title: Pharmacology of caffeinol in embolized rabbits: clinical rating scores and intracerebral hemorrhage incidence.
abstract: Caffeinol is currently being tested in acute ischemic stroke patients. However, little is known about the pharmacology or safety of caffeinol in preclinical embolic stroke models. We determined the pharmacological effects of caffeinol administration on clinical rating scores in rabbits following small clot embolic strokes (RSCEM). Male New Zealand white rabbits were embolized by injecting blood clots into the cerebral circulation via a carotid catheter. Behavioral analysis was conducted 24 h following embolization, allowing for the determination of the effective stroke dose (P50) or clot amount (mg) that produces neurological deficits in 50% of the rabbits. In the current study, the P50 values for the control groups were 1.32 +/- 0.23 and 1.66 +/- 0.29 mg for the bolus-injected and infused groups, respectively. Rabbits treated with caffeinol (bolus) starting 15 min following embolization had a P50 value of 1.70 +/- 1.18 mg. Caffeinol-infused rabbits had a P50 value of 2.05 +/- 0.47 and 1.67 +/- 0.48 mg for low- and high-dose ethanol, respectively. In tPA-treated rabbits (0.9 mg/kg), the group P50 was 1.58 +/- 0.43 mg. In caffeinol (bolus) and tPA-treated rabbits, we measured a decrease in the P50 value to 0.70 +/- 0.30 mg and an increase in the rate of intracerebral hemorrhage compared to control. This primary finding of this study indicates that neither bolus-injected nor infused caffeinol affects behavioral deficits following embolic strokes in rabbits. Moreover, the combination of caffeinol plus low-dose tPA does not improve behavioral deficits. However, our study suggests that there is the potential for exacerbation of stroke-induced behavioral deficits following caffeinol administration in combination with a thrombolytic that may be related to increased intracerebral hemorrhage.
authors.affiliation: University of California San-Diego, Department of Neuroscience, La Jolla 92093-0624, USA. plapchak@ucsd.edu
authors.forename: Paul A
authors.initials: PA
authors.lastname: Lapchak
authors.forename: Donghuan
authors.initials: D
authors.lastname: Song
authors.forename: Jiandong
authors.initials: J
authors.lastname: Wei
authors.forename: Justin A
authors.initials: JA
authors.lastname: Zivin
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002110:Caffeine / Q000009:adverse effects / Q000494:pharmacology*; D002543:Cerebral Hemorrhage / Q000209:etiology*; D004195:Disease Models, Animal; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D000431:Ethanol / Q000009:adverse effects / Q000494:pharmacology*; D005343:Fibrinolytic Agents / Q000009:adverse effects / Q000627:therapeutic use; D015994:Incidence; D007262:Infusions, Intravenous; D007267:Injections; D020766:Intracranial Embolism / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D008863:Microspheres; D018696:Neuroprotective Agents / Q000009:adverse effects / Q000494:pharmacology; D011817:Rabbits; D012720:Severity of Illness Index; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000009:adverse effects / Q000627:therapeutic use*; D017211:Treatment Failure
chemical_list: D005343:Fibrinolytic Agents; D018696:Neuroprotective Agents; D002110:Caffeine; D000431:Ethanol; D010959:Tissue Plasminogen Activator