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5evaluation (Compatibility Mode)
5evaluation (Compatibility Mode)
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animal testing
acute & subacute toxicity testing
therapeutic action (from the pharmacologic
profile in animals)
human testing
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ANIMAL TESTING
ANIMAL TESTING
A. acute toxicity
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ACUTE TOXICITY
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pharmacologic effects
hepatic & renal function monitoring
blood & urine tests
gross & histopathologic examination of
tissues
tests of reproductive effects
carcinogenicity
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A. PHARMACOLOGIC PROFILE
B. REPRODUCTIVE TOXICITY
fertility effects
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Teratogenesis
mutagenesis
is induction of changes in the genetic material of
animals of any age induction of heritable
abnormalities
The Ames test
standard in vitro test for mutagenicity
salmonella bacteria
mice
male animals are exposed to the test substance before
mating
carcinogens (eg, aflatoxin, cancer chemotherapeutic
drugs & other agents that bind to DNA) have mutagenic
effects.
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C. CARCINOGENESIS
is the induction of malignant characteristics in cells
difficult & expensive to study
Ames test is often used
correlation : mutagenicity -- carcinogenicity
carcinogenic effects :
coal tar
aflatoxin
dimethylnitrosamine & other nitrosamines
urethane
vinyl chloride
the polycyclic aromatic hydrocarbons in tobacco smoke (eg,
benzo[a]pyrene).
CLINICAL TRIALS
A. PHASE I
B. PHASE II
D. PHASE IV
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A. PHASE I
evaluation of the dose-response relationship
a small number (20-30) of normal human volunteers
an exception :
cancer chemotherapeutic agents
highly toxic drugs
administering the agents to patients with the target disease
acute effects of the agent
broad range of dosages
starting with one that produces no detectable effect
progressing to one that produces either a significant
physiologic response or a very minor toxic effect
B. PHASE II
evaluation of a drug in a moderate number of
patients (eg, 100-300)
the target disease
a placebo or positive control drug
single-blind or double-blind design
very carefully controlled conditions
patients are very closely monitored
in a hospital research ward
the goal to determine whether the agent has
the desired therapeutic effects at doses that are
tolerated by sick patients
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C. PHASE III
large design involving many patients (eg, 1000-
5000 or more)
many clinicians
placebo and positive controls
double-blind crossover design
the goal
to explore further the spectrum of beneficial actions of
the new drug
to compare it with older therapies
to discover toxicities
to be undetectable in phase II studies
D. PHASE IV
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