WO2022073954A1 - Use of pimobendan in the anaesthesia of non-human mammals - Google Patents

Abstract

The present invention is directed to the use of pimobendan in the anaesthesia of a non-human mammal, preferably a predominantly carnivorous non-human mammal, more preferably a canine or a feline, most preferably a canine, preferably for the improvement of hemodynamic values and/or cardiac output in such anaesthesia.

Description

Use of pimobendan in the anaesthesia of non-human mammals

FIELD OF THE INVENTION

The invention relates to the field of medicine, in particular to the field of veterinary medicine. The invention relates to the use of pimobendan in the anaesthesia of a non-human mammal, preferably a predominantly carnivorous non-human mammal, in particular a canine or a feline, more preferably the use of pimobendan for the improvement of hemodynamic values and/or cardiac output in the anaesthesia of a non-human mammal, preferably a predominantly carnivorous non-human mammal, in particular a canine or a feline.

BACKGROUND INFORMATION

The number of middle-aged dogs that need anaesthesia for different procedures is increasing. Although they are “healthy” many times, stable and asymptomatic in their normal life, general anaesthesia is a controlled intoxication estate, in which many drugs with lots of hemodynamic effects are used. These actions can decompensate these animals. One frequent complication is a decrease in cardiac output with a reduction of tissue perfusion, with potential severe consequences. To improve cardiac output several positive inotropes are used, such as dobutamine or dopamine. However, the use of these catecholamines is not free of adverse events, such as arrhythmias (e.g. tachycardia or bradycardia) or significant blood pressure variations. Moreover, these inotropic agents must be administered at continuous infusion rates using pumps or infusers, which complicate the administration to the dogs. Most importantly, these drugs are not authorized in veterinary medicine and are used off-label.

Further prior art is as follows:

Fitton A et al. (Drugs in Aging 1994, 4(5): 417-441) disclose a review about pimobendan and its pharmacology and therapeutic potential in congestive heart failure.

Pagel P et al. (British Journal of Pharmacology 1996, 119: 609-615) disclose the influence of levosimendan, pimobendan and milrinone on the regional distribution of cardiac output in anaesthetized dogs.

Verdouw P et al. (European Journal of Pharmacology 1986, 126: 21-30) disclose the cardiovascular profile of pimobendan.

Thus, there is a medical need for a safe, convenient and effective aid for use in anaesthesia of a non-human mammal, preferably a predominantly carnivorous non-human mammal, in particular a canine or a feline, which overcomes the problems of the prior art.

Summary of the Invention

The present invention concerns the use of pimobendan for the improvement of the hemodynamic state and/or cardiac output in the anaesthesia of a non-human mammal, preferably predominantly carnivorous non-human mammal, more preferably a canine or a feline, most preferably a canine. A corresponding method of improving the hemodynamic state and/or cardiac output in the anaesthesia of a non-human mammal, preferably predominantly carnivorous non-human mammal, more preferably a canine or a feline, most preferably a canine, comprising administering pimobendan to such non-human mammal, preferably predominantly carnivorous non-human mammal, more preferably a canine or a feline, most preferably a canine, a corresponding pimobendan for use in a method of improving the hemodynamic state and/or cardiac output in the anaesthesia of a non-human mammal, preferably predominantly carnivorous non-human mammal, more preferably a canine or a feline, most preferably a canine, as well as the corresponding use of pimobendan for the preparation of a medicament for improving the hemodynamic state and/or cardiac output in the anaesthesia of a non-human mammal, preferably predominantly carnivorous non-human mammal, more preferably a canine or a feline, most preferably a canine, are also intended to be comprised by the present invention.

The present invention further concerns the use of pimobendan in the anaesthesia of a non-human mammal, preferably predominantly carnivorous non-human mammal, more preferably a canine or a feline, most preferably a canine. A corresponding method of anaesthetising a non-human mammal, preferably predominantly carnivorous non-human mammal, more preferably a canine or a feline, most preferably a canine, comprising administering pimobendan to such non-human mammal, preferably predominantly carnivorous non-human mammal, more preferably a canine or a feline, most preferably a canine, a corresponding pimobendan for use in a method of anaesthetising a non-human mammal, preferably predominantly carnivorous non-human mammal, more preferably a canine or a feline, most preferably a canine, as well as the corresponding use of pimobendan for the preparation of a medicament for anaesthetising a non-human mammal, preferably predominantly carnivorous non-human mammal, more preferably a canine or a feline, most preferably a canine, are also intended to be comprised by the present invention.

Pimobendan (4,5-dihydro-6-[2-(4-methoxyphenyl)-lH-benzimidazol-5-yl]-5-methyl-3(2H)-pyridazinone) is disclosed in EP 0 008 391 and has the formula:

Pimobendan is a potent inotropic agent and vasodilator, with effect on systemic arterial vasculature as well. Studies in different animal models demonstrated these cardiovascular properties (Duncker et al, Van Meel et al). Pimobendan has a different mode of action than catecholamines, maintaining contractile efficiency, but improving contractile economy, by prolonging the time course of tension and increasing resting tension as well. Pimobendan also provides a greater coronary vasodilation and flow effect compared to dobutamine in non-failing hearts in dogs (Hata et al). Despite the longer period in maintaining the mechanical function, this does not cause significant alteration of the myocardial energy status compared to dobutamine (Hata et al, Ichihara et al). The benefits of the chronic use of pimobendan in dogs suffering from myxomatous mitral valve disease (MMVD) or dilated cardiomyopathy (DCM) are out of any doubt in terms of survival time and quality of life, even in preclinical phases, being the first and actually single treatment registered to be used since this stadium of both diseases (Hagstrom et al, Sumerfield et al, Boswood et al).

Pimobendan has been widely used in veterinary medicine in other species than canine, especially in cats, with a good knowledge both of pharmacokinetics and of pharmacodynamics (Hanzlicek et al, Yata et al). Pimobendan shows similar hemodynamic effects than observed in dogs, demonstrating clear benefits in terms of survival time by improving the cardiovascular state in patients suffering from different forms of cardiomyopathy as well (Oldach et al, Reyna-Doreste et al, Hambrook et al). There are also anecdotal reports of the clinical use of Pimobendan in ferrets, rabbits and even in hedgehogs (Orcutt et al, Wagner, Delke et al).

The advantages according to the present invention are one or more of the following:

- Improves cardiac output in anaesthetized patients;

- Stabilizes and/or improves hemodynamic state in anaesthetized patients;

- Counterbalances potential complications derived from a decrease in cardiac output due to anesthesia in anesthetized patients;

- Improves tissue perfusion in anesthetized patients;

- Improves contractility without increasing oxygen consumption by increasing the calcium sensitivity and not by increasing heart rate.

- Enables single dose administration to anaesthetized patients;

- Avoids arrhythmias associated with positive inotropes when administered to anaesthetized patients;

- Avoids severe blood pressure oscillations associated with positive inotropes when administered to anaesthetized patients;

- Enables a rapid onset of action;

- Avoids pump infusions needed for the administration of conventional positive inotropes in anaesthesia;

- Avoids continuous rate infusions (CRIs) for the administration of conventional positive inotropes in anaesthesia.

The experimental data of the underlying invention show that pimobendan does improve the hemodynamic state and/or cardiac output parameters in anaesthetized non-human mammals, preferably predominantly carnivorous non-human mammals, more preferably canines or felines, most preferably canines, counterbalancing the potential complications derived from a decrease in cardiac output that may lead to a reduction of tissue perfusion with potential severe consequences without cardiac, respiratory or blood pressure disturbances.

Detailed Description of the Invention

Before the embodiments of the present invention are described in further detail, it shall be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural reference unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. All given ranges and values may vary by 1 to 5 % unless indicated otherwise or known otherwise by the person skilled in the art, therefore, the term “about” was usually omitted from the description and claims. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are now described. All publications mentioned herein are incorporated herein by reference for the purpose of describing and disclosing the substances, excipients, carriers, and methodologies as reported in the publications which might be used in connection with the invention. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

In the course of the present invention the term “improvement of hemodynamic state and/or cardiac output in anaesthesia” refers to the improvement of the inotropic / afterload effect and/or to the counterbalancing of the compromised hemodynamic state due to the anaesthetic procedure, represented by an increase or decrease, respectively, as compared to non-pimobendan treatment, of one, two or more of the primary parameters “systolic distance [velocity integral time (VTi)]”, “peak velocity [aortic peak velocity (PVa)]” and “medium acceleration [aortic mean acceleration (MAa)]” as well as of one, two or more of the secondary parameters “heart rate (HR)”, blood pressure [median arterial pressure (MAP)]”, “end-tidal carbon dioxide fraction (ETCO2)” and “ fractional expired isoflurane concentration (FelSO)”.

In the course of the present invention the term “anaesthetic induction” refers to the transition from an awake state to an anaesthetized state.

In the course of the present invention the term “maintenance of anaesthesia” refers to the maintenance of a safe anaesthetic depth providing unconsciousness, amnesia, immobility and unresponsive to surgical stimulation (stage III) thereby maintaining respiratory and hemodynamic stability.

In the course of the present invention the term “a predominantly carnivorous non-human mammal” refers to any known species of predominantly carnivorous non-human mammals. Mammals are a class of vertebrate animals whose females are characterized by the possession of mammary glands while both males and females are characterized by sweat glands, hair, three middle ear bones used in hearing, and a neocortex region in the brain. Within this class the placentals are preferred, which are characterized by the use of a placenta during gestation. Mammals can further be divided with respect to their feeding. Some mammals feed on animal prey - this is a carnivorous diet (and includes insectivorous diets). Other mammals, called herbivores, eat plants. An omnivore eats both prey and plants. Carnivorous mammals have a simple digestive tract, because the proteins, lipids, and minerals found in meat require little in the way of specialized digestion. Plants, on the other hand, contain complex carbohydrates, such as cellulose. The digestive tract of an herbivore is there- fore host to bacteria that ferment these substances, and make them available for digestion. The present invention is especially designed for the anaesthesia of carnivorous or predominantly carnivorous non-human mammals. Such non-human mammals include especially all feliforms, such as domestic cats or big cats, and most caniforms, such as the dogs, wolves and foxes. Due to the economic importance of companion animals in modem life, the present invention is especially designed for the anaesthesia of dogs and/or of cats, especially of dogs.

In the course of the present invention the term “healthy middle-aged dog” refers to a dog of any breed and of American Society of Anaesthesiologists physical status classification system (ASA) grade I-II with no murmur nor pathologies that may have influence in hemodynamic state and/or cardiac output in anaesthesia, which is aged > 6 < 12 years.

In one aspect, the present invention further concerns the uses as herein disclosed and/or claimed, wherein the improvement of the hemodynamic state and/or cardiac output in the anaesthesia of a non-human mammal, preferably predominantly carnivorous non-human mammal, more preferably a canine or a feline, most preferably a canine, is represented by an increase or decrease of one, two or more of the following hemodynamic state and/or cardiac output primary parameters as compared to non-pimobendan treatment:

- systolic distance [Velocity integral time (VTi)],

- peak velocity [aortic peak velocity (PVa)], and/or

- medium acceleration [aortic mean acceleration (MAa)].

In another aspect, the present invention further concerns the uses as herein disclosed and/or claimed, wherein the non-human mammal, preferably the predominantly carnivorous non-human mammal, more preferably the canine or the feline, most preferably the canine, is to receive from 0.01 to 1.0 mg pimobendan per kg bodyweight, preferably from 0.01 to 0.6 mg pimobendan per kg bodyweight.

Even more preferably, the non-human mammal, preferably the predominantly carnivorous non-human mammal, more preferably the canine or the feline, most preferably the canine, is to receive 0.15 mg pimobendan per kg bodyweight as a single intravenous injection and/or up to 0.3 mg pimobendan per kg bodyweight twice daily (preferably every 12 hours) orally. Most preferred, the non-human mammal, preferably the predominantly carnivorous non-human mammal, more preferably the canine or the feline, most preferably the canine, is to receive 0.15 mg pimobendan per kg bodyweight as a single intravenous injection (Vetmedin® Injectable Solution for Dog 0.75 mg/ml, Boehringer Ingelheim) as exemplified in the working example(s) of the present invention.

In yet another aspect, the present invention further concerns the uses as herein disclosed and/or claimed, wherein pimobendan is to be administered during anaesthesia, preferably in the anaesthetic induction and/or during the maintenance of anaesthesia. In yet another aspect, the present invention further concerns the uses as herein disclosed and/or claimed, wherein pimobendan is to be administered intravenously (IV) to the non-human mammal, preferably the predominantly carnivorous non-human mammal, more preferably the canine or the feline, most preferably the canine.

In yet another aspect, the present invention further concerns the uses as herein disclosed and/or claimed, wherein pimobendan is to be administered as a single intravenous administration to the non-human mammal, preferably the predominantly carnivorous non-human mammal, more preferably the canine or the feline, most preferably the canine.

In yet another aspect, the present invention further concerns the uses as herein disclosed and/or claimed, wherein the anaesthesia is performed (following a standard protocol) by means of the following phases and medications:

Premedication: dexmedetomidine (preferably 2 - 3 pg/kg bodyweight intramuscularly) plus metadone (preferably 0.2 - 0.3 mg/kg bodyweight intramuscularly),

Induction: pre-oxygenation [preferably pure oxygen flux (O₂ 100%); 3 min] followed by alfaxone (preferably 0.5 - 1.5 mg/kg body weight intravenously),

Maintenance: isofluorane (FEISO)(preferably 1.2 ± 0.2%).

In yet another aspect, the present invention further concerns the uses as herein disclosed and/or claimed, wherein such use is characterized by one or more of the following achieved effects:

- improved cardiac output, represented by systolic distance (VTi), peak aortic blood flow velocity (PVa) and medium aortic blood flow acceleration (MAa),

- reduced peripheral vascular resistance,

- no blood pressure disturbances, represented by mean arterial blood pressure (MAP),

- no arrhythmias, represented by heart rate (HR),

- no respiratory disturbances, represented by end tidal carbon dioxide fraction ETCO2,

- reduced anaesthetic inhalator requirements, represented by fractional expired isoflurane concentration (FEISO).

In yet another aspect, the present invention further concerns the uses as herein disclosed and/or claimed, wherein the non-human mammal, preferably predominantly carnivorous non-human mammal, is a dog, preferably a middle-aged dog, more preferably a healthy middle-aged dog. Even more preferably, such dog does not suffer from one or more cardiac diseases selected from the group consisting of: enlarged heart size / cardiac remodelling, asymptomatic / preclinical / occult heart failure due to myxomatous mitral valve disease (MMVD) or dilated cardiomyopathy (DCM) (e.g. ACVIM stage B), asymptomatic / preclinical / occult heart failure due to mitral valve disease (MVD) (e.g. ACVIM stage B) and/or clinically overt heart failure due to myxomatous mitral valve disease (MMVD) or dilated cardiomyopathy (DCM) (e.g. ACVIM stage C and/or D).

In this context, the ACVIM system describes four basic stages of heart disease and failure for MMVD:

Stage A: patients at high risk for developing heart disease but that currently have no identifiable structural disorder of the heart (e.g., every Cavalier King Charles Spaniel without a heart murmur).

Stage B: patients with structural heart disease (e.g., the typical murmur of mitral valve regurgitation is present), but that have never developed clinical signs caused by heart failure (because of important clinical implications for prognosis and treatment, the panel fiirther subdivided Stage B into Stage Bl and B2).

Stage B 1 : asymptomatic patients that have no radiographic or echocardiographic evidence of cardiac remodelling in response to CVHD.

Stage B2: asymptomatic patients that have hemodynamically significant valve regurgitation, as evidenced by radiographic or echocardiographic findings of left-sided heart enlargement.

Stage C: patients with past or current clinical signs of heart failure associated with structural heart disease.

Stage D: patients with end-stage disease with clinical signs of heart failure caused by CVHD that are refractory to ‘ ‘ standard therapy ’ ’ .

Regarding DCM, The ESVC Task Force proposal for Canine Dilated Cardiomyopathy (DCM) classification is as follows:

Preclinical DCM: asymptomatic phase prior to development of clinical signs

Overt DCM: Clinical phase with signs in dogs with DCM and congestive heart failure (CHF) including breathlessness or dyspnoea, cough, depression, exercise intolerance, inappetence (hyporexia / lack of appetite), syncope, weight loss, abdominal distention, and polydipsia

In this context and even more preferred, the non-human mammal, preferably predominantly carnivorous nonhuman mammal, more preferably the canine, in particular the dog, does not suffer from one or more of the following diseases and/or pathophysiological states selected from the group consisting of: enlarged heart size / cardiac remodelling (as disclosed in WO 2005/092343), asymptomatic / preclinical / occult heart failure e.g. due to dilated cardiomyopathy (DCM) (as disclosed in WO 2007/054514) and/or asymptomatic / preclinical / occult heart failure due to mitral valve disease (MVD) (as disclosed in WO2017/174571).

In yet another aspect, the present invention further concerns the uses as herein disclosed and/or claimed, wherein the non-human mammal, preferably predominantly carnivorous non-human mammal is a feline, preferably a cat, more preferably a domestic cat, even more preferably with equivalent criteria in terms of health and age distribution as disclosed herein for canines, in particular dogs.

In this context and even more preferred, the non-human mammal, preferably predominantly carnivorous non- human mammal, more preferably the feline, even more preferably the cat, in particular the domestic cat, does not suffer from one or more of the following diseases and/or pathophysiological states selected from the group consisting of: cardiomyopathies, hypertrophic cardiomyopathy (HCM) (as disclosed in WO 2010/060874).

In yet another aspect, the present invention further concerns the uses as herein disclosed and/or claimed, wherein the non-human mammal, preferably the predominantly carnivorous non-human mammal, more preferably the canine or the feline, most preferably the canine, does not suffer from one or more cardiac diseases, wherein such one or more cardiac diseases are selected from the group consisting of: enlarged heart size / cardiac remodelling, asymptomatic / preclinical / occult heart failure e.g. due to dilated cardiomyopathy (DCM), asymptomatic / preclinical / occult heart failure due to mitral valve disease (MVD), clinically overt heart failure, cardiomyopathies and/or hypertrophic cardiomyopathy (HCM).

Pimobendan can be administered in such oral dosage forms as tablets, chewable tablets, chews, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, solutions, syrups, and emulsions. It may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. It can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

Preferably, in the course of the present invention, pimobendan is administered parenterally, more preferably intravenously (IV), most preferably intravenously as a single parenteral administration.

Pimobendan can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal skin patches. When administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

Pimobendan is typically administered in admixture with suitable pharmaceutical diluents, excipients and/or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulphate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, nontoxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and colouring agents can also be incorporated into the mixture. Suitable binders include starch, gelatine, natural sugars such as glucose or beta- lactose, com sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

Pimobendan can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

Pimobendan can also be administered in lipid-coated form as part of a solid pharmaceutical formulation (see for instance WO 2015/082389).

Pimobendan may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyeth- ylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.

Furthermore, Pimobendan may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, poly glycolic acid, copolymers of polylactic and poly- glycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and cross linked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 100 milligrams of active ingredient per dosage unit.

In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.

Gelatine capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain colouring and flavouring to increase patient acceptance.

In general, water, suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl-or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field. Preferably, in the course of the underlying invention, pimobendan is administered as a liquid formulation as disclosed in WO 2008/055871.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGURE 1:

Figure 1 shows the descriptive summarized results of the data measurements for the primary and secondary parameters in the pimobendan and the placebo group in dogs at the four times performed.

FIGURE 2:

Figure 2 shows the Box and Whisker plot for primary parameter “VTi” by protocol and time, showing average, interquartile range, maximum and minimum values.

FIGURE 3:

Figure 3 depicts the Box and Whisker plot for primary parameter “PVa” by protocol and time, showing average, interquartile range, maximum and minimum values.

FIGURE 4:

Figure 4 shows the Box and Whisker plot for primary parameter “MAa” by protocol and time, showing average, interquartile range, maximum and minimum values.

FIGURE 5:

Figure 5 depicts the Box and Whisker plot for secondary parameter “FEISO” by protocol and time, showing average, interquartile range, maximum and minimum values.

FIGURE 6:

Figure 6 depicts the Box and Whisker plot for secondary parameter “HR” by protocol and time, showing average, interquartile range, maximum and minimum values.

FIGURE 7:

Figure 7 shows the Box and Whisker plot for secondary parameter “MAP” by protocol and time, showing average, interquartile range, maximum and minimum values.

FIGURE 8:

Figure 8 depicts the Box and Whisker plot for secondary parameter “ETCO2” by protocol and time, showing average, interquartile range, maximum and minimum values.

FIGURE 9:

Figure 9 depicts the variance analysis and linear model showing significant differences (p<0.05) in favor of the pimobendan group in dogs for the three primary parameters as well as for the secondary parameter “FEISO” - as compared to the placebo group in dogs. No differences are observed for secondary parameters “HR”, “MAP” and for “ETCO2 as well”.

EXAMPLES

The following examples serve to further illustrate the present invention; but the same should not be construed as a limitation of the scope of the invention disclosed herein.

EXAMPLE 1 - Study in healthy middle-aged dogs

The aim of this study is to evaluate the potential hemodynamic effects of pimobendan when administered to healthy middle-aged dogs, during the anaesthetic procedure, measuring the potential counterbalance achieved by pimobendan in the improvement of hemodynamic state and/or cardiac output parameters in anaesthesia.

MATERIAL AND METHODS:

33 dogs are included in the study, randomly assigned to one of both groups, pimobendan (18) and placebo (15): Animals of the pimobendan group receive 0.15 mg/kg bodyweight (volume: 0.2 ml/kg bodyweight) intravenously (IV) pimobendan (Vetmedin® Injectable Solution for Dog 0.75 mg/ml, Boehringer Ingelheim). Animals of the placebo group receive 0.2 ml/kg bodyweight (equivalent volume) of saline solution IV.

STUDY DESIGN:

Clinic, prospective, observational, randomized, triple-blinded, placebo control. To avoid the changes in after- load and heart rate due to catecholamine release, only animals with local-regional blockade for surgical procedures or those consider minimal painless procedures (diagnostic) were included. Preventive analgesia was provided if needed. Drugs used do not have cardiovascular effects.

INCLUSION CRITERIA:

Dogs according to American Society of Anaesthesiologists physical status classification system (ASA) grade I-II not previously treated with pimobendan, or concomitant treatments, murmur or pathologies that may have influence in cardiac/hemodynamic state, any breed, and age > 6 <12 years, requiring anaesthesia for any diagnostic or surgical procedure, in which an oesophageal gavage placing is not contraindicated.

DATA MEASUREMENT:

Primary hemodynamic state and/or cardiac output parameters measured are systolic distance [Velocity integral time (VTi)], peak velocity [aortic peak velocity (PVa)] and medium acceleration [aortic mean acceleration (MAa)]. Heart rate (HR), blood pressure (MAP), end-tidal carbon dioxide fraction (ETCO2) and fractional expired isoflurane concentration (FEISO) are the secondary hemodynamic state and/or cardiac output or anaesthetic parameters evaluated.

An oesophageal doppler ecocardio monitor (CardioQ) is used to measure all parameters. Due to the characteristics of the study (data tendency), body weight normalized values are considered not necessary. Nevertheless, they are recorded in case additional information regarding this parameter would be needed.

EXPERIMENTAL DESIGN:

Anaesthetic protocol:

Premedication: dexmedetomidine (2-3 pg/kg IM) + metadone (0.2-0.3 mg/kg IM).

Induction: pre-oxygenation (02 100%) 3 min followed by alfaxone (0.5 -1.5 mg/kg IV).

Maintenance: isofluorane (FEISO 1.2 ± 0.2%).

Ideal hypnotic estate: HR and MAP stable (<15% variation).

- CR Monitoring: SBP/MAP, ECG, T, SpO2, ETCO2, FEISO, HR, RR.

An oesophageal Doppler (Cardio Q) is used for measurements in real time with an average every 20 cycles Schedule of events:

Primary and secondary parameters are recorded just the before administration of pimobendan or placebo, and at 1, 10 and 20 minutes afterwards.

Baseline and final data are compared as total variation, and interim data are useful to describe tendency of the effect observed (speed, linear, fluctuating...).

Statistical analysis:

A triple blinded model is implemented for managing the data. Thus, blinding is only opened once the statistical analysis has been done.

A two-way variance analysis for cropped measures, M-stimated and average, using the t2way() function of WRS2 Package Behavior Research Methods from Mair and Wilkox is used.

A linear model to double check the results obtained is performed as well, using the glm() lunction of the stats v 3.6.1 packet for R from R Core team.

Dependent variables are group and time.

Independent variables are VTi, PVa, MAa, HR, MAP, ETCO2 and FEISO

P<0,05 is considered significant

RESULTS AND DISCUSSION:

Thirty three dogs are enrolled and randomly distributed in both groups: eighteen in the pimobendan group and fifteen in the placebo group. Average age and bodyweight are 9 years (6-12) and 11 kg (5-25). No group differences is observed.

Descriptive summarized results of the data measurements for the primary and secondary parameters in the pimobendan and the placebo group in dogs at the four times performed are shown in Figure 1.

Results of hemodynamic parameters measured are shown in Whisker plot box graphs, showing average, interquartile range, maximum and minimum values (Figures 2-8).

Primary parameters: VTi, PVa, MAa

Secondary parameters: HR, MAP, ETCO2, FEISO

After injection VTi (13.0 cm [10.4, 22.3]), PVa (95.0 [83.0, 160] m/sec) and MAa (12.6 [9.40, 17.0] m/sec) are higher and FEISO lower (1.10 [1.00, 1.20] %) in the pimobendan group when compared to the placebo group (VTi: 10.5 [6.50, 17.4] cm, PVa: 80.0 [62.0, 103] m/sec, MAa: 10.2 [7.00, 16.0] m/sec and FEISO: 1.15 [0.900, 1.40] %. No differences are observed in the rest of variables.

Either variance analysis and linear model show significant differences in favour of the pimobendan group for the primary hemodynamic state and/or cardiac output parameters and for FEISO as well (p<0.05) compared with the placebo group. No differences are observed in HR, MAP and ETCO2 (Figure 9).

These data show that pimobendan does improve hemodynamic state and/or cardiac output parameters in anesthetized non-human mammals, preferably predominantly carnivorous non-human mammals, more preferably a canine, counterbalancing the potential complications derived from a decrease in cardiac output that may lead to a reduction of tissue perfusion with potential severe consequences without cardiac, respiratory or blood pressure disturbances. There were no adverse events observed during the study.

Abbreviations:

SBP: systolic blood pressure MAP: median arterial pres

ECG: electrocardiogram

T: temperature HR: heart rate FTc: flow time corrected

RR: respiration rate MD: minute distance BD: beat distance

VTi: velocity integral time PVa: aortic peak velocity MAa: aortic mean acceleration

ETCO2: end-tidal carbon dioxide action FEISO: end-tidal is

re concentration

REFERENCES

(1) Boswood et al, J. Vet. Int. Med. 2016, 30: 1765-177

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Claims

1. Use of pimobendan for the improvement of the hemodynamic state and/or cardiac output in the anaesthesia of a non-human mammal, preferably a predominantly carnivorous non-human mammal, more preferably a canine or a feline, most preferably a canine.

2. The use according to claim 1, wherein such improvement is represented by an increase or decrease of one, two or more of the following hemodynamic state and/or cardiac output parameters as compared to non-pimobendan treatment:

- systolic distance [Velocity integral time (VTi)],

- peak velocity [aortic peak velocity (PVa)], and/or

- medium acceleration [aortic mean acceleration (MAa)] .

3. Use of pimobendan in the anaesthesia of a non-human mammal, preferably a predominantly carnivorous non-human mammal, more preferably a canine or a feline, most preferably a canine.

4. The use according to any one of claims 1 to 3, wherein the non-human mammal, preferably the predominantly carnivorous non-human mammal, more preferably the canine or the feline, most preferably the canine, is to receive from 0.01 to 1.0 mg pimobendan per kg bodyweight, preferably from 0.01 to 0.6 mg pimobendan per kg bodyweight, most preferably 0.15 mg pimobendan per kg bodyweight.

5. The use according to any one of claims 1 to 4, wherein pimobendan is to be administered during anaesthesia, preferably in the anaesthetic induction and/or during the maintenance of anaesthesia.

6. The use according to any one of claims 1 to 5, wherein pimobendan is to be administered intravenously (IV).

7. The use according to any one of claims 1 to 6, wherein pimobendan is to be administered as a single intravenous (IV) administration.

8. The use according to any one of claims 1 to 7, wherein the anaesthesia is performed by means of the following phases and medications:

Premedication: dexmedetomidine (preferably 2 - 3 pg/kg bodyweight intramuscularly) plus metadone (preferably 0.2 - 0.3 mg/kg bodyweight intramuscularly), Induction: pre-oxygenation [preferably pure oxygen flux (O₂ 100%); 3 min] followed by alfaxone (preferably 0.5 - 1.5 mg/kg body weight intravenously), Maintenance: isofluorane (FEISO)(preferably 1.2 ± 0.2%).

9. The use according to any one of claims 1 to 8, wherein such use is characterized by one or more of the following achieved effects:

- improved cardiac output, represented by systolic distance (VTi), peak aortic blood flow velocity (PVa) and medium aortic blood flow acceleration (MAa),

- reduced peripheral vascular resistance,

- no blood pressure disturbances, represented by mean arterial blood pressure (MAP),

- no arrhythmias, represented by heart rate (HR),

- no respiratory disturbances, represented by end tidal carbon dioxide fraction ETCO2,

- reduced anaesthetic inhalator requirements, represented by fractional expired isoflurane concentration (FEISO).

10. The use according to any one of claims 1 to 9, wherein the non-human mammal, preferably the predominantly carnivorous non-human mammal, more preferably the canine or the feline, most preferably the canine, does not suffer from one or more cardiac diseases, wherein such one or more cardiac diseases are selected from the group consisting of: enlarged heart size / cardiac remodelling, asymptomatic / pre- clinical / occult heart failure e.g. due to dilated cardiomyopathy (DCM), asymptomatic / preclinical / occult heart failure due to mitral valve disease (MVD), clinically overt heart failure, cardiomyopathies and/or hypertrophic cardiomyopathy (HCM).

11. The use according to any one of claims 1 to 10, wherein the non-human mammal, preferably the predominantly carnivorous non-human mammal is a canine, preferably a dog, more preferably a middle- aged dog, even more preferably a healthy middle-aged dog.

12. The use according to any one of claims 1 to 10, wherein the non-human mammal, preferably the predominantly carnivorous non-human mammal is a feline, preferably a cat, more preferably a domestic cat.