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 黑料网吃瓜爆料 led on mice, published in the American Heart Association Stroke journal today (insert date) and funded by the Medical Research Council, the timing of anakinra must be adjusted to avoid reducing the benefits of the clot鈥慴usting 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% 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 鈥� ischemic stroke 鈥� are clot鈥慴usting drugs known as plasminogen activators, like tPA.
Though tPA can be lifesaving for acute ischemic stroke, about 2鈥�6% 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鈥檛 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鈥�1 (IL鈥�1).
Anakinra - an interleukin鈥�1 receptor antagonist (IL鈥�1Ra) - blocks IL鈥�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鈥慡TROKE based at The Northern care Alliance NHS foundation Trust found that IL鈥�1Ra did not improve patient recovery overall.
鈥淭he findings of SCIL鈥慡TROKE raise questions about whether the drug might interact negatively with standard clot鈥慴usting treatment, 鈥� said lead author , based at the University of 黑料网吃瓜爆料.
Because nearly three鈥憅uarters of patients in the SCIL鈥慡TROKE trial received the clot鈥慴usting drug tPA before IL鈥�1Ra, the researchers set out to investigate whether the two treatments might negatively interact with each other.
This study shows that timing is very likely to be a critical factor in the efficacy of IL鈥�1Ra, which will be beneficial if given after tPA rather than alongside it
They re鈥慹xamined data from the SCIL-STROKE trial and discovered that patients who received tPA before IL鈥�1Ra had significantly lower levels of IL鈥�1Ra in their blood, suggesting the drug was being broken down.
Laboratory research confirmed that IL鈥�1Ra can be cut apart by plasmin, an enzyme produced during tPA treatment, meaning the anti鈥慽nflammatory 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鈥�1Ra was given after tPA, no harmful interaction was seen, and the protective effects of tPA were preserved.
However, when IL鈥�1Ra was given at the same time as tPA 鈥� during the clot鈥慴usting process 鈥� the benefits of tPA were dramatically reduced, with brain damage shrinking by only 15% compared to 68% 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: 鈥淥ur findings suggest that IL鈥�1Ra can interfere with tPA鈥檚 ability to dissolve clots when the two drugs are present in the bloodstream at the same time.
鈥淭he results also help explain why IL鈥�1Ra levels were lower in patients who received tPA first, as plasmin generated during clot鈥慴usting appears to break down IL鈥�1Ra.
鈥滺owever, the effect of tPA on IL-RA - the opposite order - isn鈥檛 necessarily a problem as IL-1RA was still active in reducing IL-6 in the SCIL-STROKE study, but this needs further evaluation.鈥�
Co-author Professor from 黑料网吃瓜爆料 said: 鈥淭his study shows that timing is very likely to be a critical factor in the efficacy of IL鈥�1Ra, which will be beneficial if given after tPA rather than alongside it.
鈥淲e also need to test whether similar interactions occur with other clot鈥慴usting drugs such as tenecteplase, which may be less likely to break down IL鈥�1Ra due to its greater specificity.鈥�
Co-author from the University of 黑料网吃瓜爆料 said: 鈥淭his 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.鈥�
- The paper Timing-dependent cleavage of Interleukin-1 receptor antagonist by alteplase impairs neuroprotection in ischemic stroke is available