Tagamet — an advertisement in The Journal in 1977 |
If one Googles Tagamania today the search engine will come up with sites
featuring an American piebald horse of illustrious pedigree.
But 30 years
ago, you would not have needed Google to know that Tagamania referred
to the huge commercial success of the breakthrough peptic ulcer treatment,
Tagamet (cimetidine). The drug transformed the fortunes of Smith, Kline
and French (SKF) — a US company with a pre-eminence in psychotropics
which was being eroded by Swiss giant, Hoffman La Roche. The drug had
a dramatic impact on the lives of millions of people with peptic ulcer
disease.
“Before Tagamet, the only options were antacids or surgery. You needed
to drink about 8L a month of antacids to get a better effect than placebo
and you only offered people surgery when they were in so much pain that
they wouldn’t mind the dumping [of food into the intestine before
it has been broken down in the stomach], sweating and diarrhoea, which
followed vagotomy with or without removal of the antrum,” recalls
Roy Pounder, Emeritus Professor of Medicine, University of London.
“Ironically,
there had just been improvements to make vagotomy highly selective, with
less risk of side effects. But the operation was very demanding and,
if it didn’t work, the ulcers came back,” he added.
Tagamet was launched in the UK in November 1976 as the first histamine
(H2) antagonist. It emerged from a research programme started
at SKF in 1964 when Sir James Black joined the company from ICI, fresh
from
his success with beta blockers.1
Antihistamines had been available for
the treatment of allergic reactions since the 1940s but they did not
block the action of histamine in all tissues. For example, they had no
effect on histamine-mediated release of gastric acid from the parietal
cells of the stomach.
In 1966, it was proposed that there were two histamine receptors — H1,
antagonised by antihistamines such as mepyramine, and non-H1,
which were not.2 SKF scientists therefore set about developing compounds
that were
structurally similar to histamine (unlike the antihistamines marketed
at that time for allergies) and would compete with histamine at non-H1 receptors.
In the first four years of the programme around 200 compounds were synthesised,
but none showed any evidence of antagonism at non-H1 receptors.1 After much chemical manipulation, a competitive antagonist of histamine
in
non-H1 tissue systems was developed, called burimamide, and
classified as an H2 receptor antagonist.3
Unfortunately, it was not active enough in human studies and a second
H2 antagonist, called metiamide, was synthesised. This was
considerably more potent than burimamide and reduced excessive gastric
acid secretion
in human studies.
In initial trials, there were significant reductions
in pain and antacid consumption compared with placebo, and improved ulcer
healing,4, 5 but the use of metiamide was limited by reversible granulocytopenia
in a small number of patients.
It was third-time lucky for SKF with the result of a final session in
the chemistry laboratories being cimetidine. It inhibited gastric acid,
passed toxicity tests and, in doses of 0.8–2g per day over three
to four weeks, achieved 70 per cent ulcer healing rates.6
Major impact
“The first dose of Tagamet was the best because patients felt
so much better when they started taking it. You did not need to be a
gastroenterologist
to prescribe Tagamet and when it was launched every doctor wanted to
hear about it because they all had patients with dyspepsia whether they
were gastroenterologists, orthopaedic surgeons or gynaecologists,” Professor
Pounder explains.
Within weeks of its launch, Tagamet was having a major impact on ulcer
disease, but it was no cure. Within six months of stopping treatment,
80 per cent of patients relapsed but maintenance studies soon showed
that this could be reduced to less than 30 per cent with low-dose cimetidine.7
Before
long, it was proposed that patients who responded to an initial course
of treatment should follow this with maintenance therapy for six
to 12 months and, depending on how soon they relapsed after this, have
a further course of cimetidine or consider surgery.
Doctors were wary of putting patients on prolonged maintenance therapy
in case of long-term toxicity and these concerns were fuelled by studies
emerging at the end of the 1970s, which raised the spectre of stomach
cancer. Low or absent levels of stomach acid were associated with bacterial
overgrowth in the stomach and resulting bacterial conversion of exogenous
nitrates to nitrites, leading, potentially, to the synthesis of carcinogenic
N-nitrosamines.8
Increases in nitrites and N-nitrosamines were reported
with cimetidine treatment,8 and controversial extrapolations to stomach
cancer were made, although never subsequently confirmed.
Despite the rumbling safety debate about cimetidine, there was immense
interest among other pharmaceutical companies in developing rival H2 antagonists.
The reasons were obvious. In the UK alone, over a million patients were
treated with Tagamet in the first five years after its
launch.
Annual worldwide sales reached £150 million within two years of
launch and around £300 million at the start of the 1980s. Before
long, SKF was able to take over UK pharmaceutical company, Beecham, the
name of which was synonymous with cough and cold remedies.
But Smith
Kline Beecham (SKB) was, in turn, swallowed up by Glaxo, thanks partly
to the profits it made from the second H2 antagonist, ranitidine
(Zantac), which was launched in 1981 and went on to eclipse even Tagamet — becoming
the world’s best-selling drug five years later.
Professor Pounder believes that the key to Zantac’s success — aside
from the textbook marketing operation — was its easier dosing regimen
compared with Tagamet and its lack of drug interactions.
“Tagamet
had to be taken four times a day, but when Glaxo tested Zantac taken
twice a day, the results were at least as good, partly because of the
better compliance. So they launched using a twice daily regimen,” he
explains.
Cimetidine (Tagamet) is an inhibitor of cytochrome p450 and interacts
with a wide range of commonly used medicines, including some antiepileptic
and anticoagulant drugs, so that dose changes are needed. It is also
associated with male sexual dysfunction — another feature which
it does not share with ranitidine.
The final nail in the coffin for Tagamet came with two large multicentre,
head-to-head trials of night-time maintenance therapy that showed a 12-month
relapse rate of 16–23 per cent for those taking Zantac compared
with 37–43 per cent for those on Tagamet.9, 10
“British doctors were quite conservative about switching to Zantac, and
Tagamet was invented in Britain, even though SKF was an American company.
But the combination of a slightly better product and a more aggressive
marketing campaign finally won the British over to Zantac,” says
Professor Pounder.
The last challengers to enter the H2 antagonist market were
famotidine (Pepcid PM) from Merck Sharp & Dohme Limited and nizatidine
(Axid) from Lilly, both of which were launched in 1988 — over a
decade after Tagamet’s original breakthrough.
They offered comparable
ulcer healing rates to cimetidine and ranitidine, but without the drug
interactions of cimetidine. Because they were priced at the higher level
of Zantac, rather than the cheaper Tagamet, doctors were advised to stick
with the products they already had.11
However, MSD did manage to steal ahead of its more established rivals
in getting Pepcid AC on to the over-the-counter market for heartburn
and dyspepsia six weeks ahead of SKB’s Tagamet 100 in 1994 and
over a year ahead of Glaxo’s Zantac 75.
But the ink was barely dry on the licences of famotidine and nizatidine
before the first proton-pump inhibitor burst on to the scene, promising
even greater, more prolonged stomach-acid reduction than could be achieved
with the H2 antagonists.
And, with the patents expiring on
the drugs that had transformed two nice but dull companies into giants
of the pharmaceutical
industry, life moved on in the world of ulcer disease.
References
1. Brimblecombe RW, Duncan WAM, Durant GJ, Emmet JC, Ganellin CR, Leslie
GB, et al. Characterization and development of cimetidine as a histamine
H2-receptor antagonist. Gastroenterology 1978;74:339–47.
2. Ash AS, Schill HO. Receptors mediating some actions of histamine.
British Journal of Pharmacology and Chemotherapy 1966;27:427–39.
3. Black JW, Duncan WAM, Durant GJ, Ganellin CR and Parsons ME. Definition
and antagonism of histamine H2 receptors. Nature 1972;236:385–90.
4. Pounder RE, Williams JG, Milton-Thompson GJ, Misiewicz JJ. Relief
of symptoms of duodenal ulceration by oral metiamide. BMJ 1975;2:307–9.
5. No authors listed. Treatment of duodenal ulcer by metiamide. A multicentre
trial. Lancet 1975;2:1779–81.
6. Winship DH. Cimetidine in the treatment of duodenal
ulcer: review and commentary. Gastroenterology 1978;74:402–6.
7. Gray GR, Smith IS, Mackenzie I, Gillespie G. Long-term cimetidine
in the management of severe duodenal ulcer dyspepsia. Gastroenterology
1978;74:397–401.
8. Stockbrugger RW, Cotton PB, Eugenides TN, Bartholomew BA, Hill MJ,
Walters CL. Intragastric nitrites, nitrosamines, and bacterial overgrowth
during cimetidine treatment. Gut 1982;23:1048–54.
9. Gough KR, Korman MG, Bardhan KD, Lee FI, Crowe JP, Reed PI, et al.
Ranitidine and cimetidine in prevention of duodenal ulcer relapse. A
double-blind, randomised, multicentre, comparative trial. Lancet 1984;2:659–62.
10. Silvis SE. Final report on the United States Multicenter Trial comparing
ranitidine to cimetidine as maintenance therapy following healing of
duodenal ulcer. Journal of Clinical Gastroenterology 1985;7:482–7.
11. New H2-blockers: does more choice help? Drug and Therapeutics Bulletin
1988;26:65–6. |
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Pharmaceutical Journal