Hemodynamic and electrophysiologic effects of ontazolast in dogs

OBJECTIVE: To determine whether QT interval is prolonged or sudden death is caused by ventricular fibrillation resulting from torsades de pointes and to identify hemodynamic effects of ontazolast. ANIMALS: 28 Beagles. PROCEDURE: Physiologic variables were measured for 2 hours in conscious dogs given ontazolast (0, 1, or 3 mg/kg of body weight, IV) and for 1 hour in anesthetized dogs given cumulative doses of ontazolast (0, 1, 3, 6, or 8 mg/kg, IV). RESULTS: Ontazolast prolonged QT interval and QT interval corrected for heart rate (QTc) at doses of 6 mg/kg in anesthetized dogs. At 8 mg/kg, both variables remained prolonged but tended to decrease. In conscious dogs, ontazolast increased QT interval and QTc 15 minutes after administration, but both variables returned to reference ranges by 60 minutes. In conscious dogs, ontazolast increased maximum rate of increase of left ventricular pressure and maximal velocity of fiber shortening, indicators of inotropy, and increased tau, indicating a decreased rate of relaxation. One conscious dog receiving 3 mg/kg developed nonfatal torsades de pointes, but another conscious dog developed ventricular fibrillation. Two anesthetized dogs receiving 6 mg/kg developed early afterdepolarizations, and all dogs developed secondary components in theirT waves. CONCLUSION AND CLINICAL RELEVANCE: Ontazolast possesses potent class-III antiarrhythmic properties and induces prolongation of QTc in a dose-dependent fashion. Because there was a clear dose-dependent prolongation of QT interval in all instances, ontazolast may serve as a positive-control compound for studying other compounds that are believed to prolong the QT interval.     

Anatomic distribution and electrophysiologic properties of accessory atrioventricular pathways in dogs

OBJECTIVE: To evaluate the anatomic distribution and electrophysiologic properties of accessory pathways (APs) in dogs. DESIGN: Case series. ANIMALS: 10 dogs with tachyarrhythmias associated with an AP. PROCEDURES: Each dog underwent electrophysiologic testing to determine the inducibility of documented and undocumented arrhythmias and to identify location, conduction properties, and antegrade and retrograde effective refractory periods of the APs. Radiofrequency catheter ablation was then performed. RESULTS: 15 APs were identified; 7 dogs each had a single AP, and 3 had multiple APs. Fourteen of the 15 APs were right-sided (6 right free wall, 4 posteroseptal, 3 midseptal, and 1 anteroseptal), and 1 was left-sided (left free wall). All APs conducted in an all-or-none fashion. Unidirectional retrograde conduction was observed in 11 APs, and bidirectional conduction was observed in 4. All documented tachyarrhythmias could be induced during electrophysiologic testing; atrial fibrillation was also inducible in 2 dogs. Mean +/- SD cycle duration of orthodromic atrioventricular reciprocating tachycardia was 215.80 +/- 44.87 milliseconds. Mean shortest R-R interval during atrial fibrillation was 247.33 +/- 83.17 milliseconds. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that in dogs, most APs are right-sided, had unidirectional retrograde conduction, and are associated with various arrhythmias, including orthodromic atrioventricular reciprocating tachycardia and atrial fibrillation without evidence of pre-excitation.     

Haemodynamic effects of ATP in dogs during hypoxia-induced pulmonary hypertension

Pulmonary hypertension may result from an increase in vascular resistance caused by persistent hypoxia. We have investigated the effects of adenosine triphosphate (ATP), administered into the pulmonary artery, on haemodynamic changes occurring in anaesthetized adult dogs subjected to acute hypoxic pulmonary vasoconstriction. Hypoxia alone (ventilation with 10% O2/90% N2) caused significant increases in mean pulmonary arterial blood pressure (PAP), central venous pressure (CVP), and cardiac index (CI) by 71, 102 and 38%, respectively. ATP (0.03-3.0 micromol/kg/min approximately 0.02-1.65 mg/kg/min), when infused under hypoxic conditions, significantly reduced both mean PAP and systemic arterial blood pressure (ABP) in a dose-dependent manner. The maximum decrease in mean PAP amounted to 20%; mean ABP, on the other hand, was decreased by up to 52% (P<0.01). Heart rate, CI, CVP and pulmonary occlusion pressure were not dose-dependently affected by ATP. Our data indicate that while pulmonary arterial administration of ATP in mature dogs during hypoxic pulmonary hypertension causes dilation in the pulmonary vascular bed, it is even more effective in dilating the systemic vasculature. This result suggests a need for further evaluation and warrants cautious use of ATP in the treatment of hypoxic pulmonary hypertension in adult dogs.     

Neurohormonal, hemodynamic, and electrocardiographic evaluations of healthy dogs receiving long-term administration of doxorubicin

OBJECTIVE: To evaluate diagnostic testing that could be used to establish an early diagnosis of cardiotoxicosis induced by long-term administration of doxorubicin. ANIMALS: 13 adult mixed-breed dogs. Procedures-7 dogs were administered doxorubicin chloride (30 mg/m(2), IV, q 21 d for 168 days [cumulative dose, 240 mg/m(2)]), and 6 dogs received saline (0.9% NaCl) solution (5 mL, IV, q 21 d for 168 days; control group). Echocardiography, ECG, arterial blood pressure, plasma renin activity (PRA), and plasma concentrations of norepinephrine and brain natriuretic peptide (BNP) were assessed before each subsequent administration of doxorubicin and saline solution. RESULTS: Dogs that received doxorubicin had a significant decrease in R-wave amplitude, compared with values for the control group, from 30 to 210 mg/m(2). Doxorubicin-treated dogs had decreases in fractional shortening and left ventricular ejection fraction evident as early as 30 mg/m(2), but significant differences between groups were not detected until 90 mg/m(2)was reached. There was also a significant increase in PRA (>or= 120 mg/m(2)) and left ventricular end-systolic and end-diastolic dimensions (>or= 60 and >or= 180 mg/m(2), respectively). Systemic arterial pressure, remaining echocardiographic variables, and concentrations of norepinephrine and BNP had significant variations, but of no clinical importance, during doxorubicin administration. CONCLUSIONS AND CLINICAL RELEVANCE: Doxorubicininduced cardiotoxicosis developed at 120 mg/m(2), but there were no clinical signs of dilated cardiomyopathy or congestive heart failure. Echocardiography and determination of PRA were able to detect early cardiac alterations during the development of dilated cardiomyopathy, despite apparently differing degrees of sensitivity to development of doxorubicin-induced cardiotoxicosis.     

Validation of 2 techniques for electrocardiographic recording in dogs and cats

BACKGROUND: Standard electrocardiographic (ECG) recording in the dog and cat is commonly performed in right lateral recumbency, by connecting the ECG leads to the skin of the patient via metallic alligator clips. The jaws of the alligator clips are usually filed or flattened to reduce their uncomfortable pressure on the patient's skin. However, filed and flattened alligator clips can occasionally lose their grip to the skin, causing lead detachment during standard ECG recording. HYPOTHESIS: The aim of the study was to validate two novel ECG recording techniques ("gel" and "pads"). ANIMALS: Six-lead standard ECG recording was obtained from 42 dogs and 40 cats using the standard technique, as well as the two novel methods. METHODS: Measurements were taken of the amplitude and duration of P waves and QRS complexes, duration of PQ and QT intervals, and mean electrical axis (MEA). In each recording, five representative complexes were measured, and the results were averaged for each parameter. RESULTS: A good quality ECG recording was obtained with all the three different techniques, although a degree of wandering trace was observed in one third of cats with the "pads" technique. Bland-Altman analysis showed good agreement between the ECG values recorded with the two novel techniques and those recorded with the standard traditional technique. Furthermore, the observed differences were not clinically relevant, except for the R wave amplitude recorded with the "pads" method in cats (-0.35 to 0.37 mV). CONCLUSIONS AND CLINICAL IMPORTANCE: In conclusion, this study supports the reliability and clinical validity of the "gel" and "pads" techniques for ECG recording both in the dog and the cat, with some limitations for the "pads" technique in cats.     

Preclinical tolerance and pharmacokinetic assessment of MU-Gold,a novel chemotherapeutic agent,in laboratory dogs

MU-Gold, tetrakis (trishydroxymethyl) phosphine gold(I) chloride, a novel gold compound, has cytotoxic effects against human androgen-dependent and -independent prostatic, gastric, and colonic carcinoma in cell culture and against malignant lymphoma in rodent models. A pilot study was conducted to evaluate the tolerance and pharmacokinetic properties of MU-Gold in normal dogs in anticipation of clinical trials in cancer-bearing dogs. MU-Gold (10 mg/kg) was administered by i.v. injection to three purpose-bred dogs. Serum was collected from all dogs for measurement of gold levels via atomic absorption spectrometry. In addition, complete blood counts and biochemical profiles were monitored for Dogs 2 and 3 every 7 days for 30 days. A two-compartment i.v. bolus model with first-order kinetics, mean elimination half-life of approximately 40 hours, and mean volume of distribution of 0.6 L/kg was established. Serum gold concentrations ranging from 10 to 50 mcg/ml were sustained for 2 to 3 days with no clinically significant toxicities observed. Based on in vitro results in earlier studies and preliminary pharmacokinetic data collected in the present study, Phase I clinical trials should be conducted to define the optimal dosage, dose-limiting toxicities, and other characteristics of MU-Gold that will be used to design Phase II clinical trials.     

Comparison of fluoroquinolone pharmacokinetic parameters after treatment with marbofloxacin, enrofloxacin, and difloxacin in dogs

Plasma, urine, and skin drug concentrations were determined for dogs (n=12) given five daily oral doses of marbofloxacin (MAR) (2.75 mg/kg), enrofloxacin (ENR) (5.0 mg/kg) or difloxacin (DIF) (5.0 mg/kg). Concentrations of the active metabolite of ENR, ciprofloxacin (CIP), were also determined. The three-period, three-treatment crossover experimental design included a 21-day washout period between treatments. Area under the plasma drug concentration vs. time curve (AUC0-last, microg/mLxh of MAR was greater than for ENR, CIP, ENR/CIP combined, and DIF. Maximum concentration (Cmax) of MAR was greater than ENR, CIP, and DIF. Time of maximum plasma concentration (Tmax) was similar for MAR and DIF; Tmax occurred earlier for ENR and later for CIP. Plasma half-life (t1/2) of MAR was longer than for ENR, CIP, and DIF. Urine concentrations of DIF were less than MAR or ENR/CIP combined, but urine concentrations of MAR and ENR/CIP combined did not differ. DIF skin concentrations were less than the concentrations of MAR or ENR/CIP combined 2 h after dosing, but skin concentrations of MAR and ENR/CIP combined did not differ.     

Effects of levomepromazine and different desflurane concentrations upon electrocardiographic variables in dogs

Objectives To investigate the effects of levomepromazine and different desflurane concentrations upon electrocardiographic variables. Animals Twenty adult mongrel dogs of both sexes weighing 6–28 kg. Methods Dogs were divided into two groups of 10 animals. Group 1 received 1 mg kg^?1 IV of levomepromazine and 15 minutes later anesthesia was induced with propofol (3 mg kg^?1 IV). Desflurane end‐tidal concentration was set at 1.6 MAC. After 30 minutes at this concentration, measurements were taken and the end‐tidal concentration was reduced to 1.4 MAC. Thereafter, it was reduced to 1.2 and then 1.0 MAC at 15‐minute intervals. The same procedure was followed for group 2, except that levomepromazine was replaced with 0.2 mL kg^?1 of 0.9% saline solution and more propofol was needed for induction (7 mg kg^?1). The animals' body temperature was maintained between 38.3 and 39 °C using a heating pad. The electrocardiographic tracing was obtained from lead II throughout the experimental period. The measurements were taken immediately before the administration of levomepromazine or placebo (T₁), 15 minutes after pre‐medication (T₂) and 30 minutes after the establishment of 1.6 MAC (T₃). The other measurements were made at the concentrations of 1.4, 1.2, and 1.0 MAC, respectively (T_4?6). The numerical data were submitted to analysis of variance plus F‐test (p < 0.05). Results The dogs that received levomepromazine had a decrease in heart rate. However, in both groups it increased with desflurane administration. Levomepromazine, in association with desflurane, did not induce significant electrocardiographic changes, and all mean values (except P‐wave duration) were within the reference range for this species. Conclusions and clinical relevance This study documented that levomepromazine, in association with desflurane, does not induce significant changes in electrocardiographic variables, suggesting that this drug combination has minimal effect on myocardial conduction.     

Assessment of electrocardiographic parameters in healthy dogs undergoing dobutamine stress testing

The electrocardiographic effects of dobutamine stress testing (10 to 40 microg/kg/minute) were investigated in five conscious healthy dogs. We studied the changes in the duration and amplitude of P wave, PR interval, duration of QRS complex, R wave amplitude, QT interval, and heart rate. Development of arrhythmias and ST segment abnormalities were also recorded. It was observed that dobutamine significantly affects atrioventricular-nodal conduction and total electrical systole time at higher infusion rates. Only a single episode of sustained ventricular tachycardia was observed, which was promptly restored to sinus rhythm shortly after dobutamine infusion was discontinued. No ST segment abnormalities were detected. Dobutamine stress testing was concluded to play a role in some ECG parameters at higher infusion rates.     

Cardiac damage in dogs infected with T brucei; clinical and electrocardiographic features

Intravenous infection of dogs with Trypanosoma brucei resulted in an acute disease syndrome, characterised by fever, intense parasitaemia, severe anaemia and rapid weight loss. During the course of infection, evidence of severe cardiac abnormalities developed. Tachycardia and tachypnoea occurred soon after detection of parasitaemia, around day 6, progressing to severe bradycardia and dyspnoea in terminal stages of the disease in week 4. Murmurs of mitral and tricuspid incompetence were heard from day 12 by auscultation of the thoracic cavity. Electrocardiography revealed abnormalities in generation and conduction of electrical impulses, including sinus arrest and atrioventricular blocks, and accumulation of pericardial effusion in terminal stages. Effective treatment with the trypanocidal drug suramin resulted in rapid improvement of one of the dogs. When treatment was unsuccessful, however, chronic myocardial damage developed, with intramyocardial conduction defects, including S-T segment and T wave changes, and ventricular escape beats. These abnormalities were similar to those reported for human African trypanosomiasis.     

Pharmacodynamic and pharmacokinetic aspects of the non-inflammatory non-steroidal agent meloxicam in dogs

The pharmacodynamics of non-steroidal anti-inflammatory drugs (NSAIDs) are for the most part well-understood. All NSAIDs inhibit the enzyme cyclooxygenase (COX), and for this reason prostaglandin synthesis. Two isoforms of COX could be isolated. COX-1 is detectable in most tissues on a constant level and is responsible for the synthesis of prostaglandins with cytoprotective effects. COX-2 is induced through inflammation and supports the inflammatory process by producing pro-inflammatory prostaglandins. The desired effects of NSAIDs are related to inhibition of COX-2, whereas inhibition of COX-1 has been linked to the typical side-effects of NSAIDs, especially in the stomach and kidney. The great differences between effects and side-effects in the numerous substances can be explained because of different interactions of the NSAIDs on COX-1 and COX-2. In various test systems meloxicam has been shown to be a preferential inhibitor of COX-2. There are also large differences between the individual NSAIDs with regard to pharmacokinetics. Meloxicam is completely absorbed from the gastrointestinal tract and has an elimination half-life of 24 hours in the dog. It is excreted in faeces and urine. The metabolites, detectable in urine are biologically inactive and do not influence the prostaglandin synthesis in the kidney. In the underlying study, plasma concentration of meloxicam was determined after a subcutaneous injection of 0.2 mg/kg b. w. (day 1) followed by oral treatment of 0.1 mg/kg b. w. (days 2-14). The results confirm the recommended dosage regime of meloxicam with its initial loading dose and the subsequent maintenance dose. This dosing regime results in a very favourable curve of concentrations with a very rapidly attained steady state after roughly two days, without accumulation even in long-term treatment.     

Echocardiographic and electrocardiographic effects of atenolol versus sotalol in dogs with severe subaortic stenosis

BackgroundSubaortic stenosis (SAS) is a commonly diagnosed canine congenital cardiac defect, with severe forms of carrying a poor long-term prognosis. To date, an effective treatment strategy has not been developed in veterinary medicine. This study sought to determine if sotalol, a class III antiarrhythmic, may have salient echocardiographic and antiarrhythmic benefits for medical management for dogs affected with severe SAS.MethodsTen dogs diagnosed with severe SAS were enrolled in this prospective, double-blinded, crossover study. Dogs underwent physical exam, non-invasive blood pressure measurement, electrocardiography, echocardiography, and 24-h Holter monitoring. Diagnostics were repeated 12–16 days following randomization to oral atenolol (0.5–1 mg/kg) or sotalol (1–2 mg/kg) twice daily. After a medication taper and four-day washout, dogs were crossed-over to the alternate study medication, and the diagnostics were repeated in 12–16 days. Linear and multinomial mixed models were developed to evaluate the effects of treatments on echocardiographic and electrocardiographic variables.ResultsIndices of left ventricular systolic function were reduced based on the volumetric assessment when dogs received sotalol compared to atenolol. No difference was noted between groups in left ventricular systolic function based on the linear assessment. No difference was observed in the reduction in left ventricular outflow tract velocity. No significant differences were observed between treatment groups for any variable on 24-h Holter monitor.ConclusionsSotalol may be a viable therapy to consider for dogs with severe SAS based on this pilot study. A larger, prospective study is necessary to investigate further.     

Investigation of pharmacokinetic parameters of tiamulin after intramuscular and subcutaneous administration in normal dogs

Laber, G. Investigation of pharmacokinetic parameters of tiamulin after intramuscular and subcutaneous administration in normal dogs. J. vet. Pharmacol. Therap. 11 , 45–49.
Kinetic variables for tiamulin in the normal dog have been determined. Serum concentrations of tiamulin were compared after intramuscular (i.m.) and subcutaneous (s.c.) administration of a single dose of tiamulin. Following a single i.m. dose of 10 mg/kg body weight, the compound was calculated to have a C_max= 0.61 ± 0.15 μg/ml, a T _max= 6 h and a t _½= 4.7 ± 1.4 h. Tiamulin showed dose-dependent pharmacokinetics when given as a single s.c. dose of either 10 mg or 25 mg/kg body weight. For the lower dose, the values C_max= 1.55 ± 0.11 μg/ml, T _max= 8 h and 1 _max= 4.28 ± 0.18 h were obtained. For the higher dose C _max= 3.14 ± 0.04 μg/ml, T _max= 8 h and t _½= 12.4 ± 3.4 h were calculated. When tiamulin was administered subcutaneously at a dose rate of 10 mg/kg body weight, higher and better maintained serum levels were achieved than those following i.m. administration. After repeated s.c. doses no significant accumulation of tiamulin occurred. Assuming that a continuous effective serum concentration is necessary throughout the course of therapy, these data would indicate that tiamulin should be given every 24 h.     

Comparison of electrocardiographic parameters in dogs with different stages of myxomatous mitral valve disease

This study evaluated changes in electrocardiographic (ECG) parameters according to the stage of myxomatous mitral valve disease (MMVD) in dogs, as well as the utility of ECG parameters as prognostic indicators for congestive heart failure (CHF). Medical records of dogs with MMVD were retrospectively searched. Dogs with MMVD (N = 101) were classified into stages B [B1 (n = 52) and B2 (n = 23)] and C (n = 26) according to the American College of Veterinary Internal Medicine guidelines. Baseline variables were collected; these included signalment, radiographic, echocardiographic, and ECG parameters. Corrected QT intervals (QTc) were calculated using the logarithmic (QTc1) and Fridericia (QTc2) formulas. The P wave duration, QTc1, and QTc2 were significantly longer in stage C than in stage B. The P wave duration cutoff of 43.5 ms had a diagnostic accuracy of 65% for differentiating CHF, with a sensitivity of 63% and a specificity of 90%. A cutoff value of 307.8 ms for QTc1 yielded a sensitivity of 62%, a specificity of 76%, and a diagnostic accuracy of 78%, and a cutoff value of 239.2 ms for QTc2 yielded a sensitivity of 62%, a specificity of 83%, and a diagnostic accuracy of 77% for diagnosing CHF. Therefore, prolonged P wave and QTc in dogs with MMVD may facilitate the prediction of CHF. Electrocardiography could provide clinicians with a readily available and cost-effective screening tool for predicting CHF, if the usefulness of ECG parameters can be verified.     

Telomerase activity in clinically normal dogs and dogs with malignant lymphoma

OBJECTIVES: To determine whether telomerase activity was present in lymph nodes, buffy coat, and serum samples from dogs with malignant lymphoma (ML) and in liver, lymph node, buffy coat, and serum samples from clinically normal dogs SAMPLE POPULATION: Tissue specimens and blood samples were obtained from 11 clinically normal adult dogs (age range, 1 to 4 years) and 14 client-owned dogs with ML. PROCEDURE: The telomere repeat amplification protocol assay was used to quantify telomerase activity in the tissues from clinically normal dogs and dogs with ML. RESULTS: Of 11 clinically normal dogs, 8 had lymph node samples, 5 had liver samples, and 1 had buffy coat samples with detectable telomerase activity. None of the serum samples from the clinically normal dogs had detectable telomerase activity. Of 14 dogs with ML, 9 had lymph node samples, 3 had buffy coat samples, and 1 had serum samples with measurable telomerase activity. CONCLUSIONS AND CLINICAL RELEVANCE: Telomerase activity was not specific to tumor cells and overlapped with that found in cells from clinically normal dogs. Telomerase activity in neoplastic lymph nodes was not substantially different from that found in lymph nodes from clinically normal dogs. The determination of telomerase activity cannot be used as a sole diagnostic test for cancer. Therapeutic modalities directed toward the telomerase enzyme may not be feasible in dogs, because somatic tissues from clinically normal dogs possess variable amounts of telomerase activity.