PubMed · 836549
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E Fernandez, A C Fernandez-Brito. 1977-03-10. Acetaminophen toxicity.. https://doi.org/10.1056/nejm197703102961024
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Paracetamol (acetaminophen, APAP) liver and kidney cytotoxicity is associated with bioactivation by P450 and/or prostaglandin H synthetase (PGHS) to a reactive metabolite, which depletes GSH, covalently binds to proteins, and leads to oxidative stress. Although APAP may also damage the lung, little is known about the mechanism by which this occurs. We studied the in vitro 24-hr-old type II pneumocytes. A time- and concentration-dependent decrease in intracellular GSH occurred in freshly isolated type II pneumocytes and alveolar macrophages exposed to subtoxic (</= 1 mM) APAP concentrations. In 24-hr-old type II pneumocytes, there were no changes in intracellular GSH concentration after APAP exposure. Potassium ethyl xanthate (a P450 inhibitor) and indomethacin (a PGHS inhibitor) significantly decreased APAP-induced GSH depletion in freshly isolated type II pneumocytes and alveolar macrophages, suggesting that P450 and/or PGHS are involved in APAP bioactivation in these cells.
Intestinal transport and metabolism of modified kyotorphin (KTP) were studied in rats. Modified KTPs studied were C-terminally modified KTP with p-aminophenyl-beta-D-glucoside (KTP-pAPbeta glc), N-terminally modified KTP-pAPbeta glc with t-butyloxycarbonyl group (Boc-KTP-pAPbeta glc) and the N- and C-terminally modified KTP by cyclization (cyclic KTP). KTP-pAPbeta glc was metabolized at a similar rate to that of KTP, and did not appear on the serosal side. Although Boc-KTP-pAPbeta glc was also metabolized, it was more stable than KTP and appeared on the serosal side. Cyclic KTP was also quite stable and appeared on the serosal side. The modified KTPs were evaluated kinetically for absorption consisting of membrane transport and metabolism. Absorption clearance (CL(abs)) of cyclic KTP, Boc-KTP-pAPbeta glc and Boc-KTP was higher than that of KTP (0.247 microl/min/cm) (Mizuma et al., Biochim. Biophys. Acta 1335 (1997) 111-119), which is the theoretical maximum by complete inhibition of peptidase activity, indicating that derivatization of KTP increases the membrane permeability. Furthermore, the data clearly showed that the greater the metabolic clearance (CL(met)) of KTP and the KTP derivatives, the lower the absorption clearance (CL(abs)). These results and further simulation study led to the conclusion that metabolic degradation in the intestinal tissues is more critical than membrane permeability (transport) for oral delivery of peptide drugs. Based on the stability of cyclic KTP in serum, this appears to be a good candidate analgesic peptide drug.
BACKGROUND: Anti-thymocyte globulin (ATG) is used frequently as induction therapy in renal transplant recipients. It has been standard practice that the various polyclonal anti-lymphocyte preparations be administered via central line, vascular shunt, or arteriovenous fistula to avoid thrombophlebitis. METHODS: We have safely administered equine ATG (Atgam) via peripheral veins since 1978. We now retrospectively review recent experience with 83 patients transplanted between 1993 and 1998 who received Atgam induction via peripheral vein. Heparin 1000 U and Solucortef 20 mg were added to the infusion. Acetaminophen and diphenhydramine were given before infusion. RESULTS: Only two of 83 patients developed mild edema/erythema at or around the i.v. site. These reactions responded promptly to local management with warm soaks. No phlebitis or symptomatic venous thrombosis occurred in any patients. CONCLUSIONS: Equine ATG can be safely administered via peripheral vein infusion. Its use does not require continued hospitalization or placement of a central line. Peripheral vein infusion is safe, convenient, and economical.