RESUMEN
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.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Astrocitos , Autofagia , Modelos Animales de Enfermedad , Fluvoxamina , Ratones Transgénicos , Proteína con Dominio Pirina 3 de la Familia NLR , Enfermedades Neuroinflamatorias , Animales , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Ratones , Fluvoxamina/farmacología , Fluvoxamina/uso terapéutico , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Autofagia/efectos de los fármacos , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Inflamasomas/metabolismo , Inflamasomas/efectos de los fármacosRESUMEN
The RSCI and PubMed search databases have requested publications over the past 40 years on the search queries «fluvoxamine¼, «anxiety-depressive disorders¼, «anxiety¼, «depression¼, «comorbidity¼, devoted to the effectiveness of fluvoxamine in various variants of disorders of the anxiety-depressive spectrum, anxiety depressions. The data of the above studies indicate that fluvoxamine (Zovart San) in doses of 50-300 mg / day is a highly effective remedy for the treatment of not only anxiety depressions and genesis (psychogenic, organic, mixed, autochthonous-endogenous) and severity (up to psychotic), but also a wider range of anxiety-depressive disorders, including adaptation disorders, obsessive-compulsive disorder, somatized, dysmorphic, insomniac symptom complexes and eating disorders. A wide range of clinical effects of fluvoxamine is due to its main and additional mechanisms of action: blockade of serotonin reuptake, σ1-agonist activity and the effect on the metabolism of melatonin and neurosteroids catabolism.
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Trastornos de Ansiedad , Trastorno Depresivo , Fluvoxamina , Fluvoxamina/uso terapéutico , Humanos , Trastornos de Ansiedad/tratamiento farmacológico , Trastorno Depresivo/tratamiento farmacológico , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéuticoRESUMEN
There have been 774,075,242 cases of COVID-19 and 7,012,986 deaths worldwide as of January 2024. In the early stages of the pandemic, there was an urgent need to reduce the severity of the disease and prevent the need for hospitalization to avoid stress on healthcare systems worldwide. The repurposing of drugs to prevent clinical deterioration of COVID-19 patients was trialed in many studies using many different drugs. Fluvoxamine (an SSRI and sigma-1 receptor agonist) was initially identified to potentially provide beneficial effects in COVID-19-infected patients, preventing clinical deterioration and the need for hospitalization. Fourteen clinical studies have been carried out to date, with seven of those being randomized placebo-controlled studies. This systematic review and meta-analysis covers the literature from the outbreak of SARS-CoV-2 in late 2019 until January 2024. Search terms related to fluvoxamine, such as its trade names and chemical names, along with words related to COVID-19, such as SARS-CoV-2 and coronavirus, were used in literature databases including PubMed, Google Scholar, Scopus, and the ClinicalTrials.gov database from NIH, to identify the trials used in the subsequent analysis. Clinical deterioration and death data were extracted from these studies where available and used in the meta-analysis. A total of 7153 patients were studied across 14 studies (both open-label and double-blind placebo-controlled). 681 out of 3553 (19.17%) in the standard care group and 255 out of 3600 (7.08%) in the fluvoxamine-treated group experienced clinical deterioration. The estimated average log odds ratio was 1.087 (95% CI 0.200 to 1.973), which differed significantly from zero (z = 2.402, p = 0.016). The seven placebo-controlled studies resulted in a log odds ratio of 0.359 (95% CI 0.1111 to 0.5294), which differed significantly from zero (z = 3.103, p = 0.002). The results of this study identified fluvoxamine as effective in preventing clinical deterioration, and subgrouping analysis suggests that earlier treatment with a dose of 200 mg or above provides the best outcomes. We hope the outcomes of this study can help design future studies into respiratory viral infections and potentially improve clinical outcomes.
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Tratamiento Farmacológico de COVID-19 , COVID-19 , Fluvoxamina , SARS-CoV-2 , Fluvoxamina/uso terapéutico , Humanos , COVID-19/mortalidad , SARS-CoV-2/aislamiento & purificación , SARS-CoV-2/efectos de los fármacos , Resultado del Tratamiento , Deterioro Clínico , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversos , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificaciónRESUMEN
BACKGROUND: Recently, several randomized controlled trials (RCTs) of fluvoxamine have been successfully conducted for the treatment of patients with coronavirus disease 2019 (COVID-19). This systematic review and meta-analysis was to evaluate the efficacy and safety of fluvoxamine in patients with COVID-19. METHODS: MEDLINE, EMBASE, Cochrane Library and clinicaltrials.gov were searched for RCTs which were performed to evaluate fluvoxamine and placebo up to January 31, 2024. Review Manager 5.3 was used to perform meta-analysis. The risk ratio (RR) and mean difference (MD) was analyzed and calculated with a random effect model. RESULTS: We pooled 4,711 participants from six RCTs (2,382 in the fluvoxamine group and 2,329 in the placebo group). Compared to the placebo group, the fluvoxamine group had a significantly lower rate of clinical deterioration (RR, 0.73; P = 0.004; 95% CI, 0.59 to 0.90; I2 = 0%) and hospitalization (RR, 0.76; P = 0.04; 95% CI, 0.59 to 0.99; I2 = 0%). In the meantime, compared with the placebo group, fluvoxamine group did not show any higher risk of AEs (P = 0.13 and 0.91, respectively) in safety outcomes analysis. The subgroup analysis showed that fluvoxamine treatment performed more than 200 mg daily appears to be more effective than those performed less than 200 mg daily in reducing clinical deterioration and hospitalization risks, while not exhibiting higher AE and SAE risks than placebo group. CONCLUSION: Fluvoxamine for patients with COVID-19, especially those who take 200 mg or more daily, is superior to the placebo group in reducing clinical deterioration and hospitalization, and did not show any higher risk of AEs and SAEs in safety concerns, which might be a promising intervention for COVID-19.
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Tratamiento Farmacológico de COVID-19 , COVID-19 , Fluvoxamina , Ensayos Clínicos Controlados Aleatorios como Asunto , SARS-CoV-2 , Fluvoxamina/uso terapéutico , Fluvoxamina/efectos adversos , Humanos , Resultado del Tratamiento , HospitalizaciónRESUMEN
OBJECTIVE: To examine the long-term safety and tolerability of off-label high-dose serotonin reuptake inhibitors (OLHD-SRIs) in the treatment of obsessive-compulsive disorder (OCD). METHODS: A retrospective longitudinal study was performed on 105 randomly selected outpatients diagnosed with OCD and were treated with OLHD-SRIs for at least 6 months. Patients received sertraline >200 mg/day, escitalopram >20 mg/day, fluvoxamine >300 mg/day, and fluoxetine >60 mg/day, combined with exposure and response prevention therapy. Patients were divided into three dosing groups: sertraline equivalent dose (SED) ≤ 200 mg/day (n = 26, 24.7%), 201-400 mg/day (n = 51, 48.5%) and 401-650 mg/day (n = 28, 26.6%). Safety and tolerability were assessed with an electrocardiogram, blood biochemistry, complete blood count, and side-effects monitoring. RESULTS: SED ranged from 100 to 650 mg/day and the mean duration of OLHD-SRI treatment was 20.8 months. The most common side-effects reported were sexual dysfunction (n = 36, 34%), weight gain (n = 28, 27%), sedation (n = 27, 26%), hyperhidrosis (n = 20, 19%), and tremor (n = 11, 10%). Abnormal ECG was documented in one patient, and another patient experienced a first-time seizure, whereas elevated liver enzymes were seen in 4.8% of the sample (n = 5). None of the patients had serotonin syndrome or drug-induced liver injury. Side-effects did not differ among the three dosing groups. CONCLUSION: OLHD-SRIs appear to be safe and well tolerated in OCD patients in SED ≤ 650 mg/day doses and the side-effects did not differ between the three dosing groups.
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Fluvoxamina , Trastorno Obsesivo Compulsivo , Uso Fuera de lo Indicado , Inhibidores Selectivos de la Recaptación de Serotonina , Sertralina , Humanos , Trastorno Obsesivo Compulsivo/tratamiento farmacológico , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversos , Femenino , Adulto , Masculino , Estudios Retrospectivos , Fluvoxamina/uso terapéutico , Fluvoxamina/administración & dosificación , Fluvoxamina/efectos adversos , Sertralina/uso terapéutico , Sertralina/administración & dosificación , Sertralina/efectos adversos , Persona de Mediana Edad , Estudios Longitudinales , Fluoxetina/uso terapéutico , Fluoxetina/administración & dosificación , Fluoxetina/efectos adversos , Escitalopram/uso terapéutico , Escitalopram/administración & dosificación , Adulto Joven , Resultado del Tratamiento , Relación Dosis-Respuesta a DrogaRESUMEN
Cisplatin use is often limited by its ototoxic side effects, which can lead to irreversible hearing loss. Preventing cisplatin-induced ototoxicity is crucial to improve patient outcomes. Fluoxetine and fluvoxamine, both selective serotonin reuptake inhibitors antidepressants, inhibit the NLR pyrin domain-containing protein 3 inflammasome, a potential therapeutic target for preventing ototoxicity. However, human studies have not evaluated if these antidepressants may protect against cisplatin-induced ototoxicity. The object of this study is to assess the association between fluoxetine or fluvoxamine use and incidence of hearing loss or tinnitus in a large cohort of patients receiving cisplatin chemotherapy. We use a retrospective cohort study within the U.S. Department of Veterans Affairs healthcare system. Adult patients with cancer who received cisplatin chemotherapy between 2000 and 2023 are included. Incidence of ototoxicity, defined by international classification of diseases revision 9-CM or international classification of diseases revision 10-CM diagnoses of hearing loss or tinnitus is compared between concurrent use of fluoxetine or fluvoxamine and cisplatin alone. A total of 20,552 patients were included. Of those, 489 received cisplatin and fluoxetine or fluvoxamine. After propensity score adjustment, the hazard of ototoxicity was lower in the group receiving fluoxetine or fluvoxamine compared to the group receiving cisplatin alone (HR = 0.62, 95% CI = (0.41-0.94)). Fluoxetine or fluvoxamine use may be associated with a reduced risk of cisplatin-induced ototoxicity. Randomized clinical trials are needed to confirm these findings and establish the efficacy of the medications in ototoxicity prevention. Further research is also warranted to investigate the potential mechanisms underlying this protective effect.
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Cisplatino , Fluoxetina , Fluvoxamina , Pérdida Auditiva , Acúfeno , Humanos , Cisplatino/efectos adversos , Pérdida Auditiva/inducido químicamente , Estudios Retrospectivos , Masculino , Acúfeno/inducido químicamente , Femenino , Fluoxetina/efectos adversos , Fluoxetina/uso terapéutico , Persona de Mediana Edad , Fluvoxamina/efectos adversos , Fluvoxamina/uso terapéutico , AncianoRESUMEN
BACKGROUND: Clozapine is unique in its capacity to ameliorate severe schizophrenia but at high risk of toxicity. A relationship between blood concentration and clinical response and evidence for concentration-response relationships to some adverse effects justify therapeutic drug monitoring of clozapine. However, the relationship between drug dose and blood concentration is quite variable. This variability is, in part, due to inductive and inhibitory interactions varying the activity of cytochrome P450 1A2 (CYP1A2), the principal pathway for clozapine elimination. Several population pharmacokinetic models have been presented to facilitate dose selection and to identify poor adherence in individual patients. These models have faced little testing for validity in independent populations or even for persisting validity in the source population. METHODS: Therefore, we collected a large population of clozapine-treated patients (127 patients, 1048 timed plasma concentrations) in whom dosing and covariate information could be obtained with high certainty. A population pharmacokinetic model was constructed with data collected in the first 6 weeks from study enrolment (448 plasma concentrations), to estimate covariate influences and to allow alignment with previously published models. The model was tested for its performance in predicting the concentrations observed at later time intervals up to 5 years. The predictive performances of 6 published clozapine population models were then assessed in the entire population. RESULTS: The population pharmacokinetic model based on the first 6 weeks identified significant influences of sex, smoking, and cotreatment with fluvoxamine on clozapine clearance. The model built from the first 6 weeks had acceptable predictive performance in the same patient population up to the first 26 weeks using individual parameters, with a median predictive error (PE) of -0.1% to -15.9% and median absolute PE of 22.9%-27.1%. Predictive performance fell progressively with time after 26 weeks. Bayesian addition of plasma concentration observations within each prediction period improved individual predictions. Three additional observations extended acceptable predictive performance into the second 6 months of therapy. When the published models were tested with the entire data set, median PE ranged from -8% to +35% with a median absolute PE of >39% in all models. Thus, none of the tested models was successful in external validation. Bayesian addition of single patient observations improved individual predictions from all models but still without achieving acceptable performances. CONCLUSIONS: We conclude that the relationship between covariates and blood clozapine concentrations differs between populations and that relationships are not stable over time within a population. Current population models for clozapine are not capturing influential covariates.
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Antipsicóticos , Clozapina , Esquizofrenia , Humanos , Clozapina/uso terapéutico , Teorema de Bayes , Esquizofrenia/tratamiento farmacológico , Fluvoxamina/uso terapéutico , Antipsicóticos/farmacocinéticaRESUMEN
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.
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Enfermedades Autoinmunes , Diabetes Mellitus Tipo 1 , Ratones , Humanos , Animales , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Ratones Endogámicos NOD , Fluvoxamina/farmacología , Fluvoxamina/uso terapéutico , Células Th17 , Fosfatidilinositol 3-Quinasas , Células TH1RESUMEN
OBJECTIVE: To identify the frequency of administration of fluvoxamine, to determine the main targets of the drug and the expediency of its use in depression of various genesis in children and adolescents. MATERIAL AND METHODS: To assess the frequency of prescribing fluvoxamine, 195 medical histories of patients who were inpatients in the children's department of the Mental Health Research Center in 2023 were analyzed. To assess the dynamics of depression during treatment with fluvoxamine, a clinical group was formed of 12 patients aged 10 to 15 years (age 13.1±3.6 years) who received fluvoxamine for the treatment of depression with comorbid obsessive-compulsive and anxiety-phobic disorders. Clinical and psychopathological, psychometric (Hamilton Depression Rating Scale - HDRS) and statistical research methods were used. RESULTS: In total, in 2023, fluvoxamine was received by 20% (n=37) of all inpatient patients of child age (from 7 to 16 years). All patients received combination therapy. The therapeutic targets were comorbid depressive, obsessive-compulsive and anxiety symptoms developing in the structure of nosologically heterogeneous states, with the dominance of schizophrenic spectrum disorders. Against the background of the use of the drug fluvoxamine for 4 weeks in the clinical group, there was a significant reduction in depressive symptoms on the HDRS. Adverse events during complex therapy were observed in 20% of patients, but were not severe, did not require discontinuation of therapy and were unreliably associated with the use of fluvoxamine. CONCLUSION: The use of the fluvoxamine provides reduction of depressive symptoms within the framework of various nosologies, and is characterized by sufficient safety. The variety of therapeutic targets of the fluvoxamine, including antidepressant, anti-anxiety, cognitive effects, is certainly a significant advantage of the studied fluvoxamine for use in childhood.
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Fluvoxamina , Esquizofrenia , Niño , Humanos , Adolescente , Fluvoxamina/uso terapéutico , Antidepresivos/uso terapéutico , Trastornos de Ansiedad/tratamiento farmacológico , Trastornos de Ansiedad/epidemiología , Esquizofrenia/tratamiento farmacológico , Terapia CombinadaRESUMEN
Importance: The effect of higher-dose fluvoxamine in reducing symptom duration among outpatients with mild to moderate COVID-19 remains uncertain. Objective: To assess the effectiveness of fluvoxamine, 100 mg twice daily, compared with placebo, for treating mild to moderate COVID-19. Design, Setting, and Participants: The ACTIV-6 platform randomized clinical trial aims to evaluate repurposed medications for mild to moderate COVID-19. Between August 25, 2022, and January 20, 2023, a total of 1175 participants were enrolled at 103 US sites for evaluating fluvoxamine; participants were 30 years or older with confirmed SARS-CoV-2 infection and at least 2 acute COVID-19 symptoms for 7 days or less. Interventions: Participants were randomized to receive fluvoxamine, 50 mg twice daily on day 1 followed by 100 mg twice daily for 12 additional days (n = 601), or placebo (n = 607). Main Outcomes and Measures: The primary outcome was time to sustained recovery (defined as at least 3 consecutive days without symptoms). Secondary outcomes included time to death; time to hospitalization or death; a composite of hospitalization, urgent care visit, emergency department visit, or death; COVID-19 clinical progression scale score; and difference in mean time unwell. Follow-up occurred through day 28. Results: Among 1208 participants who were randomized and received the study drug, the median (IQR) age was 50 (40-60) years, 65.8% were women, 45.5% identified as Hispanic/Latino, and 76.8% reported receiving at least 2 doses of a SARS-CoV-2 vaccine. Among 589 participants who received fluvoxamine and 586 who received placebo included in the primary analysis, differences in time to sustained recovery were not observed (adjusted hazard ratio [HR], 0.99 [95% credible interval, 0.89-1.09]; P for efficacy = .40]). Additionally, unadjusted median time to sustained recovery was 10 (95% CI, 10-11) days in both the intervention and placebo groups. No deaths were reported. Thirty-five participants reported health care use events (a priori defined as death, hospitalization, or emergency department/urgent care visit): 14 in the fluvoxamine group compared with 21 in the placebo group (HR, 0.69 [95% credible interval, 0.27-1.21]; P for efficacy = .86) There were 7 serious adverse events in 6 participants (2 with fluvoxamine and 4 with placebo) but no deaths. Conclusions and Relevance: Among outpatients with mild to moderate COVID-19, treatment with fluvoxamine does not reduce duration of COVID-19 symptoms. Trial Registration: ClinicalTrials.gov Identifier: NCT04885530.
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COVID-19 , Humanos , Femenino , Persona de Mediana Edad , Masculino , Fluvoxamina/uso terapéutico , SARS-CoV-2 , Pacientes Ambulatorios , Vacunas contra la COVID-19 , Resultado del Tratamiento , Tratamiento Farmacológico de COVID-19 , Método Doble CiegoRESUMEN
BACKGROUND: Fluvoxamine (FVX) has been proposed as a potential treatment for severe COVID-19 by the σ-1 receptor agonist, which can reduce cytokine production. However, the efficacy of FVX remains controversial. METHODS: A historical retrospective cohort study was conducted in mild to moderate COVID-19 patients, 2:1 ratio of standard of care (SOC) and FVX treatments to assess the effectiveness of FVX in preventing deterioration by the fifth day of treatment. RESULTS: Of 752 eligible patients, 234 received FVX while 518 received SOC, and there was no significant difference in the effectiveness of FVX and SOC in preventing clinical deterioration. On the fifth day after treatment, 86.1 % of patients in the FVX-treated group did not experience clinical deterioration compared to 78.7 % in the SOC group. Notably, the FVX group had higher rates of pneumonia development and hospitalization, requiring more oxygen supplementation while showing less reduction in viral shedding than the SOC group. However, no difference in mechanical ventilation use, ICU admission, and survival was observed. CONCLUSION: Fluvoxamine treatment is failed to demonstrate effectiveness in preventing deterioration in mild to moderate COVID-19 and may lead to a higher incidence of pneumonia, hospitalization, and oxygen supplementation, necessitating careful consideration before prescribing the drug for COVID-19.
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COVID-19 , Deterioro Clínico , Humanos , Fluvoxamina/uso terapéutico , SARS-CoV-2 , Estudios de Cohortes , Estudios Retrospectivos , Tratamiento Farmacológico de COVID-19RESUMEN
Nebivolol is a beta-1 receptor blocker used to treat hypertension, heart failure, erectile dysfunction, vascular disease, and diabetes mellitus. This review investigated the data regarding pharmacokinetic (PK) parameters, drug-drug interactions, dextrorotatory (D), and levorotatory (L) stereoisomers of nebivolol. The articles related to the PK of nebivolol were retrieved by searching the five databases; Google Scholar, PubMed, Cochrane Library, ScienceDirect, and EBSCO. A total of 20 studies comprising plasma concentration-time profile data following the nebivolol's oral and intravenous (IV) administration were included. The area under the concentration-time curve from zero to infinity (AUC0-∞) was 15 times greater in poor metabolizers (PMs) than in extensive metabolizers (EMs). In hypertensive patients, L-nebivolol expressed a higher maximum plasma concentration (Cmax) than D-nebivolol, i.e. 2.5 ng/ml vs 1.2 ng/ml. The AUC0-∞ of nebivolol was 3-fold greater in chronic kidney disease (CKD). The clearance (CL) was increased in obese than in controls from 51.6 ± 11.6 L/h to 71.6 ± 17.4 L/h when 0.5 mg/ml IV solution was infused. Nebivolol showed higher Cmax, AUC0-∞ and half-life (t1/2) when co-administered with bupropion, duloxetine, fluvoxamine, paroxetine, lansoprazole, and fluoxetine. This concise review of nebivolol would be advantageous in assessing all PK parameters, which may be crucial for clinicians to avoid drug-drug interactions, prevent adverse drug events and optimize the dosage regimen in diseased patients diagnosed with hypertension and cardiovascular disorders.
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Hipertensión , Masculino , Humanos , Nebivolol/farmacocinética , Nebivolol/uso terapéutico , Hipertensión/tratamiento farmacológico , Fluvoxamina/uso terapéutico , Lansoprazol/uso terapéutico , Interacciones FarmacológicasRESUMEN
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.
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Trastorno Obsesivo Compulsivo , Triterpenos , Ratas , Animales , Factor 2 Relacionado con NF-E2/metabolismo , Fluvoxamina/farmacología , Fluvoxamina/uso terapéutico , 8-Hidroxi-2-(di-n-propilamino)tetralin/uso terapéutico , Trastorno Obsesivo Compulsivo/inducido químicamente , Trastorno Obsesivo Compulsivo/tratamiento farmacológico , Trastorno Obsesivo Compulsivo/metabolismo , Corteza Cerebral/metabolismo , Triterpenos/farmacología , Plasma/metabolismoRESUMEN
OBJECTIVES: Fluvoxamine (FVX) is an antidepressant proposed to its immunomodulatory effects in preventing deterioration in mild and moderate COVID-19. METHODS: An open-label, 1:1 randomized controlled trial was assigned either combination therapy 50 mg twice daily of FVX for 10 days and favipiravir (FPV) or FPV alone to assess the efficacy in preventing disease progression in mild to moderate COVID-19 on the 5th day. RESULTS: In total, 134 patients with mild COVID-19 received FPV and 132 received FVX/FPV, 31 patients with moderate COVID-19 received FPV/dexamethasone (FPV/Dex), and 30 received FVX/FPV/Dex. The intention-to-treat (ITT) analysis showed no difference of no clinical deterioration on the 5th day in both mild COVID-19 (100% in FPV vs 97% in FVX/FPV) and moderate COVID-19 (83.9% in FPV/Dex vs 86.7% in FVX/FPV/Dex). However, there was a low rate of oxygen supplemental, hospitalization, or intensive care in both groups and zero death in all groups. No significant difference in oxygen supplemental, hospitalization, radiological, virological, or biochemical outcomes, and the immunomodulatory effect was observed between the group. CONCLUSION: The combined fluvoxamine treatment did not add benefit in preventing deterioration in patients with mild to moderate COVID-19 without the immunomodulatory effect observed, although it demonstrated low hospitalization rates, oxygen supplemental, intensive care needed, and zero mortality. TRIAL REGISTRATION: Thai clinical trials registry (TCTR) no. 20210615002.
Asunto(s)
COVID-19 , Humanos , Fluvoxamina/uso terapéutico , SARS-CoV-2 , Tratamiento Farmacológico de COVID-19 , Resultado del Tratamiento , Antivirales/uso terapéuticoRESUMEN
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.
Asunto(s)
Antipsicóticos , Discinesias , Discinesia Tardía , Ratas , Masculino , Animales , Discinesia Tardía/inducido químicamente , Discinesia Tardía/tratamiento farmacológico , Haloperidol/farmacología , Fluvoxamina/farmacología , Fluvoxamina/uso terapéutico , Factor Neurotrófico Derivado del Encéfalo , Tetrabenazina/farmacología , Tetrabenazina/uso terapéutico , Ratas Wistar , Factor de Crecimiento Nervioso , Antipsicóticos/uso terapéutico , Discinesias/tratamiento farmacológico , Superóxido Dismutasa/metabolismoRESUMEN
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.
Asunto(s)
Fluvoxamina , Trastorno Obsesivo Compulsivo , Humanos , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Fluvoxamina/farmacología , Fluvoxamina/uso terapéutico , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Quimioterapia Combinada , Trastorno Obsesivo Compulsivo/tratamiento farmacológico , Glutamatos/farmacología , Glutamatos/uso terapéutico , Método Doble Ciego , Resultado del TratamientoRESUMEN
SOURCE CITATION: McCarthy MW, Naggie S, Boulware DR, et al. Effect of fluvoxamine vs placebo on time to sustained recovery in outpatients with mild to moderate COVID-19: a randomized clinical trial. JAMA. 2023;329:296-305. 36633838.