Reducing bleeding complications after thrombolytic therapy for stroke: clinical potential of metalloproteinase inhibitors and spin trap agents.

Abstract

Thrombolysis with alteplase (recombinant tissue plasminogen activator; rtPA) has proven to be beneficial for acute stroke management, despite the narrow window of opportunity for treatment and the increased risk of haemorrhage. Because of the latter, recent studies have attempted to identify compounds that may be given concomitantly with alteplase to reduce the haemorrhage rate Matrix metalloproteinase (MMP) inhibitors have been proposed as potential combination therapy candidates because they prevent MMP-induced production of the cytokine tumour necrosis factor-alpha (TNFalpha), as well as membrane and vessel remodelling following ischaemia. Spin trap agents also have been put forward due to their free radical scavenging capabilities. In the rabbit large clot embolism model, alteplase effectively lysed blood clots, whether or not other drugs were used in combination. However, haemorrhage rate also was increased compared with that in control animals. The alteplase-induced haemorrhage rate was reduced significantly by administration of the MMP inhibitor batimastat (BB-94) or the spin trap agent alpha-phenyl-N-t-butylnitrone (PBN). Other rodent studies have also demonstrated that PBN is effective in decreasing the haemorrhage rate following alteplase administration. Overall, preclinical studies indicate that MMP inhibition or free radical scavenging in combination with alteplase may circumvent the high risk of haemorrhaging with alteplase.