Use of SGLT-2 inhibitors in the drying-off of non-human mammals

1. A method of improving and/or facilitating the drying-off of a non-human mammal, comprising administering to the non-human mammal at least one SGLT2 inhibitor, wherein the at least one SGLT-2 inhibitor is selected from the group consisting of:

(1) a glucopyranosyl-substituted benzene derivative of the formula (1)

wherein R 1 denotes cyano, Cl or methyl,

R 2 denotes H, methyl, methoxy or hydroxy and

R 3 denotes cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, 3-methyl-but-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethinyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy, difluoromethyloxy, trifluoromethyloxy, 2-methyloxy-ethyloxy, methylsulfanyl, methylsulfinyl, methlysulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano,

or a derivative thereof wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are acylated with groups selected from (C 1-18 -alkyl)carbonyl, (C 1-18 -alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C 1-3 -alkyl)-carbonyl;

(2) Velagliflozin, represented by formula (2):

(3) Dapagliflozin, represented by formula (3):

(4) Canagliflozin, represented by formula (4):

(5) Empagliflozin, represented by formula (5):

(6) Luseogliflozin, represented by formula (6):

(7) Tofogliflozin, represented by formula (7):

(8) Ipragliflozin, represented by formula (8):

(9) Ertugliflozin, represented by formula (9):

(10) Atigliflozin, represented by formula (10):

(11) Remogliflozin, represented by formula (11):

(11A) Remogliflozin etabonate, represented by formula (11A):

(12) a thiophene derivative of the formula (12)

wherein R denotes methoxy or trifluoromethoxy;

(13) 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene, represented by formula (13);

(14) a spiroketal derivative of the formula (14):

wherein R denotes methoxy, trifluoromethoxy, ethoxy, ethyl, isopropyl or tert-butyl;

(15) a pyrazole-O-glucoside derivative of the formula (15):

wherein

R 1 denotes C 1-3 -alkoxy,

L 1 , L 2 independently of each other denote H or F,

R 6 denotes H, (C 1-3 -alkyl)carbonyl, (C 1-6 -alkyl)oxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl or benzylcarbonyl;

(16) Sotagliflozin, represented by formula (16):

(17) Sergliflozin, represented by formula (17):

(18) a compound represented by formula (18):

wherein

R 3 denotes cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, 3-methyl-but-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethinyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy, difluoromethyloxy, trifluoromethyloxy, 2-methyloxy-ethyloxy, methylsulfanyl, methylsulfinyl, methlysulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano,

or a derivative thereof wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are acylated with groups selected from (C 1-18 -alkyl)carbonyl, (C 1-18 -alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C 1-3 -alkyl)-carbonyl;

(19) Bexagliflozin, represented by formula (19):

(20) Janagliflozin, represented by formula (20):

(21) Rongliflozin; and

(22) Wanpagliflozin.

2. A method according to claim 1 , wherein the at least one SGLT-2 inhibitor is administered in a therapeutically effective amount without exerting any harmful and/or abortifacient effects on a pregnant non-human mammal, and/or wherein the at least one SGLT-2 inhibitor is administered in a therapeutically effective amount without exerting any negative effects on the subsequent reproduction cycle/fertility and milk yield and/or milk quality in the next lactation.

3. The method according to claim 2 , wherein the at least one SGLT-2 inhibitor is administered in a therapeutically effective amount that additionally or alternatively effects a reduction of the incidence of new intra-mammary infections (IMI) or mastitis in the first month after start of the next lactation.

4. The method according to claim 1 , wherein the non-human mammal is selected from the group consisting of: bovine, canine, caprine, equine, feline, lagomorphs, ovine, porcine, and rodent.

5. The method according to claim 1 , wherein the at least one SGLT-2 inhibitor is administered orally, parenterally, rectally, intravaginally, intravenously, subcutaneously or intramuscularly.

6. The method according to claim 1 , wherein the at least one SGLT-2 inhibitor is administered at a dose of 0.01 mg/kg bodyweight to 10 mg/kg bodyweight.

7. The method according to claim 1 , wherein the at least one SGLT-2 inhibitor is administered once, twice, three-times, four-times, five-times, six-times or daily for a week.

8. The method according to claim 1 , wherein the at least one SGLT-2 inhibitor is administered once only at start of drying-off or twice as two treatments 24 hours or 48 hours apart after last milking.

9. The method according to claim 1 , wherein the non-human mammal is a cow, a pregnant cow, and/or a lactating cow.

10. The method according to claim 1 , wherein the at least one SGLT-2 inhibitor comprises Velagliflozin, represented by formula:

11. A method of reducing milk production in a pregnant and/or lactating non-human mammal, comprising administering to the non-human mammal at least one SGLT-2 inhibitor, wherein the at least one SGLT-2 inhibitor is selected from the group consisting of:

(1) a glucopyranosyl-substituted benzene derivative of the formula (1)

wherein R 1 denotes cyano, Cl or methyl,

R 2 denotes H, methyl, methoxy or hydroxy and

R 3 denotes cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, 3-methyl-but-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethinyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy, difluoromethyloxy, trifluoromethyloxy, 2-methyloxy-ethyloxy, methylsulfanyl, methylsulfinyl, methlysulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano,

or a derivative thereof wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are acylated with groups selected from (C 1-18 -alkyl)carbonyl, (C 1-18 -alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C 1-3 -alkyl)-carbonyl;

(2) Velagliflozin, represented by formula (2):

(3) Dapagliflozin, represented by formula (3):

(4) Canagliflozin, represented by formula (4):

(5) Empagliflozin, represented by formula (5):

(6) Luseogliflozin, represented by formula (6):

(7) Tofogliflozin, represented by formula (7):

(8) Ipragliflozin, represented by formula (8):

(9) Ertugliflozin, represented by formula (9):

(10) Atigliflozin, represented by formula (10):

(11) Remogliflozin, represented by formula (11):

(11A) Remogliflozin etabonate, represented by formula (11A):

(12) a thiophene derivative of the formula (12)

wherein R denotes methoxy or trifluoromethoxy;

(13) 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene, represented by formula (13);

(14) a spiroketal derivative of the formula (14):

wherein R denotes methoxy, trifluoromethoxy, ethoxy, ethyl, isopropyl or tert-butyl;

(15) a pyrazole-O-glucoside derivative of the formula (15):

wherein

R 1 denotes C 1-3 -alkoxy,

L 1 , L 2 independently of each other denote H or F,

R 6 denotes H, (C 1-3 -alkyl)carbonyl, (C 1-6 -alkyl)oxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl or benzylcarbonyl;

(16) Sotagliflozin, represented by formula (16):

(17) Sergliflozin, represented by formula (17):

(18) a compound represented by formula (18):

wherein

R 3 denotes cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, 3-methyl-but-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethinyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy, difluoromethyloxy, trifluoromethyloxy, 2-methyloxy-ethyloxy, methylsulfanyl, methylsulfinyl, methlysulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano,

or a derivative thereof wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are acylated with groups selected from (C 1-18 -alkyl)carbonyl, (C 1-18 -alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C 1-3 -alkyl)-carbonyl;

(19) Bexagliflozin, represented by formula (19):

(20) Janagliflozin, represented by formula (20):

(21) Rongliflozin; and

(22) Wanpagliflozin.

12. A method of decreasing milk accumulation and/or engorgement in the udder and/or mammary gland of a non-human mammal, comprising administering to the non-human mammal at least one SGLT-2 inhibitor, wherein the at least one SGLT-2 inhibitor is selected from the group consisting of:

(1) a glucopyranosyl-substituted benzene derivative of the formula (1)

wherein R 1 denotes cyano, Cl or methyl,

R 2 denotes H, methyl, methoxy or hydroxy and

R 3 denotes cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, 3-methyl-but-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethinyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy, difluoromethyloxy, trifluoromethyloxy, 2-methyloxy-ethyloxy, methylsulfanyl, methylsulfinyl, methlysulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano,

or a derivative thereof wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are acylated with groups selected from (C 1-18 -alkyl)carbonyl, (C 1-18 -alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C 1-3 -alkyl)-carbonyl;

(2) Velagliflozin, represented by formula (2):

(3) Dapagliflozin, represented by formula (3):

(4) Canagliflozin, represented by formula (4):

(5) Empagliflozin, represented by formula (5):

(6) Luseogliflozin, represented by formula (6):

(7) Tofogliflozin, represented by formula (7):

(8) Ipragliflozin, represented by formula (8):

(9) Ertugliflozin, represented by formula (9):

(10) Atigliflozin, represented by formula (10):

(11) Remogliflozin, represented by formula (11):

(11A) Remogliflozin etabonate, represented by formula (11A):

(12) a thiophene derivative of the formula (12)

wherein R denotes methoxy or trifluoromethoxy;

(13) 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene, represented by formula (13);

(14) a spiroketal derivative of the formula (14):

wherein R denotes methoxy, trifluoromethoxy, ethoxy, ethyl, isopropyl or tert-butyl;

(15) a pyrazole-O-glucoside derivative of the formula (15):

wherein

R 1 denotes C 1-3 -alkoxy,

L 1 , L 2 independently of each other denote H or F,

R 6 denotes H, (C 1-3 -alkyl)carbonyl, (C 1-6 -alkyl)oxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl or benzylcarbonyl:

(16) Sotagliflozin, represented by formula (16):

(17) Sergliflozin, represented by formula (17):

(18) a compound represented by formula (18):

wherein

R 3 denotes cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, 3-methyl-but-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethinyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy, difluoromethyloxy, trifluoromethyloxy, 2-methyloxy-ethyloxy, methylsulfanyl, methylsulfinyl, methlysulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano,

or a derivative thereof wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are acylated with groups selected from (C 1-18 -alkyl)carbonyl, (C 1-18 -alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C 1-3 -alkyl)-carbonyl;

(19) Bexagliflozin, represented by formula (19):

(20) Janagliflozin, represented by formula (20):

(21) Rongliflozin; and

(22) Wanpagliflozin.

13. The method according to claim 12 , wherein the at least one SGLT-2 inhibitor comprises Velagliflozin, represented by formula:

14. A method of decreasing the discomfort associated with udder engorgement of a non-human mammal, comprising administering to the non-human mammal at least one SGLT-2 inhibitor.

15. A method of decreasing milk leakage after drying-off of a non-human mammal, comprising administering to the non-human mammal at least one SGLT-2 inhibitor.

16. A method of decreasing an incidence of intra-mammary infections (IMI) in a non-human mammal, comprising administering to the non-human mammal at least one SGLT-2 inhibitor.

17. The method according to any one of claims 14 , wherein the at least one SGLT-2 inhibitor is selected from the group consisting of:

(1) a glucopyranosyl-substituted benzene derivative of the formula (1)

wherein R 1 denotes cyano, Cl or methyl;

R 2 denotes H, methyl, methoxy or hydroxy and

R 3 denotes cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, 3-methyl-but-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethinyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy, difluoromethyloxy, trifluoromethyloxy, 2-methyloxy-ethyloxy, methylsulfanyl, methylsulfinyl, methlysulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano,

or a derivative thereof wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are acylated with groups selected from (C 1-18 -alkyl)carbonyl, (C 1-18 -alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C 1-3 -alkyl)-carbonyl;

(2) Velagliflozin, represented by formula (2):

(3) Dapagliflozin, represented by formula (3):

(4) Canagliflozin, represented by formula (4):

(5) Empagliflozin, represented by formula (5):

(6) Luseogliflozin, represented by formula (6):

(7) Tofogliflozin represented by formula (7):

(8) Ipragliflozin, represented by formula (8):

(9) Ertugliflozin, represented by formula (9):

(10) Atigliflozin, represented by formula (10):

(11) Remogliflozin represented by formula (11):

(11A) Remogliflozin etabonate, represented by formula (11A):

(12) a thiophene derivative of the formula (12)

wherein R denotes methoxy or trifluoromethoxy;

(13) 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene, represented by formula (13);

(14) a spiroketal derivative of the formula (14):

wherein R denotes methoxy, trifluoromethoxy, ethoxy, ethyl, isopropyl or tert-butyl;

(15) a pyrazole-O-glucoside derivative of the formula (15):

wherein

R 1 denotes C 1-3 -alkoxy,

L 1 , L 2 independently of each other denote H or F,

R 6 denotes H, (C 1-3 -alkyl)carbonyl, (C 1-6 -alkyl)oxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl or benzylcarbonyl;

(16) Sotagliflozin, represented by formula (16):

(17) Sergliflozin, represented by formula (17):

(18) a compound represented by formula (18):

wherein

R 3 denotes cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, 3-methyl-but-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethinyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy, difluoromethyloxy, trifluoromethyloxy, 2-methyloxy-ethyloxy, methylsulfanyl, methylsulfinyl, methlysulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano,

or a derivative thereof wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are acylated with groups selected from (C 1-18 -alkyl)carbonyl, (C 1-18 -alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C 1-3 -alkyl)-carbonyl;

(19) Bexagliflozin, represented by formula (19):

(20) Janagliflozin, represented by formula (20):

(21) Rongliflozin; and

(22) Wanpagliflozin.

18. The method according to claim 14 , wherein the method of decreasing the discomfort associated with udder engorgement of a non-human mammal is increasing the daily lying time and/or reduction of stress.

19. The method according to claim 16 , wherein the intra-mammary infections (IMI) are mastitis and/or metritis.

20. A method of improving and/or facilitating the drying-off of a non-human mammal, comprising administering to the non-human mammal velagliflozin as a single SGLT-2 inhibitor, wherein velagliflozin is administered subcutaneously or intramuscularly, once only at start of drying-off or twice (24 h or 48 h apart) at a dose of 0.01 mg/kg bodyweight to 10 mg/kg bodyweight.

21. The method according to claim 20 , wherein the at least one SGLT-2 inhibitor is administered before, after or concomitantly with administering at least one feed supplement to the non-human mammal and/or before, after or concomitantly with a reduction in feed offered to the non-human mammal.

22. The method according to claim 21 , wherein the feed supplement comprises one or more acidifying agents selected from the group consisting of: ammonium chloride, calcium chloride and calcium sulfate.

23. The method according to claim 22 , wherein the feed supplement comprises 5% (w/w) to 15% (w/w) ammonium chloride, 40% (w/w) to 60% (w/w) calcium chloride and 15% (w/w) to 25% (w/w) calcium sulfate.

24. The method according to claim 22 , wherein the feed supplement comprises 10.4% (w/w) ammonium chloride, 51.9% (w/w) calcium chloride and 20.1% (w/w) calcium sulfate.

25. The method according to claim 20 , wherein the non-human mammal is a cow, a pregnant cow, and/or a lactating cow.