Phase I double-blind, placebo-controlled trial of dolcanatide (SP-333) 27 mg to explore colorectal bioactivity in healthy volunteers.

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.

Symptoms of gluten ingestion in patients with non-celiac gluten sensitivity: A randomized clinical trial.

OBJECTIVES: Non-celiac gluten sensitivity (NCGS) is the presence of symptoms induced by gluten and relieved by a gluten-free diet (GFD) in patients without celiac disease or wheat allergy. Studies are mixed as to whether gluten is the main symptom trigger in patients with NCGS. Gluten immunogenic peptides (GIPs) in stool and urine are novel methods to monitor GFD compliance. Few studies have investigated their use in patients with NCGS. The aim of this study was to assess whether patients with NCGS have increased symptoms with gluten ingestion and to assess compliance with the GFD using stool and urine GIPs. METHOD: This was a prospective, randomized, double-blinded crossover trial evaluating symptoms in patients with NCGS. Thirty patients with NCGS and 43 healthy controls were placed on a GFD. Patients received 0.5 or 2 g/d of gluten for 7 d each. The remaining weeks, they received placebo for a total of 4 wk. Symptoms were evaluated weekly using the Celiac Symptom Index (CSI). Urine and stool samples were collected weekly and measured for the detection of GIPs to detect exposure to gluten. RESULTS: There was no difference in symptom severity within the NCGS group whether receiving placebo or gluten (32.69 versus 31.54, P = 0.64). Patients with NCGS had significantly higher CSI scores at baseline than healthy controls. Patients with NCGS were less likely to have stool and urine GIPs than healthy patients. CONCLUSION: Patients with NCGS were more adherent to the GFD based on stool and urine GIP results. Patients with NCGS had increased symptom severity at baseline compared with healthy controls. Neither group had significantly increased symptoms after ingestion of gluten.

Increased rates of pregnancy complications in women with celiac disease.

BACKGROUND: Celiac disease is an immune-mediated small bowel disorder that develops in genetically susceptible individuals upon exposure to dietary gluten. Celiac disease could have extra-intestinal manifestations that affect women's reproductive health. The aim of this study was to investigate fertility and outcomes of pregnancy among women with celiac disease. METHODS: In a retrospective cohort study, we analyzed information collected from patients at a tertiary care celiac center and from members of 2 national celiac disease awareness organizations. Women without celiac disease were used as controls. Women completed an anonymous online survey, answering 43 questions about menstrual history, fertility, and outcomes of pregnancy (329 with small bowel biopsy-confirmed celiac disease and 641 controls). RESULTS: Of the 970 women included in the study, 733 (75.6%) reported that they had been pregnant at some point; there was no significant difference between women with celiac disease (n=245/329, 74.5%) and controls (488/641, 76.1%; P=0.57). However, fewer women with celiac disease than controls (79.6% vs. 84.8%) gave birth following 1 or more pregnancies (P=0.03). Women with celiac disease had higher percentages of spontaneous abortion than controls (50.6% vs. 40.6%; P=0.01), and of premature delivery (23.6% vs. 15.9% among controls; P=0.02). The mean age at menarche was higher in the celiac disease group (12.7 years) than controls (12.4 years; P=0.01). CONCLUSIONS: In a retrospective cohort analysis examining reproductive features of women with celiac disease, we associated celiac disease with significant increases in spontaneous abortion, premature delivery, and later age of menarche.

Special considerations for women with IBD.

Inflammatory bowel diseases (IBD), namely Crohn disease (CD) and ulcerative colitis (UC), are common in Western society. Because at least half of the patients suffering from these diseases are women, it is important that physicians are aware of their gender-specific needs. There are multiple important concerns for women with UC and CD including issues of body image and sexuality, menstruation, contraception, screening for cervical cancer, matters related to menopause and hormone replacement therapy, osteoporosis, and the overlap seen between IBS and IBD. In this article, we have addressed these important, non-pregnancy-related issues faced by women with IBD.

Utilization of the office, hospital and emergency department for adult sickle cell patients: a five-year study.

Sickle cell disease (SCD) is a hematological disorder that is manifested primarily by severe pain and chronic organ damage. Little normative data exists on what the usual healthcare utilization is of a population of SCD patients, especially adults. Our study analyzed the office, emergency department (ED) and hospital use data for 142 patients who received care for three consecutive years. Relationships between health service use, patient age, gender and sickle cell phenotype were described. Multivariate analyses studied relationships between demographic and clinical characteristics and levels of office, independent ED and inpatient encounters over a five-year period (1997-2001). We found female patients were older and had less ED and hospital admissions. The 20% highest inpatient utilizers accounted for 54% of the ED total visits, 52% of the ED independent visits, 54% of hospital bed days and 24% of office visits. The ED was a common place for utilization, with a mean of 7.4 visits per patient year, a third of which resulted in a hospital admission. The healthcare utilization of our adult sickle cell population is very complex, with a subset of our patients accounting for a majority of the resources used and female patients living longer but with less ED and hospital admissions.