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Rheumatoid arthritis and the pharmaceutical
industry
Medicines to control the inflammatory stage (the NSAIDs)
Most NSAIDs have been available for many years and all help
to control mild to moderate pain. They do so because they
all block an enzyme called cyclooxygenase (COX). COX
converts certain molecules called fatty acids into active
forms called prostaglandins, some of which cause inflammation.
The discovery that aspirin worked by blocking COX led to a
very successful period of discovery and a wide range of different
NSAIDs were found. These include diclofenac, fenbufen,
indomethacin, ibuprofen, ketoprofen and naproxen,
some of whose brand names are now household names.
They belong to a variety of chemical classes and their different
properties arise from the way they are absorbed, changed and
excreted by the body. Some, such as piroxicam and nabumetone,
remain in the body for well over 18 hours after a single dose,
while ibuprofen, diclofenac and indomethacin last for less
than 6 hours. Some people respond to these medicines better
than others and the doctor may have to try several before
finding the most suitable one.
A measure of the success and continuing value of these medicines
can be gauged from the fact that an estimated 30 million people
world-wide rely on daily doses of NSAIDs to control their
pain and inflammation. However, a significant disadvantage
of NSAIDs is a tendency to damage the lining of the stomach,
sometimes leading to ulceration and, in rare cases, to severe
bleeding. This is caused by their general blockade of the
COX enzyme, thus preventing the formation of beneficial prostaglandins
that protect the gut, kidney and blood.
Improving NSAIDs
Much research has been devoted to reducing the side effects
of NSAIDs in the gut. Important approaches have been the development
of:
- specially coated tablets or slow-release medicines to
reduce contact with the stomach lining,
- new compounds that heal stomach ulcers that can be taken
together with NSAIDs,
- tablets containing a combination of a NSAIDs with a substance
protecting the stomach,
- more selective medicines which only block the formation
of harmful prostaglandins and not the beneficial ones.
The first approach to the improvement of NSAIDs is slow-release
forms of many of the early compounds, such as aspirin, diclofenac,
flurbiprofen, ibuprofen and indomethacin, which are now available
in soluble, coated, or slow release forms with improved tolerance
in the stomach. Companies involved include Knoll, Eli Lilly,
Napp, Novartis, Parke-Davis, and Trinity. In some cases, they
are also available as suppositories.
The choice of which one to use is a matter for the doctor
and patient, but each compound has its own advantages and
disadvantages in terms of potency, selectivity or the degree
of side effects. Factors likely to affect the choice of treatment
include whether they work in that person, the severity of
the condition and whether the remaining side effects are acceptable.
The second and third approaches to reducing stomach problems
are related. Searle has developed a combination pack in which
one tablet of naproxen (the NSAID component) is taken
together with one tablet of misoprostol (a compound
similar to a prostaglandin). Misoprostol is able to protect
against the ulcer-inducing action of the NSAID. Many clinical
trials of misoprostol have confirmed this protective action
and a reduction of 40 per cent in stomach complications has
been reported.
Searle has extended this approach by developing a combination
of diclofenac with misoprostol, but in this case, the two
components are in a single tablet. Clinical studies show the
risk of stomach ulcer to be reduced by up to two-thirds over
diclofenac alone.
These approaches may be of particular value in people such
as the elderly, those with a history of stomach ulcers and
those with heart disease.
The last of the new approaches, COX-2 inhibitors, is the
most exciting development in the field of NSAID research in
the past 40 years. The breakthrough came as recently as 1991,
when it was shown that at times of inflammation, much more
of the COX enzyme was present in tissue. Further studies showed
that the extra COX produced in inflammation was not the same
as the type found in tissues that were not inflamed, and so
the idea of the existence of two forms, COX-1 and COX-2, was
born.
In 1991, biologists found the gene for COX-2, thus proving
that it really was different from COX-1. Other work showed
that it was only produced during inflammation. This had an
important implication – that medicines that only inhibited
COX-2 might lack many of the undesirable side effects of the
traditional NSAIDs. The search for selective COX-2 inhibitors
had begun.
One NSAID, meloxicam, developed by Boehringer Ingelheim,
appears to inhibit COX-2 at lower concentrations than COX-1.
It is more selective for COX-2 than several older NSAIDs,
including diclofenac, ibuprofen, naproxen, indomethacin, and
piroxicam, which agrees with clinical trial results showing
that meloxicam has reduced side-effects. It is already available
in the UK for RA.
Another company in this field, Searle, was involved in many
of the early discoveries. Its scientists quickly identified
the molecule SC-58635 (now named celecoxib) which appeared
to inhibit COX-2 at a thousandth of the dose needed to inhibit
COX-1. In June 1997, clinical trial results in people with
arthritis showed that it effectively controlled pain and inflammation
without any evidence of undesirable side effects in the stomach.
It was concluded that if more detailed studies confirm these
early data, then celecoxib (and probably other COX-2 inhibitors)
would be a major advance. Phase II and III trials have now
started.
Several other companies are also actively seeking COX-2 inhibitors,
including Abbott, Glaxo Wellcome, Merck Sharp & Dohme and
Roche. Glaxo Wellcome’s compound GR253035 is at the
pre-clinical stage and MS&D’s MK966 is in early clinical
trials. Although these compounds may represent a real advance
in the NSAID field, some experts have sounded a note of caution
and it will be only in the light of greater experience that
we can see if their apparent promise is fulfilled.
Other novel ways to improve NSAIDs
Many medicines are mixtures of two mirror-image forms of
the same molecule – rather like a pair of gloves. In many
cases, the activity is only associated with one form – say
the left hand – while the other may contribute to unwanted
side effects. Chiroscience is a company that has specialised
in making existing medicines in either the left-handed or
the right-handed form.
Nabumetone, from SmithKline Beecham, is an unusual
NSAID first synthesised in 1982. It is absorbed and then converted
in the liver to an active substance and inactive fragments.
It is as effective as many other NSAIDs and has a relatively
low incidence of stomach ulcers.
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