Modulation of irinotecan-induced diarrhea by cotreatment with neomycin in cancer patients.

This study was designed to evaluate irinotecan (CPT-11) disposition and pharmacodynamics in the presence and absence of the broad-spectrum antibiotic neomycin. Seven evaluable cancer patients experiencing diarrhea graded > or =2 after receiving CPT-11 alone (350 mg/m(2) i.v. once every 3 weeks) received the same dose combined with oral neomycin at 1000 mg three times per day (days -2 to 5) in the second course. Neomycin had no effect on the systemic exposure of CPT-11 and its major metabolites (P > or = 0.22). However, it changed fecal beta-glucuronidase activity from 7.03 +/- 1.76 microg/h/mg (phenolphthalein assay) to undetectable levels and decreased fecal concentrations of the pharmacologically active metabolite SN-38. Although neomycin had no significant effect on hematological toxicity (P > 0.05), diarrhea ameliorated in six of seven patients (P = 0.033). Our findings indicate that bacterial beta-glucuronidase plays a crucial role in CPT-11-induced diarrhea without affecting enterocycling and systemic SN-38 levels.

Deviant forms of aggression in glucocorticoid hyporeactive rats: a model for 'pathological' aggression?

Deviant forms of aggressiveness have been associated with low plasma glucocorticoid concentrations in humans. Here, we report data on the development of aggressive behaviour in rats in which glucocorticoid secretion was inhibited by adrenalectomy. Such rats were compared with both sham operated rats and adrenalectomized rats in which the fight-induced elevation of plasma glucocorticoids was mimicked by acute injections. Low and stable corticosterone plasma concentrations were maintained by subcutaneous glucocorticoid pellets in adrenalectomized rats. The development of aggressive behaviour was followed over three trials performed at 2-day intervals. Adrenalectomy lead to high aggressiveness already at the first encounter, a decreased threatening (attack signalling) behaviour and a change in attack targeting. While control rats targeted biting attacks towards less vulnerable dorsal parts of the opponent's body, adrenalectomized rats attacked the head frequently. Corticosterone injections that mimicked the fight induced adrenocortical reaction abolished this behavioural pattern. Thus, a reduced responsiveness of the adrenocortical system may be causally linked to deviant forms of aggression in rats.

The active phase-related increase in corticosterone and aggression are linked.

Recently we demonstrated that corticosterone exerts an acute facilitatory effect on aggression in male rats. Corticosterone production reaches a maximum at the onset of the dark period, while male rats are more aggressive in the dark. Here we present evidence demonstrating that the corticosterone increase at the beginning of the dark period is causally linked to the increase in aggressiveness. We measured plasma corticosterone and quantified aggressive behaviour of male territorial rats at various time points of the day-night transition. Low aggression levels were observed in the full light period when plasma concentrations of corticosterone were low. An increase in plasma corticosterone occurred just prior to the dark phase, when aggressive responding was the highest. Aggressive behaviour remained high in the early dark period when corticosterone was still high. We found that blocking the high affinity mineralocorticoid receptor (MR) with spironolactone (5 or 10 mg/kg) during the early dark period dramatically and specifically reduced territorial aggression.