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1.
Pharmaceuticals (Basel) ; 15(3)2022 Mar 21.
Article in English | MEDLINE | ID: covidwho-1753661

ABSTRACT

Association between calcium channel blockers (CCBs) or functional inhibitors of acid sphingomyelinase (FIASMAs) use and decreased mortality in people with COVID-19 has been reported in recent studies. Since amlodipine is both a CCB and a FIASMA, the aim of this study was to investigate the association between chronic amlodipine use and the survival of people with hypertension infected with COVID-19. This retrospective cohort study used data extracted from the medical records of adult inpatients with hypertension and laboratory-confirmed COVID-19 between 1 March 2020 and 31 August 2020 with definite outcomes (discharged from hospital or deceased) from Erasme Hospital (Brussels, Belgium). We re-analyzed the data of the retrospective cohort study using only the 184 patients (103 males, 81 females) with a mean age of 69.54 years (SD = 14.6) with hypertension. The fifty-five participants (29.9%) receiving a chronic prescription of amlodipine were compared with the 129 patients who did not receive a chronic prescription of amlodipine. Univariate and multivariate logistic regressions were used to explore the relationships between mortality and sex, age, comorbidities, smoking, and amlodipine status. Out of the 184 participants, 132 (71.7%) survived and 52 (28.3%) died. The mortality rates were, respectively, 12.73% (n = 7) and 34.88% (n = 45) for the amlodipine and non-amlodipine groups. Multivariate logistic regression was significant (Chi square (5) = 29.11; p < 0.0001). Chronic kidney disease and malignant neoplasm were significant predictors as well as amlodipine status. For chronic kidney disease and malignant neoplasm, the odds ratio with 95% confidence interval (95% CI) were, respectively, 2.16 (95% CI: 1.04-4.5; p = 0.039) and 2.46 (95% CI: 1.01-6.01; p = 0.047). For amlodipine status the odds ratio was 0.29 (95% CI: 0.11-0.74; p = 0.009). The result of the present study suggests that amlodipine may be associated with reduced mortality in people with hypertension infected with COVID-19. Further research and randomized clinical trials are needed to confirm the potential protective effect of amlodipine in people with hypertension infected with COVID-19.

2.
Front Pharmacol ; 13: 849095, 2022.
Article in English | MEDLINE | ID: covidwho-1753401

ABSTRACT

The rapid spread of COVID-19 has become a health emergency causing an urgent need for drug treatments to control the outbreak, especially in more vulnerable individuals. This is reinforced by the fact that prophylactic vaccines and neutralizing monoclonal antibodies may not be fully effective against emerging variants. Despite all efforts made by the scientific community, efficient therapeutic options currently remain scarce, either in the initial, as well as in the advanced forms of the disease. From retrospective observational studies and prospective clinical trials, selective serotonin reuptake inhibitors (SSRIs), and other antidepressants with functional inhibition of acid sphingomyelinase (FIASMAs), have emerged as potential treatments of COVID-19. This has led to some prematurely optimistic points of view, promoting a large prescription of fluvoxamine in patients with COVID-19, that we think should be reasonably tempered.

3.
Int J Mol Sci ; 22(19)2021 Sep 22.
Article in English | MEDLINE | ID: covidwho-1438628

ABSTRACT

The reason behind the high inter-individual variability in response to SARS-CoV-2 infection and patient's outcome is poorly understood. The present study targets the sphingolipid profile of twenty-four healthy controls and fifty-nine COVID-19 patients with different disease severity. Sera were analyzed by untargeted and targeted mass spectrometry and ELISA. Results indicated a progressive increase in dihydrosphingosine, dihydroceramides, ceramides, sphingosine, and a decrease in sphingosine-1-phosphate. These changes are associated with a serine palmitoyltransferase long chain base subunit 1 (SPTLC1) increase in relation to COVID-19 severity. Severe patients showed a decrease in sphingomyelins and a high level of acid sphingomyelinase (aSMase) that influences monosialodihexosyl ganglioside (GM3) C16:0 levels. Critical patients are characterized by high levels of dihydrosphingosine and dihydroceramide but not of glycosphingolipids. In severe and critical patients, unbalanced lipid metabolism induces lipid raft remodeling, leads to cell apoptosis and immunoescape, suggesting active sphingolipid participation in viral infection. Furthermore, results indicated that the sphingolipid and glycosphingolipid metabolic rewiring promoted by aSMase and GM3 is age-dependent but also characteristic of severe and critical patients influencing prognosis and increasing viral load. AUCs calculated from ROC curves indicated ceramides C16:0, C18:0, C24:1, sphingosine and SPTLC1 as putative biomarkers of disease evolution.


Subject(s)
COVID-19/blood , Sphingolipids/blood , Adult , Aged , Aged, 80 and over , COVID-19/diagnosis , Female , Humans , Lipidomics , Male , Middle Aged , Prognosis , SARS-CoV-2/isolation & purification , Severity of Illness Index , Sphingolipids/analysis , Sphingomyelins/analysis , Sphingomyelins/blood , Young Adult
4.
Pharmaceuticals (Basel) ; 14(7)2021 Jul 18.
Article in English | MEDLINE | ID: covidwho-1314720

ABSTRACT

The SARS-CoV-2 outbreak is characterized by the need of the search for curative drugs for treatment. In this paper, we present an update of knowledge about the interest of the functional inhibitors of acid sphingomyelinase (FIASMAs) in SARS-CoV-2 infection. Forty-nine FIASMAs have been suggested in the treatment of SARS-CoV-2 infection using in silico, in vitro or in vivo studies. Further studies using large-sized, randomized and double-blinded controlled clinical trials are needed to evaluate FIASMAs in SARS-CoV-2 infection as off-label therapy.

5.
Int J Mol Sci ; 22(11)2021 May 26.
Article in English | MEDLINE | ID: covidwho-1256559

ABSTRACT

Ceramide is a lipid messenger at the heart of sphingolipid metabolism. In concert with its metabolizing enzymes, particularly sphingomyelinases, it has key roles in regulating the physical properties of biological membranes, including the formation of membrane microdomains. Thus, ceramide and its related molecules have been attributed significant roles in nearly all steps of the viral life cycle: they may serve directly as receptors or co-receptors for viral entry, form microdomains that cluster entry receptors and/or enable them to adopt the required conformation or regulate their cell surface expression. Sphingolipids can regulate all forms of viral uptake, often through sphingomyelinase activation, and mediate endosomal escape and intracellular trafficking. Ceramide can be key for the formation of viral replication sites. Sphingomyelinases often mediate the release of new virions from infected cells. Moreover, sphingolipids can contribute to viral-induced apoptosis and morbidity in viral diseases, as well as virus immune evasion. Alpha-galactosylceramide, in particular, also plays a significant role in immune modulation in response to viral infections. This review will discuss the roles of ceramide and its related molecules in the different steps of the viral life cycle. We will also discuss how novel strategies could exploit these for therapeutic benefit.


Subject(s)
Ceramides/metabolism , HIV-1/metabolism , Influenza A virus/metabolism , SARS-CoV-2/metabolism , Virus Diseases/metabolism , Virus Diseases/virology , Apoptosis/drug effects , Apoptosis/immunology , Ceramides/chemistry , Gene Expression Regulation, Viral , HIV-1/pathogenicity , Humans , Immunomodulation , Influenza A virus/pathogenicity , SARS-CoV-2/pathogenicity , Virion/growth & development , Virus Diseases/immunology , Virus Internalization , Virus Replication/drug effects , Virus Replication/immunology
6.
J Biol Chem ; 296: 100701, 2021.
Article in English | MEDLINE | ID: covidwho-1198856

ABSTRACT

The acid sphingomyelinase/ceramide system has been shown to be important for cellular infection with at least some viruses, for instance, rhinovirus or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Functional inhibition of the acid sphingomyelinase using tricyclic antidepressants prevented infection of epithelial cells, for instance with SARS-CoV-2. The structure of ambroxol, that is, trans-4-[(2,4-dibromanilin-6-yl)-methyamino]-cyclohexanol, a mucolytic drug applied by inhalation, suggests that the drug might inhibit the acid sphingomyelinase and thereby infection with SARS-CoV-2. To test this, we used vesicular stomatitis virus pseudoviral particles presenting SARS-CoV-2 spike protein on their surface (pp-VSV-SARS-CoV-2 spike), a bona fide system for mimicking SARS-CoV-2 entry into cells. Viral uptake and formation of ceramide localization were determined by fluorescence microscopy, activity of the acid sphingomyelinase by consumption of [14C]sphingomyelin and ceramide was quantified by a kinase method. We found that entry of pp-VSV-SARS-CoV-2 spike required activation of acid sphingomyelinase and release of ceramide, events that were all prevented by pretreatment with ambroxol. We also obtained nasal epithelial cells from human volunteers prior to and after inhalation of ambroxol. Inhalation of ambroxol reduced acid sphingomyelinase activity in nasal epithelial cells and prevented pp-VSV-SARS-CoV-2 spike-induced acid sphingomyelinase activation, ceramide release, and entry of pp-VSV-SARS-CoV-2 spike ex vivo. The addition of purified acid sphingomyelinase or C16 ceramide restored entry of pp-VSV-SARS-CoV-2 spike into ambroxol-treated epithelial cells. We propose that ambroxol might be suitable for clinical studies to prevent coronavirus disease 2019.


Subject(s)
Ambroxol/pharmacology , Antiviral Agents/pharmacology , SARS-CoV-2/drug effects , Sphingomyelin Phosphodiesterase/genetics , Vesiculovirus/drug effects , Virus Internalization/drug effects , Administration, Inhalation , Animals , Biological Transport , Ceramides/metabolism , Chlorocebus aethiops , Drug Repositioning , Epithelial Cells/drug effects , Epithelial Cells/enzymology , Epithelial Cells/virology , Expectorants , Gene Expression , Humans , Primary Cell Culture , Reassortant Viruses/drug effects , Reassortant Viruses/physiology , SARS-CoV-2/physiology , Sphingomyelin Phosphodiesterase/antagonists & inhibitors , Sphingomyelin Phosphodiesterase/metabolism , Sphingomyelins/metabolism , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Vero Cells , Vesiculovirus/physiology
7.
Pharmaceuticals (Basel) ; 14(3)2021 Mar 07.
Article in English | MEDLINE | ID: covidwho-1159327

ABSTRACT

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 laboratory-confirmed 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 in-hospital 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.

8.
J Clin Pharm Ther ; 46(5): 1213-1219, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1109555

ABSTRACT

WHAT IS KNOWN AND OBJECTIVE: Infection by SARS-CoV-2, the virus responsible of COVID-19, is associated with limited treatment options. The purpose of this study was to evaluate the rationale for repurposing functional inhibitors of acid sphingomyelinase (FIASMAs), several of which are approved medicines, for the treatment of SAR-CoV-2 infections. COMMENT: We propose and discuss the FIASMAs' lysosomotropism as a possible explanation for their observed in vitro activities against viruses, and more specifically against infections caused by coronaviruses such as SARS-CoV-2. Successful in vitro-to-in vivo translation of FIASMAs requires that their pharmacokinetics (dosing regimen and drug-drug interactions) are matched with viral kinetics. WHAT IS NEW AND CONCLUSION: Drug repurposing to ensure rapid patient access to effective treatment has garnered much attention in this era of the COVID-19 pandemic. The observed lysosomotropic activity of small-molecule FIASMA compounds suggests that their repurposing as potential drugs against SARS-CoV-2 is promising.


Subject(s)
COVID-19/drug therapy , Drug Repositioning/methods , Sphingomyelin Phosphodiesterase/antagonists & inhibitors , Humans , SARS-CoV-2/drug effects
9.
Cell Rep Med ; 1(8): 100142, 2020 11 17.
Article in English | MEDLINE | ID: covidwho-894264

ABSTRACT

The acid sphingomyelinase/ceramide system plays an important role in bacterial and viral infections. Here, we report that either pharmacological inhibition of acid sphingomyelinase with amitriptyline, imipramine, fluoxetine, sertraline, escitalopram, or maprotiline or genetic downregulation of the enzyme prevents infection of cultured cells or freshy isolated human nasal epithelial cells with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or vesicular stomatitis virus (VSV) pseudoviral particles (pp-VSV) presenting SARS-CoV-2 spike protein (pp-VSV-SARS-CoV-2 spike), a bona fide system mimicking SARS-CoV-2 infection. Infection activates acid sphingomyelinase and triggers a release of ceramide on the cell surface. Neutralization or consumption of surface ceramide reduces infection with pp-VSV-SARS-CoV-2 spike. Treating volunteers with a low dose of amitriptyline prevents infection of freshly isolated nasal epithelial cells with pp-VSV-SARS-CoV-2 spike. The data justify clinical studies investigating whether amitriptyline, a safe drug used clinically for almost 60 years, or other antidepressants that functionally block acid sphingomyelinase prevent SARS-CoV-2 infection.


Subject(s)
Epithelial Cells/drug effects , SARS-CoV-2/drug effects , Sphingomyelin Phosphodiesterase/antagonists & inhibitors , Amitriptyline/pharmacology , Animals , Antidepressive Agents/pharmacology , Ceramides/antagonists & inhibitors , Ceramides/metabolism , Chlorocebus aethiops , Epithelial Cells/metabolism , Epithelial Cells/virology , Humans , Nasal Mucosa/drug effects , Nasal Mucosa/metabolism , Nasal Mucosa/virology , Neutral Ceramidase/pharmacology , SARS-CoV-2/physiology , Sphingomyelin Phosphodiesterase/metabolism , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Vero Cells , Vesicular stomatitis Indiana virus/genetics
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