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1.
Lancet ; 389(10074): 1114-1123, 2017 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-28187915

RESUMO

BACKGROUND: Up to 70% of patients with primary biliary cholangitis develop pruritus (itch) during the course of their disease. Treatment of pruritus in primary biliary cholangitis is challenging and novel therapies are needed. Ursodeoxycholic acid, the standard first-line treatment for primary biliary cholangitis, is largely ineffective for pruritus. We investigated the efficacy and safety of GSK2330672, a selective inhibitor of human ileal bile acid transporter (IBAT), in patients with primary biliary cholangitis with pruritus. METHODS: We conducted this phase 2a, double-blind, randomised, placebo-controlled, crossover trial in two UK medical centres. Following 2 weeks of open placebo run-in, patients were randomly assigned in a 1:1 ratio with a block size of 4 to receive GSK2330672 or placebo twice daily during two consecutive 14-day treatment periods in a crossover sequence. The treatment periods were followed by a 14-day single-blinded placebo follow-up period. The primary endpoints were safety of GSK2330672, assessed using clinical and laboratory parameters, and tolerability as rated by the Gastrointestinal Symptom Rating Scale. The secondary endpoints were changes in pruritus scores measured using the 0 to 10 numerical rating scale (NRS), primary biliary cholangitis-40 (PBC-40) itch domain score and 5-D itch scale, changes in serum total bile acids and 7 alpha hydroxy-4-cholesten-3-one (C4), and changes in the pharmacokinetic parameters of ursodeoxycholic acid and its conjugates. The trial was registered with ClinicalTrials.gov, number NCT01899703. FINDINGS: Between March 10, 2014, and Oct 7, 2015, we enrolled 22 patients. 11 patients were assigned to receive intervention followed by placebo (sequence 1), and 11 patients were assigned to receive placebo followed by intervention (sequence 2). One patient assigned to sequence 2 withdrew consent prior to receiving randomised therapy. One patient did not attend the placebo follow-up period, but was included in the final analysis. GSK2330672 treatment for 14 days was safe with no serious adverse events reported. Diarrhoea was the most frequent adverse event during treatment with GSK2330672 (seven with GSK2330672 vs one with placebo) and headache was the most frequent adverse event during treatment with placebo (seven with placebo vs six with GSK2330672). After GSK2330672 treatment, the percentage changes from baseline itch scores were -57% (95% CI -73 to -42, p<0·0001) in the NRS, -31% (-42 to -20, p<0·0001) in the PBC-40 itch domain and -35% (-45 to -25, p<0·0001) in the 5-D itch scale. GSK2330672 produced significantly greater reduction from baseline than the double-blind placebo in the NRS (-23%, 95% CI -45 to -1; p=0·037), PBC-40 itch domain, (-14%, -26 to -1; p=0·034), and 5-D itch scale (-20%, -34 to -7; p=0·0045). After GSK2330672 treatment, serum total bile acid concentrations declined by 50% (95% CI -37 to -61, p<0·0001) from 30 to 15 µM, with a significant 3·1-times increase (95% CI 2·4 to 4·0, p<0·0001) in serum C4 concentrations from 7·9 to 24·7ng/mL. INTERPRETATION: In patients with primary biliary cholangitis with pruritus, 14 days of ileal bile acid transporter inhibition by GSK2330672 was generally well tolerated without serious adverse events, and demonstrated efficacy in reducing pruritus severity. GSK2330672 has the potential to be a significant and novel advance for the treatment of pruritus in primary biliary cholangitis. Diarrhoea, the most common adverse event associated with GSK2330672 treatment, might limit the long-term use of this drug. FUNDING: GlaxoSmithKline and National Institute for Health Research.


Assuntos
Colangite/complicações , Cirrose Hepática Biliar/complicações , Metilaminas/uso terapêutico , Prurido/tratamento farmacológico , Tiazepinas/uso terapêutico , Adulto , Proteínas de Transporte/antagonistas & inibidores , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Íleo , Masculino , Glicoproteínas de Membrana/antagonistas & inibidores , Pessoa de Meia-Idade , Prurido/etiologia , Resultado do Tratamento
2.
BMC Gastroenterol ; 16(1): 71, 2016 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-27431238

RESUMO

BACKGROUND: Pruritus (itch) is a symptom commonly experienced by patients with cholestatic liver diseases such as primary biliary cholangitis (PBC, previously referred to as primary biliary cirrhosis). Bile acids (BAs) have been proposed as potential pruritogens in PBC. The ileal bile acid transporter (IBAT) protein expressed in the distal ileum plays a key role in the enterohepatic circulation of BAs. Pharmacological inhibition of IBAT with GSK2330672 may reduce BA levels in the systemic circulation and improve pruritus. METHODS: This clinical study (BAT117213 study) is sponsored by GlaxoSmithKline (GSK) with associated exploratory studies supported by the National Institute for Health Research (NIHR). It is a phase 2a, multi-centre, randomised, double bind, placebo controlled, cross-over trial for PBC patients with pruritus. The primary objective is to investigate the safety and tolerability of repeat doses of GSK2330672, and explore whether GSK2330672 administration for 14 days improves pruritus compared with placebo. The key outcomes include improvement in pruritus scores evaluated on a numerical rating scale and other PBC symptoms in an electronic diary completed twice daily by the patients. The secondary outcomes include the evaluation of the effect of GSK2330672 on total serum bile acid (BA) concentrations, serum markers of BA synthesis and steady-state pharmacokinetics of ursodeoxycholic acid (UDCA). DISCUSSION: BAT117213 study is the first randomised controlled crossover trial of ileal bile acid transporter inhibitor, a novel class of drug to treat pruritus in PBC. The main strengths of the trial are utility of a novel, study specific, electronic symptom diary as patient reported outcome to measure the treatment response objectively and the crossover design that allows estimating the treatment effect in a smaller number of patients. The outcome of this trial will inform the trial design of future development phase of the IBAT inhibitor drug. The trial will also provide opportunity to conduct metabonomic and gut microbiome studies as explorative and mechanistic research in patients with cholestatic pruritus. TRIAL REGISTRATION: EudraCT number: 2012-005531-84, ClinicalTrials.gov Identifier: NCT01899703 , registered on 3(rd) July 2013.


Assuntos
Cirrose Hepática Biliar/complicações , Metilaminas/uso terapêutico , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Prurido/tratamento farmacológico , Simportadores/antagonistas & inibidores , Tiazepinas/uso terapêutico , Adolescente , Adulto , Idoso , Ácidos e Sais Biliares/sangue , Biomarcadores/sangue , Colagogos e Coleréticos/farmacocinética , Colagogos e Coleréticos/uso terapêutico , Estudos Cross-Over , Quimioterapia Combinada , Feminino , Humanos , Masculino , Metilaminas/administração & dosagem , Metilaminas/efeitos adversos , Metilaminas/farmacocinética , Pessoa de Meia-Idade , Transportadores de Ânions Orgânicos Dependentes de Sódio/uso terapêutico , Prurido/etiologia , Simportadores/uso terapêutico , Tiazepinas/administração & dosagem , Tiazepinas/efeitos adversos , Tiazepinas/farmacocinética , Ácido Ursodesoxicólico/farmacocinética , Ácido Ursodesoxicólico/uso terapêutico , Adulto Jovem
3.
Clin Med (Lond) ; 15(4): 351-7, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26407384

RESUMO

Pruritus (itch) is a common complication of cholestatic liver diseases (CLD). It can be a distressing and debilitating symptom, causing significant impairment in quality of life. Treatment of pruritus in liver diseases can be challenging and requires specific management with early initiation and a step-wise approach using specific drugs. Clinical trials are ongoing with novel agents that demonstrate potential efficacy. Patients with cholestatic pruritus are likely to present to a variety of clinicians who would benefit from medical awareness of available treatment options. In this review, we outline the pharmaceutical agents currently used to treat cholestatic pruritus and provide the evidence base for targeted symptom control of itch in liver diseases. We also highlight recent developments in the pathophysiology of cholestatic pruritus and the emerging novel therapies.


Assuntos
Anticolesterolemiantes/uso terapêutico , Indutores do Citocromo P-450 CYP2B6/uso terapêutico , Hepatopatias/complicações , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Humanos , Prurido/tratamento farmacológico , Prurido/etiologia , Prurido/psicologia , Qualidade de Vida
6.
Hepatology ; 52(1): 126-31, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20578267

RESUMO

UNLABELLED: Corticosteroid therapy has shown some benefit in severe acute alcoholic hepatitis (AAH); however, this is limited by uncertainty in patient selection and variable clinical response. Theophylline has been shown to ameliorate impaired steroid sensitivity in chronic obstructive pulmonary disease by facilitating corticosteroid-induced silencing of proinflammatory genes. We aimed to explore the mechanistic basis of the variable response to corticosteroid therapy seen in patients with AAH and to address the extent to which theophylline can improve this response. The ability of dexamethasone to inhibit phytohemagglutinin-induced lymphocyte proliferation was assessed by (3)H-thymidine incorporation in 12 severe AAH patients and age-matched and sex-matched controls. Steroid sensitivity was measured in terms of I(max), the maximum inhibition of proliferation. The effect of 10(-5) M theophylline and, in survivors, change in I(max) during recovery were observed. Lymphocyte steroid sensitivity was found to be significantly reduced in AAH compared with controls (I(max) 67[+/-4.5]% versus 95[+/-2.3]%, P = 0.0002) and correlated with clinical markers of steroid responsiveness. In survivors, I(max) increased in recovery. Theophylline 10(-5) M significantly increased lymphocyte steroid sensitivity (I(max) 86[+/-6.6]% versus 67[+/-5.0]%, P = 0.027). CONCLUSION: Acute alcoholic hepatitis is associated with significant lymphocyte steroid insensitivity, which improves in recovery and can be ameliorated ex vivo by theophylline. This offers potential to rationalize corticosteroid prescribing in AAH and, furthermore, justifies investigation of this novel role for an existing pharmacological agent in this common and frequently fatal condition.


Assuntos
Corticosteroides/uso terapêutico , Dexametasona/uso terapêutico , Hepatite Alcoólica/tratamento farmacológico , Teofilina/uso terapêutico , Doença Aguda , Adulto , Resistência a Medicamentos/efeitos dos fármacos , Quimioterapia Combinada , Feminino , Humanos , Linfócitos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Espanha , Resultado do Tratamento
7.
Hepatology ; 51(6): 1988-97, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20232292

RESUMO

UNLABELLED: Acute alcoholic hepatitis is characterized by disproportionate macrophage inflammatory cytokine responses to bacterial lipopolysaccharide. Lack of knowledge of the underlying mechanism has limited progress toward effective therapy. We postulated a novel mechanism by which ethanol increases histone acetylation, increasing proinflammatory gene transcription and cytokine synthesis. Cytokine responses to lipopolysaccharide in a human macrophage cell line cultured in 86 mM ethanol, 1 mM acetate, and normal media were measured by multiplex immunoassay. Changes in histone acetylation were determined by immunofluorescence microscopy and chromatin immunoprecipitation on presentation. The effect of ethanol and acetate on acetyl-coenzyme A (acetyl-coA) synthetases, which convert acetate to acetyl-coA, the substrate for histone acetylation, was determined by quantitative reverse-transcription polymerase chain reaction and immunoblotting. Knockdown of acetyl-coA synthetases by short hairpin RNA (shRNA) was used to determine their role in ethanol's enhancement of the inflammatory cytokine response. Ethanol-exposed macrophages developed enhanced interleukin 6 (IL6), IL8, and tumor necrosis factor alpha responses to lipopolysaccharide with time-dependent increases in histone acetylation that could be prevented by inhibition of ethanol metabolism. Chromatin immunoprecipitation confirmed increased histone acetylation at promoter regions of specific cytokine genes. The effect of ethanol was reproduced by incubation with acetate, the principal hepatic metabolite of ethanol, and both ethanol and acetate reduced histone deacetylase activity and up-regulated acetyl-coA synthetases. Knockdown of the acetyl-coA synthetases abrogated the effect of ethanol on cytokine production. CONCLUSION: Synthesis of metabolically available acetyl-coA from acetate is critical to the increased acetylation of proinflammatory gene histones and consequent enhancement of the inflammatory response in ethanol-exposed macrophages. This mechanism is a potential therapeutic target in acute alcoholic hepatitis.


Assuntos
Acetatos/metabolismo , Citocinas/metabolismo , Etanol/metabolismo , Regulação da Expressão Gênica , Hepatite Alcoólica/metabolismo , Macrófagos/metabolismo , Acetato-CoA Ligase/metabolismo , Acetilcoenzima A/metabolismo , Acetilação , Linhagem Celular , Etanol/efeitos adversos , Técnicas de Silenciamento de Genes , Hepatite Alcoólica/etiologia , Histona Acetiltransferases/metabolismo , Histona Desacetilases/metabolismo , Histonas/metabolismo , Humanos , Regiões Promotoras Genéticas
9.
J Hepatol ; 46(5): 980-2, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17391798
10.
Am J Trop Med Hyg ; 71(1): 43-7, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15238687

RESUMO

Heme oxygenase (HO) is thought to be induced in severe malaria, but the pathophysiologic consequences have not been examined. It is induced by hemolysis, oxidative stress, and inflammation. It degrades heme, producing carbon monoxide (CO), which causes elevated levels of carboxyhemoglobin (COHb). In a prospective study of 1,520 children admitted to a Kenyan district hospital, COHb levels were no higher in children with malaria than with other infections. The COHb levels in children with severe malarial anemia were higher than in other children with malaria, but significantly lower than in children with other causes of severe anemia such as sickle cell disease. Levels of COHb were not significantly higher in children with cerebral malaria or in those dying of malaria. These results do not support a systemic increase in HO activity in malaria compared with other infectious diseases, but the roles of HO and CO in malaria require further study.


Assuntos
Carboxihemoglobina/análise , Malária Falciparum/metabolismo , Anemia/epidemiologia , Anemia/etiologia , Anemia/patologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Quênia/epidemiologia , Malária Falciparum/complicações , Malária Falciparum/epidemiologia , Malária Falciparum/patologia , Masculino , Estudos Prospectivos
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