About 600,000 Americans suffer ischemic stroke each year, 8% of whom die within 30 days. A further 15-30% are permanently disabled and 20% require institutional care. Direct and indirect costs of stroke are therefore immense. The treatment of ischemic stroke remains one of the most challenging areas of medicine today. At present, only one agent is approved (Alteplase, rt-PA), and for only a brief window of time (onset of symptoms less than three hours). Since many patients present far beyond this three hour window, not surprisingly most patients receive only palliative care. In order to open the window of therapeutic opportunity the pharmaceutical industry is currently focusing on the development of molecules able to protect neural tissue from ischemic damage (see for example our recent report implicating glycogen synthase kinase-3 inhibitors in the treatment of stroke) as well limit the degree of ischemia.


Generation of prostacyclin (prostaglandin I2 , PGI2 ) from endothelial cells is crucial for the maintenance of homeostasis of cerebral blood flow, as PGI2 counteracts platelet-derived thromboxane. Because of its highly potent vasodilating and antiplatelet activity, PGI2 has been used to treat various types of thrombotic disorders such as ischemic cerebrovascular diseases. However the half-life of PGI2 under in vivo conditions is about 3 min limiting its benefits when given therapeutically.


Japanese researchers have recently investigated the ability of TTC-909, a product consisting of lipid microspheres loaded with the stable PGI2 analogue, clinprost, to limit cerebral infarction after permanent occlusion of the middle cerebral artery.


This study was conducted using stroke prone spontaneously hypertensive rats since chronic hypertension is a major risk factor associated with stroke and furthermore this model appears to have significant advantages over experimental procedures involving occlusion in normotensive animals.


TTC-909 administered as an i.v. injection once daily over 7 days and as a 3 hour infusion both starting immediately after occlusion significantly reduced infarct volume while infusion or daily injections alone had no effect. The authors suggest that TTC-909 both prevents the immediate effects of occlusion and may also protect against more long-term neuronal damage.
 

Adapted from Karasawa et al et al, J Pharmacol Sci 2003;91(4):305-312
 

Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk