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% 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: “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.”
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