DeepHIT: a deep learning framework for prediction of hERG-induced cardiotoxicity.

Investigating cardiotoxicity related with hERG channel blockers using molecular fingerprints and graph attention mechanism

Chapter 7 - Predictive analytics for reducing the risk of QT interval prolongation and torsades de pointes

MP03-12 ACCURACY OF MULTIPARAMETRIC MR IMAGING WITH PI-RADS V2 ASSESSMENT IN DETECTING INFILTRATIONS OF THE NEUROVASCULAR BUNDLES PRIOR TO PROSTATECTOMY

Poor metabolic stability leads to drug development failure. Therefore, it is essential to evaluate the metabolic stability of small compounds for successful drug discovery and development. However, evaluating metabolic stability in vitro and in vivo is expensive, time-consuming and laborious. In addition, only a few free software programs are available for metabolic stability data and prediction. Therefore, in this study, we aimed to develop a prediction model that predicts the metabolic stability of small compounds. We developed a computational model, PredMS, which predicts the metabolic stability of small compounds as stable or unstable in human liver microsomes. PredMS is based on a random forest model using an in-house database of metabolic stability data of 1917 compounds. To validate the prediction performance of PredMS, we generated external test data of 61 compounds. PredMS achieved an accuracy of 0.74, Matthew's correlation coefficient of 0.48, sensitivity of 0.70, specificity of 0.86, positive predictive value of 0.94 and negative predictive value of 0.46 on the external test dataset. PredMS will be a useful tool to predict the metabolic stability of small compounds in the early stages of drug discovery and development. The source code for PredMS is available at https://bitbucket.org/krictai/predms, and the PredMS web server is available at https://predms.netlify.app. Supplementary data are available at Bioinformatics online.

Drug-induced QT interval prolongation has been reported to be related to life-threatening polymorphic ventricular tachycardia (torsade de pointes). Proton pump inhibitors (PPIs) are prescribed widely for hospitalized patients; the QT interval prolongation and torsade de pointes caused by PPIs were reported. We conducted a study to determine the association between PPI treatment and QT interval prolongation in critically ill patients. This study included patients with electrocardiography (ECG) reports from the Medical Information Mart for Intensive Care III database (MIMIC-III). Patients younger than 18years, missing baseline laboratories and with QT interval prolongation before intensive care unit (ICU) admission were excluded. The end point was the diagnosis of QT interval prolongation reported by ECG. This study included 24,512 ICU patients. Of them, 11,327 patients were treated with PPIs, 4181 with histamine 2 receptor antagonists (H2RAs) and 6351 without acid suppression therapy (non-AST); the incidence of QT interval prolongation were 8.5%, 3.3% and 3.4% respectively. After adjustment for demographics, electrolytes, comorbidities and medications, PPIs were associated a higher risk of QT interval prolongation compared with H2RAs (OR 1.66, 95% CI 1.36 - 2.03) and non-AST (OR 1.54, 95% CI 1.31 - 1.82), while there was not significant difference between H2RAs and non-AST (OR 0.93, 95% CI 0.73 - 1.17). In the propensity score matching population, the results were consistent. Pantoprazole (OR 2.14, 95% CI 1.52 - 3.03) and lansoprazole (OR 1.80, 95% CI: 1.18 - 2.76) showed a higher QT prolongation risk than omeprazole. Several drugs caused higher QT prolongation risk when used in combination with PPIs. In ICU patients, the association between PPI prescription and increased risk of QT interval prolongation was independent of known QT-prolonging factors; pantoprazole and lansoprazole had a higher risk compared with omeprazole. The combination of PPIs and other QT-prolonging drugs should be avoided.

Effects of β-adrenergic blockade on dispersion of ventricular repolarization in newborn infants with prolonged QT interval

Prolonged QT interval in acute psychotic patients

To evaluate the literature on protease inhibitor (PI)-associated QT interval prolongation and risk for torsade de pointes in patients infected by HIV. Primary literature was identified through MEDLINE (1950-August 2011) and EMBASE (1980-August 2011), using the following search terms: antiretroviral agents, HIV, protease inhibitors, QTc, QT prolongation, and torsade de pointes. English-language case reports of antiretroviral therapy-associated QT interval prolongation, studies of healthy volunteers, or studies that evaluated the impact of PIs on QT interval in patients infected with HIV were reviewed and selected. Article bibliographies and conference abstracts were also reviewed. Several case reports, as well as in vitro data, have implicated PIs as a potential cause of QT interval prolongation and/or torsade de pointes. Saquinavir, therapeutically boosted with the potent CYP3A4 inhibitor ritonavir, was the only PI shown to be associated with significant QT interval prolongation in studies with healthy volunteers. While 1 case control study in HIV-infected patients found that nelfinavir or efavirenz, a nonnucleoside reverse transcriptase inhibitor, increased the risk of QT interval prolongation, larger prospective studies have not demonstrated any significant increase in QT interval following exposure to PIs. Similar risk factors for QT interval prolongation seen in non-HIV-infected patients, such as older age, female sex, ethnicity, cardiac conditions, diabetes mellitus, and concomitant use of other QT interval-prolonging medications, especially methadone, were risk factors identified in studies of HIV-infected patients. PIs do not appear to independently predispose patients to QT interval prolongation. However, other risk factors (both HIV-related and non-HIV-related) may increase the risk of QT interval prolongation. Available data suggest that baseline and follow-up electrocardiogram monitoring are unnecessary precautions, but may be considered in patients who are initiating PI therapy and are on multiple medications with proarrhythmic potential and/or have multiple comorbidities, increasing the risk.

THU0307 Qt interval and its correlations with traditional risk factors of development of cardiovascular diseases in patients with active early psoriatic arthritis

QT interval prolongation of the electrocardiogram has been associated with the occurrence of life-threatening fatal ventricular arrhythmias. To understand the relationship between preclinical cardiac conduction assessment to clinical outcome, comparisons of free (unbound)-plasma drug concentrations and their associated effects in the conscious mongrel dog were made to the free plasma concentrations in humans reported to produce QT prolongation. E-4031 (an experimental class III antiarrhythmic), cisapride, terfenadine, terodiline, and verapamil all affect cardiac repolarization and can produce QT prolongation in humans. In the conscious dog, the QT interval was assessed on a beat-to-beat basis in relation to each preceding RR interval at concentrations approximating the same unbound human concentrations. E-4031, cisapride and terodiline statistically increased the QT(RR1000) interval [the QT interval at a 60 beats/min (bpm) heart rate] 23, 8, and 9 ms, respectively, at concentrations 0.3 to 15.8 times their relevant clinical level. Increases were not observed for terfenadine or verapamil (p > 0.05 at all doses). Inspection of individual dog QT versus RR interval relationships showed clear QT interval responses specific to each treatment but not readily apparent when data are averaged at a heart rate of 60 bpm. For specific rectifier K(+) current (IKr) blockers, robust effects on mean QT prolongation can be detected. However, for drugs that affect repolarization through multiple channels, the effect on the mean QT interval may be more difficult to detect. Inspection of the beat-to-beat QT-RR interval relationship in an individual animal can increase the sensitivity for more accurate clinical prediction.

Purpose: QT prolongation can occur with both first- (FGA) and second-generation antipsychotics (SGA). QT prolongation was identified in an adult patient who presented to the emergency room with schizophrenia, fluid and electrolyte imbalances, and pneumonia. Quetiapine, an SGA, was a component of the pharmacotherapy regimen. Based on the Naranjo adverse drug reaction probability scale rating criteria, a probable causal association was made. Methods: PubMed and Ovid were searched using the terms antipsychotic, psychotropic, QT interval, corrected QT interval (QTc) prolongation, and quetiapine. References were examined for additional articles related to antipsychotic drugs and the QT interval. Discussion: In this patient, the use of quetiapine was identified as a contributing factor in QT prolongation. Prior QT prolongation was experienced with ziprasidone, another SGA. The antidepressant and dose remained consistent throughout the inpatient course of treatment. Other risk factors in this patient included hypokalemia, dehydration, pneumonia, age, gender, and concurrent usage of an antidepressant. Dual psychiatric diagnoses, preexisting cardiovascular disease, and electrolyte disturbances may increase this risk potential. Conclusion: Psychiatric patients may be more at risk of cardiovascular complications, such as QT interval prolongation. The pharmacist can help evaluate risk factors and provide input into the care of all patients, particularly those identified as at risk.

Plasma leptin in treated patients with schizophrenia

Blockade of human ether-a-go-go-related gene (hERG) potassium channels is an undesirable activity of many drugs because it may be the primary cause for the prolongation of the QT interval, which appears to be associated with the induction of potentially life-threatening ventricular arrhythmias. Despite the fact that several antipsychotic drugs exert hERG-blocking activity that may underlie their propensity to cause electrocardiogram (ECG) abnormalities, including QT interval prolongation and associated ventricular arrhythmias, a considerable number of available typical and atypical antipsychotics have not been characterized for hERG-blocking activity. This study has evaluated the hERG-blocking activity of several of these antipsychotic drugs in human embryonic kidney cells (HEK293) stably transfected with the human recombinant hERG potassium channel and using a high throughput whole-cell patch-clamp technique to determine their respective IC(50) values. The ability of antipsychotics to competitively displace [(3)H]-astemizole binding from hERG-transfected HEK293 cells was also examined to properly establish the concentration range for testing in the subsequent patch clamp assays. The results showed that most of the tested antipsychotics effectively blocked the hERG channel in a dose-dependent manner, with IC(50) values ranging from 3.37 nM for the butyrophenone benperidol to >100 microM for the substituted benzamide sulpiride. Markedly, differential potencies were obtained depending on the chemical class, so that butyrophenones and diphenylbutylpiperidines emerged as the most potent hERG-blocking antipsychotics, while dibenzoxazepines and, particularly, substituted benzamides, exhibited the lowest activity. Because the hERG-blocking properties of drugs appear to be associated with their ability to prolong the QT interval, the present results will enable the establishment of the potential arrhythmogenic risk for each antipsychotic evaluated. Thus, their cardiotoxic risk will be discussed on the basis of their hERG-blocking properties and previous clinical data when available.

Risk stratification of sudden cardiac death in patients with coronary artery disease is of great importance. We evaluated the association between ventricular repolarization and induction of malignant ventricular arrhythmias on electrophysiological study of patients with coronary artery disease. A total of 177 patients (65±10.1 years, 83.6% male, mean left ventricular ejection fraction [LVEF] 37.5±13.6%) were analyzed. For each 10 ms increment in the QT interval, there was a 7% increase in malignant ventricular arrhythmias inducibility; QT cutoff point of 452 ms had an accuracy of 0.611 for predicting malignant ventricular arrhythmias (p=0.011). Male gender (odds ratio [OR]=4.18, p=0.012), LVEF <35% (OR=2.32, p=0.013), amiodarone use (OR=2.01, p=0.038), and prolonged QT (OR=1.07, p=0.023) were associated with malignant ventricular arrhythmias. In patients with ventricular dysfunction, QT >452 ms was associated with significantly increased risk of malignant ventricular arrhythmias (OR=5.44, p=0.0004). In those with LVEF ³35%, QT dispersion (QTd) was significantly higher in patients with inducible malignant ventricular arrhythmias. QTd >20 ms had 0.638 accuracy and 81.3% negative predictive value in predicting malignant ventricular arrhythmias. QT interval is an independent factor associated with malignant ventricular arrhythmias in patients with coronary artery disease. The combination of ventricular dysfunction and prolonged QT interval is associated with a 5.44-fold increase of malignant ventricular arrhythmias induction. Male gender, amiodarone use, and decreased left ventricular ejection fraction are also associated with increased risk of inducibility of malignant ventricular arrhythmias on the electrophysiological study.

Severe chronotropic insufficiency, while uncommon in psychiatric populations, presents unique challenges in patients with psychotic disorders because many antipsychotics can adversely affect cardiac rhythm by exacerbating bradycardia or prolonging the QT interval. This case report describes a young male with a complex psychiatric history, severe substance use disorder, and coexisting cardiac abnormalities, who presented with profound sinus bradycardia and a prolonged QT interval. The patient's psychiatric symptoms were compounded by medication nonadherence and illicit drug use. The patient had a history of profound sinus bradycardia (heart rates in the 20s to 30s) with a mean heart rate of 41 beats/min (SD = 4), yet remained asymptomatic from a cardiovascular perspective. Despite the presence of bradycardia and a prolonged QT interval (mean QT = 495 ms (66), QTcB = 427 (30) (Bazett), and QTcF = 448 (32) (Fridericia)), he was treated with oral olanzapine and valproate. His psychiatric symptoms improved significantly, with no exacerbation of bradycardia or QTc prolongation noted during treatment.This is a rare case of a hemodynamically stable young man treated with second-generation antipsychotics, without any notable effect on the length of the QT interval. QT prolongation is a side effect of many antipsychotics, and bradycardia tends to further prolong the QT interval, increasing the risk of adverse cardiac outcomes, such as torsades de pointes or sudden cardiac death, for patients taking antipsychotics. An interprofessional, interdisciplinary, and cohesive team can reduce the cardiac risk to the patient while effectively treating the underlying psychiatric disorders. Nonetheless, it is essential for psychiatrists to have a solid understanding of psychotropic medications and cardiac rhythms, particularly because many free-standing psychiatric facilities do not have direct access to a cardiology consult team. In this report, the authors will attempt to provide a structured framework for psychiatrists managing patients with bradycardia who require antipsychotic therapy.