Patent Grant
12011441
The invention relates to the field of medicine, particularly veterinary medicine. In particular, the invention relates to the use of pimobendan for the reduction of heart size in patients with asymptomatic (occult, preclinical) heart failure (HF) due to (myxomatous) mitral valve disease [(M)MVD] and/or chronic valvular heart disease (CVHD; also known as chronic valve disease, CVD) and/or atrial ventricular valvular insufficiency (AVVI) and/or for the delay of onset of clinical symptoms in patients with asymptomatic (occult, preclinical) HF due to (m)MVD and/or CVHD/CVD and/or AVVI, and/or the delay of onset of heart failure due to (myxomatous) mitral valve disease [(M)MVD] and/or chronic valvular heart disease (CVHD; also known as chronic valve disease, CVD) and/or atrial ventricular valvular insufficiency (AVVI).
Heart failure is divided in different stages, which were defined by different classification systems, e.g. the International Small Animal Cardiac Health Council (ISACHC), the New York Heart Association (NYHA) functional classification systems and the currently used classification according to the Consensus Statements of the American College of Veterinary Internal Medicine (ACVIM), 2009.
Classification according to the International Small Animal Cardiac Health Council (ISACHC) System:
New York Heart Association (NYHA) functional classification system:
The ACVIM system describes four basic stages of heart disease and failure:
The pathology of the heart begins with ISACHC Class I, NYHA Class I and ACVIM stage B2 in which cardiac murmur or cardiac chamber enlargement, but no clinical symptoms are present (ISACHC Class I or asymptomatic/occult/preclinical stage). Clinical symptoms become manifest in the course of progression of the disease (ISACHC Class II or III, NYHA class II, III or IV, ACVIM stage C and D).
Known progression of (M)MVD or CVHD/CVD or AVVI heart failure is associated with an increase of the heart size. Cardiac remodelling due to the morphologic changes within the heart is generally considered as a risk factor and is linked to worsening of pathophysiologic changes of the heart leading to heart failure. One goal of the therapy of heart failure is the reduction of the heart size and the delay of morphological changes of the heart.
A known pharmaceutically active compound to treat heart failure is pimobendan (4,5-dihydro-6-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]-5-methyl-3(2H)-pyridazinone) disclosed in EP 0 008 391 and having the formula:
Pimobendan is a well-known compound for the treatment of congestive heart failure (CHF) originating for example from dilated cardiomyopathy (DCM) or mitral valve disease (MVD) in animals, especially dogs. Pimobendan is also approved as a drug product for cardiovascular treatment in humans in Japan.
Several publications disclose the use of pimobendan in the treatment of heart failure in animals, such as, for instance, the following ones.
WO 2005/092343 describes the use of PDE-III inhibitors, such as pimobendan, for the reduction of heart size of a patient suffering from heart failure without, however, mentioning patients with asymptomatic (occult, preclinical) heart failure due to mitral valve disease (MVD).
Lombard and co-workers (Lombard C W et al., J Am Anim Hosp Assoc 2006, 42: 249-261) disclose the clinical efficacy of pimobendan versus benazepril for the treatment of the clinical acquired atriventricular valvular disease in dogs.
WO 2007/054514 is directed to the use of PDE-III inhibitors, such as pimobendan, for the treatment of asymptomatic (also known as occult or preclinical) heart failure without, however, mentioning patients with asymptomatic (occult, preclinical) heart failure due to mitral valve disease (MVD).
Häggström J et al. (J Vet Intern Med 2008, 22: 1124-1135) describe the effect of pimobendan or benazepril hydrochloride on survival times in dogs with clinical congestive heart failure caused by naturally occurring myxomatous mitral valve disease without, however, mentioning patients with asymptomatic (occult, preclinical) heart failure due to mitral valve disease (MVD).
Summerfield N J and co-workers (Summerfield N J et al., J Vet Intern Med 2012, 26: 1337-1349) relate to a clinical study on the efficacy of pimobendan in the prevention of congestive heart failure or sudden death in Doberman Pinschers with preclinical dilated cardiomyopathy (DCM). However, they are silent about patients with asymptomatic (occult, preclinical) heart failure due to mitral valve disease (MVD).
Häggström J et al. (J Vet Intern Med 2013, 27: 1452-1462) describe short-term hemodynamic and neuroendocrine effects of pimobendan and benazepril in dogs with clinical myxomatous mitral valve disease and congestive heart failure. However, they are silent about patients with asymptomatic (occult, preclinical) heart failure due to mitral valve disease (MVD).
Internet website www.epictrial.com is directed to the EPIC trial, a study to investigate the effects of pimobendan in the delay of onset of clinical symptoms of congestive heart failure due to mitral valve disease (MVD). However, at the priority dates of this patent application this trial was still ongoing and no study results were publically available.
Several other publications, however, relate to the disadvantageous cardiac effects of pimobendan treatment, such as the following ones.
The objective underlying the present invention is, therefore, to provide a medical treatment which overcomes the problems of the prior art as described above.
The present invention concerns pimobendan for use in a method of reducing the heart size and/or delaying the onset of clinical symptoms in a patient suffering from asymptomatic (occult, preclinical) heart failure due to mitral valve disease (MVD), preferably asymptomatic (occult, preclinical) congestive heart failure due to mitral valve disease (MVD), more preferably asymptomatic (occult, preclinical) congestive heart failure due to myxomatous mitral valve disease (MMVD), and/or delaying the onset of heart failure in a patient suffering from asymptomatic (occult, preclinical) heart failure due to mitral valve disease (MVD), preferably delaying the onset of congestive heart failure in a patient suffering from asymptomatic (occult, preclinical) heart failure due to mitral valve disease (MVD), more preferably delaying the onset of congestive heart failure in a patient suffering from asymptomatic (occult, preclinical) heart failure due to myxomatous mitral valve disease (MMVD).
Corresponding methods of reducing the heart size and/or delaying the onset of clinical symptoms in a patient suffering from asymptomatic (occult, preclinical) heart failure due to mitral valve disease (MVD) and/or delaying the onset of (congestive) heart failure in a patient suffering from asymptomatic (occult, preclinical) heart failure due to mitral valve disease (MVD) and uses for the preparation of a pharmaceutical composition/medicament for reducing the heart size and/or delaying the onset of clinical symptoms in a patient suffering from asymptomatic (occult, preclinical) heart failure due to mitral valve disease (MVD) and/or delaying the onset of heart failure, preferably congestive heart failure, in a patient suffering from asymptomatic (occult, preclinical) heart failure due to mitral valve disease (MVD) are also intended to be within the scope of the present invention.
The present invention further concerns pimobendan for use in a method of reducing the heart size and delaying the onset of clinical symptoms in a patient suffering from asymptomatic (occult, preclinical) heart failure due to mitral valve disease (MVD), preferably asymptomatic (occult, preclinical) congestive heart failure due to mitral valve disease (MVD), more preferably asymptomatic (occult, preclinical) congestive heart failure due to myxomatous mitral valve disease (MMVD), and delaying the onset of heart failure in a patient suffering from asymptomatic (occult, preclinical) heart failure due to mitral valve disease (MVD), preferably delaying the onset of congestive heart failure in a patient suffering from asymptomatic (occult, preclinical) heart failure due to mitral valve disease (MVD), more preferably delaying the onset of congestive heart failure in a patient suffering from asymptomatic (occult, preclinical) heart failure due to myxomatous mitral valve disease (MMVD).
Corresponding methods of reducing the heart size and delaying the onset of clinical symptoms in a patient suffering from asymptomatic (occult, preclinical) heart failure due to mitral valve disease (MVD) and/or delaying the onset of (congestive) heart failure in a patient suffering from asymptomatic (occult, preclinical) heart failure due to mitral valve disease (MVD) and uses for the preparation of a pharmaceutical composition/medicament for reducing the heart size and delaying the onset of clinical symptoms in a patient suffering from asymptomatic (occult, preclinical) heart failure due to mitral valve disease (MVD) and delaying the onset of heart failure, preferably congestive heart failure, in a patient suffering from asymptomatic (occult, preclinical) heart failure due to mitral valve disease (MVD) are also intended to be within the scope of the present invention.
The advantages of the medical use(s) of pimobendan according to the present invention are as follows:
Any previously raised concerns regarding the safety of the medication should be allayed by the longer survival observed in the pimobendan group in the all-cause mortality analysis. There was no difference between groups in the rate or type of potential adverse events observed. This is despite the fact that dogs in the pimobendan group spent longer time in the study and were therefore at risk of experiencing adverse events for a longer period.
Before the embodiments of the present invention are described in further details 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.
The term “patient” as used hereinabove and herein below relates to an animal or a person suffering from (congestive) heart failure. The term “patient” embraces mammals such as primates including humans. In addition to primates, a variety of other mammals can be treated according to the method of the present invention. For instance, mammals, including but not limited to, horses, dogs, cats, or equine, canine, feline species can be treated. Preferred are human patients, dogs, cats and horses. Human patients are female or male person who are suffering from heart failure. As a rule such persons are children, young adults, adults or elderly people with an age of between 6 and 80, preferably between 30 and 65 years. Most preferred are dogs.
The term heart failure”, preferably “congestive heart failure”, as used hereinabove and herein below relates to any contractile disorder or disease of the heart. Clinical manifestations are as a rule the results of changes to the heart's cellular and molecular components and to mediators that drive homeostatic control. The heart failure, preferably congestive heart failure, is as a rule accompanied by an increase of the heart size and deterioration of cardiac functions.
The term “reduction of the heart size” as used hereinabove and herein below relates to a reduction of the size of the heart of the patient, which is diagnosed using echocardiography and which may be determined according to the radiograph methods suggested by James W. Buchanan et al. (Buchanan J W et al., J Am Vet Med Assoc 1995, 206(2), 194-199) and is expressed in the relative change of the vertebral heart size. Preferably, the relative heart size of said patient is reduced by at least 5%, preferably at least 10%, 15%, 20%, 25% or at least 30%, compared to baseline, i.e. before pimobendan treatment is initiated, more preferably within 10 to 100 days, even more preferably within about 30 to 40 days, most preferably within about 35 days of treatment with pimobendan.
The term “asymptomatic (occult, preclinical) (congestive) heart failure due to mitral valve disease (MVD)” as used hereinabove and herein below relates to any contractile disorder or disease of the heart which is due to/secondary to MVD—however, yet without any clinical symptoms of (congestive) heart failure. In particular, it relates to heart failure of ISACHC Class I (Class IA and/or Class IB), NYHA Class I and ACVIM stage B2.
The terms “delay of onset of clinical symptoms” and “prolongation of time until onset of clinical symptoms” are interchangeably used hereinabove and herein below and relate to the time period between from diagnosing the morphological changes of the heart of the patient until the beginning of clinical symptoms of heart failure, preferably congestive heart failure, due to mitral valve disease (MVD). In particular, they relate to the prolongation of time from still asymptomatic (occult, preclinical) heart failure of ISACHC Class I (Class IA and/or Class IB), NYHA Class I and ACVIM stage B2 to clinical evident heart failure, preferably congestive heart failure, of ISACHC Class II and further to Class III (Class IIIA and/or Class IIIB), NYHA Class II, III and IV and ACVIM stage C and D.
For the sake of unambiguity in the course of the present invention the medicinal indication terms “mitral valve disease (MVD)”, “myxomatous mitral valve disease (MMVD)”, “chronic valvular heart disease (CVHD)”, “chronic valve disease (CVD)” and “atrial ventricular valvular insufficiency (AVVI)” are all interchangeably used. As for ISACHC Class I (Class IA and/or Class IB), NYHA Class I and ACVIM stage B2 heart failure they are all synonymous to each other and have the identical medicinal meaning.
The term “risk reduction of reaching congestive heart failure” as used hereinabove and herein below relates to the relative risk of experiencing the clinical evident heart failure, preferably congestive heart failure. Preferably, the relative risk is reduced by at least 5%, preferably at least 10%, 15%, 20%, 25% or at least 30%.
The term “effective amount” as used herein means an amount sufficient to achieve a reduction of the heart size in patients with asymptomatic (occult, preclinical) heart failure (HF) due to mitral valve disease (MVD) and/or to achieve the delay of onset of clinical symptoms in patients with asymptomatic (occult, preclinical) HF due to MVD and/or to achieve the delay of onset of heart failure, preferably congestive heart failure, in patients with asymptomatic (occult, preclinical) HF due to MVD, when pimobendan is administered in a single dosage form.
In one aspect, the present invention relates to pimobendan for use according to the hereinabove and herein below disclosed aspects and preferred embodiments, wherein the asymptomatic (occult, preclinical) heart failure due to mitral valve disease (MVD), preferably asymptomatic (occult, preclinical) congestive heart failure due to mitral valve disease MVD, more preferably asymptomatic (occult, preclinical) congestive heart failure due to myxomatous mitral valve disease (MMVD) is of stage ISACHC Class I, preferably ISACHC Class IA or Class IB, more preferably of stage ISACHC Class IB, NYHA Class I and ACVIM stage B2.
In another aspect, the present invention relates to pimobendan for use according to the hereinabove and herein below disclosed aspects and preferred embodiments, wherein the pimobendan treatment effects a reduction of the heart size of the already pathologically enlarged heart of the patient. In other words, such patient suffers from asymptomatic (occult, preclinical) heart failure due to mitral valve disease (MVD) of ISACHC Class I (Class IA and/or Class IB), NYHA Class I and ACVIM stage B2 and already has a pathologically enlarged heart (e.g. visible by means of echocardiography), but does not yet show any clinical symptoms of heart failure, preferably congestive heart failure.
In another aspect, the present invention relates to pimobendan for use according to the hereinabove and herein below disclosed aspects and preferred embodiments, wherein the pimobendan treatment effects a prolongation of the time of survival of the patient as compared to placebo treatment or non-pimobendan treatment. In this connection, non-pimobendan treatment refers to a comparison treatment where the respective patient group receives an active pharmaceutical ingredient other than pimobendan instead of pimobendan or a placebo. Preferably such pimobendan treatment effects a prolongation of the time of survival of the patient of at least 30 days, more preferably at least 2 months, even more preferably at least 3 months, even more preferably at least 4 months, even more preferably at least 5 months, even more preferably at least 6 months, even more preferably at least 7 months, even more preferably at least 8 months, even more preferably at least 9 months, even more preferably at least 10 months, even more preferably at least 11 months, even more preferably at least 12 months, even more preferably at least 13 months, even more preferably at least 14 months, even more preferably at least 15 months, as compared to placebo treatment or non-pimobendan treatment.
In another aspect, the present invention relates to pimobendan for use according to the hereinabove and herein below disclosed aspects and preferred embodiments, wherein the pimobendan treatment effects a prolongation of the preclinical phase without exhibiting clinical symptoms of congestive heart failure, effects a delay of onset of (clinical symptoms of) congestive heart failure, increases the survival time of the treated patients as compared to placebo treatment, improves the quality of life of the treated patients, leads to a reduction of heart size of the treated patients as compared to baseline (i.e. before start of treatment), improves cardiac function/output in the treated patients, reduces sudden cardiac death/euthanasia of patients due to cardiac reasons and/or reduces the risk of reaching congestive heart failure.
In another aspect, the present invention relates to pimobendan for use according to the hereinabove and herein below disclosed aspects and preferred embodiments, wherein the patient is a mammal, preferably a human, a dog, a cat or a horse, more preferably a dog.
The dosage regimen for pimobendan will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired. A physician or veterinarian can determine and prescribe the effective amount of the drug required to prevent, counter, delay or arrest the progress of the disorder.
By way of general guidance, the daily oral dosage of pimobendan, when used for the indicated effects, will range between about 0.2 mg/kg to 0.6 mg/kg bodyweight SID, in particular from 0.2 mg/kg to 0.6 mg/kg bodyweight of pimobendan administered per day (EU) and 0.5 mg/kg bodyweight of pimobendan administered per day (US).
Preferably, the daily pimobendan dose is administered as two doses of 0.1 mg/kg to 0.3 mg/kg bodyweight, preferably two doses of 0.1 mg/kg to 0.3 mg/kg bodyweight every 12 hours (EU), more preferably two doses of 0.25 mg/kg bodyweight every 12 hours (USA).
In yet another aspect, the present invention relates to pimobendan for use according to the hereinabove and herein below disclosed aspects and preferred embodiments, wherein pimobendan is administered in a daily dose of 0.2 mg/kg to 0.6 mg/kg bodyweight SID, in particular from 0.2 mg/kg to 0.6 mg/kg bodyweight of pimobendan administered per day (EU) and 0.5 mg/kg bodyweight of pimobendan administered per day (US).
Preferably, the daily pimobendan dose is administered as two doses of 0.1 mg/kg to 0.3 mg/kg bodyweight, preferably two doses of 0.1 mg/kg to 0.3 mg/kg bodyweight every 12 hours (EU), more preferably two doses of 0.25 mg/kg bodyweight every 12 hours (USA).
According to another aspect of the present invention, pimobendan is administered in combination with at least one second active pharmaceutical ingredient (API). Such at least one second API is preferably selected from the group consisting of, afterload reducers (arteriodilators) such as ACE inhibitors, preload reducers (venodilators) such as diuretics, platelet inhibitors, beta blockers and angiotensin II antagonists, aldosterone antagonists, antiarrhythmic agents (if arrhythmias occur) and/or diuretics, in particular,
Preferably, pimobendan is administered together with one or more API selected from the group consisting of one or more ACE inhibitors and one or more diuretics.
In yet another aspect, the present invention relates to pimobendan for use according to the hereinabove and herein below disclosed aspects and preferred embodiments, wherein pimobendan is administered before, during or after administration of one or more additional active pharmaceutical ingredients selected from the group consisting of ACE inhibitors, preferably benazepril; and diuretics, preferably furosemide. More preferably, pimobendan is administered concomitantly with benazepril and furosemide.
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.
In another aspect, the present invention relates to pimobendan for use according to the hereinabove and herein below disclosed aspects and preferred embodiments, wherein pimobendan is administered orally or parenterally, preferably orally, more preferably orally in the form of a tablet or capsule, most preferably orally in the form of a tablet.
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 sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, 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, corn 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, polyhydroxyethylaspartamidephenol, 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, polyglycolic acid, copolymers of polylactic and polyglycolic 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 bisulfate, 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.
Where two or more of the foregoing second APIs are administered with pimobendan, generally the amount of each component in a typical daily dosage and typical dosage form may be reduced relative to the usual dosage of the API when administered alone, in view of the additive or synergistic effect of the APIs when administered in combination.
Particularly when provided as a single dosage unit, the potential exists for a chemical interaction between the combined APIs. For this reason, when pimobendan and at least one second API are combined in a single dosage unit they are formulated such that although the APIs are combined in a single dosage unit, the physical contact between the APIs is minimized (that is, reduced). For example, one API may be enteric coated. By enteric coating one of the APIs, it is possible not only to minimize the contact between the combined APIs, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. One of the APIs may also be coated with a material which effects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined APIs.
Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) or other appropriate materials as known in the art, in order to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component.
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.
Previous studies have suggested that pimobendan treatment significantly reduces case fatality and morbidity in dogs with CHF. The potential benefit of pimobendan treatment in delaying the progression of asymptomatic (occult, preclinical) heart failure in dogs due to mitral valve disease (MVD) has not yet been demonstrated.
Pimobendan is a benzimidazopyridazinone with a potent positive inotropic and a vasodilatory effect. This combined effect of preload and afterload reduction, together with positive inotropic support, results in a reduction in cardiac size and filling pressures in the heart of dogs with occult heart failure due to mitral valve disease.
The administration of pimobendan to dogs suffering from asymptomatic (occult, preclinical) heart failure due to mitral valve disease (MVD) prolongs the time to the onset of clinical signs of congestive heart failure by approx. 359 days (12.0 months) compared to placebo and extends survival time (all-cause mortality) by approx. 168 days (5.6 months) compared to placebo. Treatment of dogs in the preclinical phase of heart failure with pimobendan therefore leads to improved outcome.
Preliminary analysis of the final results of a blinded, placebo controlled study of 360 dogs shows that administration of pimobendan to dogs with MMVD and echocardiographic and radiographic evidence of cardiomegaly results in the prolongation of the preclinical period and is safe and well tolerated.
Median time to the primary endpoint is 1228 days (95% CI 856—NA) in the pimobendan group and 766 days (95% CI 667-875) in the placebo group (P=0.0038). Prolongation of the preclinical period by approximately 15 months represents a substantial clinical benefit. Overall survival, as determined by All Cause Mortality is also significantly longer in the pimobendan group than in the placebo group (P=0.012), and this also represents a significant clinical benefit.
Pimobendan also causes a reduction in heart size, compared to the placebo group, when measured over the first 35 days of the study (P<0.0001).
The final study results have been published in the meantime (Boswood A et al., J Vet Intern Med 2016, 30(6): 1765-1779).
Vertebral heart sum, another measure of heart size, was obtained at regular intervals—every eight months—from those animals that remained in the study. There are various ways in which this can be compared between groups. The most useful way to summarise and compare the average vertebral heart score in each group for the duration of the study is to generate an “area under the curve” value that represents a single summary statistic for each dog from which more than two measurements were obtained [Matthews J N et al., BMJ 1990, 300(6719): 230-235]. This method has been used previously in veterinary studies [Häggström J et al., J Vet Intern Med 2013, 27(6): 1441-1451].
When the average vertebral heart score for the dogs in both groups over the duration of the study is calculated and compared between groups the following results are obtained.
Thus it can be seen that the median vertebral heart score for dogs remaining in the study when averaged over the entire duration of the study is approximately 0.35 vertebrae lower for dogs receiving pimobendan (table 1). Thus the echocardiographic results show an acute reduction in heart size which is evident after one month. The radiographic findings indicate that the difference in heart size persists when a measure of heart size is averaged over the duration of the study.
| Number | Date | Country | Kind |
|---|---|---|---|
| 16164041 | Apr 2016 | EP | regional |
| 16172394 | Jun 2016 | EP | regional |
| Number | Name | Date | Kind |
|---|---|---|---|
| 3574859 | Kosti | Apr 1971 | A |
| 3822349 | Kosti | Jul 1974 | A |
| 3832460 | Kosti | Aug 1974 | A |
| 3839522 | Kosti | Oct 1974 | A |
| 3950333 | Durant et al. | Apr 1976 | A |
| 4128658 | Price et al. | Dec 1978 | A |
| 4256743 | Goldhaber | Mar 1981 | A |
| 4283400 | von Bittera et al. | Aug 1981 | A |
| 4283408 | Hirata et al. | Aug 1981 | A |
| 4293557 | Shibata et al. | Oct 1981 | A |
| 4361563 | Austel et al. | Nov 1982 | A |
| 4375547 | Pioch | Mar 1983 | A |
| 4386099 | Cereda et al. | May 1983 | A |
| 4427648 | Brickl et al. | Jan 1984 | A |
| 4569837 | Suzuki et al. | Feb 1986 | A |
| 4585790 | Padfield et al. | Apr 1986 | A |
| 4596705 | Schepky et al. | Jun 1986 | A |
| 4654342 | Slater | Mar 1987 | A |
| 4704284 | Beatty et al. | Nov 1987 | A |
| 4732915 | Ayer et al. | Mar 1988 | A |
| 4851226 | Julian et al. | Jul 1989 | A |
| 4865851 | James et al. | Sep 1989 | A |
| 4868182 | Dage | Sep 1989 | A |
| 4906628 | Coates | Mar 1990 | A |
| 4933182 | Higashi et al. | Jun 1990 | A |
| 4954501 | Herter et al. | Sep 1990 | A |
| 4973469 | Mulligan et al. | Nov 1990 | A |
| 5024998 | Bodor | Jun 1991 | A |
| 5151420 | Backstrom et al. | Sep 1992 | A |
| 5188836 | Muhammad et al. | Feb 1993 | A |
| 5364646 | Gruber et al. | Nov 1994 | A |
| 5569657 | Nore et al. | Oct 1996 | A |
| 5571533 | Santus et al. | Nov 1996 | A |
| 6407079 | Muller et al. | Jun 2002 | B1 |
| 6476078 | Jerussi et al. | Nov 2002 | B2 |
| 6669955 | Chungi et al. | Dec 2003 | B2 |
| 6713487 | Yu et al. | Mar 2004 | B2 |
| 7262165 | Lindenblatt et al. | Aug 2007 | B2 |
| 8409612 | Criere et al. | Apr 2013 | B1 |
| 8846679 | Folger et al. | Sep 2014 | B2 |
| 8980894 | Daemmgen | Mar 2015 | B2 |
| 9463199 | Daemmgen | Oct 2016 | B2 |
| 9889148 | Daemmgen | Feb 2018 | B2 |
| 10117869 | Daemmgen | Nov 2018 | B2 |
| 10537588 | Daemmgen | Jan 2020 | B2 |
| 20030059471 | Compton et al. | Mar 2003 | A1 |
| 20030162835 | Staniforth et al. | Aug 2003 | A1 |
| 20030165565 | Mehta | Sep 2003 | A1 |
| 20030190343 | Thombre et al. | Oct 2003 | A1 |
| 20030212114 | Sato | Nov 2003 | A1 |
| 20040037869 | Cleverly et al. | Feb 2004 | A1 |
| 20040152664 | Chang et al. | Aug 2004 | A1 |
| 20040157887 | Whittle et al. | Aug 2004 | A1 |
| 20050095293 | Brauns et al. | May 2005 | A1 |
| 20050203097 | Folger et al. | Sep 2005 | A1 |
| 20050239692 | Lindenblatt et al. | Oct 2005 | A1 |
| 20070112010 | Kleeman et al. | May 2007 | A1 |
| 20080207629 | Folger et al. | Aug 2008 | A1 |
| 20090082282 | Daemmgen et al. | Mar 2009 | A1 |
| 20100035889 | Daemmgen | Feb 2010 | A1 |
| 20100166857 | Yan et al. | Jul 2010 | A1 |
| 20100183718 | Ovaert et al. | Jul 2010 | A1 |
| 20100273807 | Kleeman et al. | Oct 2010 | A1 |
| 20110028457 | Roewer et al. | Feb 2011 | A1 |
| 20110189283 | Derrieu et al. | Aug 2011 | A1 |
| 20110251208 | Daemmgen et al. | Oct 2011 | A1 |
| 20110318420 | Hu et al. | Dec 2011 | A1 |
| 20120148640 | Folger et al. | Jun 2012 | A1 |
| 20120308662 | Konishi et al. | Dec 2012 | A1 |
| 20130115301 | Bele et al. | May 2013 | A1 |
| 20130203690 | Daemmgen et al. | Aug 2013 | A1 |
| 20140155338 | Daemmgen et al. | Jun 2014 | A1 |
| 20140235648 | Folger et al. | Aug 2014 | A1 |
| 20140363510 | Folger et al. | Dec 2014 | A1 |
| 20150025082 | Aven et al. | Jan 2015 | A1 |
| 20150064249 | Folger et al. | Mar 2015 | A1 |
| 20150148335 | Bova et al. | May 2015 | A1 |
| 20150150820 | Laczay | Jun 2015 | A1 |
| 20160038420 | Brunel et al. | Feb 2016 | A1 |
| 20170290829 | Schummer | Oct 2017 | A1 |
| 20190008862 | Daemmgen | Jan 2019 | A1 |
| Number | Date | Country |
|---|---|---|
| 2012101682 | Jan 2013 | AU |
| 950833 | Jul 1974 | CA |
| 1222697 | Jun 1987 | CA |
| 2034569 | Jul 1991 | CA |
| 1336498 | Aug 1995 | CA |
| 1662250 | Aug 2005 | CN |
| 1929845 | Mar 2007 | CN |
| 3728244 | Mar 1989 | DE |
| 4001623 | Jul 1991 | DE |
| 0241179 | Oct 1987 | EP |
| 0256566 | Feb 1988 | EP |
| 0268146 | May 1988 | EP |
| 0306846 | Mar 1989 | EP |
| 0330052 | Aug 1989 | EP |
| 0335545 | Oct 1989 | EP |
| 0349657 | Jan 1990 | EP |
| 439030 | Jul 1991 | EP |
| 1123703 | Aug 2001 | EP |
| 1247456 | Oct 2002 | EP |
| 1260215 | Nov 2002 | EP |
| 1579862 | Sep 2005 | EP |
| 1903039 | Mar 2008 | EP |
| 1920785 | May 2008 | EP |
| 2338493 | Jun 2011 | EP |
| 3034071 | Jun 2016 | EP |
| 2350105 | Dec 1977 | FR |
| 1045031 | Oct 1966 | GB |
| 2228004 | Aug 1990 | GB |
| 61500788 | Apr 1986 | JP |
| H029825 | Jan 1990 | JP |
| H0489428 | Mar 1992 | JP |
| H0570612 | Mar 1993 | JP |
| H11228302 | Aug 1999 | JP |
| 2005281283 | Oct 2005 | JP |
| 2007191419 | Aug 2007 | JP |
| 2008504308 | Feb 2008 | JP |
| 2011157390 | Aug 2011 | JP |
| 2012533595 | Dec 2012 | JP |
| 2013006798 | Jan 2013 | JP |
| 2013503113 | Jan 2013 | JP |
| 1985002767 | Jul 1985 | WO |
| 1989004178 | May 1989 | WO |
| 1995031963 | Nov 1995 | WO |
| 0012137 | Mar 2000 | WO |
| 2000069414 | Nov 2000 | WO |
| 2001035925 | May 2001 | WO |
| 2001064190 | Sep 2001 | WO |
| 2001097861 | Dec 2001 | WO |
| 0245693 | Jun 2002 | WO |
| 2002049646 | Jun 2002 | WO |
| 2003012030 | Feb 2003 | WO |
| 03072141 | Sep 2003 | WO |
| 2003074032 | Sep 2003 | WO |
| 2003075895 | Sep 2003 | WO |
| 2003097067 | Nov 2003 | WO |
| 2003099194 | Dec 2003 | WO |
| 2004000317 | Dec 2003 | WO |
| 2004000344 | Dec 2003 | WO |
| 2004016252 | Feb 2004 | WO |
| 2004033444 | Apr 2004 | WO |
| 2004050657 | Jun 2004 | WO |
| 2004058726 | Jul 2004 | WO |
| 2004060353 | Jul 2004 | WO |
| 2004089418 | Oct 2004 | WO |
| 2005035505 | Apr 2005 | WO |
| 2005084647 | Sep 2005 | WO |
| 2005092343 | Oct 2005 | WO |
| 2005107756 | Nov 2005 | WO |
| 2005117911 | Dec 2005 | WO |
| 2006000229 | Jan 2006 | WO |
| 2006022562 | Mar 2006 | WO |
| 2006060122 | Jun 2006 | WO |
| 2006060127 | Jun 2006 | WO |
| 2007036671 | Apr 2007 | WO |
| 2007038796 | Apr 2007 | WO |
| 2007054514 | May 2007 | WO |
| 2007112274 | Oct 2007 | WO |
| 2007128749 | Nov 2007 | WO |
| 2008055871 | May 2008 | WO |
| 2009060226 | May 2009 | WO |
| 2010010257 | Jan 2010 | WO |
| 2010055119 | May 2010 | WO |
| 2010060874 | Jun 2010 | WO |
| 2011009818 | Jan 2011 | WO |
| 2011042463 | Apr 2011 | WO |
| 2011076738 | Jun 2011 | WO |
| 2013024023 | Feb 2013 | WO |
| 2013135852 | Sep 2013 | WO |
| 2013164473 | Nov 2013 | WO |
| 2013170317 | Nov 2013 | WO |
| 2014136035 | Sep 2014 | WO |
| 2015082389 | Jun 2015 | WO |
| 2017174571 | Oct 2017 | WO |
| Entry |
|---|
| Atkins et al., “Pharmacologic management of myxomatous mitral valve disease in dogs”, Journal of Veterinary Caroliology, vol. 14, No. 1, Feb. 2012, pp. 165-184. |
| Ouellet et al., “Effect of Pimobendan on Echocardiographic Values in Dogs with Asymptomatic Mitral Valve Disease”, Journal of Veterinary Internal Medicine, vol. 23. No. 2, Jan. 2009, pp. 258-263. |
| Chetboul et al., “Comparative Adverse Cardiac Effects of Pimobendan and Benazepril Monotherapy in Dogs with Mild Degenerative Mitral Valve Disease: A Prospective, Controlled, Blinded, and Randomized Study”, Journal of Veterinary Internal Medicine, 2007; 21, pp. 742-753. |
| Boswood et al., 2011, “Evaluation of pimobendan in dogs with cardiomegaly caused by preclinical mitral valve disease”, The Veterinary Record, vol. 68, No. 8, Feb. 2011, p. 222. |
| Boswood et al., “Effect of Pimobendan in Dogs with Preclinical Myxomatous Mitral Valve Disease and Cardiomegaly: the EPIC Study—A randomized Clinical Trial”, Journal of Veterinary Internal Medicine, vol. 30, No. 6, Sep. 2016, pp. 1765-1779. |
| Beaufrere et al., “Pimobendan”, Journal of Exotic Pet Medicine, vol. 18, No. 4, Oct. 2009, pp. 311-313. |
| PCT International Search Report, PCT/EP2017/057970, dated Jun. 1, 2017, 5 pages. |
| PCT Written Opinion of the International Searching Authority, PCT/EP2017/057970, dated Jun. 1, 2017, 6 pages. |
| Fox et al., “Bradykinin-evoked sensitization of airway sensory nerves: A mechanism for ACE-inhibitor cough.” Nature Medicine, vol. 2, No. 7, Jul. 1996, pp. 814-817. |
| International Search Report and Written Opinion for PCT/EP2017/057970 dated Jun. 12, 2017. |
| Vromans et al., “Densification properties and compactibility of mixtures of pharmaceutical excipients with and without magnesium stearate.” International Journal of Pharmaceutics, vol. 46, 1988, pp. 183-192. |
| Liu et al., “Pharmacology Preparation Technology.” Chemical Industry Press, 2006, pp. 113-114. |
| Sun et al., “Pimobendan.” Chemical Industry Press, 2002, pp. 29-30. |
| Swedish University of Agricultural Sciences, Press Release dated Mar. 13, 2015, made publicly available at the webpage having the URL https://www.mynewsdesk.com/se/sveriges_lantbruksuniversitet_slu/pressreleases/the-epic-study-has-been-terminated-1130220. |
| Elliott, P., “Diagnosis and management of dilated cardiomyopathy”. Heart, vol. 83, 2000, pp. 106-112. |
| Endoh, Masao, “New Aspects of the Treatment of Myocardial Failure from a Pharmacological Standpoint”. Journal of Clinical and Experimental Medicine, vol. 187, No. 10, 1998, pp. 827-831. |
| Erhardt, L., “An Emerging Role for Calcium Sensitisation in the Treatment of Heart Failure”. Expert Opinion on Investigational Drugs, vol. 14, No. 6, 2005, pp. 659-670. |
| Ettinger et al., “Effects of enalapril maleate on survival of dogs with naturally acquired heart failure”. Journal of the American Veterinary Medical Association, vol. 213, No. 11, 1998, pp. 1573-1577. |
| Ettinger et al., “Therapeutic Considerations in Medicine and Disease”. Textbook of Veterinary Internal Medicine, Diseases of the Dog and Cat, Sixth Edition, vol. I, 2004, pp. 530-531. |
| Fitton et al., “Pimobendan. A Review of its Pharmacology and Therapeutic Potential in Congestive Heart Failure”. Drugs and Aging, vol. 4, No. 5, 1994, pp. 417-441. |
| Fox et al., “Prosepective Double-Blinded, Multicenter Evaluation of Chronic Therapies for Feline Diastolic Heart Failure: Interim Analysis”. ACVIM Abstracts, Abstract 78, 2003, pp. 398-399. |
| Fox, Philip R., “Hypertrophic Cardiomyopathy. Clinical and Pathologic Correlates”. Journal of Veterinary Cardiology, vol. 5, No. 2, Nov. 2003, pp. 39-45. |
| Fraker et al., “Reversal of phosphate induced decreases in force by the benzimidazole pyridazinone, UD-CG 212 CL, in myofilaments from human ventricle.” Molecular and Cellular Biochemistry, vol. 176, 1997, pp. 83-88. |
| Fuentes, et al., “A Double-Blind, Randomized, Placebo-Controlled Study of Pimobendan in Dogs with Dilated Cardiomyopathy,” Journal of Veterinary Internal Medicine, vol. 16, 2002, pp. 255-261. |
| Fujino et al., “Differential Effects of d-and I-Pimobendan on Cardia Myofilament Calcium Sensitivity1”. The Journal of Pharmacology and Experimental Therapeutics, vol. 247, No. 2, 1988, pp. 519-523. |
| Goineau et al., “Cardiomyopathie Syrian Hamster as a Model of Congestive Heart Failure”. Current Protocols in Pharmacology, Supp. 42, Unit 5.50, John Wiley & Sons, Inc., Sep. 2008, 12 pages. |
| Groban, Leanne, “Diastolic Dysfunction in the Older Heart”. Journal of Cardiothoracic and Vascular Anesthesia, vol. 19, No. 2, Apr. 2005, pp. 228-236. |
| Gwathmey et al., “Abnormal Intracellular Calcium Handling in Myocardium From Patients With End-Stage Heart Failure”. Circulation Research, vol. 61, No. 1, 1987, pp. 70-76. |
| Hasenfuss et al., “Influence of the calcium-sensitizer UDCG-115 on hemodynamics and myocardial energetics in patients with idiopathic dilated cardiomyopathy. Comparison with nitroprusside”. Basic Research Cardiology, vol. 84, No. 1, 1989, pp. 225-233. |
| Hauf et al., “Acute and Long-Term Hemodynamic Effects of Pimobendan (UD-CG 115 BS) in Comparison with Captopril”. Journal of Cardiovascular Pharmacology, vol. 15, Supp. 2, 1989, pp. S49-S56. |
| Hemati et al., “Fluidized bed coating and granulation: influence of process-related variables and physicochemical properties on the growth kinetics”. Powder Technology, vol. 13, 2002, pp. 18-34. |
| Häggstrom et al., “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”. Journal of Veterinary Internal Medicine, vol. 22, 2008, pp. 1124-1135. |
| Häggstrom et al., “Longitudinal Analysis of Quality of Life, Clinical, Radiographic, Echocardiographic, and aboratory Variables in Dogs with Myxomatous Mitral Valve Disease Rexceiving Pimobendan or Benazepril: The QUEST Study”. Journal of Veterinary Internal Medicine, 2013, pp. 1-11. |
| Häggström et al., “Effects of long-term treatment with enalapril or hydralazine on the renin-angiotension-aldosterone system and fluid balance in dogs with naturally acquired mitral valve regurgitation”. American Journal of Veterinary Research, vol. 57, No. 11, Nov. 1996, pp. 1645-1662. |
| Häggström et al., “New insights into degenerative mitral valve disease in dogs”. Veterinary Clinics Small Animal Practice, vol. 34, 2004, pp. 1209-1226. |
| Iwasaki et al., “Pimobendan Inhibits the Production of Proinflammatory Cytokines and Gene Expression of Inducible Nitric Oxide Synthase in a Murine Model of Viral Myocarditis”. Journal of the American College of Cardiology, vol. 33, No. 5, 1999, pp. 1400-1407. |
| Jain et al., “Effects of Milrinone on Left Ventricular Remodeling After Acute Myocardial Infarction”. Circulation, vol. 84, No. 2, Aug. 1991, pp. 798-804. |
| Kashem et al., “CardioClasp: A New Passive Device to Reshape Cardiac Enlargement”. ASAIO Journal, vol. 48, No. 3, 2002, pp. 253-259. |
| Kato et al., “Clinical Evaluation of Pimobendan (UD-CG115BS) for Chronic Heart Failure—A Multicentre Placebo-Controlled Double Blind Study”. Journal of Clinical Therapeutics & Medicines, vol. 8, No. 6, 1992, pp. 1311-1351. |
| Kato, Kazuzo, “Clinical Efficacy and Safety of Pimobendan in Treatment of Heart Failure-Experience in Japan”. Cardiology, vol. 88, Supp. 2, 1997, pp. 28-36. |
| Katz et al., “A multicenter, randomized, double-blind, placebo-controlled trial of pimobendan, a new cardiotonic and vasodilator agent, in patients with severe congestive heart failure”. American Heart Journal, vol. 123, 1992, pp. 95-103. |
| Kittleson et al., “The Acute Hemodynamic Effects of Milrinone in Dogs With Severe Idiopathic Myocardial Failure”. Journal of Veterinary Medicine, vol. 1, 1987, pp. 121-127. |
| Kitzen et al., “Pimobendan”. Cardiovascular Drug Reviews, vol. 6, No. 4, 1988, pp. 265-291. |
| Koob et al., “Acute Effects of Furosemide on Blood Electrolytes and Hemodynamics in Dogs”. Angiology, 1978, pp. 463-472. |
| Kubo et al., “Beneficial Effects of Pimobendan on Exercise Tolerance and Quality of Life in Patients with Heart Failure. Results of a Multicenter Trial”. Circulation, vol. 85, No. 3, Mar. 1992, pp. 942-949. |
| Kvart et al., “Efficacy of Enalapril for Prevention of Congestive Heart Failure in Dogs with Myxomatous Valve Disease and Asymptomatic Mitral Regurgitation”. Journal of Veterinary Internal Medicine, vol. 16, 2002, pp. 80-88. |
| Lachman et al., “The Theory and Practice of Industrial Pharmacy”., 3rd Edition, Lea & Febiger, Philadelphia, 1986, pp. 58-60. |
| Lai et al., “Real Time and Noninvasive Monitoring of Dry Powder Blend Homogeneity”. AlChE Journal, vol. 47, No. 11, Nov. 2001, pp. 2618-2622. |
| Lamb et al., “Assessment of the value of the vertebral heart scale in the radiographic diagnosis of cardia disease in dogs”. Veterinary Record, vol. 146, 2000, pp. 687-690. |
| Lantz et al., “Stability of nizatidine in extemporaneous oral liquid preparations”. American Journal of Hospital Pharmacy, vol. 47, No. 12, Dec. 1990, pp. 2716-2719. |
| Lewis et al., “Near-Infrared Chemical Imaging for Product and Process Understanding”. in Process Analytical Technology, Second Edition, John Wiley & Sons, Ltd., United Kingdom, 2010, pp. 272-276. |
| Lewis, Alan B., “Clinical Profile and Outcome of Restrictive Cardiomyopathy in Children”. American Heart Journal, vol. 123, No. 6, 1992, pp. 1589-1593. |
| Lezcano et al., “Complexation of Several Benzimidazole-Type Fungicides with Alpha and Beta-Cyclodextrins”. Journal of Agricultural and Food Chemistry, vol. 50, 2002, pp. 108-112. |
| Lip et al., “ABC of heart failure: Aetiology”. British Medical Journal, vol. 320, Jan. 2000, pp. 104-107. |
| Liu et al., “Cardiovascular Pathology: The Role of Cardiovascular Pathology in Practice”. Textbook of Canine and Feline Cardiology: Principles and Clinical Practice, Second Edition, Chapter 36, Saunders, 1999, pp. 817-844. |
| Loew, Earl R., “Gastric Secretion in Dogs Treated with Histamine Antagonist, Thymoxyethyldiethylamine”. Experimental Biology and Medicine, vol. 48, No. 1, Oct. 1941, pp. 65-68. |
| Loftsson et al., “Pharmaceutical Applications of Cyclodextrins. 1. Drug Solubilization and Stabilization”. Journal of Pharmaceutical Sciences, vol. 85, No. 10, Oct. 1996, pp. 1017-1025. |
| Lombard et al., “Clinical Efficacy of Pimobendan Versus Benazepril for the Treatment of Acquired Atrioventricular Valvular Disease in Dogs”. Journal of the American Animal Hospital Association, vol. 42, No. 4, Jul./Aug. 2006, pp. 249-261. |
| Lombard, Christophe W., “Therapy of Congestive Heart Failure in Dogs with Pimobendan”. Proceedings of the 18th Annual Veterinary Medical Forum, American College of Veterinary International Medicine, Seattle, WA, 2000, pp. 107-109. |
| Lord et al., “Radiology: Role of Radiology in Diagnosis and Management of Thoracic Disease”. Textbook of Canine and Feline Cardiology: Principles and Clinical Practice, Second Edition, Chapter 7, Saunders, 1999, pp. 111-117. |
| Luis-Fuentes, Virginia, “The effect of pimobendan in English Cocker Spaniels and Doberman dogs with heart failure and idiopathic dilated cardiomyopathy (DCM)”. Ingelheimer Dialog, Boehringer Inglehim Vetmedica GmbH, Jun. 2000, Frankfort/Mainz, pp. 8-11. |
| Lyon et al., “Near-Infrared Spectral Imaging for Quality Assurance of Pharmaceutical Products: Analysis of Tablets to Assess Powder Blend Homogeneity”. AAPS PharmSciTech, vol. 3, No. 3, Art. 17, Sep. 2002, pp. 1-15. |
| Malik et al., “Permethrin Spot-On Intoxication of Cats: Literature review and survey of veterinary practitioners in Australia”. Journal of Feline Medicine and Surgery, vol. 12, 2010, pp. 5-14. |
| Mamoru et al., “Effects of Long-term, Very-low-dose Pimobendan for Patients with Diastolic Heart Failure”. Journal of Cardial Failure, vol. 12, No. 8, Oct. 2006, p. S171. |
| “905 Uniformity of Dosage Units”. 2011 The United States Pharmacopeial Convention, Stage 6 Harmonization, Dec. 1, 2011, pp. 1-3. |
| “Cardiovascular system”. MIMS, IVS Annual, Chapter 5, 2003, p. 104. |
| “Citric Acid”. The Merck Index, An Encyclopedia of Chemicals, Drugs, and Biologicals, 13th Edition, Merck Research Laboratories Division of Merck & Co., Inc., Whitehouse Station, NJ, Index 2350, 2001, pp. 405-406. |
| “Guidance for Industry, Container Closure Systems for Packaging Human Drugs and Biologics: Chemistry, Manufacturing, and Controils Documentation”. U.S. Department of Health and Human Services Food and Drug Administration, May 1999, pp. 1-56. |
| “Pharmaceutical Necessities”. Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton, Pennsylvania, Chapter 66, 1990, pp. 1288-1300. |
| “Pimobendan”. The Merck Index, An Encyclopedia of Chemicals, Drugs, and Biologicals, 13th Edition, Merck Research Laboratories Division of Merck & Co., Inc., Whitehouse Station, NJ, Index 7515, 2001, p. 1332. |
| “Rimadyl F 50 mg”. Summary of Product Characteristics, Zoetis France, May 15, 2013, pp. 1-4. |
| “Vetmedin®—1,25 mg appetizing tablets for dogs Veterinary use”. Summary of Product Characteristics, SCS Boehringer Ingelheim Comm. V, Mar. 25, 2009, pp. 1-4. |
| Abstract in English for DE3728244, 1989. |
| Abstract in English for EP0306846, 1989. |
| Abstract in English for EP0330052, 1989. |
| Abstract in English for JP2005281283, 2005. |
| Abstract in English for JPH0489428, 1992. |
| Abstract in English of JPH0570612, 1993. |
| Abstract in English of JPH11228302, 1999. |
| Ahmed et al., “Pharmaceutical challenges in veterinary product development”. Advanced Drug Delivery Reviews, vol. 54, 2002, pp. 871-882. |
| Asanoi et al., “Disparate Inotropic and Lusitropic Responses to Pimobendan in Conscious Dogs with Tachycardia-Induced Heart Failure”. Journal of Cardiovascular Pharmacology, vol. 23, No. 2, 1994, pp. 268-274. |
| Ash et al., “Receptor Mediating Some Actions of Histamine”. British Journal of Pharmacology and Chemotherapy, vol. 27, No. 2, Aug. 1996, pp. 427-439. |
| Atkins et al., “Guidelines for the Diagnosis and Treatment of Canine Chronic Valvular Heart Disease”. Journal of Veterinary Internal Medicine, vol. 23, No. 6, 2009, pp. 1-9. |
| Banker et al., “Uniformity of Dosage Units”. Modern Pharmaceutics, Fourth Edition, Revised and Expanded, Marcel Dekker, Inc., New York, NY, 2006, p. 498. |
| Bassani et al., “Enhanced Water-Solubility of Albendazole by Hydroxy-Propyl-ß-Cyclodextrin Complexation”. Journal of Inclusion Phenomena and Molecular Recognition in Chemistry, vol. 25, No. 1-3, Mar. 1996, pp. 149-152. |
| Bastien et al., “Chronic AT receptor blockade and angiotensin-converting enzyme (ACE) inhibition in (CHF 146) cardiomyopathie hamsters: effects on cardiac hypertrophy and survival”. Cardiovascular Research, vol. 43, 1999, pp. 77-85. |
| Baur et al., “Cardiac remodelling and myocardial contractility in patients with congestive heart failure treated with furosemide and enalapril”. Basic Research in Cardiology, vol. 86, Supp. 1, 1991, pp. 157-163. |
| Beers, et al., Merck Manual of Diagnosis and Therapy, 17th Edition, Chapter 203, Section 16, Merck Research Laboratories, Whitehouse Station, NJ, USA, 1999, pp. 1688-1692. |
| Berny et al., “Review: Animal Poisoning in Europe. Part 2: Companion Animals”. The Veterinary Journal, vol. 193, 2010, pp. 255-259. |
| Black et al., “Definition and Antagonism of Histamine H2-receptors”. Nature, vol. 236, Apr. 1972, pp. 385-390. |
| Boehringer Ingelheim Vetmedica GmbH, 1st International Canine Valvular Disease Symposium, Paris, Oct. 30-31, 2004, pp. 1-45. |
| Boehringer Ingelheim Vetmedica, Inc. “Freedom of Information Summary: Original New Animal Drug Application”. NADA 141-273, Vetmedin, Pimobendan Chewable Tablets, Apr. 30, 2007, pp. 1-46. |
| Borgarelli et al., “Canine Idiopathic Dilated Cardiomyopathy. Part II: Pathophysiology and therapy”. The Veterinary Journal, vol. 162, 2001, pp. 182-195. |
| Bozzone, Scott, “Solid Oral Dosage Forms Powder Blending” and “Solid Oral Dosage Forms, Blend Uniformity: Principles and Examples”. Pfizer, IKEV Meeting, May 31, 2001, pp. 1-66. |
| Brewster et al., “Cyclodextrins as pharmaceutical solubilizers”. Advanced Drug Delivery Reviews, vol. 59, No. 7, 2007, pp. 645-666. |
| Buchanan et al. “Vertebral scale system to measure canine heart size in radiographs”. Journal of the American Veterinary Medical Association, vol. 206, No. 2, Jan. 1995, pp. 194-199. |
| Burlage et al., “Other Pharmaceutical Adjuncts”., Physical and Technical Pharmacy, The Blakiston Division: The McGraw-Hill Book Company, Inc., New York, 1963, pp. 653-662. |
| Calvert et al., “Congestive cardiomyopathy in Doberman Pinscher dogs”. Journal of the American Veterinary Medical Association, vol. 181, 1982, pp. 598-602. |
| Calvert et al., “Signalment, Survival, and Prognostic Factors in Doberman Pinschers With End-Stage Cardiomyopathy”. Journal of Veterinary Internal Medicine, vol. 11, No. 6, 1997, pp. 323-326. |
| Cambridge Dictionary, homogeneous, Last Accessed Feb. 10, 2011, 1 page, http://dictionary.cambridge.org/dictionary/british/homogeneous. |
| Chambers 21st Century Dictionary, homogeneous, Last Accessed Feb. 10, 2011, 1 page, http://www.xreferplus.com/entry/chambdict/homogeneous. |
| Chetboul, et al., “Comparitive Adverse Cardiac Effects of Pimobendan and Benazepril Monotherapy in Dogs with Mild Degenerative Mitral Valve Disease: A Prospective, Controlled, Blinded, and Randomized Study”. Journal of Veterinary Internal Medicine, vol. 21, 2007, pp. 742-753. |
| Choy et al., “Scaling of myocardial mass to flow and morphometry of coronary arteries”. Journal of Applied Physiology, vol. 104, 2008, pp. 1281-1286. |
| Cohn et al., “Cardiac Remodeling-Concepts and Clinical Implications: A Consensus Paper From an International Forum on Cardiac Remodeling”. Journal of the American College of Cardiology, vol. 35, No. 3, 2000, pp. 569-582. |
| Collins English Dictionary, homogeneous, Last Accessed Feb. 10, 2011, 1 page, http://xreferplus.com/entry/hcengdict/homogeneous. |
| Conlon, P.D., “Nonsteroidal Drugs Used in the Treatment of Inflammation”. Veterinary Clinics of North America: Small Animal Practice, vol. 18, No. 6, Nov. 1988, pp. 1115-1131. |
| Cowley et al., “Treatment of severe heart failure: quantity or quality of life? A trial of enoximone”. , British Heart Journal, vol. 72, 1994, pp. 226-230. |
| Côté et al., “Congestive Heart Failure”. Feline Cardiology, Ch. 19, Wiley-Blackwell, ISBN 978-0-8138-1242-7, 2011, p. 259. |
| Deneke et al., “Medikamentöse Therapie der Herzinsuffizienz”. Herzschr Elektrophys, vol. 15, Suppl. 1, 2004, pp. 1/74-1/80. |
| Dews et al., “The Antihistamine Substance 2786 R.P.” British Journal of Pharmacology, vol. 1, 1946, pp. 278-286. |
| Dictionary of Veterinary Drugs and Animal Health Products Marketed in France, 12th Edition, 2003, 3 pages. |
| El-Hagrasy et al., “A Process Analytical Technology Approach to Near-Infrared Process Control of Pharmaceutical Power Blending: Part II: Qualitative Near-Infrared Models for Prediction of Blend Homogeneity”. Journal of Pharmaceutical Sciences, vol. 95, No. 2, Feb. 2006, pp. 407-421. |
| El-Hagrasy et al., “Near-Infrared Spectroscopy and Imaging for the Monitoring of Powder Blend Homogeneity”. Journal of Pharmaceutical Sciences, vol. 90, No. 9, Sep. 2001,. pp. 1298-1307. |
| Matsumori et al., “Pharmacology letters: Accelerated Communication: Pimobendan inhibits the activation of transcription factor NF-Kb A mechanism which explains its inhibition of cytokine production and inducible nitric oxide synthase”. Life Sciences, vol. 67, 2000, pp. 2513-2519. |
| McCrohon et al., “Differentiation of Heart Failure Related to Dilated Cardiomyopathy and Coronary Artery Disease Using Gadolinium-Enhanced Cardiovascular Magnetic Resonance”. Circulation, vol. 108, Jul. 2003, pp. 54-59. Originally published online Jun. 23, 2003, http://circ.ahajournals.org, 7 pages. |
| Medline, homogeneous, Merriam-Webster, Last Accessed Feb. 10, 2011, 1 page, http://www.merriam-webster.com/medlineplus/homogeneous. |
| Menard et al., “Physico-Chemical Aspects of the Complexation of Some Drugs with Cyclodextrins”. Drug Development and Industrial Pharmacy, vol. 16, No. 1, 1990, pp. 91-113. |
| Merriam-Webster, homogeneous, Last Accessed Feb. 10, 2011, 2 pages, http://www.merriam-webster.com/dictionary/homogeneous. |
| Monnet et al., “Idiopathic Dilated Cardiomyopathy in Dogs: Survival and Prognostic Indicators”. 1995, Journal of Veterinary Internal Medicine, vol. 9, No. 1, pp. 12-17. |
| Nakamoto et al., “The role of ascorbic acid deficiency in human gingivitis—a new hypothesis”. Journal of Theoretical Biology, vol. 108, No. 2, May 1984, pp. 163-171. |
| Ng, Tien M.H., “Levosimendan, a New Calcium-Sensitizing Inotrope for Heart Failure”. Pharmacotherapy, vol. 24, No. 10, 2004, pp. 1366-1384. |
| O'Grady, et al., “Does Angiotensin Converting Enzyme Inhibitor Therapy Delay the Onset of Congestive Heart Failure or Sudden Death in Doberman Pinschers with Occult Dilated Cardiomyopathy?” Acvim Abstracts, 1997, p. 138. |
| Ohte et al., “The Cardia Effects of Pimobendan (But Not Amrinone) Are Preserved at Rest and During Exercise in Conscious Dogs with Pacing-Induced Heart Failure”. The Journal of Pharmacology and Experimental Therapeutics, vol. 282, No. 1, 1997, pp. 23-31. |
| Okazaki et al., “A genetic linkage map of the Syrian hamster and localization of cariomyopathy locus on chromosome 9qa2.1-b1 using RLGS spot-mapping”. Nature Genetics, vol. 13, May 1996, pp. 87-90. |
| Packer et al., “Effect Of Oral Milrinone On Mortality In Severe Chronic Heart Failure.” The New England Journal of Medicine, vol. 325, No. 21, Nov. 1991, pp. 1468-1475. |
| Pagel et al., “Comparison of the effects of levosimendn, pimobendan, and milrinone on canine left ventricular-arterial coupling and mechanical efficiency”. Basic Respiratory Cardiology, vol. 91, 1996, pp. 296-307. |
| Pagel et al., “Influence of levosimendan, pimobendan, and milrinone on the regional distribution of cardiac output in anaesthetized dogs”. British Journal of Pharmacology, vol. 119, 1996, pp. 609-615. |
| Permanetter et al., “Acute Effects of Intraveneous UD-CG 115 BS (Pimobendan) on the Cardiovascular System and Left Ventricular Pump Function”. Journal of Cardiovascular Pharmacology, vol. 14, Supp. 2, 1989, pp. S36-S40. |
| Pernsteiner et al., “Effect of Topical Application of Phenylephrine Hydrochloride on Hyperplastic Gingivitis”. Journal of Periodontology, vol. 48, No. 8, Aug. 1977, pp. 473-477. |
| Petit et al., “VETMEDIN® 1.25 mg, VETMEDIN® 5 mg, Chewable tablets, Inodilator (pimobendan) tablet for dogs”. Dictionary of Veterinary Drugs and Animal Health Products Marketed in France, 16th Edition, Les Editions du Point Vétérinaire, 2011, pp. 1658-1661. |
| Phillips et al., “The challenge of gene therapy and DNA delivery”. Journal of Pharmacy and Pharmacology, vol. 53, 2001, pp. 1169-1174. |
| Piel et al., “Development of a parenteral and of an oral formulation of albendazole with cyclodextrins”. S.T.P. Pharma Sciences, vol. 9, No. 3, 1999, pp. 257-260. |
| Pirollo et al., “Targeted Delivery of Small Interfering RNA: Approaching Effective Cancer Therapies”. Cancer Research, vol. 68, No. 5, Mar. 2008, pp. 1247-1250. |
| Rackley, Charles E., “Diseases of the Heart and Pericardium”., The Merck Manual, Chapter 25, 16th Edition, 1992, pp. 446-459. |
| Redenti et al., “Drug/Cyclodextrin/Hydroxy Acid Multicomponent Systems. Properties and Pharmaceutical Applications”. Journal of Pharmaceutical Sciences, vol. 89, 2000, pp. 1-8. |
| Remme et al., “Hemodynamic Effects of Intravenous Pimobendan in Patients with Left Ventricular Dysfunction”. Journal of Cardiovascular Pharmacology, vol. 15, Supp. 2, 1989, pp. S41-S44. |
| Remme et al., “Hemodynamic, Neurohumoral, and Myocardial Energetic Effects of Pimobendan, a Novel Calcium-Sensitizing Compound, in Patients with Mild to Moderate Heart Failure”. Journal of Cardiovascular Pharmacology, vol. 24, No. 5, 1994, pp. 730-739. |
| Rinsyo to Kenkyu, “A case of diastolic hypertrophic cardiomyopathy in which sinus bradycardia and associated cardiac failure were improved as a result of cilostazol administration.” The Japanese Journal of Clinical and Experimental Medicine, vol. 83, No. 5, May 2006, pp. 125-130. |
| Rodriguez, Damon B., “Treatment of Feline Hypertrophic Cardiomyopathy*”. Compendium, vol. 24, No. 6, Jun. 2002, pp. 470-476. |
| Roland et al., “The Use of Pimobendan in Feline Heart Failure Secondary to Spontaneous Heart Disease”. The 18th Annual ECVIM Congress, Abstract, Belgium, Sep. 2008, 1 page. |
| Rudnic et al., “Oral Solid Dosage Forms”. Remington: The Science and Practice of Pharmacy, 20th Edition, Lippincott Williams & Wilkins, Baltimore, Maryland, Chapter 45, 2000, pp. 858-870. |
| Saavedra et al., “Reverse Remodeling and Enhanced Adrenergic Reserve From Passive External Support in Experimental Dilated Heart Failure”. Journal of the American College of Cariology, vol. 39, No. 12, 2002, pp. 2069-1076. |
| Sabbah et al., “Effects of long-term monotherapy with enalapril, metoprolol, and digoxin on the progression of left ventricular dysfuntion and dilation in dogs with reduced ejection fraction”. Circulation, vol. 89, 1994, pp. 2852-2859. |
| Sabbah, Hani N., “The Cardiac Support Device and the Myosplint: Treating Heart Failure by Targeting Left Ventricular Size and Shape”. The Annals of Thoracic Surgery, vol. 75, 2003, pp. S13-S19. |
| Shiga et al., “b-Blocker Therapy Combined with Low-Dose Pimobendan in Patients with Idiopathic Dilated Cardiomyopathy and Chronic Obstructive Pulmonary Disease: Report on Two Cases”. Cardiovascular Drugs and Therapy, vol. 16, 2002, pp. 259-263. |
| Sisson et al., “Myocardial Diseases of Dogs”. Textbook of Canine and Feline Cardiology: Principles and Clinical Practice, Second Edition, Chapter 27, Saunders, 1999, pp. 581-619. |
| Sisson, David, “Lecture Notes: Cardiology”, The District of Columbia Academy of Veterinary Medicine, May 2001, pp. 1-18. |
| Stuber et al., “The Pharmaceutical and Biological Availability of Commercial Preparations of Furosemide”. Arzneimittel-Forschung, vol. 32, No. 6, 1982, pp. 693-697. |
| Summerfield et al., “Efficacy of Pimobendan in the Prevention of Congestive Heart Failure or Sudden Death in Doberman Pinschers with Preclinical Dilated Cardiomyopathy (The PROTECT Study)”. Journal of Veterinary Internal Medicine, vol. 26, 2012, pp. 1337-1349. |
| Takeda et al., “Normalization of Left Ventricular Parameters Following Combined Pimobendan and Carvedilol Treatment in a Case of Unclassified Cardiomyopathy with Longstanding Refractory Status”. Internal Medicine, vol. 41, No. 12, Dec. 2002, pp. 1147-1152. |
| The American Heritage Dictionary, homogeneous, Last Accessed Feb. 10, 2011, 1 page, http://www.xreferplus.com/entry/hmdictenglang/homogeneous. |
| Thiel et al., “Content uniformity of microdose tablets (dosage 1 μg-10 mg) produced by fluid bed granulation of interactive mixtures”. Journal of Pharmacy and Pharmacology, vol. 38, 1986, pp. 335-343. |
| Tomanek et al., “Growth of the Coronary Vasculature in Hypertrophy: Mechanisms and Model Dependence”. Cellular and Molecular Biology Research, vol. 40, No. 2, 1994, pp. 129-136. |
| Trendelenburg, U. “The Action of Histamine and 5-Hydroxytryptamine on Isolated Mammalian Atria”. The Journal of Pharmacology and Experimental Therapeutics, vol. 130, No. 4, Dec. 1960, pp. 450-460. |
| Van Meel et al., “Pimobendan Increases Survival of Cardiomyopathie Hamsters”. Journal of Cardiovascular Pharmacology, vol. 13, 1989, pp. 508-509. |
| Vidal et al., “Making sense of antisense”. European Journal of Cancer, vol. 41, 2005, pp. 2812-2818. |
| Villar et al., “Ibuprofen, Aspirin and Acetaminophen Toxicosis and Treatment in Dogs and Cats”. Veterinary and Human Toxicology, vol. 40, No. 3, Jun. 1998, pp. 156-162. |
| Wikipedia, the Free Encyclopedia, “Milrinone”. [Accessed at: http://en.wikipedia.org/wiki/Milrinone on Mar. 10, 2014]. |
| Wikipedia, the Free Encyclopedia, “Pimobendan”. [Accessed at: http://en.wikipedia.org/wiki/Pimobenan on Mar. 10, 2014]. |
| Woolley et al., “Effects of Treatment Type on Vertebral Heart Size in Dogs With Myxomatous Mitral Valve Disease”. The Journal of Applied Research in Veterinary Medicine, vol. 5, No. 1, 2007, pp. 43-48. |
| Bourezg et al., “Redispersible lipid nanoparticles of Spironolactone obtained by three drying methods.” Colloids and Surfaces A: Physicochemical and Engineering Aspects, vol. 413, 2012, pp. 191-199. |
| El-Badry et al., “Physicochemical Characterization and Dissolution Properties of Meloxicam-Gelucire 50/13 Binary Systems.” Scientia Pharmaceutica, vol. 79, 2011, pp. 375-386. |
| Fasinu et al., “Diverse approaches for the enhancement of oral drug bioavailability.” Biopharmaceutics & Drug Disposition, vol. 32, 2011, pp. 185-209. |
| Lindenberg et al., “Classification of orally administered drugs on the World Health Organization Model list of Essential Medicines according to the biopharmaceutics classification system.” European Journal of Pharmaceutics and Biopharmaceutics, vol. 58, 2004, pp. 265-278. |
| Nainar et al., “Biopharmaceutical Classification System in In-vitro/In-vivo Correlation: Concept and Development Strategies in Drug Delivery.” Tropical Journal of Pharmaceutical Research, vol. 11, No. 2, Apr. 2012, pp. 319-329. |
| Upadhyay et al., “Formulation of Fast-Release Gastroretentive Solid Dispersion of Glibenclamide with Gelucire 50/13.” Tropical Journal of Pharmaceutical Research, vol. 11, No. 3, Jun. 2012, pp. 361-369. |
| Vasconcelos et al., “Solid dispersions as strategy to improve oral bioavailability of poor water soluble drugs.” Drug Discovery Today, vol. 12, Nos. 23/24, Dec. 2007, pp. 1068-1075. |
| Ouellet et al., “Effect of Pimobendan on Echocardiographic Values in Dogs with Asymptomatic Mitral Valve Disease.” Journal of Veterinary Internal Medicine, vol. 23, 2009, pp. 258-263. |
| Kanno et al., “Effects of Pimobendan for Mitral Valve Regurgitation in Dogs.” Journal of Veterinary Medical Science, vol. 69, No. 4, Apr. 2007, pp.373-377. |
| Atkins et al., “Pharmacologic management of myxomatous mitral valve disease in dogs.” Journal of Veterinary Cardiology, vol. 14, 2012, pp.165-184. |
| Boswood et al., “Evaluation of pimobendan in dogs with cardiomegaly caused by preclinical mitral valve disease.” The Veterinary Record, vol. 168, No. 8, Feb. 2011, p. 222. |
| Boswood et al., “Effect of Pimobendan in Dogs with Preclinical Myxomatous Mitral Valve Disease and cardiomegaly: the EPIC Study—A Randomized Clinical Trial.” Journal of Veterinary Internal Medicine, vol. 30, 2016, pp. 1765-1779. |
| Beaufrere et al., “Therapeutic Review: Pimobendan.” Journal of Exotic Pet Medicine, vol. 18, No. 4, Oct. 2009, pp. 311-313. |
| Tissier R; “Increased Mitral Valve Regurgitation and Myocardial Hypertrophy in Two Dogs With Long-Term Pimobendan Therapy”; Cardiovascular Toxicology (2005) 05, 43-51. |
| Xu Yunsheng, “Pathology and Pathophysiology” pp. 110-113, China Medical Science and Technology Press, Mar. 2015. |
| Song Wenxuan et al., “Practical Cardiovascular Drug Therapy”, pp. 336-337, People's Medical Publishing House, Aug. 2001. |
| Smith PJ, French AT, Van Israrl N et al. “Efficacy and safety of pimobendan in canine heart failure caused by myxomatous mitral valve disease”, (2005) 46 J Small Anim Pract 121-130 (SMITH 2005), published no later than Mar. 2005 or, alternatively, Feb. 10, 2006. |
| Atkins C, Bonagura J, Ettinger S et al. “Guidelines for the Diagnosis and Treatment of Canine Chronic Valvular Heart Disease”, (2009) 23 Journal ofVeterinary Internal Medicine 1142-1150. |
| Boyle KL and Leech E “A review of the pharmacology and clinical uses of pimobendan”, (2012) 22(4) Journal of Veterinary Emergency and Critical Care 398-408. |
| Häggström J, Lord PF, Höglund K et al. “Short Term Hemodynamic and Neuroendocrine Effects of Pimobendan and Benazepril in Dogs with Myxomatous Mitral Valve Disease and Congestive Heart Failure” (2013) 27 Journal of Veterinary Internal Medicine 1452-1462. |
| Boswood, A., et al. “Longitudinal analysis of quality of life, clinical, radiographic, echocardiographic, and laboratory variables in dogs with preclinical myxomatous mitral valve disease receiving pimobendan or placebo: the EPIC study.” Journal of veterinary internal medicine 32.1 (2018): 72-85. |
| Keene BW, Atkins CE, Bonagura JD, et al. “ACVIM consensus guidelines for the diagnosis and treatment of myxomatous mitral valve disease in dogs.” J Vet Intern Med. 2019;1-14. https://doi.org/10.1111/jvim.15488. |
| Wess, G., et al. “European Society of Veterinary Cardiology screening guidelines for dilated cardiomyopathy in Doberman Pinschers.” Journal of Veterinary Cardiology 19.5 (2017): 405-415. |
| Oftsson et al., “Pharmaceutical Applications of Cyclodextrins. 1. Drug Solubilization and Stabilization”. Journal of Pharmaceutical Sciences, vol. 85, No. 10, Oct. 1996, pp. 1017-1025. |
| “Global clinical trial into effects of Pimobendan in dogs with Cardiomegaly (EPIC)”; Royal Veterinary Colleage—London; Mar. 17, 2015. |
| Boswood, Adrian. “Valvular heart disease in the dog.” Veterinary Focus 18.3 (2008): 25. |
| Boswood, Adrian. “Current use of pimobendan in canine patients with heart disease.” Veterinary Clinics: Small Animal Practice 40.4 (2010): 571-580. |
| Boswood 2017, Textbook of Veterinary Internal Medicine, Chapter 247, 8th edition, p. 1163-1176. |
| Boswood, Adrian. “Improving outcomes of myxomatous mitral valve disease in dogs.” In Practice 40 (2018): 12-15. |
| Borgarelli, M., et al. “Survival characteristics and prognostic variables of dogs with preclinical chronic degenerative mitral valve disease attributable to myxomatous degeneration.” Journal of veterinary internal medicine 26.1 (2012): 69-75. |
| Borgarelli, M., et al. “DELay of Appearance of symptoms of canine degenerative mitral valve disease treated with spironolactone and benazepril: the DELAY study.” Journal of Veterinary Cardiology 27 (2020): 34-53. |
| “Pimobendan,” BSAVA 2014, Small Animal Formulary 8th ed, p. 319. |
| Kvart, Clarence, et al. “Efficacy of enalapril for prevention of congestive heart failure in dogs with myxomatous valve disease and asymptomatic mitral regurgitation.” Journal of veterinary internal medicine 16.1 (2002): 80-88. |
| Lombard, Christophe W., Olaf Jons, and Claudio M. Bussadori. “Clinical efficacy of pimobendan versus benazepril for the treatment of acquired atrioventricular valvular disease in dogs.” Journal of the American Animal Hospital Association 42.4 (2007): 29-39. |
| Pouchelon, J-L., et al. “Effect of benazepril on survival and cardiac events in dogs with asymptomatic mitral valve disease: a retrospective study of 141 cases.” Journal of veterinary internal medicine 22.4 (2008): 905-914. |
| Amsallem, Emmanuel, et al. “Phosphodiesterase III inhibitors for heart failure.” Cochrane Database of Systematic Reviews 1 (2005). |
| Atkins, Clarke E., et al. “Results of the veterinary enalapril trial to prove reduction in onset of heart failure in dogs chronically treated with enalapril alone for compensated, naturally occurring mitral valve insufficiency.” Journal of the American Veterinary Medical Association 231.7 (2007): 1061-1069. |
| Keene et al., “Diseases of the Dog and the Cat,” Textbook of Veterinary Internal Medicine, Chapter 237: Guidelines for the Diagnosis and Treatment of Canine Chronic Valvular Heart Disease, p. 1196-1202. |
| Fuentes et al., “Diseases of the Dog and the Cat,” Textbook of Veterinary Internal Medicine, Seventh Edition, Chapter 238: Inotropes: Inodilators, 1202-1207. |
| Schneider, P., et al. “Comparative cardiac toxicity of the IV administered benzimidazole pyridazinon derivative Pimobendan and its enantiomers in female Beagle dogs.” Experimental and Toxicologic Pathology 49.3-4 (1997): 217-224. |
| Wess, Gerhard, et al. “Efficacy of adding ramipril (VAsotop) to the combination of furosemide (Lasix) and pimobendan (VEtmedin) in dogs with mitral valve degeneration: The VALVE trial.” Journal of Veterinary Internal Medicine 34.6 (2020): 2232-2241. |
| “Effect of mobendan in dogs with preclinical myxomatous mitral valve disease and ardiomegaly: The EPIC study—A randomized clinical trial,” Boswood 2016, ACVIM meeting. |
| Number | Date | Country | |
|---|---|---|---|
| 20190008863 A1 | Jan 2019 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/EP2017/057970 | Apr 2017 | WO |
| Child | 16131499 | US |
