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TOX 321 > Midterm 1 > Flashcards

Midterm 1 Flashcards

1
Q

what does a “hit” refer to in the drug discovery process

A

a potential compound that may have therapeutic effects, may be found through high throughput screening

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2
Q

what does a “lead” refer to in the drug discovery process

A

a hit that has optimal effects and will be tested in vivo/in vitro. while you may have thousands of hits, you only have 10-20 leads

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3
Q

what are the main concerns with pre-clinical testing

A

determining the Pharmacokinetics (ADME), the safety, efficacy, and dosing range

half life of a compound

toxicity tests (single dose/acute, repeated dose (chronic and sub-chronic), reproductive, developmental, carcinogenic)

determine elimination routes

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4
Q

most drugs fail in which phase of clinical trials

A

three - is the drug more effective than placebo

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5
Q

what does Health Products and Food Branch of health Canada do

A

regulate all health products - including pharmaceuticals, medical devices, natural health products, veterinary medicines, foods

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6
Q

the branch of health canada concerned with prescription medication

A

Pharmaceutical Drugs directorate

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7
Q

review process

A

manufacturere creates a new drug submission request with the Health Products and Food Branch, submitting information about pre-clinical and clinical trials, the claimed therapeutic effects and side effects, and information about production/packaging, and labelling. the HPFB reviews all this informatin, consulting external committees if necessary, and determines if health benefits outweigh the health risks as well as if the product label is sufficient. IF they decide the benefits do outweigh the risks, the product recieves a notice of compliance and a DIN. if a drug is not approved, it can ask for reconsideration or gather additional information and resubmit their request at a later date

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8
Q

what is the Lot Release Process

A

additional screening of each lot of manufactured products before they’re sold

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9
Q

the review by health canada usually takes

A

300 days, expedited reviews for life threatening conditions aim for 180 days

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10
Q

orphan drugs

A

those used to treat very rare conditions - often get expedited reviews

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11
Q

drug development to release to market takes roughly how long

A

15 years

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12
Q

what is the ICH

A

international council for harmonization of technical requirements for pharmaceuticals for human use

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13
Q

what does the ICH do

A

collaborate between nations to reduce the duplication of clinical trials, and create guidelines about the manufacturing, development, and testing of new pharmaceuticals

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14
Q

when was the ICH officially formed

A

2015, though nations began banding together with the common goal in 1990

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15
Q

what is the timing of an acute/single dose toxicity test

A

single dose administered (or multiple doses all in one day) and the effects are observed for 14 days

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16
Q

how long do sub-acute (repeated dose) toxicity tests last for

A

28 days

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17
Q

how long do sub-chronic toxicity tests last for

A

90 days

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18
Q

how long do chronic toxicity tests last for

A

6 months - 2 years

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19
Q

what is the main purpose of an acute toxicity test

A

tells you the LD50

potential for acute toxicity in humans and what it looks like (time course, signs/symptoms/target organs

species differences in tox

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20
Q

important things to know about your drug before you begin testing

A

chemical form and properties so you can presume its solubility

data on previous similarly structured chemicals (if possible)

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21
Q

procedure for acute oral toxicity testing

A

test animals sequentially beginning at the high end of the scale (one level below the suspected LD50). if the first animal lives (48 hours later), you increase the dose by one step, if it dies you decrease the dose by one step

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22
Q

when do you stop acute toxicity testing

A

when three consecutive animals survive at the upper bound of the toxicity scale (usually around 2000-5000 mg/kg)

when 4 animals have followed the first reversal (OXOXOX) and two likelihood ratios

five reversals in any 6 consecutive animals tested

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23
Q

what do you do if an animal unexpectedly dies in your acute tox test

A

stop all dosing and observe all animals to see if a similar effect occurs, if they also die, restart the study and begin at least two steps below the lowest dose that caused the death

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24
Q

what kinds of animals are used in acute toxicity studies

A

ideally female rats who are not/have never been pregnant, are 8-12 weeks old, and are all roughly the same weight. they should be individually housed until 48 hours post dosing, then they may be returned to the group hoiusing

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25
Q

ideal dosing in toxicity studies

A

should always use the same volume of dose

ideally prepared in water

fast animals before dosing - rats overnight, mice 3-4 hours before, and after dose for 3-4 hours for rats and 1-2 for mice

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26
Q

observations for acute toxicity studies

A

at least once in the first 30 minutes, periodically in the first 24 hours (at least four times), daily thereafter for 14 days

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27
Q

what are sub-chronic toxicity tests used for

A

assess the potential toxicity from daily exposure from 28-90 days, simulating a more common method of toxicity (most drugs cause toxic effects after building up in your system over time)

identify maximum tolerated dose

gives insight into the appropriate doses for chronic and carcinogenic studies

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28
Q

maximum tolerated dose

A

highest dose that can be given chronically without harming the subject

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29
Q

how many rats do you want to use for sub-chronic toxicity testing

A

20 - 10 in each sex group

30
Q

satellite groups

A

groups of animals you are just using to gain additional information about pharmacokinetics/take blood from

31
Q

how should the dosing work for sub-chronic toxicity testing

A

three seperate dose levels - the highest of which should cause toxicity but not death. start with the highest dose and descend in two or four-fold intervals

animals dosed seven days a week for 28 or 90 days

32
Q

observations in sub-chronic toxicity tests

A

checking daily to see if it is suffering/dying and to note changes in its appearance or habits

weekly - check its weight and food consumption

do hematology and clinical biochemistry tests, as well as an autopsy at the end of the study

33
Q

how does chronic toxicity testing work

A

12 months of daily dosing with at least three groups of dose levels descending by 2x or 4x

ideally orally administered to 40 animals (20 of each sex group)

34
Q

observations for chronic toxicity testing

A

twice daily for mortality or morbidity
daily general clinical observations
body weight and food consumption weekly for the first 13 weeks, monthly thereafter

hematological exams at 3, 6, 12 months

autopsies for all

35
Q

when are carcinogen tests not required

A

when the drug is to be used for less than 6 months
when the life expectancy of the target population is less than 2-3 years
if the drug is a replacement therapy of an endogenous substance

36
Q

what may flag a compound for carcinogenic concerns

A

the product class has carcinogenic potential
the structural - activity relationship program flags it
paraneoplastic lesions are found in repeated animal dose studies
there is long term retention of parent compounds or metabolites

37
Q

how many animals for a carcinogenicity study

A

50 per sex group, 2 year long study using dose previously determined in your repeated dose studies

38
Q

outcome of interest in male reproductive studies

A

sexual behaviour, libido, fertility, pregnancy outcomes

39
Q

outcomes of interest in female reproductive studies

A

sexual behaviour, libido, onset of puberty, fertility, gestation, parturition, lactation, premature reproductive senescence

40
Q

when are developmental toxicity studies requried

A

if the drug can be used by females of reproductive potential

41
Q

three segments of developmental toxicity test

A

1: fertility and general reproductive performance: test both male and female rats

2: teratology or embryo/fetal toxicity: in rats and rabbits

  1. perinatal and postnatal development: in rats to determine the drug effects during the last trimester and during lactation
42
Q

list what is contained in the three clinical trial application modules

A

1: administrative information, information about participant recruitment (where, who, how many), information from animal trials

2: quality information (chemistry and manufacturing)

3: supporting information

43
Q

declaration of helsinki

A

world medical association agreement about ethics in human research - primarily to protect the health, interests, and confidentiality of research subjects

44
Q

phase one clinical trials

A

main concern - is it safe for humans

  • around 80 HEALTHY volunteers for several months - a year
  • can use patients in extreme conditions but the test is not designed to treat at this point
  • want to identify the maximum tolerable dose
45
Q

maximum tolerated dose

A

the dose which will not cause severe side effects/ toxicity or impact the survival of the organism

46
Q

phase II clinical trial

A

is it effective? usually 1-2 years with 100-500 patients

47
Q

phase III clinical trials

A

is it more effective than placebo? 1-4 years long with 300-3000 patients. Looking for long-term or rare side effects

48
Q

who prevented the thalidomide crisis from being a thing in the USA

A

Frances Oldham Kelsey

49
Q

things the standard council of canada may assess to evaluate good labratory practice

A
  • personnel are well trained and responsible
  • testing facility is adequate for its purpose
  • equipment and materials are up to standard and labelled properly
  • the product is studied on a batch basis - for stability, purity, composition
  • people are aware of the standard operating procedure
  • animals in use are cared for properly
  • everything is properly documented
50
Q

what is the Standard Council of Canada (SCC)

A

the monitory authority for GLP compliance of testing facilities

51
Q

what is the regulatory operations and enforcement branch (ROEB)

A

the regulatory agency responsible for inspecting and investigating clinical trials in Canada

52
Q

good CLINICAL practice

A

for human research, regulated by the ROEB

  • research should be conducted in accordance with the declaration of Helsinki
  • research is based on adequate non-clinical studies (theory is sound)
  • protocols approved by the ethics board
  • risk analysis before and during the trials
  • use qualified medical professionals
  • get informed consent and keep participants information confidential
  • immediately report serious adverse side effects
53
Q

who does the sponsor refer to in clinical trials

A

the company/institution/organization which takes responsibility for the initiation, management, and financing of clinical trials

54
Q

who is the clinical investigator in clinical trials

A

the physician responsible for conducting the trials at the site

55
Q

what is the CCAC

A

Canadian Council on Animal Care

  • national council that provides guidelines for the basic requirements for institutional animal care
  • each institution will have an animal care committee accredited by this council to review and monitor animal studies
56
Q

what are the main concerns of animal care committees at institutions

A

make sure the study is well thought out and important, are the use of animals absolutely necessaryt

57
Q

Three R’s in the use of animal studies

A

replacement - can it be done in vitro instead

reduction - can you use less animals

refinement - can you minimize the pain and suffering of the animal

58
Q

describe the 5 purposes of animal use (PAU)

A

1 - fundamental science studies for essential structures or functions (uses the most animals)

2 - medical (vet or human) studies relating to disease and disorders

3 - regulatory product testing

4 - development of products or appliances for medicine (uses the second most animals)

5 - education and training of individuals in institutions

59
Q

categories of invasiveness for animal experiments

A

A - experiments on invertebrates or live isolates

B - Little or no discomfort

C - minor stress or pain of short duration

D - moderate - severe distress or discomfort

E - severe pain that exceeds the tolerance of the animal

60
Q

list some canadian laws and regulations regarding the use of animals

A

sec 446 and 447 of the Criminal Code of Canada - cannot abuse/neglect animals

health of animals act - prevent disease outbreaks

spending power - special grants for ethical animal research

veterinarian act of sask - exemptions made for universities whose animal care committee contains a vet

61
Q

ideal animal model (biological standpoint)

A

the ADME and characteristics of animal responses to treatment are close to that of humans

stages of life of the animal are close to that of humans

there is a close phylogenetic relationship to humans

62
Q

ideal animal model from a technical standpoint

A

low body weight, easy to bleed and large enough to collect a reasonable supply of blood, easy and inexpensive to handle/breed/dose, short lifespan

63
Q

limitations of animal models

A

differences in ADME and anatomy of the animal from humans

different strains of the same species may generate different results

the nature of pathological responses may differ at all levels (subcellular, cellular, receptor)

the dose required to produce results in animals is never the same to that in humans

the characteristics or conditions of interest in humans may not always be replicated in animals

64
Q

commonly used species in animal testing

A

rats/mice: easy to handle and breed, well understood and accepted by science, rapid metabolism and lower systemic exposure

rabbits: phylogenetically similar to humans, similar cardiovascular system, used often for ocular and dermal irritation tests, but harder to house and handle

mini-pigs: human-like kidneys - not easy to handle

zebrafish - embryos can be used for developmental toxicity screening, if they are younger than 120 hours post-fertilization they do not qualify as animal testing - but they are hard to dose since they are aquatic and so small

65
Q

advantages of in-vitro testing

A

highly standardized and controlled

fast, inexpensive, less materials used and less waste produced

human cells and tissues can be used

reduces animal testing

66
Q

limitations of in-vitro tests

A

cannot test interactions between tissues or organs

cannot evaluate systemic effects

dose-responses in-vitro not valid for in-vivo human use

67
Q

what is Reconstructed human epidermis used for

A

an in-vitro skin irritant test which uses human derived non-transformed keratinocytes to create a medium that closely matches the biochemical and physiological properties of human skin

68
Q

what are SIRC rabbit cells used for

A

cornea cells from the rabbit to test ocular cytotoxicity

69
Q

micro-physiological systems

A

a micro recreation of human organ compartments used to evaulate how a chemical interacts wtith that body system - FDA approved to test hepatotoxicity, drug metabolism/transport and intracellular accumulation

70
Q

in-silico toxicity models

A

quantitative structure activity relationship models that predict adverse effects based on the molecular structure of the compound

TOX 321 (3 decks)

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