Conscious Dogs Research Articles

AST-120, an Adsorbent of Uremic Toxins, Improves the Pathophysiology of Heart Failure in Conscious Dogs.

Several lines of evidence suggest that renal dysfunction is associated with cardiovascular toxicity through the action of uremic toxins. The levels of those uremic toxins can be reportedly reduced by the spherical carbon adsorbent AST-120. Because heart failure (HF) causes renal dysfunction by low cardiac output and renal edema, the removal of uremic toxins could be cardioprotective. To determine whether blood levels of the uremic toxin indoxyl sulfate (IS) increase in HF and whether AST-120 can reduce those levels and improve HF. We induced HF in 12 beagle dogs by 6weeks of rapid right ventricular pacing at 230 beats per min. We treated six dogs with a 1-g/kg/day oral dosage of AST-120 for 14days from week 4 after the start of rapid ventricular pacing. The other six dogs did not receive any treatment (control group). In the untreated dogs, IS levels increased as cardiac function deteriorated. In contrast, plasma IS levels in the treated dogs decreased to baseline levels, with both left ventricular fractional shortening and pulmonary capillary wedge pressure also improving when compared with untreated dogs. Finally, AST-120 treatment was shown to reduce both myocardial apoptosis and fibrosis along with decreases in extracellular signal-regulated kinase phosphorylation, the Bax/Bcl-2 ratio, and TGF-β1 expression and increases in AKT phosphorylation. IS levels are increased in HF. AST-120 treatment reduces the levels of IS and improves the pathophysiology of HF in a canine model. AST-120 could be a novel candidate for the treatment of HF.

Vagus nerve stimulation reduces ventricular arrhythmias and increases ventricular electrical stability.

Transcutaneous stimulation of the auricular branch of the vagus nerve (AB-VNS) is a potentially noninvasive, inexpensive, and safe approach for vagus nerve stimulation that suppresses the induction and duration of atrial fibrillation and reduces sympathetic nerve outflow in healthy humans. Researchers have not determined whether AB-VNS affects ventricular arrhythmias. To evaluate the antiarrhythmic effects of noninvasive AB-VNS on ventricular arrhythmias induced by myocardial infarction (MI). Twelve beagle dogs were randomly divided into the following two groups: a AB-VNS group (coronary artery occlusion and noninvasive AB-VNS) and a control group (coronary artery occlusion but without AB-VNS). We examined spontaneous ventricular arrhythmias, ventricular electrophysiological properties, and cardiac function in conscious dogs. Morphology, fibrosis, and ultrastructures were also assessed. AB-VNS significantly reduced the occurrence of spontaneous ventricular arrhythmias, including isolated premature ventricular complexes, ventricular couplets, ventricular bigeminy, ventricular trigeminy, and ventricular tachycardia. AB-VNS effectively increased ventricular electrical stability, including significantly prolonged ventricular effective refractory periods, decreased the dispersion of effective refractory period, enhanced the ventricular fibrillation threshold, and decreased the maximum slope of the monophasic action potential duration restitution curve. AB-VNS treatments alleviate ventricular interstitial fibrosis after MI. However, cardiac function was not improved, and MI-induced ultrastructural changes in the myocardium were not reversed by 4weeks of AB-VNS. In addition, AB-VNS for 4weeks resulted in mild mitochondrial swelling within the neuronal axons of the auricular vagus fiber. Noninvasive AB-VNS reduces the occurrence of spontaneous ventricular arrhythmias in conscious dogs with MI. AB-VNS increases ventricular electrical stability and alleviates ventricular interstitial fibrosis induced by MI.

Long-term endurance training-induced cardiac adaptation in new rabbit and dog animal models of the human athlete’s heart

Sudden cardiac death in athletes is rare and most often unexpectable. For a better understanding of cardiac remodeling, this study presents the effects of chronic vigorous exercise on cardiac structure and electrophysiology in new rabbit and dog athlete's heart models. Rabbits and dogs were randomized into sedentary ('Sed'), exercised (subjected to 16 weeks chronic treadmill exercise ('Ex') groups, and a testosterone-treated ('Dop') group in dogs. Echocardiography and electrocardiogram were performed. Proarrhythmic sensitivity and autonomic responses were tested in conscious dogs. 'Ex' animals exhibited left ventricular enlargement with bradycardia (mean RR in 'Ex' vs. 'Sed' rabbits: 335 ± 15 vs. 288 ±19 ms, p ≤ 0.05, and in 'Dop' vs. 'Ex' vs. 'Sed' dogs: 718 ± 6 vs. 638 ± 38 vs. 599 ± 49 ms) accompanied by an increase of heart rate variability in both species (e.g. SD RR in 'Ex' vs. 'Sed' rabbits: 3.4 ± 0.9 vs. 1.4 ± 0.1 ms, p ≤ 0.05, and in 'Dop' vs. 'Ex' vs. 'Sed' dogs: 156 ± 59 vs. 163 ± 44 vs. 111 ± 49 ms) indicating an increased vagal tone. A lower response to parasympatholytic agent atropine and more pronounced QTc interval lengthening after dofetilide challenge were found in 'Ex' and 'Dop' dogs compared to the 'Sed' group. No morphological and functional changes were found after chronic steroid treatment in dogs. The structural-functional findings share more similarities with human athlete's heart. Slight repolarization sensitivity in the exercised dogs may indicate an increased risk of arrhythmias in athletes under different circumstances. These animal models might be useful for the further investigations of the cardiovascular effects of competitive training.

Intracranial pressure monitoring in normal dogs using subdural and intraparenchymal miniature strain-gauge transducers.

BackgroundMonitoring of intracranial pressure (ICP) is a critical component in the management of intracranial hypertension. Safety, efficacy, and optimal location of microsensor devices have not been defined in dogs.Hypothesis/ObjectiveAssessment of ICP using a microsensor transducer is feasible in anesthetized and conscious animals and is independent of transducer location. Intraparenchymal transducer placement is associated with more adverse effects.AnimalsSeven adult, bred‐for‐research dogs.MethodsIn a prospective investigational study, microsensor ICP transducers were inserted into subdural and intraparenchymal locations at defined rostral or caudal locations within the rostrotentorial compartment under general anesthesia. Mean arterial pressure and ICP were measured continuously during physiological maneuvers, and for 20 hours after anesthesia.ResultsBaseline mean ± SD values for ICP and cerebral perfusion pressure were 7.2 ± 2.3 and 78.9 ± 7.6 mm Hg, respectively. Catheter position did not have a significant effect on ICP measurements. There was significant variation from baseline ICP accompanying physiological maneuvers (P < .001) and with normal activities, especially with changes in head position (P < .001). Pathological sequelae were more evident after intraparenchymal versus subdural placement.Conclusions and Clinical ImportanceUse of a microsensor ICP transducer was technically straightforward and provided ICP measurements within previously reported reference ranges. Results support the use of an accessible dorsal location and subdural positioning. Transient fluctuations in ICP are normal events in conscious dogs and large variations associated with head position should be accounted for when evaluating animals with intracranial hypertension.

Canine urethral sphincter pressure profile under incremental inflation of an artificial cuff: a cadaver study.

To determine whether artificial urethral sphincter filling volume is proportional to peak pressure exerted on the urethra. Urethral pressure profilometry was performed in five female, medium-sized, mixed-breed canine cadavers following artificial urethral sphincter placement. Maximum urethral pressure was recorded following sequential incremental inflation of 0.15 mL and compared to baseline pressure and between dogs using two-way analysis of variance. Artificial urethral sphincter placement in cadavers was associated with an increase in urethral pressure, which was significantly correlated with inflation volume. The correlation was non-linear and demonstrated considerable individual variation. Maximum urethral pressures after artificial urethral sphincter placement exceeded those reported in conscious continent dogs within a narrow volume range, in which a 0.15 mL infusion more than doubled maximal urethral pressures. Rapid increases in urethral pressure from the artificial urethral sphincter over a small range of filling volumes (0.15 mL increments) might explain why some clinical cases can become suddenly dysuric following incremental inflations. We suggest that smaller increments of filling (0.05to 0.1mL) may achieve finer pressure control.

Acute Enhancement of Cardiac Function by Phosphodiesterase Type 1 Inhibition.

Phosphodiesterase type-1 (PDE1) hydrolyzes cAMP and cGMP and is constitutively expressed in the heart, although cardiac effects from its acute inhibition in vivo are largely unknown. Existing data are limited to rodents expressing mostly the cGMP-favoring PDE1A isoform. Human heart predominantly expresses PDE1C with balanced selectivity for cAMP and cGMP. Here, we determined the acute effects of PDE1 inhibition in PDE1C-expressing mammals, dogs, and rabbits, in normal and failing hearts, and explored its regulatory pathways. Conscious dogs chronically instrumented for pressure-volume relations were studied before and after tachypacing-induced heart failure (HF). A selective PDE1 inhibitor (ITI-214) was administered orally or intravenously±dobutamine. Pressure-volume analysis in anesthetized rabbits tested the role of β-adrenergic and adenosine receptor signaling on ITI-214 effects. Sarcomere and calcium dynamics were studied in rabbit left ventricular myocytes. In normal and HF dogs, ITI-214 increased load-independent contractility, improved relaxation, and reduced systemic arterial resistance, raising cardiac output without altering systolic blood pressure. Heart rate increased, but less so in HF dogs. ITI-214 effects were additive to β-adrenergic receptor agonism (dobutamine). Dobutamine but not ITI-214 increased plasma cAMP. ITI-214 induced similar cardiovascular effects in rabbits, whereas mice displayed only mild vasodilation and no contractility effects. In rabbits, β-adrenergic receptor blockade (esmolol) prevented ITI-214-mediated chronotropy, but inotropy and vasodilation remained unchanged. By contrast, adenosine A2B-receptor blockade (MRS-1754) suppressed ITI-214 cardiovascular effects. Adding fixed-rate atrial pacing did not alter the findings. ITI-214 alone did not affect sarcomere or whole-cell calcium dynamics, whereas β-adrenergic receptor agonism (isoproterenol) or PDE3 inhibition (cilostamide) increased both. Unlike cilostamide, which further enhanced shortening and peak calcium when combined with isoproterenol, ITI-214 had no impact on these responses. Both PDE1 and PDE3 inhibitors increased shortening and accelerated calcium decay when combined with forskolin, yet only cilostamide increased calcium transients. PDE1 inhibition by ITI-214 in vivo confers acute inotropic, lusitropic, and arterial vasodilatory effects in PDE1C-expressing mammals with and without HF. The effects appear related to cAMP signaling that is different from that provided via β-adrenergic receptors or PDE3 modulation. ITI-214, which has completed phase I trials, may provide a novel therapy for HF.

Effects of 6% tetrastarch or lactated Ringer's solution on blood coagulation in hemorrhaged dogs

BackgroundTetrastarch solution (TS) can impair coagulation but the clinical relevance of this impairment is unclear in veterinary medicine.ObjectiveCompare the effects of volume replacement (VR) with lactated Ringer's solution (LRS) or 6% TS on coagulation in hemorrhaged dogs.AnimalsSix healthy English Pointer dogs (19.7‐35.3 kg).MethodsProspective crossover study. Dogs were anesthetized without hemorrhage and VR (control). Two weeks later, dogs were hemorrhaged under anesthesia on 2 occasions (8‐week washout intervals) and randomly received VR with LRS or TS at 3:1 or 1:1 of shed blood, respectively, aiming to decrease the hematocrit to 33%. Rotational thromboelastometry and other coagulation variables were determined before 0.5, 2, and 4 hours after VR during anesthesia and 24 hours after VR (conscious dogs).ResultsBuccal mucosal bleeding time did not differ between treatments after VR. Activated partial thromboplastin time increased from controls 4 hours after TS (P = 0.045). Clot formation time (CFT) and alfa‐angle increased from controls from 0.5 to 4 hours after LRS (CFT, P ≤ 0.0001‐0.02; alpha angle, P = 0.0001‐0.02) and from 0.5 to 2 hours after TS (CFT, P = 0.0002‐0.01; alpha angle, P = 0.0005‐0.02). The maximum clot firmness decreased from controls from 0.5 to 4 hours after LRS (P ≤ 0.0001‐0.01) and TS (P ≤ 0.0001‐0.04).Conclusions and Clinical RelevanceTetrastarch does not impair primary hemostasis and induces transient dilutional coagulopathy that is similar to LRS because, when compared to a 3 times higher volume of LRS in hemorrhaged dogs, it does not cause greater interference on the viscoelastic properties of the coagulum.

Gastrointestinal effects following acupuncture at Pericardium-6 and Stomach-36 in healthy dogs: a pilot study.

To quantify changes in gastric and intestinal emptying times in the conscious dog following gastrointestinal acupoint stimulation. In a randomised, blinded crossover study, six dogs were fed 30×1.5 mm barium-impregnated polyethylene spheres and underwent: (1) no acupuncture (Control); (2) stimulation of target points PC6 and ST36 (Target) and (3) stimulation of non-target points LU7 and BL55 (Sham). Abdominal radiographs were assessed immediately after feeding the spheres and every hour for 12 hours and their number in the stomach and large intestines was counted. The number of barium-impregnated polyethylene spheres found distal to the stomach was less in the Target group compared to the Control and Sham groups between hours 2 and 4, but no differences between groups were seen for the remainder of the treatment period. The number of spheres found within the colon/rectum was less in the Target group compared to the Control and Sham groups between hours 4 and 6, and compared to the Sham group only at hour 7 but no differences between groups were seen after hour 8. Acupuncture targeted at the gastrointestinal tract of dogs was associated briefly with slowed gastric emptying and gastrointestinal transit time. This foundational study lays the groundwork for additional studies of acupuncture effects associated with altered physiologic states.

Cranial versus caudal thoracic epidural anesthesia using three volumes of lidocaine in conscious Beagle dogs

ObjectiveTo compare the effects of epidural injection of three volumes of lidocaine injected at the third (T3) or eleventh thoracic vertebra (T11) in conscious dogs to induce thoracic epidural anesthesia (TEA) and to measure the epidural dispersion of iohexol under similar conditions. Study designProspective crossover experiment. AnimalsA group of five Beagle dogs weighing 10.4 ± 0.5 kg (mean ± standard deviation). MethodsEach dog was anesthetized twice, separated by 1 week, for inserting an epidural catheter at the lumbosacral space and advancing the tip to T3 (treatment TEAT3) or T11 (treatment TEAT11). For each treatment, three volumes of 2% lidocaine (0.05, 0.10 and 0.20 mL kg–1) were administered at 24 hour intervals, and sensory blockade (SB) of dermatomes was estimated by pinching the skin with mosquito forceps. Under identical conditions of injection volume and site, iohexol was administered 3 hours after lidocaine injection to identify epidural distribution (ED) using computed tomography. The effects of injection site and volume on SB of thoracic dermatomes and ED were analyzed using a linear mixed model (p < 0.05). ResultsThoracic SB and ED significantly increased as the volume increased (p < 0.001 and p < 0.001, respectively), and significantly decreased in TEAT3 than in TEAT11 (p = 0.011 and p = 0.002, respectively). Cervical SB was obtained in three of five dogs in TEAT3 and two of five dogs in TEAT11 injected with 0.20 mL kg–1. One dog showed temporary inspiratory stridor probably caused by bilateral laryngeal paralysis, but no hypoxia. Conclusions and clinical relevanceTEA induced at T3 produced less thoracic SB than did TEA at T11 with the same volumes of lidocaine. The cervical SB obtained with the highest volume of lidocaine may increase the risk of laryngeal paralysis and pulmonary aspiration.

Pharmacokinetics of intramuscular alfaxalone and its echocardiographic, cardiopulmonary and sedative effects in healthy dogs.

The pharmacokinetics and the effects of a single intramuscular (IM) dose of alfaxalone on sedation and cardiopulmonary and echocardiographic variables was studied in dogs. Twelve healthy adult Beagles (3 females, 9 males) were used in this prospective controlled cross-over trial. Echocardiography was performed with and without 4 mg kg-1 alfaxalone IM with a week wash-out interval. Sedation (19-point scale; 0 = no sedation), cardiopulmonary parameters, blood gas analysis and plasma concentration of alfaxalone were assessed every 5 minutes following the injection (T0). The influence of the alfaxalone plasma concentration and time on physiological variables was tested using a linear model whereas echocardiographic measurements were compared between conscious and alfaxalone-administered dogs using paired t-tests. Compared to baseline, alfaxalone administration was followed by an increase in heart rate (HR) from T5 to T30 and a decrease in mean arterial pressure (MAP) at T10, T25 and T30, in stroke volume (SV; 15 ± 5 to 11 ± 3 ml; P<0.0001), and end-diastolic volume (EDV; 24.7 ± 5.7 to 19.4 ± 4.9 ml). Cardiac output (CO) and blood gas analysis did not change significantly throughout. Mean plasma half-life was 29 ± 8 minutes, volume of distribution was 1.94 ± 0.63 L kg-1, and plasma clearance was 47.7 ± 14.1 ml kg-1 minute-1. Moderate to deep sedation was observed from T5 to T35. Ten dogs showed paddling, trembling, nystagmus and strong reaction to sound during the procedure. Although there were no significant changes in CO and oxygenation, the impact of HR, MAP, SV, EDV alterations requires further investigations in dogs with cardiac disease.

Enterically delivered insulin tregopil exhibits rapid absorption characteristics and a pharmacodynamic effect similar to human insulin in conscious dogs.

Current therapy fails to emulate rapid (first-phase) insulin release in relation to a meal, a key defect in types 1 and 2 diabetes. We aimed to quantify the pharmacokinetic (PK) and pharmacodynamic (PD) profile of insulin tregopil, an enterically-absorbed insulin analog that restores the normal distribution of insulin between the hepatic portal and peripheral circulations. The PK and PD profiles of insulin tregopil were studied in overnight-fasted, catheterized, conscious canines using four approaches: (1) equimolar intraportal infusions of tregopil vs human insulin; (2) escalating doses of oral tregopil; (3) identical, consecutive enteric doses of tregopil; and (4) comparison of oral tregopil to inhaled and subcutaneous human insulin administration. Equimolar intraportal infusions of tregopil and human insulin resulted in very similar PK profiles and PD profiles were nearly identical. Enteric delivery of tregopil brought about rapid absorption with tmax = 20 minutes in most cases. Median tmax was 20 minutes for oral tregopil and inhaled insulin and 88 minutes for subcutaneous human insulin. The time required for arterial plasma insulin levels to return to baseline was approximately 90, 210 and 360 minutes for oral tregopil, inhaled insulin and subcutaneous insulin, respectively. Enterically delivered tregopil is rapidly absorbed and restores a portal-to-peripheral vascular distribution. These characteristics should improve postprandial hyperglycaemia in types 1 and 2 diabetes.

Elobixibat, an ileal bile acid transporter inhibitor, induces giant migrating contractions during natural defecation in conscious dogs.

Chronic constipation affects 14%-17% of the population. Elobixibat, a novel, ileal bile acid transporter (IBAT) inhibitor, has been approved as a new chronic constipation drug in Japan in January 2018. The present study aimed to examine the pharmacological effects of elobixibat on colonic motility in conscious dogs using a telemetry system. Six male beagle dogs were surgically implanted with strain gauge force transducers for gastrointestinal (GI) motility recording. The motility index was calculated from GI motility at each recording site in conscious and nonrestraint dogs. The fasted dogs were orally administered elobixibat (3, 10, or 30mg kg-1 ) or 30mg kg-1 of sennoside as positive control or vehicle using a crossover design and washout period of more than 6days. One hour after drug administration, the dogs were fed chow, and GI motility and defecation were observed for 10hours; GI motility was quantified to calculate giant migrating contractions (GMCs). Fecal bile acids (BAs) were determined as well. Elobixibat and sennoside significantly increased the number of defecations, fecal wet weight, and water content within 10hours after administration. Elobixibat dose-dependently decreased the time to first bowel movement, increased the amount of total fecal BAs, and rapidly induced mild GMCs during defecation; however, higher strength of GMCs was observed with sennoside. Elobixibat induces bowel movements faster than sennoside through a different mechanism. Elobixibat locally inhibits IBAT in the ileal lumen, leading to elevated fecal BAs in the colon and induced mild GMCs during defecation.

A longitudinal assessment of periodontal health status in 53 Labrador retrievers.

To determine the incidence and rates of progression of gingivitis and periodontitis in Labrador retrievers. Fifty-three dogs, aged 1·1 to 5·9 years, had their periodontal health assessed every 6 months for up to 2 years. The extent of gingivitis and periodontitis was measured around the whole gingival margin of every tooth under general anaesthesia. All dogs had gingivitis at the initial assessment. The majority (64·2%) of tooth aspects had very mild gingivitis. The palatal/lingual aspect of all tooth types was most likely to show bleeding when probed: 63·0% of these aspects had mild or moderate gingivitis. Over 2 years, 56·6% of dogs developed periodontitis and dogs as young as 1·9 years were affected. There was a significant positive correlation between the proportion of teeth with periodontitis and age. In total, 124 teeth (5·7%) developed periodontitis; 88 (71·0%) of these were incisors. The palatal/lingual aspect of the incisors developed the disease first (2·8% of incisor aspects). Periodontitis developed in regions that are difficult to see in conscious dogs implying that detection and treatment of disease requires periodic sedation or anaesthesia.

Effects of Calcitonin Gene-Related Peptide on Colonic Motility and Defecation in Conscious Dogs

BackgroundAlthough intra-arterial infusion of calcitonin gene-related peptide (CGRP) reportedly stimulates giant migrating contractions (GMCs) of the small intestine in conscious dogs, the effect of intravenous CGRP administration on colonic motility remains unclear. In the present study, we investigated the effects of intravenous CGRP on colonic motility and defecation and determined the underlying mechanism of action in conscious dogs. MethodsSixteen Beagle dogs weighing 11–13 kg were included. The effects of intravenous CGRP at doses of 3.33 (with various antagonists), 0.83, and 1.67 μg/kg on colonic motility and defecation were evaluated in neurally intact dogs (n = 6). For comparison, dogs with transection/re-anastomosis (T/R) between the proximal and middle segments of the colon (n = 5) and dogs with extrinsic denervation of the ileocolonic segments (n = 5) also received intravenous CGRP at 3.33 μg/kg. All dogs were equipped with strain gauge force transducers on the ileocolon for measurement of the colonic contractile activity. ResultsIntravenous CGRP evoked GMCs and defecation in the neurally intact group; these stimulatory effects were inhibited by atropine and hexamethonium. Compared with the neurally intact group, the T/R group exhibited similar proximal colonic motility and decreased distal colonic motility after intravenous CGRP administration, whereas the extrinsic denervation group exhibited increased colonic motility overall. ConclusionsIntravenous CGRP induces colonic motility and defecation through acetylcholine release in conscious dogs. The continuity of the enteric nerves plays an important role in CGRP-induced colonic contractions and defecation, while the extrinsic nerves suppress CGRP-induced colonic motility.

Abstract 3945: CBT-102, an oral multi-kinase small molecule, demonstrates favorable activity in human hepatocellular carcinoma animal models and cardiac safety in rabbit Purkinje and beagle dogs compared to sorafenib

Abstract Background: Cancer is a complex disease involving disruption of more than one receptor or signaling pathway. Inhibiting multiple oncogenic targets have been shown to be an important strategy in managing relapse and resistance. CBT-102 is an oral mTKI inhibiting several key oncogenic drivers including angiogenesis via VEGFR and PDGFR, MAPK pathway via B-RAF and C-RAF, in addition to inhibiting RET, CSF1R, c-KIT, and FLT3. Antitumor activity of CBT-102 was compared to sorafenib in two human primary HCC carcinoma xenografts in nude mice (LIMsh050 and PLCPRF5) and cardiac safety was evaluated in rabbit heart Purkinje fibers and in conscious telemeterized beagle dogs. Methods: Female BALB/c nude mice were inoculated with LIMsh050 and PLCPRF5 tumors to establish the tumor models. In the LIMsh050 model, CBT-102 was administered orally QD x 21 days at 4, 10, and 25 mg/kg and sorafenib at 10 mg/kg (n=8/group). In the PLCPRF5 model, CBT-102 was administered orally QD x 14 days at 3, 8, and 20 mg/kg vs. 8 and 20 mg/kg sorafenib group (n=7/group). In both experiments, in addition to tumor volume, body weight and mortality were monitored. For the cardiac safety studies, rabbit Purkinje fibers were isolated from adult rabbit right heart perfused for 10 minutes with vehicle control, CBT-102 groups (1, 3, and 10 µM) or sorafenib and changes in action potentials were measured. In the second study, ECG parameters were measured after single oral administration of CBT-102 at 15, 45, and 67.5 mg/kg to beagle dogs (n=6/group) via telemetry for 24 h. Results: In both the LIMsh050 and PLCPRF5 models, CBT-102 and sorafenib doses were well tolerated with no suspension of dosing due to weight loss or deaths. CBT-102 demonstrated inhibition of tumor growth in both models, to a significantly greater extent than sorafenib at comparable doses. In the PLCPRF5 model, CBT-102 demonstrated an ED50 of 2.5 mg/kg vs. 16.8 mg/kg of sorafenib. Importantly, unlike sorafenib, CBT-102 did not show a cardiac liability: there were no changes in action potential duration in rabbit Purkinje fibers nor any changes in cardiac conduction parameters (HR, QTc, RR, PR, and QRS intervals) in beagle dogs. Conclusions: CBT-102 demonstrated improved efficacy in HCC xenografts models compared to sorafenib and does not appear to have the cardiac liability observed with sorafenib. CBT-102 will advance into GLP toxicology studies with a potential IND filing in 2H 2018. Citation Format: Sarath Kanekal, Xiquan Zhang, Yanrui Song, Tan Wenmiao, Juan Zhang, Deyi Zhang, Henry Li, Mamatha Reddy, Gavin Choy, Sanjeev Redkar. CBT-102, an oral multi-kinase small molecule, demonstrates favorable activity in human hepatocellular carcinoma animal models and cardiac safety in rabbit Purkinje and beagle dogs compared to sorafenib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3945.

Metabolic Clearance Rate of Insulin Is Not Saturable within the Physiological Range

The plasma concentration of insulin is determined by pancreatic beta cell secretion and the metabolic clearance of the hormone. It has been suggested that the concentration of insulin determines its metabolic clearance rate. Also, some reports suggest that clearance is saturable and insulin kinetics are non-linear even within physiologic ranges. We assessed the metabolic clearance rate of insulin at different physiologic concentrations to access if clearance changes with concentration. Using the dog model (n=12), insulin was infused peripherally at 3 incremental rates (dose-response) during the euglycemic clamp. Each infusion rate spanned 90mins, and the last 30mins was considered the steady state. The metabolic clearance rate of insulin was calculated as the ratio of the infusion rate to the steady state plasma concentration. The 3 infusion rates, 1.5, 3.0 and 4.5pmol/kg/min yielded steady state plasma insulin concentrations of 92 ± 8, 165 ± 12 and 256 ± 18pM respectively. The metabolic clearance rate of insulin was consistent and independent of dose (17.8 ±1.7, 19.1 ±1.2 and 18.6 ±1.4 ml/kg/min; p = ns) across the different plasma insulin infusion rates. Also, we found a strong linear correlation (r = 0.99) between the infusion rates and steady state insulin concentrations. Insulin kinetics are linear and the metabolic clearance of insulin is not saturable within physiologic ranges in the conscious dog. Though it’s possible that the site of degradation (i.e., liver vs. periphery) may change with dose.These data demonstrate that changing concentrations of plasma insulin within physiologic concentrations does not change the rate of insulin removal from the plasma. Disclosure I. Asare Bediako: None. R.L. Paszkiewicz: None. O.O. Woolcott: None. R.N. Bergman: Advisory Panel; Self; Ingredion, Inc.. Research Support; Self; AstraZeneca. Consultant; Self; GI Dynamics Inc.. Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases. Consultant; Self; Novo Nordisk A/S.

Lys5,MeLeu9,Nle10]-NKA(4-10) Elicits NK2 Receptor-Mediated Micturition and Defecation, and NK1 Receptor-Mediated Emesis and Hypotension, in Conscious Dogs.

Tachykinin neurokinin 2 (NK2) receptor agonists may have potential to alleviate clinical conditions associated with bladder and gastrointestinal underactivity by stimulating contraction of visceral smooth muscle. The ability of [Lys5,MeLeu9,Nle10]-neurokinin A(4-10) (LMN-NKA) to elicit micturition and defecation was examined after repeated administration in groups of 2-10 conscious dogs. Administration of 10-100 μg/kg, i.v., four times daily for six consecutive days, reliably elicited micturition after ≥90% of doses and defecation after ≥50% of doses. Voiding occurred <4 minutes after dosing and was short lasting (<10 minutes). LMN-NKA was well tolerated, with emesis after ∼25% of doses at 100 μg/kg, i.v. Hypotension was induced by 100 μg/kg, i.v., of LMN-NKA but not by lower doses. Administration of 30-300 μg/kg, s.c., twice daily for seven consecutive days, reliably elicited both urination and defecation after 88%-100% of doses, and was accompanied by a high rate of emesis (50%-100%). The onset of voiding was rapid (<7 minutes) but was more prolonged than after intravenous administration (30-60 minutes). Emesis induced by 30 or 300 μg/kg, s.c., of LMN-NKA was significantly reduced (from 58% to 8% and from 96% to 54%, respectively) by a 30-minute pretreatment with the neurokinin 1 (NK1) receptor antagonist, (2S,3S)-N-(2-methoxybenzyl)-2-phenylpiperidin-3-amine (CP-99,994; 1 mg/kg, s.c.). The ability of selective NK2 receptor agonists to elicit on-demand voiding could potentially address a major unmet need in people lacking voluntary control of micturition and/or defecation. LMN-NKA unexpectedly activated NK1 receptors at doses that stimulated voiding, causing emesis and hypotension that may limit the clinical utility of nonselective NK2 receptor agonists.

Influence of immune-mediated hemolytic anemia on flow velocities in the portal vein and caudal vena cava measured by use of pulsed-wave Doppler ultrasonography in dogs.

OBJECTIVE To compare blood flow velocities of the portal vein (PV) and caudal vena cava (CVC) measured by use of pulsed-wave Doppler ultrasonography in clinically normal dogs and dogs with primary immune-mediated hemolytic anemia (IMHA). ANIMALS 11 client-owned dogs admitted to a veterinary teaching hospital for management of primary IMHA and 21 staff- or student-owned clinically normal dogs. PROCEDURES Flow velocities in the PV and CVC at the porta hepatis were evaluated in conscious unsedated dogs with concurrent ECG monitoring; evaluations were performed before dogs with IMHA received heparin or blood transfusions. Three measurements of peak velocity at end expiration were obtained for each vessel, and the mean was calculated. Results were compared between IMHA and control groups. RESULTS Mean ± SD blood flow velocity in the CVC differed between control (63.0 ± 18.6 cm/s) and IMHA (104 ± 36.9 cm/s) groups. Variance in dogs with IMHA was significantly greater than that for the clinically normal dogs. No significant difference in blood flow velocity in the PV was detected between IMHA and control dogs. CONCLUSIONS AND CLINICAL RELEVANCE Higher blood flow velocities were detected by use of pulsed-wave Doppler ultrasonography in the CVC of dogs with naturally occurring IMHA and may be used to predict anemia in patients suspected of having IMHA.

Morning Hyperinsulinemia Primes the Liver for Glucose Uptake and Glycogen Storage Later in the Day.

We observed that a 4-h morning (AM) duodenal infusion of glucose versus saline doubled hepatic glucose uptake (HGU) and storage during a hyperinsulinemic-hyperglycemic (HIHG) clamp that afternoon (PM). To separate the effects of AM hyperglycemia versus AM hyperinsulinemia on the PM response, we used hepatic balance and tracer ([3-3H]glucose) techniques in conscious dogs. From 0 to 240 min, dogs underwent a euinsulinemic-hyperglycemic (GLC; n = 7) or hyperinsulinemic-euglycemic (INS; n = 8) clamp. Tracer equilibration and basal sampling occurred from 240 to 360 min, followed by an HIHG clamp (360-600 min; four times basal insulin, two times basal glycemia) with portal glucose infusion (4 mg ⋅ kg-1 ⋅ min-1). In the HIHG clamp, HGU (5.8 ± 0.9 vs. 3.3 ± 0.3 mg ⋅ kg-1 ⋅ min-1) and net glycogen storage (6.0 ± 0.8 vs. 2.9 ± 0.5 mg ⋅ kg-1 ⋅ min-1) were approximately twofold greater in INS than in GLC. PM hepatic glycogen content (1.9 ± 0.2 vs. 1.3 ± 0.2 g/kg body weight) and glycogen synthase (GS) activity were also greater in INS versus GLC, whereas glycogen phosphorylase (GP) activity was reduced. Thus AM hyperinsulinemia, but not AM hyperglycemia, enhanced the HGU response to a PM HIHG clamp by augmenting GS and reducing GP activity. AM hyperinsulinemia can prime the liver to extract and store glucose more effectively during subsequent same-day meals, potentially providing a tool to improve glucose control.

Blood pressure measurement in cats and dogs: considerations for the clinician

Blood pressure is an increasingly-measured parameter in veterinary patients; recognition of hypertension and hypotension is important, as both are associated with detrimental sequelae for patients. Direct (invasive) measurement is the clinical gold standard, but non-invasive methods provide a more convenient option for the clinician in conscious patients. Doppler and oscillometric devices are the most popular non-invasive methods; their performance has been studied in terms of accuracy and precision, but the evidence base is produced largely from studies of anaesthetised patients. Doppler has been suggested as the preferred method in conscious cats and dogs. Adhering to a set protocol for blood pressure measurement is essential for the generation of valid results; the American College of Veterinary Internal Medicine prescribes conditions for best practice. The reference range for normal blood pressure is ambiguous, with several different ranges proposed by various studies. In addition, multiple epidemiological factors such as age, breed, sex, neuter status and body weight can influence results.