midterm 2 fuck Flashcards

drug discovery is gay

1
Q

who sponsors clinical trials and where does it happen

A

sponsored by company making drug. happens at universities, private research organizations, hospitals

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2
Q

who is the principal investigator

A

medical doctor with expertise in area

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3
Q

what does trial entry criteria include

A

eligibility and inclusion

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4
Q

how are phase 1 trial dosages determinned and what are the two ways dosages are tested

A

dosing guided by preclinical, multiplied by a factor to be conservative. you have single ascending (increasing amount) and multiple ascending (tests accumulation, one dosage level over many days)

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5
Q

what does phase 1 trials try to do, exceptions?

A

it uses healthy volunteers to see if the drug is safe with the exception of risky cancer drugs. checks tolerated and safe doses. movement of drug (absorption, distribution, metabolism)

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6
Q

how do you join phase 1

A

contract research organnization, hospitals

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7
Q

how is phase 2 dosing guided

A

results from phase 1

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8
Q

biomarker

A

indirect markers of internal state, objectively

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9
Q

what is a serious ae

A

serious undesirable experience including death, hospitalization

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10
Q

how is pharmokinetic testing done in phase 1

A

frequent blood and urine tests to see how its moving, absorbed, eliminated

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11
Q

why did people die in 2016 phase 1 clinical trial disaster and how to avoid

A

due to accumulation because it happened on fifth day. a tougher selection process is needed

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12
Q

benefits of phase 2 trial participation

A

having health monitored more often than phase 1, altruism

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13
Q

risks of phase 2

A

stop other meds, could be dangerous and could make things worse. might not be able to be in future trials, do not know who is getting experimental, changes in lifestyle, stigma?

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14
Q

why do you need inclusion criteria

A

to make sure people in trial are similar enough

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15
Q

what is washout period

A

waiting for body to get rid of other drugs

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16
Q

what phases are focused on testing for efficacy

A

2 and 3

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17
Q

what are qualities of a good biomarker

A

sensitivity (accurately say people with disease are sick) and specificity (accurately say people without disease are healthy)

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18
Q

what are difference between medical signs and symptoms

A

signs are things you can observe about patient, symptoms are what the patients feel.

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19
Q

what happens after trial

A

may be told what treatment and what the treatment was after you finish, after some time. code break only after everyone is done, and exit interview for everyone asap. will recieve results of overall trial. keep in touch to see long term symptoms

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20
Q

how many patients are in phase 3

A

thousands

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21
Q

what phase is drug approval based on

A

phase 3

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22
Q

what does health canada evaluate to make a decision

A

safety, efficacy, quality

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23
Q

what can you do if your drug is refused

A

provide extra info, resubmit later with extra data, appeal.

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24
Q

what does the AIDS activists want

A

to shorten drug approval process, no more double blind, include affected populations in all stages (need people of different HIV infection stages)

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25
Q

what happened around 1990 about aids

A

drugs were passed even though some trials were not complete, organizations worked together to go faster

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26
Q

what populations are restricted in first 3 stages

A

young and old, people with mild and severe condition, comorbidities, pregnant people, ethnicities may not be representative

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27
Q

what is different about phase 4 regarding monitoring

A

more intense monitoring

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28
Q

what does phase 4 look for

A

safety over time, quality of life, cost effectiveness

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29
Q

what are reasons for recall

A

drug manufacturing/purity, mild and major effects. can be years later than release

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30
Q

what are EUAs

A

increase avaliability of unapproved mediation, or approved for unapproved uses

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31
Q

where is off label meds common

A

oncology, pediatrics, elderly

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32
Q

what is potency

A

how much drug is needed to get required effect

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33
Q

what is IC50

A

a common way to measure potency, concentration at which inhibition is 50% of the maximum effect

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34
Q

what is a common potency for approved drugs

A

20 nanomolar (low nanomolar)

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35
Q

what is a sub nanomolar potency drug and what is a high micromolar potency drug

A

subnano is scary like botox, high micro is bad cuz not potent enough

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36
Q

what are flavonoids

A

chemical junk that don’t work below 500nm, from sources you would expect to be healthy

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37
Q

how does botox not kill you

A

it doesn’t go anywhere else than the face

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38
Q

most widely prescribed drugs are big or small molecules

A

small molecules

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39
Q

what two traits do antibiotics need

A

selectivity and permeability

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40
Q

how much lower is infectious deaths in developed world than developing

A

40%

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41
Q

what is predicted to be the path of drug resistance bt 2050

A

10 million lives lost due to resistance to infectious diseases

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42
Q

when was antibiotic resistance first mentioned, examples of us procrastinating about this?

A
  1. sars drug could be used for covid but we did not
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43
Q

how many people did tuberculosis kill

A

1 in 7 people that ever lived

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44
Q

when did discovery void for antibiotics happen

A

1987ish

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45
Q

when were most of antibiotics found

A

1944-1961

46
Q

where do antibiotics come from

A

natural products and screening

47
Q

is selectivity or permeability more annoying and why

A

permeability, for example tuberculosis drugs need to get through candle wax to do anything at all

48
Q

when did we start screening for drugs and what happened

A

2000s, it all failed lmfao

49
Q

can we make antibiotics like other drugs

A

yes but rare. example is cipro

50
Q

what do ai look for when finding potential drugs

A

active against bacterial targets, penetrate cell walls of bacteria, take advantage of opportunities like triggering enzyme that releases radicals killing the bacteria

51
Q

what is the problem with targeting something other than bacteria

A

you have a shit ton of kinases but they all bind to atp and selectivity is hard. need to use gatekeeper residue that binds very specifically. has 3d complexity

52
Q

what happens if a drug binds to something you don’t want it to

A

reverse drug discovery and make it less potent there

53
Q

how selective do drugs need to be

A

100x more for our target than unwanted (our drug nM is 100x less, or more)

54
Q

why is a liver a pain in the butt

A

it protects us from toxic substances and excretes from kidneys. oxidizes drugs

55
Q

what are common ways to block rapid metabolism

A

adding fluorine groups

56
Q

how can metabolites screw you over

A

may have same or different potency, different toxicity, activity, etc.

57
Q

what is bioactivity

A

how much survived, how much absorbed in gut, how much got through liver

58
Q

what is a therapeutic window

A

a dose with high therapeutic response low toxic response. like hurt-comfort. high toxic response would be call of duty modern warfare iii fuck that shit all my homies create our own canon that’s evidently much more superior

59
Q

what types of drugs are best for dissolving

A

polar and charged

60
Q

the more potent, the more or less likely for solibility to be a problem

A

less

61
Q

what are lipophilic drugs

A

good at getting through membranes

62
Q

what drugs need good permeability

A

stuff that goes in your brain and in bacteria

63
Q

two causes of poor permeability

A

efflux out and drug not getting into membrane. kicked out twice as fast as absorbed is bad

64
Q

what is a pharmacore

A

part of structure that binds to target

65
Q

how do computers screen for new drugs

A

high throughput screening, filament screening, in silico screening

66
Q

what is the difference between drug like chemical space and biological space. how to find biological space

A

drug like chemical space is considered as an ocean and biological space are islands. biological space can be found by chemical libraries guided by nature

67
Q

what is a hit

A

a rare chemical which gives a positive response in high throughput screen (activity on enzyme, receptor/pathway, model organism)

68
Q

what is the difference between target and phenotypic screening

A

target focuses on known target, phenotypic does not care how

69
Q

why are results of high throughput screening complex and how do we deal with that

A

because there may be long transduction pathways and shit ton of stuff reacting. we try to get a dye that reacts with thing of interest to fluoresce if that thing is present. simple results

70
Q

what are three ways to find new drugs

A

collect natural products and screen libraries, in silico screening

71
Q

how does in silico screening work

A

computer evaluates how well models fit. may have false positives

72
Q

what is fragment screening and how is it better

A

filtering from a fragment of drugs to piece together drugs instead of looking for combos. it is better because we don’t need to use real compounds anymore.

73
Q

what is activity and efficacy

A

activity is what a drug does, highly active is goot at blocking. efficacy is if it will actually work to fix your problem

74
Q

what is good about potent drug

A

generally less toxic and less solubility needed and the less permeability needed

75
Q

what determines what the pharmacore for a target is

A

electronic properties, the shape doesn’t have to be the same as long as the same bonds (such as H bonds) form

76
Q

what does structural extention do

A

increases potency and finds additional binding interactions. increases selectivity

77
Q

what does rigidification do

A

increase potency and selectivity

78
Q

what do osteoblasts and osteoclasts do, which is more active when we are young

A

osteoclasts remove bone and osteoblasts build bone. osteoblasts are more active when we are young

79
Q

what is scaffold hopping and what do you achieve with it

A

slowly changing a molecule a little by a little to get a better potency and structure-activity relationship. target has spaces that are polar, hydrophobic, electron rich and electron poor that you can fill

80
Q

how do you make a pharmacore a better fit

A

intuition, experience, computer guidance, such as x ray crystal structure

81
Q

why should properties of the drug be complementary to that of the target

A

to bind with each other

82
Q

what is ADMET

A

absorption, distribution, metabolism, excretion (toxicology)

83
Q

why do you need a higher concentration than calculated

A

the drug amount falls between dosages and blood may bind to the proteins, reducing the amount avaliable to the target

84
Q

are lipophilic drugs soluable or not

A

no. they are able to get through brain barrier and not likely to be cleared by kidneys

85
Q

what is the required solubility

A

100 micromolar

86
Q

what is permeability

A

rate which a compound goes through a layer of cells

87
Q

how good does permeability need to be

A

most drugs for the brain have 150 nanomolar/sec or more

88
Q

what properties can small changes have an effect on

A

efflux ratio and permeability (changing one atom can)

89
Q

what is the average price of a new drug now and what was it in 2007

A

now is 180,000, 2007 is 2000

90
Q

what is too expensive for a drug

A

30,000 pounds per year is too muuch but public pressure might fuck with it. if a drug costs that much it takes money away from healthcare

91
Q

what is the most expensive drug and what does it do

A

costs 3.2 million, improved like nothing

92
Q

why are drugs so fucking expensive

A

high risk of failure, only a small percentage of drugs reach market. costs a lot to make drug and to market

93
Q

why do pharma companies need to be profitable

A

or else company will be gotten rid of and all the people there will lose their jobs

94
Q

what happens when a drug is patented for too much

A

some companies may reject it and yoink the formula, selling it for less

95
Q

when did people die in a year after getting aids and when was survival improved, and when was survival normal

A

1981, 1995, 2007, respectively

96
Q

why are hiv integrase inhibitors good

A

there is no human equivalent, so it is selective (only targets bacteria), also you only need one pill now

97
Q

why wasn’t HIV eliminated in a generation

A

less than half of the infected people got treatment, many people weren’t even diagnosed

98
Q

what happened with biogen’s alzheimer’s drug after it was marketed for too expensive? how effective was it

A

fda approved it in hopes people will go and make better drugs. it was only 0.45/18 better than placebo

99
Q

how are people dealing with drug price extortion

A

force collaboration and open source drug discovery, medicine patent pools, rich people donating, paying only what a country can aford

100
Q

what cancer has been cured

A

cervical

101
Q

what are some ways to improve efficiency in drug discovery and reduce wasting money

A

stop pursing borderline drugs, this decreases phase 3 failures and developmental costs. better to avoid cancer than to treat it. drugs must be applied globally, remove advertising from pharmaceuticals

102
Q

what does gartner’s hype cycle say

A

first have naive euphoria, then depths of cynicism, and benefits become apparent, find role along existing tech

103
Q

what is an undruggable target

A

if a target only has weak binding interactions with the target

104
Q

why can’t you just hit a target with a drug and be done

A

cannot find clear differences between sufferers and healthy people. you also might have many targets, targets might be needed for health

105
Q

what are polar drugs more likely to do aside from being soluable

A

less likely to be eaten by liver and less likely to hit other shit

106
Q

a druggable target is a __ of lipophilic and polar

A

mix

107
Q

what time period was for evolutionary drug discovery

A

1900-2000. got drugs from current knowledge and got lucky. many diseases with no treatments and anything was pretty much good

108
Q

how to you get selectivity on similar ligands

A

they all have slightly different shapes, you can change the shape subtly

109
Q

what percentage of world population only has folk meds

A

80%

110
Q

what is the problem with screening natural products

A

too many natural shit and you might not be able to get enough

111
Q

what is good about natural products for drug discovery

A

they are good starting points, most of our drugs are modified natural products, natural products, or mimic natural products