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1.
Hepatology ; 78(3): 709-726, 2023 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-36999529

RESUMO

BACKGROUND AND AIMS: Cholestasis is characterized by intrahepatic accumulation of bile constituents, including bile acids (BAs), which promote liver damage. The apical sodium-dependent BA transporter (ASBT) plays an important role in BA reabsorption and signaling in ileum, bile ducts, and kidneys. Our aim was to investigate the pharmacokinetics and pharmacological activity of A3907, an oral and systemically available ASBT inhibitor in experimental mouse models of cholestasis. In addition, the tolerability, pharmacokinetics, and pharmacodynamics of A3907 were examined in healthy humans. APPROACH AND RESULTS: A3907 was a potent and selective ASBT inhibitor in vitro. In rodents, orally administered A3907 distributed to the ASBT-expressing organs, that is, ileum, liver, and kidneys, and dose dependently increased fecal BA excretion. A3907 improved biochemical, histological, and molecular markers of liver and bile duct injury in Mdr2-/- mice and also had direct protective effects on rat cholangiocytes exposed to cytotoxic BA concentrations in vitro . In bile duct ligated mice, A3907 increased urinary BA elimination, reduced serum BA levels, and prevented body weight loss, while improving markers of liver injury. A3907 was well tolerated and demonstrated target engagement in healthy volunteers. Plasma exposure of A3907 in humans was within the range of systemic concentrations that achieved therapeutic efficacy in mouse. CONCLUSIONS: The systemic ASBT inhibitor A3907 improved experimental cholestatic disease by targeting ASBT function at the intestinal, liver, and kidney levels, resulting in marked clearance of circulating BAs and liver protection. A3907 is well tolerated in humans, supporting further clinical development for the treatment of cholestatic liver diseases.


Assuntos
Colestase , Simportadores , Humanos , Camundongos , Animais , Ratos , Colestase/tratamento farmacológico , Fígado , Ductos Biliares , Bile , Ácidos e Sais Biliares/uso terapêutico , Proteínas de Membrana Transportadoras , Transportadores de Ânions Orgânicos Dependentes de Sódio
2.
J Gastroenterol Hepatol ; 37(5): 883-890, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35168298

RESUMO

BACKGROUND AND AIM: Elobixibat is a locally acting inhibitor of the ileal bile acid transporter. We compared bile acid metabolism between healthy subjects and patients with chronic constipation and assessed changes in the bile acid profile after elobixibat administration in the latter group. METHODS: Healthy subjects (n = 10) and patients with chronic constipation (n = 19) were assessed as inpatients for 7 days, during which they received meals containing ~60 g/day of fat. Patients with chronic constipation remained as inpatients for a further 7 days for once-daily elobixibat administration. Assessments included concentrations of fecal and serum bile acids, serum 7α-hydroxy-4-cholesten-3-one (C4) and fibroblast growth factor 19, and bowel movements and constipation symptoms. RESULTS: Fecal total and primary bile acids were significantly lower in patients with chronic constipation versus healthy subjects. Serum C4 and fibroblast growth factor 19 levels were comparable between groups. Elobixibat treatment increased fecal total and primary bile acids and decreased levels of fecal lithocholic acid and serum total as well as secondary bile acids in patients with chronic constipation. Bowel movements and other constipation-related symptoms were also improved by elobixibat to levels almost comparable with those of healthy subjects. CONCLUSIONS: Despite comparable C4 levels, patients with chronic constipation demonstrated decreased levels of fecal bile acids versus healthy subjects. Elobixibat treatment increased fecal bile acid excretion and reduced serum bile acid concentrations. The improvement of constipation after elobixibat treatment was associated with increased total bile acids, particularly primary bile acids.


Assuntos
Ácidos e Sais Biliares , Tiazepinas , Constipação Intestinal/tratamento farmacológico , Dipeptídeos , Fezes , Fatores de Crescimento de Fibroblastos , Humanos , Tiazepinas/farmacologia , Tiazepinas/uso terapêutico
3.
J Pediatr Gastroenterol Nutr ; 71(2): 176-183, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32433433

RESUMO

OBJECTIVES: We assessed available data on impact of partial external biliary diversion (PEBD) surgery on clinical outcomes in patients with progressive familial intrahepatic cholestasis (PFIC). METHODS: We performed a systematic literature review (PubMed) and meta-analysis to evaluate relationships between liver biochemistry parameters (serum bile acids, bilirubin, and alanine aminotransferase [ALT]) and early response (pruritus improvement) or long-term outcomes (need for liver transplant) in patients with PFIC who underwent PEBD. RESULTS: Searches identified 175 publications before September 2018; 16 met inclusion criteria. Receiver operating characteristic (ROC) analysis examined ability of liver biochemistry parameters to discriminate patients who demonstrated early and long-term response to PEBD from those who did not. Regarding pruritus improvement in 155 included patients in aggregate, 104 (67%) were responders, 14 (9%) had partial response, and 37 (24%) were nonresponders. In ROC analyses of individual patient data, post-PEBD serum concentration of bile acids, in particular, could discriminate responders from nonresponders for pruritus improvement (area under the curve, 0.99; P < 0.0001; n = 42); to a lesser extent, this was also true for bilirubin (0.87; P = 0.003; n = 31), whereas ALT could not discriminate responders from nonresponders for pruritus improvement (0.74; P = 0.06; n = 28). Reductions from pre-PEBD values in serum bile acid concentration (0.89; P = 0.0003; n = 32) and bilirubin (0.98; P = 0.002; n = 18) but not ALT (0.62; P = 0.46; n = 18) significantly discriminated decreased aggregate need for liver transplant. CONCLUSION: Changes in bile acids seem particularly useful in discriminating early and long-term post-PEBD outcomes and may be potential biomarkers of response to interruption of enterohepatic circulation in patients with PFIC.


Assuntos
Procedimentos Cirúrgicos do Sistema Biliar , Colestase Intra-Hepática , Ácidos e Sais Biliares , Colestase Intra-Hepática/cirurgia , Humanos , Resultado do Tratamento
4.
Lancet Gastroenterol Hepatol ; 9(7): 632-645, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38670135

RESUMO

BACKGROUND: In patients with Alagille syndrome, cholestasis-associated clinical features can include high serum bile acids and severe pruritus that can necessitate liver transplantation. We aimed to evaluate the efficacy and safety of the ileal bile acid transporter inhibitor odevixibat versus placebo in patients with Alagille syndrome. METHODS: The ASSERT study was a phase 3, double-blind, randomised, placebo-controlled trial that enrolled patients at 21 medical centres or hospitals in ten countries (Belgium, France, Germany, Italy, Malaysia, the Netherlands, Poland, Türkiye, the UK, and the USA). Eligible patients had a genetically confirmed diagnosis of Alagille syndrome, a history of significant pruritus, and elevated serum bile acids. Patients were randomly assigned (2:1) to receive oral odevixibat 120 µg/kg per day or placebo for 24 weeks (in a block size of six and stratified by age: <10 years and ≥10 years to <18 years) via a web-based system. Patients, clinicians, study staff, and people analysing the data were masked to treatment allocation. The primary efficacy endpoint was change in caregiver-reported scratching score (on the PRUCISION instrument; range 0-4) from baseline to weeks 21-24. The prespecified key secondary efficacy endpoint was change in serum bile acid concentration from baseline to the average of weeks 20 and 24. Outcomes were analysed in patients who received at least one dose of study drug (the full analysis set for efficacy outcomes and the safety analysis set for safety outcomes). This trial is registered on ClinicalTrials.gov (NCT04674761) and EudraCT (2020-004011-28), and is completed. FINDINGS: Between Feb 26, 2021, and Sept 9, 2022, 52 patients were randomly assigned to receive odevixibat (n=35) or placebo (n=17), all of whom were included in the analysis sets. The median age was 5·5 years (IQR 3·2 to 8·9). 27 (52%) of 52 patients were male and 25 (48%) were female. The mean scratching score was elevated at baseline in both groups (2·8 [SD 0·5] for odevixibat vs 3·0 [0·6] for placebo). Mean scratching scores at weeks 21-24 were 1·1 (0·9) for odevixibat and 2·2 (1·0) for placebo, representing a least-squares (LS) mean change of -1·7 (95% CI -2·0 to -1·3) for odevixibat and -0·8 (-1·3 to -0·3) for placebo, which was significantly greater for odevixibat than for placebo (difference in LS mean change from baseline -0·9 [95% CI -1·4 to -0·3]; p=0·0024). Odevixibat also resulted in significantly greater reductions in mean serum bile acids from baseline versus placebo (237 µmol/L [SD 115] with odevixibat vs 246 µmol/L [121] with placebo) to the average of weeks 20 and 24 (149 µmol/L [102] vs 271 µmol/L [167]; LS mean change -90 µmol/L [95% CI -133 to -48] with odevixibat vs 22 µmol/L [-35 to 80] with placebo; difference in LS mean change -113 µmol/L [95% CI -179 to -47]; p=0·0012). The most common treatment-emergent adverse events were diarrhoea (ten [29%] of 35 patients in the odevixibat group vs one [6%] of 17 in the placebo group) and pyrexia (eight [23%] vs four [24%]). Seven patients had serious treatment-emergent adverse events during the treatment period: five (14%) in the odevixibat group and two (12%) in the placebo group. No patients discontinued treatment and there were no deaths. INTERPRETATION: Odevixibat could be an efficacious non-surgical intervention to improve pruritus, reduce serum bile acids, and enhance the standard of care in patients with Alagille syndrome. Longer-term safety and efficacy data of odevixibat in this population are awaited from the ongoing, open-label ASSERT-EXT study. FUNDING: Albireo Pharma, an Ipsen company.


Assuntos
Síndrome de Alagille , Prurido , Humanos , Método Duplo-Cego , Síndrome de Alagille/tratamento farmacológico , Síndrome de Alagille/complicações , Masculino , Feminino , Criança , Adolescente , Prurido/tratamento farmacológico , Prurido/etiologia , Resultado do Tratamento , Ácidos e Sais Biliares/sangue , Adulto , Pré-Escolar , Adulto Jovem , Proteínas de Transporte , Glicoproteínas de Membrana , Metilaminas , Tiazepinas
5.
JHEP Rep ; 5(8): 100782, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37456676

RESUMO

Background & Aims: PEDFIC 2, an ongoing, open-label, 72-week study, evaluates odevixibat, an ileal bile acid transporter inhibitor, in patients with progressive familial intrahepatic cholestasis. Methods: PEDFIC 2 enrolled and dosed 69 patients across two cohorts; all received odevixibat 120 µg/kg per day. Cohort 1 comprised children from PEDFIC 1, and cohort 2 comprised new patients (any age). We report data through 15 July 2020, with Week 24 of PEDFIC 2 the main time point analysed. This represents up to 48 weeks of cumulative exposure for patients treated with odevixibat from the 24-week PEDFIC 1 study (cohort 1A) and up to 24 weeks of treatment for those who initiated odevixibat in PEDFIC 2 (patients who received placebo in PEDFIC 1 [cohort 1B] or cohort 2 patients). Primary endpoints for this prespecified interim analysis were change from baseline to Weeks 22-24 in serum bile acids (sBAs) and proportion of positive pruritus assessments (≥1-point drop from PEDFIC 2 baseline in pruritus on a 0-4 scale or score ≤1) over the 24-week period. Safety monitoring included evaluating treatment-emergent adverse events (TEAEs). Results: In cohort 1A, mean change from PEDFIC 1 baseline to Weeks 22-24 of PEDFIC 2 in sBAs was -201 µmol/L (p <0.0001). For cohort 1B and cohort 2, mean changes from odevixibat initiation to weeks 22-24 in sBAs were -144 and -104 µmol/L, respectively. The proportion of positive pruritus assessments in the first 24-week period of PEDFIC 2 was 33%, 56%, and 62% in cohorts 1A, 1B, and 2, respectively. Most TEAEs were mild or moderate. No drug-related serious TEAEs occurred. Conclusions: Odevixibat in patients with progressive familial intrahepatic cholestasis was generally well tolerated and associated with sustained reductions in sBAs and pruritus. Clinical Trials Registration: This study is registered at ClinicalTrials.gov (NCT03659916). Impact and Implications: Disrupted bile flow is a hallmark feature of patients with progressive familial intrahepatic cholestasis and can result in build-up of bile constituents in the liver with spill over into the bloodstream; other effects that patients can experience include extremely itchy skin, and because not enough bile reaches the gut, patients can have problems digesting food, which may lead to poor growth. Odevixibat is an orally administered medication that shunts bile acids away from the liver. The current study, called PEDFIC 2, suggested that odevixibat can improve the problematic signs and symptoms of progressive familial intrahepatic cholestasis and was generally safe for patients.

6.
Lancet Gastroenterol Hepatol ; 7(9): 830-842, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35780807

RESUMO

BACKGROUND: Progressive familial intrahepatic cholestasis (PFIC) is a group of inherited paediatric liver diseases resulting from mutations in genes that impact bile secretion. We aimed to evaluate the effects of odevixibat, an ileal bile acid transporter inhibitor, versus placebo in children with PFIC. METHODS: Patients eligible for this 24-week, randomised, double-blind, completed, phase 3 study were paediatric outpatients diagnosed with PFIC1 or PFIC2 who had pruritus and elevated serum bile acids at screening. Patients were randomly assigned (1:1:1) using an interactive web-based system to once a day oral placebo, odevixibat 40 µg/kg, or odevixibat 120 µg/kg. Randomisation was done in a block size of six and stratified by PFIC type and patient age; patients, clinicians, and study staff were blinded to treatment allocation. Patients were enrolled at one of 33 global sites. Two primary endpoints were evaluated: proportion of positive pruritus assessments (PPAs; ie, scratching score of ≤1 or ≥1-point decrease as assessed by caregivers using the Albireo observer-reported outcome [ObsRO] PRUCISION instrument) over 24 weeks, and proportion of patients with serum bile acid response (ie, serum bile acids reduced by ≥70% from baseline or concentrations of ≤70 µmol/L) at week 24. Efficacy and safety were analysed in randomly allocated patients who received one or more doses of study drug. This study is registered with ClinicalTrials.gov, NCT03566238. FINDINGS: Between June 21, 2018, and Feb 10, 2020, 62 patients (median age 3·2 [range 0·5-15·9] years) were randomly allocated to placebo (n=20), odevixibat 40 µg/kg per day (n=23), or odevixibat 120 µg/kg per day (n=19). Model-adjusted (least squares) mean proportion of PPAs was significantly higher with odevixibat versus placebo (55% [SE 8] in the combined odevixibat group [58% in the 40 µg/kg per day group and 52% in the 120 µg/kg per day group] vs 30% [SE 9] in the placebo group; model-adjusted mean difference 25·0% [95% CI 8·5-41·5]; p=0·0038). The percentage of patients with serum bile acid response was also significantly higher with odevixibat versus placebo (14 [33%] of 42 patients in the combined odevixibat group [10 in the 40 µg/kg per day group and four in the 120 µg/kg per day group] vs none of 20 in the placebo group; adjusting for stratification factor [PFIC type], the proportion difference was 30·7% [95% CI 12·6-48·8; p=0·0030]). The most common treatment-emergent adverse events (TEAEs) were diarrhoea or frequent bowel movements (13 [31%] of 42 for odevixibat vs two [10%] of 20 for placebo) and fever (12 [29%] of 42 vs five [25%] of 20); serious TEAEs occurred in three (7%) of 42 odevixibat-treated patients and in five (25%) of 20 placebo-treated patients. INTERPRETATION: In children with PFIC, odevixibat effectively reduced pruritus and serum bile acids versus placebo and was generally well tolerated. Odevixibat, administered as once a day oral capsules, is a non-surgical, pharmacological option to interrupt the enterohepatic circulation in patients with PFIC. FUNDING: Albireo Pharma.


Assuntos
Colestase Intra-Hepática , Colestase , Adolescente , Benzodiazepinas , Ácidos e Sais Biliares , Butiratos , Criança , Pré-Escolar , Colestase Intra-Hepática/tratamento farmacológico , Humanos , Lactente , Prurido/tratamento farmacológico
7.
Clin Res Hepatol Gastroenterol ; 45(5): 101751, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34182185

RESUMO

PURPOSE: Ileal bile acid transporter inhibition is a novel therapeutic concept for cholestatic pruritus and cholestatic liver disease progression. Odevixibat, a potent, selective, reversible ileal bile acid transporter inhibitor, decreases enteric bile acid reuptake with minimal systemic exposure. Oral odevixibat safety, tolerability, and efficacy in pediatric patients with cholestatic liver disease and pruritus were evaluated. PATIENTS AND METHODS: In this phase 2, open-label, multicenter study, children received 10‒200 µg/kg oral odevixibat daily for 4 weeks. Changes in serum bile acid levels (primary efficacy endpoint), pruritus, and sleep disturbance were explored. RESULTS: Twenty patients were enrolled (8 females; 1‒17 years; 4 re-entered at a different dose). Diagnoses included progressive familial intrahepatic cholestasis (n = 13; 3 re-entries), Alagille syndrome (n = 6), biliary atresia (n = 3), and other intrahepatic cholestasis causes (n = 2; 1 re-entry). Mean baseline serum bile acid levels were high (235 µmol/L; range, 26‒564) and were reduced in the majority (-123.1 µmol/L; range, -394 to 14.5, reflecting reductions of up to 98%). Patient-reported diary data documented improved pruritus (3 scales) and sleep. With 100 µg/kg, mean (SEM) decrease was 2.8 (1.1) points for pruritus (visual analogue itch scale 0-10) and 2.9 (0.9) points for sleep disturbance (Patient-Oriented Scoring Atopic Dermatitis scale 0-10). Reduced pruritus correlated significantly with reduced serum bile acids (P ≤ 0.007). Significant correlations were also observed between autotaxin levels and pruritus. All patients completed the study. No serious adverse events were treatment related; most adverse events, including increased transaminases, were transient. CONCLUSIONS: Orally administered odevixibat was well tolerated, reduced serum bile acids, and improved pruritus and sleep disturbance in children with cholestatic diseases.


Assuntos
Benzodiazepinas/uso terapêutico , Butiratos/uso terapêutico , Colestase Intra-Hepática , Colestase , Benzodiazepinas/efeitos adversos , Ácidos e Sais Biliares , Butiratos/efeitos adversos , Criança , Colestase/complicações , Colestase/tratamento farmacológico , Colestase Intra-Hepática/complicações , Colestase Intra-Hepática/tratamento farmacológico , Feminino , Humanos , Prurido/tratamento farmacológico , Prurido/etiologia
8.
J Pharmacol Exp Ther ; 331(2): 504-12, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19648470

RESUMO

Gastroesophageal reflux disease (GERD) affects >10% of the Western population. Conventionally, GERD is treated by reducing gastric acid secretion, which is effective in most patients but inadequate in a significant minority. We describe a new therapeutic approach for GERD, based on inhibition of transient lower esophageal sphincter relaxation (TLESR) with a proposed peripherally acting GABA(B) receptor agonist, (R)-(3-amino-2-fluoropropyl)phosphinic acid (AZD3355). AZD3355 potently stimulated recombinant human GABA(B) receptors and inhibited TLESR in dogs, with a biphasic dose-response curve. In mice, AZD3355 produced considerably less central side effects than the prototypical GABA(B) receptor agonist baclofen but evoked hypothermia at very high doses (blocked by a GABA(B) receptor antagonist and absent in GABA(B)-/- mice). AZD3355 and baclofen differed markedly in their distribution in rat brain; AZD3355, but not baclofen, was concentrated in circumventricular organs as a result of active uptake (shown by avid intracellular sequestration) and related to binding of AZD3355 to native GABA transporters in rat cerebrocortical membranes. AZD3355 was also shown to be transported by all four recombinant human GABA transporters. AR-H061719 [(R/S)-(3-amino-2-fluoropropyl)phosphinic acid], (the racemate of AZD3355) inhibited the response of ferret mechanoreceptors to gastric distension, further supporting its peripheral site of action on TLESR. In summary, AZD3355 probably inhibits TLESR through stimulation of peripheral GABA(B) receptors and may offer a potential new approach to treatment of GERD.


Assuntos
Esfíncter Esofágico Inferior/efeitos dos fármacos , Agonistas GABAérgicos/farmacologia , Agonistas dos Receptores de GABA-B , Nervos Periféricos/efeitos dos fármacos , Ácidos Fosfínicos/farmacologia , Propilaminas/farmacologia , Animais , Autorradiografia , Baclofeno/farmacologia , Ligação Competitiva/efeitos dos fármacos , Cálcio/metabolismo , Cães , Relação Dose-Resposta a Droga , Esfíncter Esofágico Inferior/inervação , Feminino , Furões/metabolismo , Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo , Humanos , Hipotermia/induzido quimicamente , Técnicas In Vitro , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Relaxamento Muscular/efeitos dos fármacos , Ligação Proteica , Isoformas de Proteínas/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de GABA-B/metabolismo , Nervo Vago/efeitos dos fármacos , Nervo Vago/fisiologia
9.
Neurogastroenterol Motil ; 31(5): e13571, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30793431

RESUMO

BACKGROUND: In two phase 3 trials, elobixibat, a locally acting ileal bile acid transporter inhibitor, resolved constipation and was well tolerated in Japanese patients with chronic constipation. We analyzed the efficacy, safety, and impact on quality of life (QOL) of elobixibat in patients with symptomatically more severe constipation in the two phase 3 trials. METHODS: This post hoc analysis of elobixibat treatment outcomes included data from a 2-week, randomized, placebo-controlled, phase 3 trial (10 mg/d), and a 52-week, open-label trial (5-15 mg/d) in subgroups with severe constipation defined as ≤2 spontaneous bowel movements (SBMs) and ≤3 Bristol Stool Form Scale score during the second week of the 2-week run-in period. We also analyzed the rates of abdominal pain, diarrhea, and QOL in subgroups according to sex, presence of constipation-predominant irritable bowel syndrome (IBS-C) and side effects. KEY RESULTS: In patients with severe constipation, there was significant improvement in the 10 mg elobixibat group compared to the placebo group in change in SBMs from baseline at week 1 (primary endpoint) of the 2-week trial. The differences between groups were reduced in patients with more severe constipation. Increasing the dose to 15 mg was effective for more severe constipation in improving the number of SBMs per week in the 52-week trial. Overall, elobixibat was well tolerated and improved QOL scores, irrespective of gender, presence of IBS-C or side effects. CONCLUSIONS & INFERENCES: Elobixibat is effective for symptomatically severe constipation, is well tolerated and improves QOL, irrespective of potentially confounding patient characteristics.


Assuntos
Constipação Intestinal/tratamento farmacológico , Dipeptídeos/uso terapêutico , Fármacos Gastrointestinais/uso terapêutico , Qualidade de Vida , Tiazepinas/uso terapêutico , Adulto , Ensaios Clínicos Fase III como Assunto , Feminino , Humanos , Japão , Masculino , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos
10.
Lancet Gastroenterol Hepatol ; 3(8): 537-547, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29805116

RESUMO

BACKGROUND: A subset of patients with constipation has reduced colonic bile acid concentrations, which are associated with slow colonic transit. In a previous study, elobixibat, a locally acting ileal bile acid transporter inhibitor, accelerated colonic transit in Japanese patients with functional constipation. In this study, we aimed to determine the efficacy of elobixibat for short-term treatment of chronic constipation, and safety, patient satisfaction, and quality of life with long-term treatment. METHODS: We did two phase 3 studies of patients aged 20-80 years in Japan with at least 6 months of chronic constipation, who satisfied Rome III criteria for functional constipation, including fewer than three spontaneous bowel movements per week. The first trial, including patients enrolled at 16 clinics, was a 2-week, randomised, double-blind, placebo-controlled study in which (after a 2-week run-in period) patients were randomly assigned (1:1) to either elobixibat 10 mg/day for 2 weeks or placebo. Randomisation was done with permuted block method (block size six) without stratification. Masking to treatment allocation was achieved with identical appearances of elobixibat and placebo, which were supplied in sealed, opaque containers. Group assignment was concealed from patients, investigators, and analysts. The second trial, including patients enrolled at 34 clinics or hospitals, was an open-label, 1-year study in which all patients received elobixibat; participants could titrate the dose to 5 mg/day or 15 mg/day, or maintain the 10 mg/day dose. In both studies, participants took the study drug as an oral tablet once per day before breakfast. The primary outcome of the 2-week randomised trial was the change from baseline (ie, last week of the 2-week run-in) in the frequency of spontaneous bowel movements during week 1 of treatment. The primary outcome of the 52-week open-label trial was safety (type, severity, and incidence of adverse drug reactions) at all times from treatment initiation. All efficacy analyses were based on the modified intention-to-treat (ITT) population without imputation for any missing data. Safety analyses included all patients who received at least one dose of study drug. These trials are registered with the Japan Pharmaceutical Information Center (numbers JapicCTI-153061 and JapicCTI-153062) and have been completed. FINDINGS: Between Nov 4, 2015, and June 11, 2016, we assigned 133 patients to treatment in the 2-week randomised trial: 70 to elobixibat (69 included in the modified ITT and safety populations) and 63 to placebo. The frequency of spontaneous bowel movements per week during week 1 of treatment was greater with elobixibat (least-squares mean 6·4, 95% CI 5·3-7·6) than with placebo (1·7, 1·2-2·2), p<0·0001). Between Oct 31, 2015, and March 15, 2017, we allocated 341 patients to 52 weeks of elobixibat (340 included in the modified ITT and safety populations). 163 (48%) patients in the 52-week trial had an adverse drug reaction, the most common of which were mild gastrointestinal disorders (in 135 [40%] patients). Inguinal hernia was reported in one patient with elobixibat in the 52-week study as a moderate adverse drug reaction. The most common adverse drug reactions in both trials were mild abdominal pain (13 [19%] patients with elobixibat and one [2%] with placebo in the 2-week randomised trial, and 82 [24%] patients in the 52-week trial) and diarrhoea (nine [13%] patients with elobixibat and none with placebo in the 2-week randomised trial and 50 [15%] in the 52-week trial). INTERPRETATION: Elobixibat resolved constipation in the short-term, and was well tolerated with both short-term and long-term treatment. The evidence supports the use of this novel approach to increase intracolonic concentrations of endogenous bile acid for the treatment of chronic constipation. FUNDING: EA Pharma and Mochida Pharmaceutical.


Assuntos
Proteínas de Transporte/antagonistas & inibidores , Constipação Intestinal/tratamento farmacológico , Dipeptídeos/efeitos adversos , Dipeptídeos/uso terapêutico , Fármacos Gastrointestinais/efeitos adversos , Fármacos Gastrointestinais/uso terapêutico , Glicoproteínas de Membrana/antagonistas & inibidores , Tiazepinas/efeitos adversos , Tiazepinas/uso terapêutico , Dor Abdominal/induzido quimicamente , Adulto , Idoso , Idoso de 80 Anos ou mais , Ácidos e Sais Biliares/metabolismo , Doença Crônica , Colo/metabolismo , Constipação Intestinal/metabolismo , Método Duplo-Cego , Feminino , Gastroenteropatias/induzido quimicamente , Trânsito Gastrointestinal/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Satisfação do Paciente , Qualidade de Vida , Adulto Jovem
11.
J Comp Neurol ; 503(1): 35-46, 2007 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-17480026

RESUMO

Transient receptor potential (TRP) channels play essential roles in sensory physiology and their expression in different classes of sensory neurons reflect distinct receptive properties of these neurons. While expression of the TRPV, TRPA, and to a certain degree TRPM classes of channels has been studied in sensory neurons, little is known about the expression and regulation of TRPC channels. In this study we examined the regulation of all TRPC members (TRPC1-C7) throughout embryonic and postnatal development of the dorsal root ganglion (DRG) and nodose ganglion (NG). In adult mice, mRNAs for all channels were present in the DRG, with TRPC1, 3, and 6 being the most abundant, TRPC2, C4, and C5 at lower levels, and TRPC7 at very low levels. While TRPC2 mRNAs were downregulated from high levels at embryonic (E) day 12 and E14 until adult, TRPC4, C5, and C7 expressions increased from E12 to peak levels at E18. TRPC1, C3, and C6, the most abundant TRPC channel mRNAs, increased progressively from E12 to adult. Expression and regulation of TRPC channels mRNAs in the NG were unexpectedly similar to the DRG. TRPC1 and C2 was expressed in the neurofilament-200 (NF-200)-positive large size subclass of neurons, while TRPC3 mRNAs expression, which stained up to 35% of DRG neurons, was almost exclusively present in nonpeptidergic isolectin B4 (IB4)-positive small size neurons that were largely TRPV1-negative. Our results suggest important roles of the TRPC family of channels in sensory physiology of both nociceptive as well as nonnociceptive classes of neurons.


Assuntos
Gânglios Espinais/metabolismo , Neurônios Aferentes/metabolismo , Gânglio Nodoso/metabolismo , Canais de Cátion TRPC/metabolismo , Animais , Feminino , Gânglios Espinais/citologia , Gânglios Espinais/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento , Vértebras Lombares , Camundongos , Camundongos Endogâmicos C57BL , Neurônios Aferentes/classificação , Gânglio Nodoso/citologia , Gânglio Nodoso/crescimento & desenvolvimento , RNA Mensageiro/análise , Canais de Cátion TRPC/classificação , Canais de Cátion TRPC/genética , Vértebras Torácicas
12.
Br J Pharmacol ; 146(1): 89-97, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15980875

RESUMO

The effects of the novel GABA analogue (2R)-(3-amino-2-fluoropropyl)sulphinic acid (AFPSiA) on transient lower oesophageal sphincter relaxations (TLOSRs) were studied in the dog. In addition, the GABA(A)/GABA(B) selectivity was determined in vitro and in vivo, and the pharmacokinetics and the metabolism of the compound were studied in the dog and rat. TLOSRs were reduced by 55 +/- 8% after intragastric administration of AFPSiA at 14 mumol kg(-1) and did not decrease further at higher doses. When evaluated 2 and 4 h after administration, the effect declined to 37 +/- 6 and 16 +/- 9%, respectively. Spontaneous swallowing was only significantly inhibited at 100 micromol kg(-1). The oral availability of AFPSiA was 52 +/- 17 and 71 +/- 4% in the dog and rat, respectively. A fraction of AFPSiA was oxidised to the corresponding sulphonate, (2R)-(3-amino-2-fluoropropyl)sulphonic acid (AFPSoA) after oral administration to the rat and dog. In rat brain membranes, AFPSiA was found to have ten times higher affinity for rat brain GABA(B) (K(i) =47 +/- 4.4 nM) compared to GABA(A) (K(i) = 430 +/- 46 nM) binding sites. The compound was a full agonist at human recombinant GABA(B(1a,2)) receptors (EC(50) = 130 +/- 10 nM). In contrast, the metabolite AFPSoA was considerably more selective for binding to rat brain GABA(A) (K(i) = 37 +/- 3.1 nM) vs GABA(B) (K(i) = 6800 +/- 280 nM) receptors. In the mouse, high doses (1-8 mmol kg(-1)) of AFPSiA induced a rapid and mild hypothermia followed by a profound and sustained hypothermia at the higher doses tested (6 and 8 mmol kg(-1)). This effect was unaffected by the selective GABA(B) receptor antagonist CGP62349. AFPSoA (1 and 2 mmol kg(-1)) produced transient and moderate hypothermia while the hypothermic response was considerably larger at 4 mmol kg(-1).It is concluded that AFPSiA inhibits but does not abolish TLOSRs in the dog. High doses of the compound induce hypothermia in the mouse, which probably is attributable to activation of the GABA(A) receptor. The latter effect may be caused both by AFPSiA and its oxidised sulphonic acid metabolite AFPSoA.


Assuntos
Esfíncter Esofágico Inferior/efeitos dos fármacos , Agonistas GABAérgicos/farmacologia , Agonistas dos Receptores de GABA-B , Relaxamento Muscular/efeitos dos fármacos , Ácidos Sulfínicos/farmacologia , Animais , Temperatura Corporal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Células CHO , Cálcio/metabolismo , Cricetinae , Cricetulus , Deglutição/efeitos dos fármacos , Cães , Esfíncter Esofágico Inferior/fisiologia , Feminino , Agonistas de Receptores de GABA-A , Antagonistas de Receptores de GABA-B , Hipotermia/induzido quimicamente , Camundongos , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Receptores de GABA-A/metabolismo , Receptores de GABA-B/metabolismo , Ácidos Sulfínicos/efeitos adversos , Vesículas Sinápticas/efeitos dos fármacos , Vesículas Sinápticas/metabolismo
13.
Eur J Pharmacol ; 519(1-2): 154-7, 2005 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-16102747

RESUMO

Transient lower esophageal sphincter relaxation is the major mechanism for gastroesophageal reflux. The present study was initiated to investigate the potential effect of the metabotropic glutamate 5 (mGlu5) receptor antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), on transient lower esophageal sphincter relaxations in the conscious dog. MPEP (1.4-8.7 micromol/kg i.v.) produced a dose-dependent inhibition of transient lower esophageal sphincter relaxations (59+/-11% inhibition at 8.7 micromol/kg). In addition, there was a reduction of the number of reflux episodes and an increase in latency time to the occurrence of the first transient lower esophageal sphincter relaxation. No effect was seen on basal lower esophageal sphincter pressure or on swallowing. It is concluded that the mGlu5 receptor antagonist MPEP potently inhibits transient lower esophageal sphincter relaxations and that the mGlu5 receptor is a potential target for treatment of gastroesophageal reflux disease.


Assuntos
Esfíncter Esofágico Inferior/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Relaxamento Muscular/efeitos dos fármacos , Piridinas/farmacologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Animais , Sítios de Ligação , Ligação Competitiva , Cães , Relação Dose-Resposta a Droga , Esfíncter Esofágico Inferior/fisiologia , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/metabolismo , Feminino , Refluxo Gastroesofágico/fisiopatologia , Refluxo Gastroesofágico/prevenção & controle , Injeções Intravenosas , Masculino , Piridinas/administração & dosagem , Piridinas/metabolismo , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/metabolismo , Trítio
14.
Br J Pharmacol ; 140(2): 315-22, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12970075

RESUMO

1. Activation of GABA(B) receptors evokes hypothermia in wildtype (GABA(B(1))+/+) but not in GABA(B) receptor knockout (GABA(B(1))-/-) mice. The aim of the present study was to determine the hypothermic and behavioural effects of the putative GABA(B) receptor agonist gamma-hydroxybutyrate (GHB), and of the GABA(A) receptor agonist muscimol. In addition, basal body temperature was determined in GABA(B(1))+/+, GABA(B(1))+/- and GABA(B(1))-/- mice. 2. GABA(B(1))-/- mice were generated by homologous recombination in embryonic stem cells. Correct gene targeting was assessed by Southern blotting, PCR and Western blotting. GABA(B) receptor-binding sites were quantified with radioligand binding. Measurement of body temperature was done using subcutaneous temperature-sensitive chips, and behavioural changes after drug administration were scored according to a semiquantitative scale. 3. GABA(B(1))-/- mice had a short lifespan, probably caused by generalised seizure activity. No histopathological or blood chemistry changes were seen, but the expression of GABA(B(2)) receptor protein was below the detection limit in brains from GABA(B(1))-/- mice, in the absence of changes in mRNA levels. 4. GABA(B) receptor-binding sites were absent in brain membranes from GABA(B(1))-/- mice. 5. GABA(B(1))-/- mice were hypothermic by approximately 1 degrees C compared to GABA(B(1))+/+ and GABA(B(1))+/- mice. 6. Injection of baclofen (9.6 mg kg-1) produced a large reduction in body temperature and behavioural effects in GABA(B(1))+/+ and in GABA(B(1))+/- mice, but GABA(B(1))-/- mice were unaffected. The same pattern was seen after administration of GHB (400 mg kg-1). The GABA(A) receptor agonist muscimol (2 mg kg-1), on the other hand, produced a more pronounced hypothermia in GABA(B(1))-/-mice. In GABA(B(1))+/+ and GABA(B(1))+/- mice, muscimol induced sedation and reduced locomotor activity. However, when given to GABA(B(1))-/- mice, muscimol triggered periods of intense jumping and wild running. 7. It is concluded that hypothermia should be added to the characteristics of the GABAB(1)-/-phenotype. Using this model, GHB was shown to be a selective GABAB receptor agonist. In addition, GABAB(1)-/- mice are hypersensitive to GABAA receptor stimulation, indicating that GABAB tone normally balances GABAA-mediated effects.


Assuntos
Regulação da Temperatura Corporal/efeitos dos fármacos , Agonistas GABAérgicos/farmacologia , Agonistas dos Receptores de GABA-B , Animais , Baclofeno/farmacologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Clonagem Molecular , Agonistas de Receptores de GABA-A , Regulação da Expressão Gênica/efeitos dos fármacos , Genótipo , Hipotermia/induzido quimicamente , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Knockout , Muscimol/farmacologia , Fenótipo , Subunidades Proteicas/genética , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de GABA-A/genética , Receptores de GABA-A/fisiologia , Receptores de GABA-B/genética , Receptores de GABA-B/fisiologia , Oxibato de Sódio/farmacologia
15.
Gene Expr Patterns ; 10(1): 65-74, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19850157

RESUMO

Despite the significance of transient receptor potential (TRP) channels in sensory physiology, little is known of the expression and developmental regulation of the TRPM (melastatin) subgroup in sensory neurons. In order to find out if the eight TRPM subgroup members (TRPM1-TRPM8) have a possible role in the sensory nervous system, we characterized the developmental regulation of their expression in mouse dorsal root ganglion (DRG) from embryonic (E) day 12 to adulthood. Transcripts for all channels except for TRPM1 were detected in lumbar and thoracic DRG and in nodose ganglion (NG) with distinguishable expression patterns from E12 until adult. For most channels, the expression increased from E14 to adult with the exception of TRPM5, which displayed transient high levels during embryonic and early postnatal stages. Cellular localization of TRPM8 mRNA was found only in a limited subset of very small diameter neurons distinct in size from other populations. These neurons did not bind isolectin B4 (IB4) and expressed neither the neuropeptide calcitonin gene-related peptide (CGRP) nor neurofilament (NF)200. This suggests that TRPM8(+) thermoreceptive sensory neurons fall into a separate group of very small sized neurons distinct from peptidergic and IB4(+) subtypes of sensory neurons. Our results, showing the expression and dynamic regulation of TRPM channels during development, indicate that many TRPM subfamily members could participate during nervous system development and in the adult by determining distinct physiological properties of sensory neurons.


Assuntos
Gânglios Espinais/embriologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Células Receptoras Sensoriais/metabolismo , Canais de Cátion TRPM/metabolismo , Fatores Etários , Animais , Primers do DNA/genética , Gânglios Espinais/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento/genética , Imuno-Histoquímica , Hibridização In Situ , Camundongos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Receptoras Sensoriais/fisiologia , Canais de Cátion TRPM/classificação
16.
Pain ; 144(1-2): 187-99, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19446956

RESUMO

Neuropathic pain is a chronic disease resulting from dysfunction of the nervous system often due to peripheral nerve injury. Hypersensitivity to sensory stimuli (mechanical, thermal or chemical) is a common source of pain in patients and ion channels involved in detecting these stimuli are possible candidates for inducing and/or maintaining the pain. Transient receptor potential (TRP) channels expressed on nociceptors respond to different sensory stimuli and a few of them have been studied previously in the models of neuropathic pain. Using real-time PCR for quantification of all known TRP channels we identified several TRP channels, which have not been associated with nociception or neuropathic pain before, to be expressed in the DRG and to be differentially regulated after spared nerve injury (SNI). Of all TRP channel members, TRPML3 showed the most dramatic change in animals exhibiting neuropathic pain behaviour compared to control animals. In situ hybridisation showed a widespread increase of expression in neurons of small, medium and large cell sizes, indicating expression in multiple subtypes. Co-localisation of TRPML3 with CGRP, NF200 and IB4 staining confirmed a broad subtype distribution. Expression studies during development showed that TRPML3 is an embryonic channel that is induced upon nerve injury in three different nerve injury models investigated. Thus, the current results link for the first time a re-expression of TRPML3 with the development of neuropathic pain conditions. In addition, decreased mRNA levels after SNI were seen for TRPM6, TRPM8, TRPV1, TRPA1, TRPC3, TRPC4 and TRPC5.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Neuralgia/metabolismo , Neuralgia/patologia , Canais de Cátion TRPC/metabolismo , Animais , Axotomia/métodos , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Modelos Animais de Doenças , Feminino , Lateralidade Funcional , Gânglios Espinais/patologia , Hiperalgesia/metabolismo , Lectinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neuralgia/etiologia , Proteínas de Neurofilamentos/metabolismo , Neurônios/metabolismo , Neuropeptídeo Y/metabolismo , Estimulação Física/efeitos adversos , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Canais de Cátion TRPC/classificação , Canais de Cátion TRPC/genética , Fatores de Tempo
17.
Neurosci Lett ; 457(1): 3-7, 2009 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-19429150

RESUMO

Mechanosensitivity is a crucial but poorly understood property of the sensory nervous system. Transient receptor potential (TRP) channels, which have been found to be responsible for the detection of other sensory stimuli such as temperature and pungent chemicals, have been suggested to also recognize stretch or pressure to cell membranes. TRPC1 is one candidate from studies in oocytes but evidence in native sensory neurons has been lacking. Therefore, we have measured an increase in intracellular Ca(2+) levels upon mechanical activation of native mouse dorsal root ganglion (DRG) neurons in culture using hypoosmolar buffer. Our results show that down regulation of TRPC1 with short hairpin RNA results in a 65% reduction of neurons with stretch activated responses. These results implicate a direct or indirect involvement of TRPC1 in the mechanosensitivity of DRG neurons.


Assuntos
Gânglios Espinais/fisiologia , Mecanotransdução Celular/fisiologia , Células do Corno Posterior/fisiologia , Canais de Cátion TRPC/fisiologia , Animais , Células Cultivadas , Regulação para Baixo , Inativação Gênica , Camundongos , Camundongos Endogâmicos C57BL , RNA Interferente Pequeno/genética
18.
J Med Chem ; 51(14): 4315-20, 2008 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-18578471

RESUMO

We have previously demonstrated that the prototypical GABA B receptor agonist baclofen inhibits transient lower esophageal sphincter relaxations (TLESRs), the most important mechanism for gastroesophageal reflux. Thus, GABA B agonists could be exploited for the treatment of gastroesophageal reflux disease. However, baclofen, which is used as an antispastic agent, and other previously known GABA B agonists can produce CNS side effects such as sedation, dizziness, nausea, and vomiting at higher doses. We now report the discovery of atypical GABA B agonists devoid of classical GABA B agonist related CNS side effects at therapeutic doses and the optimization of this type of compound for inhibition of TLESRs, which has resulted in a candidate drug ( R)- 7 (AZD3355) that is presently being evaluated in man.


Assuntos
Agonistas GABAérgicos/química , Agonistas GABAérgicos/farmacologia , Agonistas dos Receptores de GABA-B , Refluxo Gastroesofágico/tratamento farmacológico , Animais , Relação Dose-Resposta a Droga , Agonistas GABAérgicos/uso terapêutico , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas de Bombardeamento Rápido de Átomos
19.
Bioorg Med Chem Lett ; 16(5): 1142-5, 2006 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-16380255

RESUMO

Fenobam (1) was developed by McNeil Laboratories as an anxiolytic agent with an unknown molecular target in the late 1970s. In a recent publication, it was revealed that fenobam is a non-competitive mGluR5 antagonist. Herein, we present the structure-activity relationship of fenobam and its analogues and similarities between the SAR of mGluR5 antagonism and the SAR of CNS properties originally reported by McNeil are discussed.


Assuntos
Creatinina/química , Creatinina/farmacologia , Imidazóis/química , Imidazóis/farmacologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Ureia/química , Amidas/química , Cloretos/química , Imidazóis/síntese química , Concentração Inibidora 50 , Estrutura Molecular , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/metabolismo , Relação Estrutura-Atividade
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