Clot buster may stop promising stroke medicine from working properly

 

Your doctor is completely familiar with this and gets update from the research analyst, right? Oh no, no research analyst and your doctor doesn't keep track of stroke research!

Anakinra (2 posts to July 2012)

Clot buster may stop promising stroke medicine from working properly

A clotbusting drug commonly used to treat ischemic stroke interacts negatively with a promising anti-inflammatory treatment (anakinra), underscoring the need to test new stroke therapies alongside existing standard care.

According to The University of Manchester led study on mice, the timing of anakinra must be adjusted to avoid reducing the benefits of the clot‑busting therapy known as tissue plasminogen activator(tPA).

Stroke is the second leading cause of death and disability worldwide; experts estimate the number of people affected could rise by more than 80 per cent over the next 25 years.But despite decades of research and thousands of experimental drugs, the only approved medicines for treating the most common type of stroke are clot‑busting drugs known as plasminogen activators, like tPA.

Though tPA can be lifesaving for acute ischemic stroke, about 2–6 per cent of treated patients develop potentially fatal brain bleeding, according to the ECASS III trial of the early 2000s.

Though it must be given within 4.5 hours of symptom onset, many patients arrive too late or don’t know when symptoms started.

Scientists now know that inflammation plays a major role in worsening brain injury after a stroke, mostly driven by a molecule called interleukin‑1 (IL‑1).

Anakinra  – an interleukin‑1 receptor antagonist (IL‑1Ra) –  blocks IL‑1 and has shown promise in reducing inflammation in both laboratory and early clinical studies of stroke.

However, a  phase II clinical trial known as SCIL‑STROKE based at The Northern care Alliance NHS foundation Trust found that IL‑1Ra did not improve patient recovery overall.

“The findings of SCIL‑STROKE raise questions about whether the drug might interact negatively with standard clot‑busting treatment, “ said lead author Dr Ioana-Emilia Mosneag, based at the University of Manchester.

Because nearly three‑quarters of patients in the SCIL‑STROKE trial received the clot‑busting drug tPA before IL‑1Ra, the researchers set out to investigate whether the two treatments might negatively interact  with each other.

They re‑examined data from the SCIL-STROKE trial and discovered that patients who received tPA before IL‑1Ra had significantly lower levels of IL‑1Ra in their blood, suggesting the drug was being broken down.

Laboratory research confirmed that IL‑1Ra can be cut apart by plasmin, an enzyme produced during tPA treatment, meaning the anti‑inflammatory drug may be degraded before it can work.

Researchers then tested the interaction in a mouse model of stroke, using dosing schedules that matched those used in the clinical trial.

When IL‑1Ra was given after tPA, no harmful interaction was seen, and the protective effects of tPA were preserved.

However, when IL‑1Ra was given at the same time as tPA — during the clot‑busting process — the benefits of tPA were dramatically reduced, with brain damage shrinking by only 15 per cent compared to 68 per cent with tPA alone.

The mice receiving both drugs together also showed poorer blood flow in the brain, more inflammatory immune cells entering damaged tissue, and higher levels of harmful structures called neutrophil extracellular traps.

This indicates that the drug interaction is also detrimental to the anti-inflammatory effect of IL-1Ra.

Dr Mosneag added: “Our findings suggest that IL‑1Ra can interfere with tPA’s ability to dissolve clots when the two drugs are present in the bloodstream at the same time.

“The results also help explain why IL‑1Ra levels were lower in patients who received tPA first, as plasmin generated during clot‑busting appears to break down IL‑1Ra.

”However, the  effect of tPA on IL-RA –  the opposite order –  isn’t necessarily a problem  as IL-1RA was still active in reducing IL-6 in the SCIL-STROKE study, but this needs further evaluation.”

Co-author Professor Stuart Allan from The University of Manchester said: “This study  shows that timing is very likely to be a critical factor in the efficacy of  IL‑1Ra, which  will be beneficial if given after tPA rather than alongside it.

“We also need to test whether similar interactions occur with other clot‑busting drugs such as tenecteplase, which may be less likely to break down IL‑1Ra due to its greater specificity.”

Co-author Professor Craig Smith from the University of Manchester said: “This study has important implications for further development of IL-1Ra as a treatment for ischaemic stroke, where there remains a focus on maximising delivery of thrombolysis drugs to eligible patients as quickly as possible in clinical care.

“Future studies will need to investigate the timing and effectiveness of IL-1Ra treatment after receiving tPA.”

New Stroke Treatments Becoming a Reality - Anakinra (IL-1Ra)

Sounds interesting. But are they considering that rodent models of inflammation aren't the same as human models? 

New Stroke Treatments Becoming a Reality - Anakinra (IL-1Ra)

Scientists led by the President of The University of Manchester have demonstrated a drug which can dramatically limit the amount of brain damage in stroke patients.

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Professor Dame Nancy Rothwell, Professor Stuart Allan and their team have spent the last 20 years investigating how to reduce damage to the brain following a stroke.
They have been testing the effectiveness of the drug Anakinra (IL-1Ra), which is already used for rheumatoid arthritis in experimental studies of stroke.
This new study builds on previous research, although the big difference is that rats with stroke risk factors such as obesity, insulin resistance and atherosclerosis were used alongside healthy rats and older ones. It means the findings have a far greater chance of being replicated in human stroke patients.
Researchers induced a stroke in the rats and the drug IL-1Ra, or a placebo for comparison, was injected under the skin. The researchers did not know which animals had been given which drug. This is a similar process to what happens in clinical trials of medicines.
The results were startling. MRI scans revealed that the rats that were given IL-1Ra up to three hours after the stroke had only about half the brain damage of the placebo group.
Professor Rothwell said: "This is the first time that we are aware of a potential new treatment for stroke being tested in animals with the same sort of diseases and risk factors that most patients have. The results are very promising and we hope to undertake further clinical studies in stroke patients soon."
IL-1Ra works by blocking the naturally occurring protein interleukin 1. Researchers at The University of Manchester have identified that it is a key cause of brain injury following a stroke.
Interleukin 1 encourages inflammation in the area of the brain affected by stroke. This sends out signals to attract white blood cells and to switch on microglia cells in the brain. Because the barrier surrounding the brain has been weakened by the stroke the white blood cells find it easier to enter the brain. But instead of helping the inflamed area they actually kill nerve cells and worsen the injury. The increasing presence of these cells also explains why the damage in the brain gets worse over time following a stroke.
IL-1Ra also reduces the amount of damage to the blood-brain barrier following a stroke so the harmful cells can't enter the brain. In the recent experiments IL-1Ra reduced the damage to the blood-brain barrier by 55% in healthy rats and 45% in rats with underlying health conditions. In all types of rats the drug reduced the amount of activated microglia cells by 40% compared to the placebo group.
The only drug treatment currently available for stroke patients is Tissue Plasminogen Activator (tPA). However, this can only be administered to patients who suffer from a blood clot (ischaemic stroke) rather than bleeding. A brain scan is required to assess which type of stroke a patient has suffered which is why it is essential to get them to hospital as quickly as possible. tPA also has to be administered within a few hours of a stroke to be effective.
Professor Stuart Allan at The University of Manchester hopes that IL-1Ra could be used for both forms of stroke, meaning it could be administered immediately.
He said: "This drug has real potential to save lives and stop hundreds of thousands of people being seriously disabled by stroke. This really could be the treatment for stroke that we've been looking for over the past two decades."
A phase 2 trial with a small number of patients has yielded encouraging results. It's hoped a much larger clinical trial will demonstrate the effectiveness of IL-1Ra in reducing brain damage in stroke patients and that eventually it will become the standard treatment.

New drug limits brain damage in stroke

I wonder when there will be research trials in humans on this. 

New drug limits brain damage in stroke

Anakinra, a drug already used for rheumatoid arthritis, has shown promising results in stroke patients by dramatically limiting the amount of brain damage, according to a study.
 Dame Nancy Rothwell and Stuart Allan, both professors at the University of Manchester and their team have spent the last 20 years investigating how to reduce damage to the brain following a stroke and testing the effectiveness of Anakinra (IL-1Ra).
 Researchers induced a stroke in the rats and the drug IL-1Ra, or a placebo for comparison, was injected under the skin. The researchers did not know which animals had been given which drug. This is a similar process to what happens in clinical trials of medicines.
 The results were startling. MRI scans revealed that the rats that were given IL-1Ra up to three hours after the stroke had only about half the brain damage of the placebo group, according to a university statement.
 Rothwell said: "This is the first time that we are aware of a potential new treatment for stroke being tested in animals with the same sort of diseases and risk factors that most patients have. The results are very promising and we hope to undertake further clinical studies in stroke patients soon."
 IL-1Ra works by blocking the naturally occurring protein interleukin 1. Researchers have identified that it is a key cause of brain injury following a stroke. Interleukin 1 encourages inflammation in the area of the brain affected by stroke.
 This sends out signals to attract white blood cells. Because the barrier surrounding the brain has been weakened by the stroke, the white blood cells find it easier to enter the brain. But instead of helping the inflamed area they actually kill nerve cells and worsen the injury. The increasing presence of these cells also explains why the damage in the brain gets worse over time following a stroke.
 IL-1Ra also reduces the amount of damage to the blood-brain barrier following a stroke so the harmful cells can't enter the brain. In the recent experiments, IL-1Ra reduced the damage to the blood-brain barrier by 55 percent in healthy rats and 45 percent in rats with underlying health conditions. In all types of rats, the drug reduced the amount of activated microglia cells by 40 percent compared to the placebo group.
 Allan said: "This drug has real potential to save lives and stop hundreds of thousands of people being seriously disabled by stroke. This really could be the treatment for stroke that we've been looking for over the past two decades." IANS