midterm 2 fuck Flashcards
drug discovery is gay
who sponsors clinical trials and where does it happen
sponsored by company making drug. happens at universities, private research organizations, hospitals
who is the principal investigator
medical doctor with expertise in area
what does trial entry criteria include
eligibility and inclusion
how are phase 1 trial dosages determinned and what are the two ways dosages are tested
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)
what does phase 1 trials try to do, exceptions?
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)
how do you join phase 1
contract research organnization, hospitals
how is phase 2 dosing guided
results from phase 1
biomarker
indirect markers of internal state, objectively
what is a serious ae
serious undesirable experience including death, hospitalization
how is pharmokinetic testing done in phase 1
frequent blood and urine tests to see how its moving, absorbed, eliminated
why did people die in 2016 phase 1 clinical trial disaster and how to avoid
due to accumulation because it happened on fifth day. a tougher selection process is needed
benefits of phase 2 trial participation
having health monitored more often than phase 1, altruism
risks of phase 2
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?
why do you need inclusion criteria
to make sure people in trial are similar enough
what is washout period
waiting for body to get rid of other drugs
what phases are focused on testing for efficacy
2 and 3
what are qualities of a good biomarker
sensitivity (accurately say people with disease are sick) and specificity (accurately say people without disease are healthy)
what are difference between medical signs and symptoms
signs are things you can observe about patient, symptoms are what the patients feel.
what happens after trial
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
how many patients are in phase 3
thousands
what phase is drug approval based on
phase 3
what does health canada evaluate to make a decision
safety, efficacy, quality
what can you do if your drug is refused
provide extra info, resubmit later with extra data, appeal.
what does the AIDS activists want
to shorten drug approval process, no more double blind, include affected populations in all stages (need people of different HIV infection stages)
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?
- 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
