The Pharmaceutical Industry - A Historical Perspective Joe Di Bussolo , Ph.D.

1. The Pharmaceutical Industry - A Historical Perspective Joe Di Bussolo, Ph.D.

2. "Ph-ar-maki", That which brings safety. P.Boussel, H.Bonnemain and F.J.Bove. History of Pharmacy and the Pharmaceutical Industry.Asklepios Press, Paris, 1983.

4. Spoken knowledge. Instinct Written knowledge. Superstition Trade Routes. Relativism Rationalism, Atomism Egyptian, Empiricism, Deductive Reasoning Greek and Inductive Reasoning Roman Astrology Social Cohesion. Alchemy Gnosticism Christian Movement. Mysticism Fall of Rome & Alexandria. Muslim Movement. Humanism Dogma Questioned Renaissance Mathematics & Experimentation Atomic Theory, Electronics, Cell Theory, Heredity Evolution, Microbiology, Radio Relativity, Nuclear Energy, TV, Computers, Space Explr. Genetic Engineering, Nanotechnology, etc. 3000 BC 1000 BC 500 BC 300 BC 100 BC 100 AD 300 AD 500 AD 1000 1300 1500 1700 1900 2001

5. Prehistoric Pharmacy Mesopotamia - first organized civilization c.3500 BC. Cuneiform writing c.3100 BC. By trial and error, plants were identified as either nutritional, medicinal or poisonous. The sick were believed to be possessed by demons. Medicines were mixed with magical incantations. Pharmaceutical Technology 25:7 (2001).

6. The First Physicians & Pharmacologistsc3000 - 2000 BC Mesopotamian medical practitioners: Ashipu (sorcerer) diagnosed ailments, dealt with spiritual cures. Asu (physician) specialized in herbal remedies, making and applying plasters (mostly antibiotic and antiseptic).

7. The First Pharmacopoeiasc3000 - 1500 BC Sumerians used various parts of plants to prepare poultices, liniments, suppositories, etc. Beer and wine made from palm tree used for taking medicines. Babylonians described the use of about 250 plants to treat ailments. The use of animal products (e.g., milk, urine, excrement, fat), minerals (e.g., sulfur) were also described. Egyptian papyri (Ebers, Smith, etc.) detail hundreds of drugs and recipes to treat a wide range of diseases.

8. The First Known Regulation of Medical Practice c2000 - 1000 BC Law code of Hammurabi, King of Babylon Doctors were held responsible for surgical errors and failures (e.g., risked having hand cut off).

9. Egyptian Medicine c2000 - 1000 BC The fertile land or "black land", called "Chim" by the Pharaohs, produced an abundance of drugs. Egyptian doctors were kinder and gentler than the Babylonians, separating magic from treatments. Origin of the prescription symbol Rx traced to Egypt.

11. Ancient Greek Medicine Asclepius (c1200 BC)Greek god of medicine. Known to the Romans as Aesculapius. Healers and those in need of healing invoked Asclepius' name in prayer and healing ceremonies in temples and at home. A clan of healers known as the Asclepiads claimed to be descendants of Asclepius and inherited a knowledge and mystical power of healing from him.

12. The Dawn of Rationalism & Empiricism c600 - 300 BC Thales (624-545 BC), Pythagoras (580-500 BC), Empedocles (490-430 BC), Democritus (460–370 BC), Socrates (470-399 BC), Plato (428-348 BC) and Aristotle (384-322 BC) laid the foundations of metaphysics, mathematics, ethics, justice, logic and science for the Western world. School of Athens - Raphael

13. The Transition from Superstition to Science Hippocrates was an "Asclepiad", a member of a guild of physicians descended from Asclepius (c1200 BC). He rejected supernatural causes of disease and used careful observation and deductive reasoning in medical practice. He taught at Cos, an ancient health resort and the first school of scientific medicine in Greece.

14. The First Western European Pharmacy c200 BC Arcagathuswas the first Greek doctor to practice in Rome (c219 BC). After the Senate granted him Roman citizenship, Archagathos founded a shop near the Forum where he treated the sick and dispensed medicines. He was called the "healer of wounds" after successful operations and the "executioner" when things didn't go so well.

16. Great Books from the First Century AD "Natural History" c75 AD by Gaius Plinius Secundus (Pliny the Elder, a Roman savant) considered to be the first encyclopedia of science. "De Materia Medica" c77 AD by Pedanius Dioscorides, (a Greek physician and pharmacologist) became the foremost pharmacological text for the next 16 centuries.

17. Early Drug Compounding c165 AD Galen(130-216 A.D.) practiced and taught pharmacy and medicine in Rome (c161 - 200 AD), developed principles of compounding medicines. Galenicals - class of pharmaceuticals compounded by mechanical means. He also developed a formula for the first cold cream., quite similar to those found today. Galen believed that human health requires an equilibrium between the four main bodily fluids, or humors -blood, yellow bile, black bile, and phlegm.

18. Medicine in China Chinese “Great Pharmacopoeia” of 16th Century - contained 1871 substances (1074 were vegetable,443 animal and 354 mineral), over 8000 recipes and nearly 16,000 prescriptions. Doctrine of Signatures - Things that resembled a part of the body were good for that part: Green, acidic remedies for the liver, Beans for the kidney, Lungwort for the lung, etc.

19. Medical Practice in India During the First Millennium BC Samhita - oldest medical treatises c500 - 400 BC written by Susruta, Charaka and Bhela. Ayurveda - Science of longevity Successful cures require a team approach: doctor, patient, remedy and nurse. The remedy should be composed of plants grown in excellent soil, picked on a good day and administered in the proper dose at the right time. Indians suffered few disease and lived to reach their 200th birthday!

20. Exchange of Medical Knowledge Among the Cultures Oribasiusof Constantinople wrote a Synopsis of the works of Galen and other leading physicians from Rome and Greece around 370 AD. Paulus Aegineta of Alexandria wrote the Epitomae medicae libri septemaround 680, which was the most complete encyclopedia of western medicine of its time. Ar-Raziof Baghdad wrote the Kitab al-Mansuri, a comprehensive book survey of Greek, Syrian, Indian and early Arabic medicine around 920 AD. He also wrote the Treatise on the Small Pox and Measles. Nicholasof Byzantium wrote On Medicines around 1280 became the apothecary's guide throughout the Middle Ages. Byzantium was a mediator of medical knowledge between Europe, Persia, Arabia, India and China.

21. Avicenna - The "Persian Galen"c980-1033 N.A. Darnami, www.afgan-etwork.net/Culture/avicenna.html

22. Patron Saints of Pharmacists and Physicians Damian, the pharmacist,and Cosmas, the physician, were twin brothers of Syrian descent. As devout Christians, they offered their medical talents free of charge. Imprisoned during the persecution of Christians by the Roman emperor Diocletian, they were tortured and finally beheaded in 303 AD. Painting by Robert Thom

23. European Medicine in the Middle Ages From the fifth to twelfth centuries monasteries practiced the art of apothecary. Monks raised their own herbs and prepared remedies, cosmetics, distilled water and alcoholic drinks (e.g., Benedictine). This "drug industry" was then regulated by the Church. A Monastic Pharmacy by Robert Thom

24. Pharmaceutical & Chemical Manufacturing in the Middle Ages Toward the end of the 1200s, Venice became a center for making cinnabar, soaps, borax, lead, etc. Venetian talc, treacle and turpentine were marketed in artistic containers. Italian Pharmacy

25. American Medicine before Columbus From the Eskimos of North America to the Incas of South America the local "Shaman" ("He Who Knows") or "Medicine Man" served as priest, sorcerer and healer. Shamans of South America were particularly skilled in the use of hallucinogenic plants and mushrooms.

26. Mayan Medicine

27. History of Medicine 2000 B.C. - "Here, eat this root." 1000 A.D. - "That root is heathen. Here, say this prayer." 1850 - "That prayer is superstition. Here, Drink this potion." 1940 - "That potion is snake oil. Here, swallow this pill." 1985 - "That pill is ineffective. Here, take this antibiotic." 2000 - "That antibiotic doesn't work. Here, eat this root." -- Anonymous

28. The Apothecary Profession Olympiodorus a 6th century philosopher first mentions separate roles of the doctor and the pharmacist -- "The doctor prescribes and the pigmentarius carries out the perscritption." Pigmentarri, forerunners of the apothecaries, appeared in Angers (Western France) in 1093. Considered the first pharmacies in Western Europe that were not part of the Church. Apothecarii, Speciarii, Piperarii & Aromatarii were merchants of remedies and spices in Avignon (S.E. France) in 1200. The Book of Statues of Marseille decreed that "all apothecaries are bound by special oath to scrupulously prepare all confections, syrups and electuaries which they will make or sell..." By the 14th century, French apothecaries enjoyed professional status and established their own guilds, as did locksmiths and barbers.

29. The Black Plague Originated in China and spread to Constantinople by 1347, Southern Europe by 1348, Scandinavia and Russia by 1350. Caused new apothecaries to become established throughout Europe. Caused opportunities for charlatans to sell ineffective remedies. Resulted in laws regulating apothecaries.

30. The Dawn of the Renaissance Nicolaus Copernicus (1473-1543), a Polish astronomer made careful observations to prove that the earth and other planets revolved around the sun. His De revolutionibus orbium coelestium libri vi ("Six Books Concerning the Revolutions of the Heavenly Orbs") printed in 1543 inspired Galileo, Kepler, Descartes, and Newton and spawned the Scientific Revolution. Paracelsus (1493-1591), a German-Swiss physician and alchemist established the role of chemistry in medicine. His Der grossen Wundartzney ("Great Surgery Book") printed in 1536 and a clinical description of syphilis printed in 1530 laid the foundations for chemotherapy. Andreas Vesalius(1514-1564), a Flemish physician, recorded careful observations as he dissected human cadavers.His De humani corporis fabrica libri septem("The Seven Books on the Structure of the Human Body") printed in 1543 was the first comprehensive textbook of human anatomy. He corrected much of the accepted Galenic anatomy, which was based on studies of dogs, pigs and monkeys, rather than humans.

31. Early Pharmacopoeias 1546 - Nuremberg (Nürnberg), West Germany 1561 - Basel northern Switzerland 1564 - Augsburg, Bavaria (southern Germany) 1618 - London, England Despite its name, the London Pharmacopoeia was mandatory for the whole of England and thus was the first example of a national pharmacopoeia.

32. Pharmacy in Great Britain The Society of Apothecaries of Londonfounded in 1617. Only a member of the society could keep an apothecary's shop and make or sell remedies. (The separation of apothecaries from grocers was authorized by King James I.) The Pharmaceutical Society of Great Britain, London, founded in 1841. placing the education and training of the pharmacist on a proper scientific basis.

33. Pharmacy in the Colonies William Davis opened one of the first Apothecary shops in Boston in 1646. New Jersey passed the first law regulating apothecaries in 1664. Virginiapassed the first law related to pharmacy in 1736. Pennsylvania Hospital became the first incorporated hospital in 1751. University of Pennsylvania started the first medical college in 1765.

34. The Pharmaceutical Industrybefore the 1800s Empirical approach to therapy: Blood letting Cathartics Emetics

35. Pharmaceutical Industry Milestonesin the 1800s 1820 - US Pharmacopoeia 1821 - Philadelphia College of Pharmacy 1843 - Tablet compression machine 1847 - American Medical Association 1848 - Drug Importation Act 1852 - American Pharmaceutical Association 1861 - Semmelweis' antisepsis theories 1879 - E. coli discovered 1887 - Laboratory of Hygiene 1897 - X-Rays discovered 1846 - Ether (anesthetic) 1847 - Chloroform 1855 - Corticosteroids 1860 - Cocaine 1874 - Salicylic Acid 1883 - Quinoline & Antipyrine 1886 - Antifebrilin 1885 - Rabies Vaccine 1892 - Tuberculin antitoxin 1897 - Aspirin

36. Patent Medicines of the 19th Century

38. Pharmaceutical Industry Milestones1900 to 1930 1900 - Mendel's work on heredity 1902 - Biologics Control Act USDA Bureau of Chemistry 1902 - Charles Wallgreen's 1st store 1905 - The Jungle published 1906 - Pure Food & Drug Act 1906 - Chromatography invented 1908 - Inborn errors of metablolism 1909 - Gene, genotype & phenotype 1914 - World War I 1928 - pH Meter introduced 1929 - Stock Market Crash 1900 - Saccharin 1910 - Salvarsan - 1st magic bullet, birth of chemotherapy 1921 - Insulin isolated 1922 - Lysozyme isolated 1928 - Penicillium notatum 1928 - Vitamin C isolated

39. Pharmaceutical Industry Milestones1930 to 1950 1934 - Chloroquine 1935 - Prontosil - 1st sulfa drug 1938 - LSD 1939 - Demerol, Tyrotricin 1940 - Dicoumarol 1941 - Penicillin G 1944 - Strptomycin 1947 - Tetracycline 1948 - Aureomycin, Cortisone 1948 - Methotrexate 1949 - Dramamine 1930 - Bureau of Chemistry’s Food & Drug Administration (FDA) 1930 - National Institutes of Health 1930 - Electrophoresis 1938 - Food, Drug & Cosmetic Act 1941 - Liquid Chromatography 1941 - FDA certifies insulin 1942 - Manhattan Project 1947 - Gas Chromatography

40. The Elixir Sulfanilamide Disaster in 1937 Massengill distributed this preparation without testing for safety (which was not required by law). Because it contained diethylene glycol as a solvent, a chemical analogue of antifreeze, over 100 people died, many of whom were children.

41. Pharmaceutical Industry Milestones1950 to 1970 1951 - Isonazid 1952 - Erythomycin 1954 - Polio Vaccine, Warfarin 1955 - Miltown 1957 - Inerferon 1958 - Thalidomide 1960 - "The Pill" 1963 - Valium 1964 - Measles Vaccine 1964 - Azidothymidine 1967 - Mumps Vaccine 1951 - Humphrey-Durham bill 1951 - National Science Foundation 1953 - DNA double helix 1955 - Insulin sequenced 1958 - Pharmaceutical Manufacturers Association 1957 - Sputnik launched 1962 - Silent Spring published 1962 - Kefauver-Harris Drug Ammendments 1969 - First Moon Walk

42. Pharmaceutical Industry Milestones1970 to 1990 1970 - FDA req. package inserts listing risks & benifits 1970 - EPA formed 1972 - Recombinant DNA 1974 - Varicella Vaccine 1976 - GMPs 1979 - Smallpox eradicated 1981 - AIDS first diagnosed 1982 - Tamper-resistant packaging 1984 - Waxman-Hatch Act 1985 - PCR Analysis 1986 - AAPS founded 1970 - Rifampicin 1973 - Sinemet 1976 - Tagamet 1982 - Humulin - 1st biotech product 1985 - Protopin 1987 - Prozac

43. Pharmaceutical Industry Milestones1990 to 2000 1990 - Human Genome Project begins 1990 - Combinatorial Chemistry 1991 - International Pharmaceutical Excipients Council 1996 - Dolly the sheep cloned 2000 - Human genome published 1994 - Synthetic Taxol 1998 - Viagra 1998 - Herceptin 1999 - Malaria vaccine

45. The Pharmaceutical Industry Today

46. http://www.phrma.org/sites/default/files/159/phrma_industry_profile.pdfhttp://www.phrma.org/sites/default/files/159/phrma_industry_profile.pdf

48. Top Ten Pharmaceutical Companies Global Sales Company ($ Billions) Change ______________________________________________________________________ Pfizer $51.9 -8.6% Novartis 50.8 2.0 Merck & Co 40.9 6.8 Sanofi 38.9 -0.9 Roche 35.0 2.7 AstraZeneca 34.5 -5.4 GlaxoSmithKline 33.6 -1.8 Johnson & Johnson 26.8 -4.5 Abbott Labs 25.8 4.1 Teva 24.0 -3.4 _______________________________________________________________________ Total/Average: $362.2 -1.2% Global Market $857.3 3.5% Sales from June 2011 to June 2012 Source: C&EN, December 10, 2012, p18.

49. Top Ten Pharmaceutical Products Global Sales Product Marketer ($ Billions) Change ______________________________________________________________________ Lipitor Pfizer $9.5 -24.6% Seretide/Advair GlaxoSmithKline 8.7 -0.4 Plavix BMS & Sanofi 8.4 -8.3 Crestor AstraZeneca 8.1 8.8 Humira Abbott 7.5 17.0 Nexium AstraZeneca 7.4 -10.2 RemicadeJanson Biotech 7.0 9.2 Enbrel Amgen & Pfizer 6.9 7.6 Seroquel AstraZeneca 6.6 -8.2 Abilify BMS & Otsuka 6.6 11.4 _______________________________________________________________________ Total/Average: $76.7 -2.3% Sales from June 2011 to June 2012 Source: C&EN, December 10, 2012, p16.

50. Pharmaceutical Pipeline Source: C&EN, December 10, 2012, p16.