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Chagas Disease is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi, affecting 6-8 million people, mainly in Latin America. The medical treatment is based on two compounds, benznidazole and nifurtimox, with limited effectiveness and that produce severe side effects; consequently, there is an urgent need to develop new, safe, and effective drugs. Amphotericin B is the most potent antimycotic known to date. A21 is a derivative of this compound with the property of binding to ergosterol present in cell membranes of some organisms. In the search for a new therapeutic drug against T. cruzi, the objective of this work was to study the in vitro and in vivo effects of A21 derivative on T. cruzi. Our results show that the A21 increased the reactive oxygen species and reduced the mitochondrial membrane potential, affecting the morphology, metabolism, and cell membrane permeability of T. cruzi in vitro. Even more important was finding that in an in vivo murine model of infection, A21 in combination with benznidazole was able to reduce blood parasitemia, diminish the immune inflammatory infiltrate in skeletal muscle and rescue all the mice from death due to a virulent T. cruzi strain.
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BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a chronic disease characterized by inflammation, steatosis, and liver fibrosis. The liver is particularly affected by alterations in lipid metabolism. Our aim was to evaluate the effect of ß-hydroxyphosphocarnitine (ß-HPC) on NASH induced in rats. METHODS: NASH was produced via the ad libitum daily chronic administration of a fructose solution (400 kcal) for 9 weeks, an oral dose of fat solution (16 kcal) for 7 weeks and a subcutaneous injection of CCl4 (30%) two times a week for 2 weeks to Wistar rats. To evaluate the effect of ß-HPC, a dose of 100 mg/kg was administered perorally for 4 weeks and its biochemical and hepatic effects on rats with NASH were analyzed. Serum levels of glucose, triglycerides, cholesterol, and liver enzymes were quantified. Histological changes were evaluated on slices stained with H&E, trichromic and PAS. Glycogen content was measured in liver samples. α-SMA and SREBP-1 immunopositive cells were identified in liver tissue. RESULTS: NASH was characterized by elevated triglycerides, elevated liver damage enzymes, and the presence of necrosis, inflammation, steatosis, and fibrosis. Significant amounts of glycogen were found, along with α-SMA positive cells in fibrosis areas. The over-expression of SREBP-1 in cytoplasm and nuclei was evident. Animals with NASH treated with ß-HPC showed a significant reduction in inflammation, necrosis, and glycogen content in the liver. A reduction in α-SMA and SREBP-1 immunopositive cells correlated with a significant reduction in the degree of fibrosis and steatosis found in liver tissue. ß-HPC reduced the levels of ALP and GGT, and significantly reduced triglyceride levels. Animals treated with ß-HPC did not show any alterations in liver enzyme function. CONCLUSIONS: Our research shows that ß-HPC can improve liver function and morphology in the case of NASH induced in rats, suggesting ß-HPC could be potentially used in the treatment of NASH.
Assuntos
Hepatopatia Gordurosa não Alcoólica , Animais , Carnitina/análogos & derivados , Colesterol , Dieta Hiperlipídica , Modelos Animais de Doenças , Frutose/metabolismo , Frutose/farmacologia , Frutose/uso terapêutico , Glucose/metabolismo , Glicogênio/metabolismo , Glicogênio/farmacologia , Glicogênio/uso terapêutico , Inflamação/tratamento farmacológico , Fígado , Cirrose Hepática/metabolismo , Necrose , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Organofosfatos , Ratos , Ratos Wistar , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/farmacologia , TriglicerídeosRESUMO
This review examined a collection of studies regarding the molecular properties of some polyene antibiotic molecules as well as their properties in solution and in particular environmental conditions. We also looked into the proposed mechanism of action of polyenes, where membrane properties play a crucial role. Given the interest in polyene antibiotics as therapeutic agents, we looked into alternative ways of reducing their collateral toxicity, including semi-synthesis of derivatives and new formulations. We follow with studies on the role of membrane structure and, finally, recent developments regarding the most important clinical applications of these compounds.
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Safety studies are essential in drug development. This study evaluates the safety of Amphotericin A21 (AmB-A21), a derivative of amphotericin B with antifungal therapeutic potential. We performed a chronic toxicity study, a targeted organ study and a dermal irritation test. To evaluate chronic toxicity, 18 male adult rats were treated orally with AmB-21 (2 mg/kg) for 26 weeks. The effects on body-weight and animal health were measured, and haematological, clinical chemistry and histopathological tests were conducted on various organs. In the target organ toxicity study, male adult rats received a daily oral dose of AmB-21 (2 mg/kg) for 6 and 17 weeks; testicle histology and testosterone levels were then evaluated. For the dermal irritation study, AmB-21 (200 and 1000 mg/kg) was placed on the skin of adult male rabbits; macroscopic and microscopic studies, as well as haematological and clinical chemistry tests were then conducted. The chronic toxicity study revealed that AmB-21 caused testicle damage, and the testicle-targeted study showed structural alterations and changes in testosterone levels at 17 weeks. However, these alterations were no longer observed 8 weeks after discontinuation of treatment, and the testes showed very similar characteristics to those in the control group. The dermal irritation study showed skin thickening and reddening in rabbits treated with 2000 mg of AmB-A21 after 14 days of exposure. This same group also showed changes in liver enzymes, renal parameters and platelet levels. Based on our results, we consider AmB-21 to be a potential candidate for safe, long-term antifungal treatment given its reduced side effects.
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Anfotericina B/toxicidade , Antifúngicos/toxicidade , Administração Oral , Anfotericina B/administração & dosagem , Anfotericina B/análogos & derivados , Animais , Antifúngicos/administração & dosagem , Masculino , Ratos , Testes de Toxicidade CrônicaRESUMO
BACKGROUND: The safe use in biomedicine of semiconductor nanoparticles, also known as quantum dots (QDs), requires a detailed understanding of the biocompatibility and toxicity of QDs in human beings. The biological characteristics and physicochemical properties of QDs entail new challenges regarding the management of potential adverse health effects following exposure. At certain concentrations, the synthesis of semiconductor nanoparticles of CdS using dextrin as capping agent, at certain concentration, to reduce their toxicity and improves their biocompatibility. RESULTS: This study successfully synthesized and characterized biocompatible dextrin-coated cadmium sulfide nanoparticles (CdS-Dx/QDs). The results show that CdS-Dx/QDs are cytotoxic at high concentrations (>2 µg/mL) in HepG2 and HEK293 cells. At low concentrations (<1 µg/mL), CdS-Dx/QDs were not toxic to HepG2 or HeLa cells. CdS-Dx nanoparticles only induced cell death by apoptosis in HEK293 cells at 1 µg/mL concentrations. The in vitro results showed that the cells efficiently took up the CdS-Dx/QDs and this resulted in strong fluorescence. The subcellular localization of CdS-Dx/QDs were usually small and apparently unique in the cytoplasm in HeLa cells but, in the case of HEK293 cells it were more abundant and found in cytoplasm and the nucleus. Animals treated with 100 µg/kg of CdS-Dx/QDs and sacrificed at 3, 7 and 18 h showed a differential distribution in their organs. Intense fluorescence was detected in lung and kidney, with moderate fluorescence detected in liver, spleen and brain. The biocompatibility and toxicity of CdS-Dx/QDs in animals treated daily with 100 µg/kg for 1 week showed the highest level of fluorescence in kidney, liver and brain. Less fluorescence was detected in lung and spleen. There was also evident presence of fluorescence in testis. The histopathological and biochemical analyses showed that CdS-Dx/QDs were non-toxic for rodents. CONCLUSIONS: The in vitro and in vivo studies confirmed the effective cellular uptake and even distribution pattern of CdS-Dx/QDs in tissues. CdS-Dx/QDs were biocompatible with tissues from rodents. The CdS-Dx/QDs used in this study can be potentially used in bio-imaging applications.
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Materiais Biocompatíveis/química , Compostos de Cádmio/química , Compostos de Cádmio/síntese química , Dextrinas/química , Dextrinas/síntese química , Diagnóstico por Imagem/métodos , Nanopartículas/química , Sulfetos/química , Sulfetos/síntese química , Morte Celular , Sobrevivência Celular , Endocitose , Células HEK293 , Células HeLa , Células Hep G2 , Humanos , Microscopia de Fluorescência , Nanopartículas/ultraestrutura , Pontos Quânticos/química , Distribuição TecidualRESUMO
The purpose of this research was to describe the pharmacokinetic parameters of ß-hydroxyphosphocarnitine (ß-HPC; CAS No. 1220955-20-3) after a single oral dose in rats and rabbits as well as to assess the impact of 14 weeks of ß-HPC (100 mg/kg) treatment on the serum metabolites and liver enzymes, body weight, and hepatic steatosis of lean and obese Zucker fa/fa rats. In the case of the rat and rabbit study, the ß-HPC area under the curve, biological half-life, and clearance were 2,174.4 versus 3,128 µg â h/ml, 23.7 versus 8.87 h, and 13.9 versus 151.1 ml/h in the rats versus the rabbits, respectively. The values for the time of maximal concentration were 0.58 versus 1.53 h, for the maximal concentration, they were 62.4 versus 221.4 µg/ml, and for the absorption rate constant 0.02 versus 2.40 h(-1), respectively. In the case of the Zucker fa/fa rat study, ß-HPC administered orally once a day reduced insulin, triglyceride, and cholesterol levels in the liver and serum; it also reduced weight gain and decreased liver steatosis in obese rats after 14 weeks. ß-HPC could therefore potentially be used in the treatment of metabolic syndrome.
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Carnitina/análogos & derivados , Fígado Gorduroso/prevenção & controle , Síndrome Metabólica/tratamento farmacológico , Obesidade/tratamento farmacológico , Organofosfatos/farmacologia , Administração Oral , Animais , Área Sob a Curva , Carnitina/farmacocinética , Carnitina/farmacologia , Colesterol/metabolismo , Fígado Gorduroso/etiologia , Fígado Gorduroso/patologia , Meia-Vida , Insulina/metabolismo , Masculino , Obesidade/complicações , Organofosfatos/farmacocinética , Coelhos , Ratos , Ratos Wistar , Ratos Zucker , Especificidade da Espécie , Triglicerídeos/metabolismo , Aumento de Peso/efeitos dos fármacosRESUMO
BACKGROUND: Semiconductor Quantum dots (QDs) have become quite popular thanks to their properties and wide use in biological and biomedical studies. However, these same properties entail new challenges in understanding, predicting, and managing potential adverse health effects following exposure. Cadmium and selenium, which are the major components of the majority of quantum dots, are known to be acutely and chronically toxic to cells and organisms. Protecting the core of nanoparticles can, to some degree, control the toxicity related to cadmium and selenium leakage. RESULTS: This study successfully synthesized and characterized maltodextrin coated cadmium sulfide semiconductor nanoparticles. The results show that CdS-MD nanoparticles are cytotoxic and embryotoxic. CdS-MD nanoparticles in low concentrations (4.92 and 6.56 nM) lightly increased the number of HepG2 cell. A reduction in MDA-MB-231 cells was observed with concentrations higher than 4.92 nM in a dose response manner, while Caco-2 cells showed an important increase starting at 1.64 nM. CdS-MD nanoparticles induced cell death by apoptosis and necrosis in MDA-MD-231 cells starting at 8.20 nM concentrations in a dose response manner. The exposure of these cells to 11.48-14.76 nM of CdS-MD nanoparticles induced ROS production. The analysis of cell proliferation in MDA-MB-231 showed different effects. Low concentrations (1.64 nM) increased cell proliferation (6%) at 7 days (p < 0.05). However, higher concentrations (>4.92 nM) increased cell proliferation in a dose response manner (15-30%) at 7 days. Exposures of chicken embryos to CdS-MD nanoparticles resulted in a dose-dependent increase in anomalies that, starting at 9.84 nM, centered on the heart, central nervous system, placodes, neural tube and somites. No toxic alterations were observed with concentrations of < 3.28 nM, neither in cells nor chicken embryos. CONCLUSIONS: Our results indicate that CdS-MD nanoparticles induce cell death and alter cell proliferation in human cell lines at concentrations higher than 4.92 nM. We also demonstrated that they are embryotoxic. However, no toxic effects were observed with doses lower than 3.28 nM in neither cells nor chicken embryos. The CdS-MD nanoparticles used in this study can be potentially used in bio-imaging applications. However, further studies using mammalian species are required in order to discard more toxic effects.
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Compostos de Cádmio/química , Compostos de Cádmio/toxicidade , Polissacarídeos/química , Polissacarídeos/toxicidade , Pontos Quânticos , Sulfetos/química , Sulfetos/toxicidade , Anormalidades Induzidas por Medicamentos/etiologia , Animais , Apoptose/efeitos dos fármacos , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Embrião de Galinha , Desenvolvimento Embrionário/efeitos dos fármacos , Células Hep G2 , Humanos , Estresse Oxidativo/efeitos dos fármacosRESUMO
Breast cancer is the most common cancer and the second leading cause of cancer-related mortality worldwide. The etiology of breast cancer is very diverse and ethanol (EtOH) consumption is a well-established risk factor for breast cancer in women. However, the mechanism by which EtOH exerts its carcinogenic activity in breast tissue remains unknown. CYP2E1 is known to metabolize ethanol and produce reactive oxygen species (ROS), including superoxide in epithelial cells. Therefore, in the present studies, we investigated whether there is an increase in ROS following overexpression of CYP2E1 in MCF-10A cells. We found that 30 and 100 mM EtOH increased ROS levels after 2 h treatment in CYP2E1 overexpressing cells. Based on these results and our previous studies with ROS-producing chemicals, we also examined epidermal growth factor receptor (EGFR) activation following exposure to ethanol. We found that there was an increase in phosphorylation of pY1086 EGFR after 18 h EtOH treatment in CYP2E1 overexpressing cells. These studies support a hypothesis that EtOH might increase human mammary cell activation, via an EGFR-dependent signaling mechanism associated with oxidative stress.
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Neoplasias da Mama/induzido quimicamente , Neoplasias da Mama/metabolismo , Citocromo P-450 CYP2E1/biossíntese , Receptores ErbB/metabolismo , Etanol/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Western Blotting , Neoplasias da Mama/enzimologia , Linhagem Celular Tumoral , Citocromo P-450 CYP2E1/genética , Citocromo P-450 CYP2E1/metabolismo , Feminino , Humanos , Fosforilação/efeitos dos fármacos , TransfecçãoRESUMO
INTRODUCTION: Immunomodulatory drugs have been reported to have anti-inflammatory and anti-fibrotic properties. Thymic humoral factor (THF), a peptide produced in the thymus, causes a potent immunomodulatory effect on different components of the immune system. OBJECTIVE: To evaluate the effect of THF on different stages of liver damage and fibrosis induced in rats through the administration of porcine serum (PS). MATERIAL AND METHODS: PS-induced liver fibrosis models serve as a primarily immunological mechanism in the development of liver damage and fibrosis. RESULTS: The intraperitoneal administration of THF in rats with PS-induced liver damage produced a reduction of ALT and AST after 60 days. Histopathological changes in liver sections showed an improved histological appearance and lower % of fibrosis after 60 days in liver damaged rats that received THF treatment. Serum IL-6 levels were visibly reduced by THF administration after 60 days and in comparison with rats that did not receive the treatment. This was due to an increment in serum IL-10 levels caused by the administration of THF, which appears to reduce the inflammatory process by decreasing immune response. CONCLUSION: THF had beneficial effects in combating liver damage and fibrosis processes in an autoimmune model of PS-induced liver fibrosis in rats.
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Fatores Imunológicos/farmacologia , Cirrose Hepática Experimental/prevenção & controle , Fígado/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Soro , Hormônios do Timo/farmacologia , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Autoimunidade/efeitos dos fármacos , Biomarcadores/sangue , Interleucina-10/sangue , Interleucina-6/sangue , Fígado/imunologia , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática Experimental/sangue , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/imunologia , Cirrose Hepática Experimental/patologia , Masculino , Ratos , Ratos Wistar , Suínos , Fatores de TempoRESUMO
BACKGROUND: Thrombocytopenia is a common hematologic disorder observed in patients with chronic hepatitis C virus (HCV) infection. Combined peginterferon (PEG-INF) and ribavirin treatment may exacerbate thrombocytopenia in patients with HCV. OBJECTIVE: The aim of this pilot clinical trial was to assess the efficacy, tolerability and safety of Danazol in thrombocytopenia associated with PEG-INF and ribavirin treatment in patients with HCV. MATERIAL AND METHODS: We included patients whose platelets were < 90,000/mm³ and who were undergoing antiviral treatment. Danazol (300-600 mg/day) was administered during and until the end of antiviral therapy [7.6 months (2 to 11 months)]. The monitoring was performed through platelet analysis and liver function tests. A viral load test was done at the beginning and end of treatment. Fortynine patients receiving a combined therapy of PEG-INF, ribavirin and Danazol increased their platelet levels to 121,081/mm³ (46,000-216,000/mm³); 10.6% of patients gained > 100,000 platelets/mm³, and 71% of patients maintained their initial platelet levels. Sustained viral response (SVR) was achieved in 63% of patients. SVR rates were high in patients with genotype non 1 (78.7%) and decreased in patients with genotype 1 (60.1%). The increase in platelet levels was associated to an increase in fibrinogen levels and a decrease in the activity of ALT. By contrast, patients without SVR presented a delayed response to increased platelet levels and showed no significant improvement in liver function when they received Danazol. CONCLUSION: Danazol can be used along with PEG-INF and ribavirin to treat thrombocytopenia in patients with HCV.
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Antivirais/efeitos adversos , Danazol/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/efeitos adversos , Polietilenoglicóis/efeitos adversos , Ribavirina/efeitos adversos , Trombocitopenia/tratamento farmacológico , Adulto , Idoso , Alanina Transaminase/sangue , Biomarcadores/sangue , Danazol/efeitos adversos , Quimioterapia Combinada , Feminino , Fibrinogênio/metabolismo , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Hepatite C Crônica/complicações , Hepatite C Crônica/diagnóstico , Humanos , Masculino , México , Pessoa de Meia-Idade , Razão de Chances , Projetos Piloto , Contagem de Plaquetas , Estudos Prospectivos , RNA Viral/sangue , Proteínas Recombinantes/efeitos adversos , Trombocitopenia/sangue , Trombocitopenia/induzido quimicamente , Trombocitopenia/virologia , Fatores de Tempo , Resultado do Tratamento , Carga ViralRESUMO
AIM: To evaluate the efficacy and safety of 2 analogs of L-carnitine on rats made insulin resistant by a high-fructose diet. METHODS: Using rats made insulin resistant by a high-fructose diet, we investigated the impact of 2 analogs of L-carnitine (25 mg/kg) and L-carnitine (250 mg/kg) on glucose, triglycerides and cholesterol blood levels, and liver glycogen. We also evaluated the safety of both analogs by the assessment of some biochemical and hematological parameters, a histological analysis and a study of embryotoxicity. RESULTS: Both analogs reduced the levels of triglycerides in the liver and plasma, but only analog 2 reduced the cholesterol levels in insulin-resistant rats. No changes were observed in glycogen content. Safety evaluations revealed alterations in blood lymphocytes and embryotoxicity data. CONCLUSION: This study demonstrated that the 2 analogs maintain the pharmacological properties of L-carnitine but have a different efficacy, potency and toxicity.
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Carnitina/farmacologia , Frutose/farmacologia , Resistência à Insulina/fisiologia , Edulcorantes/farmacologia , Complexo Vitamínico B/farmacologia , Animais , Glicemia/análise , Peso Corporal , Carnitina/análogos & derivados , Carnitina/uso terapêutico , Carnitina/toxicidade , Embrião de Galinha , Colesterol/sangue , Dieta , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Embrião não Mamífero/efeitos dos fármacos , Glicogênio/sangue , Insulina/sangue , Insulina/fisiologia , Fígado/química , Fígado/metabolismo , Masculino , Ratos , Ratos Wistar , Edulcorantes/análise , Edulcorantes/síntese química , Edulcorantes/toxicidade , Teratogênicos/toxicidade , Triglicerídeos/sangue , Complexo Vitamínico B/uso terapêutico , Complexo Vitamínico B/toxicidadeRESUMO
Tibia fractures are common in small animal practice. Over the past decade, improvements to animal internal fracture fixation have been developed. TGF-ß1 has been shown to be crucial in the development, induction and repair of bone. In present study, we investigate the effect of local application of a graft demineralized bone matrix (DBM) along with TGF-ß1 in a model of open osteotomy induced experimentally in dogs. Tibia fracture was brought about by using an open osteotomy model in young male dogs. Fracture repair was evaluated by a histological and biochemical analysis. Collagen content, proteolytic activity and urokinase-type plasminogen activator (uPA) expression were analyzed at the end of the study. Radiographic analysis, alkaline phosphatase and hematological evaluation were performed weekly. At the fifth week, there was an improvement and restoration of bone architecture in animals treated with a graft containing TGF-ß1 (5 ng/ml) compared with the control and graft groups, as was evidenced by the presence of an early formation of wide callus and bone regeneration. In addition, local application of TGF-ß1 led to an increase in collagen and proteolytic activity. More immunopositive osteoclast and mesenchymal cells were found in bone tissue from animals treated with TGF-ß1 as compared with the control group. No changes in alkaline phosphatase, hematological and clinical parameters were observed. This study shows that the combined use of DBM along with TGF-ß1 is able to improve and accelerate the bone repair.
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Matriz Óssea , Transplante Ósseo/veterinária , Doenças do Cão/cirurgia , Fraturas Ósseas/veterinária , Fator de Crescimento Transformador beta1/farmacologia , Animais , Transplante Ósseo/métodos , Cães , Consolidação da Fratura/fisiologia , Fraturas Ósseas/cirurgia , MasculinoRESUMO
In Mexico, local empirical knowledge about medicinal properties of plants is the basis for their use as home remedies. It is generally accepted by many people in Mexico and elsewhere in the world that beneficial medicinal effects can be obtained by ingesting plant products. In this review, we focus on the potential pharmacologic bases for herbal plant efficacy, but we also raise concerns about the safety of these agents, which have not been fully assessed. Although numerous randomized clinical trials of herbal medicines have been published and systematic reviews and meta-analyses of these studies are available, generalizations about the efficacy and safety of herbal medicines are clearly not possible. Recent publications have also highlighted the unintended consequences of herbal product use, including morbidity and mortality. It has been found that many phytochemicals have pharmacokinetic or pharmacodynamic interactions with drugs. The present review is limited to some herbal medicines that are native or cultivated in Mexico and that have significant use. We discuss the cultural uses, phytochemistry, pharmacological, and toxicological properties of the following plant species: nopal (Opuntia ficus), peppermint (Mentha piperita), chaparral (Larrea divaricata), dandlion (Taraxacum officinale), mullein (Verbascum densiflorum), chamomile (Matricaria recutita), nettle or stinging nettle (Urtica dioica), passionflower (Passiflora incarnata), linden flower (Tilia europea), and aloe (Aloe vera). We conclude that our knowledge of the therapeutic benefits and risks of some herbal medicines used in Mexico is still limited and efforts to elucidate them should be intensified.
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Medicina Herbária , Humanos , México , Medição de RiscoRESUMO
The aim of this study was to investigate the effects of combinations of pegilated-interferon (PEG-IFN), ribavirin, and danazol on thrombocytopenia and liver injury in rats with fibrosis. Male adult Wistar rats were treated with either mineral oil, danazol (0.83 mg/kg per day), PEG-interferon alpha-2a (PEG-IFN, 0.3 microg/ week) + ribavirin (12 mg/kg per day), PEG-IFN + ribavirin + danazol, CCl(4) (4 g/kg for eight weeks), CCl(4) + PEG-IFN + ribavirin, or CCl(4) + PEG-IFN + ribavirin+ danazol. The following assays were conducted: hematology, clinical chemistry, liver function, liver fibrosis, lymphocyte cytokine mRNA expression, and bone-marrow DNA content. Platelet counts were low in sham-treated animals and animals treated with PEG- IFN + ribavirin (30% and 25% respectively; P < 0.05). PEG-IFN + ribavirin + danazol reduced platelet counts of fibrotic animals by only 9% (P < 0.05). PEG- IFN + ribavirin reduced hepatic collagen content by 50%, whereas danazol + PEG-IFN + ribavirin reduced hepatic collagen content by 60% (P < 0.05). PEG-IFN + ribavirin reduced the total bilirubin concentration by 27%, alanine amino transferase (ALT) activity by 75% and gamma-glutamyl transpeptidase (gamma-GTP) activity by 74% (P < 0.05). In contrast, danazol + PEG-IFN + ribavirin reduced total bilirubin levels by 61%, alkaline phosphatase activity by 45%, ALT activity by 76%, and gamma-GTP activity by 74% (P < 0.05). The only treatment that increased interleukin 10 (IL-10) mRNA in fibrotic rats was PEG-IFN + ribavirin. However, danazol + PEG-IFN + ribavirin reduced the expression of IL-6, IL-10, tumor necrosis factor alpha and transforming growth factor ss. Bone-marrow DNA content was not altered by any treatment. In conclusion, PEG-IFN + ribavirin + danazol could be a new therapeutic option for patients with liver injury, fibrosis, and thrombocytopenia.
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Danazol/uso terapêutico , Interferon-alfa/uso terapêutico , Cirrose Hepática/tratamento farmacológico , Polietilenoglicóis/uso terapêutico , Ribavirina/uso terapêutico , Trombocitopenia/tratamento farmacológico , Animais , Células da Medula Óssea/fisiologia , Tetracloreto de Carbono , Ciclo Celular , Colágeno/análise , Citocinas/análise , Danazol/administração & dosagem , Quimioterapia Combinada , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Testes de Função Hepática , Contagem de Plaquetas , Polietilenoglicóis/administração & dosagem , Distribuição Aleatória , Ratos , Ratos Wistar , Proteínas Recombinantes , Ribavirina/administração & dosagem , Trombocitopenia/induzido quimicamenteRESUMO
Among the eight Calophyllum species found on the American continent, Calophyllum brasiliense is the most widely distributed. Chemical analysis of this species has shown the presence of xanthones with cancer chemopreventive properties and antifungal activity. Recently, three new coumarins with antineoplastic properties have been found. In this study, we have evaluated the biological effects of the antiproliferative activity of coumarins isolated from C. brasiliense on the survival, cell cycle and apoptosis of cells in-vitro and their antitumour effects in mice. The cytological study showed that coumarins from C. brasiliense reduce the survival of BMK cells (baby mouse kidney cells) by inducing apoptosis and, to a lesser degree, necrosis. The cell cycle was arrested in S-phase and the division of BMK cells was inhibited. Coumarins had caused a reduction of experimental tumours in 83% of animals by the end of the treatment. Therefore, coumarins have the potential to be used alone or in combination with other antineoplastic drugs, and they might increase the effectiveness of other treatments for cancer.
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Antineoplásicos/farmacologia , Calophyllum/química , Cumarínicos/farmacologia , Extratos Vegetais/farmacologia , Animais , Antineoplásicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cumarínicos/isolamento & purificação , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Mitose/efeitos dos fármacos , Necrose , Neoplasias/tratamento farmacológico , Extratos Vegetais/isolamento & purificação , Plantas Medicinais/química , Vincristina/farmacologiaRESUMO
Fibrosis accompanies most chronic liver disorders and is a major factor contributing to hepatic failure. Therefore, the need for an effective treatment with the aim of modifying the clinical course of this disease is evident. The aim of this work is to determine whether genistein, which has been shown to modulate the physiology and pathophysiology of liver, is able to decrease experimental liver fibrosis and cholestasis. In male Wistar rats, the common bile duct was ligated. Administration of genistein (5 microg rat-1, day-1, p.o.) began four weeks after biliary obstruction and continued for a further four weeks. The liver was used for histological and ultrastructural analysis and for collagen quantification (hydroxyproline content). The degradation of Matrigel(R) and collagen type I was determined in homogenized liver. Bilirubins and enzyme activities were measured in serum. Genistein was able to improve normal liver histology, ultrastructure, collagen content, and biochemical markers of liver damage. It also increased Matrigel(R) and collagen type I degradation. In summary, the present report shows that genistein inhibits the fibrosis and cholestasis induced by prolonged biliary obstruction in the rat. Genistein has therapeutic potential against liver fibrosis.
Assuntos
Colestase Extra-Hepática/complicações , Inibidores Enzimáticos/uso terapêutico , Genisteína/uso terapêutico , Cirrose Hepática Experimental/tratamento farmacológico , Animais , Colestase Extra-Hepática/tratamento farmacológico , Colestase Extra-Hepática/patologia , Doença Crônica , Seguimentos , Fígado/ultraestrutura , Cirrose Hepática Experimental/etiologia , Cirrose Hepática Experimental/patologia , Masculino , Microscopia Eletrônica , Ratos , Ratos Wistar , Fatores de Tempo , Resultado do TratamentoRESUMO
Despite steady progress in therapeutics of liver disease, portal systemic encephalopathy remains to be a great challenge for clinicians because of the heterogeneity of neuropsychiatric symptoms, multiple risk factors and complexity on achieving a sustained response. We aimed to evaluate the efficacy of L-Ornithin, L-Aspartate versus lactulose in Mexican patients with hyperammonemic hepatic encephalopathy. A total of 20 patients were randomly allocated to receive either lactulose(n = 10) or L-ornithine - L-aspartate (n = 10) for 2 weeks. At baseline, patients of both groups were comparable in age (64 +/- 7 versus 60 +/- 6) and degree of hepatic failure according to the Child-Pugh scale (9.2 +/- 1.3 versus 9.2 +/- 1.1). A significant decrease in ammonia levels was observed both in the lactulose group (120.4 +/- 8.1 versus 91.4 +/- 10, p < 0.05) and in the LOLA group (141.6 +/- 9.1 versus 96.9 +/- 9.3, p < 0.05). Moreover, in patients who received LOLA a significant improvement was observed in mental status (1.0 +/- 0.14 versus 0.4 +/- 0.16, p < 0.05), Number Connection Test (184 +/- 43 versus 88 +/- 7, p < 0.05), asterixis (14.6 +/- 2.8 versus 6.7 +/- 1.5, p < 0.05), as well as EEG findings (6.8 +/- 0.6 versus 8.1 +/- 0.2 cycles per second, p < 0.05). Compliance with study medications was similar between the lactulose group (94%) and the LOLA group (100%). No serious adverse events were reported in the two groups; however, in the lactulose group an increase in the number of weekly defecations was reported, as well as a higher incidence of abdominal pain or flatulence. Finally, both patient groups reported an improvement in the Visual Analogue Scale for EuroQol index (51.1 +/- 24.1 versus 61.5 +/- 15.8, p < 0.05, in the lactulose group; 56.5 +/- 24.5 versus 70 +/- 19.4, p < 0.05, in the LOLA group). In conclusion, oral administration of lactulose or L-ornithine - L-aspartate to Mexican patients with cirrhosis and hyperammonemic encephalopathy significantly reduced serum ammonia levels in study groups and additionally improved mental status parameters, number connection test, asterixis scores, and EEG activity in the group receiving L-ornithine-L-aspartate.
Assuntos
Dipeptídeos/uso terapêutico , Fármacos Gastrointestinais/uso terapêutico , Encefalopatia Hepática/tratamento farmacológico , Hiperamonemia/tratamento farmacológico , Lactulose/uso terapêutico , Administração Oral , Cognição , Dipeptídeos/administração & dosagem , Eletroencefalografia , Feminino , Encefalopatia Hepática/complicações , Humanos , Hiperamonemia/complicações , Lactulose/administração & dosagem , Cirrose Hepática/complicações , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
The synthesis of some monocyclic analogues of mycophenolic acid in which the lactone ring has been eliminated, leaving the aromatic ring intact and the same oxygenated substituents flanking the hexenoic acid side chain with an (E)-geometry at the double bond, has been accomplished via the Johnson ortho ester Claisen rearrangement. The synthetic methodology reported here allows the preparation of mycophenolic acid analogues bearing alkyl substituents at the alpha- and beta-positions on the side chain.
Assuntos
Ésteres/química , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/síntese química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ciclização , Humanos , Estrutura Molecular , Ácido Micofenólico/química , Ácido Micofenólico/toxicidadeRESUMO
En los últimos veinte años, ha habido considerable interés en comprender exactamente cuáles moléculas están involucradas en la patofisiología de la diseminación tumoral. Los resultados acumulados en ese tiempo indican que la propagación metastática del tumor representa la culminación de cambios malignos adquiridos durante la tumorigénesis. Uno de los hallazgos, que ha sido constante en esas observaciones, es la participación de las enzimas proteolíticas en los procesos de invasión y metástasis. En la actualidad se sabe que, para que la célula tumoral inicie la invasión del tejido adyacente y dé lugar a la metástasis, es necesaria toda una cascada de reacciones proteolíticas, en la cual participan serina, thiol y metaloproteasas. Se ha observado que algunas de esas enzimas proteolíticas se encuentran circulando, mientras que otras son sintetizadas y secretadas por las mismas células tumorales. También se sabe que existen varios inhibidores específicos de cada una de las familias de proteasas que pueden limitar la degradación de la matriz, y con esto inhibir la propagación tumoral. Este artículo resume una serie de evidencias relacionadas con la diseminación tumoral, observadas en modelos experimentales in vitro e in vivo, así como en diferentes cánceres que afectan al hombre, y hace énfasis en el papel de la proteólisis en la invasión y metástasis del cáncer.
Assuntos
Invasividade Neoplásica/fisiopatologia , Metaloendopeptidases/farmacocinética , Metástase Neoplásica/fisiopatologia , Peptídeo Hidrolases/farmacocinética , Catepsinas , Transformação Celular Neoplásica , Inibidores da AngiogêneseRESUMO
El factor de crecimiento del hepatocito (HGF), originalmente descrito como un mitógeno específico de células hepáticas, muestra ser un potente estimulador de la sintesis de DNA en una amplia variedad de tipos celulares. Además de sus efectos mitogénicos, el HGF tiene la capacidad de transmitir información que determina la organización especial de las células epiteliales en los tejidos, e inducir la motilidad celular y promover la invasión de la matriz extracelular en una gran variedad de células de estirpe epitelial. De esta manera, está implicado en procesos fisiológicos, entre ellos embriogénesis y desarrollo hepático, y en la regeneración y carcinogénesis hepáticas. Aunque el papel que juega el HGF en el cáncer no está bien definido, todo hace suponer que este factor influye sobre las células malignas. En este trabajo se presenta una revisión sobre los avances en el conocimiento del HGF, en los procesos normales y en aquéllos relacionados con enfermedades hepáticas