Comparative cardiac toxicity of the IV administered benzimidazole pyridazinon derivative Pimobendan and its enantiomers in female Beagle dogs

Schneider, P.; Güttner, J; Eckenfels, A; Heinzel, G.; Nicolai, Heleen; Trieb, G.; Lehmann, Holger

doi:10.1016/s0940-2993(97)80013-9

Cited by 20 publications

(20 citation statements)

References 13 publications

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“…However, this experiment was a short‐term study and no histopathologic examination was performed. On the other hand, a few isolated reports of possible adverse effects with the use of PIMO have been published, 7,8 and 1 clinical prospective study reported negative effects of PIMO on MR, cardiac morphology, and function of asymptomatic Beagle dogs affected by naturally occurring mild MVD 9 …”

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confidence: 99%

Effect of Pimobendan on Echocardiographic Values in Dogs with Asymptomatic Mitral Valve Disease

Ouellet

Bélanger

DiFruscia

et al. 2009

Veterinary Internal Medicne

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Background: Pimobendan (PIMO) is a novel inodilator that has shown promising results in the treatment of advanced mitral valve disease (MVD), but little is known about its hemodynamic effects, especially regarding the mitral regurgitant volume in naturally occurring MVD.Hypothesis: The addition of pimobendan to treatment decreases the regurgitant fraction (RF) in dogs with asymptomatic MVD.Animals: Twenty-four client-owned dogs affected by International Small Animal Cardiac Health Council class Ib MVD. Methods: Prospective, blinded, and controlled clinical trial. Dogs were assigned to a PIMO treatment group (n 5 19) (0.2-0.3 mg/kg q12h) or a control group (n 5 5). Echocardiographic evaluations were performed over a 6-month period.Results: The addition of PIMO to treatment did not decrease the RF of dogs affected by asymptomatic class 1b MVD over the study period (P 5 .85). There was a significant increase in the ejection fraction of the PIMO treated dogs at 30 days (80.8 AE 1.42 versus 69.0 AE 2.76, corrected P 5 .0064), and a decrease in systolic left ventricular diameter (corrected P 5 .011) within the PIMO group compared with baseline. However, this improvement in systolic function was not sustained over the 6-month trial period.Conclusion and Clinical Importance: This study did not identify beneficial long-term changes in the severity of mitral regurgitation after addition of PIMO to angiotensin converting enzyme inhibitor treatment of dogs with asymptomatic MVD.

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confidence: 99%

Effect of Pimobendan on Echocardiographic Values in Dogs with Asymptomatic Mitral Valve Disease

Ouellet

Bélanger

DiFruscia

et al. 2009

Veterinary Internal Medicne

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“…9,10 On the other hand, previous experimental data demonstrated that PIMO has potential adverse effects and that valvular and parietal endocardial jet lesions could be induced in healthy dogs, even in the absence of previous valvular disease, after 4 weeks of repeated PIMO administration at dosages close to therapeutic ones. 11 Moreover, individual reports of dogs chronically treated with PIMO recently have described adverse cardiac effects that were, at least in part, reversed after cessation of PIMO administration. 12 All of these findings, together with current views about PDE III inhibitors in human medicine, 13 have raised an important question: what are the potential cardiotoxic effects of chronic treatment with PIMO in dogs without systolic myocardial dysfunction?…”

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confidence: 99%

Comparative Adverse Cardiac Effects of Pimobendan and Benazepril Monotherapy in Dogs with Mild Degenerative Mitral Valve Disease: A Prospective, Controlled, Blinded, and Randomized Study

Chetboul

Lefebvre

Sampedrano

et al. 2007

Veterinary Internal Medicne

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Background: Pimobendan (PIMO) is an inodilator that may have some beneficial effects in canine degenerative mitral valve disease (MVD). However, little information is available about its cardiac effects in dogs without systolic myocardial dysfunction.Hypothesis: Compared to benazepril (BNZ), an angiotensin-converting enzyme inhibitor, PIMO may worsen valve regurgitation in early canine MVD.Animals: Twelve Beagles with asymptomatic MVD were randomized into 2 groups (n 5 6) receiving BNZ or PIMO at dosages of 0.25 mg/kg PO q24h and q12h respectively, for 512 days.Methods: The study followed a blinded, randomized, prospective, and parallel group design. After day 512, the dogs were necropsied, and cardiac histopathology was performed in a blinded manner.Results: A significant treatment effect was observed as soon as day 15 with increased systolic function in the PIMO group by comparison to baseline value as assessed by fractional shortening (P , .0001) and tissue Doppler variables (P 5 .001). Concurrently, the maximum area and peak velocity of the regurgitant jet signal increased (P , .001), whereas these variables remained stable in the BNZ group. Histologic grades of mitral valve lesions were more severe in the PIMO group than in the BNZ group. Moreover, acute focal hemorrhages, endothelial papillary hyperplasia, and infiltration of chordae tendinae with glycosaminoglycans were observed in the mitral valves of dogs from the PIMO group but not in those of the BNZ group.Conclusions and Clinical Importance: PIMO has adverse cardiac functional and morphologic effects in dogs with asymptomatic MVD. Additional investigation in dogs with symptomatic MVD is now warranted.

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“…Effects of pimobendan on the heart have been reported from two target animal safety studies in healthy dogs. First, intravenous administration of 0.5, 2 and 8 mg/kg pimobendan once daily for 4 weeks resulted in dose‐dependent increases in heart rate, mitral valve myxomatous thickening, left ventricular outflow tract endocardial thickening and ventricular muscle ischemic lesions (Schneider et al., ; US Freedom of Information Summary for Vetmedin ® (2007)). Second, at 3 and 5 mg/kg orally for 180 days, pimobendan caused severe left ventricular hypertrophy with multifocal subendocardial ischemic lesions, myxomatous thickening of the mitral valves, mitral valve insufficiency murmurs, left atrial jet lesions, endocardial thickening of the left ventricular outflow tract, a granulomatous lesion within the right atrial myocardium, decreased blood pressure, increased heart rate, and a small increase in ventricular premature contractions (US Freedom of Information Summary for Vetmedin ® (2007)).…”

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confidence: 99%

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

Kuntz¹,

Strehlau²,

Giraudel³

et al. 2017

Vet Pharm & Therapeutics

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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.

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Comparative cardiac toxicity of the IV administered benzimidazole pyridazinon derivative Pimobendan and its enantiomers in female Beagle dogs

Cited by 20 publications

References 13 publications

Effect of Pimobendan on Echocardiographic Values in Dogs with Asymptomatic Mitral Valve Disease

Effect of Pimobendan on Echocardiographic Values in Dogs with Asymptomatic Mitral Valve Disease

Comparative Adverse Cardiac Effects of Pimobendan and Benazepril Monotherapy in Dogs with Mild Degenerative Mitral Valve Disease: A Prospective, Controlled, Blinded, and Randomized Study

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

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