New uses for old drugs
Is it just me or are pharmaceutical companies becoming tight-fisted? You may
know what I mean. They seem to be recycling their old drugs in new guises.
That old stalwart of analgesia - aspirin - first developed in the nineteenth
century, for instance, has in the last few years become the <i>new</i> blood
in cardiovascular disease while many other old drugs are racing through the
regulations with new targets. Is there a concerted effort to cut costs by
avoiding the need for countless preclinical studies or is it a side-effect
of burgeoning structure libraries and the ability to pull out compounds so
easily on the basis of particular properties? Perhaps it just goes to show
that in drug discovery there's always been a little design and a lot of
serendipity.
Academic researchers in the medicinal sciences spend much of their time
developing and testing theories of how particular compounds might fit into a
receptor or enzyme to activate or deactivate it. The truth is though that
once this flaskful of research makes it to the pharma company labs much of
the science becomes something far more alchemical. Watch many a presentation
on drug discovery in the industry for more than five seconds and you will
see what I mean. The academics may have come up with a four-ring system (ABCD)
from a natural product original, which they reckon will have as near a
perfect shape, size and chemistry as possible for inhibiting a viral enzyme
say, but sadly, it falls at the first assay.
Never mind - swap A for E and try again. Still no luck? Well what about
adding a side chain to B to increase lipophilicity? Close, but no cigar.
Swap a carbon in C for a nitrogen and try again? After much tweaking the
medicinal chemists will likely produce something that may provide a positive
hit in the assay but its resemblance to the original scientifically designed
wonder drug is vague to say the least - [ED(R)D'(R2)F] (spot the
difference?).
This derationalisation of the drug discovery process seems to have gone one
step further with companies desperate to hang on to market shares as their
patents expire and the generics take over. Rather than going for new
blockbusters the companies seem to be aiming for ten to twelve half-decent
products each year and a catalogue of multipurpose drugs have appeared in
the last few months.
One of the growth areas in this multipurpose drug world is in using
anticancer drugs for different purposes. Many compounds, of course, are
labelled as anticancer-antibiotics because their cytotoxicity kills various
types of cell. But, with the newer anticancer drugs that restrict the growth
of new blood vessels their application in other areas is coming to the fore.
These new 'anticancer' compounds inhibit angiogenesis and so stifle growing
tumours but if targeted appropriately there is no reason why they could not
be used to inhibit blood vessel growth in other diseases where blood vessel
growth, if not the cause, is one of the effects that produces symptoms. For
instance, angiogenesis is involved in the development of macular
degeneration of the retina, which is the most common cause of blindness in
the elderly. Angiostatic cancer drugs could play a role in slowing the loss
of sight.
Anticancer against paralysis
Another angiogenesis inhibitor CM101, made by Carbomed Inc, has recently
been described as potentially useful in preventing permanent paralysis in
spinal injury. CM101 is derived from <i>B streptococci</i> and is a potent
angiogenesis inhibitor. Close Carbomed collaborator Carl Hellerqvist of the
Department of Biochemistry at Vanderbilt University in Nashville, Tennnesse
and his team reasoned that angiogenesis might also stop the growth of the
scar tissue that prevents nerves healing properly in the spinal cord after
an accident. Their early laboratory studies bode well for using CM101 to
treat spinal injury and so avoid long-term paralysis.
Thalidomide for cancer
Thalidomide, while highly controversial because of its tragic past, is among
the compounds being reinvestigated for various diseases including
amyloidosis, leprosy, and certain cancers. In December, Seema Singhal of the
Myeloma and Transplantation Research Center (MTRC), at the Arkansas Cancer
Research Center told the 40th annual meeting of the American Society of
Hematology of the latest results with the much-maligned drug into treating
multiple myeloma - a deadly form of cancer, which affects plasma cells.
Singhal and his colleagues led by Bart Barlogie have found that tumour
burden could be reduced in 34% of patients using the drug. Some patients
experienced more than a 75% reduction in tumour growth and three individuals
approached near complete response. Trial participants had end- state
refractory multiple myeloma and had all failed to respond to more
conventional chemotherapy and bone marrow transplantation.
Barlogie says that preliminary results indicate that a combination of
thalidomide with standard chemotherapy also seems to be effective in
treating plasma cell leukaemia and another form, fulminant multiple myeloma.
Cystitis to CJD
In the UK, government health officials have been studying a US cystitis drug
that might be useful in preventing Creutzfeldt-Jakob disease. The drug
pentosan polysulphate was found to delay the onset of scrapie in sheep in
the 1980s although until recently - for obvious reasons - the research lay
dormant.
Stephen Dealler from Burnley General Hospital is trying to determine whether
giving the drug to relatives of CJD victims and those who have come into
contact with 'contaminated' tissues, might be useful. The fact that Pentosan
already has regulatory approval in the US would likely help short cut red
tape.
Mental illness to antivirus
The metabolites of common antipsychotic drugs, such as clozapine, have been
found to inhibit replication of HIV in human cell cultures, which could lead
to yet another multipurpose drug. Antipsychotics have for several years been
suspected of having antiviral activity, for instance lithium inhibits <i>Herpes
simplex</i> replication. Such activity is consistent with the theory that
certain forms of mental illness are thought to have a viral component.
Johns Hopkins University scientists led by Lorraine Jones-Brando, found that
four clozapine metabolites inhibited three different strains of HIV at
non-toxic concentrations although the effective concentrations were 6000
times higher than an effective dose of AZT. 'Though the clozapine
metabolites are unlikely to be useful for the treatment of HIV infection,'
says Jones-Brando, 'it is possible they may inhibit the replication of other
viruses at much lower concentrations.'
Anticonvulsant for shingles
Clinical trials, reported in the Journal of the American Medical Association
in December of the Parke-Davis anticonvulsant gabapentin have shown it to
give significant relief from the burning pain suffered chronically by some
shingles patients. Gabapentin was first used for epilepsy in 1995 and
doctors began to notice it also acted as a painkiller and trials were
initiated to test its ability to control neuropathological pain.
Tricyclic antidepressants are usually used to treat nerve pain (neuralgia)
caused by herpes infections but they work for less than half the patients
treated and have numerous side-effects. While pharma companies may be
searching earnestly for alternatives, the finding that gabapentin has
analgesic powers once again circumvents nicely the problem of starting from
scratch.
Even if a neuropathic painkiller is rationally designed, it might not be so
effective as originally hoped for. Trials might reveal it is effective in
controlling joint pain but extended studies may then reveal this not to be
the case and he majority so it is relegated to being a general painkiller,
which because of the potential costs would make it unmarketable so it would
end up on the virtual library shelf. The chance finding that a drug designed
for one purpose might fill the gap would cut the cost-profit gap
considerably making it a viable alternative to the conventional route
through the system.
As with many drugs, gabapentin's mode of action remains unclear but author
of the JAMA paper, Michael Rowbotham, a University of California San
Francisco neurologist, has some clues, 'Gabapentin appears to affect a
completely different aspect of the nerve cell circuitry involved in chronic
pain than do opioids (morphine-like drugs) and tricyclic antidepressants,
the main drugs currently used to treat severe nerve damage pain, explained
Rowbotham who is working with the Rehabilitation Institute of Chicago,
Oregon Health Sciences University, and Parke-Davis Pharmaceutical Research,
which funded the study.
There are many more examples of drugs that are being trialled right now for
new uses and discoveries being made about old drugs and how the theory
behind them might be used in other diseases. Perhaps the seemingly haphazard
approach of trying and testing drugs for other uses has a strong rationale
behind it, after all. Time and costs are cut and with at least some of the
discoveries, there is a degree of theory to support a positive result. Then
again, the likes of sildenafil and aspirin came about almost entirely by
chance...maybe the pharma companies should face up to the fact that often
their biggest sellers are simply down to luck. This item originally appeared
in David Bradley's weekly Catalyst column on ChemWeb.com
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Elemental Discoveries 09/01, Issue 45
Read my follow-up article online in Nature Reviews Drug Discovery soon
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