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1.
Intern Med ; 60(21): 3359-3368, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34719623

RESUMO

Objective The efficacy of tolvaptan, an orally active vasopressin V2-receptor antagonist, has recently been reported in patients with massive ascites unresponsive to conventional diuretics. However, the effect of tolvaptan varies among patients. Recently, the prognostic role of the tolvaptan response in cases of decompensated liver cirrhosis (LC) has been attracting increasing attention. Using serum copeptin (vasopressin precursor), zinc-α2-glycoprotein (ZAG), cystatin C (renal biomarker), neutrophil gelatinase-associated lipocalin (NGAL) and liver-type fatty acid-binding protein (L-FABP), we explored which factors portend a good response to tolvaptan in LC patients with ascites. Methods We enrolled 113 LC patients and divided them into the tolvaptan treatment group and non-treatment group. Tolvaptan (3.75 or 7.5 mg/day) was administrated to 38 LC patients with ascites, and a follow-up assessment was performed after a 7-day tolvaptan treatment regimen. Results We determined the predictive ability for kidney and/or liver damage of serum copeptin, ZAG, cystatin C, NGAL and L-FABP levels in all patients. After 7-day tolvaptan treatment, 19 patients had lost more than 1.5 kg of body weight (Responders), while 19 showed no marked change in their body weight (Non-responders). Basal blood urea nitrogen (BUN) (p=0.0014), serum copeptin (p=0.0265) and serum ZAG levels (p=0.0142) were significantly higher in the Non-responders than in the Responders. BUN (odds ratio 7.43, p=0.0306), copeptin (odds ratio 9.12, p=0.0136) and ZAG (odds ratio 7.43, p=0.0306) were determined to be predictive factors of drug responsiveness using a multivariate logistic regression analysis. Conclusion Serum BUN, copeptin and ZAG levels predict the patient response to tolvaptan, even when measured prior to treatment.


Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos , Ascite , Adipocinas , Antagonistas dos Receptores de Hormônios Antidiuréticos/uso terapêutico , Ascite/tratamento farmacológico , Benzazepinas/uso terapêutico , Biomarcadores , Glicopeptídeos , Glicoproteínas , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/tratamento farmacológico , Tolvaptan , Zinco
2.
Can Fam Physician ; 67(10): 743-745, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34649897

RESUMO

QUESTION: An adolescent who smokes regularly came to my clinic for help quitting. While I am aware that bupropion is a first-line medication for smoking cessation among adults, is it effective and safe for adolescents? ANSWER: Most adolescent smokers in Canada would like to quit, but more than 90% of the attempts are unsuccessful. Bupropion appears to be more effective than other pharmacologic options in improving abstinence among adolescents who smoke in the short term; however, it is not approved by Health Canada for those younger than 18 years. Bupropion has not been associated with an increase in adverse events in smoking cessation trials. More research is needed on the long-term effectiveness and safety of bupropion in this population.


Assuntos
Bupropiona , Abandono do Hábito de Fumar , Adolescente , Adulto , Benzazepinas , Bupropiona/uso terapêutico , Humanos , Agonistas Nicotínicos , Quinoxalinas , Vareniclina
3.
Adv Ther ; 38(12): 5721-5736, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34693505

RESUMO

INTRODUCTION: Hyponatremia is a common condition of varying etiology among hospitalized patients and is associated with adverse outcomes. Treatment to normalize serum sodium is advisable. Tolvaptan received European Union marketing authorization for hyponatremia secondary to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Post-marketing pharmacovigilance activities were required to characterize the safety profile of tolvaptan more fully in this population, which is often elderly with a high burden of comorbid illness. METHODS: This was a prospective, observational, multinational, post-authorization pharmacovigilance study (NCT01228682) in seven European countries. Hospitalized patients were enrolled who received tolvaptan for hyponatremia associated with SIADH and consented to data collection. Tolvaptan was initiated and assessments performed at physician discretion per local standards of care. To reflect actual clinical practice, no assessments or procedures were required outside the standard of care. Patients who continued to receive long-term tolvaptan following hospital discharge and provided consent received follow-up from their community physicians. RESULTS: A total of 252 patients (mean age 70.6 years) enrolled. Mean tolvaptan treatment duration was 139.4 days, median 18.5 (range 1-1130) days; most frequent dose was 15 mg/day (used in 75% of patients). Serum sodium increased from baseline (mean 123.2 mmol/l) during treatment week 1 and remained stable during follow-up, with little difference across doses of 7.5, 15, and 30 mg/day. Hyponatremia symptoms (e.g., confusion, unsteady gait, lethargy) were present in 122/252 (48.4%) patients at pre-treatment baseline, decreasing to 46/252 (18.3%) during treatment. Sixty-two patients (24.6%; mean baseline serum sodium 120 mmol/l) experienced rapid correction of hyponatremia within 72 h. No osmotic demyelination syndrome occurred. CONCLUSION: In clinical practice, tolvaptan improved serum sodium and decreased hyponatremia symptoms in hyponatremia secondary to SIADH. Serum sodium should be monitored during treatment to minimize risk of rapid correction. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT01228682.


Assuntos
Hiponatremia , Síndrome de Secreção Inadequada de HAD , Tolvaptan , Idoso , Antagonistas dos Receptores de Hormônios Antidiuréticos , Benzazepinas/efeitos adversos , Humanos , Hiponatremia/induzido quimicamente , Hiponatremia/tratamento farmacológico , Farmacovigilância , Estudos Prospectivos , Sódio
4.
PLoS Pathog ; 17(10): e1010014, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34673825

RESUMO

One strategy for a functional cure of HIV-1 is "block and lock", which seeks to permanently suppress the rebound of quiescent HIV-1 by epigenetic silencing. For the bivalent promoter in the HIV LTR, both histone 3 lysine 27 tri-methylation (H3K27me3) and DNA methylation are associated with viral suppression, while H3K4 tri-methylation (H3K4me3) is correlated with viral expression. However, H3K27me3 is readily reversed upon activation of T-cells through the T-cell receptor. In an attempt to suppress latent HIV-1 in a stable fashion, we knocked down the expression or inhibited the activity of UTX/KDM6A, the major H3K27 demethylase, and investigated its impact on latent HIV-1 reactivation in T cells. Inhibition of UTX dramatically enhanced H3K27me3 levels at the HIV LTR and was associated with increased DNA methylation. In latently infected cells from patients, GSK-J4, which is a potent dual inhibitor of the H3K27me3/me2-demethylases JMJD3/KDM6B and UTX/KDM6A, effectively suppressed the reactivation of latent HIV-1 and also induced DNA methylation at specific sites in the 5'LTR of latent HIV-1 by the enhanced recruitment of DNMT3A to HIV-1. Nonetheless, suppression of HIV-1 through epigenetic silencing required the continued treatment with GSK-J4 and was rapidly reversed after removal of the drug. DNA methylation was also rapidly lost after removal of drug, suggesting active and rapid DNA-demethylation of the HIV LTR. Thus, induction of epigenetic silencing by histone and DNA methylation appears to be insufficient to permanently silence HIV-1 proviral transcription.


Assuntos
Benzazepinas/farmacologia , Metilação de DNA/efeitos dos fármacos , HIV-1/efeitos dos fármacos , Histona Desmetilases/antagonistas & inibidores , Pirimidinas/farmacologia , Ativação Viral/efeitos dos fármacos , Latência Viral/efeitos dos fármacos , Infecções por HIV/genética , Infecções por HIV/metabolismo , Infecções por HIV/virologia , HIV-1/fisiologia , Humanos , Provírus/efeitos dos fármacos
6.
Int J Mol Sci ; 22(18)2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34576305

RESUMO

Neuropeptide Y (NPY) has anxiolytic-like effects and facilitates the extinction of cued and contextual fear in rodents. We previously showed that intracerebroventricular administration of NPY reduces the expression of social fear in a mouse model of social fear conditioning (SFC) and localized these effects to the dorsolateral septum (DLS) and central amygdala (CeA). In the present study, we aimed to identify the receptor subtypes that mediate these local effects of NPY. We show that NPY (0.1 nmol/0.2 µL/side) reduced the expression of SFC-induced social fear in a brain region- and receptor-specific manner in male mice. In the DLS, NPY reduced the expression of social fear by acting on Y2 receptors but not on Y1 receptors. As such, prior administration of the Y2 receptor antagonist BIIE0246 (0.2 nmol/0.2 µL/side) but not the Y1 receptor antagonist BIBO3304 trifluoroacetate (0.2 nmol/0.2 µL/side) blocked the effects of NPY in the DLS. In the CeA, however, BIBO3304 trifluoroacetate but not BIIE0246 blocked the effects of NPY, suggesting that NPY reduced the expression of social fear by acting on Y1 receptors but not Y2 receptors within the CeA. This study suggests that at least two distinct receptor subtypes are differentially recruited in the DLS and CeA to mediate the effects of NPY on the expression of social fear.


Assuntos
Tonsila do Cerebelo/metabolismo , Neuropeptídeo Y/metabolismo , Fobia Social/metabolismo , Septo do Cérebro/metabolismo , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Arginina/análogos & derivados , Arginina/farmacologia , Benzazepinas/farmacologia , Medo , Masculino , Camundongos , Fobia Social/fisiopatologia , Receptores de Neuropeptídeo Y/metabolismo , Septo do Cérebro/efeitos dos fármacos
7.
Drug Alcohol Depend ; 227: 108991, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34482043

RESUMO

BACKGROUND: The opioid epidemic continues despite the availability of medications, including buprenorphine, for opioid use disorder (OUD); identifying novel and effective treatments is critical for decreasing the prevalence of OUD and ending this crisis. Buprenorphine alone does not markedly attenuate abuse-related effects of nonopioids. Treatment outcomes might be improved by combining buprenorphine with a second medication targeting substance use disorder (SUD), such as lorcaserin, a serotonin2C (5-HT2C) receptor selective agonist that decreases abuse-related effects of drugs from several pharmacological classes in preclinical studies. METHODS: This study investigated the effectiveness of buprenorphine/lorcaserin mixtures to decrease preference for heroin or cocaine in monkeys choosing between food and i.v. infusions. RESULTS: When saline was available for self-administration, monkeys chose food; when heroin or cocaine was available, monkeys dose-dependently increased choice of infusions. Noncontingent administration of heroin, cocaine, or buprenorphine before sessions increased preference for saline over food. Daily noncontingent administration of buprenorphine increased saline choice, decreased heroin choice, and increased variability across monkeys and sessions; preference for cocaine was not altered. Adding lorcaserin to daily treatment reduced variability such that choice of saline and heroin was consistently less than 20%; choice of cocaine did not change. CONCLUSIONS: Because buprenorphine/lorcaserin mixtures would not likely alter abuse of cocaine, they might not be useful for treating SUDs; nevertheless, mixtures reduced variability and decreased preference for heroin, compared with buprenorphine alone, perhaps suggesting that a different drug mixture, in which buprenorphine is combined with a second, nonopioid drug, might offer advantages over treatment with buprenorphine alone.


Assuntos
Buprenorfina , Cocaína , Transtornos Relacionados ao Uso de Opioides , Animais , Benzazepinas , Relação Dose-Resposta a Droga , Heroína , Macaca mulatta , Autoadministração
8.
Psychopharmacology (Berl) ; 238(11): 3311-3323, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34383109

RESUMO

RATIONALE: It is well known that the anterior cingulate cortex (ACC) plays an important role in acute pain perception. OBJECTIVES: In the present study, we aimed to investigate the possible involvement of the ACC dopamine D1 and D2 receptors in nicotine plus morphine-induced analgesia. METHODS: The ACC's of adult male Wistar rats were bilaterally cannulated by stereotaxic instrument and the tail-flick test was used to measure the thermal pain threshold. RESULTS: The results indicated that subcutaneous (s.c.) injection of nicotine (0.3 mg/kg) potentiated the analgesic response of intraperitoneal (i.p.) administration of morphine (3 mg/kg). Systemic administration of the same doses of nicotine or morphine alone had no effect on tail-flick latency. Intra-ACC administration of apomorphine (0.3-0.9 µg/rat), the non-selective D1/D2 receptors agonist, plus ineffective doses of nicotine (0.1 mg/kg, s.c.) plus morphine (3 mg/kg, i.p) induced analgesia in rats. In addition, the analgesia induced with co-administration of nicotine and morphine was inhibited via intra-ACC administration of SCH23390 (0.5-1 µg/rat) or sulpiride (0.5-2 µg/rat), the selective antagonists of D1 or D2 receptors, respectively. The intra-ACC microinjection of the same doses of drugs alone had no effect on tail-flick latency. Cubic interpolation analysis also confirmed that activation or inactivation of the ACC D1 and D2 receptors by different doses of drugs can modulate the nicotine-morphine analgesic response. CONCLUSIONS: The findings suggest that the ACC has an important role in acute thermal pain perception and modulates the analgesia induced by nicotine plus morphine via dopaminergic receptors.


Assuntos
Analgesia , Morfina , Animais , Benzazepinas/farmacologia , Giro do Cíngulo/metabolismo , Masculino , Morfina/farmacologia , Nicotina/farmacologia , Ratos , Ratos Wistar , Receptores de Dopamina D1/metabolismo , Sulpirida
9.
Nat Commun ; 12(1): 4319, 2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-34262032

RESUMO

Despite the genetic inactivation of SMARCA4, a core component of the SWI/SNF-complex commonly found in cancer, there are no therapies that effectively target SMARCA4-deficient tumours. Here, we show that, unlike the cells with activated MYC oncogene, cells with SMARCA4 inactivation are refractory to the histone deacetylase inhibitor, SAHA, leading to the aberrant accumulation of H3K27me3. SMARCA4-mutant cells also show an impaired transactivation and significantly reduced levels of the histone demethylases KDM6A/UTX and KDM6B/JMJD3, and a strong dependency on these histone demethylases, so that its inhibition compromises cell viability. Administering the KDM6 inhibitor GSK-J4 to mice orthotopically implanted with SMARCA4-mutant lung cancer cells or primary small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT), had strong anti-tumour effects. In this work we highlight the vulnerability of KDM6 inhibitors as a characteristic that could be exploited for treating SMARCA4-mutant cancer patients.


Assuntos
Antineoplásicos/uso terapêutico , DNA Helicases/deficiência , Histona Desmetilases/antagonistas & inibidores , Histona Desmetilases com o Domínio Jumonji/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Proteínas Nucleares/deficiência , Fatores de Transcrição/deficiência , Animais , Antineoplásicos/farmacologia , Benzazepinas/farmacologia , Benzazepinas/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , DNA Helicases/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Expressão Gênica , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Histonas/metabolismo , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Histona Desmetilases com o Domínio Jumonji/metabolismo , Camundongos , Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Fatores de Transcrição/metabolismo , Ativação Transcricional
10.
J Med Chem ; 64(14): 10445-10468, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34255509

RESUMO

A new class of selective vasopressin receptor 1A (V1A) antagonists was identified, where "methyl-scan" was performed around the benzene ring of the 5-hydroxy-triazolobenzazepine core. This led to the synthesis of two 10-methyl derivatives, each possessing a chiral axis and a stereogenic center. The four atropisomeric stereoisomers (involving two enantiomer pairs and atropisomeric diastereomers) could be successfully isolated and spectroscopically characterized. According to the in vitro pharmacological profiles of the compounds, the human V1A receptor has a strong preference toward the isomers having an aR axial chirality, the most active isomer being the aR,5S isomer. Furthermore, the structure-activity relationships obtained for the isomers and for the newly synthesized analogues could be tentatively explained by an in silico study.


Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos/farmacologia , Benzazepinas/farmacologia , Antagonistas dos Receptores de Hormônios Antidiuréticos/síntese química , Antagonistas dos Receptores de Hormônios Antidiuréticos/química , Benzazepinas/síntese química , Benzazepinas/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Receptores de Vasopressinas , Estereoisomerismo , Relação Estrutura-Atividade
11.
PLoS One ; 16(7): e0254724, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34265007

RESUMO

OBJECTIVE: To determine if men who have sex with men (MSM) with cocaine use disorder (CUD) and actively-using cocaine could be enrolled and retained in a pharmacologic intervention trial of lorcaserin-a novel 5-HT2cR agonist-and determine the degree to which participants would adhere to study procedures. METHODS: This was a phase II randomized, double-blind, placebo-controlled pilot study with 2:1 random parallel group assignment to daily extended-release oral lorcaserin 20 mg versus placebo (clinicaltrials.gov identifier-NCT03192995). Twenty-two of a planned 45 cisgender MSM with CUD were enrolled and had weekly follow-up visits during a 12-week treatment period, with substance use counseling, urine specimen collection, and completion of audio-computer assisted self-interview (ACASI) behavioral risk assessments. Adherence was measured by medication event monitoring systems (MEMS) caps and self-report. This study was terminated early because of an FDA safety alert for lorcaserin's long-term use. RESULTS: Eighty-six percent completed the trial, with 82% of weekly study follow-up visits completed. Adherence was 55.3% (lorcaserin 51.6% vs. placebo 66.2%) by MEMS cap and 56.9% (56.5% vs. placebo 57.9%) by self-report and did not differ significantly by treatment assignment. Intention-to-treat analyses (ITT) did not show differences in cocaine positivity by urine screen between the lorcaserin and placebo groups by 12 week follow-up (incidence risk ratio [IRR]: 0.96; 95%CI = 0.24-3.82, P = 0.95). However, self-reported cocaine use in timeline follow-back declined more significantly in the lorcaserin group compared to placebo (IRR: 0.66; 95%CI = 0.49-0.88; P = 0.004). CONCLUSION: We found that it is feasible, acceptable, and tolerable to conduct a placebo-controlled pharmacologic trial for MSM with CUD who are actively using cocaine. Lorcaserin was not associated with significant reductions in cocaine use by urine testing, but was associated with significant reductions in self-reported cocaine use. Future research may be needed to continue to explore the potential utility of 5-HT2cR agonists.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas , Homossexualidade Masculina , Adulto , Benzazepinas , Método Duplo-Cego , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto
12.
PLoS Med ; 18(7): e1003691, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34260595

RESUMO

BACKGROUND: Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) prevent microalbuminuria in normoalbuminuric type 2 diabetic patients. We assessed whether combined therapy with the 2 medications may prevent microalbuminuria better than ACE inhibitor or ARB monotherapy. METHODS AND FINDINGS: VARIETY was a prospective, randomized, open-label, blinded endpoint (PROBE) trial evaluating whether, at similar blood pressure (BP) control, combined therapy with benazepril (10 mg/day) and valsartan (160 mg/day) would prevent microalbuminuria more effectively than benazepril (20 mg/day) or valsartan (320 mg/day) monotherapy in 612 type 2 diabetic patients with high-normal albuminuria included between July 2007 and April 2013 by the Istituto di Ricerche Farmacologiche Mario Negri IRCCS and 8 diabetology or nephrology units in Italy. Time to progression to microalbuminuria was the primary outcome. Analyses were intention to treat. Baseline characteristics were similar among groups. During a median [interquartile range, IQR] follow-up of 66 [42 to 83] months, 53 patients (27.0%) on combination therapy, 57 (28.1%) on benazepril, and 64 (31.8%) on valsartan reached microalbuminuria. Using an accelerated failure time model, the estimated acceleration factors were 1.410 (95% CI: 0.806 to 2.467, P = 0.229) for benazepril compared to combination therapy, 0.799 (95% CI: 0.422 to 1.514, P = 0.492) for benazepril compared to valsartan, and 1.665 (95% CI: 1.007 to 2.746, P = 0.047) for valsartan compared to combination therapy. Between-group differences in estimated acceleration factors were nonsignificant after adjustment for predefined confounders. BP control was similar across groups. All treatments were safe and tolerated well, with a slight excess of hyperkalemia and hypotension in the combination therapy group. The main study limitation was the lower than expected albuminuria at inclusion. CONCLUSIONS: Risk/benefit profile of study treatments was similar. Dual renin-angiotensin system (RAS) blockade is not recommended as compared to benazepril or valsartan monotherapy for prevention of microalbuminuria in normoalbuminuric type 2 diabetic patients. TRIAL REGISTRATION: EudraCT 2006-005954-62; ClinicalTrials.gov NCT00503152.


Assuntos
Albuminúria/etiologia , Albuminúria/prevenção & controle , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Benzazepinas/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Valsartana/uso terapêutico , Idoso , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
13.
Nat Commun ; 12(1): 3495, 2021 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-34108486

RESUMO

Lysosomal storage disorders characterized by altered metabolism of heparan sulfate, including Mucopolysaccharidosis (MPS) III and MPS-II, exhibit lysosomal dysfunctions leading to neurodegeneration and dementia in children. In lysosomal storage disorders, dementia is preceded by severe and therapy-resistant autistic-like symptoms of unknown cause. Using mouse and cellular models of MPS-IIIA, we discovered that autistic-like behaviours are due to increased proliferation of mesencephalic dopamine neurons originating during embryogenesis, which is not due to lysosomal dysfunction, but to altered HS function. Hyperdopaminergia and autistic-like behaviours are corrected by the dopamine D1-like receptor antagonist SCH-23390, providing a potential alternative strategy to the D2-like antagonist haloperidol that has only minimal therapeutic effects in MPS-IIIA. These findings identify embryonic dopaminergic neurodevelopmental defects due to altered function of HS leading to autistic-like behaviours in MPS-II and MPS-IIIA and support evidence showing that altered HS-related gene function is causative of autism.


Assuntos
Transtorno do Espectro Autista/metabolismo , Dopamina/metabolismo , Heparitina Sulfato/metabolismo , Doenças por Armazenamento dos Lisossomos/metabolismo , Animais , Transtorno do Espectro Autista/tratamento farmacológico , Transtorno do Espectro Autista/patologia , Benzazepinas/uso terapêutico , Proliferação de Células , Células Cultivadas , Modelos Animais de Doenças , Antagonistas de Dopamina/uso terapêutico , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Heparitina Sulfato/farmacologia , Doenças por Armazenamento dos Lisossomos/tratamento farmacológico , Doenças por Armazenamento dos Lisossomos/patologia , Mesencéfalo/efeitos dos fármacos , Mesencéfalo/embriologia , Mesencéfalo/patologia , Camundongos , Mucopolissacaridose III/tratamento farmacológico , Mucopolissacaridose III/metabolismo , Mucopolissacaridose III/patologia , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de Dopamina D1/metabolismo
14.
Artigo em Inglês | MEDLINE | ID: mdl-34098180

RESUMO

Three sensitive and precise stability-indicating methods were developed for the determination of alcaftadine in the presence of its degradation products. Efficient separation was achieved using UPLC-UV-MS method by gradient elution with a mobile phase of 0.1% aqueous formic acid (A) and 0.1% formic acid in acetonitrile (B) over concentration range of 0.10-1.00 µg mL-1. The accuracy was 100.89% ± 0.74 and 99.73% ± 0.78 for UV and MS detection, respectively. A TLC-densitometric method was adopted to separate of the intact drug from its degradation products. Methanol: chloroform: glacial acetic acid (5:4:0.1, v/v/v) was the developing system, detection wavelength was set to 282 nm. Rf values were 0.35, 0.65 and 0.88 for alcaftadine, its acidic and oxidative degradants, respectively. The linearity range was 2.00-27.00 µg/band with mean accuracy of 100.58% ± 0.86. The proposed TLC-densitometric method was utilized for the study of degradation rates of alcaftadine. Finally, a simple UV-spectrophotometric method where an induced dual wavelength was implemented, the method showed a linearity range of 2.00-27.00 µg mL-1 with mean recovery of 100.15% ± 0.70. The proposed methods were successful for quantitation of alcaftadine in ophthalmic solution and in plasma samples. The obtained results were in accordance with those obtained by previously reported methods.


Assuntos
Benzazepinas/análise , Benzazepinas/química , Cromatografia Líquida/métodos , Imidazóis/análise , Imidazóis/química , Fotometria/métodos , Estabilidade de Medicamentos , Modelos Lineares , Soluções Oftálmicas/química , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
15.
Aging (Albany NY) ; 13(9): 12526-12536, 2021 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-33934091

RESUMO

To investigate the suppressive function of RO4929097, a potent -secretase inhibitor, on RANKL-induced osteoclastogenesis. The cytotoxicity of RO4929097 was evaluated. The suppressive effect and possible molecular mechanism of RO4929097 on RANKL-induced osteoclastogenesis was evaluated both in vitro and in vivo. The IC50 of RO4929097 was 2.93 µM. Treatment with different doses of RO4929097 (100 nM, 200 nM, and 400 nM) effectively reduced osteoclast formation (number and resorption area) in a dose-dependent manner. The qPCR results revealed that RO4929097 attenuates RANKL-induced osteoclast formation and NFATc1 protein expression. The in vivo experiments demonstrated that RO4929097 had an inhibitory effect on LPS-induced bone resorption. Our in vitro experiments showed that RO4929097 can potently inhibit osteoclastogenesis and bone resorption by down-regulating the Notch/MAPK/JNK/Akt-mediated reduction of NFATc1. In accordance with these in vitro observations, RO4929097 attenuated LPS-induced osteolysis in mice. In conclusion, our findings indicate that Notch may represent a potential therapeutic target for the treatment of osteolytic diseases.


Assuntos
Benzazepinas/farmacologia , Fluorenos/farmacologia , Cetonas/farmacologia , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Osteólise/tratamento farmacológico , Animais , Diferenciação Celular/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Osteogênese/fisiologia , Osteólise/induzido quimicamente , Transdução de Sinais/efeitos dos fármacos
16.
BMJ Open ; 11(5): e042417, 2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34035088

RESUMO

OBJECTIVES: To evaluate the real-world association between varenicline and neuropsychiatric adverse events (NPAEs) in general and chronic obstructive pulmonary disease (COPD) population with and without psychiatric disorders compared with nicotine replacement therapy (NRT) to strengthen the knowledge of varenicline safety. DESIGN: A retrospective cohort study. SETTING: Prescription database IADB.nl, the Netherlands. PARTICIPANTS: New users of varenicline or NRT among general (≥18 years) and COPD (≥40 years) population. Psychiatric subcohort was defined as people prescribed psychotropic medications (≥2) within 6 months before the index date. OUTCOME MEASURES: The incidence of NPAEs including depression, anxiety and insomnia, defined by new or naive prescriptions of related medications in IADB.nl within 24 weeks after the first treatment initiation of varenicline or NRT. RESULTS: For the general population in non-psychiatric cohort, the incidence of total NPAEs in varenicline (4480) and NRT (1970) groups was 10.5% and 12.6%, respectively (adjusted OR (aOR) 0.85, 95% CI 0.72 to 1.00). For the general population in psychiatric cohort, the incidence of total NPAEs was much higher, 75.3% and 78.5% for varenicline (1427) and NRT (1200) groups, respectively (aOR 0.82, 95% CI 0.68 to 0.99). For the COPD population (1598), there were no differences in the incidence of NPAEs between comparison groups in both the psychiatric cohort (aOR 0.97, 95% CI 0.66 to 1.44) and non-psychiatric cohort (aOR 0.81, 95% CI 0.54 to 1.20). Results from subgroup or sensitivity analyses also did not reveal increased risks of NPAEs but showed decreased risk of some subgroup NPAEs associated with varenicline. CONCLUSIONS: In contrast to the concerns of a possible increased risk of NPAEs among varenicline users, we found a relative decreased risk of total NPAEs in varenicline users of the general population in psychiatric or non-psychiatric cohorts compared with NRT and no difference for NPAEs between varenicline and NRT users in smaller population with COPD.


Assuntos
Doença Pulmonar Obstrutiva Crônica , Abandono do Hábito de Fumar , Benzazepinas , Bupropiona , Estudos de Coortes , Humanos , Países Baixos/epidemiologia , Agonistas Nicotínicos/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Quinoxalinas , Estudos Retrospectivos , Dispositivos para o Abandono do Uso de Tabaco , Vareniclina/efeitos adversos
17.
J Vet Intern Med ; 35(4): 1673-1687, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34028078

RESUMO

BACKGROUND: The renin-angiotensin-aldosterone system (RAAS), when chronically activated, is harmful and RAAS-suppressive drugs are beneficial in the treatment of congestive heart failure (CHF). Mineralocorticoid receptor antagonists are widely used in the treatment of CHF in people. HYPOTHESIS/OBJECTIVES: To determine if a mineralocorticoid receptor antagonist (spironolactone) is beneficial and safe in CHF due to myxomatous mitral valve disease (MMVD) of varying severity, we hypothesized that, when combined with furosemide, a combination product (S+BNZ) containing the ACE inhibitor (ACE-I), benazepril, and spironolactone, would be superior to benazepril alone. ANIMALS: Five hundred and sixty-nine client-owned dogs, with MMVD and CHF (ACVIM Stage C) of ≤10-days' duration. METHODS: After initial stabilization, dogs were randomized into a positive-controlled, double-blind, multicenter trial, to receive furosemide plus S+BNZ or furosemide plus benazepril. The primary outcome variable was the percentage of dogs reaching cardiac endpoint before Day 360. Cardiac endpoint was defined as cardiac death or euthanasia, recurrence of pulmonary edema, necessity for nonauthorized cardiac drug(s) or a furosemide dosage >8 mg/kg/d. RESULTS: A significantly lower percentage of dogs treated with S+BNZ reached the primary outcome variable by Day 360 (OR = 0.56; 95% CI, 0.32-0.98; P = .04) and risk of dying or worsening from cardiac causes, was significantly reduced (HR = 0.73; 95% CI = 0.59-0.89, P = .002) vs benazepril alone. Adverse events, potentially associated with treatment, were rare and equal between groups. CONCLUSION AND CLINICAL IMPORTANCE: The combination of S+BNZ is effective, safe, and superior to benazepril alone, when used with furosemide for the management of mild, moderate or severe CHF caused by MMVD in dogs.


Assuntos
Doenças do Cão , Insuficiência Cardíaca , Animais , Benzazepinas , Doenças do Cão/tratamento farmacológico , Cães , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/veterinária , Valva Mitral , Espironolactona/uso terapêutico , Resultado do Tratamento
18.
Neurochem Res ; 46(8): 2008-2018, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33993443

RESUMO

Cannabidiol (CBD) is a non-psychotomimetic compound with strong potential to decrease the psychostimulant's rewarding effect with unclear receptors. Furthermore, as a part of the reward circuit, the hippocampus plays a crucial role in regulating the reward properties of drugs as determined by conditioned place preference (CPP). In the current research, CPP was used to evaluate the role of intra-CA1 microinjection of D1-like dopamine receptor antagonists in CBD's inhibitory effect on the acquisition and expression phases of methamphetamine (METH). Animals were treated by METH (1 mg/kg; sc) in a five-day schedule to induce CPP. To find out the impact of D1-like dopamine receptor antagonist, SCH23390, in the CA1 on the inhibitory influence of CBD on the acquisition of METH, the rats received intra-CA1 administration of SCH23390 (0.25, 1, and 4 µg/0.5 µl) following ICV treatment of CBD (10 µg/5 µl) over conditioning phase of METH. Furthermore, animals were given SCH23390 in the CA1 ensuing ICV microinjection of CBD (50 µg/5 µl) in the expression phase of METH to rule out the influence of SCH23390 on the suppressive effect of CBD on the expression of METH CPP. Intra-CA1 microinjection of SCH23390 abolished CBD's suppressive impact on both METH-induced CPP phases without any side effect on the locomotion. The current research disclosed that CBD inhibited the rewarding characteristic of METH via D1-like dopamine receptors in the CA1 region of the hippocampus.


Assuntos
Região CA1 Hipocampal/efeitos dos fármacos , Canabidiol/uso terapêutico , Fármacos do Sistema Nervoso Central/farmacologia , Condicionamento Psicológico/efeitos dos fármacos , Metanfetamina/farmacologia , Receptores de Dopamina D1/metabolismo , Animais , Benzazepinas/farmacologia , Região CA1 Hipocampal/metabolismo , Antagonistas de Dopamina/farmacologia , Masculino , Ratos Wistar , Receptores de Dopamina D1/antagonistas & inibidores
19.
BMC Cancer ; 21(1): 559, 2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-34001062

RESUMO

BACKGROUND: As an H3K27me3 demethylase and counteracts polycomb-mediated transcription repression, KDM6B has been implicated in the development and malignant progression in various types of cancers. However, its potential roles in esophageal squamous cell carcinoma (ESCC) have not been explored. METHODS: The expression of KDM6B in human ESCC tissues and cell lines was examined using RT-qPCR, immunohistochemical staining and immunoblotting. The effects of KDM6B on the proliferation and metastasis of ESCC were examined using in vitro and in vivo functional tests. RNA-seq and ChIP-seq assay were used to demonstrate the molecular biological mechanism of KDM6B in ESCC. RESULTS: We show that the expression level of KDM6B increased significantly in patients with lymph node metastasis. Furthermore, we confirmed that KDM6B knockdown reduces proliferation and metastasis of ESCC cells, while KDM6B overexpression has the opposite effects. Mechanistically, KDM6B regulates TNFA_SIGNALING_VIA_NFκB signalling pathways, and H3K27me3 binds to the promoter region of C/EBPß, leading to the promotion of C/EBPß transcription. Besides, we show that GSK-J4, a chemical inhibitor of KDM6B, markedly inhibits proliferation and metastasis of ESCC cells. CONCLUSIONS: The present study demonstrated that KDM6B promotes ESCC progression by increasing the transcriptional activity of C/EBPß depending on its H3K27 demethylase activity.


Assuntos
Proteína beta Intensificadora de Ligação a CCAAT/genética , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Regulação Neoplásica da Expressão Gênica/genética , Histona Desmetilases com o Domínio Jumonji/metabolismo , Animais , Benzazepinas/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sequenciamento de Cromatina por Imunoprecipitação , Desmetilação do DNA , Conjuntos de Dados como Assunto , Progressão da Doença , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Histonas/metabolismo , Humanos , Histona Desmetilases com o Domínio Jumonji/antagonistas & inibidores , Histona Desmetilases com o Domínio Jumonji/genética , Masculino , Camundongos , Regiões Promotoras Genéticas , Pirimidinas/farmacologia , RNA-Seq , Ativação Transcricional , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
20.
J Neurosci ; 41(26): 5734-5746, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34031163

RESUMO

Obesity is a serious global health problem because of its increasing prevalence and comorbidities, but its treatments are limited. The serotonin 2C receptor (5-HT2CR), a G-protein-coupled receptor, activates proopiomelanocortin (POMC) neurons in the arcuate nucleus of hypothalamus (ARH) to reduce appetite and weight gain. However, several 5-HT analogs targeting this receptor, e.g., lorcaserin (Lor), suffer from diminished efficacy to reduce weight after prolonged administration. Here, we show that barbadin (Bar), a novel ß-arrestin/ß2-adaptin inhibitor, can prevent 5-HT2CR internalization in cells and potentiate long-term effects of Lor to reduce appetite and body weight in male mice. Mechanistically, we demonstrate that Bar co-treatment can effectively maintain the sensitivity of the 5-HT2CR in POMCARH neurons, despite prolonged Lor exposure, thereby allowing these neurons to be activated through opening the transient receptor potential cation (TRPC) channels. Thus, our results prove the concept that inhibition of 5-HT2CR desensitization can be a valid strategy to improve the long-term weight loss effects of Lor or other 5-HT2CR agonists, and also provide an intellectual framework to develop effective long-term management of weight by targeting 5-HT2CR desensitization.SIGNIFICANCE STATEMENT By demonstrating that the combination of barbadin (Bar) with a G-protein-coupled receptor (GPCR) agonist can provide prolonged weight-lowering benefits in a preclinical setting, our work should call for additional efforts to validate Bar as a safe and effective medicine or to use Bar as a lead compound to develop more suitable compounds for obesity treatment. These results prove the concept that inhibition of serotonin 2C receptor (5-HT2CR) desensitization can be a valid strategy to improve the long-term weight loss effects of lorcaserin (Lor) or other 5-HT2CR agonists. Since GPCRs represent a major category as therapeutic targets for various human diseases and desensitization of GPCRs is a common issue, our work may provide a conceptual framework to enhance effects of a broad range of GPCR medicines.


Assuntos
Benzazepinas/farmacologia , Neurônios/efeitos dos fármacos , Pirimidinas/farmacologia , Receptor 5-HT2C de Serotonina/metabolismo , Perda de Peso/efeitos dos fármacos , Animais , Apetite/efeitos dos fármacos , Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Núcleo Arqueado do Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pró-Opiomelanocortina/metabolismo , Receptor 5-HT2C de Serotonina/efeitos dos fármacos , Tempo
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