Comparison of the Adrenocorticotrophic Effect of a Synthetic Depot Corticotrophin in Normal, Dexamethasone-Blocked, and Hypophysectomised Rats

Abstract

The ACTH stimulation test for depot preparations was carried out with a synthetic depot corticotrophin (Synacthen Depot®) in normal, dexamethasone-blocked, and hypophysectomised rats. It was found that the response curves (plasma and adrenal corticosterone) were very similar in all three groups, the peak values being somewhat higher in the normal and block dexamethasone-blocked animals. Towards the end of the stimulation test, the normal animals showed a marked deviation from the nycterohemeral rhythm. This change, which complicates the determination of the duration of action of the preparation used, is indicative of a disturbance in the hypothalamo-pituitaryadrenal feedback system. In dexamethasone-blocked animals, the effects of ACTH on the adrenals and thymus cannot be studied in isolation but only in combination with those of dexamethasone. Hence, despite all the technical difficulties involved, the test with hypophysectomised rats is still the method that yields the most easily assessable responses.

Effect of ACTH, corticoids and PCN (pregnenolone-16α-carbonitrile) on drug responses and disposition

“…On the other hand, similar results can be obtained with a single injection of depot ACTH (5 IU or 500^g/kg), given 24 hr before the drug. Barthe and Desaulles (1971) found that the plasma concentrations of corticosterone in rats given 300 µg/kg of depot ACTH s.c reach a peak between 16 to 24 hr. Thus, the protection offered by ACTH against drug overdosage coincides with maximal corticosterone secretion.…”

“…It is preferred, especially in clinical medicine, because it rarely causes adverse, allergic reactions commonly seen after the use of the complete ACTH molecule. A further step in the chemical technology of ACTH was the preparation of depot forms (e.g., hormone adsorbed to a zinc hydrophosphate complex) (Besser et al, 1967; Barthe & Desaulles, 1971). Since crystalline ACTH has a very short half-life (partly due to inactivation at the site of injection), repeated administrations or constant infusion are essential to maintain significant adrenocortical stimulation (Dixon, 1964;László et al, 1970;Matsuyama et al, 1972).…”