Lewis (LEW) and Fischer 344 (F344) rats differ in responsiveness of the hypothalamo-pituitary-adrenocortical (HPA) axis as well as in their behavioral responses to drugs of abuse. The present experiments were conducted to compare hypothalamic corticotropin-releasing factor (CRF), plasma adrenocorti-cotropic hormone (ACTH) and plasma corticosterone (CS) responses to cocaine (0–60 mg/kg, i.p.) in LEW and F344 rats. Acute administration of cocaine resulted in decreases in CRF and dose-related increases in CS and ACTH with significant differences observed between the strains. Cocaine also increased plasma norepinephrine concentrations. Although the CS response was increased in the F344 compared to LEW rats, the percent change in the CS response was markedly enhanced in LEW rats. Plasma ACTH concentrations as well as the percentage of the control response were dramatically increased at the 40 mg/kg cocaine dose in the LEW compared to F344 rats. Since cocaine-induced changes in HPA axis activity may contribute to behavioral responses to cocaine, another experiment was performed to compare the locomotor responses to novelty and to acute cocaine between LEW and F344 rats. Strain differences were not observed in the locomotor response to novelty or to cocaine. These data indicate that strain differences exist in the neuroendocrine response to acute cocaine exposure.
Recent public awareness and scientific advances have launched a reversal in the historical trend to virtually ignore the importance of obtaining reliable data from pediatric patients during the process of drug development. The need for well-designed clinical trials in children is now clearly recognized, and a few regulatory bodies have addressed the requirements for the conduct of these trials. Global consensus on the unique issues related to pediatric trials, howevec has been lacking. The International Conference on Harmonization recently released a draft of its guideline, "Clinical Investigation of Medicinal Products in the Pediatric Population. The objective of this paper is to discuss critical issues addressed by the guideline. It begins with a brief overview on the underlying need for the guideline and factors that have contributed to shifting attitudes toward the conduct of pediatric clinical trials. The five major considerations outlined in the guideline are then summarized. The discussion for each of the key areas is supplemented with background information, representative cases, and points for further consideration.
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