Pharmacology of caffeinol in embolized rabbits: clinical rating scores and intracerebral hemorrhage incidence

• Published in: Experimental neurology 2004-08, Vol.188 (2), p.286-291
• Main Authors: Lapchak, Paul A., Song, Donghuan, Wei, Jiandong, Zivin, Justin A.
• Format: Article
• Language: English
• Subjects: Alteplase; Aminoacid disorders; Animals; Behavior, Animal - drug effects; Biological and medical sciences; Caffeine - adverse effects; Caffeine - pharmacology; Cerebral Hemorrhage - etiology; Disease Models, Animal; Drug Interactions; Drug Therapy, Combination; Errors of metabolism; Ethanol - adverse effects; Ethanol - pharmacology; Fibrinolytic Agents - adverse effects; Fibrinolytic Agents - therapeutic use; Incidence; Infusions, Intravenous; Injections; Intracranial Embolism - drug therapy; Intracranial Embolism - physiopathology; Ischemia; Male; Medical sciences; Metabolic diseases; Microspheres; Neurology; Neuroprotection; Neuroprotective Agents - adverse effects; Neuroprotective Agents - pharmacology; Rabbits; Reperfusion; Severity of Illness Index; Thrombolytic; Time Factors; Tissue Plasminogen Activator - adverse effects; Tissue Plasminogen Activator - therapeutic use; tPA; Treatment Failure; Vascular diseases and vascular malformations of the nervous system
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2004.03.003

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 ( P 50) or clot amount (mg) that produces neurological deficits in 50% of the rabbits. In the current study, the P 50 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 P 50 value of 1.70 ± 1.18 mg. Caffeinol-infused rabbits had a P 50 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 P 50 was 1.58 ± 0.43 mg. In caffeinol (bolus) and tPA–treated rabbits, we measured a decrease in the P 50 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.