Search Results (11)

Prior evidence indicates the potential central role of the acid sphingomyelinase (ASM)/ceramide system in the infection of cells with SARS-CoV-2. We conducted a multicenter retrospective observational study including 72,105 adult patients with laboratory-confirmed SARS-CoV-2 infection who were admitted to 36 AP-HP (Assistance Publique–Hôpitaux de Paris) hospitals from 2 May 2020 to 31 August 2022. We examined the association between the ongoing use of medications functionally inhibiting acid sphingomyelinase (FIASMA), which reduces the infection of cells with SARS-CoV-2 in vitro, upon hospital admission with 28-day all-cause mortality in a 1:1 ratio matched analytic sample based on clinical characteristics, disease severity and other medications (N = 9714). The univariate Cox regression model of the matched analytic sample showed that FIASMA medication use at admission was associated with significantly lower risks of 28-day mortality (HR = 0.80; 95% CI = 0.72–0.88; p < 0.001). In this multicenter observational study, the use of FIASMA medications was significantly and substantially associated with reduced 28-day mortality among adult patients hospitalized with COVID-19. These findings support the continuation of these medications during the treatment of SARS-CoV-2 infections. Randomized clinical trials (RCTs) are needed to confirm these results, starting with the molecules with the greatest effect size in the study, e.g., fluoxetine, escitalopram, and amlodipine. Full article

Over the past few years, COVID-19 has caused widespread suffering worldwide. There is great research potential in this domain and it is also necessary. The main objective of this study was to identify potential inhibitors against acid sphingomyelinase (ASM) in order to prevent coronavirus infection. Experimental studies revealed that SARS-CoV-2 causes activation of the acid sphingomyelinase/ceramide pathway, which in turn facilitates the viral entry into the cells. The objective was to inhibit acid sphingomyelinase activity in order to prevent the cells from SARS-CoV-2 infection. Previous studies have reported functional inhibitors against ASM (FIASMAs). These inhibitors can be exploited to block the entry of SARS-CoV-2 into the cells. To achieve our objective, a drug library containing 257 functional inhibitors of ASM was constructed. Computational molecular docking was applied to dock the library against the target protein (PDB: 5I81). The potential binding site of the target protein was identified through structural alignment with the known binding pocket of a protein with a similar function. AutoDock Vina was used to carry out the docking steps. The docking results were analyzed and the inhibitors were screened based on their binding affinity scores and ADME properties. Among the 257 functional inhibitors, Dutasteride, Cepharanthine, and Zafirlukast presented the lowest binding affinity scores of −9.7, −9.6, and −9.5 kcal/mol, respectively. Furthermore, computational ADME analysis of these results revealed Cepharanthine and Zafirlukast to have non-toxic properties. To further validate these findings, the top two inhibitors in complex with the target protein were subjected to molecular dynamic simulations at 100 ns. The molecular interactions and stability of these compounds revealed that these inhibitors could be a promising tool for inhibiting SARS-CoV-2 infection. Full article

To reduce Coronavirus Disease 2019 (COVID-19)-related mortality and morbidity, widely available oral COVID-19 treatments are urgently needed. Certain antidepressants, such as fluvoxamine or fluoxetine, may be beneficial against COVID-19. We included 388,945 adult inpatients who tested positive for SARS-CoV-2 at 36 AP–HP (Assistance Publique–Hôpitaux de Paris) hospitals from 2 May 2020 to 2 November 2021. We compared the prevalence of antidepressant use at admission in a 1:1 ratio matched analytic sample with and without COVID-19 (N = 82,586), and assessed its association with 28-day all-cause mortality in a 1:1 ratio matched analytic sample of COVID-19 inpatients with and without antidepressant use at admission (N = 1482). Antidepressant use was significantly less prevalent in inpatients with COVID-19 than in a matched control group of inpatients without COVID-19 (1.9% versus 4.8%; Odds Ratio (OR) = 0.38; 95%CI = 0.35–0.41, p < 0.001). Antidepressant use was significantly associated with reduced 28-day mortality among COVID-19 inpatients (12.8% versus 21.2%; OR = 0.55; 95%CI = 0.41–0.72, p < 0.001), particularly at daily doses of at least 40 mg fluoxetine equivalents. Antidepressants with high FIASMA (Functional Inhibitors of Acid Sphingomyelinase) activity seem to drive both associations. These treatments may reduce SARS-CoV-2 infections and COVID-19-related mortality in inpatients, and may be appropriate for prophylaxis and/or COVID-19 therapy for outpatients or inpatients. Full article

Mapping non-canonical cellular pathways affected by approved medications can accelerate drug repurposing efforts, which are crucial in situations with a global impact such as the COVID-19 pandemic. Fluoxetine and fluvoxamine are well-established and widely-used antidepressive agents that act as serotonin reuptake inhibitors (SSRI-s). Interestingly, these drugs have been reported earlier to act as lysosomotropic agents, inhibitors of acid sphingomyelinase in the lysosomes, and as ligands of sigma-1 receptors, mechanisms that might be used to fight severe outcomes of COVID-19. In certain cases, these drugs were administered for selected COVID-19 patients because of their antidepressive effects, while in other cases, clinical studies were performed to assess the effect of these drugs on treating COVID-19 patients. Clinical studies produced promising data that encourage the further investigation of fluoxetine and fluvoxamine regarding their use in COVID-19. In this review, we summarize experimental data and the results of the performed clinical studies. We also provide an overview of previous knowledge on the tissue distribution of these drugs and by integrating this information with the published experimental results, we highlight the real opportunity of using these drugs in our fight against COVID-19. Full article

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. Full article

(1) Background: Based on its antiviral activity, anti-inflammatory properties, and functional inhibition effects on the acid sphingomyelinase/ceramide system (FIASMA), we sought to examine the potential usefulness of the H1 antihistamine hydroxyzine in patients hospitalized for COVID-19. (2) Methods: In a multicenter observational study, we included 15,103 adults hospitalized for COVID-19, of which 164 (1.1%) received hydroxyzine within the first 48 h of hospitalization, administered orally at a median daily dose of 25.0 mg (SD = 29.5). We compared mortality rates between patients who received hydroxyzine at hospital admission and those who did not, using a multivariable logistic regression model adjusting for patients’ characteristics, medical conditions, and use of other medications. (3) Results: This analysis showed a significant association between hydroxyzine use and reduced mortality (AOR, 0.51; 95%CI, 0.29–0.88, p = 0.016). This association was similar in multiple sensitivity analyses. (4) Conclusions: In this retrospective observational multicenter study, the use of the FIASMA hydroxyzine was associated with reduced mortality in patients hospitalized for COVID-19. Double-blind placebo-controlled randomized clinical trials of hydroxyzine for COVID-19 are needed to confirm these results, as are studies to examine the potential usefulness of this medication for outpatients and as post-exposure prophylaxis for individuals at high risk for severe COVID-19. Full article

Major depressive disorder (MDD) is a common and severe mental disorder that is usually recurrent and has a high risk of suicide. This disorder manifests not only with psychological symptoms but also multiple changes throughout the body, including increased risks of obesity, diabetes, and cardiovascular disease. Peripheral markers of oxidative stress and inflammation are elevated. MDD is therefore best described as a multisystem whole-body disease. Pharmacological treatment with antidepressants usually requires several weeks before the desired effects manifest. Previous theories of depression, such as the monoamine or neurogenesis hypotheses, do not explain these characteristics well. In recent years, new mechanisms of action have been discovered for long-standing antidepressants that also shed new light on depression, including the sphingolipid system and the receptor for brain-derived neurotrophic factor (BDNF). Full article

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. Full article

Major depressive disorder (MDD) is a severe psychiatric condition with key symptoms of low mood and lack of motivation, joy, and pleasure. Recently, the acid sphingomyelinase (ASM)/ceramide system has been implicated in the pathogenesis of MDD. ASM is a lysosomal glycoprotein that catalyzes the hydrolysis of sphingomyelin, an abundant component of membranes, into the bioactive sphingolipid ceramide, which impacts signaling pathways. ASM activity is inhibited by several common antidepressant drugs. Human and murine studies have confirmed that increased ASM activity and ceramide levels are correlated with MDD. To define a molecular marker for treatment monitoring, we investigated the mRNA expression of SMPD1, which encodes ASM, in primary cell culture models, a mouse study, and a human study with untreated MDD patients before and after antidepressive treatment. Our cell culture study showed that a common antidepressant inhibited ASM activity at the enzymatic level and also at the transcriptional level. In a genetically modified mouse line with depressive-like behavior, Smpd1 mRNA expression in dorsal hippocampal tissue was significantly decreased after treatment with a common antidepressant. The large human study showed that SMPD1 mRNA expression in untreated MDD patients decreased significantly after antidepressive treatment. This translational study shows that SMPD1 mRNA expression could serve as a molecular marker for treatment and adherence monitoring of MDD. Full article

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. Full article

Liver dysfunction during sepsis is an independent risk factor leading to increased mortality rates. Specifically, dysregulation of hepatic biotransformation capacity, especially of the cytochrome P450 (CYP) system, represents an important distress factor during host response. The activity of the conserved stress enzyme sphingomyelin phosphodiesterase 1 (SMPD1) has been shown to be elevated in sepsis patients, allowing for risk stratification. Therefore, the aim of the present study was to investigate whether SMPD1 activity has an impact on expression and activity of different hepatic CYP enzymes using an animal model of polymicrobial sepsis. Polymicrobial sepsis was induced in SMPD1 wild-type and heterozygous mice and hepatic ceramide content as well as CYP mRNA, protein expression and enzyme activities were assessed at two different time points, at 24 h, representing the acute phase, and at 28 days, representing the post-acute phase of host response. In the acute phase of sepsis, SMPD1^+/+ mice showed an increased hepatic C16- as well as C18-ceramide content. In addition, a downregulation of CYP expression and activities was detected. In SMPD1^+/− mice, however, no noticeable changes of ceramide content and CYP expression and activities during sepsis could be observed. After 28 days, CYP expression and activities were normalized again in all study groups, whereas mRNA expression remained downregulated in SMPD^+/+ animals. In conclusion, partial genetic inhibition of SMPD1 stabilizes hepatic ceramide content and improves hepatic monooxygenase function in the acute phase of polymicrobial sepsis. Since we were also able to show that the functional inhibitor of SMPD1, desipramine, ameliorates downregulation of CYP mRNA expression and activities in the acute phase of sepsis in wild-type mice, SMPD1 might be an interesting pharmacological target, which should be further investigated. Full article