sc drugs, chemists, & the law · pharmacopoeia, official homoeopathic pharmacopoeia of the...
TRANSCRIPT
DRUGS, CHEMISTS AND THE LAW
• Drugs before chemistry
• Ethical drugs
• Street drugs
• Future of drugs
DRUGS BEFORE CHEMISTRY
• Folk/Traditional drugs
• Drugs in the Western medical tradition
• Apothecaries and Alchemy
• Transformation of Alchemy into Chemistry
• Coal tar dyes
• German dye and pharmaceutical industry
ETHICAL DRUGS: OUTLINE
• Medicinal Drug Regulation (United States)
• Examples: Two Blockbuster Drugs
– Amphetamine
– Clinical tests
– Biochemical bases of drug design
– Sildenafil
• The Medicinal Drug Machine (US)
• Outcomes
SOME PIONEERING ETHICAL
PHARMACEUTICAL FIRMS
• 1830 Smith Kline & French
• 1849 Charles Pfizer
• 1858 E. R. Squibb
• 1866 Parke Davis
• 1876 Eli Lilly
• 1887 Bristol Myers
• 1888 Abbott, G.D. Searle
PURE FOOD AND DRUG ACT
1906
• Administered by the Bureau of Chemistry
• Regulated product labeling
• Interstate shipment of mislabeled goods
subject to seizure and fine
• 1911 Law ruled not to apply to false
medical claims
• 1912 Amendment included false claims
only if intent to deceive could be proven
CONSEQUENCES OF WORLD WAR ONE
• 1915 British blockade of the Atlantic
• 1917 Trading with the Enemy Act
• 1918 US Assets of Bayer went to Sterling
Drug
• 1918 Merck established as a US company
THE FEDERAL FOOD DRUG AND COSMETIC ACT
• 1938 Law required – Pre-market safety approval of new drugs
– Truthful, complete information of drug’s effects
• 1951 Durham-Humphrey Amendment required – Prescriptions for dangerous drugs
– Adequate directions for use
• 1962 Kefauver-Harris Amendment required – Pre-market safety and effectiveness approval
– Disclosure of side effects
– Informed consent by human test subjects
– Report of adverse drug reactions to FDA
WHAT IS A DRUG? FFDCA 1938
Section 201g)(1) The term "drug" means
A) articles recognized in the official United States Pharmacopoeia, official Homoeopathic Pharmacopoeia of the United States, or official National Formulary
(B) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals
(C) articles (other than food) intended to affect the structure or any function of the body of man or other animals
(D) articles intended for use as a component of any article specified in clause (A), (B), or (C)
SOME SUBSEQUENT LEGISLATION
• 1970 Comprehensive Drug Abuse Prevention and Control Act
• 1983 Orphan Drug Act
• 1988 Prescription Drug Marketing Act
• 1990 Anabolic Steroid Act
• 1992 Prescription Drug User Fee Act
• 2004 Anabolic Steroid and Control Act
NAMES OF DRUGS
• Chemical names: (±)-1-phenylpropan-2-amine,
alpha-methylphenethylamine, beta-phenyl-isopropylamine
• Laboratory code name: ?
• Generic name: Amphetamine
• Trade name: Adderal
• Street names: Speed, Pep pills, Benzedrine, Tens, Sweeties, Strawberry Shortcake,….
AMPHETAMINE MILESTONES
• Ephedrine isolated by Nagayoshi Nagai
– Tokyo
– 1885
• Amphetamine synthesized by Lazar Eleanu
– Berlin
– 1887
• Epinephrine (adrenaline) isolated by Jokichi Takamine
– New York
– 1901
ASTHMA & ALLERGIES
• Adrenaline (Epinephrine)
– Expensive
– Undesired “side effects”
• Ephedrine
– Very popular 1920s
– Became scarce
• Opportunity for alternatives
GORDON ALLES
PhD Caltech 1926
Synthesized Amphetamine salts 1928
Alles received US Patent 1932
Gave talk to AMA1929
SKF introduced Benzedrine 1932
SKF bought rights 1934
SKF patented Dexedrine 1935
SKF introduced Dexamyl 1938
ASIDE: A WORD ABOUT PATENTS
• An intellectual property right: excludes others from making, using, selling or importing the invention in the United States for 20 years
• Utility Patent: new and useful process, composition of matter…or any improvement thereof
• USPTO issues patents and trademarks
• To preserve the right it must be defended
AMPHETAMINE APPLICATIONS 1932-1960s
• Respiratory congestion
• Narcolepsy
• ADHD
• Weight reduction
• Mild depression: Dexamyl
• Performance enhancement
– Alertness
– Mood enhancement
POST WAR
• Intense competition among suppliers
• 1945 US--800 million tablets 6/year
• 1949 Benzedrex inhaler replaces Benzedrine
• 1958 amphetamine psychosis recognized
• 1950s new antidepressants emerge to
challenge Dexamyl
DEXAMYL
• The leading anti-depressant of the 1950s
• Combined a mood elevator with a depressant
Dexamphetamine Amobarbital
ETHICAL AMPHETAMINE SALES DECLINE
• 1960s—amphetamine loses favor as an antidepressant
• 1962 US sales--8 billion tablets 50/year
• 1972 amphetamine recognized as “addictive”
• 1978 Dexamyl withdrawn from the market
• Now sold by prescription—closely controlled
• Dexamphetamine used by the military in Vietnam and Afghanistan
GETTING A DRUG TO MARKET TWO MAJOR DEVELOPMENTS
• Design and conduct of clinical trials
• Identification of biochemical targets for drug action
CLINICAL TRIALS
• Preclinical studies: test tubes, cell cultures, animals
• Phase O 10-15 human volunteers look for differences from expectations
• Phase I 20-100 healthy or terminally ill volunteers to confirm safety
• Phase II 20-300 continue safety and assess efficacy
CLINICAL TRIALS
• Phase III 300-3000 subjects
– Randomized, double blind, multicenter
– Demonstrate safety and efficacy
– Usually need two successful trials for FDA approval
• Phase IV post-marketing surveillance—safety and efficacy in large populations
• Has led to withdrawal of previously approved drugs
– Parke Davis Rezulin 2000
– Bayer Baycol 2001
– Merck Vioxx 2004
– Avastin?
BIOCHEMICAL TARGETS FOR DRUG ACTION RECEPTORS
• Extracellular
– Protein molecules on cell surfaces that react to a signal from the cell’s environment by causing a change in the cells function
– Signals: hormones, ions, neurotransmitters, drugs
• Intracellular
– Located inside cells as in the cell nucleus
– Signals: steroid hormones, thyroid hormones
BIOCHEMICAL TARGETS FOR DRUG ACTION ENZYMES
• Proteins (or sometimes RNAs) that catalyze chemical reactions
• Inhibitors block the action of an enzyme
• Many drugs are enzyme inhibitors
• Issues: specificity and potency
“RATIONAL DRUG DESIGN”
• Identify a therapeutic goal
• Identify a biochemical mechanism
• Select a lead compound
• Apply computer modeling to design geometrical and electronic properties
• Optimize the structure for safety and efficacy
• Devise a practical route to supply the drug
SELECTING A LEAD COMPOUND
• Natural products
– Plants
– Animals
– Fungi
– Microorganisms
• Non-medicinal synthetic compounds
• Known drugs
A CONTEMPORARY BLOCKBUSTER
• Chemical name: 1-[4-ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenylsulfonyl]-4-methylpiperazine
• Laboratory code name: UK-92,480
• Generic name: Sildenafil
• Trade names: Viagara, Revatio
• Street names: Hammer heading (w/Ecstasy)
SILDENAFIL • 1985 Goal: a drug to reduce blood pressure
• Approach: enhance activity of Atrial Neuropeptide
• New approach: inhibit destruction of cyclic GMP by Phosphodiesterase 5 (PDE 5)
• Lead compound an anti-allergy drug-zaprinast
• Optimization guided by the properties of c-GMP
• Synthesized & screened> 1600 compounds
• New goal selected
UK92480 cGMP Zaprinast
SILDENAFIL
• New Goal: a drug to relieve angina
• 1992 Phase II clinical trials for angina—the drug didn’t work
• But it produced an unexpected benefit!
• 1994 Phase II clinical trials for EDS—a winner!
• 1995 Scaled from 10g to 1000kg in 13 weeks
• 1998 Sildenafil was renamed
Viagara
THE MEDICINAL DRUG MACHINE • Pharmaceutical Industry
– Major pharmaceutical firms
– Generic manufacturers
– Entrepreneurial firms
• US Government
– National Institutes of Health
– Medicare/Medicaid
– Food and Drug Administration
– Drug Enforcement Agency
• Universities, medical schools, & other institutions
• Medical professionals
• Medicinal drug users
• Health Insurers
MAJOR PHARMACEUTICAL FIRMS AN EXAMPLE: PFIZER
• Built business on fermentation technology
– 1919 Citric acid
– 1936 Vitamin C
– 1941 Penicillin
• 1950 Introduced Terramycin—Pfizer’s first
proprietary product
• 1951 Started to grow by merger or acquisition
and globalized production, sales and R&D
• 1971 Established a Central Research Division
PFIZER: THE WORLD’S LARGEST PHARMACEUTICAL COMPANY
• 1980 Feldene: Pfizer’s first blockbuster drug
• 1992 Norvasc, Zoloft, Zithromax introduced
• 1997 Warner-Lambert introduced Lipitor
• 1998 Pfizer introduced Viagara
• 2000 Pfizer merged with Warner-Lambert
• 2003 Pfizer merged with Pharmacia
• 2009 Pfizer acquired Wyeth
• 2010 Pfizer sales $ 68 B; income $18 B
• 2011 Pfizer acquired King Pharmaceuticals
THE BIGGEST PHARMA
1. Pfizer
2. Novartis
3. Merck & Co
4. Bayer
5. GlaxoSmithKline
6. Johnson & Johnson
7. Sanofi
8. Hoffman-LaRoche
THE MEDICINAL DRUG MACHINE • Pharmaceutical Industry
– Major pharmaceutical firms
– Generic manufacturers
– Entrepreneurial firms
• US Government
– National Institutes of Health
– Medicare/Medicaid
– Food and Drug Administration
– Drug Enforcement Agency
• Universities, medical schools, & other institutions
• Medical professionals
• Medicinal drug users
• Health Insurers
GENERIC DRUGS
• 1984 Drug Price Competition & Patent Restoration Act
• To be approved as a generic a medication
– Must contain the same active as the branded drug
– Must demonstrate identical pharmacology within an acceptable
range to a branded drug
– Name must be approved by the US Adopted Name Council
• The benefit to consumer is lower price
GENERIC DRUG INDUSTRY
• India is the largest producer
• TEVA Pharmaceutical Industries is the largest generics
firm
– Founded in Jerusalem in 1901
– Worldwide sales 2010 $16B
– US Market share > 20%
• Generics firms are introducing branded products
THE MEDICINAL DRUG MACHINE • Pharmaceutical Industry
– Major pharmaceutical firms
– Generic manufacturers
– Entrepreneurial firms
• US Government
– National Institutes of Health
– Medicare/Medicaid
– Food and Drug Administration
– Drug Enforcement Agency
• Universities, medical schools, & other institutions
• Medical professionals
• Medicinal drug users
• Health Insurers
NATIONAL INSTITUTES OF HEALTH
• Federally funded: 2011 $31.2 B
• Eighty percent is distributed in grants
• NIH Campus: 6000 scientists ~$3 B
INSTITUTES & CENTERS
• Twenty seven in total
• National Cancer Institute $5B
• National Institute of Allergy and Infectious Diseases $4.5B
• Some Others: Eye; Heart, Lung & Blood; Human Genome Research; Aging; Alcohol Abuse & Alcoholism; Allergy & Infectious Diseases; Arthritis; Deafness; Diabetes, Drug Abuse; General Medical Sciences; Mental Health; Neurological Disorders….
AN INVENTORY OF CURRENT MEDICINALS*
• Alimentary Tract and Metabolism 334
• Blood and Blood-forming Organs 90
• Cardiovascular System 361
• Dermatologics 224
• Genitourinary System/Sex Hormones 177
• Systemic Anti-infectives 227 *Source--World Health Organization (WHO): Anatomical Therapeutic
Chemical Classification System
AN INVENTORY OF CURRENT MEDICINALS*
• Antineoplastic Agents 179
• Musculoskeletal System 87
• Nervous System 493
• Antiparasitic products 77
• Respiratory System 129
• Sensory Organs ~50
*Source--World Health Organization (WHO): Anatomical Therapeutic Chemical Classification System
EXAMPLE: THE NERVOUS SYSTEM • Anesthetics 52
• Analgesics 75
• Antiepileptics 42
• Anti-Parkinsonism Drugs 32
• Psycholeptics
– Anti-psychotics 64
– Anxiolytics 32
– Hypnotics and Sedatives 67
• Psychoanaleptics
– Antidepressants 61
– Psychostimulants 32
– Antidementia drugs 6
• Other 30
NCGC PHARMACEUTICAL COLLECTION
• NIH Chemical Genomics Center
• Provides a web-based publically accessible data base of 27,000 active pharmaceutical ingredients including
– 2,750 approved small molecule drugs
– 7,500 compounds tested in humans
– Drug candidates under clinical investigation
• Applications: rare diseases, repurposing,…