RESUMO
BACKGROUND AND AIMS: Hepatitis B virus (HBV) infection is ranked among the top health priorities worldwide. Accumulating evidence suggests that HBV infection and replication are closely associated with liver metabolism. The liver X receptors (LXRs), which belong to the superfamily of nuclear hormone receptors, are important physiological regulators of lipid and cholesterol metabolism. However, the association between the LXR pathway and HBV infection remains largely unclear. APPROACH AND RESULTS: In this study, the antiviral activity of LXR agonists was investigated using multiple HBV cellular models. We observed that in HBV-infected primary human hepatocytes (PHHs), synthetic LXR agonists (T0901317, GW3965, and LXR-623), but not an LXR antagonist (SR9238), potently inhibited HBV replication and gene expression, as demonstrated by substantial reductions in viral RNA, DNA, and antigen production following agonist treatment. However, covalently closed circular DNA (cccDNA) levels were not significantly reduced by the agonists. In addition, no rebound in viral replication was observed after treatment withdrawal, indicating a long-lasting inhibitory effect. These results suggest that LXR agonists decrease the transcriptional activity of cccDNA. In contrast, no significant anti-HBV effect was observed in HepG2-derived cell lines. Interestingly, LXR agonist treatment strongly reduced cholesterol 7α-hydroxylase 1 (CYP7A1) mRNA levels. Knockdown of CYP7A1 gene expression with small interfering RNA inhibited HBV activity in PHHs, suggesting CYP7A1 as a potential factor contributing to the antiviral effects of LXR agonists. CONCLUSIONS: We found that activation of the LXR pathway with synthetic LXR agonists could elicit potent anti-HBV activity in PHHs, possibly through sustained suppression of cccDNA transcription. Our work highlights the therapeutic potential of targeting the LXR pathway for the treatment of chronic HBV infection.
Assuntos
Antivirais/farmacologia , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B/tratamento farmacológico , Receptores X do Fígado/agonistas , Fígado/metabolismo , Antígenos Virais/genética , Antígenos Virais/isolamento & purificação , Antivirais/uso terapêutico , Benzoatos/farmacologia , Benzoatos/uso terapêutico , Benzilaminas/farmacologia , Benzilaminas/uso terapêutico , Células Cultivadas , Colesterol 7-alfa-Hidroxilase/genética , Colesterol 7-alfa-Hidroxilase/metabolismo , DNA Viral/isolamento & purificação , Avaliação Pré-Clínica de Medicamentos , Técnicas de Silenciamento de Genes , Hepatite B/virologia , Vírus da Hepatite B/fisiologia , Hepatócitos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Hidrocarbonetos Fluorados/farmacologia , Hidrocarbonetos Fluorados/uso terapêutico , Indazóis/farmacologia , Indazóis/uso terapêutico , Fígado/citologia , Receptores X do Fígado/antagonistas & inibidores , Receptores X do Fígado/metabolismo , Cultura Primária de Células , RNA Viral/isolamento & purificação , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Replicação Viral/efeitos dos fármacosRESUMO
Systemic lupus erythematosus (SLE) constitutes an autoimmune disease characterized by the breakdown of tolerance to self-antigens, sustained production of pathogenic autoantibodies, and damage to multiple organs and tissues. Nanoparticle (NP)-based therapeutics have demonstrated efficacy in attenuating the progression of SLE. However, investigations of nano-drugs that address the crucial initiating factor in the pathogenesis of SLE; e.g., inefficient clearance of apoptotic cells by phagocytes and consequent accumulation of self-antigens, have seldom been reported. Here, an apoptotic cell-mimicking gold nanocage (AuNC)-based nano drug carrier capable of correcting the impaired clearance of apoptotic cells in SLE was rationally designed and generated by conjugating phosphatidylserine (PS) on the surface of liposome-coated AuNCs for liver X receptor (LXR) agonist T0901317 delivery. Notably, PS-lipos-AuNC@T0901317 could efficiently enhance apoptotic cell clearance by elevating the expression of Mer, one of the pivotal phagocytosis-associated receptors on macrophages, resulting in decreased production of anti-dsDNA autoantibodies, reduced inflammatory response, and alleviation of kidney damage in lupus model mice. Additionally, PS-lipos-AuNC could be tracked by photoacoustic imaging for nano drug carrier biodistribution. By addressing the crucial pathogenic factor of SLE, the NP-based delivery system in this study is envisioned to provide a promising strategy to treat this complex and challenging disease.
Assuntos
Apoptose , Sistemas de Liberação de Medicamentos , Ouro/administração & dosagem , Hidrocarbonetos Fluorados/administração & dosagem , Receptores X do Fígado/agonistas , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Nanocápsulas/administração & dosagem , Sulfonamidas/administração & dosagem , Animais , Autoanticorpos/análise , Citocinas/metabolismo , Progressão da Doença , Avaliação Pré-Clínica de Medicamentos , Feminino , Ouro/farmacocinética , Hidrocarbonetos Fluorados/uso terapêutico , Hidrocarbonetos Fluorados/toxicidade , Lipossomos/administração & dosagem , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos MRL lpr , Fosfatidilserinas , Sulfonamidas/uso terapêutico , Sulfonamidas/toxicidade , Distribuição Tecidual , c-Mer Tirosina Quinase/biossíntese , c-Mer Tirosina Quinase/genéticaRESUMO
Uterine fibroids (UFs) are the most common tumors of the female genital tract. The effect of UFs on the quality of life and the overall cost of treatment are significant issues worldwide. Tumor size and location are the two specific factors which influence the occurrence of symptoms, the need for, and method of, treatment (some tumors require surgery while some can be treated with selected drugs). Primary prevention and treatment of early UF disease are worthy goals that might have a great impact on health care systems. Several treatments and prophylactic methods can be used in this endeavor. This publication presents current data about lesser-known substances which may have a beneficial effect on the treatment or prophylaxis of UFs and can be administered orally, serving as an alternative to (or complement of) surgery or selective progesterone receptor modulators (SPRMs). Early prevention and treatment of UFs in women from high-risk groups should be our priority. Innovative forms of UF management are under intensive investigation and may be promising options in the near future. Many of them evaluated vitamin D, paricalcitol, epigallocatechin gallate (EGCG), elagolix, aromatase inhibitors (AIs), and cabergoline and deemed them to be safe and effective. The next step in such projects should be properly constructed randomized control trials (RCTs), carried out by successive phases.
Assuntos
Antineoplásicos/administração & dosagem , Leiomioma/tratamento farmacológico , Neoplasias Uterinas/tratamento farmacológico , Administração Oral , Antineoplásicos/uso terapêutico , Inibidores da Aromatase/administração & dosagem , Inibidores da Aromatase/uso terapêutico , Cabergolina , Catequina/administração & dosagem , Catequina/análogos & derivados , Catequina/uso terapêutico , Ergocalciferóis/administração & dosagem , Ergocalciferóis/uso terapêutico , Ergolinas/administração & dosagem , Ergolinas/uso terapêutico , Feminino , Humanos , Hidrocarbonetos Fluorados/administração & dosagem , Hidrocarbonetos Fluorados/uso terapêutico , Pirimidinas/administração & dosagem , Pirimidinas/uso terapêutico , Qualidade de Vida , Vitamina D/administração & dosagem , Vitamina D/uso terapêuticoRESUMO
Asthma is defined by airway inflammation and hyperresponsiveness, and contributes to morbidity and mortality worldwide. Although bronchodilation is a cornerstone of treatment, current bronchodilators become ineffective with worsening asthma severity. We investigated an alternative pathway that involves activating the airway smooth muscle enzyme, soluble guanylate cyclase (sGC). Activating sGC by its natural stimulant nitric oxide (NO), or by pharmacologic sGC agonists BAY 41-2272 and BAY 60-2770, triggered bronchodilation in normal human lung slices and in mouse airways. Both BAY 41-2272 and BAY 60-2770 reversed airway hyperresponsiveness in mice with allergic asthma and restored normal lung function. The sGC from mouse asthmatic lungs displayed three hallmarks of oxidative damage that render it NO-insensitive, and identical changes to sGC occurred in human lung slices or in human airway smooth muscle cells when given chronic NO exposure to mimic the high NO in asthmatic lung. Our findings show how allergic inflammation in asthma may impede NO-based bronchodilation, and reveal that pharmacologic sGC agonists can achieve bronchodilation despite this loss.
Assuntos
Antiasmáticos/farmacologia , Asma/tratamento farmacológico , Benzoatos/farmacologia , Compostos de Bifenilo/farmacologia , Broncodilatadores/farmacologia , Guanilato Ciclase/efeitos dos fármacos , Hidrocarbonetos Fluorados/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Animais , Antiasmáticos/uso terapêutico , Asma/enzimologia , Asma/fisiopatologia , Benzoatos/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Hiper-Reatividade Brônquica/tratamento farmacológico , Hiper-Reatividade Brônquica/enzimologia , Broncodilatadores/uso terapêutico , Técnicas de Cocultura , GMP Cíclico/metabolismo , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Feminino , Humanos , Hidrocarbonetos Fluorados/uso terapêutico , Pulmão/enzimologia , Camundongos , Camundongos Endogâmicos BALB C , Músculo Liso/efeitos dos fármacos , Músculo Liso/enzimologia , Óxido Nítrico/farmacologia , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Solubilidade , Traqueia/efeitos dos fármacosRESUMO
Allergic rhinitis (AR) is a common respiratory disease, and its prevalence is increasing all over the world, both in adults and in children. Patients experience symptoms that may negatively impact on physical, social and psychological well-being. Hence, if left untreated, allergic rhinitis may significantly affect quality of life. Under current guidelines, intranasal corticosteroids are considered the most effective drugs and they are recommended as first-line therapy. Among the several corticosteroid intranasal sprays available, beclomethasone dipropionate is one of the most prescribed. Recently, new intranasal hydrofluoroalkane-propelled formulations with little or no impact on the ozone layer have been developed for the treatment of AR. The use of these devices might improve patients' adherence to treatment, avoiding some of the most common side effects associated with aqueous formulations. This review provides the most recent evidence for the efficacy and safety of beclomethasone dipropionate hydrofluoroalkane nasal aerosol in the treatment of allergic rhinitis.
Assuntos
Propelentes de Aerossol/uso terapêutico , Antiasmáticos/uso terapêutico , Beclometasona/uso terapêutico , Hidrocarbonetos Fluorados/uso terapêutico , Rinite Alérgica/tratamento farmacológico , Adulto , Animais , Criança , Humanos , Adesão à Medicação , Sprays Nasais , Qualidade de VidaRESUMO
UNLABELLED: Wilson disease (WD) is a hepatoneurological disorder caused by mutations in the copper-transporter, ATP7B. Copper accumulation in the liver is a hallmark of WD. Current therapy is based on copper chelation, which decreases the manifestations of liver disease, but often worsens neurological symptoms. We demonstrate that in Atp7b(-/-) mice, an animal model of WD, liver function can be significantly improved without copper chelation. Analysis of transcriptional and metabolic changes in samples from WD patients and Atp7b(-/-) mice identified dysregulation of nuclear receptors (NRs), especially the liver X receptor (LXR)/retinoid X receptor heterodimer, as an important event in WD pathogenesis. Treating Atp7b(-/-) mice with the LXR agonist, T0901317, ameliorated disease manifestations despite significant copper overload. Genetic markers of liver fibrosis and inflammatory cytokines were significantly decreased, lipid profiles normalized, and liver function and histology were improved. CONCLUSIONS: The results demonstrate the major role of an altered NR function in the pathogenesis of WD and suggest that modulation of NR activity should be explored as a supplementary approach to improving liver function in WD. (Hepatology 2016;63:1828-1841).
Assuntos
Degeneração Hepatolenticular/tratamento farmacológico , Hidrocarbonetos Fluorados/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Receptores X do Fígado/agonistas , Fígado/efeitos dos fármacos , Sulfonamidas/uso terapêutico , Adenosina Trifosfatases/genética , Animais , Proteínas de Transporte de Cátions/genética , Cobre/metabolismo , ATPases Transportadoras de Cobre , Avaliação Pré-Clínica de Medicamentos , Regulação da Expressão Gênica/efeitos dos fármacos , Degeneração Hepatolenticular/genética , Humanos , Hidrocarbonetos Fluorados/farmacologia , Fígado/metabolismo , Testes de Função Hepática , Receptores X do Fígado/metabolismo , Camundongos Knockout , Receptores X de Retinoides/metabolismo , Sulfonamidas/farmacologiaRESUMO
AIMS: To assess the urodynamic effects of soluble guanylyl cyclase (sGC) stimulator, BAY 41-2272, and activator, BAY 60-2770, (which both are able to induce cGMP synthesis even in the absence of nitric oxide (NO)) alone or in combination with a phosphodiesterase type 5 (PDE5) inhibitor, vardenafil, in a model of partial urethral obstruction (PUO) induced bladder overactivity (BO). METHODS: Fifty-six male Sprague-Dawley rats were used, 31 of them underwent PUO. Fourteen rats were used for Western blots to assess PDE5 and sGC expression. For drug evaluation cystometry without anesthesia was performed three days following bladder catheterization. RESULTS: Obstructed rats showed higher micturition frequency and bladder pressures than non-obstructed animals (Intermicturition Interval, IMI, 2.28 ± 0.55 vs. 3.60 ± 0.60 min (± standard deviation, SD); maximum micturition pressure, MMP, 70.1 ± 8.0 vs. 48.8 ± 7.2 cmH2O; both P < 0.05). In obstructed rats vardenafil, BAY 41-2272, and BAY 60-2770 increased IMI (2.77 ± 1.12, 2.62 ± 0.52, and 3.22 ± 1.04 min; all P < 0.05) and decreased MMP (54.4 ± 2.8, 61.5 ± 11.3, and 51.2 ± 6.3 cmH2O; all P < 0.05). When vardenafil was given following BAY 41-2272 or BAY 60-2770 no further urodynamic effects were observed. PDE5 as well as sGC protein expression was reduced in obstructed bladder tissue. CONCLUSIONS: Targeting sGC via stimulators or activators, which increase the levels of cGMP independent of endogenous NO, is as effective as vardenafil to reduce urodynamic signs of BO. Targeting the NO/cGMP pathway via compounds acting on sGC might become a new approach to treat BO.
Assuntos
Benzoatos/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Hidrocarbonetos Fluorados/uso terapêutico , Inibidores da Fosfodiesterase 5/uso terapêutico , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Obstrução Uretral/tratamento farmacológico , Bexiga Urinária Hiperativa/tratamento farmacológico , Bexiga Urinária/efeitos dos fármacos , Animais , Benzoatos/farmacologia , Compostos de Bifenilo/farmacologia , GMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Modelos Animais de Doenças , Quimioterapia Combinada , Guanilato Ciclase/metabolismo , Hidrocarbonetos Fluorados/farmacologia , Masculino , Inibidores da Fosfodiesterase 5/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Obstrução Uretral/complicações , Obstrução Uretral/metabolismo , Bexiga Urinária/metabolismo , Bexiga Urinária Hiperativa/etiologia , Bexiga Urinária Hiperativa/metabolismoRESUMO
Obesity has emerged as a major contributing risk factor for overactive bladder (OAB), but no study examined urethral smooth muscle (USM) dysfunction as a predisposing factor to obesity-induced OAB. This study investigated the USM relaxant machinery in obese mice and whether soluble guanylyl cyclase (sGC) activation with BAY 60-2770 [acid 4-({(4-carboxybutyl) [2-(5-fluoro-2-{[4-(trifluoromethyl) biphenyl-4-yl] methoxy} phenyl) ethyl] amino} methyl) benzoic] rescues the urethral reactivity through improvement of sGC-cGMP (cyclic guanosine monophosphate) signaling. Male C57BL/6 mice were fed for 12 weeks with a high-fat diet to induce obesity. Separate groups of animals were treated with BAY 60-2770 (1 mg/kg per day for 2 weeks). Functional assays and measurements of cGMP, reactive-oxygen species (ROS), and sGC protein expression in USM were determined. USM relaxations induced by NO (acidified sodium nitrite), NO donors (S-nitrosoglutathione and glyceryl trinitrate), and BAY 41-2272 [5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-pyrimidin-4-ylamine] (sGC stimulator) were markedly reduced in obese compared with lean mice. In contrast, USM relaxations induced by BAY 60-2770 (sGC activator) were 43% greater in obese mice (P < 0.05), which was accompanied by increases in cGMP levels. Oxidation of sGC with ODQ [1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one] (10 µM) potentiated BAY 60-2770-induced USM responses in the lean group. Long-term oral BAY 60-2770 administration fully prevented the impairment of USM relaxations in obese mice. Reactive-oxygen species (ROS) production was enhanced, but protein expression of ß1 second guanylate cyclase subunit was reduced in USM from obese mice, both of which were restored by BAY 60-2770 treatment. In conclusion, impaired USM relaxation in obese mice is associated with ROS generation and down-regulation of sGC-cGMP signaling. Prevention of sGC degradation by BAY 60-2770 ameliorates the impairment of urethral relaxations in obese mice.
Assuntos
Benzoatos/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Ativadores de Enzimas/uso terapêutico , Guanilato Ciclase/metabolismo , Hidrocarbonetos Fluorados/uso terapêutico , Óxido Nítrico/metabolismo , Obesidade/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares/metabolismo , Uretra/efeitos dos fármacos , Animais , Benzoatos/administração & dosagem , Compostos de Bifenilo/administração & dosagem , Relação Dose-Resposta a Droga , Ativação Enzimática , Ativadores de Enzimas/administração & dosagem , Hidrocarbonetos Fluorados/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Relaxamento Muscular/efeitos dos fármacos , Tono Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/enzimologia , Músculo Liso/metabolismo , Obesidade/complicações , Obesidade/enzimologia , Obesidade/fisiopatologia , Espécies Reativas de Oxigênio/metabolismo , Guanilil Ciclase Solúvel , Uretra/enzimologia , Uretra/metabolismo , Bexiga Urinária Hiperativa/enzimologia , Bexiga Urinária Hiperativa/etiologia , Bexiga Urinária Hiperativa/fisiopatologia , Bexiga Urinária Hiperativa/prevenção & controleRESUMO
Curcumin, a polyphenol, has pharmacological effects including antioxidant, anti-inflammatory and anti-cancer features. In this study, we have performed comparative in vivo evaluations of CDF (curcumin difluorinated) and curcumin in cisplatin-induced nephrotoxicity in rats. Male Wistar rats were divided into four groups: (1) Control; (2) Cisplatin (7 mg/kg body wt, intraperitoneal as a single dose); (3) Cisplatin and CDF (50 mg/rat/day; for 12 days); (4) Cisplatin and curcumin (50 mg/rat/day), for 12 days). Cisplatin treated rats exhibited kidney injury manifested by increased serum N-urea and creatinine (P < 0.001). Kidney from cisplatin treated rats also exhibited significant increase in malondialdehyde (MDA) and 8-isoprostane levels (P < 0.001). Treatment with CDF and curcumin prevented the rise in serum N-urea, creatinine, MDA and 8-isoprostane as compared to experimental control group in kidney (P < 0.05). Compared to curcumin, CDF had greater potential in suppressing cisplatin-induced pro-inflammatory factors NF-κB and COX-2 as well as downstream markers Nrf2 and HO-1 (P < 0.05) in kidney. The analysis on anion transport markers (OAT1 and OAT3) showed a similar trend (CDF > curcumin). CDF could reduce the expression of multi-drug resistance markers OCT1, OCT2, MRP2 and MRP4 to a much greater extent than curcumin (P < 0.05). We also demonstrate that CDF influenced the expression of p-mTOR, p-p70S6K1, p-4E-BP1 and p-Akt. These data suggest that CDF can potentially be used to reduce the chemotherapy induced nephrotoxicity thereby enhancing the therapeutic window of cisplatin. The results also proved that compared to curcumin, CDF has superior protective effect in nephrotoxicity.
Assuntos
Antineoplásicos/toxicidade , Cisplatino/toxicidade , Curcumina/uso terapêutico , Hidrocarbonetos Fluorados/uso terapêutico , Nefropatias/prevenção & controle , Rim/efeitos dos fármacos , Animais , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Curcumina/administração & dosagem , Curcumina/análogos & derivados , Hidrocarbonetos Fluorados/administração & dosagem , Rim/metabolismo , Nefropatias/sangue , Nefropatias/induzido quimicamente , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
PURPOSE: Activators of soluble guanylyl cyclase are of potential interest as treatment for cardiovascular diseases but to our knowledge they have never been proposed to treat overactive bladder. We evaluated the effects of the soluble guanylyl cyclase activator BAY 60-2270 on voiding dysfunction and detrusor overactivity in a mouse model of obesity associated overactive bladder. MATERIALS AND METHODS: C57BL/6 male mice fed for 10 weeks with standard chow or a high fat diet were treated with 1 mg/kg BAY 60-2770 per day for 2 weeks via gavage. Cystometric evaluations were done and responses to contractile agents in isolated bladders were determined. RESULTS: Obese mice showed an irregular micturition pattern characterized by significant increases in voiding and nonvoiding contractions, which were normalized by BAY 60-2770. Carbachol, KCl and CaCl2 produced concentration dependent contractions in isolated bladder strips, which were markedly greater in obese than in lean mice. BAY 60-2770 normalized bladder contractions in the obese group. A 78% increase in reactive oxygen species generation in the bladder tissue of obese mice was observed, which was unaffected by BAY 60-2770. Treatment with BAY 60-2770 generated a tenfold increase in cyclic guanosine monophosphate in the bladders of obese mice without affecting the nucleotide level in the lean group. Protein expression of the soluble guanylyl cyclase α1 and ß1 subunits was decreased 40% in the bladder tissue of obese mice but restored by BAY 60-2770. CONCLUSIONS: Two-week BAY 60-2770 therapy increased cyclic guanosine monophosphate and rescued expression of the soluble guanylyl cyclase α1 and ß1 subunits in bladder tissue, resulting in great amelioration of bladder dysfunction.
Assuntos
Benzoatos/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Ativadores de Enzimas/uso terapêutico , Guanilato Ciclase/efeitos dos fármacos , Hidrocarbonetos Fluorados/uso terapêutico , Obesidade/epidemiologia , Bexiga Urinária Hiperativa/tratamento farmacológico , Animais , Benzoatos/farmacologia , Compostos de Bifenilo/farmacologia , Western Blotting , Hidrocarbonetos Fluorados/farmacologia , Sintomas do Trato Urinário Inferior/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Espécies Reativas de Oxigênio , Bexiga Urinária Hiperativa/epidemiologia , Bexiga Urinária Hiperativa/prevenção & controleRESUMO
There has been a recently increase in the development of novel stilbene-based compounds with in vitro anti-inflamatory properties. For this study, we synthesized and evaluated the anti-inflammatory properties of 2 fluorinated stilbenes on carbon tetrachloride (CCl4)-induced acute liver damage. To achieve this, CCl4 (4 g·kg(-1), per os) was administered to male Wistar rats, followed by either 2-fluoro-4'-methoxystilbene (FME) or 2,3-difluoro-4'-methoxystilbene (DFME) (10 mg·kg(-1), per os). We found that although both of the latter compounds prevented cholestatic damage (γ-glutamyl transpeptidase activity), only DFME showed partial but consistent results in the prevention of necrosis, as assessed by both alanine aminotransferase activity and histological analysis. Since inflammatory responses are mediated by cytokines, mainly tumour necrosis factor α (TNF-α), we used the Western blot technique to determine the action of FME and DFME on the expression level of this cytokine. The observed increase in the level of TNF-α caused by CCl4 administration was only prevented by treatment with DFME, in agreement with our biochemical findings. This result was confirmed by measuring interleukin-6 (IL-6) levels, since the expression of this protein depends on the level of TNF-α. In this case, DFME completely blocked the CCl4-induced increase of IL-6. Our results suggest that DFME possesses greater anti-inflammatory properties in vivo than FME. DFME constitutes a possible therapeutic agent for liver disease and could serve as a template for structure optimization.
Assuntos
Anti-Inflamatórios/uso terapêutico , Tetracloreto de Carbono/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/uso terapêutico , Estilbenos/uso terapêutico , Animais , Anti-Inflamatórios/síntese química , Doença Hepática Induzida por Substâncias e Drogas/mortalidade , Doença Hepática Induzida por Substâncias e Drogas/patologia , Colestase/tratamento farmacológico , Colestase/metabolismo , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Interleucina-6/biossíntese , Masculino , Necrose/tratamento farmacológico , Necrose/patologia , Ratos , Ratos Wistar , Estilbenos/síntese química , Estilbenos/metabolismo , Fator de Necrose Tumoral alfa/biossínteseRESUMO
Epidemiological studies support the cancer-preventive effects of green tea and its main constituent (-)-epigallocatechin gallate [(-)-EGCG], however, (-)-EGCG is unstable under physiological conditions. Here we report that two novel fluoro-substituted (-)-EGCG analogs inhibited tumor growth with similar potency to that of Pro-EGCG (1) which has improved potency over parental compound (-)-EGCG in human breast cancer MDA-MB-231 xenografts. MDA-MB-231 tumors treated with each fluoro-substituted (-)-EGCG analog showed proteasome inhibition and apoptotic cell death, suggesting that the proteasome might be one of the cellular targets of fluoro-(-)-EGCGs and that proteasome inhibition is partially responsible for the observed antitumor activity.
Assuntos
Antineoplásicos/uso terapêutico , Catequina/análogos & derivados , Flúor , Neoplasias Mamárias Experimentais/tratamento farmacológico , Inibidores de Proteassoma , Animais , Apoptose/efeitos dos fármacos , Catequina/química , Catequina/farmacologia , Catequina/uso terapêutico , Linhagem Celular Tumoral , Feminino , Humanos , Hidrocarbonetos Fluorados/uso terapêutico , Neoplasias Mamárias Experimentais/metabolismo , Camundongos , Camundongos Nus , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
INTRODUCTION: During the 1970s, scientists suggested that the growing use of chlorofluorocarbons (CFCs) was contributing to depletion of the stratospheric ozone layer with potentially harmful results. A committee on the ozone layer organized the preparation of the Montreal Protocol. This protocol mandated the cessation of production and use of CFCs by January 1, 1996. The primary exemption to this ban is for the use of CFCs as propellants in metered dose inhalers (MDIs) for the treatment of asthma. Suitable replacement hydrofluoroalkane (HFA) propellants, such as HFA-134a, for use in MDIs have been identified. Albuterol, a selective beta-adrenergic agonist, currently widely available for inhalation asthma therapy, has been reformulated in HFA-134a (Proventil HFA). OBJECTIVE; To compare the efficacy of Proventil HFA to Ventolin, Proventil, and placebo (HFA-134a) MDI in protecting asthmatic patients from exercise-induced bronchoconstriction. METHODS: This was a randomized, single-blind, placebo-controlled, 4-period crossover study of asthmatic patients with documented exercise-induced broncho-constriction. Twenty patients self administered two puffs of either Proventil HFA, Ventolin, Proventil or placebo, from an MDI, 30 minutes prior to performing a standardized exercise challenge at the study site. Spirometry was performed predose and 5, 10, 15, 30, 45, 60, 75, and 90 minutes after completion of the exercise challenge. Heart rate and blood pressure were measured just prior to spirometry and a 12-lead ECG was performed 15 minutes after completion of the exercise challenge for measurement of the QT corrected interval. RESULTS: The primary efficacy variable was the smallest percent change from the predose FEV1 following exercise. The smallest percent change from predose FEV1 for Proventil HFA was 2.0 +/- 9.9 SD, similar to the 2.0 +/- 11.4 SD for Ventolin, and the 3.6 +/- 10.2 SD for Proventil. The smallest percent change from predose FEV1 for each of the active treatments was significantly different from placebo, -23.7 +/- 14.5. Twelve of the patients had a > or = 20% fall in FEV1 post-exercise with placebo pretreatment, but only 1, 1, and 0 had > or = 20% FEV1 falls after treatment with Proventil HFA, Ventolin, and Proventil respectively. Changes in heart rate, blood pressure and QT corrected interval were similar for the three active treatments following exercise. CONCLUSIONS: Proventil HFA provides protection against exercise-induced bronchoconstriction comparable to Ventolin and Proventil and protection superior to placebo. Proventil HFA has a safety profile similar to Ventolin when used to prevent exercise-induced bronchoconstriction.
Assuntos
Agonistas Adrenérgicos beta/uso terapêutico , Albuterol/uso terapêutico , Asma Induzida por Exercício/prevenção & controle , Broncoconstrição/fisiologia , Broncodilatadores/uso terapêutico , Hidrocarbonetos Fluorados/uso terapêutico , Adolescente , Adulto , Asma Induzida por Exercício/fisiopatologia , Broncoconstrição/efeitos dos fármacos , Tolerância a Medicamentos , Feminino , Humanos , MasculinoRESUMO
Myofascial trigger points (TPs) in a muscle are usually activated by acute or chronic overload of the muscle. They are identified by objective and subjective findings. Objective signs include a palpably firm, tense band in the muscle, production of a local twitch response, restricted stretch range-of-motion, weakness without atrophy, and no neurologic deficit. Subjectively, the patient reports stiffness and easy fatigability, spontaneous pain in a distribution predictable for that TP, an exquisite deep tenderness specifically at the TP. Sustained pressure on the TP induces referred pain in the predicted pattern. Some muscles are likely to produce additional objective and subjective autonomic concomitants. Laboratory and radiographic findings are negative. The affected muscle is treated by passive stretch while a jet stream of vapocoolant spray is applied over it, or by injection of the TP with a local anesthetic. A case report describes in detail the treatment of a patient who, for 13 years, had suffered from a medically enigmatic, intense right facial pain with severe dysfunction and who is now pain-free, with a full schedule of unrestricted activities 23 years later.
Assuntos
Neuralgia Facial/diagnóstico , Adulto , Anestesia Local , Neuralgia Facial/fisiopatologia , Neuralgia Facial/terapia , Feminino , Humanos , Hidrocarbonetos Fluorados/uso terapêutico , Modalidades de Fisioterapia/métodos , ProcaínaRESUMO
A mixture of 40% octafluorocyclobutane (C4F8) and 60% air was used clinically in eight patients with long-standing retinal detachment. In seven cases the retina reattached after intravitreal injection of C4F8 and intrascleral diathermization of the retinal tear. The one failure was due to massive vitreous retraction and preretinal proliferation prior to the surgery. Except for a slight postoperative iritis when 4 cc of gas lasted for 12 to 30 days after intravitreal injection. On the basis of this and our previous studies, we recommend the use of C4F8 in retinal detachment surgery.