PHAR1101 Lecture Notes - Lecture 11: Thalidomide, Pentobarbital, Animal Testing
Thalidomide – the horror drug:
Background:
Chemie Grunenthal GmbH
- personal products company
- founded in Germany in 1946
- many former Nazis
Successful antibiotic ventures (first company to make penicillin in post-war Germany)
95’s wished to expand lucrative tranquilizer market.
Barbiturate:
Developed late 19th early 20th century.
- Powerful sedative but serious side effects
- Nembutal – addiction, tolerace etc.
Low margin of safety – overdose concerns.
Sleep disruption in pregnancy:
Complex physical, hormonal and psychological changes in pregnancy
Insomnia common
- All trimesters
- Nausea-related in trimester 1
Severity often increases with gestation.
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 sign of toxicity
- Inactive in classic sedative tests (i.e. righting reflex)
- structure (wrogly suggested tauilize atios to Kuz’s supevisos, so
human trials begun.
Inadequate human trials:
find more resources at oneclass.com
find more resources at oneclass.com
No systematic, properly conducted human trial of thalidomide.
- No evaluation of its safety in pregnant women
Grunenthal simply distributed free packets of it to doctors
- No proper follow up or monitoring
- Also distributed free of charge to company employees.
Early hua trial results thrill Gruethal:
Early 1955 results from tests in epileptic patients in Germany and Switzerland.
- No anticonvulsant benefits
Recipients report long, deep sleep
- No effects on motor activity
- Lacked proof for hypnotic properties in animal model.
Jiggle Cage
- 8 mice treated with sedatives or thalidomide are less active than drug-free controls
- Measure H2 release with hydrogen detector
- Platinum electrode (dips into acid when mice move or jiggle cage)
Thalidomide on sale – 1 October, 1957
“old as contergan – Germany
- OTC in Germany and elsewhere
Massive marketing campaign
- 50 medical journals, 250,000 letters to doctors, 50,000 therapeutic circulars
1961, top selling sedative in Germany:
Global success story:
Rapid expansion into overseas markets (2nd only to aspirin)
- Not USA
- Under 37 different trade names
In Uk and aus – distribution rights sold to distillers
- No pharmacologist or toxicologists on staff – no further testing
- Maketed as distaval.
find more resources at oneclass.com
find more resources at oneclass.com
Bad Christmas present:
Earless daughter born to worker at Grunenthal plant
- Father supplied free pills to expectant wife
- Failed to draw link to drug
10 months before thalidomide began marketing
Not so safe:
In first year – complaints from doctors
- Dizziness
- Memory loss
- BP loss
- Cold hands and feet
- Numb hands and feet
- GI tract pain and constipation
Met with denial by Muckter
Dec 1960, letter on peripheral neuritis in BMJ
Mysterious epidemic:
Pediatric clinics across Germany report cases of phyocomelia (seal limbs
– absent or ill formed upper and/or lower limbs)
- Extremely rare
Aussie doctor draws link:
1960 – William McBride – 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 babies affected
- Dec 1961 – letter in BMJ
Short-lived fame – later shamed for debendox scandal
Extent of global tragedy:
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
Personal products company founded in germany in 1946. Successful antibiotic ventures (first company to make penicillin in post-war germany) (cid:1005)95(cid:1004)"s wished to expand lucrative tranquilizer market. Complex physical, hormonal and psychological changes in pregnancy. Discovered thalidomide (by-product while making antibiotic peptides) Commenced animal testing in rats, mice, guinea pigs etc. Inactive in classic sedative tests (i. e. righting reflex) Structure (wro(cid:374)gly(cid:895) suggested t(cid:396)a(cid:374)(cid:395)uilize(cid:396) a(cid:272)tio(cid:374)s to ku(cid:374)z"s supe(cid:396)viso(cid:396)s, so human trials begun. No systematic, properly conducted human trial of thalidomide. No evaluation of its safety in pregnant women. Grunenthal simply distributed free packets of it to doctors. Also distributed free of charge to company employees. Early 1955 results from tests in epileptic patients in germany and switzerland. Lacked proof for hypnotic properties in animal model. 8 mice treated with sedatives or thalidomide are less active than drug-free controls. Platinum electrode (dips into acid when mice move or jiggle cage) 50 medical journals, 250,000 letters to doctors, 50,000 therapeutic circulars.
