CA2051840A1 - Method of treating respiratory distress - Google Patents

Abstract

ABSTRACT

METHOD OF TREATING RESPIRATORY DISTRESS

Method of treating mammals suffering from respiratory distress comprising administering an effective amount of metrenperone.

Description

METHOl~ OF TR12ATING Rl~SPIRATORY DISTRESS

Back~ound of the invention Respi~atory dis~ess in larger fann animal species, such as luminants or pigs, and in 10 horses seems to be caused mainly by a combination of infectious agents and predisposing factors such as, for example, inclement weather, stress, inadequatehousing conditions, transportation, which factsrs tend to weaken the defense mechanism of the animal. The most common infective agents a~e ~uses, bacteria, helrninths and even fungi.
15 As principal manifestations of respiratory disfunction there may be named e.g.
dyspnoea, hyperventilation, increased resistance in the lungs, decreased lung com-pliance, and these typically result in hypoxia. The seve~ity of the disease furthermore is enhanced by the additional effect of infection and dssue deterioration, leading to lesional and functional damage.
In Iespiratory distress, the upper and lower part of the respiratoIy system may be involved. Especially in the case of cattle, this arbitrary division has relasively litde clinical merit, because many of the diseases involving the upper respiratory tract Ihave a marked tendency to spread and involve the lungs. The anatomical (a.o. naIrow ~achea, small 25 lung volume, limited number of alveolar capillary vessels) and physiological (a.o. high sensitivity for mediators such as histamine and serotonine, less alveolar macrophages) featur~s of the r~spiratory system of cattle may predispose the laLter to ~e development of pulmonary lesions.
30 The precise pathogenesis of the lesional and funceional damage has not yet been fully elucidated, but seems not only due to the direct action of the etiological agent, but is also and more especially induced by the reactions of the organism to the agent causing the distress. Numerous mediators seem to be inwlved in this process, serotonin being an important one. The influence of serotonin and serotonin antagonists has been described 35 in "Veterinary Pharmacology and Toxicology", Proceedings from the 2nd European Association for Veterinary Phalmacology and Toxicology, pp. 278-280 (published in 1~83).

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Brief description of the invention It now has been found ~hat the administration of met~enperone can ove~come the symptoms of respiratory distress. Therefore, the present invention is concemed with a method of treating mammals suffering from respiratory distress, said method comprising S the administration to these animals of an amount of metrenperone effective in reducing or even completely overcoming respiratory distress.

Description of ~he prefelred em~ocliments Metrenperone as referred to above and hereinafter is the generie narne of the 10 compound 3-[2-[4-~4-fluorobenzoyl)-1-piperidinyl]ethyy-2,7-dimethyl-4H-pyrido~l,2-a]pyrimidin-40ne which can be structurally represented as follows:

(CH2)2--N~}C ~F (1), 15 The terrn metrenperone as used hereinabove or hereinafter is meant to comprise as well the base foqrn as all pharrnaceutically acceptable acid-addition salts. The latter can be prepared by treating the base fo~n of the active ingredients of formula (I) withappropria~e acids, such as, for example, inorganic acids, e.g. hydrochloric-, hydro-bromic- and the like acids, sulfuric acid, nitric acid, phosphoIic acid and the like; or 20 organic acids, such as, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic, 2.3-dihydroxybutanedioic, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benænesulfonic, 4-methyl-benzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-25 amino-2-hydroxybenzoic and the like acids. The term "pharmaceutically acceptable salt"
is meant to also comprise the solvates which the compounds of formula (I) may fo~n and said solvates are intended to be included within the scope of the present invention.
Examples of such solvates are e.g. the hydrates9 alcoholates and the like.

30 The preparation of metrenperone as well as its phannacological properties have been described in US-4,342,870.

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Preferably, the method of the present invention is applicable to livestock such as pigs, horses and ruminants, e.g. sheep, goats and preferably to cattle, either to full-grown or to younger animals, e.g. piglets, small goats, and in particular to calfs.
5 The active ingredient metrenperone is administered in appropriate formulations which preferably are in unitary dose foqrn and may take a variety of forrns depending on the kind of animal to be treated. Said formulations contain as active ingredient and effective amount of metrenperone and a suitable carrier. The latter depends largely on the type of formulation contemplated for administration. Compositions for parenteral administration 10 seem to be most advantageous although other formulations, e.g. in bolus ~orm, may be used as well. Parenteral fomulations contain the active ingredient in aqueous solution, preferably made isotonic by adding glucose or saline or both. The parenteral compositions may be administered e.g. intrarnusculary or by intrajugular perfusion. The formulations in bolus forrn contain the active ingredient in adrnixture with solid carners 15 such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like.
A.lso comprised are the so-called sustained release or puls release boli.
The active ingredient may be administered prophylactically, i.e. in animals prone to suffer from respiratory depress;on, or curatively.
The dose of the active ingredient will vary with the kind of animal ~o be $reated, its weight and the severeness of the syrnptoms. In general it is contemplated that a dose varying from about 0.01 to 10 mg~g, in particular from 0.01 to 1 mg~g or from 0.05 to û.S mglkg will be effective. The optimal dose (in particular for cattle~ is contempla$ed to 25 be in the range from 0.075 to 0.125 mg/kg, in particular from 0.09 to 0.11 mg/kg, preferably 0.1 mg~cg. The doses as afore-mentioned are expressed in base equivalents, i.e. if addition salt forms of metrenperone are used, said doses evidently have to be multiplied by the ra~o of the rnolecular weight of the salt to that of metrenperone.

30 The active ingredient peferably is adrninistered in a single dose every 6 to 24 hours, preferably every 6 to 18 hours, more preferably every 8 to 16 hours, or 10 to 14 hours.
It is contemplated that optimal results are obtained if the dose is adrninistered every 12 hours. In some instances, it may be advantageous to administer parts of the dose in smaller intervals, e.g. half of the dose twice as frequent as described above.
To demonstrate the beneficial effect of metrenperone in respiratoIy distress thefollowing experiment was conducted. Calves suffering from respiratory distress were treated by intramuscular injection with a solution containing 0.1 mg/kg of metrenperone.

The injectis)ns were repeated every 12 hours and the condition of the animals thus treated was followed up. The condition of ~e animals evol~ed beneficially and that syrnptoms of respira~oIy distress decreased.

Claims (7)

1. A use of an effective amount of metrenperone for treating respiratory diseases in mammals suffering from said diseases.

2. A use according to claim 1 wherein the effective amount of metrenperone ranges from 0.05 to 0.5 mg/kg.

3. A use according to claim 1 wherein the effective amount of metrenperone ranges from 0.09 to 0.11 mg/kg.

4. A use according to claim 1 wherein said mammals are cattle .

5. A use according to claim 1 wherein said mammals are calfs.

6. A use according to claim 3 wherein said mammals are calfs.

7. A use according to claim 4 wherein said mammals are calfs.