Archief Roodbont

EDS = excessive daytime sleepiness

OSA= obstructive sleep apneu

The Causes of EDS

Once EDS has been identified through clinical assessment and the use of specific tools, if needed, the clinician can proceed to the next step, determining whether the EDS is related to insufficient sleep time, disrupted sleep, or a shift in circadian timing, or whether the EDS is a reflection of true hypersomnia and an increased need for sleep during a 24-hour period. In most cases, further probing will direct the need for additional testing.

Failure to allow sufficient time for sleep is a fairly common cause of EDS. In general, this can be attributed to a variety of behavioral and lifestyle issues. Each individual carries a certain sleep need as defined above (usually 7-9 hours for adults, longer for adolescents and children, and slightly shorter for older adults). A failure to meet this "quota" will lead to an increase in daytime sleepiness. This may be most noticeable during "down" times when external stimulation diminishes. A particularly vulnerable period will also occur in the middle of the afternoon, a time that is related to circadian factors. The resolution to this problem is to adjust schedules to meet this sleep need. Unfortunately, lifestyle patterns are often difficult to change and may require the persistence of the clinician.

Disrupted or inefficient sleep, even in the context of a full night of sleep, may also lead to EDS. As noted, the patient may not always be aware of the extent of the disruption. At times, other medical conditions may contribute. Chronic pain, frequent urination, and muscle cramps are a few examples. In dealing with EDS, the clinician should always look for those factors that may suggest the possibility of OSA. EDS, obesity, systemic hypertension, heavy snoring, and male gender all fit into the typical profile for OSA. On the other hand, these are relative risk factors and young, thin, normotensive women may also present with OSA. The critical diagnostic study for OSA is the overnight polysomnogram. Various treatment options are available, but continuous positive airway pressure is often the treatment of choice. Interestingly, an occasional patient may have persistent EDS even after relatively adequate treatment of OSA.

Disturbances in the circadian timing system may also play a role in EDS. At times, a shift in the timing system relative to the daily lifestyle schedule occurs, involving either a delay or advancement. This results in a situation where the individual is attempting to sleep when the circadian system is prepared for wakefulness or the individual is planning for wakefulness when the circadian system is prepared for sleep. A special case can be seen in shift workers who may suffer from a shift work sleep disorder. In some respects, these patients actually suffer from a combination of insufficient sleep and fragmented sleep, as well as the difficulties of functioning in opposition to the circadian rhythm. In some sense, they experience ongoing "jet lag." Scheduling issues frequently lead to a shortened time in bed, and sleep during the day is often fragmented. Work time function is often suboptimal because of the effects of sleep deprivation, sleepiness, and the limitations of trying to function "out of rhythm."

Finally, some patients seem to get an adequate amount of efficient sleep without a circadian disturbance, but still exhibit evidence of EDS. Obviously, the clinician should always be wary of toxic-metabolic disorders and the effects of medications and drugs. Several neurologic conditions, including certain neurodegenerative disorders and disorders with lesions of the hypothalamus, have been associated with EDS. On occasion, EDS may be a feature of a depressive syndrome. Narcolepsy, with or without cataplexy, refers to a disorder of EDS that is independent of all of the above. In addition to EDS, these patients may also complain of sleep paralysis or sleep-onset hallucinations. Cataplexy refers to a transient, emotion-induced atonia. The diagnosis is made on the basis of a clinical evaluation coupled with a polysomniogram and MSLT.

Conclusion

This walk through the identification and assessment of EDS should be viewed as something more than an academic exercise. These are disorders that may often remain undiagnosed and may lead to obvious morbidity. Although the causes may be diverse, most can be managed and treated -- but the first step requires a clinician who is alert to the possibilities and who knows the right questions to ask.

Supported by an independent educational grant from Cephalon

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Suggested Reading

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Summary

Nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with high risk for gastrointestinal bleeding. This risk can be lowered by using a cyclooxygenase-2–selective NSAID (coxib) or by adding a proton-pump inhibitor (PPI) to nonselective NSAID therapy. Recent guidelines recommend that these approaches be used for patients who require NSAIDs but have risk factors for NSAID-associated ulcers. However, neither approach completely eliminates bleeding risk. An alternative strategy is to prescribe cotherapy with a coxib and a PPI, but this approach has not been tested in randomized trials.

To address this issue, investigators recruited 441 consecutive high-risk patients with nonselective-NSAID-associated ulcer bleeding who were admitted to a single hospital in Hong Kong. NSAIDs were stopped, and the patients received PPI therapy and, if necessary, treatment for Helicobacter pylori infection. After endoscopic documentation of ulcer healing and confirmation that H. pylori had been eradicated, 273 patients were enrolled. All patients received a coxib (celecoxib; 200 mg twice daily); half were randomized to receive a PPI (esomeprazole; 20 mg twice daily), and half received twice-daily placebo. Investigators followed patients for a median of 13 months to identify GI bleeding, efficacy of symptom relief, and adherence to study protocol. Bleeding episodes were adjudicated by an independent panel.

After 13 months, 8.9% of the celecoxib-alone group had experienced GI bleeding, compared with none of the combination-therapy group (P=0.0004). Efficacy and adverse events were similar in the two groups. The authors concluded that, in high-risk patients, risk for GI bleeding was lower with a coxib plus a PPI than with a coxib alone.

Comment

These data suggest that patients with previous NSAID-associated ulcer bleeding should receive a PPI, but the investigators did not compare a nonselective NSAID plus a PPI to a coxib plus a PPI, so the benefit of the coxib is difficult to quantify. However, the complete absence of bleeding in the combination-therapy group and the results of previous studies suggest that nonselective NSAIDS are likely to impart a higher risk than do coxibs, with or without concomitant PPI therapy. The effect of PPI therapy in this study is impressive, because patients in both arms were allowed to take low-dose aspirin for cardiovascular prophylaxis (after the cardiovascular risks of coxibs were reported); other studies have shown that the protective effect of coxibs (compared with nonselective NSAIDs) is attenuated by concomitant aspirin therapy (Journal Watch Gastroenterology Mar 30 2007). When deciding on the appropriate strategy for an individual patient, a physician must weigh the potential cardiovascular risks of prescribing a coxib, whether alone or with a PPI, against potential risk for GI bleeding.

— David J. Bjorkman, MD, MSPH (HSA), SM (Epid.

Gisteren zijn Hannie en ik naar het universitair ziekenhuis Radboud in Nijmegen geweest voor controle. De hematoloog (bloedspecialist) was tevreden over het bloedbeeld. De zogenaamde kappa stukjes, die door de plasmacytoom cellen geproduceerd werden tijdens haar ziekte, blijven op hetzelfde niveau en dalen zelfs, en dat betekent dat er geen nieuwe kappa stukjes meer gemaakt worden en dat betekent weer dat er dus geen plamacytoom cellen meer in het lichaam zijn. De ontaarde witte bloedcellen (plasmacytoomcellen) maken evenals normale witte bloedcellen antistoffen, maar dat zijn antistoffen die nergens op slaan en die op den duur zelfs zeer schadelijk worden als de ziekte meer algemeen wordt en dan multipel myeloom of ook wel de ziekte van Kahler genoemd wordt. De hoeveelheid ( de titer) van deze abnormale eiwit stoffen (gammaglobulinen) worden short chain labda en kappa chains genoemd. De kappa chains kunnen in het bloed gemeten worden met behulp van zogenaamde elektroforese. Direct na de bestraling waren er nog 22 mg/L in het bloed. Drie maanden later was de titer gedaald naar 18mg/L en na zes maanden 11,8. Drie maanden geleden waren er nog 12,5 mg/L in het bloed. Dit klein verschil wil niets zeggen en wordt als normaal beschouwd. Verder was haar bloedbeeld normaal. Ze heeft geen bloedarmoede en het bloedbeeld is ook goed. Ze voelt zich verder goed en de bezwaren van de bestraling zijn helemaal verdwenen. De beweeglijkheid van de hals is echter beperkt en dat komt omdat zowel de atlas als de draaier ( de twee hoogste halswervels ) door de plasmacytoom cellen eerder zijn aangetast en ook met de bestraling geleden hebben. Door nieuwe vorming van calcium in de wervels zijn ze wel weer stevig en gezond, maar de gladheid en soepelheid heeft natuurlijk wel wat geleden.

Alles bij elkaar mogen we niet ontevreden zijn.

Groeten van Hannie en Jan.

http://www.clinicalgeriatrics.com/article/7609

CONCLUSION

Persons over 65 years of age are at increased risk

for cardiovascular disease, regardless of their

cholesterol levels. C-reactive protein, an inflam-

23

Clinical Geriatrics Volume 15, Number 8 August 2007

C - R E A C T I V E P R O T E I N A N D C A R D I O V A S C U L A R R I S K

cg0807Blaine.qxd 8/2/07 2:24 PM Page 23

matory marker, and potentially a mediator of

atherosclerotic disease, has been shown to have

predictive value that is independent of LDL-C,

and perhaps even superior to that of LDL-C.

Clinically, measurement of CRP may best be

used at this time in primary prevention patients

with moderate-to-high risk and average levels of

LDL-C to help refine degree of risk and best

treatment options. Treatment with statins has

been shown to provide superior risk reduction in

patients with elevated levels of CRP.

Dr. Blaine has received grant support, is a consultant

for, and is a member of the speaker’s bureau of

AstraZeneca; is on the speaker’s bureau of Merck and

Pfizer; and is a consultant for Daiichi Sankyo, Inc.

In the Spotlight Basics of Peptic Ulcers
Whether you suspect you have a peptic ulcer or you are newly diagnosed, you will want to know the symptoms, the causes, and the treatment of peptic ulcers.

• Peptic Ulcer Screening Quiz
• Symptoms of Peptic Ulcers
• Causes of Peptic Ulcers
• Diagnosing Peptic Ulcers
• Peptic Ulcer Treatment
• When Is Surgery Needed For Peptic Ulcers
• Complications of Peptic Ulcers
• Ulcer Warning Signs

Bisphosphonates are widely used for the treatment of bone diseases, including Paget's disease, osteoporosis, hypercalcaemia and malignant bone diseases. Bisphosphonates are active and strong inhibitors of osteoclast activity.^[4] Besides these effects on bone, bisphosphonates also possess antiinflammatory properties, explaining therapeutic trials in inflammatory rheumatic diseases such as rheumatoid arthritis (RA) and ankylosing spondylitis.We discuss the relevance of the use of bisphosphonates in ankylosing spondylitis based upon recently published clinical trial

Antiinflammatory Treatment With Bisphosphonates in Ankylosing Spondylitis

Resource Center Update

Did you miss this article? New Brain-Imaging Technique Detects Early Stages of MCI, AD From the Alzheimer's Association 2007 International Conference on Prevention of Dementia: Magnetic resonance elastography reveals differences in the "stiffness" or elasticity of normal and diseased brain tissue and could enable earlier diagnosis of dementias. Click here to read more on the Alzheimer's Disease Resource Center.

Julie M. Donohue, Ph.D., Marisa Cevasco, B.A., and Meredith B. Rosenthal, Ph.D.

Full Text PDF PDA Full Text PowerPoint Slide Set Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear PubMed Citation

ABSTRACT

Background Evidence suggests that direct-to-consumer advertising of prescription drugs increases pharmaceutical sales and both helps to avert underuse of medicines and leads to potential overuse. Concern about such advertising has increased recently owing to the withdrawal from the market of heavily advertised drugs found to carry serious risks. Moreover, the Food and Drug Administration (FDA) has been criticized for its weak enforcement of laws regulating such advertising.

Methods We examined industry-wide trends in spending by pharmaceutical companies on direct-to-consumer advertising and promotion to physicians during the past decade. We characterized the drugs for which such advertising is used and assessed the timing of advertising after a drug is introduced. Finally, we examined trends in the FDA's regulation of drug advertising.

Results Total spending on pharmaceutical promotion grew from $11.4 billion in 1996 to $29.9 billion in 2005. Although during that time spending on direct-to-consumer advertising increased by 330%, it made up only 14% of total promotional expenditures in 2005. Direct-to-consumer campaigns generally begin within a year after the approval of a product by the FDA. In the context of regulatory changes requiring legal review before issuing letters, the number of letters sent by the FDA to pharmaceutical manufacturers regarding violations of drug-advertising regulations fell from 142 in 1997 to only 21 in 2006.

Conclusions Spending on direct-to-consumer advertising has continued to increase in recent years in spite of the criticisms leveled against it. Our findings suggest that calls for a moratorium on such advertising for new drugs would represent a dramatic departure from current practices.

Source Information

From the Department of Health Policy and Management, University of Pittsburgh Graduate School of Public Health, Pittsburgh (J.M.D.); the Department of Health Policy and Management, Harvard School of Public Health, Boston (M.C., M.B.R.); and Vanderbilt School of Medicine, Nashville (M.C.).

Address reprint requests to Dr. Donohue at the Department of Health Policy and Management, University of Pittsburgh Graduate School of Public Health, Crabtree Hall A613, 130 DeSoto St., Pittsburgh, PA 15261, or at jdonohue@pitt.edu.

Solatol wordt telkens genoemd als beta-blocker in de lezingen.
Eventueel van belang in de plaats van atenolol als daar aanleiding voor zou zijn

soft drink consuption associated medscappe CME 16-08-2007

Role of Nonpharmacologic Treatments in the Management of Atrial Fibrillation
This educational program discusses the role of nonpharmacologic treatments of atrial fibrillation (AF), including evidence supporting drug use before and after AF ablation.
gebruik transcript

August 16, 2007 — New research suggests that opportunistic screening is more effective than usual care in detecting atrial fibrillation (AF) and is less costly than systematic screening in patients aged 65 years and older.

In the first large-scale study to evaluate detection methods of AF, investigators at the University of Birmingham, United Kingdom, found virtually identical rates of detection between opportunistic and systematic AF screening but found a major difference in rates of detection between AF screening of either type and usual care.

These results, the study's lead author David Fitzmaurice, MBChB, MRCGP, MD, FRCGP, told Medscape, warrant a sea change in how primary care clinicians approach older patients.

"If we're serious about identifying these patients, then we have to introduce a screening program. The clinical difficulty with atrial fibrillation is the majority of patients are asymptomatic, so you have to actively screen for it, seek it out," he said.

The study is published online in the August 2 issue of the BMJ.

Haphazard Approach

Currently, added Dr. Fitzmaurice, the approach to detection of AF is "fairly haphazard." In general, he said patients with AF are picked up once they are symptomatic or are fortuitously identified when they go to the clinician for an unrelated complaint, and, in the course of the office visit, they have their pulse or blood pressure taken.

"We know that with oral anticoagulation therapy, we can reduce stroke risk [in patients with AF] by two thirds, which is a phenomenal effect. But the key to stroke prevention lies in identifying these high-risk individuals," he said.

AF is a major risk factor for thromboembolic disease; the study suggests that prevalence of AF occurs in up to 7% of individuals older than 65 years.

This multicentered, cluster, randomized controlled trial I of computerized general practices in England included 14,802 patients aged 65 years or older from 50 practices in England. Half the practices were slated as intervention ones and were randomly allocated to either systematic screening or opportunistic case finding. The primary endpoint was new cases of AF during the 12-month study period.

Systematic screening involved inviting the entire target population — those older than 65 years — to undergo electrocardiography. The opportunistic case finding approach meant that target subjects routinely had their pulse taken and, if it was abnormal, underwent an electrocardiogram.

The remaining 25 practices, which served as controls, continued to provide usual care to their older patients and screened for and diagnosed AF as they normally would. The study's primary endpoint was newly identified AF.

Virtually Identical Rates of Detection

Investigators found the rates of detection of new cases of AF as 1.63% per year in the intervention practices vs 1.04% in the control practices. However, systematic screening and opportunistic case finding detected similar numbers of new cases: 1.62% vs 1.64%, respectively.

In light of the fact that rates of detection were essentially identical for the 2 screening methods of AF, Professor Fitzmaurice said that the more invasive approach and significant costs associated with systematic screening, which are about 5-fold greater than the opportunistic case-finding approach, cannot be justified.

"I think it is fairly clear now that we need to introduce a [AF] screening program. As long as you have an organized primary care system with good coverage of your patient population and physicians routinely take the pulse of all patients over age 65, opportunistic screening is the best and most cost-effective method of detecting atrial fibrillation," he said.

"Over and above that, it is clear that [AF] screening will pick up more patients than routine care," he added.

The NHS research and development health technology assessment programme funded the study. The authors have disclosed no relevant financial relationships..

BMJ. Published online August 2, 2007.

Clinical Cont

No Cancer Signal

In terms of potential side effects, statin therapy was not associated with an increase in any adverse events. No cases of rhabdomyolysis were reported, nor was there a risk of developing liver enzyme elevations. Importantly, there was no increase in the risk of malignancy or renal insufficiency.

"We wanted to look at various different side effects because statins appear to be a wonder drug from many perspectives, but of course we're always reticent to go so aggressive until we have long-term outcomes," said Leeper. "There have been some trials suggesting possible hazards for certain cancers, renal dysfunction, rhabdomyolysis, but in this analysis, in two years of follow-up, we didn't find any risk associated with low LDL levels."

Like other analyses, the study did not address the possible mechanisms of benefit, although it is clear that the benefit of statins extends beyond their ability to lower LDL cholesterol levels. Continued plaque stabilization and the prevention of atheroma development are possible, said Leeper, as are other benefits that have not yet been outlined.

The investigators reported no conflicts of interest.

1. Leeper NJ, Ardehali R, deGoma EM, Heidenreich PA. Statin use in patients with extremely low low-density lipoprotein levels is associated with improved survival. Circulation 2007; 116:613-618.

Viewpoint

In this study, fish oil capsules containing omega-3 fatty acids effectively lowered the AA:EPA ratio in both healthy and CAD patients. Several studies have found that lowering the AA:EPA ratio improved CAD outcomes, including the Study on Prevention of Coronary Atherosclerosis by Intervention with Marine Omega-3 Fatty Acids (SCIMO), the Lyon Diet Heart Study, and the Physician's Health Study.^[1-3] Specifically, the Lyon Diet Heart Study found that a 30% reduction in the AA:EPA ratio was associated with a 70% reduction in the risk for myocardial infarction.^[2]

The US Food and Drug Administration recently approved a prescription form of omega-3 fatty acids as an adjunct to treatment of very high (≥ 500 mg/dL) triglyceride levels.^[4] In this study, triglyceride levels in the CAD patients did not decrease after receiving omega-3 fatty acids. However, the study did not reveal whether any of the CAD participants had "very" high triglyceride levels. A larger and longer prospective study including CAD patients with documented "high" triglyceride levels may demonstrate lipid profile effects from omega-3 fatty acids.

Results: In 23 statin treatment arms with 309,506 person-years of follow-up, there was no significant relationship between percent LDL-C lowering and rates of elevated liver enzymes (R² < p =" 0.91)">2 = 0.05, p = 0.16). Similar results were obtained when absolute LDL-C reduction or achieved LDL-C levels were considered. In contrast, for any 10% LDL-C reduction, rates of elevated liver enzymes increased significantly with higher statin doses. Additional analyses demonstrated a significant inverse association between cancer incidence and achieved LDL-C levels (R² = 0.43, p = 0.009), whereas no such association was demonstrated with percent LDL-C reduction (R² = 0.09, p = 0.92) or absolute LDL-C reduction (R² = 0.05, p = 0.23).
Conclusions: Risk of statin-associated elevated liver enzymes or rhabdomyolysis is not related to the magnitude of LDL-C lowering. However, the risk of cancer is significantly associated with lower achieved LDL-C levels. These findings suggest that drug- and dose-specific effects are more important determinants of liver and muscle toxicity than magnitude of LDL-C lowering. Furthermore, the cardiovascular benefits of low achieved levels of LDL-C may in part be offset by an increased risk of cancer

Cocoa and blood pressure

Cocoa that is used to make dark chocolate contains substances called polyphenols which can have a beneficial effect on blood pressure. To look at how much effect on blood pressure it might have, investigators in Germany conducted a study in people with borderline or mild hypertension. They gave 44 adults, aged 56 through 73 years, either white chocolate or dark chocolate. The amount given was only 6.3 grams a day , about half a tablespoon of chocolate chips, so don't get too excited. White chocolate does not have the polyphenols that dark chocolate has. After 18 months they looked at how many people had high blood pressure. The prevalence of hypertension declined from 86% to 68% in the individuals who received dark chocolate with no change in incidence in those taking white chocolate. The average blood pressure only decreased 2-3 mm Hg but it was enough to shift 18% into the lower non hypertension range. This study indicates that a small amount of cocoa- based chocolate may be beneficial to individuals with high blood pressure. Please do not make the mistake that if a little is good, a lot is better. Cocoa and blood pressure

In the next few months a New Zealand-led clinical trial begins for a pill claimed by two British researchers to have the potential for “a greater impact on the prevention of disease in the Western world than any other known intervention”.

The case for the ‘polypill’ – a super-drug that combines four common medicines used to treat heart disease – was outlined in the British Medical Journal in 2003 in an issue the editor described as perhaps the most important it had published in 50 years.

The two researchers suggested the polypill could reduce cardiovascular disease by more than 80 percent.

The trial of the effectiveness of the polypill, made by the Indian-based global pharmaceutical company Dr Reddy’s, will be led by the New Zealand-based University of Auckland’s Professor Anthony Rodgers, a recognised world leader in clinical trials.

The trial, to start in the second quarter of 2007, will involve about 600 people from New Zealand, India, Australia, Brazil, China, South Africa, the United Kingdom and the United States who have a raised risk of having a heart attack or a stroke.

The global trial will attempt to confirm that the polypill medicines are safe and tolerable when taken together and are still effective when combined in one fixed-dose pill.

Dr Reddy’s’ Chief Operating Officer, Satish Reddy, says there are two notable aspects of the New Zealand-India collaboration, the first being the outstanding clinical development expertise and global credibility Professor Rodgers and his team bring to the project, and secondly, the commitment to making medicine affordable.

Professor Rodgers’ team is an example of New Zealand’s significant clinical trials’ capability. The calibre of New Zealand investigators and clinicians is rated highly internationally, costs are competitive and both ethics and regulatory standards are high.

All the medicines in the polypill – aspirin, a statin to lower cholesterol and two blood pressure drugs – are already widely used. They are also no longer covered by patents, so the polypill will be cheap to produce and at a few dollars a month will be more affordable in developing countries.

The medicines also treat several related conditions and combining them may benefit people who can’t afford regular visits to the doctor.

Professor Rodgers says the four medicines will potentially be much more effective when taken in one pill.

“Research shows that people with chronic diseases like heart disease only take half their medications.”

He says people forget or feel well so don’t take their pills, but this creates a gap in their treatment that can have serious consequences.

“We hope the polypill will provide an easier and more practical way to take the medications," says Professor Rodgers.

The World Health Organization says about 17 million people die prematurely from heart disease and stroke each year and most of those deaths occur in low/middle-income countries.

The Health Research Council of New Zealand has invested NZ$350,000 to support overall co-ordination of the trial and recruitment in New Zealand. Dr Reddy’s will invest NZ$7.5 million in developing the polypill and providing supplies for clinical trials globally.

If the first trial is successful, a full-scale one is planned involving up to 5000 people with a moderate risk of heart disease. This trial will confirm the pill’s ability to prevent heart attacks and strokes.

For more information, please contact:

michelle.sullivan@investmentnz.govt.nz

+64 9 966 9205

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Anthony is the Co-Director of the Clinical Trials Research Unit, at The University of Auckland. He has a decade of research experience in the design, conduct and analysis of large studies of the causes, prevention and treatment of cardiovascular disease. Anthony helped co-ordinate the largest ever surgical trial, testing aspirin in the prevention of deep vein thrombosis and pulmonary embolism and involving over 17,000 patients from Australasia, South Africa and Europe. Anthony also helped design and run the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) involving over 6000 patients from Australasia, Asia and Europe and a collaboration of more than 50 cohort studies in the Asia Pacific, involving more than 600,000 participants, that assesses the determinants of cardiovascular disease in the region.

Most recently, Anthony was the Principal Author of the 2002 World Health Report entitled "Reducing risks, promoting healthy life". The report assessed burden of disease due to a wide range of risks to health around the globe, and evaluated relevant interventions and policy options. The World Health Report is the main annual publication of the World Health Organisation.

Anthony graduated in medicine in the United Kingdom and trained in epidemiology and public health in New Zealand, gaining a Diploma of Public Health and a PhD at the University of Auckland and becoming a Fellow of the Australasian Faculty of Public Health Medicine. Anthony is a member of the Data and Safety Monitoring Board of the Health Research Council, and the Large Scale Clinical Trials Committee of the National Health and Medical Research Council of Australia. He is regularly invited to give presentations at national and international conferences.

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Jump ahead only 3 ½ years, and clinical trials are now getting started. In a study led by Dr. Anthony Rogers of New Zealand, a polypill (manufactured by Dr. Reddy's, a pharmaceutical company in India) will be given to 600 people recruited from 5 continents who have a raised risk of having a heart attack or stroke. The trial, which has now completed enrollment, will examine whether a polypill that consists of 4 drugs will lower blood pressure and cholesterol. If the trial is successful, a follow-up full-scale trial of up to 5,000 people with moderate risk of heart disease is planned to measure the ability of a polypill to reduce the occurrence of heart attack and stroke. ("World's First Polypill Trial" press release from Dr. Reddy's.)

Some people are concerned that a polypill could be too
effective, a 'magic bullet' that removes any incentive to adopt
healthier lifestyles. This is a weak reason to reject a potentially
effective therapy, as is the concern that the polypill would
medicalise prevention (iodine in salt and fluoride in the water
are perhaps two respectable antecedents).(HIER KUN JE HET BIJMENGEN VAN FOLIUMZUUR IN 40 LANDEN AAN HET BROOD TOEVOEGEN) However, it is
true that medical interventions can have serious unintended
consequences, and the polypill would be to the detriment of
personal and population health if it diverted funds and energy
from 'upstream' health promotion measures such as smoking
cessation, healthy food choices and active environments.
Would people take a polypill? Everyone has a relative or
friend who complains of 'rattling' with all their tablets.

Artikel met serieuze bezwaren tegen de polypil door Paul Rosch MD
president of the American institute of stress
MORE ON THE PREPOSTEROUS POLYPILL PANACEA

Polypill � Super Pill

New Pill Could Reduce Heart Disease by 80%, Say Researchers

June 26, 2003 - A single pill taken by everyone over 54 years old could reduce heart attacks and strokes by over 80 percent, according to researchers who are publishing their findings this week in the British Medical Journal.

Professors Nicholas Wald and Malcolm Law propose that a single pill containing six active components - aspirin, a cholesterol lowering drug, three blood pressure lowering drugs at half standard dose, and folic acid - taken daily by everyone from age 55 would have a huge impact on the prevention of disease in the Western world.

Their radical strategy is based on evidence from over 750 trials involving 400,000 participants. Each component of the "Polypill" would reduce one of four cardiovascular risk factors (high blood cholesterol, blood pressure, blood homocysteine levels, and platelet function).

Heart disease is a worldwide scourge. The American Heart Association estimates that in the United States alone, 61.8 million people had some form of cardiovascular disease in 2000 and that almost 1 million people died from it.

Coronary heart disease, which is caused by narrowing of the coronary arteries, is the single leading cause of death in the United States and was responsible for more than 500,000 deaths in 2000. Almost 13 million Americans have a history of heart attack, angina or both, and more than 1 million Americans will have a heart attack this year.

"The idea, supported by lots of evidence, is that if all of us at 55 take the Polypill that has six ingredients then 80 percent of heart attacks and stroke could be gotten rid of," Dr Richard Smith, the editor of the British Medical Journal (BMJ), told a news conference on Thursday.

He described the radical new proposal for dealing with cardiovascular disease, which accounted for 16.6 million or one third of global deaths in 2001, as "a step of genius."

"Because the ingredients are, or are about to be, off patent, this could be an extremely cheap and simple pill," Smith added.

Half of all people will develop heart disease if they live long enough, according to Wald who reported the findings in the BMJ.

The pill would be suitable for people aged 55 and older and many people with existing high blood pressure, heart disease or diabetes. It need not be expensive and should be safe with minimal side effects.

They say their preventive approach would result in one-third of people over 55 gaining, on average, 11 years of life free from such problems.

Trials of the "Polypill" are planned, to see if the combination is safe and effective, and may take several years.

The authors suggest that the pill would be taken without a medical examination or measurement of risk factors as treatment would be effective whatever the initial levels of the risk factors. They say their preventive approach would result in one-third of people over 55 gaining, on average, 11 years of life free from such problems

"Clearly, there's a fairly large issue as to whether in our society it makes sense," says Dr. Richard Stein, associate chairman of medicine at Beth Israel Hospital in New York City and a spokesman for the American Heart Association. "They're proposing it really for developing countries where testing [for heart disease] is not available or is too expensive."

It is time to discard the view that risk factors need to be measured and treated individually if found to be "abnormal," say the authors. Instead it should be recognised that in Western society the risk factors are high in all of us, so everyone is at risk. There is much to gain and little to lose by the widespread use of these drugs, they conclude.

So, is this bold conclusion justified? Quite possibly, says Dr. Anthony Rodgers in an accompanying editorial. Despite widespread perceptions, these medications are extremely safe and well tolerated � new problems seem unlikely since they have been studied so extensively and used so often together. Realising their enormous potential should be a major goal.

BMJ-British Medical Journal

deze stukken uit NEWS
POLYPILL HOLDS PROMISE FOR PEOPLE WITH CHRONIC DISEASE
( meer interessante gegevens in dit artikel)

Polypills are also
expected to increase
patient adherence. This
has been shown with
combination drugs for
diabetes, hypertension and HIV/
AIDS, according to a study published
in the Bulletin in December 2004.
A study to find out if this is also
the case in patients with established
cardiovascular disease is to start recruiting
from January to March 2006.
The GAP, or Guidelines Adherence to
Polypill study, set up by the George
Institute for International Health,
will randomize 1000 patients with
established cardiovascular disease to a
polypill-based approach or to standard
care. The patients will be followed for
two years.
A similar study of 600 patients is
to start in New Zealand next year, led
by Anthony Rodgers
of the University of
Auckland. Patients
with a definite indication
for all medicines,
such as following a
heart attack or stroke,
will be randomized
to polypill or conventional
care. The main
outcome measures will
include compliance,
blood-pressure and
cholesterol levels.
Fixed-dose combinations
are now a
core component of care
for people with HIV/AIDS, tuberculosis
and malaria. As well as improving
clinical outcomes, they simplify
distribution of multiple medications,
which can be an important advantage
in resource-limited health-care settings.
Some public health experts say
another way of improving access to
Farming practices, long-held lifestyle
traditions and poverty-line economics
all make recent outbreaks of avian flu
in Asia a far bigger global public health
threat than the westward spread of the
disease into Europe’s poultry flocks.
For many rural Asian communities,
backyard chickens and very
small-scale poultry farms are part of
the landscape. Children play in the
same yard where the household’s flock
scratch and where chickens that die are
typically eaten in order not to waste a
valuable source of protein.
Best defence against avian flu
is to fight the virus in Asia
The spread of avian flu to Africa and Europe
has triggered panic as misconceptions abound
over the nature of the threat this poses to
human health.
A small child with ducks outside her house in Indonesia. As shown by this picture, families in many Asian
countries live in close proximity to their poultry.
WHO/SEARO
medicines and treatment for chronic
disease would be through publicprivate
partnerships (PPPs). A report
by a team from the London School
of Economics and Political Science,
led by Dr Mary Moran, found that
PPPs have driven the recent considerable
increase in research activity into
so-called neglected diseases, such as
malaria and tuberculosis.
After a time when few new
therapies were introduced, there are
now over 60 drug research projects
under way. Three-quarters of these are
conducted under the auspices of PPPs
and should result in six or seven new
drugs being developed by 2010.
There are no PPPs working in
the area of chronic disease, a situation
Rodgers, who is director of the
Clinical Trials Research Unit at the
University of Auckland, in New
Zealand, wants to change. Rodgers
is involved in early consultations to
set up a PPP to make treatment for
chronic diseases more accessible to
people in need.
“We desperately need a not-for
profit organization that enables public-
private partnerships to make new
medicines more available. Not just
new technologies like the polypill, but
also health-care delivery solutions.” O
Jacqui Wise, Cape Town

The study, conducted by a team
led by Dr Shanthi Mendis, WHO’s
Coordinator for Cardiovascular
Diseases, sampled 10 000 patients in
10 low-and-middle-income countries
and found about one-fifth of patients
with coronary heart disease were not
receiving any aspirin and about half
the patients were not on beta-blockers,
which are low cost and widely
available.
Two of the main barriers to
providing adequate care for chronic
conditions are the
limited financial and
infrastructure resources
available for health
care in most lowerincome
countries.
“High-cost, physicianbased
models of care
for chronic diseases
developed mainly
in higher-income
countries are usually
completely unsuited
to lower-income settings,”
said Neal.
The use of fixeddose
combination
therapy in the form
of a single pill for
cardiovascular disease
prevention was first
proposed in a WHO publication on
secondary prevention of noncommunicable
diseases in 2001.
Two years later, Dr Nicholas
Wald and Dr Malcolm Law provided
evidence for the potential efficacy of a
polypill as a public health approach to
cardiovascular prevention in their paper
in the BMJ. The BMJ’s editor at
the time, Richard Smith described the
article as the journal’s most important
for 50 years. They suggested giving a
combination pill containing a statin,
a diuretic, a beta-blocker, an ACE
inhibitor, aspirin and folic acid to all
adults over 55 and to adults of any
age with diabetes or cardiovascular
disease, regardless of risk factors.
This approach contrasts with that
of the Working Group study, which
recommended such treatment for
patients who are at risk of and those
who have had a heart attack or stroke.
The Working Group said it may be
necessary to target such a combination
pill at patients who are at greatest
risk of having a heart attack or stroke
for maximum cost-effectiveness.
This approach could mean targeting
urban areas rather than rural ones.
In urban Delhi, India, 22% of people
older than 55 years of age have more
than a 20% risk of developing cardiovascular
disease over 10 years, whereas
in the rural state of Haryana only 8%
have more than a 20% risk.
WHO has also explored the
benefits of fixed-dose combination
drugs for high-risk patients. Last year,
a WHO report, Priority
Medicines for Europe
and the World: A Public
Health Approach to
Innovation, provided
compelling evidence
that high-risk patients
would enjoy clear
benefits from such
fixed-dose combinations.
Neal said: “The
chief advantages of the
polypill will be that it
will be much cheaper
to manufacture and
distribute and much
simpler to prescribe.”
Because the
components of a
polypill are no longer
covered by patent restrictions it could
be produced at a cost of little more
than US$ 1 per patient per month,
according to the WHO chronic
diseases report. Combination drug
therapy — using aspirin, beta-blocker,

diseases: a vital investment. Only
20% of chronic disease deaths occur
in high-income countries — while
80% occur in low-and-middle-income
countries and these deaths occur
in equal numbers among men and
women, the report said.
Deaths from infectious diseases,
maternal and perinatal conditions, and
nutritional deficiencies combined are
projected to decline by 3% over the next
10 years globally. However, over the
same period deaths due to chronic diseases
are projected to increase by 17%.
A recent study carried out in
Andhra Pradesh found that noncommunicable
and chronic diseases are the
leading causes of death in this rural
state of India. One of the authors of
the study, Dr Bruce Neal, Director
of the Cardiac and Renal Division at
the George Institute for International
Health, in Sydney, said that the health
delivery system was in urgent need of
“reorientation” to enable the implementation
of evidence-based strategies
to address the challenge of noncommunicable
diseases.
Neal told the Bulletin: “While
many lower-income countries have
made very substantial advances in the
treatment and prevention of acute
communicable conditions and in the
management of maternal and child

Chronic disease ‘epidemic’
affects Africa too
Infectious diseases remain a leading
cause of death in sub-Saharan African
countries, but some African countries
including Kenya, Nigeria and South Africa
are facing a high prevalence of chronic
and noncommunicable diseases.
“Coronary heart disease is a
huge problem in Africa and is reaching
epidemic proportions. This is related to
urbanization with people eating more
fast food, smoking more and exercising
less,” said Shan Biesman-Simons, Director
of Nutrition and Education for the Heart
Foundation in South Africa.
Nigeria is also taking the problem
of chronic disease seriously. President
Olusegun Obasanjo said his country
would be facing a time bomb if it did
not act now to address the problem of
chronic disease.
“We cannot afford to say ‘we must
tackle other diseases first — HIV/AIDS,
malaria, tuberculosis — then we will deal
with chronic diseases.’ If we wait even
10 years, we will find that the problem
is even larger and more expensive to
address,” Obasanjo wrote in the WHO
report, Preventing chronic diseases: a
vital investment.
Access to doctors and appropriate
treatment is a major problem in many
developing countries. “In the public sector
in South Africa it can be very difficult for
people to get access to medicines,”
Biesman-Simons told the Bulletin.
“They may have to travel long
distances to get to a clinic, then they
may have to wait in a queue all day, and
they still may be sent home without the
correct treatment,” she said.
Poor education is another problem
area, both for the medical profession and
the general public. Biesman-Simons gave
the example of rheumatic heart disease,
often called the disease of poverty,
although it is entirely preventable. A
“strep” throat can be treated extremely
cheaply with penicillin, but if left untreated
it can develop into rheumatic fever, which
can then lead to heart damage.
“Thousands of young people in
South Africa are waiting for expensive
heart valve replacement operations and
have a poor quality of life and this could
have been avoided if they had been
diagnosed and treated appropriately at
the start,” Biesman-Simons said.
Jacqui Wise, Cape Town

The researchers say the Polypill should be taken by everyone over the age of 55, and by younger people who have a history of cardiovascular disease, to achieve the maximum benefit.

"The idea, supported by lots of evidence, is that if all of us at 55 take the Polypill that has six ingredients, then 80% of heart attacks and stroke could be gotten rid of," Dr Richard Smith, the editor of the BMJ told a news conference in London.

He described the radical new proposal for dealing with cardiovascular disease, which accounted for 16.6 million (or one third) of global deaths in 2001, as "a step of genius": "Because the ingredients are, or are about to be, off patent, this could be an extremely cheap and simple pill," Smith added.

Half of all people will develop heart disease if they live long enough, according to Wald. The Polypill strategy is based on evidence from 750 clinical trials that have shown the pill's individual components cut the risk of heart disease. They believe combining them in one daily, widely used pill will save lives and have minimal side effects.

"Probably no other preventive method or treatment would have as great an impact on preventing heart disease in the Western world," Wald said.

Positive reactions to concept

The Polypill concept got the thumbs up from one Australian expert who researches 'evidence-based' medicine for general practitioners: "I've talked to some of my colleagues about it and we think this is the most important paper printed for a very long time," said Professor Chris Del Mar of the University of Queensland in Brisbane.

"I think this is going to have enormous implications for the way we work in the medical profession and the way patients get care," he told ABC Science Online. "There should be a very serious go at this approach."

Del Mar said that it was a "whole population approach" to dealing with heart disease which so far had been treated individually. Rather than monitor and treat individual risk factors such as blood pressure and cholesterol, the Polypill would be a preventative public health measure, similar to fluoridation or vaccination.

"You don't need all the monitoring and all the blood tests that goes on," he said. "Age is the biggest risk factor for coronary heart disease, so just put everyone over 55 on it."

He also said the drugs were quite safe, and even those with normal cholesterol and blood pressure might benefit from lowering these. "It's quite hard to hurt yourself with these drugs, so maybe they should be available off the shelf, without prescription," he said. "Just like we say for kids who have a fever: 'Mum, go and buy some paracetamol'."

Del Mar said a large trial to determine the effectiveness of the Polypill should explore unknowns, such as the impact of combining side-effects of each drug. He also acknowledged for some individuals, the risk of taking the pill may outweigh the benefits.

Professor Andrew Tonkin, medical and scientific director of the National Heart Foundation of Australia, described the Polypill as a "fascinating concept based on a very robust body of data", but emphasised the success of such a pill was still theoretical.

He also expressed concern that the pill would encourage complacency about the importance of lifestyle factors in preventing heart disease: "There is a minor risk that the pill would encourage people to think that a 'super pill' will solve all their problems," he told ABC Science Online, adding that a loss of flexibility in dosing may also be a problem.

Tonkin said the idea was not entirely new, and had been previously considered important for dealing with the growing problem of coronary heart disease in developing countries, as people there increasingly adopt a Western lifestyle.

zie artikel voor meer EMBO reports 7, 3, 246–249 (2006) doi:10.1038/sj.embor.7400654 Racial medicine: here to stay? The success of the International HapMap Project and other initiatives may help to overcome racial profiling in medicine, but old habits die hard Katrin Weigmann

Adverse drug reactions are an underestimated but serious problem in medicine, and are the fourth leading cause of death in the USA after cancer, coronary heart disease and stroke (Lazarou et al, 1998). Although any given drug, if prescribed correctly, is beneficial for most patients, it may have unexpected results in a small subset of users. This can range from simply having no effect at all to causing serious, sometimes life-threatening, side effects. This variation stems—at least in part—from metabolic and genetic differences between patients. It would be a big leap for medicine if physicians could identify these differences and treat patients based on their individual genetic makeup. Now that the human genome sequence is complete, several follow-up genomic projects, most notably the HapMap initiative to identify and catalogue haplotypes, are focusing on identifying such genetic variants. But it is not yet clear whether this knowledge will lead to personalized medicine. One hindrance is the fact that, for the time being, physicians and scientists have found a comfortable interim solution: racial profiling. Although, at first, this approach could help to use drugs more efficiently, in the long term, it could hinder the exploitation of genetic information in medicine. In fact, physicians increasingly use their patients' skin colour or other physiological features as a first step towards 'individual' treatment, under the assumption that specific traits cluster by race. "When I prescribe Prozac to a patient who is African-American, I start at a lower dose, [...] in part because clinical experience and pharmacological research show that blacks metabolize antidepressants more slowly than Caucasians and Asians," wrote Sally Satel, a psychiatrist and resident scholar at the American Enterprise Institute for Public Policy Research (Washington, DC, USA; Satel, 2002). She is certainly not alone: from 1995 to 1998, the prescription information for 15 new drug products contained a statement about their differing effectiveness depending on race (Tate & Goldstein, 2004). Claims have been made in peer-reviewed journals that at least 29 medications have racial or ethnic differences in safety or efficacy, although most of these claims are controversial (Tate & Goldstein, 2004). In June 2005, the US Food and Drug Administration (FDA; Rockville, MD) approved the first drug labelled for a racially identified population: BiDil® (NitroMed; Lexington, MA, USA) for the treatment of chronic heart failure in African-Americans. And in July 2005, the European Patent Office (Munich, Germany) renewed a patent for the BRCA2 gene test "for diagnosing a predisposition to breast cancer in Ashkenazi-Jewish women", because mutations of this gene are frequently found in that population. Race has been a dominant concept in our society for centuries and has concerned scientists as much as anyone else. However, most scientists agree that race makes a bad scientific concept (Rotimi, 2004; Tishkoff & Kidd, 2004; Wilson et al, 2001). Not only do humans share 99.9% of their genetic makeup, regardless of race, but most of the variants that occur in the remaining 0.01% of the genome—although they vary between individuals—are shared between whole populations. Moreover, a social or physiological concept of race is not the best strategy to identify underlying genetic differences. Relying on a few obvious characteristics, such as skin colour or eye shape, tells something, but not everything, about a person's ancestry. "It doesn't mean that if we look at these various groups as we define them now, that some of these genetic variants are not going to be more frequent in some groups, but there is overlap," said Charles Rotimi, a biochemist and genetic epidemiologist at the National Human Genome Center at Howard University (Washington, DC, USA). "What is important to recognize however, is that genetic variants cut across social demographic groups in ways that make it difficult for us to consistently say who is black or Hispanic, for example."

Solomon C. Goldberg¹, Nina R. Schooler¹, Edwin M. Davidson² and Melvin M. Kayce²

(1)	National Institute of Mental Health, USA

(2)	Boston State Hospital, USA

Received: 18 June 1965

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Some polymorphisms that raise variability in drug metabolism occur at higher frequencies in the genomes of particular races. The P-glycoprotein (PGP) is a transporter that distributes many types of drugs, including those used in chemotherapy. Globally, there is an immense genetic variation in the gene encoding PGP. What is interesting in the case of PGP is that different races have been characterized as having higher frequencies of certain PGP polymorphisms. Studies have shown that African people have about an 80% chance of having one specific version while Asian and European peoples have half that chance (Kim et al., 2001).