William R. Weimar

The effect of receptor phase composition on the permeability of hairless mouse skin in diffusion cell experiments

Abstract The effect of different antimicrobial agents (0.1% and 0.04% formaldehyde and 0.002% NaN 3 ) in the receptor phase of diffusion cells and the influence of the length of time of exposure of hairless mouse skins in the diffusion cells to the receptor phases have been evaluated by determining their effect on the flux of theophylline in diffusion cell experiments. If the length of exposure to the receptor phase was 4 h before application of theophylline, the flux of theophylline was essentially the same regardless of the antimicrobial agent used. If 0.1% formaldehyde was the agent used, the flux of theophylline remained relatively constant regardless of the time of exposure to the receptor phase. For the other two agents (0.04% formaldehyde and 0.002% NaN 3 ) the flux of theophylline increased sharply with increased time of exposure. This result is apparently due to microorganism growth in the receptor phases containing 0.04% formaldehyde and 0.002% NaN 3 .

The Origin of the Differences in (R)‐ and (S)‐Desmethyldesferrithiocin: Iron‐Clearing Propertiesa

Abstract: The iron clearance properties, toxicity, and pharmacokinetics of (R)‐ and (S)‐desmethyldesferrithiocin (DMDFT) are described. The studies were performed in rodent and primate models. While both enantiomers were found to be effective iron chelators with minimal toxicity in the rodents, only (S)‐DMDFT was able to induce the clearance of any iron in the primates. In addition, two out of nine of the monkeys given (R)‐DMDFT died within 24 h of drug administration. The reason for the differences in iron clearance properties and the apparent toxicity of the (R)‐enantiomer in the primates is likely related to the disparities in the pharmacokinetics of the two analogues. The pharmacokinetic data suggest enantioselectivity in renal clearance of the desferrithiocins and their iron complexes with (S)‐DMDFT clearance 3.5 times greater than that of (R)‐DMDFT, and FeIII [(S)‐DMDFT]2 clearance 6.8 times greater than that of FeIII [R‐DMDFT]2. In all primates studied FeIII [(R)‐DMDFT]2 in the plasma exceeded 25 mg/L (50 μM) for several hours and remained above 10 mg/L (20 μM) at 8 h while levels of FeIII [(S)‐DMDFT]2 never exceeded 50 μM and were at or below the limits of detection 8 h post‐injection.

Prevention of acetic acid-induced colitis by desferrithiocin analogs in a rat model

Iron contributes significantly to the formation of reactive oxygen species via the Fenton reaction. Therefore, we assessed whether a series of desferrithiocin analogs, both carboxylic acids and hydroxamates, could (1) either promote or diminish the iron-mediated oxidation of ascorbate, (2) quench a model radical species, 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS·+), and (3) when applied topically, prevent acetic acid-induced colitis in rats. Surprisingly, most of the desferrithiocin analogs inhibited the Fenton reaction to an approximately equivalent degree; however, substantial differences were observed in the capacity of the analogs to scavenge the model radical cation. Four carboxylic acid desferrithiocin analogs and their respective N-methylhydroxamates were tested along with desferrioxamine and Rowasa, a currently accepted topical therapeutic agent for inflammatory bowel disease (IBD), in a rodent model of acetic acid-induced colitis. The colonic damage was quantitated by two independent measurements. Although neither radical scavenging nor prevention of Fenton chemistry was a definitive predictor of in vivo efficacy, the overall trend is that desferrithiocin analogs substituted with an N-methylhydroxamate in the place of the carboxylic acid are both better free radical scavengers and more active against acetic acid-induced colitis. These results represent an intriguing alternative avenue to the development of improved IBD therapeutic agents.