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1.
Invest Ophthalmol Vis Sci ; 62(14): 8, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34757417

RESUMO

Purpose: Current melphalan-based regimens for intravitreal chemotherapy for retinoblastoma vitreous seeds are effective but toxic to the retina. Thus, alternative agents are needed. Based on the known biology of histone deacetylases (HDACs) in the retinoblastoma pathway, we systematically studied whether the HDAC inhibitor belinostat is a viable, molecularly targeted alternative agent for intravitreal delivery that might provide comparable efficacy, without toxicity. Methods: In vivo pharmacokinetic experiments in rabbits and in vitro cytotoxicity experiments were performed to determine the 90% inhibitory concentration (IC90). Functional toxicity by electroretinography and structural toxicity by optical coherence tomography (OCT), OCT angiography, and histopathology were evaluated in rabbits following three injections of belinostat 350 µg (2× IC90) or 700 µg (4× IC90), compared with melphalan 12.5 µg (rabbit equivalent of the human dose). The relative efficacy of intravitreal belinostat versus melphalan to treat WERI-Rb1 human cell xenografts in rabbit eyes was directly quantified. RNA sequencing was used to assess belinostat-induced changes in RB cell gene expression. Results: The maximum nontoxic dose of belinostat was 350 µg, which caused no reductions in electroretinography parameters, retinal microvascular loss on OCT angiography, or retinal degeneration. Melphalan caused severe retinal structural and functional toxicity. Belinostat 350 µg (equivalent to 700 µg in the larger human eye) was equally effective at eradicating vitreous seeds in the rabbit xenograft model compared with melphalan (95.5% reduction for belinostat, P < 0.001; 89.4% reduction for melphalan, P < 0.001; belinostat vs. melphalan, P = 0.10). Even 700 µg belinostat (equivalent to 1400 µg in humans) caused only minimal toxicity. Widespread changes in gene expression resulted. Conclusions: Molecularly targeted inhibition of HDACs with intravitreal belinostat was equally effective as standard-of-care melphalan but without retinal toxicity. Belinostat may therefore be an attractive agent to pursue clinically for intravitreal treatment of retinoblastoma.


Assuntos
Modelos Animais de Doenças , Inibidores de Histona Desacetilases/uso terapêutico , Ácidos Hidroxâmicos/uso terapêutico , Inoculação de Neoplasia , Retina/efeitos dos fármacos , Neoplasias da Retina/tratamento farmacológico , Retinoblastoma/tratamento farmacológico , Sulfonamidas/uso terapêutico , Animais , Anexina A5 , Antineoplásicos Alquilantes/uso terapêutico , Eletrorretinografia , Angiofluoresceinografia , Inibidores de Histona Desacetilases/farmacocinética , Inibidores de Histona Desacetilases/toxicidade , Ácidos Hidroxâmicos/farmacocinética , Ácidos Hidroxâmicos/toxicidade , Injeções Intravítreas , Dose Máxima Tolerável , Melfalan/uso terapêutico , Coelhos , Retina/fisiologia , Neoplasias da Retina/diagnóstico , Neoplasias da Retina/fisiopatologia , Retinoblastoma/diagnóstico , Retinoblastoma/fisiopatologia , Estudos Retrospectivos , Sulfonamidas/farmacocinética , Sulfonamidas/toxicidade , Tomografia de Coerência Óptica , Corpo Vítreo/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Proc Natl Acad Sci U S A ; 118(43)2021 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-34635581

RESUMO

The host cell serine protease TMPRSS2 is an attractive therapeutic target for COVID-19 drug discovery. This protease activates the Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and of other coronaviruses and is essential for viral spread in the lung. Utilizing rational structure-based drug design (SBDD) coupled to substrate specificity screening of TMPRSS2, we have discovered covalent small-molecule ketobenzothiazole (kbt) TMPRSS2 inhibitors which are structurally distinct from and have significantly improved activity over the existing known inhibitors Camostat and Nafamostat. Lead compound MM3122 (4) has an IC50 (half-maximal inhibitory concentration) of 340 pM against recombinant full-length TMPRSS2 protein, an EC50 (half-maximal effective concentration) of 430 pM in blocking host cell entry into Calu-3 human lung epithelial cells of a newly developed VSV-SARS-CoV-2 chimeric virus, and an EC50 of 74 nM in inhibiting cytopathic effects induced by SARS-CoV-2 virus in Calu-3 cells. Further, MM3122 blocks Middle East respiratory syndrome coronavirus (MERS-CoV) cell entry with an EC50 of 870 pM. MM3122 has excellent metabolic stability, safety, and pharmacokinetics in mice, with a half-life of 8.6 h in plasma and 7.5 h in lung tissue, making it suitable for in vivo efficacy evaluation and a promising drug candidate for COVID-19 treatment.


Assuntos
Benzotiazóis/farmacologia , COVID-19/tratamento farmacológico , Oligopeptídeos/farmacologia , SARS-CoV-2/efeitos dos fármacos , Serina Endopeptidases/genética , Animais , Benzamidinas/química , Benzotiazóis/farmacocinética , COVID-19/genética , COVID-19/virologia , Linhagem Celular , Desenho de Fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/virologia , Ésteres/química , Guanidinas/química , Humanos , Pulmão/efeitos dos fármacos , Pulmão/virologia , Camundongos , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Coronavírus da Síndrome Respiratória do Oriente Médio/patogenicidade , Oligopeptídeos/farmacocinética , SARS-CoV-2/patogenicidade , Serina Endopeptidases/efeitos dos fármacos , Serina Endopeptidases/ultraestrutura , Bibliotecas de Moléculas Pequenas/farmacologia , Especificidade por Substrato/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos
3.
Molecules ; 26(19)2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34641285

RESUMO

A library of bile-acid-appended triazolyl aryl ketones was synthesized and characterized by detailed spectroscopic techniques such as 1H and 13C NMR, HRMS and HPLC. All the synthesized conjugates were evaluated for their cytotoxicity at 10 µM against MCF-7 (human breast adenocarcinoma) and 4T1 (mouse mammary carcinoma) cells. In vitro cytotoxicity studies on the synthesized conjugates against MCF-7 and 4T1 cells indicated one of the conjugate 6cf to be most active against both cancer cell lines, with IC50 values of 5.71 µM and 8.71 µM, respectively, as compared to the reference drug docetaxel, possessing IC50 values of 9.46 µM and 13.85 µM, respectively. Interestingly, another compound 6af (IC50 = 2.61 µM) was found to possess pronounced anticancer activity as compared to the reference drug docetaxel (IC50 = 9.46 µM) against MCF-7. In addition, the potent compounds (6cf and 6af) were found to be non-toxic to normal human embryonic kidney cell line (HEK 293), as evident from their cell viability of greater than 86%. Compound 6cf induces higher apoptosis in comparison to 6af (46.09% vs. 33.89%) in MCF-7 cells, while similar apoptotic potential was observed for 6cf and 6af in 4T1 cells. The pharmacokinetics of 6cf in Wistar rats showed an MRT of 8.47 h with a half-life of 5.63 h. Clearly, these results suggest 6cf to be a potential candidate for the development of anticancer agents.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/síntese química , Ácidos e Sais Biliares/química , Cetonas/administração & dosagem , Cetonas/síntese química , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos , Cetonas/química , Cetonas/farmacocinética , Células MCF-7 , Masculino , Camundongos , Estrutura Molecular , Ratos , Ratos Wistar , Relação Estrutura-Atividade
4.
Nat Med ; 27(10): 1712-1717, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34608329

RESUMO

Islatravir (MK-8591) is a highly potent type 1 human immunodeficiency virus (HIV-1) nucleoside reverse transcriptase translocation inhibitor with a long intracellular half-life that is in development for the prevention and treatment of HIV-1. We conducted a randomized, double-blind, placebo-controlled, phase 1 trial in adults without HIV-1 infection. Participants received islatravir or placebo subdermal implants for 12 weeks and were monitored throughout this period and after implant removal. The co-primary end points were safety and tolerability of the islatravir implant and pharmacokinetics, including concentration at day 85, of islatravir triphosphate in peripheral blood mononuclear cells (PBMCs). Secondary end points included additional pharmacokinetic parameters for islatravir triphosphate in PBMCs and the plasma pharmacokinetic profile of islatravir. Based on preclinical data, two doses were assessed: 54 mg (n = 8, two placebo) and 62 mg (n = 8, two placebo). The most frequently reported adverse events were mild-to-moderate implant-site reactions (induration, hematoma, pain). Throughout the 12-week trial, geometric mean islatravir triphosphate concentrations were above a pharmacokinetic threshold of 0.05 pmol per 106 PBMCs, which was estimated to provide therapeutic reverse transcriptase inhibition (concentration at day 85 (percentage of geometric coefficient of variation): 54 mg, 0.135 pmol per 106 cells (27.3); 62 mg, 0.272 pmol per 106 cells (45.2)). Islatravir implants at both doses were safe and resulted in mean concentrations above the pharmacokinetic threshold through 12 weeks, warranting further investigation of islatravir implants as a potential HIV prevention strategy.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Desoxiadenosinas/administração & dosagem , Infecções por HIV/tratamento farmacológico , Inibidores da Transcriptase Reversa/administração & dosagem , Adulto , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/farmacocinética , Desoxiadenosinas/efeitos adversos , Desoxiadenosinas/farmacocinética , Método Duplo-Cego , Infecções por HIV/genética , Infecções por HIV/virologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , HIV-1/patogenicidade , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Placebos , Inibidores da Transcriptase Reversa/efeitos adversos , Inibidores da Transcriptase Reversa/farmacocinética , Replicação Viral/efeitos dos fármacos
5.
Nat Med ; 27(10): 1718-1724, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34621054

RESUMO

Human immunodeficiency virus (HIV)-1-specific broadly neutralizing monoclonal antibodies are currently under development to treat and prevent HIV-1 infection. We performed a single-center, randomized, double-blind, dose-escalation, placebo-controlled trial of a single administration of the HIV-1 V3-glycan-specific antibody PGT121 at 3, 10 and 30 mg kg-1 in HIV-uninfected adults and HIV-infected adults on antiretroviral therapy (ART), as well as a multicenter, open-label trial of one infusion of PGT121 at 30 mg kg-1 in viremic HIV-infected adults not on ART (no. NCT02960581). The primary endpoints were safety and tolerability, pharmacokinetics (PK) and antiviral activity in viremic HIV-infected adults not on ART. The secondary endpoints were changes in anti-PGT121 antibody titers and CD4+ T-cell count, and development of HIV-1 sequence variations associated with PGT121 resistance. Among 48 participants enrolled, no treatment-related serious adverse events, potential immune-mediated diseases or Grade 3 or higher adverse events were reported. The most common reactions among PGT121 recipients were intravenous/injection site tenderness, pain and headache. Absolute and relative CD4+ T-cell counts did not change following PGT121 infusion in HIV-infected participants. Neutralizing anti-drug antibodies were not elicited. PGT121 reduced plasma HIV RNA levels by a median of 1.77 log in viremic participants, with a viral load nadir at a median of 8.5 days. Two individuals with low baseline viral loads experienced ART-free viral suppression for ≥168 days following antibody infusion, and rebound viruses in these individuals demonstrated full or partial PGT121 sensitivity. The trial met the prespecified endpoints. These data suggest that further investigation of the potential of antibody-based therapeutic strategies for long-term suppression of HIV is warranted, including in individuals off ART and with low viral load.


Assuntos
Antivirais/administração & dosagem , Anticorpos Amplamente Neutralizantes/administração & dosagem , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Adulto , Terapia Antirretroviral de Alta Atividade , Antivirais/imunologia , Antivirais/farmacocinética , Anticorpos Amplamente Neutralizantes/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/virologia , Método Duplo-Cego , Feminino , Proteína gp120 do Envelope de HIV/antagonistas & inibidores , Proteína gp120 do Envelope de HIV/imunologia , Infecções por HIV/genética , Infecções por HIV/patologia , Infecções por HIV/virologia , HIV-1/patogenicidade , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/imunologia , Placebos , Carga Viral/efeitos dos fármacos , Carga Viral/imunologia , Adulto Jovem
6.
Molecules ; 26(19)2021 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-34641532

RESUMO

The present paper provides an updated overview of the methodologies applied in photodegradation studies of non-steroidal anti-inflammatory drugs. Photostability tests, performed according to international standards, have clearly demonstrated the photolability of many drugs belonging to this class, observed during the preparation of commercial forms, administration or when dispersed in the environment. The photodegradation profile of these drugs is usually monitored by spectrophotometric or chromatographic techniques and in many studies the analytical data are processed by chemometric procedures. The application of multivariate analysis in the resolution of often-complex data sets makes it possible to estimate the pure spectra of the species involved in the degradation process and their concentration profiles. Given the wide use of these drugs, several pharmaceutical formulations have been investigated to improve their photostability in solution or gel, as well as the pharmacokinetic profile. The use of lipid nanocarriers as liposomes, niosomes or solid lipid nanoparticles has demonstrated to both minimize photodegradation and improve the controlled release of the entrapped drugs.


Assuntos
Anti-Inflamatórios não Esteroides/química , Portadores de Fármacos/química , Nanoestruturas/química , Anti-Inflamatórios não Esteroides/farmacocinética , Portadores de Fármacos/farmacocinética , Estabilidade de Medicamentos , Lipídeos/química , Lipossomos/química , Lipossomos/farmacocinética , Fotólise
7.
Molecules ; 26(19)2021 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-34641543

RESUMO

A series of novel multi-substituted coumarin derivatives were synthesized, spectroscopically characterized, and evaluated for their antioxidant activity, soybean lipoxygenase (LOX) inhibitory ability, their influence on cell viability in immortalized human keratinocytes (HaCaT), and cytotoxicity in adenocarcinomic human alveolar basal epithelial cells (A549) and human melanoma (A375) cells, in vitro. Coumarin analogues 4a-4f, bearing a hydroxyl group at position 5 of the coumarin scaffold and halogen substituents at the 3-phenyl ring, were the most promising ABTS•+ scavengers. 6,8-Dibromo-3-(4-hydroxyphenyl)-4-methyl-chromen-2-one (4k) and 6-bromo-3-(4,5-diacetyloxyphenyl)-4-methyl-chromen-2-one (3m) exhibited significant lipid peroxidation inhibitory activity (IC50 36.9 and 37.1 µM). In the DCF-DA assay, the 4'-fluoro-substituted compound 3f (100%), and the 6-bromo substituted compounds 3i (80.9%) and 4i (100%) presented the highest activity. The 3'-fluoro-substituted coumarins 3e and 4e, along with 3-(4-acetyloxyphenyl)-6,8-dibromo-4-methyl-chromen-2-one (3k), were the most potent lipoxygenase (LOX) inhibitors (IC50 11.4, 4.1, and 8.7 µM, respectively) while displaying remarkable hydroxyl radical scavenging ability, 85.2%, 100%, and 92.9%, respectively. In silico docking studies of compounds 4e and 3k, revealed that they present allosteric interactions with the enzyme. The majority of the analogues (100 µΜ) did not affect the cell viability of HaCaT cells, though several compounds presented over 60% cytotoxicity in A549 or A375 cells. Finally, the human oral absorption (%HOA) and plasma protein binding (%PPB) properties of the synthesized coumarins were also estimated using biomimetic chromatography, and all compounds presented high %HOA (>99%) and %PPB (60-97%) values.


Assuntos
Cumarínicos/síntese química , Cumarínicos/farmacocinética , Inibidores de Lipoxigenase/farmacologia , Células A549 , Antioxidantes/química , Antioxidantes/farmacologia , Biomimética , Proteínas Sanguíneas/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Cumarínicos/farmacologia , Fluoresceínas/química , Corantes Fluorescentes/química , Sequestradores de Radicais Livres/química , Humanos , Queratinócitos/efeitos dos fármacos , Inibidores de Lipoxigenase/química , Inibidores de Lipoxigenase/farmacocinética , Simulação de Acoplamento Molecular , Soja/enzimologia
8.
Molecules ; 26(19)2021 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-34641545

RESUMO

Nowadays, increasing interest in olive pomace (OP) valorization aims to improve olive's industry sustainability. Interestingly, several studies propose a high-value application for OP extracts containing its main phenolic compounds, hydroxytyrosol and oleuropein, as therapy for ocular surface diseases. In this work, the stability and accessibility of OP total phenolic and flavonoid content, main representative compounds, and antioxidant activity were assessed under different pretreatment conditions. Among them, lyophilization and supercritical CO2 extraction were found to increase significantly most responses measured in the produced extracts. Two selected extracts (CONV and OPT3) were obtained by different techniques (conventional and pressurized liquid extraction); Their aqueous solutions were characterized by HPLC-DAD-MS/MS. Additionally, their safety and stability were evaluated according to EMA requirements towards their approval as ophthalmic products: their genotoxic effect on ocular surface cells and their 6-months storage stability at 4 different temperature/moisture conditions (CPMP/ICH/2736/99), together with pure hydroxytyrosol and oleuropein solutions. The concentration of hydroxytyrosol and oleuropein in pure or extract solutions was tracked, and possible degradation products were putatively identified by HPLC-DAD-MS/MS. Hydroxytyrosol and oleuropein had different stability as standard or extract solutions, with oleuropein also showing different degradation profile. All compounds/extracts were safe for ophthalmic use at the concentrations tested.


Assuntos
Olea/química , Fenóis/química , Extratos Vegetais/farmacocinética , Aldeídos/química , Aldeídos/farmacocinética , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Ensaio Cometa , Córnea/citologia , Córnea/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Estabilidade de Medicamentos , Humanos , Soluções Oftálmicas/química , Soluções Oftálmicas/farmacologia , Fenóis/farmacocinética , Álcool Feniletílico/análogos & derivados , Álcool Feniletílico/química , Álcool Feniletílico/farmacocinética , Extratos Vegetais/química , Espectrometria de Massas em Tandem
9.
PLoS One ; 16(10): e0256783, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34634057

RESUMO

BACKGROUND/OBJECTIVES: Drug-coated balloon therapy for diseased superficial femoral arteries remains controversial. Despite its clinical relevance, only a few computational studies based on simplistic two-dimensional models have been proposed to investigate this endovascular therapy to date. This work addresses the aforementioned limitation by analyzing the drug transport and kinetics occurring during drug-coated balloon deployment in a three-dimensional geometry. METHODS: An idealized three-dimensional model of a superficial femoral artery presenting with a calcific plaque and treated with a drug-coated balloon was created to perform transient mass transport simulations. To account for the transport of drug (i.e. paclitaxel) released by the device, a diffusion-reaction equation was implemented by describing the drug bound to specific intracellular receptors through a non-linear, reversible reaction. The following features concerning procedural aspects, pathologies and modelling assumptions were investigated: (i) balloon application time (60-180 seconds); (ii) vessel wall composition (healthy vs. calcified wall); (iii) sequential balloon application; and (iv) drug wash-out by the blood stream vs. coating retention, modeled as exponential decay. RESULTS: The balloon inflation time impacted both the free and specifically-bound drug concentrations in the vessel wall. The vessel wall composition highly affected the drug concentrations. In particular, the specifically-bound drug concentration was four orders of magnitude lower in the calcific compared with healthy vessel wall portions, primarily as a result of reduced drug diffusion. The sequential application of two drug-coated balloons led to modest differences (~15%) in drug concentration immediately after inflation, which became negligible within 10 minutes. The retention of the balloon coating increased the drug concentration in the vessel wall fourfold. CONCLUSIONS: The overall findings suggest that paclitaxel kinetics may be affected not only by the geometrical and compositional features of the vessel treated with the drug-coated balloon, but also by balloon design characteristics and procedural aspects that should be carefully considered.


Assuntos
Angioplastia com Balão/instrumentação , Sistemas de Liberação de Medicamentos/instrumentação , Artéria Femoral/cirurgia , Calcificação Vascular/terapia , Materiais Revestidos Biocompatíveis , Liberação Controlada de Fármacos , Desenho de Equipamento , Artéria Femoral/efeitos dos fármacos , Humanos , Modelos Biológicos , Paclitaxel/administração & dosagem , Paclitaxel/farmacocinética , Moduladores de Tubulina/administração & dosagem , Moduladores de Tubulina/farmacocinética , Calcificação Vascular/cirurgia
10.
Pediatrics ; 148(5)2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34607935

RESUMO

The over-the-counter nasal decongestant oxymetazoline (eg, Afrin) is used in the pediatric population for a variety of conditions in the operating room setting. Given its vasoconstrictive properties, it can have cardiovascular adverse effects when systemically absorbed. There have been several reports of cardiac and respiratory complications related to use of oxymetazoline in the pediatric population. Current US Food and Drug Administration approval for oxymetazoline is for patients ≥6 years of age, but medical professionals may elect to use it short-term and off label for younger children in particular clinical scenarios in which the potential benefit may outweigh risks (eg, active bleeding, acute respiratory distress from nasal obstruction, acute complicated sinusitis, improved surgical visualization, nasal decongestion for scope examination, other conditions, etc). To date, there have not been adequate pediatric pharmacokinetic studies of oxymetazoline, so caution should be exercised with both the quantity of dosing and the technique of administration. In the urgent care setting, emergency department, or inpatient setting, to avoid excessive administration of the medication, medical professionals should use the spray bottle in an upright position with the child upright. In addition, in the operating room setting, both monitoring the quantity used and effective communication between the surgeon and anesthesia team are important. Further studies are needed to understand the systemic absorption and effects in children in both nonsurgical and surgical nasal use of oxymetazoline.


Assuntos
Descongestionantes Nasais/efeitos adversos , Oximetazolina/efeitos adversos , Assistência Perioperatória , Fatores Etários , Criança , Pré-Escolar , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hipertensão/induzido quimicamente , Complicações Intraoperatórias/induzido quimicamente , Masculino , Descongestionantes Nasais/administração & dosagem , Descongestionantes Nasais/farmacocinética , Uso Off-Label , Salas Cirúrgicas , Oximetazolina/administração & dosagem , Oximetazolina/farmacocinética
11.
PLoS One ; 16(10): e0258601, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34644354

RESUMO

Infliximab (IFX) therapy has considerably improved the treatment of rheumatoid arthritis (RA). However, some patients still do not respond adequately to IFX therapy, or the efficacy of the treatment diminishes over time. Although previous studies have reported a relationship between serum IFX levels and therapeutic efficacy, the potential applications of IFX therapeutic drug monitoring (TDM) in clinical practice remain unclear. The purpose of this study was to investigate the potential applications of IFX TDM by analyzing a Japanese cohort database. Data were collected retrospectively from the Kyoto University Rheumatoid Arthritis Management Alliance cohort between January 1, 2011, and December 31, 2018. Serum IFX levels were measured using a liquid chromatography-tandem mass spectrometer. Out of the 311 RA patients that used IFX, 41 were eligible for the analysis. Serum IFX levels were significantly higher in responders than in non-responders. An optimal cut-off value was determined to be 0.32 µg/mL based on a receiver operating characteristic curve. At the IFX measurement point, a better therapeutic response was observed in the high IFX group (n = 32) than in the low IFX group (n = 9). Conversely, at the maximum effect point, when DAS28-ESR was the lowest between IFX introduction and measurement points, there were no differences in responder proportions between the low and high IFX groups. IFX primary ineffectiveness could be avoided with appropriate dose escalation without blood concentration measurement in clinical practice. In conclusion, IFX TDM could facilitate the identification of secondary non-responders and in turn, proper IFX use.


Assuntos
Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Infliximab/administração & dosagem , Adulto , Idoso , Antirreumáticos/sangue , Antirreumáticos/farmacocinética , Artrite Reumatoide/sangue , Cromatografia Líquida , Feminino , Humanos , Infliximab/sangue , Infliximab/farmacocinética , Japão , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Espectrometria de Massas em Tandem , Resultado do Tratamento
12.
Arch Pediatr ; 28(7): 588-593, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34598836

RESUMO

Phosphate homeostasis is a requirement for normal life. Phosphate is involved in the synthesis of membrane lipids, DNA, RNA, and energy-rich molecules (ATP and GTP), and the regulation of protein activity by phosphorylation/dephosphorylation. Moreover, phosphate is a component of apatite crystals, which provide stability to the bone, and is essential for normal growth. Phosphate balance in the body is the difference between net phosphate absorption through the intestine and phosphate excretion through the kidney. Numerous disorders, both genetic and acquired, may alter phosphate homeostasis. In affected individuals, it is crucial to identify the underlying mechanism(s) to provide adequate treatment; however, phosphate homeostasis assessment remains challenging. Besides the measurement of key hormones involved in the control of phosphate homeostasis (parathyroid hormone, vitamin D and metabolites, fibroblast growth factor 23), assessing the magnitude of phosphate reabsorption by the kidney is a crucial step. It makes it possible to distinguish between a primary disorder of renal phosphate reabsorption, associated with an intrinsic defect or endocrine disturbance, and a nutritional cause of phosphate deficiency. This strategy is described, and the potential consequences for therapeutic decisions are discussed.


Assuntos
Fenômenos Bioquímicos/fisiologia , Fatores de Crescimento de Fibroblastos/farmacologia , Homeostase/efeitos dos fármacos , Fosfatos/metabolismo , Fatores de Crescimento de Fibroblastos/farmacocinética , Homeostase/fisiologia , Humanos
13.
SAR QSAR Environ Res ; 32(11): 863-888, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34634208

RESUMO

The novel severe acute respiratory syndrome coronavirus (SARS CoV-2) was introduced as an epidemic in 2019 and had millions of deaths worldwide. Given the importance of this disease, the recommendation and design of new active compounds are crucial. 3-chymotrypsin-like protease (3 CLpro) inhibitors have been identified as potent compounds for treating SARS-CoV-2 disease. So, the design of new 3 CLpro inhibitors was proposed using a quantitative structure-activity relationship (QSAR) study. In this context, a powerful adaptive least absolute shrinkage and selection operator (ALASSO) penalized variable selection method with inherent advantages coupled with a nonlinear artificial neural network (ANN) modelling method were used to provide a QSAR model with high interpretability and predictability. After evaluating the accuracy and validity of the developed ALASSO-ANN model, new compounds were proposed using effective descriptors, and the biological activity of the new compounds was predicted. Ligand-receptor (LR) interactions were also performed to confirm the interaction strength of the compounds using molecular docking (MD) study. The pharmacokinetics properties and calculated Lipinski's rule of five were applied to all proposed compounds. Due to the ease of synthesis of these suggested new compounds, it is expected that they have acceptable pharmacological properties.


Assuntos
Antivirais/química , Proteases 3C de Coronavírus/antagonistas & inibidores , Inibidores de Proteases/química , SARS-CoV-2/efeitos dos fármacos , Antivirais/farmacocinética , Proteases 3C de Coronavírus/química , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Redes Neurais de Computação , Inibidores de Proteases/farmacocinética , Relação Quantitativa Estrutura-Atividade , Reprodutibilidade dos Testes , SARS-CoV-2/enzimologia
14.
Nat Commun ; 12(1): 6097, 2021 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-34671037

RESUMO

Effective treatments against Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) are urgently needed. Monoclonal antibodies have shown promising results in patients. Here, we evaluate the in vivo prophylactic and therapeutic effect of COVA1-18, a neutralizing antibody highly potent against the B.1.1.7 isolate. In both prophylactic and therapeutic settings, SARS-CoV-2 remains undetectable in the lungs of treated hACE2 mice. Therapeutic treatment also causes a reduction in viral loads in the lungs of Syrian hamsters. When administered at 10 mg kg-1 one day prior to a high dose SARS-CoV-2 challenge in cynomolgus macaques, COVA1-18 shows very strong antiviral activity in the upper respiratory compartments. Using a mathematical model, we estimate that COVA1-18 reduces viral infectivity by more than 95% in these compartments, preventing lymphopenia and extensive lung lesions. Our findings demonstrate that COVA1-18 has a strong antiviral activity in three preclinical models and could be a valuable candidate for further clinical evaluation.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticorpos Neutralizantes/administração & dosagem , Antivirais/administração & dosagem , COVID-19/tratamento farmacológico , SARS-CoV-2/imunologia , Enzima de Conversão de Angiotensina 2/genética , Animais , Anticorpos Monoclonais/farmacocinética , Antivirais/farmacocinética , COVID-19/sangue , COVID-19/imunologia , COVID-19/virologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Pulmão/metabolismo , Pulmão/virologia , Macaca fascicularis , Masculino , Mesocricetus , Camundongos , Camundongos Transgênicos , SARS-CoV-2/isolamento & purificação , Distribuição Tecidual , Carga Viral
15.
Sci Rep ; 11(1): 21308, 2021 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-34716391

RESUMO

The aim of this study was to present and evaluate novel oral vaccines, based on self-amplifying RNA lipid nanparticles (saRNA LNPs), saRNA transfected Lactobacillus plantarum LNPs, and saRNA transfected Lactobacillus plantarum, to neutralize severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) variants alpha and delta. After invitro evaluation of the oral vaccines on HEK293T/17 cells, we found that saRNA LNPs, saRNA transfected Lactobacillus plantarum LNPs, and saRNA transfected Lactobacillus plantarum could express S-protein at both mRNA and protein levels. In the next step, BALB/c mice were orally vaccinated with saRNA LNPs, saRNA transfected Lactobacillus plantarum LNPs, and saRNA transfected Lactobacillus plantarum at weeks 1 and 3. Importantly, a high titer of IgG and IgA was observed by all of them, sharply in week 6 (P < 0.05). In all study groups, their ratio of IgG2a/IgG1 was upper 1, indicating Th1-biased responses. Wild-type viral neutralization assay showed that the secreted antibodies in vaccinated mice and recovered COVID-19 patients could neutralize SARS-COV-2 variants alpha and delta. After oral administration of oral vaccines, biodistribution assay was done. It was found that all of them had the same biodistribution pattern. The highest concentration of S-protein was seen in the small intestine, followed by the large intestine and liver.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Vacinas contra COVID-19/administração & dosagem , COVID-19/prevenção & controle , Lactobacillus plantarum/genética , Lipídeos/química , Nanopartículas/química , SARS-CoV-2/imunologia , Transfecção/métodos , Vacinação/métodos , Vacinas Sintéticas/administração & dosagem , Administração Oral , Adulto , Animais , COVID-19/sangue , COVID-19/virologia , Vacinas contra COVID-19/farmacocinética , Feminino , Células HEK293 , Humanos , Imunoglobulina A/sangue , Imunoglobulina A/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Intestino Delgado/metabolismo , Lactobacillus plantarum/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Modelos Animais , Testes de Neutralização , RNA Mensageiro/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Distribuição Tecidual
16.
Molecules ; 26(19)2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34641501

RESUMO

Diabetes mellitus is a global threat affecting millions of people of different age groups. In recent years, the development of naturally derived anti-diabetic agents has gained popularity. Okra is a common vegetable containing important bioactive components such as abscisic acid (ABA). ABA, a phytohormone, has been shown to elicit potent anti-diabetic effects in mouse models. Keeping its anti-diabetic potential in mind, in silico study was performed to explore its role in inhibiting proteins relevant to diabetes mellitus- 11ß-hydroxysteroid dehydrogenase (11ß-HSD1), aldose reductase, glucokinase, glutamine-fructose-6-phosphate amidotransferase (GFAT), peroxisome proliferator-activated receptor-gamma (PPAR-gamma), and Sirtuin family of NAD(+)-dependent protein deacetylases 6 (SIRT6). A comparative study of the ABA-protein docked complex with already known inhibitors of these proteins relevant to diabetes was compared to explore the inhibitory potential. Calculation of molecular binding energy (ΔG), inhibition constant (pKi), and prediction of pharmacokinetics and pharmacodynamics properties were performed. The molecular docking investigation of ABA with 11-HSD1, GFAT, PPAR-gamma, and SIRT6 revealed considerably low binding energy (ΔG from -8.1 to -7.3 Kcal/mol) and predicted inhibition constant (pKi from 6.01 to 5.21 µM). The ADMET study revealed that ABA is a promising drug candidate without any hazardous effect following all current drug-likeness guidelines such as Lipinski, Ghose, Veber, Egan, and Muegge.


Assuntos
Abelmoschus/química , Ácido Abscísico/farmacologia , Diabetes Mellitus/metabolismo , Hipoglicemiantes/farmacologia , Proteínas/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Ácido Abscísico/química , Ácido Abscísico/metabolismo , Ácido Abscísico/farmacocinética , Aldeído Redutase/química , Aldeído Redutase/metabolismo , Simulação por Computador , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Glucoquinase/química , Glucoquinase/metabolismo , Glutamina/metabolismo , Glutamina-Frutose-6-Fosfato Transaminase (Isomerizante)/metabolismo , Quinase 3 da Glicogênio Sintase/química , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Hipoglicemiantes/química , Simulação de Acoplamento Molecular , PPAR gama/química , PPAR gama/metabolismo , Proteínas/química , Sirtuínas/química , Sirtuínas/metabolismo
17.
BMC Cancer ; 21(1): 1087, 2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34625031

RESUMO

BACKGROUND: Cancer remains one of the leading causes of death worldwide, despite the possibilities to detect early onset of the most common cancer types. The search for the optimal therapy is complicated by the cancer diversity within tumors and the unsynchronized development of cancerous cells. Therefore, it is necessary to characterize cancer cell populations after treatment has been applied, because cancer recurrence is not rare. In our research, we concentrated on small cancer cell subpopulation (microcells) that has a potential to be cancer resistance source. Previously made experiments has shown that these cells in small numbers form in specific circumstances after anticancer treatment. METHODS: In experiments described in this research, the anticancer agents' paclitaxel and doxorubicin were used to stimulate the induction of microcells in fibroblast, cervix adenocarcinoma, and melanoma cell lines. Mainly for the formation of microcells in melanoma cells. The drug-stimulated cells were then characterized in terms of their formation efficiency, morphology, and metabolic activity. RESULTS: We observed the development of cancer microcells and green fluorescent protein (GFP) transfection efficiency after stress. In the time-lapse experiment, we observed microcell formation through a renewal process and GFP expression in the microcells. Additionally, the microcells were viable after anticancer treatment, as indicated by the nicotinamide adenine dinucleotide hydrogen phosphate (NADPH) enzyme activity assay results. Taken together, these findings indicate that cancer microcells are viable and capable of resisting the stress induced by anticancer drugs, and these cells are prone to chemical substance uptake from the environment. CONCLUSION: Microcells are not only common to a specific cancer type, but can be found in any tumor type. This study could help to understand cancer emergence and recurrence. The appearance of microcells in the studied cancer cell population could be an indicator of the individual anticancer therapy effectiveness and patient survival.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Contagem de Células , Linhagem Celular Tumoral , Núcleo Celular/ultraestrutura , Autorrenovação Celular , Sobrevivência Celular/efeitos dos fármacos , Proteínas de Ligação a DNA/metabolismo , Doxorrubicina/farmacologia , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Feminino , Fibroblastos/efeitos dos fármacos , Proteínas de Fluorescência Verde/metabolismo , Células HeLa , Humanos , Indicadores e Reagentes/farmacocinética , Melanoma/metabolismo , Melanoma/patologia , Microscopia Eletrônica , NADP/metabolismo , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Neoplasias/metabolismo , Neoplasias/ultraestrutura , Vermelho Neutro/farmacocinética , Paclitaxel/farmacologia , Estresse Fisiológico , Imagem com Lapso de Tempo , Fatores de Transcrição/metabolismo , Transfecção , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia
18.
Sci Rep ; 11(1): 20191, 2021 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-34642409

RESUMO

A drug delivery system based on mesoporous particles MCM-41 was post-synthetically modified by photo-sensitive ligand, methyl-(2E)-3-(4-(triethoxysilyl)-propoxyphenyl)-2-propenoate (CA) and the pores of MCM-41 particles were loaded with Naproxen sodium salt (NAP). The CA was used as a photoactive molecule that can undergo a reversible photo-dimerization by [2π + 2π] cycloaddition when irradiated with UV light of specific wavelengths. Thus, it has a function of gate-keeper that is responsible for opening/closing the pores and minimizing premature release of NAP. The physicochemical properties of the prepared system were studied by infrared spectroscopy (IR), nitrogen adsorption measurements, thermogravimetric analysis (TGA), scanning transmission electron microscopy (STEM) and energy dispersive X-ray spectroscopy (EDX). The mechanism of the opening/closing pores was confirmed by UV measurements. In vitro and in vivo drug release experiments and the concentration of released NAP was determined by UV spectroscopy and high-performance liquid chromatography (HPLC). In vivo drug release in the blood circulatory system of rats has demonstrated the effective photo-cleavage reaction of CA molecules after UV-light stimulation. The localization and morphological changes of the particles were studied in the blood and liver of rats at different time intervals. The particles in the blood have been shown to retain their original rod-like shape, and the particles in the liver have been hydrolysed, which has resulted in spherical shape with a reduced size.


Assuntos
Portadores de Fármacos/química , Naproxeno , Dióxido de Silício/química , Animais , Liberação Controlada de Fármacos , Masculino , Naproxeno/administração & dosagem , Naproxeno/farmacocinética , Ratos , Ratos Wistar , Solubilidade
19.
Int J Mol Sci ; 22(19)2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34638992

RESUMO

Amyotrophic lateral sclerosis (ALS) is a disease with a resilient neuroinflammatory component caused by activated microglia and infiltrated immune cells. How to successfully balance neuroprotective versus neurotoxic actions through the use of anti-inflammatory agents is still under debate. There has been a boost of awareness regarding the role of extracellular ATP and purinergic receptors in modulating the physiological and pathological mechanisms in the nervous system. Particularly in ALS, it is known that the purinergic ionotropic P2X7 receptor plays a dual role in disease progression by acting at different cellular and molecular levels. In this context, we previously demonstrated that the P2X7 receptor antagonist, brilliant blue G, reduces neuroinflammation and ameliorates some of the pathological features of ALS in the SOD1-G93A mouse model. Here, we test the novel, noncommercially available, and centrally permeant Axxam proprietary P2X7 antagonist, AXX71, in SOD1-G93A mice, by assessing some behavioral and molecular parameters, among which are disease progression, survival, gliosis, and motor neuron wealth. We demonstrate that AXX71 affects the early symptomatic phase of the disease by reducing microglia-related proinflammatory markers and autophagy without affecting the anti-inflammatory markers or motor neuron survival. Our results suggest that P2X7 modulation can be further investigated as a therapeutic strategy in preclinical studies, and exploited in ALS clinical trials.


Assuntos
Esclerose Amiotrófica Lateral/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Autofagia/efeitos dos fármacos , Progressão da Doença , Antagonistas do Receptor Purinérgico P2X/uso terapêutico , Superóxido Dismutase/genética , Esclerose Amiotrófica Lateral/metabolismo , Animais , Anti-Inflamatórios/farmacocinética , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Atividade Motora/efeitos dos fármacos , Força Muscular/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2X/farmacocinética , Receptores Purinérgicos P2X/metabolismo
20.
Medicine (Baltimore) ; 100(42): e27550, 2021 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-34678890

RESUMO

RATIONALE: Thoracic endometriosis is a rare disorder that can involve airways, pleura and lung parenchyma. It is the most frequent form of extra-abdominopelvic endometriosis. Multiple lung cavitations are a rare feature of thoracic endometriosis. PATIENT CONCERNS: A 46-year-old woman was referred to our hospital after incidental finding of multiple pulmonary cavitations with surrounding areas of ground glass opacity on a thoraco-abdominal computed tomography-scan performed for abdominal pain. Retrospectively, the patient also reported mild hemoptysis occurring 4 months ago. DIAGNOSES: Positron emission tomography-computed tomography scan revealed moderate and homogeneous [18F] fluoro-2-deoxy-D-glucose (18F-FDG) uptake in pulmonary cavitations (maximum standardized uptake value 5.7). The diagnosis of thoracic endometriosis was confirmed by histological examination of surgical resection of a left lower lobe cavitation. INTERVENTIONS AND OUTCOME: Gonadotropin-releasing hormone analogues associated with add-back therapy was started. Four months after initiating pharmacological treatment, the chest computed tomography-scan showed a dramatic decrease in lung cavitations size. LESSONS: Thoracic endometriosis is a rare disorder requiring a multidisciplinary management including gynaecologist, pulmonologist, radiologist, nuclear physician, pathologist and thoracic surgeon for early diagnosis and treatment. Our case report highlights that an increased 18F-FDG uptake can be found in thoracic endometriosis syndrome presenting as multiple lung cavitations.


Assuntos
Endometriose/patologia , Pulmão/patologia , Endometriose/diagnóstico por imagem , Endometriose/cirurgia , Feminino , Fluordesoxiglucose F18/farmacocinética , Humanos , Pulmão/diagnóstico por imagem , Pulmão/cirurgia , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Compostos Radiofarmacêuticos/farmacocinética
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