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Drug experiment goes horribly wrong -- BBC


Six men are in intensive care after experiencing a serious reaction to drug taken during a clinical drugs trial in north-west London.
What happened to make the men ill, and how is such research governed?

What has happened?

The six healthy men, all under 40, had volunteered to take part in a trial of an anti-inflammatory drug, called TGN1412, to treat conditions such as rheumatoid arthritis and leukaemia being tested at an independent research unit based at Northwick Park Hospital.

The six have suffered multiple organ failure and two are said to be critically ill.

Another two men, who had been given a dummy pill in the trial, are not ill.

The trial was stopped as soon as the men fell ill.

An investigation into what happened at the unit, run by clinical trial company Parexel, is being carried out by the watchdog, the Medicines and Healthcare products Regulatory Agency (MHRA) and the police.

What is the drug?

TGN1412 is a class of drug known as a monoclonal antibody.

Antibodies are produced in the body in response to infection. Monoclonal antibodies are made in the lab - and some are already on the market being used safely and effectively.

The drug in this trial had been thought to be particularly effective form of this kind of drug, because it is capable of boosting the action of killer immune cells to help them fight cancer cells, which they usually cannot normally do.

What went wrong?

This is what the investigation is designed to find out.

Parexel say they followed all the rules set in place for drug research.

A spokesman for the German company TeGenero, whose drug was being tested, said the results were "completely unexpected" and "did not reflect the results we obtained from initial laboratory studies".

Dr Benedikte Hatz, chief executive officer for the company, said the drug had been developed in line with all regulatory and clinical guidelines, and had been shown to be safe in earlier non-human studies.

The company said its thoughts were with the patients and their friends and relatives, and would work with the doctors treating the men.

Solicitor Ann Alexander, representing at least one of the critically ill men, said families had received "mixed messages" over the course of the last few days.

Professor Kent Wood, of the Medicines and Healthcare products Regulatory Authority (MHRA) said the options to be considered would be whether or not there was a problem with the manufacturing quality of the drug, if there was evidence it had been contaminated, or whether the men were given too high a dose.

The other possibility experts will consider is whether this was a completely unpredictable severe side effect of the drug in humans, which had not been indicated by earlier research.
  Joe De Livera on 2006-03-17
This is just a forum. Assume posts are not from medical professionals.
Dear joe de livera,
every time you peresented a good news in this forum. You want to say the homoeopathic is the safest medicine in the world . and alopathy medicine is dangerous medicine in world for that now days more of peoples are turning to homeopathy.
dr.deoshlok sharma
deoshlok last decade
Scientist defends clinical trials
A top scientist has defended Britain's system of clinical testing after six men fell seriously ill during a London trial of an anti-inflammatory drug.
Fertility expert Lord Robert Winston told the BBC he rejected claims that regulation was "weak and ramshackle".

Britain's system was among the "strongest and most carefully regulated" in the world, he said.

The six men have been in intensive care since falling ill on Monday. Two of them remain in a critical condition.

Doctors at Northwick Park Hospital in north-west London said the men had been given several blood transfusions to try to rid their bodies of toxins.

Four were said to be showing signs of improvement but doctors said it was still early days.

The men suffered multiple organ failure within hours of taking the drug TGN1412 during a trial at a research unit based at the hospital.
It was the first time the drug, designed to treat conditions such as rheumatoid arthritis, leukaemia and multiple sclerosis, had been tested on humans.

Lord Winston, who is professor of fertility studies at Imperial College London and vice-chairman of the Parliamentary Office for Science and Technology, told BBC Radio 4's The World Tonight Britain's system of clinical trials had "lots of safeguards".

Responding to a question by Labour MP Paul Flynn, he said: "I think it's really unfortunate that there might be given an impression that our very ethical drug industry is actually not working according to proper practice because I think on the whole it undoubtedly is."

Animal testing

He said he was concerned about growing resistance to animal testing in Britain and the affect this might be having on drugs trials.

He said: "I wonder really whether in fact there's increasing reluctance to do the preliminary trials on animals because of the difficulties generally in doing animal research.

"That I think is a disaster for humans."

American company Parexel, which ran the trial, said it had followed recommended guidelines.

TeGenero, which manufactures the anti-inflammatory drug, apologised to the sick men's families and said the medicine had showed no signs of problems in earlier tests.

The company's chief scientific officer, Thomas Hanke, said he and his colleagues were "devastated" by what had happened.

He said TGN1412 had been tested extensively in laboratories and on rabbits and monkeys for safety with no adverse effects and no drug-related deaths.

He added that the company's first concern now was making sure the patients got the best treatment possible and to support their families.

Scotland Yard said officers were talking to the Medicines and Healthcare products Regulatory Agency and doctors.

The MHRA is investigating whether the reaction suffered by the men was caused by a manufacturing problem, contamination, a dosing error or whether it was some "completely unanticipated side-effect of the drug in humans".

Story from BBC NEWS:

Published: 2006/03/17 00:37:23 GMT
Joe De Livera last decade

Catastrophic immune response may have caused drug trial horror
14:22 17 March 2006
NewScientist.com news service
Shaoni Bhattacharya and Andy Coghlan

A catastrophic over-stimulation of the immune system may have caused the horrific reactions suffered by six men taking part in the first human clinical trial of an experimental drug.

An investigation by New Scientist suggests the drug may have caused a super-immune response Ð sending white blood cells called T cells rampaging through the body destroying its own tissues.

Several experts contacted by New Scientist agree this is the most likely explanation for the terrible incident which put all six men in hospital intensive care in London, UK, with two in a critical condition. The victims, who were healthy, paid volunteers, are said to have suffered multiple organ failure.

The drug, called TGN1412 and made by German pharmaceutical company TeGenero, works by stimulating T cells, which could help treat leukaemia and auto-immune diseases such as rheumatoid arthritis. But this super-stimulation may have backfired. Indeed, a scientific article, highlighted on TeGeneroÕs own website, may have presaged this.

"Indiscriminate attack"

TGN1412 is a monoclonal antibody but works slightly differently from other similar drugs. It is a ÒsuperagonistÓ, causing a far greater immune cell response. It also does not require a second, specific trigger to kick-start this response, as do other monoclonal antibodies affecting the same T cell receptor.

ÒFortunately, this [super-stimulation] does not occur naturally, because T cells activated in this way would lack any antigenic specificity and could indiscriminately attack normal tissues,Ó wrote Peter Linsley, from Rosetta Inpharmatics in Seattle, US, in March 2005 in a commentary accompanying a paper in Nature Immunology, which involved TGN1412.

ÒOne could certainly say that, based on what [TeGenero] has already said about TGN1412, the most plausible explanation would be the triggering of a non-specific activation of natural killer T cells leading to indiscriminate cell destruction," says Ken Campbell, clinical information officer at the Leukaemia Research Fund in London, UK. "This would be consistent with multiple organ failure.Ó

An immunologist contacted by New Scientist, but who asked not to be named, says: ÒYou donÕt need to be a rocket scientist to work out what will happen if you non-specifically activate every T cell in the body.Ó

Regulatory response

Michael Ehrenstein, at University College London, UK, who works on regulatory T cells and rheumatoid arthritis, believes the drug was intended to activate regulatory T cells. This subgroup of T-cells actually suppresses the activation of the immune system and stops it from attacking a personÕs own body. TeGenero states that this is the strategy they hoped would ease the symptoms of rheumatoid arthritis patients.

ÒItÕs possible there was contaminationÓ of the drugs the patients received, Ehrenstein notes, but he says it is just as possible that something unexpected happened. ÒInstead of damping down the immune system, itÕs activated it more. ThatÕs what it looks like to me,Ó he told New Scientist.

Multiple attempts to contact TeGenero by New Scientist were unsuccessful. Previous experiments on immuno-deficient rats by the company indicated that the effect of the drug on regulatory T cells was disproportionately greater than on other T cells, leading to a normally functioning immune system. But it is unknown whether TGN1412 had been made more specific to regulatory T cells before the human trials.

Special status

Reports from friends and relatives describe the nightmarish symptoms suffered by the men. One manÕs head was said to have swollen massively and his limbs turned purple. Another was said to resemble the deformed ÒElephant ManÓ.

TGN1412 was being tested as a treatment for a range of illnesses, including autoimmune diseases, but it had been awarded special status as a possible treatment for a type of leukaemia called B-cell chronic lymphocytic leukaemia (B-CLL).

The drug is a type of monoclonal antibody. Antibodies are produced by the immune system in response to a foreign invader like a bacterium. It recognises the particular invader, or antigen, and neutralises it as well as kick-starting a wider immune response. A monoclonal antibody is one manufactured to be specific for one antigen only. These have been used safely in treatments for a variety of diseases, including lymphoma, experts stress.

Direct stimulation

But TGN1412 differs from other monoclonal antibodies because it is a superagonist Ð massively enhancing the bodyÕs immune response. It works by binding to a molecule, or receptor, on the surface of a T cell called CD28. Normally, binding to CD28 triggers the T cell response, but only when the T cell is also bound by another factor which is specific to the tissue designated for attack.

However, TGN1412 bypasses this so-called Òco-stimulationÓ. It binds in a different place on the molecule to natural antibodies and directly causes CD28 to provoke a strong T cell response, without needing the other antigen-specific molecule to bind.

This is what was highlighted by Linsley in his article accompanying the Nature Immunology paper (vol 6, p 271). In that paper, scientists had for the first time managed to crystallise and examine the structure of CD28.

"Completely unexpected"

Whatever the cause of the terrible side-effects seen in the UK trial, it is unusual not to have seen anything similar in animal testing, says Campbell: ÒCD28 is widely conserved across species. ItÕs very, very strange if it does turn out to be some idiosyncratic case in humans,Ó he told New Scientist.

The company insists animal testing gave no hint of these side effects. ÒThese events were completely unexpected and do not reflect the results we obtained from initial laboratory studies which enabled us to progress investigations into human volunteersÓ, said CEO Benedikte Hatz, in a statement.

The UKÕs regulatory body, the Medicines and Healthcare products Regulatory Agency, which halted the trial, is currently conducting an investigation which could take weeks to reach a conclusion.

Related Articles
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Up to 140,000 heart attacks linked to Vioxx
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TGN1412, TeGenero
Leukaemia Research Fund, UK
Monoclonal antibody, Wikipedia
Regulatory T cell, Wikipedia
Medicines and Healthcare products Regulatory Agency
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Printed on Sat Mar 18 04:31:58 GMT 2006
Joe De Livera last decade
Dr.deoshlok sharma wrote:

< ....for that now days more of peoples are turning to homeopathy.>

The H5N1 virus is not far now from the place where I practise. Daily, thousands of chickens have been culled and buried for fear of posiible infection. Homeopathy is classified under Traditional Medicine in Malaysia. Most of the doctors in our medical clinics practise orthodox medicine. I am the only one practising Integrated Medicine in our group. Honestly , I will always avoid a tetanus toxoid dose called for in any traumatic injury case, given the slightest opportunity or excuse. Instead, I will feed the patient a few NO 40 globules of Hypericum or Ledum as the case may be. I do not know what emergency measures other mainstream doctors are taking in the even of an avian influenza
outbreak, and as for me, I have already started to give homeopathic No 40 globules soaked in Reckeweg 93 , an Immune System Fortifier dilution to all receptive patients a week ago. Rather than giving sweet vitamin C tablets to children in the office, I feed them a few globules of cane-sugar laced with R 93. The children love them.

The homeopathised ingredients and their mode of action:

1. Allium sativum: Immune System Fortifier
2 Coecum ,glandulae thymi,Tonsillae palatinae,Tonsillae pharyngea:
Glandulars for control of cellular and humoral immune systems.
Lymphocycte: For regulation of reticulo-endothelial system.
3. Medulla ossium, Nodi Lymphatici,splenum: Glandular stimulation and regulation of white blood cell development.

4. Zincum metallicum: Irritability of the nervous system, slow mental conception.

I fought SARS with R93, Ozone and Colloidal Silver in yesteryears and now the H5N1 virus....I can hear the distant drum.

With regards
homeopathy last decade

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