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1.
Cells ; 10(6)2021 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-34198609

RESUMO

Alcohol-related liver disease is associated with intestinal dysbiosis. Functional changes in the microbiota affect bile acid metabolism and result in elevated serum bile acids in patients with alcohol-related liver disease. The aim of this study was to identify the potential role of the bile acid sequestrant colesevelam in a humanized mouse model of ethanol-induced liver disease. We colonized germ-free (GF) C57BL/6 mice with feces from patients with alcoholic hepatitis and subjected humanized mice to the chronic-binge ethanol feeding model. Ethanol-fed gnotobiotic mice treated with colesevelam showed reduced hepatic levels of triglycerides and cholesterol, but liver injury and inflammation were not decreased as compared with non-treated mice. Colesevelam reduced hepatic cytochrome P450, family 7, subfamily a, polypeptide 1 (Cyp7a1) protein expression, although serum bile acids were not lowered. In conclusion, our findings indicate that colesevelam treatment mitigates ethanol-induced liver steatosis in mice.


Assuntos
Colesterol 7-alfa-Hidroxilase/biossíntese , Cloridrato de Colesevelam/farmacologia , Etanol/toxicidade , Fígado Gorduroso , Vida Livre de Germes , Animais , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/enzimologia , Feminino , Camundongos
2.
BMJ Open ; 11(2): e044711, 2021 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-33558360

RESUMO

INTRODUCTION: Bile acid malabsorption (BAM) is a socially debilitating disease characterised by high stool frequency and urgency caused by a spillover of bile acids into the colon. Bile acid sequestrants (BASs) have limited therapeutic effect but represent the only available treatment option. Cases reporting total remission of BAM-related symptoms after treatment with liraglutide, a glucagon-like peptide 1 analogue, prompted us to design a clinical trial investigating the therapeutic effect of this compound in patients with BAM. METHODS AND ANALYSIS: Fifty adult individuals with moderate or severe BAM as assessed by the 75selenium-homotaurocholic acid test (SeHCAT) will, after a run-in period of 10 days with no BAM treatment, be randomised to either treatment with the BAS colesevelam or liraglutide (double blinded) for 6 weeks. Daily symptom diaries and questionnaires will be filled in. Blood and faecal samples will be collected and SeHCAT will be performed at baseline, after week 3 and at end of trial. The primary endpoint is change in daily stool frequency. Secondary endpoints include changes from baseline in questionnaires, biochemistry, SeHCAT and faecal bile acid content and microbial composition. ETHICS AND DISSEMINATION: The study complies with Danish and European Union legislation and is approved by the Danish Medicines Agency, the Regional Scientific Ethics Committee of the Capital Region of Denmark and the Danish Data Protection Agency. The study is monitored by the Capital Region of Denmark's good clinical practice unit. All results, positive, negative and inconclusive, will be disseminated at national and/or international scientific meetings and in peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER: EudraCA: 2018-003575-34; Pre-results.


Assuntos
Ácidos e Sais Biliares , Liraglutida , Adulto , Cloridrato de Colesevelam , Método Duplo-Cego , Peptídeo 1 Semelhante ao Glucagon , Humanos , Hipolipemiantes , Liraglutida/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto
3.
Diabetes Res Clin Pract ; 170: 108416, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32891688

RESUMO

AIMS: The CV-CARE registry provides RWE in Canadian routine clinical practice. METHODS: CV-CARE is a multi-site, observational, prospective Canadian registry enrolling patients initiating treatment with metformin hydrochloride extended-release (MetER) for T2D; colesevelam (C) for HCh; and azilsartan (AZI), azilsartan/chlorthalidone (AZI/CHL) or diltiazem extended-release (TXC) for HTN. Patient characteristics/assessment were performed at baseline and 12 ± 6 months. Primary outcome was absolute change in HbA1c and FPG (MetER); % change in LDL-C (C); and absolute change in BP (AZI-AZI/CHL-TXC). RESULTS: Of the 4194 patients in the primary analysis population, 24% were taking MetER, 39% were taking C, 33% were taking AZI, 12% were taking AZI/CHL, and 3% were taking TXC. At 12 months, MetER-treated patients had an absolute mean (95% CI) change in HbA1c of -0.3% [-0.4; -0.2] and in FPG of 0.7 mmol/L [-1.0; -0.4]. C-treated patients had a mean (95% CI) % change in LDL-C of -13.0% [-14.6; -11.4]. Absolute mean (95% CI) changes in SBP were -18.7 mmHg [-19.7; -17.7](AZI), -21.3 mmHg [-23.1; -19.5](AZI/CHL), and -12.3 mmHg [-15.1; -9.6](TXC). CONCLUSION: In a real-world Canadian setting, MetER, C, AZI, AZI/CHL, and TXC show improvement of the cardiometabolic profile of T2D, HCh, and HTN patients.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipercolesterolemia/tratamento farmacológico , Hipertensão/tratamento farmacológico , Idoso , Anticolesterolemiantes/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Benzimidazóis/uso terapêutico , Canadá , Doenças Cardiovasculares/tratamento farmacológico , Clortalidona/uso terapêutico , Cloridrato de Colesevelam/uso terapêutico , Feminino , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , Síndrome Metabólica/tratamento farmacológico , Metformina/uso terapêutico , Pessoa de Meia-Idade , Oxidiazóis/uso terapêutico , Estudos Prospectivos , Sistema de Registros , Resultado do Tratamento
5.
J Cardiol ; 76(4): 385-394, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32473770

RESUMO

BACKGROUND: Regional differences in the profile and treatment strategies of patients with cardiometabolic diseases have been studied in several different countries. The Cardio-Vascular and metabolic treatments in Canada: Assessment of REal-life therapeutic value (CV-CARE) registry was designed to evaluate patient profiles and medical management of cardiometabolic diseases in routine clinical care settings across Canada. Primary objectives were to (1) evaluate regional variability of patient profiles with cardiometabolic disease(s) and (2) assess treatment differences of patients treated for type 2 diabetes (T2D), hypercholesterolemia (HCh), and hypertension (HTN) across Canada. METHODS: CV-CARE is a multi-center, observational, prospective registry that enrolled Canadian patients treated with metformin-extended release (MetER) for T2D, colesevelam (C) for HCh, azilsartan (AZI) for mild-to-moderate essential HTN and azilsartan/chlorthalidone (AZI/CHL) for severe, essential HTN. Patient characteristics and treatments were assessed at baseline. RESULTS: The registry enrolled 6960 patients, with a total of 4194 patients making up the primary analysis population [MetER (n=995); C (n=1639); AZI (n=1364); AZI/CHL (n=498)]. First-line use of MetER was more common in British Columbia (BC; 45.5%) compared to Ontario (ON; 29.8%), and Quebec (QC; 12.9%). C treatment for HCh was used as monotherapy most readily in BC (68.7%) compared with QC (59.7%) and ON (35.8%). Dual action of low-density lipoprotein cholesterol and hemoglobin A1c reduction was the predominant reason for C add-on therapy (46.8%), with highest usage seen in ON (62.9%). AZI treatment for HTN was most frequently used in BC (43.8%), and AZI/CHL was most commonly used in ON (12.0%). First-line use of AZI was more common in QC (50%) vs. ON (34.9%) and BC (24.1%). The primary reason for switching to AZI and AZI/CHL from prior treatment was lack of efficacy across provinces. CONCLUSION: This is the first regional description of the CV-CARE cohort. Significant variations in both baseline profile and treatments were observed which could have an impact on long-term outcomes.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipercolesterolemia/tratamento farmacológico , Hipertensão/tratamento farmacológico , Idoso , Anticolesterolemiantes/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Benzimidazóis/uso terapêutico , Canadá , Clortalidona/uso terapêutico , Cloridrato de Colesevelam/uso terapêutico , Quimioterapia Combinada , Feminino , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , Metformina/uso terapêutico , Pessoa de Meia-Idade , Oxidiazóis/uso terapêutico
6.
Am J Gastroenterol ; 115(10): 1596-1603, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32558690

RESUMO

Bile acids (BAs) are the central signals in enterohepatic communication, and they also integrate microbiota-derived signals into enterohepatic signaling. The tissue distribution and signaling pathways activated by BAs through natural receptors, farsenoid X receptor and G protein-coupled BA receptor 1 (GPBAR1, also known as Takeda G-coupled receptor 5), have led to a greater understanding of the mechanisms and potential therapeutic agents. BA diarrhea is most commonly encountered in ileal resection or disease, in idiopathic disorders (with presentation similar to functional diarrhea or irritable bowel syndrome with diarrhea), and in association with malabsorption such as chronic pancreatitis or celiac disease. Diagnosis of BA diarrhea is based on Se-homocholic acid taurine retention, 48-hour fecal BA excretion, or serum 7αC4; the latter being a marker of hepatic BA synthesis. BA diarrhea tends to be associated with higher body mass index, increased stool weight and stool fat, and acceleration of colonic transit. Biochemical markers of increased BA synthesis or excretion are available through reference laboratories. Current treatment of BA diarrhea is based on BA sequestrants, and, in the future, it is anticipated that farsenoid X receptor agonists may also be effective. The optimal conditions for an empiric trial with BA sequestrants as a diagnostic test are still unclear. However, such therapeutic trials are widely used in clinical practice. Some national guidelines recommend definitive diagnosis of BA diarrhea over empirical trial.


Assuntos
Ácidos e Sais Biliares/metabolismo , Diarreia/metabolismo , Diarreia/terapia , Dieta com Restrição de Gorduras , Sequestrantes/uso terapêutico , Benzotiazóis/uso terapêutico , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/uso terapêutico , Colestenonas/sangue , Resina de Colestiramina/uso terapêutico , Doença Crônica , Cloridrato de Colesevelam/uso terapêutico , Colestipol/uso terapêutico , Fezes/química , Humanos , Mucosa Intestinal/metabolismo , Síndrome do Intestino Irritável/metabolismo , Isoxazóis/uso terapêutico , Fígado/metabolismo , Síndromes de Malabsorção/diagnóstico , Síndromes de Malabsorção/tratamento farmacológico , Síndromes de Malabsorção/metabolismo , Receptores Citoplasmáticos e Nucleares/agonistas , Ácido Taurocólico/análogos & derivados
7.
Am J Med ; 133(11): 1322-1327, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32416177

RESUMO

BACKGROUND: Statins are the first-line therapy for reducing low-density lipoprotein cholesterol (LDL-C). However, there are secondary prevention patients who are either intolerant to maximal statin therapy or do not get adequate effects from a high-intensity statin. While data exist for the additional LDL-C-lowering effects of ezetimibe, there are no data on additional LDL-C lowering of bile acid sequestrants when combined with statin therapy. The purpose of this study was to quantify the LDL-C-lowering effects of bile acid sequestrants when added to statin therapy. METHODS: Databases (Medline via PubMed, Embase, and the Cochrane Library) were searched for randomized controlled trials comparing statin therapy to statin therapy with the addition of bile acid sequestrants. Nine studies were included in the meta-analysis. A meta-regression was performed to estimate the mean difference in LDL-C between the 2 groups. RESULTS: Without controlling for other variables, data suggest that combining statin with bile acid sequestrant increases the percentage change in LDL-C by 16.2 points, on average, compared with statin use alone. CONCLUSION: In patients unable to tolerate an adequate statin dosage, bile acid sequestrants offer a viable alternative with additional LDL-C-lowering benefit.


Assuntos
Anticolesterolemiantes/uso terapêutico , LDL-Colesterol/sangue , Resina de Colestiramina/uso terapêutico , Cloridrato de Colesevelam/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Quimioterapia Combinada , Humanos , Hipercolesterolemia/sangue , Resultado do Tratamento
8.
J Pak Med Assoc ; 70(5): 934-936, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32400758

RESUMO

Colesevelam is a bile acid sequestrant, approved for the management of both dyslipidaemia and type 2 diabetes. This review discusses the potential for the use of colesevelam in the management of type 2 diabetes. Expert opinion suggests possible indications where colesevelam may add value as a glucose lowering agent. It also highlights the limitations of the drug, and precautions that must be observed while using it.


Assuntos
Cloridrato de Colesevelam/farmacologia , Diabetes Mellitus Tipo 2 , Dislipidemias/tratamento farmacológico , Anticolesterolemiantes/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Dislipidemias/metabolismo , Humanos , Farmacovigilância
9.
Diabetes Obes Metab ; 22(10): 1722-1728, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32406601

RESUMO

AIM: To compare the efficacy and safety of colesevelam and ezetimibe as second-line low density lipoprotein-cholesterol (LDL-c)-lowering options in type 2 diabetes (T2D). MATERIALS AND METHODS: GOAL-RCT is a 24-week, open-label, randomized, pragmatic clinical trial. Subjects with T2D with uncontrolled HbA1c (7.1%-10%) and LDL-c (>2.0 mmol/L) were randomized 1:1 to colesevelam 3.75 g or ezetimibe 10 mg daily. The primary composite outcome was the proportion of participants achieving an LDL-c target of ≤2.0 mmol/L and HbA1c target of ≤7.0%. Intention to treat analysis was performed. RESULTS: Two hundred subjects were enrolled: mean age 59 ± 10 years; mean HbA1c 8.0%; mean LDL-c 2.5 mmol/L; 97% on statin therapy. The primary composite outcome was achieved by similar proportions of participants with colesevelam (14.6%) and ezetimibe (10.5%) (Pnon-inferiority < .001, Psuperiority = .41). LDL-c reduction from baseline was less with colesevelam compared with ezetimibe (14.0% vs. 23.2%, P < .01), as was the proportion of subjects achieving an LDL-c target of ≤2.0 mmol/L (47.6% and 67.0%, respectively; P = .007). Mean HbA1c was reduced with colesevelam (-0.26 ± 0.10%), while no change was observed with ezetimibe (difference P = .06). Adverse events and discontinuation rates were higher for colesevelam (20.2% and 31.1%) compared with ezetimibe (7.2% and 6.2%), respectively. CONCLUSIONS: Among subjects with T2D, the initiation of colesevelam or ezetimibe led to similar achievement of primary composite outcome (LDL-c and HbA1c within target), with ezetimibe recording a greater LDL-c reduction and better tolerability than colesevelam.


Assuntos
Anticolesterolemiantes , Diabetes Mellitus Tipo 2 , Inibidores de Hidroximetilglutaril-CoA Redutases , Hipercolesterolemia , Idoso , Anticolesterolemiantes/efeitos adversos , LDL-Colesterol , Cloridrato de Colesevelam , Diabetes Mellitus Tipo 2/tratamento farmacológico , Quimioterapia Combinada , Ezetimiba/uso terapêutico , Hemoglobina A Glicada , Objetivos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Pessoa de Meia-Idade , Resultado do Tratamento
10.
Clin Gastroenterol Hepatol ; 18(13): 2962-2970.e6, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32088296

RESUMO

BACKGROUND & AIMS: Approximately one-third of patients with IBS-diarrhea (IBS-D) have increased bile acid (BA) synthesis or excretion. An open-label study showed benefits of colesevelam on bowel functions, consistent with luminal BA sequestration by colesevelam. We compared the effects of colesevelam vs placebo on symptoms and gene expression patterns in the sigmoid colon mucosa in patients with BA diarrhea associated with IBS-D. METHODS: We performed a double-blind, parallel-group study of 30 adults with IBS-D and evidence of increased BA synthesis or fecal excretion, from December 2017 through December 2018 at a single center. Patients were randomly assigned (1:1) to groups given colesevelam (3 tablets, 625 mg each) or matching placebo, orally twice daily for 4 weeks. Stool diaries documented bowel functions for 8 days before and 28 days during colesevelam or placebo. Stool and fasting serum samples were collected for analyses of fecal BAs and serum levels of C4 and FGF19. We measured colonic transit by scintigraphy, mucosal permeability by in vivo excretion of saccharide probes, and mRNA levels in rectosigmoid biopsies. All measurements were made at baseline and on the last days of treatment. The primary endpoints were change in total fecal BA concentration and stool consistency. RESULTS: Compared with placebo, colesevelam was associated with significant changes in sequestered fecal total BA excretion (P < .001) and serum levels of C4 and FGF19 (both P < .001), and with a mean increase in fecal level of deoxycholic acid (10%; P = .07) compared to placebo. Colesevelam decreased colon mucosal expression of NR1H4 and P2RY4 and increased expression of GPBAR1, compared with baseline. Stool frequency and consistency, colonic transit, and permeability did not differ significantly between groups. Colesevelam was well tolerated. CONCLUSIONS: In a randomized trial, we found that colesevelam increases delivery of total and secondary BAs to stool, hepatic BA synthesis, and colonic mucosal expression of genes that regulate BA, farnesoid X, and GPBAR1 receptors. Larger studies are needed to determine the effects on clinical responses. ClinicalTrials.gov no: NCT03270085.


Assuntos
Ácidos e Sais Biliares , Síndrome do Intestino Irritável , Adulto , Biomarcadores , Cloridrato de Colesevelam , Colo , Diarreia , Método Duplo-Cego , Expressão Gênica , Humanos , Receptores Acoplados a Proteínas G
11.
Gastroenterology ; 158(8): 2093-2103, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32092310

RESUMO

BACKGROUND & AIMS: Refractory gastroesophageal reflux disease (GERD) reduces quality of life and creates significant financial burden on the health care system. Approximately 30% of patients with GERD who receive label-dose proton pump inhibitors (PPIs) still have symptoms. We performed a trial to evaluate the efficacy and safety of IW-3718, a bile acid sequestrant, as an adjunct to PPI therapy. METHODS: We performed a multicenter, double-blind, placebo-controlled trial, from March 2016 through April 2017, of 280 patients with confirmed GERD. The patients, stratified by esophagitis status, were randomly assigned (1:1:1:1) to groups given placebo or IW-3718 (500, 1000, or 1500 mg) twice daily, with ongoing label-dose PPI. The primary endpoint was percent change from baseline to week 8 in weekly heartburn severity score. We also analyzed percent change from baseline to week 8 in weekly regurgitation frequency score. RESULTS: Mean changes from baseline to week 8 in weekly heartburn severity scores were reductions of 46.0% in the placebo group, 49.0% in the 500 mg group, 55.1% in the 1000 mg group, and 58.0% in the 1500 mg IW-3718 group (dose-response P = .02). The treatment difference was 11.9% between the 1500 mg IW-3718 and placebo groups (P = .04, analysis of covariance). The mean change in weekly regurgitation frequency score from baseline to week 8 in the 1500 mg IW-3718 vs placebo groups was a reduction of 17.5% (95% confidence interval, reductions of 31.4% to 3.6%). The most common adverse event was constipation (in 8.1% of patients receiving IW-3718 and 7.1% of patients receiving placebo). There were no drug-related serious adverse events. CONCLUSIONS: In a randomized trial of patients with refractory GERD, adding 1500 mg IW-3718 to label-dose PPIs significantly reduced heartburn symptoms compared with adding placebo. Regurgitation symptoms also decreased. IW-3718 was well tolerated. (ClinicalTrials.gov, Number: NCT02637557).


Assuntos
Ácidos e Sais Biliares/metabolismo , Cloridrato de Colesevelam/administração & dosagem , Esofagite/tratamento farmacológico , Refluxo Gastroesofágico/tratamento farmacológico , Azia/tratamento farmacológico , Inibidores da Bomba de Prótons/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Cloridrato de Colesevelam/efeitos adversos , Cloridrato de Colesevelam/metabolismo , Preparações de Ação Retardada , Método Duplo-Cego , Quimioterapia Combinada , Esofagite/diagnóstico , Esofagite/metabolismo , Feminino , Refluxo Gastroesofágico/diagnóstico , Refluxo Gastroesofágico/metabolismo , Azia/diagnóstico , Azia/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Bomba de Prótons/efeitos adversos , Indução de Remissão , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Estados Unidos , Adulto Jovem
12.
Cardiovasc Res ; 116(10): 1710-1720, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31589318

RESUMO

AIMS: Brown fat activation accelerates the uptake of cholesterol-enriched remnants by the liver and thereby lowers plasma cholesterol, consequently protecting against atherosclerosis development. Hepatic cholesterol is then converted into bile acids (BAs) that are secreted into the intestine and largely maintained within the enterohepatic circulation. We now aimed to evaluate the effects of prolonged brown fat activation combined with inhibition of intestinal BA reabsorption on plasma cholesterol metabolism and atherosclerosis development. METHODS AND RESULTS: APOE*3-Leiden.CETP mice with humanized lipoprotein metabolism were treated for 9 weeks with the selective ß3-adrenergic receptor (AR) agonist CL316,243 to substantially activate brown fat. Prolonged ß3-AR agonism reduced faecal BA excretion (-31%), while markedly increasing plasma levels of total BAs (+258%), cholic acid-derived BAs (+295%), and chenodeoxycholic acid-derived BAs (+217%), and decreasing the expression of hepatic genes involved in BA production. In subsequent experiments, mice were additionally treated with the BA sequestrant Colesevelam to inhibit BA reabsorption. Concomitant intestinal BA sequestration increased faecal BA excretion, normalized plasma BA levels, and reduced hepatic cholesterol. Moreover, concomitant BA sequestration further reduced plasma total cholesterol (-49%) and non-high-density lipoprotein cholesterol (-56%), tended to further attenuate atherosclerotic lesion area (-54%). Concomitant BA sequestration further increased the proportion of lesion-free valves (+34%) and decreased the relative macrophage area within the lesion (-26%), thereby further increasing the plaque stability index (+44%). CONCLUSION: BA sequestration prevents the marked accumulation of plasma BAs as induced by prolonged brown fat activation, thereby further improving cholesterol metabolism and reducing atherosclerosis development. These data suggest that combining brown fat activation with BA sequestration is a promising new therapeutic strategy to reduce hyperlipidaemia and cardiovascular diseases.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Anticolesterolemiantes/farmacologia , Aterosclerose/prevenção & controle , Ácidos e Sais Biliares/sangue , Colesterol/sangue , Cloridrato de Colesevelam/farmacologia , Hiperlipidemias/prevenção & controle , Tecido Adiposo Marrom/metabolismo , Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Animais , Apolipoproteína E3/genética , Aterosclerose/sangue , Aterosclerose/genética , Proteínas de Transferência de Ésteres de Colesterol/genética , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Dioxóis/farmacologia , Modelos Animais de Doenças , Circulação Êntero-Hepática , Fezes/química , Hiperlipidemias/sangue , Hiperlipidemias/genética , Absorção Intestinal , Eliminação Intestinal , Fígado/metabolismo , Camundongos Transgênicos
13.
J Pharm Biomed Anal ; 165: 112-118, 2019 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-30529824

RESUMO

Colesevelam hydrochloride is a bile acid sequestrant used as a low density lipoprotein (LDL) reducing agent in hyperlipidemia with an additional advantage to improve glycemic control in type 2 diabetes patients. The objective of the study was to develop and validate a liquid chromatography tandem mass spectroscopic method for the simultaneous in-vitro estimation of bile acid salts of Glycocholic acid (GC), Glycochenodeoxycholic acid (GCDC) and Taurodeoxycholic acid (TDC) and its application in performing in-vitro binding study with Colesevelam Hydrochloride tablets. The method was developed using C-18 (50 x 4.6 mm, 3 µm) column with detection on negative ion mode and acquisition time of 3.5 min. The calibration range was linear from 0.0002 mM to 0.0065 mM for GC, 0.0002 mM to 0.0065 mM for GCDC and 0.0001 mM to 0.0021 mM for TDC. The precision was less than 3.0% and accuracy was found well within the range of 85 to 115%. The validated method was further applied to conduct in-vitro equilibrium binding study. The data was subjected to Langmuir isotherm and affinity constant (k1) and capacity constant (k2) were calculated.


Assuntos
Anticolesterolemiantes/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Cloridrato de Colesevelam/metabolismo , Espectrometria de Massas em Tandem/métodos , Calibragem , Ácido Glicoquenodesoxicólico/metabolismo , Ácido Glicocólico/metabolismo , Reprodutibilidade dos Testes , Comprimidos , Ácido Taurodesoxicólico/metabolismo
14.
Cancer Chemother Pharmacol ; 83(3): 531-543, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30535958

RESUMO

PURPOSE: Neratinib is an irreversible pan-ErbB tyrosine kinase inhibitor used for the extended adjuvant treatment of early-stage HER2-positive breast cancer. Its use is associated with the development of severe diarrhea in up to 40% of patients in the absence of proactive management. We previously developed a rat model of neratinib-induced diarrhea and found inflammation and anatomical disruption in the ileum and colon. Here we tested whether anti-diarrheal interventions, budesonide and colesevelam, can reduce neratinib-induced diarrhea and intestinal pathology. METHODS: Rats were treated with 50 mg/kg neratinib via oral gavage for 14 or 28 days (total n = 64). Body weight and diarrhea severity were recorded daily. Apoptosis was measured using immunohistochemistry for caspase-3. Inflammation was measured via a multiplex cytokine/chemokine assay. ErbB levels were measured using PCR and Western Blot. RESULTS: Budesonide co-treatment caused rats to gain significantly less weight than neratinib alone from day 4 of treatment (P = 0.0418). Budesonide (P = 0.027) and colesevelam (P = 0.033) each reduced the amount of days with moderate diarrhea compared to neratinib alone. In the proximal colon, rats treated with neratinib had higher levels of apoptosis compared to controls (P = 0.0035). Budesonide reduced histopathological injury in the proximal (P = 0.0401) and distal colon (P = 0.027) and increased anti-inflammatory IL-4 tissue concentration (ileum; P = 0.0026, colon; P = 0.031) compared to rats treated with neratinib alone. In the distal ileum, while budesonide decreased ErbB1 mRNA expression compared to controls (P = 0.018) (PCR), an increase in total ErbB1 protein was detected (P = 0.0021) (Western Blot). CONCLUSION: Both budesonide and colesevelam show potential as effective interventions against neratinib-induced diarrhea.


Assuntos
Budesonida/uso terapêutico , Cloridrato de Colesevelam/uso terapêutico , Diarreia/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Quinolinas/efeitos adversos , Animais , Diarreia/induzido quimicamente , Diarreia/diagnóstico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Masculino , Ratos , Ratos Wistar , Receptor ErbB-2/antagonistas & inibidores , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento
15.
Expert Opin Drug Discov ; 13(12): 1161-1167, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30336707

RESUMO

Introduction: Type 2 diabetes (T2D) is a major global health challenge associated with increased cardiovascular morbidity and mortality. Intervention strategies managing multiple risk factors (hyperglycemia, hypertension and dyslipidemia) in patients with T2D can reduce the risk of cardiovascular disease by ~50%. Areas covered: Herein, the authors provide an update on the development and clinical potential of colesevelam as a glucose-lowering drug in T2D. Furthermore, they outline the pharmacokinetics, pharmacodynamics, and the clinical efficacy and safety data from the studies carried out to obtain market authorization for colesevelam. Expert opinion: Four phase III clinical trials provide evidence that colesevelam, as a monotherapy and add-on to various background glucose-lowering treatments, confers placebo-corrected reductions in HbA1c of ~5 mmol/mol. In addition, colesevelam reduces low-density lipoprotein (LDL) cholesterol and total cholesterol. Some antidiabetic agents seem superior to colesevelam in terms of clinical efficiency (HbA1c lowering), tolerability/convenience, and price. Nonetheless, colesevelam offers a clinically relevant combination of HbA1c- and LDL-lowering that in selected patients could be relevant as add-on treatment to other glucose-lowering drugs and a statin. Potential patients include those with renal impairment, and patients that are close to reaching their lipid and glycemic treatment goals but need further LDL and HbA1c reductions.


Assuntos
Glicemia/efeitos dos fármacos , Cloridrato de Colesevelam/administração & dosagem , Diabetes Mellitus Tipo 2/tratamento farmacológico , Animais , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/farmacologia , Ensaios Clínicos Fase III como Assunto , Cloridrato de Colesevelam/efeitos adversos , Cloridrato de Colesevelam/farmacologia , Diabetes Mellitus Tipo 2/fisiopatologia , Quimioterapia Combinada , Hemoglobina A Glicada/metabolismo , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacologia , Seleção de Pacientes
16.
Am J Physiol Gastrointest Liver Physiol ; 315(5): G810-G823, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30160993

RESUMO

Colesevelam is a bile acid sequestrant approved to treat both hyperlipidemia and type 2 diabetes, but the mechanism for its glucose-lowering effects is not fully understood. The aim of this study was to investigate the role of hepatic microRNAs (miRNAs) as regulators of metabolic disease and to investigate the link between the cholesterol and glucose-lowering effects of colesevelam. To quantify the impact of colesevelam treatment in rodent models of diabetes, metabolic studies were performed in Zucker diabetic fatty (ZDF) rats and db/db mice. Colesevelam treatments significantly decreased plasma glucose levels and increased glycolysis in the absence of changes to insulin levels in ZDF rats and db/db mice. High-throughput sequencing and real-time PCR were used to quantify hepatic miRNA and mRNA changes, and the cholesterol-sensitive miR-96/182/183 cluster was found to be significantly increased in livers from ZDF rats treated with colesevelam compared with vehicle controls. Inhibition of miR-182 in vivo attenuated colesevelam-mediated improvements to glycemic control in db/db mice. Hepatic expression of mediator complex subunit 1 (MED1), a nuclear receptor coactivator, was significantly decreased with colesevelam treatments in db/db mice, and MED1 was experimentally validated to be a direct target of miR-96/182/183 in humans and mice. In summary, these results support that colesevelam likely improves glycemic control through hepatic miR-182-5p, a mechanism that directly links cholesterol and glucose metabolism. NEW & NOTEWORTHY Colesevelam lowers systemic glucose levels in Zucker diabetic fatty rats and db/db mice and increases hepatic levels of the sterol response element binding protein 2-responsive microRNA cluster miR-96/182/183. Inhibition of miR-182 in vivo reverses the glucose-lowering effects of colesevelam in db/db mice. Mediator complex subunit 1 (MED1) is a novel, direct target of the miR-96/182/183 cluster in mice and humans.


Assuntos
Ácidos e Sais Biliares/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucose/metabolismo , Mucosa Intestinal/metabolismo , Fígado/metabolismo , MicroRNAs/genética , Animais , Anticolesterolemiantes/farmacologia , Anticolesterolemiantes/uso terapêutico , Cloridrato de Colesevelam/farmacologia , Cloridrato de Colesevelam/uso terapêutico , Diabetes Mellitus Tipo 2/metabolismo , Glicólise , Células HEK293 , Humanos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Fígado/efeitos dos fármacos , Masculino , Subunidade 1 do Complexo Mediador/genética , Subunidade 1 do Complexo Mediador/metabolismo , MicroRNAs/metabolismo , Ratos , Ratos Zucker
17.
J Clin Pharm Ther ; 43(4): 587-590, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29671894

RESUMO

WHAT IS KNOWN AND OBJECTIVE: A variety of medication classes are available for diabetes; however, treatment options become limited due to adverse effect profiles and cost. Current diabetes guidelines include agents not originally developed for diabetes treatment, bromocriptine and colesevelam. COMMENT: Other non-diabetes medications demonstrating haemoglobin A1c lowering, including agents for weight loss, depression, anaemia and coronary artery disease, are described in this review article. WHAT IS NEW AND CONCLUSION: More research looking into the impact of non-diabetes medications on blood glucose may offer additional diabetes treatment strategies.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hemoglobina A Glicada/metabolismo , Hipoglicemiantes/uso terapêutico , Glicemia/efeitos dos fármacos , Bromocriptina/uso terapêutico , Cloridrato de Colesevelam/uso terapêutico , Diabetes Mellitus Tipo 2/metabolismo , Humanos
18.
Gut ; 67(9): 1683-1691, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29636383

RESUMO

BACKGROUND AND AIMS: Interruption of the enterohepatic circulation of bile acids (BAs) may protect against BA-mediated cholestatic liver and bile duct injury. BA sequestrants are established to treat cholestatic pruritus, but their impact on the underlying cholestasis is still unclear. We aimed to explore the therapeutic effects and mechanisms of the BA sequestrant colesevelam in a mouse model of sclerosing cholangitis. METHODS: Mdr2-/- mice received colesevelam for 8 weeks. Gene expression profiles of BA homeostasis, inflammation and fibrosis were explored in liver, intestine and colon. Hepatic and faecal BA profiles and gut microbiome were analysed. Glucagon-like peptide 1 (GLP-1) levels in portal blood were measured by ELISA. Furthermore, Mdr2-/- mice as well as wild-type 3,5-diethoxy-carbonyl-1,4-dihydrocollidine-fed mice were treated with GLP-1-receptor agonist exendin-4 for 2 weeks prior to analysis. RESULTS: Colesevelam reduced serum liver enzymes, BAs and expression of proinflammatory and profibrogenic markers. Faecal BA profiling revealed increased levels of secondary BAs after resin treatment, while hepatic and biliary BA composition showed a shift towards more hydrophilic BAs. Colonic GLP-1 secretion, portal venous GLP-1 levels and intestinal messenger RNA expression of gut hormone Proglucagon were increased, while ileal Fgf15 expression was abolished by colesevelam. Exendin-4 treatment increased bile duct mass without promoting a reactive cholangiocyte phenotype in mouse models of sclerosing cholangitis. Microbiota analysis showed an increase of the phylum δ-Proteobacteria after colesevelam treatment and a shift within the phyla Firmicutes from Clostridiales to Lactobacillus. CONCLUSION: Colesevelam increases faecal BA excretion and enhances BA conversion towards secondary BAs, thereby stimulating secretion of GLP-1 from enteroendocrine L-cells and attenuates liver and bile duct injury in Mdr2-/- mice.


Assuntos
Anticolesterolemiantes/uso terapêutico , Ductos Biliares/efeitos dos fármacos , Colangite Esclerosante/tratamento farmacológico , Cloridrato de Colesevelam/uso terapêutico , Fígado/efeitos dos fármacos , Animais , Colestase/tratamento farmacológico , Modelos Animais de Doenças , Peptídeo 1 Semelhante ao Glucagon/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Camundongos , Camundongos Knockout , Resultado do Tratamento
19.
J Diabetes Complications ; 31(5): 918-927, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28238556

RESUMO

AIM: To evaluate the effects of bile acid sequestrants (BASs) versus placebo, no intervention or active comparators on glycemic control in type 2 diabetes. METHODS: Data were retrieved and a systematic review with meta-analyses was performed. We evaluated bias control and subgroup and sensitivity analyses were performed to evaluate heterogeneity and bias. RESULTS: We included 17 trials with a total of 2950 patients randomized to BASs (colesevelam or colestimide) versus placebo, no intervention, statins or sitagliptin. Random-effects meta-analysis showed that patients randomized to BASs had a lower hemoglobin A1c at the end of treatment compared with the control group (mean difference-0.55%; 95% confidence interval-0.64 to -0.46). Analysis of trials with low risk of bias in all domains confirmed the findings. Data on adverse events were limited. There were no differences between trials stratified by the control group and no evidence of publication bias or small study effects. CONCLUSIONS: Our analyses found that BAS treatment improves glycemic control. The size of the effect was clinically relevant and despite limited safety data, our findings support the inclusion of BASs in current diabetes management algorithms for type 2 diabetes.


Assuntos
Ácidos e Sais Biliares/antagonistas & inibidores , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hiperglicemia/prevenção & controle , Hipoglicemia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Sequestrantes/uso terapêutico , Ácidos e Sais Biliares/efeitos adversos , Cloridrato de Colesevelam/efeitos adversos , Cloridrato de Colesevelam/uso terapêutico , Diabetes Mellitus Tipo 2/sangue , Epicloroidrina/efeitos adversos , Epicloroidrina/uso terapêutico , Hemoglobina A Glicada/análise , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/efeitos adversos , Imidazóis/efeitos adversos , Imidazóis/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Reprodutibilidade dos Testes , Resinas Sintéticas/efeitos adversos , Resinas Sintéticas/uso terapêutico , Sequestrantes/efeitos adversos
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