6. Drug Safety

Question 1

“Primum non nocere” (latin) means

Answer 1

Do no harm

Question 2

Thalidomide

Answer 2

Was a drug used for morning sickness & causes birth defects in some children whose mothers took the drug during pregnancy

Question 3

Frances Kelsey

Answer 3

a Canadian Pharmacologist working at the US FDA, considers toxicology evidence insufficient for US marketing

Question 4

Kefauver-Harris Amendments to the Food, Drug and Cosmetics Act (1962)

Answer 4

• Drug manufacturers required to prove, scientifically, that the drug is: Safe
  & Effective

Question 5

FDA Regulations on Preclinical Safety Testing

Answer 5

1) Adequate information about pharmacological and toxicological studies
2) Duration and scope of in vitro animal testing and other tests required varies
3) Guidance documents are available

Question 6

3 ways to test for Toxicity

Answer 6

1) Death of proportion of cells/ organisms
2) Pathology (microscope)
3) Surrogate measures of organ toxicity by measuring the blood or urine

Question 7

Units of Toxicity

Answer 7

mg of drug per kg of organism

Question 8

4 examples of ways Drug development is highly regulated by the FDA

Answer 8

1) Generally 2 species (one rodent, one non-rodent)
2) Drug may behave differently in different species (Not always clear which species is more predictive for human)
3) Regulatory requirements (exaggerate the dosing & exaggerate the duration of exposure)
4) Time involved (Chronic exposure studies in animal models- 6 months to 1 year)

Question 9

In vivo

Answer 9

in living organism

Question 10

In vitro

Answer 10

“in glass”. Can mean biochemistry (proteins + drug) experiment or cell culture experiment

Question 11

Example of in vivo question

Answer 11

Safety concern – does the drug cause cancer in people?

Question 12

Example of in vitro test

Answer 12

Indirect safety test – does the drug damage DNA of bacteria?

Question 13

MAJOR MECHANISMS IN DRUGS

Answer 13

1) Reversible binding of drug to receptor
2) Activation of drug to metabolite that binds/damages protein, DNA (The activation can occur by drug metabolizing enzymes)

Question 14

Pharmacokinetics

Answer 14

what the body does to the drug

Question 15

Ames Assay

Answer 15

In vitro mutagenesis test
- A biological test for the carcinogenic potential of a compound

Question 16

Ames assay for mutagenicity

Answer 16

Use a strain of bacteria that have been genetically modified to require histidine (an amino acid)

If bacterial DNA mutates (due to the drug added), then the bacteria can change to being able to grow in His-free media

Question 17

What to put into plate to determine of a drug or its metabolite cases mutations

Answer 17

Add drug + enzymes + His-requiring bacteria

Question 18

What are the 7 major target organs for Toxicity

Answer 18

1) Liver
2) Kidney
3) Heart
4) Lungs
5) Brain
6) Reproductive
7) Skin

Question 19

the 6 human organ systems

Answer 19

1) Skeletal system
2) Muscular system
3) Digestive system
4) Respiratory system
5) Nervous system
6) Circulatory system

Question 20

Cardiotoxicity

Answer 20

heart toxicity (a major concern for drug development)

Question 21

We can test a drug for reproductive toxicity using…

Answer 21

sperm morphology and motility

Question 22

Biomarkers

Answer 22

a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention
(indirect marks of internal state) (urine & blood tests)

Question 23

Toxicology considers a spectrum of undesired effects (4)

Answer 23

1) Allergic reactions
2) Abnormal reactivity to standard dose
3) Reversible vs. irreversible effects (Liver- ability to regenerate, CNS degeneration, cancer)
4) Local vs. systemic effects (site of first contact- skin, while organism & bloodstream )

Question 24

Liver toxicity can be measured through urine because

Answer 24

liver cells burst and release liver specific enzymes