Bulgakov, illness and creativity

Mikhail Bulgakov

@HealthMed The Russian playwright and novelist Mikhail Bulgakov is reported to have died in 1940 with hypertension and nephrosclerosis, said also to be the cause of his father's death. A recurring theme in the stage play by John Hodge - 'Collaborators', currently at the National Theatre in London, and winner 15th April 2012 of Olivier Award for best new play, is development of a tinge in Bulgakov's skin, obvious to his physician and friends; whether due to kidney disease - uraemic pigmentation, or some other cause such as liver disease is not made clear. A wishful twist in the play is the return to normal of all readings - blood pressure and lab tests, resulting from the 'simple' step of being seen in a hospital for the elite: an echo of reported changes in industrial output occurring merely because a Moscow bureaucrat of the time says this should happen.
A plausible medical background? Other than low salt diet, leeching and purging, little treatment was available for high blood pressure at that time. And kidney failure is a recognized complication of uncontrolled hypertension. However, his high blood pressure could also have been the consequence of progressive kidney disease, with genetic causes such as polycystic kidney disease an alternative diagnosis  - in the absence of confirmation of diagnoses in father and son by histology. A non-genetic cause in father and son could have been post-infective glomerular disease (such as Bright's disease) - Bulgakov gave up a career as a doctor because of an illness. This could have caused the onset of kidney disease, which, depending on the cause, may take up to several decades to progress to kidney failure.
This medical background raises the question: did long-term illness influence Bulgakov's literary creativity? There are two obvious potential effects: knowledge, especially as a doctor, of premature death giving the drive to create as much as possible; and effect of the disease itself on thoughts and imaginings. Of note, in the late stage, kidney disease is well-known typically to cause slowing of mental processes. There are apocryphal links between Tolstoi's novel 'War and Peace'.  However I experienced a real example as a junior doctor in London when a women was admitted to hospital in end-stage kidney disease. She was obtunded by her illness, however within a day or so of starting haemodialysis had recovered her previous passion for reading and was able to make accelerating progress through the book, obvious during successive ward rounds.
Modern science has revealed that cytokines, pathological factors involved in a wide range of medical problems, including inflammatory kidney disease, have important effects to influence mood and other aspects of brain activity, to the extent that trials are in prospect targeting cytokines as a way to treat depression. And of note Bulgakov wrote The Master and Margarita during the latter part of his last illness. Many researchers have been interested in the link between creativity and depression - and several obvious reasons for Bulgakov to be depressed in Moscow at that time, independent of his own health. For individual creative people, very challenging to differentiate between direct or indirect cause, and coincidence, both for creativity and its loss...

Pocket Prescriber Update

@HealthMed Pocket Prescriber 2012 was published on 30th March as a book and in e-format, aimed at providing core information to junior doctors, nurse and pharmacist prescribers and medical students and other health professional students interested in drugs and prescribing.
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.

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

Tuberculosis, Bel Ami and the Belle Epoque

Guy de Maupassant

@HealthMed Maupassant's 1885 book Bel Ami concerns the rise to wealth and influence of ex-soldier Georges Duroy, son of a poor rural family. Themes which still have a topical international resonance include the power of the press, foreign wars, corruption in business and government, and stock market insider trading. The anti-hero's success is largely due to the power of the wives of the rich, through their husbands, or direct involvement in political intrigue. A major subplot in Bel Ami is the impact of tuberculosis - estimated to cause the death of between 1 in 4, and 1 in 7 of the population in the mid 19th Century. In Bel Ami, Forestier, a wealthy publisher, develops rapid serious lung involvement, coughing blood, becoming breathless, and fevered. His early death provides a key opportunity for Duroy to enter formally into society.

Belle Epoque France was the outcome of cultural and economic flourishing during the latter part of 19th Century. An obvious question is what people at that time thought about tuberculosis. They knew that is was a serious and often deadly disease: Forestier's rapid death is anticipated as a matter of fact by Clothilde, a faithful companion of Duroy. An important academic view was that the 'soil'' - individual susceptibility - played a major role in the likelihood of developing consumption. There are several apparent similarities between those perceptions and public reaction to the epidemic of HIV-AIDS which emerged in the early 1980s. Tuberculosis was known as consumption because of its wasting effect. The term in translation dates back at least to Hippocrates in 460BCE: the Ancient Greeks used the term phthisis (wasting away) to describe the commonest disease of their time.  This was echoed by the description 'slim disease' for a wasting disorder which emerged in rural Uganda in the early 1980s, strongly associated with infection with the HTLV-III, and thus recognized to be a feature of HIV-AIDS. A major cause of weight loss in HIV-AIDS is associated opportunistic infections such as tuberculosis - a clear illustration of the importance of the impact of impaired host defence on development of a disease.

 

At the time of publishing Bel Ami, Maupassant was ill with syphilis. Not a socially acceptable disease to reflect in a literary work - although ample opportunity for this to be acquired by Maupassant's  anti-hero Duroy and passed on to his high society conquests. The concept of the risk of progressing from a 'night with Venus to a lifetime with Mercury' emerged shortly after the 1494 siege of Naples. In an epic poem of 1530, the Veronese doctor poet Girolamo Fracastoro refers to use of mercury as a possible cure for the disease. And its late effects were well known to Shakespeare, with examples in his play 'Timon of Athens'. One of Fracastoro's many contributions to science and medicine was the idea that certain diseases are spread by particles. In the 1600s, early inventors of microscopy went on to confirm the existence of minute particles. Antoni van Leewenhoek was the first to report single-cell micro-organisms, in 1676 correspondence to the Royal Society, which, after initial scepticism, then confirming his findings, made him a member in 1680. 

A dramatic change in medical thinking and knowledge about tuberculosis occurred in the early 1880s. In 1881, French doctor Louis Landouzy gave a series of influentual lectures on causes of consumption, including speculation that routes of transmission could included infected dust, milk and meat. And in 1882, the Prussian pathologist Robert Koch was the first to describe the causative tubercle bacillus, supported by his formulation in 1884 with Friedrich Loeffler of 4 postulates about the evidence needed to confirm disease causation by microbes. This direct work on the germ theory of disease had been anticipated 350 years before by Frascatoro. Koch's investigations and discoveries in relation to tuberculosis lead to his receipt of the 1905 Nobel Prize in Physiology and Medicine.

The timing of publication in 1885 of Maupassant's novel Bel Ami is therefore of special interest, following 3 years after Koch's discovery. There is no explicit recognition in Bel Ami of the resulting logic for isolating patients with what later became called 'open' tuberculosis - when the TB germs are free to travel from the lungs through the air to nearby contacts. However the move of Forestier to a remote house may have served both to give him a quiet place to convalesce or die, and tacitly to isolate him from at risk friends.

Modern parallels to the public response to tuberculosis in the Belle Epoque range from reactions such as fear, concern and denial for mystery illnesses with no cause known (e.g. pre-HIV 'slim disease'), the response of the public to those affected by HIV-AIDS, before the emergence of effective treatment; and responses to the many types of cancer without known cause, and other  reasons for premature illness and mortality, for example - sudden cardiac death syndromes in young athletes and older adults, despite many advances in diagnosis and treatment.

Online launch by Elsevier of FPM journal - Health Policy and Technology

@HealthMed Health Policy and Technology was launched online on 14th March by the international publisher Elsevier on behalf of the Fellowship of Postgraduate of Medicine (see Editorial on Launch). The print version of the journal will be published later in March.
The first issue of the journal features editorials, reviews and original research by an international range of contributors from USA, Norway, Holland, UK and India. 
Key themes of papers in the issue include diagnostics, technology for drug discovery, e-Health, and health technology assessment, and health policy.
There is also the first in a series of interviews with senior health service, research and industry professionals, and policy makers, starting with Clinical Pharmacologist Sir Michael Rawlins, Chairman of the UK's National Institute for Health and Clinical Excellence.

Helpful links
Podcast of interview with Sir Michael Rawlins, Chair of NICE
HPT website
Background to FPM and the launch of HPT
Fellowship of Postgraduate of Medicine website

Why a national No Smoking Day?

@HealthMed See the interview on the impact of no smoking initiatives by the University of Warwick's Knowledge Centre to coincide with the UK's National No Smoking Day.

Below is a summary of key points for smokers wanting to quit

No Smoking Day (March 14th) is an excellent time for UK smokers to think about stopping and to get started on the best ways to stop. Around 1 million people across the UK use No Smoking Day as the start to quitting smoking for good. 

World No Tobacco Day? UK smokers have two major calendar dates as prompts to stop, No Smoking Day on March 14th, a UK initiative, and World No Tobacco Day (annually on 31st May), organized by the World Health Organization.

Why stop? As well as causing well-known problems such as premature skin ageing and impotence, smoking is the leading preventable cause of death in the UK, causing around one in five deaths, and killing one in two lifetime smokers. Smoking causes increased risk of serious illness and of premature death from heart and lung disease and a wide range of cancers. And these risks not only affect smokers: they are transferred by passive smoking to adult friends and family, children and babies, and people who just happen to be near to smokers.

How quickly does quitting smoking help? Very. A recent report from Glasgow has shown a large decrease in the number of premature births and the underweight babies with reduced smoking by pregnant mothers. An for example in the first 10 months after the smoking ban in public places in Scotland, there were 1 in 7 fewer admissions to hospital for acute coronary disease among smokers, and a 1 in 5 reduction in former smokers. There was also a large early impact of reducing passive smoking, with ~1 in 5 fewer coronary events both in people who had never smoked and in ex-smokers.

How can drugs help? Drugs such as nicotine replacement treatments are helpful when smokers first start to quit. And nicotine replacement treatments and other drugs such as bupropion can help people who have stopped to stay quit of smoking. Drugs work best when combined with the kind of support available from the NHS Stop Smoking Service. Local NHS Stop Smoking staff can advise smokers on which medicines can help.

Who can help? Depending on personal preference NHS Stop Smoking support can send mailed information, text messages, emails and provide online help. Other helpful advice is available from the British Heart Foundation ‘WeQuit’, which has over 20,000 volunteers ready to help smokers who want to stop. And several helpful smartphone apps are now available.

Helpful links

More on why and how to quit smoking
WeQuit  
NHS Local Stop Smoking Services
My Last Cigarette smartphone app
Smoking, medicines and hip fracture risk

What's in a medicine?

@HealthMed Most of the weight of a tablet or capsule consists of coatings and fillers to make the enclosed active ingredient is big enough to pick up. Some common medicines such as the heart tablet digoxin or thyroid replacement treatment may have an active ingredient weight of as low as one tenth of a gram - ie it might take around 50 doses to fill a level teaspoon.
That raises the obvious question: what other ingredients are present in medicines? The range of fillers includes usually harmless chemicals such as the sugar lactose. That could prove a problem with patients who suffer lactose intolerance - due to immaturity in or loss of the enzyme needed to break down lactose.
And liquids or tablet coatings may include animal extracts, in the form of gelatin. Although this should be clearly labelled on the package insert that should accompany all medicines, a paper in the latest issue of the Postgraduate Medical Journal has reported that many patients on restricted diets are unaware of this.
The study in the Postgraduate Medical Journal reported that a quarter of patients surveyed who were on restricted diets were unaware that they had been prescribed drugs containing gelatin, contrary to their wishes or beliefs as vegetarians, or for other cultural or religious reasons.
If not clear from the packaging, patients should ask their pharmacist for further information on the non-drug contents of medicines prescribed, or bought over the counter without a prescription.

See BBC report on the PMJ article                                                                                                                                                                                                                                            

Cancer risk, premature death and sleeping tablets?

@HealthMed A team of researchers from Scripps Institute and the Jackson Hole Center for Preventive Medicine in Jackson, Wyoming, in the United States has reported in a publication in the British Medical Open Journal that use of sleeping tablets is associated with increased risk of cancer (lymphoma or cancer of the lung, colon or prostate), and  premature death. Results were obtained by interrogating electronic case records within a large US health care service: the Geisinger Health System (GHS), the largest rural integrated health system in the USA. GHS serves a 41 county area of Pennsylvania with approximately 2.5 million people.
This report has been disseminated widely in the international media, including for example in the Los Angeles Times.
The 2 major questions raised by this work are whether findings are explained by effects caused by the sleeping tablets -  or are the kind of people who are prescribed hypnotics just more likely to develop cancer or premature death, as a result, for example, of genetic factors, lifestyle reasons or associated disease causing the sleep disturbance.
Obvious more specific questions include are whether this relationship is:
- caused by the sleeping tablets (hypnotics);
- a feature of 'reverse causation - ie resulting from the initial sleep disturbance having been caused by symptoms of at that stage undiagnosed cancer, or sleep disturbance caused by cancer risk factors such as smoking, excess alcohol or obesity - ie some cancer-related factor leading to patients seeking a prescription for hyponotics
- coincidental
- or spurious - the result of some bias in subject selection.
The short, ~2.5 year average treatment duration makes this possible early cancer effect important to exclude as an explanation.
The authors say they have made reasonable efforts to exclude other causes of increased cancer risk. A wide range of hypnotics were included in the study, making it unlikely that a direct chemical action of the tablets is responsible for the cancer risk.
An intriguing possibility is that the association is a marker of chemical changes in the brain arising from sleep disturbance: it is well recognized that disordered brain function leads to production by the brain of inflammatory mediators (cytokines). One consequence is the thought to be the increased risk of heart disease reported in patients who have depression. That has lead to interest in using new biological agents to inhibit the action of these cytokines as a new approach to treatment depression and other serious neurological disorders. Taking sleeping tablets, although prolonging sleep duration, may not be sufficient to induce a normal sleep pattern.
In the context of the Scripps study, this raises the question whether  inflammatory mediators
could modulate tumour formation or accelerate the growth of early stage cancers. This concept was discussed by Reiche and colleagues in a Lancet Oncology review in 2004. As an example, the chemical - tumour necrosis factor alpha - is a potent cytokine implicated in depression and - as the name indicates - with a role in tumour biology, for example in modulating tumour blood supply.
Although in the Scripps study the reported relative risk of cancer increased from 3.5 to 5-fold with the numbers of sleeping tablets used, there needs to be a clear description of absolute events rates. And the increase in premature death was from a very wide range for causes, from accidents to asthma, flu and diabetes.
Of note, this was an observational study controlled by the authors by aiming to find well-matched subjects not on sleeping tablets (cases: 10 529 patients who received hypnotic prescriptions;  23 676 matched controls). A randomised controlled trial aimed at assessing these particular outcomes would have been needed to test these findings with more confidence of lack of bias. 
If the relationship is confirmed as having a causative link, the study would illustrate yet again the importance of balancing benefit and risk when prescribing tablets, and ensuring that any prescription is  continued for the minimum clinically indicated time.

Clinical pharmacology theme for Spring 2012 WMPA conference

@HealthMed Registration is now open for members and guests for the Spring meeting of the West Midlands Physicians Association.
The next meeting of the WMPA has updates on Clinical Pharmacology as its major theme and will be held on Wednesday 16th May 2012 at the Clinical Sciences Building at the University Hospital Campus in Coventry. Key speakers will include Dr Andrew Kicman (King's College London) on drugs in sport, Professor of Psychiatry Femi Oyebode (Birmingham) on medicines in psychiatry, Dr Richard Fitzpatrick (Liverpool) on advances in pharmacogenetics and Dr Paul Newrick (Worcestershire Royal Hospital)on medical advances in managing diabetes mellitus.
In view of the large number of high quality abstracts submitted, an attended poster session will be included in the May 2012 meeting.
Registration is open to members and guests (subject to availability of places).
For further information, contact the WMPA organizers.
See the WMPA blog or the WMPA website for more on the WMPA 2012 Spring conference and on the history of this 62 year old medical society.

Romeo's 'Sick health'

@HealthMed One of Romeo's string of oxymorons [Romeo and Juliet Act 1, Scene 1: reflecting on his heart sickness for fair Rosalind], 'sick health' illustrates the challenge of preventing more conventional heart disease - with its long prodrome of apparent health masking the development of sub-clinical disease from unrecognized risk factors, which may however be reversible if identified and addressed.

Why don't more people engage? Many reasons, including fear of finding a problem if tested, difficulty accessing advice/health checks, lack of interest or knowledge of outcomes of 'treatment', lack of confidence in self-efficacy to achieve supporting or first-line life-style changes, in diet, exercise, weight, smoking cessation, alcohol intake ...

To find out more on challenges and solutions for success in behaviour change, look for sources on Theory of Planned Behaviour e.g. this referenced link from the University of Twente.

See my previous blogs on smoking and alcohol.

Stopping smoking: why and how?

Hip fracture risk and smoking

Smoking: literary warnings

Alcohol: literary warnings

Alcohol and the French paradox