SC 203 DRUGS, CHEMISTS, & THE LAW

WEEK TWO: ETHICAL DRUGS

OCTOBER 21, 2011

JOHN BUSH

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

UNITED STATES MEDICINALS MARKET

BEFORE WORLD WAR ONE

• Ethical Pharmaceuticals

• Patent Medicines

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

EDZARD ERNST

A SNAKE OIL SALESMAN?

DRUG REGULATION IN THE

UNITED STATES

SAMUEL HOPKINS ADAMS DR. HARVEY W WILEY UPTON SINCLAIR

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

WORLD WAR ONE

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

BACK TO GERMANY BAYER PHARMACEUTICAL RESEARCH

Philipp Heinrich Hörlein

Gerhard Domagk

Joseph Klarer Fritz Mietzsh

THE FIRST SULFA DRUG

Prontosil

Sulfanilamide

Sulfamethoxazole

Sulfadiazine Sulfaguanidine

Sulfathiazole

STIRRING UP THE PUBLIC

Arthur Kallet The ergot controversy

1937-THE TIPPING POINT

JOAN MARLAR

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

TWO BLOCKBUSTER DRUGS

• (DL)Alpha-methylphenethyl amine

• Sildenafil

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

POLAND - 1940

METHAMPHETAMINE

TARAWA NORTH ATLANTIC

Amphetamine

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

NEW PSYCHOACTIVE DRUGS

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

Carl Djerassi

Bruce Merrifield Elias J Corey

Robert B Woodward

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

RECEPTOR MEMBRANE SIGNALLING COMPLEX

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

BIOCHEMICAL TARGETS FOR DRUG ACTION MEMBRANE TRANSPORT PROTEINS

“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….

WHAT HAS THE MEDICINAL DRUG MACHINE PRODUCED?

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,…

LIFE EXPECTANCY & INFANT MORTALITY

1930 59.2 Years 1915 ~ 75 deaths/1,00 live births

IMPROVED PROGNOSIS FOR CANCER PATIENTS

RATE OF CANCER

MORTALITY

NEXT CLASS-STREET DRUGS

• Drug regulation in the United States

• Drug abuse and drug safety

• Origins of illicit drugs

• What are users seeking?

• Involvement of chemists-some examples

• The illicit drug industry

• Popular street drugs