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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/08/20 08:47:09」(JST)

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Pimobendan (INN is a veterinary medication manufactured by Boehringer Ingelheim under the trade names Vetmedin and Acardi) or pimobendane. It is a calcium sensitizer with positive inotropic and vasodilator effects. It is also a selective inhibitor of phosphodiesterase III (PDE3).

Pimobendan is used in the management of heart failure in dogs, most commonly caused by myxomatous mitral valve disease (also known as endocardiosis), or dilated cardiomyopathy.^[1] Research has shown that pimobendan increases survival time and improves quality of life in patients with congestive heart failure secondary to mitral valve disease when compared with benazepril, an angiotensin-converting-enzyme (ACE) inhibitor.^[2] Under the trade name Acardi, it is available for human use in Japan.^[3]

Mechanism of action

Pimobendan is a positive inotrope. It sensitizes and increases the binding efficiency of cardiac myofibril to the calcium ions that are already present without increasing the consumption of oxygen and energy. Pimobendan also causes peripheral vasodilation by inhibiting the function of phosphodiesterase III. This results in decreased pressure, translating into smaller cardiac preload and afterload (decreases the failing heart's workload).

Pharmacokinetics

Pimobendan is absorbed rapidly when given via the oral route and has a bioavailability of 60-65%. It is metabolized into its active form by the liver. The half-life of pimobendan in the blood is 0.4 hours and the half-life of its metabolite is 2 hours. Elimination is by excretion in the bile and then feces. Pimobendan is 90–95% bound to plasma proteins in circulation. This has implications in patients suffering from low blood protein levels (hypoproteinemia/hypoalbuminemia) and with patients that are on concurrent therapies that are also highly protein bound.

Combinations

Pimobendan is often used in combination with three other drugs to palliate dogs with heart disease and reduce clinical signs of disease. These are:

Furosemide, a diuretic, to reduce pulmonary edema. This can be given intravenously if the animal is in respiratory distress (6–8 mg/kg), and then titrated down to the minimum dose required orally.
Spironolactone, an aldosterone antagonist. This has two actions, firstly, as a potassium-sparing diuretic, although its diuretic properties are small compared with those of furosemide. Secondly, it reduces aldosterone-mediated myocardial remodelling and fibrosis, slowing the progression of heart disease.
An ACE inhibitor, often enalapril (trade name Enacard) or benazepril (Fortekor). These drugs inhibit the action of angiotensin-converting enzyme, producing a balanced vasodilation, along with other favourable effects.

Other drugs may also be used as required to manage certain arrhythmias that are often associated with heart disease.

Chemistry

Pimobendan can be synthesized beginning with anisoyl chloride:^[4]

References

^ Gordon SG, Miller MW, Saunders AB (2006). "Pimobendan in heart failure therapy—a silver bullet?". J Am Anim Hosp Assoc 42 (2): 90–3. PMID 16527909.
^ Häggström J, Boswood A, O'Grady M, et al. (July 2008). "Effect of Pimobendan or Benazepril Hydrochloride on Survival Times in Dogs with Congestive Heart Failure Caused by Naturally Occurring Myxomatous Mitral Valve Disease: The QUEST Study". J. Vet. Intern. Med. 22 (5): 1124. doi:10.1111/j.1939-1676.2008.0150.x. PMID 18638016.
^ "Kusuri-no-Shiori Drug Information Sheet". RAD-AR Council, Japan. April 2005. Retrieved 2008-08-06.
^ Nicolas, C; Verny, M; Maurizis, J. C.; Payard, M.; Faurie, M (1986). "Synthesis of14C-bucromarone succinate and hydrochloride". J. Labeled Cmpd. Radiopharm. 23: 837. doi:10.1002/jlcr.2580230806.

External links

Official Vetmedin Product Website
UK Product Website
Australia Product Website
Russia Product Website
Website about the QUEST study (reference 2) (http://www.questtrial.com)
A Few Words About Pimobendan

UpToDate Contents

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1. 収縮能障害による心不全における強心剤 inotropic agents in heart failure due to systolic dysfunction
2. 肺性心 cor pulmonale
3. 心筋における興奮収縮連関 excitation contraction coupling in myocardium
4. 心臓リモデリング：臨床的評価および治療 cardiac remodeling clinical assessment and therapy

English Journal

Echocardiographic assessment of right ventricular systolic function in conscious healthy dogs following a single dose of pimobendan versus atenolol.

Visser LC1, Scansen BA2, Brown NV3, Schober KE1, Bonagura JD1.
Journal of veterinary cardiology : the official journal of the European Society of Veterinary Cardiology.J Vet Cardiol.2015 Jul 23. pii: S1760-2734(15)00039-9. doi: 10.1016/j.jvc.2015.04.001. [Epub ahead of print]
OBJECTIVE: To quantify drug-induced changes in right ventricular (RV) systolic function after administration of pimobendan and atenolol.ANIMALS: 80 healthy privately-owned dogs.METHODS: Using a prospective, blinded, fully-crossed study design with randomized drug administration, RV systolic function
PMID 26213150

Effects of Single Drug and Combined Short-term Administration of Sildenafil, Pimobendan, and Nicorandil on Right Ventricular Function in Rats With Monocrotaline-induced Pulmonary Hypertension.

Nakata TM1, Tanaka R, Yoshiyuki R, Fukayama T, Goya S, Fukushima R.
Journal of cardiovascular pharmacology.J Cardiovasc Pharmacol.2015 Jun;65(6):640-8. doi: 10.1097/FJC.0000000000000236.
This study was designed to assess the progression of pulmonary arterial hypertension (PAH) and the effectiveness of therapy using recently investigated echocardiographic parameters. PAH is characterized by the progressive elevation of pulmonary artery pressure and right ventricular hypertrophy and d
PMID 25806612

Effect of pimobendan on the incidence of arrhythmias in small breed dogs with myxomatous mitral valve degeneration.

Lake-Bakaar GA1, Singh MK1, Kass PH2, Griffiths LG3.
Journal of veterinary cardiology : the official journal of the European Society of Veterinary Cardiology.J Vet Cardiol.2015 Jun;17(2):120-8. doi: 10.1016/j.jvc.2015.01.005. Epub 2015 May 23.
OBJECTIVE: To determine if pimobendan, a phosphodiesterase III inhibitor and calcium sensitizer with positive survival benefits, has an effect on incidence of arrhythmias compared to placebo in small breed dogs with congestive heart failure (CHF) due to myxomatous mitral valve degeneration (MMVD).AN
PMID 26007710

Japanese Journal

Comparative Evaluation of Calcium-Sensitizing Agents, Pimobendan and SCH00013, on the Myocardial Function of Canine Pacing–Induced Model of Heart Failure

Hamabe Lina,Kawamura Keisuke,Kim Soo-min [他]
Journal of pharmacological sciences 124(3), 386-393, 2014-03
NAID 40020026473

血漿交換が有効だった幼児拡張型心筋症の2例

西原栄起,野村羊示,福富久,郷清貴,太田宇哉,倉石建治,田内宣生
日本小児循環器学会雑誌 30(3), 326-331, 2014
　重度心不全を伴った拡張型心筋症（Dilated cardiomyopathy：DCM）に対して血漿交換療法（Plasma exchange：PE）が有効だった2幼児例を経験したので報告する．　症例1：1歳1ヵ月女児．特発性DCM．カテコラミン等の治療を開始するもカテコラミン離脱不能なため99病日PE施行．PE後，心機能回復傾向だったがカテコラミン減量で心機能悪化するため，ピモベンダン，デノパミ …
NAID 130004879030

Comparative Evaluation of Calcium-Sensitizing Agents, Pimobendan and SCH00013, on the Myocardial Function of Canine Pacing–Induced Model of Heart Failure

Hamabe Lina,Kawamura Keisuke,Kim Soo-min,Yoshiyuki Rieko,Fukayama Toshiharu,Shimizu Miki,Fukushima Ryuji,Tanaka Ryo
Journal of Pharmacological Sciences 124(3), 386-393, 2014
… Pimobendan and SCH00013 are calcium sensitizers that possess dual action of calcium sensitization and phosphodiesterase-III inhibition. … Heart failure was induced in 20 dogs, to which pimobendan and two different doses of SCH00013 were administered orally to 15 dogs for 3 weeks, and the remaining 5 dogs served as the control. …
NAID 130003391492

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「ピモベンダン」

Pimobendan
Systematic (IUPAC) name
	(RS)-6-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]-5-methyl-4,5-dihydropyridazin-3(2H)-one
Clinical data
AHFS/Drugs.com	International Drug Names
Legal status	℞ Prescription only
Routes	Oral
Pharmacokinetic data
Bioavailability	60 to 65%
Half-life	0.4 hours
Excretion	In feces
Identifiers
CAS number	74150-27-9
ATCvet code	QC01CE90
PubChem	CID 4823
ChemSpider	4657
UNII	34AP3BBP9T
KEGG	D01133
ChEMBL	CHEMBL24646
Chemical data
Formula	C19H18N4O2
Mol. mass	334.37 g/mol
	SMILES CC1CC(=O)NN=C1C2=CC3=C(C=C2)N=C(N3)C4=CC=C(C=C4)OC;
	InChI InChI=1S/C19H18N4O2/c1-11-9-17(24)22-23-18(11)13-5-8-15-16(10-13)21-19(20-15)12-3-6-14(25-2)7-4-12/h3-8,10-11H,9H2,1-2H3,(H,20,21)(H,22,24) ; Key:GLBJJMFZWDBELO-UHFFFAOYSA-N ;
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英: pimobendan
商: アカルディ
関

[1] Gordon SG, Miller MW, Saunders AB (2006). "Pimobendan in heart failure therapy—a silver bullet?". J Am Anim Hosp Assoc 42 (2): 90–3. PMID 16527909.

[2] Häggström J, Boswood A, O'Grady M, et al. (July 2008). "Effect of Pimobendan or Benazepril Hydrochloride on Survival Times in Dogs with Congestive Heart Failure Caused by Naturally Occurring Myxomatous Mitral Valve Disease: The QUEST Study". J. Vet. Intern. Med. 22 (5): 1124. doi:10.1111/j.1939-1676.2008.0150.x. PMID 18638016.

[3] "Kusuri-no-Shiori Drug Information Sheet". RAD-AR Council, Japan. April 2005. Retrieved 2008-08-06.

[4] Nicolas, C; Verny, M; Maurizis, J. C.; Payard, M.; Faurie, M (1986). "Synthesis of14C-bucromarone succinate and hydrochloride". J. Labeled Cmpd. Radiopharm. 23: 837. doi:10.1002/jlcr.2580230806.

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pimobendan