Eight prodrugs of L-cysteine (1a-h) were synthesized by the condensation of the sulfhydryl amino acid with naturally occurring aldose monosaccharides containing three, five, and six carbon atoms. The resulting 2-(polyhydroxyalkyl)thiazolidine-4(R)-carboxylic acids (TCAs) are capable of releasing L-cysteine and the sugars by nonenzymatic ring opening and hydrolysis. Thus, when added to rat hepatocyte preparations in vitro, these TCAs (1.0 mM) raised cellular glutathione (GSH) levels 1.2-2.1-fold relative to controls. On the basis of this finding, the cysteine prodrugs were tested as protective agents against acetaminophen-induced hepatotoxicity in a mouse model. The TCA derived from D-ribose and L-cysteine (RibCys, 1d) showed the greatest therapeutic promise of the series, with a 100% (12/12) survival profile compared to 17% without treatment. However, the degree of stimulation of GSH production in rat hepatocytes by these prodrugs did not correlate with the extent of protection afforded in mice, suggesting that pharmacokinetic parameters must supervene in vivo. To evaluate the effect of increased lipid solubility, we prepared prodrugs 2a-c by using peracetylated aldehydic sugars in the condensation reaction. These compounds, however, displayed acute toxicity to mice, possibly due to liberation of the acetylated sugars themselves. Nevertheless, the efficacy of the unacetylated TCAs, and RibCys (1d) in particular, suggests that the prodrug approach for the delivery of L-cysteine to the liver represents a viable means of augmenting existing detoxication mechanisms in protecting cells against xenobiotic substances that are bioactivated to toxic, reactive metabolites.

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"Superactive" charcoal was assessed for efficacy in decreasing the lethality of both oral and parenteral exposure to T-2 toxin, a fungal metabolite which can cause death or illness upon ingestion. In vitro binding studies, analyzed using the Langmuir adsorption isotherm, showed that activated charcoal had a maximal binding capacity of 0.48 mg toxin/mg charcoal and a dissociation constant of 0.078 mg charcoal/l. In vivo, orally administered, activated charcoal was assessed for treatment of acute oral or parenteral exposure to T-2 toxin in mice. Following oral toxin administration (5 mg/kg), untreated mice showed only 6% survival after 72 hr. Charcoal treatment (7 g/kg,po) either immediately or 1 hr after toxin exposure resulted in significant improvement in survival with values of 100% and 75%, respectively. Following parenteral toxin exposure (2.8 mg/kg, sc), untreated and charcoal-treated (7 g/kg, po) mice showed 50% and 90% survival, respectively, after 72 hr. LD50 value for T-2 toxin, determined at 96 hr after intoxication, increased significantly from 2 mg/kg for untreated controls to 4.5 mg/kg for activated charcoal treatment.