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2.
J Gastroenterol Hepatol ; 35(4): 663-672, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31677185

RESUMO

BACKGROUND AND AIM: Primary biliary cholangitis (PBC) patients who are refractory to ursodeoxycholic acid (UDCA) are at risk for progression to cirrhosis and liver failure. Bezafibrate could be an alternative second-line therapeutic option in these patients. This study aimed to evaluate the long-term outcome(s) of combined UDCA and bezafibrate therapy in UDCA-refractory PBC patients and identify prognostic factors. METHODS: Among 445 patients treated with UDCA, 150 patients inadequately responded to UDCA monotherapy and received long-term UDCA plus bezafibrate (median, 15 years). Data from these patients were used for this retrospective analysis. RESULTS: Combination therapy resulted in significant improvements in serum biochemistry and liver transplantation risk estimated using the UK-PBC-risk and the GLOBE scores. The cumulative normalization rates of alkaline phosphatase, gamma-glutamyltransferase, and immunoglobulin M (IgM) were significantly higher in patients without cirrhosis-related symptoms or liver-related events than in those with them. Overall, IgM constantly emerged as a significant factor associated with cirrhosis-related symptoms and liver-related events at all time points. Cumulative survival rates were significantly lower in patients with IgM ≥ 240 mg/dL than in patients with IgM < 240 mg/dL. Thus, normalization of IgM levels was a good surrogate predictor of long-term prognosis. None of the patients discontinued combination therapy due to any adverse events during the follow-up period. CONCLUSIONS: Our findings point to the beneficial effects of long-term UDCA plus bezafibrate combination therapy for UDCA-refractory PBC patients, and IgM response can be a useful predictive biomarker of long-term clinical outcomes.


Assuntos
Bezafibrato/administração & dosagem , Imunoglobulina M/sangue , Cirrose Hepática Biliar/diagnóstico , Cirrose Hepática Biliar/tratamento farmacológico , Ácido Ursodesoxicólico/administração & dosagem , Biomarcadores/sangue , Quimioterapia Combinada , Feminino , Humanos , Cirrose Hepática Biliar/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Fatores de Tempo , Resultado do Tratamento
3.
Pharm Dev Technol ; 24(10): 1272-1277, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31557068

RESUMO

Studies in our laboratory have shown potential applications of the anti-atherosclerotic drug probucol (PB) in diabetes due to anti-inflammatory and ß-cell protective effects. The anti-inflammatory effects were optimized by incorporation of the anti-inflammatory bile acid, ursodeoxycholic acid (UDCA). This study aimed to test PB absorption, tissue accumulation profiles, effects on inflammation and type 1 diabetes prevention when combined with UDCA. Balb/c mice were divided into three equal groups and gavaged daily PB powder, PB microcapsules or PB-UDCA microcapsules for one week, at a constant dose. Mice were injected with a single dose of intraperitoneal/subcutaneous alloxan to induce type-1 diabetes and once diabetes was confirmed, treatments were continued for 3 days. Mice were euthanized and blood and tissues collected for analysis of PB and cytokine levels. The PB-UDCA group showed the highest PB concentrations in blood, gut, liver, spleen, brain, and white adipose tissues, with no significant increase in pancreas, heart, skeletal muscles, kidneys, urine or feces. Interferon gamma in plasma was significantly reduced by PB-UDCA suggesting potent anti-inflammatory effects. Blood glucose levels remained similar after treatments, while survival was highest among the PB-UDCA group. Our findings suggest that PB-UDCA resulted in best PB blood and tissue absorption and reduced inflammation.


Assuntos
Anti-Inflamatórios/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Células Secretoras de Insulina/efeitos dos fármacos , Probucol/uso terapêutico , Ácido Ursodesoxicólico/uso terapêutico , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacocinética , Combinação de Medicamentos , Composição de Medicamentos , Excipientes/química , Camundongos Endogâmicos BALB C , Tamanho da Partícula , Probucol/administração & dosagem , Probucol/farmacocinética , Distribuição Tecidual , Ácido Ursodesoxicólico/administração & dosagem , Ácido Ursodesoxicólico/farmacocinética
4.
World J Gastroenterol ; 25(33): 4959-4969, 2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31543686

RESUMO

BACKGROUND: Liver stiffness measurement (LSM) tends to overestimate fibrosis stage in nonalcoholic fatty liver disease (NAFLD). Controlled attenuation parameter (CAP), provided by LSM device, has been introduced for noninvasive quantification of hepatic steatosis. AIM: To determine the role of CAP values in predicting liver fibrosis stage by LSM in nonalcoholic steatohepatitis (NASH). METHODS: One hundred eighty-four patients with biopsy proven NASH had LSM and CAP evaluated at baseline. Among them, 130 patients had 1-year follow up LSM and analyzed for the changes of LSM after pioglitazone or ursodeoxycholic acid (UDCA) treatment. RESULTS: In Kleiner fibrosis stage F0-1, LSM values increased at higher CAP tertile (P = 0.001), and in F2, at middle and higher tertiles (P = 0.027). No difference across CAP tertiles was noticed in F3-4 (P = 0.752). Receiver operating characteristic curve for LSM cutoff in diagnosis of F ≥ 2 identified 8.05 kPa for lower CAP tertile, 9.35 kPa for middle, and 10.55 kPa for high tertile. When changes in proportion of significant fibrosis (F ≥ 2) were assessed among pioglitazone and UDCA treated patients considering CAP values, pioglitazone treated patients demonstrated decrease in proportion of high LSM. CONCLUSION: In patient with NAFLD, interpretation of LSM in association with CAP scores may provide helpful information sparing unnecessary liver biopsy.


Assuntos
Técnicas de Imagem por Elasticidade/métodos , Cirrose Hepática/diagnóstico , Fígado/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/patologia , Adulto , Biópsia , Progressão da Doença , Feminino , Seguimentos , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática/epidemiologia , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Pioglitazona/administração & dosagem , Valor Preditivo dos Testes , Prognóstico , Curva ROC , Estudos Retrospectivos , Ácido Ursodesoxicólico/administração & dosagem
5.
Sci Rep ; 9(1): 12740, 2019 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-31484954

RESUMO

The increasing prevalence of cholesterol gallstone disease places an economic burden on the healthcare system. To identify novel therapeutics, we assessed the effects of n-3 polyunsaturated fatty acids (PUFA) in combination with UDCA in a mouse model of cholesterol gallstones. Gallstone dissolution, gallbladder wall thickness, mucin gene expression in the gallbladder, and levels of phospholipids, cholesterol, and bile acids in bile and serum were analysed. RNA was extracted from the liver for mRNA sequencing and gene expression profiling. Combination treatment resulted in greater gallstone dissolution compared with the control group, and PUFA and combination treatments reduced the thickness of the gallbladder wall. Expression levels of mucin genes were significantly lower in the UDCA, PUFA, and combination groups. Transcriptome analyses revealed that combination treatment modulated hepatic lipid metabolism. The PUFA and combination groups showed elevated bile phospholipid and bile acid levels and a lower cholesterol saturation index. Combination treatment with PUFA and UDCA dissolves cholesterol gallstones in mice by decreasing mucin production, increasing levels of phospholipids and bile acids in bile, and decreasing cholesterol saturation. Further studies of the therapeutic effects of combination PUFA and UDCA treatment in patients with cholesterol gallstones are warranted.


Assuntos
Colesterol/metabolismo , Ácidos Graxos Ômega-3/administração & dosagem , Cálculos Biliares/tratamento farmacológico , Ácido Ursodesoxicólico/administração & dosagem , Animais , Ácidos e Sais Biliares/metabolismo , Quimioterapia Combinada , Vesícula Biliar/efeitos dos fármacos , Vesícula Biliar/metabolismo , Cálculos Biliares/metabolismo , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosfolipídeos/metabolismo
6.
Lancet ; 394(10201): 849-860, 2019 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-31378395

RESUMO

BACKGROUND: Intrahepatic cholestasis of pregnancy, characterised by maternal pruritus and increased serum bile acid concentrations, is associated with increased rates of stillbirth, preterm birth, and neonatal unit admission. Ursodeoxycholic acid is widely used as a treatment without an adequate evidence base. We aimed to evaluate whether ursodeoxycholic acid reduces adverse perinatal outcomes in women with intrahepatic cholestasis of pregnancy. METHODS: We did a double-blind, multicentre, randomised placebo-controlled trial at 33 hospital maternity units in England and Wales. We recruited women with intrahepatic cholestasis of pregnancy, who were aged 18 years or older and with a gestational age between 20 weeks and 40 weeks and 6 days, with a singleton or twin pregnancy and no known lethal fetal anomaly. Participants were randomly assigned 1:1 to ursodeoxycholic acid or placebo, given as two oral tablets a day at an equivalent dose of 500 mg twice a day. The dose could be increased or decreased at the clinician's discretion, to a maximum of four tablets and a minimum of one tablet a day. We recommended that treatment should be continued from enrolment until the infant's birth. The primary outcome was a composite of perinatal death (in-utero fetal death after randomisation or known neonatal death up to 7 days after birth), preterm delivery (<37 weeks' gestation), or neonatal unit admission for at least 4 h (from birth until hospital discharge). Each infant was counted once within this composite. All analyses were done according to the intention-to-treat principle. The trial was prospectively registered with the ISRCTN registry, number 91918806. FINDINGS: Between Dec 23, 2015, and Aug 7, 2018, 605 women were enrolled and randomly allocated to receive ursodeoxycholic acid (n=305) or placebo (n=300). The primary outcome analysis included 304 women and 322 infants in the ursodeoxycholic acid group, and 300 women and 318 infants in the placebo group (consent to use data was withdrawn for 1 woman and 2 infants). The primary composite outcome occurred in 74 (23%) of 322 infants in the ursodeoxycholic acid group and 85 (27%) of 318 infants in the placebo group (adjusted risk ratio 0·85 [95% CI 0·62-1·15]). Two serious adverse events were reported in the ursodeoxycholic acid group and six serious adverse events were reported in the placebo group; no serious adverse events were regarded as being related to treatment. INTERPRETATION: Treatment with ursodeoxycholic acid does not reduce adverse perinatal outcomes in women with intrahepatic cholestasis of pregnancy. Therefore, its routine use for this condition should be reconsidered. FUNDING: National Institute for Health Research Efficacy and Mechanism Evaluation Programme.


Assuntos
Colagogos e Coleréticos/administração & dosagem , Colestase Intra-Hepática/tratamento farmacológico , Complicações na Gravidez/tratamento farmacológico , Ácido Ursodesoxicólico/administração & dosagem , Administração Oral , Adulto , Alanina Transaminase/sangue , Ácidos e Sais Biliares/sangue , Biomarcadores/sangue , Colestase Intra-Hepática/sangue , Método Duplo-Cego , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Unidades de Terapia Intensiva Neonatal/estatística & dados numéricos , Nascimento Vivo/epidemiologia , Morte Perinatal/prevenção & controle , Gravidez , Complicações na Gravidez/sangue , Nascimento Prematuro/epidemiologia , Nascimento Prematuro/prevenção & controle , Prurido/prevenção & controle , Natimorto/epidemiologia
7.
Arq Gastroenterol ; 56(2): 184-190, 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31460584

RESUMO

BACKGROUND: Nowadays, pharmacological treatment of non-alcoholic fatty liver disease (NAFLD) is still limited and it is based on the treatment of conditions associated comorbities. Oxidative stress and insulin resistance are the mechanisms that seem to be mostly involved in its pathogenesis. OBJECTIVE: To evaluate the efficacy of N-acetylcysteine (NAC) in combination with metformin (MTF) and/or ursodeoxycholic acid (UDCA) for treatment of non-alcoholic steatohepatitis (NASH). METHODS: Open-label multicenter randomized trial was conducted for 48 weeks. It included patients with biopsy-proven NASH. The patients were randomized into three groups: NAC (1.2 g) + UDCA (15 mg/kg) + MTF (850-1500 mg/day) (n=26); UDCA (20 mg/kg) + MTF (850-1500 mg/day) (n=13); NAC (1.2g) + MTF (850-1500 mg/day) (n=14) for 48 weeks. Clinical, laboratory and the second liver biopsies were performed after 48 weeks. RESULTS: A total of 53 patients were evaluated; 17 (32.1%) were males; median age ±54 (IQR=15, 21-71) years. In the baseline, no difference was seen between groups according clinical and histological parameters. The groups differed only in cholesterol, LDL and triglycerides. No significant differences in biochemical and histologic parameters were found between these the three groups after 48 weeks of treatment. In the intragroup analysis (intention-to-treat) comparing histological and biochemical features, there were significant improvements in the steatosis degree (P=0.014), ballooning (0.027) and, consequently, in the NAFLD Activity Score (NAS) (P=0.005), and in the ALT levels at the end of the treatment only in the NAC + MTF group. No significant evidence of modification in the liver fibrosis could be observed in any of the groups. CONCLUSION: This multicenter study suggests that the association of NAC + MTF could reduce the liver disease activity in patients with NASH. These data stimulate further controlled studies with this therapy for these patients.


Assuntos
Acetilcisteína/administração & dosagem , Metformina/administração & dosagem , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Ácido Ursodesoxicólico/administração & dosagem , Adolescente , Adulto , Idoso , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
8.
Lancet Gastroenterol Hepatol ; 4(10): 781-793, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31345778

RESUMO

BACKGROUND: Norursodeoxycholic acid is an orally administered side chain-shortened homologue of ursodeoxycholic acid that undergoes hepatic enrichment with hepatoprotective, anti-inflammatory, and antifibrotic activity. We assessed the efficacy of two doses of norursodeoxycholic acid versus placebo for the treatment of non-alcoholic fatty liver disease. METHODS: We did a multicentre, double-blind, placebo-controlled, randomised, phase 2 dose-finding clinical trial in tertiary referral hospitals and medical centres in Austria (n=6) and Germany (n=23) for patients with non-alcoholic fatty liver disease with or without diabetes. Patients with a clinical diagnosis of non-alcoholic fatty liver disease and serum alanine aminotransferase (ALT) concentrations of more than 0·8 times the upper limit of normal were randomly assigned (1:1:1) using a computer-generated central randomisation. Patients were randomly assigned to receive either norursodeoxycholic acid capsules at 500 mg per day or 1500 mg per day, or placebo, for 12 weeks with a subsequent 4-week follow-up period. All individuals involved in the trial were masked to treatment allocation. The primary efficacy endpoint was the mean relative percentage change in ALT concentrations between baseline and end of treatment assessed in the intention-to-treat population. This trial is registered with EudraCT, number 2013-004605-38. FINDINGS: Between March 30, 2015, and Sept 20, 2016, of 198 individuals included in the analysis, 67 patients were randomly assigned to receive 500 mg norursodeoxycholic acid, 67 to 1500 mg norursodeoxycholic acid, and 64 to placebo. A dose-dependent reduction in serum ALT between baseline and end of treatment was observed with norursodeoxycholic acid versus placebo, with a significant effect in the 1500 mg group (mean change -27·8%, 95% repeated CI -34·7 to -14·4; p<0·0001). Serious adverse events (n=6) and treatment-emergent adverse events (n=314) were reported in a similar proportion of patients across groups. 112 treatment-emergent adverse events occurred in the 1500 mg group, 99 in the 500 mg group, and 103 in the placebo group. The most frequent adverse events were headache, gastrointestinal disorders, and infections (eg, diarrhoea, abdominal pain, or nasopharyngitis). INTERPRETATION: Norursodeoxycholic acid at 1500 mg resulted in a significant reduction of serum ALT within 12 weeks of treatment when compared with placebo. Norursodeoxycholic acid was safe and well tolerated encouraging further studies. FUNDING: Dr Falk Pharma GmbH.


Assuntos
Colagogos e Coleréticos/administração & dosagem , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Ácido Ursodesoxicólico/análogos & derivados , Adulto , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Glicemia/metabolismo , Colagogos e Coleréticos/efeitos adversos , Colagogos e Coleréticos/uso terapêutico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/sangue , Resultado do Tratamento , Ácido Ursodesoxicólico/administração & dosagem , Ácido Ursodesoxicólico/efeitos adversos , Ácido Ursodesoxicólico/uso terapêutico
9.
Clin Ter ; 170(3): e211-e215, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31173052

RESUMO

Different studies investigated about the role of T-helper 1 cytokines and chemokines in primary biliary cirrhosis (PBC). Animal models with autoimmune cholangitis have been used to investigate the involvement of (C-X-C motif) receptor (CXCR)3 and its ligand (C-X-C motif) ligand (CXCL)9/monokine induced by interferon (IFN)-γ (MIG) in the pathogenesis of PBC, suggesting a contribution of MIG in the development of PBC. In patients with PBC, in particular at the level of the portal areas of diseased livers, MIG expression and CXCR3+ cells have been found. MIG is positively associated with the severity of liver fibrosis. In PBC, circulating MIG levels and CXCR3+ cells are related with the progression of the disease; in fact, their expression increases significantly in PBC patients with respect to controls. Furthermore, it has been shown a significant reduction of these chemokines in the serum of PBC patients after treatment with ursodeoxycholic acid.


Assuntos
Quimiocina CXCL9/sangue , Cirrose Hepática Biliar/sangue , Receptores CXCR3/sangue , Animais , Doenças Autoimunes/imunologia , Quimiocina CXCL10/sangue , Quimiocinas/sangue , Colangite/sangue , Citocinas/sangue , Progressão da Doença , Humanos , Ácido Ursodesoxicólico/administração & dosagem
10.
Biochem Pharmacol ; 168: 48-56, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31202734

RESUMO

Lipopolysaccharide (LPS) from Gram (-) bacteria induces inflammatory cholestasis by impairing the expression/localization of transporters involved in bile formation (e.g., Bsep, Mrp2). Therapeutic options for this disease are lacking. Ursodeoxycholic acid (UDCA) is the first choice therapy in cholestasis, but its anticholestatic efficacy in this hepatopathy remains to be evaluated. To asses it, male Wistar rats received UDCA for 5 days (25 mg/Kg/day, i.p.) with or without LPS, administered at 8 a.m. of the last 2 days (4 mg/Kg/day, i.p.), plus half of this dose at 8 p.m. of the last day. Then, plasma alkaline phosphatase (ALP), bile flow, basal and taurocholate-stimulated bile acid output, total glutathione output, and total/plasma membrane liver protein expression of Bsep and Mrp2 by confocal microscopy were assessed. mRNA levels of both transporters were assessed by Real-Time PCR. Plasma pro-inflammatory cytokines (IL-6 and TNF-α) were measured by ELISA. Our results showed that UDCA attenuated LPS-induced ALP plasma release and the impairment in the excretion of the Bsep substrate, taurocholate. This was associated with an improved Bsep expression at both mRNA and protein levels, and by an improved localization of Bsep in plasma membrane. UDCA failed to reduce the increase in plasma pro-inflammatory cytokines induced by LPS and Mrp2 expression/function. In conclusion, UDCA protects the hepatocyte against the damaging effect of bile acids accumulated by the LPS-induced secretory failure. This involved an enhanced synthesis of Bsep and an improved membrane stability of the newly synthesized transporters.


Assuntos
Colagogos e Coleréticos/uso terapêutico , Colestase/induzido quimicamente , Colestase/tratamento farmacológico , Lipopolissacarídeos/farmacologia , Ácido Ursodesoxicólico/uso terapêutico , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Fosfatase Alcalina/sangue , Animais , Ácidos e Sais Biliares/metabolismo , Colagogos e Coleréticos/administração & dosagem , Colagogos e Coleréticos/farmacologia , Modelos Animais de Doenças , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Fígado/metabolismo , Masculino , Ratos , Ratos Wistar , Resultado do Tratamento , Ácido Ursodesoxicólico/administração & dosagem , Ácido Ursodesoxicólico/farmacologia
11.
BMJ Case Rep ; 12(5)2019 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-31147407

RESUMO

A 50-year-old woman presented with worsening fatigue and shortness of breath. For 2 months, she has been having increased craving for unpeeled lemons and was seen in clinic about a month prior to presentation at the emergency room. At that time, she was asymptomatic except for endorsing craving for lemons. Physical exam findings at presentation noted obesity, sinus tachycardia, pallor, mild scleral jaundice and no other stigmata for chronic liver disease. Her labs suggested iron-deficiency anaemia (IDA), elevated liver enzymes and positive antimitochondrial antibody titre. Abdominal ultrasound and CT scan showed mild scarring. She was diagnosed with primary biliary cholangitis with portal hypertension complicated by oesophageal varices and IDA. Interventions included blood transfusion, oesophageal banding and treatment with ursodeoxycholic acid. Her craving for lemons, shortness of breath and fatigue resolved within 1 week. With ongoing outpatient follow-up and oesophageal variceal surveillance, she continues to do well.


Assuntos
Anemia Ferropriva/diagnóstico , Varizes Esofágicas e Gástricas/diagnóstico , Hipertensão Portal/diagnóstico , Cirrose Hepática Biliar/diagnóstico , Pica , Administração Oral , Anemia Ferropriva/sangue , Anemia Ferropriva/complicações , Anemia Ferropriva/tratamento farmacológico , Transfusão de Sangue , Colagogos e Coleréticos/administração & dosagem , Colagogos e Coleréticos/uso terapêutico , Diagnóstico Diferencial , Procedimentos Cirúrgicos do Sistema Digestório , Varizes Esofágicas e Gástricas/complicações , Varizes Esofágicas e Gástricas/diagnóstico por imagem , Varizes Esofágicas e Gástricas/cirurgia , Feminino , Humanos , Hipertensão Portal/complicações , Hipertensão Portal/diagnóstico por imagem , Hipertensão Portal/terapia , Ferro/administração & dosagem , Ferro/uso terapêutico , Cirrose Hepática Biliar/complicações , Cirrose Hepática Biliar/diagnóstico por imagem , Cirrose Hepática Biliar/terapia , Pessoa de Meia-Idade , Ultrassonografia , Ácido Ursodesoxicólico/administração & dosagem , Ácido Ursodesoxicólico/uso terapêutico
12.
Surg Obes Relat Dis ; 15(6): 827-831, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31113752

RESUMO

BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is a definitive solution for morbid obesity and its related co-morbidities. Cholelithiasis is a postoperative complication of LSG. The use of ursodeoxycholic acid (UDCA) after LSG is a proposed solution to reduce the incidence of cholelithiasis. OBJECTIVE: To evaluate the effect of UDCA prophylaxis on cholelithiasis following LSG in morbidly obese patients. SETTING: Two university hospitals in Egypt, Cairo, and Beni Suef Universities' hospitals. METHODS: This prospective study was conducted between July 2015 and March 2018 and included 200 patients scheduled for LSG. They were randomly divided into 2 groups. The UDCA group received a postoperative prophylaxis regimen for prevention of cholelithiasis in the form of 250 mg twice daily of UDCA for 6 months. The control group did not receive prophylactic treatment. Abdominal ultrasound was done at 3, 6, 9, and 12 months for all patients to detect cholelithiasis. The primary outcome measure was cholelithiasis. RESULTS: Only 6% of the UDCA group developed cholelithiasis compared with 40% in the control group (P < .001). Age, sex, initial body mass index, and excess weight loss at 6 months did not significantly affect cholelithiasis. CONCLUSION: UDCA treatment for 6 months after LSG is effective in the prevention of cholelithiasis.


Assuntos
Cirurgia Bariátrica/efeitos adversos , Colelitíase/tratamento farmacológico , Gastrectomia/efeitos adversos , Complicações Pós-Operatórias/tratamento farmacológico , Ácido Ursodesoxicólico/uso terapêutico , Administração Oral , Adulto , Colagogos e Coleréticos/administração & dosagem , Colagogos e Coleréticos/uso terapêutico , Colelitíase/diagnóstico por imagem , Colelitíase/prevenção & controle , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade Mórbida/cirurgia , Complicações Pós-Operatórias/diagnóstico por imagem , Complicações Pós-Operatórias/prevenção & controle , Estudos Prospectivos , Ácido Ursodesoxicólico/administração & dosagem , Adulto Jovem
13.
Biomed Pharmacother ; 115: 108938, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31071511

RESUMO

Fatty liver disease is commonly associated with inflammation, oxidative stress and apoptosis of hepatocytes. This study was designed to investigate the combinational therapeutic effects of curcumin (CMN) and Ursodeoxycholic acid (UDCA) on non-alcoholic fatty liver disease (NAFLD). Male Wistar rats were divided into 8 groups: NAFLD-induced rats, NAFLD-induced rats + CMN, NAFLD-induced rats + UDCA, and NAFLD-induced rats that received CMN + UDCA. CMN (200 mg/kg) and UDCA (80 mg/kg) was administered orally for 14 and 28 consecutive days. Biochemical and histopathological analysis were conducted in all the groups. It was seen that co-administration of CMN and UDCA significantly reduced fatty degeneration, cellular necrosis, edema, and immune cell infiltration compared to non-treated NAFLD-induced rats. Whereas, combinational therapy caused a significant decrease in levels of SGOT and SGPT enzymes and expression of p53, caspase III, iNOS and bcl-2 mRNA and proteins, in variant with the treatment of CMN and UDCA, respectively. Co-administration of CMN and UDCA was also associated with the restoration of the levels of serum TG and HDL-C however, had no effect on LDL-C. It also resulted in an in TAC, GSH- PX, and SOD and decrease in MDA level. Our study concludes that combinational therapy of CMN and UDCA is effective for the treatment of NAFLD, as compared to their solo treatment.


Assuntos
Antioxidantes/metabolismo , Curcumina/uso terapêutico , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Ácido Ursodesoxicólico/uso terapêutico , Animais , Biomarcadores/sangue , Curcumina/administração & dosagem , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Quimioterapia Combinada , Fígado/enzimologia , Masculino , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Ratos Wistar , Ácido Ursodesoxicólico/administração & dosagem
14.
Hepatol Int ; 13(4): 510-518, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31069759

RESUMO

OBJECTIVES AND STUDY: Various degrees of biliary changes are considered to be part of the histological picture of children with pediatrics autoimmune liver disease (AILD), but the literature is scarce and confusing. We aimed to describe the characteristics of children with AILD (autoimmune hepatitis, AIH, and autoimmune sclerosing cholangitis, ASC) focusing on the prevalence and type of biliary abnormalities on initial biopsy to see whether ASC was predictable on histological ground. METHODS: The files of children diagnosed with AILD were reviewed. The Ishak score was used to grade inflammation and fibrosis on biopsy; a biliary score was built to grade bile duct injury. Demographic, laboratory and histological features at diagnosis were reported and compared between the two groups (AIH vs ASC). RESULTS: Forty-one patients were diagnosed with AIH (n = 24), ASC (n = 13) and PSC (n = 4) between 2009 and 2018. Twenty-nine patients [F = 76%, AIH = 20, ASC = 9, median age at diagnosis 11.7 (range 2.2-17.8)] were included in the study; 12 (4 with PSC) were excluded. Prevalence of inflammatory bowel disease was higher in ASC group (56% vs 10% in AIH, p < 0.05). On histology 17% had cirrhosis. The grade of biliopathy with AILD was moderate in 72% and severe in 31%, and overall more prominent in ASC (p = 0.031). The inflammation of the bile ducts was classified as "multifocal" or "diffuse" mainly in ASC patients (89% vs 45% in AIH, p = 0.043). Periductular fibrosis was reported in 52% of AILD patients, with a higher mean score in ASC group (p < 0.05). However, ductular reaction, biliary metaplasia and granulomatous cholangitis were equally reported in AIH and ASC, providing no clear-cut for the distinction of the two entities in the global histological evaluation. CONCLUSIONS: Majority of patients with pediatrics AILD have "moderate" or "severe" features of biliopathy; AIH and ASC are not easily distinguishable on histological ground at diagnosis, and therefore, the cholangiogram remains the only effective tool to differentiate patients with AIH from those with ASC. Further prospective studies are needed to better define histological biliary features in AILD, assess if the biliopathy responds to immunosuppressive treatment and evaluate its impact on long-term outcome.


Assuntos
Colangite Esclerosante/patologia , Colangite/patologia , Hepatite Autoimune/patologia , Adolescente , Azatioprina/administração & dosagem , Criança , Pré-Escolar , Colangite/tratamento farmacológico , Colangite Esclerosante/tratamento farmacológico , Quimioterapia Combinada , Feminino , Hepatite Autoimune/tratamento farmacológico , Humanos , Imunossupressores/administração & dosagem , Cirrose Hepática Biliar/patologia , Linfócitos/patologia , Masculino , Prednisona/administração & dosagem , Estudos Retrospectivos , Resultado do Tratamento , Ácido Ursodesoxicólico/administração & dosagem
15.
Obes Surg ; 29(8): 2464-2469, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30945151

RESUMO

PURPOSE: The use of ursodeoxycholic acid (UDCA) to prevent gallstone formation after sleeve gastrectomy (SG) is still debated. Furthermore, no study has assessed the effectiveness of UDCA on gallstone formation after the first postoperative year. Our aim was to compare the incidence of cholelithiasis (CL) at 1 and 3 years after SG between patients treated or not treated with UDCA. MATERIALS AND METHODS: From January 2008, a postoperative ultrasound monitoring was scheduled for all patients who underwent SG in our institution. Patients with a preoperative intact gallbladder who performed at least one ultrasound at 1 year after SG were included. We compared the incidence of CL between patients operated before October 2013 who did not receive UDCA and those operated from October 2013 who received UDCA 500 mg once daily for 6 months postoperatively. RESULTS: The incidence of CL at 1 year after SG was 28% in the 46 non-treated and 3.5% in the 143 treated patients (p < 0.001). UDCA reduced the proportion of cholecystectomies from 11% to 1.4% (p = 0.012). Thus, the number of patients needed to treat to avoid a cholecystectomy was about 10. Only 2 patients (1.4%) stopped UDCA for adverse effects. No gallstone appeared at 3 postoperative years in the 61 patients who performed an ultrasound at this time. CONCLUSION: UDCA 500 mg once daily for 6 months postoperatively is effective and well tolerated to prevent CL at midterm after SG. We recommend UDCA treatment in all patients after SG with an intact preoperative gallbladder. However, large randomized studies are needed to establish guidelines for prevention of gallstone formation after SG.


Assuntos
Colagogos e Coleréticos/uso terapêutico , Cálculos Biliares/prevenção & controle , Gastrectomia/efeitos adversos , Obesidade Mórbida/cirurgia , Ácido Ursodesoxicólico/uso terapêutico , Adulto , Cirurgia Bariátrica/efeitos adversos , Cirurgia Bariátrica/métodos , Colagogos e Coleréticos/administração & dosagem , Colecistectomia/estatística & dados numéricos , Esquema de Medicação , Feminino , Cálculos Biliares/diagnóstico por imagem , Cálculos Biliares/etiologia , Cálculos Biliares/cirurgia , Gastrectomia/métodos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Cuidados Pós-Operatórios/métodos , Complicações Pós-Operatórias/diagnóstico por imagem , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Fatores de Risco , Ultrassonografia , Ácido Ursodesoxicólico/administração & dosagem
16.
Pak J Pharm Sci ; 32(1(Special)): 433-437, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30852481

RESUMO

.Fructus akebiae extract (FAE) is a commonly used drug in the clinical treatment of liver cancer. FAE has many pharmacological activities, such as liver protection, anti-tumor, spasmolysis, pain relief and antifungal activity. Its clinical application is extensive, so far no toxic reports have been reported, and new drugs can be developed. This study was designed to investigate the therapeutic effect of predictor extract on non-alcoholic fatty liver disease (NAFLD). 180 patients with NAFLD were randomly divided into 2 groups. The control group was treated with ursodeoxycholic acid (UDCA), and the experimental group was treated with Fructus akebiae extract combined with ursodeoxycholic acid. The results showed that the comprehensive clinical efficacy of the treatment group was 95.56%, which was higher than that of the control group (93.33%), and P < 0.01. In the experimental group, 63 cases (70%) were improved after one course of treatment, main symptom score as (5.09 ±3.98), body mass index as (24.65±3.86), and liver CT value increased. It can be seen that the addition of FAE can significantly improve the clinical symptoms and serum biochemical indicators such as ALT, AST, TG and TC in patients with non-alcoholic fatty liver disease, which is supported by some histological evidence. These findings suggest that FAE combined with Ursodeoxycholic Acid is safe and effective in the treatment of fatty liver.


Assuntos
Colagogos e Coleréticos/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Ácido Ursodesoxicólico/uso terapêutico , Colagogos e Coleréticos/administração & dosagem , Quimioterapia Combinada , Medicamentos de Ervas Chinesas/administração & dosagem , Feminino , Humanos , Fígado/diagnóstico por imagem , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Ultrassonografia , Ácido Ursodesoxicólico/administração & dosagem
17.
Lancet Gastroenterol Hepatol ; 4(6): 445-453, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30922873

RESUMO

BACKGROUND: The aim of this study was to evaluate the long-term efficacy and safety of obeticholic acid for patients with primary biliary cholangitis using 3-year interim data from the 5-year open-label extension of the pivotal phase 3 POISE trial. METHODS: In the double-blind phase of POISE, 217 patients with primary biliary cholangitis with inadequate response to or intolerance to ursodeoxycholic acid were randomised to receive placebo, obeticholic acid 5 to 10 mg, or obeticholic acid 10 mg once daily for 12 months. During the open-label extension phase, patients received variable, adjusted doses of obeticholic acid. Markers of cholestasis and liver injury, alkaline phosphatase (ALP), and total and direct bilirubin were evaluated, and safety was assessed for up to 48 months of treatment with obeticholic acid. All analyses in the open-label extension were done in the safety population, defined as any patient randomised in the double-blind phase who received at least one dose of obeticholic acid during the open-label extension. This trial is registered at ClinicalTrials.gov (NCT01473524) and with EudraCT (2011-004728-36). FINDINGS: 193 patients were treated during the open-label extension. In this 3-year interim analysis, ALP concentrations were significantly reduced compared with baseline at 12 months (mean change -105·2 U/L [SD 87·6]), 24 months (-101·0 U/L [98·5]), 36 months (-108·6 U/L [95·7]), and 48 months (-95·6 U/L [121·1]; p<0·0001 for all yearly time points). Total bilirubin concentrations were stabilised, with significant reductions versus baseline at 12 months (mean change -0·9 µmol/L [SD 4·1]; p=0·0042) and 48 months (-0·8 µmol/L [3·8]; p=0·016). Stabilisation was also noted for direct bilirubin, with a significant change from baseline at 12 months (mean change -0·5 µmol/L [SD 3·0]; p=0·021). However, changes in total and direct bilirubin were not significant at other time points. Obeticholic acid was generally well tolerated, with pruritus (149 [77%] patients) and fatigue (63 [33%]) being the most common adverse events. No serious adverse events were considered related to obeticholic acid. INTERPRETATION: Interim analyses suggest long-term efficacy and safety of obeticholic acid in patients with primary biliary cholangitis who are intolerant to or inadequately responsive to ursodeoxycholic acid. FUNDING: Intercept Pharmaceuticals.


Assuntos
Ácido Quenodesoxicólico/análogos & derivados , Colangite/tratamento farmacológico , Fármacos Gastrointestinais/administração & dosagem , Fosfatase Alcalina/análise , Bilirrubina/análise , Ácido Quenodesoxicólico/administração & dosagem , Ácido Quenodesoxicólico/efeitos adversos , Colagogos e Coleréticos/administração & dosagem , Colagogos e Coleréticos/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Fadiga/etiologia , Feminino , Fármacos Gastrointestinais/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Prurido/etiologia , Ácido Ursodesoxicólico/administração & dosagem , Ácido Ursodesoxicólico/efeitos adversos
18.
Int J Mycobacteriol ; 8(1): 89-92, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30860185

RESUMO

Background: Tuberculosis (TB) remains a global health problem. The application of rifampicin-based regimens for antimycobacterial therapy is hampered by its marked hepatotoxicity which results in poor adherence and may contribute to prolonged therapy or treatment failure. The purpose of this prospective investigation was to evaluate the hepatoprotective effectiveness of oral ursodeoxycholic acid (UDCA) (250-500 mg TID) administered to TB- or non-TB mycobacterial (NTM)-infected patients with drug-induced hepatotoxicity and ongoing therapy. Methods: Study population: During 2009-2017, 27 patients (11 women, 16 men, aged 19-90 years; median age 44 years, 16 Caucasians, 10 Africans, 1 Asian) out of 285 patients with active TB (24/261) or NTM infections (3/24) treated at our TB Center developed clinically relevant hepatotoxicity. Oral UDCA was administered to treat hepatotoxicity. Results: Twenty-one out of 27 patients (77.8%) showed normalization of elevated enzymes (alanine transferase and aspartate aminotransferase), alkaline phosphatase, and bilirubin while continuing TB treatment and 5 patients demonstrated a significant reduction of liver enzymes (18.5%). No change was observed in 1 patient (3.7%). Drug dose was not reduced in all patients; they all showed radiological and clinical improvement. There were no significant side effects. Conclusion: Oral administration of UDCA to TB patients developing anti-TB drug-induced liver injury may reverse hepatotoxicity in adults.


Assuntos
Antituberculosos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Colagogos e Coleréticos/administração & dosagem , Infecções por Mycobacterium/tratamento farmacológico , Ácido Ursodesoxicólico/administração & dosagem , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Alanina Transaminase/sangue , Antituberculosos/administração & dosagem , Aspartato Aminotransferases/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Resultado do Tratamento , Adulto Jovem
19.
World J Gastroenterol ; 25(7): 859-869, 2019 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-30809085

RESUMO

BACKGROUND: Disorders of primary bile acid synthesis may be life-threatening if undiagnosed, or not treated with primary bile acid replacement therapy. To date, there are few reports on the management and follow-up of patients with Δ4-3-oxosteroid 5ß-reductase (AKR1D1) deficiency. We hypothesized that a retrospective analysis of the responses to oral bile acid replacement therapy with chenodeoxycholic acid (CDCA) in patients with this bile acid synthesis disorder will increase our understanding of the disease progression and permit evaluation of this treatment regimen as an alternative to the Food and Drug Administration (FDA) approved drug cholic acid, which is currently unavailable in China. AIM: To evaluate the therapeutic responses of patients with AKR1D1 deficiency to oral bile acid therapy, specifically CDCA. METHODS: Twelve patients with AKR1D1 deficiency, confirmed by fast atom bombardment ionization-mass spectrometry analysis of urine and by gene sequencing for mutations in AKR1D1, were treated with differing doses of CDCA or ursodeoxycholic acid (UDCA). The clinical and biochemical responses to therapy were monitored over a period ranging 0.5-6.4 years. Dose adjustment, to optimize the therapeutic dose, was based on changes in serum biochemistry parameters, notably liver function tests, and suppression of the urinary levels of atypical hepatotoxic 3-oxo-Δ4-bile acids measured by mass spectrometry. RESULTS: Physical examination, serum biochemistry parameters, and sonographic findings improved in all 12 patients during bile acid therapy, except one who underwent liver transplantation. Urine bile acid analysis confirmed a significant reduction in atypical hepatotoxic 3-oxo-Δ4 bile acids concomitant with clinical and biochemical improvements in those patients treated with CDCA. UDCA was ineffective in down-regulating endogenous bile acid synthesis as evidenced from the inability to suppress the urinary excretion of atypical 3-oxo-Δ4-bile acids. The dose of CDCA required for optimal clinical and biochemical responses varied from 5.5-10 mg/kg per day among patients based on maximum suppression of the atypical bile acids and improvement in serum biochemistry parameters, and careful titration of the dose was necessary to avoid side effects from CDCA. CONCLUSION: The primary bile acid CDCA is effective in treating AKR1D1 deficiency but the therapeutic dose requires individualized optimization. UDCA is not recommended for long-term management.


Assuntos
Ácido Quenodesoxicólico/administração & dosagem , Fármacos Gastrointestinais/administração & dosagem , Doenças Metabólicas/tratamento farmacológico , Oxirredutases/deficiência , Ácido Ursodesoxicólico/administração & dosagem , Administração Oral , Ácido Quenodesoxicólico/efeitos adversos , Análise Mutacional de DNA , Progressão da Doença , Relação Dose-Resposta a Droga , Feminino , Fármacos Gastrointestinais/efeitos adversos , Humanos , Recém-Nascido , Masculino , Doenças Metabólicas/genética , Doenças Metabólicas/urina , Mutação , Oxirredutases/genética , Estudos Retrospectivos , Resultado do Tratamento , Ácido Ursodesoxicólico/efeitos adversos
20.
Hepatology ; 70(6): 2035-2046, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-30737815

RESUMO

In Japan, bezafibrate (BF) is a second-line agent for primary biliary cholangitis (PBC) that is refractory to ursodeoxycholic acid (UDCA) treatment. From a retrospective cohort (n = 873) from the Japan PBC Study Group, we enrolled 118 patients who had received UDCA monotherapy for at least 1 year followed by combination therapy with UDCA+BF for at least 1 year. GLOBE and UK-PBC scores after UDCA monotherapy (i.e., immediately before UDCA+BF combination therapy) were compared with those after 1 year of UDCA+BF combination therapy. The real outcomes of enrolled patients estimated by Kaplan-Meier analysis were compared with the predicted outcomes calculated using GLOBE and UK-PBC scores. In addition, the hazard ratio of BF treatment was calculated using propensity score analysis. The mean GLOBE score before the combination therapy was 0.504 ± 0.080, which improved significantly to 0.115 ± 0.085 (P < 0.0001) after 1 year of combination therapy. The real liver transplant-free survival of enrolled patients was significantly better than that predicted by GLOBE score before introducing BF. Combination therapy did not significantly improve the real rates of liver transplantation or liver-related death compared with those predicted by UK-PBC risk score before introducing BF, but the predicted risk was significantly reduced by the addition of BF (P < 0.0001). Cox regression analysis with inverse probability of treatment weighting showed that the addition of BF significantly reduced the hazard of liver transplant or liver-related death in patients who, after 1 year of UDCA monotherapy, had normal serum bilirubin (adjusted hazard ratio 0.09, 95% confidence interval 0.01-0.60, P = 0.013). Conclusion: Addition of BF to UDCA monotherapy improves not only GLOBE and UK-PBC scores but also the long-term prognosis of PBC patients, especially those with early-stage PBC.


Assuntos
Bezafibrato/uso terapêutico , Colangite/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Bezafibrato/administração & dosagem , Colangite/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pontuação de Propensão , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Resultado do Tratamento , Ácido Ursodesoxicólico/administração & dosagem , Ácido Ursodesoxicólico/uso terapêutico
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