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It is well accepted that bacterial and virus infections elevate the levels of cytokines in serum and cerebrospinal fluids. Such high levels of cytokines might alter the integrity of the blood-brain barrier (BBB) and/or blood-cerebrospinal fluid barrier (BCSFB), subsequently affecting brain penetration of drugs. However, few reports have addressed this issue. Thus, we investigated brain penetration of cyclooxygenase (COX) inhibitors, commonly used as antipyretics, in mice treated with Shiga-like toxin II (SLT-II) derived from E. coli O157:H7, which significantly elevates cytokine levels. As antipyretics, we used diclofenac, mefenamic acid, and acetaminophen. We found that SLT-II significantly increased the brain-to-plasma concentration ratio (Kp) of diclofenac and mefenamic acid, but not of acetaminophen. Moreover, the Kp of diclofenac and mefenamic acid was increased by probenecid, an anionic compound. These results suggest that efflux anion transporters might be involved in the transport of diclofenac and mefenamic acid. Western blot analysis revealed that SLT-II decreased the expression of organic anion transporter-3, an efflux transporter located on the BBB and/or BCSFB. Taken together, these results suggest that SLT-II and/or SLT-II-stimulated cytokines might change brain penetration of drugs and could possibly increase the risk of their side-effects by altering the expression of transporters.

Time-course studies on gastric damages in rats caused by nonsteroidal anti-inflammatory drugs (NSAIDs) were performed using a gastroscope, and the readings were quantified to obtain the Congestion-Hemorrhage Index (CHI) for evaluating the potencies of the damaging properties of NSAID. The correlation between CHI and Ulcer Index (UI), the quantified value obtained by the conventional methods, was highly significant at 6 and 24 hr after forced oral administration of NSAID. The peak CHIs of aspirin (300 mg/kg), indomethacin (60 mg/kg), mefenamic acid (300 mg/kg) and fenoprofen calcium (300 mg/kg) appeared approximately 24 hr after a single forced oral administration of drugs. Thus, it was suggested that an observation at 24 hr in addition to one at 6 to 7 hr might be necessary for the examination of damaged gastric mucosa. Under the present experimental conditions, fenoprofen calcium caused the greatest damages on gastric mucosa among the four NSAIDs. Mefenamic acid showed the least damaging potency on gastric mucosa, having a smaller CHI than that of aspirin. Indomethacin possessed a stronger damaging property than aspirin.