Fluvoxamine maleate alleviates amyloid-beta load and neuroinflammation in 5XFAD mice to ameliorate Alzheimer disease pathology.

Introduction: Alzheimer pathology (AD) is characterized by the deposition of amyloid beta (Aß) and chronic neuroinflammation, with the NLRP3 inflammasome playing a significant role. This study demonstrated that the OCD drug fluvoxamine maleate (FXN) can potently ameliorate AD pathology in 5XFAD mice by promoting autophagy-mediated clearance of Aß and inhibiting the NLRP3 inflammasome. Methods: We used mice primary astrocytes to establish the mechanism of action of FXN against NLRP3 inflammasome by using various techniques like ELISA, Western blotting, confocal microscopy, Immunofluorescence, etc. The anti-AD activity of FXN was validated in transgenic 5XFAD mice following two months of treatment. This was followed by behavior analysis, examination of inflammatory and autophagy proteins and immunohistochemistry analysis for Aß load in the hippocampi. Results: Our data showed that FXN, at a low concentration of 78 nM, induces autophagy to inhibit NF-κB and the NLRP3 inflammasome, apart from directly inhibiting NLRP3 inflammasome in primary astrocytes. FXN activated the PRKAA2 pathway through CAMKK2 signaling, leading to autophagy induction. It inhibited the ATP-mediated NLRP3 inflammasome activation by promoting the autophagic degradation of NF-κB, resulting in the downregulation of pro-IL-1ß and NLRP3. The anti-NLRP3 inflammasome effect of FXN was reversed when autophagy was inhibited by either genetic knockdown of the PRKAA2 pathway or pharmacological inhibition with bafilomycin A1. Furthermore, FXN treatment led to improved AD pathology in 5XFAD mice, resulting in significant improvements in various behavioral parameters such as working memory and neuromuscular coordination, making their behavior more similar to that of wild-type animals. FXN improved behavior in 5XFAD mice by clearing the Aß deposits from the hippocampi and significantly reducing multiple inflammatory proteins, including NF-κB, GFAP, IBA1, IL-1ß, TNF-α, and IL-6, which are associated with NF-κB and NLRP3 inflammasome in the brain. Moreover, these changes were accompanied by increased expression of autophagic proteins. Discussion: Our data suggest that FXN ameliorates AD pathology, by simultaneously targeting two key pathological features: Aß deposits and neuroinflammation. As an already approved drug, FXN holds potential as a candidate for human studies against AD.

Favorable Antiviral Effect of Metformin on SARS-CoV-2 Viral Load in a Randomized, Placebo-Controlled Clinical Trial of COVID-19.

BACKGROUND: Metformin has antiviral activity against RNA viruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The mechanism appears to be suppression of protein translation via targeting the host mechanistic target of rapamycin pathway. In the COVID-OUT randomized trial for outpatient coronavirus disease 2019 (COVID-19), metformin reduced the odds of hospitalizations/death through 28 days by 58%, of emergency department visits/hospitalizations/death through 14 days by 42%, and of long COVID through 10 months by 42%. METHODS: COVID-OUT was a 2 × 3 randomized, placebo-controlled, double-blind trial that assessed metformin, fluvoxamine, and ivermectin; 999 participants self-collected anterior nasal swabs on day 1 (n = 945), day 5 (n = 871), and day 10 (n = 775). Viral load was quantified using reverse-transcription quantitative polymerase chain reaction. RESULTS: The mean SARS-CoV-2 viral load was reduced 3.6-fold with metformin relative to placebo (-0.56 log10 copies/mL; 95% confidence interval [CI], -1.05 to -.06; P = .027). Those who received metformin were less likely to have a detectable viral load than placebo at day 5 or day 10 (odds ratio [OR], 0.72; 95% CI, .55 to .94). Viral rebound, defined as a higher viral load at day 10 than day 5, was less frequent with metformin (3.28%) than placebo (5.95%; OR, 0.68; 95% CI, .36 to 1.29). The metformin effect was consistent across subgroups and increased over time. Neither ivermectin nor fluvoxamine showed effect over placebo. CONCLUSIONS: In this randomized, placebo-controlled trial of outpatient treatment of SARS-CoV-2, metformin significantly reduced SARS-CoV-2 viral load, which may explain the clinical benefits in this trial. Metformin is pleiotropic with other actions that are relevant to COVID-19 pathophysiology. CLINICAL TRIALS REGISTRATION: NCT04510194.

Fluvoxamine inhibits Th1 and Th17 polarization and function by repressing glycolysis to attenuate autoimmune progression in type 1 diabetes.

BACKGROUND: Fluvoxamine is one of the selective serotonin reuptake inhibitors (SSRIs) that are regarded as the first-line drugs to manage mental disorders. It has been also recognized with the potential to treat inflammatory diseases and viral infection. However, the effect of fluvoxamine on autoimmune diseases, particularly type 1 diabetes (T1D) and the related cellular and molecular mechanisms, are yet to be addressed. METHOD: Herein in this report, we treated NOD mice with fluvoxamine for 2 weeks starting from 10-week of age to dissect the impact of fluvoxamine on the prevention of type 1 diabetes. We compared the differences of immune cells between 12-week-old control and fluvoxamine-treated mice by flow cytometry analysis. To study the mechanism involved, we extensively examined the characteristics of CD4+ T cells with fluvoxamine stimulation using RNA-seq analysis, real-time PCR, Western blot, and seahorse assay. Furthermore, we investigated the relevance of our data to human autoimmune diabetes. RESULT: Fluvoxamine not only delayed T1D onset, but also decreased T1D incidence. Moreover, fluvoxamine-treated NOD mice showed significantly attenuated insulitis coupled with well-preserved ß cell function, and decreased Th1 and Th17 cells in the peripheral blood, pancreatic lymph nodes (PLNs), and spleen. Mechanistic studies revealed that fluvoxamine downregulated glycolytic process by inhibiting phosphatidylinositol 3-kinase (PI3K)-AKT signaling, by which it restrained effector T (Teff) cell differentiation and production of proinflammatory cytokines. CONCLUSION: Collectively, our study supports that fluvoxamine could be a viable therapeutic drug against autoimmunity in T1D setting.

Fluvoxamine Exerts Sigma-1R to Rescue Autophagy via Pom121-Mediated Nucleocytoplasmic Transport of TFEB.

Expansion of the GGGGCC-RNA repeat is a known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), which currently have no cure. Recent studies have indicated the activation of Sigma-1 receptor plays an important role in providing neuroprotection, especially in ALS and Alzheimer's disease. Nevertheless, the mechanisms underlying Sigma-1R activation and its effect on (G4C2)n-RNA-induced cell death remain unclear. In this study, we demonstrated that fluvoxamine is a Sigma-1R agonist that can increase chaperone activity and stabilize the protein expression of Pom121 in (G4C2)31-RNA-expressing NSC34 cells, leading to increased colocalization at the nuclear envelope. Interestingly, fluvoxamine treatment increased Pom121 protein expression without affecting transcription. In C9orf72-ALS, the nuclear translocation of TFEB autophagy factor decreased owing to nucleocytoplasmic transport defects. Our results showed that pretreatment of NSC34 cells with fluvoxamine promoted the shuttling of TFEB into the nucleus and elevated the expression of LC3-II compared to the overexpression of (G4C2)31-RNA alone. Additionally, even when used alone, fluvoxamine increases Pom121 expression and TFEB translocation. To summarize, fluvoxamine may act as a promising repurposed medicine for patients with C9orf72-ALS, as it stabilizes the nucleoporin Pom121 and promotes the translocation of TFEB in (G4C2)31-RNA-expressing NSC34 cells.

Upregulation by duloxetine of the transforming growth factor-α-induced migration of hepatocellular carcinoma cells via enhancement of the c-Jun N-terminal kinase activity.

Duloxetine, a selective reuptake inhibitor for serotonin and norepinephrine, is a medication widely used for major depression. Currently, duloxetine is also recommended for pain related to chemotherapy-induced peripheral neuropathy or cancer. Previously, we showed that transforming growth factor-α (TGF-α) induces the migration of human hepatocellular carcinoma (HCC)-derived HuH7 cells through the activation of c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK) and AKT. In the present study, we investigate whether duloxetine affects cell migration and its mechanism. Duloxetine significantly enhanced the TGF-α-induced migration of HuH7 cells. Fluvoxamine and sertraline, specific inhibitors of serotonin reuptake, also upregulated the TGF-α-induced cell migration. On the contrary, reboxetine, a specific norepinephrine reuptake inhibitor, failed to affect cell migration. Duloxetine significantly amplified the TGF-α-stimulated phosphorylation of JNK, but not p38 MAPK and AKT. In addition, fluvoxamine and sertraline, but not reboxetine, enhanced the phosphorylation of JNK. SP600125, a JNK inhibitor, suppressed the enhancement by duloxetine, fluvoxamine, or sertraline of TGF-α-induced migration of HuH7 cells. Taken together, our results strongly suggest that duloxetine strengthens the TGF-α-induced activation of JNK via inhibition of serotonin reuptake in HCC cells, leading to the enhancement of cell migration.

Acetyl-11-keto-beta boswellic acid(AKBA) modulates CSTC-pathway by activating SIRT-1/Nrf2-HO-1 signalling in experimental rat model of obsessive-compulsive disorder: Evidenced by CSF, blood plasma and histopathological alterations.

Obsessive-Compulsive disorder (OCD) is a long-term and persistent mental illness characterised by obsessive thoughts and compulsive behaviours. Numerous factors can contribute to the development or progression of OCD. These factors may result from the dysregulation of multiple intrinsic cellular pathways, including SIRT-1, Nrf2, and HO-1. Inhibitors of selective serotonin reuptake (SSRIs) are effective first-line treatments for OCD. In our ongoing research, we have investigated the role of SIRT-1, Nrf2, and HO-1, as well as the neuroprotective potential of Acetyl-11-keto-beta boswellic acid (AKBA) against behavioural and neurochemical changes in rodents treated with 8-OH-DPAT. In addition, the effects of AKBA were compared to those of fluvoxamine (FLX), a standard OCD medication. Injections of 8-OH-DPAT into the intra-dorso raphe nuclei (IDRN) of rats for seven days induced repetitive and compulsive behaviour accompanied by elevated oxidative stress, inflammatory processes, apoptosis, and neurotransmitter imbalances in CSF, blood plasma, and brain samples. Chronic administration of AKBA at 50 mg/kg and 100 mg/kg p.o. restored histopathological alterations in the cortico-striatal-thalamo-cortical (CSTC) pathway, including the cerebral cortex, striatum, and hippocampal regions. Our investigation revealed that when AKBA and fluvoxamine were administered together, the alterations were restored to a greater degree than when administered separately. These findings demonstrate that the neuroprotective effect of AKBA can serve as an effective basis for developing a novel OCD treatment.

Sigma-1 Receptor Agonist Fluvoxamine Ameliorates Fibrotic Response of Trabecular Meshwork Cells.

Primary open-angle glaucoma remains a global issue, lacking a definitive treatment. Increased intraocular pressure (IOP) is considered the primary risk factor of the disease and it can be caused by fibrotic-like changes in the trabecular meshwork (TM) such as increased tissue stiffness and outflow resistance. Previously, we demonstrated that the sigma-1 receptor (S1R) agonist fluvoxamine (FLU) has anti-fibrotic properties in the kidney and lung. In this study, the localization of the S1R in TM cells was determined, and the anti-fibrotic efficacy of FLU was examined in both mouse and human TM cells. Treatment with FLU reduced the F-actin rearrangement, inhibited cell proliferation and migration induced by the platelet-derived growth factor and decreased the levels of fibrotic proteins. The protective role of the S1R in fibrosis was confirmed by a more pronounced increase in alpha smooth muscle actin and F-actin bundle and clump formation in primary mouse S1R knockout TM cells. Furthermore, FLU demonstrated its protective effects by increasing the production of nitric oxide and facilitating the degradation of the extracellular matrix through the elevation of cathepsin K. These findings suggest that the S1R could be a novel target for the development of anti-fibrotic drugs and offer a new therapeutic approach for glaucoma.

Identification of the perpetrator imperatorin in Xin-yi-san-theophylline interaction: observed and predicted herb-drug interaction in rats.

OBJECTIVES: Theophylline is a bronchodilator with a narrow therapeutic index and primarily metabolised by cytochrome P450 (CYP) 1A2. Xin-yi-san (XYS) is a herbal formula frequently used to ameliorate nasal inflammation. This study aimed to investigate the effects of XYS and its ingredient, imperatorin, on theophylline pharmacokinetics in rats. METHODS: The kinetics of XYS- and imperatorin-mediated inhibition of theophylline oxidation were determined. Pharmacokinetics of theophylline were analysed. Comparisons were made with the CYP1A2 inhibitor, fluvoxamine. KEY FINDINGS: XYS extract and its ingredient, imperatorin, non-competitively inhibited theophylline oxidation. Fluvoxamine (50 and 100 mg/kg) and XYS (0.5 and 0.9 g/kg) significantly prolonged the time to reach the maximum plasma concentration (tmax) of theophylline by 3-10 fold. In a dose-dependent manner, XYS and imperatorin (0.1-10 mg/kg) treatments significantly decreased theophylline clearance by 27-33% and 19-56%, respectively. XYS (0.9 g/kg) and imperatorin (10 mg/kg) significantly prolonged theophylline elimination half-life by 29% and 142%, respectively. Compared with the increase (51-112%) in the area under curve (AUC) of theophylline by fluvoxamine, the increase (27-57%) by XYS was moderate. CONCLUSIONS: XYS decreased theophylline clearance primarily through imperatorin-suppressed theophylline oxidation. Further human studies are essential for the dose adjustment in the co-medication regimen.

The effects of sigma-1 agonist fluvoxamine on experimental induced tardive dyskinesia model in rats.

Tardive dyskinesia (TD) is a persistent involuntary complex movement disorder that is known to occur with long-term antipsychotic treatment. Despite being a well-recognized complication of this treatment, its symptoms are often masked by the antipsychotic agents, only to become apparent upon reducing or terminating the treatment. In an effort to advance our understanding of TD pathophysiology and to identify potential therapies, the current study aimed to establish an animal model of TD by administering haloperidol to rats and to evaluate the efficacy of fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), in ameliorating TD symptoms. The study compared the behavioral and biochemical parameters of rats that were treated with either fluvoxamine, tetrabenazine, haloperidol, or saline (control group). The biochemical parameters of interest included the brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), superoxide dismutase (SOD), and malondialdehyde (MDA). To achieve the study objectives, 32 male Wistar Albino rats were assigned to four different groups. The control group received physiological saline for six weeks. The haloperidol group received 1 mg/kg/ip haloperidol for the first three weeks, followed by two weeks of saline. The haloperidol+fluvoxamine group received 1 mg/kg/ip haloperidol for the first three weeks, followed by 30 mg/kg/ip fluvoxamine. The haloperidol+tetrabenazine group was administered 1 mg/kg/ip haloperidol for the first three weeks, followed by 5 mg/kg/ip tetrabenazine. Behavioral assessments of the rats were performed by measuring vacuous chewing movements. Subsequently, samples were collected from the hippocampus, striatum, and frontal lobe tissues of the rats, and BDNF, NGF, SOD, and MDA levels were measured. The results of the study demonstrated significant differences between the groups with respect to behavioral observations. Furthermore, SOD levels in the hippocampus, as well as BDNF, NGF, and SOD levels in the striatum of the haloperidol+fluvoxamine group were significantly higher than those observed in the haloperidol group. Conversely, MDA levels in the hippocampus were significantly lower in the haloperidol+fluvoxamine group than in the haloperidol group. These findings provide evidence of the beneficial effects of fluvoxamine, acting as a sigma-1 agonist, in treating TD symptoms induced experimentally. The observed benefits were supported by the biochemical investigations performed on brain tissue samples. Therefore, fluvoxamine may be considered as a potential alternative treatment for TD in clinical practice, although further research is needed to corroborate these findings.

L-theanine combination therapy with fluvoxamine in moderate-to-severe obsessive-compulsive disorder: A placebo-controlled, double-blind, randomized trial.

AIM: The main aim of this study was to investigate the additional effects of L-theanine, an amino acid in tea and an analog of glutamate with neuroprotective and anti-depressant properties, on obsessive-compulsive disorder (OCD) symptoms in combination with fluvoxamine. METHODS: Patients from either sex aged between 18 and 60 years diagnosed with OCD, based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), who had a Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score of more than 21 were enrolled in a double-blinded, parallel-group, placebo-controlled, clinical trial of 10 weeks to receive either L-theanine (100 mg twice daily) and fluvoxamine (100 mg daily initially followed by 200 mg daily after week 5) or placebo and fluvoxamine. The primary outcome of interest in this study was the Y-BOCS total score decrease from baseline. RESULTS: From a total of 95 evaluated patients, 50 completed our study; 30 were randomly assigned to each group. Multivariate analysis (ANOVA) showed a significant effect of time × $$ \times $$ treatment for L-theanine in obsession subscale (F = 5.51, P = 0.008) of the Y-BOCS score but not in the total and compulsion scores. Our results showed significantly more improvement in obsession subscale scores in L-theanine compared to placebo group (P = 0.007, Cohen's d = 0.82). Also, total Y-BOCS scores were lower in L-theanine compared to placebo group at week 5 (P = 0.039, Cohen's d = 0.60) and 10 (P = 0.008, Cohen's d = 0.80). However, there was no significant between-group differences in compulsion subscale scores. Complete response was also more frequent in the L-theanine group (P = 0.0001). CONCLUSION: Findings in this study suggest L-theanine as a relatively safe and effective adjuvant therapy for moderate to severe OCD.

Effects of CYP2C19 inhibitors on mavacamten pharmacokinetics in rats based on UPLC-MS/MS.

CONTEXT: CYP2C19 is an important member of the human cytochrome P450 2C (CYP2C) family. Mavacamten is a novel treatment of patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM) which was metabolized mainly by CYP2C19. OBJECTIVE: In this study, we firstly reported and validated a quantitative analysis method of mavacamten in rat plasma based on ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS), which was applied to the drug-drug interaction (DDI) study between mavacamten and CYP2C19 inhibitors (fluvoxamine, fluoxetine and fluconazole) in rats. MATERIALS AND METHODS: Vericiguat was used as the internal standard (IS), and the analyte and IS were measured with electrospray ion (ESI) source in positive ion mode on a XEVO TQ-S triple quadrupole tandem mass spectrometer in multiple reaction monitoring (MRM) mode. RESULTS: In the scope of 1.0-100 ng/mL, this assay had excellent linearity. Both intra-day and inter-day accuracy of the analyte ranged from -2.4% to 9.1%, while the precision was ≤4.2%. Matrix effect, recovery, and stability were evaluated and validated to meet the requirements for the guidelines of bioanalytical assay. When compared with the control group, AUC0→∞ of mavacamten in fluconazole, fluoxetine and fluvoxamine were increased by 125.5%, 110.7% and 43.6%, respectively, which demonstrated that CYP2C19 inhibitors could inhibit mavacamten metabolism. CONCLUSIONS: The results showed that CYP2C19 inhibitors could significantly improve the bioavailability of mavacamten in rats, which indicated that we should pay more attention to the patient's condition to prevent the occurrence of side effects when used mavacamten in combination with CYP2C19 inhibitors.

Effect of fluvoxamine on preventing neuropsychiatric symptoms of post COVID syndrome in mild to moderate patients, a randomized placebo-controlled double-blind clinical trial.

BACKGROUND: Shortly after the Coronavirus disease 2019 (COVID-19) pandemic, a considerable number of recovered patients reported persisting symptoms, especially neuropsychological manifestations, which were later named post-COVID syndrome (PCS). Immune dysregulation was suggested as one of the main mechanisms for PCS. Fluvoxamine, a selective serotonin reuptake inhibitor (SSRI) that is mostly used to treat depression, anxiety disorders, and obsessive-compulsive disorder, has been suggested as an anti-COVID drug due to its anti-inflammatory effects, mainly through the sigma-1 receptor. Therefore, we aimed to evaluate fluvoxamine's effect on PCS neuropsychiatric symptoms. METHOD: In this double-blind randomized clinical trial, we included confirmed mild to moderate COVID-19 outpatients using polymerase chain reaction (PCR) by an infectious disease specialist. The presence of severe COVID-19 symptoms was evaluated by the infectious disease specialist and included dyspnea, SpO2 < 94% on room air, PaO2/FiO2 < 300 mm Hg, a respiratory rate > 30 breaths/min, and lung infiltrates > 50%. Then we performed permuted block randomization and assigned patients 1:1 into two groups to either receive fluvoxamine 100 mg tablet or a placebo daily for 10 days. Eligible patients were evaluated after 12 weeks for the presence of fatigue, as the primary, and other PCS symptoms as secondary outcomes. RESULTS: We screened a total of 486 patients from March to June 2022. After 12 weeks, 42 patients receiving fluvoxamine and 43 patients receiving Placebo were evaluated for PCS. Patients had a mean age of 38.5 ± 14.1 and 48% of them were women. Fatigue was significantly lower in the fluvoxamine group (p-value 0.026). No significant differences were observed in other symptoms. CONCLUSION: We concluded that taking fluvoxamine during active COVID-19 can reduce the chance of fatigue but the advantage of fluvoxamine was not observed for other symptoms. Further studies are necessary to confirm these preliminary results.

Mechanistic Study of Xanthotoxin-Mediated Inactivation of CYP1A2 and Related Drug-Drug Interaction with Tacrine.

Xanthotoxin (XTT) is a biologically active furanocoumarin widely present in foods and plants. The present study is designed to systematically investigate the enzymatic interaction of XTT with CYP1A2, along with pharmacokinetic alteration of tacrine resulting from the co-administration of XTT. The results showed that XTT induced a time-, concentration-, and NADPH-dependent inhibition of CYP1A2, and the inhibition was irreversible. Co-incubation of glutathione (GSH) and catalase/superoxide dismutase was unable to prevent enzyme inactivation. Nevertheless, competitive inhibitor fluvoxamine exhibited a concentration-dependent protective effect against the XTT-induced CYP1A2 inactivation. A GSH trapping experiment provided strong evidence for the production of epoxide or/and γ-ketoenal intermediates resulting from the metabolic activation of XTT. Furthermore, pretreatment of rats with XTT was found to significantly increase the Cmax and area under the curve of plasma tacrine relative to those of tacrine administration alone.

SSRIs differentially modulate the effects of pro-inflammatory stimulation on hippocampal plasticity and memory via sigma 1 receptors and neurosteroids.

Certain selective serotonin reuptake inhibitors (SSRIs) have anti-inflammatory effects in preclinical models, and recent clinical studies suggest that fluvoxamine can prevent deterioration in patients with COVID-19, possibly through activating sigma 1 receptors (S1Rs). Here we examined potential mechanisms contributing to these effects of fluvoxamine and other SSRIs using a well-characterized model of pro-inflammatory stress in rat hippocampal slices. When hippocampal slices are exposed acutely to lipopolysaccharide (LPS), a strong pro-inflammatory stimulus, basal synaptic transmission in the CA1 region remains intact, but induction of long-term potentiation (LTP), a form of synaptic plasticity thought to contribute to learning and memory, is completely disrupted. Administration of low micromolar concentrations of fluvoxamine and fluoxetine prior to and during LPS administration overcame this LTP inhibition. Effects of fluvoxamine required both activation of S1Rs and local synthesis of 5-alpha reduced neurosteroids. In contrast, the effects of fluoxetine did not involve S1Rs but required neurosteroid production. The ability of fluvoxamine to modulate LTP and neurosteroid production was mimicked by a selective S1R agonist. Additionally, fluvoxamine and fluoxetine prevented learning impairments induced by LPS in vivo. Sertraline differed from the other SSRIs in blocking LTP in control slices likely via S1R inverse agonism. These results provide strong support for the hypothesis that S1Rs and neurosteroids play key roles in the anti-inflammatory effects of certain SSRIs and that these SSRIs could be beneficial in disorders involving inflammatory stress including psychiatric and neurodegenerative illnesses.

Potential targets of severe acute respiratory syndrome coronavirus 2 of clinical drug fluvoxamine: Docking and molecular dynamics studies to elucidate viral action.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has continued evolving for survival and adaptation by mutating itself into different variants of concern, including omicron. Several studies and clinical trials found fluvoxamine, an Food and Drug Administration-approved antidepressant drug, to be effective at preventing mild coronavirus disease 2019 (COVID-19) from progressing to severe diseases. However, the mechanism of fluvoxamine's direct antiviral action against COVID-19 is still unknown. Fluvoxamine was docked with 11 SARS-CoV-2 targets and subjected to stability, conformational changes, and binding free energy analyses to explore its mode of action. Of the targets, nonstructural protein 14 (NSP14), main protease (Mpro), and papain-like protease (PLpro) had the best docking scores with fluvoxamine. Consistent with the docking results, it was confirmed by molecular dynamics simulations that the NSP14 N7-MTase ((N7-guanine)-methyltransferase)-fluvoxamine, Mpro-fluvoxamine, and PLpro-fluvoxamine complexes are stable, with the lowest binding free energies of -105.1, -82.7, and - 38.5 kJ/mol, respectively. A number of hotspot residues involved in the interaction were also identified. These include Glu166, Asp187, His41, and Cys145 in Mpro, Gly163 and Arg166 in PLpro, and Glu302, Gly333, and Phe426 in NSP14, which could aid in the development of better antivirals against SARS-CoV-2.

Pediatric considerations for pharmacogenetic selective serotonin reuptake inhibitors clinical decision support.

Pharmacogenetic testing for psychiatry is growing at a rapid pace, with multiple sites utilizing results to help clinical decision-making. Genotype-guided dosing and drug selection have been implemented at several sites, including Vanderbilt University Medical Center, where clinical decision support (CDS) based on pharmacogenetic results went live for selective serotonin reuptake inhibitors in 2020 for both adult and pediatric patients. Effective and appropriate implementation of CYP2D6- and CYP2C19-guided CDS for the pediatric population requires consideration of the evidence for the pharmacogenetic associations, medication indications, and appropriate alternative therapies to be used when a pharmacogenetic contraindication is identified. In this article, we review these pediatric pharmacogenetic considerations for selective serotonin reuptake inhibitor CDS. We include a case study, the current literature supporting clinical recommendations, considerations when designing pediatric CDS, future implications, and examples of sertraline, (es)citalopram, paroxetine, and fluvoxamine alerts.

Tumor necrosis factor-alpha, prostaglandin-E2 and interleukin-1ß targeted anti-arthritic potential of fluvoxamine: drug repurposing.

Fluvoxamine, a selective serotonin re uptake inhibitor, is used to treat depression. The aim of present study was to evaluate fluvoxamine in acute (egg albumin-induced inflammation) and chronic inflammatory rat models (formaldehyde and complete Freund's adjuvant (CFA)-induced arthritis). Fluvoxamine showed highly significant (p<0.001) protective effect at dose of 50 mg/kg orally with percentage suppression 21.3% as compared to disease control group in acute model. Likewise, formaldehyde-induced arthritic experiment confirmed the significant (p<0.001) anti-arthritic behavior, showed by fluvoxamine (50 mg/kg orally) throughout the study. Moreover, In CFA-induced model, the higher dose (fluvoxamine 50 mg/kg) exhibited highly significant (p<0.001) decrease in paw thickness and arthritic score with significant increase in weight of animals from 123.8± 1.934 g to 130.2± 1.655 g, significantly decreased the level of RF and CRP to level of 12.0±0.707 and 11.40±0.50 respectively and restoration of SOD, CAT (69.8±1.5, 72.0±1.4 respectively). Furthermore, the level of TNF-α, PGE2, and IL-1ß (147.0±2.0, 406.8±2.5, and 93.8±1.3 respectively) in arthritic animals was reduced to significant (p<0.001) level (53.8±1.3, 205±3.6, and 42.0±1.4 respectively) after treatment with fluvoxamine. Furthermore, molecular docking of fluvoxamine against TNF-α, PGE2, and IL-1ß protein targets showed good binding energies which hereby from computational studies proves our compound anti-inflammatory potential. In addition, absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies reveled that fluvoxamine has very good pharmacokinetic profile with no specific hepatic toxicity and good absorption level. In addition, the skin sensitization test in vitro human cell line activation test (h-CLAT) and KeratinoSens have revealed that isolated flavone is not skin sensitive with confidence score of 59.6% and 91.6%. The current findings validated the anti-arthritic potential of fluvoxamine but it should be recommended for clinical investigation in future research.

Fluvoxamine prompts the antitumor immune effect via inhibiting the PD-L1 expression on mice-burdened colon tumor.

A colon tumor, one of the digestive tract malignant tumors, is harmful to human health. A potential new treatment still deserves attention. The development of a new drug needs more resources, including time and expense. Therefore, the old drug with new targets has become a current research hotspot. Fluvoxamine, as an antidepressant, could play an effect on inhibiting 5-hydroxytryptamine reuptake. In the present research, the antitumor effects and possible mechanisms of fluvoxamine are validated. The results showed that fluvoxamine significantly suppressed the migration and proliferation of tumor cells, and increased the apoptosis in vitro. Additionally, fluvoxamine significantly delays tumor development, and prompts the apoptosis in tumor tissues of mice-burdened colon tumors in vivo. The tumor suppression might be related with that fluvoxamine inhibits the expression of phosphorylated signal transducer and activator of transcription 3, matrix metalloproteinase 2, and cleaved-caspase 3. Importantly, fluvoxamine significantly reduces the expression level of programmed cell death ligand 1. This could be a possible reason that treatment with fluvoxamine drives the infiltration of T lymphocytes and M1-type macrophages in tumor tissues. Taken together, this research suggests that fluvoxamine might be a promising drug to treat colon cancer by inhibiting the proliferation and migration, inducing apoptosis, and even increasing the immune response of antitumor.

Fluvoxamine for the treatment of COVID-19.

BACKGROUND: Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) that has been approved for the treatment of depression, obsessive-compulsive disorder, and a variety of anxiety disorders; it is available as an oral preparation. Fluvoxamine has not been approved for the treatment of infections, but has been used in the early treatment of people with mild to moderate COVID-19. As there are only a few effective therapies for people with COVID-19 in the community, a thorough understanding of the current evidence regarding the efficacy and safety of fluvoxamine as an anti-inflammatory and possible anti-viral treatment for COVID-19, based on randomised controlled trials (RCTs), is needed. OBJECTIVES: To assess the efficacy and safety of fluvoxamine in addition to standard care, compared to standard care (alone or with placebo), or any other active pharmacological comparator with proven efficacy for the treatment of COVID-19 outpatients and inpatients. SEARCH METHODS: We searched the Cochrane COVID-19 Study Register (including Cochrane Central Register of Controlled Trials, MEDLINE, Embase, ClinicalTrials.gov, WHO ICTRP, medRxiv), Web of Science and WHO COVID-19 Global literature on COVID-19 to identify completed and ongoing studies up to 1 February 2022. SELECTION CRITERIA: We included RCTs that compared fluvoxamine in addition to standard care (also including no intervention), with standard care (alone or with placebo), or any other active pharmacological comparator with proven efficacy in clinical trials for the treatment of people with confirmed COVID-19, irrespective of disease severity, in both inpatients and outpatients. Co-interventions needed to be the same in both study arms. We excluded studies comparing fluvoxamine to other pharmacological interventions with unproven efficacy. DATA COLLECTION AND ANALYSIS: We assessed risk of bias of primary outcomes using the Cochrane Risk of Bias 2 tool for RCTs. We used GRADE to rate the certainty of evidence to treat people with asymptomatic to severe COVID-19 for the primary outcomes including mortality, clinical deterioration, clinical improvement, quality of life, serious adverse events, adverse events of any grade, and suicide or suicide attempt. MAIN RESULTS: We identified two completed studies with a total of 1649 symptomatic participants. One study was conducted in the USA (study with 152 participants, 80 and 72 participants per study arm) and the other study in Brazil (study with 1497 high-risk participants for progression to severe disease, 741 and 756 participants per study arm) among outpatients with mild COVID-19. Both studies were double-blind, placebo-controlled trials in which participants were prescribed 100 mg fluvoxamine two or three times daily for a maximum of 15 days. We identified five ongoing studies and two studies awaiting classification (due to translation issues, and due to missing published data). We found no published studies comparing fluvoxamine to other pharmacological interventions of proven efficacy. We assessed both included studies to have an overall high risk of bias. Fluvoxamine for the treatment of COVID-19 in inpatients We did not identify any completed studies of inpatients. Fluvoxamine for the treatment of COVID-19 in outpatients Fluvoxamine in addition to standard care may slightly reduce all-cause mortality at day 28 (RR 0.69, 95% CI 0.38 to 1.27; risk difference (RD) 9 per 1000; 2 studies, 1649 participants; low-certainty evidence), and may reduce clinical deterioration defined as all-cause hospital admission or death before hospital admission (RR 0.55, 95% CI 0.16 to 1.89; RD 57 per 1000; 2 studies, 1649 participants; low-certainty evidence). We are very uncertain regarding the effect of fluvoxamine on serious adverse events (RR 0.56, 95% CI 0.15 to 2.03; RD 54 per 1000; 2 studies, 1649 participants; very low-certainty evidence) or adverse events of any grade (RR 1.06, 95% CI 0.82 to 1.37; RD 7 per 1000; 2 studies, 1649 participants; very low-certainty evidence). Neither of the studies reported on symptom resolution (clinical improvement), quality of life or suicide/suicide attempt. AUTHORS' CONCLUSIONS: Based on a low-certainty evidence, fluvoxamine may slightly reduce all-cause mortality at day 28, and may reduce the risk of admission to hospital or death in outpatients with mild COVID-19. However, we are very uncertain regarding the effect of fluvoxamine on serious adverse events, or any adverse events. In accordance with the living approach of this review, we will continually update our search and include eligible trials as they arise, to complete any gaps in the evidence.

Comparing the Effects of a Herbal Drug based on Echium Amoenum With Fluvoxamine in the Treatment of Adolescents with Obsessive-compulsive Disorder.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a severe and debilitating neuropsychiatric condition. Although selective serotonin reuptake inhibitors, tricyclic antidepressants, and cognitive- behavioral therapy are the first-line medication and treatment for OCD, an estimated 30% of patients are treatment-resistant, and complete functional recovery is rare. Natural products as adjuvant or alternative therapies should be examined to find safer and more effective ways to manage OCD. OBJECTIVES: To investigate the potential benefits of a combined herbal drug based on Echium amoenum in treating OCD. METHODS: Design and Setting: In the psychiatric clinics of Mashhad University of Medical Sciences, 40 patients who met the criteria for the obsessive-compulsive disorder based on DSM-5 were studied in a parallel, double-blind, randomized clinical trial. INTERVENTION: Subjects were randomly assigned to receive Echium amoenum-Melissa officinalis syrup and fluvoxamine or placebo syrup and fluvoxamine for 8 weeks. OUTCOME MEASURES: The efficacy of treatment and recurrence of disease were surveyed and compared according to the Yale-Brown Obsessive Compulsive Scale at weeks 0, 4, and 8. RESULTS: Evaluation at the 4th and 8th week showed no significant differences between the two groups (p-value = 0.11, p-value = 0.445, respectively). At the 8th week of treatment, patients in the intervention group showed a remarkable reduction in scores on the Yale-Brown Obsessive-Compulsive Scale questionnaire (p- value= 0.003), and patients in the control group didn't ((p- value= 0.180). This study showed that the E.amoneum-M.officinalis syrup was not significantly more efficacious than the fluvoxamine tablet, but the intervention group showed a significant improving trend (p-value= 0.001). CONCLUSION: While monotherapy is usually the gold standard methodology, combination or augmentation therapy may also be of merit. Consequently, studies with larger sample sizes and the inclusion of para-clinical assessments such as serologic tests can further shed light on the mechanism of action of the E. amoneum- M. officinalis syrup and deepen our understanding of its effects.