The cardiac drug flecainide was developed to prevent and treat serious ventricular tachycardia arrhythmias - very rapid heart rates which, if unchecked, can be lethal. However, in clinical trials, flecainide and its sister molecular encainide were reported to more than double the risk of sudden cardiac death.
Joint work by researchers in Chemistry and Medicine at the University of Warwick, and at the Biotech Company SEEK, is now allowing insight into how cardiac death risk might be increased by these drugs. The methods involve persuading viruses to provide a read-out on their surface of proteins related to human diseases.
In experiments just published in the Royal Society of Chemistry journal Chem Comm, we show that proteins from the heart may be read abnormally - through slippage in the letters of the genetic code for heart muscle components - these are called alternative reading frame proteins, a bit like a very simple old cipher.
Furthermore, flecainide is able to interact with a particular abnormally read protein. Previous research has linked this type of abnormality to serious side-effects of a drug used to treat the developing world parasitic infection Schistosomiasis.
There are two obvious implications of our new work. Testing for these abnormal proteins could be a new way to identify people and their family members who should be protected from risk of serious cardiac problems - for example by avoiding triggers of heart arrhythmias and by considering implantable defibrillators.
And by understanding how flecainide interacts with the abnormal protein, there may be clues to new treatments to interfere with the part of protein linked to cardiac problems.
Adverse effects of drugs can be very serious. When chosing a
medicine, prescribers need to be aware of the balance of risks and
benefits, and to
chose the right drug for the right patient and the right disease, at the
right time and for the right duration - long enough but not too long.
However
our work shows an unexpected consequence of adverse effects of a drug:
providing clues to new causes for disease and new ideas for
treatments.
Showing posts with label adverse drug reaction. Show all posts
Showing posts with label adverse drug reaction. Show all posts
Tuesday, 10 September 2013
Monday, 25 March 2013
Another view of Side Effects - a cautionary tale from Soderbergh
@HealthMed
Below are extended comments arising from a Guardian interview by Laura Barnett in the Another View series.
Below are extended comments arising from a Guardian interview by Laura Barnett in the Another View series.
I went to see the Soderbergh film Side
Effects expecting a story about drugs and serious side-effects: a version
of the Constant
Gardner translated from Africa to New York.
Instead I was completely absorbed in a much more complex thriller set
within the overlapping worlds of big Pharma, psychiatry, US private medicine,
and financial fraud.
The title is very clever, hinting
not only at side effects of drugs, but also side effects of lax medical and
financial regulation, of a private medical system, of love of money, and of
one-to-one interactions of doctor with patient.
A key message of the film: public and
professionals should keep an open mind on cause, consequence or incidental link
between drugs and side effects.
Jude Law portrays his character Dr
Jonathan Banks as flawed but well-meaning and a very astute medical detective
when challenged and able to see beyond the US psychiatric culture he is shown
as having accepted after training in the UK. When pressed on why has moved to
work in the US, he talks about the US as taking a more positive view of health
care than the UK, commenting on a greater optimism among US physicians that
patients will return to health, rather than his view of the UK where he says
clinicians are resigned to illness as the model.
This appears simplistic as Banks
also appears drawn by the prospect of greater financial gain within the US
private system. He is likely to have moved from a UK NHS, with in the main more
severely ill patients referred to him by family doctors, within the UK
treatment for all model, in contrast to the US where many of his private
outpatients would be likely to be direct self referrals with many nearer the
healthy end of the mental health spectrum (ie without GP screening of whom to
refer). And in the US having chronic severe disease may lead to patients being
no longer able to afford to be seen privately.
This thriller uses a smokescreen of casual interactions among psychiatrists and drug researchers in Pharma, serious risk of powerful drugs, especially in vulnerable patient groups (specifically young people with depression), the judgement of patients and prescribers such as Jude Law’s Dr Jonathan Banks being clouded by financial conflicts in the dominantly private US health system, compounded by direct-to-patient advertising, and the impact of peers on preference for medicines. Both peers as friends of a patient, and advice with little supporting evidence from professional peers such as Catherine Zeta-Jones’s ‘opinion leader’ Dr Victoria Siebert during her contact with Law’s Dr Banks at an educational meeting.
This thriller uses a smokescreen of casual interactions among psychiatrists and drug researchers in Pharma, serious risk of powerful drugs, especially in vulnerable patient groups (specifically young people with depression), the judgement of patients and prescribers such as Jude Law’s Dr Jonathan Banks being clouded by financial conflicts in the dominantly private US health system, compounded by direct-to-patient advertising, and the impact of peers on preference for medicines. Both peers as friends of a patient, and advice with little supporting evidence from professional peers such as Catherine Zeta-Jones’s ‘opinion leader’ Dr Victoria Siebert during her contact with Law’s Dr Banks at an educational meeting.
Worth noting that Law’s Dr Banks
starts by using an older established treatment for depression with an SSRI
(thought to help depression by raising the level of the brain transmitter
serotonin at nerve endings). It is only when this appears to be causing
unacceptable side effects that he takes advice from Siebert and uses a very new
drug - ablixa.
There are several potential risks of private
medicine portrayed in the film:
- Rooney
Mara’s Emily threatens to move to another doctor if Jude Law’s Dr Banks does not
agree with her treatment preference, a move that would result in loss of income
for Banks.
- A
patient’s ‘informed’ consent to take part in a study being run by Law’s Dr
Banks (for a personal fee) is biased by being told by Dr Banks that she won’t
have to pay for drugs (much more expensive in US) – or tell her health
insurance company (with the risk that she would have her premium increased),
although Banks does mention his conflict of interest in telling the patient
that he is receiving money for carrying out the trial;
- doctor
colleagues ostracize Banks because of concerns about losing business ie
patients.
The film raises concerns about US pharma industry
strategy to promote selling of drugs, flawed ethics from industry and
clinicians in engaging in research ‘studies’ and questions about safeguards in
place, especially for new medicines and for people at high risk of side
effects, but also at high risks of complications if their disease is not
treated.
Side effects can be good or bad – e.g. unexpected
and surprising benefit of sildenafil (Viagra) when trialed for angina – or in
this film the apparent increase in sex drive associated with a drug prescribed
by Jude Law’s character. We see good practice with a dispensing pharmacist
listing side effects for Rooney Mara’s Emily – including some unpleasant,
others beneficial [although a list spoken too rapidly for a depressed patient
to follow].
A better term for harmful effects of drugs is adverse
drug reactions (ADRs). These are common and may be serious – estimated in the
UK to be a major cause of ~10% of hospital emergency medical admissions or
delayed discharges from hospital. The thalidomide scandal led since 1964 in the
UK to a yellow card reporting system, with everyone, including patients now
empowered to report suspected concerns.
The UK has the advantage of
stronger efforts to regulate cost-effectiveness and safety of medicines than
shown in the film – joint efforts of:
-
National Institute for Health and Clinical
Excellence (NICE) (since 1997; and other agencies
in Scotland and Wales);
-
MHRA monitoring system, its
suspected adverse drug effect reporting Yellow Card scheme in place since 1964;
-
direct marketing to the public of
prescription only medicines being illegal in UK.
-
and in prospect aims from 2015-2016
for a public database of payments from Pharma to health professionals – which would
help to reveal conflicts of interest in prescribing, research
and medical education
In UK, a new drug such as the ‘ablixa’ in the
film would at least during the 2 years after launch have had a ‘black
triangle’ warning to prescribers to report any concerns about major or
apparently minor adverse drug reactions to the government’s Medicines Agency.
Useful weblinks
Medicines and Healthcare Regulatory Agency Patients
concerned about possible drug-related unwanted side effects from psychiatric or
other drugs should talk to their doctor or pharmacist. Members of the public
can also use the online Yellow Card system to report directly to the
government Medicines Agency any serious or worrying problem suspected to be due
to a medicine, whether or not mentioned on a patient information leaflet about
a drug.
UK All
Trials initiative – recommends that all trials
should be registered, and full methods and all results reported.
Wednesday, 18 April 2012
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.
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.
Wednesday, 28 March 2012
Pocket Prescriber Update
As in previous editions, there is a listing of ~500 of the most commonly used medicines, informed by advice from experts in the wide range of therapeutic disciplines reflecting current medical practice. We have also included national guidelines aimed at improving safety and effectiveness in prescribing, and advice on management of medical emergencies, supported by guidelines from national and international professional societies, NICE guidelines and Formulary updates.
Over 100,000 copies of the Pocket Prescriber have entered national and international circulation since the first edition was published in 2004, Since 2010, the Pocket Prescriber has progressed to being an annually updated source of prescribing advice.
Saturday, 24 March 2012
MHRA alert on mislabelled high strength codeine in UK co-codamol batch
@HealthMed Co-codamol
contains two types of painkiller. Paracetamol and the opiate drug
codeine. The UK Medicines regulator, the MHRA, has warned that around 39,000 packets of these combination tablets have been issued to wholesalers and pharmacies, with the opiate codeine present in 4 times the strength on the label: 30mg instead of 8mg per tablet. The
strength of the paracetamol in the tablets said to be unaffected. Lower dose codeine forms of co-codamol (in the UK 8mg or 12.8mg per tablet) are available over the counter in pharmacies. The higher dose codeine 30mg per tablet form of co-codamol is a prescription only medicine. This dose may be quite appropriately be prescribed by a doctor, after taking into account a patient's medical history and current drug treatment.
However codeine in high dose in at risk groups of patients is more likely to cause serious adverse effects such as drowsiness, confusion, and reduced respiratory drive and blood pressure. People at particular risk include the elderly, those with liver or kidney or lung disease, and people already on medicines known to cause these adverse effects.
Codeine is a prodrug: it has to be converted in the body to its active forms (mainly to morphine) before it can be effective in relieving pain. Therefore people who are genetically able to activate codeine very rapidly are more likely to experience adverse effects when exposed to higher than expected doses of codeine.
High doses of codeine can also cause constipation as a troublesome adverse effect.
These 30mg strength codeine forms of co-codamol tablets have on them the mark "CCD30" on one side with "CP" on the second side.
As recommended by the MHRA, anyone concerned that they may have been incorrectly given the high strength co-codamol should contact their GP or pharmacist promptly. The reported batch number is LL11701, expiry date September 2014.
See also:
Reuters report
Daily Express report
New England J Med report on codeine intoxication associated with ultrarapid CYP2D6 metabolism
However codeine in high dose in at risk groups of patients is more likely to cause serious adverse effects such as drowsiness, confusion, and reduced respiratory drive and blood pressure. People at particular risk include the elderly, those with liver or kidney or lung disease, and people already on medicines known to cause these adverse effects.
Codeine is a prodrug: it has to be converted in the body to its active forms (mainly to morphine) before it can be effective in relieving pain. Therefore people who are genetically able to activate codeine very rapidly are more likely to experience adverse effects when exposed to higher than expected doses of codeine.
High doses of codeine can also cause constipation as a troublesome adverse effect.
These 30mg strength codeine forms of co-codamol tablets have on them the mark "CCD30" on one side with "CP" on the second side.
As recommended by the MHRA, anyone concerned that they may have been incorrectly given the high strength co-codamol should contact their GP or pharmacist promptly. The reported batch number is LL11701, expiry date September 2014.
See also:
Reuters report
Daily Express report
New England J Med report on codeine intoxication associated with ultrarapid CYP2D6 metabolism
Tuesday, 31 January 2012
Hip fracture risk, smoking and anti-ulcer drugs (PPIs)?
@HealthMed A report in the latest British Medical Journal by Chan and his team from the Gastro-enterology Department at the Massachusetts General Hospital in Boston, USA, suggests a small but potentially important higher risk of hip fracture in current or ex-smokers among post-menopausal women on treatment with the commonly used anti-ulcer drugs - proton pump inhibitors. The risk was small - one extra hip fracture per year for every 2000 women treated -but the risk was greater, the longer the treatment with a PPI.
The link is biologically plausible as both PPIs and smoking have actions on the body which could increase the risk of hip fracture. The authors were careful to state that the risk did not apply to non-smokers and for those at risk they were unable to attribute this to any specific type of PPI. Of note, there are several reasons why smokers are more at risk of causes of indigestion/dyspepsia which may make them more likely than non-smokers to be on PPI treatment.
This report is another example illustrating that drug choice and duration should be based on balancing clinical benefit against potential risk of adverse drug effects.
This was an older study among nurses in the US from data collected from 2000 up to 2008.
A weakness of the study is that it was not a randomised controlled trial. The report was based on following a cohort of people some of whom happened to be on PPI treatment : that means that the findings may be subject to bias ie there may be reasons unrelated to the PPIs to explain the hip fracture risk, although the authors made clear efforts to control for obvious sources of bias.
Patients who are concerned should consult their GP or pharmacist for advice.
See source reference
Khalili H, Huang ES, Jacobson BC, et al. Use of proton pump inhibitors and risk of hip fracture in relation to dietary and lifestyle factors: a prospective cohort study. British Medical Journal. Published online January 31 2012
The link is biologically plausible as both PPIs and smoking have actions on the body which could increase the risk of hip fracture. The authors were careful to state that the risk did not apply to non-smokers and for those at risk they were unable to attribute this to any specific type of PPI. Of note, there are several reasons why smokers are more at risk of causes of indigestion/dyspepsia which may make them more likely than non-smokers to be on PPI treatment.
This report is another example illustrating that drug choice and duration should be based on balancing clinical benefit against potential risk of adverse drug effects.
This was an older study among nurses in the US from data collected from 2000 up to 2008.
A weakness of the study is that it was not a randomised controlled trial. The report was based on following a cohort of people some of whom happened to be on PPI treatment : that means that the findings may be subject to bias ie there may be reasons unrelated to the PPIs to explain the hip fracture risk, although the authors made clear efforts to control for obvious sources of bias.
Patients who are concerned should consult their GP or pharmacist for advice.
See source reference
Khalili H, Huang ES, Jacobson BC, et al. Use of proton pump inhibitors and risk of hip fracture in relation to dietary and lifestyle factors: a prospective cohort study. British Medical Journal. Published online January 31 2012
Sunday, 30 October 2011
Kew, angel's trumpet and artemisia - from dream plant and poison to herbal remedy.
@HealthMed Guides to plants have a large number of entries labelled as 'medicinal use' and 'poison'.
The ancient Greeks recognized this overlap, in using the same word for drug, poison and magic charm: pharmakon. This remains in current use in the word pharmacology - the study of drugs of all types.
The Temperate House at Kew Gardens, the largest surviving Victorian glasshouse in the world, has a tantalising display of medicinal plants, for most the scientific name the only clue to properties. Nearby there are two examples of contrasting properties of plants.
Artemisia [in this case A. austriaca - Austrian wormwood] is there as scrawny, pale green, ground cover. This plant is thought to be named after 4th century BC queen of Persia and botanical expert Artemisia, or after Artemis, sister of Apollo and Greek goddess of the wilderness, the hunt, fertility and both bringer and treater of disease in women. This bitter herb is said to have been used by the ancient Greeks to treat parastic infestation by intestinal worms. A large number of medicinal properties are claimed for wormwood species. Artemisinin, the extract of Chinese Wormwood, is used as an anti-malarial however resistant strains of malaria are now being reported. Recent experimental evidence suggests that artemisinin may have anti-cancer effects through limiting proliferation and cause programmed cell death (apoptosis) in certain sub-types of cancer cell. Other research indicates that artemisinin may induce cancer cell resistance to other types of cancer treatment. Much more work is needed on effectiveness and safety of artemisia extracts in the clinic.
Angel's Trumpet [Brugmansia aurea] in contrast has more sinister properties. This tree, native to sub-tropical South America from Colombia to Ecuador, has delicate, orange, trumpet-shaped, hanging, lemon-scented flowers. All parts of the plant are considered poisonous through antagonism of muscarinic cholinergic receptors and other effects of tropane alkaloids, including the racemic mixture atropine, its laevo-stereoisomer hyoscyamine [M1-antagonist], and scopolamine. Actions include belladonna-like effects, hallucinations, sedation and pupil enlargement, which may be symmetrical or asymmetrical. Local shamans are reported still to use plant extracts to aid their ceremonies through inducing visual hallucinations. Historically it is believed that in the Americas extracts of this plant, combined with alcohol and tobacco, were used to induce sleep in slaves or wives before their immolation after the death of their king.
© DRJ Singer
The ancient Greeks recognized this overlap, in using the same word for drug, poison and magic charm: pharmakon. This remains in current use in the word pharmacology - the study of drugs of all types.
The Temperate House at Kew Gardens, the largest surviving Victorian glasshouse in the world, has a tantalising display of medicinal plants, for most the scientific name the only clue to properties. Nearby there are two examples of contrasting properties of plants.
Artemisia [in this case A. austriaca - Austrian wormwood] is there as scrawny, pale green, ground cover. This plant is thought to be named after 4th century BC queen of Persia and botanical expert Artemisia, or after Artemis, sister of Apollo and Greek goddess of the wilderness, the hunt, fertility and both bringer and treater of disease in women. This bitter herb is said to have been used by the ancient Greeks to treat parastic infestation by intestinal worms. A large number of medicinal properties are claimed for wormwood species. Artemisinin, the extract of Chinese Wormwood, is used as an anti-malarial however resistant strains of malaria are now being reported. Recent experimental evidence suggests that artemisinin may have anti-cancer effects through limiting proliferation and cause programmed cell death (apoptosis) in certain sub-types of cancer cell. Other research indicates that artemisinin may induce cancer cell resistance to other types of cancer treatment. Much more work is needed on effectiveness and safety of artemisia extracts in the clinic.
Angel's Trumpet [Brugmansia aurea] in contrast has more sinister properties. This tree, native to sub-tropical South America from Colombia to Ecuador, has delicate, orange, trumpet-shaped, hanging, lemon-scented flowers. All parts of the plant are considered poisonous through antagonism of muscarinic cholinergic receptors and other effects of tropane alkaloids, including the racemic mixture atropine, its laevo-stereoisomer hyoscyamine [M1-antagonist], and scopolamine. Actions include belladonna-like effects, hallucinations, sedation and pupil enlargement, which may be symmetrical or asymmetrical. Local shamans are reported still to use plant extracts to aid their ceremonies through inducing visual hallucinations. Historically it is believed that in the Americas extracts of this plant, combined with alcohol and tobacco, were used to induce sleep in slaves or wives before their immolation after the death of their king.
© DRJ Singer
Thursday, 29 September 2011
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.
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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.
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.
© DRJ Singer
Monday, 19 September 2011
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
© DRJ Singer
Thursday, 8 September 2011
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.
- 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
- preventing adverse drug reactions
- new UK guidelines on managing high blood pressure
Saturday, 20 August 2011
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.
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.
Monday, 15 August 2011
Taboo tablets - beta-blockers and professional string players
The following blog arose from contributing to an article in The Strad by Catherine Nelson on drugs and occupational stress amongst professional musicians.
As clinical pharmacologist and amateur violinist gives me two perspectives on performance or audition anxiety: this is due to the triggering of an extra release of
adrenaline – and other fight-or-flight response hormones – which in turn can cause
string players to feel anxious and suffer a shaking bowing arm. Beta-blockers can stop
unwanted reactions to these hormones, such as an increased heart
rate, and thus lessen detrimental effects of stress on the musician’s performance.
I had heard of a violinist who was so anxious and stiff during an audition that the bow simply flew out of his hands. Many professional musicians are worried by the stress of performance, and beta-blockers may help some players control the debilitating physical symptoms of this stress.
It is of course extremely important that musicians, for whom medical treatment of occupational stress may be indicated, work with a medical practitioner to ensure, if a beta-blocker appears worth a trial, that they take the right dose, provided it has been checked that this would be medically safe to do so. I am particularly concerned about anecdotal evidence of players sharing medicines - which may not be the right medicine, or a possible cause of severe and rapid onset harmful effects. People are increasingly turning to the internet to obtain drugs. At best these pills may be out of date – at worse they may be contaminated. Taking them without getting advice from a doctor can be very dangerous.
Beta-blockers slow the heart, helping to make people feel calmer, but they also make your heartbeat less forceful than it should be, so that even fit people may feel tired and short of breath, and some people may be tipped into heart failure. Players with certain pre-existing medical conditions may suffer worse adverse reactions. These drugs also make the airways less open, so are dangerous in asthma. Other side effects include sleep disturbance, weight gain and stomach upset, including increased stool frequency and urgency. There are also reports of people suffering depression while taking beta-blockers, though it may be that people with heightened anxiety are more prone to suffering depression. It is therefore better to avoid medicines if possible.
The message for beta-blockers should be that if they are worth a trial on medical grounds, to try a low dose under the advice of a medical practitioner; the dose may then be carefully increased if needed. If medically indicated, it is also very important always to try beta-blockers first under rehearsal conditions, as being made too relaxed or having unwanted effects could be harmful when performance really matters.
The implications of the broader issue of anecdotal widespread use of beta-blockers raise important occupational health and ethical concerns which deserve to be discussed nationally and internationally, both by the music profession and relevant medical organisations.
See The Strad for more on the article.
I had heard of a violinist who was so anxious and stiff during an audition that the bow simply flew out of his hands. Many professional musicians are worried by the stress of performance, and beta-blockers may help some players control the debilitating physical symptoms of this stress.
It is of course extremely important that musicians, for whom medical treatment of occupational stress may be indicated, work with a medical practitioner to ensure, if a beta-blocker appears worth a trial, that they take the right dose, provided it has been checked that this would be medically safe to do so. I am particularly concerned about anecdotal evidence of players sharing medicines - which may not be the right medicine, or a possible cause of severe and rapid onset harmful effects. People are increasingly turning to the internet to obtain drugs. At best these pills may be out of date – at worse they may be contaminated. Taking them without getting advice from a doctor can be very dangerous.
Beta-blockers slow the heart, helping to make people feel calmer, but they also make your heartbeat less forceful than it should be, so that even fit people may feel tired and short of breath, and some people may be tipped into heart failure. Players with certain pre-existing medical conditions may suffer worse adverse reactions. These drugs also make the airways less open, so are dangerous in asthma. Other side effects include sleep disturbance, weight gain and stomach upset, including increased stool frequency and urgency. There are also reports of people suffering depression while taking beta-blockers, though it may be that people with heightened anxiety are more prone to suffering depression. It is therefore better to avoid medicines if possible.
The message for beta-blockers should be that if they are worth a trial on medical grounds, to try a low dose under the advice of a medical practitioner; the dose may then be carefully increased if needed. If medically indicated, it is also very important always to try beta-blockers first under rehearsal conditions, as being made too relaxed or having unwanted effects could be harmful when performance really matters.
The implications of the broader issue of anecdotal widespread use of beta-blockers raise important occupational health and ethical concerns which deserve to be discussed nationally and internationally, both by the music profession and relevant medical organisations.
See The Strad for more on the article.
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