Malaria Eradication

Malaria is a shitty, piss-poor, easily-prevented, easily-treated, easily-eradicable disease that kills millions throughout the world every year.

Why?

Poverty.

Let’s talk about me (as usual) and malaria first. I’ve had it too many times to count – and, hey I’m still here! The very first time was 6 months after getting back to England from a year in China and 3 months in India. I spent two weeks with flu-like symptoms in a student house during the Easter holidays and “the flu” wasn’t clearing up so I eventually ... phoned Mum and Dad and said “I’m coming home”. I got home, they took one look at me, called the GP and I was sent to hospital.

Isolation. I could be contagious. In those days (1980s) a very very simple malaria test could only be executed at the two tropical medicine hospitals in the UK so the turn-around took a few days. Whilst we waited for the results and as my paternal grandfather had died from lymphoma, they had a cancer “specialist” come and look at me. Results came back, a course of Chloroquine and off-you-go – not that they didn’t invite me back to their Friday lunchtime general-meeting of interesting cases at which I was asked all about how I had felt. … like a long case of flu …

Six months later it recurred. Remember your father, uncle, grandfather who served in S.E. Asia during the war who always had bouts of fever for years and years? Well, nowadays and in the 1980s, there is a way of getting rid of recurring malaria. Just the doctors at the local general hospital didn’t know. I went to the local GP – she was Indian – I said I’ve got malaria, I want a prescription for chloroquine. She was very sympathetic, and knew, but she said “No … if you wanted it for arthritis, fine, but for malaria I have to have a blood-test result”.

Another four days of waiting … but this time, in addition to the Chloroquine to get the malaria out of my blood, she gave me Primaquine to get it out of its safe-storage in my liver and thus prevent it from recurring.

Malaria is caused by a parasite of the genus Plasmodium. In humans there are four species that cause malaria – P. falciparum, P. malariae, P. ovale and P. vivax. P. vivax is the one that remains dormant in your liver, if not treated. P. falciparum does not but is the most dangerous and can directly kill, if not treated. All these species are transmitted into human blood through the bite of vampiric Anopheles mosquitoes.

The malaria parasites have, over the recent past (let us say 150 years) developed resistance to the drugs used to destroy them (cunning buggers). Once upon a time P. falciparum could be treated with Chloroquine – now it is all but useless.

In our tiny African country, malaria has been a major killer ever since it was colonised (it was uninhabited at colonisation). The principle parasite is P. falciparum, although very small percentages of the other species do occur. As our country consists of two small islands at some distance from the continent, we are an ideal testing-bed for eradicating the disease – this has been achieved on other islands, for example, in the Pacific, the most notable and most relevant to this post being Taiwan which was certified as malaria-free in 1965. This is equally borne out by two outbreaks of the sleeping-sickness vector, the tse-tse fly, in the last century on the smaller of our two islands and which was eradicated twice.

Back in 1982 a WHO-sponsored initiative attempted to eradicate the malaria vector, Anopheles mosquitoes, using the notorious insecticide DDT. Although the incidence of malaria decreased, it also resulted in the death of much poultry and livestock. The campaign was “imposed”, was not integrated, was resented, was not sustained and malaria made a comeback with a vengeance.

In 2002-2003 another attempt began receiving a range of inputs from a range of donors. US and Portuguese research, education and promotion of impregnated mosquito nets by the Seventh Day Adventist development agency ADRA etc etc.

But the biggest input has been from the Taiwanese. They have some experience in its eradication.

The Taiwanese part of the programme has two main components:

• prevention through the spraying of house interiors.

• treatment with the latest anti-malarial medications.
  

The insecticide used is Alphacypermethrin. This does not require a general fumigation, as DDT, but is sprayed on the interior walls of houses. The mode of action is surprisingly simple - the mosquito bites an infected sleeping person, has a good meal and then goes off to have a fatal siesta on the nearest impregnated wall.

Supposedly, the effect of one application will last 400 days – but I am sure this will vary with the absorption capacity of the surface being sprayed. Untreated wood, varnished or painted wood or cement block, matt or gloss.

The Taiwanese claim that Alphacypermethrin is ecologically safe. However, there is no biodiversity impact evaluation as part of the study. I have certainly noticed a decline in butterflies in recent years – this could just as well be due to other factors (e.g. climate change) but monitoring could be worthwhile both for human health and biodiversity.

The second component of the Taiwanese programme is treatment. The traditional treatment, chloroquine, has been largely ineffective for several years as Plasmodium falciparum has become resistant to it. Various other drugs have been used here – Quinine, Fansidar, Mefloquine, Halfan etc – but there were no guidelines and each doctor would prescribe what s/he felt fit.

Now we are using in the first line a combination treatment of Amodiaquine and Artesunate. Clearly, the former is part of the quinine family (of which I haven’t studied the modes of action as I have with the chemotherapy drugs Kezia is taking). The latter has a fascinating history!

The mainland Chinese started studying the anti-malarial effects of the traditional anti-malarial medicine derived from the plant Artemisa anna back in the 1960s. For various reasons, including the upheavals of the Cultural Revolution, the positive results were not published internationally. When they were, in the 1990s, they were pretty much “poohed-poohed” by the developed world except … the pharmaceuticals who pricked up their ears and went for it big time! The plant’s active ingredient was Artemisin and soon the synthetic Artesunate was developed.

Artesunate is fast-acting but has a very short half-life (i.e. very quickly disappears from the blood). Amodiaquine has longer half-life. The tablets are marketed in packs of a pair a day. If there is still some residual malaria, then a second line of attack is used – the trade name Coartem, a combination of Artesunate and Lumefantrine (in turn developed from halofantrine, the basis of Halfan, which at the time of its recent development was revolutionary in its approach to killing malaria parasites).

Prophylaxis, if you are pregnant or a tourist, is more controversial and I won’t deal with here.

Anyway, the initial Taiwanese trial on our smaller island saw the hospital’s 21 beds in two months go from 100% occupation to 0% occupation. Two years later the hospital internment rates from malaria had maintained, indicating the mosquito had not developed resistance to the insecticide and the malaria parasite had not developed resistance to the treatment medications.

The programme has now been introduced to the larger island.

Chemotherapy Overdose II

It is reported in the 21 April edition of the Pharmceutical Journal that a misinterpretation of a myeloma chemotherapy protocol consisting of idarubicin and dexamethasone (Z-DEX treatment) has resulted in the deaths of two patients. The wording “40 mg/m2 in divided doses over four days” has led to 40 mg/m2 per day rather than 10 mg/m2 per day for four consecutive days.

A further letter in the 5 May edition calls our attention to the Systemic Anti-Cancer Therapy Study currently underway and run by the National Confidential Enquiry into Patient Outcome and Death (NCEPOD).

NCEPOD, a registered charity, aims to “review medical clinical practice and to make recommendations to improve the quality of the delivery of care. We do this by undertaking confidential surveys covering many different aspects of medical care and making recommendations for clinicians and management to implement.”

The aim of the study is to examine the care of adults with tumours, acute leukaemias or aggressive lymphomas who receive chemotherapy, monoclonal antibodies or cytokines and who die within 30 days of receiving treatment.

The protocol is here.

Chemotherapy Overdose

Oh dear ... something else to worry about.

Two men being treated for cancer and leukaemia at Birmingham's Heartlands Hospital died after receiving five times the correct dosage of a medication on 20 July. Apparently the drug (I wonder what) is to alleviate the side-effects of cancer treatment. A doctor and two nurses involved are apparently away from work but have not been suspended, An enquiry is taking place by both the hospital and the coroner. Press report here.

The risk is real. The UKALL 2003 protocol warns "All medical staff involved in the care of patients with leukaemia MUST be aware that the inadvertent administration of vincristine by the intrathecal route is invariably FATAL. Vincristine should NOT BE AVAILABLE when an intrathecal needle is in situ. This protocol has been written to provide separation of intrathecal methotrexate administration from intravenous vincristine administration in time. An additional precaution is that the two drugs should not be administered in the same place ...The single most crucial element in avoiding errors is the appropriate education and training of all personnel involved in the administration of chemotherapy".

In the News

Perhaps the most important health news we have come across today is that the vaccine for the human papillomavirus (HPV) that causes cervical cancer has been approved for use in the U.K. by the Joint Committee on Vaccination and Immunisation (JCVI). Department of Health press release here. BBC report here. The Scottish Executive has said it will implement vaccinations of all 12 and 13 year old girls as soon as possible (probably late 2008) but, typically, England is dragging its feet and the government wants an independent cost-effectiveness study before it will (or will not) implement a vaccination programme.

So here are some UK statistics for you culled from the web. I won't vouch for their accuracy but they are approximately correct.

Female population: 30.7 million
Females 12-13 years: c. 380,000
No. of new cases of cervical cancer per annum: 2800
No. of deaths from cervical cancer per annum: 1120
Cost of treatment per case: £2150
Cost of treatment all cases per annum: £6.02 million
Cost of annual pap smear: £12.50
Cost of vaccine: £250
No. of cases prevented by the vaccine: 70% - 1960
Cost of all treatment all cases per annum with a vaccination programme: £1.8 million (saving 4.2 million)

Make up your own mind.

In other news, a reminder that it is not just the high profile tropical diseases that kill in the developing world. An outbreak of measles in northern Nigeria has killed at least 20 children with at least 400 infected.

Staying in Nigeria, its government is suing the multinational pharmaceutical company Pfizer for deaths and disabilities caused by the 1996 trial of the meningitis treatment drug Trovan. The company claims that all participants in the trial gave verbal consent and it was acting according to Nigerian regulations. Even if it was, purely verbal consent would not be considered ethical here. Report here.

We have posted before on the importance of biodiversity to the development of new drugs and treatments. Now the drug Trabectadin, developed from a sea squirt, has been shown to control the cancer myoxid liposarcoma.

And finally, the search for a treatment for river blindness, which is thought to effect 18 million people in Africa, is documented in pictures here.

UKALL 2003 - Maintenance I

Kezia started the first maintenance phase today with Vincristine and Dexamethasone. She was also meant to start mercaptopurine and oral methotrexate but these are neutrophil and platelet count dependent and and her neutrophils had not recovered sufficiently. This was expected. Her next visit is next Tuesday, I suspect just to see if her counts have recovered enough to start these medications

Maintenance cycles run in 12 week blocks. Every 4 weeks is Vincristine (one dose) and Dexamethasone for a week, Mercapturine every day and oral MTX once a week apart from the third week of each cycle when she will receive intrathecal MTX. All the maintenance cycles follow the same pattern until the end of treatment. For girls there are six maintenance cycles, boys get more.

The Hickman Line will be removed - but there is currently a three-month waiting list for this surgery. They will not install a Portacath unless she becomes very fractious with the Vincristine injections.

Anthracycline Side Effects - Mode of Action

How the anthracyclines cause heart damage – the biochemistry of it all. This post will probably take a few days as I try to get my head around it and then explain it in as simple terms as I can muster.

First off, there is no one mechanism, but it all involves “free radicals” that are widely bandied about in the media, conventional and the full range of complementary medicine as harmful. But what exactly is a free radical? Why is it harmful ? And why to the heart ? And why should anthracyclines contribute to this?

Free radicals

The two major free radicals are known as “superoxide” and “hydroxyl”. I´ll illustrate with the superoxide.

A normal oxygen molecule is constituted of two oxygen atoms and is thus chemically written as O2. Each oxygen atom has a nucleus and six electrons with one pair shared with another normal oxygen atom with six electrons to form a normal O2 molecule. In a superoxide molecule there is a seventh electron unpaired electron and an additional negatively charged elctron (in red in the diagram below). It cannot bind to with its oxygen atom electron neighbour so is “free”, to bind with whoever it likes.


So we have a promiscuous molecule.

The hydroxyl free radical is similar in concept.

They can be called Oxidants.

The superoxide free radical is deployed by the immune system to bind to and damage the DNA of invading micro-organisms, preventing them from replicating and thus finishing them off. But in the same way (see later) it can attack the DNA of the body´s own cells as can the hydroxyl free radicals.

I´ll come back to the free radicals later but will now move onto muscle … don´t we love them! We can walk, talk, run and … breathe because of muscle. Sexy biceps and thighs!


The Heart

There is an essential difference between leg, arm, cheek etc and heart muscle. The former react to stimulation from nerves (i.e. the nerve gives a tiny electric shock to the muscle which makes it move) whilst heart (or cardiac) muscles do it by themselves (more or less) without the help of nerves.

(see diagram below of normal muscle).

You can be totally paralysed with no signals from brain to nerves to muscles but your heart keeps working and you stay (miserably) alive!

However, heart muscle cells, in comparison with the other muscle cells, are distinctly lacking in protection from our promiscuous and aggressive free radicals. This protection is principally in the form of various enzymes – superoxide dismutase (happily known under the acronym SOD), catalase, glutathione peroxidase and glutathione reductase. Unfortunately, heart cells produce a lot less of these enzymes than regular muscle cells.

According to Wikipedia, an infected mouse with SOD production genetically inhibited, can die within 21 days of birth!

Enzymes

Nicotinamide adenine dinuclenotide (NADH) and Nicotinamide adenine dinuclenotide phosphate (NADHP) are enzymes produced in cells from Niacin (or Vitamin B3 – look at the ingredients of your multivitamins) with unique roles concerning energy production and DNA synthesis.

Part of the anthracycline accepts an electron from NADH or NADPH and becomes a free-radical which immediately passes that unpaired electron to molecular oxygen (O2) thus becoming the very harmful, free radical – superoxide.

To make itself more stable the free oxygen radical has to steal an electron from mitochondrial DNA (and I can see I will have to explain the difference between mitochondrial and nuclear DNA). Without that oxygen electron the DNA molecules are damaged and the cells cannot reproduce.

Eventually, this will lead to cell death and as the heart muscle cells don’t have much protection from free reductions.

Anti-oxidants

This is an easy bit. If the anthracycline-induced anti-oxidants or free radicals, are roaming around, then introduce something that acts faster to mop them up before they hit the mitochondrial DNA in heart muscle cells.

Unfortunately, it seems that naturally-produced anti-oxidants, such as vitamins A, C and E (present in foods, drinks and vitamin supplements), are not adequate to this task so stronger anti-oxidant drugs have been introduced.

However, that is but one mechanism by which anthracyclines can damage the heart … (to be continued).

France vs England

It is tempting to think the BBC read my post on access to cancer drugs yesterday given that they posted this 30 minutes ago and someone from the Beeb visited me early this morning.

In other personal news Kezia resumed treatment today with a dose of intrathecal methotrexate. Last four doses of cytarabine in the coming days.

Cancer Drug Access

Access to cancer drugs stayed in the news this weekend with the BBC reporting the results of its survey of 180 UK cancer specialists on their views. They are anxious about access to new treatments on the NHS and they are anxious about NHS patients having to pay for NHS-administration of non-NICE approved treatments.

Mens Sana also posted about access to Tarceva, Docetaxel and Pemetrexel.

My weekend reading was the Karolinska Institute report on EU access to cancer drugs we cited here.

Research at Columbia University in the USA, cited in the report, has shown that access to more cancer drugs is directly correlated to increased one and five year survival rates. It is in the interests of cancer patients to have access to new drugs as quickly as possible.

On the situation in the UK, where the authors reported access to new drugs was one of the worst in the European Union, it made disturbing reading. I will cite come examples …

Drug regulatory and approval regimes differ widely. For EU members the first step is for the drug to be approved by Committee for Human Medical Products (CHMP). Although this approval process is not meant to take more than 180 days, the reality is a median of 418 days. The approval process then passes to national authorities, clearly leading to further delays in patient access.

In the UK these national approvals are considered by three authorities – for Wales, the All Wales Medicine Strategy Group (AWMSG), for Scotland, the Scottish Medicines Consortium (SMC) and in England, the National Institute for Health and Clinical Excellence (NICE).

The report states that referral time to NICE “can be up to 18 months and this is prior to the beginning of any review”. The report does not cite referral times to the SMC but in my calculations below I will use the same..

Budgetary allocations for new treatments are not planned during England NICE evaluations so it is only after NICE has granted approval that budgetary planning for the next financial year (April to March in the UK) can take place. Knowing a little bit about the bean counters, I can I imagine that a drug approved in March 2007 (probably earlier), will not be approved for April 2007 but will only be approved for April 2008. Let us make budgetary planning six months/180 days.

The NICE review/approval time averages is 62 weeks, SMC is 12 weeks.

England:

EU CHMP 418 days + referral to the national authority 72 days + NICE review 434 days + budgetary planning 180 days = 1104 days = 3.02 years

Scotland:

EU CHMP 418 days + referral to the national authority 72 days + SMC review 90 days + budgetary planning 180 days = 760 days = 2.08 years

One year in the life of a cancer patient is a long time.

Move to Scotland. Is Scotland negligent? Methinks not. Is Switzerland, not a member of the EU, and with excellent cancer drug uptake and treatment rates negligent? Methinks not.

Dr. Crippen has reported on a cancer patient moving from England to Scotland for treatment. Potentilla – I´m happy you´re there!

Let us move on …

Cancer research

In the US public (and I´m taking that to mean state) funding of cancer research is seven times that of the EU. Fair enough. In the EU cancer research funding is 50/50 split between state and charities. The UK, within the EU, is the highest investor in cancer research, with the charities contributing more than the average 50%.

“Yet this report illustrates that the UK lags behind other EU countries in terms of the ability of cancer patients to access new drugs.”

Political factors

And this perhaps is the most horrific of all …

In the UK, in-patient care is taken into consideration for the funding of hospitals.The more in-patients the better for a hospital´s budget request. So although there is an oral form of 5-fluorocil, used in the treatment of colorectal and breast cancers, this is not advantageous to hospital budgets, so the IV form continues to be used even though it is disadvantageous to the patient – and I will go on to say disadvantageous to the economy as a whole as the patient’s labour hours are withdrawn, s/he occupies a bed, eats on the hospital etc.

Cancer in the News

Two reports from the BBC today which have drawn my attention.

A new report from the Swedish Karolinska Institute compares access to new cancer drug therapies across Europe. To quote "The Czech Republic, Hungary, Norway, Poland and the UK were consistently identified as below-average adopters of new cancer drugs for the treatment of breast cancer, colorectal cancer, lung cancer, non Hodgkin’s lymphoma and supportive care". France had the highest five-year survival rate in Europe at 71% for women and 53% for men, compared to 53% and 43% in the UK.

The government response to the report was typically defensive. The Beeb quotes a Department of Health spokesman explaining that the National Institute for Health and Clinical Excellence (NICE) was essential in ensuring that the NHS used the most effective treatments and that measures had been taken to speed up the approval process for key drugs.

"We are making good progress in ensuring cancer patients have access to the drugs they need".

Dr Crippen has previously reported on the low rates of survival for lung cancer patients in the UK compared with some other European countries and access (rather lack of) to the drug Tarceva on the NHS.

BBC story here. The full report can be read in html here or pdf here.

In another story the BBC reports that oral sex leads to a higher risk of contracting oropharyngeal (throat) cancer. So the moral of this story must be that it is better to engage in such activities ouside the UK!

I want to live longer than you ...

... I don't know how.

Fuck off Rob ... you got me onto this, and, yes, we need to go there.

Long term side effects

It seems that most of the long-term side effects are related to radiotherapy, particularly cranial, and bone marrow/stem sell transplants. We haven’t been there (and hopefully won’t) so I won’t talk about it. But if you want to research these side effects, I recommend you start at the Pediatric Oncology Resource Center (link right).

But what Kezia may or may not suffer from are heart problems caused by the anthracycline group of drugs – in her case daunorubicin and doxorubicin.

First, let’s look at the heart. Four chambers – the right atrium and ventricle, the left atrium and ventricle. Atriums on the top, ventricles on the bottom. The right side receives blood in the atrium. The blood is passed to the right ventricle which pushes it to the lungs to receive oxygen. The blood then passes to the left atrium and then the left ventricle which then pumps it back into the blood system.

The anthracyclines can effect the thickness of the wall of the left ventricle making it thinner (I’ll go into the exact process of how they do this another time – and I really don’t understand why just the left ventricle). Any decrease in the left ventricle’s wall of muscle will both decrease its strength and increase the volume of the ventricular chamber allowing more blood to enter.

Additionally, as one part of ventricular wall is the valve between the atrium and ventricle, the valve tissue will also become thinner. The pumping action of the left ventricle becomes weaker due to less muscle (reduced contractility) and more blood and cannot keep up with pumping rate of the right side. More blood is also left in the heart after each beat (increased afterload). The increased amount of afterload will cause the ventricle to dilate further and the atrium-ventricular valve will fail to close completely.This condition is known as cardiomyopathy.

If the blood cannot be pumped out of the left ventricle, it “backlogs” into the atrium, the small blood vessels of the lungs and finally the right side of the heart causing the typical symptoms of what is known as congestive heart failure.

These symptoms include shortness of beath, chest pain, increasing fatigue, swelling of the ankles and a dry cough.

Epidemiology and risk factors

Much debate here. But the following seem to be badly prognostic in no particular order: a cumulative dosage of anthracyclines above 300 mg/m2 of body surface area (Kezia has received 315 mg/m2), female sex (as they tend to have more fat and anthracyclines are not absorbed in body fat i.e. the anthracyclines will accumulate at higher concentrations in female compared to male muscle including the heart per unit of body surface area), younger age (the heart is growing)- Kezia was just 2 at diagnosis and glucocortisoid treatment as this increases body fat (Kezia is and will be taking dexamethasone until the end of her treatment).

Whether Kezia will develop heart problems has yet to be seen. Heart tissue damage can be instantaneous on administration of anthracyclines but the heart can also recover.

Monitoring

The principal tool for checking the heart is the echocardiogram – similar to the ultrasound of an unborn foetus but of the heart. By this they can measure the thickness of the left ventricle wall.

Our consultant has advised annual checkups until puberty but other medical papers I’ve read advise an annual echocardiogram for life (although they don’t really know as long-term monitoring of childhood cancer patients has only really just begun).

Treatment

If Kezia does develop cardiac problems, there are a host of drugs that can effectively be used as treatments/prophylaxes.

So although, hopefully, I won't live longer than Kezia, I hope I'll lve long enough to alert her and she'll be able to take care of herself.

P.S. Rob, I am sorry for swaering at you. You took me here and it's taken four weeks to get a grip on it, and I appreciate it. Best wishes to Norah, lauren and Fergus.

P.P.S Thanks Patty for the papers - readers, the Ped Onc Resource Center has an excellent page on this.

Chickenpox

Jaime has come down with chickenpox. Fortunately, Kezia tested positive for chickenpox antibodies at the beginning of her treatment so she shouldn't pick it up.

But as he is now off school I will be accompanying Kezia on her hospital visit tomorrow as I need to see our consultant J. and a child with chickenpox obviously cannot go the the hospital. And it is a biggie tomorrow - the start of the reconsolidation phase of Delayed Intensification II. This involves IT methotrexate followed by the lengthy administration of cyclophosphamide (our chemical warfare drug!).

Dichloroacetate II

Someone has just visited my original post on promising research into Dichloroacetate here by searching "dichloroacetate source". Now it seems terminal cancer patients are self-dosing it before it has been clinically tested on humans (story here). Not a good idea.

Side Effects II

Potentilla's most recent post on her Metastases blog over at Auspicious Dragon discusses amongst other things drug side-effects. When you feel bad, is it the drug or your illness and other issues ... I'd like to quote her:

"Whilst researching the side-effects of Cefalexin (to see if nausea was one of them, which it is, but I think my nausea was in fact because of jaundice), I read a couple of sites which allow patients to “review” drugs. I’m not that convinced about the benefits of these, since anecdotes are not evidence, but given the difficulty of finding out what side-effects are genuinely possible or probable (as opposed to the legally-driven Patient Disinformation Leaflets), they can be of passing interest.

Anyhow, I was mildly amazed by how confident many of the posters were about what actually caused their symptoms - I mean, whether it was the drug, or the original condition, or something else. (Why have I been nauseous?) OK, the human race is collectively too ready to confidently ascribe causation where none exists - but I also realise that many of the posters have something which I no longer have, which is a default state of systemic wellness. Most of the time, they feel OK; so when they start to feel ill, it must be easier to notice what the symptoms are. (I say systemic to exclude the non-systemic chronic sources of not-wellness, like myopia, or verruccas, or piles, or cold-sores).

A default state of systemic wellness is the norm in rich countries. When we are systemically ill, we at the very least have sympathetic allowances made for us, possibly formal ones if we are, for instance, sitting exams; and if we are a bit worse, we actually opt out of normal life for a while. I was recently reading something about “national IQ” studies, including the fact that “national IQ” for many African countries, especially sub-Saharan ones, is lower than for rich countries. As you might expect, there is much discussion and dissension about possible reasons for this (measurement effects, culturally inappropriate tests, malnutrition in infancy, genetics); but one possible reason that does not seem to be much considered is that systemic wellness is not the default state in the relevant areas. In a poor country, even if you practically always have one, or several, untreated systemic infections, you can’t afford to opt out of normal life. It seems really quite likely to me that a significant proportion of people being IQ-tested in such countries are, by rich-country standards, ill. (And of course, ill people in rich countries mostly don’t take IQ tests, which would increase the effect). Being systemically ill certainly can have an effect on cognitive ability, as I know from personal experience. Perhaps the researchers need to recruit self-sacrificing people who are willing to sit IQ tests both when they are systemically ill and when they are well, to try to get an idea of the size of the adjustment that would be appropriate. Assessing what proportion of testees were systemically ill would probably be easier."

In the "developed world" we take good health very much for granted.

Side Effects

I said I should do a drug side effects post at the end of the Asparaginase post and Jessica left a comment that yes, I really should. So this weekend's offering ...

There are many resources out there dealing with side-effects of specific drugs so I won't try and reinvent the wheel but will talk in a more general way.

First off, most of these drugs are cytotoxins i.e. they are toxic, poisonous – to both bad and good cells. As well as killing the bad cells, they'll kill the good cells. Often they produce useless by-products that can do damage as well.

Many of the side-effects are common to several drugs. Both this and that and that may produce this or that or that side-effect. But there's no guarantee that you/your child will suffer any particular effect. What causes one person's hair to fall out, won't for another person.

So let's start with the common effects that everyone will suffer at some time or another (in no particular order):

Hair loss: everyone's hair falls out. Then it will start to grow back, and then you repeat the drug that caused it to fall out in the first place, and yes, you've got it, it falls out again. Kezia isn't bothered about it, (hey punk!), but for teenage girls it's a bit depressing. In the UK the NHS provides wigs. Lucia (a teenager) has some advice for teenagers on her Teenage Cancer site

Mucosis: sore and/or infected mouth. The degree to which this happens will vary from person to person. Kezia has suffered just a bit – soft foods and antiseptic mouthwash have been enough. H.'s mouth went green and she couldn't eat or drink. If it gets this far, they'll suspend the treatment that has caused it, put you on antibiotics and hydration.

Both of these occur because hair and mouth cells naturally reproduce and die very quickly compared to other cells so if you're killing them off even quicker, their reproduction cannot keep up with their loss.

Nausea and vomiting: they can give you an anti-emetic (anti-nausea) medication for this.

Stomach cramps, diarrohea etc: speaks for itself.

Odd eating habits: increased appetite, decreased appetite, manias for certain foods – at the end of Kezia's induction nothing but chips and roast chicken crisps! The glucocortisoids, dexamethasone and prednisone, are particularly good at increasing appetite leading to weight-gain and puffy faces.

Neural effects: tingling or pins-and-needles in limbs etc. At the moment Kezia has sensitive feet and doesn't want to walk.

Mood swings: depression and euphoria, temper tantrums, unco-operativeness, Irritable Bastard Syndrome, highs and lows. This is especially difficult with young children who cannot verbalise it and cannot rationalise it. As a parent carer you've got to be especially sensitive – what is normal childhood pain-in-the-neck, what is drug-induced, what is both, and then how do you draw the lines?

As an absent father, I don't have to deal with this very much. But Nanda does.

Infections: your white blood counts are low so you don't have the normal protection against infections. At the slightest sign of an infection, a temperature or whatever, into hospital, normal chemotherapy suspended and onto the antibiotics.

You will be warned that THIS WILL HAPPEN right at the beginning. It's normal. It's happened to Kezia now on two occasions.

You may need a blood and/or platelet transfusions. Even if you don't have an infection, if your blood counts are really low, then you'll get a transfusion.

With kids you really have to look out for chicken-pox – if someone at school, comes down with it, then you keep your child at home.

Photophobia: sensitivity to light in the eyes. Kezia has this right now due to the IV methotrexate she's receiving in Escalating Capizzi II (obviously she had it in Escalating Capizzi I as well).

Contracting tendons: we were taught foot exercises to help prevent this. H. got it so bad that even physiotherapy didn't help and they had to put her ankles in plaster to resolve it.

Feeling Shit: ...

So those are (some of) the common side-effects! You think that's bad?

Less common effects ... (this isn't a full list – just a sampler!)

Vincristine: convulsions, optical atrophy with blindness

6-Mercapturine: abnormal liver functions

Dexamethasone: diabetes (Lucia and H.), inhibits growth, intestinal ulcers.

Cytarabine: liver injury

Methotrexate: liver, lung, kidney damage, stoke, seizure, neurotoxicity leading to learning difficulties.

etc etc

P.S. Lucia in the comments to this post describes severe bone pains as a result of dexamethasone. This is so bad for her that it was reported as a Severe Adverse Event (severe reactions are reported) to the UKALL 2003 trial, necessitates morphine when she comes off steroids and changing from dexamethasone to prednisone.

UKALL 2003 - Asparaginase

Asparagine is an amino-acid produced by normal cells. It was the first amino-acid to be discovered back in 1806 in asparagus – hence its name. One of the twenty most common amino-acids. Because human cells produce their own it is not considered essential in your diet.

It is required for protein synthesis and thence the synthesis of RNA and DNA. Most lymphoblasts, however, cannot produce asparagine and depend on freely circulating (or exogenous) asparagine produced by healthy cells.

If we can wipe up all this freely circulating asparagine, then the lymphoblasts cannot reproduce and cell death (apoptosis) results.

L-Asparaginase breaks asparagine down into aspartic acid and ammonia. It was first discovered in guinea pig serum about 30 years ago and found to suppress the growth of lymphosarcomas in mice. But, as the UKALL 2003 points out, “Clearly it was not a viable option to source this agent from guinea pig serum ...”. However, it is widely found in nature and ideal sources were discovered in the bacteria Escherichia coli and Erwinia crysanthemi.

It has quite a fantastic chemical formula C₁₃₇₇H₂₂₀₈N₃₈₂O₄₄₂S₁₇. With that number of atoms in a molecule, you're unlikely to find a diagram of it!

Early experiments found that the half life E. coli and E. crysanthemi asparaginase was about 10-12 hours which necessitated frequent injections and higher risks of side-effects. However, when attached to polyethylene glycol (pegylated), E. coli asparaginase has a half life of 5.73 days thus necessitating less frequent injections.

The study of Peg Asparaginase is one of the objectives of the UKALL 2003 trial. More specifically, the study aims

To test whether with current dosing/scheduling/product used we achieve:-

a) Adequate Asparaginase levels for the appropriate duration
b) Whether these levels deplete asparagines?
c) What is the rate of anti-asparaginase antibodies?
d) How many of the reactions to pegaspase are inhibitory?

To test the feasibility of routine Asparaginase monitoring.

Various measures on blood samples are performed – levels of asparaginase, levels of asparagine and levels of antibodies to the asparaginase. These will then be correlated to early leukaemic cell kill as measured by peripheral blood blast clearance, Day 8/15 and Day 29 marrow clearance plus the minimal residual disease estimates that form other objectives of the UKALL 2003 trial.

The Peg Asparaginase is administered as an intramuscular injection in this trial as it is thought that this route results in decreased hypersensitivity, although it may be administered intravenously in other protocols. The brand name is Oncaspar.

Numerous possible side-effects. Maybe I'll have to do an entire post on side-effects of all these drugs!

Open Source Medicine V

In writing the last post I had a query about the way 6-Mercaptopurine and 6-Thioguanine and their modes of action were similar and different. Not being a biochemist, not even a scientist, I wrote Patty to ask for some clarification but before she had a chance to reply, I found PharmGKB.

This is database project to pool pharmogenetic and pharmogenomic data to allow researchers open access to others' data on the mechanisms of drugs and the often different reactions that patients have to the drugs due to differences in their genetic make-up.

To quote from a downloadable paper explaining the project (available here – but I couldn't get it to open in Acrobat Reader and had to use KGhostView):

“The ultimate product of this project will be a knowledge base that will provide a public infrastructure for understanding how variations in the human genome lead to variations in clinical response to medications.”

The project uses XML schema for data to be structured with modifications to the schema being made available for review by participating researchers. It provides a Java API for uploading data which conforms to the Open Knowledge Base Connectivity standard (I'll have to do some more research on that). Data can be submitted via web-based forms or directly in XML following the project's schema. Integration with other external databases is another project aim with project data being made available freely. This requires the project to monitor closely the structure of the external databases to ensure efficient and maintainable data transfer. Sorry if that's a bit technical for non-geeks.

The project is based at Stanford University in the USA.

Anyway I found my answer about 6-MP and 6-TG here – not that I really understand it! But basically 6-TG follows a more direct approach to integrating with DNA than 6-MP. Why this should have resulted in higher mortality for 6-TG in the UKALL 1997 trial I really don't know.

Several other of our chemotherapy drugs are also on the site and I'm sure I'll be using the resource again.

Patty adds "From the schemes given, no, biochemically one can't see why. But the body is such a complex system, and although biochemists try to put everything into nice little pathways, the story is rarely that simple. I know that one CCG trial found a lot of liver toxicity with 6TG".

UKALL 2003 - 6-Mercaptopurine

Also more commonly known simply as 6-MP, this is given orally at various stages of the first year of treatment and then daily throughout the maintenance phases.

Again I am indebted to Patty Feist (link on right) for her explanation of its mode of action. It appears to have three modes of action. In the liver 6-MP is converted to a corresponding ribonucleotide (i.e. links to a ribose sugar – see the post on cytarabine). This inhibits the conversion of a compound called inosinic acid to adenylic acid which is needed to make the DNA base adenine.

In its second mode of action it also inhibits the conversion of inosinic acid to xanthylic acid that is necessary for the synthesis of guanylic acid necessary for the synthesis of the DNA base guanine.

Finally, it also works by being incorporated into nucleic acids as thioguanosine deoxyribose, rendering the resulting nucleic acids (DNA, RNA) unable to direct proper protein synthesis. Thus in this case we're changing the base rather than the sugar as is the case with cytarabine. (See this abstract)

Some people have different levels of TPMT (thiopurine methyltranserase - the enzyme that metabolizes 6-MP) activity that controls the first two modes of action (but not the third). This is controlled genetically (good explanation of this here). In fact, 1 in 300 individuals cannot break down 6-MP at all. In the UKALL 2003 protocol this is tested at diagnosis and later on, if found necessary due to adverse reactions.

In an earlier clinical trial UKALL 1997 the related drug 6-Thioguanine (6-TG) was found to increase remission death rates in comparison with 6-MP and so is no longer used. However, it would seem to be still used in other protocols (e.g the CCG 1961 protocol that Patty Feist's son was on).

It will be taken at night (see this paper on chronotherapy), at least one hour after a meal and with no recent intake of milk (see this abstract) as a compound in milk converts the 6-MP into useless by-products

See this link on Gertrude Elion, the discoverer of 6-MP and 6-TG.

UKALL 2003 - Vincristine

Another drug derived from a natural source – the Madagascan Periwinkle Caranthus roseus. The plant has been in use in traditional medicine for centuries treating anything from diabetes to wasp stings to eye infections. When scientists began looking at it in the 1950s, they discovered over 70 alkaloids among which was vincristine.

Microtubules form part of the structural network, or cytoskeleton, of a cell's cytoplasm. They are made of a protein called tubulin. They form various structures and have various functions. One of these is the formation of a structure called a mitotic spindle (mitosis = cell division). This segregates chromosomes correctly during cell division so that each daughter cell receives the correct number of chromosomes. In the picture below the mitotic spindle is green and the chromosomes are blue.

Vincristine binds to tubulin and prevents the formation of microtubules and, in particular, the mitotic spindle. Thus the cell dies without being able to divide.

Unlike our other chemotherapy agents so far, this is not working directly on the cell nucleus and DNA but within the cell's cytoplasm surrounding the nucleus.

It has, like all our drugs, many side-effects. Particularly, noticeable are neurological effects – Kezia developed tingling feet making her unwilling to walk. Others report similar effects.

If given intrathecally (in the spine), it is fatal. For this reason the UKALL 2003 protocol gives the following warning:

“All medical staff involved in the care of patients with leukaemia MUST be aware that the inadvertent administration of vincristine by the intrathecal route is invariably FATAL. Vincristine should NOT BE AVAILABLE when an intrathecal needle is in situ. This protocol has been written to provide separation of intrathecal methotrexate administration from intravenous vincristine administration in time. An additional precaution is that the two drugs should not be administered in the same place.”

UKALL 2003 - Cytarabine (Ara C)

Cytarabine, more commonly known as Ara C, is administered over four consecutive days in four blocks during Augmented BFM Consolidation, and two blocks each in Delayed Intensification I and II (in Regime C of UKALL 2003). It is administered through the Hickman Line and is generally done at home as four consecutive days visiting the hospital is a bit much for both patients and carers. You'll be given a choice of learning to do it yourself or have a community nurse visit. However, the latter is a bit infeasible if a dose falls on a weekend so I would really recommend learning to do it yourself. The hospital will train you and check you are proficient as well as providing written instructions to take home.

It's really best to have two people present when administering it so the second can both check the first is doing it right, and comfort the child. We have a two-person safety rule at work for any electrical or mechanical maintenance – the second person can catch any potentially dangerous slip-ups and assist if there are difficulties – the same is true here.

The process consists of cleaning the line with saline, injecting the drug, injecting Hepsal (Heparin Sodium – an anti-clotting agent to stop the line getting blocked) and finally saline again.

The story of the development of Cytarabine is fascinating – I will try and summarise here but go to Patty Feist's page for a more in-depth account A Tale from the Sea to Ara C. Thanks also to Patty for the graphics here.

The story starts in 1945 when a young scientist, Werner Bergmann, was collecting sea sponges (Cryptotethia crypta) on the coast of Florida. He boiled them up in acetone and instead of finding a steroid as expected, discovered a new substance similar to the DNA building-block, the nucleoside thymidine. Bergmann named the new compound Spongothymidine.

The two diagrams below demonstrate the very slight difference between the two molecules. The blue portion is known as the base, and the red part is a sugar. The base of each is the same, thymine, whilst the sugars differ slightly. In thymidine the sugar is known as deoxyribose and in spongothymidine it is arabinose.

Deoxyribose sugars (plus base) form the backbone of DNA, and ribose sugars (plus base) form the backbone of RNA. So arabinose is unlike either of them.

Early research in chemotherapy concentrated on changing the base but with the discovery of spongothymidine the focus moved to changing the sugar. John Evans and Seymour Cohen bound the sugar arabinose to another of the four DNA-bases, cytosine, making Cytosine arabinoside or Ara C, and tested its anti-cancer properties with positive results.

Here's how it works (another Patty page here).

In a cell Cytosine riboside (an RNA molecule) is converted to Cytosine deoxyribose (a DNA molecule) with the help of an enzyme. The enzyme needs to bind to the riboside and strip off an oxygen atom from the OH group (on the bottom right of the sugars in the diagrams below) to make the deoxyribose. However, if cytosine arabinoside is present, the enzyme binds to it through mistaken identity but as that OH group is on the top-right of the sugar instead, it cannot find it and cannot convert it to deoxyribose. Without the cytosine deoxyribose, new DNA cannot be made and the cell will die.

Other anti-cancer drugs are now being developed from marine organisms. Patty discusses Ara G and Clofarabine in the treatment of childhood leukaemia. Other anti-cancer drugs derived from marine organisms and currently under trial include Yondelis and Apledin derived from marine tunicates and Kalahide derived from a nudibranch (a sea slug).

This just goes to show how important biodiversity conservation is – new substances, of great scientific use, are still being found in plants and animals around the world. If we lose these, before discovering what they have to offer us, we have lost an incredible resource.

UKALL 2003 - Dexamethasone 2

I've refrained from tackling this until now as I really didn't understand even a twinkling of the science behind Dexamethasone's anti-cancer properties. After much reading I discover that not even the scientists fully understand the mechanisms.

In my last post on Dexamethasone I attempted to explain its anti-emetic (nausea, vomiting) properties. However, talking to our consultant J. over the holidays, it seems the justification for its use in the treatment of leukaemia is its anti-cancer properties – the anti-emetic effects are a beneficial side-effect.

Right, I'll try and explain what is known about its anti-cancer properties. There appear to be several mechanisms at work:

• It appears to trigger programmed cell death (apoptosis). Both good and leukaemic cells.

• They inhibit the production of interleukins which are signalling chemicals which stimulate a variety of cell behaviours. The IL-2 interleukin (there are 33 of them) is produced by T-lymphocytes. The IL-2 then binds itself to the T-lymphocyte signalling it to grow and differentiate. (This self-signalling is termed autocrine). Clearly, inhibiting the production of leukaemic T-cells (or T-cell blastogenesis) is one of our goals.

• It can also (seemingly) increase the ability other chemotherapy drugs to destroy leukaemic cells

It can also prevent white blood cells from reaching sites of infection. Hence (as with most chemotherapy drugs) there is an increased risk of infection when taking it. Strangely, as the WBCs cannot reach the infection, the white blood count may be seen to go up.

I should also add that one of the lesser known and rarer side effects of the glucocortisoids is induced diabetes - this is what H. suffered from - she got over it but insulin injections in the stomach were no fun. I guess no more dexamethasone for her!

Next in the series is Cytarabine - this is kind of cool!

Update: in the comments Lucia also reports having suffered from diabetes so they have switched her to prednisone.