New genetic test to decide treatment for difficult childhood asthma

Researchers in Dundee and Brighton have reported in the journal Clinical Science a randomised study using gene testing aimed at improving treatment selection in children with asthma.
The gene variant (Arg16 genotype) they tested has previously been reported to be associated with failure to respond to commonly used beta-2 agonist bronchodilator inhaler treatment.
My comments below on the potential and limitations of the study were included in a briefing by the Science Media Centre.

Prof Donald Singer, Member of the British Pharmacological Society and Professor of Clinical Pharmacology and Therapeutics at the University of Warwick, said:
“This study is important in providing evidence that simple genetic testing can be used to personalize selection of medicine in clinical practice – in this case applied to treatment choice in children with poorly controlled asthma.
“Their main outcome – less time off school because of asthma – is important both for children and their families. The authors were careful to consider poor compliance with asthma treatment as an important alternative explanation for their findings. However this is a small study and needs to be confirmed in larger well-controlled clinical trials.”

Research paper:
Tailored second-line therapy in asthmatic children with the Arg16 genotype.  Lipworth BJ et al., published in Clinical Science on Tuesday 8^th January 2013.

Opium and mortality

@HealthMed Opium is widely used internationally. A study from Iran just published in the British Medical Journal now reports almost doubling of mortality rates in regular users of opium.

Here are my comments to the Science Media Centre on this study:

"The key message in this prospective study on opiates is of interest to pharmacologists, health professionals and members of the public: use of recreational opium, whether raw or modified, smoked or swallowed, appears associated with increased risk of death from a wide range of diseases, including circulatory and respiratory disorders, and cancer.

"However the results need to be interpreted with caution. This work is from north-east Iran and may not be typical for other ethnically or genetically different individuals. The authors note that they cannot be sure whether the relationship is causative. And oddly, risks from opiates did not appear to be amplified in people with high blood pressure, smokers or diabetics, raising some questions about the accuracy of clinical data collection."

Although some commentators have linked findings of this study to use of medically prescribed or over the counter opiates, there are too many confounders for that to be a reasonable extrapolation from the BMJ study. Nonetheless the general principle remains that medicines should only be used when clinically indicated.

See more about the study and related comments on the New Zealand Science Media Centre site.

Assessing prescribing skills

@HealthMed Doctors and other prescribers internationally find prescribing challenging. To get this right at times of high pressure, including in the emergency medicine setting, it is vital that basic skills are as well developed as possible. Add to that the need for care in calculation, avoiding the distracting effects of multi-tasking, challenges in medicines reconciliation, and risks inherent in shift-working and other complex work patterns. And electronic prescribing systems alone are not a sufficient safeguard. For example, reporting from the USA indicates that error rates may increase following the move from paper to electronic prescribing. The complex range of skills needed for safe and effective prescribing includes sound core knowledge of basic mechanisms of drug action, drug use in the clinical setting, and the impact of patient genetics, age, gender, lifestyle, the disease to be treated as well as co-existing medical conditions and the impact of other drugs and remedies. Many of these principles are easier to put into practice by adopting a personalized approach to therapeutics, with the aim of prescribing the right drug or drugs at the right dose to the right patient for the right disease and at the right time.

To help to increase focus on early training in essential prescribing principles and practice, in the United Kingdom the British Pharmacological Society and the Medical Schools Council supported by a national team of experts, to develop a Prescribing Skills Assessment that will eventually allow all students to rehearse and demonstrate competencies relevant to safe and effective initiation, monitoring, review and, when needed change in route, dose, duration or type of medicines alone and in combination in clinical practice, along with skills in communicating key points about medicines to patients, their carers and to relevant health professional colleagues.

See related blogs on
- Improving prevention of serious adverse drug reactions 
- Personalized medicine for better drug discovery

Networks and personalized medicine for better drugs?

For more on this theme see 
- article with Andrew Marsh in the inaugural March 2012 issue of Health Policy and Technology
- article in the October 2011 issue of Public Service Review: Science and Technology Review.  

For many individual patients treatments may not exist, may not be very effective, or may result in unpleasant adverse effects. How can prescribers improve drug selection andreduce the harmful effects of medicines? Are there better ways to develop drugs for patients who are difficult to treat?  And what can we do to improve poor adherence to medicines? These elements underpin ‘personalized medicine’, in current use the concept that by considering differences among patients in genetics, disease burden and other factors, more effective and safer drugs can be developed. Personalizing medicine is a path to better disease prevention and control where limited treatment options exist, such as for many cancers, resistant infections and dementia syndromes, and better drug development for new medical challenges. These concepts have in recent years attracted interest from the Royal Society, the Nuffield Council on Bioethics and cognate international institutions.

It is clear that there needs to be consistent investment and support from policy makers and regulators to develop and sustain the academic and industry pharmacology expertise and activity needed for the long-term success of a personalized medicine strategy, so that we can continue to be able to improve the health of the public and individual patients.

NICE is an international leader in developing evidence-based treatment guidelines. Its reports increasingly recognize the need to refine drug choice based on patient characteristics. For example, updated national hypertension guidelines released in August 2011 advise drug selection guided by age, gender, ethnicity, and monitoring, with treatment modified depending on clinical response. NICE also recognizes the need for research on ways, tailored to patient preference, to improve long-term adherence to drug treatment.

Pharmacologists are developing two complementary approaches aimed at achieving “precision medicine” in as many patients as possible: better drug discovery combined with high definition biomarkers for drug selection and monitoring. Network pharmacology brings together sophisticated databases of genetic mechanisms for disease, pharmacological pathways, candidate drugs, and population data describing important variants among individuals in drug handling and responsiveness.  These methods also allow ways to find previously unexpected “off-target” actions of existing or new drugs, which may accelerate discovery of new treatments for serious diseases.

Diagnostic methods are increasingly being used to improve drug selection for individual patients. For example growth tyrosine kinase receptors can be blocked using the biological agent imatinib to treat particular patterns of Philadelphia chromosome-positive chronic myeloid leukaemia, and rare gastro-intestinal tumours. Understanding genes and drugs that influence enzymes that modify drugs in the body, improves accuracy in defining patients who will not respond to a given medicine, or may develop adverse effects.  For example, to minimize risk of serious harm, pharmacogenetic testing is recommended for variability in a specific liver enzyme before deciding whether or not to prescribe the anti-HIV drug abacavir. This knowledge also allows better prediction of a patient’s risk of harm from interactions between treatments, based on recognition of medicines and other remedies that interfere with how drugs are cleared by the body. 

See my previous blogs on 
- preventing adverse drug reactions
- new UK guidelines on managing high blood pressure

Improving prevention of serious adverse drug reactions

Around 1 in 20  admissions to hospital are due to adverse drug reactions in the UK and other countries with well-developed health services. There are multiple causes for this surprisingly high rate of adverse reactions to medicines: the patient might not have followed established guidelines, such as avoiding alcohol; the wrong drug or dose might have been prescribed; an interaction between two drugs might have been overlooked; the patient's genetic makeup might cause an anomalous reaction; the patient might be taking contaminated drugs bought from unregulated sources on the internet; an unknown adverse reaction to a new drug might have been missed in the development and safety testing of that drug.
Many of the adverse drug reactions are preventable. We need to make sure medical students and prescribers are aware of how to prescribe safely, know common and high risk drugs well and, importantly, to make sure adverse reactions are recorded on patients' records so that they don't happen again. Now that people are able to obtain  prescription drugs on the internet, systems also need to be improved in order to better regulate drugs that are accessed in this way. 
Today's national and international regulations on medicine safety have evolved over than a century. In 1906 came a major focus on medicine safety in the USA, with the Food and Drugs Act signed by President Theodore Roosevelt. The UK went on in 1941 with the Pharmacy and Medicines Act to force manufacturers to list active ingredients on drug packaging, and restrict manufacturers from general advertising about medical claims of their products. The thalidomide disaster of the late 1950s and early 1960s brought about further major improvements: previously drug testing was very limited. Now great care is taken in assessing possible risks of medicines during pregnancy.
Many serious adverse drug reactions happen in people with genetic reasons for reduced ability to handle drugs in the body. Drug leaflets now specify if there is any known 'pharmacogenetic’ information on a medicine. The potential seriousness of these differences between people is shown by the example that the Japanese regulatory authorities are unwilling to license drugs for use in their country unless they have been tested on Japanese people.
New pharmacogenetic provide the opportunity to reduce exposure of patients to potentially harmful medicines based on recognizing an increased genetic risk. And new chemical genomics methods allow ways to identify safer and more effective use of current and new medicines.
For further details on these themes, see my interview with Amy McLeod from Warwick's Knowledge Centre.