Clinical Pharmacy News summary

Study confirms that salmeterol should not be used alone to treat asthma Salmeterol, a long-acting beta₂-agonist, should not be used as monotherapy to treat persistent asthma, the results of an American study confirm...[more]

New long-acting anticholinergic for chronic obstructive pulmonary disease A long-acting anticholinergic agent, tiotropium, is expected to become available early next year and will be the first once-daily, inhaled bronchodilator for patients with chronic obstructive pulmonary disease (COPD)...[more]

No differences in kidney effects seen with NSAIDs A study comparing the effects of the cyclo-oxygenase-2 (Cox-2) inhibitors rofecoxib (Vioxx), celecoxib (Celebrex) and of naproxen on sodium excretion, daily blood pressure and creatinine clearance has shown no significant differences among the three non-steroidal anti-inflammatory drugs...[more]

Review finds little evidence for beneficial placebo effects A review of clinical trials has found little evidence to support placebo treatments as being of benefit to patients. However, small beneficial effects of using placebos were identified in studies for the treatment of pain...[more]

Carvedilol benefits similar for black and non-black patients Carvedilol reduces mortality and the rate of hospital admission rates to a similar extent in black and non-black patients with heart failure, an American study has shown. It also improves cardiac function and lessens symptoms to a similar degree in both groups...[more]

CML drug to be launched in the UK by early next year Imatinib mesylate, an anticancer drug being developed by Novartis, has been granted accelerated approval by the United States Food and Drug Administration and is currently awaiting approval from the European Medicines Evaluation Agency...[more]

Study shows cholesterol absorption inhibitor is effective and safe Ezetimibe, the first in a new class of lipid-management drugs that inhibit cholesterol absorption, reduces low-density lipoprotein cholesterol and is well tolerated, according to the results of a phase III study...[more]

Parathyroid hormone reduces risk of osteoporosis-related spinal fractures Recombinant human parathyroid hormone (rhPTH 1-34), administered once daily, reduces the risk of osteoporosis-related spinal, as well as non-spinal, fractures in postmenopausal women, according to American researchers...[more]

Cancer cells used as treatment for metastasised malignant melanoma A “vaccine” made from a patient’s own cancer cells appears to prolong survival in patients with malignant melanoma that has spread to the lungs...[more]

Yeast vaccine to combat HIV A vaccine developed from yeast could be used to provide immunisation against infectious diseases such as the human immunodeficiency virus (HIV), researchers from the University of Colorado Health Science Centre suggest. It could also be used to induce cell-mediated immunity against different types of cancers...[more]

Anti-inflammatory effects of statins explained A mechanism for the anti-inflammatory properties of statins has been proposed in a paper published in Nature Medicine (2001;7:687). The mechanism appears to be unrelated to the cholesterol-lowering effects of statins, which are achieved by inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase...[more]

Study confirms that salmeterol should not be used alone to treat asthma

Salmeterol, a long-acting beta₂-agonist, should not be used as monotherapy to treat persistent asthma, the results of an American study confirm.

Dr Stephen Lazarus of the University of California, San Francisco, and colleagues conducted a randomised, controlled trial to test whether patients with persistent asthma that was well controlled by low-dose triamcinolone, an inhaled corticosteroid, could be switched to salmeterol monotherapy.

The study showed that salmeterol was highly effective at maintaining improvement in some conventional asthma outcome measures, such as peak expiratory flow (PEF), but was no more effective than placebo at preventing treatment failures and asthma exacerbations, or at suppressing airway inflammation.

Following a run-in period, in which patients received triamcinolone 400µg twice daily, 164 patients, who were stabilised on the inhaled corticosteroid, were randomised to continue triamcinolone therapy, or to switch to salmeterol (42µg twice daily) or placebo for 16 weeks. All patients then received placebo for an additional six-week run-out period.

Patients rated the severity of their asthma symptoms throughout the study and recorded daytime and night-time asthma symptom scores, as well as morning and evening PEF. Patients were evaluated in the clinic every two to four weeks.

Both active treatments were found to be superior to placebo in terms of morning and evening PEF readings, asthma symptom scores, reduced use of rescue treatment, and quality-of-life scores.

However, the researchers found that patients given salmeterol had more treatment failures than those who continued to receive triamcinolone (24 per cent compared with 6 per cent, P=0.004), as well as more asthma exacerbations (20 per cent compared with 7 per cent, P=0.04).

They also note that no evidence was found to suggest that the additional 16 weeks of triamcinolone treatment in patients who were not switched to salmeterol or placebo conferred a persistent benefit.

The researchers comment that use of long-acting beta₂-agonists as additive therapy in patients whose asthma is not controlled by inhaled corticosteroids is well supported by clinical trial results. However, they add that their use as monotherapy, which has begun to appear in clinical practice, is not supported.

They conclude that an inhaled corticosteroid is preferable to a long-acting bronchodilator as monotherapy in patients with persistent asthma. The study is published in JAMA (2001;285:2583).

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New long-acting anticholinergic for chronic obstructive pulmonary disease

A long-acting anticholinergic agent, tiotropium, is expected to become available early next year and will be the first once-daily, inhaled bronchodilator for patients with chronic obstructive pulmonary disease (COPD). New data, revealed at the American Thoracic Society meeting in San Francisco recently, showed that tiotropium was superior to placebo in improving patients’ forced expiratory volume in one second (FEV1) and their forced vital capacity (FVC), relieving dyspnoea and improving health-related quality of life.

In a study involving 599 men and 322 women, Dr I. Weisman and colleagues from the William Beaumont Centre, El Paso, Texas, United States, showed that tiotropium treatment produced a rise in trough (ie, before bronchodilator administration) FEV1 and FVC from baseline of around 11 per cent (+11.8 per cent in men and +10.7 per cent in women) after one year, compared with a deterioration of around 4 per cent (–3.7 per cent in men and –4.8 per cent in women) from baseline for placebo (P<0.001).

Commenting on the study, Professor Kenneth Chapman of the University of Toronto, Canada, said the results showed that treatment response was broadly similar in men and women. However, to date, women had tended to be misdiagnosed as being asthmatic more often than men and were less likely to be offered anticholinergic treatment. Improvements in the definition of COPD, greater use of spirometry, and two-week oral steroid trials would help more women get effective, COPD-specific treatment and reduce gender bias, he suggested.

Negative results of an oral steroid trial indicate a patient has COPD rather than asthma.

Tiotropium, currently in development by Boehringer Ingelheim, acts via continuous antagonism of the M₃ muscarinic receptor subtype. This constricts airway smooth muscle in response to acetylcholine stimulation via cholinergic nerve activity. Except in the 10 per cent of patients who suffer with both asthma and COPD, cholinergic tone is regarded as the only bronchoconstrictor pathway in COPD. Relaxation of smooth muscle and bronchodilation is therefore more likely to be achieved via anticholinergic activity.
— Contributed.

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No differences in kidney effects seen with NSAIDs

A study comparing the effects of the cyclo-oxygenase-2 (Cox-2) inhibitors rofecoxib (Vioxx), celecoxib (Celebrex) and of naproxen on sodium excretion, daily blood pressure and creatinine clearance has shown no significant differences among the three non-steroidal anti-inflammatory drugs.

Cox-2 inhibition is thought to be associated in some patients with changes in kidney function and increases in blood pressure.

Results from the randomised, controlled study were presented at the American Society of Hypertension in San Francisco, United States, recently. The study involved 67 healthy participants, aged between 60 and 80 years, who were randomised to receive rofecoxib 25mg daily, celecoxib 200mg twice daily, naproxen 500mg twice daily or placebo.

All three drugs reduced urinary sodium excretion over the first three days of the trial by a similar amount. There was no significant effect on the average change in creatinine clearance with all three drugs and the slight increases in blood pressure seen in patients given the active treatments were also similar.

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Review finds little evidence for beneficial placebo effects

A review of clinical trials has found little evidence to support placebo treatments as being of benefit to patients. However, small beneficial effects of using placebos were identified in studies for the treatment of pain.

Dr Asbjørn Hrobjartsson and Dr Peter Gøtzsche, University of Copenhagen, Denmark, conducted a systematic review of clinical trials, in which patients were randomly assigned to receive either placebo or no treatment. A placebo could be pharmacological (eg, a tablet), physical (eg, a manipluation) or psychological (eg, a conversation). The researchers included in the analysis 32 trials with binary outcomes (ie, a study where the outcome was measured as a proportion) and 82 with continuous outcomes (ie, a study where the outcome was measured as a mean number).

They found that, compared with no treatment, a placebo had no effect on binary outcomes, regardless of whether the outcomes were subjective or objective. However, in trials with continuous subjective outcomes and those involving the treatment of pain, a placebo did have a beneficial effect. The authors comment that the effect on continuous outcomes decreased with increasing sample size, indicating a possible bias related to the effects of small trials.

The researchers conclude: “The use of placebo outside the aegis of a controlled, properly designed clinical trial cannot be recommended.” The study is published in The New England Journal of Medicine (2001;
344:1594).

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Carvedilol benefits similar for black and non-black patients

Carvedilol reduces mortality and the rate of hospital admission rates to a similar extent in black and non-black patients with heart failure, an American study has shown. It also improves cardiac function and lessens symptoms to a similar degree in both groups.

Previous studies have suggested that black patients with heart failure might derive less benefit than non-blacks from using drugs such as beta-blockers and angiotensin-converting enzyme inhibitors, and black patients could even have a detrimental response to such drugs, the researchers say.

The study, led by Dr Clyde Yancy, University of Texas Southwestern Medical Centre, involved 217 black and 877 non-black patients who were randomly assigned to receive either placebo or carvedilol (6.25mg to 50mg twice daily) for up to 15 months.

The researchers say that long-term therapy with carvedilol was well tolerated by black patients, and worsening heart failure occurred with a similar frequency in both groups. They say that this result is surprising because black people are more likely than non-black people to have impaired renal blood flow and to retain sodium. Beta-blockers can cause worsening heart failure primarily by reducing renal blood flow and sodium excretion.

The authors comment that the fact that black patients were not at increased risk of heart failure could be related to the alpha-blocking actions of carvedilol (The New England Journal of Medicine 2001;344:1358).

The carvedilol postinfarct survival control in left ventricular dysfunction (CAPRICORN) study, which was presented at the 50th American College of Cardiology meeting in Florida in March (PJ, March 24, p382), has now been published in The Lancet 2001;357:1385).

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CML drug to be launched in the UK by early next year

Imatinib mesylate, an anticancer drug being developed by Novartis, has been granted accelerated approval by the United States Food and Drug Administration and is currently awaiting approval from the European Medicines Evaluation Agency.

The fast-track approval of the drug, which is to be marketed as Gleevec in the US (it is known as Glivec in the United Kingdom), follows positive clinical trial results for the treatment of chronic myeloid leukaemia (see PJ December 11, 1999, p937, and December 9, 2000, p849). Imatinib mesylate has also shown promise in the treatment of gastrointestinal stromal tumours.

A spokeswoman for Novartis UK told The Journal on May 30 that the company was hoping to launch imatinib mesylate in the UK at the end of this or the beginning of next year.

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Study shows cholesterol absorption inhibitor is effective and safe

Ezetimibe, the first in a new class of lipid-management drugs that inhibit cholesterol absorption, reduces low-density lipoprotein cholesterol and is well tolerated, according to the results of a phase III study.

The randomised, controlled trial, presented last week at the European Atherosclerosis Society meeting in Glasgow, involved 827 patients with primary hyper-cholesterolaemia. Dr Robert Knopp, director of the Northwest Lipid Research Clinic in Seattle, United States, and colleagues found that ezetimibe 10mg tablets given once daily reduced low-density lipoprotein cholesterol (LDL-C) by 17.7 per cent compared with a 0.8 per cent rise in LDL-C with placebo (P<0.01). Ezetimibe also reduced total cholesterol (–12.4 per cent compared with 0.6 per cent for placebo, P<0.01) and raised high-density lipoprotein cholesterol (1.0 per cent compared with –1.3 per cent for placebo, P<0.01). In addition, ezetimibe was found to have beneficial effects on triglyceride levels.

Cholesterol absorption inhibitors differ from statins, which are the most commonly prescribed therapy for hypercholesterolaemia, in that they act on exogenous rather than endogenous cholesterol. Ezetimibe works by selectively inhibiting the absorption of dietary and biliary cholesterol across the intestine. A subanalysis of 113 patients, showed that ezetimibe had no effect on the absorption of lipid-soluble vitamins.

Dr Knopp said in a press release issued on behalf of Schering-Plough, the manufacturer of ezetimibe: “As ezetimibe targets the exogenous cholesterol pathway, its action could be complementary and additive to that of statins.

“Ezetimibe used in co-administration with a statin may offer a new approach to cholesterol management, through which target LDL-C levels may be achieved.”

Results from two other Schering Plough-sponsored studies presented in Glasgow showed that co-administration of ezetimibe with fenofibrate and with fluvastatin resulted in additional LDL-C reductions compared with either drug given alone.

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Parathyroid hormone reduces risk of osteoporosis-related spinal fractures

Recombinant human parathyroid hormone (rhPTH 1-34), administered once daily, reduces the risk of osteoporosis-related spinal, as well as non-spinal, fractures in postmenopausal women, according to American researchers.

Dr Robert Neer, from Massachusetts General Hospital, Boston, and colleagues say that parathyroid hormone stimulates bone formation and resorption and can increase or decrease bone mass depending on the mode of administration.

Daily subcutaneous injections stimulate bone formation, which is reflected by the clinical benefits of rhPTH 1-34.

The researchers randomly assigned 1,637 postmenopausal women with prior vertebral fractures to self-inject subcutaneously either rhPTH 1-34 at a dose of 20µg or 40µg, or placebo once daily, after administering placebo daily for two weeks. All women received 1,000mg of calcium and 400iu to 1,200iu of vitamin D daily.

Daily treatment with rhPTH 1-34 reduced the risk of one or more new vertebral fractures by 65 per cent (95 per cent confidence interval, 78 per cent to 45 per cent) in the 20µg group and by 69 per cent (81 per cent to 50 per cent) in the 40µg group, compared with placebo.

The risk of developing new non-vertebral fractures was reduced by 53 per cent (75 per cent to 12 per cent) in the 20µg group and by 54 per cent (75 per cent to 14 per cent) in the 40µg group.

Treatment also resulted in a dose-dependent increase in bone mineral density of the spine and hip and in total-body bone mineral. The study is published in The New England Journal of Medicine (2001;344:1434).

In a recent press release, Eli Lilly, the company that is developing the drug, said that it was expecting to submit an application for approval of rhPTH 1-34 to the European Medicines Evaluation Agency later this year. The company added that if the drug was approved, it would be the first in a new class of bone formation agents for the treatment of osteoporosis in postmenopausal women to be made available in the United Kingdom.

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Cancer cells used as treatment for metastasised malignant melanoma

A “vaccine” made from a patient’s own cancer cells appears to prolong survival in patients with malignant melanoma that has spread to the lungs. The results, from a study by Dr David Berd, professor of medicine at Thomas Jefferson University in Philadelphia, United States, and colleagues, were presented at the recent American Society of Clinical Oncology meeting in San Francisco.

The research involved 37 patients with advanced melanoma that had spread beyond the lymph nodes who were injected with their own cancer cells, which had been inactivated and treated with dinitrophenyl. Of these patients, 20 had lung metastases.

The researchers found that following surgery to remove the cancer, 59 per cent of patients injected with their own cells were still alive after three years. Dr Berd described this as a good response. The patients with lung metastases were “doing far better” than those with soft tissue metastases, he added.

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Yeast vaccine to combat HIV

A vaccine developed from yeast could be used to provide immunisation against infectious diseases such as the human immunodeficiency virus (HIV), researchers from the University of Colorado Health Science Centre suggest. It could also be used to induce cell-mediated immunity against different types of cancers.

Dr Andrew Stubbs and colleagues found that when they vaccinated mice with a recombinant yeast vaccine that expressed HIV-1 antigens, the vaccine induced potent antigen-specific cytotoxic T lymphocyte responses (Nature Medicine 2001; 7:625).

In a press release, GlobeImmune, the company that engineered the yeast vaccine, said that it plans to seek approval from the United States Food and Drug Administration to use a yeast vaccine for HIV in human trials.

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Anti-inflammatory effects of statins explained

A mechanism for the anti-inflammatory properties of statins has been proposed in a paper published in Nature Medicine (2001;7:687). The mechanism appears to be unrelated to the cholesterol-lowering effects of statins, which are achieved by inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase.

Dr Gabriele Weitz-Schmidt from the preclinical research department of Novartis in Switzerland, and colleagues demonstrated that some statins block a previously unknown site on leukocyte function-associated antigen-1 (LFA-1), a glycoprotein that has an important role in the pathophysiology of inflammatory and autoimmune diseases.

The blocking of LFA-1-mediated T-cell co-stimulation by statins is highly selective, and this distinguishes these drugs from more broadly acting immunosuppressants, such as ciclosporin. In addition, the blocking of LFA-1 appears to be independent of HMG-CoA inhibition.

The authors propose that the development of selective, orally active LFA-1 inhibitors could have “applications in autoimmune diseases, such as psoriasis and rheumatoid arthritis, ischaemia/reperfusion injury, and transplantation”.

Dr Weitz-Schmidt and colleagues conducted the experiments because there was increasing evidence that statins had benefits that could not be fully explained by their lipid-lowering effects. They showed that lovastatin, simvastatin and mevastatin bound to LFA-1 but that pravastatin did not. Binding to LFA-1 might prevent leukocyte adhesion and extravasation to sites of inflammation and antigen presentation, they say.

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