Abstract
Erythropoietin (EPO) and its receptor play a major role in embryonic brain, are weakly expressed in normal postnatal/adult brain and up-regulated upon metabolic stress. EPO protects neurons from hypoxic/ ischemic injury. The objective of this trial is to study the safety and efficacy of recombinant human EPO (rhEPO) for treatment of ischemic stroke in man. The trial consisted of a safety part and an efficacy part. In the safety study, 13 patients received rhEPO intravenously (3.3 X 10(4) IU/50 ml/30 min) once daily for the first 3 days after stroke. In the double-blind randomized proof-of-concept trial, 40 patients received either rhEPO or saline. Inclusion criteria were age <80 years, ischemic stroke within the middle cerebral artery territory confirmed by diffusion-weighted MRI, symptom onset <8 hr before drug administration, and deficits on stroke scales. The study endpoints were functional outcome at day 30 (Barthel Index, modified Rankin scale), NIH and Scandinavian stroke scales, evolution of infarct size (sequential MRI evaluation using diffusion-weighted [DWI] and fluid-attenuated inversion recovery sequences [FLAIR]) and the damage marker S100ss. No safety concerns were identified. Cerebrospinal fluid EPO increased to 60-100 times that of nontreated patients, proving that intravenously administered rhEPO reaches the brain. In the efficacy trial, patients received rhEPO within 5 hr of onset of symptoms (median, range 2:40-7:55). Admission neurologic scores and serum S100beta concentrations were strong predictors ofoutcome. Analysis of covariance controlled for these two variables indicated that rhEPO treatment was associated with an improvement in follow-up and outcome scales. A strong trend for reduction in infarct size in rhEPO patients as compared to controls was observed by MRI. Intravenous high-dose rhEPO is well tolerated in acute ischemic stroke and associated with an improvement in clinical outcome at 1 month. A larger scale clinical trial is warranted.
Highlights
Stroke remains a leading cause of death and disability throughout the world
Serum levels of recombinant human EPO (rhEPO) obtained 3 hr after each rhEPO infusion rose to a mean Ϯ SD of 4132 ϩ 561, 4794 Ϯ 1183, and 5649 Ϯ 903 mU/ml on days 1, 2, and 3, respectively, which was not associated with any changes in blood pressure
The present data support a novel approach to neuroprotection of cerebral ischemic injury by use of rhEPO, clinically one of the bestcharacterized and well-tolerated therapeutics
Summary
Stroke remains a leading cause of death and disability throughout the world. Currently, thrombolysis using recombinant tissue plasminogen activator (rTPA) is the only pharmacologic treatment with496 Molecular Medicine, Volume 8, Number 8, August 2002 acceptable side effects shown to effectively limit neurologic damage in acute stroke [1]. We have recently observed dramatic changes in the expression of EPO and its receptor localized to regions within and around infarcts in human brain following ischemic/hypoxic injury [11]. EPO protects neurons from hypoxic/ ischemic injury The objective of this trial is to study the safety and efficacy of recombinant human EPO (rhEPO) for treatment of ischemic stroke in man. 13 patients received rhEPO intravenously (3.3 ϫ 104 IU/50 ml/30 min) once daily for the first 3 days after stroke. Patients received rhEPO within 5 hr of onset of symptoms (median, range 2:40–7:55). Conclusion: Intravenous high-dose rhEPO is well tolerated in acute ischemic stroke and associated with an improvement in clinical outcome at 1 month.
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