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1.
Chem Commun (Camb) ; 56(7): 1042-1045, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31868189

RESUMO

A novel enzyme-responsive supramolecular polysaccharide assembly composed of disulfide linked adamantane-naphthalimide fluorescent camptothecin prodrug (AdaCPT) and ß-CD modified hyaluronic acid (HACD) was constructed, possessing low cellular cytotoxicity and exhibiting targeted cellular imaging and controlled drug release at specific sites while providing a concurrent means for the real-time tracking of drug delivery.


Assuntos
Antineoplásicos/farmacologia , Camptotecina/farmacologia , Portadores de Fármacos/química , Corantes Fluorescentes/farmacologia , Pró-Fármacos/farmacologia , Adamantano/análogos & derivados , Adamantano/síntese química , Adamantano/farmacologia , Adamantano/toxicidade , Animais , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Camptotecina/síntese química , Camptotecina/toxicidade , Liberação Controlada de Fármacos , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Células HCT116 , Humanos , Ácido Hialurônico/química , Camundongos , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Células NIH 3T3 , Naftalimidas/síntese química , Naftalimidas/farmacologia , Naftalimidas/toxicidade , Pró-Fármacos/síntese química , Pró-Fármacos/toxicidade , beta-Ciclodextrinas/química
2.
Chem Commun (Camb) ; 56(2): 313-316, 2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31808779

RESUMO

A host-guest recognition-regulated aggregation-induced emission (AIE) strategy is developed based on the interaction between cyclodextrin-functionalized copper nanoclusters and di(adamantan-1-yl)phosphine as a connector, which significantly improves the AIE efficiency and stability and can be applied to long-term in situ imaging of MUC1 protein.


Assuntos
Adamantano/análogos & derivados , Nanopartículas Metálicas/química , Mucina-1/análise , Fosfinas/química , beta-Ciclodextrinas/química , Linhagem Celular Tumoral , Cobre/química , Corantes Fluorescentes/química , Humanos , Medições Luminescentes/métodos , Microscopia Confocal/métodos
3.
Chem Commun (Camb) ; 55(100): 15105-15108, 2019 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-31782427

RESUMO

Herein, we report the nor-AZADO-catalyzed exhaustive aerobic oxidations of 1,2-diols to α-keto acids. Combining oxidation with transamination using dl-2-phenylglycine led to the synthesis of free α-amino acids (AAs) in one pot. This method enables the rapid and flexible preparation of a variety of valuable unnatural AAs, such as fluorescent AAs, photoactivatable AAs, and other functional AAs for bioorthogonal reactions.


Assuntos
Álcoois/química , Aminoácidos/química , Adamantano/análogos & derivados , Adamantano/química , Catálise , Óxidos N-Cíclicos/química , Cetoácidos/química , Oxirredução
4.
Life Sci ; 239: 117017, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31678284

RESUMO

Saxagliptin (Saxa), a dipeptidyl dipeptidase-4 (DPP-4) inhibitor, is widely used for the treatment of type 2 diabetes mellitus. It has been documented to have immunomodulatory and anti-inflammatory actions. Our objective was to delineate the protective effect and the underlying mechanism of Saxa-in comparison with Dexamethasone (Dexa) - in airway inflammation induced by ovalbumin (OVA) in mice. METHODS: Mice were OVA-sensitized and challenged for the induction of acute asthma. Mice were orally administrated Saxa or Dexa. Total and differential cell counts, lactate dehydrogenase (LDH) and total protein concentrations were assessed in bronchoalveolar lavage fluid (BALF). The toll-like receptor 4 (TLR4), nuclear factor-kappa B (NF-kB), reduced glutathione (GSH), and total nitrate/nitrite products (NOx) levels as well as myeloperoxidase (MPO) activity in lung tissues were measured. Histopathological examination of the lung specimens was carried out using the hematoxylin and eosin (H & E) staining. RESULTS: Histopathological examination revealed that both Saxa and Dexa ameliorated OVA-induced inflammatory changes and significantly reduced total and differential leukocyte counts, LDH and total protein level in BALF upon comparison with OVA group. In addition, both treatments significantly mitigated OVA-induced oxidative stress as evidenced by diminished lung NOx level and MPO activity and elevated GSH level. The elevation of TLR4 and NF-kB levels in lung tissue were ameliorated by Saxa and Dexa administration. CONCLUSION: Saxa had marked antiasthmatic effect in OVA-induced allergic asthma through modulation of TLR4 and NF-κB signaling. Also, Saxa may represent a promising therapeutic agent for acute allergic asthma.


Assuntos
Adamantano/análogos & derivados , Asma/tratamento farmacológico , Dipeptídeos/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , NF-kappa B/efeitos dos fármacos , Receptor 4 Toll-Like/efeitos dos fármacos , Doença Aguda , Adamantano/uso terapêutico , Animais , Asma/induzido quimicamente , Asma/patologia , Líquido da Lavagem Broncoalveolar/citologia , Dexametasona/uso terapêutico , L-Lactato Desidrogenase/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Óxido Nítrico/metabolismo , Ovalbumina , Peroxidase/metabolismo
5.
Chemistry ; 25(62): 14169-14182, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31461189

RESUMO

An organoruthenium(II) complex with pyrithione (2-mercaptopyridine N-oxide) 1 a has previously been identified by our group as a compound with promising anticancer potential without cytotoxicity towards non-cancerous cells. To expand the rather limited research on compounds of this type, an array of novel chlorido and 1,3,5-triaza-7-phosphaadamantane (pta) organoruthenium(II) complexes with methyl-substituted pyrithiones has been prepared. After thorough investigation of the aqueous stability of these complexes, their modes of action have been elucidated at the cellular level. Minor structural alterations in the ruthenium-pyrithionato compounds resulted in fine-tuning of their cytotoxicities. The best performing compounds, 1 b and 2 b, with a chlorido or pta ligand bound to ruthenium, respectively, and a methyl group at the 3-position of the pyrithione scaffold, have been further investigated. Both compounds trigger early apoptosis, induce the generation of reactive oxygen species and G1 arrest in A549 cancer cells, and show no strong interaction with DNA. However, only 1 b also inhibits thioredoxin reductase. Wound healing assays and mitochondrial function evaluation have revealed differences between these two compounds at the cellular level.


Assuntos
Antineoplásicos/química , Complexos de Coordenação/química , Piridinas/química , Rutênio/química , Tionas/química , Adamantano/análogos & derivados , Adamantano/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Compostos Organofosforados/química , Cicatrização/efeitos dos fármacos
6.
Artif Cells Nanomed Biotechnol ; 47(1): 3239-3245, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31364869

RESUMO

Osteoarthritis (OA) is a major public health concern for which a reliable non-invasive treatment option has yet to be developed. In the present study, we investigated the effects of saxagliptin, a novel dipeptidyl peptidase IV (DPP-4) inhibitor, on several important aspects of the pathophysiology of OA using primary human chondrocytes. The results of real-time PCR and ELISA analyses show that saxagliptin treatment significantly decreased mRNA and protein expression of three key cartilage degrading enzymes: matrix metalloproteinase (MMP)-1, MMP-3, and MMP-13. The results of western blot confirmed that this decrease in MMP-1, -3, and -13 expression prevented degradation of type II collagen. We also found that saxagliptin significantly inhibited expression of a disintegrin and metalloproteinase with thrombospondin motif (ADAMTS)-4 and ADAMTS-5, which was reflected by markedly decreased degradation of aggrecan. Inhibition of DPP-4 by saxagliptin also reduced oxidative stress in human primary chondrocytes as evidenced by decreased production of reactive oxygen species (ROS) and increased glutathione (GSH) levels. Additionally, the results of western blot analysis show that the effects of saxagliptin are mediated through the p38/IκBα/NF-κB pathway, which is considered an important treatment target for OA. These findings suggest a potential role for saxagliptin as a novel treatment against OA.


Assuntos
Adamantano/análogos & derivados , Agrecanas/metabolismo , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Colágeno Tipo II/metabolismo , Dipeptídeos/farmacologia , Osteoartrite/tratamento farmacológico , Proteólise/efeitos dos fármacos , Proteína ADAMTS4/metabolismo , Proteína ADAMTS5/metabolismo , Adamantano/farmacologia , Adamantano/uso terapêutico , Condrócitos/patologia , Dipeptídeos/uso terapêutico , Progressão da Doença , Ativação Enzimática/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Produtos Finais de Glicação Avançada/farmacologia , Humanos , Metaloproteinases da Matriz/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , Osteoartrite/metabolismo , Osteoartrite/patologia , Espécies Reativas de Oxigênio/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
7.
Eur J Med Chem ; 180: 613-626, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31351393

RESUMO

The development of multitarget compounds against multifactorial diseases, such as Alzheimer's disease, is an area of very intensive research, due to the expected superior therapeutic efficacy that should arise from the simultaneous modulation of several key targets of the complex pathological network. Here we describe the synthesis and multitarget biological profiling of a new class of compounds designed by molecular hybridization of an NMDA receptor antagonist fluorobenzohomoadamantanamine with the potent acetylcholinesterase (AChE) inhibitor 6-chlorotacrine, using two different linker lengths and linkage positions, to preserve or not the memantine-like polycyclic unsubstituted primary amine. The best hybrids exhibit greater potencies than parent compounds against AChE (IC50 0.33 nM in the best case, 44-fold increased potency over 6-chlorotacrine), butyrylcholinesterase (IC50 21 nM in the best case, 24-fold increased potency over 6-chlorotacrine), and NMDA receptors (IC50 0.89 µM in the best case, 2-fold increased potency over the parent benzohomoadamantanamine and memantine), which suggests an additive effect of both pharmacophoric moieties in the interaction with the primary targets. Moreover, most of these compounds have been predicted to be brain permeable. This set of biological properties makes them promising leads for further anti-Alzheimer drug development.


Assuntos
Adamantano/farmacologia , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Fármacos Neuroprotetores/farmacologia , Tacrina/análogos & derivados , Acetilcolinesterase/metabolismo , Adamantano/análogos & derivados , Adamantano/química , Doença de Alzheimer/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Relação Estrutura-Atividade , Tacrina/química , Tacrina/farmacologia
8.
Nat Commun ; 10(1): 2945, 2019 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-31270332

RESUMO

Age- and sex-related alterations in gene transcription have been demonstrated, however the underlying mechanisms are unresolved. Neuroepigenetic pathways regulate gene transcription in the brain. Here, we measure in vivo expression of the epigenetic enzymes, histone deacetylases (HDACs), across healthy human aging and between sexes using [11C]Martinostat positron emission tomography (PET) neuroimaging (n = 41). Relative HDAC expression increases with age in cerebral white matter, and correlates with age-associated disruptions in white matter microstructure. A post mortem study confirmed that HDAC1 and HDAC2 paralogs are elevated in white matter tissue from elderly donors. There are also sex-specific in vivo HDAC expression differences in brain regions associated with emotion and memory, including the amygdala and hippocampus. Hippocampus and white matter HDAC expression negatively correlates with emotion regulation skills (n = 23). Age and sex are associated with HDAC expression in vivo, which could drive age- and sex-related transcriptional changes and impact human behavior.


Assuntos
Encéfalo/fisiologia , Epigênese Genética , Caracteres Sexuais , Adamantano/análogos & derivados , Adamantano/farmacocinética , Adolescente , Adulto , Fatores Etários , Idoso , Encéfalo/diagnóstico por imagem , Radioisótopos de Carbono/farmacocinética , Emoções , Feminino , Histona Desacetilase 1/metabolismo , Histona Desacetilase 2/metabolismo , Humanos , Ácidos Hidroxâmicos/farmacocinética , Masculino , Pessoa de Meia-Idade , Doadores de Tecidos , Substância Branca/anatomia & histologia , Substância Branca/diagnóstico por imagem , Adulto Jovem
9.
Molecules ; 24(15)2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31357420

RESUMO

For the first time, orthogonally substituted azole-carboxylate adamantane ligands were synthesized and used for preparation of coordination polymers. The angle-shaped ligands were prepared by the reaction of 1-adamantanecarboxylic acid and azoles (1H-1,2,4-triazole, 3-methyl-1H-1,2,4-triazole, 3,5-dimethyl-1H-1,2,4-triazole, 1H-tetrazole, 5-methyl-1H-tetrazole) in concentrated sulfuric acid. Variation of the solvent and substituents in azole rings allowed to prepare both 1D and 2D copper(II) and nickel(II) coordination polymers, [Cu2(trzadc)4(H2O)0.7]∙DMF∙0.3H2O, [Cu(trzadc)2(MeOH)]∙MeOH, [Ni(trzadc)2(MeOH)2] and [Cu2(mtrzadc)3(MeOH)]+NO3- (trzadc-3-(1,2,4-triazol-1-yl)-adamantane-1-carboxylic acid; mtrzadc-3-(3-methyl-1,2,4-triazol-1-yl)-adamantane-1-carboxylic acid) which were structurally characterized by single crystal X-ray diffraction. Complex [Cu(trzadc)2(MeOH)]∙MeOH was shown to act as a catalyst in the Chan-Evans-Lam arylation reaction.


Assuntos
Adamantano/análogos & derivados , Polímeros/química , Adamantano/síntese química , Adamantano/química , Adamantano/farmacologia , Catálise , Técnicas de Química Sintética , Cristalografia por Raios X , Ligantes , Estruturas Metalorgânicas , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Polímeros/síntese química , Análise Espectral
10.
Cells ; 8(6)2019 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-31181818

RESUMO

Background: This study was performed to examine the effects of the Janus kinase (JAK) inhibitor peficitinib on fibroblast-like synoviocytes (FLS) obtained from patients with rheumatoid arthritis (RA). Methods: To examine the expression of JAK1, JAK2, and JAK3 in RA synovial tissue (ST) and FLS, immunohistochemistry was performed. We investigated the effects of peficitinib on interleukin 6 and IL-6 receptor responses in RA FLS. Phosphorylation of STAT was determined by western blot. To examine the functional analysis of peficitinib, we performed a proliferation and chemotaxis assays with FLS using THP-1 and peripheral blood mononuclear cells (PBMC). The inflammatory mediator expression of FLS was estimated by enzyme-linked immunosorbent assay. Results: JAK1, JAK2, and JAK3 were expressed in RA STs and FLS. Phosphorylation of STAT1, STAT3, and STAT5 in RA FLS was suppressed by peficitinib in a concentration-dependent manner. Peficitinib-treated RA FLS-conditioned medium reduced THP-1 and PBMC migration (p < 0.05) and proliferation of RA FLS (p < 0.05). Peficitinib suppressed the secretion of MCP-1/CCL2 in the RA FLS supernatant (p < 0.05). Conclusion: Peficitinib suppressed the JAK-STAT pathway in RA FLS and also suppressed monocyte chemotaxis and proliferation of FLS through inhibition of inflammatory cytokines.


Assuntos
Adamantano/análogos & derivados , Artrite Reumatoide/patologia , Quimiotaxia/efeitos dos fármacos , Citocinas/metabolismo , Monócitos/fisiologia , Niacinamida/análogos & derivados , Adamantano/farmacologia , Proliferação de Células/efeitos dos fármacos , Fibroblastos/citologia , Fibroblastos/metabolismo , Humanos , Interleucina-6/farmacologia , Janus Quinase 1/metabolismo , Janus Quinase 2 , Janus Quinase 3 , Monócitos/imunologia , Niacinamida/farmacologia , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sinoviócitos/citologia , Sinoviócitos/metabolismo
11.
Neoplasma ; 66(5): 776-784, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31169018

RESUMO

Hypoxia-inducible factor 1α (HIF1α) has been demonstrated to be involved in the resistance of various human cancer cells to chemotherapies. However, the correlation between HIF1α and the sensitivity of human non-small cell lung cancer (NSCLC) cells to cisplatin has not been illuminated. The aim of the present study was to investigate the effects of HIF1α on drug resistance in NSCLC cells. A549 cells were incubated in 21% or 0.5% O2 followed by the assessment of the level of HIF1α with qRT-PCR and western blot and ROS level by DCFH-DA assays. Effects of hypoxia or HIF1α inhibitor LW6 on the proliferation and apoptosis of A549 cells were evaluated via CCK-8 and flow cytometry assays. IC50 of A549 cells to cisplatin was determined by MTT assay. The mitochondrial membrane potential (MMP) was measured via JC-1 staining. Moreover, the expression of apoptosis related protein (Bcl-2, Bax) and drug resistance related proteins (MDR1, MRP1) were measured by western blotting. Exposure of A549 cells to 1% O2 significantly up-regulated HIF1α expression, maintained cell viability to cisplatin but decreased the ROS level, which promoted chemoresistance to cisplatin. LW6-treated A549 cells showed an increase in ROS level that blocked the hypoxia induced resistance to cisplatin and in addition, decreased expression of MDR1 and MRP1 in cisplatin-treated cells. This study revealed that hypoxia-improved cisplatin chemoresistance of NSCLC cells by regulated MDR1 and MRP1 expression via HIF1α/ROS pathway is reversed by LW6, suggesting that LW6 may act as effective sensitizer in chemotherapy for NSCLC.


Assuntos
Acetanilidas , Adamantano/análogos & derivados , Cisplatino , Células A549 , Acetanilidas/farmacologia , Adamantano/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/fisiopatologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Concentração Inibidora 50 , Neoplasias Pulmonares/fisiopatologia
12.
Muscle Nerve ; 60(4): 443-452, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31241177

RESUMO

INTRODUCTION: There is an unmet need for mechanism-based biomarkers and effective disease modifying treatments in amyotrophic lateral sclerosis (ALS). Previous findings have provided evidence that histone deacetylases (HDAC) are altered in ALS, providing a rationale for testing HDAC inhibitors as a therapeutic option. METHODS: We measured class I and II HDAC protein and transcript levels together with acetylation levels of downstream substrates by using Western blotting in postmortem tissue of ALS and controls. [11 C]Martinostat, a novel HDAC positron emission tomography ligand, was also used to assess in vivo brain HDAC alterations in patients with ALS and healthy controls (HC). RESULTS: There was no significant difference in HDAC levels between patients with ALS and controls as measured by Western blotting and reverse-transcription quantitative polymerase chain reaction. Similarly, no differences were detected in [11 C]Martinostat-positron emission tomography uptake in ALS participants compared with HCs. DISCUSSION: These findings provide evidence that alterations in HDAC isoforms are not a dominant pathological feature at the bulk tissue level in ALS.


Assuntos
Esclerose Amiotrófica Lateral/genética , Histona Desacetilases/genética , Córtex Motor/metabolismo , Medula Espinal/metabolismo , Adamantano/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Esclerose Amiotrófica Lateral/diagnóstico por imagem , Esclerose Amiotrófica Lateral/metabolismo , Esclerose Amiotrófica Lateral/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Radioisótopos de Carbono , Estudos de Casos e Controles , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Estudos Transversais , Feminino , Histona Desacetilases/metabolismo , Histonas/metabolismo , Humanos , Ácidos Hidroxâmicos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Imagem Molecular , Córtex Motor/diagnóstico por imagem , Córtex Motor/patologia , Imagem Multimodal , Tomografia por Emissão de Pósitrons , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Medula Espinal/diagnóstico por imagem , Medula Espinal/patologia
13.
Med Hypotheses ; 128: 54-57, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31203909

RESUMO

Hypogonadotropic hypogonadism (secondary hypogonadism), congenital or acquired, is a form of hypogonadism that is due to problems with either the hypothalamus or pituitary gland affecting gonadotropin levels. Pulsatile secretion of gonadotropin-releasing hormone (GnRH) by hypothalamus is a primer step to initiate the release of pituitary gonadotropins. Kisspeptin and gonadotropin-inhibitory hormone (GnIH) are accepted as two major players in the activation and inhibition of GnRH regarding the neuroendocrine functioning of the hypothalamic pituitary gonadal axis. Kisspeptin is known as the most potent activator of GnRH. Regarding the inhibition of GnRH, RF-amide-related peptide-3 (RFRP-3) is accepted as the mammalian orthologue of GnIH in avian species. RF9 (1-adamantane carbonyl-Arg-Phe-NH2) is an antagonist of RFRP-3/GnIH receptor (neuropeptide FF receptor 1 (NPFFR1; also termed as GPR147). In recent years, several studies have indicated that RF9 activates GnRH neurons and gonadotropins in a kisspeptin receptor (Kiss1r, formerly known as GPR54) dependent manner. These results suggest that RF9 may have a bimodal function as both an RFRP-3 antagonist and a kisspeptin agonist or it may be a kiss1r agonist rather than an RFRP-3/GnIH receptor antagonist. These interactions are possible because Kisspeptin and GnIH are members of the RF-amide family, and both possibilities are not far from explaining the potent gonadotropin stimulating effects of RF9. Therefore, we hypothesize that RF9 may be a new therapeutic option for the hypogonadotropic hypogonadism due to its potent GnRH stimulating effects. A constant or repeated administration of RF9 provides a sustained increase in plasma gonadotrophin levels. However, applications in the same way with GnRH analogues and kisspeptin may result in desensitization of the gonadotropic axis. The reasons reported above contribute to our hypothesis that RF9 may be a good option in the GnRH stimulating as a kisspeptin agonist. We suggest that further studies are needed to elucidate the potential effects of RF9 in the treatment of the hypogonadotropic hypogonadism.


Assuntos
Adamantano/análogos & derivados , Dipeptídeos/farmacologia , Hormônio Liberador de Gonadotropina/metabolismo , Gonadotropinas/metabolismo , Hipogonadismo/metabolismo , Hipotálamo/metabolismo , Adamantano/farmacologia , Animais , Células CHO , Cricetinae , Cricetulus , Humanos , Hipogonadismo/terapia , Camundongos , Modelos Biológicos , Modelos Teóricos , Neuropeptídeos/metabolismo , Ratos , Receptores de Kisspeptina-1/metabolismo , Receptores de Neuropeptídeos/metabolismo
14.
Spectrochim Acta A Mol Biomol Spectrosc ; 222: 117120, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31252262

RESUMO

Dapagliflozin (DPF) and saxagliptin (SXG) are currently co-formulated in a tablet dosage form which is prescribed to improve glycemic control. The absorption spectra of DPF and SXG were highly overlapped which completely hindered their simultaneous estimation at their λmax 224 nm and 209 nm, respectively. Thus, in this work three smart and simple univariate spectrophotometric methods were originally established and validated for the first time in order to quantitatively estimate DPF and SXG in bulk forms and in combined pharmaceutical formulation without the requirement for any initial separation or treatment. These methods are; factorized zero order method (FZM), factorized derivative method (FDM) and factorized ratio difference method (FRM). These methods were capable of determining DPF and SXG over the range of 2.5-50.0 µg/mL and 2.5-60.0 µg/mL, respectively. All the developed methods are based on a novel and unique approach for the spectral recovery of unresolved spectra named; factorized response spectrum (FRS). The exclusivity of the FRS originates from its ability to completely resolve the cited drugs in the mixture and retrieve their original spectra. Selectivity of all proposed methods was assessed by comparing the obtained results of the mixture analysis with those of the pure powdered drugs. Validation of the newly developed methods was applied as recommended by the ICH demonstrating acceptable accuracy and precision. In general, these methods could be effectively employed for the routine quality control investigation of bulk materials and available market formulations.


Assuntos
Adamantano/análogos & derivados , Compostos Benzidrílicos/análise , Dipeptídeos/análise , Inibidores da Dipeptidil Peptidase IV/análise , Glucosídeos/análise , Inibidores do Transportador 2 de Sódio-Glicose/análise , Adamantano/análise , Combinação de Medicamentos , Limite de Detecção , Espectrofotometria/métodos , Comprimidos
15.
Expert Rev Clin Pharmacol ; 12(6): 547-554, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059310

RESUMO

Introduction: Rheumatoid arthritis (RA) is a chronic progressive autoimmune disease characterized by synovitis as well as symmetric and destructive arthropathy. Although several disease modified antirheumatic-drugs (DMARDs) have widely used in clinical practice, certain patients are nonresponsive to or cannot take such medications due to adverse reactions. It is evident that Janus kinase (JAK) inhibitors have the potential to provide a significant breakthrough in the treatment of RA. These potent, orally administered, JAK inhibitors simplify the treatment options for patients. Areas covered: We discuss the pharmacodynamics, pharmacokinetics, efficacy, and safety of peficitinib for the treatment of RA. Expert opinion: Peficitinib is a novel JAK3 inhibitor potently inhibiting JAK3 enzymatic activity and JAK1/3-mediated cell proliferation. Its selectivity for JAK family kinases is similar to that of tofacitinib, but slightly less potent for JAK2. It is currently being evaluated by the FDA to treat adult patients with moderately to severely active RA who show inadequate response to or are intolerant of methotrexate. It can be used either as monotherapy or combination therapy with methotrexate, or other DMARDs. However, we think that more cautious consideration and measurement for adverse events are needed, after considering the safety results of ongoing clinical studies of peficitinib.


Assuntos
Adamantano/análogos & derivados , Artrite Reumatoide/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Niacinamida/análogos & derivados , Adamantano/efeitos adversos , Adamantano/farmacologia , Adamantano/uso terapêutico , Adulto , Antirreumáticos/efeitos adversos , Antirreumáticos/farmacologia , Antirreumáticos/uso terapêutico , Artrite Reumatoide/enzimologia , Proliferação de Células/efeitos dos fármacos , Humanos , Janus Quinase 3/antagonistas & inibidores , Inibidores de Janus Quinases/efeitos adversos , Inibidores de Janus Quinases/farmacologia , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Niacinamida/efeitos adversos , Niacinamida/farmacologia , Niacinamida/uso terapêutico , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirróis/farmacologia , Pirróis/uso terapêutico
16.
Drugs ; 79(8): 887-891, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31093950

RESUMO

Peficitinib [Smyraf® (Astellas Pharma)] is a Janus kinase (JAK)1, JAK2, JAK3 and tyrosine kinase (Tyk)2 (pan-JAK) inhibitor recently approved in Japan for the treatment of rheumatoid arthritis. Inhibition of JAK suppresses the activation of cytokine signalling pathways involved in inflammation and joint destruction in rheumatoid arthritis. Peficitinib has been shown to significantly improve ACR20 and other measures of disease severity and to reduce the mean modified total Sharp score change from baseline in clinical trials. This article summarizes the milestones in the development of peficitinib leading to this first approval as a treatment for rheumatoid arthritis in patients who have an inadequate response to conventional therapies.


Assuntos
Adamantano/análogos & derivados , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Niacinamida/análogos & derivados , Inibidores de Proteínas Quinases/uso terapêutico , Adamantano/farmacologia , Adamantano/uso terapêutico , Antirreumáticos/farmacologia , Aprovação de Drogas , Humanos , Janus Quinases/antagonistas & inibidores , Niacinamida/farmacologia , Niacinamida/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores
17.
Malar J ; 18(1): 126, 2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30967148

RESUMO

BACKGROUND: Today, the development of new and well-tolerated anti-malarial drugs is strongly justified by the emergence of Plasmodium falciparum resistance. In 2014-2015, a phase 2b clinical study was conducted to evaluate the efficacy of a single oral dose of Artefenomel (OZ439)-piperaquine (PPQ) in Asian and African patients presenting with uncomplicated falciparum malaria. METHODS: Blood samples collected before treatment offered the opportunity to investigate the proportion of multidrug resistant parasite genotypes, including P. falciparum kelch13 mutations and copy number variation of both P. falciparum plasmepsin 2 (Pfpm2) and P. falciparum multidrug resistance 1 (Pfmdr1) genes. RESULTS: Validated kelch13 resistance mutations including C580Y, I543T, P553L and V568G were only detected in parasites from Vietnamese patients. In Africa, isolates with multiple copies of the Pfmdr1 gene were shown to be more frequent than previously reported (21.1%, range from 12.4% in Burkina Faso to 27.4% in Uganda). More strikingly, high proportions of isolates with multiple copies of the Pfpm2 gene, associated with piperaquine (PPQ) resistance, were frequently observed in the African sites, especially in Burkina Faso and Uganda (> 30%). CONCLUSIONS: These findings were considered to sharply contrast with the recent description of increased sensitivity to PPQ of Ugandan parasite isolates. This emphasizes the necessity to investigate in vitro susceptibility profiles to PPQ of African isolates with multiple copies of the Pfpm2 gene and estimate the risk of development of PPQ resistance in Africa. Trial registration Clinicaltrials.gov reference: NCT02083380. Study title: Phase II efficacy study of artefenomel and piperaquine in adults and children with P. falciparum malaria. https://clinicaltrials.gov/ct2/results?cond=&term=NCT02083380&cntry=&state=&city=&dist= . FSFV: 23-Jul-2014; LSLV: 09-Oct-2015.


Assuntos
Adamantano/análogos & derivados , Antimaláricos/farmacologia , Ácido Aspártico Endopeptidases/genética , Resistência a Medicamentos/genética , Peróxidos/farmacologia , Plasmodium falciparum/genética , Proteínas de Protozoários/genética , Quinolinas/farmacologia , Adamantano/farmacologia , Adolescente , Adulto , África , Idoso , Ácido Aspártico Endopeptidases/metabolismo , Biomarcadores/análise , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Combinação de Medicamentos , Feminino , Genótipo , Humanos , Lactente , Malária Falciparum , Masculino , Pessoa de Meia-Idade , Plasmodium falciparum/efeitos dos fármacos , Proteínas de Protozoários/metabolismo , Vietnã , Adulto Jovem
18.
Org Biomol Chem ; 17(18): 4640-4651, 2019 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-31020307

RESUMO

Multicomponent self-assembled supramolecular nanovesicles based on an amphiphilic derivative of ß-cyclodextrin and phosphatidylcholine liposomes (PC-liposomes) functionalized with four structurally different adamantyl guanidines were prepared and characterized. Incorporation efficiency of the examined adamantyl guanidines as well as size and surface charge of the prepared supramolecular nanovesicles was determined. Changes in the surface charge of the prepared nanovesicles confirmed that guanidinium groups were exposed on the surface. ITC and 1H NMR spectroscopy complemented by molecular dynamics (MD) simulations were used to elucidate the structural data and stability of the inclusion complexes of ß-cyclodextrin and adamantyl guanidines (AG1-5). The results are consistent and point to a significant contribution of the guanylhydrazone residue to the complexation process for AG1 and AG2 with ß-cyclodextrin. In order to evaluate the potential of the self-assembled supramolecular nanomaterial as a nonviral gene delivery vector, fluorescence correlation spectroscopy was used. It showed that the prepared nanovesicles functionalized with adamantyl guanidines AG1-4 effectively recognize and bind the fluorescently labelled DNA. Furthermore, gel electrophoretic assay confirmed the formation of nanoplexes of functionalized nanovesicles and plasmid DNA. These findings together suggest that the designed supramolecular nanovesicles could be successfully applied as nonviral gene delivery vectors.


Assuntos
Adamantano/análogos & derivados , Portadores de Fármacos/química , Guanidinas/química , Lipossomos/química , beta-Ciclodextrinas/química , Linhagem Celular Tumoral , DNA/química , DNA/genética , Difusão , Técnicas de Transferência de Genes , Células HEK293 , Humanos , Simulação de Dinâmica Molecular , Fosfatidilcolinas/química , Plasmídeos
19.
Neuroreport ; 30(8): 567-572, 2019 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-30950936

RESUMO

It is generally understood that continuing neuroinflammation after ischemic stroke can exacerbate the brain damage. During the inflammatory hematogenous recruitment process, the monocytes and macrophages are activated into proinflammatory M1 and anti-inflammatory M2 cell types. Inhibition of soluble epoxide hydrolase (sEH) activity has been reported to regulate monocytes/macrophages, and attenuates neuroinflammation. This study aimed to evaluate whether a selective sEH inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), can regulate monocyte/macrophage polarization and improve motor function in the rats with ischemic stroke induced by middle cerebral artery occlusion. We measured the infarct volume with 2,3,5-triphenyltetrazolium chloride staining and used the rotarod test to assess motor performance in rats. The monocyte/macrophage activation and mRNA expression of proinflammatory mediators were measured by flow cytometry and reverse-transcription quantitative PCR, respectively. Our results showed better neurological function and less infarct volume in the rats treated with AUDA. Compared with the vehicle group, the AUDA-treated group showed a reduction in M1 monocyte/macrophage activation and proinflammatory mRNA expressions in the infarct cortex of rats. Our data suggest that the sEH inhibition may regulate monocyte/macrophage polarization and improve neurological outcome after ischemic stroke.


Assuntos
Isquemia Encefálica/fisiopatologia , Encefalite/fisiopatologia , Epóxido Hidrolases/antagonistas & inibidores , Epóxido Hidrolases/fisiologia , Macrófagos/fisiologia , Monócitos/fisiologia , Acidente Vascular Cerebral/fisiopatologia , Adamantano/administração & dosagem , Adamantano/análogos & derivados , Animais , Polaridade Celular/efeitos dos fármacos , Modelos Animais de Doenças , Ácidos Láuricos/administração & dosagem , Macrófagos/efeitos dos fármacos , Masculino , Monócitos/efeitos dos fármacos , Ratos Endogâmicos WKY , Teste de Desempenho do Rota-Rod
20.
Artif Cells Nanomed Biotechnol ; 47(1): 1288-1294, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30942641

RESUMO

Bacteria play a pivotal role in the pathological initiation and progression of pulpitis. Lipopolysaccharide (LPS) is recognized as a major component of the outer wall of Gram-negative bacteria. Saxagliptin, a potent inhibitor of dipeptidyl peptidase-4 (DPP-4), has been licensed for the treatment of type 2 diabetes. In this study, we aimed to evaluate the protective effects of saxagliptin against LPS-induced intracellular insults in human dental pulp cells (HDPCs). We found that DPP-4 is expressed in HDPCs. Interestingly, the expression of DPP-4 was increased in response to LPS treatment. We also found that saxagliptin ameliorated LPS-induced production of ROS and reduction of glutathione (GSH). Additionally, saxagliptin prevented LPS-induced mitochondrial dysfunction by increasing the levels of mitochondrial membrane potential (MMP) and the production of adenosine triphosphate (ATP). Importantly, saxagliptin ameliorated LPS-induced reduction of cell viability and lactate dehydrogenase (LDH) release. Our results indicate that saxagliptin significantly inhibited LPS-induced expression and secretions of tumour necrosis factor alpha (TNF-α), interleukin (IL)-1ß and IL-6 in HDPCs. Mechanistically, we found that saxagliptin inhibited the phosphorylation of p38 and the activation of NF-κB. Our findings suggest that saxagliptin might have a potential therapeutic capacity for the treatment of pulpitis through mitigating inflammatory signalling in dental pulp cells.


Assuntos
Adamantano/análogos & derivados , Citoproteção/efeitos dos fármacos , Polpa Dentária/citologia , Dipeptídeos/farmacologia , Lipopolissacarídeos/efeitos adversos , Adamantano/farmacologia , Polpa Dentária/patologia , Relação Dose-Resposta a Droga , Humanos , Inflamação/induzido quimicamente , Inflamação/patologia , Inflamação/prevenção & controle , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo
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