Prevalence and Burden of Illness of Rome IV Irritable Bowel Syndrome in the United States: Results From a Nationwide Cross-Sectional Study.

BACKGROUND & AIMS: The estimated prevalence of irritable bowel syndrome (IBS) using Rome IV criteria in the United States (US) ranges from 4.7% to 5.3%, although these estimates arise from studies with relatively small sample sizes. This study assessed the prevalence of IBS and its associated burden of illness using a nationally representative data set with nearly 89,000 people in the US. METHODS: From May 3 to June 24, 2020, we performed an online survey described to participating adults aged ≥18 years old as a "national health survey." We recruited a representative sample of people in the US to complete the survey, which included the Rome IV IBS questionnaire, National Institutes of Health Patient-Reported Outcome Measurement Information System (PROMIS) gastrointestinal scales, and questions on health care-seeking behavior. RESULTS: Overall, 88,607 people completed the survey, of whom 5414 (6.1%) met Rome IV IBS criteria: mixed IBS (n = 1838 [33.9%]), constipation-predominant IBS (n = 1819 [33.6%]), diarrhea-predominant IBS (n = 1521 [28.1%]), and unsubtyped IBS (n = 236 [4.4%]). Women had higher odds for IBS compared with men, whereas racial/ethnic minorities had lower odds for IBS vs non-Hispanic Whites. Across the 3 main subtypes, 68.2% to 73.2% of people reported ever seeking care for their IBS symptoms, whereas 53.8% to 58.9% did so in the past 12 months. CONCLUSIONS: In this nationwide US survey, we found that Rome IV IBS is slightly more prevalent (6.1%) vs prior estimates (4.7%-5.3%). Additional research is needed to determine whether this higher prevalence is in part due to the coronavirus disease 2019 pandemic during which this study was conducted.

Prevalence and Burden of Illness of Rome IV Chronic Idiopathic Constipation, Opioid-Induced Constipation, and Opioid-Exacerbated Constipation in the United States.

INTRODUCTION: Chronic idiopathic constipation (CIC) and opioid-induced constipation (OIC) are disorders that negatively affect quality of life. We sought to assess the prevalence, symptom severity, and medication use among people with Rome IV CIC, OIC, and opioid-exacerbated constipation (OEC) using a nationally representative data set with nearly 89,000 people in the United States. METHODS: From May 3, 2020, to June 24, 2020, we recruited a representative sample of people in the United States ≥ 18 years to complete an online national health survey. The survey guided participants through the Rome IV CIC and OIC questionnaires, Patient-Reported Outcome Measurement Information System gastrointestinal scales (percentile 0-100; higher = more severe), and medication questions. Individuals with OEC were identified by asking those with OIC whether they experienced constipation before starting an opioid and whether their symptoms worsened afterward. RESULTS: Among the 88,607 participants, 5,334 (6.0%) had Rome IV CIC, and 1,548 (1.7%) and 335 (0.4%) had Rome IV OIC and OEC, respectively. When compared with people with CIC (Patient-Reported Outcome Measurement Information System score, 53.9 ± 26.5; reference), those with OIC (62.7 ± 28.0; adjusted P < 0.001) and OEC (61.1 ± 25.8, adjusted P = 0.048) had more severe constipation symptoms. People with OIC (odds ratio 2.72, 95% confidence interval 2.04-3.62) and OEC (odds ratio 3.52, 95% confidence interval 2.22-5.59) were also more likely to be taking a prescription medication for their constipation vs those with CIC. DISCUSSION: In this nationwide US survey, we found that Rome IV CIC is common (6.0%) while Rome IV OIC (1.7%) and OEC (0.4%) are less prevalent. Individuals with OIC and OEC have a higher burden of illness with respect to symptom severity and prescription constipation medication use.

Linaclotide Attenuates Visceral Organ Crosstalk: Role of Guanylate Cyclase-C Activation in Reversing Bladder-Colon Cross-Sensitization.

Bladder pain syndrome (BPS) is poorly understood; however, there is a female predominance and comorbidity with irritable bowel syndrome (IBS). Here we test the hypothesis that linaclotide, a guanylate cyclase-C (GC-C) agonist approved for the treatment of IBS with constipation (IBS-C), may represent a novel therapeutic for BPS acting through a mechanism involving an inhibition of visceral organ cross-sensitization. We showed previously that infusion of dilute protamine sulfate (PS) into the bladder increased sensitivity and permeability in the bladder and colon. PS was infused into the bladder of female rats; sensitivity was assessed via application of von Frey filaments applied to the suprapubic area and the frequency of withdrawal responses was recorded. Colonic sensitivity was measured via visceromotor behavioral response to graded pressures of colorectal distension (CRD). Permeability was measured in vitro via transepithelial electrical resistance (TEER) and conductance (G). Linaclotide (3 µg/kg, p.o.) or vehicle was administered daily for 7 days prior to experiments. Rats treated with PS bladder infusion exhibited visceral hyperalgesia, as shown by a significantly higher response frequency to individual von Frey filaments and increased behavioral responses to CRD. Linaclotide attenuated bladder and colonic hyperalgesia to control levels. PS infusion into the bladder increased bladder and colon permeability measured as a decrease in TEER and increased G. Linaclotide significantly inhibited PS-induced colonic hyperpermeability while having no effect on bladder hyperpermeability. Our findings suggest a novel treatment paradigm for GC-C agonism in IBS-C and BPS mediated through a mechanism involving visceral organ crosstalk.

Pharmacologic properties, metabolism, and disposition of linaclotide, a novel therapeutic peptide approved for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation.

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.

Efficiency of perchlorate consumption in road flares, propellants and explosives.

When an explosive detonates or a propellant or flare burns, consumption of the energetic filler should be complete but rarely is, especially in the presence of large amounts of non-combustible materials. Herein we examine three types of perchlorate-containing devices to estimate their potential as sources of contamination in their normal mode of functioning. Road flares, rocket propellants and ammonium nitrate (AN) emulsion explosives are potentially significant anthropogenic sources of perchlorate contamination. This laboratory evaluated perchlorate residue from burning of flares and propellants as well as detonations of ammonium nitrate emulsion explosives. Residual perchlorate in commercial products ranged from 0.094mg perchlorate per gram material (flares) to 0.012mg perchlorate per gram material (AN emulsion explosives). The rocket propellant formulations, prepared in this laboratory, generated 0.014mg of perchlorate residue per gram of material.

Discovery and Characterization of a Potent Interleukin-6 Binding Peptide with Neutralizing Activity In Vivo.

Interleukin-6 (IL-6) is an important member of the cytokine superfamily, exerting pleiotropic actions on many physiological processes. Over-production of IL-6 is a hallmark of immune-mediated inflammatory diseases such as Castleman's Disease (CD) and rheumatoid arthritis (RA). Antagonism of the interleukin IL-6/IL-6 receptor (IL-6R)/gp130 signaling complex continues to show promise as a therapeutic target. Monoclonal antibodies (mAbs) directed against components of this complex have been approved as therapeutics for both CD and RA. To potentially provide an additional modality to antagonize IL-6 induced pathophysiology, a peptide-based antagonist approach was undertaken. Using a combination of molecular design, phage-display, and medicinal chemistry, disulfide-rich peptides (DRPs) directed against IL-6 were developed with low nanomolar potency in inhibiting IL-6-induced pSTAT3 in U937 monocytic cells. Targeted PEGylation of IL-6 binding peptides resulted in molecules that retained their potency against IL-6 and had a prolongation of their pharmacokinetic (PK) profiles in rodents and monkeys. One such peptide, PN-2921, contained a 40 kDa polyethylene glycol (PEG) moiety and inhibited IL-6-induced pSTAT3 in U937 cells with sub-nM potency and possessed 23, 36, and 59 h PK half-life values in mice, rats, and cynomolgus monkeys, respectively. Parenteral administration of PN-2921 to mice and cynomolgus monkeys potently inhibited IL-6-induced biomarker responses, with significant reductions in the acute inflammatory phase proteins, serum amyloid A (SAA) and C-reactive protein (CRP). This potent, PEGylated IL-6 binding peptide offers a new approach to antagonize IL-6-induced signaling and associated pathophysiology.