Pimobendan prevents cardiac dysfunction, mitigates cardiac mitochondrial dysfunction, and preserves myocyte ultrastructure in a rat model of mitral regurgitation.

BACKGROUND: Pimobendan has been proven to delay the onset of congestive heart failure (CHF) in dogs with mitral regurgitation (MR); however, molecular underlying mechanisms have not been fully elucidated. This study aimed to investigate (1) the effects of pimobendan on cardiac function, cardiac mitochondrial quality and morphology, and cardiac ultrastructure in a rat model of chronic MR and (2) the direct effect of pimobendan on intracellular reactive oxygen species (ROS) production in cardiac cells. MR was surgically induced in 20 Sprague-Dawley rats, and sham procedures were performed on 10 rats. Eight weeks post-surgery, the MR rats were randomly divided into two groups: the MR group and the MR + pimobendan group. Pimobendan (0.15 mg/kg) was administered twice a day via oral gavage for 4 weeks, whereas the sham and MR groups received equivalent volumes of drinking water. Echocardiography was performed at baseline (8 weeks post-surgery) and at the end of the study (4 weeks after treatment). At the end of the study protocol, all rats were euthanized, and their hearts were immediately collected, weighed, and used for transmission electron microscopy and mitochondrial quality assessments. To evaluate the role of pimobendan on intracellular ROS production, preventive or scavenging properties were tested with H2O2-induced ROS generation in rat cardiac myoblasts (H9c2). RESULTS: Pimobendan preserved cardiac functions and structure in MR rats. In addition, pimobendan significantly improved mitochondrial quality by attenuating ROS production and depolarization (P < 0.05). The cardiac ultrastructure and mitochondrial morphology were significantly preserved in the MR + pimobendan group. In addition, pimobendan appeared to play as a ROS scavenger, but not as a ROS preventer, in H2O2-induced ROS production in H9c2 cells. CONCLUSIONS: Pimobendan demonstrated cardioprotective effects on cardiac function and ultrastructure by preserving mitochondrial quality and acted as an ROS scavenger in a rat model of MR.

Impact of a combination of pimobendan, furosemide, and enalapril on heart rate variability in naturally occurring, symptomatic, myxomatous mitral valve degeneration dogs.

BACKGROUND: Pimobendan, diuretics, and an angiotensin-converting enzyme inhibitor (ACEi) are widely used for the management of chronic valvular heart disease in dogs; however, the effects of that combination on heart rate variability (HRV) are unknown. The purpose of this study was to assess the HRV of symptomatic myxomatous mitral valve degeneration (MMVD) dogs in response to therapy with a combination of pimobendan, diuretics, and ACEi. RESULTS: MMVD stage C (n = 17) dogs were enrolled and a 1-hour Holter recording together with echocardiography, blood pressure measurement, and blood chemistry profiles were obtained before and 1, 3, and 6 months after oral treatment with pimobendan (0.25 mg/kg), enalapril (0.5 mg/kg), and furosemide (2 mg/kg) twice daily. The results revealed that MMVD stage C dogs at the baseline had lower values of time-domain indices, low frequency (LF), high frequency (HF), and total power, as well as higher value of LF/HF. Triple therapy significantly increases these parameters in MMVD stage C dogs (P < 0.05). A positive moderate correlation was observed between time domain parameters and a left ventricular internal diastole diameter normalized to body weight (P < 0.05). CONCLUSIONS: It can be concluded that MMVD stage C dogs possess low HRV due to either the withdrawal of parasympathetic tone or enhanced sympathetic activation, and a combination therapy was shown to enhance cardiac autonomic modulation inferred from the increased heart rate variability. Therefore, a combination therapy may be useful for restoring normal autonomic nervous system activity in dogs with MMVD stage C.

The effect of treatment with pimobendan in dogs with preclinical mitral valve disease - a placebo-controlled double-blinded crossover study.

BACKGROUND: Pimobendan is a widely used medication for the treatment of dogs with congestive heart failure (CHF) and preclinical degenerative mitral valve disease (DMVD) with cardiomegaly. The benefit of a treatment in dogs with preclinical DMVD but without cardiomegaly has not yet been elucidated. Some positive effects concerning life quality and a decrease in cardiac biomarkers could be verified. This study aimed to further investigate these results using a placebo-controlled double-blinded crossover design. Out of a total of 15 dogs, eight were allocated to sequence-group AB, in which dogs received pimobendan (A) during the first treatment period and placebo (B) during the second period. Accordingly, sequence-group BA was treated first with placebo followed by pimobendan. Each treatment period lasted six months and included a baseline investigation and follow-ups after 90 and 180 days. The investigations included a questionnaire completed by the owners, echocardiographic examination, and measurements of NT-proBNP, cTnI and lactate before and after a standardised submaximal exercise test. RESULTS: NT-proBNP values decreased significantly during the treatment period with pimobendan, and the post-exercise increase was attenuated at day 180. No significant treatment effects could be verified for cTnI and lactate, neither pre- nor post-exercise. Left ventricular size decreased under treatment, whereas no significant changes in left atrial size were detected. The owners described their dogs under treatment with pimobendan as being more active at day 90 (11/15) and day 180 (12/15). Those animals treated with placebo were described as being more active at day 90 (2/15) and day 180 (5/15). CONCLUSIONS: Pimobendan had reducing effects on the concentrations of pre- and post-exercise cardiac biomarkers and the size of the left ventricle in dogs with DMVD ACVIM B1. Exercise testing in addition to an assessment of cardiac biomarkers might improve the decision when to initiate pimobendan treatment in dogs with DMVD.

Effect of Pimobendan on NT-proBNP and c troponin I before and after a submaximal exercise test in dogs with preclinical mitral valve disease without cardiomegaly - a randomised, double-blinded trial.

BACKGROUND: Exercise testing in conjunction with measurement of cardiac biomarkers NT-proBNP and cTnI is a useful tool for monitoring the effect of treatment on cardiac patients. Administering Pimobendan in dogs with degenerative mitral valve disease (DMVD) and cardiomegaly results in delaying the onset of clinical symptoms and prolonging life. Its effect in dogs with DMVD without cardiomegaly has not been well examined. The aim of the current study was to investigate the effect of administering Pimobendan in dogs with DMVD without cardiomegaly using exercise testing in conjunction with measuring cardiac biomarkers in addition to echocardiography. Twenty-one dogs with asymptomatic DMVD without echocardiographic signs of cardiomegaly participated in a randomised, double-blinded trial. Dogs were divided into a Pimobendan-group (n = 11) and a placebo-group (n = 10) in a double-blinded study design and underwent a standardised submaximal exercise test (SSET). One dog in the Pimobendan-group was retrospectively removed from the study after being diagnosed with Leishmaniosis. Cardiac biomarkers NT-proBNP and cTnI were measured before and after exercise. Follow-up appointments were performed at days 90 and 180. RESULTS: Dogs in the Pimobendan-group had significantly lower post-exercise NT-proBNP-levels after being administered Pimobendan than at the beginning of the study. They also had lower pre- and post-exercise-NT-proBNP-levels than those dogs in the placebo-group. There was neither a significant difference regarding the measured cTnI levels nor an increase in cTnI between the groups at any time. CONCLUSIONS: Pimobendan lowers NT-proBNP in dogs with presymptomatic mitral valve disease without cardiomegaly before and after submaximal exercise. This indicates a reduction in cardiac wall stress. If dogs with asymptomatic DMVD without cardiomegaly benefit from treatment with Pimobendan (for example, through a longer survival time) warrants further investigation.

Safety of a benazepril and pimobendan combination tablet in adult healthy dogs.

The objective of the study was to investigate the safety of a combination tablet of benazepril and pimobendan, Fortekor PLUS® , in a randomized, blinded, parallel-group design study in healthy adult beagle dogs. The test article, Fortekor PLUS® tablets, was administered orally twice daily for 6 months at one, two, and four times the highest recommended dosage of 0.5 mg/kg benazepril hydrochloride/0.25 mg/kg pimobendan (four males and four females per group). An additional control group was sham-dosed. Fortekor PLUS® did not induce any treatment-related effects on body weight, food consumption, neurological, ophthalmologic or physical assessments over the 6-month treatment period. The test article was possibly associated with an increased frequency of occasional vomiting. Fortekor PLUS® was associated with small, but significant, increases in heart rate and reductions in PR and QT intervals, which were assessed by electrocardiography. These effects were most probably related to reflex tachycardia secondary to reduced systemic blood pressure. Statistically significant changes in some clinical pathology variables were noted after test article administration, but were considered to be of no clinical relevance as values remained within reference ranges and/or were not dose-dependent. No treatment-related macroscopic or microscopic findings were observed. In conclusion, Fortekor PLUS® tablets were well tolerated in healthy adult dogs when administered at one, two, and four times the highest recommended dosage for 6 months.

Effect of benazepril and pimobendan on serum angiotensin-converting enzyme activity in dogs.

To support their combined use, the objective of the study was to evaluate the effects of benazepril and pimobendan on serum angiotensin-converting enzyme (ACE) activity in dogs. A total of 48 healthy beagle dogs were randomized into four groups (n = 12 per group) in a parallel-group design study: A (control, placebo twice daily (BID)); B (0.5-1.0 mg/kg benazepril once daily (SID) in the morning, placebo in the evening); C (0.25-0.5 mg/kg benazepril BID); D (0.25-0.5 mg/kg benazepril and 0.125-0.25 mg/kg pimobendan, both BID). The test items were administered orally for 15 days. Serum ACE activity was measured on days 1 and 15. Groups B, C and D had significantly lower average serum ACE activity compared to baseline and to the control group, on both days 1 and 15. There were no significant differences in average ACE activity between groups B, C and D. Noninferiority of group C to B was demonstrated. In conclusion, 0.25-0.5 mg/kg benazepril administered BID produced noninferior inhibition of serum ACE activity compared to 0.5-1.0 mg/kg benazepril dosed SID. Pimobendan had no significant effect on benazepril's action on serum ACE activity. The results support the use of benazepril BID in dogs and in combination with pimobendan.

MEDICAL MANAGEMENT OF DILATED CARDIOMYOPATHY IN LIVINGSTONE FRUIT BATS ( PTEROPUS LIVINGSTONII).

Eleven cases of dilated cardiomyopathy have been diagnosed and treated in captive Livingstone fruit bats ( Pteropus livingstonii) in the United Kingdom over the past 7 yr. All but one case received treatment with a diuretic plus an angiotensin-converting enzyme inhibitor (ACEI), and, or pimobendan. One case is still under treatment with pimobendan alone, following diagnosis before onset of clinical signs. Diuretic treatment consisted of furosemide at a dose rate of 0.5-5 mg/kg, one to three times daily, and, or spironolactone at a dose rate of 1-4 mg/kg, once or twice daily. When used, the ACEI imidapril was given at a dose rate of 0.24-0.38 mg/kg q 24 hr, and pimobendan at a dose rate of 0.2-0.5 mg/kg bid. This report is intended to provide anyone seeking to medically manage heart failure in Pteropus species, particularly P. livingstonii, with a review of drugs and doses that have been used.

Pimobendan improves right ventricular myocardial contraction and attenuates pulmonary arterial hypertension in rats with monocrotaline-induced pulmonary arterial hypertension.

PURPOSE: The present study aimed to evaluate the therapeutic effect of pimobendan treatment for pulmonary hypertension (PH) in rats administered monocrotaline (MCT). METHODS: Fifty-four 12-week-old male Sprague-Dawley rats were injected with monocrotaline or saline solution. Serial echocardiography and right ventricular systolic pressure (RVSP) measurement via a cardiac catheter were performed. After injection of MCT, rats received oral pimobendan (MCT/pimobendan group) or no treatment (MCT group) until undergoing echocardiography and cardiac catheter insertion. RESULTS: Right ventricular systolic pressure in the MCT/pimobendan group was lower than that in the MCT group at 6 weeks. Right ventricle free wall (RVFW) myocardial systolic velocity (Sm) in the MCT group showed a reduction compared with the saline group at 2 weeks. RVFW Sm in the MCT/pimobendan group was preserved as compared with the saline group at 2 weeks. RVFW Tei index in the MCT/pimobendan group showed a reduction compared with the saline group and the MCT group at 2 weeks. Echocardiography in the MCT/pimobendan group showed improvement compared with MCT rats. CONCLUSIONS: Both a reduction in RVSP and improvement in myocardial contraction were demonstrated with administration of pimobendan in rats with PH induced by MCT. Echocardiography evaluation of systolic function seems to be useful for monitoring excess administration of pimobendan.

Reinforcement of pimobendan with guideline-directed medical therapy may reduce the rehospitalization rates in patients with heart failure: retrospective cohort study.

BACKGROUND: Pimobendan reportedly improves the subjective symptoms of heart failure. However, evidence of improved prognosis is lacking. This study aimed to determine whether reinforcing guideline-directed medical therapy (GDMT) improved rehospitalization rates for worsening heart failure in patients administered pimobendan. METHODS: A total of 175 patients with heart failure who were urgently admitted to our hospital for worsening heart failure and who received pimobendan between January 2015 and February 2022 were included. Of the 175 patients, 44 were excluded because of in-hospital death at the time of pimobendan induction. The remaining 131 patients were divided into two groups, the reduced ejection fraction (rEF) (n = 93) and non-rEF (n = 38) groups, and further divided into the GDMT-reinforced and non-reinforced groups. RESULTS: In patients with rEF, the rate of rehospitalization for heart failure was significantly lower in the GDMT-reinforced group than in the non-reinforced group (log-rank test, P = .04). However, the same trend was not observed in the non-rEF group. CONCLUSIONS: Reinforcing GDMT may reduce the heart failure rehospitalization rate in patients with pimobendan administration and rEF. However, multicenter collaborative research is needed. TRIAL REGISTRATION: IRB Approval by the Nippon Medical School Hospital Ethics Committee B-2021-433 (April 10, 2023).

Self-Reported Utilization of International (ACVIM Consensus) Guidelines and the Latest Clinical Trial Results on the Treatment of Dogs with Various Stages of Myxomatous Mitral Valve Degeneration: A Survey among Veterinary Practitioners.

BACKGROUND: Myxomatous mitral valve degeneration is the most common canine heart disease. Several clinical trials have investigated various treatments. The latest recommendations are published in the ACVIM consensus guidelines (2019). Our study aimed to investigate how closely veterinary practitioners apply the treatment recommendations of these guidelines and the latest clinical trials. METHODS: An online survey was sent to Dutch and Belgian veterinary practices via digital channels. RESULTS: The data from 363 fully completed surveys were analyzed. For stage B1 disease, 93% recommended, correctly, no treatment. For stage B2 disease, 67% of the respondents recommended starting pimobendan as monotherapy. For chronic treatment of stage C disease, 16 different drug combinations were mentioned, but nobody recommended surgery. Only 48% of the respondents recommended the only evidence-based drug combination: a loop diuretic with pimobendan. A concerning finding was the simultaneous prescription of two loop diuretics, by 19% of the respondents. CONCLUSIONS: Treatment recommendations showed an increasing variation with more advanced disease stages from B1 through B2 to C. This reflects the increasing disagreement among the panelists who prepared the ACVIM consensus guidelines. Practitioners of our study seem to practice more evidence-based medicine than veterinary cardiologists, as it was reported in a recent survey-based study.

Two cases of new-born puppies with transient pulmonary edema.

Acute pulmonary edema in puppies generally occurs due to congenital left-right shunts such as patent ductus arteriosus or large ventricular septal defects. Herein, we presented two cases of puppies with no apparent congenital cardiovascular disease. Case 1: A 12-day-old male Labrador Retriever, weighing 1.15 kg, was unable to suckle sufficiently from its dam and exhibited laboured breathing. Pulmonary edema was identified in all lung lobes by radiography, furthermore, echocardiography revealed significant enlargement of the left side of the heart. Pulmonary edema secondary to volume overload was suspected and furosemide was administered. The respiratory status was improved on the following day. Pimobendan was administered orally in addition to furosemide and both were withdrawn 6 weeks later when the heart size was normalized. Case 2: A 15-day-old female Standard Poodle, weighing 0.68 kg, was less active than other littermates and exhibited laboured breathing. Radiography revealed pulmonary edema in the right posterior lobe, dilatation of the caudal vena cava and ascites. Echocardiography revealed significant enlargement of the left atrium and ventricle perhaps owing to decreased left ventricular contractility. Furosemide and pimobendan were administered. One week later, appetite was improved and supraventricular tachycardia of 375 bpm was observed. Therefore, tachycardia-induced dilated cardiomyopathy was suspected which returned to sinus rhythm with diltiazem treatment, however, it was recurred. Upon sotalol monotherapy, a normal heart size was observed seven months later. In conclusion, we encountered two new-born puppies with transient pulmonary edema that were temporarily treated with pimobendan and furosemide.

Effects of orally administered pimobendan on platelet function in healthy adult cats.

OBJECTIVE: Several phosphodiesterase inhibitors have demonstrable antiplatelet actions when administered to human patients. Concentration-dependent inhibition of feline platelet aggregation by pimobendan has been previously demonstrated in vitro. However, there are no published reports characterizing the effect of oral pimobendan, administered at therapeutic doses, on platelet function in cats. This study aimed to evaluate the effect of orally administered pimobendan on platelet function in healthy adult cats. ANIMALS: 6 healthy purpose-bred adult cats. METHODS: Cats were administered pimobendan orally at a dosage of 0.625 mg/cat (low-dose) twice daily for 1 week, followed by 1.25 mg/cat (high-dose) twice daily for 1 week. Venous blood sampling for platelet testing and plasma drug concentration occurred at baseline, 1 hour postdose on the eighth day of treatment with low-dose pimobendan, 1 hour postdose on the eighth day of treatment with high-dose pimobendan, and after a 1-week washout period. Platelet function was assessed by whole blood aggregometry and by use of a platelet function analyzer (PFA-100®). Friedman tests were used to compare platelet function parameters among the 4 sampling timepoints. RESULTS: After 1 week of treatment, median (range) plasma pimobendan concentrations were 15.1 ng/mL (6.89-20.2 ng/mL) and 32.8 ng/mL (23.3-44.8 ng/mL) in cats receiving low-dose and high-dose pimobendan, respectively. No significant differences in PFA closure time or any aggregometry variable were found among the treatment conditions. CLINICAL RELEVANCE: Pimobendan was not associated with measurable inhibition of platelet function when administered orally to healthy adult cats at 2 clinically relevant dosages.

Haemodynamic Effects of Pimobendan during General Anaesthesia in Healthy Senior Dogs: A Prospective, Randomised, Triple-Blinded, Placebo-Controlled Clinical Study.

Pimobendan is an inotropic and vasodilator drug with no sympathomimetic effects. This study aimed to evaluate the haemodynamic effects of pimobendan during anaesthesia in healthy senior dogs. A prospective, randomised, triple-blinded, placebo-controlled clinical study was conducted. Thirty-three dogs (median [range]: 9 [7, 12] years) were anaesthetised for surgical procedures. The dogs were randomly allocated into two groups: eighteen dogs received intravenous pimobendan at a dose of 0.15 mg/kg (PIMOBENDAN), and fifteen dogs received intravenous saline solutions at a dose of 0.2 mL/kg (PLACEBO). Data were recorded before, 1 min, 10 min, and 20 min after injection. Velocity-time integral (VTI), peak-velocity (PV), and mean-acceleration (MA) were measured using an oesophageal Doppler monitor (ODM). Heart rate and mean arterial pressure were also registered. The data were analysed using a two-way ANOVA for trimmed means. Statistical differences were considered if p < 0.05. Twenty minutes after injection, the VTI (13.0 cm [10.4, 22.3]), PV (95.0 [83.0, 160] m/s), and MA (12.6 [9.40, 17.0] m/s2) were significantly higher in the PIMOBENDAN group compared to the PLACEBO group (VTI: 10.5 [6.50, 17.4] cm, PV: 80.0 [62.0, 103] m/s and MA: 10.2 [7.00, 16.0] ms2). No significant differences were observed in the rest of the variables. Using pimobendan during anaesthesia increases VTI, PV, and MA, as measured by an ODM.

Management and outcome of intracardiac heartworms in dogs.

BACKGROUND: Intracardiac heartworm (IH) disease is a serious condition that can become life threatening if the patient develops caval syndrome. We aim to describe the management and outcome of IH in dogs evaluated by Medvet's New Orleans cardiology service from November 2015 to December 2021. METHODS: Records of 27 dogs with IH were examined retrospectively. Follow-up information was obtained from phone conversations with referring veterinarians and owners. RESULTS: Nine of 27 dogs had a previous diagnosis of heartworm disease and were undergoing "slow kill" treatment; 12/27 dogs' heartworm disease was a new diagnosis, and 6/27 had either scheduled or started adulticide therapy. Nine dogs had heartworm extraction. No dogs died during the heartworm extraction procedure. Four of 9 dogs have died (survival time 1; 676; 1815 and 2184 days). One dog died the day after the procedure secondary to continued respiratory distress; the other three died of non-cardiac causes. Five of nine are alive (median follow-up 1062 (range 648-1831) days. Eleven dogs had IH resolution. In 7/11 this occurred while undergoing stabilization for heartworm extraction. In 4/11 heartworm extraction was not recommended because of low IH burden. All dogs with IH resolution were discharged from the hospital. Four of 11 have died (survival time 6; 22, 58 and 835 days), and 6/11 are alive (median follow-up 523 (range 268-2081) days. One was lost to follow-up after 18 days. Five dogs were medically managed. In one of five dogs, extraction was not recommended because of low IH burden. In four of five extraction was recommended but declined. One of five has died (survival 26 days), and four of five are alive (follow-up 155, 371, 935 and 947 days). Two dogs were killed at the time of diagnosis. Fifteen of 27 dogs were considered to have caval syndrome. CONCLUSION: The results suggest that patients with IH resolution have a good long-term prognosis. Most often IH resolution occurred while the dog was undergoing stabilization for heartworm extraction. When IHs are present, heartworm extraction should still be considered the treatment of choice and recommended as first-line therapy whenever possible.

A Novel Standardized Method for Aiding to Determine Left Atrial Enlargement on Lateral Thoracic Radiographs in Dogs.

BACKGROUND: Left atrial enlargement indicates severe cardiac disease. Although the gold standard for determining left atrial size is echocardiography, many veterinary practices lack the necessary equipment and expertise. Therefore, thoracic radiography is often used to differentiate cardiogenic pulmonary edema from primary respiratory diseases and to facilitate distinguishing dogs with stage B1 and B2 mitral valve degeneration. METHODS: The goal was to test a new standardized method for identifying radiographic left atrial enlargement. On a lateral radiograph, a straight line was drawn from the dorsal border of the tracheal bifurcation to the crossing point of the dorsal border of the caudal vena cava and the most cranial crus of the diaphragm. If a part of the left atrium extended this line dorsally, it was considered enlarged. Echocardiographic left atrial to aortic ratio (LA:Ao) was used as a reference. Thirty-nine observers with various levels of experience evaluated 90 radiographs, first subjectively, then applying the new method. RESULTS: The new method moderately correlated with LA:Ao (r = 0.56-0.66) in all groups. The diagnostic accuracy (72-74%) of the subjective assessment and the new method showed no difference. CONCLUSIONS: Though the new method was not superior to subjective assessment, it may facilitate learning and subjective interpretation.

Self-Reported Utilization of International Guidelines for Staging Dogs with Myxomatous Mitral Valve Degeneration: A Survey among Veterinary Practitioners.

BACKGROUND: ACVIM developed and published guidelines for staging myxomatous mitral valve degeneration in dogs in 2009. An updated version was published in 2019. The present study aimed to investigate whether these guidelines are actually used by the intended public more than a decade after their first publication. METHODS: An online survey was distributed among Dutch and Belgian veterinarians through online channels and mailing lists. RESULTS: Of the 524 responses, only 363 complete surveys were analyzed. The ACVIM guidelines are used by 60% of the respondents. Veterinarians find it more difficult to differentiate stage B1 from B2 in asymptomatic dogs compared to diagnosing stage C. Three-quarters of the respondents would recommend echocardiography for an incidentally detected new murmur with an intensity of 3 out of 6 in an adult dog. Two-thirds of the respondents find coughing a convincing finding for stage C disease. Close to half of the respondents associate a horizontal, dull percussion line with pulmonary edema. For confirming cardiogenic pulmonary edema, 98% of the respondents used thoracic radiographs. CONCLUSIONS: Veterinary practitioners might not have the expected training and equipment to be able to apply the guidelines in their practices, especially in the differentiation of stage B1 from stage B2.

A dog presenting with syncope due to two different etiologies.

Objective: The treatment of syncope depends largely on its possible etiology. Therefore, identifying the cause of syncope is very important in treatment planning. Herein, we report an etiology of syncope caused by pulmonary hypertension (PH) associated with canine filariasis, followed by syncope due to bradyarrhythmia 1 year later. Materials and Methods: An 8-year-old male English Cocker Spaniel was referred to our hospital for a second opinion regarding syncope that the dog had started experiencing approximately 2 months prior. Based on the examination findings, we diagnosed that the fainting was due to heartworm disease and associated PH. After increasing the dose of pimobendan (0.50 mg/kg, q12h), the syncope subsided. However, syncope recurred on the 215th day of the first episode. Results: The findings that differed from those during the initial examination were that cardiac arrest was observed for approximately 5 sec during auscultation, along with sinus arrest. Therefore, to further investigate for syncope, a Holter electrocardiograph was obtained for 3 days. Consequently, sinus arrest was identified as the etiology of the recurrent syncope, and the patient was diagnosed with sick sinus syndrome, Rubenstein classification type II. Following cilostazol (10 mg/kg, q12h) administration, the syncope subsided. Conclusion: This case reports syncope in a dog, which typically occurs due to different etiologies. When a dog has PH, it may be important to think about the possibility of arrhythmias caused by a bigger right heart.

Hemodynamic effect of pimobendan following intramuscular and intravenous administration in healthy dogs: A pilot study.

Background: Pimobendan is widely used for the treatment of dogs with heart failure via the oral route. A new injectable form of pimobendan is now available and its potential usefulness via intravenous route has been recently demonstrated in dogs. However, the cardiovascular effects of intramuscular (IM) administration of injectable pimobendan have not been investigated yet. Hypothesis: IM administration of pimobendan may have the same hemodynamic effect as the IV route. Methods: Six healthy Beagle dogs underwent a placebo-controlled double-blind crossover study. The early cardiovascular effects after a single dose of IM and IV injections of pimobendan (0.2 ml/kg; Pimo IM and Pimo IV, respectively) were compared to the same volume of IM placebo (Saline IM) in anesthetized dogs. Clinical [heart rate (HR) and blood pressure (BP)] and echocardiographic hemodynamic parameters [left ventricular (LV) inflow waveforms of diastolic early wave (eV), atrial systolic wave (aV), diastolic early mitral ring velocity (e'), peak velocity (pV), stroke volume (SV), cardiac output (CO), and systemic vascular resistance (SVR)] were monitored with 15 min intervals for 120 min. Results: Diastolic BP decreased significantly at 30 min in Pimo IM compared to Saline IM. Mean eV and CO values significantly increased from 75 min, e' from 60 min, pV from 75 min, and SV from 15 to 120 min, whereas SVR significantly decreased at 30-60 min in Pimo IM compared to those of Saline IM (P < 0.05). Compared with the Pimo IV, eV and pV were significantly lower at 30-60 min (P < 0.05) while SV was significantly higher at 90-105 min in Pimo IM (P < 0.05). Other hemodynamic parameters (BP, HR, SVR, CO, e', and E/e') did not significantly change between Pimo IM and IV. Conclusions: The hemodynamic effect of pimobendan following IM and IV injection was described. Our results suggested that IM administration of pimobendan is equally comparable and possibly interchangeable with IV administration. This warrant further studies to investigate the clinical effectiveness of IM pimobendan in treating dogs with congestive heart failure or in heart failure cases unable to receive IV or oral administration.

Pimobendan Inhibits HBV Transcription and Replication by Suppressing HBV Promoters Activity.

Current anti-HBV therapeutic strategy relies on interferon and nucleos(t)ide-type drugs with the limitation of functional cure, inducing hepatitis B surface antigen (HBsAg) loss in very few patients. Notably, the level of HBsAg has been established as an accurate indicator to evaluate the drug efficacy and predict the disease prognosis, thus exploring a novel drug targeting HBsAg will be of great significance. Herein, by screening 978 compounds from an FDA-approved drug library and determining the inhibitory function of each drug on HBsAg level in HepG2.2.15 cells supernatant, we identified that pimobendan (Pim) has a powerful antiviral activity with relatively low cytotoxicity. The inhibitory effect of Pim on HBsAg as well as other HBV markers was validated in HBV-infected cell models and HBV-transgenic mice. Mechanistically, real-time PCR and dual-luciferase reporter assay were applied to identify the partial correlation of transcription factor CAAT enhancer-binding protein α (C/EBPα) with the cccDNA transcription regulated by Pim. This indicates Pim is an inhibitor of HBV transcription through suppressing HBV promoters to reduce HBV RNAs levels and HBsAg production. In conclusion, Pim was identified to be a transcription inhibitor of cccDNA, thereby inhibiting HBsAg and other HBV replicative intermediates both in vitro and in vivo. This report may provide a promising lead for the development of new anti-HBV agent.

Preliminary Bioequivalence of an Oral Pimobendan Solution Formulation with Reference Solution Formulation in Beagle Dogs.

Oral capsule and tablet formulations of pimobendan are widely used but may present difficulties for accurately dosing small patients. This study aimed to compare the pharmacokinetic (PK) characteristics, bioequivalence, and cardiovascular effects of a custom-made oral pimobendan solution (PS) formulation compared to a reference solution (RS) formulation in conscious, healthy dogs. A randomized crossover design was performed on dogs that received RS and PS formulations at a dose of 0.3 mg/kg. Blood samples were collected at 0, 0.083, 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, and 24 h after oral administration for PK analysis; bioequivalence was also calculated. Echocardiography was also performed to assess the cardiovascular effects. The results revealed that the plasma concentrations of pimobendan and o-desmethyl-pimobendan (active metabolite) in the case of both formulations were comparable. The relative ratios of geometric mean concentrations for all significant parameters of PK were within a range of 80-125%, indicating bioequivalence. In addition, both formulations increased cardiac contraction significantly when compared with the baseline, and no differences in cardiac contractility were detected between the formulations. The PS formulation can be used as alternative to the RS formulation for the management of congestive heart disease because of the bioequivalence between the two formulations.