Resistant Hypertension in Dialysis: Epidemiology, Diagnosis, and Management.

Apparent treatment-resistant hypertension is defined as an elevated BP despite the use of ≥3 antihypertensive medications from different classes or the use of ≥4 antihypertensives regardless of BP levels. Among patients receiving maintenance hemodialysis or peritoneal dialysis, using this definition, the prevalence of apparent treatment-resistant hypertension is estimated to be between 18% and 42%. Owing to the lack of a rigorous assessment of some common causes of pseudoresistance, the burden of true resistant hypertension in the dialysis population remains unknown. What distinguishes apparent treatment-resistance from true resistance is white-coat hypertension and adherence to medications. Accordingly, the diagnostic workup of a dialysis patient with apparent treatment-resistant hypertension on dialysis includes the accurate determination of BP control status with the use of home or ambulatory BP monitoring and exclusion of nonadherence to the prescribed antihypertensive regimen. In a patient on dialysis with inadequately controlled BP, despite adherence to therapy with maximally tolerated doses of a ß -blocker, a long-acting dihydropyridine calcium channel blocker, and a renin-angiotensin system inhibitor, volume-mediated hypertension is the most important treatable cause of resistance. In daily clinical practice, such patients are often managed with intensification of antihypertensive therapy. However, this therapeutic strategy is likely to fail if volume overload is not adequately recognized or treated. Instead of increasing the number of prescribed BP-lowering medications, we recommend diet and dialysate restricted in sodium to facilitate achievement of dry weight. The achievement of dry weight is facilitated by an adequate time on dialysis of at least 4 hours for delivering an adequate dialysis dose. In this article, we review the epidemiology, diagnosis, and management of resistant hypertension among patients on dialysis.

MANAGEMENT OF RISKS OF ADVERSE DRUG REACTIONS ACCORDING TO ADR REPORT FORM DATA FROM LVIV REGION HEALTHCARE FACILITIES IN 2022.

The study aimed to analyse the adverse drug reactions report form data received by the State Expert Center of the Ministry of Health of Ukraine from healthcare professionals in the Lviv region in 2022. Regarding specific types of medicines, the ones with proven cause-and-effect relationships that caused the highest frequency of adverse drug reactions incidents were chemotherapeutic agents (35.5%), medicines affecting the cardiovascular system (20.3%), and non-steroidal anti-inflammatory drugs (8%). Within the penicillin class, amoxicillin potentiated by clavulanate (67%) and amoxicillin (29%) were the dominant drugs showing the highest incidence rate of adverse reactions. Among cephalosporins, ceftriaxone (46%) and cefixime (15%) were found to take the lead in terms of adverse reaction frequency. The highest proportion among all adverse drug reactions caused by penicillins and cephalosporins was attributed to allergic reactions. To confirm or rule out immediate or delayed type allergies in patients, as well as in patients with a history of immediate-type allergic reactions to ß-lactams and planned administration of another ß-lactam, it is necessary to conduct skin testing (skin prick test, or, in the case of parenteral administration, intradermal test) with the planned ß-lactam antibiotic. The second highest proportion of induced adverse drug reactions was attributed to drugs affecting the cardiovascular system (20.3%). The leading medications in the angiotensin-converting enzyme inhibitors category were enalapril (47%) and the combination of lisinopril with hydrochlorothiazide (24%). In the angiotensin II receptor blockers category of medications, valsartan (30%) and telmisartan-hydrochlorothiazide combination (20%) ranked highest. In the category of CCB drugs, amlodipine (66%) and nifedipine (20%) held the leading positions. among angiotensin-converting enzyme inhibitors, enalapril caused the most prevalent and predicted adverse reaction, that of cough, affecting 10.5% of patients, whereas, with the combination therapy of lisinopril and hydrochlorothiazide, the cough was observed in only 5.2% of patients. Angiotensin II receptor blockers have a better safety profile, particularly concerning cough. Analysis of adverse drug reactions reports for angiotensin II receptor blockers showed no cases of cough with valsartan and telmisartan-hydrochlorothiazide combination. Among calcium channel blocker medications, amlodipine emerged to rank highest, causing one of the predicted adverse drug reactions, that of lower extremity oedema in 64% of patients. The second position was taken by the combination of amlodipine with valsartan, which showed a statistically significant reduction of 14.3% (p≤0.05) in the incidence of oedema. Using amlodipine at a dose of 5 mg in combination with sartan medicines as angiotensin receptor blockers is an effective therapeutic alternative not only for enhancing blood pressure control in hypertensive patients but also for improving the safety profile of amlodipine. Among all the non-steroidal anti-inflammatory drugs prescribed to patients in the Lviv region in 2022, the highest number of adverse reactions was associated with the administration of diclofenac, ibuprofen, paracetamol, and nimesulide, causing adverse drug reactions in 22%, 19%, 17%, and 10% of cases, respectively. The most common systemic manifestations of adverse reactions with these non-steroidal anti-inflammatory drugs were allergic reactions (63.4%) and gastrointestinal disorders (26.8%). From an evidence-based medicine perspective, the most justified approach for primary and secondary prevention of gastrointestinal complications is the use of proton pump inhibitors.

Synthesis and Biological Assessment of 4,1-Benzothiazepines with Neuroprotective Activity on the Ca2+ Overload for the Treatment of Neurodegenerative Diseases and Stroke.

In excitable cells, mitochondria play a key role in the regulation of the cytosolic Ca2+ levels. A dysregulation of the mitochondrial Ca2+ buffering machinery derives in serious pathologies, where neurodegenerative diseases highlight. Since the mitochondrial Na+/Ca2+ exchanger (NCLX) is the principal efflux pathway of Ca2+ to the cytosol, drugs capable of blocking NCLX have been proposed to act as neuroprotectants in neuronal damage scenarios exacerbated by Ca2+ overload. In our search of optimized NCLX blockers with augmented drug-likeness, we herein describe the synthesis and pharmacological characterization of new benzothiazepines analogues to the first-in-class NCLX blocker CGP37157 and its further derivative ITH12575, synthesized by our research group. As a result, we found two new compounds with an increased neuroprotective activity, neuronal Ca2+ regulatory activity and improved drug-likeness and pharmacokinetic properties, such as clog p or brain permeability, measured by PAMPA experiments.

Telemetered common marmosets is useful for the assessment of electrocardiogram parameters changes induced by multiple cardiac ion channel inhibitors.

The objective of this study is to assess the response of telemetered common marmosets to multiple cardiac ion channel inhibitors and to clarify the usefulness of this animal model in evaluating the effects of drug candidates on electrocardiogram (ECG). Six multiple cardiac ion channel inhibitors (sotalol, astemizole, flecainide, quinidine, verapamil and terfenadine) were orally administered to telemetered common marmosets and changes in QTc, PR interval and QRS duration were evaluated. Drugs plasma levels were determined to compare the sensitivity in common marmosets to that in humans. QTc prolongation was observed in the marmosets dosed with sotalol, astemizole, flecainide, quinidine, verapamil and terfenadine. PR prolongation was noted after flecainide and verapamil administration, and QRS widening occurred following treatment with flecainide and quinidine. Drugs plasma levels associated with ECG changes in marmosets were similar to those in humans, except for verapamil-induced QTc prolongation. Verapamil-induced change is suggested due to body temperature decrease. These results indicate that telemetered common marmoset is a useful animal for evaluation of the ECG effects of multiple cardiac ion channel inhibitors and the influence of body temperature change should be considered in the assessment.

Dynamic tissue perfusion assessment reflects associations between antihypertensive treatment and renal cortical perfusion in patients with chronic kidney disease and hypertension.

PURPOSE: Renal cortical perfusion measured in noninvasive, dynamic ultrasonic method is connected with the hemodynamic cardiac properties and renal function. Antihypertensive drugs affect the functioning of the heart and kidneys. The aim of the study was to evaluate the effect of a chronic use of antihypertensive drugs on ultrasound parameters of renal cortical perfusion. METHODS: The study included 56 consecutive patients (49 M + 7 F, age 54.0 ± 13.3) with stable chronic kidney disease and hypertension. Color Doppler dynamic tissue perfusion measurement was used to assess renal cortical perfusion. RESULTS: Patients were treated with a mean of 2.7 ± 1.4 antihypertensive drugs, of which diuretics accounted for 25%, angiotensin-converting enzyme inhibitors (ACE-I) together with angiotensin receptor blockers (ARB) 24%, beta-blockers (BB) 23%, calcium channel blockers 16%, alpha-1 blockers (α1B) 9% and centrally acting drugs 3%. All investigated groups of drugs correlated significantly with parameters of renal perfusion. In multivariable regression analyses adjusted to age, diuretics were connected with the decrease (r = - 0.473) and ACE-I + ARB (r = 0.390) with the improvement of proximal and whole renal cortex perfusion (R2 = 0.28; p < 0.001), whereas BB (r = - 0.372) and α1B (r = - 0.280) independently correlated with worsened perfusion of renal distal cortex (R2 = 0.21, p < 0.01). CONCLUSIONS: The type of antihypertensive therapy had a significant influence on the ultrasound parameters of renal cortical perfusion. Noninvasive, ultrasonic dynamic tissue perfusion measurement method appears to be an adequate tool to assess the impact of drugs on renal cortical perfusion.

Comparative effectiveness of antihypertensive drugs in nondiabetic patients with hypertension: A population-based study.

The authors compared the effectiveness of thiazide diuretic (TD), angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), and calcium channel blocker (CCB) monotherapies for the treatment of nondiabetic hypertension using MarketScan Databases 2010-2014. Multivariable Cox regression models assessed whether the addition of a new antihypertensive drug, treatment discontinuation, or switch and major cardiovascular or cerebrovascular events varied across groups. A total of 565 009 patients started monotherapy with ACEIs (43.6%), CCBs (23.6%), TDs (18.8%), or ARBs (14.0%). Patients who took TDs had a higher risk for either drug addition or discontinuation than patients who took ACEIs (hazard ratio [HR], 0.69 [95% CI, 0.68-0.70] vs HR, 0.81 [95% CI, 0.80-0.81]), ARBs (HR, 0.67 [95% CI, 0.66-0.68] vs HR, 0.66 [95% CI, 0.65-0.67]), and CCBs (HR, 0.85 [95% CI, 0.84-0.87] vs HR, 0.94 [95% CI, 0.93-0.95]). Conversely, patients who took TDs experienced a lower risk of clinical events compared with patients who took ACEIs (HR, 1.24 [95% CI, 1.15-1.33]), ARBs (HR, 1.28 [95% CI, 1.18-1.39]), and CCBs (HR, 1.35 [95% CI, 1.25-1.46]). Our results provide a strong rationale for choosing TDs as first-line monotherapy for the control of hypertension.

Proarrhythmia liability assessment and the comprehensive in vitro Proarrhythmia Assay (CiPA): An industry survey on current practice.

INTRODUCTION: The Safety Pharmacology Society (SPS) has conducted a survey of its membership to identify industry practices related to testing considered in the Comprehensive In vitro Proarrhythmia Assay (CiPA). METHODS: Survey topics included nonclinical approaches to address proarrhythmia issues, conduct of in silico studies, in vitro ion channel testing methods used, drugs used as positive controls during the conduct of cardiac ion channel studies, types of arrhythmias observed in non-clinical studies and use of the anticipated CiPA ion channel assay. RESULTS: In silico studies were used to evaluate effects on ventricular action potentials by only 15% of responders. In vitro assays were used mostly to assess QT prolongation (95%), cardiac Ca2+ and Na+ channel blockade (82%) and QT shortening or QRS prolongation (53%). For de-risking of candidate drugs for proarrhythmia, those assays most relevant to CiPA including cell lines stably expressing ion channels used to determine potency of drug block were most frequently used (89%) and human stem cell-derived or induced pluripotent stem cell cardiomyocytes (46%). Those in vivo assays related to general proarrhythmia derisking include ECG recording using implanted telemetry technology (88%), jacketed external telemetry (62%) and anesthetized animal models (53%). While the CiPA initiative was supported by 92% of responders, there may be some disconnect between current practice and future expectations, as explained. DISCUSSION: Proarrhythmia liability assessment in drug development presently includes study types consistent with CiPA. It is anticipated that CiPA will develop into a workable solution to the concern that proarrhythmia liability testing remains suboptimal.

Evaluation of Batch Variations in Induced Pluripotent Stem Cell-Derived Human Cardiomyocytes from 2 Major Suppliers.

Drug-induced proarrhythmia is a major safety issue in drug development. Developing sensitive in vitro assays that can predict drug-induced cardiotoxicity in humans has been a challenge of toxicology research for decades. Recently, induced pluripotent stem cell-derived human cardiomyocytes (iPSC-hCMs) have become a promising model because they largely replicate the electrophysiological behavior of human ventricular cardiomyocytes. Patient-specific iPSC-hCMs have been proposed for personalized cardiac drug selection and adverse drug response prediction; however, many procedures are involved in cardiomyocytes differentiation and purification process, which may result in large line-to-line and batch-to-batch variations. Here, we examined the purity, cardiac ion channel gene expression profile, and electrophysiological response of 3 batches of iPSC-hCMs from each of 2 major cell suppliers. We found that iPSC-hCMs from both vendors had similar purities. Most of the cardiac ion channel genes were expressed uniformly among different batches of iCells, while larger variations were found in Cor.4U cells, particularly in the expression of CACNA1C, KCND2, and KCNA5 genes, which could underlie the differences in baseline beating rate (BR) and field potential duration (FPD) measurements. Although, in general, the electrophysiological responses of different batches of cells to Na+, Ca2+, Ikr, and Iks channel blockers were similar, with Ikr blocker-induced proarrhythmia, the sensitivities were depended on baseline BR and FPD values: cells that beat slower had longer FPD and greater sensitivity to drug-induced proarrhythmia. Careful evaluation of the performance of iPSC-hCMs and methods of data analysis is warranted for shaping regulatory standards in qualifying iPSC-hCMs for drug safety testing.

Comprehensive T wave morphology assessment in a randomized clinical study of dofetilide, quinidine, ranolazine, and verapamil.

BACKGROUND: Congenital long QT syndrome type 2 (abnormal hERG potassium channel) patients can develop flat, asymmetric, and notched T waves. Similar observations have been made with a limited number of hERG-blocking drugs. However, it is not known how additional calcium or late sodium block, that can decrease torsade risk, affects T wave morphology. METHODS AND RESULTS: Twenty-two healthy subjects received a single dose of a pure hERG blocker (dofetilide) and 3 drugs that also block calcium or sodium (quinidine, ranolazine, and verapamil) as part of a 5-period, placebo-controlled cross-over trial. At pre-dose and 15 time-points post-dose, ECGs and plasma drug concentration were assessed. Patch clamp experiments were performed to assess block of hERG, calcium (L-type) and late sodium currents for each drug. Pure hERG block (dofetilide) and strong hERG block with lesser calcium and late sodium block (quinidine) caused substantial T wave morphology changes (P<0.001). Strong late sodium current and hERG block (ranolazine) still caused T wave morphology changes (P<0.01). Strong calcium and hERG block (verapamil) did not cause T wave morphology changes. At equivalent QTc prolongation, multichannel blockers (quinidine and ranolazine) caused equal or greater T wave morphology changes compared with pure hERG block (dofetilide). CONCLUSIONS: T wave morphology changes are directly related to amount of hERG block; however, with quinidine and ranolazine, multichannel block did not prevent T wave morphology changes. A combined approach of assessing multiple ion channels, along with ECG intervals and T wave morphology may provide the greatest insight into drug-ion channel interactions and torsade de pointes risk. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov/ Unique identifier: NCT01873950.

Effectiveness of antiepileptic drug combination therapy for partial-onset seizures based on mechanisms of action.

IMPORTANCE: To our knowledge, the current study is the first to describe antiepileptic drug (AED) combination therapy patterns according to their mechanism of action (MOA) in a real-world setting and to evaluate the differences in outcomes comparing different-MOA combination therapy with same-MOA combination therapy for patients with partial-onset seizure. OBJECTIVE: To compare treatment persistence and health care use with AED combinations categorized by MOA in patients with partial-onset seizures. DESIGN, SETTING, AND PARTICIPANTS: Using the Truven Health MarketScan Commercial Claims Database containing 96 million covered lives from July 1, 2004, through March 31, 2011, adults with concomitant use of 2 different AEDs and a recent partial-onset seizure diagnosis were selected. Antiepileptic drugs were categorized by MOA: sodium channel blockers (SC), gamma-aminobutyric acid analogs (G), synaptic vesicle protein 2A binding (SV2), and multiple mechanisms (M). Patients were assigned a combination category based on their concomitant AED use. MAIN OUTCOMES AND MEASURES: Treatment persistence was measured from the start of AED combination therapy until the end of the combination. Health care resource use was measured during the combination treatment duration. Multivariate analyses evaluated AED discontinuation risk and health care use according to MOA combinations. RESULTS: Distribution of 8615 selected patients by combination was 3.3% for G+G, 7.5% for G+SV2, 8.6% for G+M, 13.9% for SC+SC, 19.0% for G+SC, 21.5% for SC+M, and 26.3% for SC+SV2. The same-MOA (G+G and SC+SC) combinations had the shortest persistence (mean [SD], 344 [345] days and 513 [530] days, respectively) and greater hazard of discontinuation compared with different-MOA combinations. Patients with different-MOA G combinations had a significantly lower risk for inpatient admission (odds ratio, 0.716; 95% CI, 0.539-0.952; P = .02) compared with G+G combinations. Patients with different-MOA SC combinations had significantly lower risks for emergency department visits (odds ratio, 0.853; 95% CI, 0.742-0.980; P = .03) compared with SC+SC combinations. CONCLUSIONS AND RELEVANCE: The findings suggest that AED combinations with different MOAs have greater effectiveness as measured by treatment persistence and lower risks for hospitalization and emergency department visits. Further research is needed to more fully understand the role of the MOA in achieving optimal outcomes.

[Comparative assessment of nephroprotective properties of potassium and calcium channel modulators in experimental renal injury].

The experiments in white laboratory rats have shown that a single intragasrtric administration of the new fluorine-containing potassium channel opener flocalin in a dose of 5 mg/kg in the initial stage of sublimate nephropathy increased the glomerular filtration rate, reduced creatininemia, increased urinary creatinine excretion, and decreased proteinuria. Under similar conditions, the administration of the calcium channel blocker diltiazem in a dose of 5 mg/kg (intragasrtric) showed a less pronounced antiproteinuric effect as compared to that of flocalin. A comparative assessment of the influence of flocalin and diltiazem on the basic renal function markers demonstrated predominant nephroprotective effect of flocalin in the treatment of acute toxic nephropathy.

[Clinical cfficacy of calcium channel blockers slow the third generation of lercanidipine in the treatment of patients with arterial hypertension].

The review describes the classification, mechanisms of action, the effects of calcium channel blockers slow and the clinical benefits of dihydropyridine calcium antagonists, the third generation. Presented modern aspects of clinical pharmacology and research results on the efficacy, safety and organoprotective lercanidipine.

Dantrolene-induced inhibition of skeletal L-type Ca2+ current requires RyR1 expression.

Malignant hyperthermia (MH) is a pharmacogenetic disorder most often linked to mutations in the type 1 ryanodine receptor (RyR1) or the skeletal L-type Ca(2+) channel (Ca(V)1.1). The only effective treatment for an MH crisis is administration of the hydantoin derivative Dantrolene. In addition to reducing voltage induced Ca(2+) release from the sarcoplasmic reticulum, Dantrolene was recently found to inhibit L-type currents in developing myotubes by shifting the voltage-dependence of Ca(V)1.1 channel activation to more depolarizing potentials. Thus, the purpose of this study was to obtain information regarding the mechanism of Dantrolene-induced inhibition of Ca(V)1.1. A mechanism involving a general depression of plasma membrane excitability was excluded because the biophysical properties of skeletal muscle Na(+) current in normal mouse myotubes were largely unaffected by exposure to Dantrolene. However, a role for RyR1 was evident as Dantrolene failed to alter the amplitude, voltage dependence and inactivation kinetics of L-type currents recorded from dyspedic (RyR1 null) myotubes. Taken together, these results suggest that the mechanism of Dantrolene-induced inhibition of the skeletal muscle L-type Ca(2+) current is related to altered communication between Ca(V)1.1 and RyR1.

SMILES-based QSAR models for the calcium channel-antagonistic effect of 1,4-dihydropyridines.

The activity of 72 1,4-dihydropyridines as calcium channel antagonists was examined. The simplified molecular input-line entry system (SMILES) was used as representation of the molecular structure of the calcium channel antagonists. Quantitative structure-activity relationships (QSARs) were developed using CORAL software (http://www.insilico.eu/CORAL) for four random splits of the data into the training and test sets. Using the Monte Carlo method, the CORAL software generated the optimal descriptors for one-variable models. The reproducibility of each model was tested performing three runs of the Monte Carlo optimization. The obtained results reveal good predictive potential of the applied approach: The correlation coefficients (r(2) ) for the test sets of the four random splits are 0.9571, 0.9644, 0.9836, and 0.9444.

Improving drug adherence using fixed combinations caused beneficial treatment outcomes and decreased health-care costs in patients with hypertension.

We enrolled 196 patients with hypertension who were already being treated with free-drug combinations of angiotensin-II receptor blocker (ARB) and amlodipine. The free-drug combinations of ARB and amlodipine were replaced with the same dose of the fixed-dose combinations. The average home blood pressure (BP) in all patients receiving fixed-dose combinations was significantly lower than those receiving free-drug combinations (131 ± 10/75 ± 8 vs. 136 ± 11/77 ± 9 mm Hg, P < .01) accompanied with increasing drug adherence. After lowering BP by fixed-dose combinations, the costs for medications decreased by 31% over the 3 months.

[Modeling and simulation activities to design sampling scheme for population pharmacokinetic study on amlodipine].

Reasonable sampling scheme is the important basis for establishing reliable population pharmacokinetic model. It is an effective method for estimation of population pharmacokinetic parameters with sparse data to perform population pharmacokinetic analysis using the nonlinear mixed-effects models. We designed the sampling scheme for amlodipine based on D-optimal sampling strategy and Bayesian estimation method. First, optimized sample scenarios were designed using WinPOPT software according to the aim, dosage regimen and visit schedule of the clinical study protocol, and the amlodipine population model reported by Rohatagi et al. Second, we created a NONMEM-formatted dataset (n = 400) for each sample scenario via Monte Carlo simulation. Third, the estimation of amlodipine pharmacokinetic parameters (clearance (CL/F), volume (V/F) and Ka) was based on the simulation results. All modeling and simulation exercises were conducted with NONMEM version 7.2. Finally, the accuracy and precision of the estimated parameters were evaluated using the mean prediction error (MPE) and the mean absolute error (MAPE), respectively. Among the 6 schemes, schemes 6 and 3 have good accuracy and precision. MPE is 0.1% for scheme 6 and -0.6% for scheme 3, respectively. MAPE is 0.7% for both schemes. There is no significant difference in MPE and MAPE of volume among them. Therefore, we select scheme 3 as the final sample scenario because it has good accuracy and precision and less sample points. This research aims to provide scientific and effective sampling scheme for population pharmacokinetic (PK) study of amlodipine in patients with renal impairment and hypertension, provide a scientific method for an optimum design in clinical population PK/PD (pharmacodynamics) research.

Predictive model for L-type channel inhibition: multichannel block in QT prolongation risk assessment.

Evaluation of the proarrhythmic potential of an investigated compound is now an integral element of the safety profile required for the approval of new drugs. The human ether-à-go-go-related gene (hERG) channel blocking potency is regarded as a surrogate marker of the proarrhythmic risk at the early stages of the research and development process. However, there is no straight correlation between QT prolongation and TdP occurrence probability, and hERG inhibition potential can be an inadequate predictor of QT prolongation. The L-type calcium channel plays a pivotal role in cardiomyocytes' physiology. Thus the main aim of this study was to develop a predictive model for drug-triggered CaL channel inhibition and also the assessment of drug-multichannel interaction effects on the heart rate-corrected QT interval. The data set, consisting of 123 records describing in vitro experimental settings, measured IC50 values and calculated physico-chemical properties for 72 various chemicals, was collected. The models were tested in a modified 10-fold cross-validation procedure. The generalization ability of the best model was as follows: root mean squared error (RMSE) = 1.10, normalized root mean squared error (NRMSE) = 16.09%. Out of the 10 most important variables, 5 described conditions of the in vitro experiments thus their description and experiment's conditions standardization might be the key to the models better performance. The simulations performed with the ToxComp system showed that the hERG block alone causes concentration-dependent QT prolongation, whereas when multichannel block is regarded, the effect could be reversed. For that reason, the multichannel interaction of tested compounds should be taken into consideration, in order to make the proarrhythmic risk assessment more reliable.

An in silico canine cardiac midmyocardial action potential duration model as a tool for early drug safety assessment.

Cell lines expressing ion channels (IC) and the advent of plate-based electrophysiology device have enabled a molecular understanding of the action potential (AP) as a means of early QT assessment. We sought to develop an in silico AP (isAP) model that provides an assessment of the effect of a compound on the myocyte AP duration (APD) using concentration-effect curve data from a panel of five ICs (hNav1.5, hCav1.2, hKv4.3/hKChIP2.2, hKv7.1/hminK, hKv11.1). A test set of 53 compounds was selected to cover a range of selective and mixed IC modulators that were tested for their effects on optically measured APD. A threshold of >10% change in APD at 90% repolarization (APD(90)) was used to signify an effect at the top test concentration. To capture the variations observed in left ventricular midmyocardial myocyte APD data from 19 different dogs, the isAP model was calibrated to produce an ensemble of 19 model variants that could capture the shape and form of the APs and also quantitatively replicate dofetilide- and diltiazem-induced APD(90) changes. Provided with IC panel data only, the isAP model was then used, blinded, to predict APD(90) changes greater than 10%. At a simulated concentration of 30 µM and based on a criterion that six of the variants had to agree, isAP prediction was scored as showing greater than 80% predictivity of compound activity. Thus, early in drug discovery, the isAP model allows integrating separate IC data and is amenable to the throughput required for use as a virtual screen.

Nifedipine increases energy expenditure by increasing PGC-1α expression in skeletal muscle.

Nifedipine, an L-type calcium (Ca) channel blocker, is one of the most widely used Ca channel-blocking medications for hypertension. Previous studies have reported an association of nifedipine hypertensive treatment with decreased body weight in obese hypertensive humans and rat models. However, the precise mechanism underlying how nifedipine functions metabolically has not been elucidated. Here, we investigated the long-term effect of a non-hypotensive nifedipine dose using a mildly obese, endothelial NO synthase-deficient mouse model. Treating these mice with nifedipine decreased their body weight gain ratio, and white adipose tissue weight compared with the untreated controls. Metabolic analyses indicated that nifedipine treatment upregulated whole-body energy expenditure through increasing oxygen consumption and reducing the respiratory exchange ratio, suggesting that nifedipine promotes lipid oxidation rather than carbohydrate utilization. Furthermore, nifedipine treatment upregulated the expression of the peroxisome proliferator-activated receptor-γ coactivator -1α (PGC-1α) in skeletal muscle. Overall, these results suggest that a non-hypotensive dose of nifedipine has pleiotropic effects on energy expenditure that could ameliorate obesity.