Kamil Fijorek

KinetDS: An Open Source Software for Dissolution Test Data Analysis

Because drug quality is the focus for pharmaceutical industry and regulatory agencies, the in vitro dissolution test bec omes a standard tool for characterization of manufactured products. However, results of the dissolution test must be expressed in mathematical terms; this is realized by fitting various models to the cumulative dissolution curves. The models might be either mechanistic or empirical. The fitting process requires software (e.g., KinetDS) for automation and determination of possible release mechanisms of drug substances from the dosage forms. The software is FOSS (Free Open Source Software) and is available at http://sourceforge.net/projects/kinetds/.

Inter-individual Variability in the Pre-clinical Drug Cardiotoxic Safety Assessment—Analysis of the Age–Cardiomyocytes Electric Capacitance Dependence

Electrical phenomena located within the plasma membrane of the mammalian cardiac cells are connected with the cells’ main physiological functions—signals processing and contractility. They were extensively studied and described mathematically in so-called Hodgkin–Huxley paradigm. One of the physiological parameters, namely cell electric capacitance, has not been analyzed in-depth. The aim of the study was to validate the mechanistic model describing the capacitive properties of cells, based on a collected experimental dataset which describes the electric capacitance of human ventricular myocytes. The gathered data was further utilized for developing an empirical correlation between a healthy individual’s age and cardiomyocyte electric capacitance.

Virtual population generator for human cardiomyocytes parameters: in silico drug cardiotoxicity assessment

Background: The anatomical and histological parameters of the human ventricle depend on many factors including age and sex. Myocyte volume and electric capacitance are significant physiological parameters of left ventricle cardiomyocyte mathematical models. They allow the assessment of inter-individual variability during in vitro–in vivo extrapolation of the drug cardiotoxic effect. Objective: The current research was carried out to analyze the relationship between age, human left ventricle cardiomyocyte volume, and electric capacitance in a healthy population. Methods: In order to collect data describing cardiomyocyte volume and membrane area, literature searches were performed. It was assumed that the cardiomyocyte volume (VOL) and area (AREA) distribution have non-negative support and are skewed to the right. A log-linear model with constant variance was used. A simulation study was run to assess the influence of physiological parameters on action potential duration. Results: The coefficient of determination for the proposed model R2 = 0.95, that is, 95% of the variability observed in log cardiomyocyte volume can be explained by the estimated regression equation. To allow simple calculation and model performance validation, a simple Excel file was developed (Supplementary material). Conclusions: To the best of our knowledge, there is no other model available, combining age, cardiomyocyte volume, and area. The main limitations of the proposed models result from the assumptions made at the data analysis stage. The limited amount of information available in the literature and the lack of differentiation between sexes results in one common equation. The developed model is a part of the computational system for drug cardiotoxicity assessment.

Electrocardiographic abnormalities in patients with acute pulmonary embolism complicated by cardiogenic shock

BACKGROUND Cardiogenic shock (CS) is a predictor of poor prognosis in patients with acute pulmonary embolism (APE). OBJECTIVES The aim of this study was to compare electrocardiography (ECG) parameters in patients with APE presenting with or without CS. METHODS A 12-lead ECG was recorded on admission at a paper speed of 25 mm/s and 10 mm/mV amplification. All ECGs were examined by a single cardiologist who was blinded to all other clinical data. All ECG measurements were made manually. RESULTS Electrocardiographic data from 500 patients with APE were analyzed, including 92 patients with CS. The following ECG parameters were associated with CS: S1Q3T3 sign, (odds ratio [OR]: 2.85, P<.001), qR or QR morphology of QRS in lead V1, (OR: 3.63, P<.001), right bundle branch block (RBBB) (OR: 2.46, P=.004), QRS fragmentation in lead V1 (OR: 2.94, P=.002), low QRS voltage (OR: 3.21, P<.001), negative T waves in leads V2 to V4 (OR: 1.81, P=.011), ST-segment depression in leads V4 to V6 (OR: 3.28, P<.001), ST-segment elevation in lead III (OR: 4.2, P<.001), ST-segment elevation in lead V1 (OR: 6.78, P<.01), and ST-segment elevation in lead aVR (OR: 4.35, P<.01). The multivariate analysis showed that low QRS voltage, RBBB, and ST-segment elevation in lead V1 remained statistically significant predictors of CS. CONCLUSIONS In patients with APE, low QRS voltage, RBBB, and ST-segment elevation in lead V1 were associated with CS.

Circadian Models of Serum Potassium, Sodium, and Calcium Concentrations in Healthy Individuals and Their Application to Cardiac Electrophysiology Simulations at Individual Level

In the article a brief description of the biological basis of the regulation of human biological clocks was presented in order to introduce the role of circadian rhythms in physiology and specifically in the pharmacological translational tools based on the computational physiology models to motivate the need to provide models of circadian fluctuation in plasma cations. The main aim of the study was to develop statistical models of the circadian rhythm of potassium, sodium, and calcium concentrations in plasma. The developed ion models were further tested by assessing their influence on QT duration (cardiac endpoint) as simulated by the biophysically detailed models of human left ventricular cardiomyocyte. The main results are model equations along with an electronic supplement to the article that contains a fully functional implementation of all models.

BDTcomparator: a program for comparing binary classifiers

SUMMARY The BDTcomparator facilitates the selection of the best performing binary classification model or binary diagnostic procedure from the many possible alternatives by comparing their predictions with a known output, measured with the use of a system recognized as the gold standard. The program calculates the estimates of accuracy, sensitivity, specificity, predictive values and diagnostic likelihood ratios along with appropriate confidence intervals. Furthermore, all pairwise comparisons with respect to the above-mentioned measures are calculated. The formatted results can be exported to a text-file. AVAILABILITY AND IMPLEMENTATION BDTcomparator is distributed under the GNU GPLv3 license and is freely available for download from http://www.tox-portal.net. We provide programs for both Linux and Windows operating systems. The source code of the program is provided in our companion website http://code.google.com/p/bdtcomparator/. CONTACT kamil.fijorek@uek.krakow.pl SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.

Mortality and morbidity in cardiac resynchronization patients: impact of lead position, paced left ventricular QRS morphology and other characteristics on long-term outcome

AIMS To investigate the effect of implantation-related characteristics, especially lead position and left ventricular (LV)-paced QRS morphology, on long-term mortality and morbidity in cardiac resynchronization therapy (CRT) patients. METHODS AND RESULTS The study retrospectively analysed 362 consecutive patients who underwent CRT device implantation over a 6 year period. Pre-implantation, LV-only paced, and biventricularly paced 12-lead electrocardiograms were obtained. Left ventricular and right ventricular (RV) lead positions were determined using biplane fluoroscopy and roentgenograms. The Kaplan-Meier method was used to estimate the survival function for all-cause death/hospitalization and cardiovascular death/hospitalization. Univariate and multivariate Cox proportional hazards models were also applied. The mean follow-up time was 24.7 ± 16.9 months. There were 79 deaths (62 cardiovascular) and 99 unplanned hospitalizations (72 cardiovascular). One year and 2 year all-cause mortality rates were 8.5 and 18.0%, respectively. Electrocardiographic and fluoroscopic descriptors of the LV lead position were found to be predictors of mortality/morbidity (as were functional class, heart failure aetiology, hyponatremia, and chronic atrial fibrillation). In particular, the antero-apical pattern of LV-only paced QRS showed a hazard ratio (HR) of 1.8 in univariate and 1.7 in multivariate analysis for predicting all-cause death/hospitalization (P = 0.006). The apical/paraseptal LV lead position showed an HR of 2.1 in univariate and 1.9 in multivariate analysis for predicting cardiovascular death/hospitalization (P = 0.018). CONCLUSION To achieve better long-term outcomes in CRT patients the antero-apical pattern of LV QRS complexes and apical or paraseptal LV lead position should be avoided.

In vitro–in vivo extrapolation of drug-induced proarrhythmia predictions at the population level

Drug cardiotoxicity is a serious issue for patients, regulators, pharmaceutical companies and health service payers because they are all affected by its consequences. Despite the wide range of data they generate, existing approaches for cardiac safety testing might not be adequate and sufficiently cost-effective, probably as a result of the complexity of the problem. For this reason, translational tools (based on biophysically detailed, mathematical models) allowing for in vitro-in vivo extrapolation are gaining increasing interest. This current review describes approaches that can be used for cardiac safety assessment at the population level, by accounting for various sources of variability including kinetics of the compound of interest.

Structure and function of large arteries in hypertension in relation to oxidative stress markers

BACKGROUND The relationship between hypertension and oxidative stress remains unexplained. Nevertheless, it is well established that reactive oxygen species have an influence on the arterial wall, endothelial function and therefore determine blood pressure. AIM The evaluation of selected oxidative stress markers in hypertensive patients and an assessment of the relationship between oxidative stress markers and the arterial structure and function. We also aimed to investigate whether the influence of oxidative stress on remodelling of arteries, their structural and functional changes is independent of hypertension or is related to hypertension. METHODS Altogether 217 subjects (114 female, 103 male) were enrolled from hypertensive families. The mean age was 45.5 ± 16 years, and the group included 155 hypertensives. In every subject, the pulse wave velocity and intima-media thickness (IMT) in carotid arteries were measured as well as selected oxidative stress markers such as asymmetric dimethylarginin (ADMA), symmetric dimethylarginin (SDMA), advanced oxidation protein products (AOPP) and oxidised low density lipoproteins (ox-LDL). RESULTS The results of multivariate analysis show that in hypertensive patients: the ADMA level increased with increasing peripheral pulse pressure (b = 0.003; p < 0.001), and AOPP was related to higher carotid IMT (b = 0.91; p = 0.036). In normotensive subjects, the following associations were found: between ADMA and central pulse pressure (b = 0.006; p = 0.008), between SDMA and the peripheral augmentation index (b = -0.03; p = 0.014), between AOPP and the peripheral augmentation index (b = 0.011; p = 0.04), and between ox-LDL/LDL ratio and the peripheral augmentation index (b = -0.025; p = 0.004). The SDMA/ADMA ratio was associated with estimated glomerular filtration rate in both groups (b = -0.0061; p < 0.0001 and b = -0.005; p < 0.017, respectively). In hypertensives, we observed a relation with peripheral pulse pressure (b = -0.0067; p = 0.0143). Moreover, in normotensives there was an association between the SDMA/ADMA ratio and uric acid (b = 1.3629; p = 0.046). CONCLUSIONS We found that the influence of oxidative stress on the structure and function of large arteries was independent of hypertension. Therefore oxidative stress may play a significant role in the development of arterial stiffness. Higher oxidative stress is associated with more advanced arterial remodelling in hypertension.

T-wave inversion in patients with acute pulmonary embolism: Prognostic value

INTRODUCTION T-wave inversion (TWI) is a common ECG finding in patients with acute pulmonary embolism (APE). OBJECTIVES To determine the prevalence of TWI in patients with APE and to describe their relationship to outcomes. METHODS Retrospective study of 437 patients with APE. TWI patterns were described in two distributions: inferior (II, III, aVF) and precordial (V1-V6). RESULTS TWI was observed in 258 (59%) patients. The mortality rate was significantly higher in the group with TWI in the inferior AND precordial leads compared to the group without TWI (OR: 2.74; p = 0.024) and the group with TWI in the inferior OR precordial leads (OR: 2.43; p = 0.035). As compared those with TWI in <5 leads, patients with TWI in ≥5 leads experienced significantly higher rates of death (17.1% vs. 6.6%, OR: 2.92; p = 0.002) and complications. CONCLUSIONS TWI and the quantitative assessment thereof can be useful to risk stratify patients with APE.