Molecular docking as a tool for the discovery of novel insight about the role of acid sphingomyelinase inhibitors in SARS- CoV-2 infectivity

BMC Public Health, Journal Year: 2024, Volume and Issue: 24(1)

Published: Feb. 6, 2024

Recently, COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants, > 6 million deaths. Symptoms included strain complications, leading to pneumonia. SARS-CoV-2 attaches the ACE-2 receptor of host cell membrane enter. Targeting entry may effectively inhibit infection. Acid sphingomyelinase (ASMase) is a lysosomal protein that catalyzes conversion sphingolipid (sphingomyelin) ceramide. Ceramide molecules aggregate/assemble on plasma form "platforms" facilitate viral intake into cell. Impairing ASMase activity will eventually disrupt In this review, we identified metabolism sphingolipids, sphingolipids' role in signal transduction cascades, infection mechanisms. Also, outlined structure underlying mechanisms inhibiting 40 with aid inhibitors acid (FIASMAs). silico molecular docking analyses FIASMAs revealed dilazep (S = - 12.58 kcal/mol), emetine 11.65 pimozide 11.29 carvedilol 11.28 mebeverine 11.14 cepharanthine 11.06 hydroxyzin 10.96 astemizole 10.81 sertindole 10.55 bepridil 10.47 kcal/mol) have higher inhibition than candidate drug amiodarone 10.43 making them better options for inhibition.

Language: Английский

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Prevalence of Contraindications to Nirmatrelvir-Ritonavir Among Hospitalized Patients With COVID-19 at Risk for Progression to Severe Disease

JAMA Network Open, Journal Year: 2022, Volume and Issue: 5(11), P. e2242140 - e2242140

Published: Nov. 15, 2022

This cohort study examines the prevalence of contraindications to nirmatrelvir-ritonavir in patients hospitalized with COVID-19.

Language: Английский

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Antidepressant Use and Its Association with 28-Day Mortality in Inpatients with SARS-CoV-2: Support for the FIASMA Model against COVID-19

Journal of Clinical Medicine, Journal Year: 2022, Volume and Issue: 11(19), P. 5882 - 5882

Published: Oct. 5, 2022

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 November 2021. compared the prevalence of antidepressant use admission in a 1:1 ratio matched analytic sample with without (N = 82,586), assessed its association 28-day all-cause 1482). Antidepressant was significantly less prevalent than control group (1.9% versus 4.8%; Odds Ratio (OR) 0.38; 95%CI 0.35−0.41, p < 0.001). associated reduced among (12.8% 21.2%; OR 0.55; 0.41−0.72, 0.001), particularly daily doses least 40 mg fluoxetine equivalents. Antidepressants high FIASMA (Functional Inhibitors Acid Sphingomyelinase) activity seem drive both associations. These infections COVID-19-related inpatients, appropriate prophylaxis and/or therapy outpatients inpatients.

Language: Английский

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Association between antidepressant use and ED or hospital visits in outpatients with SARS-CoV-2

Translational Psychiatry, Journal Year: 2022, Volume and Issue: 12(1)

Published: Aug. 22, 2022

Antidepressants have previously been associated with better outcomes in patients hospitalized COVID-19, but their effect on clinical deterioration among ambulatory has not fully explored. The objective of this study was to assess whether antidepressant exposure reduced emergency department (ED) or hospital visits SARS-CoV-2 infection. This retrospective cohort included adult (N = 25 034) a positive test performed non-hospital setting. Logistic regression analyses tested associations between home use medications and composite outcome ED visitation admission within 30 days. Secondary exposures individual antidepressants functional inhibition acid sphingomyelinase (FIASMA) activity. Patients were less likely experience the primary compared without (adjusted odds ratio [aOR] 0.89, 95% CI 0.79-0.99, p 0.04). association only observed daily doses at least 20 mg fluoxetine-equivalent (aOR 0.87, 0.77-0.99, 0.04), lower than 0.94, 0.80-1.11, 0.48). In exploratory secondary analyses, incidence also selective serotonin reuptake inhibitors 0.75-0.99, bupropion 0.70, 0.55-0.90, 0.005), FIASMA drugs 0.03). Antidepressant patients, dose-dependent manner. These data support model antidepressants' effects against COVID-19.

Language: Английский

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Fluoxetine hydrochloride loaded lipid polymer hybrid nanoparticles showed possible efficiency against SARS-CoV-2 infection

International Journal of Pharmaceutics, Journal Year: 2021, Volume and Issue: 607, P. 121023 - 121023

Published: Aug. 18, 2021

Language: Английский

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Antiviral and Anti-Inflammatory Activities of Fluoxetine in a SARS-CoV-2 Infection Mouse Model

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(21), P. 13623 - 13623

Published: Nov. 7, 2022

The coronavirus disease 2019 (COVID-19) pandemic continues to cause significant morbidity and mortality worldwide. Since a large portion of the world's population is currently unvaccinated or incompletely vaccinated has limited access approved treatments against COVID-19, there an urgent need continue research on treatment options, especially those at low cost which are immediately available patients, particularly in low- middle-income countries. Prior vitro observational studies have shown that fluoxetine, possibly through its inhibitory effect acid sphingomyelinase/ceramide system, could be promising antiviral anti-inflammatory COVID-19. In this report, we evaluated potential activities fluoxetine K18-hACE2 mouse model SARS-CoV-2 infection, variants concern vitro, i.e., ancestral strain, Alpha B.1.1.7, Gamma P1, Delta B1.617 Omicron BA.5. Fluoxetine, administrated after significantly reduced lung tissue viral titres expression several inflammatory markers (i.e., IL-6, TNFα, CCL2 CXCL10). It also inhibited replication all vitro. A modulation ceramide system tissues, as reflected by increase ratio HexCer 16:0/Cer 16:0 fluoxetine-treated mice, may contribute explain these effects. Our findings demonstrate properties activity concern, establishing very candidate for prevention infection pathogenesis.

Language: Английский

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Risk of Death in Individuals Hospitalized for COVID-19 With and Without Psychiatric Disorders: An Observational Multicenter Study in France

Biological Psychiatry Global Open Science, Journal Year: 2022, Volume and Issue: 3(1), P. 56 - 67

Published: Jan. 4, 2022

Prior research suggests that psychiatric disorders could be linked to increased mortality among patients with COVID-19. However, whether all or specific are intrinsic risk factors of death in COVID-19 these associations reflect the greater prevalence medical people has yet evaluated.We performed an observational, multicenter, retrospective cohort study examine association between and hospitalized for laboratory-confirmed at 36 Greater Paris University hospitals.Of 15,168 adult patients, 857 (5.7%) had ICD-10 diagnosis disorder. Over a mean follow-up period 14.6 days (SD = 17.9), 326 (38.0%) disorder died compared 1276 14,311 (8.9%) without such (odds ratio 6.27, 95% CI 5.40-7.28, p < .01). When adjusting age, sex, hospital, current smoking status, medications according compassionate use as part clinical trial, this remained significant (adjusted odds 3.27, 2.78-3.85, additional adjustments obesity number conditions resulted nonsignificant 1.02, 0.84-1.23, .86). Exploratory analyses after same suggested mood was significantly associated reduced mortality, which might explained by antidepressants.These findings suggest COVID-19-related individuals higher population not underlying disease.

Language: Английский

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Repurposing selective serotonin reuptake inhibitors for severity of COVID-19: A population-based study

European Neuropsychopharmacology, Journal Year: 2023, Volume and Issue: 71, P. 96 - 108

Published: April 4, 2023

The World Health Organization has proposed that a search be made for alternatives to vaccines the prevention and treatment of COVID-19, with one such alternative being selective serotonin reuptake inhibitors (SSRIs). This study thus sought assess: impact previous SSRI antidepressants on severity COVID-19 (risk hospitalisation, admission an intensive care unit [ICU], mortality), its influence susceptibility SARS-CoV-2 progression severe COVID-19. We conducted population-based multiple case-control in region north-west Spain. Data were sourced from electronic health records. Adjusted odds ratios (aORs) 95%CIs calculated using multilevel logistic regression. collected data total 86,602 subjects: 3060 cases PCR+, 26,757 non-hospitalised PCR+ 56,785 controls (without PCR+). Citalopram displayed statistically significant decrease risk hospitalisation (aOR=0.70; 95% CI 0.49-0.99, p = 0.049) (aOR=0.64; 0.43-0.96, 0.032). Paroxetine was associated mortality (aOR=0.34; 0.12 - 0.94, 0.039). No class effect observed SSRIs overall, nor any other found remaining SSRIs. results this large-scale, real-world indicate that, citalopram, could candidate drug repurposed as preventive aimed at reducing patients' progressing stages disease.

Language: Английский

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Association of fluvoxamine with mortality and symptom resolution among inpatients with COVID-19 in Uganda: a prospective interventional open-label cohort study

Molecular Psychiatry, Journal Year: 2023, Volume and Issue: 28(12), P. 5411 - 5418

Published: March 3, 2023

Abstract Prior research suggests that fluvoxamine, a selective serotonin reuptake inhibitor (SSRI) used for the treatment of obsessive-compulsive disorder and major depressive disorder, could be repurposed against COVID-19. We undertook prospective interventional open-label cohort study to evaluate efficacy tolerability fluvoxamine among inpatients with laboratory-confirmed COVID-19 in Uganda. The main outcome was all-cause mortality. Secondary outcomes were hospital discharge complete symptom resolution. included 316 patients, whom 94 received addition standard care [median age, 60 years (IQR = 37.0); women, 52.2%]. Fluvoxamine use significantly associated reduced mortality [AHR 0.32; 95% CI 0.19–0.53; p < 0.001, NNT 4.46] increased resolution [AOR 2.56; 1.53–5.51; 4.44]. Sensitivity analyses yielded similar results. These effects did not differ by clinical characteristic, including vaccination status. Among 161 survivors, time 0.81, (0.54–1.23), 0.32]. There trend toward greater side (7.45% versus 3.15%; SMD 0.21; χ 2 3.46, 0.06), most which light or mild severity none serious. One hundred mg prescribed twice daily 10 days well tolerated resolution, without significant increase discharge, Large-scale randomized trials are urgently needed confirm these findings, especially low- middle-income countries, where access vaccines approved treatments is limited.

Language: Английский

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Association of severe mental illness and septic shock case fatality rate in patients admitted to the intensive care unit: A national population-based cohort study

PLoS Medicine, Journal Year: 2023, Volume and Issue: 20(3), P. e1004202 - e1004202

Published: March 13, 2023

Background Patients with severe mental illness (SMI) (i.e., schizophrenia, bipolar disorder, or major depressive disorder) have been reported to excess mortality rates from infection compared patients without SMI, but whether SMI is associated higher lower case fatality (CFRs) among infected remains unclear. The primary objective was compare the 90-day CFR in septic shock and admitted intensive care unit (ICU), after adjusting for social disadvantage physical health comorbidity. Methods findings We conducted a nationwide, population-based cohort study of all adult ICU France between January 1, 2014, December 31, 2018, using French national hospital database. matched (within hospitals) ratio 1:up 4 (matched-controls) age (5 years range), sex, degree deprivation, year hospitalization. Cox regression models were adjustment smoking, alcohol other substance addiction, overweight obesity, Charlson comorbidity index, presence trauma, surgical intervention, Simplified Acute Physiology Score II score, organ failures, source admission (home, transfer ward), length time admission. outcome CFR. Secondary outcomes 30- 365-day CFRs, clinical profiles patients. A total 187,587 identified, including 3,812 2,258 5,246 disorder. Compared controls, significantly schizophrenia (1,052/3,269 = 32.2% versus 5,000/10,894 45.5%; adjusted hazard (aHR) 0.70, 95% confidence interval (CI) 0.65,0.75, p < 0.001), disorder (632/1,923 32.9% 2,854/6,303 45.3%; aHR CI 0.63,0.76, (1,834/4,432 41.4% 6,798/14,452 47.1%; 0.85, 0.81,0.90, 0.001). Study limitations include inability capture deaths occurring outside hospital, lack data on processes care, problems missing miscoding medico-administrative databases. Conclusions Our suggest that, comorbidity, there are improved without. This finding may be result different immunological exposures psychotropic medications, which should further explored.

Language: Английский

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