ABSTRACT
AIMS: The main objective of this study was to investigate the safety, tolerability and pharmacodynamics of the novel proteasome inhibitor PS-519 in young male volunteers. Many pro-inflammatory mediators such as cytokines and cell adhesion molecules that are responsible for the development of the cerebral infarct are under the control of the transcription factor Nuclear Factor kappa-B (NF-kappaB). The activity of NF-kappaB is itself tightly regulated through the multicatalytic enzyme known as the proteasome. PS-519 is a novel and highly selective small molecule that inhibits the proteasome. An ex vivo assay of 20S proteasome activity allows monitoring of the drug effect in blood. PS-519 is protective in multiple animal models of cerebral ischaemia over a range of doses that achieve 20S inhibition of 40%-80%. METHODS: PS-519 has been administered to healthy male volunteers as single and repeated doses up to 1.6 mg m(-2). It was given as an intravenous bolus over 20-30 s in a double blind, randomized, placebo-controlled phase I study, examining vital signs, safety, tolerability and blood 20S proteasome inhibition. RESULTS: Thirty-nine subjects received single doses of 0.012 mg m-2-1.6 mg m(-2) and 28 subjects received doses of 0.5 mg m(-2)-1.6 mg m(-2) on three consecutive days. The drug was well tolerated. There was no clear treatment-emergent symptom or abnormality of laboratory tests. Proteasome inhibition in blood samples as measured by 20S assay achieved the intended maximum target level of 70-80% with 1.6 mg m(-2), and was reproducible with repeated dosing. CONCLUSIONS: This study has demonstrated that proteasome inhibition is well tolerated by healthy subjects at levels that are maximally neuroprotective in experimental conditions. Further clinical evaluation appears justified.
