Lecture 14

Question 1

Common drug targets

Answer 1

Proteins, e.g. receptors, enzymes and transport proteins

Question 2

Chemical libraries

Answer 2

All big companies have one, a large compound library with over a million chemical entities, put through their assay to look for a specific interaction

Question 3

Ames test

Answer 3

Various strands of salmonella specifically isolated so they cannot grow on a media that is missing the amino acid histolene, apply drug to growing media and if the bacteria now grows the drug has caused a mutation

Question 4

Positive ames test

Answer 4

No go because it can cause mutations

Question 5

Arrhythmia biomarker

Answer 5

hERG potassium ion channel - Human ethergogo channels

Drugs that bind to this channel give rise to long QT syndrome

Question 6

Exploratory studies in vivo

Answer 6

Repeat administration for 14 days, eventually extending the study to see effects of prolonged exposure, can see any metabolism toxicology

Question 7

Pre-clinical development stages

Answer 7

Extending studies within mammals and looking at genotoxicity, observing fertility and foetal development, also behavioural outputs

Question 8

Small molecules

Answer 8

Safety pharmacology, 1,3 and 6 month studies, range-finding studies, developmental toxicity studies, 1 year non-rodent, 4.5 years

Question 9

Biomolecules

Answer 9

2.5 years, don’t enter cells so less worries for mutations

Question 10

Toxicity

Answer 10

On/off target and reversibility

Question 11

Toxicokinetics

Answer 11

Relate toxicity to exposure

Maximum non-toxic dose and minimum affective dose

Question 12

exaggerated pharmacology

Answer 12

More extreme reaction than expected, relates to specificity and effectiveness of molecules

Question 13

Anti drug antibody responses

Answer 13

Accelerated response, prolonged exposure and neutralises the pharmacological activity

Question 14

Small molecules immunotoxicology

Answer 14

Often unexpected and off-target, haematological change, weight changes and histopathology

Question 15

Biopharmaceuticals immunotoxicolgy

Answer 15

Higher risks, infusion reaction, cytokine storms, immunosuppression and autoimmunity

Question 16

Cytokine storm

Answer 16

After first injection, massive reaction that can lead to organ failure

Question 17

Irwin activity screen

Answer 17

3 dose levels and control groups observed for 4-6 hours, physical factors and gross appearance, behaviour observation, reflexes and reactions, motor coordination

Question 18

Cardiovascular pharmacology

Answer 18

In vitro electrophysiology for QT prolongation and in vivo assessment of QT

Question 19

genetic toxicology

Answer 19

Damage to DNA, Ames test, testing across dose concentrations

Question 20

Elixir sulfanilamide

Answer 20

Contained diethylene glycol, killing 107 people

Question 21

Sulfathiazole tablets

Answer 21

Tainted with the sedative phenobarbital, caused 300 deaths

Question 22

Thalidomide disaster

Answer 22

Sleeping pill caused severe birth defect of arms and legs in Western Europe
Withdrawal after 7 years

Question 23

Repurposing drugs

Answer 23

Using a drug for a different condition

Question 24

Phase 1 trial

Answer 24

8-20 healthy volunteers to ascertain drug safety, side effects and pharmacokinetic properties
Also checking ability to exert effects on wanted targets

Question 25

Phase II trial

Answer 25

testing for drug effectiveness in people with the condition, dose conc, how well treatment works, low 100s volunteers

Question 26

Phase III trial

Answer 26

1000+ patients, definitive results in many centres internationally, blind test, marketing application, medical regulatory bodies

Question 27

Phase IV trial

Answer 27

Post-marketing surveillance, detecting rare or long-term adverse effects, may react badly with other drugs and directs labelling of the product

Question 28

Sibutramine

Answer 28

Appetite suppression, heart attack and stroke, 13 years

Question 29

Prpoxyphene

Answer 29

Opioid painkiller, 15 years, heart attack and stroke

Question 30

Drotrecogin alfa

Answer 30

Severe sepsis drug, 9 years, just no benefit

Question 31

Rimonabant

Answer 31

2 years, anti-obesity drug, severe depression and suicide

Question 32

Hydromorphone

Answer 32

Narcotic painkiller, 6 months, high risk of accidental overdose with alcohol