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1.
Urol Clin North Am ; 47(1): 111-118, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31757294

RESUMO

Due to significant risks of cancer recurrence and progression, and limited options after intravesical Bacillus Calmette Guerin (BCG) therapy, there is a critical unmet need to identify novel treatments for those patients with BCG-unresponsive bladder cancer. There is active investigation of immunotherapies which provide both biologic and clinical rationales for indoleamine-2,3- dioxygenase inhibitors in salvage therapy for non-muscle invasive bladder cancer.


Assuntos
Acetamidas/administração & dosagem , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Oximas/administração & dosagem , Quinolinas/administração & dosagem , Terapia de Salvação/métodos , Sulfonamidas/administração & dosagem , Triptofano/análogos & derivados , Neoplasias da Bexiga Urinária/terapia , Administração Intravesical , Inibidores Enzimáticos/administração & dosagem , Humanos , Invasividade Neoplásica , Resultado do Tratamento , Triptofano/administração & dosagem , Triptofano Oxigenase , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/patologia
2.
Lakartidningen ; 1162019 Oct 01.
Artigo em Sueco | MEDLINE | ID: mdl-31573668

RESUMO

Prilocaine/lidocaine is widely used as local anesthetic in children for cannulation and minor surgical procedures. Usually it is unproblematic but it is important to adhere to recommended dose to avoid serious complications. Excessive amount of prilocaine/lidocaine, large application area, prolonged application time or repeated application can, especially in infants, cause methemoglobinemia with clinical symptoms. In severe cases intensive care and antidote treatment with Methylene blue may be required. We report three infants who were overdosed with prilocaine/lidocaine, two of them due to incorrect use after circumcision and one premature baby where prilocaine/lidocaine was not removed in time. Two of the babies had MetHb levels > 33% and were seriously affected with hypoxia, tachycardia and fatigue. After Methylene blue was given the infants recovered within 15 minutes and MetHb levels returned to normal.


Assuntos
Anestésicos Combinados/efeitos adversos , Anestésicos Locais/efeitos adversos , Combinação Lidocaína e Prilocaína/efeitos adversos , Metemoglobinemia/induzido quimicamente , Gasometria , Overdose de Drogas/complicações , Overdose de Drogas/tratamento farmacológico , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/uso terapêutico , Humanos , Recém-Nascido , Masculino , Metemoglobinemia/sangue , Metemoglobinemia/tratamento farmacológico , Azul de Metileno/administração & dosagem , Azul de Metileno/uso terapêutico
3.
Cancer Sci ; 110(10): 3275-3287, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31368616

RESUMO

p97/VCP is an endoplasmic reticulum (ER)-associated protein that belongs to the AAA (ATPases associated with diverse cellular activities) ATPase family. It has a variety of cellular functions including ER-associated protein degradation, autophagy, and aggresome formation. Recent studies have shown emerging roles of p97/VCP and its potential as a therapeutic target in several cancer subtypes including multiple myeloma (MM). We conducted a cell-based compound screen to exploit novel small compounds that have cytotoxic activity in myeloma cells. Among approximately 2000 compounds, OSSL_325096 showed relatively strong antiproliferative activity in MM cell lines (IC50 , 100-500 nmol/L). OSSL_325096 induced apoptosis in myeloma cell lines, including a bortezomib-resistant cell line and primary myeloma cells purified from patients. Accumulation of poly-ubiquitinated proteins, PERK, CHOP, and IREα, was observed in MM cell lines treated with OSSL_325096, suggesting that it induces ER stress in MM cells. OSSL_325096 has a similar chemical structure to DBeQ, a known p97/VCP inhibitor. Knockdown of the gene encoding p97/VCP induced apoptosis in myeloma cells, accompanied by accumulation of poly-ubiquitinated protein. IC50 of OSSL_325096 to myeloma cell lines were found to be lower (0.1-0.8 µmol/L) than those of DBeQ (2-5 µmol/L). In silico protein-drug-binding simulation suggested possible binding of OSSL_325096 to the ATP binding site in the D2 domain of p97/VCP. In cell-free ATPase assays, OSSL_325096 showed dose-dependent inhibition of p97/VCP ATPase activity. Finally, OSSL_325096 inhibited the growth of subcutaneous myeloma cell tumors in vivo. The present data suggest that OSSL_325096 exerts anti-myeloma activity, at least in part through p97/VCP inhibition.


Assuntos
Adenosina Trifosfatases/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Inibidores Enzimáticos/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Proteínas Nucleares/metabolismo , Bibliotecas de Moléculas Pequenas/administração & dosagem , Adenosina Trifosfatases/antagonistas & inibidores , Adenosina Trifosfatases/química , Animais , Sítios de Ligação , Bortezomib/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático , Endorribonucleases/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Camundongos , Modelos Moleculares , Mieloma Múltiplo/metabolismo , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/química , Proteínas Serina-Treonina Quinases/metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Fator de Transcrição CHOP/metabolismo , Ubiquitinação , Ensaios Antitumorais Modelo de Xenoenxerto , eIF-2 Quinase/metabolismo
4.
Chem Pharm Bull (Tokyo) ; 67(8): 824-838, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31366832

RESUMO

We synthesized and evaluated novel 5-[2-(thiophen-2-yl)propan-2-yl]-4H-1,2,4-triazole derivatives as 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibitors. Optimization of the thiophene ring and the substituents on the 1,2,4-triazole ring produced 3,4-dicyclopropyl-5-{2-[3-fluoro-5-(trifluoromethyl)thiophen-2-yl]propan-2-yl}-4H-1,2,4-triazole monohydrochloride (9a), which showed potent and selective inhibitory activity against human 11ß-HSD1. Compound 9a was also metabolically stable against human and mouse liver microsomes. Oral administration of 9a to diabetic ob/ob mice lowered corticosterone levels in adipose tissue, and thereby reduced plasma glucose and insulin levels in a dose-dependent manner.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Diabetes Mellitus Tipo 2/tratamento farmacológico , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Hipoglicemiantes/farmacologia , Triazóis/farmacologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Administração Oral , Animais , Diabetes Mellitus Tipo 2/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Células HEK293 , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/química , Masculino , Camundongos , Camundongos Obesos , Estrutura Molecular , Relação Estrutura-Atividade , Triazóis/administração & dosagem , Triazóis/química
5.
Cancer Sci ; 110(10): 3306-3314, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31361380

RESUMO

Isocitrate dehydrogenase 2 (IDH2), an important mitochondrial metabolic enzyme involved in the tricarboxylic acid cycle, is mutated in a variety of cancers. AG-221, an inhibitor primarily targeting the IDH2-R140Q mutant, has shown remarkable clinical benefits in the treatment of relapsed or refractory acute myeloid leukemia patients. However, AG-221 has weak inhibitory activity toward IDH2-R172K, a mutant form of IDH2 with more severe clinical manifestations. Herein, we report TQ05310 as the first mutant IDH2 inhibitor that potently targets both IDH2-R140Q and IDH2-R172K mutants. TQ05310 inhibited mutant IDH2 enzymatic activity, suppressed (R)-2-hydroxyglutarate (2-HG) production and induced differentiation in cells expressing IDH2-R140Q and IDH2-R172K, but not in cells expressing wild-type IDH1/2 or mutant IDH1. TQ05310 bound to both IDH2-R140Q and IDH2-R172K, with Q316 being the critical residue mediating the binding of TQ05310 with IDH2-R140Q, but not with IDH2-R172K. TQ05310 also had favorable pharmacokinetic characteristics and profoundly inhibited 2-HG production in a tumor xenografts model. The results of the current study establish a solid foundation for further clinical investigation of TQ05310, and provide new insight into the development of novel mutant IDH2 inhibitors.


Assuntos
Substituição de Aminoácidos , Inibidores Enzimáticos/administração & dosagem , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Neoplasias/tratamento farmacológico , Animais , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Feminino , Células HEK293 , Humanos , Isocitrato Desidrogenase/antagonistas & inibidores , Isocitrato Desidrogenase/química , Camundongos , Modelos Moleculares , Simulação de Acoplamento Molecular , Neoplasias/genética , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Rinsho Shinkeigaku ; 59(7): 418-424, 2019 Jul 31.
Artigo em Japonês | MEDLINE | ID: mdl-31243247

RESUMO

A 76-year-old man, diagnosed with chronic myeloid leukemia in 2010, had been on nilotinib for 7 years. He presented with right hemiparesis in September 2017. He had no history of hypertension, diabetes, hyperlipidemia, heart disease, or smoking. Brain MRI revealed a border-zone infarction of the left cerebral hemisphere and a rapidly progressing severe left internal carotid artery (ICA) stenosis. He was initiated on clopidogrel and bosutinib instead of nilotinib. He presented with right hemiparesis once again in December 2017. Brain MRI revealed the border-zone infarction of the left cerebral hemisphere and a more progressed, severe bilateral ICA stenosis. A carotid ultrasound demonstrated iso-intense and concentrically narrowed ICA on both sides. Carotid artery stenting of the left ICA was performed in February 2018, and clopidogrel was replaced by cilostazol to provide a drug-induced rush. Carotid artery stenting of the right ICA was performed in June 2018 and cervical angiogram demonstrated that there were no residual artery stenoses in the bilateral stent. In recent years, several case reports suggest that tyrosine kinase inhibitors (TKIs) are associated with progressive artery stenosis and cause cerebral infarction. Brain imaging tests should be conducted to evaluate arterial stenosis progression for patients with a history of taking TKI when an arterial vascular event occurs.


Assuntos
Compostos de Anilina/administração & dosagem , Compostos de Anilina/efeitos adversos , Infarto Cerebral/induzido quimicamente , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Nitrilos/administração & dosagem , Nitrilos/efeitos adversos , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos , Administração Oral , Idoso , Artéria Carótida Interna , Estenose das Carótidas/induzido quimicamente , Estenose das Carótidas/cirurgia , Infarto Cerebral/diagnóstico por imagem , Clopidogrel/administração & dosagem , Imagem de Difusão por Ressonância Magnética , Humanos , Masculino , Recidiva , Stents
7.
AAPS PharmSciTech ; 20(5): 218, 2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31187334

RESUMO

The aim of this study was to develop a self-microemulsifying drug delivery system (SMEDDS) for enhancement of the oral bioavailability of isoliquiritigenin (ISL) as well as evaluate its in vivo anti-hyperuricemic effect in rats. The ISL-loaded self-microemulsifying drug delivery system (ISL-SMEDDS) was comprised of ethyl oleate (EO, oil phase), Tween 80 (surfactant), and PEG 400 (co-surfactant). The ISL-SMEDDS exhibited an acceptable narrow size distribution (44.78 ± 0.35 nm), negative zeta potential (- 10.67 ± 0.86 mV), and high encapsulation efficiency (98.17 ± 0.24%). The in vitro release study indicated that the release rates of the formulation were obviously higher in different release media (HCl, pH 1.2; PBS, pH 6.8; double-distilled water, pH 7.0) compared with the ISL solution. The oral bioavailability of the ISL-SMEDDS was enhanced by 4.71 times in comparison with the free ISL solution. More importantly, ISL-SMEDDS significantly reduced uric acid level by inhibiting xanthine oxidase (XOD) activity in the model rats. Collectively, the prepared ISL-SMEDDS proved to be potential carriers for enhancing the solubility and oral bioavailability of ISL, as well as ameliorating its anti-hyperuricemic effect.


Assuntos
Chalconas/administração & dosagem , Chalconas/sangue , Sistemas de Liberação de Medicamentos/métodos , Hiperuricemia/sangue , Hiperuricemia/tratamento farmacológico , Administração Oral , Animais , Disponibilidade Biológica , Emulsões , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/sangue , Masculino , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/metabolismo , Ratos , Ratos Sprague-Dawley , Solubilidade , Tensoativos/administração & dosagem , Tensoativos/metabolismo
8.
Food Chem Toxicol ; 131: 110535, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31154083

RESUMO

This study endeavours to investigate the phytochemical composition, biological properties and in vivo toxicity of methanol and dichloromethane extracts of Zaleya pentandra (L.) Jeffrey. Total bioactive contents, antioxidant (phosphomolybdenum and metal chelating, DPPH, ABTS, FRAP and CUPRAC) and enzyme inhibition (cholinesterases, tyrosinase α-amylase, and α-glucosidase) potential were assessed utilizing in vitro bioassays. UHPLC-MS phytochemical profiling was carried out to identify the essential compounds. The methanol extract was found to contain highest phenolic (22.60 mg GAE/g) and flavonoid (31.49 mg QE/g) contents which correlate with its most significant radical scavenging, reducing potential and tyrosinase inhibition. The dichloromethane extract was most potent for phosphomolybdenum, ferrous chelation, α-amylase, α-glucosidase, and cholinesterase inhibition assays. UHPLC-MS analysis of methanol extract unveiled to identify 11 secondary metabolites belonging to five sub-groups, i.e., phenolic, alkaloid, carbohydrate, terpenoid, and fatty acid derivatives. Additionally, in vivo toxicity was conducted for 21 days and the methanol extract at different doses (150, 200, 250 and 300 mg/kg) was administered in experimental chicks divided into five groups each containing five individuals. Different physical, haematological and biochemical parameters along with the absolute and relative weight of visceral body organs were studied. Overall, no toxic effect was noted for the extract at tested doses.


Assuntos
Aizoaceae/química , Extratos Vegetais/farmacologia , Extratos Vegetais/toxicidade , Administração Oral , Animais , Galinhas , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/toxicidade , Depuradores de Radicais Livres/administração & dosagem , Depuradores de Radicais Livres/química , Depuradores de Radicais Livres/farmacologia , Depuradores de Radicais Livres/toxicidade , Metanol/química , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química
9.
J Agric Food Chem ; 67(22): 6202-6211, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31091873

RESUMO

Allopurinol is the first-line medication for hyperuricemia treatment. However, severe drug-related adverse effects have often been reported among patients who received allopurinol administration. This study is aimed at evaluating the possible attenuation effects of highly acylated anthocyanins from purple sweet potato (HAA-PSP) on hyperuricemia and kidney inflammation in hyperuricemic mice treated with allopurinol. In comparison with 5 mg kg-1 allopurinol used alone, the combination of 25 mg kg-1 HAA-PSP and 2.5 mg kg-1 allopurinol could not only reduce serum uric acid level in hyperuricemic mice but also attenuate the kidney damage, as indicated by the level of serum biomarkers as well as histopathological examination. The inflammatory response was partially mitigated by inhibiting the protein expression of typical cytokines in the kidney. Our findings provide new evidence for the supplementary therapeutic potential of HAA-PSP with allopurinol on hyperuricemia and inflammation-related syndromes. Moreover, this study provides a theoretical basis for assessing the potential of anthocyanin-rich foods in health.


Assuntos
Antocianinas/administração & dosagem , Antocianinas/química , Hiperuricemia/tratamento farmacológico , Ipomoea batatas/química , Rim/imunologia , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Acilação , Alopurinol/administração & dosagem , Alopurinol/química , Animais , Modelos Animais de Doenças , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Humanos , Hiperuricemia/sangue , Hiperuricemia/imunologia , Rim/efeitos dos fármacos , Masculino , Camundongos , Ácido Úrico/sangue
10.
Emerg Microbes Infect ; 8(1): 624-636, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30999821

RESUMO

Flaviviruses are (re)-emerging RNA viruses strictly dependent on lipid metabolism for infection. In the search for host targeting antivirals, we explored the effect of pharmacological modulation of fatty acid metabolism during flavivirus infection. Considering the central role of acetyl-Coenzyme A carboxylase (ACC) on fatty acid metabolism, we analyzed the effect of three small-molecule ACC inhibitors (PF-05175157, PF-05206574, and PF-06256254) on the infection of medically relevant flaviviruses, namely West Nile virus (WNV), dengue virus, and Zika virus. Treatment with these compounds inhibited the multiplication of the three viruses in cultured cells. PF-05175157 induced a reduction of the viral load in serum and kidney in WNV-infected mice, unveiling its therapeutic potential for the treatment of chronic kidney disease associated with persistent WNV infection. This study constitutes a proof of concept of the reliability of ACC inhibitors to become viable antiviral candidates. These results support the repositioning of metabolic inhibitors as broad-spectrum antivirals.


Assuntos
Acetil-CoA Carboxilase/antagonistas & inibidores , Vírus da Dengue/fisiologia , Dengue/enzimologia , Inibidores Enzimáticos/administração & dosagem , Febre do Nilo Ocidental/enzimologia , Vírus do Nilo Ocidental/fisiologia , Infecção por Zika virus/enzimologia , Zika virus/fisiologia , Acetil-CoA Carboxilase/metabolismo , Animais , Antivirais/administração & dosagem , Dengue/tratamento farmacológico , Dengue/virologia , Vírus da Dengue/efeitos dos fármacos , Vírus da Dengue/genética , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Replicação Viral/efeitos dos fármacos , Febre do Nilo Ocidental/tratamento farmacológico , Febre do Nilo Ocidental/virologia , Vírus do Nilo Ocidental/efeitos dos fármacos , Vírus do Nilo Ocidental/genética , Zika virus/efeitos dos fármacos , Zika virus/genética , Infecção por Zika virus/tratamento farmacológico , Infecção por Zika virus/virologia
11.
Drug Des Devel Ther ; 13: 757-766, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30863015

RESUMO

Purpose: Hormone-dependent breast cancer is the most common form of breast cancer, and inhibiting 17ß-HSD1 can play an attractive role in decreasing estrogen and cancer cell proliferation. However, the majority of existing inhibitors have been developed from estrogens and inevitably possess residual estrogenicity. siRNA knockdown provides a highly specific way to block a targeted enzyme, being especially useful to avoid estrogenicity. Application of 17ß-HSD1-siRNA in vivo is limited by the establishment of an animal model, as well as the potential nuclease activity in vivo. We tried to reveal the in vivo potential of 17ß-HSD1-siRNA-based breast cancer therapy. Materials and methods: To establish a competent animal model, daily subcutaneous injection of an estrone micellar aqueous solution was adopted to provide the substrate for estradiol biosynthesis. The effects of three different doses of estrone (0.1, 0.5, and 2.5 µg/kg/day) on tumor growth in T47D-17ß-HSD1-inoculated group were investigated and compared with the animals inoculated with wild type T47D cells. To solve in vivo delivery problem of siRNA, "17ß-HSD1-siRNA/LPD", a PEGylated and modified liposome-polycation-DNA nanoparticle containing 17ß-HSD1-siRNA was prepared by the thin film hydration method and postinsertion technology. Finally, "17ß-HSD1-siRNA/LPD" was tested in the optimized model. Tumor growth and 17ß-HSD1 expression were assessed. Results: Comparison with the untreated group revealed significant suppression of tumor growth in "17ß-HSD1-siRNA/LPD"-treated group when HSD17B1 gene expression was knocked down. Conclusion: These findings showed promising in vivo assessments of 17ß-HSD1-siRNA candidates. This is the first report of an in vivo application of siRNA for steroid-converting enzymes in a nude mouse model.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Estradiol Desidrogenases/antagonistas & inibidores , RNA Interferente Pequeno/farmacologia , Animais , Antineoplásicos/administração & dosagem , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/administração & dosagem , Estradiol Desidrogenases/metabolismo , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , RNA Interferente Pequeno/administração & dosagem , Relação Estrutura-Atividade , Células Tumorais Cultivadas
12.
Ecotoxicol Environ Saf ; 173: 142-148, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-30771657

RESUMO

Microcystin-LR (MC-LR) is the most toxic and abundant microcystin that produced by cyanobacteria. Previous studies have shown MC-LR had acute toxic to thyroid, however, the mechanism is still unclear, and the effect of long-term, low-dose MC-LR on thyroid remains uncertain. In this study, we investigated the chronic, low-dose effect of MC-LR on mouse thyroid tissues and thyroid hormone metabolism. MC-LR was orally administered to mice at 0, 1, 10, 20 and 40 µg/L for 6 consecutive months for histopathological and immunoblot analysis. Nthy-ori 3-1 cells were cultured in various concentrations of MC-LR (0, 0.5, 5, 50, 500 nmol/L) for indicated time, meanwhile the cell viability and proteins change were tested. From our study, the chronic, low-dose MC-LR exposure can disturb thyroid hormone synthesis and metabolism through activating the p38/MAPK and MEK/ERK signaling pathways, then up-regulating the expression of type 3 deiodinase. These data support the potential toxic effects of MC-LR on thyroid tissue and thyroid hormone metabolism.


Assuntos
Inibidores Enzimáticos/toxicidade , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Microcistinas/toxicidade , Hormônios Tireóideos/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Linhagem Celular , Inibidores Enzimáticos/administração & dosagem , Feminino , Humanos , Iodeto Peroxidase/genética , Camundongos Endogâmicos BALB C , Microcistinas/administração & dosagem , Glândula Tireoide/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
13.
Pain ; 160(4): 945-953, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30730862

RESUMO

A study published in PAIN in 2010 showed remarkable effects of intradiscal methylene blue (MB) injections compared with placebo on pain intensity in patients with chronic discogenic low back pain (CD-LBP). Both groups received lidocaine hydrochloride injections for pain associated with the procedure. We replicated the design of the previously published study and performed a multicenter, double-blind, randomized, placebo-controlled trial to assess whether the extraordinary effects of MB on pain intensity could be confirmed. The primary outcomes were treatment success defined as at least 30% reduction in pain intensity and the Patients' Global Impression of Change 6 months after the intervention. We included 84 patients with CD-LBP of which 14 (35%) in the MB plus lidocaine group showed treatment success compared with 11 (26.8%) in the control group who received placebo plus lidocaine (P = 0.426). Twenty-seven percent of all participants treated with MB stated that their overall health improved much or very much (Patients' Global Impression of Change), vs 25.6% in the placebo group (P = 0.958). We were unable to confirm that intradiscal MB injections are better capable of significantly reducing pain in patients with CD-LBP 6 months after treatment compared with placebo. We observed that over one-quarter of patients receiving only lidocaine injections reported treatment success, which is in contrast with the previously published study. Our results do not support the recommendation of using intradiscal MB injections for patients with CD-LBP.


Assuntos
Inibidores Enzimáticos/administração & dosagem , Disco Intervertebral/fisiologia , Dor Lombar/tratamento farmacológico , Azul de Metileno/administração & dosagem , Adulto , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Disco Intervertebral/efeitos dos fármacos , Deslocamento do Disco Intervertebral/complicações , Dor Lombar/etiologia , Dor Lombar/psicologia , Masculino , Pessoa de Meia-Idade , Medição da Dor , Qualidade de Vida/psicologia , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento
14.
MBio ; 10(1)2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30782662

RESUMO

Primary effusion lymphoma (PEL) is caused by Kaposi's sarcoma-associated herpesvirus (KSHV). PEL has a highly active mTOR pathway, which makes mTOR a potential therapeutic target. MLN0128 is an ATP-competitive inhibitor of mTOR that has entered clinical trials for solid tumors. Our results demonstrated that MLN0128 has a greater effect on inhibiting proliferation than the allosteric mTOR inhibitor rapamycin. MLN0128 has ∼30 nM 50% inhibitory concentration (IC50) across several PEL cell lines, including PEL that is resistant to conventional chemotherapy. MLN0128 induced apoptosis in PEL, whereas rapamycin induced G1 arrest, consistent with a different mechanism of action. MLN0128 inhibited phosphorylation of mTOR complex 1 and 2 targets, while rapamycin only partially inhibited mTOR complex 1 targets. PEL xenograft mouse models treated with MLN0128 showed reduced effusion volumes in comparison to the vehicle-treated group. Rapamycin-resistant (RR) clones with an IC50 for rapamycin 10 times higher than the parental IC50 emerged consistently after rapamycin exposure as a result of transcriptional adaptation. MLN0128 was nevertheless capable of inducing apoptosis in these RR clones. Our results suggest that MLN0128 might offer a new approach to the treatment of chemotherapy-resistant PEL.IMPORTANCE Primary effusion lymphoma (PEL) is an aggressive and incurable malignancy, which is usually characterized by lymphomatous effusions in body cavities without tumor masses. PEL has no established treatment and a poor prognosis, with a median survival time shorter than 6 months. PEL usually develops in the context of immunosuppression, such as HIV infection or post-organ transplantation. The optimal treatment for PEL has not been established, as PEL is generally resistant to traditional chemotherapy. The molecular drivers for PEL are still unknown; however, PEL displays a constitutively active mammalian target of rapamycin (mTOR) pathway, which is critical for metabolic and cell survival mechanisms. Therefore, the evaluation of novel agents targeting the mTOR pathway could be clinically relevant for the treatment of PEL.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Benzoxazóis/farmacologia , Inibidores Enzimáticos/farmacologia , Linfoma de Efusão Primária/tratamento farmacológico , Pirimidinas/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Antibióticos Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Benzoxazóis/administração & dosagem , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Modelos Animais de Doenças , Inibidores Enzimáticos/administração & dosagem , Xenoenxertos , Humanos , Concentração Inibidora 50 , Linfoma de Efusão Primária/patologia , Camundongos , Transplante de Neoplasias , Pirimidinas/administração & dosagem , Sirolimo/administração & dosagem , Sirolimo/farmacologia , Resultado do Tratamento
15.
J Agric Food Chem ; 67(5): 1429-1436, 2019 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-30628451

RESUMO

The aim of this work was to determine bioavailability and in vivo calmodulin-dependent-phosphodiesterase (CaMPDE)-inhibitory activity of six flaxseed-protein-derived peptides (AGA, AKLMS, QIAK, RWIQ, QQAKQ, and KQLSTGC) after oral administration to Wistar rats. Initial experiments tested the cytotoxicity and cellular-transport potentials of the peptides using Caco-2 cells. The cytotoxicity assay indicated that none of the six peptides had an adverse effect on the proliferation and viability of the Caco-2 cells, whereas the transport assay confirmed peptide translocation across the cell membrane. However, only two of the peptides (AGA and RWIQ) were detected in the rat serum up to 90 min postgavage, with traces of RWIQ persisting in serum 1 week after oral gavage. The six peptides inhibited plasma activity of CaMPDE with AGA (34.63%), QIAK (36.66%), and KQLSTGC (34.21%) being the most effective 30 min after gavage. In contrast, only AGA maintained significant plasma-CaMPDE-activity inhibition (44.35%) after 60 min.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/antagonistas & inibidores , Inibidores Enzimáticos/química , Linho/química , Peptídeos/química , Animais , Disponibilidade Biológica , Transporte Biológico , Células CACO-2 , Proliferação de Células/efeitos dos fármacos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/metabolismo , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Feminino , Linho/genética , Humanos , Masculino , Mapeamento de Peptídeos , Peptídeos/administração & dosagem , Peptídeos/efeitos adversos , Ratos , Ratos Wistar
16.
Zoo Biol ; 38(2): 214-219, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30653720

RESUMO

Housing bachelor groups is a necessary aspect of the care and husbandry of non-breeding individuals in zoological collections. Intraspecific aggressive behaviors may occur in this setting despite management strategies designed to mitigate these behaviors. Androgens (including testosterone) are associated with aggression in male species and interventional techniques to alter the animals' physiology to modify aggressive behavior are sometimes required. When agonistic behavior and physical aggression in two mature male Amur leopards housed together at Tayto Park escalated, despite all strategic management involvements, further intervention to moderate aggression was required. The gonadotropin-releasing hormone (GnRH) agonist, deslorelin, has been found to be effective in reducing androgens in domestic and non-domestic carnivores. We hypothesized that deslorelin's suppressive effect on hypothalamic-pituitary-gonadal axis would mitigate intraspecific aggression in two male intact leopards. Behavioral observations were carried out pre- and post-implant implantation of 9.4 mg deslorelin implant. The frequency of agonistic/aggressive behaviors for both leopards declined significantly (p < 0.05), as did marking behaviors post-implantation (p < 0.001). The insertion of deslorelin implants in two male intact leopards demonstrating increased frequency and severity of aggressive behaviors resulted in a reduction of the frequency of these behaviors. Deslorelin implantation should be considered for management of interspecific aggression of intact male leopards in bachelor groups.


Assuntos
Agressão/efeitos dos fármacos , Animais de Zoológico , Hormônio Liberador de Gonadotropina/agonistas , Panthera/fisiologia , Pamoato de Triptorrelina/análogos & derivados , Animais , Implantes de Medicamento , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Masculino , Pamoato de Triptorrelina/administração & dosagem , Pamoato de Triptorrelina/farmacologia
17.
Protein Pept Lett ; 26(3): 215-220, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30678610

RESUMO

BACKGROUND: Paraoxonase (PON; arilesterase, [EC 3.1.8.1]) is an enzyme from the group arilesterases (ARE). This enzyme is capable of hydrolyzing paraoxone which is the active metabolite of parathion, an organic phosphorus insecticide. PON activity was found to be low in individuals prone to development of atherosclerosis such as diabetes, familial hypercholesterolemia and kidney disorders. It was noted that PON enzyme activity decreases in relation to age increase in adults. PON enzyme activity is approximately half of that in newborns and premature babies. Approximately one year after birth, it reaches the adult level. It can be said that PON1 has significant role on living organisms. For this reason, many studies on interactions of PON-drugs are needed. OBJECTIVE: In this article, our aim is to investigate in vitro effects of four pharmaceutically active agents (fosfomycin, cefuroxime axetil, cefaclor monohydrate, and cefixime) which are often used in patients after surgery on human serum paraoxanase-I (PON1) enzyme activity. METHODS: In this article, we purify paraoxonase-I enzyme from human serum by using ammonium sulfate precipitation (in the range of 60-80%), ion exchange and gel filtration chromatography. We use electrophoresis to check the purity of the enzyme. We investigate the paraoxonase activity of the enzyme at 412 nm the inhibition effects of the active substances. Paraoxone is used as the substrate. Activity measurements arw made at different inhibitor concentrations related to inhibitor studies and % Activity- [I] graphs are drawn for drug active substances. Lineweaver-Burk graphics are used to determine the Ki constants. Finally, to determine the types of inhibition we interpret these graphs. RESULTS: The active agents used after surgery decreased the PON1 enzyme activity. They showed different inhibition mechanism. The inhibition mechanism of fosfomycin and cefaclor monohydrate was noncompetitive, cefixime was uncompetitive and cefuroxime axetil was a competitive inhibitor. The IC50 values for fosfomycin, cefuroxime axetil, cefaclor monohydrate, and cefixime were calculated to be 31.5 mM, 1.03 mM, 4.18 mM and 0.781 mM, respectively, and the Ki constants were determined to be 27.98 ± 12.25 mM, 2.20 ± 0.22 mM, 4.81 ± 2.25 mM and 1.12 ± 0.32 mM, respectively. The IC50 and Ki values showed that cefixime active agent has the maximum inhibition. CONCLUSION: In this study, we have detected that cefuroxime axetil inhibited competitively in vitro paraoxonase activity of this enzyme. According to this information, we thought that cefuroxime axetil linked to the active site of the enzyme. Fosfomycin and cefaclor monohydrate can be attached with amino acids out of the active site of the enzyme because they inhibit enzyme noncompetitively. Cefixime can be attached only to the enzyme-substrate complex because it inhibits enzyme uncompetitively.


Assuntos
Antibacterianos , Arildialquilfosfatase , Inibidores Enzimáticos , Procedimentos Cirúrgicos Operatórios , Antibacterianos/administração & dosagem , Antibacterianos/química , Arildialquilfosfatase/antagonistas & inibidores , Arildialquilfosfatase/sangue , Arildialquilfosfatase/química , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Feminino , Humanos , Masculino
18.
Neuropathology ; 39(2): 71-77, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30632221

RESUMO

MYC amplification is common in Group 3 medulloblastoma and is associated with poor survival. Group 3 and Group 4 medulloblastomas are also known to have elevated levels of histone H3-lysine 27-tri-methylation (H3K27me3), at least in part due to high expression of the H3K27 methyltransferase enhancer of zest homologue 2 (EZH2), which can be regulated by MYC. We therefore examined whether MYC expression is associated with elevated EZH2 and H3K27me3 in medulloblastoma, and if high-MYC medulloblastomas are particularly sensitive to pharmacological EZH2 blockade. Western blot analysis of low (DAOY, UW228, CB SV40) and high (DAOY-MYC, UW228-MYC, CB-MYC, D425) MYC cell lines showed that higher levels of EZH2 and H3K27me3 were associated with elevated MYC. In fixed medulloblastoma samples examined using immunohistochemistry, most MYC positive tumors also had high H3K27me3, but many MYC negative ones did as well, and the correlation was not statistically significant. All high MYC lines tested were sensitive to the EZH2 inhibitor EPZ6438. Many low MYC lines also grew more slowly in the presence of EPZ6438, although DAOY-MYC cells responded more strongly than parent DAOY cultures with lower MYC levels. We find that higher MYC levels are associated with increased EZH2, and pharmacological blockade of EZH2 is a potential therapeutic strategy for aggressive medulloblastoma with elevated MYC.


Assuntos
Neoplasias Cerebelares/enzimologia , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Inibidores Enzimáticos/administração & dosagem , Meduloblastoma/enzimologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias Cerebelares/tratamento farmacológico , Técnicas de Silenciamento de Genes , Humanos , Meduloblastoma/tratamento farmacológico
19.
J Cardiothorac Vasc Anesth ; 33(5): 1301-1307, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30606508

RESUMO

OBJECTIVE: To compare the efficacy of methylene blue with combination therapy with hydroxocobalamin in patients experiencing vasoplegic syndrome after cardiac surgery. DESIGN: Retrospective cohort study. SETTING: Tertiary medical center. PARTICIPANTS: Patients who received methylene blue with or without hydroxocobalamin for refractory vasoplegic syndrome rescue therapy. MEASUREMENTS AND MAIN RESULTS: The primary outcome was 0.the ability to maintain mean arterial pressure (MAP) >60 mmHg beyond 1hour after study drug administration. Other pertinent outcomes included MAP at hours 6, 12, and 24 post-administration; both raw and proportional changes of vasopressor doses from baseline at hours 1, 6, 12, and 24 post-administration; and change in pulmonary artery catheter hemodynamics. Overall, 28 doses were administered in 14 patients in the monotherapy group and 17 doses (10 methylene blue, 7 hydroxocobalamin) were administered in 6 patients in the combination therapy group. There were no differences in ability to maintain MAP at 1hour, with 71% of the monotherapy and 82% of combination therapy patients meeting MAP goals (p = 0.49). Pairwise comparisons demonstrated vasopressor reductions at 6, 12, and 24hours in both groups, but only significant reductions at 1hour were observed in the combination therapy group (-0.06 µg/kg/min; p = 0.003) but not in the monotherapy group (-0.015 µg/kg/min; p = 0.14). CONCLUSION: This is the first study to compare methylene blue monotherapy with combination therapy, which suggests there may be an advantage to combination therapy. Further characterization of ideal dosing, timing, and agent selection should be investigated on a larger scale format.


Assuntos
Hidroxocobalamina/administração & dosagem , Azul de Metileno/administração & dosagem , Vasoconstritores/administração & dosagem , Vasoplegia/tratamento farmacológico , Vasoplegia/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Quimioterapia Combinada , Inibidores Enzimáticos/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Vasoplegia/diagnóstico , Complexo Vitamínico B/administração & dosagem
20.
Biomed Pharmacother ; 109: 708-715, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30551523

RESUMO

Hyperglycemia invoke number of pathways resulting in development of diabetic retinopathy (DR), including protein kinase C activation, increased expression of VEGF, advanced glycation end product (AGEs) formation and activation of polyol pathway, among which the pathophysiology of aldose reductase (ALR2) of the polyol pathway is evident by more than a decade of research. Subtle involvement of ALR2 in invoking various pathways of diabetic complications has caused an increase in attention towards the identification of novel aldose reductase inhibitors (ARIs). Numerous ARIs of different classes were employed in the treatment of diabetic complications initially, but few came into light as drugs. Though no ALR2 inhibitor has been used for the treatment or control of DR, Epalrestat has been used worldwide for treating diabetic neuropathy. This review critically analyses different treatments available for diabetic retinopathy, their limitations and the importance of the development of novel inhibitors of ALR2 that could prevent progression of DR, by causing a direct or indirect effect on controlling factors associated with DR.


Assuntos
Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Aldeído Redutase/antagonistas & inibidores , Aldeído Redutase/metabolismo , Animais , Sistemas de Liberação de Medicamentos/tendências , Inibidores Enzimáticos/administração & dosagem , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , PPAR gama/agonistas , PPAR gama/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Resultado do Tratamento
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