Application of a probabilistic method for the determination of drug-induced QT prolongation in telemetered cynomolgus monkeys: Effects of moxifloxacin

2007 ◽  
Vol 55 (3) ◽  
pp. 244-254 ◽  
Author(s):  
Henry H. Holzgrefe ◽  
Icilio Cavero ◽  
Lewis V. Buchanan ◽  
Michael W. Gill ◽  
Stephen K. Durham
Keyword(s):  
Probabilistic Method ◽  
Qt Prolongation ◽  
Drug Induced ◽  
Cynomolgus Monkeys

DEFINITION OF TIME SPENT ON REPAIR OF BUS TRANSMISSION UNITS TAKING INTO ACCOUNT TECHNOLOGICAL EQUIPMENT RELIABILITY

2020 ◽  
Vol 2020 (9) ◽  
pp. 29-33
Author(s):  
Sergey Bulatov
Keyword(s):  
Negative Impact ◽  
Probabilistic Method ◽  
Technological Equipment ◽  
Quality And Safety ◽  
Transmission Unit ◽  
Equipment Reliability ◽  
Hours Of Work ◽  
Definition Of ◽  
Time Decrease

The paper purpose is the effectiveness estimation in the technological equipment use, taking into account its reliability and productivity for defective transmission units of buses. The problem consists in the determination of time to be spent on repair of bus transmission units taking into account technological equipment reliability. In the paper there is used a probabilistic method for the prediction bus transmission units, and also a method of the dynamics of averages which allow ensuring minimum of costs for units downtime during repair and equipment cost. The need for repair of transmission units (gear box) arises on an average after 650 hours, the average productivity of the bench makes 4.2 bus / hour. The bench fails on the average after 4600 hours of work, the average time of the bench makes 2 hours. In such a way the solution of the problem specified allows analyzing the necessity of time decrease for transmission unit repair to avoid long downtimes of buses in repair areas without negative impact upon high repair quality and safety during the further operation.

scholarly journals An explainable algorithm for detecting drug-induced QT-prolongation at risk of torsades de pointes (TdP) regardless of heart rate and T-wave morphology

2021 ◽  
Vol 131 ◽  
pp. 104281
Author(s):  
Alaa Alahmadi ◽  
Alan Davies ◽  
Jennifer Royle ◽  
Leanna Goodwin ◽  
Katharine Cresswell ◽  
...  
Keyword(s):  
At Risk ◽  
Heart Rate ◽  
Torsades De Pointes ◽  
Qt Prolongation ◽  
Drug Induced ◽  
T Wave ◽  
Wave Morphology

Obstructive Protein Cast Nephropathy in Cynomolgus Monkeys Treated with Small Organic Molecules

2008 ◽  
Vol 45 (6) ◽  
pp. 945-948 ◽  
Author(s):  
R. E. Guzman ◽  
K. Datta ◽  
N. K. Khan
Keyword(s):  
Renal Toxicity ◽  
Obstructive Nephropathy ◽  
Drug Induced ◽  
Cast Material ◽  
Small Organic Molecules ◽  
Cynomolgus Monkeys ◽  
Cast Nephropathy ◽  
Cynomolgus Macaques ◽  
Species Specific ◽  
Tubular Dilatation

We have observed a renal toxicity consistent with an obstructive protein cast nephropathy in cynomolgus macaques but not in other species treated with different therapeutic candidates having a common carboxylic acid moiety, suggesting a species-specific sensitivity. Here, we present renal toxicity findings consistent with a protein cast nephropathy in a 2–week safety study in cynomolgus monkeys. Light microscopic changes consisted of intratubular cast formation, tubular dilatation, interstitial inflammation, and expansion of the medullary interstitium. Tubular cast material was identified as Tamm-Horsfall protein (THP) and, on ultrastructure, crystalloid material was present in vacuoles of tubular epithelium. It is hypothesized that microcrystal formation in the urinary tubular spaces induces aggregation of THP protein and cast formation in monkeys. Drug-induced obstructive nephropathy is not identified as a major problem in humans; thus, the clinical relevance of the above findings in monkeys is not clear.

Drug-induced QT Prolongation Atlas (DIQTA) for enhancing cardiotoxicity management

2021 ◽  
Author(s):  
Shihai Li ◽  
Zili Xu ◽  
Mingkun Guo ◽  
Menglong Li ◽  
Zhining Wen
Keyword(s):  
Qt Prolongation ◽  
Drug Induced

Abstract 15056: Machine Learning Prediction of Long QT Syndrome

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Steven Simon ◽  
Divneet Mandair ◽  
Michael A Rosenberg ◽  
Premanand Tiwar
Keyword(s):  
Machine Learning ◽  
Classification Accuracy ◽  
Improve Patient Safety ◽  
Accurate Method ◽  
Qt Prolongation ◽  
Common Data Model ◽  
Qtc Interval ◽  
Drug Induced ◽  
Sensitivity Specificity ◽  
Physician Order Entry

Introduction: Drug-induced QT prolongation causes significant morbidity and mortality but could be preventable with prediction of susceptible individuals. Machine learning (ML) algorithms applied to electronic health record (EHR) data may provide a method for identifying these individuals and could be automated to directly alert providers of risk. This study applies ML techniques to EHR data to identify an integrated model that can be deployed to predict risk of drug-induced QT prolongation. Methods: We examined data from the UCHealth EHR that has been harmonized to the Observational Medical Outcomes Partnership common data model and identified inpatients who had received a medication known to prolong the QT interval and had an electrocardiogram (ECG) performed within 24 hours. We used a binary outcome of the development of a QTc interval > 500 ms by ECG within 24 hours of medication initiation or no ECG with a QTc interval > 500 ms throughout the encounter. We compared multiple machine learning methods (logistic regression, random forest, naïve Bayes, and deep neural network (DNN)) by classification accuracy as assessed by AUC and F 1 score. We performed calibration and scaling of the final model. Results: We identified 35639 inpatients who received a known QT-prolonging medication and had an ECG within 24 hours. Of those, 4558 patients developed a QTc > 500 ms and 31081 patients did not. The DNN model provided reasonable classification accuracy (F1 score 0.404; AUC 0.71) and was the most accurate method tested. A range of decision cutpoints were plotted with respective sensitivity/specificity (Figure 1). Conclusions: We found that by applying a DNN to EHR data, we could reasonably predict individuals susceptible to drug-induced QT prolongation. Varying cutpoints can be used to tailor the model to the desired sensitivity. Future studies are needed to validate this model in novel EHRs and within the physician order entry system to assess ability to improve patient safety.

scholarly journals Mechanisms of amphipath-induced stomatocytosis in human erythrocytes

Blood ◽  
1992 ◽  
Vol 79 (3) ◽  
pp. 782-786 ◽  
Author(s):  
SL Schrier ◽  
A Zachowski ◽  
PF Devaux
Keyword(s):  
Blood Cells ◽  
Shape Change ◽  
Drug Induced ◽  
Inhibiting Effect ◽  
Outer Leaflet ◽  
Human Red Blood Cells ◽  
Spin Resonance ◽  
Vanadate Inhibition

Abstract We studied stomatocytosis induced in human red blood cells (RBC) by vinblastine and chlorpromazine, monitoring the movements of spin- labeled phosphatidylcholine (PC*) and sphingomyelin (SM*) by electron spin resonance (ESR) spectroscopy. This technique allows determination of the fraction of labeled lipids, respectively, on the external leaflet, on the cytosol face, or trapped in endocytic vacuoles. Both vinblastine and chlorpromazine produce a time- and concentration- dependent stomatocytic shape change, which is paralleled by a shift of approximately 10% to 33% of outer leaflet SM* and PC* inward. Of this amount, 8% to 12% was trapped in endocytic vacuoles and 8% to 19% had flipped to the inner leaflet. Vanadate, while inhibiting the stomatocytosis, did not block the flip of either SM* or PC* to the inner leaflet. To explain the inhibiting effect of vanadate, as well as the adenosine triphosphate (ATP) requirement for drug-induced stomatocytosis, we propose the following model: (1) addition of amphipath partially scrambles the bilayer; and (2) the flop of phosphatidylserine (PS) and phosphatidylethanolamine (PE) to the outer leaflet provides substrate for the aminophospholipid translocase (APLT), which flips back PS and PE inward faster than PC or SM can diffuse outward--thereby producing inner layer expansion or stomatocytosis. This role of APLT accounts for the vanadate inhibition of amphipath stomatocytosis. However, the vanadate effect can be overcome by increasing the amphipath concentration, which at such levels probably passively expands the inner leaflet.

scholarly journals Drug-induced QT prolongation in COVID-19 pneumonia: influence on in-hospital survival

2021 ◽  
Vol 74 (1) ◽  
pp. 111-112
Author(s):  
Daniel García-Rodríguez ◽  
Paloma Remior ◽  
Eusebio García-Izquierdo ◽  
Jorge Toquero ◽  
Víctor Castro ◽  
...  
Keyword(s):  
Qt Prolongation ◽  
Drug Induced ◽  
Hospital Survival

scholarly journals Managing drug-induced QT prolongation in clinical practice

2020 ◽  
pp. postgradmedj-2020-138661
Author(s):  
Rani Khatib ◽  
Fatima R N Sabir ◽  
Caroline Omari ◽  
Chris Pepper ◽  
Muzahir Hassan Tayebjee
Keyword(s):  
Qt Interval ◽  
Simple Algorithm ◽  
Torsades De Pointes ◽  
Daily Practice ◽  
Qt Prolongation ◽  
Key Factors ◽  
Drug Induced ◽  
Electrolyte Disturbances ◽  
Related Risk ◽  
Life Threatening

Many drug therapies are associated with prolongation of the QT interval. This may increase the risk of Torsades de Pointes (TdP), a potentially life-threatening cardiac arrhythmia. As the QT interval varies with a change in heart rate, various formulae can adjust for this, producing a ‘corrected QT’ (QTc) value. Normal QTc intervals are typically <450 ms for men and <460 ms for women. For every 10 ms increase, there is a ~5% increase in the risk of arrhythmic events. When prescribing drugs associated with QT prolongation, three key factors should be considered: patient-related risk factors (eg, female sex, age >65 years, uncorrected electrolyte disturbances); the potential risk and degree of QT prolongation associated with the proposed drug; and co-prescribed medicines that could increase the risk of QT prolongation. To support clinicians, who are likely to prescribe such medicines in their daily practice, we developed a simple algorithm to help guide clinical management in patients who are at risk of QT prolongation/TdP, those exposed to QT-prolonging medication or have QT prolongation.

Two automated procedures for N-acetyl-beta-D-glucosaminidase determination evaluated for detection of drug-induced tubular nephrotoxicity.

1986 ◽  
Vol 32 (11) ◽  
pp. 2052-2055 ◽  
Author(s):  
M P Goren ◽  
R K Wright ◽  
S Osborne
Keyword(s):  
Enzymatic Activity ◽  
Methotrexate Therapy ◽  
Tubular Damage ◽  
Sample Treatment ◽  
Urine Ph ◽  
Drug Induced ◽  
Alkaline Urine ◽  
Automated Procedures ◽  
Drugs And Metabolites

Abstract We automated two procedures for determination of urinary N-acetyl-beta-D-glucosaminidase (NAG; EC 3.2.1.30) concentrations and evaluated their reliability for detecting drug-induced tubular damage in children receiving cisplatin, methotrexate, or ifosfamide. Results for 174 patient specimens correlated well (r = 0.98), but NAG concentrations determined by the m-cresolsulfonphthaleinyl (MCP) procedure were about 40% lower than those obtained with p-nitrophenyl-N-acetyl-beta-D-glucosaminide substrate. Dialysis and assay of 50 specimens disclosed no evidence of activators or inhibitors of enzymatic activity. Drugs and metabolites added to urine had negligible effect on NAG determinations; however, NAG was unstable in alkaline urine (pH greater than 8) associated with methotrexate therapy. Both procedures detect tubular damage equally well and neither requires laborious sample treatment. The MCP procedure, being more sensitive and not requiring a sample blank, is better suited for rapid automated assays. Comparisons of clinical data obtained by the two procedures require standardization against human NAG.

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