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Objectives:This study assessed the efficacy and safety of plecanatide, a guanylate cyclase-C (GC-C) agonist and the first uroguanylin analog approved for the treatment of chronic idiopathic constipation (CIC).Methods:This phase III, multicenter, double-blind, placebo-controlled study randomized 1,394 patients with CIC. Patients received either plecanatide (3 or 6 mg) or placebo, orally, once daily, for 12 weeks. The primary efficacy endpoint was the percentage of patients who were durable overall complete spontaneous bowel movement (CSBM) responders over the 12-week treatment period. Patients were instructed to record their daily bowel movements, stool consistency scores, and abdominal symptoms in an electronic diary. Treatment-emergent adverse events (AEs) were collected.Results:Each dose of plecanatide resulted in a significantly greater percentage of durable overall CSBM responders (21.0%, 3 mg; 19.5%, 6 mg) as compared with placebo (10.2% P<0.001 for both). Plecanatide (3 and 6 mg) also significantly increased mean weekly CSBM frequency from baseline (increase of 2.5 and 2.2/week, respectively) vs. placebo (1.2/week; P<0.001 for both) and mean weekly spontaneous bowel movement frequency (increase of 3.2 and 3.1/week, respectively) vs. placebo (1.3/week; P<0.001, for both) over the 12-week treatment period. Both plecanatide doses significantly improved all secondary and additional efficacy endpoints. The most common AE, diarrhea, occurred in 1.3% (placebo), 5.9% (3 mg) and 5.7% (6 mg) of patients.Conclusions:Plecanatide significantly improved constipation and its related symptoms with a low rate of adverse events. These results suggest that plecanatide will be a useful treatment option in the management of CIC. ClinicalTrials.gov: NCT01982240.

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If 24-hour esophageal pH monitoring is to be a useful diagnostic tool, it must reliably discriminate gastroesophageal reflux patients despite daily variations in distal esophageal acid exposure. To address this issue, we studied 53 subjects (14 healthy normals, 14 esophagitis patients, and 25 patients with atypical symptoms) with two ambulatory pH tests performed within 10 days of each other. Intrasubject reproducibility of 12 pH parameters to discriminate the presence of abnormal acid reflux was determined. As a group, the parameters of percent time with pH less than 4 (total, upright, recumbent) were most reproducible (80%). Therefore, a subject was defined as having gastroesophageal reflux disease if at least one of these three values were abnormal. Intrasubject reproducibility for the diagnosis of reflux disease was 89% for the entire sample. Among subsets, the reproducibility was 93% for the normals and esophagitis patients and 84% for the atypical symptom patients. Total percent time with pH less than 4 was the single most discriminate pH parameter (85%) and nearly equaled that of the three combined parameters (89%). The intrasubject variability of this parameter was determined by the mean +/- 2 SD of the relative differences between the two test results for all 53 subjects. Total percent time with pH less than 4 may vary between tests by a factor of 3.2-fold or less (218% higher to 69% lower). We conclude: (1) ambulatory 24-hr esophageal monitoring is a reproducible test for the diagnosis of gastroesophageal reflux disease; and (2) the large intrastudy variability in 24-hr total acid exposure may limit this test's usefulness as a measurement of therapeutic improvement.

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Background Pre-hospital resuscitation with crystalloid exacerbates fibrinolysis, which is associated with high mortality. We hypothesize that plasma compared to crystalloid resuscitation prevents hyperfibrinolysis in a tissue plasminogen activator (tPA) rich environment via preservation of proteins essential for regulation of fibrinolysis. Study Design Healthy individuals donated blood, which was assayed using a native (non activated) thrombelastography (TEG). Whole-blood (WB) was mixed with normal saline (NS) or platelet poor plasma (PPP) at progressive dilutions. TPA was added to promote a fibrinolytic environment. In a separate experiment PPP was run through 100 KD filter and liquid remaining on top of the filter (TFP) and below the filter (BFP) was obtained. Whole blood was diluted by 50% with TFP, BPF and NS and assayed with tPA TEG challenge. TFP and BFP were assayed for protein concentration and protein composition. Results NS and PPP dilution of WB with out tPA did not affect clot lysis at 30 minutes (LY30) (NS Spearman’s Rho 0.300 p=0.186 and PPP 0.294 p=0.288). When tPA was added NS dilution of whole blood increased LY30 in a percentage dependent manner (0.844 p<0.001) but did not significantly increase with PPP dilution (0.270 p=0.202). The difference in LY30 from WB to diluted WB with PPP (mean change −1.05 95% CI −9.42 to 7.33) was similar with TFP (1.23 95%CI −5.20 to 7.66 p=0.992). However, both BPF (37.65 95%CI 24.47 to 50.82 p=0.001) and NS (47.36 95%CI 34.3–60.45 p<0.001) showed large increases in fibrinolysis compared to PPP. Conclusions Crystalloid and plasma dilution of whole blood does not increase fibrinolysis. However NS dilution of WB, increases susceptibility to tPA mediated fibrinolysis. Plasma resuscitation, simulated by plasma dilution of whole blood, attenuates increased susceptibility to tPA mediate fibrinolysis. The benefits of plasma resuscitation are mediated through preservation of plasma proteins.

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Introduction Metabolites are underappreciated for their effect on coagulation. Taurocholic acid (TUCA), a bile acid, has been shown to regulate cellular activity and promote fibrin sealant degradation. We hypothesize that TUCA impairs whole blood clot formation and promotes fibrinolysis. Methods TUCA was exogenously added to whole blood obtained from volunteers. A titration from 250 μM to 750 μM was utilized due to biologic relevance. Whole blood mixtures were assayed using thrombelastography (TEG) for clot strength (MA) and fibrinolysis (LY30) quantification. Tranexamic acid (TXA) was used to block plasmin mediated fibrinolysis. Platelet microfluidics were performed. A proteomic analysis was completed on citrated plasma obtained from a shock and resuscitation rat model. Results Fibrinolysis increased, when 750 μM TUCA was added to whole blood (median LY30 0.08 to 5.7, p=0.010), and clot strength decreased (median MA of 53.3 to 43.8, p=0.010). The addition of TXA, to a 750 μM TUCA titration, partially reversed the induced fibrinolysis (LY30: without 7.7 vs. with 2.7) and the decrease in clot strength (MA: without 48.2 vs. with 53.2), but did not reverse the effects to whole blood levels. Platelet function reduced by 50% in the presence of 100 μM TUCA. Rats had a median 52-fold increase in TUCA, following a shock state that stayed elevated following resuscitation. Conclusion TUCA reduces clot strength and promotes fibrinolysis. The clot strength reduction is attributable to platelet inhibition. This metabolic effect on coagulation warrants further investigation, as localized areas of the body, with high levels of bile acid, may be at risk for postoperative bleeding.