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1.
Molecules ; 26(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201675

RESUMO

The complex pathophysiology of depression, together with the limits of currently available antidepressants, has resulted in the continuous quest for alternative therapeutic strategies. Numerous findings suggest that pharmacological blockade of α2-adrenoceptor might be beneficial for the treatment of depressive symptoms by increasing both norepinephrine and serotonin levels in certain brain areas. Moreover, the antidepressant properties of 5-HT7 receptor antagonists have been widely demonstrated in a large set of animal models. Considering the potential therapeutic advantages in targeting both α2-adrenoceptors and 5-HT7 receptors, we designed a small series of arylsulfonamide derivatives of (dihydrobenzofuranoxy)ethyl piperidines as dually active ligands. Following green chemistry principles, the designed compounds were synthesized entirely using a sustainable mechanochemical approach. The identified compound 8 behaved as a potent α2A/5-HT7 receptor antagonist and displayed moderate-to-high selectivity over α1-adrenoceptor subtypes and selected serotonin and dopaminergic receptors. Finally, compound 8 improved performance of mice in the forced swim test, displaying similar potency to the reference drug mirtazapine.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 2/química , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Atividade Motora/efeitos dos fármacos , Receptores Adrenérgicos alfa 2/metabolismo , Receptores de Serotonina/metabolismo , Antagonistas de Receptores Adrenérgicos alfa 2/síntese química , Antagonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Animais , Antidepressivos/uso terapêutico , Escala de Avaliação Comportamental , Depressão/fisiopatologia , Células HEK293 , Humanos , Ligantes , Masculino , Camundongos , Mirtazapina/farmacologia , Mirtazapina/uso terapêutico , Norepinefrina/metabolismo , Piperidinas/química , Ratos , Receptores de Serotonina/genética , Serotonina/metabolismo , Natação
2.
Expert Rev Clin Pharmacol ; 14(8): 1039-1050, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34030558

RESUMO

OBJECTIVES: This study was conducted to evaluate the potential nephroprotective effects of febuxostat, mirtazapine, and their combination against gentamicin-induced nephrotoxicity. METHODS: Induction of nephrotoxicity was achieved via gentamicin injection (100 mg/kg, I.P., for 7 days). Two different doses of mirtazapine (15-30 mg/kg), febuxostat (5-10 mg/kg), and their combination were administered daily for 14 days prior to gentamicin injection and then concomitantly with gentamicin for additional 7 days. Nephrotoxicity was evaluated histopathologically and biochemically. Renal caspase-3, extracellular signal-regulated protein kinase 1/2 (ERK1/2), nuclear factor-kappa-ß (NF-κß), and monocyte chemoattractant protein (MCP-1) were assayed. RESULTS: Febuxostat and mirtazapine significantly (p < 0.05) alleviated biochemical and histopathological alterations that were induced by gentamicin and, for the first time, significantly decreased the renal levels of ERK1/2 and MCP-1. Conclusion: Febuxostat and mirtazapine were found to have a synergistic impact in reducing gentamicin-induced nephrotoxicity. EXPERT OPINION: The utility of nonpurine xanthine oxidase inhibitor, such as febuxostat and mirtazapine are offering a new potential opportunity for the future nephroprotective effects therapy: Febuxostat and mirtazapine are found to have a synergistic impact in reducing gentamicin-induced nephrotoxicity.


Assuntos
Febuxostat/farmacologia , Gentamicinas/toxicidade , Nefropatias/prevenção & controle , Mirtazapina/farmacologia , Animais , Antibacterianos/administração & dosagem , Antibacterianos/toxicidade , Antidepressivos/administração & dosagem , Antidepressivos/farmacologia , Quimiocina CCL2/metabolismo , Sinergismo Farmacológico , Febuxostat/administração & dosagem , Gentamicinas/administração & dosagem , Supressores da Gota/administração & dosagem , Supressores da Gota/farmacologia , Nefropatias/induzido quimicamente , Masculino , Mirtazapina/administração & dosagem , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , NF-kappa B/metabolismo , Ratos
3.
Sci Rep ; 10(1): 20698, 2020 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-33244123

RESUMO

Mirtazapine, a noradrenergic and specific serotonergic antidepressant (NaSSA), is known to activate serotonin (5-HT) 1A receptor. Our recent study demonstrated that stimulation of astrocytic 5-HT1A receptors promoted astrocyte proliferation and upregulated antioxidative property in astrocytes to protect dopaminergic neurons against oxidative stress. Here, we evaluated the neuroprotective effects of mirtazapine against dopaminergic neurodegeneration in models of Parkinson's disease (PD). Mirtazapine administration attenuated the loss of dopaminergic neurons in the substantia nigra and increased the expression of the antioxidative molecule metallothionein (MT) in the striatal astrocytes of 6-hydroxydopamine (6-OHDA)-injected parkinsonian mice via 5-HT1A receptors. Mirtazapine protected dopaminergic neurons against 6-OHDA-induced neurotoxicity in mesencephalic neuron and striatal astrocyte cocultures, but not in enriched neuronal cultures. Mirtazapine-treated neuron-conditioned medium (Mir-NCM) induced astrocyte proliferation and upregulated MT expression via 5-HT1A receptors on astrocytes. Furthermore, treatment with medium from Mir-NCM-treated astrocytes protected dopaminergic neurons against 6-OHDA neurotoxicity, and these effects were attenuated by treatment with a MT-1/2-specific antibody or 5-HT1A antagonist. Our study suggests that mirtazapine could be an effective disease-modifying drug for PD and highlights that astrocytic 5-HT1A receptors may be a novel target for the treatment of PD.


Assuntos
Astrócitos/efeitos dos fármacos , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Mirtazapina/farmacologia , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Animais , Antioxidantes/farmacologia , Astrócitos/metabolismo , Células Cultivadas , Neurônios Dopaminérgicos/metabolismo , Feminino , Masculino , Metalotioneína/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Estresse Oxidativo/efeitos dos fármacos , Oxidopamina/farmacologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Gravidez , Ratos Sprague-Dawley , Receptor 5-HT1A de Serotonina/metabolismo , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo
4.
Front Immunol ; 11: 578654, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33250892

RESUMO

Background and Aims: Mirtazapine is an atypical antidepressant with antagonist activity for serotonin and histamine receptors. Clinical and experimental evidence suggests that, in addition to treating depression, mirtazapine also alters liver innate immunity and suppresses immune-driven hepatic macrophage activation. Liver macrophages, Kupffer cells, represent the largest collection of fixed macrophages in the body and are critical in regulating hepatic immunity. In addition to their capacity to regulate inflammation, Kupffer cells are key sentinels for clearing blood-borne pathogens, preventing their dissemination within the body. This process involves pathogen capture, phagocytosis, and activation-induced killing via reactive oxygen species (ROS) production. Therefore, we speculated that mirtazapine might adversely alter Kupffer cell pathogen-associated activation and killing. Methods: Mice were treated with mirtazapine and time-dependent changes in Kupffer cells were characterized using intravital microscopy. Macrophage and neutrophil responses, bacterial dissemination, and liver damage were assessed following i.v. infection with a pathogenic strain of S. aureus. Results: Mirtazapine rapidly (within 1.5 h) activates Kupffer cells, indicated by a loss of elongated shape with cellular rounding. However, this shape change did not result in impaired pathogen capture function, and, in fact, generated enhanced ROS production in response to S. aureus-induced sepsis. Neutrophil dynamics were altered with reduced cellular recruitment to the liver following infection. Bacterial dissemination post-intravenous administration was not altered by mirtazapine treatment; however, hepatic abscess formation was significantly reduced. Conclusions: Mirtazapine rapidly activates Kupffer cells, associated with preserved bacterial capture functions and enhanced ROS generation capacity. Moreover, these changes in Kupffer cells were linked to a beneficial reduction in hepatic abscess size. In contrast to our initial speculation, mirtazapine may have beneficial effects in sepsis and warrants further exploration.


Assuntos
Antidepressivos/farmacologia , Macrófagos do Fígado/efeitos dos fármacos , Abscesso Hepático/tratamento farmacológico , Fígado/efeitos dos fármacos , Ativação de Macrófagos/efeitos dos fármacos , Mirtazapina/farmacologia , Fagocitose/efeitos dos fármacos , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/patogenicidade , Animais , Modelos Animais de Doenças , Interações Hospedeiro-Patógeno , Macrófagos do Fígado/metabolismo , Macrófagos do Fígado/microbiologia , Fígado/metabolismo , Fígado/microbiologia , Fígado/patologia , Abscesso Hepático/metabolismo , Abscesso Hepático/microbiologia , Abscesso Hepático/patologia , Camundongos Endogâmicos C57BL , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Neutrófilos/microbiologia , Espécies Reativas de Oxigênio/metabolismo , Infecções Estafilocócicas/metabolismo , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/patologia , Fatores de Tempo
5.
J Clin Psychiatry ; 81(6)2020 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-33084254

RESUMO

OBJECTIVE: The aim of this study was to determine the efficacy of mirtazapine, a tetracyclic antidepressant, as monotherapy for the treatment of posttraumatic stress disorder (PTSD). METHODS: This multisite, randomized, double-blind, placebo-controlled trial was conducted between April 2006 and November 2010 at the Tuscaloosa and Birmingham Veterans Affairs Medical Centers in Alabama. US military veterans who met DSM-IV criteria for PTSD were randomly assigned to placebo (n = 39) or mirtazapine (n = 39) titrated up to 45 mg/d for an 8-week double-blind period followed by an 8-week open-label phase of mirtazapine treatment. The primary outcome efficacy measure was the Structured Interview for Posttraumatic Stress Disorder (SIP). Secondary measures included other measures of PTSD, depression, and sleep. Analyses of treatment groups involved mixed-model procedures using a random intercept to test the hypotheses that mirtazapine would be more effective than placebo in reducing symptoms of PTSD and depression and improving quality of sleep. RESULTS: Seventy-eight participants were randomized with 61 completing the 8-week controlled phase and 48 completing the open-label phase. No significant differences were observed between groups on the primary outcome of SIP scores during the controlled phase (P = .418). In secondary outcomes, significant improvements per the Clinical Global Impressions-Improvement scale were found for the mirtazapine group compared to the placebo group (P = .041). The 8-week open-label phase demonstrated significant symptom improvement in SIP total score (P = .0003) and in scores on the SIP re-experiencing (P = .0007), avoidance (P = .0309), and hyperarousal (P = .0014) subscales. There were no significant differences in the occurrence of adverse events between groups. CONCLUSIONS: This study did not show efficacy of mirtazapine monotherapy in the treatment of PTSD. Identification of more effective treatments, either as monotherapy or adjunctive, for PTSD is imperative. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00302107.


Assuntos
Antidepressivos/farmacologia , Mirtazapina/farmacologia , Avaliação de Resultados em Cuidados de Saúde , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Adulto , Antidepressivos/administração & dosagem , Antidepressivos/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mirtazapina/administração & dosagem , Mirtazapina/efeitos adversos , Estados Unidos , United States Department of Veterans Affairs , Veteranos
6.
Horm Behav ; 125: 104817, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32682854

RESUMO

BACKGROUND: Epidemiological studies have described that women are more vulnerable to the reinforcing effects of cocaine. In animals, the findings are similar: female rats show higher levels of cocaine self-administration and increased cocaine-induced locomotor activity. In contrast, women with depression respond better to treatment with antidepressants, however their therapeutic response to tetracyclic antidepressants is lower. Several studies have shown that mirtazapine-a tetracyclic antidepressant-decreases the behavioral effects of cocaine in male rats. The objective of this study was to evaluate the efficacy of daily dosing of mirtazapine on cocaine-induced locomotor activity and sensitization in naive female rats compared to male rats. METHODS: Male and female Wistar rats were daily dosed with 10 mg/kg of cocaine. During extinction, cocaine was withdrawn and the groups received daily mirtazapine (30 mg/kg, i.p.) or saline. Tamoxifen was administered during the antagonism phase. After each administration, locomotor activity for each animal was recorded for 30 min in transparent Plexiglass activity chambers. RESULTS: In this study, a higher cocaine locomotor response was found in females than in males and the mirtazapine was equally effective in decreasing cocaine-induced locomotor activity and the expression of locomotor sensitization in male and female rats. In addition, co-administration of mirtazapine and tamoxifen enhanced the efficacy of mirtazapine in female rats. CONCLUSION: The results suggest that mirtazapine may be considered an effective therapeutic option for the treatment of cocaine use disorder in men and women.


Assuntos
Transtornos Relacionados ao Uso de Cocaína , Cocaína/efeitos adversos , Locomoção/efeitos dos fármacos , Mirtazapina/farmacologia , Animais , Antidepressivos/administração & dosagem , Antidepressivos/farmacologia , Sensibilização do Sistema Nervoso Central/efeitos dos fármacos , Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Transtornos Relacionados ao Uso de Cocaína/fisiopatologia , Transtornos Relacionados ao Uso de Cocaína/psicologia , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Masculino , Mirtazapina/administração & dosagem , Ratos , Ratos Wistar , Tamoxifeno/administração & dosagem , Tamoxifeno/farmacologia
7.
J Feline Med Surg ; 22(12): 1176-1183, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32462966

RESUMO

OBJECTIVES: The aim of the study was to evaluate the appetite-stimulating effect of gabapentin by comparing it with mirtazapine in healthy cats in the first 8 h after ovariectomy surgery. METHODS: This double-masked, placebo-controlled, prospective clinical trial included 60 healthy cats presented to the hospital for ovariectomy: 20 received gabapentin, 21 received mirtazapine and 19 received a placebo immediately before and 6 h after surgery. Food was offered at 2, 4, 6 and 8 h post-ovariectomy. After each meal, food intake was measured. Data were analysed using repeated-measure ANOVA and a linear mixed-model analysis. Post-hoc Tukey's honest significant difference test was performed for multiple comparisons. RESULTS: Food intake increased in both treatment groups vs placebo. No statistically significant difference was found between cats treated with gabapentin or mirtazapine. CONCLUSIONS AND RELEVANCE: Cats receiving gabapentin ate more than cats in the placebo group. Thirty percent of cats in the gabapentin group covered their resting energy requirements, while none of the cats in the placebo group did. Gabapentin and mirtazapine produced similar effects on food intake.


Assuntos
Estimulantes do Apetite/farmacologia , Gabapentina/farmacologia , Mirtazapina/farmacologia , Ovariectomia/veterinária , Analgésicos/administração & dosagem , Animais , Anticonvulsivantes/administração & dosagem , Apetite/efeitos dos fármacos , Gatos , Método Duplo-Cego , Feminino , Estudos Prospectivos
8.
Pharmacol Rep ; 72(3): 563-570, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32240535

RESUMO

BACKGROUND: Experimental and clinical studies indicate that neuronal death with the presence of high levels of reactive oxygen species are present in depressed patients and antidepressants might display neuroprotective effects against them. However, the mechanisms underlying antidepressant neuroprotection are not completely understood. In our previous study, we showed that mirtazapine modulated the expression of pro- and anti-apoptotic proteins in mouse brain structures, but there are no data in human cells. Thus, this work was designed to study the possible neuroprotective properties of mirtazapine and imipramine, two commercially available antidepressants with different primary mechanisms of action, in human neuroblastoma SH-SY5Y cells against an oxidative insult. METHODS: SH-SY5Y cells were preincubated with mirtazapine and imipramine (1-20 µM) for 24 h, then hydrogen peroxide (H2O2) was added into the medium containing the antidepressants for additional 24 h, and MTT assay was carried out subsequently. Also, to elucidate the molecular mechanism underlying the neuroprotective properties of antidepressants, we investigated the effects of mirtazapine and imipramine (2 µM) in pro- and anti-apoptotic proteins gene expression in SH-SY5Y cells. RESULTS: Mirtazapine (1 and 2 µM) and imipramine (1and 2 µM) protected against hydrogen peroxide-induced cellular viability impairment. Most importantly, both compounds reduced p53 mRNA expression, but only imipramine enhanced the Bcl-2/Bax ratio. CONCLUSIONS: The obtained data indicate that mirtazapine and imipramine have neuroprotective effects against H2O2-induced cell death. Although both antidepressants reduced Bax and p53 mRNA expression, only the protection mediated by imipramine might be due to its ability to enhance Bcl-2/Bax ratio.


Assuntos
Apoptose/efeitos dos fármacos , Imipramina/farmacologia , Mirtazapina/farmacologia , Fármacos Neuroprotetores/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular , Humanos , Neuroblastoma/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteína de Morte Celular Associada a bcl/metabolismo
9.
Neuropharmacology ; 170: 108030, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32171677

RESUMO

Myotonic dystrophy type 1 (DM1) is a multisystemic disorder characterized by muscle weakness and wasting and by important central nervous system-related symptoms including impairments in executive functions, spatial abilities and increased anxiety and depression. The Mbnl2 gene has been implicated in several phenotypes consistent with DM1 neuropathology. In this study, we developed a tissue-specific knockout mouse model lacking the Mbnl2 gene in forebrain glutamatergic neurons to examine its specific contribution to the neurobiological perturbations related to DM1. We found that these mice exhibit long-term cognitive deficits and a depressive-like state associated with neuronal loss, increased microglia and decreased neurogenesis, specifically in the dentate gyrus (DG). Chronic treatment with the atypical antidepressant mirtazapine (3 and 10 mg/kg) for 21 days rescued these behavioral alterations, reduced inflammatory microglial overexpression, and reversed neuronal loss in the DG. We also show that mirtazapine re-established 5-HT1A and histaminergic H1 receptor gene expression in the hippocampus. Finally, metabolomics studies indicated that mirtazapine increased serotonin, noradrenaline, gamma-aminobutyric acid and adenosine production. These data suggest that loss of Mbnl2 gene in the glutamatergic neurons of hippocampus and cortex may underlie the most relevant DM1 neurobiological and behavioral features, and provide evidence that mirtazapine could be a novel potential candidate to alleviate these debilitating symptoms in DM1 patients.


Assuntos
Ácido Glutâmico , Mirtazapina/uso terapêutico , Distrofia Miotônica/genética , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Prosencéfalo/efeitos dos fármacos , Proteínas de Ligação a RNA/genética , Animais , Animais Geneticamente Modificados , Drosophila , Feminino , Ácido Glutâmico/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Mirtazapina/farmacologia , Distrofia Miotônica/tratamento farmacológico , Distrofia Miotônica/metabolismo , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Prosencéfalo/metabolismo , Proteínas de Ligação a RNA/metabolismo
10.
Sci Rep ; 10(1): 2491, 2020 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-32051524

RESUMO

Dendritic atrophy, defined as the reduction in complexity of the neuronal arborization, is a hallmark of several neurodevelopmental disorders, including Rett Syndrome (RTT). RTT, affecting 1:10,000 girls worldwide, is mainly caused by mutations in the MECP2 gene and has no cure. We describe here an in vitro model of dendritic atrophy in Mecp2-/y mouse hippocampal primary cultures, suitable for phenotypic drug-screening. Using High-Content Imaging techniques, we systematically investigated the impact of culturing determinants on several parameters such as neuronal survival, total dendritic length, dendritic endpoints, soma size, cell clusterization, spontaneous activity. Determinants included cell-seeding density, glass or polystyrene substrates, coating with poly-Ornithine with/without Matrigel and miniaturization from 24 to 96-half surface multiwell plates. We show that in all plate-sizes at densities below 320 cells/mm2, morphological parameters remained constant while spontaneous network activity decreased according to the cell-density. Mecp2-/y neurons cultured at 160 cells/mm2 density in 96 multiwell plates, displayed significant dendritic atrophy and showed a marked increase in dendritic length following treatment with Brain-derived neurotrophic factor (BDNF) or Mirtazapine. In conclusion, we have established a phenotypic assay suitable for fast screening of hundreds of compounds, which may be extended to other neurodevelopmental diseases with dendritic atrophy.


Assuntos
Dendritos/patologia , Avaliação Pré-Clínica de Medicamentos/métodos , Fármacos Neuroprotetores/farmacologia , Fenótipo , Síndrome de Rett/genética , Animais , Fator Neurotrófico Derivado do Encéfalo/farmacologia , Células Cultivadas , Dendritos/efeitos dos fármacos , Hipocampo/citologia , Proteína 2 de Ligação a Metil-CpG/genética , Camundongos , Camundongos Endogâmicos C57BL , Mirtazapina/farmacologia , Síndrome de Rett/patologia
11.
World J Biol Psychiatry ; 21(8): 595-611, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-31104538

RESUMO

Objectives: Concurrent abuse of cocaine and nicotine is considered a public health problem. To date, no effective therapy has been known to reduce the reinforcing effects of concurrent use of cocaine and nicotine. Mirtazapine, an antagonist of the α2-adrenoceptor and the 5-HT2A/C and the 5-HT3 receptors has proven effective in reducing the cocaine, nicotine and methamphetamine behavioural effects in humans and animals. Our study evaluated the effect of mirtazapine on enhancing locomotor activity during the induction and expression of locomotor sensitisation induced by a cocaine + nicotine mixture.Methods: Wistar rats were dosed with cocaine, nicotine or cocaine + nicotine combination. Mirtazapine (30 mg/kg, i.p.) was administered during the extinction phase.Results: Mirtazapine decreased cocaine + nicotine-induced locomotor activity and induction and expression of locomotor sensitisation. In addition, we found that co-administration of mecamylamine and mirtazapine significantly enhanced the effect of mirtazapine on cocaine + nicotine-induced locomotor activity during induction and expression of behavioural sensitisation.Conclusions: Our results suggest that mirtazapine demonstrated efficacy in decreasing the psycho-stimulant effects of concurrent use of cocaine and nicotine.


Assuntos
Cocaína/farmacologia , Locomoção/efeitos dos fármacos , Mirtazapina/farmacologia , Nicotina/farmacologia , Animais , Masculino , Ratos , Ratos Wistar
13.
Pharmacol Biochem Behav ; 187: 172817, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31655085

RESUMO

INTRODUCTION: Depression is a psychiatric disorder with higher incidence in women. Among the most common and less investigated adverse effects of antidepressants are the female sexual dysfunctions. Up to one third of the patients fail to respond to antidepressants; therefore, more treatment alternatives are necessary. The combination of mirtazapine plus venlafaxine, known as "California Rocket Fuel" has shown to be an option for treatment-resistant depression. However, there are no reports of the effects of this combination in animal models and its action on female sexual behavior is unknown. AIM: To analyze the effect of mirtazapine and venlafaxine alone or combined -given at doses with actions on the forced swim test- on female rat sexual behavior. METHODS: Mirtazapine (10, 20 or 40 mg/kg) and venlafaxine (15, 30 or 60 mg/kg) or their combinations (2.5/3.75, 5/7.5, 10/15 and 20/30 mg/kg mirtazapine and venlafaxine, respectively) were injected to sexually receptive female rats. We evaluated their effect on the forced swim test (FST). The doses that reduced immobility were tested on proceptivity and receptivity. RESULTS: Mirtazapine (40 mg/kg) and venlafaxine (60 mg/kg), administered alone, or combined (mirtazapine, 5, 10 and 20 mg/kg plus venlafaxine, 7.5, 15 and 30 mg/kg) reduced immobility, but affected motor activity. However, the reduced locomotion after the lowest combination (5/7.5 mg/kg) was smaller. Mirtazapine at 40 mg/kg reduced proceptivity and receptivity, while 60 mg/kg venlafaxine only decreased proceptivity. The combination of 5/7.5 mg/kg mirtazapine and venlafaxine did not affect female sexual behavior. CONCLUSIONS: Mirtazapine and venlafaxine exerted an effect in the FST, which was also evident when sub-effective doses of both antidepressants were combined. This combination also lacked adverse effects on female sexual behavior. The results suggest that "California Rocket Fuel" could be an effective antidepressant therapy with no adverse sexual effects in women.


Assuntos
Antidepressivos de Segunda Geração/farmacologia , Mirtazapina/farmacologia , Comportamento Sexual Animal/efeitos dos fármacos , Cloridrato de Venlafaxina/farmacologia , Animais , Antidepressivos de Segunda Geração/administração & dosagem , Antidepressivos de Segunda Geração/uso terapêutico , Depressão/tratamento farmacológico , Relação Dose-Resposta a Droga , Quimioterapia Combinada/efeitos adversos , Feminino , Locomoção/efeitos dos fármacos , Masculino , Mirtazapina/administração & dosagem , Mirtazapina/uso terapêutico , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Wistar , Natação , Cloridrato de Venlafaxina/administração & dosagem , Cloridrato de Venlafaxina/uso terapêutico
14.
Environ Toxicol Pharmacol ; 72: 103244, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31557707

RESUMO

The glucose metabolism in the pentose cycle is essential to the source of NADPH. Deficiency of these enzymes have been linked to depression and psychotic disorders. Depression is an increasingly prevalent mental disorder which may cause loss of labor. Antidepressant drugs are commonly employed in treatments of mood disorders and anxiety treatment. The purpose of this study is to investigate the effects of aripiprazole, mirtazapine, risperidone, escitalopram and haloperidol on the activity of 6-phosphogluconate dehydrogenase (6PGD) and glucose-6-phosphate dehydrogenase (G6PD) enzymes purified from human erythrocytes. It was found that aripiprazole, mirtazapine, risperidone, escitalopram and haloperidol show effective inhibitor properties on purified G6PD and 6PGD enzymes. The IC50 values of these drugs were found in the range of 26.34 µM-5.78 mM for 6PGD and 16.26 µM-3.85 mM for G6PD. The Ki values of the drugs were found in the range of 30.21 ± 4.31 µM-4.51 ± 1.83 mM for 6PGD and 14.12 ± 3.48 µM-4.98 ± 1.14 mM for G6PD. Usage of drugs with significant biological effects may be a hazard in some conditions.


Assuntos
Antidepressivos/farmacologia , Eritrócitos/efeitos dos fármacos , Glucosefosfato Desidrogenase/antagonistas & inibidores , Via de Pentose Fosfato/efeitos dos fármacos , Fosfogluconato Desidrogenase/antagonistas & inibidores , Aripiprazol/farmacologia , Citalopram/farmacologia , Eritrócitos/enzimologia , Haloperidol/farmacologia , Humanos , Mirtazapina/farmacologia
15.
Eur J Pharmacol ; 860: 172539, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31306636

RESUMO

Different classes of antidepressants, such as tricyclic antidepressants, selective serotonin reuptake inhibitor (SSRI), and serotonin and norepinephrine reuptake inhibitor (SNRI), have been shown to increase GDNF production in astrocytes, which could be a key mechanism of the psychotropic effect of antidepressants. The antidepressant mirtazapine is a noradrenaline and specific serotonergic antidepressant (NaSSA) and does not block reuptake of catecholamines and serotonin. The present study examined the effect of mirtazapine on GDNF expression in rat C6 astroglial cells (C6 cells) and rat primary cultured cortical astrocytes (primary astrocytes). Mirtazapine treatment significantly increased GDNF mRNA expression and GDNF release in both C6 cells and primary astrocytes. In primary astrocytes, mirtazapine also increased the expressions of brain-derived neurotrophic factor mRNA. To mimic mirtazapine's putative mechanism of action, cells were treated with either a α2-adrenoceptor antagonist (yohimbine), 5-HT2 receptor antagonist (ketanserin), 5-HT3 receptor antagonist (ondansetron), or a mixture of these--no effect on GDNF mRNA expression was observed. Mirtazapine treatment increased phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, and the mirtazapine-induced GDNF and BDNF expression were blocked by MAPK/ERK kinase (MEK) inhibitor (U0126). Furthermore, the effect of mirtazapine on ERK phosphorylation and expressions of GDNF and BDNF was antagonized by Gi/o inhibitor (pertussis toxin), lysophosphatidic acid-1 (LPA1) receptor antagonist (AM966), and LPA1/LPA3 receptors antagonist (Ki16425). The current findings demonstrate that the NaSSA mirtazapine, similar to other classes of antidepressants, increases GDNF expression through a Gi/o coupled LPA1 receptor-mediated ERK pathway. The current findings suggest a general mechanism underlying the psychotropic effect antidepressants.


Assuntos
Antidepressivos/farmacologia , Astrócitos/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fator Neurotrófico Derivado de Linhagem de Célula Glial/biossíntese , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Mirtazapina/farmacologia , Receptores de Ácidos Lisofosfatídicos/metabolismo , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Animais , Astrócitos/citologia , Astrócitos/metabolismo , Linhagem Celular Tumoral , Regulação da Expressão Gênica/efeitos dos fármacos , Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fosforilação/efeitos dos fármacos , RNA Mensageiro/genética , Ratos , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Antagonistas do Receptor 5-HT3 de Serotonina/farmacologia
16.
Can J Physiol Pharmacol ; 97(8): 781-785, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31100205

RESUMO

The objective of the study was to investigate the effects of CYP2D6 activity on the efficacy and safety of mirtazapine in patients with depressive disorders and comorbid alcohol use disorder who received mirtazapine. The study included 109 Russian patients who received mirtazapine at a dose of 30.0 [15.0; 45.0] mg per day. Genotyping of CYP2D6*4 (1846G > A, rs3892097) was performed using real-time polymerase chain reaction with allele-specific hybridization. The activity of CYP2D6 was evaluated by determining the concentration of endogenous substrate of the enzyme and its urinary metabolite - pinoline to 6-hydroxy-1,2,3,4-tetrahydro-beta-carboline ratio, using high-performance liquid chromatography - mass spectrometry. The statistically significant differences between the scores on the Hamilton Depression Rating Scale (HAMD) in patients with different genotypes were revealed by day 16: (GG) 5.0 [3.0; 6.0], (GA) 1.5 [1.0; 3.2] (p < 0.001), and for the The UKU Side Effects Rating Scale (UKU): (GG) 6.0 [6.0; 7.0], (GA) 8.5 [8.0; 10.0] (p < 0.001). The calculation of correlation coefficients between the differences in scale scores and metabolic rate showed the presence of statistically significant weak inverse correlation with the efficacy indicator evaluated by HAMD (r = -0.278, p < 0.05), but not by UKU (r = 0.274, p > 0.05). This study demonstrated that an increased CYP2D6 activity reduces the efficacy of treatment with mirtazapine.


Assuntos
Alcoolismo/tratamento farmacológico , Citocromo P-450 CYP2D6/metabolismo , Transtorno Depressivo/tratamento farmacológico , Mirtazapina/efeitos adversos , Mirtazapina/farmacologia , Segurança , Adulto , Alcoolismo/enzimologia , Alcoolismo/epidemiologia , Alcoolismo/genética , Comorbidade , Citocromo P-450 CYP2D6/genética , Transtorno Depressivo/enzimologia , Transtorno Depressivo/epidemiologia , Transtorno Depressivo/genética , Feminino , Genótipo , Humanos , Masculino , Mirtazapina/uso terapêutico , Polimorfismo Genético
17.
Am J Geriatr Psychiatry ; 27(9): 920-931, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31084994

RESUMO

OBJECTIVE: Studies have shown that antidepressants are no better than placebo in treating depression in dementia. The authors examined antidepressant efficacy in subgroups of depression in dementia with different depressive symptom profiles. METHODS: This study focuses on exploratory secondary analyses on the randomized, parallel-group, double-blind, placebo-controlled Health Technology Assessment Study of the Use of Antidepressants for Depression in Dementia (HTA-SADD) trial. The setting included old-age psychiatry services in nine centers in England. The participants included 326 patients meeting National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association probable/possible Alzheimer disease criteria, and Cornell Scale for Depression in Dementia (CSDD) scores of 8 or more. Intervention was placebo (n = 111), sertraline (n = 107), or mirtazapine (n = 108). Latent class analyses (LCA) on baseline CSDD items clustered participants into symptom-based subgroups. Mixed-model analysis evaluated CSDD improvement at 13 and 39 weeks by randomization in each subgroup. RESULTS: LCA yielded 4 subgroups: severe (n = 34), psychological (n = 86), affective (n = 129), and somatic (n = 77). Mirtazapine, but not sertraline, outperformed placebo in the psychological subgroup at week 13 (adjusted estimate: -2.77 [standard error (SE) 1.16; 95% confidence interval: -5.09 to -0.46]), which remained, but lost statistical significance at week 39 (adjusted estimate: -2.97 [SE 1.59; 95% confidence interval: -6.15 to 0.20]). Neither sertraline nor mirtazapine outperformed placebo in the other subgroups. CONCLUSION: Because of the exploratory nature of the analyses and the small sample sizes for subgroup analysis there is the need for caution in interpreting these data. Replication of the potential effects of mirtazapine in the subgroup of those with depression in dementia with "psychological" symptoms would be valuable. These data should not change clinical practice, but future trials should consider stratifying types of depression in dementia in secondary analyses.


Assuntos
Antidepressivos/farmacologia , Demência/tratamento farmacológico , Depressão/tratamento farmacológico , Mirtazapina/farmacologia , Sertralina/farmacologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/classificação , Doença de Alzheimer/complicações , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/psicologia , Antidepressivos/administração & dosagem , Demência/classificação , Demência/complicações , Demência/psicologia , Depressão/etiologia , Método Duplo-Cego , Inglaterra , Feminino , Humanos , Masculino , Mirtazapina/administração & dosagem , Sertralina/administração & dosagem
18.
Front Immunol ; 10: 803, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31031775

RESUMO

Activation of the innate immune system, including tissue macrophages and associated neutrophil infiltration, is an important driver of subsequent adaptive immune responses in many autoimmune diseases, including autoimmune hepatitis (AIH). The antidepressant mirtazapine has a unique complex pharmacology, altering signaling through a number of serotonin and histamine receptors that can impact macrophage function; an effect potentially influencing AIH outcome. In the mouse model of concanavalin A (Con A) induced liver injury (mimics many aspects of human AIH), in which early innate immune activation (i.e., stimulated hepatic macrophages/monocytes recruit neutrophils and additional monocytes to the liver) critically drives immune-mediated hepatitis induction, mirtazapine strikingly and dose-dependently inhibited Con A-induced liver injury. This inflammation-suppressing effect of mirtazapine was linked to an attenuation of Con A-stimulated early innate immune responses within the liver, including inhibition of hepatic macrophage/monocyte activation, decreased hepatic macrophage/monocyte-derived pro-inflammatory cytokine (e.g., TNFα) and chemokine (e.g., CXCL1 and CXCL2) production, suppression of Con A-induced increases in the hepatic expression of the neutrophil relevant endothelial cell adhesion molecule ICAM-1, with the resultant significant reduction in neutrophil recruitment into the liver. Consistent with our findings in the Con A model, mirtazapine also significantly reduced activation-induced release of cytokine/chemokine mediators from human CD14+ monocytes in vitro. Conclusion: Our data suggest that mirtazapine can attenuate hepatic innate immune responses that critically regulate the subsequent development of autoimmune liver injury. Therefore, given that it is a safe and widely used medication, mirtazapine may represent a novel therapeutic approach to autoimmune liver disease.


Assuntos
Antidepressivos/farmacologia , Imunidade Inata/efeitos dos fármacos , Imunomodulação/efeitos dos fármacos , Hepatopatias/etiologia , Hepatopatias/patologia , Mirtazapina/farmacologia , Animais , Biomarcadores , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Concanavalina A/efeitos adversos , Citocinas/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Imunossupressores/farmacologia , Mediadores da Inflamação/metabolismo , Hepatopatias/tratamento farmacológico , Hepatopatias/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Infiltração de Neutrófilos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Neutrófilos/patologia
19.
Ultrastruct Pathol ; 43(1): 66-79, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30929557

RESUMO

Cisplatin (CP) is a chemotherapy medication used to treat different types of organs cancers. It has damaging effects on testes. Mirtazapine is an antidepressant, which is used primarily in the treatment of depression and other anxiety disorders. Ginger is a naturally growing plant with antioxidant properties. Thirty-six adult male albino rats, subdivided into six groups (six animals each) received treatment for 30 days. Group I (control) received saline solution orally; group II received mirtazapine (20 mg/kg). Group III received ginger (200 mg/kg/day), group IV received CP (7 mg/kg) IP single dose, at day 23rd, group V received mirtazapine (200 mg/day) orally till day 23rd, CP (7 mg/kg) IP at day 23rd, mirtazapine till day 30th, group VI received ginger (200 mg/Kg/day) orally till day 23rd, CP (7 mg/kg) IP at day 23rd, and then ginger at the previous dose till day 30th. This study examined the microscopic changes associated with CP and the possible testicular protective role of mirtazapine versus ginger of adult male rats. Mirtazapine and ginger resulted in cellular protection of testicular tissue as evident from microscopic changes including Sertoli cells, spermatogonia, and Leydig cells. Ginger showed to have a more protective effect than mirtazapine on testicular tissue against CP treatment.


Assuntos
Antioxidantes/farmacologia , Mirtazapina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Testículo/efeitos dos fármacos , Animais , Cisplatino/farmacologia , Gengibre/efeitos dos fármacos , Masculino , Extratos Vegetais/farmacologia , Ratos , Espermatozoides/efeitos dos fármacos
20.
Psychiatry Clin Neurosci ; 73(7): 400-408, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30973181

RESUMO

AIM: Previous studies indicate that mirtazapine is unique in its quick responsiveness compared to other antidepressants. Although some other studies have evaluated its cost-effectiveness, they have not considered its early stage remission rate. The aim of this study was to address this research gap by using precise clinical data to evaluate the cost-effectiveness of mirtazapine in Japan. METHODS: We developed a Markov model to reflect the week-by-week transition probabilities. The Markov cycle was set as 1 week. While our clinical parameters were obtained largely from existing meta-analyses, cost data were derived from government reports. Cost-effectiveness was evaluated by incremental cost-effectiveness ratios (ICERs) per quality-adjusted life year estimated based on the probability sensitivity analyses. The ICERs were estimated at 2, 8, 26, and 52 weeks. RESULTS: In severe depression, the ICERs ranged between JPY 872 153 and 1 772 723. The probability of mirtazapine being cost-effective ranged from 0.75 to 0.99 when the ICER threshold was JPY 5 000 000. In moderate depression, the ICERs ranged between JPY 2 356 499 and 4 770 145. The probability of mirtazapine being cost-effective ranged from 0.55 to 0.83 when the ICER threshold was JPY 5 000 000. CONCLUSION: When considering the early stage efficacy of mirtazapine, it appeared to be cost-effective compared to selective serotonin reuptake inhibitors, especially for severe depression and in the early stage treatment in the Japanese setting. However, our study has some limitations. First, mirtazapine is compared with batched selective serotonin reuptake inhibitors rather than individual ones. Second, we did not consider antidepressant combination therapy as treatment options.


Assuntos
Antidepressivos/farmacologia , Análise Custo-Benefício , Transtorno Depressivo/tratamento farmacológico , Mirtazapina/farmacologia , Avaliação de Resultados em Cuidados de Saúde/métodos , Inibidores de Captação de Serotonina/farmacologia , Adulto , Antidepressivos/economia , Transtorno Depressivo/economia , Humanos , Japão , Mirtazapina/economia , Modelos Estatísticos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Anos de Vida Ajustados por Qualidade de Vida , Recidiva , Indução de Remissão , Inibidores de Captação de Serotonina/economia , Índice de Gravidade de Doença
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