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My theory on the gastrin antagonist


Inspiration from a Hammersmith Medicines Research report
James Black Scientist
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When we were doing the gastrin work here, a paper was published as an abstract from Hammersmith Medicines Research, and that’s a Phase I study operation over at the Central Middlesex Hospital, and they reported this gastrin antagonist, which we knew from the literature – from the laboratory work – was the most potent of all the beta blockers which had ever been synthesised.

[Q] Gastrin antagonist?

Pardon? Gastrin... I beg your pardon, gastrin antagonist. And so they reported the testing of it in man, and the way it was tested was these volunteers swallowed a pH electrode and they were measuring the affect of the gastrin antagonist on the pH inside the stomach. Now, if you take a proton pump inhibitor then, and you do that experiment, the pH goes right up to nearly 7, and physicians teach... teach all the time that to be effective a gastrin antagonist has to have the pH above 4, on average, in the 24 hour period. And so there then comes this gastrin antagonist. On day one it was as good as a proton pump inhibitor, but by day seven: no change. The pH stayed right down low at about 2. They repeated it after 14 days, and again, the same result: lost activity. And so, this compound was made originally by money, made in Southampton by a little group funded by Ferring, a small Danish company – privately owned – and they found this compound... I don’t know why they were doing the work because they were mainly interested in women’s products, but anyway, they found it. And, they got a big pharma to help them which turned out to be Yamanouchi, and... big Japanese company. So Yamanouchi Ferring... and their number is YF476, Yamanouchi Ferring. And we knew about it; the most active compound, here it was failing the test, and I didn’t believe it. No antagonist loses its activity, it's impossible, so it had to be another story. So I managed to persuade Mr Wilson, whom you remember, to get J&J to take a license out on this compound. And so we had this compound to ourselves for the year and we showed that if, instead of measuring pH, you measure, you know, the total amount of acid secretion being produced, and stimulate the acid secretion with histamine, then if you give the... not with histamine, with... with gastrin. If you stimulate with gastrin and then give this compound it blocks that acid on day one, on day seven, on day 14, on day 21, and then you stop, pardon me, and it comes back after a few days. So, as I expected, it doesn’t lose blocking potency, and this was then repeated again with Johnson & Johnson money at Hammersmith and, again, we showed there that we’d got... but here was the interesting thing. You withdraw juice from the stomach and you measured its acidity with a glass electrode, and you measured its volume. Now, the pH affect was as he’d originally described, present on day one, it wasn’t present on day seven, but the volume of secretion, which was down on day one, was down on day... so the total amount of acid being produced was greatly inhibited. Now you may remember, going back to the metiamide days, that we found that: that the effect on the volume of acid being produced was much more dramatic in terms of the acidity.

The late Scottish pharmacologist Sir James W Black (1924-2010) revolutionised medical treatment of hypertension and angina with his invention of propranolol, the first ever beta blocker. This and his synthesis of cimetidine, used for the treatment of peptic ulcers, earned him the Nobel Prize in Physiology or Medicine in 1988.

Listeners: William Duncan

After graduating with a BSc Bill Duncan went on to gain a PhD from Edinburgh University in 1956. He joined the Pharmaceuticals Division of ICI where he contributed to the development of a number of drugs. In 1958, he started a collaboration with Jim Black working on beta blockers and left ICI with him in 1963 to join the Research Institute of Smith Kline & French as Head of Biochemistry. He collaborated closely with Black on the H2 antagonist programme and this work continued when, in 1968, Duncan was appointed the Director of the Research Institute. In 1979, he moved back to ICI as Deputy Chairman (Technical), a post he occupied until 1986 when he became Chairman and CEO of Coopers Animal Health. He ‘retired’ in 1989 but his retirement was short-lived and he held a number of directorships in venture capital backed companies. One of his part-time activities was membership of the Bioscience Advisory Board of Johnson and Johnson who asked him to become Chairman of the Pharmaceutical Research Institute of Johnson and Johnson in New Jersey. For personal reasons he returned to the UK in 1999, but was retained by Johnson and Johnson until 2006 in a number of senior position in R&D working from the UK. From 1999 to 2007 he was a non-executive director of the James Black Foundation. He is now fully retired.

Tags: Hammersmith Medicines Research, Central Middlesex Hospital, Southampton, Ferring, Yamanouchi Pharmaceutical Co., Johnson & Johnson

Duration: 4 minutes, 32 seconds

Date story recorded: August 2006

Date story went live: 02 June 2008