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1.
Cancer Biol Ther ; 22(10-12): 544-553, 2021 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-34632925

RESUMO

Guanylyl cyclase C (GUCY2C) is a tumor-suppressing receptor silenced by loss of expression of the luminocrine hormones guanylin and uroguanylin early in colorectal carcinogenesis. This observation suggests oral replacement with a GUCY2C agonist may be an effective targeted chemoprevention agent. Previous studies revealed that linaclotide, an oral GUCY2C agonist formulated for gastric release, did not persist to activate guanylyl cyclase signaling in the distal rectum. Dolcanatide is an investigational oral uroguanylin analog, substituted with select D amino acids, for enhanced stability and extended persistence to activate GUCY2C in small and large intestine. However, the ability of oral dolcanatide to induce a pharmacodynamic (PD) response by activating GUCY2C in epithelial cells of the colorectum in humans remains undefined. Here, we demonstrate that administration of oral dolcanatide 27 mg daily for 7 d to healthy volunteers did not activate GUCY2C, quantified as accumulation of its product cyclic GMP, in epithelial cells of the distal rectum. These data reveal that the enhanced stability of dolcanatide, with persistence along the rostral-caudal axis of the small and large intestine, is inadequate to regulate GUCY2C across the colorectum to prevent tumorigenesis. These results highlight the importance of developing a GUCY2C agonist for cancer prevention formulated for release and activity targeted to the colorectum.


Assuntos
Neoplasias Colorretais , GMP Cíclico , Método Duplo-Cego , Voluntários Saudáveis , Humanos , Peptídeos , Receptores de Enterotoxina , Receptores Acoplados a Guanilato Ciclase
2.
Cancer Prev Res (Phila) ; 10(6): 345-354, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28396341

RESUMO

Guanylate cyclase C (GUCY2C) is a tumor-suppressing receptor silenced by loss of expression of its luminocrine hormones guanylin and uroguanylin early in colorectal carcinogenesis. This observation suggests oral replacement with a GUCY2C agonist may be an effective targeted chemoprevention agent. Linaclotide is an FDA-approved oral GUCY2C agonist formulated for gastric release, inducing fluid secretion into the small bowel to treat chronic idiopathic constipation. The ability of oral linaclotide to induce a pharmacodynamic response in epithelial cells of the colorectum in humans remains undefined. Here, we demonstrate that administration of 0.87 mg of oral linaclotide daily for 7 days to healthy volunteers, after oral colon preparation with polyethylene glycol solution (MoviPrep), activates GUCY2C, resulting in accumulation of its product cyclic (c)GMP in epithelial cells of the cecum, transverse colon, and distal rectum. GUCY2C activation by oral linaclotide was associated with homeostatic signaling, including phosphorylation of vasodilator-stimulated phosphoprotein and inhibition of proliferation quantified by reduced Ki67-positive epithelial cells. In the absence of the complete oral colonoscopy preparation, linaclotide did not alter cGMP production in epithelial cells of the colorectum, demonstrating that there was an effect related to the laxative preparation. These data show that the current FDA-approved formulation of oral linaclotide developed for small-bowel delivery to treat chronic idiopathic constipation is inadequate for reliably regulating GUCY2C in the colorectum to prevent tumorigenesis. The study results highlight the importance of developing a novel GUCY2C agonist formulated for release and activity targeted to the large intestine for colorectal cancer prevention. Cancer Prev Res; 10(6); 345-54. ©2017 AACR.


Assuntos
Colo/efeitos dos fármacos , Neoplasias Colorretais/prevenção & controle , Agonistas da Guanilil Ciclase C/farmacologia , Peptídeos/farmacologia , Receptores de Enterotoxina/metabolismo , Reto/efeitos dos fármacos , Administração Oral , Animais , Moléculas de Adesão Celular/metabolismo , Colo/diagnóstico por imagem , Colonoscopia , GMP Cíclico/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Hormônios Gastrointestinais/metabolismo , Agonistas da Guanilil Ciclase C/uso terapêutico , Voluntários Saudáveis , Humanos , Antígeno Ki-67/metabolismo , Proteínas dos Microfilamentos/metabolismo , Peptídeos Natriuréticos/metabolismo , Peptídeos/uso terapêutico , Fosfoproteínas/metabolismo , Fosforilação , Polietilenoglicóis/farmacologia , Reto/diagnóstico por imagem
3.
Ann Intern Med ; 166(3): SS1, 2017 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-28166569
4.
Gastrointest Endosc ; 69(2): 262-70, 270.e1, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18851851

RESUMO

BACKGROUND: Capsule endoscopy (CE) is a powerful tool for evaluating the small bowel. Assessment of small-bowel cleansing for CE is an essential quality measure. OBJECTIVE: Our purpose was to validate 3 new scales that grade small-bowel cleansing for CE. DESIGN: Prospective, randomized, single-center study. SETTING: Tertiary university hospital. INTERVENTION: Five experienced capsule endoscopists read 40 CEs twice, separated by 1 month, to grade small-bowel cleansing on 3 scales-quantitative index (QI; 0-10), qualitative evaluation (QE; poor, fair, good, excellent), and overall adequacy assessment (OAA; inadequate, adequate). The QI and QE evaluated both the entire and distal small bowel. Investigators received no prior training in these scales. MAIN OUTCOME MEASUREMENTS: Intraclass correlation coefficients to assess intraobserver (test-retest) and interobserver reliability. PATIENTS: Forty patients who underwent 1 CE between June 2005 and May 2006 and who satisfied entry criteria. RESULTS: Intraobserver reliability was moderate to substantial for the QI (0.60-0.66), moderate for the OAA (0.56), and fair to moderate for the QE (0.37-0.47). Interobserver scores were lower: QI and OAA moderate (0.47-0.52, 0.41, respectively) and slight to fair for the QE (0.20-0.24). QI scores for the entire and distal small bowel were highly correlated for each reader (0.57-0.87), and distal small-bowel scores were lower by 1.3 points, indicating poorer cleansing (P = .001). A dichotomized QE of excellent/good versus fair/poor had moderate to substantial intraobserver and interobserver reliability (0.58-0.66, 0.41-0.49, respectively). There was a strong and highly significant association among all 3 scales (P < .001 between QI and both QE and OAA). CONCLUSION: We have described and validated 3 scales for grading small-bowel cleansing for CE. An evaluation of small-bowel cleansing should be routinely incorporated into the CE report.


Assuntos
Endoscopia por Cápsula , Intestino Delgado , Irrigação Terapêutica/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Estudos Prospectivos
5.
Dig Dis Sci ; 53(3): 747-56, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18060495

RESUMO

Low-grade lesions of graft-versus-host disease (GVHD) in the colon are not uncommon. To determine if minimal diagnostic criteria can be established in such biopsies, we correlated histologic findings with clinical history and investigated the role of endoscopy and electron microscopy in establishing GVHD. About 85 colonic biopsies that were histologically consistent with GVHD from 47 bone-marrow transplant recipients were reviewed retrospectively. Of nine cases showing only a single apoptotic cell in the intestinal epithelium, only four lacked any confounding factors of GVHD. These cases, while too few to assess the utility of finding one apoptotic cell with statistical significance, appear to support the idea that in the appropriate clinical setting, a single apoptotic cell could be reported as possibly representing early GVHD. Endoscopic findings did not reliably correlate with histology. Although electron microscopy can be a useful adjunct, it does not contribute to the diagnosis of GVHD.


Assuntos
Apoptose , Transplante de Medula Óssea/efeitos adversos , Doenças do Colo/patologia , Doença Enxerto-Hospedeiro/patologia , Adolescente , Adulto , Idoso , Biópsia , Doenças do Colo/etiologia , Colonoscopia , Feminino , Doença Enxerto-Hospedeiro/etiologia , Humanos , Masculino , Microscopia Eletrônica , Pessoa de Meia-Idade , Estudos Retrospectivos
6.
J Clin Gastroenterol ; 38(5): 425-8, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15100522

RESUMO

GOALS: To compare the incidence of peri-procedure adverse events in patients undergoing colon cleansing with sodium phosphate tablets or polyethylene glycol solution prior to colonoscopy with propofol-based sedation. BACKGROUND: Propofol is a rapidly acting hypnotic sedative general anesthetic agent increasingly being used for colonoscopy. Although traditionally patients fast overnight prior to a general anesthetic, a new Food and Drug Administration-approved sodium phosphate tablet purgative requires ingestion of 20 tablets with 56 ounces of clear liquid 3 to 5 hours prior to colonoscopy. STUDY: We retrospectively reviewed 97 outpatients who received propofol-based sedation for colonoscopy. This was a subset of a randomized, investigator-blinded, multicenter trial comparing sodium phosphate tablets with polyethylene glycol. Study data and anesthesia records were reviewed for peri-procedure hemodynamic, cardiac, and pulmonary adverse events as well as the need for hospital admission. RESULTS: There were no statistically significant differences between the 2 groups when analyzed for the development of tachycardia, decrease in mean arterial pressure below 50 mmHg, or a reduction in the mean arterial pressure greater than 30% from the pre-procedure value. No patients in either group experienced hypoxia (oxygen saturation < 90%), excessive regurgitation, pneumonia, or hospital admission. CONCLUSIONS: Peri-procedure adverse events occurred rarely and with no increased frequency in patients using the sodium phosphate tablet purgative and receiving propofol-based sedation. The sodium phosphate tablet purgative is safe for patients receiving propofol-based sedation for colonoscopy.


Assuntos
Catárticos/farmacologia , Colonoscopia , Hipnóticos e Sedativos/farmacologia , Fosfatos/farmacologia , Propofol/farmacologia , Idoso , Pressão Sanguínea/efeitos dos fármacos , Catárticos/efeitos adversos , Catárticos/uso terapêutico , Sedação Consciente/métodos , Feminino , Humanos , Hipnóticos e Sedativos/efeitos adversos , Hipnóticos e Sedativos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Fosfatos/efeitos adversos , Fosfatos/uso terapêutico , Propofol/efeitos adversos , Propofol/uso terapêutico , Estudos Retrospectivos , Método Simples-Cego , Comprimidos , Taquicardia/induzido quimicamente , Resultado do Tratamento
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