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Mol Med
. 2022 Nov 8;28(1):131.
doi: 10.1186/s10020-022-00553-x.
Pyridostigmine reduces mortality of patients with severe SARS-CoV-2 infection: A phase 2/3 randomized controlled trial
Sergio Fragoso-Saavedra 1 2 3 , Isaac Núñez 2 , Belem M Audelo-Cruz 4 3 , Sarahi Arias-Martínez 3 , Daniel Manzur-Sandoval 5 , Alejandro Quintero-Villegas 2 , H Benjamín García-González 2 , Sergio L Carbajal-Morelos 2 , Sergio PoncedeLeón-Rosales 6 , José Gotés-Palazuelos 1 7 , José A Maza-Larrea 5 , J Javier Rosales-de la Rosa 8 , Dafne Diaz-Rivera 1 9 , Edgar Luna-García 9 , Elvira Piten-Isidro 9 , Perla M Del Río-Estrada 9 , Mario Fragoso-Saavedra 10 , Yanink Caro-Vega 11 , Isabella Batina 3 , León Islas-Weinstein 12 , David A Iruegas-Nunez 3 13 , Juan J Calva 11 , Pablo F Belaunzarán-Zamudio 11 , Juan Sierra-Madero 11 , José C Crispín 14 13 , Sergio Iván Valdés-Ferrer 15 16 17
Affiliations
- PMID: 36348276
- DOI: 10.1186/s10020-022-00553-x
Abstract
Background: Respiratory failure in severe coronavirus disease 2019 (COVID-19) is associated with a severe inflammatory response. Acetylcholine (ACh) reduces systemic inflammation in experimental bacterial and viral infections. Pyridostigmine increases the half-life of endogenous ACh, potentially reducing systemic inflammation. We aimed to determine if pyridostigmine decreases a composite outcome of invasive mechanical ventilation (IMV) and death in adult patients with severe COVID-19.
Methods: We performed a double-blinded, placebo-controlled, phase 2/3 randomized controlled trial of oral pyridostigmine (60 mg/day) or placebo as add-on therapy in adult patients admitted due to confirmed severe COVID-19 not requiring IMV at enrollment. The primary outcome was a composite of IMV or death by day 28. Secondary outcomes included reduction of inflammatory markers and circulating cytokines, and 90-day mortality. Adverse events (AEs) related to study treatment were documented and described.
Results: We recruited 188 participants (94 per group); 112 (59.6%) were men; the median (IQR) age was 52 (44-64) years. The study was terminated early due to a significant reduction in the primary outcome in the treatment arm and increased difficulty with recruitment. The primary outcome occurred in 22 (23.4%) participants in the placebo group vs. 11 (11.7%) in the pyridostigmine group (hazard ratio, 0.47, 95% confidence interval 0.24-0.9; P = 0.03). This effect was driven by a reduction in mortality (19 vs. 8 deaths, respectively).
Conclusion: Our data indicate that adding pyridostigmine to standard care reduces mortality among patients hospitalized for severe COVID-19.
Keywords: ACh; COVID-19; Immunomodulation; Inflammatory reflex; Invasive mechanical ventilation; Mortality; Placebo-controlled trial; Pyridostigmine; SARS-CoV-2.