While
working on my latest post, I became quite distracted. I’m a fan of the website retraction watch
(everyone loves to gawk at the car accident), although in my opinion they
really only skim the problems that permeate the sciences, and while following
one of their links I came across one of the most dismaying publications I've
seen in a while.
So to
clarify this paper was not featured on retraction watch, and I don’t imagine it
ever will end up there, the link I was following just dumped me out in the PubMed
commons website, a website devoted to allowing researchers to comment on papers
post publication and the only comment I saw seemed to be from one of the
authors letting people know about a blog established to help them use the
database described by the paper effectively.
The
International Union of Pharmacology, were announcing an update of their database
called the IUPHAR/BPS guide to pharmacology with the tagline “An
expert-driven guide to pharmacological targets and the substances that act on
them.”
Now
this is actually a great resource however I found it quite conspicuous that none
of the basic theories of how drugs act on their enzymatic targets or any of
their more convoluted cousins made the cut for inclusion in this database.
Well,
that's not entirely true, I was able to find a few inhibition constants in the
database (the values used in these equations or Ki if you look in their
database). However, I can only guess
that they somehow snuck in when an appropriate IC50 values couldn't be found in
the journals used to generate the database. But since these inhibition
constants are usually associated with equations that are known to be wrong it's
not really too much of a shame that that the Ki values were excluded.
But
the exclusive use of IC50s is a little troubling due to the amount of data
IC50s obscure. To make IC50s a little more tangible, say you ask a friend to
study the driving habits of people on a stretch of road close to a speed
trap. Later you ask him what happened
when there was no police officers around versus what happened when there was a
police vehicle there. Getting an IC50
value woud be akin to him saying something like the majority of the cars were
speeding then they stopped. This seems
like a reasonable response but with an
IC50 that's the only information you get.
So can you assume that the cars stopped speeding or did traffic come to
a complete stop? I guess that’s a surprise
better left for the for the clinical trials.
But nonetheless I was interested to see
how the International Union of Pharmacology was handling their drug
characterization so was happy to see the helpful guide “International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. XXXVIII. Update on Terms and Symbols in Quantitative Pharmacology” because who knows maybe the pharmacologists
had figured out something new and just weren't sharing with the enzyme kineticists. But no, all the characterization has been
reduced to IC50 or EC50 values, not even
an effort to examine things any further, or define these anomalous Ki values
peppering the database. Yup, so as I
said in the last post rip out that page on enzyme inhibition out of your text
book. Those inhibition equations and the
equations developed from them, have been around for 100 years and they can’t
make the cut as a relevant method for characterizing drugs according to the
consensus of an international committees of experts in drug theory.
There seems to be an attitude these days
that the early stage thorough characterization of drug activity is not
important since it will all come clean in the pharmacokinetic studies (or in other
words, well if it sort of does what we think it does any problems with it will
show up in the animal studies and clinical trials). This is in a sense true, compounds that are
dangerous, have unexpected properties or are not effective do not make it to
market. (Or I hope Ben Goldacre and ALLTrials have fixed that by now)
However, they do waste huge amounts of
money, resources and time. This terrible
line of thinking suggests that a clear understanding of how things work is not important.
Just throw money at it and the problem will go away. This approach seems to be treating the drug industry
well, with massive cutbacks/layoffs and a clear reduction in the number of drugs
coming to market.
It has been suggested that all the easy diseases
have been already been cured, all the “low hanging fruit picked”. I would counter they haven’t been picking the
low hanging fruit they have been picking it off the floor but maybe someday
regulatory bodies and the pharmaceutical industry will figure out that
developing a better understanding at the molecular level may provide the
theoretical basis for understanding and treating diseases. But since the problems generated through this
superficial analysis of drug interactions haven’t affected their bottom lines
too drastically yet who knows when that will happen.
