PolyPill- Treating the Healthy

 PolyPill was an idea conceived by two professors: Nicolas Ward and Malcolm Law in 2001. The idea was simple. On pill, taken once a day by all people over 55, all diabetics over 35 and all people with cardiovascular disease, containing a mixture of drugs and vitamins could be a cheap and easy solution to reduce the risk  (according to their research) of ischaemic heart disease (IHD) by 88% and strokes by 80%¹. They claimed that such a pill, which they called PolyPill, would have “a greater impact on the prevention of disease in the western world than any single intervention.

 Whilst the concept is easy to understand the exact composition and research for the PolyPill is more complicated. The trial Ward and Law used to justify their idea di not take people give them a pill containing a drug-vitamin mix and then record how many suffered from IHD and strokes. Rather the study looked was a meta-analysis. It looked at all previous research into the drugs they were interested in and cleverly linked them together.  IHD and strokes are not like a broken bone or a pathogenic disease in that they have a single obvious cause. Both are related to a number of risk factors. Having high levels of such risk factors would not mean you would get IHD or strokes it would only be more probable. There are similar difficulties in trying to persuade smoker of the link between smoking and lung cancer. All smokers will know one lucky sod that smoked for years without developing cancer and forget the large numbers of people who unfortunately do.

 Previous trial targeted people at risk of developing IDH due to being on the extremely high or low end of one one risk factor distribution and tested to see if they could reduce the number of people developing IHD by using a drug that is designed to return that single risk factor to within normal limits. What Ward and law did was to suggest that if all these drugs were taken together in one pill it could return all known risk factor to normal limits and have a significant effect on the majority of people not just people in the extreme ends of one risk factor distribution.
 The suggested ingredient of a PolyPill would be:

• A number of drugs to reduce blood pressure (a significant risk factor of IHD) such as: 

1.  a diuretic (a chemical that increases the excretion of fluid from the body via the kidney nephrons
2.     a beta-blocker (a drug that reduces the effect of the hormones epinephrine and norepinephrine (see my post on Brunner’s syndrome))
3. an ACE inhibitor ( a chemical that inhibits the enzyme angiotensin-converting enzyme (ACE) which is part of the blood pressure regulating system. The net result is a reduction in blood volume and therefore a reduction in blood pressure)

How ACE Inhibitors work

• A statin which is a drug that reduces blood cholesterol levels by inhibiting the enzyme HMG-CoA reductase thus slowing a chain of metabolic reactions leading to cholesterol production.
• Aspirin, which among other things reduces clot formation by inhibiting the production of thromboxane a chemical that binds platelets together.  
• Folic acid, a vitamin that among other things, reduces the levels of the non-protein amino acid Homocystiene in the blood.

a Folic acid molecule

Homocystiene: Like cysteine but with an extra methyl group 

The advantages of PolyPill are that it could significantly reduce the human and financial cost of IHD and strokes which are together responsible for a third of all deaths in western countries. The pill helpfully contains ingredients that cannot be patented by drug companies so it could be made as cheaply a 10p for one daily pill. (this does however explain why drug companies have been unwilling to fund trial into PolyPill despite its huge potential benefits).

 PolyPill has not gone without criticism however. Ignoring entertaining but pretty irrelevant satire such as proposals for a PolyMeal² (a daily meal containing a small number of healthy ingredients such as almonds, garlic and fruit) the concept has also come under considerable criticism about some of the contents (it appears homocystine which the folic acid is there to reduce has only a correlative role not a causative role in IHD so the folic acid will not reduce IDH just make the blood tests look better) and because it appears Ward and law were too enthusiastic in describing PolyPill as a solution to preventing IHD and strokes (primary prevention) not preventing existing conditions of the early stages of IHD developing to the stage where it causes significant morbidity (secondary prevention). Also bear in mind that the drugs in PolyPill are not without risk. Ward and Law admit that 8-15% of people may experience some side effect.

 But PolyPill has come under most criticism for discouraging people from taking care of dietary and social risk factors associated with IHD. Why have a moderate alcohol intake, healthy diet and lots of exercise if there is a pill to do it for you? It worries me that PolyPill may become a danger to public health by medicalizing your chemical intake and distracting from simple causes of disease however much I like the idea for its simplicity and apparent efficiency. 

1-Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. http://www.bmj.com/content/326/7404/1419.full

2- PolyMeal- http://www.ncbi.nlm.nih.gov/pubmed/15604180

PET scans- Lets's Antimatter your Brain

 On my work experience recently in radiology I unfortunately didn’t get the chance to look at one of these, which was in the realm of the mysterious nuclear medicine nearby. I did however get to see the final images from this type of scan combined with a CT scan and wanted to research PET further.

How it works

   PET scans are where particle physics meets clinical medicine. The procedure involves injecting a radioactive isotope into the patient inside a scanner. The radioisotope decays emitting a positron, the antimatter alternative of an electron, same in mass but positively charged. The positron travels through typically 1mm of tissue during which it loses speed enough to collide with an electron. The two particles annihilate each other and two gamma rays are emitted around 180^o from each other. The scanner detects gamma rays and stores information about it if two rays are detected roughly 180^o from each other. All other rays are ignored. By getting lots of gamma ray pairs and by tracing back the rays to their source a three-dimensional picture of the body showing where the radioactive isotope has gone. PET scans are usually combined with a CT scan to make a PET-CT scan so that the two can be registered together and the anomalies of can be corrected by the other.

 The radioactive isotopes used in PET are typically normal biological molecules such as glucose with a few radioactive atoms such as carbon-11. The isotope needs to be such that it has a long enough half-life to be made off site and imported and short enough so that the patient is not in the scanner for weeks to get enough data. A common tracer is fludeoxyglucose (¹⁸F) or FDG, which is essentially a glucose molecule with the hydroxyl group on the second carbon replaced with an atom of fluorine-18.

A FDG molecule

  The advantage of FDG is that like normal glucose it is quickly take in up by cells that are respiring quickly such as brain, kidney and more importantly cancer cell. Because the hydroxyl group on the second carbon in the ring (that FDG lacks) is involved part way through the process of breaking down glucose, the FGD molecule is only half way converted to water and carbon dioxide. The FGD-phosphate that results when the process is stopped at this point remains in the cell due to its ionic charge until the fluorine-18 decays leading to the positron emission that is then detected. The decay helpfully leaves non-radioactive products that are metabolised normally.

  Scans of cancerous tumours are 90% of all PET scans. In the area they are especially useful for tracing the spread of cancer cells. Cancers spread by metastasis. This is when the primary tumour formed by a mutation grows into the path of a lymph node or blood vessel. Cells from the tumour are spread through the lymph or blood system and end up elsewhere in the body. By doing a PET scan using FDG on people with cancers that commonly metastasize it is possible to assess how much the cancer has spread which is a significant factor in the treatment and prognosis of the disease. 

The result of a PET-CT scan to assess the spread of a lung cancer tumour

 There are however a few problems with a PET scan. Due to the quick decay of the tracers the hospital in which it is situated must have a very speedy transport link to the location the tracer is made so the isotope doesn’t decay on route. Few hospitals can afford the costs involved. The scan also gives the patient a significant dose of radiation that could cause more harm than good if used unwisely. A typical PET and CT combination gives a combined dose of 23-26mSv of radiation compared with 0.2mSv for a chest x-ray or 7mSv for a normal CT.    

PolyHeme®- Signed you up without you knowing

 Blood substitutes would no doubt be a huge benefit to mankind. Outside of hospital it is difficult to store human blood and impossible to find the right blood type. Paramedics are restricted to saline solutions to increase the volume of the blood for patients with severe bleeding. A fluid that mimics the ability of blood to get oxygen to the tissue would provide a huge advantage. Unlike real blood the substitutes would be universally compatible so there would be no need for time-consuming blood testing. Real blood is also in short supply due to lack of donors and expires after only 42 days. An easily manufactured blood substitute could be made quickly so it would never run out and could have a shelf life of up to 12 months. Blood substitutes would also reduce the risk of viruses and other pathogens such as the HIV virus slipping through the net of donor blood testing. As an extra bonus blood substitutes can be made thinner than blood so they can be transfused more quickly in an emergency. PolyHeme manufactured by Northfield Laboratories Inc. was a blood substitute that has come furthest in clinical trials. It was designed to replace blood for a short time until human blood can be given. It was made from expired human blood, which means it could only reduce not remove the need for blood donors.

  Effective blood substitutes are remarkably difficult to make. The main type of blood substitute is called haemoglobin-based oxygen carriers, which use haemoglobin molecules in some form to get blood to the tissues. The problem is that outside cells haemoglobin tends to remain dissociated with oxygen and takes up nitric oxide causing vasoconstriction. The liver also struggles to remove it leading to liver failure. The solution to these problems is to join the haemoglobin molecules together somehow. PolyHeme did this by polymerisation, joining monomers of 4 haemoglobin molecules into a long chain. By controlling the polymerisation the liver problems and vasoconstriction can be ironed out.

 PolyHeme was trialled successfully in a hospital setting before and after surgery and showed clear benefits in those receiving PolyHeme over those not receive blood or blood substitute. However Northfield laboratories Inc. wanted to trial the substitute in an emergency setting where it would be of most use.

 The trouble with trying to research things in an emergency medicine setting is that the patients are usually too busy bleeding everywhere to give informed consent into an experimental trial. To get round this problem of not obtaining consent for its phase III Northfield laboratories Inc. had to agree with certain conditions set by the American FDA (Food and Drug Administration):

1  ) The subject must be suffering from a life-threatening condition necessitating immediate treatment.

2  ) Obtaining informed consent from a legally authorized representative must be infeasible given the time frame in which the subject must be treated.

3  )  Previous clinical evidence must indicate that the investigated therapy will grant a serious benefit to the subject.

4  ) The investigators must make an effort to contact a legally authorized representative during the given therapeutic window.

5  ) An independent committee must review collected data of the ongoing study.

6  ) Available treatments must be “unproven and unsatisfactory”

7) Principal investigators must meet with the communities from which the subjects will be drawn, and publicly disclose pertinent aspects of the study including the risks and benefits.  

 In the phrase III trials involving 32 trauma centres across 19 US states it was the 7^th condition that made it, to put it mildly, ethically dubious. The trial split patients with severe bleeding (car accident victims, victims of violence etc. and patients who were pregnant or suffered serious head injuries or possibly fatal injuries could were excluded) into a control group, who received saline solution before reaching hospital then donated blood at hospital, and the test group, who received PolyHeme before reaching hospital and then PolyHeme afterwards for 12 hours even though more effective donated blood was available.

Signing people up without permission understandably caused a lot of controversy. To avoid some of the criticism the hospitals involved had an opt-out process available. Anyone who did not want to participate in the trial could carry a bracelet with the words: “I decline the PolyHeme trial.’ There are some quite clear flaws with this method. To decline the trial you must first have heard of it and Northfield appeared less than enthusiastic about having to organise community meeting or advertise the trial despite the 7^th condition they agreed on with the FDA. At the community meetings they did organise they were secretive about the exact trial protocol in order to protect its intellectual property (which definitely seems to contradict the agreement that “pertinent aspects of the study including risks and benefits” should be publicly disclosed).

 Northfield Laboratories also came under criticism for targeting minority and low-income neighborhoods for the study. In San Diego, only ambulances working south of Interstate 8, a traditionally bad neighborhood, were equipped with PolyHeme. The company claimed that they wanted to perform the study in neighborhoods with lots of traumatic violence. In this area especially the trial was poorly publicized: ads were supposed to be posted in newspapers and on television indicating the nature of the study and ways to opt out, but never were. Its also appears a little too convenient for the company that the controversial trial was done on people without the money to sue for damages.

 The ethical issues surrounding the PolyHeme trial would have been ignored if it showed a clear benefit over the standard treatment of saline solution. However when the trial results were announced in Nov. 2006 it was revealed that 13.25 of PolyHeme patients died compared with 9.6% of the control group. People fled Northfield Labs like rats from a sinking ship and its share price plummeted. In 2009 the company entered bankruptcy. Various hospitals involved denied they actually ever used the product. The FDA however stood by its decision to approve the trial to the rage of ethical groups. Whilst the human losses from the trial are regrettable the lack of success of blood substitutes is also a shame. New research is looking into the possibility of using stem cells instead for a quick fix of the blood shortage.

Reflexes-A No Brainer

 Reflexes aren’t just useful in evolutionary terms, protecting the body from danger; they also have clinical significance in diagnosing neurological disorders. As the reflex arc (the pathway of a nerve impulse from the sensory receptors along a motor neurone to the spinal cord and to a muscles along a motor neurone) involves all the parts of the peripheral nervous system, reflexes can quickly test how well all these nerves are working.

the Knee Jerk Reflex Arc

  One of the most commonly tested reflexes is the knee-jerk response. The reflex has evolved to keep the body in a standing position. As the knees buckle due to the weigh of the body the tendons in the knee stretch and activate stretch receptors in your thigh. This sets of a reflex that activates the thigh muscles to straighten the leg and stop you falling over. This happens many times a minutes without you noticing. In a clinical setting the reflex can be activated by tapping the patella tendon with a rubber hammer and the knee should extend. It is strongly recommended that you don’t stand in front of the patient when doing this. If the reflex is not present it can be a sign of an injury to the spinal cord.

  Another set of reflexes commonly used to diagnose is the pupillary and blink reflexes. The pupillary reflex is the dilation of the pupils to a bright light. Normally both pupils will dilate even if the light is only shone into one eye. If for instance the right pupil dilates when a light is shone into it but the left remains undilated then this could suggest damage to the motor nerve to the left eye. If both pupils dilate when a light is shone into the left eye but no response from either pupil if the light is shone in the right eye then this suggests a sensory problem in the right eye such as retina damage or damage to the right optic nerve. No response at all from either eye could suggest damage to the sensory nerves or brain stem or could be a sign of drug abuse.

An Abnormal Pupillary Reflex Response

    The blink reflex evolved to protect the eye from object coming towards it. It’s particularly useful because it can be conditioned out by the brain (for example by any one like me who wears contact lenses and so has to move object towards their eye). A good way of testing it is by tapping some one lightly on the forehead repeatedly (Try this one at home, I found it quite entertaining). For the first few taps they will blink fully but after that they won’t or only twitch their eyelids slightly. This is because the cerebellum begins to tune down the reflex when the brain realises there is no apparent danger. An absence of this response could suggest damage to the cerebellum. 

  Another interesting set of reflexes is the primitive or infantile reflexes. These are reflexes that are present at birth but slowly disappear. They have mostly evolved to protect or aid the baby such as the sucking reflex that aids breastfeeding and the swimming reflex where the baby attempts to paddle if its face is placed into water giving its mother longer to save it (don’t try this at home however tempting). A common reflex is the Moro reflex (after the Austrian paediatrician Ernst Moro). When startled or experiencing falling the baby will fling its arms to the side, look shocked and then start crying. This probably evolved to help the baby cling to its mother when being carried. It usually disappears around 3-4 months after birth. If it persists it could suggest a birth injury or neurological problems.

A- The Babinski Response
B- Normal adult response

 Another infantile reflex is the Babinski or plantar reflex (after Joseph Jules Francois Felix Babinski a French neurologist with a very long name). If the sole of the foot is stroked from the heel to near the big toe with a probe adults curl the toes downwards. Infants show the Babinski response which is when the toes curling upwards. If adults show the Babinski response or other infantile reflexes such as the Moro reflex this could mean the patient has dementia or has suffered a stroke.