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1.
Chem Res Toxicol ; 32(6): 1027-1039, 2019 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-31012303

RESUMO

Pyrrolizidine alkaloids (PAs) are naturally occurring phytotoxins widely distributed in about 3% of flowering plants. The formation of PA-derived pyrrole-protein adducts is considered as a primary trigger initiating PA-induced hepatotoxicity. The present study aims to (i) further validate our previous established derivatization method using acidified ethanolic AgNO3 for the analysis of pyrrole-protein adducts and (ii) apply this method to characterize the binding tendency, dose-response, and elimination kinetics of pyrrole-protein adducts in blood samples. Two pyrrole-amino acid conjugates, (±)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5 H-pyrrolizine (DHP)-cysteine (7-cysteine-DHP) and 9-histidine-DHP, were synthesized and used to demonstrate that acidified ethanolic AgNO3 derivatization can cleave both S-linkage and N-linkage of pyrrole-protein adducts. Subsequently, using precolumn AgNO3 derivatization followed by ultra-high-pressure liquid chromatography/mass spectrometry analysis, we quantified pyrrole-protein adducts in monocrotaline-treated rat blood protein fractions, including hemoglobin (Hb), plasma, albumin, and plasma residual protein fractions, and found that the amount of pyrrole-Hb adducts was significantly higher than that in all plasma fractions. Moreover, elimination half-life of pyrrole-Hb adducts was also significantly longer than pyrrole-protein adducts in plasma fractions (12.08 vs 2.54-2.93 days). In addition, we also tested blood samples obtained from five PA-induced liver injury patients and found that the amount of pyrrole-protein adducts in blood cells was also remarkably higher than that in plasma. In conclusion, our findings for the first time confirmed that the AgNO3 derivatization method could be used to measure both S- and N-linked pyrrole-protein adducts and also suggested that pyrrole-Hb adducts with remarkably higher level and longer life span could be a better biomarker of PA exposure.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/sangue , Hemoglobinas/análise , Pirróis/sangue , Alcaloides de Pirrolizidina/efeitos adversos , Idoso , Animais , Biomarcadores/sangue , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estrutura Molecular , Alcaloides de Pirrolizidina/administração & dosagem , Alcaloides de Pirrolizidina/metabolismo , Ratos , Ratos Sprague-Dawley , Nitrato de Prata/química , Nitrato de Prata/farmacologia
2.
J Gastroenterol Hepatol ; 34(4): 634-642, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30669184

RESUMO

Hepatic sinusoidal obstruction syndrome (HSOS) is a hepatic vascular disease presenting with abdominal distension, pain in the hepatic region, ascites, jaundice, and hepatomegaly. In China, this disease is often associated with the oral intake of plants that contain pyrrolidine alkaloids. The existing guidelines are limited to HSOS associated with hematopoietic stem cell transplantation in Western countries. The Hepatobiliary Diseases Committee of the Chinese Society of Gastroenterology convened an expert consensus conference on the diagnosis and treatment of PA-HSOS to evaluate current research in China and abroad. The "Nanjing criteria" developed by the committee to diagnose PA-HSOS include a confirmed history of PA-containing plant use and (i) abdominal distention and/or pain in the hepatic region, hepatomegaly, and ascites; (ii) elevation of serum total bilirubin or abnormal laboratory liver tests; (iii) evidence on enhanced computed tomography or magnetic resonance imaging; or (iv) pathological evidence that rules out other known causes of liver injury. Supportive symptomatic treatment, anticoagulant therapy, and placement of a transjugular intrahepatic portosystemic shunt for patients who do not respond to medical treatment are effective for the treatment of PA-HSOS. The benefits of glucocorticoids and prostaglandin E1 in PA-HSOS are not clear.


Assuntos
Consenso , Hepatopatia Veno-Oclusiva/induzido quimicamente , Hepatopatia Veno-Oclusiva/terapia , Plantas/química , Alcaloides de Pirrolizidina/efeitos adversos , Anticoagulantes/uso terapêutico , Bilirrubina/sangue , Biomarcadores , China , Hepatopatia Veno-Oclusiva/diagnóstico , Hepatopatia Veno-Oclusiva/fisiopatologia , Humanos , Testes de Função Hepática , Imagem por Ressonância Magnética , Derivação Portossistêmica Cirúrgica/métodos , Alcaloides de Pirrolizidina/isolamento & purificação , Tomografia Computadorizada por Raios X
3.
Methods Mol Biol ; 1905: 211-219, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30536103

RESUMO

Hepatic progenitor cells are defined as cells exhibiting potency for active proliferation and capacity for bipotential differentiation into hepatocytes and cholangiocytes. To prove the capacity of target cells for terminal differentiation and reconstitution of organs, cell transplantation models have been widely used in previous studies, including those involving the liver. Here we describe a protocol for transplantation of hepatic progenitor cells using retrorsine pretreatment and partial hepatectomy. This transplantation assay reveals the potential for reconstitution of hepatocytes in recipient livers by primary hepatic progenitor cells. Donor cells are detected as a colony composed of 5-10 mature hepatocytes.


Assuntos
Hepatócitos/citologia , Fígado/lesões , Alcaloides de Pirrolizidina/efeitos adversos , Transplante de Células-Tronco/métodos , Animais , Diferenciação Celular , Células Cultivadas , Feminino , Hepatectomia , Fígado/citologia , Fígado/efeitos dos fármacos , Fígado/cirurgia , Regeneração Hepática , Masculino , Camundongos , Modelos Animais , Células-Tronco/citologia
4.
Int J Mol Sci ; 21(1)2019 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-31887985

RESUMO

In this study, we reveal that liver organoid transplantation through the portal vein is a safe and effective method for the treatment of chronic liver damage. The liver organoids significantly reconstituted the hepatocytes; hence, the liver was significantly enlarged in this group, compared to the monolayer cell transplantation group in the retrorsine/partial hepatectomy (RS/PH) model. In the liver organoid transplantation group, the bile ducts were located in the donor area and connected to the recipient bile ducts. Thus, the rate of bile reconstruction in the liver was significantly higher compared to that in the monolayer group. By transplanting liver organoids, we saw a level of 70% replacement of the damaged liver. Consequently, in the transplantation group, diminished ductular reaction and a decrease of placental glutathione S-transferase (GST-p) precancerous lesions were observed. After trans-portal injection, the human induced pluripotent stem cell (hiPSC)-derived liver organoids revealed no translocation outside the liver; in contrast, the monolayer cells had spread to the lungs. The hiPSC-derived liver organoids were attached to the liver in the immunodeficient RS/PH rats. This study clearly demonstrates that liver organoid transplantation through the portal vein is a safe and effective method for the treatment of chronic liver damage in rats.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/terapia , Transplante de Fígado/métodos , Organoides/citologia , Veia Porta/cirurgia , Alcaloides de Pirrolizidina/efeitos adversos , Animais , Células Cultivadas , Feminino , Glutationa Transferase/metabolismo , Hepatectomia , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Regeneração Hepática , Técnicas de Cultura de Órgãos , Ratos , Resultado do Tratamento
5.
Biomed Res Int ; 2018: 9804582, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30009181

RESUMO

We retrospectively identified 89 consecutive patients from January 2004 to January 2012 to investigate efficacy of direct intrahepatic portocaval shunt (DIPS) combined with inferior vena cava (IVC) stenting for sinusoidal obstruction syndrome (SOS) associated with hepatotoxicity of pyrrolizidine alkaloids. Indications for treatment were variceal hemorrhage and/or refractory ascites. Patients were treated with DIPS plus IVC stenting (group A, n=68) or DIPS alone (group B, n=21). A technical success rate of 100% was obtained in all 89 patients, and there were no early procedure-related adverse events or 30-day mortality. Mean portosystemic gradient decreased in both groups. Changes in aspartate and alanine aminotransferases and total bilirubin did not differ between the groups. Ascites disappeared in group A but was not obvious in group B until IVC stenting. During follow-up, recurrent bleeding and ascites and incidence of hepatic encephalopathy did not differ between the groups. The 1-, 3-, and 5-year survival rate was 98, 89.59, and 80%, respectively. Satisfactory clinical results were obtained for combined DIPS and IVC stenting for SOS associated with pyrrolizidine-alkaloid-related decompensated cirrhosis.


Assuntos
Varizes Esofágicas e Gástricas , Hepatopatia Veno-Oclusiva/terapia , Derivação Portossistêmica Transjugular Intra-Hepática , Alcaloides de Pirrolizidina/efeitos adversos , Stents , Adulto , Doença Hepática Induzida por Substâncias e Drogas , Feminino , Hemorragia Gastrointestinal , Hepatopatia Veno-Oclusiva/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
6.
Nutrients ; 10(7)2018 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-29932143

RESUMO

OBJECTIVES: Pyrrolizidine alkaloids (PA) exist ubiquitously in our environment. More than 6000 plants, about 3% of the world’s flowering plants, are known to synthesize PA. As a consequence, many herbal ingredients, including St. John’s wort (SJW), are contaminated with PA that can possess acute and subchronic toxic effects as well as mutagenic and genotoxic properties. Therefore, the possible benefits of SJW as an herbal remedy against depression need to be weighed against the possible risks of unwanted PA intake. METHODS: We searched the literature regarding the current knowledge on PA and evaluated the evidence on the antidepressant effects of quantified SJW extract based on a Cochrane Review and the current practice guidelines on depression. Risks are depicted in form of a risk ladder and benefits in form of an icon array. RESULTS: Evidence from clinical studies indicates that quantified SJW extract is an effective treatment option for mild to moderate depression with fewer side effects than conventional antidepressants. Health statistics from different countries do not quantify cases of death caused by PA intake. However, deaths due to suicide, often triggered by depression, are common (11 in 1000 in Germany in 2015) and rank between fatalities due to liver diseases (16 in 1000) and household accidents (10 in 1000). CONCLUSIONS: Quantified SJW extract is a safe and effective treatment option, and its potential of treating depression outweighs the (hypothetical) risk of unwanted PA intake.


Assuntos
Antidepressivos/administração & dosagem , Hypericum/química , Fitoterapia , Extratos Vegetais/administração & dosagem , Plantas Medicinais/química , Alcaloides de Pirrolizidina/administração & dosagem , Antidepressivos/efeitos adversos , Depressão/tratamento farmacológico , Humanos , Extratos Vegetais/efeitos adversos , Alcaloides de Pirrolizidina/efeitos adversos , Medição de Risco , Resultado do Tratamento
7.
Liver Int ; 38(10): 1867-1874, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29297975

RESUMO

BACKGROUND AND AIMS: Hematopoietic stem cell transplantation related hepatic vein occlusive disease (HSCT-HVOD) has been researched extensively; however, little is known about the clinical features and treatment of pyrrolizidine alkaloid-induced HVOD (PA-HVOD). This retrospective single centre study examined the clinical and laboratory characteristics of 108 patients with acute PA-HVOD and explored the efficacy of anticoagulation and TIPS therapy. METHODS: The study included 108 consecutive patients with PA-HVOD between July 2008 and June 2016. The clinical manifestations and the results of laboratory and imaging tests were evaluated. The survival rates of patients treated with different approaches were recorded. RESULTS: Serum total bilirubin was <34.2 µmol/L (2 mg/dL) in approximately 40% of patients. More than 90% of patients were presented with hepatomegaly, uneven liver perfusion in the balance phase, compressive stenosis of the hepatic segmental inferior vena cava and decreased peak velocity of portal vein blood flow. Severe portal hypertension was observed in all patients undergoing HVPG examination or TIPS operation. Anticoagulation therapy with low molecular weight heparin combined with warfarin was significantly more effective than liver protection and supportive therapy, and TIPS further improved the prognosis of patients who did not respond to anticoagulation therapy. The total effective rate of the anticoagulation-TIPS ladder therapeutic strategy was 91%. CONCLUSIONS: Patients with PA-HVOD had different characteristics than those with HSCT-HVOD. Anticoagulation and TIPS treatment may be effective for patients with PA-HVOD.


Assuntos
Hepatopatia Veno-Oclusiva/induzido quimicamente , Fígado/patologia , Alcaloides de Pirrolizidina/efeitos adversos , Idoso , Anticoagulantes/uso terapêutico , Bilirrubina/sangue , Feminino , Hepatopatia Veno-Oclusiva/terapia , Humanos , Hipertensão/etiologia , Masculino , Pessoa de Meia-Idade , Derivação Portossistêmica Transjugular Intra-Hepática , Prognóstico , Estudos Retrospectivos
8.
J Ethnopharmacol ; 210: 88-94, 2018 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-28807851

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: From early times man has used medicinal plants for the treatment of various ailments and basic health care needs. The use of herbal medicines has increased day by day and with this, so do reports of adverse events, poisoning, and suspected toxicity. Similarly, the indigenous communities of Neelum Valley in Azad Kashmir commonly use Arnebia benthamii (Wall. ex G.Don) I.M.Johnst. for medicinal purposes to treat various human aliments. Besides their medicinal uses, it also contains hepatotoxic pyrrolizidine alkaloids (PAs). AIM OF THE STUDY: This explorative study underscores two major aspects about this herbal medicine. Firstly we aimed to document the traditional therapeutic uses of Arnebia benthamii in Neelum Valley, Azad Kashmir. Secondly, to determine the presence or absence of hepatotoxic pyrrolizidine alkaloids and if they are within the suggested limit for the use of herbs in excess. MATERIALS AND METHODS: Interviews, group discussions, and inquiries were carried out from July to September 2016 with local indigenous and elder people. In the laboratory, the plant was investigated for pyrrolizidine alkaloids by using high performance liquid chromatography (HPLC). RESULTS: A total of 30 respondents were interviewed. They explained the preferred preparation, parts used, and treatment indications. Treatment of fever along with kidney and liver problems are the three principle uses. Among the different parts of Arnebia benthamii, 43% respondents preferred aerial parts for the herbal formulation, followed by whole plants, and leaves. Decoction was the major mode of preparation and all herbal preparations were administrated orally. This study reports, for the first time according to our literature review, a study of Arnebia benthamii with regard to PA determination. By using column Zorbax SB-Aq and acetonitrile-water gradient as the mobile phase, HPLC results showed that the aerial parts of the plant were PA positive, and (1) Europine, Heliotrine (2), Lycopsamine (3), and Echimidine (4) were identified. CONCLUSIONS: This study has revealed two new findings of significance to herbal medicine producers, practitioners, and consumers of Arnebia benthamii First, local knowledge regarding the medicinal uses of Arnebia benthamii were documented in five sites of Neelum Valley, Azad Kashmir. The use of this plant by a large part of the population in the study area shows the importance for their therapeutic benefits. Unfortunately, the second finding of this study shows that Arnebia benthamii contains hepatotoxic PAs. Hence, we advised to the government regulatory authorities and non-governmental organizations that use of this plant as herbal medicine should be excluded before more accurate quality control tests.


Assuntos
Boraginaceae/química , Medicina Tradicional/métodos , Preparações de Plantas/administração & dosagem , Alcaloides de Pirrolizidina/análise , Adulto , Idoso , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Cromatografia Líquida de Alta Pressão/métodos , Etnofarmacologia , Humanos , Índia , Medicina Tradicional/efeitos adversos , Pessoa de Meia-Idade , Fitoterapia/efeitos adversos , Fitoterapia/métodos , Preparações de Plantas/efeitos adversos , Alcaloides de Pirrolizidina/administração & dosagem , Alcaloides de Pirrolizidina/efeitos adversos
10.
Rev Esp Enferm Dig ; 109(11): 804, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29032695

RESUMO

The potential hepatotoxic effects of products containing medicinal herbs, which are increasingly used without adequate control by health authorities, is well known. We report a case of toxic hepatic veno-occlusive disease (HVOD) presumably associated with the use of such herbal remedies.


Assuntos
Medicamentos de Ervas Chinesas/efeitos adversos , Hepatopatia Veno-Oclusiva/induzido quimicamente , Hepatopatia Veno-Oclusiva/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Alcaloides de Pirrolizidina/efeitos adversos
11.
Nutrients ; 9(7)2017 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-28686224

RESUMO

Humans are exposed to pyrrolizidine alkaloids (PA) through different sources, mainly from contaminated foodstuff. Teas and herbal infusions (T&HI) can be contaminated by PA producing weed. PA can possess toxic, mutagenic, genotoxic, and carcinogenic properties. Thus, possible health risks for the general population are under debate. There is a strong safety record for T&HI and additionally epidemiological evidence for the preventive effects of regular tea consumption on cardiovascular events and certain types of cancer. There is no epidemiological evidence, however, for human risks of regular low dose PA exposure. Recommended regulatory PA-threshold values are based on experimental data only, accepting big uncertainties. If a general risk exists through PA contaminated T&HI, it must be small compared to other frequently accepted risks of daily living and the proven health effects of T&HI. Decision making should be based on a balanced riskbenefit analysis. Based on analyses of the scientific data currently available, it is concluded that the benefits of drinking T&HI clearly outweigh the negligible health risk of possible PA contamination. At the same time, manufacturers must continue their efforts to secure good product quality and to be transparent on their measures of quality control and risk communication.


Assuntos
Contaminação de Alimentos/análise , Alcaloides de Pirrolizidina/efeitos adversos , Alcaloides de Pirrolizidina/análise , Medição de Risco , Chá/química , Chás de Ervas/análise , Doenças Cardiovasculares/prevenção & controle , Promoção da Saúde , Humanos , Neoplasias/prevenção & controle , Alcaloides de Pirrolizidina/toxicidade , Fatores de Risco
12.
Arch Toxicol ; 91(12): 3913-3925, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28620673

RESUMO

Pyrrolizidine alkaloids (PAs) are among the most potent phytotoxins widely distributed in plant species around the world. PA is one of the major causes responsible for the development of hepatic sinusoidal obstruction syndrome (HSOS) and exerts hepatotoxicity via metabolic activation to form the reactive metabolites, which bind with cellular proteins to generate pyrrole-protein adducts, leading to hepatotoxicity. PA N-oxides coexist with their corresponding PAs in plants with varied quantities, sometimes even higher than that of PAs, but the toxicity of PA N-oxides remains unclear. The current study unequivocally identified PA N-oxides as the sole or predominant form of PAs in 18 Gynura segetum herbal samples ingested by patients with liver damage. For the first time, PA N-oxides were recorded to induce HSOS in human. PA N-oxide-induced hepatotoxicity was further confirmed on mice orally dosed of herbal extract containing 170 µmol PA N-oxides/kg/day, with its hepatotoxicity similar to but potency much lower than the corresponding PAs. Furthermore, toxicokinetic study after a single oral dose of senecionine N-oxide (55 µmol/kg) on rats revealed the toxic mechanism that PA N-oxides induced hepatotoxicity via their biotransformation to the corresponding PAs followed by the metabolic activation to form pyrrole-protein adducts. The remarkable differences in toxicokinetic profiles of PAs and PA N-oxides were found and attributed to their significantly different hepatotoxic potency. The findings of PA N-oxide-induced hepatotoxicity in humans and rodents suggested that the contents of both PAs and PA N-oxides present in herbs and foods should be regulated and controlled in use.


Assuntos
Medicamentos de Ervas Chinesas/efeitos adversos , Medicamentos de Ervas Chinesas/química , Hepatopatia Veno-Oclusiva/induzido quimicamente , Alcaloides de Pirrolizidina/efeitos adversos , Animais , Humanos , Masculino , Camundongos Endogâmicos ICR , Óxidos/análise , Óxidos/química , Alcaloides de Pirrolizidina/análise , Alcaloides de Pirrolizidina/farmacocinética , Alcaloides de Pirrolizidina/toxicidade , Ratos Sprague-Dawley
13.
Redox Biol ; 12: 264-273, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28282614

RESUMO

Pyrrolizidine alkaloids (PAs) are a group of compounds found in various plants and some of them are widely consumed in the world as herbal medicines and food supplements. PAs are potent hepatotoxins that cause irreversible liver injury in animals and humans. However, the mechanisms by which PAs induce liver injury are not clear. In the present study, we determined the hepatotoxicity and molecular mechanisms of senecionine, one of the most common toxic PAs, in primary cultured mouse and human hepatocytes as well as in mice. We found that senecionine administration increased serum alanine aminotransferase levels in mice. H&E and TUNEL staining of liver tissues revealed increased hemorrhage and hepatocyte apoptosis in liver zone 2 areas. Mechanistically, senecionine induced loss of mitochondrial membrane potential, release of mitochondrial cytochrome c as well as mitochondrial JNK translocation and activation prior to the increased DNA fragmentation and caspase-3 activation in primary cultured mouse and human hepatocytes. SP600125, a specific JNK inhibitor, and ZVAD-fmk, a general caspase inhibitor, alleviated senecionine-induced apoptosis in primary hepatocytes. Interestingly, senecionine also caused marked mitochondria fragmentation in hepatocytes. Pharmacological inhibition of dynamin-related protein1 (Drp1), a protein that is critical to regulate mitochondrial fission, blocked senecionine-induced mitochondrial fragmentation and mitochondrial release of cytochrome c and apoptosis. More importantly, hepatocyte-specific Drp1 knockout mice were resistant to senecionine-induced liver injury due to decreased mitochondrial damage and apoptosis. In conclusion, our results uncovered a novel mechanism of Drp1-mediated mitochondrial fragmentation in senecionine-induced liver injury. Targeting Drp1-mediated mitochondrial fragmentation and apoptosis may be a potential avenue to prevent and treat hepatotoxicity induced by PAs.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Dinaminas/metabolismo , GTP Fosfo-Hidrolases/metabolismo , Hepatócitos/efeitos dos fármacos , Proteínas Associadas aos Microtúbulos/metabolismo , Mitocôndrias/efeitos dos fármacos , Proteínas Mitocondriais/metabolismo , Alcaloides de Pirrolizidina/efeitos adversos , Alanina Transaminase/sangue , Animais , Sobrevivência Celular/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/genética , Modelos Animais de Doenças , Dinaminas/genética , GTP Fosfo-Hidrolases/genética , Técnicas de Inativação de Genes , Hepatócitos/citologia , Hepatócitos/metabolismo , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Proteínas Associadas aos Microtúbulos/genética , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , Alcaloides de Pirrolizidina/farmacologia
15.
Sci Rep ; 6: 37998, 2016 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-27897243

RESUMO

Hepatic sinusoidal obstruction syndrome (HSOS) can be caused by pyrrolizidine alkaloids(PAs)-containing herbals. Since PAs exposure is obscure and clinical presentation of HSOS is unspecific, it is challenge to establish the diagnosis of PAs-induced HSOS. Gynura segetum is one of the most wide-use herbals containing PAs. The aim of our study is to describe the features of contrast-enhanced computed tomography (CT) in gynura segetum-induced HSOS, and then determine diagnostic performance of radiological signs. We retrospectively analyzed medical records and CT images of HSOS patients (71 cases) and the controls (222 cases) enrolled from January 1, 2008, to Oct 31, 2015. The common findings of contrast CT in PAs-induced HSOS included: ascites (100%), hepatomegaly (78.87%), gallbladder wall thickening (86.96%), pleural effusion (70.42%), hepatic vein narrowing (87.32%), patchy liver enhancement (92.96%), and heterogeneous hypoattenuation (100%); of these signs, patchy enhancement and heterogeneous hypoattenuation were valuable features. Then, the result of diagnostic performance demonstrated that contrast CT possessed better performance in diagnosing PAs-induced HSOS compared with various parameters of Seattle criteria. In conclusion, the patients with PAs-induced HSOS display distinct radiologic features at CT-scan, which reveals that contrast-enhanced CT provides an effective noninvasive method for diagnosing PAs-induced HSOS.


Assuntos
Meios de Contraste , Medicamentos de Ervas Chinesas/química , Hepatopatia Veno-Oclusiva/diagnóstico , Hepatomegalia/diagnóstico , Alcaloides de Pirrolizidina/efeitos adversos , Tomografia Computadorizada por Raios X/métodos , Adulto , Estudos de Casos e Controles , Feminino , Hepatopatia Veno-Oclusiva/induzido quimicamente , Hepatopatia Veno-Oclusiva/diagnóstico por imagem , Hepatomegalia/induzido quimicamente , Hepatomegalia/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos
16.
Clin Res Hepatol Gastroenterol ; 40(4): 378-85, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27038846

RESUMO

Sinusoidal obstruction syndrome (SOS) is characterized by damage to small hepatic vessels affecting particularly sinusoidal endothelium. Damaged sinusoids can be associated with a partial or complete occlusion of small hepatic veins, hence the previous denomination of hepatic veno-occlusive disease (VOD). Exposure to certain exogenous toxins appears to be specific to this condition and is frequently included in its definition. Typical histopathological features of SOS in a liver biopsy specimen are presented in the text. The purpose of this article is to provide an overview on the different entities corresponding to this general definition. Such entities include: (i) liver disease related to pyrrolizidine alcaloids; (ii) liver injury related to conditioning for hematopoietic stem cell transplantation; (iii) vascular liver disease occurring in patients treated with chemotherapy for liver metastasis of colorectal cancer; and (iv) other liver diseases related to toxic agents.


Assuntos
Hepatopatia Veno-Oclusiva/etiologia , Antineoplásicos/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Alcaloides de Pirrolizidina/efeitos adversos
17.
Regul Toxicol Pharmacol ; 73(2): 494-500, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26399164

RESUMO

Pyrrolizidine alkaloids (PA) are common plantal toxins directed against insect herbivores. Unsaturated PAs are known to be hepatotoxic. Many of the PAs are in addition mutagenic and some may possibly be carcinogenic for humans. The risk of an exposure to PAs associated with their occurrence in herbal medicinal products and in foodstuff is under current discussion. The present risk assessment for herbal medicinal products containing PAs is based on a margin of safety derivation for foodstuff indicating that a life-long exposure to maximally 0.007 µg/kg bw/day is not expected to be associated with safety concerns. This approach offers a possibility to estimate the potential risk of PA-containing herbal medicinal products irrespective of the route of administration. It assumes PA levels in the final herbal medicinal product below 0.01 ppm and considers for dermal administration a 100% skin penetration of the PAs reflecting a worst-case scenario. As a result, the calculated margins of safety show a potential exposure using herbal medicinal products 70-, 45.5-, and 19.3-fold lower on a one-day base and 608-, 396-, and 168- fold lower on a one-year base for adults, children aged 12 years, and children aged 4 years, respectively, than the thresholds considered acceptable for foodstuff.


Assuntos
Alimentos/efeitos adversos , Fitoterapia/efeitos adversos , Plantas Medicinais/efeitos adversos , Alcaloides de Pirrolizidina/efeitos adversos , Adulto , Criança , Pré-Escolar , Exposição Ambiental/efeitos adversos , Exposição Ambiental/normas , Feminino , Humanos , Masculino , Fitoterapia/normas , Medição de Risco/métodos
18.
Drug Des Devel Ther ; 9: 4861-8, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26346783

RESUMO

BACKGROUND: The diagnosis of hepatic sinusoidal obstruction syndrome (HSOS) induced by pyrrolizidine alkaloids is mainly based on clinical investigation. There is currently no prognostic index. This study evaluated the quantitative measurement of blood pyrrole-protein adducts (PPAs) as a diagnostic and prognostic index for pyrrolizidine alkaloid-induced HSOS. METHODS: Suspected drug-induced liver injury patients were prospectively recruited. Blood PPAs were quantitatively measured using ultra-performance liquid chromatography-tandem mass spectrometry. Patients' age, sex, biochemistry test results, and a detailed drug history were recorded. The patients were divided into two groups, ie, those with HSOS induced by pyrrolizidine alkaloid-containing drugs and those with liver injury induced by drugs without pyrrolizidine alkaloids. The relationship between herb administration, clinical outcomes, blood sampling time, and blood PPA concentration in pyrrolizidine alkaloid-associated HSOS patients was analyzed using multiple linear regression analysis. RESULTS: Forty patients met the entry criteria, among whom 23 had pyrrolizidine alkaloid-associated HSOS and 17 had liver injury caused by drugs without pyrrolizidine alkaloids. Among the 23 patients with pyrrolizidine alkaloid-associated HSOS, ten recovered, four developed chronic disease, eight died, and one underwent liver transplantation within 6 months after onset. Blood PPAs were detectable in 24 of 40 patients with concentrations from 0.05 to 74.4 nM. Sensitivity and specificity of the test for diagnosis of pyrrolizidine alkaloid-associated HSOS were 100% (23/23) and 94.1% (23/24), respectively. The positive predictive value was 95.8% and the negative predictive value was 100%, whereas the positive likelihood ratio was 23.81. The level of blood PPAs in the severe group (died or received liver transplantation) was significantly higher than that in the recovery/chronicity group (P=0.004). CONCLUSION: Blood PPAs measured by ultra-performance liquid chromatography-tandem mass spectrometry are highly sensitive and specific for pyrrolizidine alkaloid-associated HSOS. The blood PPA concentration is related to the severity and clinical outcome of pyrrolizidine alkaloid-associated HSOS.


Assuntos
Proteínas Sanguíneas/análise , Doença Hepática Induzida por Substâncias e Drogas/sangue , Hepatopatia Veno-Oclusiva/sangue , Pirróis/sangue , Alcaloides de Pirrolizidina/efeitos adversos , Adulto , Idoso , Biomarcadores/sangue , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Cromatografia Líquida de Alta Pressão , Feminino , Hepatopatia Veno-Oclusiva/induzido quimicamente , Hepatopatia Veno-Oclusiva/diagnóstico , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Alcaloides de Pirrolizidina/sangue , Índice de Gravidade de Doença , Espectrometria de Massas em Tandem
19.
Ger Med Sci ; 13: Doc09, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26195922

RESUMO

Understanding the toxic effects of xenobiotics requires sound knowledge of physiology and biochemistry. The often described lack of understanding pharmacology/toxicology is therefore primarily caused by the general absence of the necessary fundamental knowledge. Since toxic effects depend on exposure (or dosage) assessing the risks arising from toxic substances also requires quantitative reasoning. Typically public discussions nearly always neglect quantitative aspects and laypersons tend to disregard dose-effect-relationships. One of the main reasons for such disregard is the fact that exposures often occur at extremely low concentrations that can only be perceived intellectually but not by the human senses. However, thresholds in the low exposure range are often scientifically disputed. At the same time, ignorance towards known dangers is wide-spread. Thus, enhancing the risk competence of laypersons will have to be initially restricted to increasing the awareness of existing problems.


Assuntos
Conhecimentos, Atitudes e Prática em Saúde , Gestão de Riscos , Toxicologia , Alumínio/efeitos adversos , Animais , Monóxido de Carbono/toxicidade , Relação Dose-Resposta a Droga , Humanos , Nível de Efeito Adverso não Observado , Alcaloides de Pirrolizidina/efeitos adversos , Medição de Risco , Fatores de Risco
20.
Pesqui. vet. bras ; 35(1): 33-38, 01/2015. tab, graf
Artigo em Português | LILACS | ID: lil-746558

RESUMO

Diversas espécies de Senecio estão amplamente difundidas nas pastagens de propriedades rurais do Sul do Brasil. Criadores dessa região relatam quedas nos índices reprodutivos dos rebanhos bovinos, muitas vezes de causas não determinadas. Várias plantas tóxicas são capazes de causar alterações reprodutivas diretas e indiretas em bovinos em diversos países, incluindo o Brasil, no entanto seus mecanismos patogenéticos ainda são pouco compreendidos. O objetivo desse trabalho é descrever lesões ovarianas em vacas com seneciose crônica proveniente de propriedades rurais da mesorregião Sudoeste Rio-grandense. Foram estudados 21 casos positivos de seneciose crônica diagnosticados entre 2011 e 2014. O estudo revelou que a seneciose crônica é a principal causa de morte de bovinos adultos na região. Quatro vacas prenhes apresentaram lesões hepáticas clássicas da intoxicação por Senecio spp. Essas vacas tiveram seus ovários avaliados histologicamente e células luteínicas grandes (CLG) desses ovários apresentavam megalocitose e pseudoinclusões nucleares. Algumas CLG apresentaram núcleos com até 23,69μm de diâmetro e o aumento no tamanho desses núcleos foi significativamente maior que os de vacas controle. Conclui-se que a intoxicação por Senecio spp. causa alterações ovarianas em vacas e é possível que a intoxicação cause perdas reprodutivas nos rebanhos bovinas da região...


Several species of Senecio are widely distributed on pasture lands in Southern Brazil. Farmers from this region are known to complain about declines in reproductive rates in cattl from undetermined causes. Several poisonous plants can cause direct and indirect reproductive disorders in cattle in several countries, including Brazil. However, their pathogenetic mechanisms are still poorly understood. The aim of this study is to describe ovarian lesions in cows with chronic seneciosis, from farms located in the Southwest Mesoregion of Rio Grande do Sul, a southern state in Brazil. Twenty-one cases of bovine chronic seneciosis diagnosed between 2011 and 2014 were analyzed. The study showed that chronic seneciosis is the major cause of death in adult cattle in the region. Four pregnant cows showing classical necropsy large luteal cells (LLG) from the ovaries of these four cows had marked megalocytosis and nuclear pseudo-inclusions. Some LLG showed nuclei with up to 23.69μm in diameter and the increase in size of these nuclei was significantly greater than measured those of control cows. It is concluded that the ingestion Senecio spp. induces ovarian changes in cows and the intoxication should be considered as a possible cause of reproductive failure in cattle herds from this region...


Assuntos
Animais , Feminino , Bovinos , Células Lúteas , Ovário/fisiopatologia , Senécio/efeitos adversos , Alcaloides de Pirrolizidina/efeitos adversos , Prenhez
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