Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Weinberg DS

PROVIDER: S-EPMC8726613 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Weinberg David S DS Foster Nathan R NR Della'Zanna Gary G McMurray Ryan P RP Kraft Walter K WK Pallotto Angela A Kastenberg David M DM Katz Leo C LC Henry Christopher H CH Moleski Stephanie M SM Limburg Paul J PJ Waldman Scott A SA

Cancer biology & therapy 20211010 10-12

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 investiga ...[more]

PMID: 34632925

Similar Datasets

Project description:BackgroundDasiglucagon is a novel glucagon analog that is stable in aqueous formulation and approved for use in severe hypoglycemia. Concentration QTc analyses are critical for assessing risk of drug-induced QTc prolongation and potential for fatal cardiac arrhythmias such as torsades de pointes.ObjectiveThe aim of this study was to determine whether dasiglucagon treatment resulted in any clinically relevant effect on cardiac repolarization in healthy volunteers.MethodsThis double-blind, placebo-controlled, dose-escalation Phase I trial was conducted at a single center in Germany between November 2018 and June 2019. Sixty healthy volunteers aged 18 to 45 years were randomized within dose cohorts to receive intravenous dasiglucagon, intravenous placebo, or subcutaneous dasiglucagon. In the intravenous administration cohorts, doses ranged from 0.03 mg to 1.5 mg. The subcutaneous administration cohort received the approved 0.6 mg dose. In the intravenous administration cohorts, serial electrocardiograms were extracted from continuous Holter monitors at prespecified time points beginning the day before dosing and through 24 hours postdose. Heart rate, PR interval, and QRS duration were evaluated. Concentration-QT analyses corrected by Fridericia's formula (QTcF) were performed using both a linear mixed-effects and a maximum estimated effect (Emax) model.ResultsAt the doses studied, dasiglucagon did not have any clinically relevant effect on heart rate, PR interval, or QRS duration. A minor prolongation of the QTcF interval was observed without any clear dose or concentration dependency. Both the linear and Emax models predicted mean and 90% CIs of placebo-corrected change in QTcF remained below 10 ms (the threshold of regulatory concern), although the linear model did not fit the data well at low dasiglucagon plasma concentrations. In the Emax model, the Emax of dasiglucagon was 3.6 ms (90% CI, 1.23-5.95 ms), and the amount to produce half the effect of Emax) was 426.0 pmol/L (90% CI, -48.8 to 900.71 pmol/L). The treatment effect-specific intercept was -0.44 ms (90% CI, -2.37 to 1.49 ms). The most frequently observed treatment-emergent adverse events reported in the trial were gastrointestinal disorders such as nausea and vomiting.ConclusionsDasiglucagon does not cause clinically relevant QTc prolongation in concentrations up to ≈30,000 pmol/L, a level 5-fold higher than the highest observed plasma concentrations in clinical trials investigating use of the approved 0.6 mg SC dose. ClinicalTrials.gov Identifier: NCT03735225; EudraCT identifier: 2018-002025-32. (Curr Ther Res Clin Exp. 2022; 83:XXX-XXX).

Project description:IntroductionDuloxetine has demonstrated efficacy in chronic low back pain (CLBP). We examined the predictors of response to duloxetine for CLBP.Patients and methodsThis was a post hoc analysis of pooled data from 4 double-blind, ran-domized, placebo-controlled trials of duloxetine (60 mg/day for 12-14 weeks) in adult patients with CLBP. Primary outcome was proportion of patients with ≥30% reduction in Brief Pain Inventory (BPI) average pain ("pain reduction") at 12-14 weeks. The proportion of patients with ≥30% and ≥50% (secondary outcome) pain reduction in duloxetine and placebo groups was compared. Variables for responder analyses were early improvement (≥15% pain reduction at Week 2), sex, age, baseline BPI average pain score, duration of CLBP, and number of painful body sites according to the Michigan Body Map (≥2 vs 1 [isolated CLBP]; 1 trial); relative risk (RR) and 95% confidence interval (CI) were calculated.ResultsCompared with placebo (n = 653), a greater proportion of duloxetine-treated patients (n = 642) achieved ≥30% (59.7% vs 47.8%; P < 0.001) and ≥50% pain reduction (48.6% vs 35.1%; P < 0.001). Among duloxetine-treated patients, early improvement was associated with greater likelihood of ≥30% (RR [95% CI], 2.91 [2.30-3.67]) or ≥50% (3.24 [2.44-4.31]) pain reduction. Women were slightly more likely than men to achieve ≥30% (RR [95% CI], 1.14 [1.00-1.30]) or ≥50% (1.17 [0.99-1.38]) pain reduction. Response rates were similar between age, CLBP duration, and baseline BPI average pain score subgroups. Patients with ≥2 painful sites were more likely to respond to duloxetine 60 mg relative to placebo than patients with isolated CLBP (RR, duloxetine vs placebo [95% CI]: ≥30% reduction, ≥2 painful sites 1.40 [1.18-1.66], isolated CLBP 1.07 [0.78-1.48]; ≥50% reduction, ≥2 painful sites 1.51 [1.20-1.89], isolated CLBP 1.23 [0.81-1.88]).ConclusionEarly pain reduction was indicative of overall response. Patients with multiple painful sites had more benefit from duloxetine than patients with isolated CLBP.

Project description:Background and rationaleAtypical antipsychotics exhibit metabolic side effects including diabetes mellitus and obesity. The adverse events are preceded by acute worsening of oral glucose tolerance (oGTT) along with reduced plasma free fatty acids (FFA) and leptin in animal models. It is unclear whether the same acute effects occur in humans.Methodology/principal findingsA double blind, randomized, placebo-controlled crossover trial was conducted to examine the potential metabolic effects of olanzapine in healthy volunteers. Participants included male (8) and female (7) subjects [18-30 years old, BMI 18.5-25]. Subjects received placebo or olanzapine (10 mg/day) for three days prior to oGTT testing. Primary endpoints included measurement of plasma leptin, oral glucose tolerance, and plasma free fatty acids (FFA). Secondary metabolic endpoints included: triglycerides, total cholesterol, high- and low-density lipoprotein cholesterol, heart rate, blood pressure, body weight and BMI. Olanzapine increased glucose Area Under the Curve (AUC) by 42% (2808±474 vs. 3984±444 mg/dl·min; P = 0.0105) during an oGTT. Fasting plasma leptin and triglycerides were elevated 24% (Leptin: 6.8±1.3 vs. 8.4±1.7 ng/ml; P = 0.0203) and 22% (Triglycerides: 88.9±10.1 vs. 108.2±11.6 mg/dl; P = 0.0170), whereas FFA and HDL declined by 32% (FFA: 0.38±0.06 vs. 0.26±0.04 mM; P = 0.0166) and 11% (54.2±4.7 vs. 48.9±4.3 mg/dl; P = 0.0184), respectively after olanzapine. Other measures were unchanged.Conclusions/significanceOlanzapine exerts some but not all of the early endocrine/metabolic changes observed in rodent models of the metabolic side effects, and this suggest that antipsychotic effects are not limited to perturbations in glucose metabolism alone. Future prospective clinical studies should focus on identifying which reliable metabolic alterations might be useful as potential screening tools in assessing patient susceptibility to weight gain and diabetes caused by atypical antipsychotics.Trial registrationClinicalTrials.gov NCT00741026.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets