BRIAN DEER: HARD SELL Page 5

Confronted by Elion's world-weary eyes and no-nonsense charm, it is certainly ill-mannered, and perhaps even cruel, to say anything ill of her offspring. In stories of a childhood in Brooklyn, she talks about how a favourite grandfather died from cancer, propelling her into a lifelong quest. It is a similar story with Hitchings, who grew up on the Pacific coast of Washington state, and was 12 when his father died. For some 45 years this pair shared a lab, sometimes seven days a week.

But, as was revealed last week in the first part of our investigation, research suggests that three of Wellcome's big four products - the antibiotic Septrin, the Aids drug AZT, and the herpes treatment acyclovir - have all been promoted by the company’s marking people beyond the best medical opinion. Much of their yield has come from prescriptions to patients who might not need them, or for whom they were unduly dangerous.

It can take years for independent investigators to get the measure of a drug’s benefits and risks. So it is the older product, Septrin (also branded as Bactrim), that has prompted the most forceful concerns. In this antibiotic, a relatively safe and effective compound called trimethoprim (invented by Hitchings) was mixed with a more dangerous, and largely redundant, sulpha chemical (sulphamethoxazole), in a controversial marketing deal.

Since its launch in the late 1960s, research suggests that this combination drug may have been associated worldwide with what could be thousands of deaths and injuries. Even during the past week, people have contacted The Sunday Times to talk of their personal misfortunes.

One mother complained that her four-year-old son had been rushed, close to death, to hospital after taking Septrin for a chest complaint. Another user recounted how her life had been "ruined" from a chronic syndrome that set in immediately afterwards. Meanwhile, Wellcome’s solicitors said that our reports "appalled" their clients, and that they were considering their legal position.

The fourth big earner - the gout drug allopurinol - was not examined in last week's reports. It too has greatly helped a relatively defined group of patients, but was marketed far beyond its best usage. Like the others among Elion and Hitchings’s creations, it reveals a system in which some patients can be prescribed medicines for whom advantages and dangers may be skewed.

Gout is a disease for which there is still no cure, caused by an excess of uric acid in the blood ("hyperuricaemia"). It mostly shows in old people, when it super-saturates tissues, sometimes causing swellings and pain. In its chronic state, the acid forms crystals - particularly in the kidneys and joints - producing deformities and a condition like arthritis.

Elion and Hitchings conceived allopurinol almost by accident, while searching for cancer treatments. But in 1956, they stumbled on its effects, and so a gout drug was born. It was the kind of mix'n'match discovery that was common in those days, and which even now makes Hitchings smile.

"We said: 'Now we've got the drugs,"' he chortles, during an interview in his office, along a wide, carpeted corridor from Elion’s. "'All we've got to do is find the diseases that go with them."'

When allopurinol was first marketed, in 1963, it seemed like an unqualified success. Many thousands of gout sufferers (Elion included) found that the drop it brought to uric acid levels meant that the disease, at last, became bearable. Although reliance on it may have distracted from much-needed diet and lifestyle changes, it at least relieved symptoms for most users.

But even the commonest drugs are not free of downsides, and it soon became clear that some patients on allopurinol found that it caused rather than relieved gout symptoms. Side-effects, meanwhile, could range from mild skin rashes to fatal blood disorders and a hypersensitivity syndrome.

In 1970, The New England Journal of Medicine - the world’s top medical publication - reported the first strongly-linked death. It was of a 72-year-old man who had been diagnosed with gouty arthritis in 1944, but who was stable until discovering allopurinol.

By January 1986, 22 deaths linked with the drug had been published in the medical press - and were reviewed in the journal Arthritis and Rheumatism. This noted "significant morbidity and mortality associated with the allopurinol hypersensitivity syndrome," and warned doctors to temper their prescribing.
In the intervening years, however, Wellcome had promoted the drug heavily, with advertising and sales visits to doctors. These advocated its use not just for people with gout, but also for those with only raised uric acid levels - so called “asymptomatic hyperuricaemia”. In the same way that the company was later to argue that AZT should be used to prevent Aids developing in HIV-positive people, rather than merely for treating the sick, allopurinol was prescribed to the much greater patient numbers who were only predisposed to gout.

"Remember Zyloprim the original (allopurinol)," was one popular advertising campaign for doctors, which kept the complexities to mandatory small-print. Another - which ran at the front of the Journal of Rheumatology continuously between 1974 and 1986 - declared bluntly: "In hyperuricaemia or chronic gouty arthritis, Zyloprim."

Although such ads may have been technically accurate, the increased consumption that they encouraged inevitably raised the numbers exposed to side-effects. While most patients handled allopurinol well, studies showed that about 2% experienced adverse events, with one hospital survey finding that, of every 260 patients treated, one had a life-threatening reaction.

Other research showed that most of those who suffered or died, should not have been taking the drug in the first place. "The vast majority of patients, both in our series (7 of 8), and reported in the literature (51 of 59), who developed allopurinol hypersensitivity, did not have proper indications for receiving the drug," reported researchers in the journal Arthritis and Rheumatism. "Serious and often fatal allopurinol hypersensitivity is a high price to pay for inappropriate therapy."

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This report is copyright, Brian Deer. Responses, information and other feedback concerning this resource on Henry Wellcome, the Wellcome Trust and the Wellcome Foundation are appreciated - via the briandeer.com homepage.