Toll-like receptor on brain glial cells - a new target to reduce acute toxic effects of alcohol?

@HealthMed Researchers in Adelaide, Australia led by Mark Hutchinson have attracted international media interest with headlines heralding a new treatment to protect from hazards of alcohol. How close is the research to human treatment? And is there a risk this could be a drug of abuse for people over-indulging in alcohol and hoping to avoid harmful effects? My discussion below complements two radio interviews, one with a Californian station, the other with BBC Radio Ulster. To listen to the interviews, use the podcast links at the foot of this blog.

This was an experimental study looking in mice at ways to prevent some of the harmful effects of a single large dose of alcohol. The authors were following up previous research suggesting a link between alcohol and the immune system. The Toll-like Receptor 4 is a member of a family of inflammation-inducing receptors, first described in the fruit fly. TLR-4 is present on immune defence white blood cells in the circulation. TLR-4 is also present on glial cells in the brain. Glial cells make up around 90% of cells in the brain and have an important defence role against brain infection.

The scientists used two approaches to find out whether TLR-4 is involved in unwanted effects of a large single intake of alcohol: animals with genetic absence of TLR-4 and its pro-inflammatory signalling pathway partner MyD88; and the drug (+)-naloxone.  This is the mirror-image version of the (-)-naloxone in clinical use to treat an overdose of an opiate such as diamorphine (heroin) or morphine. (+)-naloxone blocks TLR-4 without blocking the enkephalin receptor through which opiates act.

Hutchinson and colleagues studied two adverse effects of alcohol overdose: sedation and unsteadiness. Their model of sedation was the time taken to regain normal posture (loss of righting reflex). Their model of unsteadiness was the mouse equivalent of keeping balance on a rolling log.

What did they find? The drug (+)-naloxone halved the duration of sedation after acute alcohol and shortened the recovery time for loss of balance.  These effects could have been due to 'off-target' effects of the naloxone, however findings were similar in animals genetically deficient in TLR-4 and MyD88 - reduction in severity and duration of sedation and unsteadiness. The authors also showed that alcohol switched on inflammatory protein production by cells from the hippocampal part of the brain; and they ruled out differences in alcohol metabolism between models.

What do these results mean for people?

Firstly, they are important in raising the question whether genetic variation in activity of TLR-4 inflammatory pathways plays a role in explaining major differences in tolerance of alcohol.

These results provide an interesting complementary mechanism for protective effects of naloxone on alcohol-toxicity to those reported by Badawy and Evans 30 years ago using different experimental methods.

Secondly, these findings suggest that targeting TLR-4 in the brain may be a new way to reverse some of the serious adverse effects of major alcohol overdose in patients attending emergency departments.

What about (+)-naloxone as the drug to use? Studies would be needed to confirm that TLR-4 is also important in alcohol-mediated toxicity in humans, and if so to understand more about the wider range of adverse effects of alcohol which may be prevented or reduced.

What about cautions? 

- This is experimental research which would need to be repeated in human subjects with TLR-4 blocking strategies which pose minimal toxic risk.

- Naloxone has to be given by injection - it is not sufficiently absorbed by mouth to be clinically active.

- Use (+)-naloxone is no exception to the rule that all drugs can have harmful effects. There is concern that risks of harmful effects from (+)- naloxone mean that is unlikely to be safe to use in general alcohol users.

-  (+)-naloxone may block some of the wanted mood-altering effects of more moderate alcohol intake. For example, it is known to affect other brain pathways e.g. blocking stimulant effects of cocaine and amphetamines. This may well lead to loss with this drug of the wanted effects of alcohol.

- The published study showed reduction in severity and duration of alcohol's effects not their prevention: if confirmed in people, general hazards of alcohol, for example when driving, would remain.

- (+)- naloxone is unlikely to prevent the 'hangover' from alcohol, which is recognized to be due to many factors, including dehydration (alcohol is a diuretic), low blood sugar, and other chemicals (congeners) present in alcoholic drinks and contributing to colour and taste.

The most interesting aspects of this study are that:

- if confirmed in further research in humans, assessment of TLR-4 variability may be developed as a test for susceptibility to alcohol;

- safe, effective TLR-4 inhibitors for use in humans could be a treatment for some of the physical effects of a severe overdose of alcohol in people presenting to hospital.

See the article

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Podcasts of radio interviews with Professor Donald Singer about research on alcohol, the immune system and new potential treatment:

Interview with Jon Bristow on San Francisco KGO Radio     12.17 PDT 29th Sep, 2011.

Interview with Seamus McKee on BBC Radio Ulster  16.15 GMT 28th Sep 2011. 

San Francisco KGO Radio
BBC Radio Ulster 

© DRJ Singer

Companion diagnostics to personalise medicine

@HealthMed What common link is there between confusion, dementia, dyspepsia, heart failure, hypertension, liver failure and stroke (apart of course from excess alcohol in some)? They are all syndromes - clusters of symptoms and physical signs with many possible causes, risk factors and co-morbidities.
Earlier approaches to treating these health-related conditions were largely based on trial on error until the most effective treatment(s) were identified. While pragmatic, in many that may lead to a delay in achieving effective disease control, while exposing some patients to unnecessary risk of adverse drug reactions.
The relatively new term 'companion diagnostics' describes the concept that coupling careful selection of biomarkers of disease and risk factor phenotype, of therapeutic response and early warning of risk of adverse reactions, will provide a more rapid route to safe and effective drug selection and monitoring.
Major current challenges include the relative immaturity of research evidence on cost and clinical effectiveness of combining companion diagnostics with specific therapeutic strategies. A major potential driver to improve systematic assessment of companion diagnostics will come from the extension of the activities of NICE (the UK's National Institute for Health and Clinical Excellence) from pharmaceutical and other treatments into assessment of diagnostic technologies (Diagnostics Assessment Programme), including companion diagnostics. This will be complemented by the role of NICE in commissioning new research where significant gaps are identified. 
A further important challenge is the fragmentation of diagnostic services within clinical health services. There are practical reasons for having multiple local diagnostic capacity for serious acute illnesses for which very rapid access to sophisticated diagnostics is potentially life-saving or critical to minimise preventable complications, from early selection of effective treatment. Where there is the luxury of more than a few hours delay without significant risk to the patient, e.g. while using 'holding' empirical treatment, there needs to be more research on relative effectiveness of local compared with remote lab diagnostic strategies. There are also practical issues to be resolved among biotechnology companion diagnostic developers where joint licensing agreements are needed when multiple diagnostics are indicated from different source providers. And standardisation of testing is needed across national health service and private laboratories to ensure that results of these new diagnostic tests are validated.
And of course when there is a single test, implementation is more straightforward. However where multiple tests are needed within a companion diagnostics portfolio, there will need to be a regular programme of induction and refresher education for prescribers on how best to use and interpret results of this new testing strategy. This will be particularly important for interpreting the currently less familiar genotype based tests.

Ritalin and delayed puberty? More questions than answers.

@HealthMed In the US medical journal Proceedings of the National Academy of Sciences by Mattison and colleagues reported September 19th 2011 that the ADHD treatment methylphenidate delays puberty in male non-human primates.

This experimental study suggests that continued use of methylphenidate hydrochloride (Ritalin) in young animals is associated with a delay in the pace of normal puberty, based on hormonal measurements and rate of testicular growth. Should this be a cause for concern for the use of this drug in humans? The eventual changes expected during puberty still occurred and  the authors themselves note that ‘the effects were transient and no permanent deficits were found', including normal testicular size at the end of the study. They note the need for further studies in humans.

 There are several important criticisms of this study. A major weakness in experimental design is the absence of a further treatment group given a chemically different behaviour altering treatment. This would have given insight into whether or not the changes observed are simply due to a change in behaviour pattern, as suggested by the observation that effects are transient, rather than to a harmful chemical effect of the treatment. 

This possible effect of behaviour change alone was reported in the same journal [PNAS] the previous week [12th September, 2011] in a study by Gettler and colleagues noting that testosterone levels decrease in men who take part in child care. The authors also provide no information on important potential consequences of their findings. For example, it would have been important to know whether or not there was any impact on intellectual or psychological development or on fertility.

© DRJ Singer

Information on health and disease from the patient's perspective

@HealthMed Where can patients and their family, friends and carers go for advice from the patient's perspective about  health-related conditions? And how can health professionals gain insight into patients' perspectives on their health or illnesses. Individual disease-focused charities and patient associations are ever better at providing patient friendly advice.
A further excellent web resource is Health Talk Online, with over 60 serious and common diseases represented, based on the experience of over 2000 patients. Conditions and issues covered range from heart risk and disease to cancer and women's health. This resource was established by the Charity DIPEx, in collaboration with health scientists from the University of Oxford (the Health Experiences Research Group), and is coupled to the website Youth Health Talk, which is about 'young people's real life experiences of health and lifestyle'. Health Talk Online aims to use the real life experience of people to discuss health, health-related conditions and illnesses, including insight into tests and therapies (and their possible adverse effects), what outcomes to expect from treatment with drugs and/or devices, news, and updates on progress in medical research, patients' viewpoints about the impact on their life of the health conditions of interest,  and discussion forums.
It is vital that information sources such as this are reliable. With that in mind it is noteworthy that the charity DIPEx has been selected by the UK's Department of Health to help to pilot an accreditation scheme  using 'kite marking' to indicate reliability of organisations that provide information about health and social care.

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

Advances in treating acute lung syndromes

@HealthMed Although only described as recently as 1967, a range of important contributory factors have been defined for acute respiratory distress syndrome (ARDS), which is now recognized to be at the severe end of a spectrum of acute lung injury, which imposes high risk for patients and which confers a major burden on health services. Outcome of treating the syndrome has been much improved by developments in devices to treat lung and other organ failure, supported by advances in expertise in intensive care. However, other than treatments for underlying causes, there is still important unmet need with regard to effective specific pharmacological treatments.

A timely review of ARDS by Dushianthan and colleagues is the Editor’s choice article in the September issue of the Postgraduate Medical Journal.  These experts from Southampton provide an update on knowledge of risk factors, including genetic biomarkers, for development of ARDS and other acute lung injury variants, and an up-to-date commentary on general and specific treatment options.

The authors note that ‘sepsis, pneumonia, and trauma with multiple transfusions’ account for most episodes. They highlight the importance for recovery of ‘general supportive measures such as appropriate antimicrobial therapy, early enteral nutrition, prophylaxis against venous thrombo-embolism and gastrointestinal ulceration’.

They discuss encouraging experimental evidence from trials of corticosteroids, nitric oxide, prostacyclins, exogenous surfactants, ketoconazole and antioxidants, however note that these findings have not as yet being translated into benefits for patients. They note as further treatment targets of interest, new approaches to modulating inflammation, and use of mesenchymal stem cells.

See the free full article for further details.

Stress and recovery in junior doctors

@HealthMed This blog is the start of a series of occasional notes highlighting articles of note published in the Postgraduate Medical Journal, the Fellowship of Postgraduate Medicine's first journal, launched in 1925, with the continued aim of educating doctors and other health professionals.
In the September 2011 issue, Dr Elke Ochsmann and colleagues from Aachen in north-west Germany report on a study of almost 1500 junior doctors. The authors report that 'Overtime work seems to be the important work related factor concerning junior doctors' level of strain'.
They add that for recovery from work-related stress 'performance feedback from colleagues seems to be a major resource'.
The conclude that the 'findings have implications regarding work time regulations and the necessity of leadership skill development training' in developing a better support system for junior doctors.

See the article for further information.

Why have a National Blood Pressure Week?

 In the UK, over 1,500 venues are offering free blood pressure checks during National Blood Pressure Week (12-18 September 2011). Why all that effort?   High blood pressure is a major preventable and treatable risk factor for serious heart diseases and stroke syndromes throughout the world. And even at the age of 20 around one in 20 people may already have high blood pressure, increasing to around 1 in 2 people by the age of 70.

An annual blood pressure week provides an important focus to remind the public and health professionals about risks of high blood pressure, how to prevent it, measure it accurately and use lifestyle and drugs in people in whom blood pressure is too high.

Blood pressure should be as low as possible, with, for adults, the upper level, when the heart has contracted, below 140mmHg and the lower level below 90mmHg, when the heart is relaxed between heartbeats. These thresholds should be much lower in people at increased risk of blood pressure complications, such as diabetics and people with kidney disease.

Provided people are otherwise healthy, the ideal blood pressure is now considered by international experts for the upper value to below 120, the lower below 80, recorded as ‘below 120/80mmHg’.

It is very important that patients help by following a healthy lifestyle. This is both helpful to prevent high blood pressure, and for patients with hypertension, to reduce its severity. People should aim for a healthy weight, using fresh foods as far as possible, keep salt intake low, and alcohol intake within healthy limits, be active and have regular good sleep.

This year it is timely the UK’s National Blood Pressure Week comes just after the launch of important new blood pressure guidelines prepared by the National Institute for Health and Clinical Excellence (NICE) advised by experts from the British Hypertension Society (BHS).

The NICE guidelines contain new advice on blood pressure measurement, including involvement of patients in their own management, supported by home blood pressure readings.

It is of course very important that any blood pressure monitor, whether for clinical or home use, should be accurate. A helpful list of accurate devices is on the British Hypertension Society's website.’

If you have high blood pressure, you should make sure that your doctor knows about any over the counter tablets or herbal remedies you are taking, as these can interfere with the actions of blood pressure tablets.

There are now seven major types of blood pressure treatments. For best blood pressure control, prescribers need to the right drug options for the right kind of patient, taking into account, for example, age, ethnicity and potential risks in pregnancy. If single drugs are not sufficient to control blood pressure, the NICE guidelines provide advice on which drug combinations are best to use.

Useful websites:
British Hypertension Society – includes information on which blood pressure monitors are accurate  http://www.bhsoc.org
Blood Pressure Association – includes a list of venues for free blood pressure checks http://www.bpassoc.org.uk/
NICE guidance on hypertension for patients and carers: http://guidance.nice.org.uk/CG127/PublicInfo/pdf/English

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