Reducing bleeding complications after thrombolytic therapy for stroke - Clinical potential of metalloproteinase inhibitors and spin trap agents

Thrombolysis with alteplase (recombinant tissue plasminogen activator; rtPA ) has proven to be beneficial for acute stroke management, despite the narr ow window of opportunity for treatment and the increased risk of haemorrhag e. Because of the latter, recent studies have attempted to identify compoun ds that may be given concomitantly with alteplase to reduce the haemorrhage rate Matrix metalloproteinase (MMP) inhibitors have been proposed as potential c ombination therapy candidates because they prevent MMP-induced production o f the cytokine tumour necrosis factor-alpha (TNF alpha), as well as membran e and vessel remodelling following ischaemia. Spin trap agents also have be en 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, haemor rhage rate also was increased compared with that in control animals. The al teplase-induced haemorrhage rate was reduced significantly by administratio n of the MMP inhibitor batimastat (BB-94) or the spin trap agent alpha -phe nyl-N-t-butylnitrone (PBN). Other rodent studies have also demonstrated tha t PBN is effective in decreasing the haemorrhage rate following alteplase a dministration. Overall, preclinical studies indicate that MMP inhibition or free radical s cavenging in combination with alteplase may circumvent the high risk of hae morrhaging with alteplase.