Sandoz FK 33-824

To further elucidate the site of action of opioids on the pituitary-adrenal axis, we studied the effect of D-Ala2,MePhe4,met-(O)enkephalin-ol (Sandoz, FK 33-824) on plasma ACTH and beta-endorphin immunoreactivity and serum cortisol in 7 normal subjects and 11 patients with Cushing's syndrome (Cushing's disease, n = 7; adrenal adenoma, n = 2; ectopic Cushing's syndrome, n = 2) after administration of human corticotropin-releasing hormone (hCRH). hCRH (0.1 mg; Bachem) was injected iv after pretreatment with 0.5 mg FK 33-824, im, or 0.9% saline. In normal subjects, the hCRH-induced ACTH, beta-endorphin, and cortisol increases were almost completely abolished by pretreatment with FK 33-824. Mean peak (+/- SEM) hormone concentrations were significantly reduced (ACTH, 16.7 +/- 3.5 vs. 45.3 +/- 7.8 pg/ml; beta-endorphin, 151 +/- 25 vs. 277 +/- 51 pg/ml; cortisol, 8.1 +/- 1.2 vs. 19.5 +/- 2.6 micrograms/dl; P less than 0.02), as were secretory areas (P less than 0.02). These results indicate a direct pituitary action of the synthetic met-enkephalin. In contrast, in patients with Cushing's disease, FK 33-824 did not inhibit hCRH-induced hormone release. Instead, maximum ACTH and beta-endorphin concentrations were slightly but not significantly higher after the administration of FK 33-824 (ACTH, 292 +/- 143 vs. 131 +/- 32 pg/ml; beta-endorphin, 2409 +/- 763 vs. 1921 +/- 600 pg/ml). These findings indicate a defect in inhibitory opiodergic control of ACTH secretion in patients with Cushing's disease, which may contribute to the pathological ACTH hypersecretion. In patients with Cushing's syndrome due to an adrenal adenoma or ectopic ACTH secretion, neither hCRH nor FK 33-824 altered hormone concentrations.

D-Ala, Mephe, Met, enkephalin (Sandoz FK 33-824) is a stable long acting analog of methionine-enkephalin. FK 33-824 (0.5 or 1.0 mg), elicited plasma GH and PRL responses in normal subjects. In 23 patients with pituitary dwarfism, the response of plasma GH was markedly impaired, while PRL responded to a variable degree. In patients with acromegaly, there was little or no increase in GH and PRL after FK 33-824. Plasma GH increased to a variable degree after FK 33-824 in patients with hyperprolactinemia, with little change in plasma PRL. FK 33-824 decreased plasma cortisol in normal subjects and patients with pituitary disease. These results show that patients with acromegaly and hyperprolactinemia due to pituitary adenomas and patients with pituitary dwarfism do not respond well to FK 33-824, presumably because of hypothalamic or pituitary derangement.

To assess a possible regulatory influence of opioids upon anterior pituitary function in the chimpanzee, we evaluated the effects of the specific opiate receptor antagonist naloxone and the agonistic enkephalin analog [D-Ala2, MePhe4,Met(o)-ol]enkephalin (FK 33-824; Sandoz) on serum levels of PRL, cortisol, FSH, and LH. Under ketamine anesthesia, the following were administered by iv injection during the early follicular phase of successive menstrual cycles in nine female chimpanzees: naloxone (10 mg; n = 7) or saline vehicle (n = 7) randomly assigned in the first two cycles, FK 33-824 0.25 mg (n = 3) in the third cycle, FK 33-824 0.50 mg (n = 4) in the fourth cycle, and FK 33-824 (0.50 mg) immediately preceded by naloxone (10 mg; n = 4) in the last cycle. Five pretreatment and 12 posttreatment serum samples were obtained at 10- to 15-min intervals for subsequent RIA. Naloxone caused a significant reduction in PRL levels from a pretreatment mean of 29.3 ng/ml to a mean of 11.1 ng/ml at 180 min. Values from 60-180 min were significantly below the saline control group at comparable times. A dose-related increment in PRL levels was seen after FK 33-824 administration, with mean peak values at 30 min of 61.0 and 92.3 ng/ml after the low and high doses, respectively. Naloxone pretreatment markedly attenuated the response to high dose FK 33-824. Cortisol levels rose in all groups throughout the study period, a presumed effect of the ketamine anesthesia. Compared to the saline group, no effects of FK 33-824 were observed. Naloxone, given alone or with FK 33-824, had a small, but significant, stimulatory effect on cortisol from 60-120 min posttreatment compared to the control group. Naloxone caused a significant increment in LH levels from a pretreatment mean of 11.7 micrograms/dl to a peak of 19.1 micrograms/dl at 30 min and in FSH level from 33.2 micrograms/dl before therapy to 40.0 micrograms/dl at 45 min. There was no influence of FK 33-824 on gonadotropin levels, although the high dose did blunt the response to naloxone. Taken together, these effects suggest that opiate agonists and endogenous opioid pathways may modulate anterior pituitary function in the chimpanzee, as in man.