DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for constipation disorder — screening already-approved drugs against its 8-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleConstipation disorder maps to a 8-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Structures already discussed alongside constipation disorder in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
Molecular view
thyroid hormone receptor alpha (THRA) — THRA is one of the genes in this disease's Open Targets module — part of the target space DeCure's repurposing candidates point at. The protein backbone is drawn as a cartoon. The structure has {4-[4-hydroxy-3-(1-methylethyl)benzyl]-3,5-dimethylphenoxy}acetic acid bound in it, shown as sticks.
Loading structure…
helix sheet 1-methylethyldrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 3ILZ · 1.85 Å · ligand {4-[4-hydroxy-3-(1-methylethyl)benzyl]-3,5-dimethylphenoxy}acetic acid (B72). Experimental structure, not a prediction.
What the evidence adds up to
In two 12-week trials involving 1276 patients with chronic constipation, linaclotide at 145 μg or 290 μg once daily produced primary end point rates of 21.2% and 16.0% (145 μg) and 19.4% and 21.3% (290 μg) versus 3.3% and 6.0% for placebo. Diarrhoea led to discontinuation in 4.2% of patients in both linaclotide groups. An earlier pilot study of 42 patients given linaclotide 100, 300, or 1000 μg daily for two weeks showed dose-dependent increases in weekly complete spontaneous bowel movements (range 2.2–3.2) and improvements in stool consistency and straining, with placebo increases of 1.3, 0.4, and 0.4 respectively; diarrhoea was the most common adverse event.
Tegaserod 6 mg twice daily in a 12-week multinational study of 1264 patients gave a responder rate of 40.2% versus 26.7% for placebo, with a number needed to treat of 7.3. In a separate trial of 322 men, tegaserod 6 mg twice daily produced a 40.5% response rate versus 29.3% for placebo. Headache and abdominal pain were more frequent with placebo than with tegaserod. A systematic review and meta-analysis of lactitol involving 663 patients found a significant increase in weekly stool frequency (standardised mean difference 1.56) and improved stool consistency (1.04) compared with baseline; about one-third of patients reported adverse events, mostly mild, and 5% withdrew. In head-to-head randomised trials, lactitol was slightly more effective than lactulose for weekly stool frequency (SMD 0.19, P=0.06).
Prucalopride 2 mg once daily (or 1 mg in patients over 65) was assessed in a Korean post-marketing surveillance of 601 patients, of whom 67.7% were female and mean age 62.3 years. Adverse events occurred in 17.7% (headache 3.2%, diarrhoea 2.8%); seven serious adverse events in five patients (0.8%) were assessed as unlikely related to prucalopride. Chronic constipation improved in 72.7% of patients during the study period. A 2010 review described prucalopride as efficacious and generally safe but noted that current therapies do not restore normal bowel function in all patients.
What is still missing are long-term safety data beyond 12 weeks for linaclotide and tegaserod, direct comparisons between these agents and prucalopride or lactitol in adequately powered trials, and studies that stratify patients by baseline bowel frequency, age, or prior laxative failure to identify who benefits most. No trial has yet tested these drugs against each other in a head-to-head design with patient-reported quality of life as the primary outcome.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
New England Journal of Medicine · 2011 · 373 citations · open access
Two Randomized Trials of Linaclotide for Chronic Constipation
AbstractBACKGROUND: Linaclotide is a minimally absorbed peptide agonist of the guanylate cyclase C receptor. In two trials, we aimed to determine the efficacy and safety of linaclotide in patients with chronic constipation. METHODS: We conducted two randomized, 12-week, multicenter, double-blind, parallel-group, placebo-controlled, dual-dose trials (Trials 303 and 01) involving 1276 patients with chronic constipation. Patients received either placebo or linaclotide, 145 μg or 290 μg, once daily for 12 weeks. The primary efficacy end point was three or more complete spontaneous bowel movements (CSBMs) per week and an increase of one or more CSBMs from baseline during at least 9 of the 12 weeks. Adverse events were also monitored. RESULTS: For Trials 303 and 01, respectively, the primary end point was reached by 21.2% and 16.0% of the patients who received 145 μg of linaclotide and by 19.4% and 21.3% of the patients who received 290 μg of linaclotide, as compared with 3.3% and 6.0% of those who received placebo (P<0.01 for all comparisons of linaclotide with placebo). Improvements in all secondary end points were significantly greater in both linaclotide groups than in the placebo groups. The incidence of adverse events was similar among all study groups, with the exception of diarrhea, which led to discontinuation of treatment in 4.2% of patients in both linaclotide groups. CONCLUSIONS: In these two 12-week trials, linaclotide significantly reduced bowel and abdominal symptoms in patients with chronic constipation. Additional studies are needed to evaluate the potential long-term risks and benefits of linaclotide in chronic constipation. (Funded by Ironwood Pharmaceuticals and Forest Research Institute; ClinicalTrials.gov numbers, NCT00765882 and NCT00730015.).
The American Journal of Gastroenterology · 2005 · 197 citations
Tegaserod for the Treatment of Chronic Constipation: A Randomized, Double-Blind, Placebo-Controlled Multinational Study
AbstractOBJECTIVES: Chronic constipation is a common, persistent disorder with limited effective treatment options. This study investigated the efficacy, safety, and tolerability of tegaserod in the treatment of chronic constipation. METHODS: After a 2-wk baseline period, patients were randomized to double-blind treatment of 12 wk with tegaserod (2 or 6 mg b.i.d.) or placebo. Response during weeks 1-4 (primary variable) was defined as an increase in complete spontaneous bowel movement (CSBM)/wk. Secondary variables included response during weeks 1-12, patient evaluation of individual symptoms, and global assessment of bowel habits and constipation. RESULTS: One thousand two hundred and sixty-four patients were randomized to tegaserod or placebo. Responder rates for the primary efficacy variable were 35.6% for tegaserod 2 mg b.i.d. (p= 0.0059 vs placebo), 40.2% for 6 mg b.i.d. (p < 0.0001 vs placebo) and 26.7% for placebo. The number needed to treat was 7.3 for the 6 mg b.i.d. dose compared with 11.1 for tegaserod 2 mg b.i.d. Tegaserod 6 mg b.i.d. reduced straining, abdominal bloating/distension, and abdominal pain/discomfort during the 12-wk treatment period compared with placebo (p < 0.05 for all symptoms). Significant improvements were also seen in stool form and in global assessment of bowel habits and constipation. The most common adverse events, headache and abdominal pain, were more frequent with placebo than with tegaserod. CONCLUSIONS: Tegaserod was efficacious in relieving symptoms of chronic constipation and was well tolerated.
The American Journal of Gastroenterology · 2008 · 119 citations
Pilot Study on the Effect of Linaclotide in Patients With Chronic Constipation
AbstractOBJECTIVES: Chronic constipation is a common gastrointestinal disorder with limited treatment options. Oral administration of linaclotide, a novel peptide agonist of guanylate cyclase-C receptors, has been shown in animal studies to stimulate intestinal fluid secretion and transit. In Phase 1 studies in healthy human volunteers, linaclotide was well-tolerated, increased bowel movement frequency, and loosened stool consistency. METHODS: This randomized, double-blind, placebo-controlled pilot study evaluated the safety, tolerability, and exploratory efficacy of oral linaclotide in 42 patients with chronic constipation. Patients were randomized to linaclotide (100, 300, or 1,000 microg) or placebo once daily for 2 weeks. Bowel habits (stool frequency, consistency, straining, completeness of evacuation) and degree of abdominal discomfort were monitored daily using an interactive voice response system. Patient-reported outcomes of severity of constipation and overall relief were evaluated weekly. RESULTS: Linaclotide treatment produced dose-dependent increases from the pretreatment baseline values in weekly complete spontaneous bowel movement frequency (range: 2.2-3.2), stool consistency scores (range: 1.1-2.6, 7-point scale), and straining scores (range: 0.4-1.5, 7-point scale); corresponding placebo increases were 1.3, 0.4, 0.4, respectively. Clinical improvements were also demonstrated in abdominal discomfort, severity of constipation, and overall relief. Compared to placebo, linaclotide 100 microg/day significantly increased spontaneous bowel movement frequency, and linaclotide 1,000 microg/day significantly improved stool consistency (P<0.05). Adverse events were primarily gastrointestinal, with diarrhea being the most common. CONCLUSIONS: In this pilot study, linaclotide treatment improved bowel habits and symptoms of patients with chronic constipation. Further randomized controlled trials are warranted.
Clinical and Experimental Gastroenterology · 2014 · 53 citations · open access
Efficacy and tolerance of lactitol supplementation for adult constipation: a systematic review and meta-analysis
AbstractBACKGROUND: Constipation is a common complaint in adults. Lactitol is an osmotic disaccharide laxative that increases fecal volume and stimulates peristalsis. In this paper, we present the first meta-analysis on the efficacy and tolerance of lactitol for adult constipation. METHODS: We searched MEDLINE(®) and Embase, with no date or language restrictions, for studies of lactitol supplementation on adult constipation. A random-effects meta-analysis was performed on pre- to posttreatment changes in stool frequency and consistency with lactitol among all studies, as well as a comparison of efficacy and tolerance outcomes in randomized controlled trials (RCTs) of lactitol versus lactulose. RESULTS: A total of eleven studies representing 663 distinct patients were included in the final analysis, including five single-arm studies, four RCTs comparing lactitol with lactulose, one RCT comparing lactitol with placebo, and one nonrandomized controlled trial comparing lactitol with stimulant laxatives. Weekly stool frequency was significantly increased with lactitol compared with baseline (standardized mean difference [SMD]: 1.56, P<0.001). Stool consistency also improved over the supplementation period with lactitol (SMD: 1.04, P<0.001). Approximately one-third of patients experienced an adverse event; however, symptoms were generally mild and rarely (5%) resulted in study withdrawal. In RCTs of lactitol versus lactulose, lactitol was slightly more effective than lactulose in increasing weekly stool frequency (SMD: 0.19, P=0.06). No statistically significant differences between lactitol and lactulose were identified in any other efficacy or tolerance outcome. Lactitol demonstrated favorable efficacy and tolerance in individual studies when compared to stimulant laxatives and placebo. CONCLUSION: Lactitol supplementation is well tolerated and improves symptoms of adult constipation. The efficacy and tolerance of lactitol and lactulose are similar, with a trend for more frequent stools with lactitol. Limited evidence suggests lactitol is superior to stimulant laxatives and placebo for relieving constipation symptoms.
Expert Opinion on Pharmacotherapy · 2010 · 39 citations
Prucalopride for constipation
AbstractIMPORTANCE OF THE FIELD: Chronic constipation has a high prevalence, and current medical and pharmacological therapies do not restore normal bowel function in all patients. AREAS COVERED IN THE REVIEW: A PubMed search (1965 - 2009) using the following terms alone or in combination: prucalopride, 5-HT(4), R093877, safety, toxicity, pharmacokinetics, pharmacodynamics, transit, cardiac, hERG, arrhythmia, potassium current, elderly. WHAT THE READER WILL GAIN: Understanding of the mechanisms of action, safety, efficacy and indications for prucalopride in patients with chronic constipation. TAKE HOME MESSAGE: Prucalopride is an efficacious and generally safe, new therapeutic option in the management of chronic constipation.
The American Journal of Gastroenterology · 2006 · 25 citations
Efficacy of Tegaserod in Chronic Constipation in Men
AbstractOBJECTIVES: Chronic constipation/idiopathic constipation is highly prevalent in western countries and traditional treatments are suboptimal. This multicenter study evaluated the efficacy and safety of tegaserod, a selective 5-HT(4) agonist and promotility agent, in men with chronic constipation. METHODS: After screening and baseline phases, men with chronic constipation were randomized to receive either tegaserod 6 mg twice daily or placebo in a double-blind manner for 12 wk. Patients recorded symptoms using a diary. Primary efficacy variable was the response rate for an increase in complete spontaneous bowel movements (CSBMs) during the first 4 wk of double-blind treatment. Other efficacy measures included patient assessment of symptoms and satisfaction with symptom relief. Safety and tolerability were also evaluated. RESULTS: In total, 322 patients were randomized to tegaserod (N = 158) or placebo (N = 164). Increases of at least one CSBM per wk during the first 4 wk of treatment observed for tegaserod compared with placebo (40.5%vs 29.3%, P= 0.03) were sustained throughout the 12-wk treatment period. Response rate for CSBM was also superior for tegaserod (P= 0.04 vs placebo) over the treatment period. Benefits for tegaserod over placebo were also observed for some secondary efficacy variables, however, statistical significance was not achieved at all weeks. Frequency of adverse events was similar with tegaserod and placebo. CONCLUSIONS: Tegaserod 6 mg twice daily was effective and well tolerated in the treatment of chronic constipation in men. Tegaserod provided rapid relief of constipation within 1 wk and the effects were sustained for up to 12 wk.
Expert Opinion on Drug Metabolism & Toxicology · 2011 · 22 citations
The pharmacokinetics, pharmacodynamics, clinical efficacy, safety and tolerability of linaclotide
AbstractINTRODUCTION: Linaclotide is a novel intestinal secretagogue that is in the advanced stages of development for the treatment of irritable bowel syndrome with constipation (IBS-C) and chronic constipation. These functional gastrointestinal disorders are highly prevalent in adults and children and often do not respond satisfactorily to available treatments. Linaclotide appears to be a promising new agent for patients who are not satisfied with currently available agents. AREAS COVERED: This article is formed from a literature review of all the studies published about linaclotide up to January 2011. It covers the pharmacodynamics and pharmacokinetics of this novel agent. It also provides a summary of the published clinical trials concerning efficacy and safety in patients with chronic constipation and IBS-C. The authors provide the reader with a better understanding of how the molecular pathophysiology of certain enteropathic diarrheal bacteria lead to the development of this novel prosecretory drug. The reader will also learn about the development of molecularly-based treatment options for chronic constipation and other constipation-associated disorders such as IBS-C. EXPERT OPINION: Linaclotide appears to be a well-tolerated and effective agent for many patients with chronic constipation and IBS-C. Two Phase III studies in chronic constipation and two in IBS-C have provided promising data on the efficacy and safety of this agent for these two disorders. The positioning of linaclotide among the various available agents for these two disorders remains to be established after approval from the FDA is granted.
Korean Journal of Gastroenterology · 2021 · 2 citations · open access
Safety/Efficacy of Prucalopride in Korean Patients with Chronic Constipation: Post-marketing Surveillance
AbstractBackground/Aims: Constipation is a common gastrointestinal disorder. Prucalopride is a dihydrobenzofurancarboxamide derivative with gastrointestinal prokinetic activities and is recommended as an appropriate choice in patients unresponsive to laxatives. This study assessed the safety and efficacy of prucalopride in Korean patients with chronic constipation, in whom laxatives were ineffective. Methods: This prospective, non-interventional post-marketing surveillance of prucalopride was conducted from 2012 to 2018 at 28 hospitals in Korea. Adults who received prucalopride for the symptomatic treatment of chronic constipation were included. The patients received 2 mg of prucalopride once daily or 1 mg once daily in patients older than 65 years. The baseline characteristics, adverse events (AEs), and seven-point scale of Clinical Global Impression-Improvement were collected. Results: Of 601 patients, 67.7% were female, and the mean age was 62.3 years. Three hundred patients (49.9%) were older than 65 years. At the baseline, 70.0% of patients reported less than two instances of spontaneous complete bowel movements per week. AEs were reported in 107 patients (17.7%), including headache (3.2%) and diarrhea (2.8%). Seven serious AEs (SAEs) were reported in five patients (0.8%). The SAEs were resolved without complications; there were no cases of death. All SAEs were assessed as 'unlikely' causality with prucalopride. In 72.7% of patients, chronic constipation was improved by the prucalopride treatment during the study period. Conclusions: This study demonstrated the promising safety and efficacy profile of prucalopride in clinical practice. Thus, prucalopride should be considered in patients with chronic constipation when bowel symptoms are refractory to simple laxatives.
Disease module: DeepOracle (Open Targets). Approved indication: ChEMBL drug_indication (max_phase=4). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works, resolved on OpenAlex.
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