ABSTRACT
Tissue plasminogen activator (tPA) thrombolysis continues to be the gold standard therapy for ischemic stroke. Due to the time-limited treatment window, within 4.5 h of stroke onset, and a variety of potentially deadly complications related to delayed administration, particularly hemorrhagic transformation (HT), clinical use of tPA is limited. Combination therapies with other interventions, drug or nondrug, have been hypothesized as a logical approach to enhancing tPA effectiveness. Here, we discuss various potential pharmacological and nondrug treatments to minimize adverse effects, primarily HT, associated with delayed tPA administration. Pharmacological interventions include many that support the integrity of the blood-brain barrier (i.e., atorvastatin, batimastat, candesartan, cilostazol, fasudil, and minocycline), promote vascularization and preserve cerebrovasculature (i.e., coumarin derivative IMM-H004 and granulocyte-colony stimulating factor), employing other mechanisms of action (i.e., oxygen transporters and ascorbic acid). Nondrug treatments are comprised of stem cell transplantation and gas therapies with multi-faceted approaches. Combination therapy with tPA and the aforementioned treatments demonstrated promise for mitigating the adverse complications associated with delayed tPA treatment and rescuing stroke-induced behavioral deficits. Therefore, the conjunctive therapy method is a novel therapeutic approach that can attempt to minimize the limitations of tPA treatment and possibly increase the therapeutic window for ischemic stroke treatment.
ABSTRACT
Tissue plasminogen activator (tPA) thrombolysis remains the gold standard treatment for ischemic stroke. A time-constrained therapeutic window, with the drug to be given within 4.5 h after stroke onset, and lethal side effects associated with delayed treatment, most notably hemorrhagic transformation (HT), limit the clinical use of tPA. Co-administering tPA with other agents, including drug or non-drug interventions, has been proposed as a practical strategy to address the limitations of tPA. Here, we discuss the pharmacological and non-drug approaches that were examined to mitigate the complications-especially HT-associated with delayed tPA treatment. The pharmacological treatments include those that preserve the blood-brain barrier (e.g., atovarstatin, batimastat, candesartan, cilostazol, fasudil, minocycline, etc.), enhance vascularization and protect the cerebrovasculature (e.g., coumarin derivate IMM-H004 and granulocyte-colony stimulating factor (G-CSF)), and exert their effects through other modes of action (e.g., oxygen transporters, ascorbic acid, etc.). The non-drug approaches include stem cell treatments and gas therapy with multi-pronged biological effects. Co-administering tPA with the abovementioned therapies showed promise in attenuating delayed tPA-induced side effects and stroke-induced neurological and behavioral deficits. Thus, adjunctive treatment approach is an innovative therapeutic modality that can address the limitations of tPA treatment and potentially expand the time window for ischemic stroke therapy.
