Table 2.

Approaches to improve tPA efficacy

tPA delivery directly to the site of the clot (catheterization)

tPA + Ultrasound [35, 37]

tPA + Ultrasound +gaseous lipid microspheres containing octofluropropane or sulfur hexafluoride (agitate fluid and enhance mechanical grinding of a thrombus) [36]

tPA + Mechanical Embolus Removal in Cerebral Ischemia (MERCI™) retriever (a tiny corkscrew threaded through an artery to remove the clot) [38]

tPA + clot vacuuming (PENUMBRA Inc., a California based company).

tPA + activated protein C (combination showed benefit in experimental studies, clinical trials not yet initiated [39]. Note: APC inhibits MMP-9 that may be needed in the recovery phase after stroke by promoting neurovascular repair through VEGF. APC may also have hemorrhagic risk by itself [40, 41].

tPA + plasminogen activator inhibitor-1 attenuated tPA-mediated signal transduction without compromising its catalytic activity [88].

tPA + neuroserpin (an endogenous tPA inhibitor) [25, 89, 90].

tPA + CDP-choline showed benefit in an animal model of stroke [91]. A high dose of CDP-choline (1000 mg/kg) was better than tPA alone and equally as good as the combination with tPA [92]. Note: One difference between the animal studies vs clinical trials is that animal studies typically use much higher doses of CDP-choline (500-1000 mg/kg i.p. or i.v. immediately after stroke, whereas clinical trials administer 2000 mg/patient within 24 hrs of stroke symptoms [93], for a 70 kg patient receiving 2000 mg citicoline, the dose amounts to 28 mg/kg). Although a dose used in animal studies cannot extrapolate to humans, these represent vastly different dosing. Even 2000 mg/day CDP-choline (citicoline) was safe and had virtually no side effects. On a similar note, CDP-choline encapsulated in liposomes (18 mg/kg i.v.) significantly reduced infarction compared to free CDP-choline (500 mg/kg) in a rat stroke model [5, 74, 75, 94].

tPA + uric acid [42, 43] (may decrease lipid peroxidation and endogenous MMP-9).