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1.
Chemosphere ; 240: 124970, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31726584

RESUMO

Measurement of specific biomarkers identified by proteomics provides a potential alternative method for risk assessment, which is required to discriminate between hepatotoxicity and endocrine disruption. In this study, adult zebrafish (Danio rerio) were exposed to the hepatotoxic substance acetaminophen (APAP) for 21 days, in a fish short-term reproduction assay (FSTRA). The molecular changes induced by APAP exposure were studied in liver and gonads by applying a previously developed combined FSTRA and proteomics approach. We observed a significant decrease in egg numbers, an increase in plasma hyaluronic acid, and the presence of single cell necrosis in liver tissue. Furthermore, nine common biomarkers (atp5f1b, etfa, uqcrc2a, cahz, c3a.1, rab11ba, mettl7a, khdrbs1a and si:dkey-108k21.24) for assessing hepatotoxicity were detected in both male and female liver, indicating hepatic damage. In comparison with exposure to fadrozole, an endocrine disrupting chemical (EDC), three potential biomarkers for liver injury, i.e. cahz, c3a.1 and atp5f1b, were differentially expressed. The zebrafish proteome response to fadrozole exposure indicated a significant regulation in estrogen synthesis and perturbed binding of sperm to zona pellucida in the ovary. This study demonstrates that biomarkers identified and quantified by proteomics can serve as additional weight-of-evidence for the discrimination of hepatotoxicity and endocrine disruption, which is necessary for hazard identification in EU legislation and to decide upon the option for risk assessment.


Assuntos
Biomarcadores/análise , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Disruptores Endócrinos/toxicidade , Monitoramento Ambiental/métodos , Proteômica/métodos , Acetaminofen/metabolismo , Acetaminofen/toxicidade , Animais , Biomarcadores/metabolismo , Diagnóstico Diferencial , Fadrozol/toxicidade , Feminino , Gônadas/efeitos dos fármacos , Masculino , Reprodução/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/metabolismo
2.
Medicine (Baltimore) ; 98(50): e18322, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31852121

RESUMO

BACKGROUND: Drug induced liver injury (DILI) is an increasing cause of acute liver injury especially with increasing need for pharmacotherapy of widening comorbidities amongst our ever-aging population. Uncertainty however remains regarding both acceptable and widely agreeable diagnostic algorithms as well a clear understanding of mechanistic insights that most accurately underpins it. In this review, we have explored the potential role of emerging novel markers of DILI and how they could possibly be integrated into clinical care of patients. METHODS: We explored PUBMED and all other relevant databases for scientific studies that explored potential utility of novel biomarkers of DILI, and subsequently carried out a narrative synthesis of this data. As this is a narrative review with no recourse to patient identifiable information, no ethics committee's approval was sought or required. RESULTS: Novel biomarkers such as microRNA-122 (miR-122) profiles, high mobility group box-1 (HMGB1), glutamate dehydrogenase (GLDH), and cytokeratin-18 (K-18), amongst others do have the potential for reducing diagnostic uncertainties associated with DILI. CONCLUSION: With the increasing validation of some of the novel liver biomarkers such as K-18, mir-122, HMGB-1, and GLDH, there is the potential for improvement in the diagnostic uncertainty commonly associated with cases of DILI.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Glutamato Desidrogenase/análise , Proteína HMGB1/análise , Queratina-18/análise , MicroRNAs/análise , Medição de Risco/métodos , Biomarcadores/análise , Humanos
3.
Nihon Shokakibyo Gakkai Zasshi ; 116(11): 944-951, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31708507

RESUMO

This case report presents two males with drug-induced liver injury acquired from working at a glass factory dealing with silica and 2,2-dichloro-1,1,1-trifluoroethane (HCFC-123). Within one month of work, both patients presented with fever, icterus with liver dysfunction, and eosinophilia. Case 1 had experienced recurrence of symptoms twice while working and showed positive results for the drug-induced lymphocyte stimulation test (DLST). Meanwhile, case 2 was diagnosed by liver biopsy and clinical course but was negative for DLST. Hazard of exposure to non-crystalline silica is low, but drug-induced liver injury after exposure to HCFC-123 has been reported. Allergic liver injury is also caused by chemical substances;however, the insight into whether this injury is caused by exposure to silica or HCFC-123 remains unclear. Further studies are required to examine the influence of silica and HCFC-123 on drug-induced liver injury among glass-factory employees.


Assuntos
Poluentes Ocupacionais do Ar/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Etano Clorofluorcarbonos/toxicidade , Clorofluorcarbonetos , Dióxido de Silício/toxicidade , Humanos , Masculino , Exposição Ocupacional
4.
World J Gastroenterol ; 25(35): 5388-5402, 2019 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-31558881

RESUMO

BACKGROUND: Abnormal liver chemistry is a common problem in human immunodeficiency virus (HIV)-infected patients. Common causes of abnormal liver enzymes in this population include viral hepatitis B/C or opportunistic infection, drug toxicity, and neoplasm. Autoimmune hepatitis is a rare cause of hepatitis in HIV-infected individuals; however, this condition has been increasingly reported over the past few years. CASE SUMMARY: We present 13 HIV-infected patients (5 males and 8 females) who developed autoimmune hepatitis (AIH) after their immune status was restored, i.e. all patients had stable viral suppression with undetectable HIV viral loads, and median CD4+ counts of 557 cells/× 106 L. Eleven patients presented with chronic persistent elevation of aminotransferase enzyme levels. One patient presented with acute hepatitis and the other patient presented with jaundice. The median levels of aspartate aminotransferase and alanine aminotransferase enzymes were 178 and 177 U/mL, respectively. Elevation of immunoglobulin G levels was present in 11 (85%) patients. Antinuclear antibody and anti-smooth muscle antibody were positive in 11 (85%) and 5 (38%) patients. Liver biopsy was performed in all patients. They had histopathological findings compatible with AIH. The patients were started on prednisolone for remission induction, with good response. After improvement of the liver chemistry, the dose of prednisolone was tapered, and azathioprine was added as life-long maintenance therapy. At the last follow-up visit, all were doing well, without HIV viral rebound or infectious complications. CONCLUSION: This report underscores the emergence of autoimmune hepatitis in the context of HIV infection.


Assuntos
Carga Global da Doença , Infecções por HIV/complicações , Hepatite Autoimune/epidemiologia , Adulto , Alanina Transaminase/sangue , Fármacos Anti-HIV/uso terapêutico , Anticorpos Antinucleares/sangue , Anticorpos Antinucleares/imunologia , Aspartato Aminotransferases/sangue , Biópsia , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Diagnóstico Diferencial , Feminino , Glucocorticoides/uso terapêutico , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Hepatite Alcoólica/diagnóstico , Hepatite Autoimune/diagnóstico , Hepatite Autoimune/tratamento farmacológico , Hepatite Autoimune/imunologia , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Incidência , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Prednisolona/uso terapêutico , Prevalência , Indução de Remissão/métodos , Resultado do Tratamento
5.
Medicine (Baltimore) ; 98(31): e16717, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31374067

RESUMO

This study aims to determine the non-invasive, reliable and sensitive biochemical parameters for the diagnosis of drug-induced liver injury (DILI).Ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) and selected reaction monitoring (SRM) were used to profile the serum metabolome and quantify 15 targeted bile acid metabolites, respectively, in samples obtained from 38 DILI patients and 30 healthy controls.A comparison of the resulting serum metabolome profiles of the study participants revealed significant differences between DILI patients and healthy controls. Specifically, serum palmitic acid, taurochenodeoxycholic acid, glycocholic acid (GCA), and tauroursodeoxycholic acid (TUDCA) levels were significantly higher, and serum lysophosphatidylethanolamine levels were significantly lower in DILI patients vs healthy controls (P < .001). Furthermore, the SRM assay of bile acids revealed that the increase in GCA, taurocholic acid (TCA), TUDCA, glycochenodeoxycholic acid (GCDCA), glycochenodeoxycholic sulfate (GCDCS), and taurodeoxycholic acid (TDCA) corresponded to a higher degree of liver damage. These results also indicate that serum concentrations of chenodeoxycholic acid (CDCA), deoxycholic acid (DCA) and lithocholic acid (LCA) were significantly lower in patients with severe DILI, when compared to healthy controls, and that this decrease was closely correlated to the severity of liver damage.Taken together, these results demonstrate that bile acids could serve as potential biomarkers for the early diagnosis and severity of DILI.


Assuntos
Ácidos e Sais Biliares/sangue , Doença Hepática Induzida por Substâncias e Drogas/sangue , Metaboloma , Biomarcadores/sangue , Estudos de Casos e Controles , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Cromatografia Líquida , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Índice de Gravidade de Doença , Espectrometria de Massas em Tandem
7.
AACN Adv Crit Care ; 30(3): 232-248, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31462520

RESUMO

3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) has become a popular recreational drug of abuse among young adults, partly because of the belief that it is relatively safe compared with other drugs with the same stimulant and hallucinogenic effects. However, MDMA use has been associated with a wide spectrum of organ toxicities, with the liver being severely affected by its deleterious effects. This article discusses the essential pharmacology of MDMA and describes the effects MDMA has on various organ systems of the body, with particular focus on the liver. The putative mechanisms by which MDMA can cause liver damage are explored, with emphasis on patient-related factors that explain why some individuals are more susceptible than others to damage from MDMA. The incidence of hepatotoxicity related to MDMA use is presented, and the nursing management of patients who develop acute liver failure due to MDMA overuse is explored in light of current evidence.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/enfermagem , Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Enfermagem de Cuidados Críticos/educação , Enfermagem de Cuidados Críticos/normas , Alucinógenos/efeitos adversos , N-Metil-3,4-Metilenodioxianfetamina/efeitos adversos , Adolescente , Adulto , Educação Continuada em Enfermagem , Feminino , Humanos , Masculino , Guias de Prática Clínica como Assunto , Estados Unidos , Adulto Jovem
8.
Int J Mol Sci ; 20(17)2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31443562

RESUMO

Drug-induced liver injury (DILI) is a major factor in the development of drugs and the safety of drugs. If the DILI cannot be effectively predicted during the development of the drug, it will cause the drug to be withdrawn from markets. Therefore, DILI is crucial at the early stages of drug research. This work presents a 2-class ensemble classifier model for predicting DILI, with 2D molecular descriptors and fingerprints on a dataset of 450 compounds. The purpose of our study is to investigate which are the key molecular fingerprints that may cause DILI risk, and then to obtain a reliable ensemble model to predict DILI risk with these key factors. Experimental results suggested that 8 molecular fingerprints are very critical for predicting DILI, and also obtained the best ratio of molecular fingerprints to molecular descriptors. The result of the 5-fold cross-validation of the ensemble vote classifier method obtain an accuracy of 77.25%, and the accuracy of the test set was 81.67%. This model could be used for drug-induced liver injury prediction.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/etiologia , Biologia Computacional , Suscetibilidade a Doenças , Modelos Biológicos , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Biologia Computacional/métodos , Bases de Dados de Produtos Farmacêuticos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Preparações Farmacêuticas/química , Relação Quantitativa Estrutura-Atividade , Reprodutibilidade dos Testes
9.
Expert Rev Clin Pharmacol ; 12(9): 875-883, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31269818

RESUMO

Introduction: Drug-induced liver injury (DILI) has become the most frequent cause of acute liver failure in high-income countries. However, little is known about the determinants of DILI in sub-Saharan Africa (SSA), where the prescription of antimicrobials and the use of potentially hepatotoxic traditional medicine are common. Areas covered: Based on an extensive literature search, we summarize current data available on the epidemiology and risk factors of DILI in SSA. We discuss the most likely causes of DILI in the region, including antimicrobial therapies and traditional medicine. We also highlight research gaps as well as barriers to diagnosis and management of the condition, and explore ways to address these important challenges. Expert opinion: DILI is underestimated in SSA and several factors challenge its early diagnosis, including lack of information on the causes of DILI in the region, sub-optimal knowledge about the condition among clinicians, and structural difficulties faced by health care systems. In order to better prevent the occurrence of DILI and its complications, it is crucial to enhance awareness among health care providers and patients, adapt drug prescription habits and regulations, and improve current knowledge on the main risk factors for DILI, including host genetic and environmental determinants.


Assuntos
Anti-Infecciosos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , África ao Sul do Saara , Anti-Infecciosos/administração & dosagem , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Humanos , Medicina Tradicional Africana/efeitos adversos , Medicina Tradicional Africana/métodos , Fatores de Risco
10.
Adv Pharmacol ; 85: 165-193, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31307586

RESUMO

Idiosyncratic Drug-Induced Liver Injury (IDILI) is a rare but potentially life-threatening event that is caused by drugs that, at usual therapeutic doses, do not cause any biochemical or clinical evidence of liver injury in the majority of treated patients. The most common clinical phenotypes of IDILI are "acute hepatitis," "mixed hepatocellular-cholestatic hepatitis," and "cholestatic hepatitis" and these are distinguished by clinical, biochemical and histologic characteristics. Anti-microbials, herbals and dietary supplements are now the agents most often implicated in the US Drug-Induced Liver Injury Network registry. There are several scales that have been used to characterize the severity of IDILI events. There are no reliable means to accurately predict the course of an IDILI event at presentation. In clinical trials, the "gold standard" liver safety signal is the occurrence of "Hy's Law Cases." Making the diagnosis of IDILI, and when a patient is taking multiple drugs, identifying the most likely culprit can be challenging, but many drugs cause IDILI with characteristic clinical and biochemical presentations, or "signatures." In a clinical trial, it is sometimes possible to identify an overlooked "signature" of IDILI by characterizing more minor, asymptomatic, and transient elevations in liver chemistries. This observation can be helpful in assessing causation in rare serious liver events occurring in the clinical trial, or first recognized post-marketing.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/patologia , Índice de Gravidade de Doença , Controle Social Formal , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Doença Crônica , Ensaios Clínicos como Assunto , Humanos , Fenótipo
11.
Adv Pharmacol ; 85: 221-239, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31307588

RESUMO

Drug-induced liver injury (DILI) is a major clinical and regulatory challenge. As a result, interest in DILI biomarkers is growing. So far, considerable progress has been made in identification of biomarkers for diagnosis (acetaminophen-cysteine protein adducts), prediction (genetic biomarkers), and prognosis (microRNA-122, high mobility group box 1 protein, keratin-18, glutamate dehydrogenase, mitochondrial DNA). Many of those biomarkers also provide mechanistic insight. The purpose of this chapter is to review major advances in DILI biomarker research over the last decade, and to highlight some of the challenges involved in implementation. Although much work has been done, more liver-specific biomarkers, more DILI-specific biomarkers, and better prognostic biomarkers for survival are all still needed. Furthermore, more work is needed to define reference intervals and medical decision limits.


Assuntos
Biomarcadores/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Animais , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Humanos , Fígado/metabolismo , Prevalência , Prognóstico
12.
Adv Pharmacol ; 85: 263-272, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31307590

RESUMO

A review of the typical clinical course, diagnosis and treatment of acetaminophen toxicity is provided. For an acute overdose, most adults must ingest about 12g or more acetaminophen (APAP) before risk of serious hepatotoxicity is of concern. A nomogram of serum APAP concentration vs hours post-ingestion can assist in determining risk of liver injury and need for treatment. However, histories concerning the time of ingestion and the amount of drug ingested are usually unreliable. Peak serum transaminase activities usually occur 48-96h after acute ingestion. It is possible for patients to present in liver failure days after ingestion with undetectable serum APAP concentrations. Patients who have chronically ingested excessive APAP doses and develop hepatotoxicity usually present with such, and renal failure is more common in this population. Current treatment centers on administration of N-acetylcysteine (NAC) to prevent hepatotoxicity, though NAC also improves outcomes in patients who present with acute liver failure. When given early after APAP ingestion, NAC's main mechanism of action is to maintain intracellular glutathione stores so to detoxify the electrophilic APAP metabolite, NAPQI. NAC is generally well-tolerated when given intravenously, with the main concern being anaphylactoid reactions. These reactions usually occur during loading doses and are easily treated with discontinuation of the NAC infusion, administration of antihistamines, and then restarting the loading dose at a slower infusion rate. There is concern that current NAC dosing is not large enough to adequately treat large APAP ingestions. Patients with acute liver failure may be candidates for orthotopic liver transplantation.


Assuntos
Acetaminofen/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/terapia , Acetaminofen/administração & dosagem , Doença Aguda , Animais , Progressão da Doença , Humanos , Fígado/efeitos dos fármacos , Fatores de Risco
13.
Gastroenterology ; 157(5): 1245-1252.e3, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31302142

RESUMO

BACKGROUND & AIMS: Patients with drug-induced liver injury (DILI) frequently have comorbid conditions, but the effects of non-liver comorbidities on outcomes are not well understood. We investigated the association between comorbidity burden and outcomes of patients with DILI, and developed and validated a model to calculate risk of death within 6 months. METHODS: A multiple logistic regression model identified variables independently associated with death within 6 months of presenting with suspected DILI (6-month mortality) for 306 patients enrolled in the Drug-Induced Liver Injury Network prospective study at Indiana University (discovery cohort). The model was validated using data from 247 patients with suspected DILI enrolled in the same study at the University of North Carolina (validation cohort). Medical comorbidity burden was calculated using the Charlson Comorbidity Index-patients with scores higher than 2 were considered to have significant comorbidities. RESULTS: Six-month mortality was 8.5% in the discovery cohort and 4.5% in the validation cohort. In the discovery cohort, significant comorbidities (odds ratio, 5.4; 95% confidence interval [CI], 2.1-13.8), Model for End-Stage Liver Disease score (odds ratio, 1.11; 95% CI, 1.04-1.17), and serum level of albumin at presentation (odds ratio, 0.39; 95% CI, 0.2-0.76) were independently associated with 6-month mortality. A model based on these 3 variables identified patients who died within 6 months, with c-statistic values of 0.89 (95% CI, 0.86-0.94) in the discovery cohort and 0.91 (95% CI, 0.83-0.99) in the validation cohort. We developed a web-based calculator for use in the clinic to determine risk of death within 6 months for patients with suspected DILI. CONCLUSIONS: We developed and validated a model based on comorbidity burden, Model for End-Stage Liver Disease score, and serum level of albumin that predicts 6-month mortality in patients with suspected DILI.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Indicadores Básicos de Saúde , Adulto , Idoso , Causas de Morte , Doença Hepática Induzida por Substâncias e Drogas/mortalidade , Doença Hepática Induzida por Substâncias e Drogas/terapia , Comorbidade , Feminino , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Risco , Fatores de Tempo
14.
Zhonghua Gan Zang Bing Za Zhi ; 27(6): 420-423, 2019 Jun 20.
Artigo em Chinês | MEDLINE | ID: mdl-31357756

RESUMO

Idiosyncratic (unpredictable) drug-induced liver injury (iDILI) is one of the most challenging liver diseases encountered by hepatologists due to its diverse clinical and pathological manifestations and lack of specific diagnostic markers. An increasing awareness of iDILI diagnosis and carefully excluding liver damage induced by other causes is the key to a proper diagnosis of iDILI. However, delayed diagnosis, inappropriate monitor and care leads to serious clinical consequences, such as acute liver failure or even liver-related death. In addition, there is presently no effective treatment for iDILI. Herein, we presented the main recommendations of the recent EASL published first DILI guidelines into Chinese language to facilitate liver disease authors and health workers to understand the latest research progress of DILI.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/terapia , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , China , Humanos
15.
Korean J Gastroenterol ; 73(6): 360-364, 2019 Jun 25.
Artigo em Coreano | MEDLINE | ID: mdl-31234627

RESUMO

Albendazole is used as a typical antiparasitic agent worldwide. The side effects of albendazole may include nausea, vomiting, abdominal pain, dizziness, headache, alopecia, and increased liver enzymes. Mild elevation of the liver enzyme has been reported in more than 10% of cases, but drug induced liver injury was reported to be very rare. A 30-year-old woman visited the Dong-A University Hospital with anorexia, nausea, jaundice, and elevated liver enzyme. For diagnosis, other acute hepatitis etiologies were excluded, but the prophylactic administration of albendazole was verified. This paper introduces a case of drug-induced liver injury through the prophylactic administration of albendazole. Physicians should be aware of severe liver injury as one of the side effects of albendazole.


Assuntos
Albendazol/efeitos adversos , Anti-Helmínticos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Adulto , Alanina Transaminase/sangue , Albendazol/uso terapêutico , Anti-Helmínticos/uso terapêutico , Aspartato Aminotransferases/sangue , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Feminino , Humanos , Ultrassonografia
16.
Molecules ; 24(12)2019 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-31212965

RESUMO

The goal of this study was to investigate the potential for a cannabidiol-rich cannabis extract (CRCE) to interact with the most common over-the-counter drug and the major known cause of drug-induced liver injury-acetaminophen (APAP)-in aged female CD-1 mice. Gavaging mice with 116 mg/kg of cannabidiol (CBD) [mouse equivalent dose (MED) of 10 mg/kg of CBD] in CRCE delivered with sesame oil for three consecutive days followed by intraperitoneally (i.p.) acetaminophen (APAP) administration (400 mg/kg) on day 4 resulted in overt toxicity with 37.5% mortality. No mortality was observed in mice treated with 290 mg/kg of CBD+APAP (MED of 25 mg/kg of CBD) or APAP alone. Following CRCE/APAP co-administration, microscopic examination revealed a sinusoidal obstruction syndrome-like liver injury-the severity of which correlated with the degree of alterations in physiological and clinical biochemistry end points. Mechanistically, glutathione depletion and oxidative stress were observed between the APAP-only and co-administration groups, but co-administration resulted in much greater activation of c-Jun N-terminal kinase (JNK). Strikingly, these effects were not observed in mice gavaged with 290 mg/kg CBD in CRCE followed by APAP administration. These findings highlight the potential for CBD/drug interactions, and reveal an interesting paradoxical effect of CBD/APAP-induced hepatotoxicity.


Assuntos
Acetaminofen/efeitos adversos , Canabidiol/efeitos adversos , Hepatopatia Veno-Oclusiva/diagnóstico , Hepatopatia Veno-Oclusiva/etiologia , Animais , Biomarcadores , Canabidiol/química , Cannabis/química , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Feminino , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Camundongos , Camundongos Endogâmicos , Compostos Fitoquímicos/efeitos adversos , Compostos Fitoquímicos/química , Extratos Vegetais/efeitos adversos
17.
Cochrane Database Syst Rev ; 6: CD013171, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31158920

RESUMO

BACKGROUND: Lipid emulsions (LE) form a vital component of infant nutrition for critically ill, late preterm or term infants, particularly for those with gastrointestinal failure. Conventionally used soybean oil-based LE (S-LE) have high polyunsaturated fatty acid (PUFA) content and phytosterols, which may contribute to adverse effects including parenteral nutrition-associated liver disease (PNALD). OBJECTIVES: To compare the safety and efficacy of all LE for parenteral nutrition (PN) in term and late preterm infants (between 34 weeks' gestation and 36 weeks' and six days' gestation) with or without surgical conditions or PNALD within first six months of life, using all possible direct comparisons. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2018, Issue 5), MEDLINE (1946 to 18 June 2018), Embase (1974 to 18 June 2018), CINAHL (1982 to 18 June 2018), MIDRIS (1971 to 31 May 2018), conference proceedings, trial registries (ClinicalTrials.gov and the WHO's Trials Registry), and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: Randomised or quasi-randomised controlled studies in term and late preterm infants, with or without surgical conditions or PNALD. DATA COLLECTION AND ANALYSIS: Data collection and analysis conformed to the methods of Cochrane Neonatal. We used the GRADE approach to assess the quality of evidence for important outcomes in addition to reporting the conventional statistical significance of results. MAIN RESULTS: The review included nine randomised studies (n = 273). LE were classified in three broad groups: 1. all fish oil-containing LE including pure fish oil (F-LE) and multisource LE (e.g. medium-chain triglycerides (MCT)-olive-fish-soybean oil-LE (MOFS-LE), MCT-fish-soy oil-LE (MFS-LE) and olive-fish-soy-LE (OFS-LE)); 2. conventional pure S-LE; 3. alternative-LE (e.g. MCT-soy-LE (MS-LE), olive-soy-LE (OS-LE) and borage oil-based LE).We considered four broad comparisons: 1. all fish oil LE versus non-fish oil LE (6 studies; n = 182); 2. fish oil LE versus another fish oil LE (0 studies); 3. alternative-LE versus S-LE (3 studies; n = 91); 4. alternative-LE versus another alternative-LE (0 studies) in term and late preterm infants (0 studies), term and late preterm infants with surgical conditions (7 studies; n = 233) and term and late preterm infants with PNALD/cholestasis (2 studies; n = 40).PNALD/cholestasis was defined as conjugated bilirubin (Cbil) 2 mg/dL or greater and resolution of PNALD/cholestasis as Cbil less than 2 mg/dL. We put no restriction on timing of PNALD detection. There was heterogeneity in definitions and time points for detecting PNALD in the included studies.We found one study each in surgical infants and in infants with cholestasis, showing no evidence of difference in incidence or resolution of PNALD/cholestasis (Cbil cut-off: 2 mg/dL) with use of fish oil-containing LE compared to S-LE.We considered an outcome allowing for any definition of PNALD (different Cbil cut-off levels). In infants with surgical conditions and no pre-existing PNALD, meta-analysis showed no difference in the incidence of PNALD/cholestasis (any definition) with use of fish oil-containing LE compared to S-LE (typical risk ratio (RR) 1.20, 95% confidence interval (CI) 0.38 to 3.76; typical risk difference (RD) 0.03, 95% CI -0.14 to 0.20; 2 studies; n = 68; low-quality evidence). In infants with PNALD/cholestasis (any definition), use of fish oil-LEs was associated with significantly less cholestasis compared to the S-LE group (typical risk ratio (RR) 0.54, 95% confidence interval (CI) 0.32 to 0.91; typical risk difference (RD) -0.39, 95% CI -0.65 to -0.12; number needed to treat for additional beneficial outcome (NNTB) 3, 95% CI 2 to 9; 2 studies; n = 40; very low-quality evidence). This outcome had very low number of participants from two small studies with differences in study methodology and early termination in one study, which increased uncertainty about the effect estimates.One study in infants with cholestasis reported significantly better weight gain with a pure fish oil LE compared to a 10% S-LE (45 g/week, 95% CI 15.0 to 75.0; n = 16; very low-quality evidence). There were no significant differences in growth parameters in studies with surgical populations.For the secondary outcomes, in infants with cholestasis, one study (n = 24) reported significantly lower conjugated bilirubin levels but higher gamma glutamyl transferase levels with MOFS-LE (SMOFlipid) versus S-LE (Intralipid) and another study (n = 16), which was terminated early, reported significantly higher rates of rise in alanine aminotransferase (ALT) and conjugated bilirubin levels in the S-LE group compared to pure F-LE (Omegaven).In surgical infants, two studies each reported on hypertriglyceridaemia and Cbil levels with one study in each outcome showing significant benefit with use of a F-LE and the other study showing no difference between the groups. Meta-analysis was not performed for either of these outcomes as there were only two studies showing conflicting results with high heterogeneity between the studies.There was no evidence of differences in death, sepsis, alkaline phosphatase and ALT levels in infants with surgical conditions or cholestasis (very low-quality evidence).One study reported neurodevelopmental outcomes at six and 24 months in infants with surgical conditions (n = 11) with no evidence of difference with use of pure F-LE versus S-LE. Another study in infants with cholestasis (n = 16) reported no difference in head growth velocity between pure F-LE versus S-LE.GRADE quality of evidence ranged from low to very low as the included studies were small single-centre studies. Three of the six studies that contributed data to the review were terminated early for various reasons. AUTHORS' CONCLUSIONS: Based on the current review, there is insufficient data from randomised studies to determine with any certainty, the potential benefit of any LE including fish oil-containing LEs over another LE, for prevention or resolution of PNALD/cholestasis or any other outcomes in term and late preterm infants with underlying surgical conditions or cholestasis. There were no studies in infants without surgical conditions or cholestasis.Further research is required to establish role of fish oil or lipids from other sources in LEs to improve PNALD/cholestasis, and other clinical outcomes in parenterally fed term and late preterm infants.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Colestase/prevenção & controle , Óleos de Peixe/administração & dosagem , Recém-Nascido Prematuro , Nutrição Parenteral , Óleo de Soja/efeitos adversos , Bilirrubina/sangue , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Colestase/induzido quimicamente , Colestase/diagnóstico , Emulsões/efeitos adversos , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro/crescimento & desenvolvimento , Azeite de Oliva/administração & dosagem , Nutrição Parenteral/efeitos adversos , Fosfolipídeos/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Óleo de Soja/administração & dosagem , Óleo de Soja/química , Procedimentos Cirúrgicos Operatórios , Nascimento a Termo
18.
Biofactors ; 45(5): 740-749, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31120577

RESUMO

BACKGROUND: Valproic acid (VPA) is a clinical medicine primarily prescribed to control epileptic symptoms. VPA has potential side-effects, such as hepatotoxicity. Fibroblast growth factor 21 (FGF21) is a functional cytokine for metabolic regulation. In this article, we aimed to evaluate the possible clinical application of FGF21 in VPA-treated livers in early undetected liver injury (EULI). METHODS: Methodologically, plasma samples of VPA-treated epileptic patients were isolated for biochemical and high-performance liquid chromatography tests. In addition, VPA-dosed mice were subjected to determinations of serological parameters, key regulatory effectors and FGF21 expressions through biochemical analyses, enzyme-linked immunosorbent assay, immunohistochemistry stain, immunofluorescence stain, and reverse transcription-polymerase chain reaction (RT-PCR) test, respectively. RESULTS: The serological data suggested that VPA-treated epileptic patients showed visibly elevated FGF21 contents in plasma samples. However, other diagnostic parameters showed inconspicuous changes. As revealed in animal study, VPA-dosed mice exhibited undetected morphological alterations and hormonal changes in the liver, pancreas, and kidneys. Furthermore, serological parameters and key regulatory proteins in VPA-dosed livers and controls showed inconspicuous changes. Interestingly, endogenous FGF21 expressions in VPA-dosed mice were increased in sera. In further experiments, the findings showed that intracellular expressions of FGF21 mRNA and protein were upregulated in VPA-dosed livers as revealed in RT-PCR and immunoassay. CONCLUSIONS: Taken together, these preliminary data reveal that functional FGF21 cytokine may serve as a potent predictor in VPA-related EULI.


Assuntos
Anticonvulsivantes/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Epilepsia/tratamento farmacológico , Fatores de Crescimento de Fibroblastos/genética , RNA Mensageiro/genética , Ácido Valproico/efeitos adversos , Adulto , Animais , Anticonvulsivantes/administração & dosagem , Biomarcadores/sangue , Estudos de Casos e Controles , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Preparações de Ação Retardada , Epilepsia/metabolismo , Epilepsia/fisiopatologia , Feminino , Fatores de Crescimento de Fibroblastos/sangue , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Metaboloma/efeitos dos fármacos , Camundongos , Pessoa de Meia-Idade , RNA Mensageiro/sangue , Ácido Valproico/administração & dosagem
19.
Anal Bioanal Chem ; 411(15): 3361-3372, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31119349

RESUMO

Methamphetamine (METH) is one of the most highly addictive illicit drugs abused all over the world. Much evidence indicates that METH abuse leads to major toxicity, medical consequences, and even severe public health consequences. Existing studies usually focus on the pathomechanism of METH-induced toxicity; therefore, data on metabolites and elements correlating with particular toxicity remain scarce. The objective of the present study is to develop appropriate analytical procedures to identify the differential metabolic and elemental biomarkers on METH-induced hepatic injury to rats. The rats were administrated with METH (15 mg/mL/kg, two times per day) via intraperitoneal (i.p.) injections for four consecutive days. The alanine aminotransferase and aspartate aminotransferase activity levels of in the rat serum of the METH group increase significantly compared with those of the control group, suggesting obvious hepatic injury. The results are further confirmed by the histopathological microscopic observation. A total of 18 small molecular metabolites and 19 elements are selected to perform the simultaneous quantification based on the combination of liquid chromatography coupled with tandem mass spectrometry and inductively coupled plasma mass spectrometry. Sample preparation was optimized to cover all the analytes. Both methods are optimized and validated according to developed guidelines such as limits of detection, limits of quantification, linearity, precision, and recovery. All the obtained data are within the satisfactory range. The normalized data were processed according to the partial least squares discrimination analysis (PLS-DA) model. Five differential metabolic and six elemental markers are identified in rat plasma based on the variable importance in projection (VIP) (> 1) and t test results. Overall, the results obtained in this study demonstrate the developed methods are suitable for simultaneous determination of metabolic and elemental markers in the hepatic injury to rats induced by METH. Graphical abstract.


Assuntos
Estimulantes do Sistema Nervoso Central/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Metabolômica/métodos , Metanfetamina/efeitos adversos , Espectrometria de Massas em Tandem/métodos , Animais , Biomarcadores/análise , Biomarcadores/sangue , Biomarcadores/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/patologia , Cromatografia Líquida/métodos , Elementos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Ratos Sprague-Dawley , Sensibilidade e Especificidade
20.
PLoS One ; 14(5): e0212157, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31125338

RESUMO

BACKGROUND: The recently established association between higher levels of DNA-incorporated thioguanine nucleotides and lower relapse risk in childhood acute lymphoblastic leukaemia (ALL) calls for reassessment of prolonged 6-thioguanine (6TG) treatment, while avoiding the risk of hepatotoxicity. OBJECTIVES: To assess the incidence of hepatotoxicity in patients treated with 6TG, and to explore if a safe dose of continuous 6TG can be established. DATA SOURCES: Databases, conference proceedings, and reference lists of included studies were systematically searched for 6TG and synonyms from 1998-2018. METHODS: We included studies of patients with ALL or inflammatory bowel disorder (IBD) treated with 6TG, excluding studies with 6TG as part of an intensive chemotherapy regimen. We uploaded a protocol to PROSPERO (registration number CRD42018089424). Database and manual searches yielded 1823 unique records. Of these, 395 full-texts were screened for eligibility. Finally, 134 reports representing 42 studies were included. RESULTS AND CONCLUSIONS: We included data from 42 studies of ALL and IBD patients; four randomised controlled trials (RCTs) including 3,993 patients, 20 observational studies including 796 patients, and 18 case reports including 60 patients. Hepatotoxicity in the form of sinusoidal obstruction syndrome (SOS) occurred in 9-25% of the ALL patients in two of the four included RCTs using 6TG doses of 40-60 mg/m2/day, and long-term hepatotoxicity in the form of nodular regenerative hyperplasia (NRH) was reported in 2.5%. In IBD patients treated with 6TG doses of approximately 23 mg/m2/day, NRH occurred in 14% of patients. At a 6TG dose of approximately 12 mg/m2/day, NRH was reported in 6% of IBD patients, which is similar to the background incidence. According to this review, doses at or below 12 mg/m2/day are rarely associated with notable hepatotoxicity and can probably be considered safe.


Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doenças Inflamatórias Intestinais/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Tioguanina/efeitos adversos , Antimetabólitos Antineoplásicos/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/terapia , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Fígado/efeitos dos fármacos , Fígado/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Viés de Publicação , Tioguanina/uso terapêutico
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