An Integrative Approach for Improved Assessment of Cardiovascular Safety Data.

Cardiovascular adverse effects in drug development are a major source of compound attrition. Characterization of blood pressure (BP), heart rate (HR), stroke volume (SV), and QT-interval prolongation are therefore necessary in early discovery. It is, however, common practice to analyze these effects independently of each other. High-resolution time courses are collected via telemetric techniques, but only low-resolution data are analyzed and reported. This ignores codependencies among responses (HR, BP, SV, and QT-interval) and separation of system (turnover properties) and drug-specific properties (potencies, efficacies). An analysis of drug exposure-time and high-resolution response-time data of HR and mean arterial blood pressure was performed after acute oral dosing of ivabradine, sildenafil, dofetilide, and pimobendan in Han-Wistar rats. All data were modeled jointly, including different compounds and exposure and response time courses, using a nonlinear mixed-effects approach. Estimated fractional turnover rates [h-1, relative standard error (%RSE) within parentheses] were 9.45 (15), 30.7 (7.8), 3.8 (13), and 0.115 (1.7) for QT, HR, total peripheral resistance, and SV, respectively. Potencies (nM, %RSE within parentheses) were IC 50 = 475 (11), IC 50 = 4.01 (5.4), EC 50 = 50.6 (93), and IC 50 = 47.8 (16), and efficacies (%RSE within parentheses) were I max = 0.944 (1.7), Imax = 1.00 (1.3), E max = 0.195 (9.9), and Imax = 0.745 (4.6) for ivabradine, sildenafil, dofetilide, and pimobendan. Hill parameters were estimated with good precision and below unity, indicating a shallow concentration-response relationship. An equilibrium concentration-biomarker response relationship was predicted and displayed graphically. This analysis demonstrates the utility of a model-based approach integrating data from different studies and compounds for refined preclinical safety margin assessment. SIGNIFICANCE STATEMENT: A model-based approach was proposed utilizing biomarker data on heart rate, blood pressure, and QT-interval. A pharmacodynamic model was developed to improve assessment of high-resolution telemetric cardiovascular safety data driven by different drugs (ivabradine, sildenafil, dofetilide, and pimobondan), wherein system- (turnover rates) and drug-specific parameters (e.g., potencies and efficacies) were sought. The model-predicted equilibrium concentration-biomarker response relationships and was used for safety assessment (predictions of 20% effective concentration, for example) of heart rate, blood pressure, and QT-interval.

Assessment of Sotalol and Dofetilide Dosing at a Large Academic Medical Center.

BACKGROUND: Patients initiated on sotalol and dofetilide require inpatient monitoring and dose adjustments due to risks of corrected QT (QTc) prolongation and Torsades de pointes (TdP). Patients may receive higher initial doses than recommended due to close monitoring by specialized practitioners. The objective of this study was to describe prescribing practices of sotalol and dofetilide and to compare safety outcomes between standard and nonstandard dosing strategies. METHODS: This was a single-center retrospective analysis of adult inpatients who underwent sotalol or dofetilide initiation between June 1, 2015, and August 1, 2018. The end points of this study included the percentage of patients who received standard and nonstandard dosing, incidence of QTc prolongation (≥500 milliseconds or ≥15% from baseline), incidence of TdP, and dose reduction or medication discontinuation. RESULTS: A total of 379 patients (195 sotalol and 184 dofetilide) were included in this analysis. There were 110 (56.4%) patients in the sotalol group and 111 (58.4%) patients in the dofetilide group that received nonstandard initial dosing. Nonstandard dosing was associated with a greater incidence of QTc prolongation compared to standard dosing (57.5% vs 43.0%, P = .005). Only one patient in the nonstandard dosing group experienced TdP. Patients initiated on nonstandard dosing required dose reduction or therapy discontinuation (37.6% vs 23.4%, P = .003) more frequently. CONCLUSION: Higher than recommended initial doses of sotalol or dofetilide were associated with higher incidence of QTc prolongation and more frequent therapy modification.

Applications of machine learning in decision analysis for dose management for dofetilide.

BACKGROUND: Initiation of the antiarrhythmic medication dofetilide requires an FDA-mandated 3 days of telemetry monitoring due to heightened risk of toxicity within this time period. Although a recommended dose management algorithm for dofetilide exists, there is a range of real-world approaches to dosing the medication. METHODS AND RESULTS: In this multicenter investigation, clinical data from the Antiarrhythmic Drug Genetic (AADGEN) study was examined for 354 patients undergoing dofetilide initiation. Univariate logistic regression identified a starting dofetilide dose of 500 mcg (OR 5.0, 95%CI 2.5-10.0, p<0.001) and sinus rhythm at the start of dofetilide loading (OR 2.8, 95%CI 1.8-4.2, p<0.001) as strong positive predictors of successful loading. Any dose-adjustment during loading (OR 0.19, 95%CI 0.12-0.31, p<0.001) and a history coronary artery disease (OR 0.33, 95%CI 0.19-0.59, p<0.001) were strong negative predictors of successful dofetilide loading. Based on the observation that any dose adjustment was a significant negative predictor of successful initiation, we applied multiple supervised approaches to attempt to predict the dose adjustment decision, but none of these approaches identified dose adjustments better than a probabilistic guess. Principal component analysis and cluster analysis identified 8 clusters as a reasonable data reduction method. These 8 clusters were then used to define patient states in a tabular reinforcement learning model trained on 80% of dosing decisions. Testing of this model on the remaining 20% of dosing decisions revealed good accuracy of the reinforcement learning model, with only 16/410 (3.9%) instances of disagreement. CONCLUSIONS: Dose adjustments are a strong determinant of whether patients are able to successfully initiate dofetilide. A reinforcement learning algorithm informed by unsupervised learning was able to predict dosing decisions with 96.1% accuracy. Future studies will apply this algorithm prospectively as a data-driven decision aid.

Characterization of an anesthetized dog model of transient cardiac ischemia and rapid pacing: a pilot study for preclinical assessment of the potential for proarrhythmic risk of novel drug candidates.

INTRODUCTION: Preclinical proarrhythmic risk assessment of drug candidates is focused predominantly on arrhythmias arising from repolarization abnormalities. However, drug-induced cardiac conduction slowing is associated with significant risk of life-threatening ventricular arrhythmias, particularly in a setting of cardiac ischemia. Therefore, we optimized and characterized an anesthetized dog model to evaluate the potential proarrhythmic risk of drug candidates in ischemic heart disease patients. METHODS: Anesthetized dogs were instrumented with atrial and ventricular epicardial electrodes for pacing and measurement of conduction times, and a balloon occluder and flow probe placed around the left anterior descending coronary artery (LAD) distal to the first branch. Conduction times, ECG intervals and incidence of arrhythmias were assessed serially at the end of each dose infusion (flecainide: 0.32, 0.63, 1.25, 2.5 and 5mg/kg, i.v.; dofetilide:1.25, 2.5, 5, 10 and 20 µg/kg, i.v.; or vehicle; n=6/group) both during normal flow (with and without rapid pacing) and during 5-min LAD occlusion (with and without rapid pacing). Compound X, a development candidate with mild conduction slowing activity, was also evaluated. RESULTS: Flecainide produced pronounced, dose-dependent slowing of conduction that was exacerbated during ischemia and rapid pacing. In addition, ventricular tachycardia (VT) and fibrillation (VF) occurred in 4 of 6 dogs (3 VF @ 0.63 mg/kg; 1VT @ 2.5mg/kg). In contrast, no animals in the vehicle group developed arrhythmias. Dofetilide, a potent IKr blocker that does not slow conduction, prolonged QT interval but did not cause further conduction slowing during ischemia with or without pacing and there were no arrhythmias. Compound X, like flecainide, produced marked conduction slowing and arrhythmias (VT, VF) during ischemia and pacing. DISCUSSION: This model may be useful to more accurately define shifts in safety margins in a setting of ischemia and increased cardiac demand for drugs that slow conduction.

Comparative effects of supplementing beef steers with zilpaterol hydrochloride, ractopamine hydrochloride, or no beta agonist on strip loin composition, raw and cooked color properties, shear force, and consumer assessment of steaks aged for fourteen or twenty-one days postmortem.

Beef steers (n = 1,914) were assigned to 1 of 3 ß-adrenergic agonist (ßAA) supplementation treatments-zilpaterol hydrochloride (ZH; 8.3 mg/kg of DM for 20 d with 3-d withdrawal), ractopamine hydrochloride (RH; 308 mg·head(-1)·d(-1) for 28 d), or no ßAA (CON)-to determine the effects on consumer eating quality. Strip loins (n = 1,101; CON = 400, RH = 355, and ZH = 346) were obtained and fabricated into 2.5-cm-thick steaks for proximate, Warner-Bratzler shear force (WBSF), slice shear force (SSF), and consumer analyses; steaks were aged until 14 or 21 d postmortem. Fat and moisture contents were not affected by ßAA supplementation (P > 0.05), but strip steaks from steers fed ZH had more protein (P < 0.01) than those from steers fed CON or RH, which were similar. An interaction between ßAA and aging was observed (P < 0.01) for WBSF but not SSF. Within steaks aged 14 d, ZH steaks required the most force to shear, RH steaks were intermediate, and CON steaks had the lowest WBSF values; however, RH steaks had a stronger response to aging than CON or ZH steaks, resulting in the lowest WBSF values at 21 d. Slice shear force values were greater (P < 0.01) in steaks from steers fed ZH than in steaks from steers fed CON or RH, which did not differ. Following shear force analyses, steaks within 2 SD of each treatment mean for WBSF were selected randomly for consumer assessment of eating quality. Consumer testing (n = 400; 200/postmortem aging period) was arranged in a 3 × 3 factorial representing 3 quality grades (Select, Low Choice, and Premium Choice) and 3 treatments (ZH, RH, and CON). In steaks aged 14 d, ßAA supplementation affected (P < 0.01) tenderness, flavor, and overall liking and tenderness acceptability, resulting in lower consumer scores for ZH than CON and RH; however, juiciness, flavor, and overall acceptability were similar (P > 0.05). In steaks aged 21 d, feeding ßAA influenced (P < 0.01) only tenderness and juiciness scores. Despite these differences, ßAA did not affect (P > 0.05) acceptability. Quality grade impacted (P < 0.01) all traits and acceptability in steaks aged 14 and 21 d. In 14-d steaks, Premium Choice typically was scored higher than Low Choice or Select; however, consumers rated 21-d Low Choice and Premium Choice similarly-both receiving greater scores than Select. Consumers detected several differences in eating quality at 14 d because of ßAA supplementation. Increasing aging from 14 to 21 d mitigated differences in shear force and tenderness scores because of feeding ZH, so that tenderness and overall acceptability were similar between ZH, RH, and CON.

Assessment of efficacy of proarrhythmia biomarkers in isolated rabbit hearts with attenuated repolarization reserve.

Isolated hearts with reduced repolarization reserve would be suitable for assessing the proarrhythmic liability of drugs. However, it is not known which proarrhythmia biomarkers indicate the increased susceptibility to torsades de pointes arrhythmia (TdP) in such experimental setting. Thus, we estimated the efficacy of proarrhythmia biomarkers in isolated hearts with attenuated repolarization reserve. Langendorff-perfused rabbit hearts were used. Repolarization reserve was reduced by concomitant inhibition of the rapid (IKr) and slow (IKs) delayed rectifier potassium currents by dofetilide and HMR-1556, respectively. Rate corrected QT (QTc) interval and beat-to-beat variability of the QT interval measured in sinus rhythm or irrespective of rhythm even during arrhythmias (sinus and absolute QT variability, respectively) were tested. QTc failed to predict increased proarrhythmic risk. Sinus QT variability indicated proarrhythmic liability when low concentration of dofetilide was used. However, when arrhythmias compromised sinus variability measurement during coperfusion of catecholamines and elevated concentration of dofetilide, only absolute QT variability indicated increased proarrhythmic risk. Absolute QT variability parameters seem to be the most practical and sensitive biomarkers of proarrhythmic liability in rabbit hearts with reduced repolarization reserve. Absolute QT variability parameters could serve as surrogates for torsades de pointes in drug-safety investigations in isolated rabbit hearts with attenuated repolarization reserve.

Effects of sequential feeding of ß-adrenergic agonists on cull cow performance, carcass characteristics, and mRNA relative abundance.

The objectives of this study were to determine the effects of supplementation with a single ß-adrenergic agonist (ß-AA) or a sequence of ß-AA on cow performance, carcass characteristics, and mRNA relative abundance of cull cows implanted and fed a concentrate diet. Sixty cull cows were implanted with Revalor-200 (200 mg of trenbolone acetate and 20 mg of estradiol) and assigned to 1 of 4 treatments (n = 15/treatment): CON = fed a concentrate diet only; RH = supplemented with ractopamine-HCl for the last 25 d before slaughter; ZH = supplemented with zilpaterol-HCl for 20 d before a 3-d withdrawal before slaughter; RH + ZH = supplemented with RH for 25 d, followed by ZH for 20 d before a 3-d withdrawal before slaughter. Ractopamine-HCl was supplemented at a dose of 200 mg·animal(-1)·d(-1), and ZH was supplemented at 8.33 mg/kg (100% DM basis) of feed. All cows were fed a concentrate diet for 74 d. Each treatment had 5 cows per pen and 3 replicate pens. Body weights were collected on d 1, 24, 51, and 72. Muscle biopsies from the LM were collected on d 24, 51, and at slaughter from a subsample of 3 cows per pen. Carcass traits were evaluated postslaughter. The 2 ZH treatments averaged 15.3 kg more BW gain, 0.20 kg greater ADG, and 7.8 cm(2) larger LM area than CON and RH treatments, and 21 kg more HCW than CON, but these differences were not significant (P > 0.10), likely due to a sample size of n = 15/treatment. The sequence of RH followed by ZH tended to optimize the combination of HCW, LM area, percent intramuscular fat, and lean color and maturity compared with the ZH treatment. Abundance of ß(2)-adrenergic receptor (AR) mRNA was not altered in the RH + ZH treatment during RH supplementation from d 24 to 51 of feeding. However, the abundance of ß(2)-AR mRNA increased (P < 0.05) the last 23 d of feeding for the RH treatment and tended (P = 0.10) to increase in ZH cows during ZH supplementation. For all cows, abundance of type IIa myosin heavy chain (MHC-IIa) mRNA decreased (P < 0.05) after 24 d of feeding. Abundance of MHC-IIx mRNA increased (P < 0.05) for ZH and RH + ZH treatments the last 23 d of feeding during ZH supplementation. Although few significant differences were observed in performance or carcass traits, mRNA quantification indicated that ß-AA supplementation elicited a cellular response in cull cows. Implanting and feeding cull cows for 74 d, regardless of ß-AA supplementation, added economic value by transitioning cows from a cull cow to what is referred to in industry as a white cow market in which cows have white fat resulting from grain feeding.

[Effectiveness of duspatalin therapy in the treatment and prevention of post-cholecystectomy syndrome].

Results of evaluation of the efficiency of myotropic spasmolytic Duspatalin during long-term therapy and preventive treatment of functional post-cholecystectomy syndrome are presented. The influence of the treatment on manifestations of clinical symptoms, quality of a life estimated based on a visual-analog scale, and intestinal microbiocenosis (changes in the activity of short-chain fatty acids) are discussed.

Cost of hospital admission for antiarrhythmic drug initiation in atrial fibrillation.

BACKGROUND: Initiation of some rhythm-control therapies for atrial fibrillation (AF) requires an inpatient hospital stay and telemetry monitoring, adding to the cost burden of AF. However, specific cost data for inpatient initiation of AF therapies are lacking. OBJECTIVE: To examine costs associated with initiating sotalol or dofetilide in the inpatient setting in the US. METHODS: This retrospective cohort study used data from billing/discharge records in the Premier Perspective Database for adults with a primary diagnosis of AF, hospitalized between January 2002 and September 2007. Patients had to have received 4 or more sotalol doses or 5 or more dofetilide doses starting within 2 days of admission (with >/=1 dose within 3 days of discharge). Patients admitted solely for AF drug initiation were identified by excluding patients who were admitted on an emergency basis, received care in the emergency department, or underwent major surgical procedures. The primary outcome was direct medical costs for in-hospital services during the stay. RESULTS: Among 7290 patients included in the analysis (4847 sotalol, 2443 dofetilide), mean total inpatient costs per patient were $3278 in the sotalol group and $3610 in the dofetilide group. The greatest costs were for room/board ($1874 sotalol, $1985 dofetilide) and cardiology/electrocardiograms ($394 sotalol, $443 dofetilide). Pharmacy costs were $230 and $201 per patient in the sotalol and dofetilide groups, respectively. CONCLUSIONS: The admission of patients for in-hospital initiation of AF rhythm-control therapy represents a high cost burden in the US.

Evaluation of the dofetilide risk-management program.

BACKGROUND: Dose-dependent torsades de pointes has been shown to occur with dofetilide (Tikosyn) and sotalol HCl (Betapace AF); thus, detailed dosing and monitoring recommendations to minimize this risk are included in the product labeling for both drugs. Only dofetilide, however, has a mandated risk-management program that restricts distribution of the drug and requires prescriber education on the drug. We investigated whether this program improved adherence to dosing and monitoring recommendations for dofetilide as compared with sotalol. METHODS: Charts for 47 patients taking dofetilide and 117 patients taking sotalol were reviewed. RESULTS: The recommended starting dose was prescribed more frequently in the dofetilide group than in the sotalol group (79% vs 35%, P <.001). A higher number of patients in the dofetilide group compared with the sotalol group received the recommended baseline tests for potassium (100% vs 82%, P <.001), magnesium (89% vs 38%, P <.001), serum creatinine (100% vs 82%, P <.001), and electrocardiography (94% vs 67%, P <.001). A significantly greater proportion of patients in the dofetilide group received recommended electrocardiograms obtained after the first dose (94% for dofetilide vs 43% for sotalol, P <.001) and subsequent doses (80% for dofetilide vs 3.5% for sotalol, P <.001). CONCLUSION: Better adherence to several dosing and monitoring recommendations in the dofetilide group may be caused by the presence of the risk-management program. However, low usage of dofetilide during the study period may signify an unintended, negative consequence of the risk-management program.

A comparative assessment of carbuterol, fenoterol and hexoprenaline in allergic asthma.

Carbuterol tablets (2,0 mg) were compared with the tablets of fenoterol (2,5 mg) and hexoprenaline (1 mg). The three drugs were shown to be equally effective for a period of 4 hours, but carbuterol and fenoterol exerted a statistically significant bronchodilating action for 7 and 8 hours respectively, while the action of hexoprenaline lasted for 4 hours in the majority of patients. The aerosols of carbuterol (200 mg) and fenoterol (400 mg) appeared to be similar in inhibiting exercise-induced asthma, whereas hexoprenaline (200 mg) did not appear to be as effective.