ISSN 0006-2979, Biochemistry (Moscow), 2013, Vol. 78, No. 9, pp. 1043-1047. © Pleiades Publishing, Ltd., 2013. Original Russian Text © F. F. Severin, B. A. Feniouk, V. P. Skulachev, 2013, published in Biokhimiya, 2013, Vol. 78, No. 9, pp. 1331-1336. Advanced Glycation of Cellular Proteins as a Possible Basic Component of the “Master Biological Clock” F. F. Severin1,2, B. A. Feniouk2
Vetmedin.comPrevalence was similar in the active control group. The mg/kg orally. The effect was still present 8 hours only 4 and 7% of the tablets offered, the average prevalence of renal failure was higher in the active con- after dosing. There was a delay between peak blood trol group (4%) compared to the Vetmedin group (1%).
levels of pimobendan and active metabolite and the maximum physiologic response (peak LV dP/dtmax). Animal Safety: In a laboratory study, Vetmedin chew-
Adverse reactions/new clinical findings were seen in Blood levels of pimobendan and active metabolite able tablets were administered to 6 healthy Beagles both treatment groups and were potentially related to Vetmedin®
began to drop before maximum contractility was seen. per treatment group at 0 (control), 1, 3, and 5 times CHF, the therapy of CHF, or both. The following adverse Repeated oral administration of pimobendan did not the recommended dosage for 6 months. See Table 3 reactions/new clinical findings are listed according to result in evidence of tachyphylaxis (decreased positive for cardiac pathology results. The cardiac pathology/ body system and are not in order of prevalence: CHF inotropic effect) or drug accumulation (increased histopathology noted in the 3X and 5X dose groups is death, sudden death, chordae tendineae rupture, left typical of positive inotropic and vasodilator drug toxicity positive inotropic effect). Laboratory studies indicate atrial tear, arrhythmias overall, tachycardia, syncope, that the positive inotropic effect of pimobendan may in normal dog hearts, and is associated with exagger- weak pulses, irregular pulses, increased pulmonary Caution: Federal law restricts this drug to use by or on
be attenuated by the concurrent use of a ß-adrenergic ated hemodynamic responses to these drugs. None of edema, dyspnea, increased respiratory rate, coughing, the order of a licensed veterinarian.
blocker or a calcium channel blocker.
the dogs developed signs of heart failure and there was gagging, pleural effusion, ascites, hepatic congestion, Description: Vetmedin (pimobendan) is supplied as
decreased appetite, vomiting, diarrhea, melena, weight Effectiveness: In a double-masked, multi-site, 56-day
oblong half-scored chewable tablets containing 1.25, loss, lethargy, depression, weakness, collapse, shaking, field study, 355 dogs with modified NYHA Class II, III, Table 3: Incidence of Cardiac Pathology/
2.5 or 5 mg pimobendan per tablet. Pimobendan, trembling, ataxia, seizures, restlessness, agitation, or IV CHF due to AVVI or DCM were randomly assigned Histopathology in the Six-month Safety Study
a benzimidazole-pyridazinone derivative, is a non- pruritus, increased water consumption, increased to either the active control (enalapril maleate) or the sympathomimetic, non-glycoside inotropic drug urination, urinary accidents, azotemia, dehydration, Vetmedin (pimobendan) treatment group. Of the 355 Severe left ventricular hypertrophy
One 3X and
with vasodilatative properties. Pimobendan exerts a abnormal serum electrolyte, protein, and glucose dogs, 52% were male and 48% were female; 72% with multifocal
two 5X dogsa
stimulatory myocardial effect by a dual mechanism values, mild increases in serum hepatic enzyme levels, were diagnosed with AVVI and 28% were diagnosed subendocardial ischemic lesions
of action consisting of an increase in calcium and mildly decreased platelet counts.
with DCM; 34% had Class II, 47% had Class III, and sensitivity of cardiac myofilaments and inhibition of 19% had Class IV CHF. Dogs ranged in age and weight Moderate to marked myxomatous
Three 5X dogs
See Table 1 for mortality due to CHF (including phosphodiesterase (Type III). Pimobendan exhibits from 1 to 17 years and 3.3 to 191 lb, respectively. The thickening of the mitral valves
euthanasia, natural death, and sudden death) and for vasodilating activity by inhibiting phosphodiesterase most common breeds were mixed breed, Doberman the development of new arrhythmias (not present in a III activity. The chemical name of pimobendan is 4,5- Pinscher, Cocker Spaniel, Miniature/Toy Poodle, Maltese, Myxomatous thickening of the
One 3X and
dog prior to beginning study treatments) by treatment chordae tendineae
two 5X dogs
dihydro-6-[2-(4-methoxyphenyl)-1H-benzimidazole-5- Chihuahua, Miniature Schnauzer, Dachshund, and group and type of heart disease (AVVI or DCM) in the yl]-5-methyl-3(2H)-pyridazinone. The structural formula Cavalier King Charles Spaniel. The 180 dogs (130 AVVI, Endocardial thickening of the left
One 1X, two 3X,
50 DCM) in the active control group received enalapril ventricular outflow tract
and two 5X dogs
Table 1: CHF Death and New Arrhythmias in the 56-Day
maleate (0.5 mg/kg once or twice daily), and all but 2 Field Study
received furosemide. Per protocol, all dogs with DCM in Left atrial endocardial thickening
One 3X and
the active control group received digoxin. The 175 dogs (jet lesions) in 2 of the dogs that
one 5X dog
(126 AVVI, 49 DCM) in the Vetmedin group received developed murmurs of mitral valve
Active Control Group
pimobendan (0.5 mg/kg/day divided into 2 portions that were not necessarily equal, and the portions were Granulomatous inflammatory lesion
One 3X dog
administered approximately 12 hours apart), and all but in the right atrial myocardium
Indications: Vetmedin (pimobendan) is indicated for
4 received furosemide. Digoxin was optional for treating the management of the signs of mild, moderate, or supraventricular tachyarrhythmia in either treatment Most of the gross and histopathologic findings oc- Dogs that
severe (modified NYHA Class IIa , IIIb , or IVc ) congestive group, as was the addition of a ß-adrenergic blocker if heart failure in dogs due to atrioventricular valvular digoxin was ineffective in controlling heart rate. After Murmurs of mitral valve insufficiency were detected in insufficiency (AVVI) or dilated cardiomyopathy (DCM). initial treatment at the clinic on Day 1, dog owners were one 3X (Day 65) and two 5X dogs (Days 135 and 163). Vetmedin is indicated for use with concurrent therapy to administer the assigned product and concurrent These murmurs (grades II-III of VI) were not associated for congestive heart failure (e.g., furosemide, etc.) as appropriate on a case-by-case basis.
The determination of effectiveness (treatment success) Indirect blood pressure was unaffected by Vetmedin at a A dog with modified New York Heart Association for each case was based on improvement in at least Dogs that
the label dose (1X). Mean diastolic blood pressure was (NYHA) Class II heart failure has fatigue, shortness of 2 of the 3 following primary variables: modified developed
decreased in the 3X group (74 mmHg) compared to the breath, coughing, etc. apparent when ordinary exercise NYHA classification, pulmonary edema score by a control group (82 mmHg). Mean systolic blood pressure arrhythmiasa
masked veterinary radiologist, and the investigator’s overall clinical effectiveness score (based on physical was decreased in the 5X group (117 mmHg) compared b A dog with modified NYHA Class III heart failure is to the control group (124 mmHg). None of the dogs had examination, radiography, electrocardiography, and comfortable at rest, but exercise capacity is minimal.
clinical pathology). Attitude, pleural effusion, coughing, activity level, furosemide dosage change, cardiac New arrhythmias included supraventricular premature A dog with modified NYHA Class IV heart failure has On 24-hour Holter monitoring, mean heart rate was beats and tachycardia, atrial fibrillation, atrioventricular size, body weight, survival, and owner observations no capacity for exercise and disabling clinical signs are increased in the 5X group (101 beats/min) compared to block, sinus bradycardia, ventricular premature beats were secondary evaluations contributing information the control group (94 beats/min). Not counting escape supportive to product effectiveness and safety. Based beats, the 3X and 5X groups had slightly higher num- Dosage and Administration: Vetmedin should be
on protocol compliance and individual case integrity, bers of isolated ventricular ectopic complexes (VEs). The administered orally at a total daily dose of 0.23 mg/lb Following the 56-day masked field study, 137 dogs 265 cases (134 Vetmedin, 131 active control) were maximum number of non-escape VEs recorded either at (0.5 mg/kg) body weight, using a suitable combination in the Vetmedin group were allowed to continue evaluated for treatment success on Day 29. See Table 2 baseline or in a control group dog was 4 VEs/24 hours. of whole or half tablets. The total daily dose should be on Vetmedin in an open-label extended-use study At either Week 4 or Week 20, three 3X group dogs had divided into 2 portions that are not necessarily equal, without restrictions on concurrent therapy. The adverse Table 2: Effectiveness Results for the
maximums of 33, 13, and 10 VEs/24 hours, and two 5X and the portions should be administered approximately reactions/new clinical findings in the extended-use 56-Day Field Study
group dogs had maximums of 22 and 9 VEs/24 hours. 12 hours apart (i.e., morning and evening). The tablets study were consistent with those reported in the 56-day One 1X group dog with no VEs at baseline had 6 VEs/24 are scored and the calculated dosage should be study, with the following exception: One dog in the hours at Week 4 and again at Week 20. Second-degree provided to the nearest half tablet increment.
extended-use study developed acute cholestatic liver Vetmedin® Group
Active Control Group
atrioventricular heart block was recorded in one 3X failure after 140 days on Vetmedin and furosemide.
group dog at Weeks 4 and 20, and in one dog from each Contraindications: Vetmedin should not be given in
of the 1X and 5X groups at Week 20. None of the dogs cases of hypertrophic cardiomyopathy, aortic stenosis, In foreign post-approval drug experience reporting, had clinical signs associated with these electrocardio- or any other clinical condition where an augmentation the following additional suspected adverse reactions Treatment
of cardiac output is inappropriate for functional or were reported in dogs treated with a capsule formula- Success on
tion of pimobendan: hemorrhage, petechia, anemia, Treatment was associated with small differences in hyperactivity, excited behavior, erythema, rash, drooling, mean platelet counts (decreased in the 3X and 1X Warnings: Only for use in dogs with clinical evidence
constipation, and diabetes mellitus.
groups), potassium (increased in the 5X group), glucose of heart failure. At 3 and 5 times the recommended (decreased in the 1X and 3X groups), and maximum dosage, administered over a 6-month period of time, To report suspected adverse reactions, to obtain a blood glucose in glucose curves (increased in the 5X pimobendan caused an exaggerated hemodynamic Material Safety Data Sheet, or for technical assistance group). All individual values for these variables were response in the normal dog heart, which was associated within the normal range. Three 1X and one 5X group with cardiac pathology (See Animal Safety).
Clinical Pharmacology: Pimobendan is oxidatively
dogs had mild elevations of alkaline phosphatase (less Success on
than two times normal). Loose stools and vomiting were Human Warnings: Not for use in humans. Keep this
demethylated to a pharmacologically active metabolite and all medications out of reach of children. Consult a which is then conjugated with sulfate or glucuronic physician in case of accidental ingestion by humans.
acid and excreted mainly via feces. The mean extent Storage Information: Store at controlled room tempera-
of protein binding of pimobendan and the active Precautions: The safety of Vetmedin has not been
metabolite in dog plasma is >90%. Following a single No increase in
established in dogs with asymptomatic heart disease or oral administration of 0.25 mg/kg Vetmedin tablets furosemide
in heart failure caused by etiologies other than AVVI or the maximal mean (± 1 SD) plasma concentrations dose between
Vetmedin® (pimobendan) Chewable Tablets: DCM. The safe use of Vetmedin has not been evaluated (Cmax) of pimobendan and the active metabolite were Available at 1.25, 2.5 or 5 mg oblong half-scored chew- in dogs younger than 6 months of age, dogs with 3.09 (0.76) ng/mL and 3.66 (1.21) ng/mL, respectively. congenital heart defects, dogs with diabetes mellitus or Individual dog Cmax values for pimobendan and the At the end of the 56-day study, dogs in the Vetmedin other serious metabolic diseases, dogs used for breed- active metabolite were observed 1 to 4 hours post-dose group were enrolled in an unmasked field study to ing, or pregnant or lactating bitches.
(mean: 2 and 3 hours, respectively). The total body monitor safety under extended use, without restrictions clearance of pimobendan was approximately 90 Adverse Reactions: Clinical findings/adverse reactions
mL/min/kg, and the terminal elimination half-lives were recorded in a 56-day field study of dogs with of pimobendan and the active metabolite were Vetmedin was used safely in dogs concurrently congestive heart failure (CHF) due to AVVI (256 dogs) approximately 0.5 hours and 2 hours, respectively. receiving furosemide, digoxin, enalapril, atenolol, or DCM (99 dogs). Dogs were treated with either Boehringer Ingelheim Vetmedica, Inc.
Plasma levels of pimobendan and active metabolite spironolactone, nitroglycerin, hydralazine, diltiazem, Vetmedin (175 dogs) or the active control enalapril were below quantifiable levels by 4 and 8 hours after antiparasitic products (including heartworm maleate (180 dogs). Dogs in both treatment groups oral administration, respectively. The steady-state prevention), antibiotics (metronidazole, cephalexin, received additional background cardiac therapy (See volume of distribution of pimobendan is 2.6 L/kg amoxicillin-clavulanate, fluoroquinolones), topical Effectiveness for details and the difference in digoxin
Vetmedin® is a registered trademark of Boehringer indicating that the drug is readily distributed into ophthalmic and otic products, famotidine, theophylline, administration between treatment groups).
Ingelheim Vetmedica GmbH licensed to Boehringer tissues. Food decreased the bioavailability of an levothyroxine sodium, diphenhydramine, hydrocodone, aqueous solution of pimobendan, but the effect of The Vetmedin group had the following prevalence (per- metoclopramide, and butorphanol, and in dogs on food on the absorption of pimobendan from Vetmedin cent of dogs with at least one occurrence) of common Copyright 2007 Boehringer Ingelheim Vetmedica, Inc. adverse reactions/new clinical findings (not present in a or an affiliated company. All Rights Reserved.
Palatability: In a laboratory study, the palatability of
dog prior to beginning study treatments): poor appetite In normal dogs instrumented with left ventricular Vetmedin was evaluated in 20 adult female Beagle dogs (38%), lethargy (33%), diarrhea (30%), dyspnea (29%), (LV) pressure transducers, pimobendan increased offered doses twice daily for 14 days. Ninety percent (18 azotemia (14%), weakness and ataxia (13%), pleural LV dP/dtmax (a measure of contractility of the heart) of 20 dogs) voluntarily consumed more than 70% of the effusion (10%), syncope (9%), cough (7%), sudden in a dose dependent manner between 0.1 and 0.5 28 tablets offered. Including two dogs that consumed death (6%), ascites (6%), and heart murmur (3%).
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