midterm 2 fuck Flashcards by catboy ghost enthusiast hehe

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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Q

who is the principal investigator

A

medical doctor with expertise in area

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Q

what does trial entry criteria include

A

eligibility and inclusion

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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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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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Q

how do you join phase 1

A

contract research organnization, hospitals

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Q

how is phase 2 dosing guided

A

results from phase 1

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Q

biomarker

A

indirect markers of internal state, objectively

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Q

what is a serious ae

A

serious undesirable experience including death, hospitalization

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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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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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Q

benefits of phase 2 trial participation

A

having health monitored more often than phase 1, altruism

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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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Q

why do you need inclusion criteria

A

to make sure people in trial are similar enough

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Q

what is washout period

A

waiting for body to get rid of other drugs

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Q

what phases are focused on testing for efficacy

A

2 and 3

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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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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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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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Q

how many patients are in phase 3

A

thousands

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Q

what phase is drug approval based on

A

phase 3

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Q

what does health canada evaluate to make a decision

A

safety, efficacy, quality

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Q

what can you do if your drug is refused

A

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

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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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what happened around 1990 about aids

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

what populations are restricted in first 3 stages

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

what is different about phase 4 regarding monitoring

more intense monitoring

what does phase 4 look for

safety over time, quality of life, cost effectiveness

what are reasons for recall

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

what are EUAs

increase avaliability of unapproved mediation, or approved for unapproved uses

where is off label meds common

oncology, pediatrics, elderly

what is potency

how much drug is needed to get required effect

what is IC50

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

what is a common potency for approved drugs

20 nanomolar (low nanomolar)

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

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

what are flavonoids

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

how does botox not kill you

it doesn't go anywhere else than the face

most widely prescribed drugs are big or small molecules

small molecules

what two traits do antibiotics need

selectivity and permeability

how much lower is infectious deaths in developed world than developing

40%

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

10 million lives lost due to resistance to infectious diseases

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

1999. sars drug could be used for covid but we did not

how many people did tuberculosis kill

1 in 7 people that ever lived

when did discovery void for antibiotics happen

1987ish

when were most of antibiotics found

1944-1961

where do antibiotics come from

natural products and screening

is selectivity or permeability more annoying and why

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

when did we start screening for drugs and what happened

2000s, it all failed lmfao

can we make antibiotics like other drugs

yes but rare. example is cipro

what do ai look for when finding potential drugs

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

what is the problem with targeting something other than bacteria

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

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

reverse drug discovery and make it less potent there

how selective do drugs need to be

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

why is a liver a pain in the butt

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

what are common ways to block rapid metabolism

adding fluorine groups

how can metabolites screw you over

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

what is bioactivity

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

what is a therapeutic window

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

what types of drugs are best for dissolving

polar and charged

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

less

what are lipophilic drugs

good at getting through membranes

what drugs need good permeability

stuff that goes in your brain and in bacteria

two causes of poor permeability

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

what is a pharmacore

part of structure that binds to target

how do computers screen for new drugs

high throughput screening, filament screening, in silico screening

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

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

what is a hit

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

what is the difference between target and phenotypic screening

target focuses on known target, phenotypic does not care how

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

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

what are three ways to find new drugs

collect natural products and screen libraries, in silico screening

how does in silico screening work

computer evaluates how well models fit. may have false positives

what is fragment screening and how is it better

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.

what is activity and efficacy

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

what is good about potent drug

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

what determines what the pharmacore for a target is

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

what does structural extention do

increases potency and finds additional binding interactions. increases selectivity

what does rigidification do

increase potency and selectivity

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

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

what is scaffold hopping and what do you achieve with it

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

how do you make a pharmacore a better fit

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

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

to bind with each other

what is ADMET

absorption, distribution, metabolism, excretion (toxicology)

why do you need a higher concentration than calculated

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

are lipophilic drugs soluable or not

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

what is the required solubility

100 micromolar

what is permeability

rate which a compound goes through a layer of cells

how good does permeability need to be

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

what properties can small changes have an effect on

efflux ratio and permeability (changing one atom can)

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

now is 180,000, 2007 is 2000

what is too expensive for a drug

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

what is the most expensive drug and what does it do

costs 3.2 million, improved like nothing

why are drugs so fucking expensive

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

why do pharma companies need to be profitable

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

what happens when a drug is patented for too much

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

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

1981, 1995, 2007, respectively

why are hiv integrase inhibitors good

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

why wasn't HIV eliminated in a generation

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

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

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

how are people dealing with drug price extortion

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

what cancer has been cured

cervical

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

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

what does gartner's hype cycle say

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

what is an undruggable target

if a target only has weak binding interactions with the target

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

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

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

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

a druggable target is a __ of lipophilic and polar

mix

what time period was for evolutionary drug discovery

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

how to you get selectivity on similar ligands

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

what percentage of world population only has folk meds

80%

what is the problem with screening natural products

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

what is good about natural products for drug discovery

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