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1.
Expert Rev Clin Pharmacol ; 12(12): 1073-1079, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31842637

RESUMO

Introduction: Netarsudil and latanoprost ophthalmic solution (0.02%/0.005%) is indicated for intraocular pressure (IOP) lowering in open-angle glaucoma (OAG) or ocular hypertension (OHTN). The once-daily agent combines the mechanism of action for each of the individual components and provides a new avenue for long-term intraocular pressure control. This review aims to cover the agent's current efficacy and safety data and opine as to its role in glaucoma management.Areas covered: This article will cover Phase II-III clinical efficacy and safety data as well as basic science literature pertaining to the agent's mechanism of action and pharmacodynamics. In selecting articles for inclusion in this review, a literature search using the PubMed database was carried out. Cross-referencing was carried out where applicable. We did not use any date or language restrictions in electronic searches.Expert opinion: Netarsudil and latanoprost ophthalmic solution plays a pivotal role in management of individuals with OAG and OHTN. The agent may be used as first-line therapy to provide substantial IOP-lowering or when additional lowering is indicated and prostaglandins have provided insufficient IOP lowering. The once-daily dosing regimen decreases the risk of inadequate treatment due to nonadherence.


Assuntos
Benzoatos/administração & dosagem , Glaucoma de Ângulo Aberto/tratamento farmacológico , Latanoprosta/administração & dosagem , Hipertensão Ocular/tratamento farmacológico , beta-Alanina/análogos & derivados , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/efeitos adversos , Benzoatos/efeitos adversos , Combinação de Medicamentos , Humanos , Pressão Intraocular , Latanoprosta/efeitos adversos , Soluções Oftálmicas , beta-Alanina/administração & dosagem , beta-Alanina/efeitos adversos
2.
Drugs Today (Barc) ; 55(9): 563-574, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31584573

RESUMO

The fixed-dose combination (FDC) of netarsudil 0.02%/ latanoprost 0.005% was approved by the United States Food and Drug Administration (FDA) on March 12, 2019, for the reduction of intraocular pressure (IOP) in patients with open-angle glaucoma (OAG) and ocular hypertension (OHT). Netarsudil is a Rho kinase (ROCK) inhibitor and latanoprost is a prostaglandin analogue (PGA). Once-daily administration of this FDC reduces IOP by enhancing aqueous outflow through both the trabecular pathways (ROCK inhibition) and uveoscleral pathways (PGA). Two phase III clinical trials, MERCURY-1 and MERCURY-2, confirmed significantly greater efficacy of the FDC than the individual components, with IOP reductions of 30% or greater observed in 59-65% of subjects treated with FDC compared with 29-37% of subjects treated with latanoprost alone and 21-29% of subjects treated with netarsudil alone. The FDC was well tolerated with mostly mild ocular side effects and limited systemic side effects. This paper will review the work leading to FDA approval and the clinical indications for the use of this combination.


Assuntos
Benzoatos/uso terapêutico , Glaucoma de Ângulo Aberto/tratamento farmacológico , Latanoprosta/uso terapêutico , Hipertensão Ocular/tratamento farmacológico , beta-Alanina/análogos & derivados , Anti-Hipertensivos/uso terapêutico , Aprovação de Drogas , Quimioterapia Combinada , Humanos , Estados Unidos , United States Food and Drug Administration , beta-Alanina/uso terapêutico
3.
Expert Opin Ther Pat ; 29(10): 753-759, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31438732

RESUMO

Introduction: Glaucoma refers to a heterogeneous group of optic neuropathies characterized by an enhanced intraocular pressure (IOP). To date, there are six available different drug classes for the treatment of glaucoma and ocular hypertension: ß-adrenergic antagonists, prostaglandins, carbonic anhydrase inhibitors, α2-selective adrenergic, muscarinic agonists and rho kinase inhibitors, which act by reducing the production or increasing the drainage of aqueous humor. Areas covered: This manuscript reviews patent US2018244666A1, that describes the synthesis of novel potential rho kinase and monoamine transporters inhibitors with a benzamide or isoquinoline amide scaffolds, and patent US2018256595A1 that investigates the long-term treatment of glaucoma or ocular hypertension with ripasudil, a rho kinase inhibitor. Expert opinion: A variety of netarsudil congeners were synthesized as rho kinases inhibitors in patent US2018244666A1. Results of patent US2018256595A1 showed that ripasudil is among the best candidates for glaucoma long-term treatment, as IOP continuously dropped over the course of the treatment.


Assuntos
Glaucoma/tratamento farmacológico , Hipertensão Ocular/tratamento farmacológico , Quinases Associadas a rho/antagonistas & inibidores , Benzoatos/administração & dosagem , Benzoatos/farmacologia , Glaucoma/patologia , Humanos , Pressão Intraocular/efeitos dos fármacos , Isoquinolinas/administração & dosagem , Isoquinolinas/farmacologia , Hipertensão Ocular/patologia , Patentes como Assunto , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacologia , beta-Alanina/administração & dosagem , beta-Alanina/análogos & derivados , beta-Alanina/farmacologia , Quinases Associadas a rho/metabolismo
4.
Chemotherapy ; 64(1): 22-27, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31167192

RESUMO

BACKGROUND: Pantothenate, the fundamental precursor to coenzyme A, is required for optimal growth and virulence of microbial pathogens. It is synthesized by the enzyme-catalyzed condensation of ß-alanine and pantoate, which has shown susceptibility to inhibition by analogs of its molecular constituents. Accordingly, analogs of ß-alanine are gaining inquiry as potential antimicrobial chemotherapeutics. METHODS: We synthesized and evaluated 35 derivatives of ß-alanine, substituted at the α, ß, amine, and carboxyl sites, derived from in silico, dynamic molecular modeling to be potential competitive inhibitors of pantothenate synthetase. Employing the Clinical Laboratory Standards M7-A6 broth microdilution method, we tested these for inhibition of growth in Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa. RESULTS: All compounds proved entirely ineffective in all species tested, with no inhibition of growth being observed up to 200 µM/mL. CONCLUSIONS: Upon revision of the literature, we conclude that high enzyme selectivity or external salvage mechanisms may render this strategy futile against most bacteria.


Assuntos
Proteínas de Bactérias/metabolismo , Peptídeo Sintases/metabolismo , beta-Alanina/metabolismo , Proteínas de Bactérias/antagonistas & inibidores , Sítios de Ligação , Escherichia coli/efeitos dos fármacos , Escherichia coli/enzimologia , Escherichia coli/crescimento & desenvolvimento , Simulação de Acoplamento Molecular , Peptídeo Sintases/antagonistas & inibidores , Estrutura Terciária de Proteína , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/crescimento & desenvolvimento , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimento , beta-Alanina/análogos & derivados , beta-Alanina/farmacologia
5.
Drugs ; 79(10): 1031-1036, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31134520

RESUMO

Glaucoma, a group of progressive optic neuropathies with similar patterns of tissue loss, is primarily treated with medical therapy, followed by laser therapy and, later, incisional surgery. Aside from the introduction of prostaglandin analogs, topical carbonic anhydrase inhibitors, and topical alpha-agonists in the 1990s, no new pharmaceutical agents to lower intraocular pressure (IOP) have been introduced for approximately 20 years. The Rho kinase inhibitors represent a new class of glaucoma medications that inhibit the downstream pathway of the Rho family of small G-proteins to increase outflow from the conventional (trabecular) outflow pathway in the eye. Several of these Rho kinase inhibitors, ripasudil and netarsudil, have recently reached the market and are used in clinical practice in several countries. A fixed-dose combination of latanoprost and netarsudil was also very recently approved (2019) by the US FDA. Several other novel agents are undergoing clinical trials. These drugs are poised to act as adjuncts to already established medical therapy for further lowering of IOP in the treatment of glaucoma.


Assuntos
Glaucoma/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Quinases Associadas a rho/antagonistas & inibidores , Animais , Benzoatos/farmacologia , Quimioterapia Combinada/métodos , Olho , Humanos , Pressão Intraocular/efeitos dos fármacos , Isoquinolinas/farmacologia , Latanoprosta/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais , Sulfonamidas/farmacologia , beta-Alanina/análogos & derivados , beta-Alanina/farmacologia
6.
Yakugaku Zasshi ; 139(4): 609-615, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-30930396

RESUMO

Diseases of the motor-conducting system that cause moving disability affect socio-economic activity as well as human dignity. Neurolathyrism, konzo, and amyotrophic lateral sclerosis-parkinsonism-dementia complex (ALS-PDC) have attracted researchers to study the pathology of motor neuron (MN) diseases such as ALS. I have been studying neurolathyrism, which is caused by overconsumption of a legume grass pea (Lathyrys sativus L.). Among people who consume the legume as a food staple, many developed life-long paraparesis in their legs. ß-N-oxalyl-l-α,ß- diaminopropionic (l-ß-ODAP; BOAA), contained in this plant, is a neurotoxic analog of l-glutamic acid. We have clarified that in addition to the causal involvement of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type glutamatergic receptor in MN death, a toxic role of group I metabotropic glutamate receptors as well as transient receptor potential channels were involved in the MN insult by l-ß-ODAP using primary MN culture. We have also established a neurolathyrism rat model by repeated, peripheral l-ß-ODAP treatment to newborn rats under mild stress. Rats showing hind-leg paraparesis with an incidence rate of around 25% were useful to study the in vivo pathology of MN disease. MNs of these rats were greatly decreased at their lumbo/sacral segments at various ages. Intra-parenchymal hemorrhage was consistently observed in paraparetic rats but not in cripple-free, treated rats. MN were depleted even at an acute period around bleeding spots, suggesting catastrophic neuro-vascular-glial interaction in this MN disease. Summaries of konzo and ALS-PDCs studies are also introduced.


Assuntos
Fabaceae/efeitos adversos , Latirismo/etiologia , Lathyrus/efeitos adversos , beta-Alanina/análogos & derivados , Animais , Morte Celular/efeitos dos fármacos , Modelos Animais de Doenças , Fabaceae/química , Humanos , Latirismo/patologia , Lathyrus/química , Doença dos Neurônios Motores/etiologia , Doença dos Neurônios Motores/patologia , Neurônios Motores/patologia , Ratos , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico , beta-Alanina/isolamento & purificação , beta-Alanina/toxicidade
7.
Biomed Pharmacother ; 114: 108801, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30928803

RESUMO

BACKGROUND: Diabetic nephropathy (DN) is one of the most serious and dangerous chronic complications of diabetes mellitus.Panax notoginseng has been widely used with great efficacy in the long-term treatment of kidney disease. However, the mechanism by which it exerts its effects has not been fully elucidated. AIM: We sought to identify the major components ofPanax notoginseng that are effective in reducing the symptoms of DN in vitro and in vivo. METHODS: Inhibition of cell proliferation and collagen secretion were used to screen the ten most highly concentrated components ofPanax notoginseng. The STZ-induced DN rat model on a high-fat-high-glucose diet was used to investigate the renal protective effect of Panax notoginseng and dencichine and their underlying molecular mechanisms. RESULTS: Among the ten components analysed, dencichine (ß-N-oxalyl-L-α,ß-diaminopropionic acid) was the most protective against DN. Dencichine andPanax notoginseng attenuated glucose and lipid metabolic disorders in STZ-induced DN rats on a high-fat-high-glucose diet. In the untreated DN rats, we observed albuminuria, renal failure, and pathological changes. However, treatment with dencichine and Panax notoginseng alleviated these symptoms. We also observed that dencichine suppressed the expression of TGF-ß1 and Smad2/3, which mediates mesangial cell proliferation and extracellular matrix (ECM) accumulation in the glomerulus, and enhanced the expression of Smad7, the endogenous inhibitor of the TGF-ß1/Smad signalling pathway. CONCLUSION: From these results, we concluded that dencichine is the main compound inPanax notoginseng that is responsible for alleviating renal injury in the experimental DN model. Its mechanism may be related to the reduction of the deposition of ECM in glomeruli and inhibition of the epithelial mesenchymal transformation (EMT) by inhibition of the TGF-ß1/Smad signalling pathway.


Assuntos
Diamino Aminoácidos/farmacologia , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Cinuramina/farmacologia , Panax notoginseng/química , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Nefropatias Diabéticas/metabolismo , Matriz Extracelular/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , beta-Alanina/análogos & derivados , beta-Alanina/farmacologia
10.
Am J Ophthalmol ; 200: 130-137, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30653957

RESUMO

PURPOSE: To evaluate netarsudil 0.02% ophthalmic solution in patients with open-angle glaucoma (OAG) and ocular hypertension (OHT). DESIGN: Double-masked, randomized, multicenter, parallel-group, noninferiority clinical study. METHODS: After a washout of all prestudy ocular hypotensive medications, 756 eligible patients with elevated IOP were randomized to receive netarsudil 0.02% once a day (q.d.) (251); netarsudil 0.02% twice a day (b.i.d.) (254); or timolol 0.5% b.i.d. (251) for 12 months, as well as a noninterventional Corneal Observation Study (COS) for patients manifesting cornea verticillata. RESULTS: On treatment, mean IOP at 8:00 AM decreased from a baseline IOP of 22.5-22.6 mm Hg to 17.9-18.8 mm Hg, 17.2-18.0 mm Hg, and 17.5-17.9 mm Hg for netarsudil q.d., netarsudil b.i.d., and timolol, respectively, over 12 months. The most frequently reported adverse events (AEs) were ocular, with the most frequent ocular AE being conjunctival hyperemia, with an incidence of 61%, 66%, and 14%, respectively. The next most frequent AEs were corneal deposits (corneal verticillata), with an incidence of 26%, 25%, and 1%, respectively, and conjunctival hemorrhage (typically petechial), with an incidence of 20%, 19%, and 1%, respectively. All 3 AEs were generally scored as mild, with conjunctival hyperemia and/or hemorrhage appearing sporadically during the study. In the observational follow-up component of this study, there was no clinically meaningful impact of corneal verticillata on visual function in affected patients. CONCLUSIONS: In this randomized, double-masked trial, once-daily dosing of netarsudil 0.02% was effective, consistently lowering IOP through 12 months, and was tolerated by the majority of patients.


Assuntos
Anti-Hipertensivos/uso terapêutico , Benzoatos/uso terapêutico , Glaucoma de Ângulo Aberto/tratamento farmacológico , Pressão Intraocular/efeitos dos fármacos , beta-Alanina/análogos & derivados , Quinases Associadas a rho/antagonistas & inibidores , Administração Oftálmica , Antagonistas Adrenérgicos beta/administração & dosagem , Antagonistas Adrenérgicos beta/uso terapêutico , Adulto , Idoso , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/efeitos adversos , Benzoatos/administração & dosagem , Benzoatos/efeitos adversos , Método Duplo-Cego , Feminino , Glaucoma de Ângulo Aberto/diagnóstico , Glaucoma de Ângulo Aberto/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Hipertensão Ocular/diagnóstico , Hipertensão Ocular/tratamento farmacológico , Hipertensão Ocular/fisiopatologia , Soluções Oftálmicas , Timolol/administração & dosagem , Timolol/uso terapêutico , Resultado do Tratamento , beta-Alanina/administração & dosagem , beta-Alanina/efeitos adversos , beta-Alanina/uso terapêutico
11.
Nature ; 565(7737): 112-117, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30542153

RESUMO

Many enzymes catalyse reactions that proceed through covalent acyl-enzyme (ester or thioester) intermediates1. These enzymes include serine hydrolases2,3 (encoded by one per cent of human genes, and including serine proteases and thioesterases), cysteine proteases (including caspases), and many components of the ubiquitination machinery4,5. Their important acyl-enzyme intermediates are unstable, commonly having half-lives of minutes to hours6. In some cases, acyl-enzyme complexes can be stabilized using substrate analogues or active-site mutations but, although these approaches can provide valuable insight7-10, they often result in complexes that are substantially non-native. Here we develop a strategy for incorporating 2,3-diaminopropionic acid (DAP) into recombinant proteins, via expansion of the genetic code11. We show that replacing catalytic cysteine or serine residues of enzymes with DAP permits their first-step reaction with native substrates, allowing the efficient capture of acyl-enzyme complexes that are linked through a stable amide bond. For one of these enzymes, the thioesterase domain of valinomycin synthetase12, we elucidate the biosynthetic pathway by which it progressively oligomerizes tetradepsipeptidyl substrates to a dodecadepsipeptidyl intermediate, which it then cyclizes to produce valinomycin. By trapping the first and last acyl-thioesterase intermediates in the catalytic cycle as DAP conjugates, we provide structural insight into how conformational changes in thioesterase domains of such nonribosomal peptide synthetases control the oligomerization and cyclization of linear substrates. The encoding of DAP will facilitate the characterization of diverse acyl-enzyme complexes, and may be extended to capturing the native substrates of transiently acylated proteins of unknown function.


Assuntos
Biocatálise , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Tioléster Hidrolases/química , Tioléster Hidrolases/metabolismo , Valinomicina/biossíntese , beta-Alanina/análogos & derivados , Vias Biossintéticas , Cisteína/metabolismo , Cisteína Proteases/química , Cisteína Proteases/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Modelos Moleculares , Peptídeos/química , Peptídeos/metabolismo , Domínios Proteicos , Serina/metabolismo , Especificidade por Substrato , beta-Alanina/metabolismo
12.
Nature ; 565(7737): 28-29, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30573786
13.
Toxicol Lett ; 298: 164-170, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30315949

RESUMO

A method for the quantitation of α-fluoro-ß-alanine (AFBA), the main metabolite of capecitabine (Cape) and 5-fluoruracil (5-FU), is described. Among antineoplastic drugs (ADs), 5-FU and Cape (the new oral prodrug) are the most commonly applied drugs in cancer therapy. The main objective of this study was to develop a reliable method that would be easy to run on a reversed-phase UHPLC system coupled to tandem mass spectrometry. AFBA was derivatized with Sanger's reagent to ensure complete yield of a stable 2,4 dinitrophenil-α-fluoro-ß-alanine derivative. This method was based on the use of a mixed-mode anion exchange solid phase extraction enabling urinary extracts to be clear of endogenous interferences affecting quantitative results. The assay was validated in human urine according to FDA criteria with the use of a labeled internal standard (ß-alanine-d4) to minimize experimental error. Good accuracy and precision were demonstrated by determining spiked urine QC samples in four consecutive days. The recovery of AFBA was between 70.0 and 82.6%, with a matrix effect that was 12.8%-18.5%. The lower limit of quantitation (LOQ) was 0.5 ng/mL with a coefficient of variation of 5.3%. This assay was successfully applied to determine the levels of this metabolite in a large number of urine samples taken from personnel who were occupationally exposed to ADs.


Assuntos
Cromatografia Líquida de Alta Pressão , Cromatografia de Fase Reversa , Pessoal de Saúde , Espectrometria de Massas em Tandem , beta-Alanina/análogos & derivados , Antineoplásicos/efeitos adversos , Antineoplásicos/metabolismo , Biotransformação , Calibragem , Capecitabina/efeitos adversos , Capecitabina/metabolismo , Cromatografia Líquida de Alta Pressão/normas , Cromatografia de Fase Reversa/normas , Fluoruracila/efeitos adversos , Fluoruracila/metabolismo , Humanos , Exposição Ocupacional/efeitos adversos , Saúde do Trabalhador , Padrões de Referência , Reprodutibilidade dos Testes , Medição de Risco , Espectrometria de Massas em Tandem/normas , Urinálise , beta-Alanina/efeitos adversos , beta-Alanina/urina
14.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1102-1103: 17-22, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30366208

RESUMO

Alpha-fluoro-beta-alanine (FBAL), the final metabolite of capecitabine, is a toxic compound excreting with urine. Magnesium isoglycyrrhizinate injection is a traditional Chinese medicine prescribed with capecitabine as a hepatoprotective agent. The purposes of this study are to develop an ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method for direct, efficient and sensitive determination of FBAL in urine and explore the influence of magnesium isoglycyrrhizinate on the excretion of FBAL in rat model. The method development and validation were successfully achieved. The run time was 3 min based on an HILIC column and linear range was 0.02-10.00 µg/mL. The mass detection was completed using electrospray ionization in positive ionization mode with a multiple reaction monitoring mode. A simplified sample pretreatment procedure was performed by direct dilution using 50% acetonitrile aqueous solution with the matrix effect range 48.98%-52.10% and the recovery range 78.68%-83.28%. The intra-day and inter-day precision and accuracy were <11% and within ±6%, and the stability, specificity, carry-over, dilution effect and linearity all conformed to the criterions. This study presented preliminary results that the influence of magnesium isoglycyrrhizinate on the excretion of FBAL was insignificant in rats based on this new developed method.


Assuntos
Saponinas/química , Triterpenos/química , beta-Alanina/análogos & derivados , Animais , Cromatografia Líquida de Alta Pressão/métodos , Limite de Detecção , Modelos Lineares , Masculino , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos , beta-Alanina/urina
16.
Int J Oncol ; 53(6): 2737-2744, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30334568

RESUMO

The non­natural amino acid positron emission tomography tracers, 2­amino[3­11C]isobutyric acid ([3­11C]AIB) and 2­amino[11C]methyl­isobutyric acid ([11C]MeAIB), are metabolically stable in vivo and accumulate in tumors. [3­11C]AIB is transported into cells mainly via the amino acid transport system A and partially via systems L and ASC, whereas [11C]MeAIB is transported into cells specifically via system A. How transport via the different systems affects the tumor uptake of these tracers, however, is unclear. In the present study, the tumor uptake of the two tracers was directly compared in eight lung cancer models (A549, H82, H441, H460, H1299, H1650, PC14, and SY), and the correlation of tumor uptake with several factors (amino acid transporter expression, contribution of amino acid transport systems to AIB uptake and tumor proliferation indices) was analyzed. Biodistribution analyses revealed that the tumor uptake of [3­11C]AIB (4.9 to 19.2% injected dose per gram [ID/g]) was higher than that of [11C]MeAIB (3.1 to 15.9% ID/g) in all eight tumors, with a statistically significant difference in three tumors (P<0.01 in H441 and H460 tumors, P<0.05 in H82 tumors). A significant correlation was observed between the tumor uptake of the two tracers (r=0.95, P<0.01). The mRNA expression levels of the amino acid transporters of system A (SLC38A1 and SLC38A2), system L (SLC7A5) and system ASC (SLC1A5) were higher in all eight tumors than in the normal lung, with widely varying expression patterns. Although the contributions of the amino acid transport systems, Ki­67 indices and tumor doubling times greatly differed among the eight models, these factors did not correlate with the tumor uptake of either tracer. The higher tumor uptake of [3­11C]AIB and the correlation of tumor uptake between [3­11C]AIB and [11C]MeAIB warrant further investigation in clinical studies in order to clarify the role of [3­11C]AIB PET in oncology imaging.


Assuntos
Sistemas de Transporte de Aminoácidos Neutros/genética , Ácidos Aminoisobutíricos/farmacocinética , Neoplasias Pulmonares/diagnóstico por imagem , beta-Alanina/análogos & derivados , Células A549 , Ácidos Aminoisobutíricos/administração & dosagem , Animais , Linhagem Celular Tumoral , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Camundongos , Tomografia por Emissão de Pósitrons , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto , beta-Alanina/administração & dosagem , beta-Alanina/farmacologia
17.
J Food Sci ; 83(10): 2662-2668, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30229907

RESUMO

3-Aminopropanamide (3-APA) is the direct precursor of acrylamide produced in the Maillard reaction between asparagine and reducing sugars. In this research, we found that 3-APA could reduce acrylamide by the formation of adducts between acrylamide and 3-APA via Michael addition. The effects of temperature, heating duration and 3-APA/acrylamide ratio on the reduction of acrylamide were investigated. Addition of 3-APA to acrylamide at a molar ratio of 5:3 at 160 °C for 20 min reduced acrylamide by up to 47.29%. The major adduct was identified as 3,3',3'-nitrilotris, and its cytotoxicity on Caco-2 cells was evaluated to be much lower than acrylamide. The viability of Caco-2 cells retained at 88.31% and 86.43% after incubation with 16 mM 3,3',3'-nitrilotris for 24 and 48 hr, respectively, while those incubated with the same concentration of acrylamide were 23.33% and 19.12%, respectively. PRACTICAL APPLICATION: The current study reported 3-APA could reduce acrylamide through the Micheal addition reaction between 3-APA and acrylamide. The adduct showed significantly reduced cytotoxicity compared to acrylamide. The research is critical in evaluation and control of food contaminants. The results brought new insights in the area of food safety, especially in the mechanism researches on formation and mitigation of endogenous contaminants in thermal-processed foods.


Assuntos
Acrilamida/análise , Fast Foods , Contaminação de Alimentos , Reação de Maillard , beta-Alanina/análogos & derivados , Acrilamida/química , Asparagina , Células CACO-2 , Sobrevivência Celular , Temperatura Alta , Humanos , beta-Alanina/química
18.
J Neuroendocrinol ; 30(11): e12642, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30168642

RESUMO

The astrocytic glutamine (Gln)-glutamate (Glu) cycle (GGC) supplies Gln for the regulation of glutamatergic synaptic transmission (GST) in the adult hippocampus. Increased synaptic Glu release in the perinatal ventrolateral ventromedial nucleus of the hypothalamus (vlVMH) modulates sexual differentiation, however, whether GGC regulates GST in the perinatal vlVMH has not been determined. Sex differences in oestradiol (E2 ) levels exist in the neonatal hypothalamus, and E2 increases levels of glutamine synthetase and glutaminase, two key enzymes involved in the GGC. Thus, it is hypothesised that sexually dimorphic phenotypes may exist in glutamatergic synapses associated with the GGC in the vlVMH in perinatal rats. Whole-cell voltage-clamp recordings in vlVMH neurones in brain slices from male and female pups revealed that pharmacological disruption of the GGC by α-(methylamino) isobutyric acid (5 mmol L-1 ), which blocks neuronal Gln uptake; or by l-methionine sulphoximine (1.5 mmol L-1 ), which inhibits astrocytic Gln synthesis, decreased miniature excitatory postsynaptic current (mEPSC) amplitudes in female but not male pups. By contrast, GGC interruptions decreased evoked (e)EPSC amplitudes in both sexes following increased synaptic activity produced by a period of stimulation. In male pups, the decreased eEPSCs were attributable to reduced Glu release, as assessed by paired-pulse stimulations, whereas, in female pups, they were attributable to decreased Glu content in the synaptic vesicles, as measured by strontium-evoked mEPSCs. The l-methionine sulphoximine-mediated decrease in eEPSCs was rapidly rescued by exogenous Gln in female but not male pups. The reductions in mEPSCs and eEPSCs in female pups were accompanied by enhanced blocking effects of the low-affinity Glu AMPA receptor antagonist, γ-d-glutamylglycine, consistent with diminished Glu release. In conclusion, female, but not male pups, rely on constitutive astrocytic Gln for sustained synaptic Glu release in the vlVMH. This glutamatergic synaptic phenotype may be associated with brain and behaviour feminisation and/or defeminisation in rats.


Assuntos
Astrócitos/metabolismo , Ácido Glutâmico/metabolismo , Glutamina/metabolismo , Neurônios/fisiologia , Núcleo Hipotalâmico Ventromedial/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores , Feminino , Glutamina/administração & dosagem , Hipotálamo Médio/efeitos dos fármacos , Hipotálamo Médio/metabolismo , Masculino , Potenciais Pós-Sinápticos em Miniatura , Neurônios/efeitos dos fármacos , Ratos Sprague-Dawley , Receptores de AMPA/metabolismo , Caracteres Sexuais , Núcleo Hipotalâmico Ventromedial/efeitos dos fármacos , beta-Alanina/administração & dosagem , beta-Alanina/análogos & derivados
19.
Drugs Today (Barc) ; 54(8): 467-478, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30209441

RESUMO

Once-daily (p.m.) netarsudil ophthalmic solution 0.02% (Rhopressa) is approved in the United States for lowering elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. Netarsudil, a Rho kinase (ROCK) inhibitor that lowers IOP primarily by increasing trabecular outflow, produces statistically and clinically significant reductions in mean IOP from baseline, with comparable effects on nocturnal and diurnal IOP. In three phase III trials of patients with elevated IOP, the ocular hypotensive efficacy of once-daily netarsudil 0.02% met the criteria for noninferiority to twice-daily timolol 0.5% at all time points over 3 months in patients with baseline IOP less than 25 mmHg. The most frequent adverse event (AE) was generally mild conjunctival hyperemia, the severity of which did not increase with continued dosing. Netarsudil was associated with minimal treatment-related serious or systemic AEs, likely due to the lack of systemic exposure. This report summarizes the available preclinical and clinical data on netarsudil.


Assuntos
Benzoatos/administração & dosagem , Olho/efeitos dos fármacos , Glaucoma de Ângulo Aberto/tratamento farmacológico , Pressão Intraocular/efeitos dos fármacos , Hipertensão Ocular/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , beta-Alanina/análogos & derivados , Administração Oftálmica , Animais , Benzoatos/efeitos adversos , Benzoatos/farmacocinética , Interações de Medicamentos , Olho/enzimologia , Olho/fisiopatologia , Glaucoma de Ângulo Aberto/diagnóstico , Glaucoma de Ângulo Aberto/enzimologia , Glaucoma de Ângulo Aberto/fisiopatologia , Humanos , Hipertensão Ocular/diagnóstico , Hipertensão Ocular/enzimologia , Hipertensão Ocular/fisiopatologia , Soluções Oftálmicas , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Resultado do Tratamento , beta-Alanina/administração & dosagem , beta-Alanina/efeitos adversos , beta-Alanina/farmacocinética , Quinases Associadas a rho/antagonistas & inibidores , Quinases Associadas a rho/metabolismo
20.
Contrast Media Mol Imaging ; 2018: 1292746, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30026674

RESUMO

Introductions: [N-methyl-C-11]α-Methylaminoisobutyric acid (MeAIB) is an artificial amino acid radiotracer used for PET study, which is metabolically stable in vivo. In addition, MeAIB is transported by system A neutral amino acid transport, which is observed ubiquitously in all types of mammalian cells. It has already been shown that MeAIB-PET is useful for malignant lymphoma, head and neck cancers, and lung tumors. However, there have been no reports evaluating the usefulness of MeAIB-PET in the diagnosis of brain tumors. The purpose of this study is to investigate the efficacy of system A amino acid transport PET imaging, MeAIB-PET, in clinical brain tumor diagnosis compared to [S-methyl-C-11]-L-methionine (MET)-PET. Methods: Thirty-one consecutive patients (male: 16, female: 15), who were suspected of having brain tumors, received both MeAIB-PET and MET-PET within a 2-week interval. All patients were classified into two groups: Group A as a benign group, which included patients who were diagnosed as low-grade astrocytoma, grade II or less, or other low-grade astrocytoma (n=12) and Group B as a malignant group, which included patients who were diagnosed as anaplastic astrocytoma, glioblastoma multiforme (GBM), or recurrent GBM despite prior surgery or chemoradiotherapy (n=19). PET imaging was performed 20 min after the IV injection of MeAIB and MET, respectively. Semiquantitative analyses of MeAIB and MET uptake using SUVmax and tumor-to-contralateral normal brain tissue (T/N) ratio were evaluated to compare these PET images. ROC analyses for the diagnostic accuracy of MeAIB-PET and MET-PET were also calculated. Results: In MeAIB-PET imaging, the SUVmax was 1.20 ± 1.29 for the benign group and 2.94 ± 1.22 for the malignant group (p < 0.005), and the T/N ratio was 3.77 ± 2.39 for the benign group and 16.83 ± 2.39 for the malignant group (p < 0.001). In MET-PET, the SUVmax was 3.01 ± 0.94 for the benign group and 4.72 ± 1.61 for the malignant group (p < 0.005), and the T/N ratio was 2.64 ± 1.40 for the benign group and 3.21 ± 1.14 for the malignant group (n.s.). For the analysis using the T/N ratio, there was a significant difference between the benign and malignant groups with MeAIB-PET with p < 0.001. The result of ROC analysis using the T/N ratio indicated a better diagnosis accuracy for MeAIB-PET for brain tumors than MET-PET (p < 0.01). Conclusions: MeAIB, a system A amino acid transport-specific radiolabeled agents, could provide better assessments for detecting malignant type brain tumors. In a differential diagnosis between low-grade and high-grade astrocytoma, MeAIB-PET is a useful diagnostic imaging tool, especially in evaluations using the T/N ratio. Clinical trial registration: This trial was registered with UMIN000032498.


Assuntos
Astrocitoma/diagnóstico por imagem , Neoplasias Encefálicas/diagnóstico , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/normas , Adolescente , Adulto , Idoso , Sistema A de Transporte de Aminoácidos , Neoplasias Encefálicas/diagnóstico por imagem , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Metionina/farmacocinética , Metionina/normas , Pessoa de Meia-Idade , Curva ROC , Compostos Radiofarmacêuticos/farmacocinética , Adulto Jovem , beta-Alanina/análogos & derivados , beta-Alanina/farmacocinética , beta-Alanina/normas
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