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BMSC3149 Drug Discovery > Toxicology > Flashcards

Toxicology Flashcards

(79 cards)

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1
Q

Potential toxicities of new drugs are assessed after..

A

the pharmacological efficacy of the drug is proven

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2
Q

Requirement of the FDA to assess potential toxicities is due to..

A

how drugs can cause adverse effects in man

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3
Q

What is involved in tox testing?

A

acute tests that provide the basis for further study and chronic tox performed under GLP to determine long-term tox potential

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4
Q

Instance of tox of a drug not being found before being on market

A

1956-60 thalidomide was prescribed to pregnant women for morning sickness and resulted in malformed children
Thalidomide was not tested on the most sensitive species

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5
Q

In silico approaches

A

developed to characterise and predict toxic outcomes

methods already used for regulatory purposes, will be more prominent in future

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6
Q

Why are in silico tests important

A

large scale of chemicals studied, endpoints and pathways, exposure etc. all analysed and conditions considered simultaneously
(Kavlock et al, 2008)

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7
Q

Software for in silico

A

DEREK used to compare test drugs structures to highlight any tox

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8
Q

Single dose acute studies

A

tox that results from a single dose of compound

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9
Q

What does single dose acute studies give..

A

an early warning whether a drug is highly toxic

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10
Q

What can single dose acute studies establish

A

a non-lethal dose range and aids the choice of doses for repeat dose studies
provide information on target organs and limiting tox due to pharmacological effects

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11
Q

Single dose acute studies is carried out on..

A

2 different species
one rodent
one non-rodent

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12
Q

Investigational product in single dose studies is administered..

A

at different dose levels and observed for 14 days

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13
Q

Single does studies allow..

A

LD50 to be determined, 50% lethal dose

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14
Q

Stage 2 of acute dose studies

A

repeat of stage 1 in small groups (3-5 animals per sex)

span estimated NTEL

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15
Q

Observations made throughout and blood samples taken .. example

A

Irwin’s test for nervous system

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16
Q

Parasuraman 2011 example

A

Used Draize test
acute tox test to measure harmfulness of chemicals on rabbits and guinea pigs
(0.5g of substance and observe for 24 days)
Dermal and ophthalmic preparations tested
Look for redness, swelling, discharge etc

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17
Q

Dose ranging studies

A

Tox of repeated doses at dose levels ranging from ED50 to max non-lethal dose

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18
Q

Dose ranging studies help establish

A

Max tolerated dose (MTD)

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19
Q

MTD

A

highest dose that can be given to animals for the duration of the test that doesnt produce overt tox

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20
Q

Dose ranging studies are carried out in..

A

rodent and non-rodent

they are sacrificed and post mortem and histological analysis of major organs and tissues taken

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21
Q

One month repeated dose can be used to..

A

support clinical trials

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22
Q

One month repeated dose allow

A

administration of single or multiple doses in man for up to 6 months

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23
Q

One month repeated dose aid..

A

selection of doses for long-term investigations and help to identify possible target organs and tissues

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24
Q

Use what for one month repeated dose

A

proposed administration route
minimum of 3 dose levels
dosed for 29 days
Survivors sacrificed day 30

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25
Detailed monitoring of what in one month repeated dose studies
``` food/ water intake body weight general behaviour blood/ urine chemistry haematology ```
26
Important feature of one month repeated dose studies
recovery group for both species can be observed for up today 56 usually have 2nd satellite group of dosed rates so toxicokinetics can be assessed in this species
27
Greaves et al 2004
Showed if tox studies are shorter than 1 month, risk of certain organ tox being overlooked single studies have capacity to detect many of most important tox
28
Six month repeat dose studies (chronic)
necessary for long-term clinical trials (Phase II and III) and for marketing approval
29
Six month repeat dose studies are similar to..
30-day study treatments and free recovery period assess reversibility of tox effects after 3 months
30
Acute short and long term studies are standard as..
performed for majority of candidate drugs Specialist test later in development: oncogenicity and reproductive tox
31
Oncogenicity studies required when ..
compound is intended for long-term use in man (>6 months) if drug has long half-life where there is concern because of the compound pharmacologies or toxic effects if mutagenicity tests are positive
32
Oncogenicity tests procedure
administered orally in 2 rodent species | 18 months in mice and 2 years in rats
33
Terminal investigations of oncogenicity studies aim to..
determine total incidence of tumour bearing animals total number of tumours incidence of benign and malignant tumours dose-response relationship time to tumour recognition
34
oncogenicity studies serve as..
long-term tox test
35
Reproduction studies are used to determine..
Whether the compound has any adverse effects on reproductive function male/ female fertility foetal and post-natal development
36
Repro studies are done..
to support phase II/III trials and for marketing approval
37
Teratology studies are usually carried out if..
that women of child bearing age are going to be prescribed the drug
38
Dosing of teratology studies
during organogenesis | a period when embryonic tissues undergo rapid development
39
Development stage is a target of teratogen
chemicals that cause foetal malformation
40
Repro studies procedure
pregnant animales sacrificed 1 day before parturition day 22 for rats day 29 for rabbits delivered by Caesarean section
41
Post-natal development tests
Usually use rats investigate effect of compound on late uterine growth, parturition and post-natal development may also reveal if agent affects lactation
42
Pups are assessed for
behaviour and physical development | some pups may be mated to assess their reproductive capacity
43
In vitro approaches
harmful effect of chemicals on DNA due to mutagenic quality of the drugs rely on detection of DNA damage (or its immediate outcome) as an indicator of potential mutagenicity or carcinogenicity in man expected to detect virtually all human mutagens all test methods use some measure of tox and chemicals are generally assessed at levels below prescribed level of tox, in absence of tox and conc up to standard limit set by regulatory authorities
44
Ames test
widely used method for detecting mutagenic chemicals that induce mutations in DNA (Zeiger and Mortelmans, 2001) detect point mutations
45
Use S. typhimurium because ..
has a mutant gene so its incapable of synthesising histidine strain cant grow in normal culture medium unless supplemented with amino acid
46
Affected S. typhimurium can mutate back to active form similar to WT then..
can grow in absence of amino acid | reverse mutation resulting in colonies that are revertants
47
His (-) strain undergoes spontaneous mutation to..
His (+)
48
Chemical mutagens increase frequency of..
back mutation
49
Ames is a sensitive test..
Large number of bacteria exposed to the chemical Test organism divides in the presence of compound Test bacteria carry mutations that increase permeability to foreign molecules and compromise bacteriums ability to repair any damage that DNA test substrate may cause
50
Ames test is
Cheap, fast (48 hour incubation period) and results are easy to analyse and interpret
51
Main disadvantage of Ames test - false negatives
Not all carcinogens are mutagens (e.g. asbestos) target is small, single gene (can be overcome by using several test strains or different micro-organisms with different existing mutations
52
Mammalian cell mutation test
detect gene mutation and chromosome aberration
53
ICH recommend what for mammalian cell mutation test
L5178Y cells and TK locus
54
Mammalian cells have 2 copies of each gene but mouse lymphoma cell line only has..
1 functional copy of TK +/-
55
Tk is not an essential enzyme and
scavenges free thymidine which incorporates into cell DNA
56
Measure resistance to lethal nucleoside analogue TFT..
Interferes with cell metabolism and results in cell death | Lloyd and Kidd, 2002
57
Chromosome aberration test
Used to detect chromosome breakage
58
Chromosome aberration test procedure..
Treatment of cells with DNA-damaging agents can result in unrepairable lesions in both strands of DNA Lead to chromosome breakage which can be seen in cell division
59
Chromosome aberration assay performed
with cultured human peripheral blood lymphocytes | various cultured cell lines, e.g. chinese hamster lung
60
Problem with cultured cell lines..
tend to lose and gain chromosome and parts of chromosomes spontaneously show high and unpredictable rate of chromosome aberrations (Ishidate and Sofuni, 1985)
61
Cells assed for what in Chromosome aberration assay..
different types of chromosome aberrations | e.g. gaps, deletions and exchanges
62
Initial proportion of metaphase in test compound is compared to..
control range also treated in cell culture
63
Micronucleus test
to determine chromosome breakage and loss
64
Traditionally micronucleus test is..
performed in rats
65
Micronuclei form as a result of
chromosomal breakage or spindle damage
66
Fragments of whole chromosomes may not be included in nuclei of daughter cells following division they form..
single or multiple micronuclei (Howell-Joly bodies) in the cytoplasm of cells
67
Erythrocytes used for micronuclei test as
they no obstruction by main nucleus and easily detected
68
Micronuclei stain
Acrinide organe | assessed under fluorescent light
69
Bone marrow cell tox (or depression) indicated by
Decrease in proportion of immature erythrocytes | V large decrease in proportion indicative of cytostatic or cytotoxic effects
70
Comet assay
to detect DNA damage and chromosome breakage
71
Comet assay further developed by
Singh et al | Involving electrophoresis under alkaline pH
72
Single cell gel electrophoresis is
Simple, rapid and sensitive for analysing and quantifying DNA damage in individual cells
73
Comet assay can distinguish between
genotoxicity and cytotoxicity induced chromosomal damage
74
DNA damage induces relaxation in ..
supercoiled DNA coils or results in small fragments
75
Why is alkaline condition required
to ensure DNA is unwound especially if tox causes single-strand break (Tice et al., 2000)
76
Comet assay end result
Pulled to one side by electrophoresis
77
Extent of DNA liberated from head of comet is directly proportional to
DNA damage
78
Tail length in comet assay
measurement from point of greatest intensity within comet head to end of fluorescing tail
79
Tail movement
product of tail length and fraction of total DNA present in tail

BMSC3149 Drug Discovery (2 decks)

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