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1.
Medicine (Baltimore) ; 99(52): e23453, 2020 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-33350727

RESUMO

BACKGROUND: Bronchial asthma (BA) is a chronic airway inflammatory disease with reversible airflow limitation as the main clinical manifestations, such as wheezing, cough, shortness of breath, chest tightness, etc, mediated by a variety of inflammatory cells, which can be recurrent. Clinical can improve symptoms, but cannot be cured; glucocorticoid is the most important first-line medication. Clinical practice has shown that montelukast sodium combined with fluticasone in the treatment of adult BA can improve clinical efficacy and reduce adverse reactions. The purpose of this study is to systematically study the efficacy and safety of montelukast sodium combined with fluticasone in the treatment of adult BA. METHODS: The Chinese databases (CNKI, VIP, Wanfang, Chinese Biomedical Database) and English databases (PubMed, the Cochrane Library, Embase, Web of Science) were searched by computer, for the randomized controlled clinical studies of montelukast sodium combined with fluticasone in the treatment of adult BA from establishment of database to October 2020. Two researchers independently extracted the relevant data and evaluated the quality of the literatures, and used RevMan5.3 software to conduct meta-analyze of the included literatures. RESULTS: This study assessed the efficacy and safety of montelukast sodium combined with fluticasone in the treatment of adult BA through total effective rate, pulmonary function (FEV1, FVC, PEF, FEV1/FVC), and adverse reactions. CONCLUSION: This study will provide reliable evidence-based evidence for the clinical application of montelukast sodium combined with fluticasone in the treatment of adult BA. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/CKQFM.


Assuntos
Acetatos/administração & dosagem , Antiasmáticos/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Asma/tratamento farmacológico , Ciclopropanos/administração & dosagem , Fluticasona/administração & dosagem , Metanálise como Assunto , Quinolinas/administração & dosagem , Projetos de Pesquisa , Sulfetos/administração & dosagem , Revisões Sistemáticas como Assunto/métodos , Acetatos/efeitos adversos , Adulto , Antiasmáticos/efeitos adversos , Anti-Inflamatórios/efeitos adversos , Ciclopropanos/efeitos adversos , Combinação de Medicamentos , Fluticasona/efeitos adversos , Humanos , Quinolinas/efeitos adversos , Sulfetos/efeitos adversos , Resultado do Tratamento
2.
Life Sci ; 256: 117855, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32473245

RESUMO

OBJECTIVE: Subjects with type 2 diabetes (T2D) have lower circulating hydrogen sulfide (H2S) levels following myocardial ischemia and a higher risk of mortality. The aim of this study was to determine the dose-dependent favorable effects of sodium hydrosulfide (NaSH) on myocardial ischemia-reperfusion (IR) injury in rats with T2D. METHODS: T2D was induced using a high-fat diet (HFD) and low-dose of streptozotocin. Rats were divided into control, T2D, and T2D + NaSH groups. NaSH (0.28, 0.56, 1.6, 2.8, and 5.6 mg/kg) was administered intraperitoneally for 9 weeks. At the end of the study, heart from all rats were isolated and left ventricular developed pressure (LVDP) and the peak rates of positive and negative changes in LV pressure (±dp/dt) were recorded during baseline and following myocardial IR injury. In addition, infarct size as well as mRNA expression of H2S- and nitric oxide (NO)-producing enzymes were measured. RESULTS: In diabetic rats, NaSH only at doses of 0.56 and 1.6 mg/kg increased recovery of LVDP (16% and 42%), +dp/dt (25% and 35%) and -dp/dt (23% and 32%) as well as decreased infarct size (44% and 35%). At these doses, NaSH increased expressions of cystathionine γ-lyase (CSE) (440% and 271%) and endothelial NO synthase (eNOS) (232% and 148%) but it decreased the expressions of inducible NOS (iNOS) (55% and 71%). NaSH at 0.28, 2.8 and 5.6 mg/kg had no significant effects on these parameters. CONCLUSION: NaSH had a bell-shaped cardioprotective effect against myocardial IR injury in rats with T2D. Higher tolerance to IR injury in heart isolated from type 2 diabetic rats treated with intermediate doses of NaSH is associated with higher CSE-derived H2S and eNOS-derived NO as well as lower iNOS-derived NO.


Assuntos
Cardiotônicos/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Sulfetos/farmacologia , Animais , Cardiotônicos/administração & dosagem , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Dieta Hiperlipídica , Relação Dose-Resposta a Droga , Sulfeto de Hidrogênio/metabolismo , Masculino , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Obesidade/complicações , Ratos , Ratos Wistar , Estreptozocina , Sulfetos/administração & dosagem
3.
Life Sci ; 255: 117834, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32454158

RESUMO

AIMS: Hydrogen sulfide (H2S) is shown in ocular tissues and suggested to involve in the regulation of retinal circulation. However, the mechanism of H2S-induced relaxation on retinal artery is not clarified yet. Herein, we aimed to evaluate the role of several calcium (Ca2+) signaling and Ca2+ sensitization mechanisms in the relaxing effect of H2S donor, NaHS, on retinal arteries. MATERIALS AND METHODS: Relaxing effects of NaHS (10-5-3 × 10-3M) were determined on precontracted retinal arteries in Ca2+ free medium as well as in the presence of the inhibitors of Ca2+ signaling and Ca2+ sensitization mechanisms. Additively, Ca2+ sensitivity of the contractile apparatus were evaluated by CaCl2-induced contractions in the presence of NaHS (3 × 10-3M). Functional experiments were furtherly assessed by protein and/or mRNA expressions, as appropriate. KEY FINDINGS: The relaxations to NaHS were preserved in Ca2+ free medium while NaHS pretreatment decreased the responsiveness to CaCl2. The inhibitors of plasmalemmal Ca2+-ATPase, sarcoplasmic-endoplasmic reticulum Ca2+-ATPase, Na+-Ca2+ ion-exchanger and myosin light chain kinase (MLCK) unchanged the relaxations to NaHS. Likewise, Ca2+ sensitization mechanisms including, rho kinase, protein kinase C and tyrosine kinase were unlikely to mediate the relaxation to NaHS in retinal artery. Whereas, a marked reduction was determined in NaHS-induced relaxations in the presence of MLCP inhibitor, calyculin A. Supportively, NaHS pretreatment significantly reduced phosphorylation of MYPT1-subunit of MLCP. SIGNIFICANCE: The relaxing effect of NaHS in retinal artery is likely to be related to the activation of MLCP and partly, to decrement in Ca2+ sensitivity of contractile apparatus.


Assuntos
Cálcio/metabolismo , Sulfeto de Hidrogênio/metabolismo , Fosfatase de Miosina-de-Cadeia-Leve/metabolismo , Artéria Retiniana/metabolismo , Animais , Cloreto de Cálcio/administração & dosagem , Sinalização do Cálcio/fisiologia , Bovinos , Membrana Celular/metabolismo , Retículo Endoplasmático/metabolismo , Feminino , Masculino , Fosforilação/fisiologia , Sulfetos/administração & dosagem , Sulfetos/farmacologia
4.
PLoS One ; 15(3): e0229322, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32176696

RESUMO

Tetradecylthioacetic acid (TTA) is a synthetic fatty acid with a sulfur substitution in the ß-position. This modification renders TTA unable to undergo complete ß-oxidation and increases its biological activity, including activation of peroxisome proliferator activated receptors (PPARs) with preference for PPARα. This study investigated the effects of TTA on lipid and lipoprotein metabolism in the intestine and liver of mice fed a high fat diet (HFD). Mice receiving HFD supplemented with 0.75% (w/w) TTA had significantly lower body weights compared to mice fed the diet without TTA. Plasma triacylglycerol (TAG) was reduced 3-fold with TTA treatment, concurrent with increase in liver TAG. Total cholesterol was unchanged in plasma and liver. However, TTA promoted a shift in the plasma lipoprotein fractions with an increase in larger HDL particles. Histological analysis of the small intestine revealed a reduced size of lipid droplets in enterocytes of TTA treated mice, accompanied by increased mRNA expression of fatty acid transporter genes. Expression of the cholesterol efflux pump Abca1 was induced in the small intestine, but not in the liver. Scd1 displayed markedly increased mRNA and protein expression in the intestine of the TTA group. It is concluded that TTA treatment of HFD fed mice leads to increased expression of genes involved in uptake and transport of fatty acids and HDL cholesterol in the small intestine with concomitant changes in the plasma profile of smaller lipoproteins.


Assuntos
HDL-Colesterol/sangue , Dieta Hiperlipídica/efeitos adversos , Lipoproteínas/metabolismo , PPAR alfa/agonistas , Sulfetos/administração & dosagem , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Sulfetos/farmacologia , Triglicerídeos/sangue
5.
Int J Pharm ; 578: 119091, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32007591

RESUMO

The objective of the current study is to design and delivery of targeted PEG-PCL nanopolymersomes encapsulated with Gadolinium based Quantum Dots (QDs) and Doxorubicin (DOX) as magnetic resonance-florescence imaging and anti-cancer agent. Diagnostic and therapeutic efficiency of the prepared theranostic formulation was evaluated in vitro and in vivo. Hydrophobic QDs based on indium-copper-gadolinium-zinc sulfide were synthesized and characterized extensively. Hydrophobic QDs and hydrophilic DOX were loaded in PEG-PCL polymersomes through double emulsion method. Drug release pattern was studied in both citrate (pH 5.4) and phosphate (pH 7.4) buffer during 10 days. Both fluorescence and magnetic properties of bare QDs and prepared formulations were studied entirely. AS1411 DNA aptamer was covalently attached to the surface of polymersomal formulation in order to prepare targeted drug delivery system. Cellular cytotoxicity and cellular uptake analysis were performed in both nucleolin positive (MCF7 and 4T1) and nucleolin negative (CHO) cell lines. After in vitro evaluations, anti-tumor efficiency and diagnostic capability of the formulation was investigated in 4T1 tumor baring mice. Scanning emission electron microscopy (SEM) confirmed spherical shape and around 100 nm size of prepared formulations. Transmission electron microscopy (HRTEM) showed crystal shape of QDs with size of 2-3 nm. Drug release study obtained controlled release of encapsulated DOX and stability of formulation in physiologic condition. MTT and flow cytometry results demonstrated that AS1411 aptamer could enhance both toxicity and cellular uptake in nucleolin overexpressing cell lines (P < 0.05). Moreover, aptamer targeted formulation could increase survival rate and tumor inhibitory growth effect in 4T1 tumor baring mice (P < 0.05). Our results verify that aptamer targeted polymersomes loaded with non-toxic QDs as a diagnostic agent and DOX as an anti-cancer drug, could provide a theranostic platform with the purpose of optimization of treatment process and minimization of systemic side effects.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Aptâmeros de Nucleotídeos/administração & dosagem , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos , Neoplasias Mamárias Experimentais/tratamento farmacológico , Oligodesoxirribonucleotídeos/administração & dosagem , Pontos Quânticos/administração & dosagem , Animais , Antibióticos Antineoplásicos/química , Aptâmeros de Nucleotídeos/química , Células CHO , Linhagem Celular Tumoral , Cricetulus , Doxorrubicina/química , Liberação Controlada de Fármacos , Óxido de Etileno/administração & dosagem , Óxido de Etileno/química , Feminino , Humanos , Lactonas/administração & dosagem , Lactonas/química , Imagem por Ressonância Magnética , Neoplasias Mamárias Experimentais/patologia , Metais/administração & dosagem , Metais/química , Camundongos Endogâmicos BALB C , Oligodesoxirribonucleotídeos/química , Imagem Óptica , Pontos Quânticos/química , Sulfetos/administração & dosagem , Sulfetos/química
6.
J Vet Emerg Crit Care (San Antonio) ; 30(3): 302-307, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32077228

RESUMO

OBJECTIVE: To describe a case series of systemic lime sulfur toxicosis secondary to topical administration in 2 cats. CASE SUMMARY: Two cats from the same household that were being previously treated for Microsporum canis were presented following topical administration of an incorrectly diluted lime sulfur dip. A 30% solution was used rather than the recommended 3% solution, resulting in a 10-fold concentration overdose. The cats presented to the emergency service 1 hour after dermal application of the lime sulfur product at home. The first cat, a 2-year-old female, intact Cornish Rex, had severe hypotension, bradycardia, and hypothermia. Chemical burns were also present on the ventrum and paws. Clinicopathological data revealed profound acid-base disturbances, hypercalcemia, hyperphosphatemia, and azotemia. After aggressive fluid resuscitation, electrolyte supplementation, and treatment, the patient was stabilized and discharged after 5 days of hospitalization; full recovery was later reported. The second littermate, also a 2-year-old female, intact Cornish Rex, presented the following day with similar clinical signs, physical examination findings, and clinicopathological findings. After supportive care and 2 days of hospitalization, the patient was also discharged and reported to fully recover. NEW OR UNIQUE INFORMATION PROVIDED: This case series is the first to report systemic toxicosis secondary to dermal exposure of lime sulfur. As lime sulfur is commonly used in veterinary medicine for the treatment of ectoparasites, veterinary professionals should be aware of the significant signs of poisoning that can be seen as a result of iatrogenic dosing errors by pet owners or veterinary professionals.


Assuntos
Antifúngicos/efeitos adversos , Compostos de Cálcio/efeitos adversos , Doenças do Gato/induzido quimicamente , Sulfetos/efeitos adversos , Administração Tópica , Animais , Anti-Infecciosos , Antifúngicos/administração & dosagem , Antifúngicos/uso terapêutico , Compostos de Cálcio/administração & dosagem , Compostos de Cálcio/uso terapêutico , Doenças do Gato/tratamento farmacológico , Gatos , Feminino , Microsporum , Sulfetos/administração & dosagem , Sulfetos/uso terapêutico
7.
Oxid Med Cell Longev ; 2020: 6325378, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32064027

RESUMO

In addition to the lung, the liver is considered another major target for paraquat (PQ) poisoning. Hydrogen sulfide (H2S) has been demonstrated to be effective in the inhibition of oxidative stress and inflammation. The aim of this study was to investigate the protective effect of exogenous H2S against PQ-induced acute liver injury. The acute liver injury model was established by a single intraperitoneal injection of PQ, evidenced by histological alteration and elevated serum aminotransferase levels. Different doses of NaHS were administered intraperitoneally one hour before exposure to PQ. Analysis of the data shows that exogenous H2S attenuated the PQ-induced liver injury and oxidative stress in a dose-dependent manner. H2S significantly suppressed reactive oxygen species (ROS) generation and the elevation of malondialdehyde content while it increased the ratio of GSH/GSSG and levels of antioxidant enzymes including SOD, GSH-Px, HO-1, and NQO-1. When hepatocytes were subjected to PQ-induced oxidative stress, H2S markedly enhanced nuclear translocation of Nrf2 via S-sulfhydration of Keap1 and resulted in the increase in IDH2 activity by regulating S-sulfhydration of SIRT3. In addition, H2S significantly suppressed NLRP3 inflammasome activation and subsequent IL-1ß excretion in PQ-induced acute liver injury. Moreover, H2S cannot reverse the decrease in SIRT3 and activation of the NLRP3 inflammasome caused by PQ in Nrf2-knockdown hepatocytes. In summary, H2S attenuated the PQ-induced acute liver injury by enhancing antioxidative capability, regulating mitochondrial function, and suppressing ROS-induced NLRP3 inflammasome activation. The antioxidative effect of H2S in PQ-induced liver injury can at least partly be attributed to the promotion of Nrf2-driven antioxidant enzymes via Keap1 S-sulfhydration and regulation of SIRT3/IDH2 signaling via Nrf2-dependent SIRT3 gene transcription as well as SIRT3 S-sulfhydration. Thus, H2S supplementation can form the basis for a promising novel therapeutic strategy for PQ-induced acute liver injury.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Hepatócitos/efeitos dos fármacos , Sulfeto de Hidrogênio/farmacologia , Inflamação/metabolismo , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Paraquat/toxicidade , Animais , Linhagem Celular , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Glutationa/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Hepatócitos/enzimologia , Hepatócitos/metabolismo , Hepatócitos/patologia , Inflamassomos/efeitos dos fármacos , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Isocitrato Desidrogenase/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Masculino , Mitocôndrias/metabolismo , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/genética , Fragmentos de Peptídeos/metabolismo , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Sirtuínas/metabolismo , Sulfetos/administração & dosagem , Superóxido Dismutase-1/metabolismo , Transaminases/metabolismo
8.
Curr Drug Deliv ; 17(2): 148-158, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31939730

RESUMO

BACKGROUND: Realgar, a traditional Chinese medicine, has shown antitumor efficacy in several tumor types. We previously showed that realgar nanoparticles (nano-realgar) had significant antileukemia, anti-lung cancer and anti-liver cancer effects. In addition, the anti-tumor effects of nanorealgar were significantly better than those of ordinary realgar. OBJECTIVE: To explore the inhibitory effects and molecular mechanisms of nano-realgar on the migration, invasion and metastasis of mouse breast cancer cells. METHODS: Wound-healing migration assays and Transwell invasion assays were carried out to determine the effects of nano-realgar on breast cancer cell (4T1) migration and invasion. The expression levels of matrix metalloproteinase (MMP)-2 and -9 were measured by Western blot. A murine breast cancer metastasis model was established, administered nano-realgar for 32 days and monitored for tumor growth and metastasis by an in vivo optical imaging system. Finally, living imaging and hematoxylin and eosin (HE) staining were used to measure the morphology and pathology of lung and liver cancer cell metastases, respectively. Angiogenesis was assessed by CD34 immunohistochemistry. RESULTS: Nano-realgar significantly inhibited the migration and invasion of breast cancer 4T1 cells and the expression of MMP-2 and -9. Meanwhile, nano-realgar effectively suppressed the abilities of tumor growth, metastasis and angiogenesis in the murine breast cancer metastasis model in a time- and dosedependent manner. CONCLUSION: Nano-realgar significantly inhibited migration and invasion of mouse breast cancer cells in vitro as well as pulmonary and hepatic metastasis in vivo, which may be closely correlated with the downexpression of MMP-2 and -9 and suppression of tumor neovascularization.


Assuntos
Antineoplásicos/administração & dosagem , Arsenicais/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Mamárias Experimentais/tratamento farmacológico , Inibidores de Metaloproteinases de Matriz/administração & dosagem , Nanopartículas/administração & dosagem , Neovascularização Patológica/tratamento farmacológico , Sulfetos/administração & dosagem , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Feminino , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Metaloproteinases da Matriz/metabolismo , Camundongos Endogâmicos BALB C , Neovascularização Patológica/metabolismo , Cicatrização
9.
J Ethnopharmacol ; 247: 111576, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-30385423

RESUMO

AIM OF THE STUDY: Because the toxicity and efficacy of arsenic is closely related to its chemical species, we conducted examinations of arsenic species accumulation and distribution in the rat body after one-time and 30-day realgar administration and then elucidated the probable roles of different arsenic species in the short-term toxicity of realgar. MATERIALS AND METHODS: According to ICH M3 guidelines for non-clinical repeated dose toxicity studies and OECD Test guideline TG407 "Repeated Dose 28-Day oral Toxicity Study in Rodents, the doses of realgar set were 10.6 mg/kg, 40.5 mg/kg and 170 mg/kg. Rats were orally administered with realgar for one-tme and 30 days, respectively. Thereafter, biological samples (plasma, urine, liver, kidney, and brain) were obtained from rats and analyzed using high-performance liquid chromatography-inductively coupled plasma-mass spectrometry (HPLC-ICP-MS) to determine realgar metabolism, arsenic species accumulation and distribution. Additionally, the toxicity of realgar in rats was evaluated. RESULTS: The absorption, distribution and elimination half-life of total arsenic species in realgar were 3.33 hs, 16.08 hs and 24.65 hs, respectively. After 30 days of oral administration of realgar in rats, no significant drug-related toxicity occurred in the rats. Dimethylarsenic acid (DMA) is the most abundant arsenic species. The DMA contents of the liver and kidney of the high-dose realgar group were approximately 40-fold and 50-fold higher than those in the corresponding tissues of the control group, respectively. The arsenic species (III) was mainly detected in the liver and its content was about 40-fold higher than that of the control group. MMA was mainly detected in rat kidney, and the MMA content of the realgar treatment group was more than 2000 times higher than that of the control group. CONCLUSIONS: Arsenic is rapidly absorbed and distributed over the liver, kidneys and brain, and the distribution and elimination of arsenic in the blood is slow. The realgar doses corresponded to human equivalent doses (HED) of 1.7, 6.4 and 27.2 mg/kg, respectively. Considering that humans are 10 times more sensitive than animals, the realgar dose is equivalent to 0.17, 0.64 and 2.7 mg/kg HED. It can be considered that if patients take no more than 2.7 mg/kg realgar for 2 weeks, there will be no adverse reactions.


Assuntos
Arsenicais/farmacocinética , Sulfetos/farmacocinética , Administração Oral , Animais , Arsenicais/administração & dosagem , Encéfalo/metabolismo , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/farmacocinética , Medicamentos de Ervas Chinesas/toxicidade , Feminino , Absorção Gastrointestinal , Meia-Vida , Rim/metabolismo , Fígado/metabolismo , Masculino , Espectrometria de Massas , Ratos , Sulfetos/administração & dosagem , Sulfetos/toxicidade , Distribuição Tecidual , Testes de Toxicidade Aguda
10.
J Antibiot (Tokyo) ; 73(2): 82-90, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31723217

RESUMO

Methicillin-resistant Staphylococcus aureus (MRSA) infection is a major threat to human health due to its resistance to almost all classes of antibiotics. Discovery of novel antibacterial agents with new structures which combat the pathogens responsible for MRSA is urgent. In this study, three series of benzyl phenyl sulfide derivatives were designed and synthesized, and their antibacterial activity against eleven MRSA strains were evaluated. The results showed that two series of the synthetic compounds (5a-5l and 12p-12u) exhibit potent antibacterial activity against S. aureus and MRSA, with minimum inhibitory concentrations of 2-64 µg/mL. The structure-activity relationships are discussed and the mechanism of the antibacterial activity was shown to involve the destruction of the bacterial cell membrane. Finally, the MTT assay results suggest that the toxicity of compounds 5f and 5h is selective between bacteria and mammalian cells.


Assuntos
Antibacterianos/farmacologia , Compostos de Benzil/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Sulfetos/farmacologia , Antibacterianos/administração & dosagem , Antibacterianos/química , Compostos de Benzil/administração & dosagem , Compostos de Benzil/química , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade , Sulfetos/administração & dosagem , Sulfetos/química
11.
Eur J Pharm Sci ; 143: 105181, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31852628

RESUMO

Steroid hormones became increasingly interesting as active pharmaceutical ingredients for the treatment of endocrine disorders. However, medical applications of many steroidal drugs are inhibited by their very low aqueous solubilities giving rise to low bioavailabilities. Therefore, the prioritized oral administration of steroidal drugs remains problematic. Cyclodextrins are promising candidates for the development of drug delivery systems for oral route applications, since they solubilize hydrophobic steroids and increase their rate of transport in aqueous environments. In this study, the synthesis and characterization of polymeric ß-cyclodextrin derivates is described, which result from the attachment of a hydrophilic ß-CD-thioether to hyaluronic acid. Host-guest complexes of the synthesized ß-cyclodextrin hyaluronic acid conjugates were formed with two poorly soluble model steroids (ß-estradiol, dexamethasone) and compared to monomeric ß-cyclodextrin derivates regarding solubilization and complexation efficiency. The ß-cyclodextrin-drug (host-guest) complexes were evaluated in vitro for their suitability (cytotoxicity and transport rate) as intestinal drug carriers for steroid hormones. In case of ß-estradiol, higher solubilities could be achieved by complexation with both synthesized ß-cyclodextrin derivates, leading to significantly higher intestinal transport rates in vitro. However, this success could not be shown for dexamethasone, which namely solubilized better, but could not enhance the transport rate significantly. Thus, this study demonstrates the biocompatibility of the synthesized and characterized ß-cyclodextrin derivates and shows their potential as new candidate for intestinal drug carrier for steroid hormones like ß-estradiol.


Assuntos
Dexametasona/administração & dosagem , Portadores de Fármacos/administração & dosagem , Estradiol/administração & dosagem , Ácido Hialurônico/administração & dosagem , Sulfetos/administração & dosagem , beta-Ciclodextrinas/administração & dosagem , Células CACO-2 , Dexametasona/química , Portadores de Fármacos/química , Estradiol/química , Células HT29 , Humanos , Ácido Hialurônico/química , Absorção Intestinal , Solubilidade , Sulfetos/química , beta-Ciclodextrinas/química
12.
Andrologia ; 52(2): e13496, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31793716

RESUMO

The main aim of this study was to assay the testicular H2 S levels in the varicocele rat model and then to investigate the protective effects of NaHS on morphometric changes, sperm parameters, oxidative stress and apoptosis markers in rat's testis. D,L-propargylglycine (PAG) was administrated to show the effects of cystathionine γ-lyase enzyme (CSE) inhibition in the varicocele. Rats were assigned to four groups: (a) Sham, (b) varicocele, (c) varicocele + PAG and (d) varicocele + NaHS. Animals in varicocele + NaHS group received 30 µmol/L NaHS in drinking water for 56 days. In the varicocele + PAG group, animals received PAG 19 mg/kg twice a week. Morphometric assessment, oxidative stress markers, testicular H2 S levels, sperm parameters, TUNEL assay and expression of Bax/Bcl2 were evaluated at the end of experiment. Testicular H2 S levels were significantly decreased in varicocele group. NaHS significantly improved sperm parameters, morphometric characteristics and oxidative stress compared to varicocele group. Oxidative stress status deteriorated in the PAG group compared to the varicocele group. This study showed that a low testicular H2 S level might play a critical role in male infertility. Thus, NaHS administration may be a promising treatment strategy for male infertility in varicocele. In addition, CSE may not be the only important enzyme in testicular H2 S production.


Assuntos
Alquinos/administração & dosagem , Glicina/análogos & derivados , Sulfetos/administração & dosagem , Testículo/efeitos dos fármacos , Varicocele/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Glicina/administração & dosagem , Sulfeto de Hidrogênio/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Espermatozoides/efeitos dos fármacos , Testículo/metabolismo , Testículo/patologia , Varicocele/patologia
13.
Sci Rep ; 9(1): 15774, 2019 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-31673051

RESUMO

Imrecoxib is a registered treatment for osteoarthritis pain symptoms in China. This study aims to assess the effect of imrecoxib on the pharmacodynamics and pharmacokinetics of warfarin. 12 healthy male volunteers with CYP2C9*3 AA and VKORC1 AA genotypes took a 5 mg dose of warfarin both alone and concomitantly with steady-state imrecoxib. Both warfarin alone and concomitantly with imrecoxib have safey and good tolerance across the trial. Following warfarin and imrecoxib co-administration, neither Cmax, AUC0-t and t1/2 of warfarin enantiomers nor AUC of international normalized ratio (INR) were markedly different from those of warfarin alone. The geometric mean ratios (GMRs) (warfarin + imrecoxib: warfarin alone) of INR(AUC) was 1 (0.99, 1.01). The GMRs of warfarin AUC0-∞ (90% confidence interval, CIs) for warfarin + imrecoxib: warfarin alone were 1.12 (1.08, 1.16) for R-warfarin and 1.13 (1.07, 1.18) for S- warfarin. The 90% CIs of the GMRs of AUC0-∞, Cmax and INR (AUC) were all within a 0.8-1.25 interval. The combination of warfarin and imrecoxib did not impact the pharmacodynamics and pharmacokinetics of single-dose warfarin; therefore, when treating a patient with imrecoxib and warfarin, it is not required to adjust the dosage of warfarin.


Assuntos
Inibidores de Ciclo-Oxigenase 2 , Citocromo P-450 CYP2C9/genética , Genótipo , Testes Farmacogenômicos , Pirróis , Sulfetos , Vitamina K Epóxido Redutases/genética , Varfarina , Adolescente , Adulto , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Inibidores de Ciclo-Oxigenase 2/farmacocinética , Humanos , Masculino , Pirróis/administração & dosagem , Pirróis/farmacocinética , Sulfetos/administração & dosagem , Sulfetos/farmacocinética , Varfarina/administração & dosagem , Varfarina/farmacocinética
14.
Eur J Pharmacol ; 863: 172707, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31568786

RESUMO

Hydrogen sulfide plays an important role in the regulation of the cardiovascular system, insulin secretion, and glucose homeostasis. The aim of the present study was to examine the effects of chronic treatment with sodium hydrosulfide (NaHS), L-Cysteine (L-Cys) and DL-Propargylglycine (DL-PAG) on the changes induced by a high-fat diet (HFD) in zoometric and metabolic variables as well as cardiovascular changes such as hypertension and sympathetic hyperactivity. For this purpose, male Wistar rats were fed a normal fat diet (NFD) or HFD for 12 weeks. Next, the HFD rats were divided into 5 subgroups which received daily i.p. injections during 4 weeks of: (1) nothing (no injection, Control); (2) vehicle (PBS; 1ml/kg); (3) NaHS (5.6 mg/kg); (4) L-Cys (300mg/kg); or (5) DL-PAG (1mg/kg). Then, an oral glucose tolerance test, hormone serum levels and blood pressure were determined. The cardiovascular responses to stimulation of the vasopressor sympathetic tone or intravenous administration of the agonists noradrenaline (α1/2-adrenoceptors), methoxamine (α1-adrenoceptors) and UK 14,304 (α2-adrenoceptors) were determined in pithed rats. Lastly, the heart, liver and adipose tissue were weighted. HFD significantly increased: (1) zoometric variables, which were decreased by NaHS and L-Cys; (2) metabolic variables, ameliorated by DL-PAG; (3) haemodynamic variables, which were reversed by NaHS and L-Cys; and (4) the vasopressor responses induced by sympathetic stimulation, which were diminished by NaHS and L-Cys. In conclusion, chronic treatment with NaHS and L-Cys are effective in reducing adipose tissue and ameliorating the cardiovascular changes induced by obesity; meanwhile, DL-PAG ameliorates metabolic variables.


Assuntos
Sistema Cardiovascular/efeitos dos fármacos , Cisteína/administração & dosagem , Cisteína/farmacologia , Dieta Hiperlipídica/efeitos adversos , Recuperação de Função Fisiológica/efeitos dos fármacos , Sulfetos/administração & dosagem , Sulfetos/farmacologia , Agonistas de Receptores Adrenérgicos alfa 1/farmacologia , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Animais , Sistema Cardiovascular/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Fatores de Tempo
15.
Future Oncol ; 15(28): 3189-3196, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31512497

RESUMO

Devimistat (CPI-613®) is a novel lipoate analog that inhibits the tricarboxcylic acid cycle at two key carbon entry points. Through its inhibition of pyruvate dehydrogenase and a-ketoglutarate dehydrogenase complexes, devimistat inhibits the entry of glucose and glutamine derived carbons, respectively. Pancreatic cancer is dependent on mitochondrial function for enhanced survival and aggressiveness. In a Phase I study of modified FOLFIRINOX, in combination with devimistat for metastatic pancreatic cancer patients, there was a 61% objective response rate including a 17% complete response rate. This report outlines the rationale and design of the AVENGER 500 study, a Phase III clinical trial of devimistat in combination with modified FOLFIRINOX compared with FOLFIRINOX alone for patients with previously untreated metastatic adenocarcinoma of the pancreas. Clinical trial registration: NCT03504423.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/secundário , Adulto , Idoso , Caprilatos/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Agências Internacionais , Irinotecano/administração & dosagem , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Oxaliplatina/administração & dosagem , Neoplasias Pancreáticas/patologia , Prognóstico , Estudos Prospectivos , Sulfetos/administração & dosagem , Taxa de Sobrevida
16.
Future Oncol ; 15(28): 3197-3208, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31512500

RESUMO

Devimistat (CPI-613®) is an intravenously administered, novel lipoate analog that inhibits two key tricarboxcylic acid (TCA) cycle enzymes, pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase complexes (KGDH). These complexes control TCA cycle entry of glucose and glutamine-derived carbons, respectively. Acute myeloid leukemia (AML) cells upregulate the TCA cycle in response to DNA damaging agents and treatment with devimistat increases sensitivity to them. A Phase I study of devimistat in combination with cytarabine and mitoxantrone produced a complete remission rate of 50% in patients with relapsed or refractory AML. In the combined Phase I/II experience, older patients with R/R AML treated with 2000 mg/m2 of devimistat had a 52% complete remission/complete remission with incomplete hematologic recovery rate and a median survival of 12.4 months. This report outlines the rationale and design of the ARMADA 2000 study, a Phase III clinical trial of devimistat in combination with high dose cytarabine and mitoxantrone compared with high dose cytarabine and mitoxantrone alone for older patients (≥60 years of age) with relapsed or refractory AML. Clinical trial registration: NCT#03504410.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Terapia de Salvação , Idoso , Caprilatos/administração & dosagem , Citarabina/administração & dosagem , Feminino , Seguimentos , Humanos , Agências Internacionais , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Mitoxantrona/administração & dosagem , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Prospectivos , Sulfetos/administração & dosagem , Taxa de Sobrevida
17.
Int J Nanomedicine ; 14: 6297-6311, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496687

RESUMO

Purpose: Mn-doped ZnS quantum dots (QDs) with special luminescent properties have been widely researched and applied in various fields. Thus, their release toxicity and security cannot be ignored. Methods: In the present study, the toxicity and non-targeted metabolomics of Mn-doped ZnS QDs were investigated after single intravenous injection. Serum metabolites were evaluated based on gas chromatography-mass spectrometry together with multivariate statistical analyses [principal component analysis, partial least squares discriminant analysis, and orthogonal PLS-DA]. Results: The modified metabolites (variable importance in the projection (VIP) >1 and p<0.05) revealed that Mn-doped ZnS QDs exposure disturbed glycolysis, tricarboxylic acid cycle, ketoplasia, glutaminolysis, and amino acid and lipid metabolism. The behavior, coefficients of organs, and histological changes were the same as in the control group, and the disturbance of hematology and serum biochemistry was not dose- or time-dependent. Conclusion: Our study provides a general observation regarding the toxicity and potential metabolic responses of mice exposed to Mn-doped ZnS QDs.


Assuntos
Manganês/química , Metabolômica , Pontos Quânticos/toxicidade , Sulfetos/sangue , Sulfetos/toxicidade , Compostos de Zinco/sangue , Compostos de Zinco/toxicidade , Animais , Peso Corporal/efeitos dos fármacos , Masculino , Metaboloma , Camundongos Endogâmicos BALB C , Análise Multivariada , Tamanho do Órgão/efeitos dos fármacos , Pontos Quânticos/administração & dosagem , Pontos Quânticos/química , Sulfetos/administração & dosagem , Compostos de Zinco/administração & dosagem
18.
Kidney Int ; 96(4): 906-917, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31307778

RESUMO

The Renin-Angiotensin System (RAS) possesses a counter-regulatory axis composed of angiotensin converting enzyme (ACE)2, angiotensin-(1-7) [Ang-(1-7)] and the Mas receptor, which opposes many AT1-receptor-mediated effects of ligand angiotensin II. Ang-(1-7), as a ligand of the Mas receptor, has inhibitory effects on renal inflammation and fibrosis in experimental diabetes. However, Ang-(1-7) has a short half-life in plasma, which may render it unsuitable for use in clinics. Here, we investigated the effects of the lanthionine-stabilized Ang-(1-7), cyclic (c)Ang-(1-7), a lanthipeptide that is more peptidase-resistant than the linear peptide, in BTBR ob/ob mice with type 2 diabetic nephropathy. BTBR ob/ob mice received vehicle, cAng-(1-7), or the ACE inhibitor lisinopril. The treatment started at ten weeks of age, when the animals had already developed albuminuria, and ended at 19-20 weeks of age. cAng-(1-7) limited albuminuria progression, and limited podocyte dysfunction similarly to lisinopril. cAng-(1-7), unlike lisinopril, reduced glomerular fibrosis and inflammation, and counteracted glomerular capillary rarefaction. Furthermore, when cAng-(1-7) was combined with lisinopril, a superior antiproteinuric effect than with lisinopril alone was found, in association with better preservation of podocyte proteins and amelioration of capillary density. Thus, adding cAng-(1-7) to ACE-inhibitor therapy could benefit those diabetic patients who do not respond completely to ACE-inhibitor therapy.


Assuntos
Angiotensina I/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/tratamento farmacológico , Fragmentos de Peptídeos/administração & dosagem , Proteinúria/tratamento farmacológico , Alanina/administração & dosagem , Alanina/análogos & derivados , Alanina/química , Alanina/farmacocinética , Angiotensina I/química , Angiotensina I/farmacocinética , Animais , Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/patologia , Modelos Animais de Doenças , Quimioterapia Combinada/métodos , Meia-Vida , Humanos , Glomérulos Renais/irrigação sanguínea , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/patologia , Glomérulos Renais/ultraestrutura , Lisinopril/administração & dosagem , Masculino , Camundongos , Camundongos Transgênicos , Microscopia Eletrônica de Transmissão , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/farmacocinética , Peptídeos Cíclicos/administração & dosagem , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacocinética , Proteinúria/diagnóstico , Proteinúria/etiologia , Proteinúria/patologia , Sulfetos/administração & dosagem , Sulfetos/química , Sulfetos/farmacocinética
19.
Life Sci ; 232: 116650, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31302196

RESUMO

BACKGROUND: Inhalation of NO2 leads to a progressive airflow limitation and the development of emphysema-like lesions. We report on the efficacy of hydrogen sulfide (NaHS) for alleviating NO2-induced pulmonary impairment. METHODS: Sprague Dawley rats were exposed to 20 ppm NO2 for 6 h over six consecutive days for 75 days. At day 75, rats who had developed NO2-induced emphysema were then divided into sodium hydrosulfide (NaHS) administrated group, placebo (NaCl) group and spontaneous recovery group for about one month (days 76-105); Pulmonary function (PF) and hematological and biochemical indices were measured at days 14, 45, 75, and 105. RESULTS: NO2 exposure for 75 days was associated with a significant decrease in FEV100/FVC%, an increased in functional residual capacity (FRC), and histologic evidence of emphysema, moreover; NO2 exposure led to elevated triglyceride (TG), red blood cell (RBC), hemoglobin (HGB), and hematocrit (HCT) levels. Impaired rats treated with NaHS showed no further deterioration in PF compared to rats exposed to ambient air and elevated WBC, granulocyte and lymphocyte counts and HDL-C levels to rats given NaCl. CONCLUSIONS: NO2 exposure causes emphysema and a decline in PF in rats. NaHS could alleviate the PF decline as possible indicated by an elevation of HDL-C levels and leukocyte. NaHS has therapeutic potential for emphysema caused by air pollutant NO2.


Assuntos
Testes Hematológicos , Pulmão/efeitos dos fármacos , Dióxido de Nitrogênio/toxicidade , Sulfetos/administração & dosagem , Sulfetos/farmacologia , Administração por Inalação , Animais , Pulmão/fisiopatologia , Masculino , Ratos , Ratos Sprague-Dawley , Testes de Função Respiratória
20.
Parasitol Res ; 118(9): 2669-2678, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31278518

RESUMO

The aims of this study were to produce biogenic antimony sulfide nanoparticles (NPs) using Serratia marcescens (S. marcescens) and investigate the potential anti-leishmanial effects of these NPs on Leishmania major (L. major) (MRHO/IR/75/ER) in both in vitro and in vivo experiments. Biogenic antimony sulfide NPs were synthesized through intracellular biological methods using S. marcescens. The efficiency of various concentrations of antimony sulfide NPs was assessed using in vitro experiments on amastigotes of L. major at various times post-infection. In vivo experiments were carried out in BALB/c mice inoculated subcutaneously with 2 × 106L. major promastigotes (MHROM/IR/75/ER) and treated with antimony sulfide NPs (70 µg/mL, tropically), meglumine antimoniate (glucantime) as positive control and sterile phosphate-buffered saline (PBS, pH 7.4) as vehicle control. Results of in vitro experiments revealed that the anti-leishmanial activity increased when the antimony sulfide NPs concentration increased. The IC50 (50% inhibitory concentration) of antimony sulfide NPs against amastigotes was calculated as 62.5 µg/mL. In in vivo experiments, the average size of lesions significantly decreased to 8.6 ± 2.7 mm2 in mice inoculated with L. major promastigotes and treated with antimony sulfide NPs, compared with that in the negative control group (P = 0.015). Furthermore, results showed that antimony sulfide NPs significantly decreased the parasite load in the test group, compared with the negative control group (P = 0.001). Various concentrations of antimony sulfide NPs showed a great anti-leishmanial efficiency against L. major (MRHO/IR/75/ER), with the greatest efficiency shown by a concentration of 62.5 µg/mL in in vitro and in vivo experiments.


Assuntos
Antimônio/administração & dosagem , Antiprotozoários/administração & dosagem , Antipruriginosos/administração & dosagem , Leishmania major/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Nanopartículas/administração & dosagem , Sulfetos/administração & dosagem , Animais , Humanos , Concentração Inibidora 50 , Leishmania major/fisiologia , Leishmaniose Cutânea/parasitologia , Camundongos , Camundongos Endogâmicos BALB C
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