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1.
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
2.
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
3.
Biomed Pharmacother ; 113: 108768, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30889486

RESUMO

Pulmonary fibrosis (PF) progression may be involved with arginine (Arg) metabolism and immune balance. The present study aimed to explore the effects of L-Arginine (L-Arg) and L-Norvaline (L-Nor) on bleomycin (BLM)-induced PF in mice, meanwhile, and observe dynamic changes of Arg metabolism, immune balance and crosstalk between them in PF progression. Followed intratracheal instillation of BLM or saline, Kunming mice were treated orally with saline, L-Arg, L-Nor and L-Arg + L-Nor three times a day. And the mice were sacrificed on Day 3, 14 and 28 after treatment. Changes of body weight, lung index, lung hydroxyproline and histopathology were analyzed to evaluate the PF degree. Peripheral blood Arg, Citrulline (Cit), Ornithine (Orn) and Proline (Pro), lung NO, NOS and arginase were analyzed to evaluate the Arg metabolism. Peripheral blood Tregs, Th17 and γδT cells were analyzed to evaluate the immune balance. Our data showed that combination of L-Arg and L-Nor dynamically reversed the weight loss, decreased lung index and hydroxyproline, and improved lung histopathological damages induced by BLM. The combination dynamically and significantly rectified Tregs, Th17, γδT and Tregs/Th17 abnormal changes. Meanwhile, these disorders of peripheral blood Arg, Cit, Orn, Pro, Orn/Cit and Pro/Orn, and lung NO, iNOS and TNOS were also improved accordingly. These results demonstrated that combination of L-Arg and L-Nor had inhibitory effects on BLM-induced PF progression, possibly due to their corrective action on immune imbalance, Arg metabolism disorder and crosstalk abnormality in the progression of PF.


Assuntos
Arginina/administração & dosagem , Pulmão/efeitos dos fármacos , Fibrose Pulmonar/prevenção & controle , Valina/análogos & derivados , Administração Oral , Animais , Arginina/farmacologia , Bleomicina/toxicidade , Modelos Animais de Doenças , Progressão da Doença , Quimioterapia Combinada , Linfócitos Intraepiteliais/imunologia , Pulmão/patologia , Masculino , Camundongos , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/patologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Valina/administração & dosagem , Valina/farmacologia
4.
Clin Neuropharmacol ; 42(2): 37-41, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30870235

RESUMO

OBJECTIVES: The aim of this study was to review our "real-world" experience with the vesicular monoamine transporter 2 (VMAT2) inhibitors tetrabenazine (TBZ), deutetrabenazine (DTBZ), and valbenazine (VBZ) for treatment of hyperkinetic movement disorders. Access and adherence to VMAT2 inhibitors may be limited by insurance and regulatory issues, inexperience with their use by the prescribing physician, lack of efficacy, or side effects. METHODS: We performed a retrospective chart review, supplemented with a questionnaire, of all our patients treated with a VMAT2 inhibitor between January 1, 2017, and August 30, 2018. RESULTS: We identified 135 patients (57.8% male) and 178 prescriptions for VMAT2 inhibitors (TBZ, n = 45 [25.3%]; DTBZ, n = 104 [58.4%]; VBZ, n = 29 [16.3%]). Tourette syndrome/tics was the most common diagnosis (n = 67 [49.6%]) for which VMAT2 inhibitors were prescribed. The VMAT2 inhibitor mean treatment durations (range; SD) and daily dosages (range; SD) were as follows: TBZ (n = 31), 5.1 months (1-19; 3.9) at 48.8 mg (12.5-112.5; 29.6); DTBZ (n = 51), 8.0 months (0.25-16.5; 4.4) at 34.4 mg (6-96; 20.7); and VBZ (n = 20), 6.0 months (0.1-16; 5.6) at 64 mg (40-160; 35.3). The VMAT2 inhibitors effectively controlled hyperkinetic movement disorders as measured by a 1- to 4-point Likert scale (1 = normal or mildly ill, 4 = severely ill) comparing illness severity before starting and while on treatment (score of 1 in 13.0%-26.7% vs 60.9%-71.9% of patients). Side effects were mild and improved or resolved following dose reduction, drug cessation, or addition of adjunctive medications. CONCLUSIONS: The VMAT2 inhibitors are effective and safe in a range of hyperkinetic movement disorders but are not readily accessible by patients in the United States for indications not approved by the Food and Drug Administration.


Assuntos
Tetrabenazina/análogos & derivados , Tetrabenazina/uso terapêutico , Tiques/tratamento farmacológico , Síndrome de Tourette/tratamento farmacológico , Valina/análogos & derivados , Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tetrabenazina/farmacologia , Tiques/diagnóstico , Síndrome de Tourette/diagnóstico , Valina/farmacologia , Valina/uso terapêutico , Adulto Jovem
5.
Forensic Sci Int ; 297: 372-377, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30850157

RESUMO

Synthetic cannabinoids (SCs) belong to the group of new psychoactive substances (NPS) which appear sprayed on herbal mixtures on the "street" drug market and are intended for smoking like marijuana. In the present report we discuss a fatal case of 18-years-old boy, who had smoked SCs since several months and an overuse of SCs during last 48 h of his life has been apprised. The autopsy findings revealed acute respiratory distress syndrome (ARDS). Both toxicological analysis of deceased blood and urine samples and chemical analysis of the herbal mixture seized revealed presence of two SCs - 5F-ADB and FUB-AMB. The amount of 5F-ADB in blood was found to be 3.7 ng/mL by standard addition method. Severe and irreversible morphology changes in lung specimen, leading to ischemic damage of all internal organs and tissues, were observed during histological examination. The present case can be discussed as an example of both drug-induced and drug-related death resulting from acute intoxication with 5F-ADB and FUB-AMB as well as from systematic use of both synthetic cannabinoids.


Assuntos
Canabinoides/efeitos adversos , Drogas Desenhadas/efeitos adversos , Indazóis/efeitos adversos , Insuficiência Respiratória/induzido quimicamente , Valina/análogos & derivados , Adolescente , Canabinoides/sangue , Canabinoides/urina , Drogas Desenhadas/análise , Overdose de Drogas , Humanos , Indazóis/sangue , Indazóis/urina , Extração Líquido-Líquido , Pulmão/patologia , Masculino , Transtornos Relacionados ao Uso de Substâncias/complicações , Valina/efeitos adversos , Valina/sangue , Valina/urina
6.
Toxicol In Vitro ; 56: 163-171, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30703532

RESUMO

In addition to the 20 protein amino acids that are encoded for protein synthesis, hundreds of other naturally occurring amino acids, known as non-proteinogenic amino acids (NPAAs) exist. It is well known that some NPAAs are toxic through their ability to mimic protein amino acids, either in protein synthesis or in other metabolic pathways, and this property is utilised by some plants to inhibit the growth of other plants or kill herbivores. L-norvaline is an NPAA readily available for purchase as a dietary supplement. In light of previous evidence of l-norvaline's antifungal, antimicrobial and herbicidal activity, we examined the toxicity of l-norvaline to mammalian cells in vitro and showed that l-norvaline decreased cell viability at concentrations as low as 125 µM, caused necrotic cell death and significant changes to mitochondrial morphology and function. Furthermore, toxicity was reduced in the presence of structurally similar 'protein' amino acids, suggesting l-norvaline's cytotoxicity could be attributed to protein amino acid mimicry.


Assuntos
Suplementos Nutricionais/toxicidade , Valina/análogos & derivados , Apoptose/efeitos dos fármacos , Cálcio/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , Valina/toxicidade
7.
Drug Test Anal ; 11(4): 610-616, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30604522

RESUMO

Synthetic cannabinoid receptor agonists were first identified in herbal products in 2008 advertised as a legal replacement for cannabis. These herbal incense are usually called "spice" and among these, one product in particular has gained popularity: AB-PINACA (N-[(2S)-1-Amino-3-methyl-1-oxobutan-2-yl]-1-pentyl-1H-indazole-3-carboxamide). This drug has been discovered to have a stronger binding to human cannabinoid CB1 and CB2 receptors than ∆9 -THC.While some articles have been published regarding the presence of AB-PINACA in biological fluids such as blood and urine, none reports the presence of AB-PINACA in hair. We have developed and validated a method for detection of AB-PINACA in hair using a liquid chromatography-tandem mass spectrometry system and applied it to head and pubic hair obtained in a case of intoxication. The validation procedure demonstrated a limit of detection and a limit of quantification of 0.5 and 1 pg/mg, respectively and acceptable linearity, repeatability, and reproducibility. AB-PINACA tested positive in the blood (5.7 ng/mL) and less than 1 ng/mL was found in urine. The analysis of the hair specimens resulted in an unusual distribution of the drug between head and pubic hair. AB-PINACA was identified at a higher concentration in head hair (195 pg/mg) versus in pubic hair (5 pg/mg). The very low concentration of AB-PINACA in the urine after consumption, due to rapid metabolism, could explain this infrequent distribution, as pubic hair can be contaminated by urine. In any case, it cannot be excluded that the high concentration in head hair may be due to environmental contamination.


Assuntos
Agonistas de Receptores de Canabinoides/farmacocinética , Cabelo/química , Indazóis/farmacocinética , Drogas Ilícitas/farmacocinética , Valina/análogos & derivados , Adulto , Cromatografia Líquida/métodos , Humanos , Limite de Detecção , Masculino , Reprodutibilidade dos Testes , Detecção do Abuso de Substâncias/métodos , Espectrometria de Massas em Tandem/métodos , Valina/farmacocinética
8.
J Affect Disord ; 246: 217-223, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30583148

RESUMO

BACKGROUND: Few studies have assessed the treatment of tardive dyskinesia (TD) in patients with primary mood disorders who are managed with antipsychotics. The effects of once-daily valbenazine on TD were evaluated in adults with a bipolar or depressive disorder. METHODS: Data were pooled from two 6-week double-blind placebo-controlled trials (KINECT 2 and KINECT 3; 114 mood participants) and a long-term blinded extension study (KINECT 3 extension; 77 mood participants) of valbenazine in adults with TD. Efficacy assessments included Abnormal Involuntary Movement Scale (AIMS) total score (sum of items 1-7), Clinical Global Impression of Change-Tardive Dyskinesia (CGI-TD), and Patient Global Impression of Change (PGIC). Safety assessments included treatment-emergent adverse events (TEAEs), Young Mania Rating Scale, and Montgomery-Åsberg Depression Rating Scale. RESULTS: At Week 6, mean improvements in AIMS total score were significantly greater with valbenazine versus placebo (40 mg/day, -3.1 [P < 0.01]; 80 mg/day, -3.5 [P < 0.001]; placebo, -0.9). Significant differences between valbenazine (80 mg/day) and placebo were also found for Week 6 AIMS response (≥50% total score improvement) and CGI-TD response ("much improved" or "very much improved"), but not PGIC response. Sustained improvements in AIMS, CGI-TD, and PGIC were found through 48 weeks. Valbenazine was generally well tolerated, with no unexpected TEAEs, worsening in psychiatric symptoms, or emergence of suicidality. LIMITATIONS: Pooled analyses were conducted post hoc, and neither study was designed to focus solely on mood disorder patients. CONCLUSIONS: In participants with primary mood disorders, once-daily treatment with valbenazine was generally well tolerated and resulted in 6-week and sustained TD improvements.


Assuntos
Transtornos do Humor/tratamento farmacológico , Discinesia Tardia/tratamento farmacológico , Tetrabenazina/análogos & derivados , Valina/análogos & derivados , Antipsicóticos/efeitos adversos , Antipsicóticos/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos do Humor/complicações , Discinesia Tardia/induzido quimicamente , Discinesia Tardia/complicações , Tetrabenazina/efeitos adversos , Tetrabenazina/uso terapêutico , Valina/efeitos adversos , Valina/uso terapêutico
9.
Elife ; 72018 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-30556810

RESUMO

Dopamine (D2) receptors provide autoinhibitory feedback onto dopamine neurons through well-known interactions with voltage-gated calcium channels and G protein-coupled inwardly-rectifying potassium (GIRK) channels. Here, we reveal a third major effector involved in D2R modulation of dopaminergic neurons - the sodium leak channel, NALCN. We found that activation of D2 receptors robustly inhibits isolated sodium leak currents in wild-type mice but not in NALCN conditional knockout mice. Intracellular GDP-ßS abolished the inhibition, indicating a G protein-dependent signaling mechanism. The application of dopamine reliably slowed pacemaking even when GIRK channels were pharmacologically blocked. Furthermore, while spontaneous activity was observed in nearly all dopaminergic neurons in wild-type mice, neurons from NALCN knockouts were mainly silent. Both observations demonstrate the critical importance of NALCN for pacemaking in dopaminergic neurons. Finally, we show that GABA-B receptor activation also produces inhibition of NALCN-mediated currents. Therefore, we identify NALCN as a core effector of inhibitory G protein-coupled receptors.


Assuntos
Canais de Cálcio Tipo N/metabolismo , Neurônios Dopaminérgicos/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/metabolismo , Canais Iônicos/genética , Proteínas do Tecido Nervoso/genética , Receptores de Dopamina D2/metabolismo , Receptores de GABA-B/metabolismo , 6-Ciano-7-nitroquinoxalina-2,3-diona/farmacologia , Animais , Canais de Cálcio Tipo N/genética , Dopamina/farmacologia , Neurônios Dopaminérgicos/citologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/antagonistas & inibidores , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/genética , Expressão Gênica , Guanosina Difosfato/análogos & derivados , Guanosina Difosfato/farmacologia , Canais Iônicos/deficiência , Transporte de Íons/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microtomia , Proteínas do Tecido Nervoso/deficiência , Técnicas de Patch-Clamp , Picrotoxina/farmacologia , Receptores de Dopamina D2/genética , Receptores de GABA-B/genética , Tionucleotídeos/farmacologia , Técnicas de Cultura de Tecidos , Valina/análogos & derivados , Valina/farmacologia , Área Tegmentar Ventral/citologia , Área Tegmentar Ventral/metabolismo
10.
Proc Natl Acad Sci U S A ; 115(38): 9616-9621, 2018 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-30185555

RESUMO

African trypanosomes cause lethal and neglected tropical diseases, known as sleeping sickness in humans and nagana in animals. Current therapies are limited, but fortunately, promising therapies are in advanced clinical and veterinary development, including acoziborole (AN5568 or SCYX-7158) and AN11736, respectively. These benzoxaboroles will likely be key to the World Health Organization's target of disease control by 2030. Their mode of action was previously unknown. We have developed a high-coverage overexpression library and use it here to explore drug mode of action in Trypanosoma brucei Initially, an inhibitor with a known target was used to select for drug resistance and to test massive parallel library screening and genome-wide mapping; this effectively identified the known target and validated the approach. Subsequently, the overexpression screening approach was used to identify the target of the benzoxaboroles, Cleavage and Polyadenylation Specificity Factor 3 (CPSF3, Tb927.4.1340). We validated the CPSF3 endonuclease as the target, using independent overexpression strains. Knockdown provided genetic validation of CPSF3 as essential, and GFP tagging confirmed the expected nuclear localization. Molecular docking and CRISPR-Cas9-based editing demonstrated how acoziborole can specifically block the active site and mRNA processing by parasite, but not host CPSF3. Thus, our findings provide both genetic and chemical validation for CPSF3 as an important drug target in trypanosomes and reveal inhibition of mRNA maturation as the mode of action of the trypanocidal benzoxaboroles. Understanding the mechanism of action of benzoxaborole-based therapies can assist development of improved therapies, as well as the prediction and monitoring of resistance, if or when it arises.


Assuntos
Fator de Especificidade de Clivagem e Poliadenilação/antagonistas & inibidores , Proteínas de Protozoários/antagonistas & inibidores , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/fisiologia , Tripanossomíase Africana/prevenção & controle , Animais , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Compostos de Boro/farmacologia , Compostos de Boro/uso terapêutico , Sistemas CRISPR-Cas , Núcleo Celular/genética , Núcleo Celular/metabolismo , Fator de Especificidade de Clivagem e Poliadenilação/genética , Fator de Especificidade de Clivagem e Poliadenilação/metabolismo , Resistência a Medicamentos/efeitos dos fármacos , Resistência a Medicamentos/genética , Técnicas de Silenciamento de Genes , Biblioteca Gênica , Ensaios de Triagem em Larga Escala/métodos , Humanos , Simulação de Acoplamento Molecular , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Processamento Pós-Transcricional do RNA/efeitos dos fármacos , RNA Mensageiro/metabolismo , RNA de Protozoário/metabolismo , Tripanossomicidas/uso terapêutico , Trypanosoma brucei brucei/efeitos dos fármacos , Tripanossomíase Africana/transmissão , Tripanossomíase Africana/veterinária , Valina/análogos & derivados , Valina/farmacologia , Valina/uso terapêutico
12.
Chem Commun (Camb) ; 54(77): 10832-10834, 2018 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-30159569

RESUMO

The Strecker reaction is broadly used for the preparation of α-amino acids. However, control of enantioselectivity remains challenging. We here couple the Strecker reaction to Viedma ripening for the absolute asymmetric synthesis of highly sterically hindered α-amino acids. As proof-of-principle, the enantiomerically pure α-amino acids tert-leucine and α-(1-adamantyl)glycine were obtained.


Assuntos
Glicina/análogos & derivados , Glicina/química , Valina/análogos & derivados , Glicina/isolamento & purificação , Estrutura Molecular , Estereoisomerismo , Valina/química , Valina/isolamento & purificação
13.
J Vasc Interv Radiol ; 29(8): 1078-1084, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29910164

RESUMO

PURPOSE: To assess feasibility and efficacy of CKD-516, a vascular disrupting agent, in transarterial chemoembolization in a liver tumor model. MATERIALS AND METHODS: A VX2 carcinoma strain was implanted in rabbit liver (n = 40) and incubated for 2 weeks. After confirmation of tumor growth using computed tomography, transarterial chemoembolization was performed. CKD-516 was dissolved in ethiodized oil, and animals were allocated to 4 treatment groups (n = 10 in each): group A, ethiodized oil; group B, ethiodized oil/CKD-516; group C, ethiodized oil + doxorubicin; group D, ethiodized oil/CKD-516 + doxorubicin. To assess hepatic damage, serum aspartate transaminase and alanine transaminase levels were measured on day 1, 3, and 7 after delivery. To assess tumor necrosis, animals were euthanized on day 7, and explanted tumors were stained with hematoxylin and eosin and a terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling assay. Percentage areas of viable tumors were calculated using digitalized histopathologic specimen images. RESULTS: Tumor viability rates were 47.1% ± 11.4%, 27.5% ± 13.6%, 14.4% ± 12.5%, and 0.7% ± 1.0% in groups A, B, C, and D (P < .001). Liver enzyme levels were elevated after drug delivery but recovered during follow-up. Significant between-group differences were observed on days 1, 3, and 7 (aspartate transaminase and alanine transaminase: P = .0135 and P = .0134, P = .0390 and P = .0084, and P = .8260 and P = .0440). CONCLUSIONS: Treatment with a combination of CKD-516 and conventional transarterial chemoembolization showed therapeutic benefit in a liver tumor model.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Benzofenonas/administração & dosagem , Quimioembolização Terapêutica/métodos , Doxorrubicina/administração & dosagem , Óleo Etiodado/administração & dosagem , Neoplasias Hepáticas Experimentais/irrigação sanguínea , Neoplasias Hepáticas Experimentais/terapia , Valina/análogos & derivados , Alanina Transaminase/sangue , Inibidores da Angiogênese/toxicidade , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Aspartato Aminotransferases/sangue , Benzofenonas/toxicidade , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quimioembolização Terapêutica/efeitos adversos , Doxorrubicina/toxicidade , Óleo Etiodado/toxicidade , Neoplasias Hepáticas Experimentais/diagnóstico por imagem , Neoplasias Hepáticas Experimentais/patologia , Masculino , Necrose , Coelhos , Fatores de Tempo , Tomografia Computadorizada por Raios X , Carga Tumoral/efeitos dos fármacos , Valina/administração & dosagem , Valina/toxicidade
14.
Artigo em Inglês | MEDLINE | ID: mdl-29945109

RESUMO

It is challenging to conduct a pharmacokinetic (PK) study on mice due to the limited amount of plasma one can obtain, which is also true for some clinical studies. Here, we developed and validated a simple, sensitive and robust LC-MS/MS method for measuring the prodrug valacyclovir (VACV) and its metabolite acyclovir (ACV) in mouse and human plasma. This assay utilized an acetonitrile protein precipitation method with isotope-labeled internal standards (IS) and enabled precise and accurate quantification of VACV and ACV in 10 µL plasma samples with a nine-min gradient. The analytes were separated on a Waters Atlantis T3 C18 column. The precursor-product ion transitions for VACV (m/z 325.2 > 152.1), ACV (m/z 226.2 > 152.1), VACV-D4 (m/z 329.2 > 152.1, IS) and ACV-D4 (m/z 230.2 > 152.1, IS) were detected in a multiple reaction monitoring (MRM) positive ion mode using an API4000 LC-MS/MS system. The lower limit of quantification (LLOQ) was 2 nM for both VACV and ACV. The linear range was validated over the concentration ranges of 2-200 nM and 200-5000 nM for both compounds. The matrix effect and stability of VACV and ACV were also evaluated. This assay was successfully applied to a PK study in mice.


Assuntos
Aciclovir/análogos & derivados , Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem/métodos , Valina/análogos & derivados , Aciclovir/sangue , Aciclovir/química , Aciclovir/farmacocinética , Animais , Estabilidade de Medicamentos , Humanos , Modelos Lineares , Camundongos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Valaciclovir , Valina/sangue , Valina/química , Valina/farmacocinética
15.
Ear Nose Throat J ; 97(4-5): E1-E4, 2018 Apr-May.
Artigo em Inglês | MEDLINE | ID: mdl-29940684

RESUMO

We conducted a prospective study to investigate the effectiveness of pharmacologic treatment on alleviating facial paralysis, as well as the anxiety and depression that are associated with it. Our study population was made up of 105 patients-59 men and 46 women, aged 18 to 60 years (mean: 38.2)-who had acute idiopathic peripheral facial paralysis. Before treatment, paralysis was classified as House-Brackmann grade II or III in 44 patients (41.9%) and grade IV to VI in the remaining 61 (58.1%). After treatment, 73 patients (69.5%) improved to grade I, 29 (27.6%) were at grade II or III, and only 3 (2.9%) remained at grade IV or higher. Mean scores on the Beck anxiety inventory, the Beck depression inventory, and the Beck hopelessness scale were 20.30, 19.75, and 7.57, respectively, before treatment and 5.72, 5.68, and 2.85 afterward; the difference in all three measures was statistically significant (p < 0.001). We found no correlation between the degree of facial paralysis and anxiety levels (r = 0.094, p = 0.338) or depression levels (r = 0.181, p = 0.064). Clinicians should consider asking patients with peripheral facial paralysis about their feelings of anxiety, depression, and hopelessness and refer them for a psychiatric consultation if necessary.


Assuntos
Antivirais/uso terapêutico , Ansiedade/etiologia , Depressão/etiologia , Paralisia Facial/psicologia , Glucocorticoides/uso terapêutico , Inibidores da Bomba de Prótons/uso terapêutico , Aciclovir/análogos & derivados , Aciclovir/uso terapêutico , Adolescente , Adulto , Ansiedade/tratamento farmacológico , Depressão/tratamento farmacológico , Paralisia Facial/tratamento farmacológico , Feminino , Esperança , Humanos , Lansoprazol/uso terapêutico , Masculino , Pessoa de Meia-Idade , Prednisolona/uso terapêutico , Estudos Prospectivos , Escalas de Graduação Psiquiátrica , Valaciclovir , Valina/análogos & derivados , Valina/uso terapêutico , Adulto Jovem
16.
Toxicol Lett ; 298: 76-80, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29936296

RESUMO

Ethylene oxide (EO), an industrial intermediate and gaseous sterilant for medical devices, is carcinogenic to humans, which warrants minimization of exposure in the workplaces. The principal analytical strategy currently used in biomonitoring of exposure to EO consists in the conversion of N-(2-hydroxyethyl) adduct at the N-terminal valine (HEV) in globin to a specific thiohydantoin derivative accessible to GC-MS analysis (modified Edman degradation, MED). Though highly sensitive, the method is laborious and, at least in our hands, not sufficiently robust. Here we developed an alternative strategy of HEV determination based on acidic hydrolysis (AH) of globin followed directly by HPLC-ESI-MS2 analysis. Limit of quantitation is ca. 25 pmol HEV/g globin. Comparative analyses of globin samples from EO-exposed workers by both the AH-based and MED-based methods provided results that correlated well with each other (R2 > 0.95) but those obtained with AH were significantly more accurate (according to external quality control programme G-EQUAS) and repeatible (5% and 6% for intra-day and between-day analyses, respectively). In conclusion, the new AH-based method surpassed MED being similarly sensitive, much less laborious and more reliable, thus applicable as an effective tool for biomonitoring of EO in exposure control and risk assessment.


Assuntos
Cromatografia Líquida de Alta Pressão , Monitoramento Ambiental/métodos , Óxido de Etileno/sangue , Globinas/análise , Exposição por Inalação , Exposição Ocupacional , Saúde do Trabalhador , Espectrometria de Massas por Ionização por Electrospray , Valina/análogos & derivados , Ácidos/química , Biomarcadores Ambientais , Óxido de Etileno/efeitos adversos , Humanos , Hidrólise , Exposição por Inalação/efeitos adversos , Masculino , Exposição Ocupacional/efeitos adversos , Reprodutibilidade dos Testes , Medição de Risco , Valina/sangue
17.
Drug Des Devel Ther ; 12: 1215-1238, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29795977

RESUMO

Aim: The aim of this study was to summarize the characteristics, efficacy, and safety of vesicular monoamine transporter-2 (VMAT-2) inhibitors for treating tardive dyskinesia (TD). Materials and methods: We conducted a literature search in PubMed, Cochrane Database, and ClinicalTrials.gov, screening for systematic reviews, meta-analyses or double-blind, randomized, placebo-controlled trials (DBRPCTs) reporting efficacy or safety data of VMAT-2 inhibitors (tetrabenazine, deutetrabenazine, and valbenazine) in patients with TD. A random effects meta-analysis of efficacy and safety data from DBRPCTs was performed. Results: Two acute, 12-week DBRPCTs with deutetrabenazine 12-48 mg/day (n=413) and 4 acute, 4-6-week double-blind trials with valbenazine 12.5-100 mg/day (n=488) were meta-analyzable, without meta-analyzable, high-quality data for tetrabenazine. Regarding reduction in total Abnormal Involuntary Movement Scale (AIMS) scores (primary outcome), both deutetrabenazine (k=2, n=413, standardized mean difference [SMD] =-0.40, 95% confidence interval [CI] =-0.19, -0.62, p<0.001; weighted mean difference (WMD) =-1.44, 95% CI =-0.67, -2.19, p<0.001) and valbenazine (k=4, n=421, SMD =-0.58, 95% CI =-0.26, -0.91, p<0.001; WMD =-2.07, 95% CI =-1.08, -3.05, p<0.001) significantly outperformed placebo. Results were confirmed regarding responder rates (≥50% AIMS total score reduction; deutetrabenazine: risk ratio [RR] =2.13, 95% CI =1.10, 4.12, p=0.024, number-needed-to-treat [NNT] =7, 95% CI =3, 333, p=0.046; valbenazine: RR =3.05, 95% CI =1.81, 5.11, p<0.001, NNT =4, 95% CI =3, 6, p<0.001). Less consistent results emerged from patient-rated global impression-based response (p=0.15) and clinical global impression for deutetrabenazine (p=0.088), and for clinical global impression change for valbenazine (p=0.67). In an open-label extension (OLE) study of deutetrabenazine (≤54 weeks) and a dose-blinded valbenazine study (≤48 weeks), responder rates increased over time. With valbenazine, discontinuation effects were studied, showing TD symptom recurrence towards baseline severity levels within 4 weeks after valbenazine withdrawal. No increased cumulative or specific adverse (AEs) events versus placebo (acute trials) in extension versus acute trial data were observed. Conclusion: The 2 VMAT-2 inhibitors, valbenazine and deutetrabenazine, are effective in treating TD, both acutely and long-term, without concerns about increased risk of depression or suicide in the TD population. No head-to-head comparison among VMAT-2 inhibitors and no high-quality, meta-analyzable data are available for tetrabenazine in patients with TD.


Assuntos
Antipsicóticos/farmacologia , Discinesia Tardia/tratamento farmacológico , Tetrabenazina/análogos & derivados , Tetrabenazina/farmacologia , Valina/análogos & derivados , Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Valina/farmacologia , Proteínas Vesiculares de Transporte de Monoamina/metabolismo
18.
Int J Oncol ; 53(1): 99-112, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29658567

RESUMO

Castration-resistant prostate cancer (CRPC) continues to be a major challenge in the treatment of prostate cancer (PCa). The expression of hepatocyte cell adhesion molecule (HepaCAM), a novel tumor suppressor, is frequently downregulated or lost in PCa. Overactivated Notch signaling is involved in the development and progression of PCa, including CRPC. In this study, we found that the activities of Notch signaling were elevated, while HepaCAM expression was decreased in CRPC tissues compared with matched primary prostate cancer (PPC) tissues. In addition, HepaCAM negativity was found to be associated with a worse progression­free survival (PFS). Furthermore, the overexpression of HepaCAM induced by transfection with a HepaCAM overexpression vector (Ad­HepaCAM) exerted antitumor effects by decreasing the proliferation, and suppressing the invasion and migration of bicalutamide­resistant (Bica­R) cells and enzalutamide­resistant (Enza­R) cells. Importantly, we found that the antitumor effects of HepaCAM on the resistant cells were associated with the downregulation of Notch signaling. Moreover, we revealed that PF­3084014 (a γ­secretase inhibitor) re­sensitized Enza­R cells to enzalutamide, and sequential dual­resistant (E+D­R) cells to docetaxel. Additionally, the findings of this study demonstrated that the use of PF­3084014 alone exerted potent antitumor effect on the resistant cells in vitro. On the whole, this study indicates that HepaCAM potentially represents a therapeutic target and PF­3084014 may prove to a promising agent for use in the treatment of refractory PCa.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Proteínas/genética , Tetra-Hidronaftalenos/administração & dosagem , Valina/análogos & derivados , Adulto , Idoso , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Intervalo Livre de Doença , Docetaxel , Humanos , Masculino , Pessoa de Meia-Idade , Feniltioidantoína/administração & dosagem , Feniltioidantoína/efeitos adversos , Feniltioidantoína/análogos & derivados , Próstata/efeitos dos fármacos , Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Notch/antagonistas & inibidores , Receptores Notch/genética , Transdução de Sinais/efeitos dos fármacos , Taxoides/administração & dosagem , Taxoides/efeitos adversos , Valina/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Consult Pharm ; 33(4): 188-198, 2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-29609697

RESUMO

Five new drugs marketed within the last year, which are used for medical problems often experienced by the elderly, have been selected for consideration in this review. The uses and most important properties of these agents are discussed, and a rating for each new drug is determined using the New Drug Comparison Rating system developed by the author (DAH). Advantages, disadvantages, and other important information regarding each new drug are identified and used as the basis for determining the rating. The drugs include an anticoagulant, an antiparkinson agent, an agent for tardive dyskinesia, an agent for psoriasis, and an agent for constipation. The drugs reviewed are betrixaban, safinamide mesylate, valbenazine tosylate, guselkumab, and plecanatide.


Assuntos
Aprovação de Drogas , Idoso , Alanina/análogos & derivados , Alanina/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Anticoagulantes/uso terapêutico , Antiparkinsonianos/uso terapêutico , Benzamidas/uso terapêutico , Benzilaminas/uso terapêutico , Constipação Intestinal/tratamento farmacológico , Humanos , Peptídeos Natriuréticos/uso terapêutico , Psoríase/tratamento farmacológico , Piridinas/uso terapêutico , Discinesia Tardia/tratamento farmacológico , Tetrabenazina/análogos & derivados , Tetrabenazina/uso terapêutico , Valina/análogos & derivados , Valina/uso terapêutico
20.
Consult Pharm ; 33(4): 201-209, 2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-29609698

RESUMO

OBJECTIVE: To provide a review of tardive dyskinesia (TD) symptoms, etiology, pathophysiology, and treatments. DATA SOURCES: PubMed, Web of Science, ClinicalTrials. gov, and Google Scholar were searched for relevant literature using a combination of the following terms: tardive dyskinesia, treatment, management, guidelines, tetrabenazine, deutetrabenazine, and valbenazine. Sources were limited to human data. STUDY SELECTION/DATA EXTRACTION: Articles were reviewed for relevance to TD therapy. Reference lists were manually searched for other relevant articles. Selected literature was published between 1968 and 2017. DATA SYNTHESIS: This article reviews treatment options available for patients with TD. Many agents have been tried off-label to manage symptoms, with limited evidence of benefit. The Food and Drug Administration approved the first drug to treat TD valbenazine on April 11, 2017. CONCLUSION: TD is largely iatrogenic. Valbenazine's approval by the Food and Drug Administration was followed by the approval of deutetrabenazine, a drug with similar mechanism of action. Further data from postmarketing studies will be needed to verify that valbenazine's adverse effect profile is different from the profiles of tetrabenazine and deutetrabenazine.


Assuntos
Aprovação de Drogas , Discinesia Tardia/tratamento farmacológico , Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores , Humanos , Guias de Prática Clínica como Assunto , Discinesia Tardia/fisiopatologia , Tetrabenazina/efeitos adversos , Tetrabenazina/análogos & derivados , Tetrabenazina/farmacologia , Tetrabenazina/uso terapêutico , Estados Unidos , United States Food and Drug Administration , Valina/efeitos adversos , Valina/análogos & derivados , Valina/farmacologia , Valina/uso terapêutico
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