Risk Of QT Interval Prolongation Research Articles

Potential drug-drug interactions and associated factors among hospitalized pediatric patients in Adigrat general hospital, Tigrai, north Ethiopia: a retrospective cross-sectional study

BackgroundDrug-drug interactions (DDIs) are associated with increased or decreased adverse effects and decreased or decreased therapeutic effects. Hospitalized pediatric patients are exposed to a number of potential DDIs (pDDIs). There are limited studies on pDDIs among pediatric patients in Ethiopia. This study was aimed to evaluate the pDDIs and associated factors among hospitalized pediatric patients in Adigrat general hospital, Tigrai, northern Ethiopia.MethodsA retrospective cross-sectional study was carried out among hospitalized pediatric patients in Adigrat general hospital from 01 July 2020 to 31 August 2020. A simple random sampling technique was used to select medical charts. Micromedex 2.0 database was used to screen pDDIs. Data was analyzed using statistical package for social science version 21 and a P-value of ≤ 0.05 was considered statistically significant.ResultsOf the total 146 patients studied, 100 (68.5%) were exposed for at least one pDDI. A total of 158 pDDIs consisting of 33 distinct interacting drug pairs were identified. About 19.3% of the patients had at least one major pDDI, 6.7% at least one moderate and 68.9% at least one minor pDDIs. On the other hand, 63.3% of the total pDDIs were minor and 25.9% major while 3. 8% were contraindicated pDDIs with 15.2% fair and 81.6% good level of documentation. The overall mean duration of pDDIs exposure was about 4.9 (1-23) days. The frequently occurring potential clinical consequences of pDDIs comprised increased risk of QT-interval prolongation (10.1%), theophylline toxicity (5.1%), antiepileptic toxicity (5.1%) and formation of ceftriaxone calcium precipitates (3.8%). Infant/toddler age group (adjusted odds ratio [AOR] = 31.961, 95% CI: 1.117-914.528), number of diseases (AOR = 0.255, 95% CI: 0.069-0.939) and polypharmacy (AOR = 0.276, 95% CI: 0.091-0.838) were associated with pDDIs exposures.ConclusionsA large number of pediatric patients were exposed to a various pDDIs. Age, number of diseases and polypharmacy predicted for the occurrence of pDDIs. Besides, the major severity pDDIs encounted frequently in the current study can potentially lead to a life threatening cardio-vascular toxicicty from QT-interval prolongation. Clinicians should be vigilant to pDDIs to prevent potential clinical consequences of pDDIs. Moreover, computerized drug interaction screening and clincal pharmacy services should be practiced to improve patients’ safety.

Dofetilide, sotalol: risk of QT-interval prolongation in patients with heart failure with preserved ejection fraction

Dofetilide, sotalol: risk of QT-interval prolongation in patients with heart failure with preserved ejection fraction

Drug-induced QT interval prolongation in patients with heart failure with preserved ejection fraction.

Heart failure (HF) with reduced ejection fraction (HFrEF) is a risk factor for drug-induced QT interval prolongation. It is unknown if HF with preserved ejection fraction (HFpEF) is also associated with an increased risk. Dofetilide and sotalol are potent QT interval-prolonging agents that are frequently used in patients with HFpEF, in whom atrial fibrillation is a common comorbidity. We tested the hypothesis that the risk of QT interval prolongation associated with dofetilide and sotalol is increased in patients with HFpEF. We conducted a retrospective cohort study conducted using electronic health records from the Indiana Network for Patient Care (January 31, 2010 -May 3, 2021). After removing patients with overlapping diagnoses of HFpEF and HFrEF, no diagnosis code, and absence of QT interval records, we identified patients taking dofetilide or sotalol among three groups: HFrEF (n = 138), HFpEF (n = 109), and no HF (n = 729). QT prolongation was defined as heart rate-corrected QT (QTc) > 500 ms during dofetilide/sotalol therapy. Unadjusted odds ratios (OR) for QT prolongation were determined by univariate analysis. Adjusted ORs were determined by generalized estimating equations (GEE) with logit link to account for an individual cluster with different times of hospitalization and covariates. QTc prolongation associated with dofetilide or sotalol occurred in 53.2%, 71.7% and 30.0% of patients with HFpEF, HFrEF, and patients with no HF, respectively. After adjusting for age, sex, race, serum potassium and magnesium concentrations, kidney function, concomitant drug therapy, and comorbid conditions, the adjusted odds of QTc prolongation were significantly higher in patients with HFpEF [OR = 1.98 (95% CI 1.17-3.33)], and in those with HFrEF [OR = 5.23, (3.15-8.67)], compared to those with no evidence of HF. The odds of QT prolongation among inpatients receiving dofetilide or sotalol were increased in patients with HFpEF and HFrEF compared to those who did not have HF.

Risk of corrected QT interval prolongation in patients receiving antipsychotics.

Antipsychotic (AP) use has been associated to QT interval prolongation on the surface electrocardiogram (ECG). Our study aimed to determine the incidence of corrected QT (QTc) interval prolongation among patients admitted to a psychiatric hospitalization unit requiring AP treatment and to assess the relationship between administered dose and QTc interval changes. We enrolled 179 patients admitted to the Hospital Psiquiátrico Departamental Universitario del Valle in Cali, Colombia. ECGs were conducted upon admission, and again at 3 and 7 days postadmission. The QT interval was measured, and QTc interval correction was performed using Bazzet's formula. QTc interval prolongation at time points B or C was observed in 9.5% of patients. Clozapine was the most common AP associated with QTc interval prolongation (20.59%), followed by olanzapine (15.38%). The relative risk of QT interval prolongation with clozapine compared to haloperidol was 4.17 (95% confidence interval, 1.14-15.17, P = 0.02). AP use upon hospital admission was linked to early (within 3 days) QTc interval prolongation. Clozapine and olanzapine were associated with a greater increase in QTc interval compared to haloperidol, indicating a need for rigorous electrocardiographic monitoring with their use.

Lisdexamfetamine-related risk of QT-interval prolongation

Lisdexamfetamine-related risk of QT-interval prolongation

A real-world pharmacovigilance study of drug-induced QT interval prolongation: analysis of spontaneous reports submitted to FAERS.

To identify the most commonly reported drugs associated with QT interval prolongation in the FDA Adverse Event Reporting System (FAERS) and evaluate their risk for QT interval prolongation. We employed the preferred term (PT) "electrocardiogram QT prolonged" from the Medical Dictionary for Regulatory Activities (MedDRA) 26.0 to identify adverse drug events (ADEs) of QT interval prolongation in the FAERS database from the period 2004-2022. Reporting odds ratio (ROR) was performed to quantify the signals of ADEs. We listed the top 40 drugs that caused QT interval prolongation. Among them, the 3 drugs with the highest number of cases were quetiapine (1,151 cases, ROR = 7.62), olanzapine (754 cases, ROR = 7.92), and citalopram (720 cases, ROR = 13.63). The two most frequently reported first-level Anatomical Therapeutic Chemical (ATC) groups were the drugs for the nervous system (n = 19, 47.50%) and antiinfectives for systemic use (n = 7, 17.50%). Patients with missing gender (n = 3,482, 23.68%) aside, there were more females (7,536, 51.24%) than males (5,158, 35.07%) were involved. 3,720 patients (25.29%) suffered serious clinical outcomes resulting in deaths or life-threatening conditions. Overall, most drugs that caused QT interval prolongation had early failure types according to the assessment of the Weibull's shape parameter (WSP) analysis. Our study offered a list of drugs that frequently caused QT interval prolongation based on the FAERS system, along with a description of some risk profiles for QT interval prolongation brought on by these drugs. When prescribing these drugs in clinical practice, we should closely monitor the occurrence of ADE for QT interval prolongation.

Comparison of QTc interval changes in drug-resistant tuberculosis patients on delamanid-containing regimens versus shorter treatment regimens.

Delamanid (DLM) is a relatively new drug for drug-resistant tuberculosis (DR-TB) that has been used in Indonesia since 2019 despite its limited safety data. DLM is known to inhibit hERG potassium channel with the potential to cause QT prolongation which eventually leads to Torsades de pointes (TdP). This study aims to analyse the changes of QTc interval in DR-TB patients on DLM regimen compared to shorter treatment regimens (STR). A retrospective cohort was implemented on secondary data obtained from two participating hospitals. The QTc interval and the changes in QTc interval from baseline (ΔQTc) were assessed every 4 weeks for 24 weeks. The maximum increased of QTc interval and ΔQTc interval were smaller in the DLM group with mean difference of 18,6 (95%CI 0.3 to 37.5) and 31.6 milliseconds (95%CI 14.1 to 49.1) respectively. The proportion of QTc interval prolongation in DLM group were smaller than STR group (RR=0.62; 95%CI 0.42 to 0.93). This study has shown that DLM regimens are less likely to increase QTc interval compared to STR. However, close monitoring of the risk of QT interval prolongation needs to be carried out upon the use of QT interval prolonging antituberculoid drugs.

Practice recommendations to manage Alzheimer’s disease based on the targeted behavioral and psychological symptoms

IntroductionBehavioral and psychological symptoms (BPS) of Alzheimer’s disease, known as neuropsychiatric symptoms, involve a range of symptoms that include agitation, psychosis (hallucinations, delusions), affective symptoms (depression and anxiety), apathy, and sleep disturbances. These behavioral and psychological symptoms harm the patients’ daily lives and significantly burden their families. Managing BPS of Alzheimer’s disease requires a targeted approach focused on each symptom to achieve a better therapeutic response.ObjectivesProviding practice pharmacological recommendations targeted to each of the behavioral and psychological symptoms of Alzheimer’s disease.MethodsA literature review was conducted using Medline via PubMed, Embase, PsycINFO, and Cochrane databases until September 2023.ResultsThere is a consensus in the literature that non-pharmacological approaches should be recommended as the first-line treatment for most behavioral and psychological symptoms of Alzheimer’s.Second-generation antipsychotics (risperidone and olanzapine, with improved efficacy; aripiprazole and quetiapine, with better tolerance) are recommended for severe agitation states with a risk of self or hetero-aggression, as well as for persistent psychotic symptoms in Alzheimer’s disease. The benefit-risk balance of these agents must be assessed, with close monitoring of heart arrhythmias, metabolic risk, orthostatic hypotension, and extrapyramidal symptoms. The recommendations suggest tapering antipsychotics within the first three months of their prescription. Selective serotonin reuptake inhibitors (SSRIs) such as Escitalopram, Citalopram, and Sertraline can be considered a therapeutic option for persistent affective symptoms (depression and anxiety) with significant functional impairment or suicidal risk, severe apathy, or constant agitation. Minimum effective doses are recommended for Escitalopram and Citalopram due to the risk of QT interval prolongation. There is limited evidence regarding the effectiveness of benzodiazepines, mood stabilizers, cholinesterase inhibitors, and memantine for various behavioral and psychological symptoms; the benefit-risk ratio and therapeutic response do not support the prescription of these agents. Melatonin and Mirtazapine have limited benefits for sleep disturbances, while benzodiazepines, antihistamines, and antipsychotics should be avoided.ConclusionsThe pharmacological approach should target a thorough clinical assessment of the psychopathological dimensions of behavioral and psychological symptoms of Alzheimer’s disease. The prescription should be based on evaluating the benefit-risk balance and adherence to literature recommendations for patient safety.Disclosure of InterestNone Declared

A case with a trend of QT interval prolongation due to the introduction of methadone to a pancreatic cancer patient on levofloxacin

BackgroundAs methadone can prevent the development of opioid resistance, it has application in alleviating cancer-related pain that proves challenging to manage with other opioids. QT interval prolongation is a serious side effect of methadone treatment, with some reported deaths. In particular, owing to the increased risk of QT interval prolongation, caution should be exercised when using it in combination with drugs that also prolong the QT interval.Case presentationThis study presents a case in which methadone was introduced to a patient (a man in his 60s) already using levofloxacin, which could prolong the QT interval—a serious side effect of methadone treatment—and whose QTc value tended to increase. Given that levofloxacin can increase the risk of QT interval prolongation, we considered switching to other antibacterial agents before introducing methadone. However, because the neurosurgeon judged that controlling a brain abscess was a priority, low-dose methadone was introduced with continuing levofloxacin. Owing to the risks, we performed frequent electrocardiograms. Consequently, we responded before the QTc increased enough to meet the diagnostic criteria for QT interval prolongation. Consequently, we prevented the occurrence of drug-induced long QT syndrome.ConclusionsWhen considering the use of methadone for intractable cancer pain, it is important to eliminate possible risk factors for QT interval prolongation. However, as it may be difficult to discontinue concomitant drugs owing to comorbidities, there could be cases in which the risk of QT interval prolongation could increase, even with the introduction of low-dose methadone. In such cases, frequent monitoring, even with simple measurements such as those used in this case, is likely to prevent progression to more serious conditions.

PPARγ Agonist Pioglitazone Prevents Hypoxia-induced Cardiac Dysfunction by Reprogramming Glucose Metabolism.

The heart relies on various defense mechanisms, including metabolic plasticity, to maintain its normal structure and function under high-altitude hypoxia. Pioglitazone, a peroxisome proliferator-activated receptor γ (PPARγ), sensitizes insulin, which in turn regulates blood glucose levels. However, its preventive effects against hypoxia-induced cardiac dysfunction at high altitudes have not been reported. In this study, pioglitazone effectively prevented cardiac dysfunction in hypoxic mice for 4 weeks, independent of its effects on insulin sensitivity. In vitro experiments demonstrated that pioglitazone enhanced the contractility of primary cardiomyocytes and reduced the risk of QT interval prolongation under hypoxic conditions. Additionally, pioglitazone promoted cardiac glucose metabolic reprogramming by increasing glycolytic capacity; enhancing glucose oxidation, electron transfer, and oxidative phosphorylation processes; and reducing mitochondrial reactive ROS production, which ultimately maintained mitochondrial membrane potential and ATP production in cardiomyocytes under hypoxic conditions. Notably, as a PPARγ agonist, pioglitazone promoted hypoxia-inducible factor 1α (HIF-1α) expression in hypoxic myocardium. Moreover, KC7F2, a HIF-1α inhibitor, disrupted the reprogramming of cardiac glucose metabolism and reduced cardiac function in pioglitazone-treated mice under hypoxic conditions. In conclusion, pioglitazone effectively prevented high-altitude hypoxia-induced cardiac dysfunction by reprogramming cardiac glucose metabolism.

Effect of QT interval-prolonging drugs taken in pregnancy on the neonatal QT interval.

Introduction: Acquired QT interval prolongations due to drug side effects can result in detrimental arrhythmia. Maternal use of placenta-permeable drugs may lead to fetal exposure, thus leading to an increased risk of neonatal QT prolongation and arrhythmia. Objectives: This study aimed to evaluate the influence of maternal QT-prolonging medication on the neonatal QT interval. Methods: In the prospective KUNO-Kids health study, an ongoing population-based birth cohort, we classified maternal medications according to the known risk of QT interval prolongation. Effects on the neonatal QT interval were tested by linear regression analyses, correcting for perinatal confounders (birth weight, gestational age, birth mode, and age at ECG recording). Subgroup analyses were performed for selective serotonin reuptake inhibitors, proton pump inhibitors, and antihistamine dimenhydrinate. Logistic regression analysis was performed using a QTc of 450ms as the cut-off value. Results: A total of 2,550 pregnant women received a total of 3,990 medications, of which 315 were known to increase the risk of QT prolongation, resulting in 105 (4.1%) neonates exposed in the last month of pregnancy. Overall, the mean age of the neonates at ECG was 1.9 days and the mean QTc (Bazett) was 414ms. Univariate (regression coefficient -2.62, p = 0.288) and multivariate (regression coefficient -3.55, p = 0.146) regression analyses showed no significant effect of fetal medication exposure on the neonatal QT interval, neither in the overall nor in the subgroup analysis. Logistic regression analysis showed no association of exposure to maternal medication with an increased risk of neonatal QT interval prolongation (OR (odds ratio) 0.34, p = 0.14). Conclusion: The currently used maternal medication results in a relevant number of fetuses exposed to QT interval-prolonging drugs. In our cohort, exposure was found to have no effect on the neonatal QT interval.

Effects of hydroxychloroquine on atrial electrophysiology in in silico wild-type and PITX2+/- atrial cardiomyocytes.

Hydroxychloroquine (HCQ) is commonly used in the treatment of autoimmune diseases and increases the risk of QT interval prolongation. However, it is unclear how HCQ affects atrial electrophysiology and the risk of atrial fibrillation (AF). We quantitatively examined the potential atrial arrhythmogenic effects of HCQ on AF using acomputational model of human atrial cardiomyocytes. We measured atrial electrophysiological markers after systematically varying HCQ concentrations. The HCQ concentrations were positively correlated with the action potential duration (APD), resting membrane potential, refractory period, APD alternans threshold, and calcium transient alternans threshold (p < 0.05). By contrast, HCQ concentrations were inversely correlated with the maximum upstroke velocity and calcium transient amplitude (p < 0.05). When the therapeutic concentration (Cmax) of HCQ was applied, HCQ increased APD90 by 1.4% in normal sinus rhythm, 1.8% in wild-type AF, and 2.6% in paired-like homeodomain transcription factor2 (PITX2)+/- AF, but did not affect the alternans thresholds. The overall in silico results suggest no significant atrial arrhythmogenic effects of HCQ at Cmax, instead implying apotential antiarrhythmic role of low-dose HCQ in AF. However, at an HCQ concentration of fourfold Cmax, arapid pacing rate of 4 Hz induced prominent APD alternans, particularly in the PITX2+/- AF model. Our in silico analysis suggests a potential antiarrhythmic role of low-dose HCQ in AF. Concomitant PITX2 mutations and high-dose HCQ treatments may increase the risk of AF, and this potential genotype/dose-dependent arrhythmogenic effect of HCQ should be investigated further.

The Association of Proton Pump Inhibitors and QT Interval Prolongation in Critically Ill Patients.

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.

Linezolid and the risk of QT interval prolongation: A pharmacovigilance study of the Food and Drug Administration Adverse Event Reporting System.

Few studies have investigated linezolid (LZD)-associated cardiotoxicity. This study explored the potential association between LZD and QT interval prolongation. Adverse event reports of QT interval prolongation associated with LZD from the Food and Drug Administration Adverse Event Reporting System from January 2013 to December 2021 were analysed and the reporting odds ratio (ROR) with 95% confidence intervals were calculated. A total of 6738 adverse event reports of LZD as the primary and secondary suspected drug were obtained from the database, including 192 reports with electrocardiogram QT prolonged (QTp), and the ROR value was 26.1 (95% CI = 22.6-30.2). There were 8 reports of long QT syndrome, ROR 14.2 (95% CI =7.1-28.5); 5 reports of torsade de pointes, ROR 3.2 (95% CI =1.3-7.6); and 5 reports of ventricular tachycardia, ROR 1.9 (95% CI =0.8-4.5). Subgroup analysis revealed that patients with tuberculosis treated with LZD had a higher reporting rate among all QTp reports, exhibiting an odds ratio of 330.0 (95% CI = 223.1-488.1). The odds ratios of QTp associated with LZD treatments in patients with and without tuberculosis were 4.2 (95% CI =3.4-5.3) and 1.2 (95% CI =0.8-1.6), respectively. The study showed an association between LZD and QT interval prolongation. In the report on patients with tuberculosis, the incidence of QTp was higher when treated with LZD.

Abstract 13289: Risk of QT Interval Prolongation Associated With Dofetilide and Sotalol in Patients With Heart Failure With Preserved Ejection Fraction

Introduction: Heart failure (HF) with reduced ejection fraction (HFrEF) is a risk factor for drug-induced QT interval prolongation. It is unknown if HF with preserved ejection fraction (HFpEF) also increases the risk. Dofetilide (D) and sotalol (S) are potent QT interval-prolonging agents that are commonly used in patients with HFpEF, in whom atrial fibrillation is a common comorbidity. Hypothesis: The risk of QTc prolongation associated with D or S (D/S) is increased in patients with HFpEF. Methods: The data source was electronic health records from the Indiana Network for Patient Care (February 2010 to May 2021). After removing patients with overlapping diagnoses of HFpEF and HFrEF, no diagnosis code, absence of QT interval records, and no validated record of using D/S, we identified patients taking D/S among three groups: HFrEF (n=138), HFpEF (n=109), and no HF (n=729). Cochran-Mantel-Haenszel statistics were used to compare baseline characteristics. QT interval prolongation was defined as heart rate-corrected QT (QTc) &gt; 500 ms during D/S therapy. Unadjusted odds ratios (OR) of QT interval prolongation were determined by univariate analysis, and adjusted ORs were determined by generalized estimating equations (GEE) with logit link to account for an individual cluster with different times of hospitalization and covariates. Results: QTc prolongation associated with D/S occurred in 51.2% of patients with HFpEF, 70.1% of patients with HFrEF, and 29.4% of patients with no HF. After adjusting for age, sex, race, serum potassium and magnesium concentrations, kidney function, concomitant drug therapy, and comorbid conditions, the adjusted odds of QTc prolongation were significantly higher in patients with HFpEF, as well as in those with HFrEF, compared to those with no evidence of HF (Table). Conclusions: The odds of QT interval prolongation among inpatients receiving D/S were increased in patients with HFpEF and HFrEF compared to those who did not have HF.

Use of Drugs Associated with QT Interval Prolongation at the Hospital Level during the COVID-19 Pandemic in Colombia.

Background Many of the therapeutic proposals for COVID-19 have been associated with adverse effects, including the risk of QT interval prolongation and torsades de pointes (TdP). The objective was to determine the use of drugs with a risk of QT interval prolongation in 21 clinics/hospitals in Colombia from January to December 2020. Methods This cross-sectional study identified drug use according to pharmacological groups with potential risk of QT interval prolongation according to a risk classification: conditional, possible, and known risk of TdP. Descriptive analyses were performed. Results A total of 355,574 patients who received QT-prolonging drugs were identified (equivalent to 51.4% of all inpatients treated during the study period). Of the group of patients on QT drugs, 54.4% used at least one drug with conditional risk, 52.6% with possible risk, and 40.3% with known risk. The most commonly used belonged to the group of drugs for the nervous system (63.0%), alimentary tract and metabolism (56.8%), anti-infectives for systemic use (13.0%), and the cardiovascular system (11.7%). On average, patients received 2.0 ± 1.5 risk drugs. Regarding drugs initially considered against COVID-19, 2,120 patients (0.6%) received azithromycin, 802 (0.2%) received chloroquine, 517 received hydroxychloroquine (0.1%), and 265 received lopinavir/ritonavir (0.1%). Conclusion The high proportion of patients treated at the hospital level who receive drugs with risk of prolonging the QT interval should alert those responsible for their care to avoid fatal outcomes, especially during the COVID-19 epidemic, when some QT drugs are being used more frequently.

QTc Prolongation in Poison Center Exposures to CredibleMeds List of Substances with "Known Risk of Torsades de Pointes".

Many drugs carry some risk of QT interval prolongation, which can lead to life-threatening dysrhythmias including Torsades de Pointes (TdP). CredibleMeds.org identifies medications categorized as "Known Risk of TdP" but does not stratify risk in acute supratherapeutic ingestions. We sought to determine the proportion of cases exhibiting QTc prolongation and life-threatening dysrhythmias including ventricular tachycardia (VT)/ventricular fibrillation (VF), TdP, and asystole in patients exposed to these substances. Retrospective chart review of cases reported to our Regional Poison Center from 2014 to 2019 of exposures to one or more of the "Known Risk" substances was performed. Demographics, therapies, clinical effects, and medical outcome for each case were analyzed. There were 1125 exposures, of which 760 had a documented QTc interval. QTc ≥ 500ms was reported in 138 (18.2%) of the 760 cases. The most common "Known Risk" substances were citalopram, escitalopram and cocaine. Although not in the "Known Risk" category, mirtazapine, amitriptyline, diphenhydramine, and trazodone had a statistically significant association with QTc > 500ms. Life-threatening dysrhythmias occurred in 13 cases, with VT/VF in 6 of the 760 (0.8%) cases, and one case of TdP. Flecainide (OR 11.1, 95% CI 2.2-55.8) and methadone (OR 7.1, 95% CI 2.1-23.4) were associated with increased risk of all life-threatening dysrhythmias. Exposures to medications on the Credible Meds list of "Known Risk of TdP" QTc prolongation is common, but life-threatening dysrhythmias are rare. Mirtazapine, amitriptyline, diphenhydramine, and trazodone were associated with prolonged QTc. Flecainide and methadone had the highest associated risk of life-threatening dysrhythmias.

Cholinesterase inhibitors: risk of QT-interval prolongation, torsade de pointes

Cholinesterase inhibitors: risk of QT-interval prolongation, torsade de pointes

Identifying Acute Cardiac Hazard in Early Drug Discovery Using a Calcium Transient High-Throughput Assay in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

Introduction: Early identification of cardiac risk is essential for reducing late-stage attrition in drug development. We adapted the previously published cardiac hazard risk-scoring system using a calcium transient assay in human stem cell-derived CMs for the identification of cardiac risks recorded from the new hiPSC-CM line and investigated its predictivity and translational value based on the screening of a large number of reference and proprietary compounds. Methods: Evaluation of 55 reference drugs provided the translation of various pharmacological effects into a single hazard label (no, low, high, or very high hazard) using a Ca2+-sensitive fluorescent dye assay recorded by -by FDSS/µCell Functional Drug Screening System (Hamamatsu on hiPSC-CM line (FCDI iCell Cardiomyocytes2). Results: Application of the adapted hazard scoring system in the Ca2+ transient assay, using a second hiPS-CM line, provided comparable scoring results and predictivity of hazard, to the previously published scoring approach, with different pharmacological drug classes, as well as screening new chemical entities (NCE’s) using a single hazard label from four different scoring levels (no, low, high, or very high hazard). The scoring system results also showed minimal variability across three different lots of hiPSC-CMs, indicating good reproducibility of the cell line. The predictivity values (sensitivity and specificity) for drug-induced acute cardiac risk for QT-interval prolongation and Torsade de pointes (TdPs) were >95% and statistical modeling confirmed the prediction of proarrhythmic risk. The outcomes of the NCEs also showed consistency with findings in other well-established in vitro and in vivo cardiac risk assays. Conclusion: Evaluation of a large list of reference compounds and internal NCEs has confirmed the applicability of the adaptations made to the previously published novel scoring system for the hiPSC-CMs. The validation also established the predictivity for drug-induced cardiac risks with good translation to other established preclinical in vitro and in vivo assays, confirming the application of this novel scoring system in different stem cell-CM lines for early cardiac hazard identification.

Improving the treatment of Parkinson's disease: Structure-based development of novel 5-HT2A receptor antagonists/inverse agonists

Pimavanserin is a selective 5-HT2A receptor antagonist and inverse agonist approved by the FDA in 2016, which is used to treat patients with Parkinson's disease psychosis (PDP). But pimavanserin has potential risk with increasing mortality in elderly patients and also increasing the risk of QT interval prolongation in patients. Therefore, searching for new drugs with high efficacy and low toxicity is urgently needed. Based on the docking study of pimavanserin, a series of novel pimavanserin derivatives (7–1∼7–37) were designed and synthesized. The biological activities were evaluated by cell assays and compound 7–16 exhibited 50-fold higher 5-HT2A receptor antagonist activity (IC50 = 0.54 vs 27.3 nM) and 23-fold higher inverse agonist activity (IC50 = 2.1 vs 50 nM) than pimavanserin. Moreover, 7–16 showed increased potency window between the 5-HT2A and hERG activities than pimavanserin. Furthermore, compound 7–16 demonstrated excellent in vitro and in vivo pharmacokinetics, 4-fold more improvement in functional activity in vivo, and good safety profile. Therefore, compound 7–16 represents a potentially promising candidate as a novel anti-PDP agent that warrants further investigation.