NUSCTX 11, FINAL - UC BERKELEY
EXAM QUESTIONS AND ANSWERS
What is the difference between on- and off-target toxicities? - Answer-On-Target
Toxicity: Toxic effect due to the drug interacting with the intended therapeutic target
Off-Target Toxicity: Toxic effect due to the drug interacting with an unintended
biological target or unintended tissue
For non-steroidal anti-inflammatory drugs like aspirin and ibuprofen that block
inflammation and fever, what types of toxicity are associated with these drugs? Is
this on- or off-target? - Answer-Toxicities associated with NSAIDs like aspirin and
ibuprofen that block inflammation and fever is gastrointestinal bleeding. This is
caused by the inhibition of COX1. This is an on-target toxicity because NSAIDS
inhibit COX1 and COX2 in order to reduce pro-inflammatory eicosanoids like
prostaglandins; prostaglandins help to maintain the gut mucosal protective barrier
Benadryl is prescribed as an anti-allergenic, but also causes drowsiness. Benadryl
causes anti-allergenic effects through blocking the histamine receptor. How does
Benadryl cause drowsiness? Is this on- or off-target? - Answer-Benadryl causes
drowsiness because it crosses the blood brain barrier where H1 histamine receptor
antagonism causes sleepiness.
This is an on-target toxicity because Benadryl is an antihistamine that antagonizes
the H1 histamine receptor to reduce unpleasant symptoms of histamine release in
allergic conditions; Benadryl is able to cross the blood brain barrier where inhibition
of H1 receptor in this location causes sleepiness.
Terfenadine (Seldane) was also an anti-histamine that was used to alleviate allergic
symptoms. However, it also caused increased incidence of heart attacks. Why? Was
this an on- or off-target effect? - Answer-Terfenadine caused increased incidence of
heart attacks because it inhibited hERG, a cardiac potassium channel, and
increased the retention of terfenadine, a prodrug, which is metabolized to
fexofenadine, a drug associated with high risks of cardiac arrhythmia. This is an off-
target toxicity because terfenadine interacted with an unintended biological target,
hERG.
Thalidomide was used as a morning sickness pill for pregnant women. However, it
ended up causing birth defects in a lot of babies born. What type of birth defects
were observed? What was the mechanism? Was this an on- or off-target effect? -
Answer-The types of birth defects observed on babies whose mother took
thalidomide was that of shortened limbs. Thalidomide was a racemic mixture of R-
and S-thalidomide. R-thalidomide stimulates the GABA receptor to cause sedative
effects. S-thalidomide, a teratogen, binds to cereblon which is important in producing
insulin growth factor (IGF), fibroblast growth factor (FGF) and Cul4A which are
involved in limb outgrowth. IGF1 and FGF2 stimulate angiogenesis in developing
limbs. This is an off-target effect because thalidomide interacted with an unintended
biological target, cereblon.
, Why is thalidomide now used for cancer treatment? - Answer-Thalidomide is now
used for cancer treatment because of its anti-angiogenesis properties. By depleting
the the blood supply to aggregates of cancer cells you kill the cancer.
Preclinical Development - Answer-6-7 years of preclinical testing
Manufacturer completes synthesis and purification of the drug and conducts animal
testing
Of 5000 compounds tested, ~5 will appear promising enough for a company to file
an Investigational New Drug Application
If the IND is approved, then the company can begin Phase I clinical trials
Essential Pharmaceutics - Answer-Structural characterization
Impurity identification
Solubility assessment
Prototype formulation
Stability testing
Screening Efficacy - Answer-In vitro models
In vivo models
Other
Early ADME - Answer-In silico profiling
Develop simple analytical method
Measure membrane permeability
Plasma stability
Early toxicology - Answer-Off target screen
In vitro cytotoxicity
Preliminary AMES
hERG binding
ADME/PK - Answer-Test materials with respect to absorption, distribution,
metabolism, and excretion (ADME)
Duration: hours to days
Animals required: 2 species
Safety Pharmacology - Answer-To investigate any toxicity-use single dose with 2
species and test cardiovascular, respiratory, CNS effects
Acute Toxicity - Answer-Determine Maximum Tolerated Dose (MTD) and No
Observable Effect Level (NOAEL)
14 days after single dose in 2 species
EXAM QUESTIONS AND ANSWERS
What is the difference between on- and off-target toxicities? - Answer-On-Target
Toxicity: Toxic effect due to the drug interacting with the intended therapeutic target
Off-Target Toxicity: Toxic effect due to the drug interacting with an unintended
biological target or unintended tissue
For non-steroidal anti-inflammatory drugs like aspirin and ibuprofen that block
inflammation and fever, what types of toxicity are associated with these drugs? Is
this on- or off-target? - Answer-Toxicities associated with NSAIDs like aspirin and
ibuprofen that block inflammation and fever is gastrointestinal bleeding. This is
caused by the inhibition of COX1. This is an on-target toxicity because NSAIDS
inhibit COX1 and COX2 in order to reduce pro-inflammatory eicosanoids like
prostaglandins; prostaglandins help to maintain the gut mucosal protective barrier
Benadryl is prescribed as an anti-allergenic, but also causes drowsiness. Benadryl
causes anti-allergenic effects through blocking the histamine receptor. How does
Benadryl cause drowsiness? Is this on- or off-target? - Answer-Benadryl causes
drowsiness because it crosses the blood brain barrier where H1 histamine receptor
antagonism causes sleepiness.
This is an on-target toxicity because Benadryl is an antihistamine that antagonizes
the H1 histamine receptor to reduce unpleasant symptoms of histamine release in
allergic conditions; Benadryl is able to cross the blood brain barrier where inhibition
of H1 receptor in this location causes sleepiness.
Terfenadine (Seldane) was also an anti-histamine that was used to alleviate allergic
symptoms. However, it also caused increased incidence of heart attacks. Why? Was
this an on- or off-target effect? - Answer-Terfenadine caused increased incidence of
heart attacks because it inhibited hERG, a cardiac potassium channel, and
increased the retention of terfenadine, a prodrug, which is metabolized to
fexofenadine, a drug associated with high risks of cardiac arrhythmia. This is an off-
target toxicity because terfenadine interacted with an unintended biological target,
hERG.
Thalidomide was used as a morning sickness pill for pregnant women. However, it
ended up causing birth defects in a lot of babies born. What type of birth defects
were observed? What was the mechanism? Was this an on- or off-target effect? -
Answer-The types of birth defects observed on babies whose mother took
thalidomide was that of shortened limbs. Thalidomide was a racemic mixture of R-
and S-thalidomide. R-thalidomide stimulates the GABA receptor to cause sedative
effects. S-thalidomide, a teratogen, binds to cereblon which is important in producing
insulin growth factor (IGF), fibroblast growth factor (FGF) and Cul4A which are
involved in limb outgrowth. IGF1 and FGF2 stimulate angiogenesis in developing
limbs. This is an off-target effect because thalidomide interacted with an unintended
biological target, cereblon.
, Why is thalidomide now used for cancer treatment? - Answer-Thalidomide is now
used for cancer treatment because of its anti-angiogenesis properties. By depleting
the the blood supply to aggregates of cancer cells you kill the cancer.
Preclinical Development - Answer-6-7 years of preclinical testing
Manufacturer completes synthesis and purification of the drug and conducts animal
testing
Of 5000 compounds tested, ~5 will appear promising enough for a company to file
an Investigational New Drug Application
If the IND is approved, then the company can begin Phase I clinical trials
Essential Pharmaceutics - Answer-Structural characterization
Impurity identification
Solubility assessment
Prototype formulation
Stability testing
Screening Efficacy - Answer-In vitro models
In vivo models
Other
Early ADME - Answer-In silico profiling
Develop simple analytical method
Measure membrane permeability
Plasma stability
Early toxicology - Answer-Off target screen
In vitro cytotoxicity
Preliminary AMES
hERG binding
ADME/PK - Answer-Test materials with respect to absorption, distribution,
metabolism, and excretion (ADME)
Duration: hours to days
Animals required: 2 species
Safety Pharmacology - Answer-To investigate any toxicity-use single dose with 2
species and test cardiovascular, respiratory, CNS effects
Acute Toxicity - Answer-Determine Maximum Tolerated Dose (MTD) and No
Observable Effect Level (NOAEL)
14 days after single dose in 2 species
