is illustrated in “The Pill” (Chapter 4), where a synthetic hormone analog revolutionized contraceptive choices for women; and in Chapter 5, where the isolation of insulin, the first hormone therapy for treating diabetes, is examined. Smallpox (Chapter 6) led to a vaccine that ultimately eradicated the disease and was the impetus for the development of other vaccines to combat infectious diseases (Chapter 7). Syphilis (Chapter 8) provided the spark for a cure through chemotherapy (salvarsan), which