ACTH 1-24 and other melanocortins for COVID-19 treatment

Abstract

To the Editor: In the April 09 issue of this Journal, Feldman et al. (1) commented on the “urgent need for trials of anti-tumor necrosis factor (TNF) therapy for COVID-19.” In both animal and human studies we have demonstrated the impressive effect of several melanocortin peptides (particularly ACTH 1-24 and alpha-MSH) in extremely severe conditions of shock, respiratory arrest, and cardiac arrest, while being almost completely devoid of cardiovascular effects under normal conditions (2–7). The in-depth studies on these novel, unknown activities of melanocortins and of the underlying mechanism(s) of action, involving groups of researchers from several Universities (Modena, Bologna, Messina, Pavia, Milano, Napoli, Uppsala), coordinated by one of us and financially supported by Italian Ministry of University and Research and by Ministry of Defense, disclosed a rather complex picture. In brief, in experimental conditions of tissue hypoperfusion/hypoxia, induced in anesthetized animals (hemorrhagic shock, respiratory arrest, cardiac arrest), the i.v. bolus injection of melanocortins (ACTH 1-24 and alpha-MSH the most effective) induces a dose-dependent reversal of hypotension and of respiratory depression, and the restoration of cardiac output. Adrenals are not involved, because the effect is the same either in intact or in adrenalectomized animals, and is obtained to the same degree with ACTH fragments with full adrenocorticotropic activity (ACTH 1–24) or with fragments practically devoid of such activity (alpha-MSH = ACTH 1–13). In fact, the above effects are mostly due to the activation of melanocortin receptors (predominantly MC1 and MC3) on immunocytes. This causes the inhibition of the nuclear factor kB-dictated massive production of several factors of the inflammatory response (cell adhesion molecules, chemokines, cytokines, and cytokines receptors) with consequent impressive reduction of free radicals in blood, decrease of liver TNF-alpha mRNA and of plasma levels of TNF-alpha, inhibition of inducible nitric oxide (NO) syntheses and normalization of NO blood levels, and reduced expression of adhesion molecules. Furthermore, melanocortins activate the so-called “cholinergic anti-inflammatory pathway” through binding prevalently to MC4 receptors in the dorsal motor nucleus of the vagus, activation of efferent vagus fibers, acetylcholine release in organs of the reticulum endothelial system (especially liver, spleen, gastrointestinal tract, heart) (cholinergic anti-inflammatory pathway, or “inflammatory reflex”), activation of alpha7-nicotinic receptors on tissue macrophages, inhibition of the production of pro-inflammatory cytokines (mainly TNF-alpha and other actors of the early “cytokine storm” and acute endotheliopathy), and, on the other hand, stimulation of the production of anti-inflammatory cytokines (8). Finally, melanocortins exert a functional antagonism against endogenous opioids, which are massively released in shock conditions and contribute to the circulatory disaster: opioids inhibit sympathetic outflow and noradrenalin release from sympathetic terminals, contribute to peripheral pooling of blood, decrease venous return, and reduce cardiac output. In clinical studies, the melanocortin ACTH 1–24 has been used, because marketed from several years for other clinical conditions and thus freely available also in off label pathologies, and completely devoid of acute toxicity up to the dose of 100 mg in adult subjects. After some anecdotal case reports showing that the i.v. bolus injection of 5–10 mg of ACTH 1–24, in addition to the conventional therapeutic protocol, produced a dramatic improvement in extremely critical conditions, a phase 2 clinical trial enrolling 32 subjects, all with type A aortic dissection complicated by aortic rupture and cardiac tamponade, and with clinical signs of severe shock, confirmed the life-saving effect of ACTH 1–24 (survival 1 month after surgery: 87% in the ACTH group, 47% in the standard treatment group) (9). Moreover, a randomized phase 3 clinical study conducted on 100 critically ill patients and emergency surgery, has shown that early treating with 10 mg bolus of tetracosactide, have reduced the mortality at 30 days and normalization of the cytokine overload at 18 hours after surgery, toward the expected mortality of > 20% and to observed 18.8% of the untreated (10). Furthermore, the use of melanocortins has had a cytokine contrasting action in the interstitial pneumonia of the Ebola virus as well as a drug authorized by EMA and AIFA for compassionate use in Italy for the Ebola outbreak (11). In conclusion, in view of all the above data and prompted by the considerations of Feldman et al., we suggest that the treatment protocol of COVID patients should include the twice daily i.v. bolus injection of 10 mg of ACTH 1–24 (or of other agonists at MC1, MC3, and MC4 receptors). In the case of ACTH 1–24, an anti-aldosterone diuretic should also be administered to avoid the fluid retention caused by the ACTH stimulated overproduction of aldosterone by the adrenals.