State-dependent bioelectronic interface to control bladder function.

Electrical stimulation therapies to promote bladder filling and prevent incontinence deliver continuous inhibitory stimulation, even during bladder emptying. However, continuous inhibitory stimulation that increases bladder capacity (BC) can reduce the efficiency of subsequent voiding (VE). Here we demonstrate that state-dependent stimulation, with different electrical stimulation parameters delivered during filling and emptying can increase both BC and VE relative to continuous stimulation in rats and cats of both sexes. We show that continuous 10 Hz pudendal nerve stimulation increased BC (120-180% of control) but decreased VE (12-71%, relative to control). In addition to increasing BC, state-dependent stimulation in both rats and cats increased VE (280-759% relative to continuous stimulation); motor bursting in cats increased VE beyond the control (no stimulation) condition (males: 323%; females: 161%). These results suggest that a bioelectronic bladder pacemaker can treat complex voiding disorders, including both incontinence and retention, which paradoxically are often present in the same individual.

The concordance between nonclinical and phase I clinical cardiovascular assessment from a cross-company data sharing initiative.

It is widely accepted that more needs to be done to bring new, safe, and efficacious drugs to the market. Cardiovascular toxicity detected both in early drug discovery as well as in the clinic, is a major contributor to the high failure rate of new molecules. The growth of translational safety offers a promising approach to improve the probability of success for new molecules. Here we describe a cross-company initiative to determine the concordance between the conscious telemetered dog and phase I outcome for 3 cardiovascular parameters. The data indicate that, in the context of the methods applied in this analysis, the ability to detect compounds that affect the corrected QT interval (QTc) was good within the 10-30x exposure range but the predictive or detective value for heart rate and diastolic blood pressure was poor. These findings may highlight opportunities to refine both the animal and the clinical study designs, as well as refocusing the assessment of value of dog cardiovascular assessments beyond phase 1. This investigation has also highlighted key considerations for cross-company data sharing and presents a unique learning opportunity to improve future translational projects.

Comparison of non-invasive and implanted telemetric measurement of blood pressure and electrocardiogram in conscious beagle dogs.

INTRODUCTION: The objective of this study was to evaluate the ability of a non-invasive telemetry monitoring system to detect and quantify changes in blood pressure and electrocardiogram (ECG) parameters in response to vehicle, L-NAME or minoxidil administration to freely moving beagle dogs. Data from a non-invasive telemetry monitoring system were compared to data captured from an invasive telemetry implant in the same animals. METHODS: Blood pressure and ECG data were simultaneously acquired from male dogs using a non-invasive and an invasive implanted telemetry system for 2 hours predose and 24 hours post dosing with vehicle (n=5), minoxidil at 1 mg/kg (n=4) and L-NAME at 10 mg/kg (n=5) on separate test days. Values for mean blood pressure, systolic blood pressure, diastolic blood pressure, pulse pressure, heart rate, RR, PR, QRS, QT and QTcL (heart rate corrected QT interval) interval were reported for both methods. RESULTS: Statistically significant reductions in blood pressure and pulse pressure and increases in heart rate, with associated ECG interval changes were apparent following dosing with minoxidil using both methods. Statistically significant increases in blood pressure and pulse pressure were apparent following dosing with L-NAME when using the invasive telemetry system, changes were apparent when using the non-invasive telemetry system, however, no change was apparent for pulse pressure, they were of shorter duration and not statistically significant. Statistically significant decreases in heart rate, with associated changes in ECG intervals, were apparent following treatment with L-NAME for both invasive and non-invasive methods. DISCUSSION: This study shows that the non-invasive system can be successfully used to acquire both ECG and blood pressure data in freely moving jacketed dogs for at least 26 hours, yet requires further technique refinement to improve system sensitivity to detect smaller changes in blood pressure.