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1.
Am J Gastroenterol ; 116(9): 1929-1937, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34465695

RESUMO

INTRODUCTION: Linaclotide improves abdominal pain and constipation in patients with constipation-predominant irritable bowel syndrome (IBS-C). Patients report additional bothersome abdominal symptoms of bloating and discomfort. The intention of this study was to evaluate linaclotide's efficacy in relieving IBS-C-related abdominal symptoms (bloating, discomfort, and pain) using a novel multi-item Abdominal Score (AS). METHODS: Patients with IBS-C with abdominal pain ≥3 (0-10 scale) were randomized to linaclotide 290 µg or placebo daily for 12 weeks. The AS, derived from the Diary for IBS Symptoms-Constipation, is the average of abdominal bloating, discomfort, and pain at their worst (0 = none, 10 = worst possible). The primary end point was overall change from baseline (CFB) in AS. Secondary end points included CFB in 12-week AS evaluated using cumulative distribution function and 6-week/12-week AS responder (AS improvement ≥2 points for ≥6-week/12-week). RESULTS: Overall, 614 patients (mean age 46.7 years; 81% female) were randomized. All prespecified end points showed significant benefit of linaclotide vs placebo. The mean overall CFB AS reduction for linaclotide was -1.9 vs -1.2 for placebo (P < 0.0001); the 6-week/12-week AS responder rate was 40.5% for linaclotide vs 23.4% for placebo (odds ratio = 2.2 [95% confidence interval, 1.55-3.12; P < 0.0001]). Diarrhea was the most common treatment-emergent adverse event (linaclotide = 4.6%, placebo = 1.6%). DISCUSSION: Linaclotide significantly reduced multiple abdominal symptoms important to patients with IBS-C (bloating, discomfort, and pain) compared with placebo, as measured by a novel multi-item AS. The AS, derived from the Diary for IBS Symptoms-Constipation, should be considered for use in future IBS-C clinical studies to measure clinically meaningful improvements beyond traditional end points.


Assuntos
Dor Abdominal/tratamento farmacológico , Constipação Intestinal/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Agonistas da Guanilil Ciclase C/uso terapêutico , Peptídeos/uso terapêutico , Adulto , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do Tratamento
2.
Artigo em Inglês | MEDLINE | ID: mdl-34508047

RESUMO

OBJECTIVES: Guanylate cyclase-C (GC-C) agonists, which increase intestinal secretion and accelerate transit, are used to treat chronic constipation and constipation-predominant irritable bowel syndrome and are being evaluated for pediatric use. Prior studies suggest GC-C receptor density may be higher in young children, potentially amplifying GC-C agonism with treatment implications. We aimed to quantitate duodenal and colonic GC-C mRNA expression in children. METHODS: Mucosal biopsies were obtained from subjects aged 6 months to 18 years during clinically indicated upper, i.e., esophago-gastro-duodenal, and/or colonic endoscopy. Tissue samples without histologic abnormalities were grouped by subject age (<24 months, 24 months to <6 years, 6 to <12 years, and 12 to <18 years) and analyzed for GC-C mRNA expression by qPCR. The relationship between GC-C mRNA levels and age was modeled using regression analyses. RESULTS: Ninety-nine subjects underwent upper endoscopy/colonoscopy; 93 had evaluable samples. Mean relative GC-C mRNA expression was 2.36 (range 2.21-2.46) for duodenal samples and 1.56 (range 1.22-1.91) for colonic samples. Predicted and observed normalized GC-C mRNA expression in each region were comparable among age groups. Pooled expression by region demonstrated lower expression in colonic versus duodenal samples. CONCLUSIONS: Uniform levels of GC-C mRNA expression were detected in children aged >6 months in the duodenum and >12 months in the colon. Higher expression was observed in all age groups in duodenal versus colonic samples, indicating regional variability in GC-C receptor density. These data are reassuring for further studies of GC-C agonists in children.

3.
Am J Gastroenterol ; 116(2): 354-361, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33065589

RESUMO

INTRODUCTION: Immediate-release (IR) formulation of linaclotide 290 µg improves abdominal pain and constipation (APC) in patients with irritable bowel syndrome (IBS) with constipation. Delayed-release (DR) formulations were developed on the premise that targeting the ileum (delayed-release formulation 1 [DR1]) or ileocecal junction and cecum (MD-7246, formerly DR2) would modulate linaclotide's secretory effects while preserving pain relief effects. METHODS: This phase 2b study randomized patients with IBS with constipation to placebo or 1 of 7 once-daily linaclotide doses (DR1 30, 100, or 300 µg; MD-7246 30, 100, or 300 µg; or IR 290 µg) for 12 weeks. Key efficacy endpoints were change from baseline in abdominal pain and complete spontaneous bowel movement frequency, and 6/12-week combined APC+1 responder rate. RESULTS: Overall, 532 patients were randomized; mean age was 45.1 years, and most were women (83.3%) and White (64.7%). All linaclotide DR1 and MD-7246 groups experienced greater improvements in abdominal pain from baseline and vs placebo throughout treatment. Linaclotide DR1 and IR led to numerically greater improvements from baseline in complete spontaneous bowel movement frequency and higher APC+1 responder rates compared with placebo; MD-7246 results were similar to placebo. Diarrhea was the most common adverse event with DR1 and IR; rates were similar between MD-7246 and placebo. DISCUSSION: Altering the site of drug delivery in the intestine might uncouple linaclotide's pain relief from secretory effects. Persistent, modest abdominal pain improvement with limited impact on bowel symptom parameters, as seen across MD-7246 doses, warrants further study of MD-7246 as a novel treatment for abdominal pain, regardless of IBS subtype.


Assuntos
Constipação Intestinal/tratamento farmacológico , Agonistas da Guanilil Ciclase C/administração & dosagem , Síndrome do Intestino Irritável/tratamento farmacológico , Peptídeos/administração & dosagem , Dor Abdominal/fisiopatologia , Adulto , Constipação Intestinal/fisiopatologia , Defecação , Preparações de Ação Retardada , Diarreia/induzido quimicamente , Método Duplo-Cego , Feminino , Humanos , Síndrome do Intestino Irritável/fisiopatologia , Masculino , Pessoa de Meia-Idade
4.
J Pharmacol Exp Ther ; 344(1): 196-206, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23090647

RESUMO

Linaclotide, a potent guanylate cyclase C agonist, is a therapeutic peptide approved in the United States for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation. We present for the first time the metabolism, degradation, and disposition of linaclotide in animals and humans. We examined the metabolic stability of linaclotide in conditions that mimic the gastrointestinal tract and characterized the metabolite MM-419447 (CCEYCCNPACTGC), which contributes to the pharmacologic effects of linaclotide. Systemic exposure to these active peptides is low in rats and humans, and the low systemic and portal vein concentrations of linaclotide and MM-419447 observed in the rat confirmed both peptides are minimally absorbed after oral administration. Linaclotide is stable in the acidic environment of the stomach and is converted to MM-419447 in the small intestine. The disulfide bonds of both peptides are reduced in the small intestine, where they are subsequently proteolyzed and degraded. After oral administration of linaclotide, <1% of the dose was excreted as active peptide in rat feces and a mean of 3-5% in human feces; in both cases MM-419447 was the predominant peptide recovered. MM-419447 exhibits high-affinity binding in vitro to T84 cells, resulting in a significant, concentration-dependent accumulation of intracellular cyclic guanosine-3',5'-monophosphate (cGMP). In rat models of gastrointestinal function, orally dosed MM-419447 significantly increased fluid secretion into small intestinal loops, increased intraluminal cGMP, and caused a dose-dependent acceleration in gastrointestinal transit. These results demonstrate the importance of the active metabolite in contributing to linaclotide's pharmacology.


Assuntos
Constipação Intestinal/tratamento farmacológico , Síndrome do Intestino Irritável/tratamento farmacológico , Peptídeos/farmacologia , Alquilação , Animais , Área Sob a Curva , Disponibilidade Biológica , Biotransformação , Constipação Intestinal/complicações , AMP Cíclico/metabolismo , Fezes/química , Feminino , Trânsito Gastrointestinal/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Técnicas In Vitro , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Síndrome do Intestino Irritável/complicações , Masculino , Peptídeo Hidrolases/química , Peptídeos/farmacocinética , Peptídeos/uso terapêutico , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley
5.
J Pharmacol Exp Ther ; 336(2): 423-30, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20966038

RESUMO

Dopaminergic therapies remain the most efficacious symptomatic treatments for Parkinson's disease (PD) but are associated with motor complications, including dyskinesia, and nonmotor complications, such as psychosis, impulse control disorders (ICD), and dopamine dysregulation syndrome (DDS). Nondopaminergic neurotransmitter systems, including the endocannabinoid system, are probably critical to the development of these complications. The role of fatty acid amide hydrolase (FAAH) in mediating l-3,4-dihydroxyphenylalanine (L-DOPA)-induced behaviors was explored in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned marmoset model of PD. Pharmacodynamic and locomotor effects of the selective FAAH inhibitor [3-(3-carbamoylphenyl)phenyl] N-cyclohexylcarbamate (URB597) were assessed via bioanalytical (liquid chromatography-tandem mass spectrometry) and behavioral observation approaches. URB597 (3, 10, 30, or 60 mg/kg p.o.) increased plasma levels of the FAAH substrates N-arachidonoyl ethanolamide (anandamide), N-oleoyl ethanolamide, and N-palmitoyl ethanolamide by 10.3 ± 0.3-, 7.8 ± 0.2-, and 1.8 ± 0.1-fold (mean of URB597 groups ± S.E.M.), respectively, compared with vehicle (all p < 0.001) 4 h after administration. Treatment with L-DOPA (20 mg/kg s.c.) alleviated parkinsonism but elicited dyskinesia, psychosis-like-behaviors and hyperactivity, a potential correlate of ICD and DDS. During the 2 to 4 h after L-DOPA, corresponding to 4 to 6 h after URB597 administration, URB597 reduced total L-DOPA-induced activity and the magnitude of hyperactivity by 32 and 52%, respectively, to levels equivalent to those seen in normal animals. Treatment with URB597 (10 mg/kg p.o.) did not modify the antiparkinsonian actions of L-DOPA or L-DOPA-induced dyskinesia and psychosis. URB597 did not alter plasma L-DOPA levels and was without behavioral effects when administered alone. Inhibition of FAAH may represent a novel approach to reducing L-DOPA-induced side effects, such as ICD and DDS, while maintaining the antiparkinsonian benefits of L-DOPA treatment.


Assuntos
Amidoidrolases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Levodopa/efeitos adversos , Intoxicação por MPTP/tratamento farmacológico , Atividade Motora/efeitos dos fármacos , Amidas , Animais , Benzamidas/farmacologia , Callithrix , Carbamatos/farmacologia , Modelos Animais de Doenças , Discinesia Induzida por Medicamentos/prevenção & controle , Endocanabinoides , Etanolaminas/sangue , Feminino , Intoxicação por MPTP/enzimologia , Ácidos Oleicos , Ácidos Palmíticos/sangue , Psicoses Induzidas por Substâncias/prevenção & controle
6.
Eur J Pharmacol ; 649(1-3): 328-35, 2010 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-20863829

RESUMO

Linaclotide is a first-in-class, orally administered 14-amino acid peptide that is in development for the treatment of irritable bowel syndrome with constipation and chronic constipation. We have characterized the solution structure of linaclotide, the in vitro binding and agonist activity to guanylate cyclase C receptors, the stability of linaclotide under conditions mimicking the gastric environment, oral bioavailability, and the pharmacodynamic effects in rat models of gastrointestinal transit and intestinal secretion. Nuclear magnetic resonance spectroscopy analysis determined that the molecular structure of linaclotide is stabilized by three intramolecular disulfide bridges. Linaclotide exhibited high affinity and pH-independent binding (K(i): 1.23-1.64 nM) to guanylate cyclase C receptors on human colon carcinoma T84 cells and concomitantly, linaclotide binding resulted in a significant, concentration-dependent accumulation of intracellular cyclic guanosine-3', 5'-monophosphate (cGMP) (EC50:99 nM). Linaclotide was stable after 3 h incubation in simulated gastric fluid (pH 1) and similarly, was completely resistant to hydrolysis by pepsin. Pharmacokinetic analysis of linaclotide showed very low oral bioavailability (0.1%). Orally administered linaclotide elicited a significant, dose-dependent increase in gastrointestinal transit rates in rats at doses of ≥5 µg/kg. Exposure of surgically ligated small intestinal loops to linaclotide induced a significant increase in fluid secretion, accompanied by a significant increase in intraluminal cGMP levels. These results suggest that the guanylate cyclase C agonist linaclotide elicits potent pharmacological responses locally in the gastrointestinal tract, and that orally administered guanylate cyclase C agonists may be capable of improving bowel habits in patients suffering from irritable bowel syndrome with constipation and chronic constipation.


Assuntos
Trânsito Gastrointestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Laxantes/farmacologia , Peptídeos/farmacologia , Receptores Acoplados a Guanilato Ciclase/agonistas , Receptores de Peptídeos/agonistas , Animais , Ligação Competitiva , Disponibilidade Biológica , Linhagem Celular , Células Cultivadas , Constipação Intestinal/tratamento farmacológico , GMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Feminino , Humanos , Mucosa Intestinal/citologia , Secreções Intestinais/metabolismo , Síndrome do Intestino Irritável/tratamento farmacológico , Laxantes/química , Laxantes/metabolismo , Laxantes/farmacocinética , Masculino , Peptídeos/química , Peptídeos/metabolismo , Peptídeos/farmacocinética , Conformação Proteica , Estabilidade Proteica , Ratos , Receptores de Enterotoxina
7.
Life Sci ; 86(19-20): 760-5, 2010 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-20307554

RESUMO

AIMS: Linaclotide is an orally administered 14-amino acid peptide being developed for the treatment of constipation-predominant irritable bowel syndrome (IBS-C) and chronic constipation. We determined the stability of linaclotide in the intestine, measured the oral bioavailability, and investigated whether the pharmacodynamic effects elicited in rodent models of gastrointestinal function are mechanistically linked to the activation of intestinal guanylate cyclase C (GC-C). MAIN METHODS: Linaclotide binding to intestinal mucosal membranes was assessed in competitive binding assays. Stability and oral bioavailability of linaclotide were measured in small intestinal fluid and serum, respectively, and models of gastrointestinal function were conducted using wild type (wt) and GC-C null mice. KEY FINDINGS: Linaclotide inhibited in vitro [(125)I]-STa binding to intestinal mucosal membranes from wt mice in a concentration-dependent manner. In contrast, [(125)I]-STa binding to these membranes from GC-C null mice was significantly decreased. After incubation in vitro in jejunal fluid for 30 min, linaclotide was completely degraded. Pharmacokinetic analysis showed very low oral bioavailability (0.10%). In intestinal secretion and transit models, linaclotide exhibited significant pharmacological effects in wt, but not in GC-C null mice: induction of increased fluid secretion into surgically ligated jejunal loops was accompanied by the secretion of elevated levels of cyclic guanosine-3',5'-monophosphate and accelerated gastrointestinal transit. SIGNIFICANCE: Linaclotide is a potent and selective GC-C agonist that elicits pharmacological effects locally in the gastrointestinal tract. This pharmacological profile suggests that orally administered linaclotide may be capable of improving the abdominal symptoms and bowel habits of patients suffering from IBS-C and chronic constipation.


Assuntos
Fármacos Gastrointestinais/farmacologia , Peptídeos/farmacologia , Receptores de Peptídeos/agonistas , Administração Oral , Animais , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Feminino , Fármacos Gastrointestinais/administração & dosagem , Fármacos Gastrointestinais/farmacocinética , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/metabolismo , Trânsito Gastrointestinal/efeitos dos fármacos , Guanilato Ciclase/genética , Mucosa Intestinal/metabolismo , Secreções Intestinais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Peptídeos/administração & dosagem , Peptídeos/farmacocinética , Receptores de Enterotoxina , Receptores Acoplados a Guanilato Ciclase , Receptores de Peptídeos/genética
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