tetano
Editor, Senior Moderator
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[SUP] 1 2 3 [/SUP], Isaac Núñez[SUP] 2 [/SUP], Belem M Audelo-Cruz[SUP] 4 3 [/SUP], Sarahi Arias-Martínez[SUP] 3 [/SUP], Daniel Manzur-Sandoval[SUP] 5 [/SUP], Alejandro Quintero-Villegas[SUP] 2 [/SUP], H Benjamín García-González[SUP] 2 [/SUP], Sergio L Carbajal-Morelos[SUP] 2 [/SUP], Sergio PoncedeLeón-Rosales[SUP] 6 [/SUP], José Gotés-Palazuelos[SUP] 1 7 [/SUP], José A Maza-Larrea[SUP] 5 [/SUP], J Javier Rosales-de la Rosa[SUP] 8 [/SUP], Dafne Diaz-Rivera[SUP] 1 9 [/SUP], Edgar Luna-García[SUP] 9 [/SUP], Elvira Piten-Isidro[SUP] 9 [/SUP], Perla M Del Río-Estrada[SUP] 9 [/SUP], Mario Fragoso-Saavedra[SUP] 10 [/SUP], Yanink Caro-Vega[SUP] 11 [/SUP], Isabella Batina[SUP] 3 [/SUP], León Islas-Weinstein[SUP] 12 [/SUP], David A Iruegas-Nunez[SUP] 3 13 [/SUP], Juan J Calva[SUP] 11 [/SUP], Pablo F Belaunzarán-Zamudio[SUP] 11 [/SUP], Juan Sierra-Madero[SUP] 11 [/SUP], José C Crispín[SUP] 14 13 [/SUP], Sergio Iván Valdés-Ferrer[SUP] 15 16 17 [/SUP]
Affiliations
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.
. 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[SUP] 1 2 3 [/SUP], Isaac Núñez[SUP] 2 [/SUP], Belem M Audelo-Cruz[SUP] 4 3 [/SUP], Sarahi Arias-Martínez[SUP] 3 [/SUP], Daniel Manzur-Sandoval[SUP] 5 [/SUP], Alejandro Quintero-Villegas[SUP] 2 [/SUP], H Benjamín García-González[SUP] 2 [/SUP], Sergio L Carbajal-Morelos[SUP] 2 [/SUP], Sergio PoncedeLeón-Rosales[SUP] 6 [/SUP], José Gotés-Palazuelos[SUP] 1 7 [/SUP], José A Maza-Larrea[SUP] 5 [/SUP], J Javier Rosales-de la Rosa[SUP] 8 [/SUP], Dafne Diaz-Rivera[SUP] 1 9 [/SUP], Edgar Luna-García[SUP] 9 [/SUP], Elvira Piten-Isidro[SUP] 9 [/SUP], Perla M Del Río-Estrada[SUP] 9 [/SUP], Mario Fragoso-Saavedra[SUP] 10 [/SUP], Yanink Caro-Vega[SUP] 11 [/SUP], Isabella Batina[SUP] 3 [/SUP], León Islas-Weinstein[SUP] 12 [/SUP], David A Iruegas-Nunez[SUP] 3 13 [/SUP], Juan J Calva[SUP] 11 [/SUP], Pablo F Belaunzarán-Zamudio[SUP] 11 [/SUP], Juan Sierra-Madero[SUP] 11 [/SUP], José C Crispín[SUP] 14 13 [/SUP], Sergio Iván Valdés-Ferrer[SUP] 15 16 17 [/SUP]
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.