gms | German Medical Science

Objective: Despite a distinct reduction of mortality during the course of aneurysmal subarachnoid hemorrhage (aSAH), the effective reduction of delayed cerebral ischemia (DCI), thus poor functional outcome, remains challenging. However, in this respect, the intrathecal application of prolonged-release nimodipine microparticles (EG 1962, Edge Therapeutics Inc.) following experimental SAH in 2 different animal models demonstrated promising results. Therefore, we investigated in a pilot series the effect of EG-1962) in patients suffering from severe aSAH.

Method: After obtaining an informent consent from legal representatives, EG 1962 was administered in a dose of either 40 (presumed non-therapeutic dose) or 100mg in patients suffering from high grade SAH (WFNS ° II-V and/or Fisher °III-IV). Administration was performed either intracisternally, following surgical aneurysm repair, or intraventricularly, via an external ventricular drain. Patients were closely monitored for occurrence of DCI using perfusion-CT imaging, transcranial doppler sonography and digital subtraction angiography. In addition to common toxicity criteria, patients were specifically observed for increased occurrence of systemic hypotension. Additionally, the pharmacokinetic profile of intrathecal and plasma nimodipine levels was analyzed in all patients. Clinical outcome was assessed using the Glasgow Outcome Score (GOS).

Results: To date, a total of 7 patients were treated in this human pilot series. There were no adverse events, such as toxic drug effects or systemic hypotension. In patient #1 (treated with 40 mg), the plasma- and CSF-levels were not measurable whereas in all patients treated with the dose of 100 mg, the plasma- and CSF-levels of nimodipine were within the therapeutic range over the analyzed period. Expect Except patient #1 (treated with 40mg) all subsequently treated patients with 100 mg of EG 1962 demonstrated no clinical or radiological features of DCI or cerebral infarction on CT.in. At 6 weeks after SAH, GOS in patient #1 was 4 whereas all patients treated with 100 mg of EG 1962 reached a GOS of 5.

Conclusions: EG 1962 appears to be a promising new concept for prevention of DCI. Our encouraging initial results of the first clinical application of EG 1962 will be further investigated in the upcoming PROMISE (Prolonged Release Nimodipine Microparticles after Subarachnoid Hemorrhage)-Trial.