Deserelin for attenuating odor of animal urine

Abstract

The present invention relates to deserelin for attenuating urine and faeces odors in non-human animals, preferably mammals, preferably companion animals.

Description

Technical Field

[0001] The present disclosure generally relates to pharmaceutical compositions of deserorelin for use in reducing urine odor and feces odor in non-human animals, preferably mammals, preferably companion animals. Background Art

[0002] Deserorelin is a gonadotropin analog of gonadotropin-releasing hormone (GnRH) that, when administered at low doses, acts to suppress pituitary-gonadal axis function.

[0003] GnRH is a hypothalamic decapeptide that acts at the apex of a cascade that coordinates the function of the hypothalamic-pituitary-gonadal axis. GnRH binds to the GnRH receptor (7 transmembrane receptors), causing the pituitary to produce and release two key gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which in turn control gonadal function.

[0004] - LH (luteinizing hormone), which, in addition to its role in gametogenesis, promotes the production of sex steroids (androgens, estrogens and progesterone);

[0005] - FSH (Follicle Stimulating Hormone) stimulates the production of gametes (sperm and eggs).

[0006] When GnRH binds to the receptor, it increases the synthesis of its own receptor mRNA and increases the sensitivity of the pituitary to GnRH. Continuous secretion of GnRH has the opposite effect (a decrease in LH and FSH secretion is observed: this can be called desensitization). (Finch AR et al., Agonist-induced internalization and downregulation of gonadotropin-releasing hormone receptors. Am. J. Physiol. Cell Physiol. 2009 Sep, 297(3)).

[0007] Internalization of the GnRH receptor (which is no longer bound to the cell surface) and inactivation of the intracellular signaling cascade triggers desensitization of the pituitary to GnRH. Once pituitary cells begin to desensitize to GnRH, LH concentrations drop to undetectable levels and are therefore unable to support testosterone and sperm production.

[0008] To solve the contraceptive problem in animals, some people came up with the idea of ​​using GnRH agonists as contraceptives for a long time. This is how the idea of ​​designing a deserorelin implant that continuously diffuses the GnRH agonist (deserorelin) came about.

[0009] This type of implant is used in two different ways:

[0010] - Fertility induction (short-term implantation): Ovuplant

[0011] - Inducing infertility through long-term action: Suprelorin

[0012] It is known in the prior art that these agonist-based implants have two phases of action. During the injection of the implant, there is a release of deserorelin, which will induce a strong stimulation of the LH and FSH production cascade, a step called "burst". In male dogs, this will induce the production of LH and FSH, leading to a strong synthesis of testosterone. Males thus gain super fertility (improved sperm quality, increased motility).

[0013] After this “burst” period, an infertile period is established with adverse effects on all aspects of sperm quality and testosterone concentrations (Goericke-Pesch S., Long-term effects of GnRH agonists on fertility and behavior., Reprod Domest Anim., 2017, 52 Suppl 2:336-347).

[0014] In addition to the trials in dogs, studies have been conducted in cats and kittens (Fontaine C., Long-term contraception in a small implant: A review of Suprelorin (deslorelin) studies in cats., J Feline Med Surg., 2015, 17(9), pages 766-771). This showed that the implant is effective as a contraceptive in both males and females. During the period of fertility suppression, steroid hormone concentrations of progesterone below 1 ng / ml and estradiol below 10 pg / ml were detected in female cats; in male cats, plasma testosterone concentrations were maintained at basal levels (<0.1 ng / ml). The duration of action of the 4.7 mg implant in males was 78.8 weeks ± 12.9 weeks, with a range of 61.7 weeks (approximately 15 months) to 100.7 weeks (approximately 25 months).

[0015] So far, the known data do not show a PK / PD (pharmacokinetic / pharmacodynamic) relationship, and the efficacy of the product can be explained by a very large burst shortly after implantation and a very long duration of GNRH receptor saturation. The current RCP data in dogs show that deserorelin persists for 2.5 months, and this effect is observed to last for at least 6 months (Source: EMA website: https: / / www.ema.europa.eu / en / documents / product-information / suprelorin-epar-product-information_en.pdf).

[0016] New data have been generated which indicate that deserorelin can be detected as long as this effect is observed in male and female dogs and cats.

[0017] In addition, it was demonstrated that maintaining the concentration range of deserorelin in the blood to obtain and maintain the castration effect is related to a PK / PD interaction. Contrary to the prior art and the prevailing view on the mode of action of deserorelin, a PK / PD relationship between the in vivo levels of deserorelin and the PD effect was clearly demonstrated, allowing us to identify a threshold for efficacy.

[0018] In addition to the contraceptive effect of deserorelin, other effects on sexual behavior and urine marking and / or urine odor have been noted as reported in the examples illustrating the invention.

[0019] Urine markers are normal and intentional depositions of urine that:

[0020] Pheromone signals to other animals; especially intact male cats

[0021] Territorial signal

[0022] Signs of stress or excitement related to the social or physical environment.

[0023] In this case, the urine may also have a pungent odor, which, particularly for pet owners, is desirable to eliminate or mask and / or mitigate or reduce. After washing the area with a mild detergent, several commercially available enzymatic urine odor neutralizers should be applied to the surface, which can be used to remove odors, but they are difficult to handle. Spaying or neutering is an effective treatment, particularly for cats that are marked for reproductive or territorial notification. One of the reasons for surgical castration is to mitigate the strong and persistent urine odor of male animals, particularly cats and ferrets. Urine odor is known to improve within a few days after surgical castration.

[0024] However, considering the cause of the problem, using surgery to solve the problem is more painful and may cause adverse effects.

[0025] One of the purposes of the present application is to demonstrate that the administration of deserorelin (e.g., when administered in the form of an implant such as Suyiqing®) reduces urine odor and / or feces odor. Surprisingly, the inventors have demonstrated that the odor reduction is mediated by at least two pathways. In fact, one of the pathways is a testosterone-mediated sex hormone pathway. The inventors have also demonstrated at least another pathway that is unrelated to sex hormones as described herein, which exhibits an improved reduction in unpleasant urine odor and / or feces odor.

[0026] Therefore, this problem is solved by using deserorelin to reduce urine odor and / or feces odor in a manner that induces chemical castration in non-human animals to which deserorelin is administered.

[0027] A recent study by Chumki Banik et al. (Simultaneous Chemical and Sensory Analysis of Domestic Cat Urine and Feces with Headspace Solid-Phase Microextraction and GC-MS-Olfactometry Separations 2021, 8, 15 pp1 of 19) aimed to identify volatile organic chemicals (VOCs) and associated odors in cat urine and feces by gas chromatography-mass spectrometry and simultaneous sensory analysis of fresh and aged samples. The purpose of this study is different from the present invention. Summary of the invention

[0028] The present invention relates to deserorelin for attenuating or reducing urine odor and / or feces odor, in particular unpleasant odor, of non-human animals, wherein after administration to the non-human animal, the plasma concentration of deserorelin in the non-human animal is higher than 10 pg / mL. In a preferred embodiment, the plasma concentration of deserorelin is between 10 pg / mL and 400 pg / ml from 8 days to at least 6 months after administration. In another preferred embodiment, deserorelin is continuously administered or continuously released after administration in the non-human animal. For example, deserorelin is substantially continuously released at a plasma concentration of less than 400 pg / mL from 8 days to at least 6 months after administration.

[0029] In another preferred embodiment, after administration, deserorelin modulates, ie downregulates or upregulates, molecules responsible for urine odor and / or feces odor selected from the group consisting of felinaline-derived compounds, volatile organic compounds (VOCs), sulfur-containing compounds and testosterone-induced compounds.

[0030] In certain embodiments, deserorelin modulates, i.e., downregulates or upregulates, a molecule responsible for urine odor and / or feces odor selected from:

[0031] - Sulfur compounds selected from the group consisting of: 4-methyl-4-mercapto-pentan-2-one; 3-methyl-3-mercapto-butan-1-ol; 3-methyl-3-mercapto-1-butylcarboxylate;

[0032] - VOCs: 2,5-dimethylpyrazine; 1,2-dichloropropane; 4,4-dimethyl-2-pentanone; and 3-methyl-2-butene-1-ol;

[0033] - a compound selected from the group consisting of: 2-(methylthio)-1-ethanol; 2-methyl-3-furanthiol; oxathiolane; 4-(methylthio)-2-butanone; 3-methylbutyl-3-mercaptoformate; and 3-methyl-3-(methylthio)-1-butanol;

[0034] - p-Cresol;

[0035] - Feline and its derivatives, such as: 3-mercapto-3-methyl-1-butanol; 3-mercapto-3-methylbutylcarboxylate; 3-methyl-3-methylthio-1-butanol; and 3-methyl-3-(2-methyldimercapto)-1-butanol;

[0036] - Feline precursors, such as N-acetylfeline, γ-glutamylfelineylglycine and 3-methylbutyricysteinylglycine;

[0037] - cauxin;

[0038] - 2-phenylethylamine and S-(1-hydroxy-3,7-dimethyl-6-octen-3-yl)cysteine;

[0039] - Isovaline;

[0040] - isobuteine;

[0041] - Trimethylamine;

[0042] - Indole;

[0043] - cadaverine and cadaverine derivatives, such as N-acetylcadaverine (also known as acetylcadaverine) and glutathione aminopropylcadaverine,

[0044] - Short-chain free fatty acids, such as acetic acid, propionic acid, 2-methylpropionic acid, butyric acid, 3-methylbutyric acid and valeric acid;

[0045] - Crotonic acid;

[0046] - Putrescine and its derivatives, such as N-acetylputrescine and p-coumaroylputrescine;

[0047] - mercapto derivatives, such as 2-mercapto-3-butanone, 2-mercaptoethanol, 3-mercaptohexylbutyrate, mercaptopyruvic acid, 3-mercaptopropionic acid, 3-mercapto-3-methylbutan-1-ol, 7-mercaptoheptanoylthreonine, 1α,5α-dimercaptoandrostane-3α,17β-diol, mercaptopyruvic acid, and 2-mercapto-2-methylpentan-4-one; and

[0048] - Taurine

[0049] - Valine.

[0050] In a more preferred embodiment, the molecules causing urine odor and / or feces odor on which Desorelin has an effect are selected from the group consisting of:

[0051] - Sulfur compounds selected from the group consisting of: 4-methyl-4-mercapto-pentan-2-one; 3-methyl-3-mercapto-butan-1-ol; 3-methyl-3-mercapto-1-butylcarboxylate;

[0052] - VOCs: 2,5-dimethylpyrazine; 1,2-dichloropropane; 4,4-dimethyl-2-pentanone; and 3-methyl-2-butene-1-ol;

[0053] - a compound selected from the group consisting of: 2-(methylthio)-1-ethanol; 2-methyl-3-furanthiol; oxathiolane; 4-(methylthio)-2-butanone; 3-methylbutyl-3-mercaptoformate; and 3-methyl-3-(methylthio)-1-butanol;

[0054] - p-Cresol

[0055] - Feline and derivatives: 3-mercapto-3-methyl-1-butanol; 3-mercapto-3-methylbutyl carboxylate; 3-methyl-3-methylthio-1-butanol; and 3-methyl-3-(2-methyldimercapto)-1-butanol;

[0056] - Feline precursors: N-acetylfeline, γ-glutamylfelineylglycine and 3-methylbutanolcysteinylglycine;

[0057] - cauxine;

[0058] - 2-phenylethylamine and S-(1-hydroxy-3,7-dimethyl-6-octen-3-yl)cysteine;

[0059] - Isovaline;

[0060] - isobuteine;

[0061] - trimethylamine,

[0062] - Indole,

[0063] - cadaverine and cadaverine derivatives, such as N-acetylcadaverine and glutathione aminopropylcadaverine;

[0064] - Short-chain free fatty acids, such as acetic acid, propionic acid, 2-methylpropionic acid, butyric acid, 3-methylbutyric acid and valeric acid;

[0065] - Crotonic acid; and

[0066] - Putrescine and its derivatives, such as N-acetylputrescine and p-coumaroylputrescine;

[0067] - mercapto derivatives, such as 2-mercapto-3-butanone, 2-mercaptoethanol, 3-mercaptohexylbutyrate, mercaptopyruvic acid, 3-mercaptopropionic acid, 3-mercapto-3-methylbutan-1-ol, 7-mercaptoheptanoylthreonine, 1α,5α-dimercaptoandrostane-3α,17β-diol, mercaptopyruvic acid;

[0068] - Taurine.

[0069] In an even more preferred embodiment, the molecule is selected from:

[0070] - trimethylamine,

[0071] - 3-Methylbutyric acid

[0072] - Indole

[0073] - Cadaverine and derivatives, such as acetylcadaverine, glutathione aminopropylcadaverine,

[0074] - Short-chain free fatty acids: acetic acid, propionic acid, 2-methylpropionic acid, butyric acid, 3-methylbutyric acid and valeric acid

[0075] - Crotonic acid

[0076] - Putrescine and its derivatives, such as N-acetylputrescine and p-coumaroylputrescine;

[0077] - mercapto derivatives, such as 2-mercapto-3-butanone, 2-mercaptoethanol, 3-mercaptohexylbutyrate, mercaptopyruvic acid, 3-mercaptopropionic acid, 3-mercapto-3-methylbutan-1-ol, 7-mercaptoheptanoylthreonine, 1α,5α-dimercaptoandrostane-3α,7β-diol, mercaptopyruvic acid;

[0078] - Taurine.

[0079] According to another preferred embodiment, deserorelin downregulates molecules responsible for urine odor and / or feces odor, said molecules being selected from the group consisting of:

[0080] - Sulfur compounds selected from the group consisting of: 4-methyl-4-mercapto-pentan-2-one; 3-methyl-3-mercapto-butan-1-ol; 3-methyl-3-mercapto-1-butylcarboxylate;

[0081] - VOCs: 2,5-dimethylpyrazine; 1,2-dichloropropane; 4,4-dimethyl-2-pentanone; and 3-methyl-2-butene-1-ol;

[0082] - a compound selected from the group consisting of: 2-(methylthio)-1-ethanol; 2-methyl-3-furanthiol; oxathiolane; 4-(methylthio)-2-butanone; 3-methylbutyl-3-mercaptoformate; and 3-methyl-3-(methylthio)-1-butanol;

[0083] - p-Cresol

[0084] - Feline and its derivatives, such as: 3-mercapto-3-methyl-1-butanol; 3-mercapto-3-methylbutylcarboxylate; 3-methyl-3-methylthio-1-butanol; and 3-methyl-3-(2-methyldimercapto)-1-butanol;

[0085] - Feline precursors, such as N-acetylfeline, γ-glutamylfelineylglycine and 3-methylbutyricysteinylglycine;

[0086] - cauxine;

[0087] - 2-phenylethylamine and S-(1-hydroxy-3,7-dimethyl-6-octen-3-yl)cysteine;

[0088] - Isovaline;

[0089] - isobuteine;

[0090] - Trimethylamine;

[0091] - Indole;

[0092] - Cadaverine and derivatives, such as N-acetylcadaverine and glutathioneaminopropylcadaverine;

[0093] - Short-chain free fatty acids, such as acetic acid, propionic acid, 2-methylpropionic acid, butyric acid, 3-methylbutyric acid and valeric acid;

[0094] - Crotonic acid;

[0095] - Putrescine and its derivatives, such as N-acetylputrescine and p-coumaroylputrescine;

[0096] - mercapto derivatives, such as 2-mercapto-3-butanone, 2-mercaptoethanol, 3-mercaptohexylbutyrate, mercaptopyruvic acid, 3-mercaptopropionic acid, 3-mercapto-3-methylbutan-1-ol, 7-mercaptoheptanoylthreonine, 1α,5α-dimercaptoandrostane-3α,17β-diol, mercaptopyruvic acid, and 2-mercapto-2-methylpentan-4-one; and

[0097] - Taurine.

[0098] According to another preferred embodiment, deserorelin upregulates molecules responsible for urine odor and / or feces odor selected from the group consisting of 2-mercapto-2-methylpentan-4-one and valine.

[0099] According to another embodiment, the present invention relates to a non-pharmaceutical or non-therapeutic use of deserorelin for modulating, i.e., down-regulating or up-regulating, the level of a molecule in the urine and / or feces of a non-human animal, the molecule being selected from the group consisting of:

[0100] - Sulfur compounds selected from the group consisting of: 4-methyl-4-mercapto-pentan-2-one; 3-methyl-3-mercapto-butan-1-ol; 3-methyl-3-mercapto-1-butylcarboxylate;

[0101] - VOCs: 2,5-dimethylpyrazine; 1,2-dichloropropane; 4,4-dimethyl-2-pentanone; and 3-methyl-2-butene-1-ol;

[0102] - a compound selected from the group consisting of: 2-(methylthio)-1-ethanol; 2-methyl-3-furanthiol; oxathiolane; 4-(methylthio)-2-butanone; 3-methylbutyl-3-mercaptoformate; and 3-methyl-3-(methylthio)-1-butanol;

[0103] - p-Cresol;

[0104] - Feline urinary acid and derivatives: 3-mercapto-3-methyl-1-butanol; 3-mercapto-3-methylbutyl carboxylate; 3-methyl-3-methylthio-1-butanol; 3-methyl-3-(2-methyldimercapto)-1-butanol and 3-mercapto-3-methyl-1-butanol.

[0105] - Feline precursors, such as N-acetylfeline, γ-glutamylfelineylglycine and 3-methylbutyricysteinylglycine;

[0106] - cauxine;

[0107] - 2-phenylethylamine and S-(1-hydroxy-3,7-dimethyl-6-octen-3-yl)cysteine;

[0108] - Isovaline;

[0109] - isobuteine;

[0110] - Trimethylamine;

[0111] - Indole;

[0112] - Cadaverine and cadaverine derivatives, such as acetylcadaverine and glutathione aminopropylcadaverine;

[0113] - Short-chain free fatty acids, such as acetic acid, propionic acid, 2-methylpropionic acid, butyric acid, 3-methylbutyric acid and valeric acid;

[0114] - Crotonic acid

[0115] - Putrescine and its derivatives, such as N-acetylputrescine and p-coumaroylputrescine;

[0116] - mercapto derivatives, such as: 2-mercapto-3-butanone, 2-mercaptoethanol, 3-mercaptohexylbutyrate, mercaptopyruvic acid, 3-mercaptopropionic acid, 3-mercapto-3-methylbutan-1-ol, 7-mercaptoheptanoylthreonine, 1α,5α-dimercaptoandrostane-3α,17β-diol, mercaptopyruvic acid, and 2-mercapto-2-methylpentan-4-one,

[0117] - Taurine, and

[0118] - Valine.

[0119] In a preferred embodiment, the non-pharmaceutical or non-therapeutic use of deserorelin is to modulate, i.e., downregulate or upregulate, the level of a molecule in a non-human animal, said molecule being selected from the group consisting of:

[0120] - trimethylamine,

[0121] - 3-Methylbutyric acid,

[0122] - Indole,

[0123] - Cadaverine and cadaverine derivatives, such as acetylcadaverine and glutathionylaminopropylcadaverine,

[0124] - short-chain free fatty acids such as acetic acid, propionic acid, 2-methylpropionic acid, butyric acid, 3-methylbutyric acid and valeric acid,

[0125] - Crotonic acid,

[0126] - Putrescine and its derivatives, such as N-acetylputrescine and p-coumaroylputrescine;

[0127] - mercapto derivatives, such as 2-mercapto-3-butanone, 2-mercaptoethanol, 3-mercaptohexylbutyrate, mercaptopyruvic acid, 3-mercaptopropionic acid, 3-mercapto-3-methylbutan-1-ol, 7-mercaptoheptanoylthreonine, 1α,5α-dimercaptoandrostane-3α,17β-diol, mercaptopyruvic acid, and 2-mercapto-2-methylpentan-4-one; and

[0128] - Taurine.

[0129] In yet another preferred embodiment, deserorelin modulates, ie downregulates or upregulates, the level of a molecule in the urine.

[0130] In other preferred embodiments, deserorelin modulates, ie, downregulates or upregulates, the level of a molecule in feces.

[0131] In yet another preferred embodiment, the present invention relates to the non-therapeutic use of deserorelin to down-regulate the level of a molecule in the urine and / or feces of a non-human animal, the molecule being selected from the group consisting of:

[0132] - Sulfur compounds selected from the group consisting of: 4-methyl-4-mercapto-pentan-2-one; 3-methyl-3-mercapto-butan-1-ol; 3-methyl-3-mercapto-1-butylcarboxylate;

[0133] - VOCs: 2,5-dimethylpyrazine; 1,2-dichloropropane; 4,4-dimethyl-2-pentanone; and 3-methyl-2-butene-1-ol;

[0134] - a compound selected from the group consisting of: 2-(methylthio)-1-ethanol; 2-methyl-3-furanthiol; oxathiolane; 4-(methylthio)-2-butanone; 3-methylbutyl-3-mercaptoformate; and 3-methyl-3-(methylthio)-1-butanol;

[0135] - p-Cresol;

[0136] - Feline and its derivatives, such as: 3-mercapto-3-methyl-1-butanol; 3-mercapto-3-methylbutylcarboxylate; 3-methyl-3-methylthio-1-butanol; and 3-methyl-3-(2-methyldimercapto)-1-butanol;

[0137] - Feline precursors, such as N-acetylfeline, γ-glutamylfelineylglycine and 3-methylbutyricysteinylglycine;

[0138] - cauxine;

[0139] - 2-phenylethylamine and S-(1-hydroxy-3,7-dimethyl-6-octen-3-yl)cysteine;

[0140] - Isovaline;

[0141] - isobuteine;

[0142] - Trimethylamine;

[0143] - Indole;

[0144] - cadaverine and cadaverine derivatives, such as N-acetylcadaverine and glutathione aminopropylcadaverine;

[0145] - Short-chain free fatty acids, such as acetic acid, propionic acid, 2-methylpropionic acid, butyric acid, 3-methylbutyric acid and valeric acid;

[0146] - Crotonic acid;

[0147] - Putrescine and its derivatives, such as N-acetylputrescine and p-coumaroylputrescine;

[0148] - mercapto derivatives, such as 2-mercapto-3-butanone, 2-mercaptoethanol, 3-mercaptohexylbutyrate, mercaptopyruvic acid, 3-mercaptopropionic acid, 3-mercapto-3-methylbutan-1-ol, 7-mercaptoheptanoylthreonine, 1α,5α-dimercaptoandrostane-3α,17β-diol, mercaptopyruvic acid; and

[0149] - Taurine.

[0150] In another preferred embodiment, the present invention relates to the non-therapeutic use of Deserorelin to upregulate the level of a molecule selected from 2-mercapto-2-methylpentan-4-one and valine in the urine and / or feces of a non-human animal.

[0151] The present invention also relates to a method for attenuating or reducing urine odor and / or feces odor of a non-human animal, the method comprising administering to the non-human animal an amount of deserorelin, wherein after administration to the non-human animal, the plasma concentration of deserorelin in the non-human animal is greater than 10 pg / mL.

[0152] Another object of the present invention is also a method for attenuating or reducing the urine odor and / or feces odor of a non-human animal, the method consisting in administering to the non-human animal an amount of deserorelin that will induce a modulation, i.e. downregulation or upregulation, of the levels of odor molecules in urine and / or feces. Preferably, the non-human animal is a healthy male cat. According to this embodiment, deserorelin induces a modulation, i.e. downregulation or upregulation, of the levels of odor molecules in urine and / or feces via the sex hormone synthesis pathway.

[0153] In another embodiment, the present invention also relates to a method for improving the attenuation or reduction of urine odor and / or feces odor in non-human healthy male animals compared to sterilized males, the method comprising administering to the non-human healthy male animal an amount of deserorelin that induces the regulation, i.e. downregulation or upregulation, of the levels of odor molecules in urine and / or feces. According to this embodiment, deserorelin induces the regulation, i.e. downregulation or upregulation, of the levels of odor molecules in urine and / or feces through a sex hormone-independent pathway.

[0154] The present invention also encompasses deserorelin for use in improving the attenuation or reduction of urine odor and / or feces odor in non-human animals.

[0155] Finally, the present invention also generally relates to the use of deserorelin for the preparation of a medicament for: - attenuating or reducing urine odour and / or feces odour in a non-human animal, wherein after administration to said non-human animal the plasma concentration of deserorelin in said non-human animal is above 10 pg / mL.

[0156] It has been demonstrated that administration of deserorelin in male or female cats or dogs modulates, ie, downregulates or upregulates, the levels of a molecule in urine, while at the same time, the levels of a derivative of the molecule in urine increase or decrease.

[0157] It has been found that administration of deserorelin in male or female cats or dogs modulates, ie, downregulates or upregulates, the levels of a molecule in feces, while at the same time, the levels of a derivative of the molecule in feces increase or decrease.

[0158] It has also been found that administration of deserorelin in male or female cats or dogs can modulate, ie, downregulate or upregulate, the levels of a molecule in the urine, while at the same time the levels of the molecule or its derivatives in the feces are increased or decreased.

[0159] It has also been found that administration of deserorelin in male or female cats or dogs modulates, ie, downregulates or upregulates, the levels of a molecule in the feces, while at the same time the levels of the molecule or its derivatives in the urine are increased or decreased.

[0160] In addition, several metabolomic molecules were identified in feces. In fact, the following molecules have been selected from the data: trimethylamine, 3-methylbutyric acid, and crotonic acid.

[0161] In fact, cat feces contains trimethylamine, which smells like rotten fish, which is not detected by GC-MS in fresh fecal samples. However, odor experts have recorded the foul smell of fish, confirming that living sensory organs can detect trace concentration levels. Therefore, how to reduce the odor caused by trimethylamine is sought.

[0162] The present invention provides several advantages including but not limited to the following:

[0163] First, by acting on at least two synthesis pathways for urine odor or feces odor, it is obvious that the result in terms of odor reduction will be at least additive of the results of these two pathways and will certainly be superior to an effect based solely on urine odor / feces odor synthesis mediated by the sex hormone pathway alone.

[0164] Animals that were now chemically sterilized by desmorelin administration showed changes in the quantity and quality of the molecules responsible for urine or feces odor compared to surgically sterilized animals; some were attenuated or reduced.

[0165] Furthermore, the present disclosure demonstrates that the method of using deserorelin as described herein is a reliable, reversible, non-surgical sterilization solution that can promote the well-being of pet families while keeping options open.

[0166] Deserorelin, acting at least through the testosterone pathway, specifically by reducing its blood levels, may help prevent kidney disease in the animals, as these diseases are known to be associated with the accumulation of molecules such as trimethylamine.

[0167] It should also be mentioned that in safety studies in cats, the administration of high doses of deserorelin showed neither serious adverse events nor life-threatening events. In addition, based on several tolerability studies conducted in male and female species, it has been concluded that deserorelin, especially deserorelin administered as an implant (i.e., Susorelin®), is well tolerated. BRIEF DESCRIPTION OF THE DRAWINGS

[0168] In addition to the exemplary aspects and exemplary embodiments described above, further aspects and embodiments of the present invention will become apparent by reference to the drawings and by study of the following descriptions.

[0169] Figure 1 The coordinated synthesis of isovale and isobuteine ​​by the liver and kidney has been shown in some feline species.

[0170] Figure 2 Shown is the change in serum testosterone concentration (in pg / mL) in male cats implanted with one 4.7 mg deserorelin implant (Seril®) (continuous curve) or administered saline (discontinuous curve) on D0 as described in Example 1 (p<0.05).

[0171] Figure 3 Four male cats ( Figure 3 A—each curve corresponds to one of the four cats) and the three male cats given saline ( Figure 3B - Each curve corresponds to testosterone plasma levels in one of three cats.

[0172] Figure 4 is a graph showing the mean relative abundance of feline amino acid present in urine samples of male cats collected on D63 following administration of saline (control group) or implantation of one 4.7 mg deserorelin implant (Serveline®) (chemically treated group) or in surgically castrated male cats (surgically castrated group) according to the protocol detailed in Example 2.

[0173] Figure 5 The mean relative abundance of MBCG present in urine samples of male cats collected at D63 after administration of saline (control group) or implantation of a 4.7 mg deserorelin implant (Suyiqing®) (chemical treatment group) according to the protocol detailed in Example 2 is shown. Figure 5 A), and the mean relative abundance of MBCG present in urine samples of male cats collected on D63 after administration of saline (control group) and in surgically castrated male cats (surgical castration group) ( Figure 5 B).

[0174] Figure 6 The mean relative abundance of N-acetylcadaverine present in urine samples of male cats collected on D63 following administration of saline (control group) or implantation of one 4.7 mg deserorelin implant (Sulfamethoxazole®) (chemical treatment group) according to the protocol detailed in Example 3 is shown. Figure 6 A), and the mean relative abundance of N-acetylcadaverine present in urine samples of male cats collected on D63 after administration of saline (control group) and in surgically castrated male cats (surgical castration group).

[0175] Figure 7 Shown is the mean relative abundance of N-acetylputrelin present in urine samples from male cats collected on D63 following administration of saline (control group) or implantation of one 4.7 mg deserorelin implant (Sulfamethoxazole®) (chemically treated group) according to the protocol detailed in Example 3.

[0176] Figure 8 Shown is the change in p-coumaroylputrescineurinary levels in urine in the desserelin cat treatment group (Suyiqing®) (chemical treatment group, discontinuous curve) compared to the cat control group (continuous curve) according to the protocol of Example 3.

[0177] Fig. 9 Shown is the mean relative abundance of taurine present in urine samples from male cats collected on D63 following administration of saline (control group) or implantation of one 4.7 mg deserorelin implant (Seril®) (chemically treated group) according to the protocol detailed in Example 3.

[0178] Fig.10 The mean relative abundance of valine present in urine samples of male cats collected on D42 following administration of saline (control group) or implantation of a 4.7 mg deserorelin implant (Sulfatin®) (chemical treatment group) according to the protocol detailed in Example 3 is shown. Fig.10 A), and the mean relative abundance of valine present in urine samples of male cats collected on D42 after administration of saline (control group) and in surgically castrated male cats (surgical castration group) Fig.10 B).

[0179] Fig.11 Figure 3 shows the mean relative abundance of indole present in urine samples collected at D63 after administration of saline (control group) or implantation of a 4.7 mg deserorelin implant (Sulfamethoxazole®) (chemical treatment group) according to the protocol detailed in Example 3. Fig.11 A), and the mean relative abundance of indole present in urine samples collected on D63 in male cats after saline administration (control group) and in surgically castrated male cats (surgical castration group) Fig.11 B) diagram.

[0180] Fig.12 Shown is the mean relative abundance of isovaline present in urine samples from male cats collected on D63 following administration of saline (control group) or implantation of one 4.7 mg deserorelin implant (Serezole®) (chemically treated group) according to the protocol detailed in Example 3.

[0181] Fig.13 Figure 3 shows the mean relative abundance of mercaptopyruvic acid present in urine samples of male cats collected on D63 after administration of saline (control group) or implantation of a 4.7 mg deserorelin implant (Sulfamethoxazole®) (chemical treatment group) according to the protocol detailed in Example 3. Fig.13 A), and the mean relative abundance of mercaptopyruvic acid present in urine samples of male cats collected on D63 after administration of saline (control group) and in surgically castrated male cats (surgical castration group) ( Fig.13 B) diagram.

[0182] Fig.14 Shown is the average relative abundance of 3-mercaptopropionic acid present in cat urine samples collected on D63 following administration of saline (control group) or implantation of one 4.7 mg deserorelin implant (Serezole®) (chemically treated group) according to the protocol detailed in Example 3.

[0183] Fig.15Figure 3 shows the mean relative abundance of 7-mercaptoheptanoylthreonine present in urine samples of male cats collected on D63 after administration of saline (control group) or implantation of a 4.7 mg deserorelin implant (Sulfamethoxazole®) (chemical treatment group) according to the protocol detailed in Example 3. Fig.15 A), and the mean relative abundance of 7-mercaptoheptanoylthreonine present in urine samples of male cats collected on D63 after administration of saline (control group) and in surgically castrated male cats (surgical castration group) ( Fig.15 B) diagram.

[0184] Fig.16 Shown is the average relative abundance of 2-mercapto-2-methylpentan-4-one present in urine samples from male cats collected on D63 following administration of saline (control group) or implantation of one 4.7 mg deserorelin implant (Serrellin®) (chemically treated group) according to the protocol detailed in Example 3.

[0185] Fig.17 Shown is the mean relative abundance of crotonic acid present in fecal samples of male cats collected on D63 following administration of saline (control group) or implantation of one 4.7 mg deserorelin implant (Serezole®) (chemically treated group) according to the protocol detailed in Example 3.

[0186] Fig.18 Graph showing the mean % efficacy of 4.7 mg of tamoxifen in male cats in Study A and Study B of Example 4 at different observation time points.

[0187] Fig.19 A and Fig.19 B shows the detailed levels of testosterone concentration (pg / mL) in Study 1 according to Example 4 ( Fig.19 Detailed levels of testosterone concentrations (pg / mL) in Study A) and Study 2 ( Fig.19 B).

[0188] Fig. 20 A and Fig. 20 B shows the average values ​​of the total scores of sexual behavior in Study 1 of Example 4 ( Fig. 20 A) and the mean of the total sexual behavior scores in Study 2 ( Fig. 20 B).

[0189] Fig.21 A and Fig.21 B shows the average phonation changes in Study 1 of Example 4 ( Fig.21 A) and mean vocalization changes in Study 2 ( Fig.21 B).

[0190] Fig. 22 A and Fig. 22B shows the % change of urine markers from baseline in Study 1 of Example 4 ( Fig. 22 A) and Study 2( Fig. 22 B) % change in urine markers from baseline.

[0191] Fig.23 A and Fig.23 B shows the change / reduction in urine odor measured relative to baseline change in Study 1 of Example 4 ( Fig.23 A) and Study 2( Fig.23 Change / reduction in urine odor measured relative to baseline in B).

[0192] Fig.24 A and Fig.24 B shows the change in testicular volume in % in Study 1 of Example 4 ( Fig.24 A) and % change in testicular volume in Study 2 ( Fig.24 B).

[0193] Fig.25 A and Fig.25 B shows the change in penile thorn appearance in Study 1 of Example 4 (% ( Fig.25 A) and % change in penile spines appearance in Study 2 ( Fig.25 B). DETAILED DESCRIPTION

[0194] One of the purposes of the present application is to demonstrate that the administration of deserorelin (e.g., when administered in the form of an implant such as Suyiqing®) reduces urine odor and / or feces odor, particularly unpleasant urine odor and / or feces odor. Surprisingly, the inventors have demonstrated that the odor reduction is mediated by at least two pathways. In fact, one of the pathways is the "classical" testosterone-mediated sex hormone pathway. The inventors have also demonstrated at least another pathway that is unrelated to sex hormones as described in the present application.

[0195] Thus, the purpose of reducing the urine odor and / or feces odor of an animal is achieved by using deserorelin to attenuate or reduce the unpleasant odor of urine and / or feces in a manner that induces chemical castration of the non-human animal to which it is administered.

[0196] In fact, the inventors have demonstrated that the administration of deserorelin has an effect on different molecules involved in urine excretion and / or fecal excretion. Depending on the degradation or synthesis of these molecules, they also contribute to the urine odor or fecal odor. Therefore, one object of the present invention is to use deserorelin to intervene in the composition of urine odor and / or fecal odor by adjusting or changing, in particular down-regulating or up-regulating, the concentration of specific molecules in urine and / or feces. Examples of the effect of deserorelin will be further explained below.

[0197] The term "modulation" herein refers to a change in the amount of a molecule that occurs in response to administration of deserorelin. Modulation includes up-regulation and down-regulation.

[0198] The term "down-regulate" herein refers to a decrease in the amount of a molecule that occurs in response to deserorelin administration relative to the amount of said molecule in the urine and / or feces before deserorelin administration began.

[0199] The term "up-regulated" herein refers to the increase in the amount of a molecule that occurs in response to deserorelin administration relative to the amount of said molecule in the urine and / or feces before the start of deserorelin administration.

[0200] The terms "continuously" and "substantially continuously" with respect to the administration of deserorelin mean that deserorelin is administered without interruption or substantially without interruption, for example by implantation of a sustained release drug release system.

[0201] The molecules can be detected by methods known to those skilled in the art, including tandem mass spectrometry (also known as MS / MS or MS2), two-dimensional gas chromatography-mass spectrometry (also known as GC×GC-MS, such as described by C. Suzuki et al., Journal of Chemical Ecology, 45, 579-587 (2019)) and liquid chromatography-MS / MS.

[0202] According to a preferred embodiment of the present invention, deserorelin downregulates the concentration of a molecule selected from the group consisting of p-cresol, feline, feline precursors such as 3-methylbutanolcysteinylglycine (MBCG), feline derivatives such as N-acetylfeline and 3-mercapto-3-methylbutan-1-ol, isovaline, isobuteine, indole, cadaverine and its derivatives such as N-acetylcadaverine, putrescine and its derivatives such as N-acetylputrescine and p-coumaroylputrescine, sulfhydryl compounds such as mercaptopyruvic acid, 3-mercaptopropionic acid, 7-mercaptoheptanoylthreonine and taurine in urine.

[0203] According to the most preferred embodiment, deserorelin downregulates the concentration of a molecule in urine selected from the group consisting of feline and its feline precursors such as 3-methylbutanolcysteinylglycine, indole, cadaverine and its derivatives such as N-acetylcadaverine, putrescine and its derivatives such as N-acetylputrescine and p-coumaroylputrescine, mercaptopyruvic acid, 3-mercaptopropionic acid, 7-mercaptoheptanoylthreonine and taurine.

[0204] According to another preferred embodiment of the present invention, Deserorelin upregulates the concentration of molecules in urine selected from the group consisting of: 2-mercapto-2-methylpentan-4-one (rather pleasant onion key food odor) and valine (pleasant vanilla and maple syrup odor).

[0205] According to a most preferred embodiment of the present invention, deserorelin upregulates the concentration of valine in urine.

[0206] According to another preferred embodiment of the present invention, deserorelin downregulates the concentration of a molecule in feces selected from the group consisting of crotonic acid and trimethylamine.

[0207] As explained below, down- and up-regulation of these different molecules can be effected by two different synthetic pathways.

[0208] Synthetic pathways of urine odor or feces odor through sex hormones

[0209] It is known from the prior art that testosterone increases the free excretion of felinine, N-acetylfelinine and 3-methylbutanolglutathione in sterilized adult male cats and healthy female cats, while estradiol does not modulate this effect (Hendriks WH et al., Testosterone increases urinary free felinine, N-acetylfelinine andmethylbutanolglutathione excretion in cats (Felis catus)., J Anim Physiol Anim Nutr (Berl)., 2008 Feb; 92(1):53-62).

[0210] Felinine and N-acetylfelinine were also detected in multiple tissues. In addition, all of these compounds were detected in cat bile and fecal samples, indicating that felinine is excreted from the liver into the feces via bile (LC-MS / MS quantification of felinine metabolites in tissues, fluids, and excretionsfrom the domestic cat (Felis catus), Futsuta et al., J Chromatogr B AnalytTechnol Biomed Life Sci., 2018 Jan 1;1072:94-99).

[0211] Therefore, a decrease in feline urinary levels and / or its metabolite levels as well as other molecules will affect urine odor or fecal odor.

[0212] It is also known from the prior art (M. Miyazaki et al., Comp Biochem Physicl B Biochem Mol Biol, 2006 Nov-Dec; 145(3-4):270-7) that cauxin excretion is sex-dependent. In adult cats, cauxin excretion in healthy males is higher than in castrated males or healthy females or ovariectomized females. After castration, the daily excretion of cauxin decreases immediately. Immunohistochemistry confirmed that cauxin expression in healthy males is higher than that in castrated males in the proximal straight tubules of the kidney.

[0213] These results suggest that the excretion of cauxin is regulated by sex hormones such as testosterone, and that the breakdown products of cauxin are excreted in a species-dependent, sex-dependent, and age-dependent manner, as is cauxin itself.

[0214] In addition, cauxin is a carboxylesterase excreted as a major urinary component that regulates the production of feline. In vitro enzyme assays have shown that cauxin hydrolyzes the feline precursor 3-methylbutanolcysteinylglycine to feline and glycine.

[0215] Surprisingly, the inventors of the present invention have discovered and demonstrated that chemical castration induced by deserorelin release affects the production of cauxin and feline. Feline, as well as derivative molecules such as N-acetylfeline, 3-methylbutanolcysteinylglycine (MBCG) and 3-mercapto-3-methylbutan-1-ol, also contribute to urine odor.

[0216] An object of the present invention is to reduce or attenuate urine odor through the synthetic pathway of urine odor or fecal odor via sex hormones by using deserorelin in non-human animals, wherein the plasma concentration of deserorelin in the non-human animal is higher than 10 pg / mL after administration to the non-human animal.

[0217] Therefore, according to a first object, the present invention relates to deserorelin for use in attenuating or reducing urine odour and / or feces odour in a non-human animal, wherein after administration to said non-human animal, the plasma concentration of deserorelin in said non-human animal is above 10 pg / mL.

[0218] More specifically, after administration to the non-human animal, the plasma concentration of deserorelin is 10 pg / mL to 400 pg / ml from 8 days to at least 6 months after administration. Preferably, deserorelin is continuously administered or continuously released after administration in the non-human animal.

[0219] A second object of the present invention is also a method for attenuating or reducing the urine odor and / or feces odor of a non-human animal, the method consisting in administering to the non-human animal an amount of deserorelin, wherein after administration to the non-human animal, the plasma concentration of deserorelin in the non-human animal is higher than 10 pg / mL.

[0220] According to another embodiment, the present invention relates to a method for attenuating or reducing the urine odor and / or feces odor of a non-human animal, the method consisting in administering to the non-human animal an amount of deserorelin that will induce a modulation, i.e. downregulation or upregulation, of the levels of odor molecules in the urine and / or feces.

[0221] Preferably, according to this embodiment, the non-human animal is an able-bodied male animal, preferably a canine or a feline, even more preferably a dog or a cat, most preferably a cat.

[0222] Preferably, according to this embodiment, deserorelin induces the modulation or down-regulation or up-regulation of the levels of odor molecules in urine and / or feces via the sex hormone synthesis pathway.

[0223] As has been demonstrated in the examples illustrating the present invention, the concentrations of felin and felin precursors such as 3-methylbutanolcysteinylglycine are reduced following administration of deserorelin in healthy adult male cats.

[0224] Therefore, according to a particularly preferred embodiment, the present invention relates to Deserorelin for use in downregulating the concentration of felin and felin derivatives in the urine of non-human animals.

[0225] Synthesis of urine or fecal odor via a sex hormone-independent pathway

[0226] In addition to the classical sex hormone pathway mediated by testosterone that causes urine odor and / or feces odor, the inventors have also discovered another pathway that is unrelated to sex-dependent hormones. In fact, as shown in the examples, the inventors have identified new molecules that serve as molecules that cause urine odor and / or feces odor. These molecules are secreted outside the sex hormone pathway. In fact, these molecules are not derivatives of the testosterone cascade.

[0227] Thus, one aspect of the invention is the use of deserorelin for modulating or altering or for downregulating or upregulating the level of a molecule selected from the group consisting of: crotonic acid; indole; p-cresol; cadaverine and cadaverine derivatives, such as acetylcadaverine and glutathionylaminopropylcadaverine; putrescine and putrescine derivatives, such as N-acetylputrescine and p-coumaroylputrescine; a thiol derivative selected from the group consisting of 2-mercapto-3-butanone, 2-mercaptoethanol, 3-mercaptohexylbutyrate, mercaptopyruvic acid, 3-mercaptopropionic acid, 3-mercapto-3-methylbutan-1-ol, 7-mercaptoheptanoylthreonine, 1α,5α-dimercaptoandrostane-3α,17β-diol, 2-mercapto-2-methylpentan-4-one, taurine, valine, isovaline, isobuteine ​​and trimethylamine.

[0228] According to a preferred embodiment, deserorelin downregulates the levels of molecules in urine selected from the group consisting of isovaline, isobuteine, indole, cadaverine and its derivatives such as N-acetylcadaverine, putrescine and its derivatives such as N-acetylputrescine and p-coumaroylputrescine, thiol compounds such as mercaptopyruvic acid, 3-mercaptopropionic acid and 7-mercaptoheptanoylthreonine and taurine.

[0229] According to a most preferred embodiment, deserorelin downregulates the level of a molecule selected from the group consisting of indole, cadaverine and its derivatives such as N-acetylcadaverine, putrescine and its derivatives such as N-acetylputrescine and p-coumaroylputrescine, and mercaptopyruvic acid.

[0230] According to another preferred embodiment, deserorelin upregulates the level of a molecule in urine selected from the group consisting of 2-mercapto-2-methylpentan-4-one and valine.

[0231] According to another most preferred embodiment, deserorelin upregulates the level of valine.

[0232] Isovalein is a branched-chain sulfur amino acid that has been found in normal cat urine. The concentration of isovalein in the urine of healthy adult cats is about 24 micromol / L to 66 micromol / L and is not affected by the sex of the cat.

[0233] In other species (rat, rabbit, guinea pig, human, dog), isovalinuria can be induced following administration of certain inducing agents such as certain cholesterol-lowering agents, bile acids, hormones, or cholesterol precursors. Methods of inducing isovalinuria were extensively studied in the 1960s, and efforts were made to understand its biosynthesis.

[0234] However, despite Figure 1As shown, the sulfur atom in isovaline has been shown to be derived from cysteine ​​or methionine, but the origin of the carbon skeleton remains unknown. Interest in isovaline metabolism has arisen in part because it is believed to be found in the urine of patients with hypercholesterolemia. Therefore, little is known about isovaline.

[0235] The present inventors have now discovered that isovaline is a molecule that causes urine odor. Urine is known to be a mixture of various molecules, so isovaline is believed to be one of the molecules that plays an active role in odor release.

[0236] Less is known about isobuteine, also known as 2-amino-6-carboxy-4-thiaheptanoic acid. This amino acid has been isolated from the urine of healthy humans and cats, but the biological role of isobuteine ​​remains unclear.

[0237] The present inventors have now discovered that isobuteine ​​is a molecule that causes urine odor. Urine is known to be a mixture of various molecules, so isobuteine ​​is considered to be one of the molecules that plays an active role in odor release.

[0238] In addition, several metabolomic molecules were identified in the feces. In fact, the following molecules have been identified from the data: trimethylamine and 3-methylbutyric acid.

[0239] Thus, by chemical castration induced by administration of desorelin, urine odor and / or feces odor also decreases in the same time. The inventors surprisingly found that by chemical castration using desorelin, urine odor decreases after several weeks. Generally, the odor decreases in 21 to 42 days; i.e., approximately 3 to 6 weeks.

[0240] In one aspect of the invention, urine odor is reduced in intact animals, particularly domestic male cats, by administering desmorelin to the animals.

[0241] It was also noted that some molecules were down-regulated in urine but up-regulated in feces, or vice versa. This suggests a compensatory mechanism between the elimination of molecular levels in urine and feces at different levels compared to non-chemically castrated animals (data not shown).

[0242] Therefore, the present invention also relates to a method for improving the attenuation or reduction of urine odor and / or feces odor in non-human healthy male animals compared to sterilized males, the method comprising administering to the non-human healthy male animal an amount of deserorelin that will induce the regulation or downregulation or upregulation of the levels of odor molecules in urine and / or feces.

[0243] According to this embodiment, deserorelin will induce modulation or down-regulation or up-regulation of odor molecule levels in urine and / or feces via a sex hormone-independent pathway.

[0244] According to another embodiment, the present invention relates to deserorelin for use in improving the attenuation or reduction of urine odor and / or feces odor in non-human animals.

[0245] Example 1: Effect of a single 4.7 mg deserorelin implant on testosterone, sexual behavior, and urine odor in male cats Large-scale field evaluation of efficacy and safety

[0246] The aim of this multisite, double-blind, placebo-controlled, randomized study was to confirm that the deserorelin implant can be used as a sterilization option for male cats and also to reduce its associated sexual behaviors in male cats.

[0247] Materials and methods

[0248] Privately owned indoor male cats [aged 3 months to 11 years] were divided into two groups, one group was implanted with a 4.7 mg desorelin implant (Seril® 4.7 mg, Virbac, France) and the other group received sodium chloride. On day 0 (D0), the implant and saline were administered subcutaneously between the shoulder blades. Serum testosterone concentration (T) in ng / mL, sexual behavior (presence of urine marking, frequency of vocalization, frequency of aggression) and the presence of urine odor in able-bodied male cats were evaluated until month 12 (M12) (D372). Routine safety assessments, body weight, appetite and adverse reactions were followed up regularly.

[0249] Ethical approval was obtained for the protocol. Comparisons between groups were performed using the Cochran–Mantel–Haenszel test stratified by center combined with the RIDIT transformation and the general association statistic.

[0250] Of the n=205 male cats, n=154 received 4.7 mg of Suyiqing® (treatment group) and n=51 received saline as the control group.

[0251] 1.2 Results:

[0252] like Figure 1 As shown, in the treatment groups, the mean T values ​​decreased and were significantly decreased from D45 (0.13±0.375 ng / mL vs. 1.74±1.547 ng / mL) to M12 (0.64±1.138 ng / mL vs. 2.04±1.708 ng / mL) compared to the control group.

[0253] Sexual behavior scores, testicular volume, penile thorn visibility, and urine odor were also significantly reduced in the deserorelin group throughout the study and were significantly lower than in the saline group. No sexual outbursts or safety issues were observed.

[0254] 1.3 Conclusion:

[0255] This study showed that the 4.7 mg neutering implant can be used as an effective and safe sterilization option for male cats aged 3 months and older, with an associated reduction in sexual behavior and urine odor for at least 1 year.

[0256] Example 2: Assessment of molecular level changes associated with sex hormone-dependent pathways

[0257] The aim of these studies was to quantify the levels of certain molecules responsible for urine odor. The aim of this study was also to evaluate plasma testosterone levels and metabolomic parameters present in urine in chemically and surgically castrated male cats treated with desorelin. Therefore, several parameters were evaluated. In particular, dose determinations were performed on serum / plasma and urine.

[0258] 2.1 Materials and methods

[0259] The first study A was conducted in two groups of seven healthy male cats aged 12 to 13 months and weighing 4 to 6 kg, including:

[0260] Control group: n=3 healthy males, administered sodium chloride (saline) on day 0 (D0),

[0261] Chemical treatment group: n=4, one Suyiqing® 4.7 mg was implanted on day 0 (D0).

[0262] Study A was conducted within 63 days after implantation of SUYET® 4.7 mg.

[0263] From D21 to D7, cats were clinically examined (weight, temperature), and urine and fecal samples were collected. On D0, cats in the treatment group were implanted subcutaneously with Supremo® 4.7 mg (Virbac, France).

[0264] From D7 to D63, cats were clinically examined (weight, temperature), and urine and fecal samples were collected weekly.

[0265] The non-classical analytical technique based on tandem mass spectrometry, also known as MS / MS or MS2, analyzes samples and retrieves molecules that cause odor in urine and feces samples. With this unique technology, the metabolome present in the sample is evaluated.

[0266] Plasma testosterone levels in the chemically treated and control groups were also assessed.

[0267] Metabolomic analysis of urine and fecal samples collected before treatment (on D14) allowed comparison of the groups and confirmed the presence of the same molecules observed between the two groups (which were confirmed, data not shown).

[0268] Metabolomic analysis of feces was performed on D49 and of urine on D63 after treatment to compare the levels of molecules between treated and control animals and to assess the effect of castration on the levels of odor molecules.

[0269] The second study B was conducted in two groups of 4 male healthy cats aged 12 to 13 months and weighing 4 to 6 kg:

[0270] Control group: n=2 healthy males, administered sodium chloride (saline) on day 0 (D0),

[0271] Surgical castration group: n=4 (surgical castration by removal of testicles; adult cats neutered over 6 months old), administered sodium chloride (saline) on day 0 (D0).

[0272] The protocol was identical to that of the first study A.

[0273] LC-MS / MS analysis

[0274] Metabolomic analysis was performed using LC-MS / MS.

[0275] Liquid chromatography was performed using a DIONEX Ultimate 3000 HPLC system (Thermo Fisher Scientific). 10 μL of each sample was injected into a Synergi 4 μm Hydro-RP 80 Å, 250 mm × 3.0 mm column (Phenomenex, Le Pecq, France). The mobile phase consisted of 0.1% formic acid (Thermo Fisher Scientific) in water (study A) and 0.1% formic acid in acetonitrile (study B). The flow rate was 0.9 mL / min, and the gradient was set as follows: 0% B phase from 0 min to 5 min, 0% to 95% B phase from 5 min to 21 min, hold at 95% B phase for 21.5 min, 95% to 0% B phase from 21.5 min to 22 min, hold at 0% B phase until 25 min to equilibrate the column. Mass spectrometry was performed on a Q exclusive Plus Orbitrap mass spectrometer (Thermo Fisher Scientific) equipped with a heated electrospray ion source HESI II, operating in positive / negative switching mode. Other analyses of samples were performed in positive ion mode. High-resolution accurate mass full scan MS and top 5 MS2 spectra were acquired in a data-dependent manner at m / z 400 with resolving powers of 70,000 and 35,000, respectively. All samples were processed consecutively in the same batch.

[0276] Metabolomics analysis

[0277] Data were post-processed using Compound Discovers 3.2 (Thermo Fisher Scientific).

[0278] The workflow template was untargeted metabolomics combined with statistical methods, and used online databases and mzLogic to detect the IDs of unknown substances. The mzLogic obtained from positive and negative ionization modes were also analyzed using MZmine (version 2.39).

[0279] Mass detector tool (mass detector: wavelet transform, MS level 1; noise level 10^5, scale level: 5, wavelet window size: 30%) was used. Chromatograms were detected using ADAP chromatogram builder (MS level: 1, minimum number of group scans: 5, group intensity threshold: 5×10^2, minimum maximum intensity: 10^5, m / z tolerance: 10 ppm). Peaks were separated using Peak Extender module (m / z tolerance: 10 ppm, minimum height: 10^5). Retention times were normalized using Retention Time Alignment module (m / z tolerance: 10 ppm; retention time tolerance (relative): 10%, minimum height: 10^5). Peaks were then aligned using RANSACaligner (random sampling consensus) algorithm with a tolerance of 10 ppm in m / z and a retention time of 1 minute. Peaks were then identified using the Human Metabolome Database (HMDB, version 3.0) with a mass tolerance of 10 ppm. Missing values ​​were filled using the gap filler in the same m / z and RT range with a tolerance of 10 ppm in m / z. The results obtained for each polarity were merged and for metabolites identified in both modes, only the mode with the highest mean peak intensity was considered.

[0280] 2.2 Results

[0281] Feline urinary acid:

[0282] The results are attached Figure 4 In this figure, the mean relative abundance peak of felinine present in urine samples of male cats collected on D63 after saline administration (control group) is compared to counterparts of cats implanted with a 4.7 mg desmorelin implant (Servoy®) (chemically treated group) and surgically castrated male cats (surgically castrated group).

[0283] The average relative abundance peaks of feline urinary amino acids in the two control groups of Study A and Study B were the same, as shown in the combined figure ( Figure 4 ) as shown.

[0284] These results showed that at day 63, felinaine was significantly reduced in both the chemically treated and surgically castrated groups compared with the control group.

[0285] MBCG:

[0286] The results are attached Figure 5 A and attached Figure 5 As shown in B. Figure 5In A, the mean relative abundance of MBCG present in urine samples of male cats collected on D63 after saline administration (control group) was compared with that of cats implanted with a 4.7 mg desorelin implant (Sulfamethoxazole®) (chemically treated group). Figure 5 In B, the mean relative abundance of MBCG present in urine samples of male cats collected on D63 after saline administration (control group) was compared to that of surgically castrated male cats (surgical castration group).

[0287] These results showed that at day 63, MBCG was significantly reduced in both the chemically treated and surgically castrated groups compared with the control group.

[0288] Example 3: Assessment of molecular level changes associated with sex hormone-independent pathways

[0289] The purpose of the study was to evaluate whether the use of desorelin could modulate or change or downregulate or upregulate the levels of molecules identified as causing urine odor.

[0290] The study also aimed to show that the use of desorelin could also modify the levels of crotonic acid in stool, one of the molecules responsible for stool odor.

[0291] 3.1 Materials and Methods

[0292] This study was conducted identically to the protocol in Example 2 with the same groups of cats.

[0293] An unconventional analytical technique based on tandem mass spectrometry, also known as MS / MS or MS2, was used to analyze the samples and retrieve the molecules responsible for the odor in urine and feces samples, as described in Example 2. With this unconventional technique, the metabolome present in the samples was evaluated:

[0294] The levels of the following metabolites were measured in urine samples collected from each group during the study period: N-acetylcadaverine, N-acetylputrescine, p-coumaroylputrescine, taurine, valine, indole, isovaline, and thiol derivatives, namely mercaptopyruvic acid, mercaptopropionic acid, 3-mercaptoheptanoylthreonine, and 2-mercapto-2-methylpentan-4-one, which are all associated with sex hormone-independent pathways. These molecules have been identified as one of the molecules responsible for urine odor.

[0295] Crotonic acid levels were measured in stool samples collected from each group during the study period.

[0296] Tandem mass spectrometry (MS / MS or MS 2)At least two mass analyses are performed when a dissociation process or chemical reaction is performed to change the mass or charge of the ions. MS / MS increases specificity beyond separation by molecular weight and provides insights into structural elucidation and identification of elemental composition. The most common dissociation method is collision-induced dissociation (CID), where the first analyzer is used to isolate the designated target ion (precursor ion), followed by a fragmentation process to produce neutral fragments and fragment ions (product ions). The second analyzer analyzes these product ions and establishes a unique pattern based on the precursor ion structure and composition. (Richard A. McPherson, Methods in Enzymology, 2019).

[0297] MS / MS is particularly useful for analyzing complex mixtures and involves two stages of MS. In the first stage of MS / MS, a predetermined set of m / z ions are separated from the remaining ions from the ion source and fragmented by chemical reactions. In the second stage, a mass spectrum for the fragments is generated. Tandem MS is commonly used for bioanalysis of drugs. The identification and determination of Phase I and Phase II drug metabolites are completed by tandem mass spectrometry (TANDEM MS) combined with high performance liquid chromatography (HPLC) (Glish, GL and Vachet, RW, 2003. Nature Reviews Drug Discovery 2(2):140; Holčapek, M. et al., 2008., Analytical and Bioanalytical Chemistry391(1):59–78).

[0298] 3.2 Research Results :

[0299] N-Acetylcadaverine:

[0300] The results are attached Figure 6 In this figure, the mean relative abundance peak of N-acetylcadaverine present in urine samples of male cats collected on D63 after saline administration (control group) is compared to the counterparts of cats implanted with one 4.7 mg deserorelin implant (Susorelin®) (chemically treated group) ( Figure 6 A) and their counterparts in surgically castrated male cats (surgically castrated group) ( Figure 6 B) were compared.

[0301] These results showed that N-acetylcadaverine, known to have a foul odor of decayed flesh, was significantly reduced in the chemically treated group compared with the control group on day 63, whereas in contrast there was no significant difference in the concentration of N-acetylcadaverine detected in urine samples between the surgically castrated group and the control group.

[0302] N-Acetylputrescine:

[0303] The results are attached Figure 7 In this figure, the mean relative abundance of N-acetylputrelin present in urine samples of male cats collected on D63 after saline administration (control group) is compared to that of cats implanted with a 4.7 mg desmorelin implant (Surocept®) (chemically treated group).

[0304] The results demonstrated that, on day 63, N-acetylputrescine, known to have a foul smell of rotten meat, was significantly reduced in the chemically treated group according to the present invention compared to the control group.

[0305] p-Coumaryl putrescine:

[0306] The results are attached Figure 8 In this figure, the changes in the average relative abundance of p-coumaroylputrescine in the control group (continuous curve) and the chemically treated group (discontinuous curve) are shown as a function of time (days).

[0307] These results indicate that deserorelin administration resulted in a decrease in p-coumaroylputrescine concentrations (chemically treated group) compared to the control group.

[0308] Taurine:

[0309] The results are attached Fig. 9 In this figure, the mean relative abundance of taurine present in urine samples of male cats collected on D63 after saline administration (control group) is compared to that of cats implanted with a 4.7 mg desmorelin implant (Surotec®) (chemically treated group).

[0310] The results showed that at day 63, taurine was significantly reduced in the chemically treated group according to the present invention compared to the control group.

[0311] Valine:

[0312] The results are attached Fig.10 In this figure, the mean relative abundance peak of valine present in urine samples of male cats collected on D42 after saline administration (control group) is compared with that of cats implanted with one 4.7 mg deserorelin implant (Susorelin®) (chemically treated group) ( Fig.10 A) and their counterparts in surgically castrated male cats (surgically castrated group) ( Fig.10 B) were compared.

[0313] These results indicate that valine, which is known to have a pleasant sweet odor, was significantly elevated in the chemically treated group compared with the control group on day 42, whereas in contrast there was no significant difference in valine concentration detected in urine samples between the surgically castrated group and the control group.

[0314] Indole:

[0315] The results are attached Fig.11 In this figure, the mean relative abundance peaks of indole present in urine samples of male cats collected on D63 after saline administration (control group) are compared to the counterparts of cats implanted with one 4.7 mg desorelin implant (Susorelin®) (chemically treated group) ( Fig.11 A) and their counterparts in surgically castrated male cats (surgically castrated group) ( Fig.11 B) were compared.

[0316] These results indicate that on day 63, indole, known to have a strong fecal odor, was significantly reduced in the chemically treated group compared with the control group, whereas in contrast there was no significant difference between the indole concentrations detected in urine samples from the surgically castrated group and the control group.

[0317] Isovaline:

[0318] The results are attached Fig.12 In this figure, the mean relative abundance of isovaline present in urine samples of male cats collected on D63 after saline administration (control group) is compared to that of cats implanted with a 4.7 mg desmorelin implant (Surocept®) (chemically treated group).

[0319] The results showed that at day 63, isovaline, known to have a foot / cheese odor, was reduced in the chemically treated group according to the invention compared to the control group.

[0320] Mercaptopyruvic acid:

[0321] The results are attached Fig.13 In this figure, the mean relative abundance peak of mercaptopyruvic acid present in urine samples of male cats collected on D63 after saline administration (control group) is compared to the counterparts of cats implanted with one 4.7 mg deserorelin implant (Susorelin®) (chemically treated group) ( Fig.13 A) and their counterparts in surgically castrated male cats (surgically castrated group) ( Fig.13 B) were compared.

[0322] These results indicate that mercaptopyruvic acid, known as a malodorous compound, was significantly reduced in the chemically treated group compared to the control group on day 63, whereas in contrast there was no significant difference in mercaptopyruvic acid concentration detected in urine samples between the surgically castrated group and the control group.

[0323] 3-Mercaptopropionic acid:

[0324] The results are attached Fig.14In this figure, the mean relative abundance of 3-mercaptopropionic acid present in urine samples of male cats collected on D63 after saline administration (control group) is compared to that of cats implanted with a 4.7 mg desmorelin implant (Sulfamethoxazole®) (chemically treated group).

[0325] The results showed that on day 63, 3-mercaptopropionic acid, known as a malodorous compound, was significantly reduced in the chemically treated group according to the present invention compared to the control group.

[0326] 7-Mercaptoheptanoylthreonine:

[0327] The results are attached Fig.15 In this figure, the mean relative abundance peak of 7-mercaptoheptanoylthreonine present in urine samples of male cats collected on D63 after saline administration (control group) is compared to the counterparts of cats implanted with one 4.7 mg deserorelin implant (Susorelin®) (chemically treated group) ( Fig.15 A) and their counterparts in surgically castrated male cats (surgically castrated group) ( Fig.15 B) were compared.

[0328] These results indicate that at day 63, 7-mercaptoheptanoylthreonine was significantly reduced in the chemically treated and surgically castrated groups compared with the control group.

[0329] 2-Mercapto-2-methylpentan-4-one:

[0330] The results are attached Fig.16 In this figure, the mean relative abundance of 2-mercapto-2-methylpentan-4-one present in urine samples from male cats collected on D63 after saline administration (control group) is compared to its counterpart in cats implanted with a 4.7 mg desmorelin implant (Sulfamethoxazole®) (chemically treated group).

[0331] The results showed that on day 63, 2-mercapto-2-methylpentan-4-one, which is known to have a rather pleasant onion odor, was significantly increased in the chemically treated group according to the present invention compared to the control group.

[0332] Crotonic Acid:

[0333] The results are attached Fig.17 In this figure, the mean relative abundance of crotonic acid present in fecal samples of male cats collected on D63 after saline administration (control group) is compared to that of cats implanted with one 4.7 mg desmorelin implant (Surocept®) (chemically treated group).

[0334] The results showed that on day 63, crotonic acid, which is known to have an unpleasant odor, was significantly reduced in the chemically treated group compared to the control group.

[0335] All results related to the determination of thiol derivatives in urine samples indicate that the concentration of thiol derivatives in urine is affected by physical castration and (for the first time) deserorelin treatment. Without wishing to be bound by any theory, the inventors assume that these changes are not directly related to testosterone, since the changes in surgically castrated cats and deserorelin-castrated cats are different (e.g. mercaptopyruvic acid). In addition, the reduction in urine odor and, therefore, the reduction in urine markers, caused by the reduction in thiol derivatives, seems to be more important in deserorelin-treated cats than in surgically castrated cats.

[0336] These results also show that other tested odor compounds in urine (unpleasant or pleasant odors) are affected by castration via desmorelin treatment but not by surgical castration (demonstrated for the first time). Since the changes were different in surgically castrated cats and desmorelin castrated cats, these changes do not seem to be directly related to the testosterone pathway. In addition, the reduction in urine odor and therefore urine markers via the reduction of compounds other than thiol derivatives seems to be more important in desmorelin treated cats than in surgically castrated cats.

[0337] These data surprisingly demonstrate that deserorelin has an effect on the regulation of the levels of several metabolic molecules. Specifically, deserorelin can downregulate the levels of the following molecules alone or at least two of them: cadaverine, indole, p-cresol, isovaline and isobuteine.

[0338] The results showed that deserorelin has effects on the levels of molecules associated with sex hormone-independent pathways. These data suggest that urine odor and / or fecal odor also depend on molecules that are not associated with sex hormone pathways.

[0339] In summary, it was unexpectedly noted that molecules responsible for unpleasant odors were downregulated, while molecules responsible for more pleasant odors were upregulated.

[0340] Example 4: Cat Field Study

[0341] 4.1 Study plan

[0342] The purpose of these studies was to demonstrate suppression of fertility and durability of sterility in male cats.

[0343] This example presents data collected from 2 combined studies (double-blind placebo-controlled randomized) that were conducted sequentially according to the following schedule:

[0344] Study 1: Study 1 was conducted in a group of 205 male cats divided into two groups, a control group (n=51 subcutaneously administered) receiving 1 mL of saline and a treatment group (n=154) receiving the 4.7 mg implant of Sulfamethoxazole (deserelin acetate subcutaneously implanted).

[0345] Study 2: At the end of the 12-month first phase, the Suyiqing® implant was removed from all male cats belonging to the treatment group. Then, saline (1 mL subcutaneously) was administered to 12 male cats in the treatment group from Study 1 (Saline Group), and 22 cats in the treatment group from Study 1 were re-implanted with new Suyiqing® 4.7 mg implants for a 12-month second phase (Twice Treatment Group). The efficacy and safety of the re-implantation were followed up during this additional 12 months, i.e. a total of 24 months.

[0346] The observation schedule is as follows:

[0347] Study 1: V1: Day -14 to Day -7; V2: Day 0; V3: 1.5 months ± 3 days; V4: 3 months ± 5 days, V5: 6 months ± 5 days, V6: 9 months ± 5 days; V7: 12 months ± 5 days;

[0348] Study 2: V8: 12 months ± 3 days; V9: 13.5 months ± 3 days; V10: 15 months ± 5 days; V11: 18 months ± 5 days; V12: 21 months ± 5 days; V13: 24 months ± 5 days.

[0349] Regarding the inclusion criteria, the criteria for both studies were as follows:

[0350] - House cat

[0351] - Age > 3 months or > 15 months in Study 2

[0352] - Healthy indoor male

[0353] - Client Owned (including shelter cats / rehomed from foster homes)

[0354] The additional criterion for Study 2 was success in Study 1.

[0355] In these studies, the following primary endpoints were measured:

[0356] - For Study 1: Suppression of fertility (testosterone ≤ 0.10 ng / mL *from V4 to V7* – 3 months to 12 months)

[0357] - Study 2: Suppression of fertility (testosterone ≤ 0.10 ng / mL *from V8 to V13* – 12 months to 24 months) and time to reversal of effect.

[0358] In addition to safety parameters (hematology and blood biochemistry, urinalysis, local reactions at the implantation site, changes in body weight, appetite, assessment of abnormal testicles, adverse events), the following secondary endpoints were reported:

[0359] - Sexual Behavior Total Score

[0360] - Aggression

[0361] - Vocalization

[0362] - Urine markers

[0363] - Urine odor / smell

[0364] - Penis piercing

[0365] - Testicular volume

[0366] 4.2 Results

[0367] - Testosterone:

[0368] Fig.18 Mean percentage efficacy results are shown. Overall, the success rates were very similar in both studies for 1 or 2 implants, with efficacy >87% at all time points in Study 2.

[0369] Fig.19 A and Fig.19 B shows the detailed levels of testosterone in Study 1 and Study 2, respectively.

[0370] - Reversibility:

[0371] The reversibility of the effects of deserelin was investigated. In fact, n=12 subjects in the deserelin-treated group of Study 1 were enrolled in the saline group of Study 2, as described above in point 4.1.

[0372] Results showed that cats released from the treatment group in Study 1 and enrolled in the saline group in Study 2 had 100% reversal by D279 after enrolment in Study 2. The median time to reversibility was D379 ± 178 as measured by serum testosterone concentrations.

[0373] - Secondary endpoints:

[0374] Efficacy results for secondary endpoints are reported as follows:

[0375] · Fig. 20 A and Fig. 20 B shows the mean of the total score of sexual behavior in Study 1 and the mean of the total score of sexual behavior in Study 2,

[0376] · Fig.21A and Fig.21 B shows the change in mean phonation in Study 1 and the change in mean phonation in Study 2, respectively.

[0377] · Fig. 22 A and Fig. 22 B shows the % change from baseline for urine markers in Study 1 and Study 2, respectively.

[0378] · Fig.23 A and Fig.23 B shows the change / reduction in urine odor measured as change from baseline in Study 1 and the change / reduction in urine odor measured as change from baseline in Study 2, respectively.

[0379] · Fig.24 A and Fig.24 B shows the % change in testicular volume in Study 1 and the % change in testicular volume in Study 2, respectively.

[0380] · Fig.25 A and Fig.25 B shows the % change in penile thorn appearance in Study 1 and the % change in penile thorn appearance in Study 2, respectively.

[0381] During the study, there were no safety issues and the desmorelin implant was well tolerated.

[0382] In summary, these combined studies demonstrate that:

[0383] Deserorelin was effective for chemical castration of subjects for at least 12 months. This effect has been shown to be reversible at the end of the treatment course. These studies also demonstrated that sexual behavior has been reduced and that the onset of action in reducing behavior is rapid (about 7 days to about 31 days). In addition, no safety issues have been reported with either single or repeated administration.

[0384] Therefore, it can be concluded that extended-release administration of deserorelin, especially via implant, is a good alternative to surgical castration and a safe, nonsurgical method for controlling reproduction in male cats.

[0385] The use of desorelin as described herein is a reliable, reversible, nonsurgical sterilization solution that promotes the well-being of pet families while keeping options open.

Claims

1. Deserorelin for use in attenuating or reducing urine odor and / or feces odor in a non-human animal, wherein after administration to the non-human animal, the plasma concentration of deserorelin in the non-human animal is greater than 10 pg / mL.

2. Deserorelin for use according to claim 1, wherein after administration to the non-human animal, the plasma concentration of deserorelin is 10 pg / mL to 400 pg / ml from 8 days to at least 6 months after administration.

3. Deserorelin for use according to claim 2, wherein deserorelin is continuously administered or continuously released after administration in the non-human animal.

4. Deserorelin for use according to claim 3, wherein after administration, deserorelin is released substantially continuously at a plasma concentration of less than 400 pg / mL from 8 days to at least 6 months after administration.

5. Deserorelin for use according to claim 3, wherein after administration, deserorelin downregulates or upregulates molecules that cause urine odor and / or feces odor, said molecules being selected from felin-derived compounds, volatile organic compounds (VOCs), sulfur-containing compounds and testosterone-induced compounds.

6. Deserorelin for use according to claim 5, wherein after administration, deserorelin downregulates molecules that cause urine odor and / or feces odor, said molecules being selected from the following substances: - Sulfur compounds selected from the group consisting of: 4-methyl-4-mercapto-pentan-2-one; 3-methyl-3-mercapto-butan-1-ol; 3-methyl-3-mercapto-1-butylcarboxylate; - VOCs: 2,5-dimethylpyrazine; 1,2-dichloropropane; 4,4-dimethyl-2-pentanone; and 3-methyl-2-butene-1-ol; - a compound selected from the group consisting of: 2-(methylthio)-1-ethanol; 2-methyl-3-furanthiol; oxathiolane; 4-(methylthio)-2-butanone; 3-methylbutyl-3-mercaptoformate; and 3-methyl-3-(methylthio)-1-butanol; - p-Cresol - Feline and its derivatives, such as: 3-mercapto-3-methyl-1-butanol; 3-mercapto-3-methylbutylcarboxylate; 3-methyl-3-methylthio-1-butanol; and 3-methyl-3-(2-methyldimercapto)-1-butanol; - Feline precursors, such as N-acetylfeline, γ-glutamylfelineylglycine and 3-methylbutyricysteinylglycine; - cauxine; - 2-phenylethylamine and S-(1-hydroxy-3,7-dimethyl-6-octen-3-yl)cysteine; - Isovaline; - Isobutylcysteine; - Trimethylamine; - Indole; - Cadaverine and derivatives, such as N-acetylcadaverine and glutathioneaminopropylcadaverine; - Short-chain free fatty acids, such as acetic acid, propionic acid, 2-methylpropionic acid, butyric acid, 3-methylbutyric acid and valeric acid; - Crotonic acid; - Putrescine and its derivatives, such as N-acetylputrescine and p-coumaroylputrescine; - mercapto derivatives, such as 2-mercapto-3-butanone, 2-mercaptoethanol, 3-mercaptohexylbutyrate, mercaptopyruvic acid, 3-mercaptopropionic acid, 3-mercapto-3-methylbutan-1-ol, 7-mercaptoheptanoylthreonine, 1α,5α-dimercaptoandrostane-3α,17β-diol, mercaptopyruvic acid, and 2-mercapto-2-methylpentan-4-one; and - Taurine.

7. Deserelin for use according to claim 6, wherein the molecule is selected from indole, cadaverine and its derivatives such as N-acetylcadaverine, putrescine and its derivatives such as N-acetylputrescine and p-coumaroylputrescine, and mercaptopyruvic acid.

8. Deserorelin for use according to claim 5, wherein after administration, deserorelin upregulates molecules responsible for urine odor and / or feces odor selected from 2-mercapto-2-methylpentan-4-one and valine.

9. Non-therapeutic use of deserorelin for downregulating the level of a molecule in the urine and / or feces of a non-human animal, wherein the molecule is selected from the group consisting of: - Sulfur compounds selected from the group consisting of: 4-methyl-4-mercapto-pentan-2-one; 3-methyl-3-mercapto-butan-1-ol; 3-methyl-3-mercapto-1-butylcarboxylate; - VOCs: 2,5-dimethylpyrazine; 1,2-dichloropropane; 4,4-dimethyl-2-pentanone; and 3-methyl-2-butene-1-ol; - a compound selected from the group consisting of: 2-(methylthio)-1-ethanol; 2-methyl-3-furanthiol; oxathiolane; 4-(methylthio)-2-butanone; 3-methylbutyl-3-mercaptoformate; and 3-methyl-3-(methylthio)-1-butanol; - p-Cresol; - Feline and its derivatives, such as: 3-mercapto-3-methyl-1-butanol; 3-mercapto-3-methylbutylcarboxylate; 3-methyl-3-methylthio-1-butanol; and 3-methyl-3-(2-methyldimercapto)-1-butanol; - Feline precursors, such as N-acetylfeline, γ-glutamylfelineylglycine and 3-methylbutyricysteinylglycine; - cauxine; - 2-phenylethylamine and S-(1-hydroxy-3,7-dimethyl-6-octen-3-yl)cysteine; - Isovaline; - Isobutylcysteine; - Trimethylamine; - Indole; - cadaverine and cadaverine derivatives, such as N-acetylcadaverine and glutathione aminopropylcadaverine; - Short-chain free fatty acids, such as acetic acid, propionic acid, 2-methylpropionic acid, butyric acid, 3-methylbutyric acid and valeric acid; - Crotonic acid; - Putrescine and its derivatives, such as N-acetylputrescine and p-coumaroylputrescine; - mercapto derivatives, such as 2-mercapto-3-butanone, 2-mercaptoethanol, 3-mercaptohexylbutyrate, mercaptopyruvic acid, 3-mercaptopropionic acid, 3-mercapto-3-methylbutan-1-ol, 7-mercaptoheptanoylthreonine, 1α,5α-dimercaptoandrostane-3α,17β-diol, mercaptopyruvic acid, and 2-mercapto-2-methylpentan-4-one; and - Taurine.

10. The non-therapeutic use of deserorelin for upregulating the level of a molecule selected from 2-mercapto-2-methylpentan-4-one and valine in the urine and / or feces of a non-human animal.

11. A method for attenuating or reducing urine odor and / or feces odor in a non-human animal, the method comprising administering to the non-human animal an amount of deserorelin, wherein after administration to the non-human animal, the plasma concentration of deserorelin in the non-human animal is greater than 10 pg / mL.

12. A method for attenuating or reducing urine odor and / or feces odor in a non-human animal, wherein the method comprises administering to the non-human animal an amount of deserorelin that will induce a downregulation or upregulation of the levels of odor molecules in urine and / or feces.

13. The method of claim 11 or 12, wherein the non-human animal is an able-bodied tomcat.

14. The method according to any one of claims 11 to 13, wherein deserorelin induces down-regulation or up-regulation of odor molecule levels in urine and / or feces via the sex hormone synthesis pathway.

15. A method for improving the attenuation or reduction of urine odor and / or feces odor in a non-human healthy male animal compared to a neutered male, the method comprising administering to the non-human healthy male animal an amount of deserorelin that induces downregulation or upregulation of odor molecule levels in urine and / or feces.

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