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Introduction Cardiovascular safety assessment requires accurate evaluation of QT interval, which depends on the length of the cardiac cycle and also on core body temperature (BT). Increases in QT interval duration have been shown to be associated with decreases in BT in dogs. Methods An example of altered QT interval duration associated with changes in body temperature observed during a 4-week regulatory toxicology study in dogs is presented. Four groups of Beagle dogs received the vehicle or test item once on Day 1, followed by a 4-week observation period. Electrocardiogram (ECG) parameters were continuously recorded on Days 1 and 26 by jacketed external telemetry (JET). Core body temperature (BT) was measured with a conventional rectal thermometer at appropriate time-points during the Day 1 recording period. Results Decreased BT was observed approximately 2 h after treatment on Day 1, along with increased QT interval duration corrected according to the Van de Water formula (QTcV), but the effect was no longer observed after correction for changes in BT [QTcVcT = QTcV − 14(37.5 − BT)] according to the Van der Linde formula. No significant changes in QTcV were reported at the end of the observation period, on Day 26. Discussion The present study demonstrates that core body (rectal) temperature can easily be monitored at appropriate time-points during JET recording in regulatory toxicology studies in dogs, in order to correct QT interval duration values for treatment-related changes in BT. The successful application of the Van der Linde formula to correct QTc prolongation for changes in BT was demonstrated.

Introduction When the no observed adverse effect level (NOAEL) is determined by respiratory safety pharmacology, follow-up studies are warranted and may include airway resistance and compliance. Respiratory mechanics in commonly used large animal species (Beagle dogs, Cynomolgus monkeys, and Gottingen minipigs) were compared. Methods: Eighteen animals were used (3/sex/species) in an anesthetized model (propofol infusion) with pancuronium as a neuromuscular blocker. Parameters of respiratory mechanics were evaluated at baseline and at peak drug effect. Resistance (R rs ) and elastance (E rs ) were measured by applying a single frequency forced oscillation (0.5 Hz) to the subject's airway opening and fitting the flow, volume and pressure data to the single compartment model of the lung. Increasing doses of intravenous (IV) methacholine were administered in all three species, as well as doubling aerosolized concentrations of the same bronchoconstrictor agent before and after inhaled albuterol. Results: The slope of the IV methacholine dose-response curve for R rs was similar in dogs and monkeys and both species differed from minipigs, which showed greater reactivity. At the highest IV dose tested, minipigs also reached higher levels of bronchoconstriction than the other two species. They were followed, in decreasing order, by dogs and monkeys. Albuterol induced a significant decrease in the slope of the dose-response curve only in dogs and monkeys. Discussion: Scientific literature is available on respiratory mechanics in monkeys and dogs but not in minipigs. Our results suggest that minipigs were more reactive than dogs and monkeys to IV methacholine while less sensitive to inhaled albuterol.

Introduction Power spectral analysis of heart rate variability is a tool known to provide information of interest on the autonomic control of heart rate in human. However, its use and its conditions of application and interpretation for safety purposes are not well defined for cardiovascular safety pharmacology studies. Likewise, data of power spectral analysis of heart rate variability in cynomolgus monkeys, a species often appropriate for use as second non rodent species in preclinical safety programmes, are not available. This study was designed to evaluate the relevance of this biomarker in this non human primate species, and to compare results with those from beagle dogs under the conditions of safety evaluation studies. Methods Power spectral analysis of heart rate variability was performed on data collected in both species by telemetry following a standard design for cardiovascular safety pharmacology studies. Various pharmacological agents were tested in order to compare the profile of responses in both species after modifying the autonomic nervous balance. Results Heart rate variability in cynomolgus monkeys is mainly driven by the parasympathetic nervous system as in beagle dogs although vagal tone is less than in dogs. Power spectral analysis of heart rate variability allows detection of interaction with the autonomic nervous system in both species in all investigated situations, i.e. sympatholytic/sympathomimetic and parasympatholytic/parasympathomimetic drug induced effects. However, due to species difference in the autonomic control of heart rate, cynomolgus monkeys are likely to be more sensitive than beagle dogs for assessment of sympatholytic properties. Discussion This study confirms that power spectral analysis of heart rate variability from data derived from ECG recordings in telemetry studies is applicable in cardiovascular safety pharmacology studies and may provide relevant information about possible interaction with the autonomic nervous system when new drug entities are evaluated in either species. However, interspecies differences in autonomic control must be taken into account when interpreting possible drug effects.

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.

Introduction The gastrointestinal (GI) tract is one of the target organs of adverse drug effects in different phases of drug development. This study aimed to investigate the feasibility of population pharmacokinetic modeling to quantify the rate of gastric emptying (GE) and small intestinal transit time (SITT) in response to drugs that affect GI motility in fed and fasted dogs. Paracetamol and sulfapyridine (sulfasalazine metabolite) pharmacokinetics were used as markers for GE and SITT, respectively. Methods In two separate studies, under fed and fasted conditions, six male beagle dogs received a 15 min intravenous infusion of vehicle, atropine (0.06 mg/kg) or erythromycin (1 mg/kg) followed by an intragastric administration of a mixture of paracetamol (24 mg/kg) and sulfasalazine (20 mg/kg). Food was given just before or at 6 h after drug administration in the fed and fasted study, respectively. Blood samples were collected for analysis of paracetamol and sulfapyridine in plasma. Population pharmacokinetic analysis of paracetamol and sulfapyridine in plasma was used to determine the rate of GE and SITT. Results The quantitative parameter estimates demonstrated a detailed and significant influence of atropine, erythromycin and food on GE and SITT. Compared to fasted conditions food intake delayed GE in pharmacologically treated dogs and SITT was shortened after treatment with vehicle or erythromycin. Atropine substantially delayed GE in fed and fasted conditions but the effect on SITT was evident only under fed condition. Erythromycin, in contrast, increased GE only in fasted conditions, and generally delayed SITT. Discussion Population pharmacokinetic modeling of paracetamol and sulfapyridine provides a suitable preclinical non-invasive experimental method for quantification of drug- and food-induced changes in the rate of GE and SITT in conscious beagle dogs for use in safety evaluations to predict changes in GI transit and/or to explain the pharmacokinetic profile of drugs under development.

Introduction Pharmacokinetic–pharmacodynamic relationships are crucial in understanding a drug's arrhythmogenic potential. Models assist to quantitatively relate parent and metabolite concentrations to adverse electrocardiographic effects, including an apparent delay between effect and circulating parent species concentration. Here, we used an effect compartment model to investigate PR and QRS prolongation previously observed in preclinical studies with the NK1–NK3 antagonist R1551. Method Using a cross-over design, beagle dogs received a single oral dose of R1551 (0–100 mg/kg), and cynomolgus monkeys received oral doses of 0–30 mg/kg once daily for 5 days. PR and QRS intervals and heart rate were measured by telemetry, for ≥ 24 h after each dose in dogs, and on treatment days 1, 3, and 5 in monkeys. Pharmacokinetic parameters were estimated by fitting a two-compartment model to the data. For each species, a linear effect compartment model was used to relate PR and QRS intervals to effect compartment concentrations. Results The effect compartment model provided a good fit to the observed data for both ECG parameters in dogs, and for QRS interval in monkeys (PR 0 = 95.1 ms ± 2.74 and 64.9 ms ± 1.46, QRS 0 = 42.5 ms ± 1.24 and 46.5 ms ± 1.11 in dog and monkey, respectively). For PR interval in monkeys, the fit was improved by adding a placebo effect compartment to the linear model. R1551 effects on intervals in dogs suggested the presence of responder and non-responder sub-populations. In monkeys, only the highest R1551 dose prolonged PR intervals. Effect slope factors were similar between dog and monkey for both intervals (S PR = 0.00930 ms mg −1 kg −1 l −1 ± 0.00133 in dog and 0.00934 ms mg −1 kg −1 l −1 ± 0.00141 in monkey; S QRS = 0.00274 ms mg −1 kg −1 l −1 ± 0.00101 in dog and 0.00200 ms mg −1 kg −1 l −1 ± 0.000552 in monkey). Discussion Our results indicate a non-linear relationship between R1551 plasma kinetics and electrophysiological effects and suggest that the parent was not responsible for the observed ECG effects. In addition, the population based approach allows exploitation of sparse PK data in dog and monkey, analysis throughout the complete effect time course, and assessment of inter-individual variability, all in a single comprehensive model.

Introduction The objective of this study was to describe an optimised neurobehavioural observation battery in the beagle dog and to demonstrate that it can be used for an integrated assessment of cardiovascular and neurobehavioural functions within a single Safety Pharmacology study. Methods A standardised and detailed observation battery was established based on the direct examination of 44 signs, including behavioural responses and a full, systematic neurological examination, using clearly defined numerical scores. To complete the neurobehavioural assessment the remote observation of animals by video recording was also performed. Results from two studies, where cardiovascular and neurobehavioural parameters were assessed using drugs that either showed or did not show cardiovascular effects, are presented to show the influence of the direct neurobehavioural exam on the telemetrically acquired cardiovascular parameters. Results Heart rate and systolic blood pressure were affected by the handling required for the neurobehavioural procedure for a total of approximately 25 min, consisting in 20 min needed for the sequential neurobehavioural observation of four dogs (requiring approximately 5 min each) and approximately 5 min to return to baseline. Drug related cardiovascular effects were not affected by the changes associated with these neurobehavioural observations. More evident cardiovascular changes were observed with other routine procedures such as feeding. Discussion The direct neurobehavioural examination caused fluctuations of the telemetric cardiovascular parameters for no more than 5 min from the end of the procedure and this did not alter or jeopardise the analysis and interpretation of the cardiovascular parameters. These results confirmed that this optimised neurobehavioural observation battery can be used in the beagle dog for a reliable integrated assessment of neurobehavioural and cardiovascular changes during the course of Safety Pharmacology evaluations.

Introduction Regulatory guidelines recommend the use of conscious, unrestrained animals for comprehensive cardiovascular safety assessment of a new therapeutic agent. Cardiovascular safety pharmacology studies normally use internal telemetry (surgical implants) in free-moving animals to monitor key ECG endpoints, like the QTc interval, but this technical approach is highly resource intensive. In toxicology studies, ECG recording is also typically performed under chemical or physical restraint, which has a number of disadvantages, e.g., anesthesia confounds, handling stress and limited data collection. External telemetry for ECG recording has the potential to overcome many of these restraint limitations, with the benefit of being a surgically non-invasive method. To evaluate this method, we used two jacket systems: Data Sciences International (DSI) JET™ and Integrated Telemetry Systems (ITS) PhysioJacket™ in implanted beagle dogs. Methods Heart rate and cardiac intervals were monitored continuously for 22–24 h following oral administration of vehicle (water) or 1 mg/kg E-4031. Data obtained from each jacket system was compared with implant-derived data in the same animal. Results Significant increases in QT/QTcV (25–30 ms) were noted following treatment with 1 mg/kg E-4031 in both external jacket systems and with implanted telemetry. Throughout the recording periods, the normal variations in heart rate and ECG intervals observed in conscious dogs as detected with the jacket systems, mirrored the changes observed via implant telemetry. Discussion The overall findings from this study support the use of external telemetry technology as a viable alternative to implants. The data demonstrated that jackets were sufficiently sensitive to detect QT/QTcV changes following E-4031 administration, that were comparable to those derived from implants. As such, this method is an invaluable tool for obtaining high quality ECG data from repeat-dose toxicology studies.

Introduction The purpose of this study was to collect and estimate the general prevalence of spontaneous irregularities in cardiac rhythms in three standard laboratory animal species: Beagle dog ( N = 2450), cynomolgus monkey ( N = 1563), and domestic swine ( N = 704) during standard preclinical screening. Methods Standard prestudy Lead II hardwire ECG tracings were collected in purpose-bred, drug-, and experimentally-naive animals following receipt from an institutionally-approved vendor and prior to placement onto general toxicology or safety pharmacology studies over the course of 18 months. The ECGs were independently reviewed by two veterinary cardiologists/internists for the presence or absence of arrhythmias (dysrhythmia), conduction disturbances, or other normal variants or clinically significant waveform changes. Results Greater than 98% of all ECGs recorded in animals bred for laboratory use demonstrated sinus rhythms without morphologic abnormalities or arrhythmias.

Introduction Preclinical evaluation of delayed ventricular repolarization manifests electrocardiographically as QT interval prolongation and is routinely used as an indicator of potential risk for pro-arrhythmia (potential to cause Torsades de Pointes) of novel human pharmaceuticals. In accordance with ICH S7A and S7B guidelines we evaluated the sensitivity and validity of the beagle dog telemetry (Integrated Telemetry Services (ITS)) model as a preclinical predictor of QT interval prolongation in humans. Methods Cardiovascular monitoring was conducted for 2 h pre-dose and 24 h post-dosing with moxifloxacin (MOX), haloperidol (HAL), and MK-499, with a toxicokinetic (TK) evaluation in a separate group of dogs. In both cardiovascular and TK studies, MOX (0, 10, 30 and 100 mg/kg), HAL (0, 0.3, 1, 3 mg/kg) and MK-499 (0, 0.03, 0.3 and 3 mg/kg) were administered orally by gavage in 0.5% methylcellulose. Each dog received all 4 doses using a dose-escalation paradigm. Inherent variability of the model was assessed with administration of vehicle (0.5% methylcellulose) alone for 4 days. Results Significant increases in QT c were evident with 10, 30 and 100 mg/kg of MOX ( C max ≤ 40 μM), 0.3, 1 and 3 mg/kg of HAL ( C max ≤ 0.36 μM) and 0.3 and 3 mg/kg of MK-499 ( C max ≤ 825 nM) with peak increases of 45 (20%), 31 (13%), and 45 (19%) ms, respectively ( p ≤ 0.05). Discussion In conclusion, we have demonstrated that the ITS-telemetry beagle dog exhibits low inherent intra-animal variability and high sensitivity to detect small but significant increases in QT/QT c interval (∼ 3–6%) with MOX, HAL and MK-499 in the same range of therapeutic plasma concentrations attained in humans. Therefore, this dog telemetry model should be considered an important preclinical predictor of QT prolongation of novel human pharmaceuticals.

Introduction: The aim of the present study was to compare sensitivity in detecting the drug-induced QT interval prolongation in three dog models: conscious telemetered at sinus rhythm and conscious and anesthetized dogs during atrial pacing. The test substances used represent different chemical classes with different pharmacological and pharmacokinetic profiles. Method: Dofetilide and moxifloxacin were tested in all models, whereas cisapride and terfenadine were tested in the conscious telemetered and paced models. All substances were given as two consecutive 1.5-h intravenous infusions (infusions 1 and 2). The individual concentration–time courses of dofetilide, moxifloxacin, and cisapride were linked to the drug-induced effects on the QT interval and described with a pharmacokinetic–pharmacodynamic model to obtain an estimate of the unbound plasma concentrations at steady state that give a 10- and 20-ms drug-induced QT interval prolongation (CE10ms and CE20ms). Results: In the conscious telemetered, conscious paced, and anesthetized dog models, the mean CE10ms values were 1.4, 4.0, and 2.5 nM for dofetilide and 1300, 1800, and 12,200 nM for moxifloxacin. For cisapride, the CE10ms values were 8.0 and 4.4 nM in the conscious telemetered and conscious paced dog models. The drug-induced QT interval prolongation during the last 30 min of infusions 1 and 2 was comparable in the conscious models, but smaller in the anesthetized dog model. Terfenadine displayed a marked delay in onset of response, which could only be detected by the extended ECG recording. Discussion: All dog models investigated detected QT interval prolongation after administration of the investigated test substances with similar sensitivity, except for a lower sensitivity in the anesthetized dogs following moxifloxacin administration. The conscious telemetered dog model was favorable, mainly due to the extended continuous ECG recording, which facilitated detection and quantification of delayed temporal differences between systemic exposure and drug-induced QT interval prolongation.

Introduction: Drug-induced QT interval prolongation may lead to ventricular arrhythmias. The aim of the study was to optimize QT interval data processing to quantify drug-induced QT interval prolongation in the telemetry instrumented conscious dog model. Methods: The test substances cisapride, dofetilide, haloperidol, and terfenadine and corresponding vehicles were given to male and female beagle dogs during two consecutive 90-min intravenous infusions. Cardiovascular parameters were recorded for 24 h and exposure to the drugs was measured. The delayed response in the QT interval after an abrupt change in heart rate was investigated. Eight mathematical models to describe the QT interval–heart rate relationship were compared and different sets of covariates were used to quantify the drug-induced effect on the QT interval. Results: After an abrupt decrease in heart rate, a 75% adaptation of the QT interval was reached after 54 ± 9 s. A linear model was preferred to correct the drug-induced effect on the QT interval for heart rate, vehicle effect, serial correlation, plasma concentration and time of day. All test substances significantly prolonged the QT interval. Discussion: To optimize the processing of QT interval data, the delay in QT interval response after an abrupt change in heart rate should be considered. The QT interval–heart rate relationship and vehicle response were individual-specific and corrections were therefore made individually. When estimating the drug-induced effect on the QT interval it is considered advantageous to use plasma concentration as a covariate, as well as adjusting for vehicle effect and serial correlation in measurements. The conscious dog model detected significant increases in the QT interval for all test substances investigated.

Introduction The cardiovascular liability of candidate compounds can be evaluated by a number of methods including implanted telemetry, jacketed telemetry and surface lead electrocardiogram (ECG). The utility of the new PhysioTel™ Digital M11 cardiovascular telemetry implant was evaluated in monkeys and dogs. Methods Eight monkeys and dogs (4 males and 4 females per species) were implanted with the M11 device utilizing a femoral blood pressure catheter and periosteal ECG leads. The signal quality of the ECGs was determined as a percentage of software-matched waveforms and as a percentage of signal loss during the recording periods. To investigate sensitivity for detecting changes in QT/QTc and HR/BP, moxifloxacin and doxazosin were administered to monkeys and dogs implanted with the M11 device. Additionally, histopathological evaluation of the implant site was completed. Results For both monkey and dog, the percentage of recognizable waveforms was high (65% and 85%, respectively), while the average amount of signal loss was low (1% and 3%, respectively), indicating that the M11 implants delivered data of sufficient quality. In monkeys, moxifloxacin (90 mg/kg) induced QT and QTc prolongation up to 22 and 12 ms, respectively, while at 30 mg/kg in dogs, the maximal increases in QT and QTc were 13 and 16 ms, respectively. Doxazosin (1.5 and 1.0 mg/kg) produced HR increases up to 35 and 29 bpm with decreases in blood pressure up to − 14 and − 26 mm Hg in monkeys and dogs, respectively. The histopathological impact of the implant, catheter and biopotential leads was limited to expected minor local inflammatory changes as assessed at necropsy and with microscopic examination. Discussion Based upon the results of this study, the PhysioTel™ Digital M11 is a suitable technology for assessing cardiovascular parameters in monkeys and dogs, and because of the size and limited invasiveness of the implant, is well positioned for use on toxicology studies.

Noxafil® (posaconazole; POS) is a potent, selective triazole antifungal approved for use in adults as an oral suspension, oral tablet and intravenous (IV) Solution. In support of pediatric administration of POS IV Solution to childrentwo years of age, a nonclinical study in juvenile pre-weaning Beagle dogs was conducted, which showed enlarged lateral ventricles in the brain at the conclusion of a 6 week dosing period.To evaluate the impact of this finding on older age dogs, which would support administration to childrentwo years of age, two studies were undertaken using magnetic resonance imaging (MRI) to monitor brain ventricle size longitudinally during three months administration of POS IV in adult and juvenile dogs. Necropsy was performed on all animals at the end of the studies. From the baseline MRI images, great variability in ventricle size was noted in both the adult and juvenile dogs; these images were used to distribute differently sized ventricles between treatment and vehicle groups as to not skew group means during the course of the study.POS IV Solution had no effect on ventricle volume at any timepoint during dosing in either the adult or the juvenile dogs. Further, no gross or histomorphologic differences between groups were observed in either study. Compared to juvenile dogs, MRI analysis showed that adult dogs had larger ventricles, lower variability in all ventricle volumes, and a greater rate of increase in total ventricle volume.Information on growth and development of brains is one of the few areas in which more detailed information is available about humans than about the standard laboratory animals used to model disease and predict toxicities. The use of MRI helped elucidate large natural variabilities in the dog brain, which could have altered the interpretation of this de-risking study, and provided a valuable noninvasive means to monitor the brain ventricles longitudinally.

Introduction The objectives of this study were to provide baseline normative values for circadian changes in the time-series data collected over the course of a normal day in laboratory-housed dogs and to assess the relative efficiency of standard correction formulas to correct for the variations in QT intervals and heart rate functions. Methods One hundred and twenty-three beagle dogs (65 M, 58 F) were equipped with radiotelemetry transmitters and continuously monitored, while freely moving in their home cages. Electrocardiograms (ECGs), hemodynamic parameters (diastolic, systolic, and mean arterial pressures) as well as core body temperatures were recorded for 22 h. Results and discussion Blood pressures and core body temperatures demonstrated only very slight variations in their respective values over the 22-h monitoring period. ECGs were measured by a computerized waveform analysis program and quantitative elements reported as RR, PR, QRS, and QT intervals. Little circadian rhythmicity was demonstrated in the ECG intervals. Standard study-specific correction formulas appeared to satisfactorily normalize (i.e., compensate for) the relationship between heart rate and QT intervals in these beagle dogs but elevated the values of the QTc as compared to the uncorrected QT intervals. In sharp contrast, a subject-specific correction method based on analysis of covariance produced a more linear function between heart rates and QT intervals and, more importantly, provided QTc values within the normal range of actual, recorded QT interval data.

The beagle dog has been widely used in cardiovascular research, but the adequacy of QT prediction formulas in dogs over a wide range of RR intervals has not been evaluated sufficiently. We investigated the QT-RR relation in beagles by analysis of the QT and preceding RR intervals obtained from 24-h ambulatory electrocardiograms. The acceptability of 14 QT prediction formulas was evaluated by use of 100-150 selected pairs of QT-RR points per animal in seven male and seven female beagles. The accuracy of fit with the measured data was assessed according to the minimum Akaike information criterion. The best fit was given by the logarithmic and inverse Kovács' formulas among one- and two-parameter linear regression equations, respectively. Exponential formulas produced a better fit than did the linear regression formulas, but are impractical because of the complicated interpretation of parameters due to the nonlinearity. In addition, the results obtained under physiological conditions were also confirmed by those of the pharmacological intervention study with disopyramide. Consequently, we propose a one-parameter logarithmic formula (QTc= log600 x QT/logRR) for correcting the QT interval for a heart rate of 100 bpm and the inverse Kovács' formula for evaluating a reverse-use-dependency of QT prolongation.

Introduction Contemporary best practice recommendations in preclinical cardiovascular safety assessment promote 3Rs principles. This includes the employment of within-subjects experimental designs to evaluate discrete, acute doses of investigational new drugs, as well as the maintenance of stock colonies of appropriate large animal test systems. Such colony species are often tested repeatedly on independent studies with provision of appropriate recovery periods and requisite health status evaluations (e.g., physical examinations, electrocardiographic assessments, clinical pathology evaluations). Methods To investigate the utility of the often reiterative process of pre- or inter-study clinical pathology testing to help ascertain health status of non-naive, telemetered canines (beagle dogs), the present study collated the results of a randomly selected set of animals approximately every three months for a period of three years. Results Although occasionally a few routine hematology or clinical chemistry endpoints did demonstrate evidence of systematic trending over time, none of the observed fluctuations fell outside the range of expected biological variability, nor would have prevented assignment of any given animal to study. Discussion The present findings illustrate a high degree of consistency in routinely assessed clinical pathology parameters during the course of chronic telemetry instrumentation in the canine, including relative to historical control data in healthy, experimentally naive animals of the same species and source, maintained under analogous laboratory conditions. The data suggest that routine assessment of such parameters for the purposes of facilitating judgments concerning suitability for study may represent a pursuit of little overall value, and which may be reasonably accomplished based on alternative, observation-based screening procedures.

Introduction: The duration of the QRS interval is determined by the ion currents involved in cardiac depolarization. Class I antiarrhythmic drugs reduce cardiac excitability and conduction by inhibiting Nav1.5 channels responsible for I Na , thus increasing the QRS interval. Previous studies in humans as well as in animal models have demonstrated a more pronounced effect on QRS-prolongation during higher heart rates. In the present study, the effects of the Nav1.5 inhibitor flecainide on cardiovascular parameters, were studied in the telemetered beagle dog under normal autonomic control. The heart rate dependency of QRS prolongation was characterized using pharmacokinetic–pharmacodynamic (PKPD) modeling. Methods: Four male telemetered beagle dogs were administered placebo or flecainide (100, 150 and 200 mg) in a Latin square design. The QRS interval and heart rate were recorded, and blood samples were taken. Plasma concentrations of flecainide were fitted to a one compartment oral model and the intrapolated plasma concentrations were fitted to QRS and heart rate data sampled during 5 h after dosing. Results: Flecainide increased the QRS interval in all dogs, whereas there were no effects on heart rate. Using the PKPD model, a statistically significant heart rate-dependent QRS prolongation was linked to individual concentration–time profiles of flecainide. Discussion: PKPD analysis of QRS interval data from unrestrained dogs with sinus rhythm can elucidate mechanisms previously only described during controlled heart rhythm. Specific questions can therefore be addressed in generically designed cardiovascular telemetry safety studies and different types of relationships between parameters can be uncovered. In addition, the present approach can be used to better characterize drug-induced QRS effects in cardiovascular dog models.

Introduction The purpose of this study was: (1) to characterize and assess the incidence of spontaneous arrhythmias in totally naive Beagle dogs (n = 51; 10 males + 41 females): (2) to study the effects of permanent ECG- and LVP-probe telemetry implants both acutely and up to 233 days after surgery in a subset of 11 female Beagle dogs. Methods Naive ECG assessments were conducted by means of 6 external telemetry leads in jacketed dogs. Telemetry ECG recordings were captured by means of implanted telemetry devices suitable for ECG, LVP and aortic blood pressure recording. Experienced laboratory personnel visually evaluated all 22 h ECG recordings at different time points after implantation and evaluated the incidence and type of arrhythmia. Results The 51 healthy and totally naive Beagle dogs showed a prevalence of: 49.0% 2°AVB; 58.8% single atrial premature complexes; 17.6% junctional tachycardia; 27.5% ventricular complexes; 13.7% ventricular escape complexes; 21.6% ventricular premature complexes; 3.9% runs of ventricular complexes; 3.9% runs of ventricular escape complexes. As such, a high percentage of clinically normal Beagle dogs showed different types of arrhythmias when ECG's obtained by external telemetry leads were fully evaluated for a 22 h period. The chronic implantation of a ventricular probe through the apex of the heart in 11 dogs only, resulted in higher incidences and frequencies of ventricular episodes, which (in some dogs) extended up to 8 weeks. Eight months after surgery none of the implanted dogs showed ventricular tachycardia and only 10% had single ventricular or ventricular premature complexes at low frequencies. Discussion A thorough evaluation of the ECG's of Beagle dogs selected for telemetry implantation can help to avoid inherent arrhythmia-burdened dogs being implanted and used in studies where these arrhythmias will confound drug assessment by increasing the number of potential false positives.

Introduction Assessment of cardiovascular parameters, including the electrocardiogram (ECG) is required by the regulatory guidelines. In safety pharmacology studies, this is typically done using chronically implanted radiotelemetry devices in non-rodent species. Methods We compared ECG signal quality from ten male beagle dogs and 10 male cynomolgus monkeys with telemetry transmitters implanted using two surgical approaches: i) epicardial ECG lead placement via single incision, left side thoracotomy or ii) subcutaneous ECG lead placement via laparotomy. In addition, epicardial leads and semi-automated scoring were used in combination to detect changes in ECG values caused by moxifloxacin. Telemetry-instrumented male beagle dogs (n = 8) and male cynomolgus monkeys (n = 8) were given moxifloxacin at 10, 30, or 100 mg/kg (dogs) and 10, 50, or 175 mg/kg (monkeys) as a single dose by oral gavage. Results ECG signals were of excellent quality with epicardial lead placement, and human activity in the room did not significantly alter signal quality. Administration of moxifloxacin was associated with prolongation of QTc interval, in both dogs and monkeys in a dose-dependant pattern. Dogs given 30 mg/kg and 100 mg/kg, the maximum QTcf interval prolongations were 22 ms (+ 9%, 8 h postdose) and 60 ms (+ 24%, 15 h postdose). In monkeys given 50 and 175 mg/kg, the QTcb interval was significantly prolonged from 1 to 6 h postdose, and QTcb interval prolongation persisted in monkeys given 175 mg/kg through 19 h postdose. In monkeys given 175 mg/kg, the maximum QTcb interval prolongation was 43 ms (+ 12.9%, 16 h postdose). Discussion The present study demonstrated that placing leads directly on the epicardium drastically diminishes signal disruption due to room disturbances and subsequent animal excitement. This novel surgical model demonstrated adequate sensitivity to detect changes in ECG parameters, specifically QTc interval prolongation in both the dog and monkey.

Introduction Animals are commonly used in toxicological research for the evaluation of drug effects on the cardiovascular system. Accurate and reproducible determination of blood pressure (BP) in conscious, manually restrained monkeys and dogs is a challenge with current non-invasive cuff techniques. The High Definition Oscillometry (HDO) technique enables real time measurements with immediate visual feedback via PC screen on data validity. HDO measurements are considerably faster with a duration of approximately 8 to 15 s than conventional cuff methods that can take several minutes. Methods HDO Memo Diagnostic Model Science and Cardell BP Monitor Model 9401 measurements were compared for accuracy and reliability with simultaneously recorded direct blood pressure data captured via radiotelemetry. Six monkeys and six dogs implanted with DSI PCT telemetry transmitters were used; BP data were collected by all methods under manual constraint and compared. Measurements were performed with HDO and Cardell in the presence of a BP lowering drug (hexamethonium bromide). Systolic, diastolic, mean arterial pressure, and pulse rate were determined before, during and following up to 10 mg/kg hexamethonium administration via intravenous slow bolus injection. Results Drug induced hemodynamic changes could be detected in monkeys and dogs with the HDO method but only in dogs with the Cardell method. Correlation coefficients were generally higher for HDO versus Telemetry than Cardell versus Telemetry comparisons, indicating that this novel, non-invasive technique produces reliable blood pressure data and is able to detect drug-induced hemodynamic changes. Discussion HDO provides an alternative approach for invasive telemetry surgeries to obtain reliable hemodynamic data in animal models for cardiovascular research when invasive techniques are not warranted.

Introduction The primary objective of this investigation was to evaluate the sensitivity of a non-invasive telemetry system for the detection of drug-induced electrocardiogram (ECG) changes in conscious, freely moving dogs. A secondary objective was to compare, in the same set of dogs, ECG data acquired by a non-invasive system with data acquired from a surgically implanted telemetry device (invasive system). Methods Continuous beat-to-beat Lead II ECG data were simultaneously acquired from 6 male dogs using a non-invasive and an invasive telemetry system for 1 h pre-dose and 6 h following a sham control dose or single oral doses of (±) sotalol (4, 8 or 16 mg/kg). ECG parameters of heart rate, RR, PQ, QRS, QT and QT corrected for heart rate according to Van de Water (QTcV) and by an individual linear regression formula (QTcR), were determined. Results and discussion Statistically significant dose-dependent reduction of heart rate, and increases in PQ, QT and QTc (V and R) were detected at all dose levels of (±) sotalol, with partial recovery during the 6-hour monitoring period. Statistically significant correlations for heart rate, RR, PQ, QT and QTc (V and R) were found between the two systems. QRS duration did not correlate. However, the difference between the two systems was consistent over the range studied. Based on these findings, the non-invasive system is quantitatively comparable to invasive telemetry, and can be used successfully to acquire continuous ECG data on a beat-to-beat basis from conscious freely moving dogs for at least 6 h post-dose.