Thalidomide & Toxicology Flashcards
Lecture Outcomes
1) summarise social, commercial, and medical factors that contributed to
the 1960’s thalidomide disaster
2) summarise key factors and events in the botched development of
thalidomide by Chemie Grunenthal
3) describe thalidomide toxicity, its impact on newborn and elderly victims,
and the likely toxicological mechanisms
4) describe the global impacts of the thalidomide disaster and the main lessons
learned
5) list the current therapeutic use of thalidomide and its safer derivatives
The Titanic & Thalidomide - the Two Major Technology
Disasters of the 20th Century
- Reveal the risks accompanying blind faith in new technologies
Aim of Lecture
To explore the scientific and
historical aspects of the
worst drug-induced medical
tragedy of the 20th century.
The Background to Thalidomide - I
Chemie Grünenthal GmbH, personal products
company
Founded in Germany in 1946
Many former Nazis in company
Successful antibiotic ventures
First company to make penicillin in post-war
Germany
1950s, wished to expand into lucrative
tranquiliser market
The Background to Thalidomide - III
“The Baby Boom” and Sleep Disruption in Pregnancy
The Baby Boom that occurred after WW-2 left
many mothers experiencing pregnancy
Many complex physical, hormonal, psychological
changes in pregnancy
Expectant mothers frequently experience
insomnia
Occurs in all trimesters
Nausea-related in trimester 1
Severity often increases with gestational age
(e.g., backache, nocturia, etc
)
The Infamous Grunenthal “Jiggle Cage”
October 1, 1957 – Thalidomide on Sale
Sold as “Contergan” (Germany)
OTC in Germany + elsewhere
Massive marketing campaign
50 medical journals
250,000 letters to doctors
50,000 “therapeutic circulars”
1961, top-selling sedative in Germany (5X
nearest competitor)
The Background to Thalidomide - II
Barbiturate class of hypnosedatives (sleep
inducers) were developed late 19th C/early
20th
C
Powerful sedatives but serious side-effects
e.g., Nembutal: addiction, tolerance
A low “margin of safety” → high risk of
overdoses
Early Human “Trial” Results Thrill Grunenthal Executives
Early 1955, results from tests in
epileptic patients in Germany &
Switzerland
No anticonvulsant benefits but
apparent hypnotic effects
Recipients report long, deep sleep
No effects on motor activity
Lacked proof for hypnotic properties in
animal model
“A New Drug in Search of a Disease”
Wilhelm Kunz, Grunenthal chemist
Discovered thalidomide (by-product while making
antibiotic peptides)
Secured 20-year patent
Commenced animal testing in rats, mice, guinea
pigs, etc
No signs of toxicity (“nontoxic”)
Inactive in classic sedative tests (e.g., “righting
reflex”)
Structure (wrongly) suggested tranquilizer actions
to Kunz’s supervisor, so human trials begun
Chemie Grunenthals’ Woefully Inadequate “Human Trials”
No systematic, properly conducted human
trial of thalidomide
No evaluation of thalidomide safety in pregnant
women
Grunenthal simply distributed free packets
of thalidomide to doctors
No proper follow-up or patient monitoring
Also distributed free of charge to company
employees
Thalidomide: A Global Success Story
Rapid expansion into overseas markets
(2nd only to aspirin!)
e.g., Europe, Asia, Africa, Americas (not
USA!)
Sold under 37 different trade names
In UK & Australia – distribution rights
sold to Distillers
No pharmacologists or toxicologists on
staff – no further testing in UK!
Marketed as “Distaval
Not So Safe After All?
In 1st year of marketing, written complaints
from doctors:
Dizziness
Memory loss
Blood pressure loss
Cold hands and feet
Numb hands & feet
GI-tract pain & constipation
Met with denial by Muckter
Dec 1960, letter on peripheral neuritis in BMJ
Alexander Leslie Florence (Scottish doctor)
A Worrying Christmas Present
1956, December 25, Stolberg, Germany
“Earless” daughter born to worker at
Grunenthal plant
Father had supplied free pills to his
expectant wife
Failed to draw link to drug
10 months before thalidomide
marketing began in Germany
A Shocking & Mysterious Epidemic Unfolds
Pediatric clinics across Germany report cases of
phocomelia
Lit. “seal limbs” – absent or ill-formed upper or
lower limbs
Amelia
– both upper and lower limbs affected
Extremely rare condition (normally)
Germany was the cradle of emerging disaster
News slowly emerged of affected infants elsewhere
Widukind Lenz [1919-1995] – University of
Hamburg paediatrician – November 1961 began
exploring likely role of thalidomide
Nov 16, 1961, phoned Chemie Grünenthal to
express his concerns re: teratogenicity
1961: An Aussie Doctor Draws the Link
1960, William McBride, Sydney gynaecologist, gave
thalidomide to pregnant patients
Early 1961, several phocomelia babies
Drug removed from hospital pharmacy
Began testing in pregnant mice and guinea pigs
(unsuccessful)
Sept 1961, 2 more affected babies
Dec 1961, famous letter published in The Lancet
Short-lived fame (later disgraced)
Extent of the Global Tragedy
Grunenthal eventually bowed to inevitable
Drug withdrawn from all global markets
Not marketed in US – Dr Frances Kelsey
1957-1962: ~10,000 malformed babies worldwide
Excludes miscarriages & stillbirths (occurred when
mothers took drug outside “window of susceptibility”)
High mortality rate in newborns
40% died by 1 y.o.
Scope of Thalidomide Prenatal Toxicity
Phocomelia “Window of Susceptibility”:
Day-20 to Day-36 post-fertilization
Day 34 to Day 50 after last menstrual cycle
1 pill sufficient within this period
Non-phocomelia malformations:
Eyes (e.g. small)
Ears (e.g. small or absent)
Hearing loss
Heart
Kidneys
GI-tract
CNS (autism & low IQ in some victims)
Abnormal genitalia (Vargesson, 2009)
Scientific Puzzles I – Species Selectivity
60 Years Later: Disability Issues in Ageing Thalidomiders
Scientific Puzzles II – Mechanisms?
Things We Learned from the Thalidomide Tragedy
High level care needed when developing new drugs
Must assess drug toxicity systematically (birth of modern
toxicology)
Need for global and national drug laws &
pharmaceutical industry oversight
Drug companies must be accountable for the harm their
products cause
New uses have emerged from knowledge of
thalidomide effects
Thalidomide’s Comeback
Used to slow down body wasting in leprosy
victims
Used to prevent weight loss &
mucocutaneous ulcers in HIV-infected
patients
Used to treat some types of cancer:
e.g., multiple myeloma, glioma
Safer thalidomide-based drugs, e.g., lenalidomide
Also used to limit vomiting [antiemetic] in
some cancer chemotherapy patients
Key Question: Is the Drug Safe?
- Since thalidomide, toxicologists have been key
members of drug discovery and development teams in
Big Pharma companies –Oversee toxicological evaluation of new molecules as they
move along the drug discovery and development conveyor
belt - Toxicologists are also employed by federal regulatory
agencies where they review scientific data in dossiers
submitted by pharmaceutical company sponsors.
Further Reading
Lecture Outcomes
Aim of Lecture
To review the scientific
strategies used and the
questions that are asked during
the evaluation of new
pharmaceuticals for toxic
potential.
Key Questions in Early “Preclinical” Toxicity Testing - I
Methods Used during each Phase of Toxicological Assessment
Discovery Phase
Preclinical Testing
* Metabolism studies
* “In vitro” cell-based
toxicity assays
* Animal-based safety
and toxicity testing
Development Phase
Clinical Testing
* Conducted in human
volunteers
* Small scale pilots and
large-scale trials
* Pharmacokinetics,
metabolism & safety
Paracetamol – A Classic Example of Drug Bioactivation in the Body
Very safe at recommended doses, but at high doses (i.e., overdose
conditions), paracetamol is converted to a toxic metabolite
The Example of Ketotifen (“Zaditen”)
Establishing the Metabolic Profile of Drugs in Cells and Tissues of
Human & Animal Origin
Mass spectrometry is key enabling technology during
metabolic studies
Aim is to identify any metabolites with toxic potential
Knowing metabolic profiles in humans is most important
Need to identify any differences between
humans & animals during the
metabolism of new drugs
Cultured cells expressing human drug
metabolising enzymes are widely
used in industry
Key Questions in Early “Preclinical” Toxicity Testing - II
Ethical Factors in Animal-Based Drug Testing
Animal use in medical research and
pharmaceutical testing is a privilege that
is subject to strict oversight
e.g., legislation, government regulators,
vets, welfare groups, etc
Animal suffering kept to a minimum
3R’s of animal use:
Reduce
Refine
Replace
Toxicological Issues that are Assessed in Animals
Short-term toxicity (e.g., limited doses)
Accumulation in body tissues
Ability to cause allergies (sensitisation)
Long-term toxicity (repeated dosing)
Toxicity to unborn animals
Cancer-causing ability (“carcinogenicity”)
Which Animal Species?
Rats and mice are preferred:
Affordable to maintain
Convenient lifespan
Genetically defined
Large database of drug effects
Similar to humans in drug handling – i.e.,
ADME (pharmacokinetic properties)
Some Animal Species Predict the Human Toxicity of Drugs Better
than Others (Cancer Drugs Only)
Animal Toxicity Data Can Sometimes Halt Drug
Development Programs
Novo Nordisk, Danish drug company
2002, dropped diabetes drug ragaglitazar
during final-stage human trials
Due to finding unexpected bladder
tumours in rats and mice
Millions of $$$$ lost
“Organs on Chips” - Emerging Alternatives to Animal-Based Drug
Safety and Toxicity Testing
In vitro 2D cultured cells long used to test drugs
Poor reproduction of rich multicellularity and 3D complexity
of whole organs
Now many labs are studying microfluidic models as
alternatives to animals/2D cultures
Allow multiple cell types to be grown in artificial environment
that mimics intact tissue
Can use induced pluripotent stem cells (iPSCs)
e.g., Liver on Chip, Kidney on Chip, etc
Body on Chip – hook up multiple organ chips
Not yet fully accepted by drug regulatory bodies
Key companies: Mimetas, Emulate, etc
The Transition from Drug Discovery to Development Occurs
when a Promising Molecule is Judged Safe and Effective and
Worthy of Human Testing
Key Questions in “Clinical” Drug Testing - I
The 5 Phases of Clinical Testing
Phase 0 Clinical Testing
Enabled by advances in mass spectrometry equipment that
allow detection of tiny amounts of drugs in blood or urine
A recent addition to modern clinical drug testing protocols
Also called “Pre-Phase 1” testing
Assess human safety of drug and obtain preliminary PK
and PD data
Is the molecule suitable as a drug?
Small groups: 10 to 12 healthy volunteers
Tiny doses used (“microdoses”)
Measure drug concentrations in blood, urine, etc
Phase 3 Clinical Testing
Main purpose is large-scale testing of
drugs (1 - safety & 2- effectiveness)
Normally conducted in >2000
disease-affected patients
Recruited in different cities, countries
(= “multisite trial”)
Takes 3-5 years, complex organisation
Phase 1 Clinical Testing
Main purpose is to assess human safety
of expected drug doses
Normally conducted in 10 to 100
healthy volunteers
Dose starts low, may increase with study
progression
Measure drug concentrations in
blood, urine, etc
Phase 2 Clinical Testing
Main purpose is to assess effectiveness of drug
in target population
Normally conducted in 50-500 disease-affected
patients
Controls may have received existing drug in
current use
Success rate ~30%
Phase 4 Clinical Testing
Purpose is to monitor drug safety under “realworld” use patterns
AKA “post-marketing surveillance”
Can involve 50,000+ subjects (sometimes 1
million+)
Reporting system uses doctors, pharmacists,
patients to report side-effects
Also assesses quality of life measures &
economic considerations
Lecture Conclusions
Attentive toxicity testing has likely helped to make
drugs safer but high caution is still needed
Combination of in vitro cell-based, whole animal
and human testing methods
Important to identify any tendency for metabolic
bioactivation (associated with organ damage)
Animal models allow comprehensive study of
drug-induced toxicity
Short term, long term, multigenerational, etc
Human studies allow preliminary confirmation
of drug safety, but vigilance needed upon
human release of any drug
Further Reading
1) Burcham, PC (2013) The emergence of modern toxicology, Chapter 1 in An
Introduction to Toxicology, Springer (UK).
2) Cairns, R et al (2019) Paracetamol poisoning-related hospital admissions and deaths
in Australia, 2004–2017. Medical Journal of Australia, 211, 218-223
3) Gallo, MA (2013) “History and Scope of Toxicology.” Casarett and Doull’s Toxicology:
The Basic Science of Poisons, Eighth Edition Ed. Curtis D. Klaassen. New York, NY:
McGrawHill.
4) Hill, RG & Rang, HP (2013) Drug Discovery & Development: Technology in Transition,
Churchill Livingstone.
5) Erickson MA & Penning TM (2018) Drug toxicity and poisoning. Chapter 4 in
Goodman & Gilman’s The Pharmacological basis of Therapeutics, 13th ed. McGraw
Hill.
