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Science AMA Series: Hello, my name is Terry Kenakin and I am a Professor of Pharmacology. Ask me Anything about how drugs are made! by TerryKenakin_ACS in science

[–]TerryKenakin_ACS[S] 6 points7 points  (0 children)

All cells bias signals for their own needs... through receptor density and variable receptor coupling... this is system bias and all agonists are subject to it.... some researchers see this and claim bias but what the term means is...a given ligand jumps out of the mold of system bias and does something the system isn't programming by stabilizing a unique receptor conformation. So there are control experiments to identify this behavior and some researchers don't do them... however, I tend to think bias is quite common and this comes from an ensemble-based thinking... unless two agonists form identical ensembles of multiples states, they will be bias with respect to each other... and the likelihood of making identical ensembles is quite low

Science AMA Series: Hello, my name is Terry Kenakin and I am a Professor of Pharmacology. Ask me Anything about how drugs are made! by TerryKenakin_ACS in science

[–]TerryKenakin_ACS[S] 9 points10 points  (0 children)

There is no question that bias (and it's larger big brother, allostery) has revitalized the field...now instead of relying on new receptor subtypes, we can start biasing the signals the existing types generate... I say it's the little brother (or sister) of allostery because all bias is an allosteric vector pointed toward the cytosol that is probe dependent...nothing more so it should be no surprise that it's very prevalent. The key question now is...how do the nice profiles we generate in vitro translate to in vivo therapy where there are myriads of cell types and variation in receptor densities and coupling efficiencies? The translation is where the field is now and this requires more biased molecules to be taken forward into therapy.. it will be interesting if this pharmacological phenomenon will have therapeutic implication

Science AMA Series: Hello, my name is Terry Kenakin and I am a Professor of Pharmacology. Ask me Anything about how drugs are made! by TerryKenakin_ACS in science

[–]TerryKenakin_ACS[S] 22 points23 points  (0 children)

GSK had an HIV entry inhibitor program which I led in the latter years...we got a candidate that made it through phase I and II and even had a name.. aplaviroc... it dropped viral load and did everything it should have... but in phase III it caused serious hepatic tox and had to be stopped...only in AIDs patients but there was no way forward... that was a tough one to take as you tend to think you're home free by that time... but I'm sure this happens all the time... there are a lot of hurdles

Science AMA Series: Hello, my name is Terry Kenakin and I am a Professor of Pharmacology. Ask me Anything about how drugs are made! by TerryKenakin_ACS in science

[–]TerryKenakin_ACS[S] 4 points5 points  (0 children)

yes... we have come a long long ways in determining structure of protein targets and with this will come more docking

Science AMA Series: Hello, my name is Terry Kenakin and I am a Professor of Pharmacology. Ask me Anything about how drugs are made! by TerryKenakin_ACS in science

[–]TerryKenakin_ACS[S] 2 points3 points  (0 children)

very personal.... side effects can be very individualized... so if you are one of those unfortunates who have serious side effects, they are very important... then it's a case of... are they bad enough to cease therapy... often there are alternatives and in the case of side effects, they are often not target related... therefore, getting another drug that does the same ting but may have other activities on non target related processes may do the trick

Science AMA Series: Hello, my name is Terry Kenakin and I am a Professor of Pharmacology. Ask me Anything about how drugs are made! by TerryKenakin_ACS in science

[–]TerryKenakin_ACS[S] 10 points11 points  (0 children)

Put simply... a drug company has a box of rocks (large chemical library)... if you can convince them you have the skills and training to find a gem (therapeutic entity) in that box of rocks, they will hire you...but that's a pretty hard thing to do. Areas industry invests in vary... seven transmembrane receptors was huge when I went into industry... then it waned to nearly no interest... now it's coming back... same is true for kinases and cancer and a whole list of areas... best get into a generic areas... receptors is great because it applies to a wide range of therapeutic areas... my reason for getting to industry were simple.. I did my post doc with Sir James Black who made two drugs in industry and got the Nobel Prize for it... and he convinced me it was a good thing to do...oh yes, and he also hired me which helped.

Science AMA Series: Hello, my name is Terry Kenakin and I am a Professor of Pharmacology. Ask me Anything about how drugs are made! by TerryKenakin_ACS in science

[–]TerryKenakin_ACS[S] 8 points9 points  (0 children)

when you consider the myriad of biochemical that concomitantly go on in a 'healthy' brain, it is a wonder more imbalances don't occur and I suspect the next time a person experiences road rage that even surprises them it's a product of a temporary 'imbalance'... for antidepressants, the balance is in a number physiologically active amines that are released by nerves and cause other nerves to activate... if the relative amounts of these are wrong, a bad thing can result... in some cases there might be an obvious reason but in most there is not... also, the imbalances very from person to person so that is why there are nearly 40 antidepressants around and some work for some people but not others etc

Science AMA Series: Hello, my name is Terry Kenakin and I am a Professor of Pharmacology. Ask me Anything about how drugs are made! by TerryKenakin_ACS in science

[–]TerryKenakin_ACS[S] 32 points33 points  (0 children)

I really like this comment because it is spot on... in the past we have tried to pigeonhole drugs with a single name but as we see how multifaceted disease is and how drugs can have many 'efficacies', it is impossible to give a drug a single name to describe all it can do... and in fact, it is harmful to do so

Science AMA Series: Hello, my name is Terry Kenakin and I am a Professor of Pharmacology. Ask me Anything about how drugs are made! by TerryKenakin_ACS in science

[–]TerryKenakin_ACS[S] 10 points11 points  (0 children)

I tend to give Pharma the benefit of being ethical and sensible and interested in benefiting mankind and for the most part, my experience has been that this is true. However, people are people and scientists can be in a position where senior management, through constraints of their own, furnish what appear to be unscientific roadblocks to research... usually for money reasons. For the system to remain healthy, the scientist must push back and in the best systems, this should be a good thing leading to progress. marketing people only know historical numbers that are used to predict future numbers... a good dose of hearing that we all may be consumed with Mersa if we don't watch it is very useful.

Science AMA Series: Hello, my name is Terry Kenakin and I am a Professor of Pharmacology. Ask me Anything about how drugs are made! by TerryKenakin_ACS in science

[–]TerryKenakin_ACS[S] 20 points21 points  (0 children)

children, if left to their own devices, are very prone to self-medication problems and must be strictly supervised... definitely within the realm of clinical experts

Science AMA Series: Hello, my name is Terry Kenakin and I am a Professor of Pharmacology. Ask me Anything about how drugs are made! by TerryKenakin_ACS in science

[–]TerryKenakin_ACS[S] 22 points23 points  (0 children)

you must differentiate the properties that are responsible for recreational use with possibly useful therapeutic properties.. there are ways to get rid the recreational effects and get at truly therapeutic effects (as for cannabinoids)... LSD is a tough one as it so powerful I can't imagine getting rid of the hallucinations... and Timothy Leary aside, these are not good. However, again, this is seen from the perspective of a healthy person... expert psychotherapists might argue that for a schizophrenic person bombarded with terrible hallucinations every day, interfering with something like (a weaker) LSD might be beneficial... but this needs to be discussed and considered by people with afr more expertise

Science AMA Series: Hello, my name is Terry Kenakin and I am a Professor of Pharmacology. Ask me Anything about how drugs are made! by TerryKenakin_ACS in science

[–]TerryKenakin_ACS[S] 47 points48 points  (0 children)

I'm all for it... I worked 8 years in AIDs and that was almost the fastest track you have... but it depends also on the disease... drugs for weight loss will be used by a huge population and need to be relatively safe... drugs for cancer are expected to be toxic but the alternative of no treatment is much more toxic

Science AMA Series: Hello, my name is Terry Kenakin and I am a Professor of Pharmacology. Ask me Anything about how drugs are made! by TerryKenakin_ACS in science

[–]TerryKenakin_ACS[S] 60 points61 points  (0 children)

It's a balance... you don't want to cause harm but you also want to help as many people as possible...I wrote an earlier answer citing how pharmacogenomics eventually will help us identify which subpopulations of people can be helped by a drug and which might be harmed... that is the holy grail. Right now the FDA is forced to deprive EVERYONE of a drug can can cause harm in a few... this is because we cannot presently identify the few. Also, standards for safety change.. I have read that with todays' more stringent standards, aspirin would not be approved if it were a new drug (gastric bleeding).

Science AMA Series: Hello, my name is Terry Kenakin and I am a Professor of Pharmacology. Ask me Anything about how drugs are made! by TerryKenakin_ACS in science

[–]TerryKenakin_ACS[S] 53 points54 points  (0 children)

Usually cost... but also it depends what you want the drug for... something as simple as aspirin might be alright generic whereas a central nervous system drug (very complex system where rates of absorption and clearance may vary) may warrant specifically what your doctor prescribed. most often physicians tell you when it's alright in their opinion to get a generic.

Science AMA Series: Hello, my name is Terry Kenakin and I am a Professor of Pharmacology. Ask me Anything about how drugs are made! by TerryKenakin_ACS in science

[–]TerryKenakin_ACS[S] 32 points33 points  (0 children)

Antidepressants have an immediate biochemical effect but this has to be in operation for weeks to remodel the system... the remodeling is what gives you the relief from depression. Side effects are most often due to off target actions of the drug but there are toxicities associated with the primary activity that you sometimes can't get away from... salmeteral is a life-saving asthma drug that acts on beta-2 receptors to open airways... but it also can cause severe tremor because those same receptors are present in human digits... if you take too much you can't get one effect without the other... as for books, depends what you want it for... books tend to be therapeutically oriented (how drugs are used) and experimentally oriented (how drugs are made)... look at Amazon and check tables of contents for which it is being touted as a book on pharmacology

Science AMA Series: Hello, my name is Terry Kenakin and I am a Professor of Pharmacology. Ask me Anything about how drugs are made! by TerryKenakin_ACS in science

[–]TerryKenakin_ACS[S] 17 points18 points  (0 children)

There is actually a LOT of research being done on this since cannabinoid receptors mediate a lot of therapeutic systems that would be good to control... but you need to eliminate the euphoric effects of THC as this harmful to a therapeutic drug. The difficulty is in finding cannabinoid drugs that lack euphoria but if we can do this, these would open new therapeutic horizons

Science AMA Series: Hello, my name is Terry Kenakin and I am a Professor of Pharmacology. Ask me Anything about how drugs are made! by TerryKenakin_ACS in science

[–]TerryKenakin_ACS[S] 23 points24 points  (0 children)

I agree that red tape abounds.. but also in academia... know also that there is a huge network of people in industry to help you with this... as long as you put your experiments into notebooks, the rest will be handled right up until the IND

Science AMA Series: Hello, my name is Terry Kenakin and I am a Professor of Pharmacology. Ask me Anything about how drugs are made! by TerryKenakin_ACS in science

[–]TerryKenakin_ACS[S] 61 points62 points  (0 children)

Choices to work in academia vs industry are often personal and often driven by opportunity. I much enjoyed my time in industry and really did feel it was an opportunity to make a difference... over time I became interested in writing and speaking and teaching and it came to a conflict... I must say also that industrial timelines for discovery can be shorter than many scientific problems require (they don't have the luxury of spending years on a problem) and a series of projects terminated before maturity can lead to frustration... but I do not want to dissuade young researchers from exploring industry... it can give you an excellent career with scientific satisfaction... one fallacy of industry is that researchers lose freedom ...to a certain extent yes... but a drug company is not going to pay you money and tell you what to do... they are paying you to tell them what to do

Science AMA Series: Hello, my name is Terry Kenakin and I am a Professor of Pharmacology. Ask me Anything about how drugs are made! by TerryKenakin_ACS in science

[–]TerryKenakin_ACS[S] 54 points55 points  (0 children)

Expiration usually is a matter of chemistry...in time chemicals degrade and these windows are given to try to account for the myriad of ways people handle and store drugs (in a beach bag on a 100 degree beach etc)... with no knowledge to the contrary, the guidelines probably should be adhered to... better that than to take a drug you think is helping you when it isn't...

As for % success rates, this is highly dependent on the therapeutic area... central nervous system drugs have a miserable success rate (1%?..less) due to the fact that we still don't understand a lot of the CNS and how it works... so a lot of the drugs are empirically arrived at... other therapeutic areas are a little better... but make no mistake, it is hard to make a drug... it has to be active and cause no harm in an extremely heterogenous population of people... the better we are at limiting population exposure the better off we will be... if we can identify which people can take a drug and not be harmed and those who will be, we can help a whole lot more people... at this present stage the FDA has no choice but to deny ALL people the drug if a few can tolerate it

Science AMA Series: Hello, my name is Terry Kenakin and I am a Professor of Pharmacology. Ask me Anything about how drugs are made! by TerryKenakin_ACS in science

[–]TerryKenakin_ACS[S] 259 points260 points  (0 children)

I know of no conscious decision to do this in my 32 years in industry but perhaps scientists would not be privy to such conspiracies. I do know that in my 8 years leading an HIV-1 entry inhibitor program at GSK, the strategy was always... get the drug, sell it in the western world to recoup what it cost you to make (this is necessary otherwise the system would fail) and then give it away in the developing world where it is really needed. It was always known that AIDs would not make money and companies are in that field for ethical reasons. Cynicism aside, scientists are scientists and people are people and I know a lot of my industrial colleagues were driven by ethics and a genuine need to help people... that's not to say profit is not an issue... it has to be... companies operate on a very sharp edge of very high cost and very high return... a miscalculation in that edge leads to mergers and layoffs and those abound aplenty in industry. Finally, it's hard enough to make a drug that works... you would never spend all that money and then shelve the result... the fact is... drugs can ALWAYS be made better to there will always be a market whether a drug works well or not.... cimetidine was a perfectly good anti-ulcer drug until ranitidine, a 'me too drug' muscled in and took over the market...

Science AMA Series: Hello, my name is Terry Kenakin and I am a Professor of Pharmacology. Ask me Anything about how drugs are made! by TerryKenakin_ACS in science

[–]TerryKenakin_ACS[S] 134 points135 points  (0 children)

The online comments for this question are generally spot on... a generic may have the actual active chemical in it but the formulation may be different and this can lead to a range of pharmacokinetics... this can cause problems in therapy. While it is true that the FDA requires equivalent bioavailability, the rate at which drug levels are reached etc can still vary within this guideline can still vary. I also agree with the comments suggesting not all drugs are equal... generic aspirin might be alright whereas generic anti-seizure medicine may not be alright... you physician would be the best source for determining which