title: Pilot dose-escalation study of caffeine plus ethanol (caffeinol) in acute ischemic stroke.
abstract: OBJECTIVE
  In animal models, the combination of caffeine and ethanol (caffeinol) provides robust neuroprotection at blood levels that should be easily and safely achieved in humans. This study was designed to determine the safety and tolerability of ascending doses of this combination in stroke patients.
  
  
  METHODS
  This Food and Drug Administration-approved open-label, single-arm, dose-escalation study had 3 original dose groups: group 1, caffeine 6 mg/kg plus ethanol 0.2 g/kg; groups 2 and 3, incremental increases of caffeine and ethanol by 2 mg/kg and 0.2 g/kg, respectively. Intravenous thrombolysis was encouraged if patients qualified. Drug was started within 6 hours of stroke onset, and blood levels of caffeine and ethanol were drawn at baseline and end of infusion. The target blood caffeine and ethanol ranges were 8 to 10 microg/mL and 30 to 50 mg/dL, respectively. Clinical outcome measurements included the National Institutes of Health Stroke Scale at the end of infusion, at 24 hours, and at discharge. Potential complications from caffeine and ethanol were recorded. Cases were reviewed by an independent stroke neurologist for safety.
  
  
  RESULTS
  A total of 23 patients were recruited. Target blood caffeine and ethanol levels were reached in 0 of the 4 patients in the first group. The second dose group (caffeine 8 mg/kg plus ethanol 0.4 g/kg) included 8 patients. The median end-of-infusion caffeine and ethanol levels were within the desired target ranges. Two days after infusion, 1 patient in this group with preexisting cardiac disease and end-of-infusion caffeine and ethanol levels of 10.7 microg/mL and 69 mg/dL developed reversible congestive heart failure and required transfer to an intensive care unit. The original third dose group was canceled given achievement of target blood caffeine and ethanol levels in group 2. However, 3 new dose groups were created in an attempt to minimize the dose of ethanol. Although blood levels were proportional to dose, none of these new dose groups provided optimal blood levels. Congestive heart failure occurred in 1 other patient with previously asymptomatic cardiomyopathy. No other side effects were noted. Concomitant thrombolytic therapy was given in 8 patients, 1 of whom died of intracerebral hemorrhage.
  
  
  CONCLUSIONS
  Caffeinol alone or combined with intravenous tissue plasminogen activator can be administered safely. Caffeine 8 mg/kg plus ethanol 0.4 g/kg produces target caffeine and ethanol levels of 8 to 10 microg/mL and 30 to 50 mg/dL, respectively. A randomized, placebo-controlled trial is needed to determine the neuroprotective effect of this combination.
authors.affiliation: Stroke Program, Department of Neurology, University of Texas, Houston Medical School, USA.
authors.forename: Paisith
authors.initials: P
authors.lastname: Piriyawat
authors.forename: Lise A
authors.initials: LA
authors.lastname: Labiche
authors.forename: W Scott
authors.initials: WS
authors.lastname: Burgin
authors.forename: Jaroslaw A
authors.initials: JA
authors.lastname: Aronowski
authors.forename: James C
authors.initials: JC
authors.lastname: Grotta
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002545:Brain Ischemia / Q000097:blood / Q000188:drug therapy*; D002110:Caffeine / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D002543:Cerebral Hemorrhage / Q000139:chemically induced; D004359:Drug Therapy, Combination; D004677:Encephalocele / Q000139:chemically induced; D000431:Ethanol / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D005240:Feasibility Studies; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D006333:Heart Failure / Q000150:complications; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000097:blood / Q000188:drug therapy; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D010865:Pilot Projects; D012449:Safety; D012720:Severity of Illness Index; D020521:Stroke / Q000097:blood / Q000188:drug therapy*; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D005343:Fibrinolytic Agents; D018696:Neuroprotective Agents; D002110:Caffeine; D000431:Ethanol; D010959:Tissue Plasminogen Activator