Repurposing an old drug to improve the use and safety of tissue plasminogen activator for acute ischemic stroke: minocycline.
Tissue plasminogen activator (tPA) is the only drug approved by the United States Food and Drug Administration for treatment of acute ischemic stroke. Because the drug must be used soon after symptom onset and is associated with intracerebral hemorrhage, tPA remains underutilized. Research has therefore focused on identifying other drugs that can be used concomitantly with tPA to improve the odds of a favorable recovery and to reduce the risk of intracerebral hemorrhage. Minocycline is a broad-spectrum antibiotic that has been found to be a neuroprotective agent in preclinical ischemic stroke models. Minocycline inhibits matrix metalloproteinase-9, a biomarker for intracerebral hemorrhage associated with tPA use. Minocycline is also an antiinflammatory agent and inhibits poly(ADP-ribose) polymerase-1. Minocycline has been safe and well tolerated in clinical trials. Additional safety and efficacy data are needed, and a phase III trial of minocycline with tPA in patients experiencing acute ischemic stroke is planned.
Hess
David C
DC
Department of Neurology, Medical College of Georgia, Augusta, Georgia 30912, USA. dhess@mail.mcg.edu
Fagan
Susan C
SC
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy / Q000209:etiology; D058492:Drug Repositioning; D005260:Female; D005343:Fibrinolytic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008911:Minocycline / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D020521:Stroke / Q000188:drug therapy*; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*
D005343:Fibrinolytic Agents; D018696:Neuroprotective Agents; D010959:Tissue Plasminogen Activator; D020780:Matrix Metalloproteinase 9; D008911:Minocycline