Anti-Pharma

From boingboing ... this is marvellous especially given Indian, Brazilian and South African efforts to develop their own drugs. I wonder how much success it will have ...

"Jamie Love sez, "Senator Bernie Sanders (I-VT) has introduced legislation in the US Senate that would use prizes to reward medical R&D, and eliminate all drug monopolies. It includes an open source dividend of $4 billion per year."

Both bills would eliminate all legal barriers to the manufacture and sale of generic versions of drugs and vaccines. The more ambitious bill is the Medical Innovation Prize Fund Act, which would apply to all prescription drugs. The narrower proposal is the Prize Fund for HIV/AIDS Act, which would only apply to treatments for HIV/AIDS. The Medical Innovation Prize Fund would create a prize fund equal of .55 percent of US GDP, which is more than $80 billion per year at current levels of U.S. GDP. The HIV/AID Prize Fund would be funded at .02 percent of U.S. GDP, which is equal to more than $3 billion per year at current levels of U.S. GDP.

The federal government and private health insurance companies would co-fund the prizes, according to formulas set out in the bills. The cost of the prize funds would be more than offset by the savings from the introduction of generic competition for products.

Both bills have some similar features to Senator Sanders' earlier prize fund bills, but there are also a number of changes. Among those changes are the introduction of an open source dividend element to the bills, which would have at least 5 percent of the prize money going to persons or communities that put knowledge, data, materials or technology into the public domain, or provide royalty free and non-discriminatory access to patents and other intellectual property rights. Annually, this would be more than $4 billion for S. 1137, and $147 million for S. 1138, at 2010 levels of GDP, as an incentive to open source research."

Original article here.

Mitoxantrone

A long time since I blogged anything about leukaemia and medicine.

However, I have been pointed (thanks Andy - didn't realise until today you had commented way back when!) to this report on the Beeb about research just published in The Lancet regarding the highly successful use of Mitoxantrone in the treatment of relapsed childhood Acute Lymphoblastic Leukaemia. So successful in fact that the trial abandoned use of the traditional medication, Idarubicin - "Randomisation was stopped in December, 2007 because of differences in progression-free and overall survival between the two groups".

And seemingly the drug is cheap as well!

Maintenance Cycle 5

Starts today with a Vincristine injection and then the dreaded D for the rest of the week. One more maintenance cycle and six months to go.

I called on my Anglo-Peruvian friend Talia down in the city on Sunday to find her being visited by a silly French woman who runs a local business. When the subject turned to Kezia, she started twittering about alternative treatment, and my hackles began to rise. She insisted. Even after all her years here she hardly speaks our local language, doesn't speak English and, although I have some French, I couldn't get angry enough in French to tell her what bullshit she was spouting and ended up asking Talia to translate – which, given my increasing annoyance, she did diplomatically.

I couldn' t take any more and abruptly left.

Link, Link, Link, Link

Medical Update

Kezia's counts today are low and her daily mercapturine and weekly oral methotrexate have been suspended. Let's hope they recover for next week as, if satisfactory, John has promised they can skip a consultation when they go on holiday to the seaside the following week. So today was just the vincristine injection and over the next five the dreaded dexamethasone.

She also has a back tooth coming through which is hurting.

Jaime celebrated his birthday yesterday - 8 years old and a Transformer Cake.

Cancer Quackery revisited

We posted back in May about Complementary and Alternative approaches to cancer and leukaemia treatment and linked to Respectful Insolence's post Magical Thinking versus Lymphoma about parents opting out of chemotherapy and therefore sentencing their children to certain death.

He now reports another case in which the child died when his parents took him off chemotherapy after just three months!

Again I will urge parents who foolishly consider this to read Commonweal's guide to complementary and alternative medicine.

Another Milestone

Kezia has just come out of operating theatre without her Hickman Line! Congratulations!

Dr. Who

Kezia and Nanda have just got back from hospital - her counts were good enough that she can start nightly 6-mercapturine and weekly oral methotrexate.

Apparently, our consultant J. is known by Kezia as Dr Who! I wonder if he has a Tardis!

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.

Commonweal

Commonweal is a nonprofit health and environmental research institute in Bolinas, California. Founded in 1976, Commonweal conducts programs that contribute to human and ecosystem health — to a safer world for people and for all life. One part of their work is a Cancer Help Program.

Choices In Healing: Integrating The Best of Conventional and Complementary Approaches to Cancer by the organisation's founder Michael Lerner and available for free on Commonweal's website seems to be a very sensible guide to and survey of complementary approaches. It summarises any scientific evidence for an approach, is not afraid to admit it when there is no scientific evidence.

"I have seen no systematic cure for any form of cancer among the therapies currently described as "unconventional." This is an important finding. Conventional therapies, for all their real shortcomings, are capable of curing a number of cancers reliably. When I say I have seen no systematic cure for cancer among the unconventional therapies, this does not mean that I have seen no individual cures among people who have used unconventional therapies. In fact, there are well-documented examples of people who have recovered from "terminal" cancers using various unconventional cancer therapies. But these examples of individual recoveries from terminal cancers are not frequent enough to form a pattern that would allow me to say that there is a cure for any cancer among the unconventional therapies."

However, the role of complementary approaches in pain relief, psychological well-being, potential enhancement of conventional treatment, prevention. palliative care etc are discussed and in many cases there is solid evidence that they can be beneficial.

It also provides very sensible advice concerning the patient and physician's attitudes and approaches to conventional treatment.

Perhaps one glaring omission is the lack of a section on paediatric and young adult care. The use of music, art, drama, laughter, "bravery" stickers and certificates etc as therapy - a highpoint for Kezia of her stays at hospital have been the visits of the hospital clown!

UKALL 2003 - Delayed Intensification II contd

Finished!!

Small Island States

I would be interested to know about cancer control strategies for small island states. One radiotherapy machine in our own country, with a population of c.150,000, would bring us to a developed world ratio. Is this economically viable? The economies of scale make small island states, in every sector, very expensive.

Here we have an agreement with the ex-colonial power that serious medical cases are evacuated to Europe for treatment – this is clearly expensive and open to abuse and equally, the bureaucratic delays involved in such a system put the patient’s life at risk. Kezia would have been dead if we had had to rely on this system. Once a patient is within the healthcare system of the ex-colonial power, institutional racism often leads to unsatisfactory treatment.

But, even if cancer treatment facilities are to remain unavailable here, diagnostic facilities require vast improvement. The techniques/skills to accurately diagnose Kezia’s leukaemia were unavailable. A programme to promote PAP smear testing (or even vaccination) for cervical cancer (one of the most common forms of cancer in Africa) would be economically viable and effective.

I imagine in the Caribbean, with far more small island states than around Africa, the inter-state healthcare network is far more developed. But still the expense, both to the states involved and the individuals must be crippling. In the Pacific I imagine the far-greater distances involved make the challenge of providing adequate heathcare even greater.

I hope to look into this further.

International Atomic Nuclear Agency

We normally associate the IAEA with monitoring nuclear power and weapons programmes in countries such as Iran and North Korea. Its current head, Mohamed El-Baradei, ever the diplomat and much respected, is often seen on television talking about such issues. I have much respect for him, a voice of calm and reason in wars of rhetoric that seem to be on the brink of actual wars.

However, there are other aspects to the agency’s work. As its charter says, “the IAEA carries out programmes to maximize the useful contribution of nuclear technology to society while verifying its peaceful use”.

One little known activity of the IAEA is, therefore, the promotion of radiotherapy techniques, equipment and training for cancer treatment in the “developing” world through its Programme of Action for Cancer Therapy (PACT).

In most developed countries there is a ratio of one radiotherapy machine per 250,000 inhabitants. In developing countries it is more common to find ratios of one machine per several million inhabitants. Fifteen countries in Africa have no radiotherapy facilities at all. In Ethiopia the IAEA has provided one machine which serves a population of c. 60 million (i.e. comparable to the U.K. which has 207 machines, one per 290,000 inhabitants: reference). In its first four years of operation 1300 people were treated with a four year survival rate of 50%. The survival rate is not as good as the developed world, principally because diagnosis is frequently at a stage when the disease is far advanced. The IAEA is working with 22 countries (not ours) in Africa.

The IAEA estimates that $2.5 billion over ten years is needed to provide adequate facilities in the developing world with half that sum being allocated to training (refreshingly given Friday´s post on human resources).

The recent Cancer Control in Africa conference (posts here, here and here) was a joint initiative between AfrOx and the IAEA.

Reference here.

Cancer in Africa II

The ex-colonial power has been running its neo-colonialist Africa television channel here for 24 hours a day for several years. Today it took a programme from the television service of another ex-colony, much much larger than ours, and interviewed an African oncologist, working in his own country.

He certainly tried to explain as he best could to the general public the ins-and-outs of white blood counts and regretted that a haematologist had not also been invited on the programme. He described the limited facilities in his country. A country with a population of 14.5 million, a geographical area of 1.25 million square kilometres and only two hospitals in the capital city that can treat cancer.

Meanwhile the BBC here discusses a Medecins Sans Frontieres report (and press release) bemoaning the vast shortages of medical staff in Africa (albeit in the context of HIV/AIDS but it applies to all areas of medical care). It cites, for example, the fact that in 2005 in Malawi only 44 nurses qualified whilst 86 left the country. The shortage of doctors has led the head of MSF in South Africa to suggest that nurses be given the power to write prescriptions (you'd love that Dr Crippen!). The WHO recommends a minimum of 20 doctors per 100, 000 people - Lesotho has five, Malawi has two and Mozambique has 2.6. MSF points to the irony of donors loving to build new health facilities but who are unwilling to invest in the human resources to staff them and thus they stand empty.

UKALL 2003 - Delayed Intensification II contd

Kezia had Vincristine and her last PegAsparaginase today and they are home already.

Lots of small milestones the last few weeks - the last of this drug, the last of that drug, Next week sees the first Big Milestone - the last dose of this phase (Vincristine) and then we're into the much less intensive maintenance phases! Looking forward to it! Vinvcristine once a month through the maintenance phases.

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).

Cancer in Africa

Yesterday and today see a major conference in London on cancer in Africa.

We see so many reports on "African" illnesses - malaria, HIV/Aids, malnutrition, guinea worm etc etc - it is easy to forget that people who live on this continent are just as prone to cancer as people in the "developed" world.

Kezia's story might even be considered typical - to a point. Born in Africa, growing up in Africa, seriously sick but no means available to diagnose what is wrong and even if there were, no resources to treat her leukaemia. She was lucky - her dad is British and had the resources to get her back to the UK for diagnosis and treatment. Otherwise she would be dead.

The University of Oxford's Africa-Oxford Cancer Consortium (AfrOx), set up by Professor David Kerr has organised the conference along with the International Atomic Energy Agency's Programme of Action for Cancer Therapy.

The Cancer Control in Africa conference brings together health ministers or their representatives from 22 African countries, donors, healthcare professionals, the pharmaceutical industry, cancer charities, research organisations and others aiming to begin creating an action plan for cancer control in Africa.

As David Kerr says "People don’t perceive cancer as a developing-world problem, but more than 70 per cent of all cancer deaths occur in low and middle income countries ... This figure is rising due to increased life expectancy, increased tobacco use and chronic viral infection. Survival rates for cancer in the developing world are often less than half those of more developed countries, and there is little pain relief. In Africa, cancer is a sentence to a painful and distressing death."

Mirroring yesterday's post on access to cancer drugs David Kerr announced in an interview with last Sunday's

Observer that exploratory talks had begun with GlaxoSmithKline (GSK), about how to make its new vaccine for cervical cancer, Cervarix, available in Africa. The vaccine, Cervarix, is not yet available in Britain on the NHS!

Photo: Child with a tumour in the jaw due to Burkitt’s lymphoma cancer. Credit: Dr MA Ansary/Science Photo Library.

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!

Something seems to have gone wrong today

Kezia and Nanda are still stuck in the hospital. Kezia hasn't been seen by a doctor since Sunday but seemingly the chicken pox is cured. Numerous calls to Nanda, the Borchardt Clinic and my brother. The Borchardt Clinic told me they would get a doctor to her twice, then they couldn't hear me. Nanda has been up to see them - same message. Then I had my brother ring and he spoke to both the Clinic and Heywood Ward where they are "interned". He got the same message.

Kafka-esque - you would have thought with bed shortages they would be keen to get rid of her!

Anyway, my brother is picking Jaime up from school and then going to the hospital. Hopefully, they will be ready for discharge. Update tomorrow.

Update: They finally got out of hospital around 18:00.

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.

Complementary and Alternative Medicine

An online paper "The use of complementary and alternative medicine by cancer patients" from th International Seminars in Surgical Oncology has just gone up here.

It starts with definitions - alternative is difficult as it can be defined both as "not mainstream" or as a substitute for proven medical practice.

As a whole medical practitioners accept, even welcome, complementary medicine when it alleviates the psychological stress of cancer and cancer treatment. There is an obvious concern that some common CAM products may adversely interact with commonly prescribed medicines so it would be wise to consult a medical professional before taking this or that.

We were advised by our consultant at the beginning of treatment "to be cautious of web sites claimimg alternative cures for cancer".

Indeed the horror stories presented at Respectful Insolence's post Magical Thinking versus Lymphoma (and follow-up here) where parents withdrew their children from standard treatments and put them on unproven quackery are beyond belief! And in this context I would recommend Quackwatch if you really are so gullible.

Kezia's exposure to complementary approaches has been minimal - if you count the hospital clown and music sessions and play as complementary, although I think everyone would agree that Laughter is Medicine.