Minocycline to improve neurologic outcome in stroke (MINOS): a dose-finding study.
OBJECTIVE
Minocycline is a promising anti-inflammatory and protease inhibitor that is effective in multiple preclinical stroke models. We conducted an early phase trial of intravenous minocycline in acute ischemic stroke.


METHODS
Following an open-label, dose-escalation design, minocycline was administered intravenously within 6 hours of stroke symptom onset in preset dose tiers of 3, 4.5, 6, or 10 mg/kg daily over 72 hours. Minocycline concentrations for pharmacokinetic analysis were measured in a subset of patients. Subjects were followed for 90 days.


RESULTS
Sixty patients were enrolled, 41 at the highest dose tier of 10 mg/kg. Overall age (65±13.7 years), race (83% white), and sex (47% female) were consistent across the doses. The mean baseline National Institutes of Health Stroke Scale score was 8.5±5.8 and 60% received tissue plasminogen activator. Minocycline infusion was well tolerated with only 1 dose limiting toxicity at the 10-mg/kg dose. No severe hemorrhages occurred in tissue plasminogen activator-treated patients. Pharmacokinetic analysis (n=22) revealed a half-life of approximately 24 hours and linearity of parameters over doses.


CONCLUSIONS
Minocycline is safe and well tolerated up to doses of 10 mg/kg intravenously alone and in combination with tissue plasminogen activator. The half-life of minocycline is approximately 24 hours, allowing every 24-hour dosing. Minocycline may be an ideal agent to use with tissue plasminogen activator.
Fagan
Susan C
SC
Departmentof Neurology, College of Pharmacy, University of Georgia, Medical College of Georgia, Augusta, Ga 30912, USA.
Waller
Jennifer L
JL
Nichols
Fenwick T
FT
Edwards
David J
DJ
Pettigrew
L Creed
LC
Clark
Wayne M
WM
Hall
Christiana E
CE
Switzer
Jeffrey A
JA
Ergul
Adviye
A
Hess
David C
DC
D000368:Aged; D000369:Aged, 80 and over; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000627:therapeutic use; D002545:Brain Ischemia / Q000188:drug therapy*; D002851:Chromatography, High Pressure Liquid; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D008911:Minocycline / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D012720:Severity of Illness Index; D020521:Stroke / Q000188:drug therapy*; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000627:therapeutic use; D016896:Treatment Outcome
D000893:Anti-Inflammatory Agents; D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator; D008911:Minocycline