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1.
Behav Brain Res ; 425: 113827, 2022 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-35248650

RESUMO

Our aims were to assess the effect of melatonin on fluphenazine-induced hypokinesia during the light (ZT 9.5-10.5) and dark (ZT 17.5-18.5) phases in mice lacking endogenous pineal melatonin (C57BL/6 mouse), and to investigate the effects of the manipulation of environmental lighting in mice with a targeted deletion of the MT1 melatonin receptor. In both knockout (C57KO MT1) and wild type (C57WT) mice, fluphenazine (1 mg/kg) induced hypokinesia during the light phase (C57WT: M=105, SEM=31.2 s, n = 31; C57 MT1KO:M=118, SEM = 32.6 s, n = 29). During the light phase melatonin (10 mg/kg, sc) significantly reduced hypokinesia in both genotypes (C57WT: M=33.1, SEM=8.4 s; C57 MT1KO: M=33.3, SEM=13.0 s). In the dark, fluphenazine did not induce a substantial hypokinesia in either C57WT or C57 MT1KO mice. Manipulating the lightning environment during testing, experiments conducted during the light phase in a dark environment served to abolish the hypokinetic effect of fluphenazine in all groups regardless of melatonin treatment. Conversely, experiments conducted during the dark phase in a light environment showed mice to have hypokinetic effects by fluphenazine treatment in both C57WT (M=98.4, SEM=20.2 s) and C57 MT1KO (M=40.4 SEM=9.5 s) groups. These data suggest that fluphenazine-induced hypokinesia is more pronounced under light than dark conditions, and that melatonin is only able to counteract hypokinesia during the light phase. Importantly, our data suggest that the effect of melatonin on hypokinesia was not solely mediated by the MT1 melatonin receptor in the C57BL/6 mouse, leaving the possible activation of MT2 receptor as the mechanism of action which is regulated by the light/dark environment.


Assuntos
Melatonina , Glândula Pineal , Animais , Ritmo Circadiano , Flufenazina/efeitos adversos , Hipocinesia/induzido quimicamente , Melatonina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Glândula Pineal/metabolismo , Receptor MT1 de Melatonina/genética , Receptor MT2 de Melatonina/genética
2.
J Clin Pharm Ther ; 47(4): 562-566, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34750842

RESUMO

WHAT IS KNOWN AND OBJECTIVE: Long-acting injectable (LAI) antipsychotics are an integral part of mental health treatment. Modifying an LAI regimen poses several challenges because of the extended half-life of the drug. CASE SUMMARY: An acutely psychotic patient with schizoaffective disorder received aripiprazole lauroxil without resolution of symptoms. She was started on a previously successful regimen of oral fluphenazine. Due to continued psychosis, oral carbamazepine was initiated to expedite the LAI's metabolism allowing subsequent doses of fluphenazine to impart activity. WHAT IS NEW AND CONCLUSION: Potent cytochrome enzyme inducers may help in transitioning patients from LAI antipsychotics to other therapies.


Assuntos
Antipsicóticos , Esquizofrenia , Aripiprazol , Benzodiazepinas , Carbamazepina/uso terapêutico , Preparações de Ação Retardada , Feminino , Flufenazina/uso terapêutico , Humanos , Esquizofrenia/tratamento farmacológico
3.
Am J Psychiatry ; 178(5): 424-436, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33596679

RESUMO

OBJECTIVE: This study compared relapse prevention and acceptability of long-acting injectable (LAI) antipsychotics in the maintenance treatment of adults with nonaffective psychoses. METHODS: The authors searched MEDLINE, Embase, PsycINFO, CINAHL, CENTRAL, and online registers for randomized controlled trials published until June 2020. Relative risks and standardized mean differences were pooled using random-effects pairwise and network meta-analysis. The primary outcomes were relapse rate and all-cause discontinuation ("acceptability"). The quality of included studies was rated with the Cochrane Risk of Bias tool, and the certainty of pooled estimates was measured with GRADE (Grading of Recommendations Assessment, Development, and Evaluation). RESULTS: Of 86 eligible trials, 78 (N=11,505) were included in the meta-analysis. Regarding relapse prevention, most of the 12 LAIs included outperformed placebo. The largest point estimates and best rankings of LAIs compared with placebo were found for paliperidone (3-month formulation) and aripiprazole. Moderate to high GRADE certainty for superior relapse prevention compared with placebo was also found for (in descending ranking order) risperidone, pipothiazine, olanzapine, and paliperidone (1-month formulation). In head-to-head comparisons of LAIs, only haloperidol was inferior to aripiprazole, fluphenazine, and paliperidone. For acceptability, most LAIs outperformed placebo, with moderate to high GRADE certainty for (in descending ranking order) zuclopenthixol, aripiprazole, paliperidone (3-month formulation), olanzapine, flupenthixol, fluphenazine, and paliperidone (1-month formulation). In head-to-head comparisons, only LAI aripiprazole had superior acceptability to other LAIs (bromperidol, fluphenazine, paliperidone [1-month formulation], pipothiazine, and risperidone). CONCLUSIONS: LAI formulations of paliperidone (3-month formulation), aripiprazole, olanzapine, and paliperidone (1-month formulation) showed the highest effect sizes and certainty of evidence for both relapse prevention and acceptability. Results from this network meta-analysis should inform frontline clinicians and guidelines.


Assuntos
Antipsicóticos/administração & dosagem , Aceitação pelo Paciente de Cuidados de Saúde , Transtornos Psicóticos/tratamento farmacológico , Esquizofrenia/tratamento farmacológico , Aripiprazol/administração & dosagem , Clopentixol/administração & dosagem , Preparações de Ação Retardada , Flupentixol/administração & dosagem , Flufenazina/administração & dosagem , Haloperidol/administração & dosagem , Humanos , Injeções Intramusculares , Metanálise em Rede , Olanzapina/administração & dosagem , Palmitato de Paliperidona/administração & dosagem , Fenotiazinas/administração & dosagem , Risperidona/administração & dosagem , Prevenção Secundária
4.
J Appl Toxicol ; 41(1): 82-94, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32852120

RESUMO

Drug repositioning is an approach that could accelerate the clinical use of compounds in different diseases. The goal is to take advantage of the fact that approved drugs have been tested on humans and detailed information is available on their pharmacology, toxicity and formulation. It can significantly reduce the costs and time needed to implement necessary therapies on the market. In recent years, phenothiazines are being tested for cancer, viral, bacterial, fungal and other diseases. Most research focuses on chlorpromazine as a model drug in this class, but other drugs such as fluphenazine, perphenazine and prochlorperazine have been proven to inhibit the viability of different cancer cell lines. In this study, we performed an extensive literature search to find and summarize all papers on the chosen phenothiazines and their potential in treating different types of cancerin vitro for further animal/clinical trials. Fluphenazine, perphenazine and prochlorperazine possess anticancer activity towards different types of human cancer. The antitumor activity is mainly mediated by an effect of the drugs on the cell cycle, proliferation or apoptosis. Possible molecular targets of phenothiazine derivatives are the drug's efflux pumps (ABCB1 and P-glycoprotein) and two parallel pathways (AKT and Wnt) regulated by the D2 receptor antagonists. The drugs have the potential to reduce the viability of human cancer cell lines, fragment the DNA, stimulate apoptosis, inhibit cell migration and invasiveness as well as impair the production of reactive oxygen species. In addition, due to the sedative and antiemetic properties antipsychotics can be used as an adjuvant for the treatment of chemotherapy side effects.


Assuntos
Antineoplásicos/uso terapêutico , Antipsicóticos/uso terapêutico , Antagonistas de Dopamina/uso terapêutico , Reposicionamento de Medicamentos , Flufenazina/uso terapêutico , Neoplasias/tratamento farmacológico , Perfenazina/uso terapêutico , Proclorperazina/uso terapêutico , Humanos , Técnicas In Vitro
5.
Mol Cell Neurosci ; 109: 103562, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32987141

RESUMO

Abnormal dendritic arbor development has been implicated in a number of neurodevelopmental disorders, such as autism and Rett syndrome, and the neuropsychiatric disorder schizophrenia. Postmortem brain samples from subjects with schizophrenia show elevated levels of NOS1AP in the dorsolateral prefrontal cortex, a region of the brain associated with cognitive function. We previously reported that the long isoform of NOS1AP (NOS1AP-L), but not the short isoform (NOS1AP-S), negatively regulates dendrite branching in rat hippocampal neurons. To investigate the role that NOS1AP isoforms play in human dendritic arbor development, we adapted methods to generate human neural progenitor cells and neurons using induced pluripotent stem cell (iPSC) technology. We found that increased protein levels of either NOS1AP-L or NOS1AP-S decrease dendrite branching in human neurons at the developmental time point when primary and secondary branching actively occurs. Next, we tested whether pharmacological agents can decrease the expression of NOS1AP isoforms. Treatment of human iPSC-derived neurons with d-serine, but not clozapine, haloperidol, fluphenazine, or GLYX-13, results in a reduction in endogenous NOS1AP-L, but not NOS1AP-S, protein expression; however, d-serine treatment does not reverse decreases in dendrite number mediated by overexpression of NOS1AP isoforms. In summary, we demonstrate how an in vitro model of human neuronal development can help in understanding the etiology of schizophrenia and can also be used as a platform to screen drugs for patients.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Dendritos/ultraestrutura , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Neurais/citologia , Neurônios/citologia , Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Proteínas Adaptadoras de Transdução de Sinal/genética , Células Cultivadas , Clozapina/farmacologia , Avaliação Pré-Clínica de Medicamentos , Flufenazina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Ácido Glutâmico/fisiologia , Haloperidol/farmacologia , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Canais Iônicos/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Células-Tronco Neurais/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Oligopeptídeos/farmacologia , Técnicas de Patch-Clamp , Isoformas de Proteínas/fisiologia , Esquizofrenia/etiologia , Esquizofrenia/genética , Serina/farmacologia
6.
Eur J Pharmacol ; 887: 173553, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32949606

RESUMO

In 2020 the whole world focused on antivirus drugs towards SARS-CoV-2. Most of the researchers focused on drugs used in other viral infections or malaria. We have not seen such mobilization towards one topic in this century. The whole situation makes clear that progress needs to be made in antiviral drug development. The first step to do it is to characterize the potential antiviral activity of new or already existed drugs on the market. Phenothiazines are antipsychotic agents used previously as antiseptics, anthelminthics, and antimalarials. Up to date, they are tested for a number of other disorders including the broad spectrum of viruses. The goal of this paper was to summarize the current literature on activity toward RNA-viruses of such drugs like chlorpromazine, fluphenazine, perphenazine, prochlorperazine, and thioridazine. We identified 49 papers, where the use of the phenothiazines for 23 viruses from different families were tested. Chlorpromazine, fluphenazine, perphenazine, prochlorperazine, and thioridazine possess anti-viral activity towards different types of viruses. These drugs inhibit clathrin-dependent endocytosis, cell-cell fusion, infection, replication of the virus, decrease viral invasion as well as suppress entry into the host cells. Additionally, since the drugs display activity at nontoxic concentrations they have therapeutic potential for some viruses, still, further research on animal and human subjects are needed in this field to verify cell base research.


Assuntos
Antipsicóticos/farmacologia , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Fenotiazinas/farmacologia , Pneumonia Viral/tratamento farmacológico , Vírus de RNA/efeitos dos fármacos , Animais , Antipsicóticos/uso terapêutico , Antivirais/uso terapêutico , COVID-19 , Clorpromazina/farmacologia , Clorpromazina/uso terapêutico , Flufenazina/farmacologia , Flufenazina/uso terapêutico , Humanos , Pandemias , Perfenazina/farmacologia , Perfenazina/uso terapêutico , Fenotiazinas/uso terapêutico , Proclorperazina/farmacologia , Proclorperazina/uso terapêutico , SARS-CoV-2 , Tioridazina/farmacologia , Tioridazina/uso terapêutico
7.
SLAS Discov ; 25(10): 1123-1140, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32804597

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative pathogen of pandemic coronavirus disease 2019 (COVID-19). So far, no approved therapy has been developed to halt the spread of the pathogen, and unfortunately, the strategies for developing a new therapy will require a long time and very extensive resources. Therefore, drug repurposing has emerged as an ideal strategy toward a smart, versatile, quick way to confine the lethal disease. In this endeavor, natural products have been an untapped source for new drugs. This review represents the confederated experience of multidisciplinary researchers of 99 articles using several databases: Google Scholar, Science Direct, MEDLINE, Web of Science, Scopus, and PubMed. To establish the hypothesis, a Bayesian perspective of a systematic review was used to outline evidence synthesis. Our docking documentation of 69 compounds and future research agenda assumptions were directed toward finding an effective and economic anti-COVID-19 treatment from natural products. Glucosinolate, flavones, and sulfated nitrogenous compounds demonstrate direct anti-SARS-CoV-2 activity through inhibition protease enzymes and may be considered potential candidates against coronavirus. These findings could be a starting point to initiate an integrative study that may encompass interested scientists and research institutes to test the hypothesis in vitro, in vivo, and in clinics after satisfying all ethical requirements.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , COVID-19/epidemiologia , Flufenazina/farmacologia , Glucosinolatos/farmacologia , SARS-CoV-2/genética , Antivirais/química , Teorema de Bayes , Produtos Biológicos/química , Produtos Biológicos/farmacologia , COVID-19/etiologia , Coronavirus/genética , Flufenazina/química , Predisposição Genética para Doença , Variação Genética , Genoma Viral , Glucosinolatos/química , Interações Hospedeiro-Patógeno , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/patogenicidade , Simulação de Acoplamento Molecular , Uso Off-Label , Pneumonia Viral/etiologia , Estudos Retrospectivos , SARS-CoV-2/patogenicidade
8.
Mol Syst Biol ; 16(7): e9628, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32729248

RESUMO

The COVID-19 pandemic caused by SARS-CoV-2 has is a global health challenge. Angiotensin-converting enzyme 2 (ACE2) is the host receptor for SARS-CoV-2 entry. Recent studies have suggested that patients with hypertension and diabetes treated with ACE inhibitors (ACEIs) or angiotensin receptor blockers have a higher risk of COVID-19 infection as these drugs could upregulate ACE2, motivating the study of ACE2 modulation by drugs in current clinical use. Here, we mined published datasets to determine the effects of hundreds of clinically approved drugs on ACE2 expression. We find that ACEIs are enriched for ACE2-upregulating drugs, while antineoplastic agents are enriched for ACE2-downregulating drugs. Vorinostat and isotretinoin are the top ACE2 up/downregulators, respectively, in cell lines. Dexamethasone, a corticosteroid used in treating severe acute respiratory syndrome and COVID-19, significantly upregulates ACE2 both in vitro and in vivo. Further top ACE2 regulators in vivo or in primary cells include erlotinib and bleomycin in the lung and vancomycin, cisplatin, and probenecid in the kidney. Our study provides leads for future work studying ACE2 expression modulators.


Assuntos
Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Células A549 , Enzima de Conversão de Angiotensina 2 , Betacoronavirus , Bleomicina/farmacologia , COVID-19 , Dexametasona/farmacologia , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Cloridrato de Erlotinib/farmacologia , Flufenazina/farmacologia , Células HEK293 , Humanos , Rim/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Células MCF-7 , Pandemias , Peptidil Dipeptidase A , SARS-CoV-2 , Biologia de Sistemas , Regulação para Cima , Vemurafenib/farmacologia
11.
Elife ; 92020 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-32167471

RESUMO

Ion selectivity is a defining feature of a given ion channel and is considered immutable. Here we show that ion selectivity of the lysosomal ion channel TPC2, which is hotly debated (Calcraft et al., 2009; Guo et al., 2017; Jha et al., 2014; Ruas et al., 2015; Wang et al., 2012), depends on the activating ligand. A high-throughput screen identified two structurally distinct TPC2 agonists. One of these evoked robust Ca2+-signals and non-selective cation currents, the other weaker Ca2+-signals and Na+-selective currents. These properties were mirrored by the Ca2+-mobilizing messenger, NAADP and the phosphoinositide, PI(3,5)P2, respectively. Agonist action was differentially inhibited by mutation of a single TPC2 residue and coupled to opposing changes in lysosomal pH and exocytosis. Our findings resolve conflicting reports on the permeability and gating properties of TPC2 and they establish a new paradigm whereby a single ion channel mediates distinct, functionally-relevant ionic signatures on demand.


Assuntos
Agonistas dos Canais de Cálcio/farmacologia , Canais de Cálcio/metabolismo , Macrófagos/metabolismo , Cloridrato de Raloxifeno/farmacologia , Animais , Benzilisoquinolinas/farmacologia , Cálcio/metabolismo , Agonistas dos Canais de Cálcio/química , Canais de Cálcio/genética , Flufenazina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Células HeLa , Humanos , Ionomicina/farmacologia , Macrófagos/efeitos dos fármacos , Camundongos , NADP/análogos & derivados , NADP/metabolismo , Fosfatos de Fosfatidilinositol/farmacologia , Imagem Individual de Molécula , Sódio/metabolismo
12.
J Antimicrob Chemother ; 75(5): 1187-1193, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32011702

RESUMO

BACKGROUND: In recent decades, Candida glabrata has emerged as a frequent cause of life-threatening fungal infection. In C. glabrata, echinocandin resistance is associated with mutations in FKS1/FKS2 (ß-1,3-glucan synthase). The calmodulin/calcineurin pathway is implicated in response to antifungal stress and calcineurin gene disruption specifically reverses Fks2-mediated resistance of clinical isolates. OBJECTIVES: We evaluated the impact of calmodulin inhibition by fluphenazine in two caspofungin-resistant C. glabrata isolates. METHODS: C. glabrata isolates were identified by ITS1/ITS4 (where ITS stands for internal transcribed spacer) sequencing and the echinocandin target FKS1/FKS2 genes were sequenced. Susceptibility testing of caspofungin in the presence of fluphenazine was performed by a modified CLSI microbroth dilution method. The effect of the fluphenazine/caspofungin combination on heat stress (37°C or 40°C), oxidative stress (0.2 and 0.4 mM menadione) and biofilm formation (polyurethane catheter) was analysed. A Galleria mellonella model using blastospores (1 × 109 cfu/mL) was developed to evaluate the impact of this combination on larval survival. RESULTS: F659del was found in the FKS2 gene of both resistant strains. In these clinical isolates, fluphenazine increased susceptibility to caspofungin and reduced their thermotolerance. Furthermore, the fluphenazine/caspofungin combination significantly impaired biofilm formation in an in vitro polyurethane catheter model. All these features participated in the increasing survival of infected G. mellonella after combination treatment in comparison with caspofungin alone. CONCLUSIONS: In a repurposing strategy, our findings confirm that calmodulin could provide a relevant target in life-threatening fungal infectious diseases.


Assuntos
Candida glabrata , Flufenazina , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Biofilmes , Calmodulina/genética , Candida glabrata/genética , Caspofungina , Farmacorresistência Fúngica , Equinocandinas/farmacologia , Flufenazina/farmacologia , Testes de Sensibilidade Microbiana , Virulência
13.
Arch. Soc. Esp. Oftalmol ; 95(2): 84-89, feb. 2020. ilus, graf
Artigo em Espanhol | IBECS | ID: ibc-195331

RESUMO

La dopamina es sintetizada por la tirosina hidroxilasa y es considerada como una catecolamina mayor en la retina de los vertebrados, incluyendo el pez cebra. Sin embargo, se conoce poco sobre la función del receptor de dopamina D2 (DRD2) en la fisiología retiniana. Por lo tanto, para dilucidar el papel del DRD2 en el desarrollo y la función de los ojos en el pez cebra, los peces fueron expuestos a la flufenazina, quinpirol, o la combinación de ambos, y luego se evaluó el tamaño del ojo, el diámetro del nervio óptico (ONd) y la adaptación visual al fondo. Los resultados mostraron que la flufenazina (flufenazina, antagonista DRD2) disminuyó el tamaño del ojo y el diámetro del nervio óptico seguido de una interrupción de la función visual. La adición de quinpirol (quinpirol, agonista DRD2) invirtió los efectos causados por flufenazina, lo que implica que DRD2 es necesario para el desarrollo y la función normal del ojo en el pez cebra. Considerando el papel de las neuronas dopaminérgicas en el desarrollo y la función de la retina, la disfunción de las vías de señalización de las neuronas dopaminérgicas en la retina puede causar anormalidades visuales, particularmente en la participación de la dopamina en la regulación de la respuesta de la luz


Dopamine is synthesized by tyrosine hydroxylase and is considered as a major catecholamine in the vertebrate retina, including zebrafish. However, little is known about the role of dopamine D2 receptor (DRD2) in retinal physiology. Therefore, to elucidate the role of DRD2 in the eye development and function in zebrafish, fish were exposed to fluphenazine, quinpirole, or combination of both. Subsequently, the eye size, optic nerve diameter (ONd), and visual background adaptation were evaluated. The results showed that fluphenazine (fluphenazine, DRD2 antagonist) decreased eye size and optic nerve diameter followed by disruption of visual function. The addition of Quinpirole (quinpirole, DRD2 agonist) reversed the effects caused by fluphenazine, implying that DRD2 is necessary for normal eye development and function in zebrafish. Considering the role of dopaminergic neurons in retinal development and function, dysfunction of dopaminergic neuron signaling pathways in the retina may cause visual abnormalities, particularly in the involvement of dopamine in regulating light response


Assuntos
Animais , Antagonistas dos Receptores de Dopamina D2/farmacologia , Olho/embriologia , Fenômenos Fisiológicos Oculares , Receptores de Dopamina D2/fisiologia , Olho/anatomia & histologia , Olho/crescimento & desenvolvimento , Flufenazina/farmacologia , Imuno-Histoquímica , Tamanho do Órgão , Quimpirol/farmacologia
14.
Arch Soc Esp Oftalmol (Engl Ed) ; 95(2): 84-89, 2020 Feb.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-31955999

RESUMO

Dopamine is synthesized by tyrosine hydroxylase and is considered as a major catecholamine in the vertebrate retina, including zebrafish. However, little is known about the role of dopamine D2 receptor (DRD2) in retinal physiology. Therefore, to elucidate the role of DRD2 in the eye development and function in zebrafish, fish were exposed to fluphenazine, quinpirole, or combination of both. Subsequently, the eye size, optic nerve diameter (ONd), and visual background adaptation were evaluated. The results showed that fluphenazine (fluphenazine, DRD2 antagonist) decreased eye size and optic nerve diameter followed by disruption of visual function. The addition of Quinpirole (quinpirole, DRD2 agonist) reversed the effects caused by fluphenazine, implying that DRD2 is necessary for normal eye development and function in zebrafish. Considering the role of dopaminergic neurons in retinal development and function, dysfunction of dopaminergic neuron signaling pathways in the retina may cause visual abnormalities, particularly in the involvement of dopamine in regulating light response.


Assuntos
Antagonistas dos Receptores de Dopamina D2/farmacologia , Olho/embriologia , Fenômenos Fisiológicos Oculares , Receptores de Dopamina D2/fisiologia , Animais , Olho/anatomia & histologia , Olho/crescimento & desenvolvimento , Flufenazina/farmacologia , Imuno-Histoquímica , Tamanho do Órgão , Quimpirol/farmacologia
15.
Spectrochim Acta A Mol Biomol Spectrosc ; 227: 117563, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31689607

RESUMO

Phenothiazines are very effective antipsychotic drugs, which also have anticancer and antimicrobial activities. Despite being used in human treatment, the molecular mechanism of the biological actions of these molecules is not yet understood in detail. The role of the interactions between phenothiazines and proteins or lipid membranes has been much discussed. Herein, fourier-transform infrared (FTIR) spectroscopic studies were used to investigate the effect of three phenothiazines: fluphenazine (FPh); chlorpromazine (ChP); and propionylpromazine (PP) on the structures of a positively charged poly-l-lysine (PLL) peptide, a negatively charged dipalmitoylphosphatidylcholine/dipalmitoylphosphatidylglycerol (DPPC/DPPG) membrane, and on the mutual interactions between electrostatically associated PLL molecules and DPPC/DPPG membranes. Phenothiazine-induced alterations in the secondary structure of PLL, the conformational state (trans/gauche) of the hydrocarbon lipid chains, and the hydration of the DPPC/DPPG membrane interface were studied on the basis of amide I' vibrations, antisymmetric and symmetric stretching vibrations of the CH2 groups of the lipid hydrocarbon chains (νsCH2), and stretching vibrations of the lipid C=O groups (νC = O), respectively. It was shown that in the presence of negatively charged DPPC/DPPG membranes, the phenothiazines were able to modify the secondary structure of charged PLL molecules. Additionally, the effect of PLL on the structure of DPPC/DPPG membranes was also altered by the presence of the phenothiazine molecules.


Assuntos
1,2-Dipalmitoilfosfatidilcolina/metabolismo , Antipsicóticos/farmacologia , Clorpromazina/farmacologia , Flufenazina/farmacologia , Fosfatidilgliceróis/metabolismo , Promazina/análogos & derivados , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Humanos , Polilisina/metabolismo , Promazina/farmacologia , Espectroscopia de Infravermelho com Transformada de Fourier
16.
Artigo em Português | Coleciona SUS, Coleciona SUS, CONASS, SES-GO | ID: biblio-1118711

RESUMO

Tecnologia: Palmitato de Paliperidona (PP) é um antipsicótico injetáveis de efeito prolongado (AIEP). Indicação: Tratamento sintomático da esquizofrenia. Objetivo: Comparar a eficácia, segurança e efetividade terapêutica entre PP e outros AIEP para o tratamento de esquizofrenia em adultos. Pergunta: O PP é mais eficaz e seguro que os outros AIEP (Decanoato de Haloperidol, Enantato de Flufenazina, Decanoato de Zuclopentixol, Risperidona-IEP) para o tratamento sintomático de esquizofrenia em adultos? Métodos: Levantamento bibliográfico, com estratégias estruturadas de busca, na base de dados PUBMED. Foi feita avaliação da qualidade metodológica das revisões sistemáticas (RS), ensaios clínicos randomizados (ECR) e dos estudos observacionais de efetividade no mundo real (EOEMR) com as ferramentas Assessing the Methodological Quality of Systematic Reviews (AMSTAR), Delphi List e Newcastle-Ottawa Scale (NOS), respectivamente. Resultados: Foram selecionadas 3 RS, 1 ECR e 3 EOEMR. Conclusão: PP (de aplicação mensal) tem similar eficácia e segurança com a Risperidona-IEP para o tratamento de esquizofrenia, exceto que provoca menor incidência de sintomas extrapiramidais. PP e Decanoato de Haloperidol são similares na eficácia e segurança para o tratamento de esquizofrenia, inclusive no risco de sintomas extrapiramidais (discinesias tardias e parkinsonismo), exceto que PP tem menor incidência de acatisia. PP é similar aos outros AIEP nos vários desfechos de eficácia e segurança terapêutica, inclusive mortalidade


Technology: Paliperidone palmitate (PP) is a long-acting injectable (LAI) antipsychotics. Indication: Symptomatic treatment of schizophrenia. Objective: To compare the therapeutic efficacy, safety and effectiveness in the real world between PP and other LAI antipsychotics for the treatment of schizophrenia in adults. Question: Is PP more effective and safer than other LAI antipsychotics (Haloperidol Decanoate, Fluphenazine Enanthate, Zuclopentixol Decanoate, Risperidone-LAI), for the symptomatic treatment of schizophrenia? Methods: Bibliographic survey, with structured search strategies, in the PUBMED database. Na evaluation was made of the methodological quality of systematic reviews (SR), randomized clinical trials (RCT) and observational studies (OS) of effectiveness in the real world with Assessing the Methodological Quality of Systematic Reviews (AMSTAR), Delphi List and Newcastle-Ottawa Scale (NOS) tools, respectively. Results: 3 SR, 1 RCT and 3 OE were included. Conclusion: PP (monthly dose presentation) has similar efficacy and safety with Risperidone-LAI for the treatment of schizophrenia, except that it causes a lower incidence of extrapyramidal symptoms. PP and Haloperidol Decanoate are similar in efficacy and safety for the treatment of schizophrenia, including the risk of extra-pyramidal symptoms (tardive dyskinesias and parkinsonism), except that PP has a lower incidence of akathisia. PP has similar outcomes of efficacy and safety to the other LAI antipsychotics, including mortality risk


Assuntos
Humanos , Esquizofrenia/tratamento farmacológico , Antipsicóticos/uso terapêutico , Palmitato de Paliperidona/uso terapêutico , Clopentixol/uso terapêutico , Risperidona/uso terapêutico , Medicina Baseada em Evidências , Flufenazina/uso terapêutico , Haloperidol/uso terapêutico
17.
Anticancer Res ; 39(7): 3757-3765, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262902

RESUMO

BACKGROUND/AIM: The study focused on identifying the mechanisms or drugs that might sensitize resistant KBV20C human oral squamous carcinoma cells overexpressing P-glycoprotein (P-gp) to antimitotic drug treatment. MATERIALS AND METHODS: Five HIV protease inhibitors (atazanavir, nelfinavir, darunavir, lopinavir, and ritonavir) were tested to identify drugs that could be used at a relatively low dose for sensitizing antimitotic drug-resistant KBV20C cells. Fluorescence-activated cell sorting, annexin V analyses, and rhodamine uptake tests were performed to further investigate the mechanism of action. RESULTS: Co-treatment with nelfinavir or lopinavir had a high sensitizing effect on vincristine-treated KBV20C cells. Nelfinavir and lopinavir reduced cell viability, increased G2 phase arrest, and up-regulated apoptosis when used as a co-treatment with vincristine. We also demonstrated that eribulin co-treatment with nelfinavir and lopinavir similarly increased sensitization of KBV20C cells. Only lopinavir was found to have a high P-gp-inhibitory activity (similar to verapamil). Interestingly, nelfinavir had very low P-gp-inhibitory activity, suggesting that vincristine-nelfinavir sensitization is independent of the P-gp-inhibitory effect of nelfinavir. We also demonstrated this same combination mainly caused sensitization due to late apoptosis in P-gp-overexpressing drug-resistant KBV20C cells. CONCLUSION: Highly antimitotic drug-resistant KBV20C cells can be sensitized by co-treatment with the repositioned HIV protease inhibitors nelfinavir and lopinavir. In particular, the sensitizing effect of co-treatment with nelfinavir on antimitotic drug-resistant cancer cells was found to be strong and independent of P-gp-inhibitory activity. As P-gp inhibition can be toxic to normal cells, selecting nelfinavir may be safer for normal cells in patients with drug-resistant cancer.


Assuntos
Antimitóticos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Furanos/farmacologia , Inibidores da Protease de HIV/farmacologia , Cetonas/farmacologia , Lopinavir/farmacologia , Nelfinavir/farmacologia , Vincristina/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Sinergismo Farmacológico , Flufenazina/farmacologia , Humanos , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/metabolismo , Ritonavir/farmacologia
18.
J Psychopharmacol ; 33(8): 1015-1029, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31219367

RESUMO

BACKGROUND: The functional role of dopamine D1 and D2 receptors in gambling disorder (GD) remains unclear. AIMS: This study aimed to investigate the role of D1 activation and the moderating effects of impulsivity, a trait linked with weaker D2-mediated inhibition of dopamine release, in GD subjects. METHODS: Thirty (nine female) non-comorbid GD subjects with low (LI), moderate (MI), or high impulsivity (HI) received the preferential D2 antagonist haloperidol (HAL; 3 mg) or the mixed D1-D2 antagonist fluphenazine (FLU; 3 mg), on separate sessions before a 15-minute slot machine game or amphetamine (AMPH; 20 mg), in a placebo-controlled, double-blind, counterbalanced design. RESULTS: On their own, HAL and FLU led to linear increases and decreases, respectively, in desire to gamble across increasing levels of impulsivity. The slot machine and AMPH each evoked an inverted-U pattern of desire to gamble across increasing impulsivity. HAL reversed this effect of the game, whereas FLU did not alter post-game desire. HAL and FLU decreased and increased psychostimulant-like effects of the game, respectively, in LI and MI subjects, but consistently reduced these effects in HI subjects. HAL also altered the salience of negative affective words on a reading task, such that greater salience of negative words coincided with lower post-game desire to gamble. CONCLUSIONS: D1 receptors appear to gauge the incentive value of gambling in GD subjects. D1 activation has negative reinforcing effects in HI gamblers and positive reinforcing effects in LI gamblers. Medications that activate D1 could curtail chasing in HI gamblers. D1 blockade could benefit HI gamblers whose main concern is craving.


Assuntos
Antagonistas dos Receptores de Dopamina D2/uso terapêutico , Jogo de Azar/tratamento farmacológico , Jogo de Azar/fisiopatologia , Comportamento Impulsivo/efeitos dos fármacos , Comportamento Impulsivo/fisiologia , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Adulto , Anfetamina/uso terapêutico , Estimulantes do Sistema Nervoso Central/uso terapêutico , Método Duplo-Cego , Feminino , Flufenazina/uso terapêutico , Haloperidol/uso terapêutico , Humanos , Masculino , Motivação/efeitos dos fármacos , Motivação/fisiologia , Reforço Psicológico
19.
Appl Microbiol Biotechnol ; 103(16): 6701-6709, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31201451

RESUMO

Candida albicans causes a high mortality rate in immunocompromised individuals, but the increased drug resistance challenges the current antifungal therapeutics. Fluphenazine (FPZ), a commonly used antipsychotic medication, can induce the expression of drug efflux pumps in C. albicans and, thus, may interfere with the therapeutic efficacy of antifungals, such as fluconazole (FLC) and amphotericin B (AmB). Here, we investigated the combined effects of FLC/FPZ and AmB/FPZ against C. albicans in vitro and in a systemic candidiasis mouse model. The antifungal activity of FLC was significantly reduced when supplemented with FPZ. The inhibitory effects of FLC on the expression of the Candida virulence-related genes ALS3 and HWP1 were antagonized by FPZ. However, FPZ enhanced the susceptibility of C. albicans to AmB and further downregulated the expression of ALS3 and HWP1 in a synergistic manner with AmB. FPZ also enhanced the gene expression of ERG11, a key gene of the ergosterol biosynthesis pathway that has been associated with the activities of both FLC and AmB. In our mammalian infection model, mice treated with FLC/FPZ showed notably poor living status and increased fungal burden in their kidneys and brains compared with those treated with FLC alone. Conversely, the combined application of AmB/FPZ significantly improved the survival rate, attenuated the weight loss and reduced the organ fungal burdens of the infected mice. These data suggest that FPZ antagonized the therapeutic efficacy of FLC but enhanced the antifungal activity of AmB in the treatment of candidiasis.


Assuntos
Anfotericina B/farmacologia , Antifúngicos/farmacologia , Antipsicóticos/farmacologia , Candida albicans/efeitos dos fármacos , Interações Medicamentosas , Fluconazol/farmacologia , Flufenazina/farmacologia , Anfotericina B/administração & dosagem , Estruturas Animais , Animais , Antifúngicos/administração & dosagem , Antipsicóticos/administração & dosagem , Candidíase/tratamento farmacológico , Contagem de Colônia Microbiana , Modelos Animais de Doenças , Fluconazol/administração & dosagem , Flufenazina/administração & dosagem , Perfilação da Expressão Gênica , Regulação Fúngica da Expressão Gênica/efeitos dos fármacos , Camundongos , Resultado do Tratamento
20.
Photochem Photobiol Sci ; 18(9): 2232-2239, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30860541

RESUMO

The cytotoxic activity of fluphenazine (FPZ) in combination with UVA light was evaluated on three human tumor cell lines, HeLa, MSTO-211H and A431. The photobiological effect was determined following irradiation treatment in the presence of/or after the removal of incubated FPZ. Under both conditions, FPZ proved to be very effective in killing tumor cells, with GI50 values in the micromolar range. However, when FPZ was present during irradiation, the photocytotoxicity was at least two times higher than that after its removal suggesting the contribution of the drug both outside and inside the cells. The uptake of FPZ was very fast and, after only 15 minutes of incubation, the compound was accumulated inside lysosomes, as evidenced through fluorescence microscopy. FPZ distribution covered also the nucleus and the cytoplasm without significant plasma membrane association. After irradiation, the membrane of lysosomes in which FPZ was accumulated lost its integrity suggesting that the released lysosomal enzymes played an important role in cell death, and mitochondria were damaged as well, following apoptosis. Indeed, cytofluorimetric studies demonstrated that apoptosis was the main mechanism of cell death. Finally, an extremely high production of ROS was found, indicating a significant photodynamic mechanism involved in the photocytotoxic effect of FPZ. Taken together, our data show that FPZ following UVA irradiation behaves as an effective photoantiproliferative compound inducing apoptosis on various human tumor cells.


Assuntos
Antipsicóticos/farmacologia , Apoptose/efeitos dos fármacos , Flufenazina/farmacologia , Raios Ultravioleta , Anticorpos Monoclonais/imunologia , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Lisossomos/imunologia , Microscopia de Fluorescência , Mitocôndrias/imunologia , Imagem Óptica , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
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