• Risk of asthma "increased" in breastfed children of asthmatic mothers
• Early diet and risk of heart disease
• Merec Bulletin update
• Bleeding disorder not a contraindication for MMR vaccination, say researchers
• The human genome
• No bone benefit with pravastatin?
• Childhood epilepsy
• "Natural" progesterone creams reviewed
• No new safety issues for amfebutamone
• New treatment found to reduce sepsis deaths
• Herpes simplex virus shows promise as a treatment for skin cancer
• Concerns raised over use of zanamivir
• Alternatives to thioridazine

Risk of asthma "increased" in breastfed children of asthmatic mothers

Breastfeeding may increase the risk of asthma developing in children born to asthmatic mothers, according to research led by Dr Anne Wright (University of Arizona, United States). However, the researchers say that even if a relationship is proved by other studies, the effects would have to be weighed against benefits, such as optimal nutrition, protection against infection, potential cognitive advantages and maternal health.

Data regarding the breastfeeding status and respiratory health of 1,043 children were obtained from the Tucson Children's Respiratory Study. The majority of the children (83.7 per cent) were breastfed, although 58.8 per cent of those breastfed were given formula or other foods in the first three months of life.

The researchers found that in children with a maternal history of asthma there was a direct relationship between the duration of breastfeeding and asthma. By the age of 13 years, children with asthmatic mothers were five times more likely to develop asthma if they had been breastfed for more than four months than if they had never been breastfed. However, exclusive breastfeeding for more than four months was associated with lower rates of recurrent wheeze (rather than diagnosed asthma) in the first few years of life, regardless of the presence or absence of maternal asthma and child atopy.

The authors suggest that the relationship seen may be explained by the fact that milk of asthmatic mothers may differ from that of non-asthmatic mothers in ways that affect subsequent allergic susceptibility. They add: "Since it is unknown whether a child will become atopic until well past the time that infant feeding choices are made, there is no need to reconsider current recommendations that infants be exclusively breastfed for six months." (Thorax 2001;56:192.)

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Early diet and risk of heart disease

Introducing solid food into babies' diets too soon may lead to them developing early signs of risk factors for heart disease and diabetes, according to a press release from the University of Dundee.

Professor Jill Belch (Institute of Cardiovascular Research) and colleagues found that babies who had solid foods introduced into their diets before the age of 15 weeks were more likely to have problems with vasodilation of their blood vessels in childhood.

A sample of 159 children from the Dundee Infant Feeding Study, when they reached the age of 11 and 14 years, were asked to return for a series of tests. The researchers found that 20 per cent of the children had cholesterol and blood sugar levels that were above the recommended levels and that the same proportion had abnormalities of the blood vessels. These effects were directly linked with the introduction of solid food before the baby was 15 weeks old, they say.

The researchers also found that babies fed on formula milk were more likely to have higher cholesterol and blood sugar levels than breastfed babies.

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Merec Bulletin update

The latest Merec Bulletin reviews the role of inhaled corticosteroids in the management of chronic obstructive pulmonary disease (COPD).

The bulletin, which is issued by the National Prescribing Centre, concludes that routine use of inhaled corticosteroids for COPD is not supported by evidence from recent trials, and that smoking cessation is the only way to slow declining lung function (Merec Bulletin 2000;11:21).

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Bleeding disorder not a contraindication for MMR vaccination, say researchers

Children with a history of idiopathic thrombocytopenic purpura (ITP) prior to the first dose of measles, mumps and rubella (MMR) vaccine are not at increased risk of a vaccine-associated episode, researchers say. A causal relationship between MMR and ITP has been known for many years. A new study has quantified this risk, finding that the absolute risk of ITP within six weeks of immunisation with MMR is 1 in 22,300 doses.

Dr E. Miller (immunisation division, Public Health Laboratory Service) and colleagues analysed hospital admission records for children under five years of age over a three-year period. There were 28 verified admissions for ITP in the second year of life in 21 children with MMR immunisation records. Of these, nine were admitted within 42 days of receiving MMR. Combining these data with those from an earlier study, the researchers found that the relative incidence of an admission for ITP in the six weeks post-immunisation, compared with a control period, was 3.27. Vaccine-associated cases of ITP tended to be milder, shorter in duration of hospital stay and were not associated with subsequent recurrence. Children with a history of ITP were not found to be at increased risk of a vaccine-associated episode. Therefore, the researchers suggest that a history of ITP should not be considered a contraindication to MMR immunisation. They add that the incidence of ITP after MMR vaccine is considerably less than that after natural measles, rubella or mumps (Archives of Disease in Childhood 2001;84:227).

ITP is a disorder associated with a shortage of platelets and is characterised by bleeding under the skin.

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The human genome

Results of the sequencing and mapping of the human genome, together with the implications for medicine and biology, have been revealed in special issues of Nature and Science.

Researchers have found that just over 30 per cent of inherited diseases that are caused by a single gene defect are associated with genes that encode enzymes. In addition, it should now be possible to study subtle changes in one or several genes that can result in common diseases.

The articles include an analysis of the draft sequences, insights into cancer biology and possible genetic causes of diseases, such as diabetes and cardiovascular disease. According to the researchers, it will now be possible to look for new regulators and mediators of the immune system and to develop treatments for aberrations in the immune system.

The special issues are Nature, February 15 and Science, February 16.

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No bone benefit with pravastatin?

Researchers from New Zealand and Australia have suggested that statins should not be used to prevent osteoporosis until further studies have been performed.

Professor Ian Reid (University of Auckland, New Zealand) and colleagues looked at the effect of pravastatin on the frequency of fractures in patients enrolled in a randomised, controlled trial comparing pravastatin and placebo (the Long-term Intervention with Pravastatin in Ischaemic Disease [LIPID] study).

Previous observational studies had suggested that statins, which are used to treat hypercholesterolaemia, might be useful for the management of osteoporosis. However, analysis of data from the LIPID study did not support this hypothesis, they say. The researchers comment that a possible explanation for their negative finding is that there may be differences between statins in their access to bone cells (see PJ, September 23, 2000, p465).

A total of 9,014 patients with ischaemic heart disease received either pravastatin 40mg daily or placebo, and were followed up for an average of six years. The researchers found that the fracture risk in both groups was similar, with 183 patients suffering a fracture in the placebo group and 175 in the pravastatin group. When the researchers analysed data for women alone and for individuals aged 65 years and over, they found similar results.

The researchers comment that although a small effect cannot be ruled out, pravastatin is unlikely to have a clinically significant effect against fractures. They conclude that statins should not be used to prevent osteoporosis until there is evidence for their efficacy based on further randomised, controlled trials. The study is published in the Lancet (2001;357:509).

A spokesperson for Bristol-Myers Squibb Sankyo (manufacturer of pravastatin) told The Journal on February 21 that further randomised, controlled trials were required before a conclusion could be reached over the role of pravastatin in osteoporosis.

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Childhood epilepsy

This month's Drug and Therapeutics Bulletin reviews the diagnosis, investigation and treatment of childhood epilepsy (2001;39:12).

It says that, in most children with epilepsy, seizures can be controlled with carbamazepine or sodium valporate. While newer drugs have improved seizure control and may be better tolerated, overall, they had not been shown to be better than more traditional first-line drugs, the bulletin says.

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"Natural" progesterone creams reviewed

So-called "natural" progesterone creams may improve vasomotor symptoms in some postmenopausal women, says the Drug and Therapeutics Bulletin. However, they should not be used for prevention or treatment of osteoporosis, or to protect against treatment-induced endometrial hyperplasia and cancer.

The bulletin explains that claims that the progesterone is "natural" are based on the fact that it is derived from plant sources, and is structurally similar to human progesterone. In terms of clinical efficacy, the bulletin says that a trial of 90 postmenopausal women indicated that there was no difference in changes in bone density between women treated with "natural" progesterone creams and placebo after one year. An improvement in vasomotor symptoms was found in 25 of 30 women using "natural" progesterone cream compared with five of 26 using placebo.

Results from other trials indicated that it was unlikely that "natural" progesterone cream could deliver enough progesterone to adequately oppose estrogenic stimulation of the endometrium by exogenous estrogen. Pharmacokinetic data suggested that the creams were unlikely to deliver physiologically adequate levels of progesterone.

The bulletin adds that "natural" progesterone creams (Pro-Gest and Pro-Juven) are not licensed in the United Kingdom but that they can be obtained either on a named-patient basis on prescription or by mail/internet-order from abroad (2001;39:10).

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No new safety issues for amfebutamone

There are no new safety concerns relating to amfebutamone (bupropion, Zyban), says the Medicines Control Agency, despite recent reports in the media. A spokeswoman for the MCA told The Journal on February 21 that the majority of suspected adverse drug reactions that had been reported were known to occur with amfebutamone and were listed in the drug's summary of product characteristics. There had been 18 reports of deaths suspected to be as a result of taking the drug. She added: "It should be noted that patients may be required to stop smoking because of underlying diseases and these may well explain some of the reported deaths in patients taking amfebutamone."

The most recent safety update statement for amfebutamone was issued by the MCA last year (see PJ, November 11, 2000, p712).

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New treatment found to reduce sepsis deaths

Drotrecogin alfa activated (Zovant), a recombinant version of human activated protein C, reduces the risk of death from severe sepsis, a study has shown.

Researchers from the PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) study group found that treatment of patients with drotrecogin alfa activated reduced the relative risk of death from sepsis by 19.4 per cent and the absolute risk of death by 6.1 per cent compared with placebo. However, treatment was associated with an increased risk of bleeding. The study will be published in the New England Journal of Medicine on March 8 but can currently be found on the journal's website (www.nejm.org).

In a press release issued on behalf of Eli Lilly, Dr Peter Nightingale (intensive care consultant, Withington hospital, Manchester) said: "Sepsis is one of the most common causes of death in intensive care units. Zovant is the only compound tested to date that has been shown to reduce blood clotting and inflammation, and it is this distinctive method of action that could benefit a wide variety of patients with this syndrome."

Reduced levels of protein C are found in the majority of patients with sepsis and are associated with an increased risk of death.

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Herpes simplex virus shows promise as a treatment for skin cancer

A study investigating the herpes simplex virus as a treatment for malignant melanoma has shown that the virus replicates in patients' cancerous cells and causes necrosis, without being toxic to adjacent normal tissue.

In a study led by Professor Rona MacKie (department of dermatology, University of Glasgow) the cancerous lesions of five patients with advanced metastatic melanoma were injected directly with non-virulent herpes simplex virus.

After 14 days, two patients had their lesions surgically removed and the remaining patients received further virus injections.

The researchers found that all five patients tolerated the injections and, in one patient who had received two virus injections in each of two nodules, there was a flattening of both injected lesions. Examination of excised lesions from the three patients who had received two or more injections showed evidence of tumour necrosis, say the researchers.

In addition, immunohistochemical staining of the virus-injected cells showed that viral replication had only occurred within the tumour. They comment that this finding is encouraging since previous animal studies had suggested other metabolically active cells in the skin might support replication of the injected herpes simplex virus (Lancet 2001;357:525).

Professor MacKie told The Journal on February 20 that the work was still at a very early stage and that, so far, the lack of toxicity and cell death had only been shown when the virus was in direct contact with melanoma cells. "Obviously, one of the problems to be overcome is how to stimulate a cytotoxic effect on melanoma cells distant from the site of injection," she said.

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Concerns raised over use of zanamivir

Zanamivir (Relenza) should not be used in the National Health Service for treating influenza, according to February's Drug and Therapeutics Bulletin. The bulletin disagrees with National Institute for Clinical Excellence (NICE) guidance which recommended the use of zanamivir in at-risk patients.

In 1999, the NICE concluded that zanamivir should not be used for management of patients with influenza. However, it issued revised guidance in November, 2000, recommending zanamivir for at-risk patients (PJ, November 25, 2000, p777).

At the time, the NICE said that the turn-around was a result of additional trial evidence. The bulletin questions the value of this evidence. It says that the evidence appears to be meta-analyses of pooled data from six randomised, controlled trials of zanamivir involving "some 800" at-risk patients. Most of the trials did not specifically recruit at-risk patients, and at-risk patients formed a small minority of study participants.

The bulletin states: "The suggestion that zanamivir shortens symptom duration by about one day in at-risk patients is not a compelling reason for prescribing the drug."

It adds that no published evidence has compared zanamivir's effect on the symptoms of influenza with that of symptomatic therapy, such as paracetamol or ibuprofen.

Other issues highlighted by the bulletin include the fact that the summary of product characteristics for zanamivir refers to a risk of bronchospasm, which is not discussed in the NICE guidance. It also mentions that the NHS Executive advises that great care should be taken when including antimicrobials in patient group directions.

"Despite guidance given by the NICE, and having considered the data published by the institute, we believe that, on current advice, zanamivir should not be used in the NHS for treating patients with influenza; this includes those at particular risk of developing complications of the infection," the bulletin concludes (2001;39:9).

The NICE responded by saying that it was satisfied that its guidance was "robust". It said in a press statement issued on February 15: "The institute's processes for accessing and interpreting evidence are rigorous and its arrangements for consulting on its conclusions are comprehensive. The NHS expects health professionals to take the institute's guidance fully into account."

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Alternatives to thioridazine

A survey commissioned on behalf of Janssen-Cilag (manufacturer of risperidone [Risperdal]) has shown that out of 205 general practitioners, over a third have not replaced the restricted antipsychotic thioridazine with an alternative treatment.

Almost all the GPs surveyed had heard about the Committee on Safety of Medicines restrictions on thioridazine use (PJ, December 16, 2000, p877) and had run treatment reviews, but many were still discussing whether to prescribe replacement treatment at all. For patients who had been given an alternative, risperidone was found to be the treatment most frequently chosen.

Mr Stephen Bazire (pharmacy services director, Norfolk Mental Health NHS trust) told The Journal on February 20 that, when choosing an alternative therapy to thioridazine, it was important to consider what the drug had been prescribed for originally. "Thioridazine has a wide range of effects and side effects, and may have been prescribed for any one of these effects," he said. If it was being used primarily for its antipsychotic properties, then another antipsychotic agent would be appropriate. He added that risperidone was one of a number of options available, and that for many patients it would be a reasonable choice.

If thioridazine was being prescribed because of its sedative effect, or to reduce anxiety, then an alternative should be chosen that also had hypnotic or anxiolytic properties, he said.

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