At therapeutic doses, acetaminophen (APAP) is a safe and effective analgesic. However, overdose of APAP is the principal cause of acute liver failure in the West. Binding of the reactive metabolite of APAP (NAPQI) to proteins is thought to be the initiating event in the mechanism of hepatotoxicity. Early work suggested that APAP-protein binding could not occur without glutathione (GSH) depletion, and likely only at toxic doses. Moreover, it was found that protein-derived APAP-cysteine could only be detected in serum after the onset of liver injury. On this basis, it was recently proposed that serum APAP-cysteine could be used as diagnostic marker of APAP overdose. However, comprehensive dose-response and time course studies have not yet been done. Furthermore, the effects of co-morbidities on this parameter have not been investigated. We treated groups of mice with APAP at multiple doses and measured liver GSH and both liver and plasma APAP-protein adducts at various timepoints. Our results show that protein binding can occur without much loss of GSH. Importantly, the data confirm earlier work that showed that protein-derived APAP-cysteine can appear in plasma without liver injury. Experiments performed in vitro suggest that this may involve multiple mechanisms, including secretion of adducted proteins and diffusion of NAPQI directly into plasma. Induction of liver necrosis through ischemia-reperfusion significantly increased the plasma concentration of protein-derived APAP-cysteine after a subtoxic dose of APAP. While our data generally support the measurement of serum APAP-protein adducts in the clinic, caution is suggested in the interpretation of this parameter.

No abstract

No abstract

Depression of the ventilatory response to hypoxia after the administration of intrathecal morphine is similar in magnitude to, but longer-lasting than, that after the administration of an equianalgesic dose of intravenous morphine.

Objective To determine levels of environmental chemotherapy contamination in a new cancer hospital that has exclusively used a closed-system drug transfer device (PhaSeal) for preparing and administering all compatible antineoplastics. Methods After 6 months of operation, surface samples were collected from pharmacy and nursing areas to determine levels of contamination with cyclophosphamide and ifosfamide. In addition, urine samples were collected from pharmacists, pharmacy technicians, and nurses to determine employee exposure to these agents. All samples were analyzed using liquid chromatography/tandem mass spectrometry. Results Twenty-one percent (7/34) of surface samples collected tested positive for cyclophosphamide contamination. Twelve percent (4/34) of surface samples tested positive for ifosfamide. To place this into perspective, historical data collected at our outpatient oncology infusion clinic 6 months after converting to PhaSeal from conventional methods of antineoplastic preparation showed 33% (7/21) and 71% (15/21) of samples tested positive for cyclophosphamide and ifosfamide, respectively. The level of ifosfamide contamination found in samples that tested positive at our new hospital also appeared to be lower than in positive samples at the outpatient infusion clinic. In the current study, the urine of one participant (1/11), a pharmacy technician, tested positive for low levels of cyclophosphamide and ifosfamide. To compare, 71% and 0% of participants tested at the outpatient infusion clinic had positive urine samples prior to and 6 months after implementation of PhaSeal, respectively. Conclusions: Compared with historical levels of contamination in our outpatient oncology infusion clinic, levels of chemotherapy contamination appeared lower. However, some contamination was still present in our new cancer hospital where PhaSeal had been used exclusively.