Therapeutic dose and timing of administration of RNA synthesis inhibitors for preventing cerebral vasospasm after subarachnoid hemorrhage.
A RNA synthesis inhibitor, dactinomycin, intended to suppress induction of vasoconstrictor peptide endothelin, prevented cerebral vasospasm almost completely in the dog subarachnoid hemorrhage (SAM) model [8]. Since endothelin receptor antagonists have not shown so potent effect as dactinomycin in animal SAH models, we aimed clinical use of dactinomycin for improvement of final outcomes of severe SAH patients now suffering vasospasm. Before clinical application, we examined therapeutic dose and timing of administration of dactinomycin in animal models. In the dog two-hemorrhage model, dactinomycin treatment (0.01 mg/kg i.v. for 5 days) started at 6 hours after the second blood injection on Day 2 prevented vasospasm, but that started on Day 3 did not. Low dose of dactinomycin (0.003 mg/kg i.v. for 5 days) rather aggravated vasospasm even though the treatment started on Day 0. In the rat vasospasm model, high dose of dactinomycin (0.03 mg/kg i.p. for 3 days) or relatively low dose of doxorubicin (0.6 mg/kg i.p. once) prevented vasospasm even though the treatment started on Day 4. The present study suggests that RNA synthesis inhibitors, such as dactinomycin and doxorubicin, may aufficiently prevent or ameliorate cerebral vasospasm in severe SAH patients.