Dermal irritation of petrolatum in rabbits but not in mice, rats or minipigs.

Petrolatum is widely used in cosmetics, topical pharmaceuticals and also as a vehicle in dermal toxicity studies. New Zealand white rabbits treated with white petrolatum (vehicle control) in a 2-week dermal irritation study exhibited moderate to severe erythema starting on Day 7 that subsided towards the end of the study. Histological examination of abraded and non-abraded petrolatum-treated skin obtained at termination (Day 15) revealed mild acanthosis, hyperkeratosis, dermal edema with mixed inflammatory cells in the dermis. Macroscopic and microscopic features noted in rabbits were consistent with dermal irritation to petrolatum. Wistar-Han rats, CD1 mice, C57/Bl/6J mice and Göttingen minipigs treated topically with white petrolatum did not exhibit clinical or histologic evidence of dermal irritation. Therapeutic agents developed for topical application are generally tested in rabbits during some point in development. Interpretation of skin irritation data from a single species can impact risk assessment for humans and on product labeling.

Effect of acute alcohol withdrawal on sensitivity to pro- and anticonvulsant treatments in WSP mice.

Through the genetic technique of selective breeding, a mouse line [Withdrawal Seizure Prone (WSP)] has been developed that expresses severe handling-induced convulsions (HIC) after cessation of chronic ethanol exposure. These mice also display rebound elevations in HIC after a single ethanol injection. In the current studies, we tested WSP mice in several paradigms. WSP mice were found to be marginally sensitive to the effects of acute doses of dizocilpine to reduce HIC. However, when tested during acute withdrawal from a single ethanol injection, WSP were more sensitive to this compound. Although N-methyl-D-aspartate significantly elevated HIC in naive WSP mice, it was more effective at low doses when given during acute withdrawal. Withdrawing mice were slightly more sensitive than naive mice to kainic acid. Pentylenetetrazole elevated HIC in naive and withdrawing mice; it was marginally more effective in naive mice. Diazepam inhibited HIC in both naive and withdrawing mice, and was slightly more effective during acute withdrawal. This pattern of results suggests that acute alcohol withdrawal is accompanied by altered sensitivity to convulsants and anticonvulsants. These changes include enhanced sensitivity in at least two excitatory amino acid-gated ion channel binding sites.

Alcohol dependence and withdrawal: a genetic animal model.

Using the techniques of selective breeding, mouse lines have been developed that express severe (Withdrawal Seizure Prone: WSP) or mild (Withdrawal Seizure Resistant: WSR) handling induced convulsions after cessation of chronic ethanol exposure. These lines differ at least ten-fold in severity of withdrawal after identical ethanol treatment. One feature of the genetic model is that other traits which distinguish these lines are presumably influenced by those genes determining ethanol withdrawal severity. WSP and WSR mice do not differ markedly in the metabolism of ethanol. In addition to handling induced convulsions, they also differ in other withdrawal signs: for example, WSP mice show more pronounced tremor. WSP and WSR mice do not differ in sensitivity to ethanol's hypothermic, anesthetic, or locomotor stimulant effects, nor in the magnitude of tolerance development to these responses. This suggests that sensitivity, tolerance and dependence are distinct genetic entities. WSP mice also display more severe withdrawal from diazepam, phenobarbital, and nitrous oxide than WSR mice, suggesting that some genes generally predispose mice to withdrawal from depressants. WSP mice display withdrawal handling induced convulsions after a single dose of ethanol, pentobarbital, or diazepam. The effective dose for producing drug seizures is not markedly different between WSP and WSR mice for a number of compounds with varied mechanisms of action. However, WSP mice are more sensitive than WSR mice to the effects of acute doses of convulsants to elevate handling induced convulsions. WSP mice have more binding sites in hippocampus for the N-methyl-D-aspartate antagonist MK 801. Binding of this ligand is increased during ethanol dependence in both mouse lines.(ABSTRACT TRUNCATED AT 250 WORDS)