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1.
Rev Med Suisse ; 16(681): 314-317, 2020 Feb 12.
Artigo em Francês | MEDLINE | ID: mdl-32049453

RESUMO

Suicide is a common cause of death in Switzerland. It often occurs during a period of crisis marked by a disruption of the subject's intrapsychic, interpersonal or social balance. The management of this crisis is crucial and essentially psychotherapeutic. Drug therapy may be necessary for the management of acute symptoms or for the prevention of long-term suicidal risk. Benzodiazepines and atypical antipsychotics are often used for acute symptoms such as anxiety or sleep disorders while other molecules are recognized in reducing long-term suicidal risk. Some disorders, such as borderline personality disorder, account for more frequent suicidal behaviors. The pharmacological management of these specific situations is discussed.


Assuntos
Antipsicóticos/farmacologia , Suicídio/prevenção & controle , Suicídio/psicologia , Benzodiazepinas/farmacologia , Transtorno da Personalidade Borderline/psicologia , Humanos , Fatores de Risco , Ideação Suicida , Suíça
2.
Life Sci ; 239: 117033, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31697950

RESUMO

AIMS: Benzodiazepines (BZDs) produce various pharmacological actions by binding to and allosterically regulating GABAA receptors. Several in vitro studies have demonstrated diazepam, the prototypic BZD, produces a high-dose action that cannot be countered with the classical BZD-binding site antagonist flumazenil. Here, we investigate the existence and behavioral relevance of non-classical BZD binding sites in zebrafish larvae. MAIN METHODS: Zebrafish larvae were treated with a series of BZDs alone or combined with flumazenil, bicuculline (a non-selective GABAA receptor antagonist), or RO 15-4513 (a general BZD antagonist and a proposed antagonist interacting with α+/ß- interfaces in α4/6/ß3δ receptors), and their locomotor activities and behavioral phenotypes were recorded. KEY FINDINGS: Diazepam-induced hypolocomotion (sedation-like state) at low doses (10 and 20 mg L-1) was effectively antagonized by flumazenil or bicuculline, while diazepam-induced immobility (anesthesia-like state) at higher dose (30 mg L-1) was prevented by bicuculline (3 mg L-1) but not flumazenil, even at doses up to 150 mg L-1. Ro 15-4513 also failed to efficiently antagonize diazepam-induced immobility. Immobility induced by high dose of another 1,4-BZD, clonazepam, was also resistant to flumazenil. SIGNIFICANCE: These results provide direct in vivo evidence for non-classical BZD-binding sites, which may be located at the second transmembrane domain of GABAA receptors and contribute to BZD-induced anesthesia.


Assuntos
Benzodiazepinas/metabolismo , Benzodiazepinas/farmacologia , Flumazenil/farmacologia , Moduladores GABAérgicos/farmacologia , Atividade Motora/efeitos dos fármacos , Receptores de GABA-A/efeitos dos fármacos , Animais , Azidas/farmacologia , Benzodiazepinas/toxicidade , Bicuculina/farmacologia , Sítios de Ligação/efeitos dos fármacos , Clonazepam/farmacologia , Relação Dose-Resposta a Droga , Feminino , Flumazenil/toxicidade , Antagonistas GABAérgicos/farmacologia , Moduladores GABAérgicos/toxicidade , Larva , Masculino , Peixe-Zebra
3.
PLoS Negl Trop Dis ; 13(11): e0007826, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31730614

RESUMO

Parasitic flatworm infections (e.g. tapeworms and fluke worms) are treated by a limited number of drugs. In most cases, control is reliant upon praziquantel (PZQ) monotherapy. However, PZQ is ineffective against sexually immature parasites, and there have also been several concerning reports on cestode and trematode infections with poor PZQ cure-rates, emphasizing the need for alternative therapies to treat these infections. We have revisited a series of benzodiazepines given the anti-schistosomal activity of meclonazepam (MCLZ). MCLZ was discovered in the 1970's but was not brought to market due to dose-limiting sedative side effects. However, in the decades since there have been advances in our understanding of the benzodiazepine GABAA receptor sub-types that drive sedation and the development of sub-type selective, non-sedating ligands. Additionally, the sequencing of flatworm genomes reveals that parasitic trematodes and cestodes have lost GABAAR-like ligand gated anion channels, indicating that MCLZ's anti-parasitic target is distinct from the human receptors that drive sedation. Therefore, we have screened a library of classical and non-sedating 1,4-benzodiazepines against Schistosoma mansoni and identified a series of imidazobenzodiazepines that immobilize worms in vitro. One of these hits, Xhe-II-048 also disrupted the parasite tegument, resulting in extensive vacuole formation beneath the apical membrane. The hit compound series identified has a dramatically lower (~1000×) affinity for the human central benzodiazepine binding site and is a promising starting point for the development of novel anti-schistosomal benzodiazepines with minimal host side-effects.


Assuntos
Anti-Helmínticos/farmacologia , Benzodiazepinas/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Animais , Avaliação Pré-Clínica de Medicamentos , Locomoção/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/patologia
4.
Eur J Med Chem ; 182: 111670, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31499359

RESUMO

A series of novel structurally-related tubulin polymerization inhibitors based on benzodiazepine were designed, synthesized, and evaluated for anticancer activity. Extensive structure modifications were performed to investigate the detailed structure and activity relationships (SARs). Most compounds exhibited potent antiproliferative activity against a panel of cancer cell lines. Among these compounds, the optimal compound, 9a, possessed the most superior activity, including cytotoxicity against five cancer cell lines (IC50 = 6-15 nM) and inhibition of tubulin polymerization (IC50 = 1.65 ±â€¯0.11 µM). Mechanistic studies revealed that 9a could disrupt intracellular microtubule organization, arrest cell cycle at the G2/M phase and eventually induce cell apoptosis. Compound 9a exhibited good metabolic stability with a t1/2 of 161.2 min, which was much better than the reference compound CA-4. Moreover, the disodium salt of 9a, 9a-P, exhibited excellent in vivo antitumor activity in xenograft mice model with inhibitory rate of 89.3%, which was better than the reference compounds CA-4P (inhibitory rate: 52.8%) and Y-01P (inhibitory rate: 77.7%). Altogether, 9a could serve as a promising lead compound for the development of highly efficient anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Benzodiazepinas/farmacologia , Desenho de Drogas , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Benzodiazepinas/química , Benzodiazepinas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Polimerização/efeitos dos fármacos , Relação Estrutura-Atividade , Moduladores de Tubulina/química , Moduladores de Tubulina/metabolismo
5.
Chem Commun (Camb) ; 55(68): 10128-10131, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31386708

RESUMO

Fueled by the therapeutic potential of the epigenetic machinery, BET bromodomains have seen high interest as drug targets. Herein, we introduce different linkers to a BET bromodomain benzodiazepine ligand (I-BET762) to gauge its implications in the development of hybrid drugs, imaging probes and small molecule drug conjugates. Biophysical studies confirmed minimal disruption to binding of the BRD4 cavity by the synthesized entities, which includes imaging probes. Target engagement was confirmed in a cellular context, but poor membrane diffusion was found despite efficient localization in the nuclei after membrane disruption. Our study highlights challenges and opportunities for the successful design of benzodiazepine-derived drug-delivery systems.


Assuntos
Benzodiazepinas/farmacologia , Fluoresceínas/farmacologia , Corantes Fluorescentes/farmacologia , Proteínas Nucleares/antagonistas & inibidores , Benzodiazepinas/síntese química , Benzodiazepinas/química , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Desenho de Drogas , Fluoresceínas/síntese química , Fluoresceínas/química , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Humanos , Ligantes , Estrutura Molecular , Proteínas Nucleares/química , Domínios Proteicos
6.
Eur J Med Chem ; 179: 591-607, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31279293

RESUMO

Antibody-drug conjugates (ADCs) containing pyrrolobenzodiazepine (PBD) dimers are currently being evaluated in human oncology clinical trials with encouraging results. To further improve the therapeutic window, next-generation PBD drug-linker design has focused on the inclusion of additional tumor-selective triggers and use of lower-potency PBDs. ß-Glucuronidase is a well-known target for discovery prodrugs due to increased presence in tumor cells and microenvironment. In this study, a ß-glucuronidase cleavable cap was investigated at the PBD N10-position and compared with corresponding free imine ADCs. SG3600 (glucuronide) ADCs showed in vitro and in vivo efficacy/tolerability comparable to SG3400 (imine) ADCs, and good 50% inhibitory concentration differentials were observed in vitro between control non-antigen-targeted ADCs and targeted ADCs. Dependence on ß-glucuronidase for SG3600 activity was demonstrated through CRISPRCas9 knockdown studies and addition of exogenous ß-glucuronidase. SG3600 showed better serum stability, improved conjugation efficiency and was able to reach high drug-to-antibody ratio without aggregation.


Assuntos
Benzodiazepinas/farmacologia , Dipeptídeos/farmacologia , Glucuronídeos/farmacologia , Imunoconjugados/farmacologia , Pirróis/farmacologia , Benzodiazepinas/síntese química , Benzodiazepinas/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dipeptídeos/química , Relação Dose-Resposta a Droga , Glucuronídeos/química , Humanos , Imunoconjugados/química , Estrutura Molecular , Pirróis/síntese química , Pirróis/química , Relação Estrutura-Atividade
7.
Drug Des Devel Ther ; 13: 1033-1047, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31037028

RESUMO

Background: Remimazolam is an ultra-short acting benzodiazepine under development for procedural sedation and general anesthesia. It is hydrolyzed by CES1 to an inactive metabolite (CNS7054). Purpose: In this study, the effect of continuous remimazolam exposure on its metabolism and on CES1 expression was investigated in a dynamic 3-D bioreactor culture model inoculated with primary human hepatocytes. Methods: Remimazolam was continuously infused into bioreactors for 5 days at a final concentration of 3,000 ng/ml (6.8 µM). In parallel, 2-D cultures were run with cells from the same donors, but with discontinuous exposure to remimazolam. Results: Daily measurement of clinical chemistry parameters (glucose, lactate, urea, ammonia, and liver enzymes) in culture supernatants indicated no noxious effect of remimazolam on hepatocyte integrity as compared to untreated controls. Concentrations of remimazolam reached steady-state values of around 250 ng/ml within 8 hours in 3-D bioreactors whereas in 2-D cultures remimazolam concentrations declined to almost zero within the same time frame. Levels of CNS7054 showed an inverse time-course reaching average values of 1,350 ng/ml in perfused 3-D bioreactors resp. 2,800 ng/ml in static 2-D cultures. Analysis of mRNA expression levels of CES1 indicated no changes in gene expression over the culture period. Conclusion: The results indicated a stable metabolism of remimazolam during 5 days of continuous exposure to clinically relevant concentrations of the drug. Moreover, there was no evidence for a harmful effect of remimazolam exposure on the integrity and metabolic activity of in vitro cultivated primary human hepatocytes.


Assuntos
Benzodiazepinas/metabolismo , Reatores Biológicos , Hepatócitos/metabolismo , Benzodiazepinas/administração & dosagem , Benzodiazepinas/farmacologia , Hidrolases de Éster Carboxílico/biossíntese , Hepatócitos/efeitos dos fármacos , Humanos
8.
Curr Top Med Chem ; 19(9): 741-752, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30931859

RESUMO

Background & Introduction: Pyrrolobenzodiazepine (PBD) dimers are highly potent DNA cross-linking agents used as warheads in Antibody Drug Conjugates (ADCs) for cancer therapy. We propose to investigate the correlation existing between the lipophilicity of those molecules and their activity (both in vitro and in vivo) as well as any effect observed during conjugation. MATERIALS AND METHODS: Reaction progress was monitored by Thin-Layer Chromatography (TLC) using Merck Kieselgel 60 F254 silica gel, with a fluorescent indicator on aluminium plates. Visualisation of TLC was achieved with UV light or iodine vapour unless otherwise stated. Flash chromatography was performed using Merck Kieselgel 60 F254 silica gel. RESULTS: We have successfully designed and synthesized a novel PBD warhead (SG3312) with enhanced physicochemical properties. The warhead also displayed increased potency in vitro. After overcoming some epimerization issues, the synthesis of enantiomerically pure payload was achieved (SG3259) and fulfilled our criteria for a simplified and more efficient conjugation. No addition of propylene glycol was required, and high DAR and excellent monomeric purity were achieved. CONCLUSION: The ADC (Herceptin-maia-SG3259) has been shown to release the active warhead (SG3312) upon exposure to Cathepsin B and demonstrated encouraging activity both in vitro and in vivo.


Assuntos
Antineoplásicos/farmacologia , Benzodiazepinas/farmacologia , Pirróis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Benzodiazepinas/síntese química , Benzodiazepinas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cromatografia em Camada Delgada , Dimerização , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Géis/química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Estrutura Molecular , Pirróis/síntese química , Pirróis/química , Dióxido de Silício/química , Relação Estrutura-Atividade
10.
Neurol Res ; 41(5): 385-398, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30821663

RESUMO

OBJECTIVE: JM-20, a novel hybrid synthetic molecule, has been reported to have antioxidant, mitoprotective, anti-excitotoxic, anti-apoptotic and anti-inflammatory properties. However, the neuroprotective effect of JM-20 against memory impairment in preclinical AD-like models has not been analyzed. The aim of this study was to evaluate the potential neuroprotection of JM-20 that preserves essential memory process from cholinergic dysfunction and other molecular damages. METHODS: The effects of JM-20 on scopolamine (1 mg/kg)-induced cognitive disorders were studied. Male Wistar rats (220-230 g) were treated with JM-20 and/or scopolamine, and behavioral tasks were performed. The AChE activity, superoxide dismutase activity, catalase activity, MDA and T-SH level on brain tissue were determined by spectrophotometric methods. Mitochondrial functionality parameters were measured after behavioral tests. Histological analyses on hippocampus and prefrontal cortex were processed with hematoxylin and eosin, and neuronal and axonal damage were determined. RESULTS: The behavioral, biochemical and histopathological studies revealed that oral pre-treatment with JM-20 (8 mg/kg) significantly attenuated the scopolamine-induced memory deficits, mitochondrial malfunction, oxidative stress, and prevented AChE hyperactivity probably due to specific inhibition of AChE enzyme. It was also observed marked histological protection on hippocampal and prefrontal-cortex regions. CONCLUSIONS: The multimodal action of this molecule could mediate the memory protection here observed and suggest that it may modulate different pathological aspects of memory deficits associated with AD in humans.


Assuntos
Benzodiazepinas/farmacologia , Inibidores da Colinesterase/farmacologia , Disfunção Cognitiva/tratamento farmacológico , Memória/efeitos dos fármacos , Niacina/análogos & derivados , Nootrópicos/farmacologia , Acetilcolinesterase/metabolismo , Animais , Antioxidantes/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/fisiologia , Masculino , Memória/fisiologia , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Niacina/farmacologia , Distribuição Aleatória , Ratos Wistar , Escopolamina
11.
Cent Nerv Syst Agents Med Chem ; 19(2): 146-151, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30827267

RESUMO

BACKGROUND: Approach for green chemistry for chemical synthesis is found to be very efficient as it makes the reaction more easily, less tedious, maximize desired products and minimize by-products. MATERIALS & METHODS: Utilizing this approach 1, 5-benzodiazepines and its derivatives have been synthesized and evaluated for skeletal muscle and antianxiety activity. 1, 5-benzodiazepine derivatives have attracted great attention due to its diversity of pharmacological activities and its application in heterocyclic synthesis and medicines. The target compounds were synthesized by first reacting o-phenylenediamine with acetophenone to yield 1, 5-benzodiazepines. In the next step the NH of 1, 5-benzodiazepines were chloroacetylated and then the chloro group was substituted with different anilines. The structures were confirmed on the basis of their TLC, IR, 1H NMR and CHN elemental studies. The physicochemical parameters were determined for BBB penetration through online software. RESULTS: The Log P values of the compounds tested showed that compounds have the potential to be CNS active. The compounds were evaluated for the skeletal muscle relaxant activity and antianxiety activity. It was investigated that 1, 5-benzodiazepines derivatives possess significant differences between control group and treated group. CONCLUSION: Among these derivatives, the compound bearing chloro group possesses the highest skeletal muscle relaxant and antianxiety activity.


Assuntos
Ácido Acético/síntese química , Ansiolíticos/síntese química , Benzodiazepinas/síntese química , Fármacos do Sistema Nervoso Central/síntese química , Química Verde/métodos , Relaxantes Musculares Centrais/síntese química , Ácido Acético/farmacologia , Ácido Acético/uso terapêutico , Animais , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Ansiedade/tratamento farmacológico , Ansiedade/psicologia , Benzodiazepinas/farmacologia , Benzodiazepinas/uso terapêutico , Catálise , Fármacos do Sistema Nervoso Central/farmacologia , Fármacos do Sistema Nervoso Central/uso terapêutico , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Relaxantes Musculares Centrais/farmacologia , Relaxantes Musculares Centrais/uso terapêutico , Relação Estrutura-Atividade
12.
J Neurooncol ; 142(3): 411-422, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30725256

RESUMO

PURPOSE: Pediatric brain cancer medulloblastoma (MB) standard-of-care results in numerous comorbidities. MB is comprised of distinct molecular subgroups. Group 3 molecular subgroup patients have the highest relapse rates and after standard-of-care have a 20% survival. Group 3 tumors have high expression of GABRA5, which codes for the α5 subunit of the γ-aminobutyric acid type A receptor (GABAAR). We are advancing a therapeutic approach for group 3 based on GABAAR modulation using benzodiazepine-derivatives. METHODS: We performed analysis of GABR and MYC expression in MB tumors and used molecular, cell biological, and whole-cell electrophysiology approaches to establish presence of a functional 'druggable' GABAAR in group 3 cells. RESULTS: Analysis of expression of 763 MB tumors reveals that group 3 tumors share high subgroup-specific and correlative expression of GABR genes, which code for GABAAR subunits α5, ß3 and γ2 and 3. There are ~ 1000 functional α5-GABAARs per group 3 patient-derived cell that mediate a basal chloride-anion efflux of 2 × 109 ions/s. Benzodiazepines, designed to prefer α5-GABAAR, impair group 3 cell viability by enhancing chloride-anion efflux with subtle changes in their structure having significant impact on potency. A potent, non-toxic benzodiazepine ('KRM-II-08') binds to the α5-GABAAR (0.8 µM EC50) enhancing a chloride-anion efflux that induces mitochondrial membrane depolarization and in response, TP53 upregulation and p53, constitutively phosphorylated at S392, cytoplasmic localization. This correlates with pro-apoptotic Bcl-2-associated death promoter protein localization. CONCLUSION: GABRA5 expression can serve as a diagnostic biomarker for group 3 tumors, while α5-GABAAR is a therapeutic target for benzodiazepine binding, enhancing an ion imbalance that induces apoptosis.


Assuntos
Benzodiazepinas/farmacologia , Neoplasias Cerebelares/patologia , Meduloblastoma/patologia , Receptores de GABA-A/química , Regulação Alostérica , Morte Celular/efeitos dos fármacos , Neoplasias Cerebelares/tratamento farmacológico , Neoplasias Cerebelares/metabolismo , Perfilação da Expressão Gênica , Humanos , Meduloblastoma/tratamento farmacológico , Meduloblastoma/metabolismo , Receptores de GABA-A/metabolismo , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
13.
Artigo em Inglês | MEDLINE | ID: mdl-30790623

RESUMO

INTRODUCTION: Organophosphorus nerve agents (OPNAs) irreversibly block acetylcholinesterase activity, resulting in accumulation of excess acetylcholine at neural synapses, which can lead to a state of prolonged seizures known as status epilepticus (SE). Benzodiazepines, the current standard of care for SE, become less effective as latency to treatment increases. In a mass civilian OPNA exposure, concurrent trauma and limited resources would likely cause a delay in first response time. To address this issue, we have developed a rat model to test novel anticonvulsant/ neuroprotectant adjuncts at delayed time points. METHODS: For model development, adult male rats with cortical electroencephalographic (EEG) electrodes were exposed to soman and administered saline along with atropine, 2-PAM, and midazolam 5, 20, or 40 min after SE onset. We validated our model using three drugs: scopolamine, memantine, and phenobarbital. Using the same procedure outlined above, rats were given atropine, 2-PAM, midazolam and test treatment 20 min after SE onset. RESULTS: Using gamma power, delta power, and spike rate to quantify EEG activity, we found that scopolamine was effective, memantine was minimally effective, and phenobarbital had a delayed effect on terminating SE. Fluoro-Jade B staining was used to assess neuroprotection in five brain regions. Each treatment provided significant protection compared to saline + midazolam in at least two brain regions. DISCUSSION: Because our data agree with previously published studies on the efficacy of these compounds, we conclude that this model is a valid way to test novel anticonvulsants/ neuroprotectants for controlling benzodiazepine-resistant OPNA-induced SE and subsequent neuropathology.


Assuntos
Anticonvulsivantes/farmacologia , Benzodiazepinas/farmacologia , Memantina/farmacologia , Agentes Neurotóxicos/farmacologia , Fármacos Neuroprotetores/farmacologia , Fenobarbital/farmacologia , Escopolamina/farmacologia , Estado Epiléptico/tratamento farmacológico , Animais , Atropina/farmacologia , Encéfalo/efeitos dos fármacos , Eletroencefalografia/métodos , Masculino , Midazolam/farmacologia , Ratos , Ratos Sprague-Dawley , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Soman/farmacologia , Estado Epiléptico/induzido quimicamente
14.
Biol Pharm Bull ; 42(2): 280-288, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30713259

RESUMO

The present study aimed to investigate the potential inhibitory effects of 21 clinically available hypnotics on acetylcholine (ACh)-induced contractions in rat urinary bladder smooth muscle (UBSM) in order to predict whether these hypnotics could induce voiding impairment. ACh-induced contraction in rat UBSM was inhibited only by diphenhydramine (a histamine H1 receptor antagonist) at a concentration that was clinically relevant. ACh-induced contraction was also significantly inhibited by flurazepam (a benzodiazepine hypnotic) and suvorexant (an orexin receptor antagonist), albeit at concentrations that substantially exceeded clinically achievable blood levels. These three drugs (at 10-5 M) also inhibited high-KCl (80 mM) Locke-Ringer solution-induced contractions. In contrast to the effects of the abovementioned hypnotics, ACh-induced contractions were not significantly affected by triazolam, etizolam, brotizolam, lormetazepam, estazolam, flunitrazepam, nitrazepam (benzodiazepine hypnotics), thiopental, thiamylal, pentobarbital, amobarbital, secobarbital, phenobarbital (barbiturate hypnotics), zolpidem (an imidazopyridine hypnotic), zopiclone (a cyclopyrrolone hypnotic), ramelteon (a melatonin receptor agonist), bromovalerylurea, and chloral hydrate. These findings suggest that most clinically used hypnotics are not likely to result in anticholinergic-induced dysuria within their clinically achievable blood concentration ranges. Diphenhydramine may, however, induce voiding impairment, an action attributable to diminished UBSM contractility within its clinical dose range.


Assuntos
Acetilcolina/antagonistas & inibidores , Acetilcolina/farmacologia , Hipnóticos e Sedativos/farmacologia , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Bexiga Urinária/efeitos dos fármacos , Animais , Atropina/farmacologia , Barbitúricos/farmacologia , Benzodiazepinas/farmacologia , Interações de Medicamentos , Masculino , Contração Muscular/fisiologia , Ratos , Ratos Wistar , Bexiga Urinária/fisiologia
15.
Mol Pharm ; 16(2): 737-743, 2019 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-30652875

RESUMO

Honokiol (HNK) is a small-molecule lignin extracted from Magnolia Officinalis, demonstrating high potency in promoting nonrapid eye movement (NREM) sleep by modulating the benzodiazepine site of the GABAA receptor. However, the clinical use of HNK in the treatment of insomnia is restricted by its extremely low oral bioavailability. In the present work, enhanced oral bioavailability of HNK was achieved by loading it into poly lactide-glycolide acid microparticles (HNK-MP). After oral administration, HNK-MP demonstrated 15-fold increase of AUC0-12 h in comparison to free HNK. The maximum blood concentration ( Cmax) of HNK in HNK-MP-treated rats was 3.6 µg/mL at 2 h after oral administration, which was 6.5-fold of that in free HNK-treated rats. Oral administration of HNK-MP (20 mg/kg) efficiently increased NREM sleep by 60% by enhancing the transition from wakefulness to NREM sleep in rats. The biosafety of HNK-MP was assessed in vivo, and no damage occurred in the gastrointestinal tract. The present study provides a promising oral HNK formulation for the treatment of insomnia.


Assuntos
Compostos de Bifenilo/farmacologia , Movimentos Oculares/efeitos dos fármacos , Lignanas/farmacologia , Administração Oral , Animais , Benzodiazepinas/farmacologia , Compostos de Bifenilo/administração & dosagem , Portadores de Fármacos/química , Eletroencefalografia , Feminino , Lignanas/administração & dosagem , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/metabolismo , Sono de Ondas Lentas/efeitos dos fármacos
16.
Clin Obstet Gynecol ; 62(1): 156-167, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30628916

RESUMO

Benzodiazepine use and dependence are on the rise as well as the number of deaths attributable to the combination of opioids and benzodiazepines. Anxiety, the most frequent condition for which benzodiazepines are prescribed, occurs commonly, and is increasingly noted to coincide with pregnancy. Use of both benzodiazepine anxiolytics and anxiety in pregnancy is associated with preterm delivery and low birth weight. Short-term neonatal effects of hypotonia, depression, and withdrawal are described but long-term sequelae, if any, are poorly understood. Benzodiazepines are associated with physical dependence and withdrawal symptoms which can be serious. To avoid withdrawal, tapering off these medications is recommended. What is known about the pharmacology and pharmacokinetics, pregnancy implications, tapering schedules, and alternative strategies for anxiety are discussed.


Assuntos
Ansiolíticos/efeitos adversos , Benzodiazepinas/efeitos adversos , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Ansiolíticos/administração & dosagem , Ansiolíticos/farmacocinética , Ansiolíticos/farmacologia , Ansiedade/complicações , Ansiedade/terapia , Benzodiazepinas/administração & dosagem , Benzodiazepinas/farmacocinética , Benzodiazepinas/farmacologia , Feminino , Humanos , Gravidez , Nascimento Prematuro/etiologia , Efeitos Tardios da Exposição Pré-Natal/etiologia , Síndrome de Abstinência a Substâncias/fisiopatologia
17.
Neuropharmacology ; 148: 169-177, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30629989

RESUMO

Transmembrane AMPA receptor (AMPAR) regulatory proteins (TARP) increase neuronal excitability. However, it is unknown how TARP affect rhythmic neural network activity. Here we studied TARP effects on local field potential (LFP) bursting, membrane potential and cytosolic Ca2+ (Cai) in locus coeruleus neurons of newborn rat brain slices. LFP bursting was not affected by the unselective competitive ionotropic glutamate receptor antagonist kynurenic acid (2.5 mM). TARP-AMPAR complex activation with 25 µM CNQX accelerated LFP rhythm 2.2-fold and decreased its irregularity score from 63 to 9. Neuronal spiking was correspondingly 2.3-fold accelerated in association with a 2-5 mV depolarization and a modest Cai rise whereas Cai was unchanged in neighboring astrocytes. After blocking rhythmic activities with tetrodotoxin (1 µM), CNQX caused a 5-8 mV depolarization and also the Cai rise persisted. In tetrodotoxin, both responses were abolished by the non-competitive AMPAR antagonist GYKI 53655 (25 µM) which also reversed stimulatory CNQX effects in control solution. The CNQX-evoked Cai rise was blocked by the L-type voltage-activated Ca2+ channel inhibitor nifedipine (100 µM). The findings show that ionotropic glutamate receptor-independent neonatal locus coeruleus network bursting is accelerated and becomes more regular by activating a TARP-AMPAR complex. The associated depolarization-evoked L-type Ca2+ channel-mediated neuronal Cai rise may be pivotal to regulate locus coeruleus activity in cooperation with SK-type K+ channels. In summary, this is the first demonstration of TARP-mediated stimulation of neural network bursting. We hypothesize that TARP-AMPAR stimulation of rhythmic locus coeruleus output serves to fine-tune its control of multiple brain functions thus comprising a target for drug discovery.


Assuntos
Locus Cerúleo/fisiologia , Receptores de AMPA/fisiologia , 6-Ciano-7-nitroquinoxalina-2,3-diona/antagonistas & inibidores , 6-Ciano-7-nitroquinoxalina-2,3-diona/farmacologia , Animais , Animais Recém-Nascidos , Benzodiazepinas/farmacologia , Cálcio/metabolismo , Ácido Cinurênico/farmacologia , Locus Cerúleo/efeitos dos fármacos , Locus Cerúleo/metabolismo , Potenciais da Membrana/fisiologia , Neurônios/fisiologia , Ratos , Receptores de AMPA/agonistas , Receptores de AMPA/antagonistas & inibidores , Tetrodotoxina/farmacologia
18.
J Oral Pathol Med ; 48(3): 214-221, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30618144

RESUMO

BACKGROUND: Despite improvements in oral squamous cell carcinoma (OSCC) management, survival rates remain relatively low and novel anti-neoplastic agents are needed. Bromodomain and extra-terminal (BET) inhibitors proved to be promising agents for cancer treatment. We investigated the effects of three BET inhibitors (JQ1, IBET-151, IBET-762) on SCC-25 cell line and primary oral cancer cell culture. METHODS: Cell viability was evaluated by MTT. Protein levels of MCM5 and cleaved-PARP were estimated by Western blot. Clonogenic and migratory abilities were determined by colony forming and scratch assays. BET inhibitors effects on mRNA levels of E-Cadherin, Vimentin, SNAI1, SNAI2, CLU, SERPINI1, MCM5, c-Myc, E2F, IL7R, and PPARg were analyzed by qPCR. RESULTS: BET inhibitors significantly reduced oral cancer cell viability. JQ1 showed the greatest effect reducing cell viability to 10%, both in SCC-25 and primary OSCC cultures (P < 0.001), compared to control cells. Cells treated with BET inhibitors displayed a reduction to 50% in colony forming capacity compared to control cells (P < 0.0001) and the colonies were smaller; they also had a 50%-60% reduction in migratory capacity (P < 0.05) compared to untreated cells. BET inhibitors had a significant impact on genes related to epithelial to mesenchymal transition and other cancer cell markers, notably on MCM5, a gene related to cell cycle control. CONCLUSIONS: BET inhibitors induce both OSCC cell death and reduction of tumor aggressiveness. Molecular mechanisms of BET inhibition involve among others, MCM5 downregulation. Importantly, this study demonstrates for the first time the anti-tumoral effect of IBET-151 and IBET-762 in oral cancer.


Assuntos
Antineoplásicos/farmacologia , Azepinas/farmacologia , Benzodiazepinas/farmacologia , Carcinoma de Células Escamosas/patologia , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Bucais/patologia , Triazóis/farmacologia , Carcinoma de Células Escamosas/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Neoplasias Bucais/genética , Células-Tronco Neoplásicas/efeitos dos fármacos
19.
Nature ; 565(7740): 454-459, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30602790

RESUMO

Type-A γ-aminobutyric (GABAA) receptors are ligand-gated chloride channels with a very rich pharmacology. Some of their modulators, including benzodiazepines and general anaesthetics, are among the most successful drugs in clinical use and are common substances of abuse. Without reliable structural data, the mechanistic basis for the pharmacological modulation of GABAA receptors remains largely unknown. Here we report several high-resolution cryo-electron microscopy structures in which the full-length human α1ß3γ2L GABAA receptor in lipid nanodiscs is bound to the channel-blocker picrotoxin, the competitive antagonist bicuculline, the agonist GABA (γ-aminobutyric acid), and the classical benzodiazepines alprazolam and diazepam. We describe the binding modes and mechanistic effects of these ligands, the closed and desensitized states of the GABAA receptor gating cycle, and the basis for allosteric coupling between the extracellular, agonist-binding region and the transmembrane, pore-forming region. This work provides a structural framework in which to integrate previous physiology and pharmacology research and a rational basis for the development of GABAA receptor modulators.


Assuntos
Alprazolam/química , Bicuculina/química , Microscopia Crioeletrônica , Diazepam/química , Picrotoxina/química , Receptores de GABA-A/química , Receptores de GABA-A/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação Alostérica/efeitos dos fármacos , Alprazolam/farmacologia , Benzodiazepinas/química , Benzodiazepinas/farmacologia , Bicuculina/farmacologia , Ligação Competitiva/efeitos dos fármacos , Diazepam/farmacologia , Moduladores GABAérgicos/química , Moduladores GABAérgicos/farmacologia , Humanos , Ligantes , Modelos Moleculares , Nanoestruturas/química , Picrotoxina/farmacologia
20.
Mol Neurobiol ; 56(1): 502-512, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29725905

RESUMO

Stroke is frequently associated with severe neurological decline and mortality, and its incidence is expected to increase due to aging population. The only available pharmacological treatment for cerebral ischemia is thrombolysis, with narrow therapeutic windows. Efforts aimed to identify new therapeutics are crucial. In this study, we look into plausible molecular and cellular targets for JM-20, a new hybrid molecule, against ischemic stroke in vivo. Male Wistar rats were subjected to 90 min middle cerebral artery occlusion (MCAO) following 23 h of reperfusion. Animals treated with 8 mg/kg JM-20 (p.o., 1 h after reperfusion) showed minimal neurological impairment and lower GABA and IL-1ß levels in CSF when compared to damaged rats that received vehicle. Immunocontent of pro-survival, phosphorylated Akt protein decreased in the cortex after 24 h as result of the ischemic insult, accompanied by decreased number of NeuN+ cells in the peri-infarct cortex, cornu ammonis 1 (CA1) and dentate gyrus (DG) areas. Widespread reactive astrogliosis in both cortex and hippocampus (CA1, CA3, and DG areas) was observed 24 h post-ischemia. JM-20 prevented the activated Akt reduction, neuronal death, and astrocytes reactivity throughout the brain. Overall, the results reinforce the pharmacological potential of JM-20 as neuroprotective agent and provide important evidences about its molecular and cellular targets in this model of cerebral ischemia.


Assuntos
Astrócitos/patologia , Benzodiazepinas/uso terapêutico , Infarto Encefálico/tratamento farmacológico , Encéfalo/patologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/patologia , Neurônios/patologia , Niacina/análogos & derivados , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Benzodiazepinas/farmacologia , Infarto Encefálico/líquido cefalorraquidiano , Infarto Encefálico/patologia , Região CA3 Hipocampal/efeitos dos fármacos , Região CA3 Hipocampal/metabolismo , Região CA3 Hipocampal/patologia , Morte Celular/efeitos dos fármacos , Giro Denteado/efeitos dos fármacos , Giro Denteado/metabolismo , Giro Denteado/patologia , Proteína Glial Fibrilar Ácida/metabolismo , Gliose/metabolismo , Gliose/patologia , Infarto da Artéria Cerebral Média/líquido cefalorraquidiano , Interleucina-10/líquido cefalorraquidiano , Interleucina-1beta/líquido cefalorraquidiano , Masculino , Neurônios/efeitos dos fármacos , Niacina/farmacologia , Niacina/uso terapêutico , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Wistar , Resultado do Tratamento , Ácido gama-Aminobutírico/líquido cefalorraquidiano
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