FLUTAMIDE - A NOVEL AGENT FOR RESTORING THE DEPRESSED CELL-MEDIATED-IMMUNITY FOLLOWING SOFT-TISSUE TRAUMA AND HEMORRHAGIC-SHOCK

Recent studies indicate beneficial effects of androgen depletion in ma le mice, before trauma-hemorrhage on cell-mediated immunity following soft-tissue trauma and hemorrhagic shock. Nonetheless, it remains unkn own whether androgen receptor blockade following the insult has any sa lutary effects. To study this, male C3H/HeN mice were either sham-oper ated or subjected to soft-tissue trauma (i.e., 2.5 cm midline laparoto my) followed by hemorrhagic shock (blood pressure 35 +/- 5 mmHg for 90 min) and then adequately resuscitated (shed blood and lactated Ringer 's). Immediately after the completion of resuscitation, as well as 24 and 48 h thereafter, the animals received either vehicle, 10 mg/kg bod y weight (BW) flutamide or 25 mg/kg BW flutamide subcutaneously. At 72 h after resuscitation, all animals were killed. The spleens and perit oneal macrophages (M phi) were then harvested and cultures established to determine IL-2 and IL-3 release, splenocyte proliferative capacity , as well as splenic and peritoneal M phi IL-1 release. Moreover, plas ma testosterone and corticosterone levels were measured. Our results i ndicate that trauma-hemorrhage resulted in significant depression of s plenocyte and M phi functions in vehicle-treated and animals receiving 10 mg/kg BW flutamide. Treatment with 25 mg/kg BW flutamide following trauma-hemorrhage, however, resulted in levels of cytokine release wh ich were comparable with those found in sham-operated animals. No sign ificant alterations in plasma corticosterone and testosterone levels w ere observed in any of the experimental groups. These findings indicat e that short-term therapy of males with the androgen receptor blocker, flutamide at 25 mg/kg BW, following trauma-hemorrhage has protective effects on immune functions. This protective effect is dose dependent, since 10 mg/kg BW flutamide did not produce significant salutary effe cts. Thus, flutamide represents a novel and safe agent for improving t he depressed functions in male trauma patients suffering severe blood loss.