Association between Functional Inhibitors of Acid Sphingomyelinase (FIASMAs) and Reduced Risk of Death in COVID-19 Patients: A Retrospective Cohort Study
Gil Darquennes, Pascal Le Corre, Olivier Le Moine, Gwenolé Loas
Pharmaceuticals, doi:10.3390/ph14030226
Given the current scarcity of curative treatment of COVID-19, the search for an effective treatment modality among all available medications has become a priority. This study aimed at investigating the role of functional inhibitors of acid sphingomyelinase (FIASMAs) on in-hospital COVID-19 mortality. In this retrospective cohort study, we included adult in-patients with laboratoryconfirmed COVID-19 between 1 March 2020 and 31 August 2020 with definite outcomes (discharged hospital or deceased) from Erasme Hospital (Brussels, Belgium). We used univariate and multivariate logistic regression models to explore the risk factors associated with in-hospital mortality. We included 350 patients (205 males, 145 females) with a mean age of 63.24 years (SD = 17.4, range: 21-96 years). Seventy-two patients died in the hospital and 278 were discharged. The four most common comorbidities were hypertension (184, 52.6%), chronic cardiac disease (110, 31.4%), obesity (96, 27.8%) and diabetes (95, 27.1%). Ninety-three participants (26.6%) received a long-term prescription for FIASMAs. Among these, 60 (64.5%) received amlodipine. For FIASMAs status, multivariable regression showed increasing odds ratio (OR) for in-hospital deaths associated with older age (OR 1.05, 95% CI: 1.02-1.07; p = 0.00015), and higher prevalence of malignant neoplasm (OR 2.09, 95% CI: 1.03-4.22; p = 0.039). Nonsignificant decreasing OR (0.53, 95% CI: 0.27-1.04; p = 0.064) was reported for FIASMA status. For amlodipine status, multivariable regression revealed increasing OR of inhospital deaths associated with older age (OR 1.04, 95% CI: 1.02-1.07; p = 0.0009), higher prevalence of hypertension (OR 2.78, 95% CI: 1.33-5.79; p = 0.0062) and higher prevalence of malignant neoplasm (OR 2.71, 95% CI: 1.23-5.97; p = 0.013), then secondarily decreasing OR of in-hospital death associated with long-term treatment with amlodipine (OR 0.24, 95% CI: 0.09-0.62; p = 0.0031). Chronic treatment with amlodipine could be significantly associated with low mortality of COVID-19 in-patients.
The Strengthening the Reporting of Cohort Studies in Epidemiology statement guidelines were followed in the conduct and reporting of the study (see online Supplemental File, Table S1 ). Two physicians (G.D. and G.L.) were responsible for data collection. The characteristics of the sample are given in Table 1 . Particular attention was given to the prescription of FIASMAs at admission. Patients with a long-term prescription of FIASMAs at admission were noted as FIASMAs positive (F+). Chronicity was defined as duration equal to or higher than seven half-life for each FIASMA (half-life range: 35-50 min (melatonin) to 20-100 days (amiodarone)). The prescribed daily dose of each FIASMA was given using the rate of defined daily dose (DDD), defined by the World Health Organization (WHO) Collaborating Centre for Drug Statistics Methodology. In Belgium, 28 FIASMAs are available: nine psychoanaleptics-amitriptyline, clomipramine, fluoxetine, fluvoxamine, imipramine, maprotiline, nortriptyline, paroxetine, sertraline; five psycholeptics-flupentixol, hydroxyzine, melatonin, pimozide, sertindole; two antivertigo-cinnarizine, flunarizine; two antihistamines for systemic use-desloratadine, loratadine; two drugs for functional gastrointestinal disorders-alverine, mebeverine; one calcium channel blocker-amlodipine; one anticholinergic agent-biperiden; one antipropulsiveloperamide; one Class 1 and 3 antiarrhythmic drug-amiodarone; one beta blocking agentcarvedilol; one..
References
Beigel, Tomashek, Dodd, Remdesivir for the treatment of covid-19-Preliminary report, N. Engl. J. Med,
doi:10.1056/NEJMoa2007764Borbone, Piccialli, Roviello, Oliviero, Nucleoside Analogs and Nucleoside Precursors as Drugs in the Fight against SARS-CoV-2 and Other Coronaviruses, Molecules,
doi:10.3390/molecules26040986Carpinteiro, Edwards, Hoffmann, Kochs, Gripp et al., Inhibition of Acid Sphingomyelinase Blocks Infection with SARS-CoV-2,
doi:10.2139/ssrn.3646562Carpinteiro, Edwards, Hoffmann, Kochs, Gripp et al., Pharmacological Inhibition of Acid Sphingomyelinase Prevents Uptake of SARS-CoV-2 by Epithelial Cells, Cell Rep. Med,
doi:10.1016/j.xcrm.2020.100142Du, Zuo, Meng, Wu, Zhao et al., Combinatorial screening of a panel of FDA-approved drugs identifies several candidates with anti-Ebola activities, Biochem. Biophys. Res. Commun,
doi:10.1016/j.bbrc.2019.11.065Hernández, Carvajal, Armas-De Hernández, Guerrero-Pajuelo, Armas-Padilla et al., The effects of the calcium antagonist amlodipine on blood pressure and platelet aggregation in hypertensive patients, Postgrad. Med. J
Hoertel, Sánchez-Rico, Vernet, Beeker, Jannot et al., Association between antidepressant use and reduced risk of intubation or death in hospitalized patients with COVID-19: Results from an observational study, Mol. Psychiatry,
doi:10.1038/s41380-021-01021-4Hoertel, Sánchez-Rico, Vernet, Jannot, Neuraz et al., Observational Study of Chlorpromazine in Hospitalized Patients with COVID-19, Clin. Drug Investig
Johansen, Dewald, Shoemaker, Hoffstrom, Lear-Rooney et al., A screen of approved drugs and molecular probes identifies therapeutics with anti-Ebola virus activity, Sci. Transl. Med,
doi:10.1126/scitranslmed.aaa5597Le Corre, Loas, Repurposing functional inhibitors of acid sphingomyelinase (FIASMAs): An opportunity against SARS-CoV-2 infection, J. Clin. Pharm. Ther
Lenze, Mattar, Zorumski, Stevens, Schweiger et al., Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients with Symptomatic COVID-19: A Randomized Clinical Trial, JAMA,
doi:10.1001/jama.2020.22760Pastenkos, Miller, Pritchard, Nicola, Role of Sphingomyelin in Alphaherpesvirus Entry, J. Virol,
doi:10.1128/JVI.01547-18Schloer, Brunotte, Goretzko, Mecate-Zambrano, Korthals et al., Targeting the endolysosomal host-SARS-CoV-2 interface by clinically licensed functional inhibitors of acid sphingomyelinase (FIASMA) including the antidepressant fluoxetine, Emerg. Microbes Infect,
doi:10.1080/22221751.2020.1829082Solaimanzadeh, Nifedipine and Amlodipine Are Associated With Improved Mortality and Decreased Risk for Intubation and Mechanical Ventilation in Elderly Patients Hospitalized for COVID-19, Cureus,
doi:10.7759/cureus.8069Stadler, Ha, Ciminale, Spirli, Saletti et al., Amiodarone alters late endosomes and inhibits SARS coronavirus infection at a post-endosomal level, Am. J. Respir Cell Mol. Biol,
doi:10.1165/rcmb.2007-0217OCXia, Beckmann, Winer, Kim, Goetzman et al., Amitriptyline Treatment Mitigates Sepsis-Induced Tumor Necrosis Factor Expression and Coagulopathy, Shock,
doi:10.1097/SHK.0000000000001146Xia, Beckmann, Winer, Pugh, Pritts et al., Amitriptyline Reduces Inflammation and Mortality in a Murine Model of Sepsis, Cell Physiol. Biochem,
doi:10.33594/000000040Xiao, Wang, Chang, Wang, Dong et al., Identification of Potent and Safe Antiviral Therapeutic Candidates Against SARS-CoV-2, Front. Immunol,
doi:10.3389/fimmu.2020.586572Zhang, Peng, Ai, Li, Zhao et al., Amitriptyline Reduces Sepsis-Induced Brain Damage Through TrkA Signaling Pathway, J. Mol. Neurosci,
doi:10.1007/s12031-020-01611-xZhang, Sun, Zeng, Wang, Jiang et al., Calcium channel blocker amlodipine besylate therapy is associated with reduced case fatality rate of COVID-19 patients with hypertension, Cell Discov,
doi:10.1038/s41421-020-00235-0
