Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

• the present invention relates to compositions for treating animals with heart failure, said compositions comprising torasemide.
• Torasemide is a loop diuretic that acts on the ascending part of Henle's loop of the kidney.
• This molecule belongs to the class of pyridine sulfonyl urea and is used in the treatment of edema associated with heart failure, kidney disease and treatment of hypertension in human and veterinary therapy.
• Heart failure is a serious disease of the dog that affects up to 10% of the overall canine population. If this condition remains complex and serious, the knowledge of its physiopathology has progressed in recent years, making its diagnosis easier, and allowing new therapies to emerge. The prognosis has been significantly improved and it is not uncommon now to see dogs survive for several years with heart failure.
• cardiopulmonary disease In congestive heart failure, so-called compensatory mechanisms are used to maintain sufficient cardiac output and tissue perfusion during the first phase of the disease, during which there are no clinical symptoms; heart failure is said to be asymptomatic or compensated. When the compensatory mechanisms are exceeded, the first clinical symptoms appear: it is the Decompensated or Symptomatic Heart Failure phase.
• Heart failure can be categorized according to the NYHA or ISACHC classification (see Table 1).
• the asymptomatic phase of heart failure corresponds to class I of the ISACHC classification
• classes II and III correspond to stages where the disease is symptomatic.
• furosemide a loop diuretic
• Torasemide is considered an equivalent of furosemide.
• Ghys et al. (Drug Research, 1985) compared the effects of torasemide and furosemide on healthy rats and dogs, and found a relationship between administered and the importance of the diuretic effect and the secretion of ions. The effects measured are as a result of a single administration, and not during prolonged treatments.
• Caro-Vadillo et al. (Veterinary Record, 2007) measured the effect of torasemide, administered at a dose of 0.2 mg / kg / day in a morning dose for 28 days, on the blood and urinary sodium, potassium, chloride ions, calcium, phosphorus and magnesium. They showed that, in treated dogs, the excretion of potassium in the urine is increased, but that the excretion of sodium is not.
• New therapeutic compositions are therefore actively sought to overcome the adverse side effects of treatments using loop diuretics.
• the question is all the more important when the treated animals are old animals.
• the inventors of the present application have developed a new dosage of torasemide, which preserves the beneficial effects of this treatment while significantly reducing the adverse effects described above.
• the present invention relates to a veterinary pharmaceutical composition
• a veterinary pharmaceutical composition comprising torasemide for use in the treatment of heart failure, torasemide being administered at a daily dosage of 0.02 mg / kg to 0.1 mg / day. kg during a long-term treatment.
• This composition is particularly suitable for the treatment of cats or dogs suffering from heart failure, at all stages of the disease including during the asymptomatic phase, and then during the decompensation phase, and especially when the cats or dogs are aged.
• the "tiles” pattern represents the values obtained without treatment; the pattern “horizontal stripes” represents the values obtained with treatment at 0.05 mg / kg of torasemide; the “uni white” pattern represents the values obtained with treatment at 0.5 mg / kg of torasemide; the “plain gray” pattern represents the values obtained with treatment at 5 mg / kg of furosemide.
• Figure 2 Mean ( ⁇ standard deviation) of urinary sodium clearance expressed in ml / h (y-axis) between 0-24h after repeated dosing of torasemide 0.05 mg / kg / day, torasemide 0.5 mg / day kg / day or furosemide 5 mg / kg / day at D-7 (before administration), D7 (first administration), D18 (twelfth administration) and D28 (twenty-second and last administration).
• Figure 3 Mean ( ⁇ standard deviation) of urine volume expressed in ml (y-axis) between 0-24h after repeated administrations of torasemide 0.05 mg / kg / day, torasemide 0.5 mg / kg / day or furosemide 5 mg / kg / day at D-7 (before administration), D7 (first administration), D18 (twelfth administration) and D28 (twenty-second and last administration).
• Figure 4 Mean ( ⁇ standard deviation) of the volume of absorbed water expressed in ml (y-axis) between 0-24h after repeated dosing of torasemide 0.05 mg / kg / day, torasemide 0.5 mg / kg / day or furosemide 5 mg / kg / day at D-7 (before administration), D7 (first administration), D18 (twelfth administration) and D28 (twenty-second and last administration).
• Figure 5 Mean ( ⁇ standard deviation) of urinary potassium clearance expressed in ml / h (y-axis) between 0-24h after repeated dosing of torasemide 0.05 mg / kg / day, torasemide 0.5 mg / day kg / day or furosemide 5 mg / kg / day at D-7 (before administration), D7 (first administration), D18 (twelfth administration) and D28 (twenty-second and last administration).
• Figure 6 Mean ( ⁇ standard deviation) of urinary creatinine clearance expressed in ml / min (y-axis) between 0-24h after repeated dosing of torasemide 0.05 mg / kg / day, torasemide 0.5 mg / kg / day or furosemide 5 mg / kg / day at D-7 (before administration), D7 (first administration), D18 (twelfth administration) and D28 (twenty-second and last administration).
• Figure 8 Mean ( ⁇ standard deviation) of plasma aldosterone concentration expressed in ⁇ g / ml (y-axis) between 0-24h after repeated dosing of torasemide 0.05 mg / kg / day, torasemide 0.5 mg / kg / day or furosemide 5 mg / kg / day at D-7 (before administration), at D7 (first administration), D18 (twelfth administration) and D28 (twenty-second and last administration).
• Figure 9 Mean ( ⁇ standard deviation) of sodium fractional urinary excretion expressed in% (y-axis) between 0-24h without treatment (1) after a single administration of torasemide 0.05 mg / kg (2) or torasemide 0.5 mg / kg (3) in beagle female dogs.
• Figure 10 Mean ( ⁇ standard deviation) of sodium fractional urinary excretion expressed in% (y-axis) between 0-24h after repeated dosing of torasemide 0.05 mg / kg / day, torasemide 0.5 mg / day kg / day or furosemide 5 mg / kg / day at D-7 (before administration), D7 (first administration), D18 (twelfth administration) and D28 (twenty-second and last administration).
• the present invention relates to a veterinary pharmaceutical kit for its use in the treatment and / or prevention of heart failure, comprising a plurality of dosage units, each dosage unit comprising torasemide, and being adapted for administration.
• the present invention also relates to a composition comprising torasemide for use as a veterinary medicament for treating and / or preventing mammalian heart failure, wherein torasemide is administered at a daily dosage of 0.02 mg / ml. kg and 0.1 mg / kg during long-term treatment.
• the present invention thus relates to a kit or a veterinary composition, in particular for the use of domestic animals, especially domestic mammals, and more particularly cats, dogs, hamsters, rabbits, guinea pigs, ferrets, and other mammal species listed in the decree of 11 August 2006, issued by the Ministry of Ecology and Sustainable Development.
• veterinary pharmaceutical kit means a kit comprising:
• dosage units as defined below, comprising pharmaceutical compositions for veterinary use, and
• a notice for the user specifying the animal to which the dosage units are intended, and the dosage, in particular according to the weight of the animal,
• a packaging adapted to the packaging of the dosage units.
• heart failure refers to the inability of the heart to meet the metabolic needs of the organs, that is, to provide sufficient perfusion pressure to ensure the diffusion of oxygen and nutrients from the blood to the tissues. . It occurs especially when congenital or acquired cardiac disease impairs cardiac performance.
• the "treatment of cardiac insufficiency” begins as soon as cardiac insufficiency is observed clinically, even if the symptoms are not yet apparent during the first so-called 'asymptomatic' or 'compensated' phase of the disease ( class I ISACHC).
• prevention of heart failure is meant the administration of torasemide assayed according to the invention to animals that have not been diagnosed as having heart failure, but presenting risks, particularly genetic risks, of developing a heart failure at some point in their life.
• the invention also makes it possible to treat so-called “symptomatic” animals (class II or III ISACHC).
• doctor unit means any convenient package that allows the user, the pet owner or the veterinarian to administer to an animal the desired daily dose of torasemide, from 0.02 mg / kg to 0 , 1 mg / kg.
• daily dosage refers to the amount of active ingredient administered to the animal over a period of 24 hours.
• “Torasemide” refers to the molecule of formula: N - [(isopropylamino) carbonyl] -4 - [(3-methylphenyl) amino] pyridine-3-sulfonamide, CAS number 56211-40-6.
• long-term treatment refers to a treatment of at least seven days, comprising the administration of a daily dose of torasemide at the doses indicated in the present application, in one or more doses.
• the treatment may last at least 14 days, at least 21 days, at least 28 days, at least 30 days, at least one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, twelve months or years.
• torasemide is administered at lower daily doses than usual, which makes it possible to prolong its administration over longer treatment periods, in particular of at least 7 days, while minimizing side effects.
• torasemide is administered to animals suffering from stage I, II or IIIa heart failure, in any case to animals whose disease has not reached a too severe stage and / or irreversible.
• the dosage units are suitable for administering a daily dosage of torasemide of less than 0.1 mg / kg.
• the pharmaceutical composition is suitable for administering a daily dosage of torasemide of less than 0.10 mg / kg. This dosage is particularly indicated for the treatment of dogs and cats.
• torasemide is administered at a daily dosage of between 0.02 mg / kg and 0.09 mg / kg during a long-term treatment. In another aspect, torasemide is administered at a daily dosage of from 0.03 mg / kg to 0.08 mg / kg during long-term treatment. In another aspect, torasemide is administered at a daily dosage of from 0.04 mg / kg to 0.06 mg / kg during long-term treatment. These dosages are particularly indicated for the treatment of dogs and cats.
• the dosage units are suitable for administering a daily dosage of torasemide about 0.05 mg / kg.
• the pharmaceutical composition is suitable for administering a daily dosage of torasemide of about 0.05 mg / kg.
• torasemide is administered at a daily dosage of about 0.050 mg / kg. This dosage is particularly indicated for the treatment of dogs and cats.
• each daily dosage unit comprises two subunits for administration in two daily doses.
• the pharmaceutical composition can be administered in two daily doses.
• samples taken 12 hours after the administration of torasemide show that the diuretic effect begins to decrease between 12 and 24 hours post-administration; it may therefore be advisable to administer the composition bi-daily, to maintain the maximum effect over a longer period.
• the pharmaceutical kit as defined above has dosage units, each comprising a quantity of torasemide ranging from 0.02 mg (animal of 2 kg x 2 taken daily) to 5 mg (animal of 50 kg ⁇ 1 daily intake).
• dosage units each comprising a quantity of torasemide ranging from 0.02 mg (animal of 2 kg x 2 taken daily) to 5 mg (animal of 50 kg ⁇ 1 daily intake).
• Each kit will be adapted to the weight of the animal to be treated; different dosages particularly adapted to dogs and cats are thus illustrated below:
• the daily intake should be 0.04 mg / day.
• the kit will therefore include dosage units comprising 0.04 mg for daily administration, and 0.02 mg for bi-daily administration.
• the daily dose should be 0.1 mg / day.
• the kit will therefore include dosing units comprising 0.1 mg for daily administration and 0.05 mg for bi-daily administration.
• the daily dose should be 0.2 mg / day.
• the kit will therefore include dosing units comprising 0.2 mg for daily administration, and 0.1 mg for bi-daily administration.
• the daily dose should be 1 mg / day.
• the kit will therefore include dosage units comprising 1 mg for daily administration, and 0.5 mg for bi-daily administration.
• the kit will therefore include dosing units comprising 0.2 mg for daily administration, and 0.1 mg for bi-daily administration.
• the daily intake should be 0.5 mg / day.
• the kit will therefore include dosage units comprising 0.5 mg for daily administration, and 0.25 mg for bi-daily administration.
• the daily dose should be 1 mg / day.
• the kit will therefore include dosage units comprising 1 mg for daily administration, and 0.5 mg for bi-daily administration.
• the daily dose should be 5 mg / day.
• the kit will therefore include dosage units comprising 5 mg for daily administration, and 2.5 mg for bi-daily administration.
• the pharmaceutical kit as defined above comprises dosage units suitable for administration of 0.05 mg / day of torasemide, that is to say units comprising a quantity of torasemide ranging from 0.05 mg to 2.5 mg / day. mg.
• the kit will therefore include dosing units comprising 0.1 mg for daily administration and 0.05 mg for bi-daily administration.
• the daily intake should be 0.25 mg / day.
• the kit will therefore include dosage units comprising 0.25 mg for daily administration, and 0.125 mg for bi-daily administration.
• the daily intake should be 0.5 mg / day.
• the kit will therefore include dosage units comprising 0.5 mg for daily administration, and 0.25 mg for bi-daily administration.
• the daily intake should be 2.5 mg / day.
• the kit will therefore include dosage units comprising 2.5 mg for daily administration, and 1.25 mg for bi-daily administration.
• the daily dose in two administrations may consist of the administration of two doses each equivalent to half the daily dose but not only in this way.
• the dose administered bi-daily can for example be adjusted according to the time elapsed between two administrations. So a dog that is treated to 8am and 18h at night, may have 10/24 times the dose at 8am and 14/24 times the dose at 18h in the evening.
• the number of dosage units that can be administered daily to an animal of a given weight can be easily determined on the basis of (i) the appropriate daily dosage of torasemide, per unit weight and (ii) the weight of the animal.
• a pharmaceutical kit adapted for an animal of a weight P1 and comprising dosage units each comprising a known quantity of torasemide, and to administer to an animal of a weight P2 greater than P1 the number of units. dosages required to achieve, at least approximately, the daily dosage of torasemide that must receive said weight P2 animal.
• the term "0.1 mg / kg” is interchangeable with the term "0.10 mg / kg".
• the upper limit daily dose of 0.1 mg / kg should be understood as being a dose of 0.10 mg / kg, this dose being included in the indicated range.
• Higher figures, such as 0.11, 0.12 or 0.13 mg / kg, are excluded from the range indicated.
• the lower limit daily dose of 0.02 mg / kg is interchangeable with a dose of 0.020 mg / kg, this dose being included in the range indicated.
• the pharmaceutical kit is suitable for long-term treatment.
• said kit comprises at least seven daily dosage units, or 14 units for bi-daily administration.
• the kit may include seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty, and one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine or thirty units of daily dosage.
• the composition comprising torasemide, for use in the treatment of heart failure is characterized in that it is administered to an animal during treatment for at least seven days and preferably at least 14 days, at least 21 days, at least 28 days, at least 30 days, and more preferably for more than three months.
• the dosage units are suitable for oral administration.
• the veterinary pharmaceutical composition is administered orally.
• the active ingredient "torasemide” will be coupled with agents and excipients well known to those skilled in the art, allowing the non-destruction and re-absorption of the active ingredient during its passage through the esophagus and stomach of the animal having ingested it.
• galenics for administering drugs to animals orally, especially to domestic animals, these galenics including in particular oral solutions, dragees, capsules, gels, emulsions, pastes, suspensions, sublingual films, swallowing or chewable tablets, chewable tablets, film-coated tablets, effervescent tablets, soluble tablets, dispersible tablets, orodispersible tablets, chewable tablets, soft or hard capsules, soft chewable capsules, granules or granules for dissolving or dispersing on the food, in the drinking water or other suitable vehicles (in the form of, for example, a presentation in sachets or a pot with pods), powders for dissolving or dispersing on the food, drinking water or other suitable vehicles (for example, n sachets or a pot with pod), syrups, functional foods, liquids to disperse on the food and hydrogels.
• suitable vehicles in the form of, for example, a presentation in sachets or a pot with pod
• torasemide is administered as a constituent of a complete animal feed.
• these different galenics will have an appetent appearance for the animal to be treated, that is to say that the animal will want to swallow the galenic comprising torasemide, according to the daily dosage defined above.
• the dosage units or the composition are in an appetite form, especially in the form of palatable tablets, either covered with an appetent film coating or in an appetite form (for example, in the form of 'a treat).
• the dosage units or the composition are in the form of palatable chewable tablets.
• compositions according to the invention can be prepared by conventional methods of making pharmaceutical oral forms using one or more physiologically acceptable functional vehicles or excipients.
• the oral compositions according to the invention can be obtained by one or more steps of intermediate preparation of the active such as matrix encapsulation processes (dry granulation, wet granulation, extrusion, granulation by spray cooling - spray cooling or prilling - , solvent evaporation atomization - spray drying -, polymeric precipitation, lipid solids nanoparticles - SLN-), membrane encapsulation processes (non-film film coating, particle coating, ionotropic encapsulation, coacervation encapsulation, liposomes, emulsion) and inclusion methods (absorption on porous solid supports, complexation in cyclodextrin, adsorption on ion exchange resins).
• matrix encapsulation processes dry granulation, wet granulation, extrusion, granulation by spray cooling - spray cooling or prilling - , solvent evaporation atomization - spray drying -, polymeric precipitation, lipid solids nanoparticles -
• compositions may for example be prepared with excipients or vehicles chosen from the following non-exhaustive list:
• diluents such as, for example, lactose, sucrose, glucose, dextrose and other sugars, microcrystalline cellulose and other cellulose derivatives, starches of various origins, calcium phosphate and its derivatives, carbonates and bicarbonates of calcium, sodium, potassium, sodium glycine carbonate, sorbitol, mannitol, maltitol, xylitol, isomalt, and other polyols, glycine,
• - mounting or absorption supports dry and wet process binders such as, for example, cellulose derivatives (ethyl cellulose (EC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose (HPC), methylcellulose (ME)), polyvinylpyrrolidone (PVP), pregelatinized starch, macrogols, polyethylene glycol (PEG), glycerol palmitostearate, esters of glycerol and benenic acid, gums (arabic, acacia and tragacanth), gelatin, starch (in the form of starches), sugar solutions (sucrose, glucose, sorbitol), maltodextrin,
• cellulose derivatives ethyl cellulose (EC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose (HPC), methylcellulose (ME)
• PVP polyvinylpyrrolidone
• pregelatinized starch macrogols
• PEG polyethylene glycol
• disintegrators or disintegrants such as, for example, sodium starch glycolate, croscarmellose sodium, pregelatinized starch, starches of various origins, microcrystalline cellulose, starchy carboxymethylsodium, crosslinked polyvinylpyrrolidone (crosslinked PVP), alginic acid, the effervescent couples (combination of citric acid with an alkaline carbonate or bicarbonate),
• flow regulators such as, for example, colloidal or precipitated silicas, hydrophilic or hydrophobic, talc, starch, stearic acid,
• lubricants such as, for example, talc, zinc magnesium stearates of calcium, sodium or aluminum, sodium stearyl fumarate, mineral oils, hydrogenated vegetable oils, glycerol palmitostearate, polyethylene glycol, carnauba wax, stearic acid, boric acid, sodium benzoate,
• suspending agents such as, for example, sucrose, glucose or sorbitol syrups, cellulose derivatives, hydrogenated fats, silicas, gums, alginates,
• wetting agents or surfactants such as, for example, sodium lauryl sulphate, polysorbate 80, lecithin, gum arabic,
• aqueous or non-aqueous vehicles such as, for example, water, hydrogenated or non-hydrogenated vegetable oils (olive oil, peanut oil), ethyl alcohol, glucose or sorbitol syrups, glycerine , propylene glycol, polyethylene glycol, mineral oils (Vaseline oil),
• Flavors such as for example, natural flavors of meat or fish, synthetic flavors, natural or synthetic aromatic compositions, yeasts of beer, sweeteners, such as, for example, sucralose, aspartame, acesulfame-potassium, neotame, alitame, cyclamate, sucrose, glucose, fucatose, maltitol, sorbitol, xilitol , stevia and saccharin,
• sweeteners such as, for example, sucralose, aspartame, acesulfame-potassium, neotame, alitame, cyclamate, sucrose, glucose, fucatose, maltitol, sorbitol, xilitol , stevia and saccharin
• dyes such as, for example, iron oxides, titanium dioxide,
• masking agents such as, for example, acidifiers including citric acid, tartaric acid, malic acid, fumaric acid, succinic acid, adipic acid,
• flavor enhancers such as, for example, glutamates, guanylates, inosinates, maltol, ethyl maltol, glycine, L-leucine, lactic acid, thaumatin, neohesperidine,
• film coating or coating such as for example plasticizers (glycerol, propylene glycol, PEG (macrogols), glycerol triacetate, triethyl citrate, triethyl acetyl citrate, castor oil, tributyl citrate (insoluble), tributyl acetyl citrate, diethyl phthalate, film-forming agents (cellulose derivatives such as ethyl cellulose (EC), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl methylcellulose (HPC), methylcellulose (ME), cationic copolymers of acrylic acid and methacrylic esters, copolymers of dimethylamionoethyl methacrylate and neutral methacrylic esters, shellac, cellulose acetylphthalate ( CAP), polyvinyl acetylphthalate (PVPA), HPMC phthalate (HPMCP) and anionic copolymers of
• fillers such as, for example, sugar, silicas, talc, liquid or pasty silicones, titanium dioxide,
• antioxidants such as, for example, ascorbic acid, sodium and calcium ascorbates, 5-6-1-ascorbic acid diacetyl, palmityl 6-1-ascorbic acid, citric acid, sodium citrate potassium and calcium, tartaric acid, sodium tartrates of potassium and sodium and potassium, butylhydroxyanisol, butylhydroxytoluol, octyl or dodecyl gallates, sodium, potassium or calcium, lecithins, alpha-tocopherol, gamma-tocopherol and delta-tocopherol, all of the tocopherols constituting vitamin E, preservatives, such as, for example, sorbic, fumaric and benzoic acids, parahydrobenzoic acid esters, alcohol, benzyl alcohol, chlorocresol, sulphites, nitrates and nitrites.
• preservatives such as, for example, sorbic, fumaric and benzoic acids, parahydrobenzoic acid est
• the tablets may be gastroresistant or modified-release.
• the oral solid forms may be divisible to facilitate a dosage suitable for the treatment of the animal, such as, for example, a scored tablet in 2, 3, 4, 5, 6, 7 or 8 equivalent dose units.
• each dosage unit comprises torasemide in combination with at least one other active ingredient, in particular an active ingredient used in the treatment of heart failure.
• the veterinary pharmaceutical composition comprises torasemide in combination with at least one other active ingredient, in particular an active ingredient used in the treatment of heart failure.
• the active ingredients conventionally used in the treatment of heart failure are the following:
• ACE angiotensin converting enzyme
• This active ingredient may in particular be chosen from the following active ingredients:
• PDEIII phosphodiesterase III
• pimobendan selective inhibitors of phosphodiesterase III
• ACE inhibitors and in particular benazepril, enalapril, imidapril and ramipril, used according to the dosages well known to those skilled in the art (see http://www.cbip-vet.be/fr/texts/FCVOOOLlAL2o php);
• antihypertensives and in particular antagonists of aldosterone, preferably spironolactone, used in particular at a dose of 2 mg / kg / day.
• aldosterone preferably spironolactone
• the following combinations may in particular be present in the veterinary pharmaceutical kit according to the invention, in the form of daily units:
• kits according to the invention For a kit intended for an animal weighing 10 kg, the following dosage units may be present in the kits according to the invention:
• the invention also relates to the veterinary pharmaceutical kit presented above, for its use in the treatment and / or prevention of heart failure in mammals, preferably cats or dogs.
• the invention also relates to the veterinary pharmaceutical composition set forth above for use in the treatment and / or prevention of heart failure in mammals, preferably cats or dogs. The composition will therefore be administered to a cat or a dog.
• the invention also relates to the veterinary pharmaceutical kit presented above, for its use in the treatment and / or prevention of heart failure in older dogs.
• the invention also relates to a veterinary pharmaceutical composition as presented above, for its use in the treatment and / or prevention of heart failure in aged dogs.
• “Elderly dog” means a dog in the last quarter of his life, calculated on the basis of his average life expectancy. Life expectancy varies according to the breed of the dog. For example, a Beagle usually lives between 12 and 15 years (average life expectancy 13.3 years) and a Scottish terrier usually lives between 10 and 16 years (average life expectancy of 12 years). In the western world, the “bastard dog” has an average life expectancy of 13.2 years. Thus, "aged dog” means for a bastard dog a dog older than 9.9 years, especially equal to or greater than 10 years.
• composition according to the invention is also more particularly intended for purebred dogs having a predisposition to cardiac pathologies such as dogs of the following breeds: Poodle, Chihuahua, Bichon, England, Cavalier King Charles, Pekingese, Pinscher, Spitz Wolf, Dogls, Springer Dogl, Pomeranian, Basset, Beagle, Westie, Whippet, Terriers, Fox Terrier, England Terrier.
• composition can therefore be administered to an elderly dog and / or a dog breed predisposed to heart diseases.
• the invention also relates to the veterinary pharmaceutical kit presented above, for its use in the treatment and / or prevention of heart failure of an animal in the decompensation phase.
• the invention also relates to the veterinary pharmaceutical composition presented above, for its use in the treatment and / or prevention of heart failure of an animal in the decompensation phase.
• the invention also relates to the veterinary pharmaceutical kit presented above, for its use in the treatment and / or prevention of the appearance of edema in an animal in the decompensation phase.
• the invention also relates to the veterinary pharmaceutical composition presented above, for its use in the treatment and / or prevention of the appearance of edema in an animal in the decompensation phase.
• the invention also relates to the veterinary pharmaceutical kit presented above for its use in maintaining sodium balance in an animal suffering from sodium imbalance.
• the invention also relates to the veterinary pharmaceutical composition set forth above for its use in maintaining sodium balance in an animal suffering from sodium imbalance.
• Sodium imbalance can be defined as abnormal sodium levels observed in the plasma and / or urine of an animal. Those skilled in the art will easily find the 'normal' reference values for each type of animal, and in particular for each breed of dog. In particular the article by Laroute et al, 2005, gives normal values for urinary sodium clearance in female beagles, and that of Bennett et al. (Australian Veterinary J., 2006) indicates reference values for fractional sodium excretion in Greyhound breed dogs.
• the amount of sodium present in the mammalian body regulates blood volume, blood pressure, and general osmotic balance.
• Sodium is absorbed via the diet and its concentration in the body is regulated by the renin-angiotensin system.
• the entire renin-angiotensin system is disrupted and the functioning of many organs is affected.
• An animal suffering from sodium imbalance may in particular be an animal treated for heart failure.
• the invention also relates to the following objects A method for treating an animal suffering from heart failure, comprising administering to the animal daily a composition comprising torasemide at a dosage of between 0.02 mg / kg and 0.1 mg / kg during a treatment long term.
• composition comprising torasemide at a dosage of 0.05 mg / kg.
• composition being administered in two daily doses.
• composition being administered during treatment for at least seven days.
• composition being in the form of tablets, possibly palatable.
• composition also comprising at least one second active ingredient selected from selective inhibitors of phosphodiesterase III (PDEIII), ACE inhibitors and antihypertensives.
• PDEIII phosphodiesterase III
• composition is administered to a dog or a cat, in particular an elderly dog or a dog breed predisposed to heart diseases.
• a method for maintaining the sodium balance of the body in an animal suffering from sodium imbalance comprising administering to the animal daily a composition comprising torasemide at a dosage of 0.02 mg / kg to 0.1 mg / kg during a long-term treatment.
• a method as described above, for preventing a sodium imbalance in an animal suffering from heart failure comprising administering a composition to this animal on a daily basis comprising torasemide at a dosage of 0.02 mg / kg to 0.1 mg / kg during long-term treatment.
• plasma sodium, potassium, urea, aldosterone.
• torasemide is tested at two single doses: 0.05 mg / kg or 0.5 mg / kg for daily administration for three weeks.
• Continuous diuretic administration causes a clear deficit of sodium ions in the body, but renal compensatory mechanisms adapt sodium excretion in line with sodium intake. This phenomenon is known as "diuretic braking". This braking effect appears in healthy dogs as soon as a single dose of 0.5 mg / kg of torasemide is administered.
• the reference value for urinary sodium clearance in female beagles is 5.23 ⁇ 2.74 ml / h (Laroute et al, 2005).
• Example 2 Dose-Dependent Effect of Torasemide Administration for Three Weeks in Healthy Dogs on Urinary Volume and Water Consumption
• the urine volume observed at D-7, D7, D18 and D28 is shown in Figure 3.
• Dogs treated with the low dose of torasemide (0.05 mg / kg / day) showed no change in urinary volume.
• administration of 0.5 mg / kg / day of torasemide, or furosemide (5 mg / kg / day) results in a marked increase in urinary volume from the first day of treatment (D7), this effect being maintained over the three weeks of treatment.
• the excretion of potassium ions in the urine of the treated dogs is measured over a period of 24 hours, and is shown in Figure 5.
• the excretion of potassium ions is slightly increased regardless of the treatment after a few days of treatment (D18 and D28). On the first day of treatment, the effect of low-dose treatment with torasemide is lower than other treatments.
• Example 4 Verification of the safety of treatment with torasemide 0.05 mg / kg / day for long-term treatment
• the treatment has no effect on plasma creatinine concentration, regardless of the day of collection, or on creatinine clearance (see Figure 6).
• Concerning the concentration of urea in the plasma while the high doses of torasemide and furosemide lead to an increase in the plasma urea concentration at D18 and D28, this adverse collateral effect is not observed during a treatment with a low dose of torasemide.
• Frenora represents the percentage of sodium filtered by the kidney that is ultimately excreted in the urine. It is determined using equation 1 below:
• Na urine and Na plasma are the concentrations of sodium in urine and plasma, respectively
• Creatinine p iasma and Creatinme urine are creatinine concentrations in plasma and urine, respectively.
• Fractional excretion of sodium is the excretion of sodium, divided by the glomerular filtration rate (GFR), the GFR being estimated by the clearance of creatinine.
• Fractional sodium excretion was measured in healthy dogs after a single administration of torasemide 0.05 mg / kg or 0.5 mg / kg ( Figure 9), and after repeated administration of torasemide 0.05 mg / kg / day, torasemide 0.5 mg / kg / day or furosemide 5 mg / kg / day for three weeks ( Figure 10).

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