Propranolol and ascorbic acid in control of fibrodysplasia ossificans progressiva flare-ups due to accidental falls

Abstract

Fibrodysplasia ossificans progressiva (FOP) is a rare, intractable and devastating genetic connective tissue disorder characterized by progressive ectopic ossification in the soft tissues and skeleton. Three patients, one teenage girl (P1), one male adult (P2) and one male child (P3), were studied and treated with FOPCON (combined formulation of 14 mg of propranolol and 250 mg of ascorbic acid), given three times per day. P1 started treatment in March 2012, P2 in October 2012 and P3 in July 2015. The clinical follow-up of these three patients, before initiating treatment with FOPCON, showed that FOP flare-ups used to occur frequently and that under FOPCON therapy, none of these patients had flareups. The striking feature of this treatment with FOPCON, is that, all three cases suffered accidental falls with documented injures until complete healing and that where major flare-ups should occur, injures or sequels, there was none. The present clinical observation shows that ascorbic acid plus the nonspecific beta blocker propranolol can be effectively useful, when administered previously and continually, in the prophylaxis of FOP flare-ups, especially for accidental falls. In this regard, FOPCON could be a prophylactic aid in cases of surgery of patients with FOP, hoping that it may benefit patients from having the severe sequels, characteristic of heterotopic bone formation. All three patients reported, to date, they no longer had flare-ups nor heterotopic ossification and showed normal scar healing.

Modulatory Anti- Diarrheal Effects of Ascorbic Acid in Swiss Albino Mice

“…The report suggests that AA has an inhibitory effect on this receptor (Wolfman et al 1983). Moreover, in a recent clinical trial, AA together with the non-specific beta blocker, PRO, were found effective, when administered previously and continually, in the prophylaxis of fibro dysplasia ossificans progressive flare-ups (Palhares et al, 2019). This study establishes the combined potencies of AA and/or PRA/PRO in diarrheal-induced mice.…”

Rare and intractable fibrodysplasia ossificans progressiva shows different PBMC phenotype possibly modulated by ascorbic acid and propranolol treatment

“…Genes ADRB1 and 2 were overexpressed in FOP PBMC before treatment. AA+PP downregulated ADRB2, suggesting ADRB2 receptor as putative candidate in a FOP pathophysiological pathway and its response to AA+PP may benefit FOP as suggested by Palhares et al (10). These results may provide possible routes to be explored in pharmacotherapy studies of FOP and HO.…”

“…This suggests that AA treatment may inhibit osteoblast maturation. High doses of AA can act as a pro-oxidant that drives ALPL activity increases after osteogenic induction by BMP2 facilitated by oxidative stress (10,44). Indeed, downregulation of RUNX2 may benefit FOP clinical conditions by minimizing HO.…”

“…In some patients, FOP symptoms are improved by ascorbic acid (AA). This antioxidant, anti-inflammatory and modulator of collagen synthesis is reported to reduce outbreaks, and transiently stabilize crisis, either used alone or in combination with disodium etidronate (10). Long studied and approved for various clinical indications, ascorbic acid is a therapeutic possibility for anti-growth and invasiveness of solid cancers, and is a useful therapeutic supplement in several angiogenic diseases (11,12).…”

“…Since AA may help in FOP treatment, and the nonspecific adrenergic β-blocker propranolol (PP) has surfaced as an important treatment of infantile hemangioma with potential antiangiogenic effects (15), Palhares et al (10), have suggested using propranolol with ascorbic acid (FOPCON) for continuous administration to FOP patients. However, the mechanisms by which AA+PP work are not yet clarified.…”