Reduction in caffeine toxicity by acetaminophen

A patient who allegedly consumed 100 tablets of an over-the-counter analgesic containing sodium acetylsalicylate, caffeine, and acetaminophen displayed no significant CNS stimulation despite the presence of 175 micrograms of caffeine per mL of serum. Because salicylates have been reported to augment the stimulatory effects of caffeine on the CNS, attention was focused on the possibility that the presence of acetaminophen (52 micrograms/mL) reduced the CNS toxicity of caffeine. Studies in DBA/2J mice showed that: 1) pretreatment with acetaminophen (100 mg/kg) increased the interval between the administration of caffeine (300 to 450 mg/kg IP) and the onset of fatal convulsions by a factor of about two; and 2) pretreatment with acetaminophen (75 mg/kg) reduced the incidence of audiogenic seizures produced in the presence of caffeine (12.5 to 75 mg/kg IP). The frequency of sound-induced seizures after 12.5 or 25 mg/kg caffeine was reduced from 50 to 5% by acetaminophen. In the absence of caffeine, acetaminophen (up to 300 mg/kg) did not modify the seizures induced by maximal electroshock and did not alter the convulsant dose of pentylenetetrezol in mice (tests performed by the Anticonvulsant Screening Project of NINCDS). Acetaminophen (up to 150 micrograms/mL) did not retard the incorporation of radioactive adenosine into ATP in slices of rat cerebral cortex. Thus the mechanism by which acetaminophen antagonizes the actions of caffeine in the CNS remains unknown.