RESUMO
BACKGROUND AND AIMS: Nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NASH) is one of the primary causes of chronic liver disease worldwide. Obeticholic acid (OCA), a potent farnesoid X nuclear receptor activator, has shown promise for treating NASH-related fibrosis due to its anti-fibrotic effects. This study aimed to examine the efficacy of OCA for patients with NASH as well as to investigate its impact on dyslipidemia. METHOD: A search of databases including PubMed, Embase, and Cochrane Library from January 1, 2010, to November 1, 2022, was conducted to identify systematic reviews of randomized controlled trials involving NASH patients. Inclusion criteria comprised randomized controlled trials that specifically addressed NASH as diagnosed through magnetic resonance imaging, computed tomography, or histology. The results were then categorized, with consideration given to both biochemical and histological outcomes. RESULT: Five NASH studies were ultimately selected for further analysis. In terms of biochemical indicators, patients receiving OCA treatment showed improvements in alanine transaminase (mean difference: -19.48, 95% confidence interval [CI]: -24.39 to 14.58; Pâ <â .05) and aspartate aminotransferase (mean difference: -9.22, 95% CI: -12.70 to 5.74; Pâ <â .05). As for histological improvement, OCA treatment reduced fibrosis (odds ratio [OR]: 1.95, 95% CI: 1.47-2.59; Pâ =â .001) and steatosis (OR: 1.95, 95% CI: 1.47-2.59; Pâ =â .001). No significant differences were observed regarding adverse events (1.44, 95% CI: 0.57-3.62; Pâ >â .001). Regarding dyslipidemia, mean differences between total cholesterol and low-density lipoprotein were found to be high (0.33, 95% CI: 0.01-0.64, Pâ <â .05; 0.39, 95% CI: 0.04-0.73, Pâ <â .05). In the case of pruritus, OCA achieved a high OR (3.22, 95% CI: 2.22-4.74) compared with placebo. CONCLUSION: OCA also reduced several liver test markers compared to placebo, including the biochemical indicators alanine transaminase, aspartate aminotransferase, alkaline phosphatase, and γ-glutamyl transpeptidase, and improved hepatocellular ballooning, fibrosis, steatosis, and lobular inflammation. Although the incidence of adverse events did not significantly differ between OCA and placebo groups among NASH patients, OCA treatment was found to elevate total cholesterol and low-density lipoprotein levels, and the reported severity of pruritus increased with higher doses of OCA.
Assuntos
Ácido Quenodesoxicólico/análogos & derivados , Dislipidemias , Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Alanina Transaminase , Ensaios Clínicos Controlados Aleatórios como Assunto , Ácido Quenodesoxicólico/efeitos adversos , Fibrose , Lipoproteínas LDL , Dislipidemias/tratamento farmacológico , Prurido/tratamento farmacológico , Aspartato Aminotransferases , ColesterolRESUMO
BACKGROUND & AIMS: Fibrosis stage is a strong predictor of nonalcoholic steatohepatitis (NASH) outcomes. Two blinded studies evaluated the pharmacokinetics, pharmacodynamics and safety of obeticholic acid (OCA) in subjects with staged NASH fibrosis or cirrhosis. METHODS: Study 747-117 randomized 51 subjects with NASH (fibrosis stages F1-F4) to daily placebo, OCA 10 or OCA 25 mg (1:2:2) for 85 days. Study 747-118 randomized 24 subjects with NASH cirrhosis (F4; Child-Pugh [CP]-A) and normal liver control subjects matched for similar body weight to daily OCA 10 or OCA 25 mg (1:1) for 28 days. Individual and combined study data were analysed. RESULTS: No severe or serious adverse events (AEs) or AEs leading to discontinuation or death occurred. Pruritus was the most frequent AE. Plasma OCA exposure (dose-normalized area under the curve) increased with fibrosis stage but was a relatively poor predictor of hepatic OCA exposure (primary site of action), which remained constant across fibrosis stages F1-F3 and increased 1.8-fold compared with F1 in subjects with cirrhosis due to NASH. Both cohorts showed robust changes in farnesoid X receptor activation markers with OCA treatment and marked decreases in alanine transaminase, aspartate transaminase and gamma-glutamyltransferase. CONCLUSIONS: Despite higher drug exposures in subjects with NASH cirrhosis, short-term daily treatment with OCA 10 or 25 mg was generally safe and well tolerated in subjects with NASH fibrosis or NASH CP-A cirrhosis. Both cohorts experienced improvements in nonhistologic pharmacodynamic markers consistent with previously conducted OCA phase 2 and phase 3 studies in NASH fibrosis.
Assuntos
Ácido Quenodesoxicólico/análogos & derivados , Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/patologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/patologia , Ácido Quenodesoxicólico/efeitos adversosRESUMO
The treatment of gallbladder (GB) stones depends on condition severity. Ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA) are commonly used to treat GB stones, but the factors affecting response rates have not been fully identified. Therefore, we investigated the relationship between response to UDCA/CDCA treatment and changes in the gut microbiomes of patients with GB stones with the intention of identifying gut microbiomes that predict susceptibility to UDCA/CDCA treatment and treatment response. In this preliminary, prospective study, 13 patients with GB stones were treated with UDCA/CDCA for 6 months. Patients were classified into responder and non-responder groups based on treatment outcomes. Gut microbiomes were analyzed by 16S rDNA sequencing. Taxonomic compositions and abundances of bacterial communities were analyzed before and after UDCA/CDCA treatment. Alpha and beta diversities were used to assess similarities between organismal compositions. In addition, PICRUSt2 analysis was conducted to identify gut microbial functional pathways. Thirteen patients completed the treatment; 8 (62%) were assigned to the responder group and the remainder to the non-responder group. Low abundances of the Erysipelotrichi lineage were significantly associated with favorable response to UDCA/CDCA treatment, whereas high abundances of Firmicutes phylum indicated no or poor response. Our results suggest that a low abundance of the Erysipelotrichi lineage is significantly associated with a favorable response to UDCA/CDCA and that a high abundance of Firmicutes phylum is indicative of no or poor response. These findings suggest that some gut microbiomes are susceptible to UDCA/CDCA treatment and could be used to predict treatment response in patients with GB stones.
Assuntos
Cálculos Biliares , Microbioma Gastrointestinal , Humanos , Ácido Ursodesoxicólico/uso terapêutico , Ácido Quenodesoxicólico/efeitos adversos , Cálculos Biliares/tratamento farmacológico , Estudos ProspectivosRESUMO
BACKGROUND: Low phospholipid-associated cholelithiasis (LPAC) syndrome is a rare genetic cause of hepatolithiasis. A pathogenic variant of the ABCB4 gene is reported in half of all patients. Ursodeoxycholic acid (UDCA) is the only drug approved. However, in some patients, UDCA fails to prevent recurrence of symptoms and complications. Experimental evidence suggests that agonists of the farnesoid-X receptor (FXR), the main transcription factor regulating ABCB4, may be beneficial in this context. AIM: To study the efficacy of obeticholic acid (OCA) in patients with LPAC syndrome with an inadequate response or intolerance to UDCA. METHODS: This was a retrospective study of patients with LPAC syndrome treated with OCA, a selective FXR agonist. RESULTS: We reviewed the records of five OCA-treated patients (4 women; median age 29; ABCB4 variant in 4; no hepatic fibrosis). All patients received OCA at an initial dose of 5 mg daily and then 10 mg daily for a median period of 36 months in combination with UDCA (4 patients) or as a monotherapy (one patient). There were no adverse effects reported. Four patients had improvement in their symptoms - three completely and one partially. One patient had no clinical benefit. Abnormalities of blood liver tests persisted in one patient despite resolution of symptoms. Radiological signs of hepatolithiasis persisted in three of the four patients who responded clinically to OCA. CONCLUSIONS: These preliminary observations suggest that OCA may have the potential to effectively treat LPAC syndrome in patients with inadequate response or intolerance to UDCA. Larger studies are needed to confirm these data.
Assuntos
Colelitíase , Litíase , Hepatopatias , Humanos , Feminino , Adulto , Hepatopatias/tratamento farmacológico , Estudos Retrospectivos , Litíase/tratamento farmacológico , Colelitíase/tratamento farmacológico , Colelitíase/genética , Ácido Quenodesoxicólico/efeitos adversos , Ácido Ursodesoxicólico/efeitos adversos , FosfolipídeosRESUMO
BACKGROUND AND AIMS: Obeticholic acid (OCA) is a farnesoid X receptor agonist used in primary biliary cholangitis (PBC) treatment. Recent studies have expanded OCA use for NASH treatment and results from phase 3 clinical trial have shown beneficial reduction of ≥1 stage of fibrosis with no NASH worsening. However, safety concerns still preside, thus we systematically examine the safety profile of OCA in chronic liver disease. MATERIALS AND METHODS: A search was conducted in Medline and Embase databases for OCA randomized controlled trials in chronic liver disease. Binary events were pooled with Paule-Mandel random effects model and proportional events were examined in a generalized linear mixed model with Clopper-Pearson intervals. RESULTS: A total of 8 studies and 1878 patients were analyzed. There was a 75% [risk ratio (RR): 1.75, 95% CI: 1.43-2.15, p < 0.01] increased pruritis risk. OCA increased constipation incidence (RR: 1.88, 95% CI: 1.45-2.43, p < 0.01), decreased diarrhea (RR: 0.62, 95% CI: 0.50-0.77, p < 0.01), and increased development of hyperlipidemia (RR: 2.69, 95% CI: 1.85-3.92, p < 0.01) relative to placebo. Sensitivity analysis in NASH-only studies found a dose-dependent effect with pruritis which increases to RR: 3.07 (95% CI: 1.74-5.41) at 25 mg. However, up to 9.98% (95% CI: 5.01%-18.89%) of NAFLD patients with placebo similarly experience pruritis events. Overall, 16.55% (95% CI: 6.47%-36.24%) of patients with NAFLD on OCA experienced pruritis. There was no significant increase in cardiovascular events. CONCLUSIONS: OCA may represent the first pharmacological treatment approved for NASH. However, pruritis, constipation, diarrhea, and hyperlipidemia were major events with evident dose-dependent effect that affect tolerability in NASH. Future long-term studies for longitudinal safety events are required.
Assuntos
Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Ácido Quenodesoxicólico/efeitos adversos , Estudos Longitudinais , Prurido/tratamento farmacológicoRESUMO
Secondary bile acids (SBAs) with high hydrophobicity are abundant in the colonic lumen. However, both aggravating and protective roles of SBAs have been proposed in the pathogenesis of inflammatory bowel diseases (IBDs). We observed that oral administration of hyodeoxycholic acid (HDCA), a hydrophilic bile acid, prevented the development of dextran sulfate sodium (DSS)-induced colitis in mice. We then examined the individual effects of DSS and HDCA as well as their combined effects on fecal bile acid profile in mice. HDCA treatment increased the levels of most of fecal bile acids, whereas DSS treatment had limited effects on the levels of fecal bile acids. The combined treatment with DSS and HDCA synergistically increased the levels of fecal chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA) in feces, which are potent activators of the farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5 (TGR5). The overall hydrophobicity of fecal bile acids was not modified by any treatments. Our data suggest that the preventive effect of HDCA on DSS-induced colitis in mice is due to the synergism between DSS and HDCA in increasing the levels of the fecal bile acids with potencies to activate FXR and TGR5.
Assuntos
Colite , Animais , Ácidos e Sais Biliares , Ácido Quenodesoxicólico/efeitos adversos , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/prevenção & controle , Ácido Desoxicólico/efeitos adversos , Sulfato de Dextrana , Camundongos , Receptores Acoplados a Proteínas GRESUMO
BACKGROUND & AIMS: The Primary Biliary Cholangitis (PBC) Obeticholic Acid (OCA) International Study of Efficacy (POISE) randomized, double-blind, placebo-controlled trial demonstrated that OCA reduced biomarkers associated with adverse clinical outcomes (ie, alkaline phosphatase, bilirubin, aspartate aminotransferase, and alanine aminotransferase) in patients with PBC. The objective of this study was to evaluate time to first occurrence of liver transplantation or death in patients with OCA in the POISE trial and open-label extension vs comparable non-OCA-treated external controls. METHODS: Propensity scores were generated for external control patients meeting POISE eligibility criteria from 2 registry studies (Global PBC and UK-PBC) using an index date selected randomly between the first and last date (inclusive) on which eligibility criteria were met. Cox proportional hazards models weighted by inverse probability of treatment assessed time to death or liver transplantation. Additional analyses (Global PBC only) added hepatic decompensation to the composite end point and assessed efficacy in patients with or without cirrhosis. RESULTS: During the 6-year follow-up, there were 5 deaths or liver transplantations in 209 subjects in the POISE cohort (2.4%), 135 of 1381 patients in the Global PBC control (10.0%), and 281 of 2135 patients in the UK-PBC control (13.2%). The hazard ratios (HRs) for the primary outcome were 0.29 (95% CI, 0.10-0.83) for POISE vs Global PBC and 0.30 (95% CI, 0.12-0.75) for POISE vs UK-PBC. In the Global PBC study, HR was 0.20 (95% CI, 0.03-1.22) for patients with cirrhosis and 0.31 (95% CI, 0.09-1.04) for those without cirrhosis; HR was 0.42 (95% CI, 0.21-0.85) including hepatic decompensation. CONCLUSIONS: Patients treated with OCA in a trial setting had significantly greater transplant-free survival than comparable external control patients.
Assuntos
Cirrose Hepática Biliar , Ácido Ursodesoxicólico , Humanos , Ácido Ursodesoxicólico/efeitos adversos , Cirrose Hepática Biliar/diagnóstico , Cirrose Hepática Biliar/tratamento farmacológico , Cirrose Hepática Biliar/cirurgia , Ácido Quenodesoxicólico/efeitos adversos , Cirrose Hepática/complicaçõesAssuntos
Colangite , Cirrose Hepática Biliar , Ácido Quenodesoxicólico/efeitos adversos , Ácido Quenodesoxicólico/análogos & derivados , Colangite/induzido quimicamente , Colangite/tratamento farmacológico , Humanos , Cirrose Hepática Biliar/complicações , Cirrose Hepática Biliar/tratamento farmacológico , Ácido Ursodesoxicólico/uso terapêuticoRESUMO
BACKGROUND AND AIMS: Currently, there is no pharmacotherapy for non-alcoholic steatohepatitis (NASH), a common liver disorder. In contrast, primary biliary cholangitis (PBC) is a chronic cholestatic liver disease for which ursodeoxycholic acid (UDCA) is the drug of choice. However, 50% of PBC patients may not respond to UDCA. Obeticholic acid (OCA) is emerging as a vital pharmacotherapy for these chronic disorders. We aimed to analyse the safety and efficacy of OCA. METHODS: We performed an extensive search of electronic databases from 01/01/2000 to 31/03/2020. We included randomized controlled trials of OCA in patients with NASH, PBC, and primary sclerosing cholangitis (PSC). We assessed the histological improvement in NASH, reduction in alkaline phosphatase (≤1.67â¯ULN) in PBC, and the adverse effects of OCA. RESULTS: Seven RCTs (nâ¯=â¯2834) were included. Of the total RCTs, there were three on both NASH and PBC and one on PSC. OCA improved NASH fibrosis [OR: 1.95 (1.47-2.59; pâ¯<â¯0.001)]. With the 10â¯mg OCA dose, the odds of improvement was 1.61 (1.03-2.51; pâ¯=â¯0.03), while with the 25â¯mg dose, it was 2.23 (1.55-3.18; pâ¯<â¯0.001). However, 25â¯mg OCA led to significant adverse events and discontinuation of the drug [2.8 (1.42-3.02); pâ¯<â¯0.001)] compared with 10â¯mg OCA [0.95 (0.6-1.5); pâ¯=â¯0.84] in NASH patients. In PBC patients, the response to 5â¯mg OCA was better than with the higher doses [5â¯mg: 7.66 (3.12-18.81; pâ¯<â¯0.001), 10â¯mg: 5.18 (2-13.41; pâ¯=â¯0.001), 25â¯mg: 2.36 (0.94-5.93; pâ¯=â¯0.06), 50â¯mg: 4.08 (1.05-15.78; pâ¯=â¯0.04)]. The risk of pruritus was lowest with 5â¯mg OCA. CONCLUSIONS: Lower doses of OCA are effective and safe in NASH and cholestatic liver disease. While 10â¯mg OCA is effective for NASH fibrosis regression, only 5â¯mg OCA is required for PBC.
Assuntos
Ácido Quenodesoxicólico/análogos & derivados , Hepatopatia Gordurosa não Alcoólica , Ácido Quenodesoxicólico/efeitos adversos , Ácido Quenodesoxicólico/uso terapêutico , Colestase , Humanos , Cirrose Hepática Biliar , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Preparações Farmacêuticas , Ácido Ursodesoxicólico/efeitos adversosRESUMO
BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent chronic liver disease characterized by excess accumulation of fat in hepatocytes. Because no drug has been approved for NAFLD treatment, this work analyzed the effects of agents resulting from 2 research hotspots, metabolic target agents, and natural plant drugs, on NAFLD with network meta-analysis. METHODS: Public databases were searched through August 14, 2020. Randomized controlled trials that compared obeticholic acid, elafibranor, cenicriviroc, selonsertib, curcumin, silymarin, and resveratrol to placebo were included. Liver pathology improvement, hepatic biochemical indicators, and lipid metabolism indicators were analyzed. RESULTS: Thirty-five studies were included in the meta-analysis. Obeticholic acid was found to significantly increase the frequency of liver biopsy improvement compared to placebo (OR: 2.10; 95% CI: 1.60, 2.77). The ranking results among the hepatic biochemical indicators showed that obeticholic acid (94.9%) and elafibranor (86.3%) have a relative advantage in reducing alanine aminotransferase (ALT) levels, and obeticholic acid also had an advantage (95.4%) in reducing aspartate aminotransferase (AST) levels. Considering lipid metabolic indicators, elafibranor (expSMD: 0.01; 95% CI: 0.00, 0.05; SUCRA: 100%), and obeticholic acid (expSMD: 0.48; 95% CI: 0.28,0.84; SUCRA: 75.6%) significantly reduced triglyceride (TG) levels compared with placebo; moreover, obeticholic acid, but not elafibranor, caused a serious increase in total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels and a decrease in high-density lipoprotein cholesterol (HDL-C) levels. CONCLUSIONS: Novel metabolic targeted agents generally have better effects than natural plant drugs, especially obeticholic acid, and elafibranor. However, obeticholic acid showed serious adverse effects such as increasing LDL-C levels and decreasing HDL-C levels. Curcumin showed potential advantages for NAFLD but lacked statistical significance.
Assuntos
Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Preparações de Plantas/uso terapêutico , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Chalconas/uso terapêutico , Ácido Quenodesoxicólico/efeitos adversos , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/uso terapêutico , HDL-Colesterol/sangue , HDL-Colesterol/efeitos dos fármacos , LDL-Colesterol/sangue , LDL-Colesterol/efeitos dos fármacos , Curcumina/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Humanos , Metanálise em Rede , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/enzimologia , Propionatos/uso terapêutico , Triglicerídeos/sangueRESUMO
The present study assessed the pharmacokinetics and bioequivalence of a single 10-mg dose of a generic and the branded formulation (Ocaliva) of obeticholic acid (OCA) in healthy Chinese subjects under fasting and fed conditions. The possible effects of food and sex on the pharmacokinetics of OCA and its 2 active metabolites (glyco-OCA and tauro-OCA) were evaluated. Plasma concentrations of OCA and its 2 active metabolites were measured by liquid chromatography-tandem mass spectrometry. The 90%CIs of the ratios of the test and reference formulations for Cmax , AUC0-t , and AUC0-∞ of OCA, glyco-OCA, and tauro-OCA were contained entirely within the 80% to 125% range required for bioequivalence under fasting and fed conditions. Plasma exposure of OCA was 30% to 36% higher under fed compared with fasting conditions. Plasma exposure of OCA, glyco-OCA, and tauro-OCA was 39% to 66%, 22% to 58%, and 37% to 84% higher, respectively, in women compared with men under fasting and fed conditions. In conclusion, OCA was well tolerated in healthy Chinese subjects under fasting and fed conditions. The single 10-mg dose of a generic OCA formulation was bioequivalent to Ocaliva. Food and sex impacted the pharmacokinetics of OCA and/or its 2 active metabolites. Further studies are required to determine if these effects are clinically relevant.
Assuntos
Ácido Quenodesoxicólico/análogos & derivados , Medicamentos Genéricos/administração & dosagem , Interações Alimento-Droga , Adolescente , Adulto , Área Sob a Curva , Povo Asiático , Ácido Quenodesoxicólico/administração & dosagem , Ácido Quenodesoxicólico/efeitos adversos , Ácido Quenodesoxicólico/farmacocinética , Cromatografia Líquida , Estudos Cross-Over , Medicamentos Genéricos/efeitos adversos , Medicamentos Genéricos/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores Sexuais , Espectrometria de Massas em Tandem , Equivalência Terapêutica , Adulto JovemAssuntos
Bezafibrato , Ácido Quenodesoxicólico/análogos & derivados , Colestase , Cirrose Hepática Biliar , Prurido , Fosfatase Alcalina/sangue , Bezafibrato/administração & dosagem , Bezafibrato/efeitos adversos , Bilirrubina/sangue , Ácido Quenodesoxicólico/administração & dosagem , Ácido Quenodesoxicólico/efeitos adversos , Colestase/diagnóstico , Colestase/tratamento farmacológico , Colestase/etiologia , Colestase/fisiopatologia , Colesterol/sangue , Relação Dose-Resposta a Droga , Interações Medicamentosas , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Hipolipemiantes/administração & dosagem , Hipolipemiantes/efeitos adversos , Cirrose Hepática Biliar/sangue , Cirrose Hepática Biliar/complicações , Cirrose Hepática Biliar/terapia , Testes de Função Hepática/métodos , Masculino , Pessoa de Meia-Idade , Prurido/induzido quimicamente , Prurido/prevenção & controle , Resultado do TratamentoRESUMO
Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent, dynamic disease that occurs across the age spectrum and can lead to cirrhosis and hepatocellular carcinoma. There are currently no US Food and Drug Administration (FDA) approved treatments for NAFLD; however, this is a field of active research. This review summarizes emerging pharmacotherapies for the treatment of adult and pediatric NAFLD. Investigated pharmacotherapies predominantly target bile acid signaling, insulin resistance, and lipid handling within the liver. Three drugs have gone on to phase III trials for which results are available. Of those, obeticholic acid is the single agent that demonstrates promise according to the interim analyses of the REGENERATE trial. Obeticholic acid showed reduction of fibrosis in adults with nonalcoholic steatohepatitis (NASH) taking 25 mg daily for 18 months (n = 931, reduction in fibrosis in 25% vs. 12% placebo, P < 0.01). Ongoing phase III trials include REGENERATE and MAESTRO-NASH, which investigates thyroid hormone receptor-ß agonist MGL-3196. Outcomes of promising phase II trials in adults with NASH are also available and those have investigated agents, including the fibroblast growth factor (FGF)19 analogue NGM282, the GLP1 agonist liraglutide, the FGF21 analogue Pegbelfermin, the sodium glucose co-transporter 2 inhibitor Empagliflozin, the ketohexokinase inhibitor PF-06835919, the acetyl-coenzyme A carboxylase inhibitor GS-0976, and the chemokine receptor antagonist Cenicriviroc. Completed and ongoing clinical trials emphasize the need for a more nuanced understanding of the phenotypes of subgroups within NAFLD that may respond to an individualized approach to pharmacotherapy.
Assuntos
Cirrose Hepática/tratamento farmacológico , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Adulto , Compostos Benzidrílicos/administração & dosagem , Compostos Benzidrílicos/efeitos adversos , Ácido Quenodesoxicólico/administração & dosagem , Ácido Quenodesoxicólico/efeitos adversos , Ácido Quenodesoxicólico/análogos & derivados , Criança , Ensaios Clínicos Fase III como Assunto , Fatores de Crescimento de Fibroblastos/administração & dosagem , Fatores de Crescimento de Fibroblastos/efeitos adversos , Fatores de Crescimento de Fibroblastos/análogos & derivados , Glucosídeos/administração & dosagem , Glucosídeos/efeitos adversos , Humanos , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Isobutiratos/administração & dosagem , Isobutiratos/efeitos adversos , Liraglutida/administração & dosagem , Liraglutida/efeitos adversos , Fígado/patologia , Cirrose Hepática/diagnóstico , Cirrose Hepática/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Oxazóis/administração & dosagem , Oxazóis/efeitos adversos , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Piridazinas/administração & dosagem , Piridazinas/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Índice de Gravidade de Doença , Sulfóxidos/administração & dosagem , Sulfóxidos/efeitos adversos , Resultado do Tratamento , Uracila/administração & dosagem , Uracila/efeitos adversos , Uracila/análogos & derivadosRESUMO
The role of weak acids with pH values in the range of 4-7 has been implicated in the symptoms of gastroesophageal reflux disease (GERD). Prostaglandin E2 (PGE2) is associated with heartburn symptom in GERD patients; however, the precise productive mechanisms remain unclear. In this study, we revealed that exposure to weak acids increases PGE2 production with a peak at pH 4-5, slightly in human normal oesophageal cells (Het-1A), and robustly in oesophageal squamous carcinoma cells (KYSE-270). Release of PGE2 from the oesophageal mucosa was augmented by weak acid treatment in rat. Chenodeoxycholic acid (CDCA), a bile acid, upregulated cyclooxygenase-2 (COX-2) expression in Het-1A and KYSE-270 and induced PGE2 production in KYSE-270 cells. Weak acid-induced PGE2 production was significantly inhibited by cytosolic phospholipase A2 (cPLA2), ERK, and transient receptor potential cation channel subfamily V member 4 (TRPV4), a pH-sensing ion channel, inhibitors. Hangeshashinto, a potent inhibitor of COX-2, strongly decreased weak acid- and CDCA-induced PGE2 levels in KYSE-270. These results indicated that weak acids induce PGE2 production via TRPV4/ERK/cPLA2 in oesophageal epithelial cells, suggesting a role in GERD symptoms like heartburn. Interventions targeting pH values up to 5 may be necessary for the treatment of GERD.
Assuntos
Ácidos/efeitos adversos , Dinoprostona/biossíntese , Mucosa Esofágica/efeitos dos fármacos , Mucosa Esofágica/metabolismo , Refluxo Gastroesofágico/etiologia , Refluxo Gastroesofágico/metabolismo , Animais , Células Cultivadas , Ácido Quenodesoxicólico/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Refluxo Gastroesofágico/tratamento farmacológico , Azia/etiologia , Azia/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Modelos Biológicos , Prostaglandina-Endoperóxido Sintases/metabolismo , Ratos , Canais de Cátion TRPV/metabolismoRESUMO
BACKGROUND: Although the efficacy of ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) for primary biliary cholangitis (PBC) has been suggested by small trials, a meta-analysis to summarize the evidence has not yet been carried out. The aim of this study was to evaluate the clinical outcomes of the combination therapy of UDCA and OCA compared with UDCA monotherapy in patients with PBC. METHODS AND MATERIALS: We searched the PubMed, EMBASE, the web of science, and the Cochrane Library databases for English-language studies published before September 2018. Studies were included if they were randomized controlled trials (RCTs) and reported relative risk (RR) estimates with 95% confidence intervals (CIs) or related data for the clinical outcomes of different therapies in patients with PBC. RESULTS: Of the 1169 titles identified, two studies meeting the inclusion criteria were included in the meta-analysis. Approximately 222 patients with PBC were included in this analysis. The results of this study indicated that combination therapy was significantly superior to monotherapy in reducing serum alanine transaminase (mean difference: -15.63 IU/L; 95% CI, -21.59 to -9.68), aspartate transaminase (mean difference: -6.63 IU/L; 95% CI, -11.03 to -2.24), gamma-glutamyl transpeptidase (mean difference: -131.30 IU/L; 95% CI, -177.52 to -85.08), and C-reactive protein (mean difference = -1.17 mg/L; 95% CI, -2.19 to -0.14), but NS in improving primary endpoints of alkaline phosphatase level with 15.0% reduction from baseline, and equal or higher than the upper limit of normal serum total bilirubin (RR = 2.75; 95% CI, 0.43-17.68), conjugated bilirubin (mean difference = -0.06 mg/dL; 95% CI, -0.28 to 0.15), IgM (mean difference = -41.18 mg/dL; 95% CI, -244.45 to 162.09), and adverse events (P > 0.05). CONCLUSION: This meta-analysis demonstrated that combination therapy with UDCA and OCA provided satisfactory clinical outcomes, which may be a promising alternative for patients with PBC who had an inadequate response to UDCA therapy. Therefore, high-quality RCTs on the safety and efficacy of the combination therapy of UDCA and OCA compared with UDCA monotherapy in patients with PBC should be performed in the future.
Assuntos
Cirrose Hepática Biliar , Ácido Ursodesoxicólico , Alanina Transaminase , Ácido Quenodesoxicólico/efeitos adversos , Ácido Quenodesoxicólico/análogos & derivados , Humanos , Cirrose Hepática Biliar/diagnóstico , Cirrose Hepática Biliar/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Ácido Ursodesoxicólico/efeitos adversosRESUMO
INTRODUCTION: NAFLD has grown to become the most prevalent liver disease in the world, with a quarter of the general population estimated to have the disease. NASH, characterized as NAFLD with inflammation, is associated with worsening fibrosis along with increased incidence of HCC. Despite high prevalence of this disease, no pharmacologic treatments approved by regulatory agencies are available. AREAS COVERED: This review briefly discusses present understanding of NASH pathology and currently available treatments. We also discuss data on the role of OCA as an FXR agonist in modulating disease in NASH. A comprehensive literature search of review articles, original research articles, and prospective clinical trials from 1998 to the present was performed. EXPERT OPINION: Based on 18-month interim findings of the REGENERATE trial, OCA likely improves fibrosis in NASH and therefore may have a beneficial effect in delaying or even preventing cirrhosis. The side effect of an atherogenic lipoprotein profile may adversely affect long-term outcomes, though studies have shown that co-administration of statins is able to mitigate this effect. OCA is likely to become an option for treatment, but the specific context within which it may be prescribed still needs to be clarified.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Ácido Quenodesoxicólico/análogos & derivados , Cirrose Hepática/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares/agonistas , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/farmacologia , Ácido Quenodesoxicólico/efeitos adversos , Ácido Quenodesoxicólico/farmacologia , Ácido Quenodesoxicólico/uso terapêutico , Ensaios Clínicos como Assunto , Progressão da Doença , Fármacos Gastrointestinais/efeitos adversos , Fármacos Gastrointestinais/farmacologia , Fármacos Gastrointestinais/uso terapêutico , Estilo de Vida Saudável , Humanos , Fígado/efeitos dos fármacos , Cirrose Hepática/diagnóstico , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/terapia , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/terapiaRESUMO
BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is a rare, cholestatic liver disease with no currently approved therapies. Obeticholic acid (OCA) is a potent farnesoid X receptor (FXR) agonist approved for the treatment of primary biliary cholangitis. We investigated the efficacy and safety of OCA in patients with PSC. METHODS: AESOP was a phase II, randomized, double-blind, placebo-controlled, dose-finding study. Eligible patients were 18 to 75 years of age with a diagnosis of PSC and serum alkaline phosphatase (ALP) ≥2× the upper limit of normal (ULN) and total bilirubin <2.5× ULN. Patients were randomized 1:1:1 to receive placebo, OCA 1.5-3.0 mg, or OCA 5-10 mg once daily for a 24-week, double-blind phase followed by a 2-year, long-term safety extension (LTSE). Primary endpoints were change in ALP from baseline to week 24, and safety. RESULTS: The intent-to-treat population comprised 76 patients randomized to placebo (n = 25), OCA 1.5-3.0 mg (n = 25), and OCA 5-10 mg (n = 26). At week 24, serum ALP was significantly reduced with OCA 5-10 mg vs. placebo (least-square [LS] mean difference = -83.4 [SE = 40.3] U/L; 95% CI -164.28 to -2.57; p = 0.043). Serum ALP was not significantly reduced with OCA 1.5-3.0 mg vs. placebo at week 24 (LS mean [SE] difference = -78.29 [41.81] U/L; 95% CI -162.08 to 5.50; p = 0.067). Total bilirubin remained comparable to baseline in all groups. The most common treatment-emergent adverse event was dose-related pruritus (placebo 46%; OCA 1.5-3.0 mg 60%; OCA 5-10 mg 67%). Reductions in ALP were maintained during the LTSE, and no new safety signals emerged. CONCLUSIONS: Treatment with OCA 5-10 mg reduced serum ALP in patients with PSC. Mild to moderate dose-related pruritus was the most common adverse event. REGISTRATION: ClinicalTrials.gov: NCT02177136; EudraCT: 2014-002205-38. LAY SUMMARY: Primary sclerosing cholangitis (PSC) is a long-term disease that damages the bile ducts in the liver over time. In the AESOP clinical study in patients with PSC, obeticholic acid reduced serum alkaline phosphatase (a potential marker of disease severity) during an initial 24-week treatment period. The result was sustained during the 2-year, long-term extension of the study. The most common side effect of obeticholic acid in the study was itchy skin, which is consistent with earlier clinical studies.
Assuntos
Fosfatase Alcalina/sangue , Ácido Quenodesoxicólico/análogos & derivados , Cirrose Hepática Biliar , Prurido , 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 , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Cirrose Hepática Biliar/sangue , Cirrose Hepática Biliar/diagnóstico , Cirrose Hepática Biliar/tratamento farmacológico , Testes de Função Hepática/métodos , Masculino , Pessoa de Meia-Idade , Prurido/induzido quimicamente , Prurido/diagnóstico , Resultado do TratamentoRESUMO
OBJECTIVE: To evaluate the safety and effectiveness of chenodeoxycholic acid (CDCA) treatment in patients with cerebrotendinous xanthomatosis (CTX). METHODS: Two retrospective cohort studies were conducted in CTX patients who underwent CDCA treatment: one in the Netherlands (NL; CDCA-STUK-15-001) and one in Italy (IT; CDCA-STRCH-CR-14-001). Eligible patients were aged 2-75 years, had been diagnosed with CTX, and were treated with CDCA orally for ≥1 year. The impact of CDCA treatment on biochemical markers (including serum cholestanol levels) and disease signs and symptoms were assessed, in addition to the safety and tolerability of CDCA treatment. RESULTS: A total of 35 patients were screened in the NL study and were diagnosed with CTX at 25.6 (± 13.7 SD) years on average. These patients were treated with CDCA and followed up for a median of 9.00 (range: 0.4-26.3) years. In addition, 28 patients were enrolled in the IT study and were diagnosed at 35.0 (± 11.4 SD) years on average (median duration of CDCA treatment: 5.75 [range: 0.0-25.0] years). Signs and symptoms of disease resolved, improved, or remained stable in many patients, with concomitant improvements in biochemical marker levels (serum cholestanol, p < 0.001; 7α-hydroxy-4-cholesten-3-one, p < 0.001 [IT study]). CONCLUSIONS: The outcomes of these retrospective cohort studies indicate that CDCA is effective in the long-term treatment of CTX, with an acceptable safety profile.
Assuntos
Ácido Quenodesoxicólico/farmacologia , Colestanol/sangue , Fármacos Gastrointestinais/farmacologia , Xantomatose Cerebrotendinosa/sangue , Xantomatose Cerebrotendinosa/tratamento farmacológico , Adulto , Biomarcadores/sangue , Ácido Quenodesoxicólico/administração & dosagem , Ácido Quenodesoxicólico/efeitos adversos , Seguimentos , Fármacos Gastrointestinais/administração & dosagem , Fármacos Gastrointestinais/efeitos adversos , Humanos , Itália , Pessoa de Meia-Idade , Países Baixos , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemAssuntos
Doença Hepática Induzida por Substâncias e Drogas/etiologia , Ácido Quenodesoxicólico/análogos & derivados , Cirrose Hepática Biliar/tratamento farmacológico , Idoso , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Ácido Quenodesoxicólico/efeitos adversos , Ácido Quenodesoxicólico/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a chronic, progressive, and severe form of nonalcoholic fatty liver disease. In FLINT, obeticholic acid (OCA) treatment improved multiple histological NASH features. The design and endpoints of REGENERATE, an ongoing phase 3 study, further evaluate OCA treatment in patients with fibrosis due to NASH. AIMS: The Month 18 interim analysis assesses the effect of OCA on liver histology, defined as improvement of fibrosis by ≥1 stage with no worsening of NASH or resolution of NASH with no worsening of fibrosis. The end-of-study analyses evaluate the effect of OCA on mortality, liver-related clinical outcomes, and long-term safety. METHODS: REGENERATE is a pivotal, long-term study of ~2400 patients with NASH, including ~2100 patients with stage 2 or 3 liver fibrosis. Additionally, ~300 patients with stage 1 fibrosis andâ¯≥1 accompanying comorbidity are included to gather information on the safety of OCA and liver disease progression. Patients are randomised 1:1:1 to receive placebo or OCA (10 or 25â¯mg). A liver biopsy evaluation occurs at screening, Months 18 and 48, and end of study. The duration of the study is dependent upon accrual of a predetermined number of clinical outcome events. CONCLUSIONS: REGENERATE is designed in conjunction with regulatory authorities to support regulatory approvals in NASH. This robust phase 3 study assesses the effect of OCA on liver histology as a surrogate for transplant-free survival and liver-related outcomes, including progression to cirrhosis and mortality, and will ultimately assess clinical benefit through specific evaluation of these outcomes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov with the identifier NCT02548351.