High-Dose Acetaminophen with Concurrent CYP2E1 Inhibition Has Profound Anticancer Activity without Liver Toxicity.

Acetaminophen (AAP) is metabolized by a variety of pathways such as sulfation, glucuronidation, and fatty acid amide hydrolase-mediated conversion to the active analgesic metabolite AM404. CYP2E1-mediated metabolism to the hepatotoxic reactive metabolite NAPQI (N-acetyl-p-benzoquinone imine) is a minor metabolic pathway that has not been linked to AAP therapeutic benefits yet clearly leads to AAP liver toxicity. N-acetylcysteine (NAC) (an antioxidant) and fomepizole (a CYP2E1 inhibitor) are clinically used for the treatment of AAP toxicity. Mice treated with AAP in combination with fomepizole (plus or minus NAC) were assessed for liver toxicity by histology and serum chemistry. The anticancer activity of AAP with NAC and fomepizole rescue was assessed in vitro and in vivo. Fomepizole with or without NAC completely prevented AAP-induced liver toxicity. In vivo, high-dose AAP with NAC/fomepizole rescue had profound antitumor activity against commonly used 4T1 breast tumor and lewis lung carcinoma lung tumor models, and no liver toxicity was detected. The antitumor efficacy was reduced in immune-compromised NOD-scid IL2Rgammanull mice, suggesting an immune-mediated mechanism of action. In conclusion, using fomepizole-based rescue, we were able to treat mice with 100-fold higher than standard dosing of AAP (650 mg/kg) without any detected liver toxicity and substantial antitumor activity. SIGNIFICANCE STATEMENT: High-dose acetaminophen can be given concurrently with CYP2E1 inhibition to allow for safe dose escalation to levels needed for anticancer activity without detected evidence of toxicity.

A comparison of ferumoxytol with gadolinium as contrast agents for the diagnostic magnetic resonance imaging of osteomyelitis.

BACKGROUND: Ferumoxytol, an FDA-approved superparamagnetic iron oxide nanoparticle (SPION) preparation used for the treatment of iron deficiency anemia, is also known to be taken up by macrophages in areas of infection or inflammation, where it produces negative contrast changes on T2-weighted MR images. PURPOSE: We sought to compare Ferumoxytol-induced MRI contrast changes with those observed using standard-of-care Gadolinium in patients presenting with symptoms suggestive of osteomyelitis. SUBJECTS: Out of eighteen enrolled patients, 15 had MR imaging with both ferumoxytol and gadolinium. Based on clinical and/or pathologic criteria, 7 patients were diagnosed with osteomyelitis, 5 patients had osteomyelitis ruled out, and in 3 patients a definitive diagnosis could not be made. FIELD STRENGTH: 1.5 Tesla. SEQUENCES: Used included STIR, T1-weighted and T2-weighted spin echo. ASSESSMENT: The mean contrast changes upon ferumoxytol and gadolinium administration were measured from lesion regions of interest and compared with control regions. STATISTICAL TESTS: Student's t-test, propagation of errors. Data are reported as means ± S.E. RESULTS: The mean contrast changes, ΔC, associated with a diagnosis of osteomyelitis were found to be ΔCFe = -2.7 ± 0.7 when Ferumoxytol and T2w imaging sequences were used and ΔCGd = +3.1 ± 1.1 (P < 0.001) when Gadolinium and a T1w imaging sequence was used. The MRI contrast changes for both agents correlated with systemic markers of inflammation, such as the erythrocyte sedimentation rate. In patients without osteomyelitis, no significant contrast changes were observed in T2-weighted, Ferumoxytol-contrasted MRI. The macrophages in osteomyelitic lesions were found to take up at least 16 times as much iron as benign bone marrow. DATA CONCLUSION: We conclude that in terms of its MRI diagnostic accuracy for osteomyelitis Ferumoxytol-contrasted MRI is a promising approach for diagnosing osteomyelitis that merits further study.