Adrenocorticotropic Hormone

ACTH (adrenocorticotropin, corticotropin) is a medicinal agent that has been the center of much research. In the late 1950s, its structure was elucidated, and the total synthesis was accomplished in the 1960s. Related peptides also have been synthesized, and some of these possess similar physiological action. Human ACTH has 39 amino acid units within the polypeptide chain.

SAR studies of ACTH24 showed that the COOH-terminal sequence is not particularly important for biological activity. Removal of the NH2-terminal amino acid results in complete loss of steroidogenic activity. Full activity has been reported for synthetic peptides containing the first 20 amino acids. A peptide containing 24 amino acids has full steroidogenic activity, without allergenic reactions. This is of practical importance because natural ACTH preparations sometimes produce clinically dangerous allergic reactions.

Corticotropin exerts its major action on the adrenal cortex, promoting steroid synthesis by stimulating the formation of pregnenolone from cholesterol.25 An interaction between ACTH and specific receptors is implicated in the mechanism leading to stimulation of adenylate cyclase and acceleration of steroid production. The rate-limiting step in the biosynthesis of steroids from cholesterol is the oxidative cleavage of the side chain of cholesterol, which results in the formation of pregnenolone. This rate-limiting step is regulated by cyclic adenosine monophosphate (cAMP). Corticotropin, through cAMP, stimulates the biosynthesis of steroids from cholesterol by increasing the availability of free cholesterol. This involves activation of cholesterol esterase by phosphor-ylation. Corticotropin also stimulates the uptake of cholesterol from plasma lipoproteins. Other biochemical effects exerted by ACTH include stimulation of phosphorylase and hydroxylase activities. Glycolysis also is increased by this hormone. Enzyme systems that catalyze processes involving the production of reduced nicotinamide adenine dinucleotide phosphate (NADPH) are also stimulated. (NADPH is required by the steroid hydroxylations that take place in the overall transformation of cholesterol to hydrocortisone, the major glucocorticoid hormone.) Pharmaceutically important ACTH products are listed in Table 27.4.

cAMP

Corticotropin Injection, USP. Adrenocorticotropin injection (ACTH injection, Acthar) is a sterile preparation of the principle, or principles derived from the anterior lobe of the pituitary of mammals used for food by humans. It occurs as a colorless or light straw-colored liquid, or a soluble, amorphous solid by drying such liquid from the frozen state. It exerts a tropic influence on the adrenal cortex. The solution has a pH range of 3 to 7 and is used for its adrenocorticotropic activity.

Repository Corticotropin Injection, USP. ACTH purified (ACTH-80, corticotropin gel, purified corticotropin) is corticotropin in a solution of partially hydrolyzed gelatin to be used intramuscularly for a more uniform and prolonged maintenance of activity.

Sterile Corticotropin Zinc Hydroxide Suspension, USP. Sterile corticotropin zinc hydroxide suspension is a sterile suspension of corticotropin, adsorbed on zinc hydroxide, which contains no less than 45 and no more than 55 fig of zinc for each 20 USP corticotropin units. Because of its prolonged activity caused by slow release of corticotropin, an initial dose of 40 USP units can be administered intramuscularly, followed by a maintenance dose of 20 U 2 or 3 times a week.

1Ser Val20—Lys

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