Download e History of 5-ASA Compounds and their Use in Ulcerative Colitis

EDITORIAL
The History of 5-ASA Compounds and their Use in Ulcerative
Colitis – Trailblazing Discoveries in Gastroenterology
John Mayberry
University Hospitals of
Leicester
NHS Trust
Leicester, UK
Address for correspondence:
John Mayberry
University Hospitals of
Leicester
NHS Trust
Leicester, UK
[email protected]
Received: 14.08.2013
Accepted: 14.08.2013
5 aminosalicylates have
had a dramatic effect on the
management of patients with
inflammatory bowel disease.
Their success in reducing
the frequency of flare-ups
in ulcerative colitis laid the
foundations of long-term disease
control in gastroenterology.
As a result the concept that
medication should be taken to
prevent disease episodes was
present at the beginning of
therapeutic gastroenterology.
5 aminosalic ylates were
amongst t he f irst dis e as e
specific therapeutic agents of
the twentieth century. They
were conceived as drugs that
could be targeted at the cause
of disease. The original idea of
dealing directly with infection
and inflammation through the
combining of sulphonamides
and aspirin derivatives was a
reflection of the growing belief of
the 1930s that treatment should
be targeted.
The demonstration in 1935
that sulphanilamide was the
active component in Prontosil
Rubrum led to the production of
a large number of sulphonamides.
The subsequent discovery that
sulphonamides blocked a specific
metabolic activity in bacteria
due to competitive inhibition
with naturally occurring PABA
(p ara-aminob enzoic acid)
confirmed their role as potential
anti-bacterials [1]. May and
Baker 693 (or sulphapyridine),
which was developed by Jewins and Phillips, proved to be
the most potent and broad spectrum [2, 3]. It was the agent
that was to be combined with a 5 aminosalicylate to produce
sulphasalazine. The stimulus to this development was the
belief that rheumatoid arthritis was, at least in part, due to a
bacterial infection.
Nanna Svartz was the first woman to become a professor
of medicine at a state university in Sweden. As head of the
medical clinic at the Karolinska Hospital she practiced as
a rheumatologist. She was keen to develop a twin pronged
approach to the management of rheumatoid arthritis and
planned to capitalise on the penetration of connective tissue
by 5 aminosalicylic acid. She hoped to use this molecule to
carry sulphapyridine into the tissues [4]. Through a chance
meeting with Phillip Willstaedt, Pharmacia, the Swedish
pharmaceutical company, produced a number of candidate
drugs of which salicylazosulphapyridine or sulphasalazine held
the most promise. Almost through serendipity, sulphasalazine
was found to be effective in the control of ulcerative colitis.
A small study of 9 patients which depended upon clinical
observation suggested that the drug was effective [5]. At this
time there was no real alternative treatment and sulphasalazine
spread around the world as the agent of choice for patients with
ulcerative colitis. Its mechanism of action was unclear and it
was associated with significant side effects.
As early as 1937, Dr. Arnold Bargen from the Mayo Clinic
in Rochester, Minnesota started to investigate the potential
role of sulfanilamide in the treatment of ulcerative colitis.
Two deaths from acute yellow liver atrophy led to a search
for a preparation which might “possess a therapeutic effect
comparable to that of sulphanilamide without its toxicity”[6].
A number of potential agents were assessed, including azosulfamide and sulfathiazole. However, the most effective agent
was to be salicylazosulfapyridine or Salazopyrin [7].
Despite these difficulties in 1965 the first placebo controlled
trial of sulphasalazine treatment was conducted in the UK
[8]. After one year of treatment with 2g of sulphasalazine, 24
of 34 patients with ulcerative colitis remained in remission.
In 1972 Dissanayake and Truelove showed in a placebo
controlled trial of 64 patients with objective end-points that
long-term use of sulphasalazine suppressed disease activity
up to 5 years in ulcerative colitis and introduced the concept
J Gastrointestin Liver Dis, December 2013 Vol. 22 No 4: 375-377
376
that life-long therapy was central to the successful treatment
of this condition [9]. With its role as a long-term preventive
treatment the problem of side effects became one of the driving
factors behind the search for which part of the molecule was
responsible for sulfasalazine’s anti-inflammatory activity.
This search identified 5 aminosalicylate (Mesalazine) and not
sulfapyridine as the active component within sulfasalazine.
Azad Khan and Sidney Truelove performed an elegant series
of studies using three separate retention enemas in a blind
clinical study over a period of two weeks. Sulfasalazine and 5
aminosalicylate (5-ASA) enemas produced a significant clinical
improvement in 30% of patients compared with a 5% response
in those who received sulfapyridine [10].
The problem with 5-ASA is its lack of stability. Solutions
to this problem have centred around three main approaches:
A. delivery directly to the colon as a retention or foam enema;
B. encapsulating the drug within a pharmaceutical coating; C.
binding the 5-ASA moiety to a carrier molecule.
Perhaps the most innovative approach was the use of
5-ASA as its own carrier molecule. Sidney Truelove’s group
investigated the effect of two 5-ASA molecules linked back to
back. The resulting compound was disodium azodisalicylate
or Olsalazine. Although effective, its role has been limited by
the occurrence of diarrhea as a significant side effect.
During the 1980s John Rhodes and Brian Evans investigated
the role of eudragit-S coating as a way of stabilising mesalazine.
Their novel idea was to develop a product which would split
open with the change in pH as intestinal content crossed the
ileocaecal valve into the colon [11]. The rupture of the outer
capsule released active mesalazine into the colon. The product
was marketed as Asacol by Tillotts Laboratories Ltd. The role
of entrepreneurs, such as David Slagel, in bringing these new
products to market cannot be overemphasised.
Eva Paulsen was a civil engineer whose specialty laid in
the development of production techniques for a range of
pharmaceuticals. During the late 1970s she became interested
in ways of stabilising 5-ASA so that it could be given as an oral
medication [12]. Together with Søren Halskov, she developed a
technique for encapsulating mesalazine within microgranules.
These prolonged release through coating made from a polymer,
alchyl-cellulose, which was independent of the pH. The product
was marketed as Pentasa.
In 1980, Hugh Baron and John Lennard-Jones approached
Siegfried Gottfried and Lily Baxendale of Biorex Laboratories
to investigate the possibility of linking the 5-ASA moiety
to an inert carrier molecule. Dr. Rosalind Chan, a chemist,
suggested four possible molecules with a diazo link to 5-ASA.
This resulted in the production of two compounds with branch
chains containing an amino acid [13]. In one case this was
4-aminobenzoyl-β-alanine or Balsalazide and the other was
Ipsalazide which was based around a glycine chain [13 -15].
Balsalazide has been shown to be effective in a large number
of clinical trials. The azo-bonds, which link the moieties, are
split by azo-reductase present in bacteria in the large bowel.
However, its mode of action cannot be simply attributed to
the release of active 5-ASA from an inactive carrier molecule.
Pharmacokinetic studies would suggest that it is metabolised
and excreted in a distinct way. In 1988, 79 patients were treated
in a comparative study with sulphasalazine [15]. Balsalazide
J Gastrointestin Liver Dis, December 2013 Vol. 22 No 4: 375-377
Mayberry J
Dr. Siegfrid Gottfried, a Roumanian Physician,
founded Biorex Pharmaceuticals and received
a Queen’s Award for Industry in the UK. His
company conceived and developed balsalazide
in response to suggestions by gastroenterologists.
proved effective and to have fewer side effects and again the
entrepreneurial spirit of a relatively small developmental
company had played a significant role in converting the ideas
of practising gastroenterologists into prescribing reality.
During the early 1980s the search for better stability and
less side effects led to an interest in 4-ASA rather than 5-ASA.
It has been investigated in several clinical trials, but always
as an enema. In general it appears as effective as 5-ASA but
exhibits fewer side effects [16-18]. It is commercially available
as Quadrasa in a number of European countries.
In the 1990s the pharmaceutical industry took a more
active interest in the development of 5-ASA products. One
aspect of this interest centred around the need to improve
long-term compliance with 5-ASA therapy. Clinical studies
had been restricted to follow-up periods of no greater than
18 months and compliance with therapy was clearly an
issue [19, 20]. One approach to such difficulties has been to
develop a once daily preparation. In 2000, Villa et al filed a
patent which had a three component matrix structure [21].
It described a structure which was formed by successive
amphiphilics: lipophilic or inert matrices incorporated or
dispersed in hydrophilic matrices. As a result, the dissolution
rate of the active constituents could be controlled. Cosmo
Pharmaceuticals SpA developed this Multi Matrix System
(MMX) at Lainate in Italy. The combination of more than one
release controlling mechanism prevents dissolution in the
upper gastrointestinal tract and allows delivery of mesalazine
uniformly throughout the colon. A study of 79 patients in Rome
by Prantera et al demonstrated that this system was as effective
but more acceptable than enema treatment [22].
It was during this period that interest focused on the
potential of 5-ASA compounds to reduce inflammatory activity
and so potentially to reduce the risk of colorectal cancer in
ulcerative colitis. In 1994 sulfasalazine was first shown to
reduce the risk of colorectal cancer by between 31% and 80%
5-ASA compounds and their use in ulcerative colitis
amongst a cohort of 3,112 patients from Uppsala in Sweden
[23]. Confirmation came from a study in Leicester UK where
the risk was reduced by 28% [24]. A UK nationwide study
of patients with ulcerative colitis who developed colorectal
cancer in 2000 confirmed a reduction in risk of more than
70%, especially for those taking mesalazine [25]. These studies
emphasised the importance of regular therapy with 5-ASA
medication and raised the question of what was the minimum
duration of treatment to achieve this benefit.
Conflicts of interest: No conflict to declare.
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