4 th millennium B.C. : the oldest preserved remains of cultivated seeds and pods of Papaver somniferum (Opium) have been discovered from this period in Neolithic, pile-dwelling villages in Switzerland . (Opium predates alcohol, which requires fermentation.) Over 25 different alkaloids can be isolated from Papaver somniferum, including: Morphine, Codeine, Narceine, Narcotine, Thebaine, and Papaverine. (NOTE: the earliest forms of writing predate 1) Cuneiform , and 2) Hieroglyphics (e.g., Hattic, Hurrian, Elamite) ; all were relatively simple languages, having only a few hundred word signs at the height of their development. Nevertheless, surviving tablets written in a pre-cuneiform script from about 3500 B.C. contain descriptions of ancient medicines.) The largest producer of Opium today is India, 2 nd is Australia. 1700 B.C. - the Edwin Smith papyrus (found in 1862); seems to be a translation of a much older document, dating from perhaps 3000 B.C. 1500 B.C. - the George Ebers papyrus (found in 1873) lists over 700 remedies, many of which included opium or its extracts as ingredients. It includes about one-third of the medicinal plants in use today. 1500 B.C. - the Chinese develop a form of writing with about 50,000 word signs. Here we are given our first, rich descriptions of ancient medicines; e.g., the Ben Cao Kong Mo (may date from 2700 B.C.) and the Pen Tsoa – lists over 360 medicinal plants and their uses. 600 B.C. - first written, “classical form” of the Hindu Vedas describes a large number of plants used for their curative and therapeutic effects. (NOTE: the Aryan invasion of India occurred about 1500 B.C.)
Greece 500 B.C. - extracts from Willow to treat pain, gout and other diseases. Opium was commonplace in Greek civilization “rediscovered” by the Romans about 40 A.D. 400 B.C. - Hippocrates takes medicine out of hands of religion (for the time being); compiles Corpus Hippocraticum based on four humours: Black Bile (or “Gall”) - kidneys & spleen; Blood ; Phlegm ; Yellow Bile (or “Choler”) - liver . 330 B.C. - Theophrastus accompanies Alexander-the-Great, vast, new medical knowledge flows into Greece from Persia and India. Classification of over 550 species from the Atlantic to India. “rediscovered” during the Renaissance. Egypt 50 B.C. - Cleopatra (the last of the Ptolemies) holds the largest collection of medicinal botanicals in the world. Alexandrian library, with over 400,000 scrolls, is partially burned by the Romans under Julius Caesar in 47 B.C.; completely destroyed by Muslims in 700 A.D. Rome 200 A.D. - 200 A.D. Claudius Galen founds a system of medicine followed in Europe for the next 1300 years, Methodus medendi , based on 4 qualities and 4 humours, largely herbal. Physicians should assess not only the cause of the illness, but all aspects of the patient.
Persia 900 A.D. “ Rhazes ,” Muhammad ibn Zakariya al-Razi. Liber Continens – an encyclopedia of medical practice & treatment, De variolis et morbillis – a treatise on smallpox and measles. 1000 A.D. - “ Avicenna ,” Abu al-Husayn ibn ‘Abdallah ibn Sina. Kitah-ash-shifa (The Book of Healing), al-Quanum fil-Tibb (The Canon of Medicine). 1204 A.D. - 4 th Crusade; Constantinople falls to Doge of Venice . 1477 A.D. - Leonardo Da Vinci is given a studio in the Medici gardens, receives a copy of the great text by Theophrastus on plants; later begins study of anatomy.
1494 - Sack of the Medici palace and gardens; library dispersed. 1500 - “ Paracelsus ,” Philip von Hohenheim breaks with Galen and Parisian school of medicine; e.g., influenza, malaria, measles, smallpox, syphilis, typhus. “ Active principles ; Fight poisons with poisons .” 1516 - Da Vinci moves to France; anatomical drawings cause a sensation among physicians in Paris. 1550 - Regency of Catherine de Medici ; garden becomes Jardin du Roi in 1626 (known today as the Jardin des Plants ) . 1639 - Spanish physician, Juan del Vego , introduces cinchona as a treatment for malaria. 1658 - Antimony successfully used as an emetic on Louis XIV . (Ten elements known to the ancients: carbon, sulfur, copper, silver, gold, iron, tin, antimony, mercury, and lead. ) 1717 - Lady Mary Wortley Montagu , wife of the British consul in Constantinople, observes the practice of smallpox inoculation among Turkish peasant women. 1743 - Charles Marie de la Condamine brings curare back from the Amazon. 1763 - Edmund Stone uses Willow bark to successfully treat rheumatic fever. 1785 - William Withering demonstrates that digitalis has a powerful stimulating effect on the heart, reducing the edema common in heart disease. 1793 - Humphry Davy discovers the “euphoriant properties” of nitrous oxide . 1804 - Alexander von Humboldt returns with a sample of guano from Peru. 1806 - Friedrich Wilhelm Sert ü rner isolates pure morphine (the 1 st alkaloid) from opium. 1818 - Michael Faraday discovers ether . 1828 - Friedrich W ö hler synthesizes urea , an organic compound found in urine, from two substances considered minerals, ammonium chloride and silver cyanate , evaporation of ammonium cyanate , discrediting the doctrine of “ vital force .” 1831 - Justus von Liebig synthesizes chloroform from acetone & chlorine ; first used as an anesthetic (hypnotic) in 1847 by James Simpson . 1853 - Hermann Kolbe synthesizes salicylic acid from phenol .
1763 - Edmund Stone uses Willow bark to successfully treat rheumatic fever. 1785 - William Withering demonstrates that digitalis has a powerful stimulating effect on the heart, reducing the edema common in heart disease. 1793 - Humphry Davy discovers the “euphoriant properties” of nitrous oxide . 1804 - Alexander von Humboldt returns with a sample of guano from Peru. 1806 - Friedrich Wilhelm Sert ü rner isolates pure morphine (the 1 st alkaloid) from opium. 1818 - Michael Faraday discovers ether . 1828 - Friedrich W ö hler synthesizes urea , an organic compound found in urine, from two substances considered minerals, ammonium chloride and silver cyanate , evaporation of ammonium cyanate , discrediting the doctrine of “ vital force .” 1831 - Justus von Liebig synthesizes chloroform from acetone & chlorine ; first used as an anesthetic (hypnotic) in 1847 by James Simpson . 1853 - Hermann Kolbe synthesizes salicylic acid from phenol .
The Past, Present and Future Structure of the North American and Global Pharmaceutical Industry and its Impact on Planning Functions
p-Courmaric Acid, Chlorogenic Acid, Sulforaphane, etc.
9) Dietary Supplements :
Chondroitin Sulfate, Creatine, Shark Cartilage, etc.
10) Nutraceuticals .
Ancient Period Oldest cultivated opium Sumer Edwin Smith papyrus George Ebers papyrus 4000 BC_ 3400 BC_ 3000 BC_ 1700 BC_ 600 BC_ Ben Cao Kong Mo Hindu Vedas – “classical” Pen Tsoa
Classical Period Cleopatra Hippocrates Theophrastus 50 BC_ 400 BC_ 500 BC_ 300 BC_ 200 AD_ Claudius Galen
Medieval Period Da Vinci in Medici gardens “Rhazes” “Avicenna” 4 th Crusade 1300 AD_ 1400 AD_ 1000 AD_ 900 AD_ 1100 AD_ 1200 AD_ 1500 AD_
Age of Discovery - 1 Sack of Medici palace 1650_ 1700_ 1500_ 1450_ 1550_ 1600_ 1750_ “Paracelsus” Da Vinci moves to France Regency of Catherine de Medici Juan del Vego Antimony as emetic (Louis XIV) Lady Mary Wortley Montagu Charles Marie de la Condamine
The Proposition of the Usual Dose Paracelsus (1493-1541) “ The dose makes the poison”
1824 - William S. Merrell & Co. , Cincinnati, Ohio., purveyor of medicinal botanicals and their extracts; became notorious as the manufacturer of Thalidomide in 1950s-1960s.
1830 - Philadelphia pharmacy that became Smith, Kline & Co. in 1875 and Smith, Kline and French (SKF) in 1891 . Manufactured extracts, elixirs, syrups, tablets and pills. Supplied U.S. troops with quinine during the Mexican-American War (1846-1848) and the Union army during the American Civil War (1861-1865).
1836 - Powers and Weightman Company began as Philadelphia manufacturing apothecary; 1905 merged with Rosengarten & Co.; 1927 merged with Merck & Co. 1849 - Charles Pfizer & Co. founded in Brooklyn, NY, to produce a flavored candy form of the drug santonin , an anthelmintic Wormseed plant extract. Supplied the Union army with large quantities of borax , camphor , chloroform , cream of tartar , iodine , morphine , tartaric acid , and mercurial compounds .
1857 - E.R. Squibb & Co. founded in Brooklyn, NY, to produce ether and chloroform in more consistent form than currently available. Contracted to supply the Union army with sturdy medicine chests, suitable for field use, each containing 52 standardized medicines in unbreakable tins, for $100.00 each.
1860 - John Wyeth & Brother , Philadelphia pharmacy that established a mail-order catalog for pharmaceutical products in 1862 ; became the Wyeth-Ayerst division of American Home Products in 1931 .
1866 - Parke-Davis , Detroit, Michigan . Together with H.K. Mulford was 1 st American company to produce diphtheria antitoxin . In 1902 was 1 st American pharmaceutical company to build its own research laboratory; also 1902 , 1 st company ever to manufacture epinephrine (Adrenalin) -- by extraction from adrenal glands. In 1928 production of 2 pituitary hormones, vasopressin & oxytocin -- also by extraction.
1876 - Eli Lilly , Indianapolis, Indiana
1885 - Upjohn , Kalamazoo, Michigan
1888 - Abbott Laboratories , Chicago, Illinois
1888 - G.D. Searle , Chicago, Illinois
Pierre Pelletier and Joseph Caventou established the first modern pharmaceutical company to produce pure quinine from imported cinchona bark in 1826 .
Dyes and Drugs – the fundamental relationship. (Blessings of the by-product coke oven)
In the beginning, reds came from the female cochineal , kermes insects , brazil wood , and the madder plant ( of southern France ); blues came from woad and the indigo plant ( of northern India ); and quinine came from cinchona .
Quinine Alizarin Indigo Aniline Naphthalene Anthracene Murexide Picric Acid Manchester Brown
Aniline Companies Following Perkin’s Discovery Company Country Date K.G.R. Oehler (Griesheim Elektron) Germany 1856 Perkin & Sons Britain 1857 Renard Frères (Societe la Fuchsine/1864) France 1858 Read Holliday Britain 1858 Girard et Georges de Laire France 1860 Alexandre Clavel (Gesellschaft für Chemische Industrie Basel – CIBA/1884) Switzerland 1860 J.J. Müller (Geigy/1862) Switzerland 1860 J. Poirrier (S.A. des Matières Colorantes et Produits Chimiques de St. Denis/1881) France 1861 Badische Anilin und Soda Fabrik (BASF) Germany 1861 Meister Lucius & Bruning (Farbwerke Hoechst) Germany 1862 Durand & Huguenin Switzerland 1862 Friedrich Bayer (Farben Fabrik vormals Friedrich Bayer) Germany 1863 Kalle & Co. Germany 1864 Leopold Cassella & Cie. Germany 1867 Aktien Gesellschaft für Anilin Fabrikation (AGFA) Germany 1867 Schoellkoph Aniline & Chemical Co. USA 1879 Sandoz AG Switzerland 1886 Benzol Products USA 1910 DuPont USA 1916 Calco USA 1916 Dow USA 1916 National Aniline and Chemical Company USA 1917
Bayer and Hoechst created the modern pharmaceutical industry beginning in the 1880s .
Status of U.S. companies in 1914: Still largely centered on natural products and imports, primarily from Germany.
At the time of WWI, the U.S. and China were the world’s largest consumers of synthetic dyestuffs. However, out of a total worldwide production of 160,000 tons, the U.S. produced only 3,000 tons. ( Germany produced over 140,000 tons)
Forced companies to merge (eventually) in order to attain the size and financial strength to improve their scientific capabilities:
1902 Licensing Act – required manufacturers of vaccines, serums, & toxins to be licensed by the Secretary of Treasury through Laboratory of Hygiene.
1906 Pure Food and Drug Act – regulated labeling & marketing claims about efficacy.
Permitted U.S. companies to manufacture German patented drugs:
1917 Trading with the Enemy Act .
The Formation of Interessen Gemeinschaft Farbenindustrie Aktiengesellschaft (I.G.Farben) Carl Duisberg – Bayer Carl Bosch – BASF Chairman of the Aufsichtsrat , 1925-35 Chairman of the Vorstand , 1925-1935 Chairman of the Aufsichtsrat , 1935-1940
I.G.Farben A series of sequentially more powerful trusts
1904 – the Dreiverband – the very profitable Hoechst and its two satellites.
Cassella (acquired by Hoechst in 1909)
Kalle (acquired by Hoechst in 1908)
1906 – the Dreibund – A counter-measure to Hoechst’s growing power.
1916 – the “ Little I.G. ” – (Interessengemeinschaft der deutschen Teerfarbenfabriken)
Dreibund + Dreiverband + the “Two Independents”
Chemische Fabrik vormals Weiler-terMeer , and
Chemische Fabrik Griesheim Elektron)
1925 – Final integration of I.G. Farben
Cassella and Kalle remained almost wholly owned subsidiaries, legally distinct but administered as part of the new corporation.
Following World War I, Read Holliday , Bradford Dyers , and Calico Printers merged to form British Dyes, Ltd.
1919 – British Dyes, Ltd. merged with Ivan Levinstein and several smaller British Dyestuffs companies to form the British Dyestuff Corporation , in which the British Government took a stake until 1925 .
1926 – British Dyestuffs Corporation merged with Brunner, Mond & Co. , Nobel Industries, Ltd. , United Alkalai Co. , and the British Alizarin Company to form Imperial Chemical Industries .
Still, they were no match for I.G. Farben!
Aftermath of World War II I.G. Farben BASF (Ludwigshafen) BASF (Leuna, etc.) Bayer Hoechst USSR France UK USA “In the interests of peace and democracy.”
Perceptions of the short- and medium-term outlook for an industry can change almost overnight, but structural change to diversify feedstocks and supply lines of intermediates can take years, if not decades to accomplish.
1. Discovery of “active principles” in natural products, fermentations, and simple coal-tar derivatives: analgesics, antipyretics, anesthetics, hypnotics, sedatives (1820 - 1880).
2. Experimental therapeutics and chemotherapy. Use of synthetic organic dyes to identify pathogenic microorganisms and to manufacture antiprotozoal medicines, serums, toxins, and vaccines (1880 - 1930).
3. Introduction of sulfa drugs, antibiotics, antihistamines, vitamins, corticosteroids, and sex hormones (1930 - 1960).
4. Drugs to treat hypertension and other cardiovascular diseases; antianxiety drugs, antidepressants, other CNS; oral contraceptives; semisynthetic penicillins, cephalosporins; and NSAIDS (1960 - 1980).
5. Bio-engineered proteins, antineoplastics, antivirals; new drug delivery systems, and diagnostic tests based on recombinant DNA and monoclonal antibodies (1980 - ?).
The Present What do we think we know? And why do we think we know it?
Worldwide approximately 5 million people die each year from just 3 infectious diseases:
Worldwide Sales of Leading Therapeutic Classes (in BILLIONS of $USD) and Percent Growth (in local currency)
Pharmaceutical Sales in 13 Key Markets Retail Pharmacy Sales (plus hospital sales in Japan only); Sept. to Sept.; in MILLIONS of (current; i.e., variable exchange rate) $US Dollars and Percent Change from Previous Year (at a constant exchange rate; i.e., in local currency).
Companies Ranked by Pharmaceutical Sales (Ethicals + OTC); also shows Total Sales -1
Companies Ranked by Pharmaceutical Sales (Ethicals + OTC); also shows Total Sales - 2
Companies Ranked by Pharmaceutical Sales (Ethicals + OTC); also shows Total Sales - 3
The Future Assumptions, Paradigms, and Prospects
1. In what direction is the pharmaceutical industry heading globally?
2. What are the key determining factors that will affect the future structure?
3. What impact will the future structure have on planning needs and functions?
In what direction is the pharmaceutical industry heading globally?
The industry is simultaneously pursuing three macro -objectives:
A) Increased specialization;
A function of the complex and highly technical nature of virtually all aspects of the discovery, development, manufacturing and marketing of pharmaceutical products.
B) Global consolidation;
A function of economies of scale, eliminating redundancies, reducing costs, streamlining operations, garnering larger shares of emerging markets, and monopolizing intellectual property.
A function of the growing potential for natural and/or engineered biological systems (e.g., botanical, microbial, mammalian cell cultures, etc.) to produce economic (large-scale, low-cost) quantities of active pharmaceutical ingredients or their intermediates, particularly (though not exclusively) those involving novel targets and/or peculiar disease states.
What are the key determining factors that will affect the future structure?
The key determining factors will include:
A) managed care, formularies, and the worldwide trend toward socialized medicine;
B) the growth of generics;
C) D-T-C advertising and more, better brand management and marketing;
D) the availability of capital;
E) better drug delivery;
What are the key determining factors that will affect the future structure? (continued)
The key determining factors will (also) include:
G) economic geography;
H) improved chemical engineering, industrial processes, and better yields;
I) new forms of leadership, and superior managerial ability;
J) patent and tax reform, other legal inducements or obstacles, and moral impediments.
What impact will the future structure have on planning needs and functions?
The impact on planning needs and functions will be largely four-fold:
A) a need for better methods of monitoring, analyzing, and interpreting emergent and potential new innovations;
B) a need for increased quality of communication with and paradigm sharing among firms and operating units that represent various areas of specialization within the organization or channel of distribution;
C) a need for generalists with broad backgrounds and experiences to understand and manage the growing herds of “cat-like” specialization and entrepreneurship that will continue to characterize the industry;
D) a need for better methods of conceptualizing and operationalizing the consolidation and integration of discovery, development, manufacturing, and marketing processes in order to minimize price.
Patent Expirations – Pre-2002-2004 Global Sales 2000-2001 (in MILLIONS of $USD) Year Brand Sales Manufacturer Therapeutic Class
Patent Expirations – 2005-2007 Global Sales 2000-2001 (in MILLIONS of $USD) Year Brand Sales Manufacturer Therapeutic Class
2. Those that widen the scope and markets of existing sectors or subsectors by applying new scientific principles, technology, or materials to displace existing products or processes; and serve as models for further innovation by imitation:
Barbital (Veronal), 1 st barbiturate hypnotic (1903) – 32 imitations;
Chlorothiazide (Diuril), 1 st antihypertensive diuretic (1958) – 15 i’s;
Chlordiazepoxide (Librium), 1 st benzodiazepine anxiolytic (1960) – 37 i’s;
Propranolol (Inderal), 1 st antihypertensive ß-blocker (1964) – 24 i’s;
Cimetidine (Tagamet), 1 st treatment for peptic ulcers (1977) – 7 i’s.
The systematic use of small molecules to explore biology.
Transition from ad hoc or “targeted” organic synthesis.
Biological space – region of multidimensional, biological descriptor space, e.g., specific diseases (cancer, diabetes) or areas of biology having common characteristics, e.g., cell-cycle check points.
Chemical space – region of multidimensional, chemical descriptor space, “analogs;” i.e., molecules having similar overall properties (volume, charge, number of bonds with low barriers to rotation, etc.)