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1.
J Chromatogr A ; 1625: 461255, 2020 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-32709316

RESUMO

A three-dimensional (3D) HPLC system in combination with fluorescence derivatization has been developed for the highly sensitive and selective analysis of chiral amino acids in extraterrestrial samples. As the targets, alanine (Ala), 2-aminobutyric acid (2AB), valine (Val), norvaline (nVal) and isovaline (iVal), frequently found chiral amino acids in the carbonaceous chondrites, were selected. These amino acids were pre-column derivatized with 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F), and the target analytes were separated from other amino acids and organic compounds by a reversed-phase column in the first dimension. The targets were further separated from interferences by an anion-exchange column in the second dimension, and their enantiomers were separated and determined in the third dimension by a Pirkle-type enantioselective column. The present 3D-HPLC system was validated and applied to the Murchison meteorite and the Antarctic meteorites, and all of the target amino acid enantiomers were clearly observed (0.78-22.33 nmol/g in the Murchison meteorite and 1.79-78.84 nmol/g in the Antarctic meteorites) without severe interferences. The %L values of the non-proteinogenic amino acids were almost 50% in both meteorites, and even the proteinogenic amino acids were almost racemic in the Antarctic meteorites.


Assuntos
Aminoácidos/análise , Cromatografia Líquida de Alta Pressão/métodos , Meteoroides , Alanina/análise , Aminoácidos/química , Aminobutiratos/análise , Cromatografia por Troca Iônica , Limite de Detecção , Estereoisomerismo , Valina/análogos & derivados , Valina/análise
2.
Toxicol Lett ; 332: 82-87, 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-32569803

RESUMO

BACKGROUND: Glycidol, a probable human carcinogen, is a reactive chemical released in the gastrointestinal tract from glycidyl fatty acid esters, which are heat-induced dietary contaminants. OBJECTIVES: To investigate the prenatal transfer of glycidol, a specific hemoglobin adduct was measured as a biomarker for internal glycidol exposure in paired cord and maternal blood samples. METHODS: In 100 mother-newborn pairs from the Belgian ENVIRONAGE (ENVIRonmental influence ON AGEing in early life) birth cohort, we studied the correlation between levels of the glycidol-derived hemoglobin adduct N-(2,3-dihydroxypropyl)-valine (2,3-diHOPr-Val) in paired cord and maternal blood samples. The adduct levels were determined after cleavage with a modified Edman degradation by using ultra-high performance liquid chromatography-tandem mass spectrometry and an isotope-labeled reference standard. RESULTS: 2,3-DiHOPr-Val was detectable in all 100 maternal blood samples and in 96 cord blood samples (LOD =0.5 pmol 2,3-diHOPr-Val/g hemoglobin), with medians of 5.4 (range: 2.3-29.2) and 1.6 (range: LOD - 8.9) pmol/g hemoglobin), respectively. In blood samples of mothers who smoked during pregnancy and in the cord blood samples of their newborns (n = 6), the median 2,3-diHOPr-Val levels were 16.7 (range: 6.4-29.2) and 6.2 (range: LOD - 8.6) pmol/g hemoglobin, respectively. The median ratio of 2,3-diHOPr-Val levels of cord to maternal blood was 0.35 (range: 0.19-1.14) (n = 49). The Spearman correlation coefficient between 2,3-diHOPr-Val levels in cord and maternal blood samples was 0.63 (p < 0.001) among all mother-newborn pairs and 0.59 (p < 0.001) among mother-newborn pairs of non-smoking mothers. DISCUSSION: Maternal data confirm widespread exposure to glycidol, also in non-smokers. Neonatal levels indicate prenatal exposure to glycidol, due to an obviously relatively unhindered passive transfer through the placental barrier. Possible health effects of fetal (and postnatal) glycidol exposure in children may be addressed in epidemiological studies.


Assuntos
Compostos de Epóxi/metabolismo , Sangue Fetal/química , Hemoglobinas/metabolismo , Troca Materno-Fetal , Propanóis/metabolismo , Valina/análogos & derivados , Adulto , Biomarcadores/sangue , Cromatografia Líquida de Alta Pressão , Estudos de Coortes , Eritrócitos/química , Feminino , Hemoglobinas/análise , Humanos , Recém-Nascido , Gravidez , Fumar/sangue , Espectrometria de Massas em Tandem , Valina/sangue
3.
Neurol Clin ; 38(2): 379-396, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32279716

RESUMO

Tardive dyskinesia (TD) is an iatrogenic condition that encompasses a wide phenomenological spectrum of movement disorders caused by exposure to dopamine receptor blocking agents (DRBAs). TD may cause troublesome or disabling symptoms that impair quality of life. Due to frequent, often inappropriate, use of DRBAs, TD prevalence rates among patients exposed to DRBAs continue to be high. The judicious use of DRBAs is key to the prevention of TD, reduction of disease burden, and achieving lasting remission. Dopamine-depleting vesicular monoamine transporter type 2 inhibitors are considered the treatment of choice of TD.


Assuntos
Discinesia Tardia/terapia , Antipsicóticos/uso terapêutico , Toxinas Botulínicas/uso terapêutico , Estimulação Encefálica Profunda/métodos , Eletroconvulsoterapia , Humanos , Antagonistas Muscarínicos/uso terapêutico , Fármacos Neuromusculares/uso terapêutico , Tetrabenazina/análogos & derivados , Tetrabenazina/uso terapêutico , Triexifenidil/uso terapêutico , Valina/análogos & derivados , Valina/uso terapêutico , Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores
4.
J Clin Psychiatry ; 81(2)2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32078259

RESUMO

The use of second-generation antipsychotics has not eliminated tardive dyskinesia (TD), and the prevalence of the disorder is higher than commonly realized. The involuntary movements of TD can decrease patients' quality of life, cause embarrassment, and lead to social withdrawal. Clinicians must evaluate patients taking DRBAs for TD risk factors and regularly screen them for TD using a rating scale. Familiarity with tools and diagnostic criteria will enable clinicians to conduct a differential diagnosis. Once a diagnosis is made, medications approved by the US Food and Drug Administration can be used to treat the condition. These medications are effective, but clinicians should be aware of key differences. A baseline assessment and regular follow-up evaluations will allow the clinician to monitor the patient's progress and make adjustments to meet treatment goals.​.


Assuntos
Inibidores da Captação Adrenérgica/farmacologia , Antipsicóticos/efeitos adversos , Antagonistas de Dopamina/efeitos adversos , Esquizofrenia/tratamento farmacológico , Discinesia Tardia/diagnóstico , Discinesia Tardia/tratamento farmacológico , Discinesia Tardia/etiologia , Tetrabenazina/análogos & derivados , Valina/análogos & derivados , Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores , Inibidores da Captação Adrenérgica/administração & dosagem , Adulto , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Discinesia Tardia/induzido quimicamente , Tetrabenazina/administração & dosagem , Tetrabenazina/farmacologia , Valina/administração & dosagem , Valina/farmacologia
6.
J Clin Psychiatry ; 81(2)2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31995679

RESUMO

Valbenazine and deutetrabenazine are FDA-approved as treatment for tardive dyskinesia (TD). Both medications are vesicular monoamine transporter type 2 (VMAT2) inhibitors, and both are effective for reducing TD symptoms. Clinicians need to be aware of the adverse effects of valbenazine and deutetrabenazine, as well as other key differences between the two, in order to individualize treatment. Using the Abnormal Involuntary Movement Scale assists clinicians in assessing progress for each patient. Treating TD effectively with these new medications will reduce the burden of the condition for patients.


Assuntos
Exame Neurológico/métodos , Discinesia Tardia , Tetrabenazina/análogos & derivados , Valina/análogos & derivados , Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores , Monitoramento de Medicamentos/métodos , Humanos , Conduta do Tratamento Medicamentoso , Moduladores de Transporte de Membrana/administração & dosagem , Moduladores de Transporte de Membrana/efeitos adversos , Administração dos Cuidados ao Paciente/métodos , Administração dos Cuidados ao Paciente/normas , Psiquiatria/educação , Discinesia Tardia/induzido quimicamente , Discinesia Tardia/diagnóstico , Discinesia Tardia/tratamento farmacológico , Tetrabenazina/administração & dosagem , Tetrabenazina/efeitos adversos , Resultado do Tratamento , Valina/administração & dosagem , Valina/efeitos adversos
7.
Forensic Sci Int ; 307: 110107, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31951949

RESUMO

New psychoactive substances have emerged as a vast and diverse group of illicit drugs over the past decade, with synthetic cannabinoids comprising the largest of the categories. Commonly, a single synthetic cannabinoid is applied to plant material, creating a product that is designed to be smoked by the user. The clandestine preparation process can result in an unevenly distributed product, with varying concentration within and between plant materials. This investigation describes the novel co-detection of the synthetic cannabinoid AMB-FUBINACA, with the piperazine para-fluorophenylpiperazine (pFPP), in a number of plant material samples analysed in New Zealand in 2017. Of 157 samples of plant material containing AMB-FUBINACA, pFPP was detected in 55 of them. A range of pFPP concentrations was observed between the plant material samples, as well as intra-batch variation. The presence of both drugs may be designed to enhance, prolong or balance the psychoactive effects caused from smoking the plant material. However the intended purpose has not been verified. This is the first reported combination of a synthetic cannabinoid and a piperazine in plant material.


Assuntos
Canabinoides/análise , Indazóis/análise , Piperazinas/análise , Plantas/química , Psicotrópicos/análise , Valina/análogos & derivados , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Drogas Ilícitas/análise , Nova Zelândia , Valina/análise
8.
Parkinsonism Relat Disord ; 71: 35, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31982730

RESUMO

This letter to the editor acknowledges the contribution of Akbar et al. to the field of tardive dyskinesia (TD) and provides important regulatory information about the potential for parkinson-like symptoms in patients with TD who are treated with valbenazine.


Assuntos
Antipsicóticos , Transtornos Parkinsonianos , Discinesia Tardia , Humanos , Tetrabenazina/análogos & derivados , Valina/análogos & derivados
9.
Gene ; 722: 144057, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31430519

RESUMO

OBJECTIVE: Fork head domain-containing transcription factor family (FOX), is comprised of >20 members. Members of FOX family have been implicated in a wide range of physiological and/or diseased conditions. Many of FOX members have been shown to be involved in tumorigenesis and progression. The potential roles in carcinogenesis of FOXN4, a member as one of the vast FOX family, remains relatively unknown. METHOD: Here, we explored the potential involvement of FOXN4 in breast cancer. RESULTS: First, observed that a higher FOXN4 was identified in the normal adjacent breast tissue as compared to that in the breast cancer samples; an increased FOXN4 level was associated with a better prognosis in patients with breast cancer. In addition, ectopically expression of FOXN4 led to the decreased cell proliferation, reduced colony formation and metastatic abilities (EMT, migration and invasion) in breast cancer cell lines. Furthermore, we showed the direct interaction between FOXN4 and TP53 and FOXN4 binding led to the increased activity of TP53. Silencing FOXN4 led to reduced TP53 and increased expression of Dll4, Notch and survivin, providing a link between FOXN4 and Notch signaling. Finally, we used patient-derived xenograft mouse model to demonstrate the tumor inhibitory effects of Notch-inhibitor, PF-3084014. We found that PF-3084014 treatment led to a significantly smaller tumor burden and higher survival ratio in patient-derived xenograft mice as compared to the vehicle. This tumor suppressive effect was accompanied by the increased expression of TP53, FOXN4 and decreased Dll4 and Notch. CONCLUSION: Collectively, our data strongly suggested the tumor suppressive roles of FOXN4 in breast tumorigenesis via the activation of TP53 while suppressing Notch signaling. Future studies are warranted to explore the clinical application of PF-3084104 (Notch inhibitor) for the treatment of breast cancer patients.


Assuntos
Neoplasias da Mama/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Adulto , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carcinogênese , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Fatores de Transcrição Forkhead/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/metabolismo , Camundongos , Metástase Neoplásica , Prognóstico , Receptores Notch/antagonistas & inibidores , Receptores Notch/metabolismo , Transdução de Sinais , Tetra-Hidronaftalenos/uso terapêutico , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteínas Supressoras de Tumor/genética , Valina/análogos & derivados , Valina/uso terapêutico
10.
J Clin Psychiatry ; 81(1)2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31851437

RESUMO

Tardive dyskinesia (TD), a condition characterized by involuntary movements, is found in patients taking antipsychotics or other agents that block dopamine receptors. Symptoms of TD are associated with reduced quality of life, psychosocial problems, and medication nonadherence. Few agents tested in the treatment of TD had sufficient data to support or refute their use, until recently. A review of new evidence was combined with the existing guideline to provide new treatment recommendations. This activity provides an overview of treatments for patients with TD, including valbenazine and deutetrabenazine, which both received FDA approval for the treatment of TD.


Assuntos
Discinesia Tardia/tratamento farmacológico , Humanos , Adesão à Medicação , Guias de Prática Clínica como Assunto , Tetrabenazina/análogos & derivados , Tetrabenazina/uso terapêutico , Valina/análogos & derivados , Valina/uso terapêutico
11.
J Clin Psychopharmacol ; 39(6): 620-627, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31688452

RESUMO

PURPOSE/BACKGROUND: Valbenazine is approved to treat tardive dyskinesia (TD) in adults. KINECT 4 (NCT02405091) was conducted to explore the long-term effects of once-daily valbenazine in patients with TD. METHODS/PROCEDURES: The study included a 48-week, open-label treatment period and 4-week washout. Dosing was initiated at 40 mg/d, with escalation to 80 mg/d at week 4 based on efficacy and tolerability. Standard safety methods were applied, including treatment-emergent adverse event (TEAE) reporting. Valbenazine effects on TD were assessed using the Abnormal Involuntary Movement Scale (AIMS), Clinical Global Impression of Change-TD, and Patient Global Impression of Change. FINDINGS/RESULTS: After week 4, <15% of all participants had a serious TEAE (13.7%) or TEAE leading to discontinuation (11.8%). Participants experienced TD improvements during long-term treatment as indicated by mean change from baseline to week 48 in AIMS total score (sum of items 1-7, evaluated by site raters) with valbenazine 40 mg/d (-10.2 [n = 45]) or 80 mg/d (-11.0 [n = 107]). At week 48, most participants had ≥50% improvement from baseline in AIMS total score (40 mg/d, 90.0%; 80 mg/d, 89.2%), Clinical Global Impression of Change-TD rating of much or very much improved (40 mg/d, 90.0%; 80 mg/d, 95.9%), and Patient Global Impression of Change rating of much or very much improved (40 mg/d, 90.0%; 80 mg/d, 89.2%). No dose effects were apparent by week 36. Week 52 results indicated some loss of effect after washout. IMPLICATIONS/CONCLUSIONS: Valbenazine was generally well tolerated, and no new safety concerns were detected. Substantial clinician- and patient-reported improvements were observed in adults with TD who received once-daily valbenazine for up to 48 weeks.


Assuntos
Antipsicóticos/efeitos adversos , Transtornos do Humor/tratamento farmacológico , Avaliação de Resultados em Cuidados de Saúde , Transtornos Psicóticos/tratamento farmacológico , Esquizofrenia/tratamento farmacológico , Discinesia Tardia/tratamento farmacológico , Tetrabenazina/análogos & derivados , Valina/análogos & derivados , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Pessoa de Meia-Idade , Discinesia Tardia/etiologia , Tetrabenazina/administração & dosagem , Tetrabenazina/efeitos adversos , Tetrabenazina/sangue , Tetrabenazina/farmacologia , Valina/administração & dosagem , Valina/efeitos adversos , Valina/sangue , Valina/farmacologia , Adulto Jovem
12.
Int J Mol Sci ; 20(18)2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31540372

RESUMO

Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the leading cause of dementia. The disease progression is associated with the build-up of amyloid plaques and neurofibrillary tangles in the brain. However, besides the well-defined lesions, the AD-related pathology includes neuroinflammation, compromised energy metabolism, and chronic oxidative stress. Likewise, the blood-brain barrier (BBB) dysfunction is suggested to be a cause and AD consequence. Accordingly, therapeutic targeting of the compromised BBB is a promising disease-modifying approach. We utilized a homozygous triple-transgenic mouse model of AD (3×Tg-AD) to assess the effects of L-norvaline on BBB integrity. We scrutinized the perivascular astrocytes and macrophages by measuring the immunopositive profiles in relation to the presence of ß-amyloid and compare the results with those found in wild-type animals. Typically, 3×Tg-AD mice display astroglia cytoskeletal atrophy, associated with the deposition of ß-amyloid in the endothelia, and declining nitric oxide synthase (NOS) levels. L-norvaline escalated NOS levels, then reduced rates of BBB permeability, amyloid angiopathy, microgliosis, and astrodegeneration, which suggests AD treatment agent efficacy. Moreover, results undergird the roles of astrodegeneration and microgliosis in AD-associated BBB dysfunction and progressive cognitive impairment. L-norvaline self-evidently interferes with AD pathogenesis and presents a potent remedy for angiopathies and neurodegenerative disorders intervention.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Barreira Hematoencefálica/efeitos dos fármacos , Valina/análogos & derivados , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/análise , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Barreira Hematoencefálica/patologia , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Angiopatia Amiloide Cerebral/tratamento farmacológico , Angiopatia Amiloide Cerebral/patologia , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Valina/uso terapêutico
13.
Org Biomol Chem ; 17(37): 8618-8627, 2019 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-31528932

RESUMO

A rational approach that may be applied to a broad class of enzyme-catalyzed reactions to design enzyme inhibitors affords a powerful strategy, facilitating the development of drugs and/or molecular probes of enzyme mechanisms. A strategy for the development of substrate-product analogues (SPAs) as inhibitors of racemases and epimerases is elaborated using isoleucine 2-epimerase from Lactobacillus buchneri (LbIleE) as a model enzyme. LbIleE catalyzes the PLP-dependent, reversible, racemization or epimerization of nonpolar amino acids at the C-2 position. The enzyme plays an important role in the biosynthesis of branched-chain d-amino acids and is a potential target for the development of antimicrobial agents. 3-Ethyl-3-methyl-l-norvaline (Ki = 2.9 ± 0.2 mM) and 3-ethyl-3-methyl-d-norvaline (Ki = 1.5 ± 0.2 mM) were designed as SPAs based on the movement of the sec-butyl side chain of the substrate l-Ile during catalysis, and were competitive inhibitors with binding affinities exceeding that of l-Ile by 1.3- and 2.5-fold, respectively. Surprisingly, these compounds were not substrates, but the corresponding compounds lacking the 3-methyl group were substrates. Unlike serine, glutamate, and proline racemases, which exhibit stringent steric requirements at their active sites, the active site of LbIleE was amenable to binding bulky SPAs. Moreover, LbIleE bound the SPA 2,2-di-n-butylglycine (Ki = 11.0 ± 0.2 mM) as a competitive inhibitor, indicating that the hydrophobic binding pocket at the active site was sufficiently plastic to tolerate gem-dialkyl substitution at the α-carbon of an amino acid. Overall, these results reveal that amino acid racemases/epimerases are amenable to inhibition by SPAs provided that they possess a capacious active site.


Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Glicina/farmacologia , Isoleucina/antagonistas & inibidores , Lactobacillus/enzimologia , Racemases e Epimerases/antagonistas & inibidores , Valina/análogos & derivados , Sítios de Ligação/efeitos dos fármacos , Biocatálise/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Glicina/análogos & derivados , Glicina/química , Isoleucina/metabolismo , Modelos Moleculares , Conformação Molecular , Racemases e Epimerases/metabolismo , Especificidade por Substrato , Valina/síntese química , Valina/química , Valina/farmacologia
14.
Drug Test Anal ; 11(9): 1358-1368, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31192526

RESUMO

Synthetic cannabinoids (SCs) represented 45% of new psychoactive substances seizures in Europe (data from 2016). The consumption of SCs is an issue of concern due to their still unknown toxicity and effects on human health, the great variety of compounds synthetized, and the continuous modifications being made to their chemical structure to avoid regulatory issues. These compounds are extensively metabolized in the organism and often cannot be detected as the intact molecule in human urine. The monitoring of SCs in forensic samples must be performed by the analysis of their metabolites. In this work, a workflow for the comprehensive study of SC consumption is proposed and applied to 5F-APP-PICA (also known as PX 1 or SRF-30) and AMB-FUBINACA (also known as FUB-AMB or MMB-FUBINACA), based not only on the elucidation of their metabolites but also including functional data using the NanoLuc approach, previously published. Both cannabinoids were completely metabolized by human hepatocytes (12 and 8 metabolites were elucidated by high resolution mass spectrometry for 5F-APP-PICA and AMB-FUBINACA, respectively) and therefore suitable consumption markers are proposed. The bioassays revealed that 5F-APP-PICA presented lower activity than AMB-FUBINACA at CB1 and CB2 receptors, based on the half maximal effective concentration (EC50 ) and the maximum response (Emax ). These results are in agreement with the different intoxication cases found in the literature for AMB-FUBINACA.


Assuntos
Canabinoides/metabolismo , Hepatócitos/metabolismo , Indazóis/metabolismo , Psicotrópicos/metabolismo , Valina/análogos & derivados , Canabinoides/química , Humanos , Indazóis/química , Redes e Vias Metabólicas , Psicotrópicos/química , Espectrometria de Massas em Tandem , Valina/química , Valina/metabolismo
15.
Metab Brain Dis ; 34(4): 1171-1180, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31115726

RESUMO

Morphine addiction is known as a serious social problem. Medial prefrontal cortex (mPFC) and ventral tegmental area (VTA) are two important sites of the brain that contribute to this type of addiction, and a complicated relation exists in between. In addition, neurotransmitters like glutamate and γ--Amino Butyric Acid (GABA) play an important role in the formation of these relations. Thus, the present study was undertaken to investigate these relations by evaluating the level of associated changes in the indicated neurotransmitters in the VTA, using HPLC method. This was performed after electrical stimulation and inducing lesion of mPFC and through microinjections of N-Methyl-D-Aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists, respectively AP5 and CNQX, into the VTA of addicted rats. Our results showed that intra-peritoneal (i.p.) administration of morphine in 9 days in the morphine group, and also electrical stimulation (100 µA) of mPFC, receiving (i.p.) morphine, caused an increase in the glutamate release in the VTA, compared to the control group, but the increase of glutamate levels in the VTA in the morphine-stimulation group was not significant, compared to the morphine group. Moreover, GABA release into this area was decreasing in morphine and morphine- stimulation groups, compared to the control group. Our findings also showed that electrical lesion (0.4 mA) of mPFC, and also microinjection of glutamate antagonists into the VTA, receiving (i.p.) morphine in rats, caused a decrease of glutamate in the VTA. Therefore, it could be concluded that the relation between mPFC and VTA is highly effective in the formation of reward system.


Assuntos
Ácido Glutâmico/metabolismo , Dependência de Morfina/metabolismo , Morfina/farmacologia , Entorpecentes/farmacologia , Córtex Pré-Frontal/metabolismo , Área Tegmentar Ventral/metabolismo , 6-Ciano-7-nitroquinoxalina-2,3-diona/farmacologia , Animais , Estimulação Elétrica , Antagonistas de Aminoácidos Excitatórios/farmacologia , Masculino , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Wistar , Valina/análogos & derivados , Valina/farmacologia , Área Tegmentar Ventral/efeitos dos fármacos
16.
J Psychosoc Nurs Ment Health Serv ; 57(5): 11-14, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31042295

RESUMO

Tardive dyskinesia (TD), the choreoathetoid movements of fingers, arms, legs, and trunk and irregular stereotypical movements of the mouth, face, and tongue, has been the scourge of antipsychotic medications since the approval of chlorpromazine. TD tends to occur late in treatment and sometimes remains after discontinuation of the antipsychotic medication. With the recent approval of two medications, valbenazine (Ingrezza®) and deutetrabenazine (Austedo®), there are now treatments for this disfiguring consequence of dopamine-blocking medications. The current article distinguishes the movement disorder adverse effects of dopamine antagonists, explains the putative mechanism of action, and describes how best to treat TD with the new vesicular monamine transporter 2 (VMAT2) medications now approved by the U.S. Food and Drug Administration. [Journal of Psychosocial Nursing and Mental Health Services, 57(5), 11-14.].


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Discinesia Tardia/tratamento farmacológico , Tetrabenazina/análogos & derivados , Valina/análogos & derivados , Antipsicóticos/uso terapêutico , Clorpromazina/uso terapêutico , Humanos , Enfermagem Psiquiátrica , Tetrabenazina/farmacologia , Tetrabenazina/uso terapêutico , Valina/farmacologia , Valina/uso terapêutico
17.
Neuropharmacology ; 151: 64-73, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30943384

RESUMO

Behavioral studies using pharmacological tools have implicated histamine H1 receptors in cognitive function via their interactions with N-methyl-D-aspartate receptors (NMDARs) in the hippocampus. However, little is known about the neurophysiological mechanism that underlies the interaction between H1 receptors and NMDARs. To explore how H1 receptor activation affects hippocampal excitatory neurotransmission and synaptic plasticity, this study aimed to examine the effect of H1 receptor ligands on both NMDAR-mediated synaptic currents and long-term potentiation (LTP) at synapses between Schaffer collaterals and CA1 pyramidal neurons using acute mouse hippocampal slices. We found that the H1 receptor antagonist/inverse agonists, pyrilamine (0.1 µM) and cetirizine (10 µM), decreased the NMDAR-mediated component of stimulation-induced excitatory postsynaptic currents (EPSCs) recorded from CA1 pyramidal neurons without affecting the AMPA receptor-mediated component of EPSCs and its paired pulse ratio. Pretreatment of slices with either the glial metabolism inhibitor, fluoroacetate (5 mM), or D-serine (100 µM) diminished the pyrilamine- or cetirizine-induced attenuation of the NMDAR-mediated EPSCs. Furthermore, the LTP of field excitatory postsynaptic potentials induced following high frequency stimulation of Schaffer collaterals was attenuated with application of pyrilamine or cetirizine. Pretreatment with D-serine again attenuated the pyrilamine-induced suppression of LTP. Our data suggest that H1 receptors in the CA1 can undergo persistent activation induced by their constitutive receptor activity and/or tonic release of endogenous histamine, resulting in facilitation of the NMDAR activity in a manner dependent of astrocytes and the release of D-serine. This led to the enhancement of NMDA-component EPSC and LTP at the Schaffer collateral-CA1 pyramidal neuron synapses.


Assuntos
Astrócitos/efeitos dos fármacos , Região CA1 Hipocampal/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos H1/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Receptores Histamínicos H1/metabolismo , Serina/farmacologia , Animais , Astrócitos/metabolismo , Região CA1 Hipocampal/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciação de Longa Duração/fisiologia , Camundongos , N-Metilaspartato/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Pirilamina/farmacologia , Receptores de N-Metil-D-Aspartato/agonistas , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Valina/análogos & derivados , Valina/farmacologia
18.
J Biol Chem ; 294(21): 8543-8554, 2019 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-30940724

RESUMO

Prostate cancer is the second leading cause of cancer death among men in the United States. The androgen receptor (AR) antagonist enzalutamide is a Food and Drug Administration-approved drug for treatment of patients with late-stage prostate cancer and is currently under clinical study for early-stage prostate cancer treatment. After a short positive response period, tumors will develop drug resistance. In this study using RNA-Seq and bioinformatics analyses, we observed that NOTCH signaling is a deregulated pathway in enzalutamide-resistant cells. NOTCH2 and c-MYC gene expression positively correlated with AR expression in samples from patient with hormone refractory disease in which AR expression levels correspond to those typically observed in enzalutamide resistance. Cleaved NOTCH1, HES1 (Hes family BHLH transcription factor 1), and c-MYC protein expression levels are elevated in two enzalutamide-resistant cell lines, MR49F and C4-2R, indicating NOTCH signaling activation. Moreover, inhibition of the overexpressed ADAM metallopeptidase domain 10 (ADAM10) in the resistant cells induces an exclusive reduction in cleaved NOTCH1 expression. Furthermore, exposure of enzalutamide-resistant cells to both PF-03084014 and enzalutamide increased cell death, decreased colony formation ability, and resensitized cells to enzalutamide. Knockdown of NOTCH1 in C4-2R increased enzalutamide sensitivity by decreasing cell proliferation and increasing cleaved PARP expression. In a 22RV1 xenograft model, PF-03084014 and enzalutamide decreased tumor growth through reducing cell proliferation and increasing apoptosis. These results indicate that NOTCH1 signaling may contribute to enzalutamide resistance in prostate cancer, and inhibition of NOTCH signaling can resensitize resistant cells to enzalutamide.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feniltioidantoína/análogos & derivados , Receptor Notch1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tetra-Hidronaftalenos/farmacologia , Valina/análogos & derivados , Animais , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Masculino , Camundongos , Camundongos Nus , Feniltioidantoína/farmacologia , Neoplasias da Próstata , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Receptor Notch1/genética , Receptor Notch2/genética , Receptor Notch2/metabolismo , Transdução de Sinais/genética , Fatores de Transcrição HES-1/genética , Fatores de Transcrição HES-1/metabolismo , Valina/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Drug Test Anal ; 11(8): 1183-1191, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31021521

RESUMO

Indole- and indazole-based synthetic cannabinoid receptor agonists (SCRAs), featuring valine or tert-leucine substituents, are commonly abused new psychoactive substances (NPS). A major metabolic pathway for these SCRAs is hydrolysis of the terminal amide or methylester functionalities. Although these hydrolysis products were already detected as main ingredients in some "legal highs," these metabolites are often poorly characterized. Here, we report a systematic investigation of the activity of 7 common hydrolysis metabolites of 15 SCRAs featuring scaffolds based on L-valine or L-tert-leucine in direct comparison to their parent compounds. An activity-based cannabinoid receptor 1 (CB1 ) bio-assay was used for activity profiling of SCRAs and their metabolites in a stable HEK293T cell system. The recruitment of ß-arrestin2 to the activated CB1 (each fused to one part of a split Nanoluciferase) was provoked by adding the (putative) SCRAs. Luminescence of the functionally complemented luciferase was monitored by a 96-well plate-reader. The major hydrolysis metabolites of 5F-AB-PINACA, ADB-CHMICA, ADB-CHMINACA, ADB-FUBICA, and their methyl- and ethylester derivatives showed no detectable CB1 activation at concentrations up to 1 µM. On the other hand, metabolites of 5F-ADB-PINACA, AB-CHMINACA, and ADB-FUBINACA did retain activity, although significantly reduced as compared to the parent compounds (EC50 values >100 nM). Activity-based characterization of SCRAs and their metabolites at CB1 may not only allow a better insight into the complex interplay between SCRAs and their metabolites in intoxications, but may also allow application of the concept of "activity equivalents" present in biological fluids or, alternatively, in confiscated materials.


Assuntos
Agonistas de Receptores de Canabinoides/metabolismo , Agonistas de Receptores de Canabinoides/farmacologia , Valina/análogos & derivados , Valina/metabolismo , Valina/farmacologia , Agonistas de Receptores de Canabinoides/química , Drogas Desenhadas/química , Drogas Desenhadas/metabolismo , Drogas Desenhadas/farmacologia , Células HEK293 , Humanos , Psicotrópicos/química , Psicotrópicos/metabolismo , Psicotrópicos/farmacologia , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/metabolismo , Valina/química
20.
Neurotoxicology ; 73: 161-167, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30953678

RESUMO

A recent push to provide more translationally relevant preclinical models for examination of pharmacological mechanisms underlying inhaled substances of abuse has resulted in the development of equipment and methods that allows exposure of freely moving rodents to aerosolized psychoactive drugs. In the present study, synthetic cannabinoids (CP55,940, AB-CHMINACA, and AMB-FUBINACA) were administered intraperitoneally (i.p.) or aerosolized via a modified electronic cigarette device. Subsequently, the compounds were evaluated in adult male and female C57/Bl6 mice trained to discriminate i.p. 5.6 mg/kg Δ9-tetrahydrocannabinol (THC) for food reinforcement. When administered i.p., THC and AB-CHMINACA were equally potent at producing THC-like effects in both sexes, but CP55,940 and AMB-FUBINACA were more potent in males. Upon aerosol exposure, all compounds continued to produce THC-like effects in both sexes, with AMB-FUBINACA remaining the most potent. In contrast, aerosolized CP55,940 showed substantial decreases in potency in both sexes. Aerosolized nicotine did not substitute for THC in either sex. In females, aerosolized cumyl-4CN-BINACA produced concentration-dependent increases in responding on the THC-associated nosepoke. In addition, the effects of an active concentration of AMB-FUBINACA were reversed by rimonabant, suggesting CB1 receptor mediation. These results show that synthetic cannabinoids produce THC-like effects when injected i.p. or after aerosolization. This study adds to a growing literature suggesting that evaluation of abuse liability of substances via aerosol exposure is feasible and may provide a translationally relevant method that allows for investigation of factors important to the abuse of drugs which humans typically smoke or vape.


Assuntos
Comportamento Animal/efeitos dos fármacos , Canabinoides/administração & dosagem , Condicionamento Operante/efeitos dos fármacos , Cicloexanóis/administração & dosagem , Sistemas Eletrônicos de Liberação de Nicotina , Indazóis/administração & dosagem , Valina/análogos & derivados , Vaping , Administração por Inalação , Aerossóis , Animais , Canabinoides/síntese química , Cicloexanóis/síntese química , Feminino , Indazóis/síntese química , Injeções Intraperitoneais , Masculino , Camundongos Endogâmicos C57BL , Valina/administração & dosagem , Valina/síntese química
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