drug safety

Question 1

why are we concerned about drug safety

Answer 1

historical context
- thalidomide was given to pregnant mothers
- it caused birth defects

Question 2

drug safety testing

Answer 2

• highly regulate by FDA
• need two species, rodents and non-rodent
• could react differently in other species, eg. different in rodents to humans

regulatory requirements
- exaggerate dosage
- exaggerate duration of exposure

• chronic exposure studies in animal models take 6 months- 1 year

Question 3

how do we test for toxicity

Answer 3

types of toxicity endpoints
- death of proportion of cells/organisms
- pathology
- surrogate measures of organ toxicity by measuring blood/urine

Question 4

types of safety tests

Answer 4

in vivo
- in living organisms
- does drug cause cancer in people

in vitro
- “in glass”, experiments or cell culture experiments
- indirect safety test; does drug damage DNA of bacteria

Question 5

toxicology

Answer 5

• toxicity can be caused by drug or by one of its metabolites

major mechanisms
- reversible binding of drug to receptor
- activation of drug to metabolite that binds/damages protein/DNA

Question 6

ames assay

Answer 6

• in vitro mutagenesis test; does it cause bacterial damage
• a biological test for the carcinogenic potential of a compound; does it cause cancer

Question 7

ames assay for mutagenicity

Answer 7

• use a strain of bacteria that have been genetically modified to require histidine (amino acid)
• usually none of the bacteria grow in media lacking his
• if the bacterial DNA mutates, then it can change to growing in his-free media

Question 8

what organs need to be assessed for toxicity

Answer 8

• all major organs
• even if unrelated to target use

Question 9

toxicology

Answer 9

• considers a spectrum of undesired effects
• allergic reactions
• abnormal reactivity to standard dose
• Reversible vs. irreversible effects
• local vs. systemic effects (site of first contact, whole organism)