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1.
J Med Chem ; 64(14): 9649-9676, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34254805

RESUMO

Translocator protein 18 kDa [TSPO or peripheral-type benzodiazepine receptor (PBR)] was identified in the search of binding sites for benzodiazepine anxiolytic drugs in peripheral regions. In these areas, binding sites for TSPO ligands were recognized in steroid-producing tissues. TSPO plays an important role in many cellular functions, and its coding sequence is highly conserved across species. TSPO is located predominantly on the membrane of mitochondria and is overexpressed in several solid cancers. TSPO basal expression in the CNS is low, but it becomes high in neurodegenerative conditions. Thus, TSPO constitutes not only as an outstanding drug target but also as a valuable marker for the diagnosis of a number of diseases. The aim of the present article is to show the lesson we have learned from our activity in TSPO medicinal chemistry and in approaching the targeted delivery to mitochondria by means of TSPO ligands.


Assuntos
Benzodiazepinas/farmacologia , Compostos de Boro/metabolismo , Mitocôndrias/efeitos dos fármacos , Receptores de GABA/metabolismo , Benzodiazepinas/química , Química Farmacêutica , Humanos , Ligantes , Mitocôndrias/metabolismo , Estrutura Molecular , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Receptores de GABA/genética
2.
Molecules ; 26(9)2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-34068533

RESUMO

The synthesis of organometallic compounds with potential pharmacological activity has attracted the attention of many research groups, aiming to take advantage of aspects that the presence of the metal-carbon bond can bring to the design of new pharmaceutical drugs. In this context, we have gathered studies reported in the literature in which psychoactive benzodiazepine drugs were used as ligands in the preparation of organometallic and metal complexes and provide details on some of their biological effects. We also highlight that most commonly known benzodiazepine-based drugs display molecular features that allow the preparation of metallacycles via C-H activation. These organometallic compounds merit further attention regarding their potential biological effects, not only in terms of psychoactive drugs but also in the search for drug replacements, for example, for cancer treatments.


Assuntos
Benzodiazepinas/farmacologia , Preparações Farmacêuticas/química , Benzodiazepinas/química , Metais/química , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia
3.
Neurology ; 97(7): e720-e727, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34187862

RESUMO

OBJECTIVE: To investigate whether receiving a second-line anticonvulsant medication that is part of a patient's home regimen influences outcomes in benzodiazepine-refractory convulsive status epilepticus. METHODS: Using the Established Status Epilepticus Treatment Trial data, allocation to a study drug included in the patient's home anticonvulsant medication regimen was compared to receipt of an alternative second-line study medication. The primary outcome was cessation of clinical seizures with improved consciousness by 60 minutes after study drug initiation. Secondary outcomes were seizure cessation adjudicated from medical records and adverse events. We performed inverse probability of treatment-weighted (IPTW) logistic regressions. RESULTS: Of 462 patients, 232 (50%) were taking 1-2 of the 3 study medications at home. The primary outcome was observed in 39/89 (44%) patients allocated to their home medication vs 76/143 (53%) allocated to a nonhome medication (IPTW odds ratio [OR] 0.66, 95% confidence interval [CI] 0.39-1.14). The adjudicated outcome occurred in 37/89 (42%) patients vs 82/143 (57%), respectively (IPTW OR 0.52, 95% CI 0.30-0.89). There was no interaction between study levetiracetam and home levetiracetam and there were no differences in adverse events. CONCLUSION: There was no difference in the primary outcome for patients who received a home medication vs nonhome medication. However, the retrospective evaluation suggested an association between receiving a nonhome medication and seizure cessation. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with refractory convulsive status epilepticus, use of a home second-line anticonvulsant compared to a nonhome anticonvulsant did not significantly affect the probability of stopping seizures.


Assuntos
Anticonvulsivantes/farmacologia , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Levetiracetam/farmacologia , Avaliação de Resultados em Cuidados de Saúde , Estado Epiléptico/tratamento farmacológico , Adolescente , Adulto , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/efeitos adversos , Benzodiazepinas/farmacologia , Criança , Pesquisa Comparativa da Efetividade , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Levetiracetam/administração & dosagem , Levetiracetam/efeitos adversos , Masculino , Pessoa de Meia-Idade , Fenitoína/farmacologia , Autoadministração , Ácido Valproico/farmacologia , Adulto Jovem
5.
Psychopharmacology (Berl) ; 238(9): 2449-2457, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34002246

RESUMO

RATIONALE: Gut microbiota plays an important role in host metabolism. Antipsychotic drugs can result in metabolic abnormalities. Probiotics may ameliorate the antipsychotic drug-induced metabolic abnormalities by regulating gut microbiota. OBJECTIVE: To determine whether Bifidobacterium intervention can ameliorate olanzapine-induced weight increase. METHODS: Enrolled patients were assigned to either the olanzapine or olanzapine plus Bifidobacterium group. The following were assessed: body weight, body mass index (BMI), appetite, latency to increased appetite, and baseline weight increase of more than 7%. All assessments were conducted at baseline and at 4, 8, and 12 weeks of treatment. RESULTS: We enrolled 70 patients with schizophrenia or schizophrenic affective disorder, and 67 completed the study. Treatment for 4 weeks led to between-group differences in weight change (2.4 vs. 1.1 kg, p < 0.05) and BMI (0.9 vs. 0.4, p < 0.05). However, this difference disappeared at 8 and 12 weeks of treatment (both p > 0.05). The two groups did not differ in appetite increase at any time point (p > 0.05). The mean time from olanzapine initiation to appetite increase was also not significantly different between the two groups (t = 1.243, p = 0.220). CONCLUSIONS: Probiotics may mitigate olanzapine-induced weight gain in the early stage of treatment and delay olanzapine-induced appetite increase.


Assuntos
Antipsicóticos , Transtornos Psicóticos , Antipsicóticos/uso terapêutico , Apetite/efeitos dos fármacos , Benzodiazepinas/farmacologia , Bifidobacterium , Índice de Massa Corporal , Peso Corporal/efeitos dos fármacos , Humanos , Olanzapina/uso terapêutico , Transtornos Psicóticos/tratamento farmacológico
6.
PLoS One ; 16(5): e0251632, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34014994

RESUMO

BACKGROUND: The major sites for fast synaptic inhibition in the central nervous system (CNS) are ion channels activated by γ-aminobutyric acid (GABA). These receptors are referred as GABA(A) receptors (GABA(A)R). Recent evidence indicates a role of GABA(A)R in modulating the immune response. This work aimed to discern the role of GABA and GABA(A)Rs in human and mouse T cell activity. METHODS: Mouse splenocytes or human peripheral blood mononuclear cells (PBMCs) were activated with anti-CD3 antibodies and the proliferation of both CD8+ and CD4+ T cells assessed through flow cytometry. Subsequently, the effects on T cell proliferation of either GABA(A)R modulation by diazepam that is also capable of activating mitochondrial based translocator protein (TSPO), alprazolam and allopregnanolone or inhibition by bicucculine methiodide (BMI) and (1,2,5,6-Tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA) were assessed. RESULTS: Positive modulation of GABA(A)Rs either by benzodiazepines or the neurosteroid allopregnanolone inhibits both mouse and human T cell proliferation. GABAergic inhibition of T cell proliferation by benzodiazepines could be rescued by GABA(A)R blocking. Our data suggest that benzodiazepines influence T cell proliferation through both TSPO and GABA(A)Rs activation. CONCLUSIONS: We conclude that activation of GABA(A)Rs provides immunosuppression by inhibiting T cell proliferation.


Assuntos
Benzodiazepinas/farmacologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Proliferação de Células/efeitos dos fármacos , Pregnanolona/farmacologia , Receptores de GABA-A/metabolismo , Animais , Humanos , Camundongos , Receptores de GABA/metabolismo
7.
Biol Pharm Bull ; 44(5): 701-706, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33952826

RESUMO

We previously reported that exposure of human colon adenocarcinoma (Caco-2) cells to the bitter substance phenylthiocarbamide (PTC) rapidly enhanced the transport function of P-glycoprotein (P-gp). In this study, we investigated the short-term effect of etoposide, another bitter-tasting P-gp substrate, on P-gp transport function in the same cell line. We found that etoposide exposure significantly increased both the P-gp protein level in the plasma membrane fraction and the efflux rate of rhodamine123 (Rho123) in Caco-2 cells within 10 min. The efflux ratio (ratio of the apparent permeability coefficient in the basal-to-apical direction to that in the apical-to-basal direction) of Rho123 in etoposide-treated cells was also significantly increased compared with the control. These results indicated that etoposide rapidly enhances P-gp function in Caco-2 cells. In contrast, P-gp expression in whole cells at both the mRNA and protein level was unchanged by etoposide exposure, compared with the levels in non-treated cells. Furthermore, etoposide increased the level of phosphorylated ezrin, radixin and moesin (P-ERM) proteins in the plasma membrane fraction of Caco-2 cells within 10 min. P-gp functional changes were blocked by YM022, an inhibitor of cholecystokinin (CCK) receptor. These results suggest that etoposide induces release of CCK, causing activation of the CCK receptor followed by phosphorylation of ERM proteins, which recruit intracellular P-gp for trafficking to the gastrointestinal membrane, thereby increasing the functional activity of P-gp.


Assuntos
Etoposídeo/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Benzodiazepinas/farmacologia , Células CACO-2 , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Colecistocinina/metabolismo , Proteínas do Citoesqueleto/metabolismo , Humanos , Proteínas de Membrana/metabolismo , Proteínas dos Microfilamentos/metabolismo , Fosforilação/efeitos dos fármacos , Receptor de Colecistocinina B/antagonistas & inibidores , Receptor de Colecistocinina B/metabolismo
8.
Rev. int. androl. (Internet) ; 19(1): 62-68, ene.-mar. 2021. ilus
Artigo em Inglês | IBECS | ID: ibc-201672

RESUMO

INTRODUCTION: Normal sexual functioning of both men and women, being a very complex process, is affected by numerous issues besides aging. Many factors affect the sexual function and lifestyle of the young population. In this article, we tried to review the literature to update the knowledge on benzodiazepine-related (BZD) sexual dysfunction (SD) and involved mechanisms of actions based on animal and human studies. METHODS: Different standard websites such as PubMed were used to review the literature and keywords including benzodiazepines, sexual dysfunction, gammaaminobutyric acid A (GABAA) receptor and erectile dysfunction were used. RESULTS: SD is one of the most common disorders in males and females which has recently been demonstrated to be associated with psychotropic medications such as antihypertensive agents, tranquilizers, antihistamines, appetite suppressants, antidepressants and anxiolytics. BZDs are among the most common psychotropic agents worldwide. SD including decreased libido, erectile dysfunction (ED) and other undesired sexual urges were observed in the patients receiving BZDs. DISCUSSION: The mechanisms of action of BZDs to induce SD mainly relate to enhanced GABAA receptor function which reduces penile erection


INTRODUCCIÓN: El funcionamiento sexual normal de los varones y las mujeres, al ser un proceso muy complejo, se ve afectado por numerosos problemas, además del envejecimiento. Muchos factores afectan a la función sexual y al estilo de vida de la población joven. En este artículo intentamos revisar la literatura para actualizar el conocimiento sobre las disfunciones sexuales (SD, por sus siglas en inglés) relacionadas con benzodiacepinas (BZD) y los mecanismos de acción involucrados en estudios con animales y humanos. MÉTODOS: Se utilizaron diferentes sitios web estándar, como PubMed, para revisar la literatura y las palabras clave que incluyen BZD, disfunciones sexuales, ácido gamma-aminobutírico A y disfunción eréctil. RESULTADOS: Las SD son uno de los trastornos más comunes en los varones y las mujeres, ya que recientemente se ha demostrado que están asociados a medicamentos psicotrópicos como agentes antihipertensivos, tranquilizantes, antihistamínicos, supresores del apetito, antidepresivos y ansiolíticos. Las BZD son uno de los agentes psicotrópicos más comunes en todo el mundo. Las SD que incluían disminución de la libido, la disfunción eréctil (DE) y otros impulsos sexuales no deseados, se observaron en los pacientes que recibieron BZD. DISCUSIÓN: Los mecanismos de acción de las BZD para inducir SD se relacionan principalmente con la función mejorada del receptor de ácido gamma-aminobutírico A (GABAA) que reduce la erección del pene


Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Disfunção Erétil/induzido quimicamente , Benzodiazepinas/efeitos adversos , Benzodiazepinas/farmacologia , Ácido gama-Aminobutírico/efeitos adversos , Disfunção Erétil/fisiopatologia , Ejaculação/efeitos dos fármacos , Psicotrópicos/efeitos adversos , Libido/efeitos dos fármacos , Agonistas GABAérgicos/farmacologia , Receptores de GABA/efeitos dos fármacos
9.
Am J Psychiatry ; 178(7): 651-659, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33653119

RESUMO

OBJECTIVE: Persons with opioid use disorder who take benzodiazepines are at high risk for overdose. The objective of this study was to evaluate the association of benzodiazepine and Z-drug use with drug-related poisonings among patients receiving buprenorphine maintenance treatment. METHODS: A case-crossover study design was used to analyze prescription claims among persons ages 12-64 with opioid use disorder who had buprenorphine prescriptions and had claims data in the IBM MarketScan databases (2006-2016), encompassing 14,213,075 person-days of observation time for 23,036 individuals who experienced drug-related poisoning. The exposures were buprenorphine prescriptions and benzodiazepine or Z-drug prescriptions, standardized as daily diazepam-equivalent milligram doses and separated by pharmacologic properties (short-acting or long-acting benzodiazepines, Z-drugs). The outcome of interest was nonfatal drug-related poisoning. Conditional logistic regression was used to evaluate variation in benzodiazepine or Z-drug and buprenorphine use between poisoning and nonpoisoning days. RESULTS: Buprenorphine treatment days were associated with a nearly 40% reduction in the risk of poisoning events (odds ratio=0.63, 95% CI=0.60, 0.66) compared with nontreatment days, whereas benzodiazepine or Z-drug treatment days were associated with an 88% increase in the risk of such events (95% CI=1.78, 1.98). In stratified analyses by dose, we observed a 78% (95% CI=1.67, 1.88) and 122% (95% CI=2.03, 2.43) increase in poisonings associated with low-dose and high-dose benzodiazepine or Z-drug treatment days, respectively. High-dose, but not low-dose, benzodiazepine or Z-drug treatment was associated with increased poisonings in combination with buprenorphine cotreatment (odds ratio=1.64, 95% CI=1.39, 1.93), but this was lower than the odds risk associated with benzodiazepine or Z-drug treatment in the absence of buprenorphine (low-dose: odds ratio=1.69, 95% CI=1.60, 1.79; high-dose: odds ratio=2.23, 95% CI=2.04, 2.45). CONCLUSIONS: Increased risk of nonfatal drug-related poisoning is associated with benzodiazepine or Z-drug treatment in patients with opioid use disorder, but this risk is partially mitigated by buprenorphine treatment. Dose reduction of benzodiazepines or Z-drugs while maintaining buprenorphine treatment may provide the advantage of lowering drug-related poisoning risk.


Assuntos
Benzodiazepinas/farmacologia , Buprenorfina/uso terapêutico , Overdose de Drogas/etiologia , Hipnóticos e Sedativos/envenenamento , Adolescente , Adulto , Criança , Prescrições de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tratamento de Substituição de Opiáceos , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Estudos Retrospectivos , Adulto Jovem
10.
Psychopharmacology (Berl) ; 238(5): 1373-1386, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33594504

RESUMO

RATIONALE: Benzodiazepines induce electroencephalography (EEG) changes in rodents and humans that are associated with distinct behavioral effects and have been proposed as quantitative biomarkers for GABAA receptor modulation. Specifically, central EEG beta and occipital EEG delta activity have been associated with anxiolysis and sedation, respectively. The extent to which nonhuman primates show the same dose- and topography-dependent effects remained unknown. OBJECTIVES: We aimed at establishing a nonhuman primate model for the evaluation of benzodiazepine EEG pharmacology. METHODS: Four adult male rhesus monkeys were prepared with fully implantable telemetry devices that monitored activity, peripheral body temperature, and contained two EEG (central and occipital), one electromyography (EMG), and one electrooculography channel. We investigated daytime alprazolam-induced changes in EEG spectral power, sleep-wake states, EMG activity, locomotor activity, and body temperature. Alprazolam (0.01-1.8 mg/kg, i.m.) or vehicle was administered acutely, and telemetry recording was conducted for 1 h. RESULTS: Daytime alprazolam dose-dependently increased central EEG power (including beta activity), increased occipital EEG delta power, and decreased occipital EEG alpha, theta, and sigma power. There was an ~8-fold difference in the potency of alprazolam to increase central EEG beta vs. occipital EEG delta activity (based on relative EEG power). The highest dose, which increased both central EEG beta and occipital EEG delta relative power, induced sedative effects (increased time spent in N1 and N2 sleep stages) and decreased peripheral body temperature and locomotor activity. CONCLUSIONS: Alprazolam induces dose- and topography-dependent EEG changes in rhesus monkeys and provides a valuable model for studying benzodiazepine pharmacology.


Assuntos
Alprazolam/farmacologia , Benzodiazepinas/farmacologia , Eletroencefalografia/efeitos dos fármacos , Hipnóticos e Sedativos/farmacologia , Animais , Eletromiografia , Eletroculografia , Humanos , Macaca mulatta , Masculino , Sono/efeitos dos fármacos
11.
Proc Natl Acad Sci U S A ; 118(9)2021 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-33619107

RESUMO

Reactivation of human cytomegalovirus (HCMV) from latency is a major health consideration for recipients of stem-cell and solid organ transplantations. With over 200,000 transplants taking place globally per annum, virus reactivation can occur in more than 50% of cases leading to loss of grafts as well as serious morbidity and even mortality. Here, we present the most extensive screening to date of epigenetic inhibitors on HCMV latently infected cells and find that histone deacetylase inhibitors (HDACis) and bromodomain inhibitors are broadly effective at inducing virus immediate early gene expression. However, while HDACis, such as myeloid-selective CHR-4487, lead to production of infectious virions, inhibitors of bromodomain (BRD) and extraterminal proteins (I-BETs), including GSK726, restrict full reactivation. Mechanistically, we show that BET proteins (BRDs) are pivotally connected to regulation of HCMV latency and reactivation. Through BRD4 interaction, the transcriptional activator complex P-TEFb (CDK9/CycT1) is sequestered by repressive complexes during HCMV latency. Consequently, I-BETs allow release of P-TEFb and subsequent recruitment to promoters via the superelongation complex (SEC), inducing transcription of HCMV lytic genes encoding immunogenic antigens from otherwise latently infected cells. Surprisingly, this occurs without inducing many viral immunoevasins and, importantly, while also restricting viral DNA replication and full HCMV reactivation. Therefore, this pattern of HCMV transcriptional dysregulation allows effective cytotoxic immune targeting and killing of latently infected cells, thus reducing the latent virus genome load. This approach could be safely used to pre-emptively purge the virus latent reservoir prior to transplantation, thereby reducing HCMV reactivation-related morbidity and mortality.


Assuntos
Proteínas de Ciclo Celular/genética , Citomegalovirus/imunologia , DNA Viral/genética , Epigênese Genética , Histona Desacetilases/genética , Fator B de Elongação Transcricional Positiva/genética , Fatores de Transcrição/genética , Azepinas/farmacologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Benzodiazepinas/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/imunologia , Ciclina T/genética , Ciclina T/imunologia , Quinase 9 Dependente de Ciclina/genética , Quinase 9 Dependente de Ciclina/imunologia , Citomegalovirus/efeitos dos fármacos , Citomegalovirus/genética , Infecções por Citomegalovirus/genética , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/patologia , Replicação do DNA/efeitos dos fármacos , DNA Viral/antagonistas & inibidores , DNA Viral/imunologia , Genes Precoces , Genes Reporter , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/imunologia , Interações Hospedeiro-Patógeno , Humanos , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Modelos Biológicos , Fator B de Elongação Transcricional Positiva/imunologia , Cultura Primária de Células , Regiões Promotoras Genéticas , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/virologia , Células THP-1 , Talidomida/análogos & derivados , Talidomida/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/imunologia , Transcrição Genética , Ativação Viral/efeitos dos fármacos , Latência Viral/efeitos dos fármacos
12.
Biomed Res Int ; 2021: 8845129, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33490280

RESUMO

Background: We investigated the potential safety of remimazolam and propofol in malignant hyperthermia- (HM-) susceptible patients using ryanodine receptor 1- (RYR1-) expressing human embryonic kidney- (HEK-) 293 cells. Methods: We compared the enhanced responsiveness of HEK-293 cells expressing wild-type RYR1 with that of mutant RYR1 to caffeine following perfusion with remimazolam or propofol. Furthermore, we investigated whether RYR1 enhanced the responsiveness of cells to remimazolam or propofol and compared the median effective concentration (EC50; i.e., the concentration required to reach half-maximal activation) using an unpaired two-tailed t-test while a P < 0.05 was considered significant. Results: Remimazolam and propofol did not promote the caffeine-induced increase in intracellular Ca2+ levels in HEK-293 cells expressing mutant RYR1 even with exposure to approximately 100-fold the clinically used concentration. In wild-type RYR1, EC50 values of remimazolam following refusion vs. nonperfusion were 2.86 mM vs. 2.75 mM (P = 0.76) while for propofol perfusion vs. nonperfusion, they were 2.76 mM vs. 2.75 mM, respectively (P = 0.83). In mutant RYR1, EC50 values of remimazolam refusion vs. nonperfusion were 1.58 mM vs. 1.71 mM, respectively (P = 0.63) while for propofol perfusion vs. nonperfusion, they were 1.65 mM vs. 1.71 mM, respectively (P = 0.73). Remimazolam and propofol increased intracellular Ca2+ levels in a concentration-dependent manner, but the effect was not enhanced by RYR1. EC50 values of remimazolam with non-RYR1 vs. wild-type RYR1 were 1.00 mM vs. 0.92 mM, respectively (P = 0.91) while those of propofol were 1.09 mM vs. 1.05 mM, respectively (P = 0.84). Conclusions: The increase in intracellular Ca2+ concentration caused by remimazolam or propofol was not considered an RYR1-mediated reaction. We conclude that remimazolam and propofol can be safely used as an anesthetic in MH-susceptible patients with RYR1-mutation without causing MH and may be safely substituted for an MH-triggering anesthetic when RYR1-mediated MH occurs.


Assuntos
Benzodiazepinas/farmacologia , Cálcio/metabolismo , Hipertermia Maligna/genética , Propofol/farmacologia , Canal de Liberação de Cálcio do Receptor de Rianodina , Anestésicos/farmacologia , Cafeína/metabolismo , Células HEK293 , Humanos , Mutação/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo
13.
J Pediatr ; 232: 220-228.e3, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33484700

RESUMO

OBJECTIVES: To determine how continuous spike and wave during slow wave sleep (CSWS) is currently managed and to compare the effectiveness of current treatment strategies using a database from 11 pediatric epilepsy centers in the US. STUDY DESIGN: This retrospective study gathered information on baseline clinical characteristics, CSWS etiology, and treatment(s) in consecutive patients seen between 2014 and 2016 at 11 epilepsy referral centers. Treatments were categorized as benzodiazepines, steroids, other antiseizure medications (ASMs), or other therapies. Two measures of treatment response (clinical improvement as noted by the treating physician; and electroencephalography improvement) were compared across therapies, controlling for baseline variables. RESULTS: Eighty-one children underwent 153 treatment trials during the study period (68 trials of benzodiazepines, 25 of steroids, 45 of ASMs, 14 of other therapies). Children most frequently received benzodiazepines (62%) or ASMs (27%) as first line therapy. Treatment choice did not differ based on baseline clinical variables, nor did these variables correlate with outcome. After adjusting for baseline variables, children had a greater odds of clinical improvement with benzodiazepines (OR 3.32, 95%CI 1.57-7.04, P = .002) or steroids (OR 4.04, 95%CI 1.41-11.59, P = .01) than with ASMs and a greater odds of electroencephalography improvement after steroids (OR 3.36, 95% CI 1.09-10.33, P = .03) than after ASMs. CONCLUSIONS: Benzodiazepines and ASMs are the most frequent initial therapy prescribed for CSWS in the US. Our data suggests that ASMs are inferior to benzodiazepines and steroids and support earlier use of these therapies. Multicenter prospective studies that rigorously assess treatment protocols and outcomes are needed.


Assuntos
Anticonvulsivantes/uso terapêutico , Benzodiazepinas/uso terapêutico , Síndromes Epilépticas/tratamento farmacológico , Padrões de Prática Médica/estatística & dados numéricos , Sono de Ondas Lentas/efeitos dos fármacos , Esteroides/uso terapêutico , Adolescente , Anticonvulsivantes/farmacologia , Benzodiazepinas/farmacologia , Criança , Pré-Escolar , Esquema de Medicação , Eletroencefalografia , Síndromes Epilépticas/diagnóstico , Síndromes Epilépticas/fisiopatologia , Feminino , Seguimentos , Humanos , Masculino , Estudos Retrospectivos , Esteroides/farmacologia , Resultado do Tratamento , Estados Unidos
14.
FEBS J ; 288(3): 995-1007, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32543078

RESUMO

Ionotropic glutamate receptors are ligand-gated ion channels governing neurotransmission in the central nervous system. Three major types of antagonists are known for the AMPA-type receptor GluA2: competitive, noncompetitive (i.e., negative allosteric modulators; NAMs) used for treatment of epilepsy, and uncompetitive antagonists. We here report a 4.65 Å resolution X-ray structure of GluA2, revealing that four molecules of the competitive antagonist ZK200775 and four molecules of the NAM GYKI53655 are capable of binding at the same time. Using negative stain electron microscopy, we show that GYKI53655 alone or ZK200775/GYKI53655 in combination predominantly results in compact receptor forms. The agonist AMPA provides a mixed population of compact and bulgy shapes of GluA2 not impacted by addition of GYKI53655. Taken together, this suggests that the two different mechanisms of antagonism that lead to channel closure are independent and that the distribution between bulgy and compact receptors primarily depends on the ligand bound in the glutamate binding site. DATABASE: The atomic coordinates and structure factors from the crystal structure determination have been deposited in the Protein Data Bank under accession code https://doi.org/10.2210/pdb6RUQ/pdb. The electron microscopy 3D reconstruction volumes have been deposited in EMDB (EMD-4875: Apo; EMD-4920: ZK200775/GYKI53655; EMD-4921: AMPA compact; EMD-4922: AMPA/GYKI53655 bulgy; EMD-4923: GYKI53655; EMD-4924: AMPA bulgy; EMD-4925: AMPA/GYKI53655 compact).


Assuntos
Benzodiazepinas/metabolismo , Antagonistas de Aminoácidos Excitatórios/metabolismo , Organofosfonatos/metabolismo , Quinoxalinas/metabolismo , Receptores de AMPA/metabolismo , Proteínas Recombinantes/metabolismo , Regulação Alostérica , Animais , Benzodiazepinas/química , Benzodiazepinas/farmacologia , Cristalografia por Raios X , Antagonistas de Aminoácidos Excitatórios/química , Antagonistas de Aminoácidos Excitatórios/farmacologia , Células HEK293 , Humanos , Modelos Moleculares , Estrutura Molecular , Organofosfonatos/química , Organofosfonatos/farmacologia , Ligação Proteica , Domínios Proteicos , Quinoxalinas/química , Quinoxalinas/farmacologia , Ratos , Receptores de AMPA/antagonistas & inibidores , Receptores de AMPA/genética , Proteínas Recombinantes/química , Células Sf9 , Spodoptera
15.
Haematologica ; 106(4): 958-967, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32381576

RESUMO

Chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) are incurable hematological malignancies that are pathologically linked with aberrant NF-κB activation. In this study, we identified a group of novel C8-linked benzofused Pyrrolo[2,1-c][1,4]benzodiazepines (PBD) monomeric hybrids capable of sequence-selective inhibition of NF-κB with low nanomolar LD50 values in CLL (n=46) and MM cell lines (n=5). The lead compound, DC-1-192, significantly inhibited NF-κB DNA binding after just 4h exposure and demonstrating inhibitory effects on both canonical and non-canonical NF-κB subunits. In primary CLL cells, sensitivity to DC-1-192 was inversely correlated with RelA subunit expression (r2=0.2) and samples with BIRC3 or NOTCH1 mutations showed increased sensitivity (P=0.001). RNA-sequencing and gene set enrichment analysis confirmed the over-representation of NF-κB regulated genes in the down-regulated gene list. Furthermore, In vivo efficacy studies in NOD/SCID mice, using a systemic RPMI 8226 human multiple myeloma xenograft model, showed that DC-1-192 significantly prolonged survival (P=0.017). In addition, DC1-192 showed synergy with bortezomib and ibrutinib; synergy with ibrutinib was enhanced when CLL cells were co-cultured on CD40L-expressing fibroblasts in order to mimic the cytoprotective lymph node microenvironment (P = 0.01). Given that NF-κB plays a role in both bortezomib and ibrutinib resistance mechanisms, these data provide a strong rationale for the use of DC-1-192 in the treatment of NF-κB-driven cancers, particularly in the context of relapsed/refractory disease.


Assuntos
Neoplasias Hematológicas , Leucemia Linfocítica Crônica de Células B , Adenina/análogos & derivados , Animais , Apoptose , Benzodiazepinas/farmacologia , Bortezomib/farmacologia , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , NF-kappa B , Piperidinas , Pirróis , Microambiente Tumoral
16.
Ann Pharmacother ; 55(3): 294-302, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32830517

RESUMO

BACKGROUND: Benzodiazepine is first-line therapy for alcohol withdrawal syndrome (AWS), and phenobarbital is an alternative therapy. However, its use has not been well validated in the surgical-trauma patient population. OBJECTIVE: To describe the use of fixed-dose phenobarbital monotherapy for the management of patients at risk for AWS in the surgical-trauma intensive care unit. METHODS: Surgical-trauma critically ill patients who received phenobarbital monotherapy, loading dose followed by a taper regimen, for the management of AWS were included in this evaluation. The effectiveness of phenobarbital monotherapy to treat AWS and prevent development of AWS-related complications were evaluated. Safety end points assessed included significant hypotension, bradycardia, respiratory depression, and need for invasive mechanical ventilation. RESULTS: A total of 31 patients received phenobarbital monotherapy; the majority of patients were at moderate risk for developing AWS (n = 20; 65%) versus high risk (n = 11; 35%). None of the patients developed AWS-related complications; all patients were successfully managed for their AWS. Nine patients (29%) received nonbenzodiazepine adjunct therapy for agitation post-phenobarbital initiation. Three patients (10%) experienced hypotension, and 3 (10%) were intubated. None of the patients had clinically significant bradycardia or respiratory depression. CONCLUSION AND RELEVANCE: Fixed-dose phenobarbital monotherapy appears to be well tolerated and effective in the management of AWS. Further evaluation is needed to determine the extent of benefit with the use of phenobarbital monotherapy for management of AWS.


Assuntos
Benzodiazepinas/uso terapêutico , Hipnóticos e Sedativos/uso terapêutico , Fenobarbital/uso terapêutico , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Ferimentos e Lesões/tratamento farmacológico , Benzodiazepinas/farmacologia , Feminino , Humanos , Hipnóticos e Sedativos/farmacologia , Masculino , Fenobarbital/farmacologia , Estudos Retrospectivos
17.
Mol Psychiatry ; 26(2): 534-544, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-30504824

RESUMO

Benzodiazepines (BZDs) have been a standard treatment for anxiety disorders for decades, but the neuronal circuit interactions mediating their anxiolytic effect remain largely unknown. Here, we find that systemic BZDs modulate central amygdala (CEA) microcircuit activity to gate amygdala output. Combining connectome data with immediate early gene (IEG) activation maps, we identified the CEA as a primary site for diazepam (DZP) anxiolytic action. Deep brain calcium imaging revealed that brain-wide DZP interactions shifted neuronal activity in CEA microcircuits. Chemogenetic silencing showed that PKCδ+/SST- neurons in the lateral CEA (CEAl) are necessary and sufficient to induce the DZP anxiolytic effect. We propose that BZDs block the relay of aversive signals through the CEA, in part by local binding to CEAl SST+/PKCδ- neurons and reshaping intra-CEA circuit dynamics. This work delineates a strategy to identify biomedically relevant circuit interactions of clinical drugs and highlights the critical role for CEA circuitry in the pathophysiology of anxiety.


Assuntos
Ansiolíticos , Núcleo Central da Amígdala , Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Benzodiazepinas/farmacologia , Diazepam
18.
Bioorg Chem ; 106: 104504, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33279247

RESUMO

A new series of 5-(2-aryloxy-4-nitrophenyl)-4H-1,2,4-triazoles and 5-(2-aryloxy-3-pyridyl)-4H-1,2,4-triazoles, possessing C-3 thio or alkylthio substituents, was synthesized and evaluated for their benzodiazepine receptor affinity and anti-seizure activity. These analogues revealed similar to significantly superior affinity to GABAA/benzodiazepine receptor complex (IC50 values of 0.04-4.1 nM), relative to diazepam as the reference drug (IC50 value of 2.4 nM). To determine the onset of anti-seizure activity, the time-dependent effectiveness of i.p. administration of compounds on pentylenetetrazole induced seizure threshold was studied and a very good relationship was observed between the lipophilicity (cLogP) and onset of action of studied analogues (r2 = 0.964). The minimum effective dose of the compounds, determined at the time the analogues showed their highest activity, was demonstrated to be 0.025-0.1 mg/kg, relative to diazepam (0.025 mg/kg).


Assuntos
Anticonvulsivantes/farmacologia , Benzodiazepinas/farmacologia , Receptores de GABA-A/química , Convulsões/tratamento farmacológico , Triazóis/farmacologia , Animais , Anticonvulsivantes/síntese química , Anticonvulsivantes/química , Benzodiazepinas/síntese química , Benzodiazepinas/química , Ligação Competitiva/efeitos dos fármacos , Relação Dose-Resposta a Droga , Interações Hidrofóbicas e Hidrofílicas , Masculino , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química
19.
Int J Radiat Oncol Biol Phys ; 109(4): 1040-1053, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33289666

RESUMO

PURPOSE: Most patients with metastatic melanoma show variable responses to radiation therapy and do not benefit from immune checkpoint inhibitors. Improved strategies for combination therapy that leverage potential benefits from radiation therapy and immune checkpoint inhibitors are critical. METHODS AND MATERIALS: We analyzed metastatic melanoma tumors in the TCGA cohort for expression of genes coding for subunits of type A γ-aminobutyric acid (GABA) receptor (GABAAR), a chloride ion channel and major inhibitory neurotransmitter receptor. Electrophysiology was used to determine whether melanoma cells possess intrinsic GABAAR activity. Melanoma cell viability studies were conducted to test whether enhancing GABAAR mediated chloride transport using benzodiazepine-impaired viability. A syngeneic melanoma mouse model was used to assay the effect of benzodiazepine on tumor volume and its ability to potentiate radiation therapy or immunotherapy. Treated tumors were analyzed for changes in gene expression by RNA sequencing and presence of tumor-infiltrating lymphocytes by flow cytometry. RESULTS: Genes coding for subunits of GABAARs express functional GABAARs in melanoma cells. By enhancing GABAAR-mediated anion transport, benzodiazepines depolarize melanoma cells and impair their viability. In vivo, benzodiazepine alone reduces tumor growth and potentiates radiation therapy and α-PD-L1 antitumor activity. The combination of benzodiazepine, radiation therapy, and α-PD-L1 results in near complete regression of treated tumors and a potent abscopal effect, mediated by increased infiltration of polyfunctional CD8+ T cells. Treated tumors show expression of cytokine-cytokine receptor interactions and overrepresentation of p53 signaling. CONCLUSIONS: This study identifies an antitumor strategy combining radiation and/or an immune checkpoint inhibitor with modulation of GABAARs in melanoma using benzodiazepine.


Assuntos
Inibidores de Checkpoint Imunológico/uso terapêutico , Melanoma/terapia , Receptores de GABA-A/fisiologia , Linfócitos T/imunologia , Animais , Benzodiazepinas/farmacologia , Benzodiazepinas/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Terapia Combinada , Feminino , Humanos , Melanoma/patologia , Proteínas de Membrana/análise , Camundongos , Camundongos Endogâmicos C57BL , Radiossensibilizantes/farmacologia , Receptores de GABA-A/análise
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