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The Pharmaceutical Journal Vol 266 No 7149 p705-708
May 26, 2001

Clinical Pharmacy News summary

Trial supports use of amfebutamone in long-term smokers with COPD Amfebutamone (bupropion, Zyban) nearly doubles the rate of abstinence from smoking in people with chronic obstructive pulmonary disease (COPD) compared with placebo, American researchers have found...[more]

New anti-obesity drug launched Sibutramine (Reductil), an anti-obesity drug, has been launched by Knoll in the United Kingdom this week...[more]

Antithrombolytic injection launched An injectable antithrombolytic agent, tenecteplase (Metalyse), was launched this week by Boehringer Ingelheim. The drug is licensed for the treatment of suspected acute myocardial infarction within six hours after the onset of symptoms...[more]

DTB gives advice on lowering blood pressure in certain patient groups The aim of managing patients with hypertension should be to lower absolute coronary heart disease risk, as well as lowering blood pressure, according to the May issue of the Drug and Therapeutics Bulletin ...[more]

Interferon beta could help patients with early signs of multiple sclerosis A new study has suggested that giving interferon beta-1a (Rebif) to patients with early signs of multiple sclerosis (MS) could lower the proportion who go on to develop a definite diagnosis. However, the significance of the results has been questioned...[more]

US guideline on cholesterol An update of a United States guideline for the management of cholesterol has been published...[more]

Information about minor illnesses does not reduce consultations Sending information about minor illnesses to the public can increase their confidence in managing illness but it is unlikely to reduce demand for health services...[more]

New data on IBS drug New data on tegaserod have confirmed its efficacy in treating irritable bowel syndrome (IBS)...[more]

Alternative therapies could save money Using alternative therapies for patients with chronic musculoskeletal disorders or anxiety could reduce prescribing costs, according to a researcher from the Tavistock Institute in London...[more]

Inhaled insulin likely to be submitted for regulatory approval later this year A dry-powder formulation of insulin for inhalation into the lungs is in the late stages of development by Aventis Pharma. The new formulation, Exubera, is targeted at patients with type 1 or type 2 diabetes...[more]

Further positive results for IC351 The phosphodiesterase-5 inhibitor IC351 could give men with erectile dysfunction the ability to achieve improved erections up to 24 hours after the drug first takes effect, new data suggests...[more]

Antioxidants could prevent HIV-related cognitive difficulties Antioxidant drugs may help prevent dementia caused by the human immunodeficiency virus (HIV), according to a study presented at the 53rd annual American Academy of Neurology meeting in Philadelphia this month...[more]

Mucolytic drugs beneficial in COPD The treatment of chronic bronchitis and chronic obstructive pulmonary disease with oral mucolytic drugs is associated with a reduction in both acute exacerbations and the number of days of illness, according to Dr Phillippa Poole and Professor Peter Black, University of Auckland, New Zealand. However, they add that the reductions are modest and treatment might not be cost effective...[more]

Clinical news in brief

Is esomeprazole better than other PPIs? Esomeprazole suppresses acid more effectively than other proton pump inhibitors, according to data presented at the Digestive Diseases Week meeting held this week in the United States. Dr Clive Wilder-Smith of the University of Berne, Switzerland, reviewed four separate studies of PPIs. He found that esomeprazole (40mg once daily) maintained intragastric pH above four in patients with gastro-oesophageal reflux disease for an additional six hours compared with omeprazole (20mg once daily), and an additional three hours compared with lansoprazole (30mg once daily) in healthy volunteers.

Pegylated interferon adds benefit for hepatitis C Patients with chronic hepatitis C who receive a combination of a pegylated interferon (PEG-IFN alfa-2a, Pegasys) and ribavirin have a higher response rate than with standard interferon alfa plus ribavirin, according to data presented during Digestive Diseases Week in the United States this week. The data also suggests that responders to the PEG-IFN alfa-2a combination can be identified earlier than is possible with the current standard treatment (12 weeks compared with 24 weeks or more).

Gene for Crohn's disease found A gene for Crohn's disease has been found by two groups of scientists working independently in America and in France. The gene, which encodes a protein called Nod2, is mutated in a subset of patients with Crohn's disease. It occurs on chromsosome 16, which has previously been implicated in the disease. The work will be published in Nature on May 31.

Atorvastatin lowers C-reactive protein The lipid-lowering agent atorvastatin (Lipitor) reduces levels of C-reactive protein (CRP) in patients with diabetic or mixed dyslipidaemia. Results from the DALI (diabetes atorvastatin lipid intervention) study, presented this week at the European Atherosclerosis Society meeting in Glasgow, showed a dose-dependent reduction in CRP in patients with type 2 diabetes who were treated with atorvastatin. The second study, known as ATOMIX (atorvastatin in mixed dyslipidemia), showed a reduction in CRP levels with atorvastatin but not bezafibrate, another lipid-lowering agent, in patients with mixed dyslipidemia.

Trial supports use of amfebutamone in long-term smokers with COPD

Amfebutamone (bupropion, Zyban) nearly doubles the rate of abstinence from smoking in people with chronic obstructive pulmonary disease (COPD) compared with placebo, American researchers have found.

Amfebutamone is known to be effective at increasing cessation rates, but no data exist on its use in patients with COPD. Now Dr Don Tashkin, division of pulmonary and critical care medicine, University of California school of medicine, Los Angeles, and colleagues have found that the drug is effective and well-tolerated in people with mild to moderate COPD. They investigated the effect of amfebutamone in 404 patients aged over 35 years with COPD. All patients were chronic smokers. They had smoked a mean number of 28 cigarettes per day during the previous year and were motivated to stop smoking.

Patients were randomly assigned amfebutamone 150mg twice daily for 12 weeks or placebo (with a three-day run-in on half the dose). [Amfebutamone is recommended for a maximum treatment period of nine weeks.] Study medication started a week before the patient's earliest quit date. All patients also received cessation counselling. Rates of continuous abstinence were significantly better for patients taking amfebutamone compared with those on placebo in weeks four to seven (28 per cent and 16 per cent, respectively, P=0.003) and weeks eight to 12 (22 per cent and 12 per cent, respectively, P=0.011). Rates were also higher in the amfebutamone group after 26 weeks.

Adverse events occurred in 30 per cent of patients receiving placebo and 44 per cent on amfebutamone. The most common events were insomnia, headache and dry mouth. Medication was discontinued by 13 people on placebo and 14 on amfebutamone, most commonly as a result of anxiety and insomnia in the amfebutamone group.

“The favourable safety profile and beneficial effects on withdrawal and craving symptoms suggest that amfebutamone is a useful medication for smoking cessation in patients with COPD,” the authors conclude. They comment that smoking leads to COPD in more than 80 per cent of cases, and stopping smoking reduces the decline in pulmonary function (Lancet 2001;357:1571).

In an accompanying leading article, researchers from the Monash Institute of Health Services Research, Melbourne, Australia, say that the real questions that remain unanswered are what is the true relative effectiveness of amfebutamone compared with nicotine replacement therapy, and what is the rate of serious side effects outside of strict trial conditions. They also ask what level of supportive counselling is required to ensure the effectiveness of the drug (ibid, p1550).

This week, Anthony Cox, adverse drug reaction pharmacist at the West Midlands Centre for Adverse Drug Reaction Reporting, City Hospital NHS Trust, Birmingham, and colleagues have written to The Journal (see p721) with a full list of potential drug interactions with amfebutamone following recent publicity over the drug's safety (PJ, May 5, p611).

New anti-obesity drug launched

Sibutramine (Reductil), an anti-obesity drug, has been launched by Knoll in the United Kingdom this week. Studies have shown that the drug is useful for maintaining weight loss when prescribed in conjunction with a calorie-controlled diet (see PJ, January 6, p8).

Sibutramine is licensed for use within a weight management programme for obese patients (with a body mass index of 30kg/m² or higher) or for overweight patients (with a body mass index of 27kg/m² or higher), if other obesity-related risk factors, such as type 2 diabetes or dyslipidaemia, are present. It should only be prescribed to patients who have not responded adequately to a weight-reducing regimen alone. The initial dose of sibutramine is 10mg taken once daily, with or without food (details of sibutramine's summary of product characteristics will be given in next week's Journal).

Knoll says that patients prescribed sibutramine will be encouraged to use a patient support package (HELP programme) that provides education on healthy eating and physical activity, and that encourages permanent behaviour changes.

A spokeswoman for the The National Institute for Clinical Excellence told The Journal on May 23 that the NICE was to hold its initial appraisal committee meeting for sibutramine on June 27 and expected to issue guidance on the drug in November.

Antithrombolytic injection launched

An injectable antithrombolytic agent, tenecteplase (Metalyse), was launched this week by Boehringer Ingelheim. The drug is licensed for the treatment of suspected acute myocardial infarction within six hours after the onset of symptoms (see p731).

Tenecteplase should be administered as a single bolus intravenous injection over 10 seconds and the dose adjusted according to the patient's body weight. At a press briefing on May 21, Professor Allan Ross of George Washington University, United States, said that tenecteplase was the easiest and fastest fibrinolytic to administer. He also commented that the drug caused less major bleeding than alteplase.

The summary of product characteristics says that re-administration of tenecteplase is not currently recommended since there is no experience of this use. However, no antibody formation to tenecteplase has been observed.

DTB gives advice on lowering blood pressure in certain patient groups

The aim of managing patients with hypertension should be to lower absolute coronary heart disease risk, as well as lowering blood pressure, according to the May issue of the Drug and Therapeutics Bulletin (2001;39:37).

The bulletin discusses the use of antihypertensive drugs in groups of patients in which treatment can cause particular problems (eg, older people, patients with co-existing disease, patients from certain racial backgrounds and pregnant women). According to the bulletin, older patients gain greater benefit than younger patients from treatment of hypertension. It adds that the drug of first choice in older people should be a low-dose thiazide diuretic, such as bendrofluazide.

In patients with renal disease, the bulletin recommends that antihypertensive therapy should be aimed at lowering blood pressure to below 130/85mmHg. It suggests that an angiotensin converting enzyme (ACE) inhibitor might help to prevent deterioration of renal function, but warns that these drugs should be avoided if renal artery stenosis is present.

The bulletin recommends that treatment should reduce blood pressure to below 130/80mmHg in patients with type 1 diabetes and to below 140/80mmHg in patients with type 2 diabetes, where possible. It adds that two or more drugs are usually needed to control hypertension and that, in type 1 diabetes, one of these should probably be an ACE inhibitor. It notes that there is no clear first choice of antihypertensive drug for the treatment of type 2 diabetes.

The bulletin says that, as a group, African-Caribbean people are particularly responsive to monotherapy with either a diuretic or a calcium-channel blocker, but are relatively resistant to ACE inhibitors or beta-blockers. However, it adds that when a diuretic or calcium-channel blocker is used in combination with an ACE inhibitor or beta-blocker, treatment might be as effective as in the general population. For pregnant women with raised blood pressure, the bulletin says that methyldopa remains the drug of choice.

The May issue of The Drug and Therapeutics Bulletin also reviews acute complications of sickle cell disease in children (ibid, p33).

Interferon beta could help patients with early signs of multiple sclerosis

A new study has suggested that giving interferon beta-1a (Rebif) to patients with early signs of multiple sclerosis (MS) could lower the proportion who go on to develop a definite diagnosis. However, the significance of the results has been questioned.

Professor Giancarlo Comi from the department of neuroscience, St Raphael Hospital, Milan, Italy, and colleagues, assessed the effect of giving 22µg of interferon beta-1a weekly for two years to patients in the earliest detectable phase of the disease.

They say that the proportion of patients who went on to develop clinically definite MS (ie, a second exacerbation) was reduced, as was the frequency of relapses overall in the group given interferon beta-1a (Lancet 2001;357:1576).

In a commentary on the trial (ibid, p1547), Dr George Ebers from the department of clinical neurology at the Radcliffe Infirmary, Oxford, says that the study was stopped “far too soon” to answer the question definitively, and that the delay in time to second exacerbation was no greater than that seen in patients given methylprednisolone. “It remains to be proven whether interferons have any impact on the progression of the disease, apart from their effect on relapses,” he concludes.

US guideline on cholesterol

An update of a United States guideline for the management of cholesterol has been published in JAMA (2001;285:2486).

The guideline was produced by an expert panel of the US National Cholesterol Education Program and updates the existing recommendations for lipid lowering therapy in certain groups of people. It focuses on primary prevention of coronary heart disease in people with multiple risk factors. The guideline, which is the third in a series of recommendations drawn up by the expert panel for the clinical management of high blood cholesterol, is available on the US National Heart, Lung, and Blood Institute website (www.nhlbi.nih.gov).

Information about minor illnesses does not reduce consultations

Sending information about minor illnesses to the public can increase their confidence in managing illness but it is unlikely to reduce demand for health services, researchers have shown. The findings come from two controlled trials, in which patients were randomised either to receive or not to receive a patient information booklet on managing minor illnesses (BMJ 2001;322: 1214 and 1218).

The first study, which involved patients from six general practices in southern England, was conducted by Dr Paul Little of the Aldermoor Health Centre in Southampton, and colleagues. They found that of 551 patients who received an information booklet, 178 reported feeling more confident about managing minor illnesses compared with 42 out of 338 patients who were not given a booklet. Those who received a booklet also attended their general practice less commonly with minor illnesses than the control group, but the overall effect was not significant. “This raises important questions about whether such booklets provide sufficient benefit to justify the use of National Health Service funds,” they conclude.

The second study, led by Dr David Heaney of the department of community health sciences at the University of Edinburgh, Scotland, looked at the impact of sending patients in 20 general practices in Lothian information booklets on the management and treatment of minor illnesses. They found that receipt of a booklet had no significant effect on health service use compared with a control group who did not receive a book. This included consultations for minor illness. They conclude that more sophisticated interventions are required to reduce demand for general practice services.

New data on IBS drug

New data on tegaserod have confirmed its efficacy in treating irritable bowel syndrome (IBS). Tegaserod (Zelmac), manufactured by Novartis, is a 5HT₄ partial agonist that stimulates motility and modulates visceral sensitivity. It is being developed for treatment of IBS in women where constipation is the predominant symptom.

At the Digestive Disease Week conference in Atlanta this week, Novartis researchers reported a multicentre, placebo-controlled study in 1,519 female patients. The main efficacy measurement was patients' global assessment of relief, encompassing abdominal pain, bowel function and overall well-being. Significant improvement was reported, with benefit shown in the first week. This was maintained during the 12-week study period. Symptoms returned when treatment was withdrawn.

Discontinuation because of adverse events occurred in 6.4 per cent of patients given tegaserod and 4.7 per cent of those given placebo. Adverse events caused by tegaserod included diarrhoea and headache.

Another paper reported an assessment of whether early response to tegaserod predicts continued efficacy. Data on 3,199 patients, from three phase III trials, showed that around 75 per cent of responders at month one remained responders at 16 weeks. Only 25 per cent of non-responders at month one had become responders at week 16.

Novartis has assessed the cardiac safety of tegaserod because of cardiovascular problems associated with cisapride, another gastrointestinal motility stimulating agent with actions on 5HT receptors. The company report that analysis of electrocardiogram data from over 2,500 patients found no difference between tegaserod and placebo in terms of QT interval prolongation or overall ECG abnormalities.

Tegaserod will be marketed by Novartis and Bristol-Myers Squibb. The companies are hoping to receive a product licence in the United Kingdom later this year.

Meanwhile, it has been suggested that GlaxoSmithKline's drug alosetron (Lotronex) might be re-introduced with restricted use (The Lancet 2001;357:1544). Alosetron, a 5HT₃ antagonist for treatment of diarrhoea-predominant IBS, was withdrawn in the US, its only market, last year after reports of serious adverse reactions. GSK confirmed on May 22 that it was in discussion with the United States Food and Drug Administration about a possible re-introduction of alosetron but no decisions had been made. Plans for European marketing of the drug were on hold.
— Contributed.

Alternative therapies could save money

Using alternative therapies for patients with chronic musculoskeletal disorders or anxiety could reduce prescribing costs, according to a researcher from the Tavistock Institute in London.

Dr Dione Hills, a senior researcher from the institute, described a study that she undertook at a practice in Glastonbury, at the regional scientific meeting of the United Kingdom Drug Utilisation Group in Birmingham on May 18.

She found that the costs of treating patients with alternative therapies seemed to be balanced by the savings made by a reduction in orders for, among other things, X-rays and physiotherapy.

She said: “There was a marked reduction in both the number of visits to the general practitioner and in the number of prescriptions issued for that particular condition over the next year.”

The practice gained funding from its health authority for a three-year study to assess the impact on prescribing costs of three hours of treatment with alternative therapies per patient.

Four patients with chronic psychosocial problems, such as anxiety, and 14 with chronic musculoskeletal disorders were referred for alternative therapy — most received either acupuncture or osteopathy.

After treatment, 26 per cent of the patients thought that they were a great deal better, 62 per cent that they had experienced some improvement, 10 per cent that they were the same, and 3 per cent that they were worse.

When the therapists who had treated the patients assessed them, they said that 28 per cent were much improved, 58 per cent showed some improvement, 11 per cent were the same and 4 per cent were worse.

“We need to look at the mechanisms that make these medicines work because it is unclear whether it is the therapy or the extra time that therapists can spend with patients advising them on things like lifestyle that makes the difference,” Dr Hills said.

Inhaled insulin likely to be submitted for regulatory approval later this year

A dry-powder formulation of insulin for inhalation into the lungs is in the late stages of development by Aventis Pharma. The new formulation, Exubera, is targeted at patients with type 1 or type 2 diabetes.

Speaking at the Aventis Pharma research and development day in London last week, Professor Sol Rajfer, head of product realisation at Aventis Pharma AG, said that the company had entered into agreements with Pfizer to co-develop, co-market and co-manufacture the drug and planned to submit it for regulatory approval in both the European Union and the United States later this year. He said that clinical studies had shown that Exubera was easy to use and had high patient satisfaction.

Aventis Pharma currently has more than 30 projects moving through clinical development and among its range of antidiabetic agents is Lantus (insulin glargine), a recombinant basal human insulin analogue, which was launched in the US this week and in Germany last year. Professor Rajfer said that Lantus had a relatively constant glucose-lowering profile over 24 hours. It also provided effective glycaemic control with once daily dosing.

Two further antidiabetic agents in late stage development highlighted at the meeting include 1964, a fast-acting insulin anologue for the treatment of hyperglycaemia in type 1 and 2 diabetes and dexlipotam, an oral antihyperglycaemic agent for the treatment of type 2 diabetes. Dexlipotam has been added to the Aventis portfolio through a licensing agreement, and is being co-developed with ASTA Medica. It is currently in phase II development and has been shown to improve nerve function in diabetic rats. EU and US submissions are planned for 2004 or 2005.

Other developments close to launch include telithromycin (Ketek), the first agent in a new class of antibiotics know as ketolides. Aventis Pharma is currently awaiting EU and US approval. Telithromycin exhibits a potent bacterial activity against Streptococcus pneumoniae and is active against penicillin and macrolide resistant strains. It is effective in the treatment of respiratory tract infections such as community-acquired pneumonia, acute exacerbation of chronic bronchitis, acute sinusitis and tonsillitis or pharyngitis.

Among the new compounds in early stages of development announced at the meeting is the anti-obesity agent 1426. Professor Claude Benedict, head of lead optimisation at Aventis Pharma AG, said that 1426 had a peripheral mode of action resulting in delayed gastric emptying and had no central nervous system effects. Its appetite suppressant effects were evident in patients after only a few days of treatment. He said that the agent was well tolerated and was moving into phase IIa trials.

A number of new antineoplastic agents are also in development. LIT-976, a new formulation of docetaxel (taxotere) with an improved safety profile is on target to enter phase I trials in patients with metastatic breast cancer and non-small-cell lung cancer by the end of this year. Taxoid 109881, another antineoplastic agent, is currently in phase II trials and has demonstrated clinical activity in patients with brain metastases. Aventis said that taxoid 109881 crosses the blood brain barrier and targets and kills taxoid-resistant tumours. It is being evaluated for oral administration.

Cancer vaccines for preventing metastatic cancers have completed phase I trials. The vaccines work by using antigens which are specific for targeting tumour cells. They are designed to elicit an immune response without toxicity.

Aventis is also in the process of developing human immuno-deficiency virus (HIV) vaccines. A prophylactic vaccine and a vaccine for treating the virus are in development and the company expects first results next year.

Further positive results for IC351

The phosphodiesterase-5 inhibitor IC351 could give men with erectile dysfunction the ability to achieve improved erections up to 24 hours after the drug first takes effect, new data suggests. The results follow those of another recent trial which found that IC351 improved erections in 64 per cent of men with diabetes-related erectile dysfunction (PJ, April 28, p569).

In the first of two trials to assess erectile responsiveness over 24 hours, led by Dr Padma-Nathan, professor of urology at the University of Southern California School of Medicine, United States, 61 men with mild to severe erectile dysfunction were randomised to receive placebo or IC351 10mg, in a clinical setting. The researchers found that men in the IC351 group were more successful in achieving erections, using visual sexual stimulation, than those in the placebo group. The majority of men being given the drug were still able achieve an erection 24 hours later.

In the second, home-based trial, 223 men were assigned to receive either placebo or up to 20mg IC351. The researchers say that the average time to erection in the IC351 group was 20 minutes and those in this group had more success at second sexual encounters up to 24 hours after dosing, than those in the placebo group.

In a press release issued recently by Eli Lilly and company, Dr Padma-Nathan added that the side effects, including headache, were consistent with previous studies of the drug.

Antioxidants could prevent HIV-related cognitive difficulties

Antioxidant drugs may help prevent dementia caused by the human immunodeficiency virus (HIV), according to a study presented at the 53rd annual American Academy of Neurology meeting in Philadelphia this month.

The researchers say that HIV affects healthy brain cell mitochondria and that damage can cause problems such as cognitive difficulties and weakness.

Dr Avindra Nath, University of Kentucky, and colleagues tested seven antioxidant drugs on cell cultures of healthy brain cells with cerebrospinal fluid from 30 patients with HIV-related dementia.

In a press release issued recently, Dr Nath said that six of the drugs reversed the effects of toxicity caused by the cerebro-spinal fluid. However, further studies were required to determine their effectiveness in practice.

Mucolytic drugs beneficial in COPD

The treatment of chronic bronchitis and chronic obstructive pulmonary disease with oral mucolytic drugs is associated with a reduction in both acute exacerbations and the number of days of illness, according to Dr Phillippa Poole and Professor Peter Black, University of Auckland, New Zealand. However, they add that the reductions are modest and treatment might not be cost effective.

Dr Poole and Professor Black reviewed 23 randomised, controlled trials involving outpatients in Europe and the United States. They found that regular use of mucolytics resulted in an odds ratio for having no exacerbation in the study period of 2.22 (95 per cent confidence interval 1.93 to 2.54, P<0.0001). Days of illness per subject per month were reduced by 0.56 days (-0.77 to �0.35, P<0.0001).

They conclude that because oral mucolytic drugs have to be taken long-term, they could be most useful in patients who have repeated, prolonged, or severe exacerbations of COPD. The study is published in the BMJ (2001;322:1271).