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BMSC3149 Drug Discovery > Toxicology > Flashcards

Toxicology Flashcards

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
Q

Detailed monitoring of what in one month repeated dose studies

A 
food/ water intake 
body weight 
general behaviour 
blood/ urine chemistry 
haematology
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26
Q

Important feature of one month repeated dose studies

A

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

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27
Q

Greaves et al 2004

A

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

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28
Q

Six month repeat dose studies (chronic)

A

necessary for long-term clinical trials (Phase II and III) and for marketing approval

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29
Q

Six month repeat dose studies are similar to..

A

30-day study
treatments and free recovery period
assess reversibility of tox effects after 3 months

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30
Q

Acute short and long term studies are standard as..

A

performed for majority of candidate drugs

Specialist test later in development: oncogenicity and reproductive tox

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31
Q

Oncogenicity studies required when ..

A

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

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32
Q

Oncogenicity tests procedure

A

administered orally in 2 rodent species

18 months in mice and 2 years in rats

33
Q

Terminal investigations of oncogenicity studies aim to..

A

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
Q

oncogenicity studies serve as..

A

long-term tox test

35
Q

Reproduction studies are used to determine..

A

Whether the compound has any adverse effects on reproductive function
male/ female fertility
foetal and post-natal development

36
Q

Repro studies are done..

A

to support phase II/III trials and for marketing approval

37
Q

Teratology studies are usually carried out if..

A

that women of child bearing age are going to be prescribed the drug

38
Q

Dosing of teratology studies

A

during organogenesis

a period when embryonic tissues undergo rapid development

39
Q

Development stage is a target of teratogen

A

chemicals that cause foetal malformation

40
Q

Repro studies procedure

A

pregnant animales sacrificed 1 day before parturition
day 22 for rats
day 29 for rabbits
delivered by Caesarean section

41
Q

Post-natal development tests

A

Usually use rats
investigate effect of compound on late uterine growth, parturition and post-natal development
may also reveal if agent affects lactation

42
Q

Pups are assessed for

A

behaviour and physical development

some pups may be mated to assess their reproductive capacity

43
Q

In vitro approaches

A

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
Q

Ames test

A

widely used method for detecting mutagenic chemicals that induce mutations in DNA (Zeiger and Mortelmans, 2001)
detect point mutations

45
Q

Use S. typhimurium because ..

A

has a mutant gene so its incapable of synthesising histidine
strain cant grow in normal culture medium unless supplemented with amino acid

46
Q

Affected S. typhimurium can mutate back to active form similar to WT then..

A

can grow in absence of amino acid

reverse mutation resulting in colonies that are revertants

47
Q

His (-) strain undergoes spontaneous mutation to..

A

His (+)

48
Q

Chemical mutagens increase frequency of..

A

back mutation

49
Q

Ames is a sensitive test..

A

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
Q

Ames test is

A

Cheap, fast (48 hour incubation period) and results are easy to analyse and interpret

51
Q

Main disadvantage of Ames test - false negatives

A

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
Q

Mammalian cell mutation test

A

detect gene mutation and chromosome aberration

53
Q

ICH recommend what for mammalian cell mutation test

A

L5178Y cells and TK locus

54
Q

Mammalian cells have 2 copies of each gene but mouse lymphoma cell line only has..

A

1 functional copy of TK +/-

55
Q

Tk is not an essential enzyme and

A

scavenges free thymidine which incorporates into cell DNA

56
Q

Measure resistance to lethal nucleoside analogue TFT..

A

Interferes with cell metabolism and results in cell death

Lloyd and Kidd, 2002

57
Q

Chromosome aberration test

A

Used to detect chromosome breakage

58
Q

Chromosome aberration test procedure..

A

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
Q

Chromosome aberration assay performed

A

with cultured human peripheral blood lymphocytes

various cultured cell lines, e.g. chinese hamster lung

60
Q

Problem with cultured cell lines..

A

tend to lose and gain chromosome and parts of chromosomes spontaneously show high and unpredictable rate of chromosome aberrations
(Ishidate and Sofuni, 1985)

61
Q

Cells assed for what in Chromosome aberration assay..

A

different types of chromosome aberrations

e.g. gaps, deletions and exchanges

62
Q

Initial proportion of metaphase in test compound is compared to..

A

control range also treated in cell culture

63
Q

Micronucleus test

A

to determine chromosome breakage and loss

64
Q

Traditionally micronucleus test is..

A

performed in rats

65
Q

Micronuclei form as a result of

A

chromosomal breakage or spindle damage

66
Q

Fragments of whole chromosomes may not be included in nuclei of daughter cells following division they form..

A

single or multiple micronuclei (Howell-Joly bodies) in the cytoplasm of cells

67
Q

Erythrocytes used for micronuclei test as

A

they no obstruction by main nucleus and easily detected

68
Q

Micronuclei stain

A

Acrinide organe

assessed under fluorescent light

69
Q

Bone marrow cell tox (or depression) indicated by

A

Decrease in proportion of immature erythrocytes

V large decrease in proportion indicative of cytostatic or cytotoxic effects

70
Q

Comet assay

A

to detect DNA damage and chromosome breakage

71
Q

Comet assay further developed by

A

Singh et al

Involving electrophoresis under alkaline pH

72
Q

Single cell gel electrophoresis is

A

Simple, rapid and sensitive for analysing and quantifying DNA damage in individual cells

73
Q

Comet assay can distinguish between

A

genotoxicity and cytotoxicity induced chromosomal damage

74
Q

DNA damage induces relaxation in ..

A

supercoiled DNA coils or results in small fragments

75
Q

Why is alkaline condition required

A

to ensure DNA is unwound especially if tox causes single-strand break (Tice et al., 2000)

76
Q

Comet assay end result

A

Pulled to one side by electrophoresis

77
Q

Extent of DNA liberated from head of comet is directly proportional to

A

DNA damage

78
Q

Tail length in comet assay

A

measurement from point of greatest intensity within comet head to end of fluorescing tail

79
Q

Tail movement

A

product of tail length and fraction of total DNA present in tail

BMSC3149 Drug Discovery (2 decks)

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