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THE MAKERS of the two leading drugs for treating ulcers of the digestive
tract have clashed horns in a dispute over a new test for detecting damage
to genes in the acid-secreting cells in the stomach.

Glaxo, which makes one of the drugs, claims in a letter to The Lancet
that its new DNA test has revealed that the drug made by Astra, the other
company, irreparably damages the genetic material of the cells that line
rats’ stomachs. As a result, says Glaxo, Astra’s drug may be potentially
carcinogenic. Glaxo’s test reveals no such damage by its own drug. Astra,
a Swedish manufacturer, responds flatly that ‘the method used by Glaxo is
scientifically unsound and that the results therefore have no clinical consequence’
(The Lancet, 17 February, p 419).

Both firms are in the market for anti-ulcer drugs, worth an estimated
$5.5 billion a year. Glaxo claims to hold more than 40 per cent of this
market with its drug, which was licensed in Britain in 1981, while Astra’s
alternative has won less than 2 per cent since its launch here last summer.

Both drugs – ranitidine, made by Glaxo, and omeprazole, made by Astra
– ‘heal’ ulcers by reducing the secretions from acid-producing cells in
the gastric mucosa, the lining of the stomach. However, both drugs also
induce the creation of nodules in the stomachs of rats. The nodules, called
carcinoids, subside when the rats stop receiving the drug.

The first drug, ranitidine, acts by blocking the action of histamine,
a biochemical produced at an early stage of the process of acid secretion.
Ranitidine is thus known as an H₂-blocker. The second drug acts
at the final stage of acid production by inhibiting the enzyme that ‘pumps’
hydrogen ions from the cell into the stomach.

When the secretion of gastric acid is heavily reduced in these ways,
the output of gastrin, a hormone, rises from other mucosal cells. The gastrin
returns to the stomach from the circulation and stimulates further secretion
of the gastric juice. In rats, high levels of gastrin are associated with
the proliferation of another type of cell and with the formation of carcinoids.

Glaxo is standing by its findings on Astra’s drug. ‘We have repeated
the omeprazole results five times, and regard them as significant,’ said
Robert Smith, a pharmacologist at Glaxo. ‘That’s why we published them.’

Glaxo’s results led it on 22 January to cancel a trial on 420 patients
in West Germany. The trial was intended to compare ranitidine with omeprazole.
When Astra heard of the plans it contacted Glaxo, discussed the DNA test
results with the researchers and drew up its response. Meanwhile, Astra
is continuing its own clinical comparison of the two drugs.

In a leading article entitled ‘Omeprazole and Genotoxicity (poisoning
of genes)’, The Lancet describes Glaxo’s halting of its German trial as
being ‘bound to have an effect on prescribers’. The article also comments
that Glaxo’s decision ‘seems premature.’

The leader criticises some of the methods used by the team at Glaxo
that developed the DNA test – specifically, the way they isolated the gastric
mucosal cells for the experiments. The article also lists three ‘fairly
standard procedures’ that Glaxo might have used to control and validate
its experiments. The article calls for urgent work to validate the new method
and further investigations of omeprazole’s action.

Omeprazole is recommended for ulcers that are resistant to conventional
therapy, but not for long-term treatment. Astra points out that its licence
was granted because it had carried out all the standard safety tests on
the drug’s potential to alter genes. The tests are required by Britain’s
Committee on Safety of Medicines.

‘Omeprazole,’ says Astra, ‘has been subjected to an expensive series
of established genotoxicity tests that are much more specific and sensitive
than the method used by Glaxo.’ Glaxo has not suggested to the CSM that
its new DNA test should now be included in that battery of tests.

The leader also draws attention to the unsatisfactory situation in which
one firm is investigating the potential toxicity of its competitor’s product,
instead of an independent evaluation taking place.