L4/5: Drug safety Flashcards
what is the first consideration for releasing a drug to the public? where did this stem from?
first - do no harm.
concept from the hippocratic oath
its a guiding principle for physicians
what is dose-dependency of toxicity concept
that all things are poison but its the dose of it that doesnt make it a poison
Why are we concerned about drug safety of new drugs in the pipeline? give an example
- its a historical concern - due to safety concerns in the past
for ex. 1950s thalidomide - it was intended to be used for morning sickness
- however when mothers took it during drug pregnancy, it caused birth defects, such as missing limbs, in their children
who was frances kelsey and what was her skill?
she is a canadian pharmacologist that considers toxicology evidence insufficient in US marketing.
she works in the US FDA
- John F Kennedy said her judgement prevented major tragedy of birth deformities in the US
what is the highly regulated FDA drug development safety procedure?
- Get data from generally two species
ie. one rodent and one non-rodent - this is due to drugs and how they can behave differently in different species.
- not always clear which species is more predictive for humans
- exaggerate the dosing and duration of exposure to the drug
this will help with testing for intended clinical use. - moderate the long term effects
ie. for 6 month to 1 year
how do we test for toxicity?
7 ways
- the three toxicity end points
- ames assys (in vitro)
- in vivo tests
- testing reproductive toxicity with sperms
- cardiotoxicity
- stem cells
- using biomarkers
what are three ways we can determine toxicity endpoints
- Does it kill cells in a dish
- Pathology (microscope) –does it have a unique shape, is form and function effected
- looking at blood or urine samples for seeing if the drug is safe
how do we visualize toxicity?
collect data on the changes in cell number before and after drug treatment
what are three ranks of toxicity
water = very low
caffeine = moderate
1080 ie poison = high
toxicity of botox vs alcohol
botox is 1M times more toxic than alcohol (ethanol)
- we insert poison into our face to stop our nerves in our skin to communicate with each other
safety test 1: does your compound under development have the potential to cause cancer?
what is the in vivo and in vitro tests for this question
- In vivo = in living organism
- In vitro = “in glass”. Can mean a biochemistry (proteins +
drug) experiment or cell culture experiment
questions:
* safety concern: does the drug cause cancer in people? (in vivo question)
* Indirect safety test: does the drug damage DNA of bacteria? (in vitro test)
what can cause toxicity and by which mechanisms is this caused?
- toxicity may be by the drug or by one of its metabolites (ie. what the body converts the drug into)
- when we see safety problems pre-clinically, they are usually happening by one of two mechanism:
1. unbindingthe drug to the receptor
2. when the drug converts to a metabolite, that binds/damages protein, DNA - This occurs by drug- metabolizing enzymes (pharmacokinetics – what the body does to the drug)
what is the ames assay
- An in vitro mutagenesis test
- A biological test for the carcinogenic (cancerous) potential of a compound
concern: does the drug cause cancer?
test: does the drug damage bacterial DNA?
how does the ames assay work? what would the experimental set up look like?
- use bacteria that has been genetically modified to require histidine (an amino acid)
- this modification means that the bacteria will only grow when His is present
- If bacterial DNA mutates when the drug added, then the bacteria will be able to grow in His-free media
experiment:
- two mixtures: one (experimental) with the mutagen (molecule that we suspect damages DNA) and metabolizing enzymes. the other (control) with just the metabolizing enzymes.
- spread mixtures on culture dish, both without His
- suspect, the control dish to have no colony growth (as lacking His so nothing will grow)
- if the experimental dish has growth, this means the mutagen mutated the DNA, allowing it be grown without His.
how do we interpret the lab tests of ames assays
no colony = the drug or its metabolite did not cause mutations (good)
some colony = the drug or its metabolite caused some mutations
a lot of colony = the drug or its metabolite caused many mutations (evidence is that lots of bacteria can now grow in media where they usually aren’t able to. This indicates that they have developed a mutation that allows them to survive)
