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1.
Sci Rep ; 11(1): 17747, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34493757

RESUMO

Deregulation of synaptic function and neurotransmission has been linked with the development of major depression disorder (MDD). Tianeptine (Tian) has been used as antidepressant with anxiolytic properties and recently as a nootropic to improve cognitive performance, but its mechanism of action is unknown. We conducted a proteomic study on the hippocampal synaptosomal fractions of adult male Wistar rats exposed to chronic social isolation (CSIS, 6 weeks), an animal model of depression and after chronic Tian treatment in controls (nootropic effect) and CSIS-exposed rats (lasting 3 weeks of 6-week CSIS) (therapeutic effect). Increased expression of Syn1 and Camk2-related neurotransmission, vesicle transport and energy processes in Tian-treated controls were found. CSIS led to upregulation of proteins associated with actin cytoskeleton, signaling transduction and glucose metabolism. In CSIS rats, Tian up-regulated proteins involved in mitochondrial energy production, mitochondrial transport and dynamics, antioxidative defense and glutamate clearance, while attenuating the CSIS-increased glycolytic pathway and cytoskeleton organization proteins expression and decreased the expression of proteins involved in V-ATPase and vesicle endocytosis. Our overall findings revealed that synaptic vesicle dynamics, specifically exocytosis, and mitochondria-related energy processes might be key biological pathways modulated by the effective nootropic and antidepressant treatment with Tian and be a potential target for therapeutic efficacy of the stress-related mood disorders.


Assuntos
Antidepressivos/farmacologia , Transtorno Depressivo/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Nootrópicos/farmacologia , Proteoma/efeitos dos fármacos , Isolamento Social , Vesículas Sinápticas/efeitos dos fármacos , Tiazepinas/farmacologia , Animais , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Antidepressivos/uso terapêutico , Transtorno Depressivo/fisiopatologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/ultraestrutura , Masculino , Mitocôndrias/fisiologia , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Nootrópicos/uso terapêutico , Mapeamento de Interação de Proteínas , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Tiazepinas/uso terapêutico
2.
Molecules ; 26(15)2021 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-34361628

RESUMO

In excitable cells, mitochondria play a key role in the regulation of the cytosolic Ca2+ levels. A dysregulation of the mitochondrial Ca2+ buffering machinery derives in serious pathologies, where neurodegenerative diseases highlight. Since the mitochondrial Na+/Ca2+ exchanger (NCLX) is the principal efflux pathway of Ca2+ to the cytosol, drugs capable of blocking NCLX have been proposed to act as neuroprotectants in neuronal damage scenarios exacerbated by Ca2+ overload. In our search of optimized NCLX blockers with augmented drug-likeness, we herein describe the synthesis and pharmacological characterization of new benzothiazepines analogues to the first-in-class NCLX blocker CGP37157 and its further derivative ITH12575, synthesized by our research group. As a result, we found two new compounds with an increased neuroprotective activity, neuronal Ca2+ regulatory activity and improved drug-likeness and pharmacokinetic properties, such as clog p or brain permeability, measured by PAMPA experiments.


Assuntos
Doenças Neurodegenerativas/tratamento farmacológico , Neurônios/efeitos dos fármacos , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores , Acidente Vascular Cerebral/tratamento farmacológico , Tiazepinas , Animais , Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/síntese química , Bloqueadores dos Canais de Cálcio/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Humanos , Mitocôndrias , Neurônios/patologia , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/farmacologia , Ratos , Tiazepinas/síntese química , Tiazepinas/farmacologia
3.
Actas Esp Psiquiatr ; 49(4): 135-144, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34195969

RESUMO

The depressive disorder coexists in a high prevalence with a substance-related disorder, which is asso- ciated with a worst prognosis. The therapeutic interventions for this co-morbidity lack of the appropriate scientific sup- port. The existing evidence suggest that the currently avail- able anti-depressive drugs are of minor efficacy in this group of patients. An alternative would be the use of different drugs with distinctive neurobiological mechanism of action. The aim of this study was to describe the clinical develop- ment of a series of patients affected by this comorbidity un- der treatment with tianeptine under usual clinical practices.


Assuntos
Transtorno Depressivo Maior , Transtornos Relacionados ao Uso de Substâncias , Tiazepinas , Antidepressivos Tricíclicos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Humanos , Transtornos Relacionados ao Uso de Substâncias/complicações , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Tiazepinas/uso terapêutico
5.
Oncologist ; 26(10): e1862-e1869, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34180099

RESUMO

BACKGROUND: Constipation is a common, distressing complication in patients with cancer receiving palliative care. Elobixibat is a novel inhibitor of the ileal bile acid transporter that is used to treat chronic constipation by stimulating bowel function. However, its efficacy in patients with cancer has not been examined. This study investigated the drug's effectiveness in patients with cancer with chronic constipation. PATIENTS AND METHODS: This prospective-sampling, single-center, observational study included hospitalized patients with cancer diagnosed, using the Rome IV criteria, with chronic constipation. Within 2 weeks of hospitalization, each participant was administered elobixibat (5-15 mg) daily until discharge. Spontaneous bowel movements (SBMs), complete spontaneous bowel movements (CSBMs), Bristol stool form scale (BSFS) scores, and the Patient Assessment of Constipation Quality of Life questionnaire (PAC-QOL) scores were assessed before and after elobixibat administration. We also evaluated the relationship between the amount of food consumed and the SBM frequency. RESULTS: Among the 83 participants, the mean pre- and post-treatment frequencies of daily SBMs were 0.3 and 1.2 (p < .0001) and those of CSBMs were 0.1 and 0.6 (p < .0001), respectively. The mean pretreatment BSFS score was 1.6, whereas the post-treatment value was 3.5 (p < .0001); the mean PAC-QOL score (overall) improved from 1.01 to 0.74 (p = .01). There was no significant change in the daily SBM frequency between fasting and feeding states (1.2 vs. 1.3; p = .8), and there was no correlation between the amount of food intake and the SBM frequency after elobixibat administration (r = .03). Serious adverse events were not observed. CONCLUSION: This study showed that elobixibat is safe and effective for patients with cancer with chronic constipation, regardless of the food intake amount. IMPLICATIONS FOR PRACTICE: Elobixibat was effective at relieving chronic constipation in patients with various cancers. Serious adverse events were not observed, and the relief of constipation was independent of variation in food intake.


Assuntos
Neoplasias , Qualidade de Vida , Constipação Intestinal/tratamento farmacológico , Constipação Intestinal/etiologia , Dipeptídeos , Ingestão de Alimentos , Humanos , Neoplasias/complicações , Estudos Prospectivos , Tiazepinas
6.
Molecules ; 26(9)2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33946996

RESUMO

Respiratory syncytial virus (RSV) is a major pathogen that causes severe lower respiratory tract infection in infants, the elderly and the immunocompromised worldwide. At present no approved specific drugs or vaccines are available to treat this pathogen. Recently, several promising candidates targeting RSV entry and multiplication steps are under investigation. However, it is possible to lead to drug resistance under the long-term treatment. Therapeutic combinations constitute an alternative to prevent resistance and reduce antiviral doses. Therefore, we tested in vitro two-drug combinations of fusion inhibitors (GS5806, Ziresovir and BMS433771) and RNA-dependent RNA polymerase complex (RdRp) inhibitors (ALS8176, RSV604, and Cyclopamine). The statistical program MacSynergy II was employed to determine synergism, additivity or antagonism between drugs. From the result, we found that combinations of ALS8176 and Ziresovir or GS5806 exhibit additive effects against RSV in vitro, with interaction volume of 50 µM2% and 31 µM2% at 95% confidence interval, respectively. On the other hand, all combinations between fusion inhibitors showed antagonistic effects against RSV in vitro, with volume of antagonism ranging from -50 µM2 % to -176 µM2 % at 95% confidence interval. Over all, our results suggest the potentially therapeutic combinations in combating RSV in vitro could be considered for further animal and clinical evaluations.


Assuntos
Antivirais/farmacologia , Descoberta de Drogas , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Antivirais/química , Antivirais/uso terapêutico , Descoberta de Drogas/métodos , Sinergismo Farmacológico , Quimioterapia Combinada , Humanos , Quinazolinas/química , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/virologia , Bibliotecas de Moléculas Pequenas , Tiazepinas/química , Tiazepinas/farmacologia , Tiazepinas/uso terapêutico , Inibidores de Proteínas Virais de Fusão/química , Inibidores de Proteínas Virais de Fusão/farmacologia , Inibidores de Proteínas Virais de Fusão/uso terapêutico
7.
Am J Drug Alcohol Abuse ; 47(4): 455-466, 2021 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-33909525

RESUMO

Background: Originally believed to be an atypical antidepressant acting at serotonin transporters, tianeptine is now known to also be an atypical agonist at mu-opioid receptors. Its nonmedical use may be increasing amidst the broader context of novel drug and supplement use.Objectives: To analyze social-media text from current, former, and prospective tianeptine users for better understanding of their conceptualizations of tianeptine, motives for and patterns of use, and reported benefits and harms.Methods: Reddit posts were obtained and thematically coded; additional quantitative analyses were conducted.Results: A total of 210 posts mentioning tianeptine were made between 2012 and 2020. Eighteen thematic categories were identified, 10 of which were consistent with expected themes. Two independent raters coded all text, generating 1,382 unique codes, of which 1,090 were concordant (78.9% interrater agreement). Tianeptine use was frequently associated with use of other drugs, particularly kratom, phenibut, and racetams. People conceptualized and variously used tianeptine as an opioid, antidepressant, and "nootropic" (cognitive enhancer). Between 2014 and 2020, mentions of positive effects decreased, while mentions of adverse effects and withdrawal increased. Motivations for use included substitution or withdrawal mitigation for other drugs (especially opioids) and for kratom itself; self-treatment for psychiatric symptoms; and improvement of quality of life, mood, or performance. Descriptions of tolerance, withdrawal, and addiction were evident. Intravenous use was rare and strongly discouraged, with detrimental effects described.Conclusion: Tianeptine is recognized as an opioid (though not only an opioid) in online communities. Posts describe benefits, acute risks, and patterns of co-use that warrant greater clinical attention.


Assuntos
Usuários de Drogas/psicologia , Mídias Sociais , Tiazepinas/administração & dosagem , Humanos , Receptores Opioides mu/agonistas
10.
Mol Autism ; 12(1): 14, 2021 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-33608048

RESUMO

BACKGROUND: Autism spectrum disorder (ASD) is associated with deficits in executive functioning (EF), and these have been suggested to contribute to core as well as co-occurring psychiatric symptoms. The biological basis of these deficits is unknown but may include the serotonergic system, which is involved both in regulating EF in neurotypical populations and in the pathophysiology of ASD. We previously demonstrated that reducing serotonin by acute tryptophan depletion (ATD) shifts differences in brain function during performance of EF tasks towards control levels. However, ATD cannot be easily used in the clinic, and we therefore need to adopt alternative approaches to challenge the serotonin system. Hence, we investigated the role of the serotonergic modulator tianeptine on EF networks in ASD. METHOD: We conducted a pharmacological magnetic resonance imaging study, using a randomized double-blind crossover design, to compare the effect of an acute dosage of 12.5 mg tianeptine and placebo on brain activation during two EF tasks (of response inhibition and sustained attention) in 38 adult males: 19 with ASD and 19 matched controls. RESULTS: Under placebo, compared to controls, individuals with ASD had atypical brain activation in response inhibition regions including the inferior frontal cortex, premotor regions and cerebellum. During sustained attention, individuals with ASD had decreased brain activation in the right middle temporal cortex, right cuneus and left precuneus. Most of the case-control differences in brain function observed under placebo conditions were abolished by tianeptine administration. Also, within ASD individuals, brain functional differences were shifted significantly towards control levels during response inhibition in the inferior frontal and premotor cortices. LIMITATIONS: We conducted a pilot study using a single dose of tianeptine, and therefore, we cannot comment on long-term outcome. CONCLUSIONS: Our findings provide the first evidence that tianeptine can shift atypical brain activation during EF in adults with ASD towards control levels. Future studies should investigate whether this shift in the biology of ASD is maintained after prolonged treatment with tianeptine and whether it improves clinical symptoms.


Assuntos
Antidepressivos Tricíclicos/uso terapêutico , Transtorno Autístico/tratamento farmacológico , Encéfalo/diagnóstico por imagem , Função Executiva/efeitos dos fármacos , Tiazepinas/uso terapêutico , Adulto , Atenção/efeitos dos fármacos , Transtorno Autístico/diagnóstico por imagem , Transtorno Autístico/fisiopatologia , Transtorno Autístico/psicologia , Encéfalo/fisiopatologia , Estudos Cross-Over , Método Duplo-Cego , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Adulto Jovem
11.
Spectrochim Acta A Mol Biomol Spectrosc ; 251: 119412, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33433378

RESUMO

A rapid, cost effective, simple and reliable method was developed for the determination of Tianeptine (TIA) drug in bulk and in pharmaceutical formulation. The fluorescence of Vilazodone was measured in isopropanol at room temperature. The method was optimized by measuring the factors that may affect the fluorescence intensity such as: pH, diluting solvent, temperature and mixing time. The developed method was validated according to ICH guidelines in terms of accuracy, precision, linearity, range, LOD and LOQ. The concentration range was found to be linear in the range of 10-100 ng/ml. The LOD and LOQ values were found to be very small (1.86, 5.62 ng/mL. The % RSD and the % R were found within the acceptable range. Unlike the HPLC procedures, the proposed method for TIA determination has many advantages over the reported analytical methods represented in its rapidity, lower cost and environmental safety as the instrument is simple with low operating cost.


Assuntos
Tiazepinas , Cloridrato de Vilazodona , Cromatografia Líquida de Alta Pressão , Espectrometria de Fluorescência
13.
Bioorg Chem ; 108: 104585, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33508676

RESUMO

In this work, a series of diaryl benzo[b][1,4]thiazepine derivatives D1-D36 were synthesized and screened as tubulin polymerization inhibitors with anti-tumor potency. They were designed by introducing the seven-member ring benzothiazepine as the linker for CA-4 modification for the first time. Among them, the hit compound D8 showed potential on inhibiting the growth of several cancer cell lines (IC50 values: 1.48 µM for HeLa, 1.47 µM for MCF-7, 1.52 µM for HT29 and 1.94 µM for A549), being comparable with the positive controls Colchicine and CA-4P. The calculated IC50 value of D8 as an tubulin polymerization inhibitor was 1.20 µM. The results of the flow cytometry assay revealed that D8 could induce the mitotic catastrophe and the death of living cancer cells. D8 also indicated the anti-vascular activity. The possible binding pattern was implied by docking simulation, inferring the possibility of introducing interactions with the nearby tubulin chain. Since the novel structural trial has been conducted with preliminary discussion, this work might stimulate new ideas in further modification of tubulin-related anti-cancer agents and therapeutic approaches.


Assuntos
Antineoplásicos/farmacologia , Tiazepinas/farmacologia , Moduladores de Tubulina/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Polimerização/efeitos dos fármacos , Relação Estrutura-Atividade , Tiazepinas/síntese química , Tiazepinas/química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química
14.
Hepatol Int ; 15(2): 392-404, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33398776

RESUMO

BACKGROUND: Recent studies have suggested that several types of toxic bile acids (BAs) are involved in the pathogenesis of non-alcoholic steatohepatitis (NASH). In the present study, we aimed to determine whether elobixibat, an ileal bile acid transporter (IBAT) inhibitor, would ameliorate NASH in mice. METHODS: C57BL/6N mice were fed a methionine and choline-deficient (MCD) to induce NASH or standard diet as control for 8 weeks (n = 5 per group). The MCD diet-fed mice were administered elobixibat 5 days a week for 4 weeks by gavage (n = 5). The effects of the treatments on liver histopathology, proinflammatory cytokine concentrations, intestinal epithelial tight junctions, and the intestinal microbial composition were then assessed. RESULTS: In MCD-fed mice, hepatic fibrosis and inflammatory cell infiltration developed, and the serum aspartate transaminase activity and BA concentration were higher than the control. In addition, the proinflammatory cytokine concentrations were high in the liver and mesenteric lymph nodes (MLN), and the expression of intestinal epithelium tight junction proteins, claudin1, was increased. In the intestinal microbial composition, the abundance of the Lachnospiraceae and Ruminococcaeae were decreased, whereas that of the Enterobacteriaceae was increased. Treatment with elobixibat reduced the serum BA and increased the fecal BA concentration, and ameliorated the liver inflammation and fibrosis. It also reduced the expression of proinflammatory cytokines in the liver and MLNs, and transforming growth factor-ß expression in the liver. Finally, elobixibat normalized intestinal tight junction protein level and the composition of the intestinal microbiota. CONCLUSION: Elobixibat ameliorates NASH-related histopathology, reduces cytokine expression, and normalizes the intestinal microbial composition in MCD-fed mice, which suggests that it may represent a promising candidate for the therapy of NASH.


Assuntos
Dipeptídeos/uso terapêutico , Hepatopatia Gordurosa não Alcoólica , Tiazepinas/uso terapêutico , Animais , Proteínas de Transporte , Modelos Animais de Doenças , Íleo , Glicoproteínas de Membrana , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico
15.
Dig Dis ; 39(4): 341-350, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33142288

RESUMO

INTRODUCTION: Elobixibat is a new laxative, but its efficacy and adverse events (AEs) are insufficiently examined compared with those of other laxatives. Hence, by propensity score (PS) matching, we compared the effects and AEs between elobixibat and lubiprostone. METHODS: We retrospectively analyzed 1,887 Japanese patients with chronic constipation (CC) treated at our hospital between October 2013 and April 2020. Enrolled patients were divided into three treatment groups, namely, elobixibat (10 mg daily) (E10 group, n = 293), lubiprostone (24 µg daily) (L24 group, n = 772), and lubiprostone (48 µg daily) (L48 group, n = 822), as their first treatment. We then investigated the changes on the weekly average number of spontaneous bowel movements, stool consistency scores (SCSs), and AEs starting from the baseline until the end of the 2-week treatment. To adjust for patients' background, we performed one-to-one nearest neighbor matching without replacement between elobixibat- and lubiprostone-treated patients according to the individual estimated PSs. RESULTS: After treatment, for SCSs, both the L24 and L48 groups significantly improved compared with the E10 group (p < 0.05), but their stools were soft (Bristol Stool Form Scale: 4.8). Notably, the E10 group had less frequent AEs than the L24 group (26 [9.0%] vs. 43 [14.8%], p = 0.03). Particularly, nausea was significantly less in the E10 group than that in the L48 group (2 [0.7%] vs. 7 [2.4%], p = 0.01). CONCLUSION: Elobixibat is a beneficial drug for patients with mildly symptomatic CC and is safe to use, given its few AEs.


Assuntos
Constipação Intestinal/tratamento farmacológico , Dipeptídeos/uso terapêutico , Laxantes/uso terapêutico , Lubiprostona/uso terapêutico , Tiazepinas/uso terapêutico , Doença Crônica , Defecação/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pontuação de Propensão , Estudos Retrospectivos , Resultado do Tratamento
16.
Clin Toxicol (Phila) ; 59(2): 152-157, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32552075

RESUMO

BACKGROUND: Tianeptine is an antidepressant structurally similar to tricyclic antidepressants which is approved abroad but is currently a drug of abuse in the United States since at least 2000. In 2019, our poison center experienced an increase in calls relating to this xenobiotic. The goal of this report is to describe the characteristics of acute tianeptine intoxication and withdrawal. METHODS: All calls to a statewide poison center regarding tianeptine were reviewed from January 1, 2015 to March 15, 2020. Cases were identified using the American Association of Poison Control Centers' substance code for "other types of tricyclic antidepressants." Cases were excluded if they did not involve tianeptine. Date of call, patient demographics, symptoms, cardiac intervals if available, and disposition were recorded. RESULTS: Eighty-four cases of atypical tricyclic antidepressants were identified in the study period. Forty-eight cases involving tianeptine met inclusion criteria and were reviewed. Of these, 37 (77%) occurred from May 2019 to March 2020. Twenty-seven (56%) required medical admission including 17 cases (35%) that were managed in an intensive care unit. Seventeen of the 48 cases resulted from acute tianeptine intoxication. Lethargy was the most common presentation, but some patients also presented with agitation. Thirty-one (65%) of the cases resulted from tianeptine withdrawal, which usually exhibited agitation, anxiety, gastrointestinal distress. Naloxone was used in 4 cases (24%) of the acute intoxication cohort and benzodiazepines were frequently used both in acutely intoxicated patients and in patients experiencing tianeptine withdrawal. No patients in either cohort had cardiac conduction disturbances. CONCLUSION: Our center observed a dramatic rise in tianeptine toxicity, particularly in patients experiencing withdrawal symptoms, beginning in May 2019. More than half of the cases required medical admission including a third who were treated in the intensive care unit. Health care practitioners should be increasingly aware of this xenobiotic as usage may be on the rise.


Assuntos
Saúde Pública , Tiazepinas/envenenamento , Doença Aguda , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Centros de Controle de Intoxicações , Estudos Retrospectivos , Síndrome de Abstinência a Substâncias/epidemiologia , Adulto Jovem
17.
Cell Biochem Funct ; 39(2): 248-257, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32643225

RESUMO

Oocyte activation deficiency leads to female infertility. [Ca2+ ]i oscillations are required for mitochondrial energy supplement transition from the resting to the excited state, but the underlying mechanisms are still very little known. Three mitochondrial Ca2+ channels, Mitochondria Calcium Uniporter (MCU), Na+ /Ca2+ Exchanger (NCLX) and Voltage-dependent Ca2+ Channel (VDAC), were deactivated by inhibitors RU360, CGP37157 and Erastin, respectively. Both Erastin and CGP37157 inhibited mitochondrial activity significantly while attenuating [Ca2+ ]i and [Ca2+ ]m oscillations, which caused developmental block of pronuclear formation. Thus, NCLX and VDAC are two mitochondria-associated Ca2+ transporter proteins regulating oocyte activation, which may be used as potential targets to treat female infertility. SIGNIFICANCE OF THE STUDY: NCLX and VDAC are two mitochondria-associated Ca2+ transporter proteins regulating oocyte activation.


Assuntos
Canais de Cálcio/metabolismo , Cálcio/metabolismo , Oócitos/metabolismo , Animais , Canais de Cálcio/química , Feminino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Mitocôndrias/metabolismo , Oócitos/citologia , Oócitos/efeitos dos fármacos , Compostos de Rutênio/farmacologia , Rutênio Vermelho/farmacologia , Trocador de Sódio e Cálcio/antagonistas & inibidores , Trocador de Sódio e Cálcio/metabolismo , Tiazepinas/farmacologia , Canais de Ânion Dependentes de Voltagem/antagonistas & inibidores , Canais de Ânion Dependentes de Voltagem/metabolismo
18.
Aliment Pharmacol Ther ; 53(2): 234-242, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33296518

RESUMO

BACKGROUND: A subset of patients with chronic constipation has associated slow colonic transit and reduced faecal bile acid excretion. In addition to traditional approaches to treat chronic constipation, a novel therapeutic option is to increase the colonic concentration of intraluminal bile acids. This can be achieved through inhibition of the ileal bile acid transporter. AIM: To evaluate the evidence for efficacy and safety of an ileal bile acid transport inhibitor in the treatment of chronic constipation METHODS: We reviewed published literature on elobixibat, based on a PubMed search. RESULTS: Elobixibat is a novel ileal bile acid transport inhibitor that has demonstrated efficacy in proof of concept studies in experimental animals as well as phase 1, 2 and 3 trials in humans. Phase 4 studies have now documented that the beneficial effects are related to increase in the secretory bile acids in the colon as measured by stool bile acid content. The studies documented efficacy in patients with severe constipation, which is often associated with slow colonic transit. These changes in bile acid composition were associated with minor differences in the faecal microbiota in patients treated with elobixibat compared to placebo. Elobixibat appears to be safe. The only adverse effects of note are associated with its pharmacological actions in patients with chronic constipation,namely the induction of diarrhoea and abdominal pain. CONCLUSION: This new class of compound appears to be safe and efficacious in the treatment of chronic constipation.


Assuntos
Tiazepinas , Animais , Ácidos e Sais Biliares , Constipação Intestinal/tratamento farmacológico , Dipeptídeos , Trânsito Gastrointestinal , Humanos
19.
Transl Psychiatry ; 10(1): 378, 2020 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-33154348

RESUMO

Polymorphisms of genes involved in the hypothalamic-pituitary-adrenocortical (HPA) axis have been associated with response to several antidepressant treatments in patients suffering of depression. These pharmacogenetics findings have been reported from independent cohorts of patients mostly treated with selective serotonin reuptake inhibitors, tricyclic antidepressant, and mirtazapine. Tianeptine, an atypical antidepressant, recently identified as a mu opioid receptor agonist, which prevents and reverses the stress induced by glucocorticoids, has been investigated in this present pharmacogenetics study. More than 3200 Caucasian outpatients with a major depressive episode (MDE) from real-life settings were herein analyzed for clinical response to tianeptine, a treatment initiated from 79.5% of the subjects, during 6-8 weeks follow-up, assessing polymorphisms targeting four genes involved in the HPA axis (NR3C1, FKPB5, CRHR1, and AVPR1B). We found a significant association (p < 0.001) between CRHR1 gene variants rs878886 and rs16940665, or haplotype rs878886*C-rs16940665*T, and tianeptine antidepressant response and remission according to the hospital anxiety and depression scale. Analyses, including a structural equation model with simple mediation, suggest a moderate effect of sociodemographic characteristics and depressive disorder features on treatment response in individuals carrying the antidepressant responder allele rs8788861 (allele C). These findings suggest direct pharmacological consequences of CRHR1 polymorphisms in the antidepressant tianeptine response and remission, in MDE patients. This study replicates the association of the CRHR1 gene, involved in the HPA axis, with (1) a specificity attributed to treatment response, (2) a lower risk of chance finding, and in (3) an ecological situation.


Assuntos
Transtorno Depressivo Maior , Receptores de Hormônio Liberador da Corticotropina , Tiazepinas , Antidepressivos/uso terapêutico , Proteínas de Transporte/genética , Hormônio Liberador da Corticotropina/metabolismo , Transtorno Depressivo Maior/tratamento farmacológico , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Proteínas com Domínio LIM/genética , Masculino , Pacientes Ambulatoriais , Sistema Hipófise-Suprarrenal/metabolismo , Receptores de Hormônio Liberador da Corticotropina/genética , Tiazepinas/farmacologia
20.
PLoS One ; 15(10): e0240610, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33049001

RESUMO

Presynaptic mitochondrial Ca2+ plays a critical role in the regulation of synaptic transmission and plasticity. The presynaptic bouton of the hippocampal mossy fiber (MF) is much larger in size than that of the Schaffer collateral (SC) synapse. Here we compare the structural and physiological characteristics of MF and SC presynaptic boutons to reveal functional and mechanistic differences between these two synapses. Our quantitative ultrastructural analysis using electron microscopy show many more mitochondria in MF presynaptic bouton cross-section profiles compared to SC boutons. Consistent with these results, post-tetanic potentiation (PTP), a form of presynaptic short-term plasticity dependent on mitochondrial Ca2+, is reduced by inhibition of mitochondrial Ca2+ release at MF synapses but not at SC synapses. However, blockade of mitochondrial Ca2+ release results in reduction of PTP at SC synapses by disynaptic MF stimulation. Furthermore, inhibition of mitochondrial Ca2+ release selectively decreases frequency facilitation evoked by short trains of presynaptic stimulation at MF synapses, while having no effect at SC synapses. Moreover, depletion of ER Ca2+ stores leads to reduction of PTP at MF synapses, but PTP is unaffected by ER Ca2+ depletion at SC synapses. These findings show that MF and SC synapses differ in presynaptic mitochondrial content as well as mitochondrial Ca2+ dependent synaptic plasticity, highlighting differential regulatory mechanisms of presynaptic plasticity at MF and SC synapses.


Assuntos
Cálcio/metabolismo , Hipocampo/metabolismo , Fibras Musgosas Hipocampais/metabolismo , Plasticidade Neuronal/fisiologia , Animais , Sinalização do Cálcio/efeitos dos fármacos , Sinalização do Cálcio/fisiologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/ultraestrutura , Masculino , Camundongos , Microscopia Eletrônica , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fibras Musgosas Hipocampais/efeitos dos fármacos , Fibras Musgosas Hipocampais/ultraestrutura , Plasticidade Neuronal/efeitos dos fármacos , Oniocompostos/farmacologia , Compostos Organofosforados/farmacologia , Técnicas de Patch-Clamp , Tiazepinas/farmacologia
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