• Aggressive lowering of cholesterol is safe and beneficial
• Increase in sudden cardiac death rate reported
• No link between coronary disease and raised homocysteine levels?
• Novel anti-obesity drugs in development do not act on CNS
• Change to dose schedule may reduce drug toxicity
• Use combination preparations for TB to limit resistance
• Patients might need to try several triptans, doctors say
• Success for pharmacist-led diabetes clinic
• NICE rosiglitazone guidance criticised

News in brief

Aggressive lowering of cholesterol is safe and beneficial

Aggressive lipid lowering is indicated, beneficial and safe in patients with familial hypercholesterolaemia (FH), researchers say.

Dr T. Smilde (department of medicine, university medical centre, Nijmegen, Netherlands) and colleagues conducted a randomised, double-blind trial to investigate whether aggressive low density lipoprotein (LDL)-cholesterol lowering would slow atherosclerosis progression compared with standard treatment. Disease progression was measured by atherosclerotic changes in carotid intima media thickness (IMT), which has been used to predict coronary artery disease, they say. Trial participants were men and women aged between 30 and 70 years with FH. Patients received either aggressive therapy with atorvastatin 80mg daily (160 patients) or simvastatin 40mg daily (165 patients).

After two years, mean IMT had decreased in the atorvastatin group (from 0.93mm to 0.89mm) but increased in the simvastatin group (from 0.92mm to 0.96mm). Regression of carotid IMT was seen in 66 per cent and 42 per cent of the atorvastatin and simvastatin groups, respectively.

In addition, greater reductions in LDL-cholesterol levels were seen in the atorvastatin group compared with the simvastatin group (51 per cent versus 41 per cent). High density lipoprotein (HDL)-cholesterol levels were increased in both groups by similar amounts but a greater reduction of triglyceride levels was seen in the atorvastatin group. Both drugs were equally well tolerated, the researchers say.

They comment that progression of IMT in the simvastatin group was slower than expected, but that the more aggressive lipid lowering with atorvastatin "actually reversed the process of IMT". They expect that the difference in IMT changes between the two groups will be relevant to the reduction of future cardiovascular events. But they note that results from trials investigating the effect of aggressive lipid lowering on cardiovascular events and death will not be available for three to five years. However, the researchers believe that their findings on IMT will have implications for clinical practice (Lancet 2001;357:577).

In an accompanying leading article, Dr Paul Durrington (University of Manchester clinical research division) comments that "the lower the better rule" for LDL levels should be applied wherever possible in the management of patients with FH. For many such patients there was a need for new adjunctive therapies to produce lower LDL concentrations than were currently attainable with statins alone. He adds that many patients with FH are either untreated or inappropriately treated because their risk of coronary heart disease has been wrongly assessed (ibid, p574).

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Increase in sudden cardiac death rate reported

The number of young people dying from sudden cardiac death has increased in the past decade, American data show.

Researchers from the Centres for Disease Control and Prevention, Atlanta, report a 10 per cent increase in yearly death totals from sudden cardiac death from 2,719 in 1989 to 3,000 in 1996. Overall, the rate of sudden cardiac death was twice as high among men than women but the largest increase in death rate was seen in young women. The researchers suggest that the trend may be related to an increase in the prevalence of cardiovascular risk factors among adolescents. They add that the study highlights the need for young people to adopt healthy lifestyles, such as taking adequate physical activity and developing healthy eating habits.

The research was presented at the American Heart Association's 41st annual conference on cardiovascular disease epidemiology and prevention on March 1.

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No link between coronary disease and raised homocysteine levels?

Raised homocysteine concentrations do not provide a strong independent risk factor for coronary disease, researchers say.

Dr Una Fallon (University of Bristol) and colleagues report that a 10-year follow up of 2,290 men revealed only a small and non-significant association between increasing homocysteine concentration and coronary heart disease. They conclude that since initial excitement over homocysteine concentration has already been tempered by a more realistic appraisal of its importance, public health policy makers should be wary of generalising early positive results.

The researchers add that only randomised controlled trials of folic acid supplementation will provide evidence as to whether interventions that lower homocysteine concentrations will prevent coronary heart disease (Heart 2001;85:153).

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Novel anti-obesity drugs in development do not act on CNS

Glaxo Smithkline is investigating novel approaches to treating obesity. The company has two drugs in early clinical development. One, SB418790, is an agonist at b₃ receptors and stimulates metabolism in fat cells. The other, GI181771, is a cholecystokinin-A agonist that decreases appetite.

At a media briefing on February 22, at which GSK outlined its research strategy (see p276), Dr Jean-Pierre Garnier (chief executive) said that the two drugs were exciting in that, unlike current anti-obesity drugs, they did not act on the central nervous system and they did not have the gastrointestinal side effects of fat absorption reducers.

GSK currently has 117 new chemical entities, vaccines and line-extensions in clinical studies. Many of the new drugs involve novel targets. Dr Garnier said that other "promising" compounds in early stage development included a tachykinin (NK₃) receptor antagonist being investigated for both urinary incontinence and chronic obstructive pulmonary disease (COPD), and an osteoclast vitronectin antagonist designed to prevent bone loss in osteoporosis and rheumatoid arthritis.

Among drugs in phase II studies that GSK has licensed in from other companies are an endotoxin binder for sepsis, and an oral anti-inflammatory drug — a dual a₄ integrin antagonist — which is said to have potential activity in a range of conditions, including asthma, rheumatoid arthritis and multiple sclerosis.

Nearer to market, developments with existing products include a sustained-release formulation of Augmentin with increased amoxicillin concentration, and nabu-metone Q, a microparticulate formulation which is claimed to produce rapid onset of pain relief. There are also plans to market the 5-HT₁ agonist naratriptan for menstrual migraine prophylaxis.

Other new compounds in phase III studies are tranilast (an endothelial cell proliferation/migration inhibitor) for preventing restenosis after coronary revascularisation, and gemifloxacin (Factive), a broad spectrum quinolone antibiotic. GSK recently had its licence application for oral Factive turned down in the United States but the company says that it is hopeful that the issues raised by the Food and Drug Administration will be resolved.

Last December, Glaxo Wellcome launched the protease inhibitor amprenavir (Agenerase) in the United Kingdom for treatment of HIV infection. Its use is limited by gastrointestinal side effects and the number of capsules that have to be taken. GSK now has an amprenavir prodrug in phase III trials and says that early signs are that it produces less nausea and diarrhoea and will allow a reduction in "pill burden" from 16 to six a day. Licence applications are expected to be made in 2002.

In the respiratory field, GSK says that its "strategy for unlocking the COPD market" includes gaining COPD indications for Seretide and regulatory approval for its phosphodiesterase-4 inhibitor, cilomilast (Ariflo). Licence applications for the extension of Seretide's use are scheduled to be made in September. Ariflo, an oral anti-inflammatory drug, is in phase III trials.

At the press briefing, GSK's chairman of research and development (Dr Tadataka Yamada) described cardiovascular disease as "one of the few areas where we are not a top player". But the company had cardiovascular drugs in the pipeline, including an inhibitor of lipoprotein-associated phospholipase A₂ (Lp-PLA₂) for treating atherosclerosis. Lp-PLA2 enzyme had been reported to be an independent risk factor for coronary heart disease, he said.

Asked about alosetron (Lotronex), GSK's drug for irritable bowel syndrome, Dr Yamada said that the company was discussing how to resolve the safety issues. Alosetron was forecast to be a major drug for the company but last December it was withdrawn in the US, the only country in which it was marketed, at the request of the FDA after reports of serious complications of constipation and ischaemic colitis.
— Contributed.

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Change to dose schedule may reduce drug toxicity

Repeated administration of interferon_a to mice disturbs their body clock's ability to be cued by light, which might explain some of the drug's toxic effects, say researchers from Japan. Changing the dosing schedule minimises this disturbance, they add.

Dr Shigehiro Ohdo (division of pharmaceutical sciences, Kyushu university) and colleagues investigated the effects of interferon_a on circadian rhythms in mice and found that repeated administration had a disruptive effect on the 24-hour rhythms of locomotor activity, body temperature and expression of clock-gene mRNA in the periphery and suprachiasmatic nuclei (Nature Medicine 2001;7:356).

They say: "Attention should be paid to the alteration of clock-gene expression, and it should be considered an adverse effect when it leads to altered regulation of the circadian systems. . . . One approach to increasing the efficiency of pharmacotherapy is administering drugs at times during which they are best tolerated."

Dr Maxwell Summerhayes (principal oncology pharmacist, Guy's and St Thomas's hospital, London) told The Journal on February 27 that there was evidence to suggest that certain drugs did affect circadian rhythms but there was a lack of large-scale phase III studies to support the theory.

In most cases, giving drugs in a set circadian pattern had not been adopted as standard practice because it was too difficult, although new portable infusion pumps could now make it possible, he said.

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Use combination preparations for TB to limit resistance

The spread of drug-resistant tuberculosis can be limited by the use of combination preparations of drugs, according to the World Health Organisation (WHO).

A team of experts says that combination products, containing up to four different anti-tuberculosis drugs, can simplify prescribing and supply, reduce the number of tablets that patients have to take, and improve compliance. Use of these preparations was first proposed by the WHO in the mid-1990s but not all countries adopted the practice because single drugs were cheaper, they say.

They comment: "In view of the enormous costs and difficulties in treating drug-resistant tuberculosis, the highest priority must be given to preventing the emergence of drug resistance in the first place."
The article is available on the World Health Organisation website (www.who.int/bulletin).

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Patients might need to try several triptans, doctors say

The use of triptans in migraine must be tailored to the individual patient, according to Dr Andrew Dowson (director, King's Headache Service, London).

Response to these drugs varied from patient to patient and if one drug in the group did not work, another should be tried. Some of his patients had tried four different triptans before finding one that worked. There was, as yet, no way of predicting which patient might respond best to which drug.

Dr Dowson was speaking on February 21 at the launch of Lundbeck's new triptan, almotriptan (Almogran) (PJ, February 10, p198). He said that almotriptan should be a useful addition to the group. He reported a clinical trial (unpublished) which had found almotriptan to have efficacy comparable to sumatriptan 100mg — the "gold standard" — and better tolerability.

Dr Giles Elrington (consultant neurologist, Oaks hospital, Colchester) said that about 50 per cent of patients did not respond to simple oral analgesics, the recommended first-line treatment for acute migraine. For these patients, he would move straight to a triptan. (He advised against analgesic combinations containing caffeine or codeine, as they tended to cause rebound headache.) Referring to the individual response to treatment, Dr Elrington said: "Patients must be encouraged to go back to the doctor if their prescribed drug does not work. They should not abandon treatment."

Mrs Ann Turner (director, Migraine Action Association) commented that the introduction of the triptans had made a huge difference to patients with migraine. But the drugs were not widely used. In a recent postal survey of 10,000 patients with self-reported migraine, only 23 per cent had tried a triptan. There were anecdotal reports of GPs refusing to prescribe a triptan, or limiting the number of tablets patients could have.

For the future, Dr Dowson said that he thought over-the-counter triptans would be useful but he did not expect any to be classified as pharmacy medicines for at least five years. Although it did now appear that the chest and throat tightness reported with triptans was not related to the cardiovascular system, more safety data were needed before they could be sold over the counter.

The net price of almotriptan is £29.25 for nine tablets. Lundbeck says that a typical primary care group could potentially save around £29,000 a year by prescribing this drug in preference to existing triptans.
— Contributed.

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Success for pharmacist-led diabetes clinic

A pharmacist-led diabetes clinic has improved glycaemic control and reduced glycosylated haemoglobin (HbA_lc) levels in all attending patients with type 2 diabetes.

Dr Labib Tadros (clinical lead pharmacist, South Durham health care trust) told The Journal on February 27, that the clinic at Darlington Memorial hospital had been a success and that there were plans to expand it to other parts of the trust.

Since the clinic started in June, 2000, glycaemic control had improved and HbA_lc levels had been reduced by at least 50 per cent in all patients referred. In addition, all patients had become normotensive, thus potentially reducing the risk of developing long-term secondary complications of diabetes. Dr Tadros said that, eventually, all patients with type 2 diabetes who were seen by the consultant endocrinologist would be referred to the clinic.

In a press release issued on February 21, Dr Tadros said that the clinic had been set up to evaluate the impact of a clinical pharmacist providing direct patient care on the glycaemic control of patients with type 2 diabetes. A total of 50 patients with HbA_lc levels higher than 8 per cent who were already receiving oral hypoglycaemic drugs and who suffered hypertension with one or more secondary complications, were referred to the pharmacist. Patients visited the clinic every three weeks for blood pressure testing and a full urine analysis. Fasting plasma glucose levels and HbA_lc concentrations were recorded every three months. The press release highlighted the pharmacist's responsibilities, which include evaluation of current hypoglycaemic and adjunctive therapy, medication management and dosage adjustment, patient education, and training on self-monitoring of blood glucose and recognition and treatment of hyperglycaemia.

He concluded: "Pharmacists working as members of multidisciplinary care teams can positively impact glycaemic control in patients with type 2 diabetes."

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NICE rosiglitazone guidance criticised

National Institute for Clinical Excellence (NICE) guidance on the use of rosiglitazone for type 2 diabetes has been criticised in a letter published in the British Medical Journal. Dr Stephen Robinson (consultant physician, St Mary's hospital, London) says that the guidance suggests using rosiglitazone later than he believes it ideally should be (2001;322:491).

Paragraph 1.2 of the guidance states that patients with inadequate blood glucose control on oral monotherapy (metformin or sulphonylurea) should be prescribed metformin and sulphonylurea combination therapy before being given rosiglitazone, unless there are contraindications or tolerability problems. The authors of the letter comment: "The prescription of rosiglitazone at a late stage of type 2 diabetes mellitus means that it will be used for a relatively short period, if at all, before insulin is required."

Mrs Irene Gummerson (a pharmacist on three national diabetes committees) told The Journal on February 28 that the NICE recommendations were more restrictive than the licensed indications for rosiglitazone. "In practice, there is very little difference, as the licence effectively restricts use of rosiglitazone to people who cannot take the metformin/sulphonylurea combination. . . . The important point is that the NICE has approved rosiglitazone, and this has given people with type 2 diabetes another treatment option."

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News in brief

Family heart disease study

The British Heart Foundation is undertaking a family heart study to identify genes that contribute to coronary heart disease. It hopes that this will allow the development of new strategies to prevent and treat heart disease.

The foundation aims to recruit 2,000 families with members who have experienced heart disease below the age of 65. People can obtain details of the project by telephoning 0800 052 7154.

Guidelines recommend aspirin/ dipyridamole combination

The combination of aspirin and modified-release dipyridamole (Asasantin Retard) is more effective than aspirin alone for reducing risk of secondary stroke or transient ischaemic attack (TIA), according to new guidance.

A consensus statement issued by the American College of Chest Physicians says that the combination treatment might also be more effective than clopidogrel for the same indications. However, it recommends that aspirin, clopidogrel and aspirin/modified-release dipyridamole are all acceptable options for initial therapy after stroke or TIA (Chest 2001;119:300S).

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