DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Prolonged QT interval — screening already-approved drugs against its 44-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleProlonged QT interval maps to a 44-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
Current lead
No approved-drug candidate for prolonged qt interval is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
LIM domain binding 3 (LDB3) — LDB3 is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet gludrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 4YDP · 1.4 Å · ligand GLUTAMIC ACID (GLU). Experimental structure, not a prediction.
What the evidence adds up to
In a study of 4,655 first graders, 4,655 seventh graders, and 5,273 tenth graders (ages 6, 12, and 15 years), researchers proposed tentative Fridericia-corrected QT cut-offs for screening prolonged QT intervals: 430 ms for first graders, 445 ms for seventh graders, and 440 ms for tenth-grade boys and 455 ms for tenth-grade girls. These cut-offs were based on an assumed prevalence of abnormal electrocardiographic phenotypes of 1 in 1,164 and the upper 0.025 percentile of the QTc distribution from earlier studies. The authors stated that further studies are needed to confirm the validity of these cut-offs.
A multicentre study of 1,270 patients receiving drug treatment in everyday clinical practice found that 9.9% had a QTc (Bazett-corrected) above 450/470 ms, 3% had QTc above 500 ms, 12.7% had a ΔQTc greater than 30 ms, and 5.2% had a ΔQTc greater than 60 ms. QTc prolongation was associated with congestive heart failure, ischaemic cardiopathy, diabetes, renal failure, arrhythmias, hypothyroidism, and bradycardia. At univariate analysis, clarithromycin, haloperidol, tramadol, amiodarone, glyceryl trinitrate, several beta-lactam antibiotic combinations, fentanyl, and diazepam prolonged QTc. After multivariate analysis, only furosemide, clarithromycin, glyceryl trinitrate, and beta-lactamase inhibitors remained significantly associated. The authors concluded that QT interval prolongation in everyday practice is frequent and can be identified for monitoring.
A review of molecularly targeted agents noted that QT interval prolongation is a recognised adverse effect of several classes of cancer drugs, including histone deacetylase inhibitors, multi-targeted tyrosine kinase inhibitors, vascular disruption agents, farnesyl protein transferase inhibitors, Src/Abl kinase inhibitors, and protein kinase C inhibitors. The review stated that this prolongation can induce fatal arrhythmia but provided no quantitative data on incidence, dose-response, or clinical outcomes.
What remains missing are prospective trials that validate screening cut-offs against actual arrhythmic events, large-scale pharmacovigilance studies that quantify absolute risk for each drug in real-world populations, and mechanistic work to stratify patients by genetic or metabolic susceptibility before exposure. No drug is recommended here for any purpose.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Circulation Journal · 2010 · 45 citations · open access
Cut-Offs for Screening Prolonged QT Intervals From Fridericia's Formula in Children and Adolescents
AbstractBACKGROUND: The corrected QT interval (QTc) according to Bazett's formula (QTc = QT/RR(1/2)) has been used in clinical practice. Bazett's formula, however, overcorrects the QT interval at fast heart rates and undercorrects it at low heart rates. Guidelines and some investigators have recommended using Fridericia's formula (QTc = QT/RR(1/3)) in these cases, especially in tachycardic subjects. The aim of the present study was to determine cut-offs for QTc suitable for screening pediatric subjects with prolonged QT intervals, based on manually measured values corrected by Fridericia's formula in a large number of subjects. METHODS AND RESULTS: Three consecutive QT and RR intervals were measured in 4,655, 4,655, and 5,273 1st, 7th, and 10th graders, aged 6, 12, and 15 years, respectively. Each QT interval was corrected by Fridericia's formula, and mean values were calculated. Determination of the cut-offs for screening was based on the prevalence of abnormal electrocardiographic phenotypes of 1:1,164 and on the upper 0.025 percentile in the QTc distribution derived from previous studies. The tentative cut-offs suitable for screening subjects with prolonged QT intervals were 430 ms for 1st graders, 445 ms for 7th graders, and 440 and 455 ms for 10th grade boys and girls, respectively. CONCLUSIONS: These tentative cut-offs can be used to screen subjects with prolonged QT intervals in the clinical setting. Further studies are needed to confirm their validity.
Drug-Induced QTc Interval Prolongation: A Multicenter Study to Detect Drugs and Clinical Factors Involved in Every Day Practice
AbstractOBJECTIVE: The actual prevalence of drug induced QTc prolongation in clinical practice is unknown. Our objective was to determine the occurrence and characteristics of drug-induced QT prolongation in several common clinical practices. Additionally, a subgroup of patients treated with dextropropoxyphene of particular interest for the regulatory authority was analysed. RESEARCH DESIGN AND METHODS: Medical history and comorbidities predisposing to QT interval prolongation were registered for 1270 patient requiring medical assistance that involved drug administration. Three ionograms and ECGs were performed: baseline, intra- and after treatment; QT interval was corrected with Bazzet formula. RESULTS: Among patients, 9.9% presented QTc >450/470 ms, 3% QTc > 500 ms, 12.7% ΔQTc >30 ms and 5.2% ΔQTc >60 ms. QTc prolongation associated with congestive heart failure, ischemic cardiopathy, diabetes, renal failure, arrhythmias, hypothyroidism, and bradycardia. At univariate analysis, clarithromycin, haloperidol, tramadol, amiodarone, glyceryl trinitrate, amoxicillin + clavulanic acid, amoxicillin + sulbactam, ampicillin + sulbactam, fentanyl, piperacillin + tazobactam, and diazepam prolonged QTc. Prolongation remained significantly associated with furosemide, clarithromycin, glyceryl trinitrate and betalactamase inhibitors after multivariate analysis. CONCLUSION: QT interval prolongation in everyday practice is frequent, in association to clinical factors and drugs that can be easily identified for monitoring and prevention strategies.
Rational Pharmacotherapy in Cardiology · 2013 · 8 citations · open access
CLINICAL SIGNIFICANCE OF DRUGINDUCED INTERVALS QT AND QTC PROLONGATION
AbstractInterval QT prolongation is a predictor of the life-threatening cardiac arrhythmias — polymorphic ventricular tachycardia (torsade de pointes). Long QT syndrome may be congenital or acquired. It is known that a wide range of both antiarrhythmic and non-cardiac medications might lead to QT interval prolongation. List of drugs that cause QT prolongation is constantly growing and being updated. The review contains current data on the clinical significance of the control of QT interval duration within drug therapy. Clinical conditions associated with an increased risk of QT interval prolongation are described. Drugs that can induce QT prolongation are also discussed.
International Journal of Clinical Pharmacology and Therapeutics · 2020 · 4 citations
Relationship between serum bepridil concentration and corrected QT interval
AbstractOBJECTIVE: Bepridil prolongs the QT interval and can induce torsade de pointes. Although increased bepridil concentration may be a primary cause of prolonged QT, the relationship between serum bepridil concentration and prolonged QT remains unclear. We investigated the relationship between serum bepridil concentration and the corrected QT (QTc) interval in patients treated with bepridil. MATERIALS AND METHODS: A retrospective study was performed at the National Cerebral and Cardiovascular Center in Japan. Patients with atrial fibrillation who were treated with bepridil from January 2014 to December 2015 were enrolled in the study. Serum bepridil concentrations and electrocardiogram data collected more than 21 days after the initiation of bepridil were used for analysis. RESULTS: A total of 60 patients were included in this study. There was a significant difference in mean QTc interval before and after initiation of bepridil (p < 0.0001). A significant relationship was observed between bepridil dose (p = 0.014) or serum bepridil concentration (p < 0.001) and QTc interval. Additionally, a significant relationship was observed between serum bepridil concentration and ΔQTc (p = 0.034). In the study, 4 patients developed QTc prolongation ≥ 500 ms after the initiation of bepridil. Serum bepridil concentration in this group was significantly higher compared with the group that did not display prolonged QTc (973 ± 651 vs. 526 ± 310 ng/mL, p = 0.01). CONCLUSION: This study revealed that the QTc interval was significantly associated with serum bepridil concentration. Serum bepridil concentration beyond a therapeutic range may be a critical risk factor for developing QTc prolongation.
Antimicrobial Agents and Chemotherapy · 2022 · 3 citations · open access
Development and Validation of a Nomogram for Prediction of QT Interval Prolongation in Patients Administered Bedaquiline-Containing Regimens in China: a Modeling Study
AbstractCorrected QT duration (QTc) interval prolongation is the most frequent adverse event associated with bedaquiline (BDQ) use. It may affect the safety of antituberculosis therapy, which leads to the consequent demands of needing to monitor during therapy. Our objective was to establish and validate a prediction model for estimating the risk of QTc prolongation after initiation of BDQ-containing regimens to multidrug-resistant tuberculosis (MDR-TB) patients. We constructed an individualized nomogram model based on baseline demographic and clinical characteristics of each patient within a Chinese cohort during BDQ treatment. The generalizability of this model was further validated through use of externally acquired data obtained from Beijing Chest Hospital from 2019 to 2020. Overall, 1,215 and 165 patients were included in training and external validation cohorts, respectively, whereby during anti-TB drug treatment, QTc prolongation was observed in 273 (22.5%) and 29 (17.6%) patients within these respective cohorts, for whom QTc values were >500 ms in 86 (31.5%) and 10 (34.7%) patients, respectively. Next, a total of four Cox proportional hazards models were created and assessed; then, nomograms derived from the models were plotted based on independent predictors of clofazimine, baseline QTc interval, creatinine, extensive drug-resistance (XDR), moxifloxacin, levofloxacin, and sex. Nomogram analysis revealed concordance index values of 0.723 (95% confidence interval [CI], 0.695 to 0.750) for the training cohort and 0.710 (95% CI, 0.627 to 0.821) for the external validation cohort, thus indicating relatively fair agreement between predicted and observed probabilities of QTc prolongation occurrence based on data obtained during 8-week, 16-week, and 24-week anti-TB treatment of both cohorts. Taken together, results obtained using these models demonstrated that coadministration of clofazimine and abnormal baseline QTc interval significantly contributed to QTc prolongation development during MDR-TB patient treatment with a BDQ-containing anti-TB treatment regimen.
Molecularly targeted agents and QT interval prolongation
AbstractUtilization of molecularly targeted agents has induced various of drug adverse effects which are different from conventional chemotherapy. QT interval prolongation is one of them,it can induce fatal ar-rhythmia. Molecularly targeted agents that can prolong QT interval include histone deacetylase inhibitors, multi-targeted tyrosinc kinase inhibitors, vascular disruption agents,farnesyl protein transferase inhibitors,Src/Abl ki-nase inhibitors and protein kinase C inhibitors.
Key words:
Neoplasms; Drug therapy; Long QT syndrome
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
