RU2846098C1 - Veterinary antiprolactin composition for ruminants, used by administration to mammary gland - Google Patents

Abstract

FIELD: agriculture; veterinary science.

SUBSTANCE: invention relates to agriculture and veterinary medicine and is a method for reducing milk production in dairy ruminants, comprising administering a veterinary composition comprising cabergoline to said dairy ruminant in the mammary gland. Introduction of cabergoline into mammary gland allows to prevent hypocalcemia in comparison with cabergoline applied intramuscularly, especially during first 24 hours after termination of milking.

EFFECT: invention increases bioavailability of cabergoline in ruminant animals.

10 cl, 7 dwg, 5 tbl, 2 ex

Description

The present invention relates to a veterinary composition and a method for reducing milk production in dairy ruminants in a more effective and safe manner, especially at the beginning of the dry period (i.e., abrupt cessation of milking). It consists in introducing the said composition into the mammary gland (IMM) during the start-up, i.e., after the last milking.

In dairy ruminants, lactation typically lasts between 5 and 20 months. In dairy cows, it is most often 10 months. After this lactation period, milking ceases, usually abruptly, and the dairy ruminant does not produce milk until calving, when the next lactation begins. This period between the cessation of milking and the next lactation, which usually occurs after parturition (or calving in cows), is known as the "dry period", and is usually approximately 2 months (i.e. 45-70 days) in dairy cows.

Although the dry period is necessary to ensure optimal milk production during subsequent lactation, this dry period requires several dietary changes and transitions to adapt to the physiological needs of an animal that is no longer producing milk. These dietary changes cause numerous physiological disturbances and stresses in ruminants. This dry period results in a metabolism in dairy ruminants that is very different from that observed during lactation. The transition from lactation to non-lactation status favors the outcome of the transient disturbance of homeostasis in dairy cows.

During the dry period, and more specifically during the first 24 hours after weaning, milk synthesis in the mammary gland continues, especially in lactating ruminants that have high milk production rates. Consequently, the need to transfer calcium from the blood to the milk in the udder continues during these first 24 hours. In addition, when the dry period begins, dairy farmers very often reduce the feed ration, which further reduces calcium intake and levels in the circulation. Furthermore, antiprolactin products that promote drying also have a known effect of reducing intestinal absorption of dietary calcium when given by the general parenteral route, such as intramuscularly (IM). All of this contributes to the increased risk of hypocalcemia during weaning.

Therefore, upon discontinuation, some dairy cows receiving the veterinary composition by the intramuscular route after the last milking may experience hypocalcemia for 24 hours after administration of the product. Hypocalcemia may in some cases cause the cow to become recumbent, which requires appropriate therapy by a veterinarian. A way to determine if dairy cows are experiencing hypocalcemia is to test their blood calcium concentrations during the first 1-2 days after the last milking. Dairy cows with blood calcium concentrations at or below 8.8 mg/dL (2.2 mmol/L), but without clinical signs, are considered subclinically hypocalcemic. This latter status is also considered unfavorable for the health of the cow, which may contribute to the further development of various metabolic disorders in the cow.

There is a need for a treatment that effectively reduces milk production so that the mammary gland quickly stops milk synthesis without excessive udder enlargement due to milk accumulation and stagnation. This will help to avoid negative impacts on the health of dairy cows. In fact, less udder enlargement is associated with reduced milk leakage, which is a high-risk factor for new mammary gland infections in dairy cows. It also reduces the cow's pain and discomfort during the day after weaning. Finally, it enhances mammary gland involution during the dry period, a key physiological process for the health and regeneration of the gland for the next lactation.

In veterinary medicine, prolactin inhibitor compositions such as ^Galastop® (cabergoline, Ceva Sante Animale) can be administered for the treatment of lactation during false pregnancy in females. They are also indicated for the cessation of milk production in ruminants. WO 2010040765 on behalf of the applicant describes the administration of anti-prolactin dopamine receptor agonist compounds such as cabergoline to ruminants during pregnancy to facilitate the cessation of lactation and promote mammary gland involution, in particular by intramuscular administration. However, such intramuscular administration of cabergoline may potentially cause hypocalcemia in dairy cows, in particular during the first 24 hours after administration with subsequent triggering for the reasons described in the previous sections.

The applicant has surprisingly found that the administration of a veterinary composition containing cabergoline to ruminants by intramammary administration during the start can more effectively reduce milk production. Surprisingly, intramammary administration of the veterinary compositions according to the present invention increases the bioavailability of cabergoline in ruminants, which allows for more satisfactory results in terms of effectiveness in terms of reducing milk production and/or reducing udder volume. In addition, and surprisingly, it has also been found that intramammary administration of cabergoline allows for the prevention and/or reduction of hypocalcemia compared to cabergoline administered intramuscularly, especially during the first 24 hours after milking has ceased.

The essence of the invention

The present invention relates to veterinary compositions containing cabergoline for use in reducing lactation or milk production in a dairy ruminant, wherein said composition is administered to dairy ruminants by intramammary administration, preferably during the dry period, i.e., during the start-up.

According to the present invention, the said compositions are administered into the mammary gland in effective therapeutic amounts, preferably during the onset of the dry period of dairy ruminants, to cause a decrease in milk production in dairy ruminants.

The compositions were administered by intramammary injection to dairy ruminants in a single treatment and/or in multiple treatments, preferably in a single treatment.

Furthermore, the administration of the veterinary compositions according to the present invention into the mammary gland does not affect the milk production capacity and/or milk quality of the ruminant animal during subsequent lactation.

The present invention also relates to kits for reducing milk production in dairy ruminants, comprising a veterinary composition as defined above and, optionally, means for administering cabergoline into the mammary gland.

In one aspect of the present disclosure, there is provided the use of cabergoline for the manufacture of a veterinary composition for reducing milk production in dairy ruminants, wherein said composition is administered to dairy ruminants into the mammary gland, preferably during the onset of the dry period.

In another aspect of the present description, a method for reducing milk production in dairy ruminants is provided, wherein a veterinary composition containing cabergoline is administered in a therapeutically effective amount to said ruminants into the mammary gland, preferably during the onset of the dry period.

Description of figures

Fig. 1: Milk production (l) during morning milking from D2 to D9 - cabergoline treatment during evening milking on D4 (arrow). Average value per group.

Fig. 2: Interteat perimeter (cm) from treatment day D0 to post-treatment day D9. Group average (control group: upper curve; treated cows: lower curve).

Fig. 3: Interteat perimeter delta (ITP) (cm) from treatment day D0 to D9 (+216 h) after treatment. Group average (control: upper curve; treated cows: lower curve).

Fig. 4: Mean and sd plasma concentration (pg/ml) - time (hour) profiles of intramammary administration of cabergoline.

Fig. 5: Mean and sd plasma concentration (pg/ml) - time (hour) profiles of intramuscular administration of cabergoline (comparative study).

Fig. 6A and 6B: mean (sd) blood Ca concentration (mmol/l) (graph A: control group “cont, gr.” cows versus IMM cabergoline-treated “cab. IMM” cows) and the difference from baseline (0 h) before treatment with time (hour) (graph B: control group “cont, gr.” cows versus IMM cabergoline-treated “cab. IMM” cows).

Fig. 7: Comparison of mean blood Ca concentrations as a function of time between different studies: IMM study (upper curve) and IM study (2 lower curves, called IM studies 1 and 2).

Detailed description of the invention

The term "dry period" includes the period of time between the last milking of a lactation and the next lactation of the subsequent lactation, which usually begins at parturition. The dry period usually lasts approximately 2 months, more specifically 56 to 70 days in dairy cows.

In the context of the present invention, the terms "last milking", "starting" or "stopping milking" may be used interchangeably. They correspond to the time of implementation of the dry period.

The present invention relates to veterinary compositions containing cabergoline for use in reducing milk production, wherein said composition is administered into the mammary gland of dairy ruminants, preferably during the dry period.

The present invention also relates to a veterinary composition containing cabergoline, administered into the mammary gland in a single treatment and/or in multiple treatments, preferably during the dry period, for use in order to reduce milk production.

The compositions used according to the present invention also make it possible to reduce milk production, to cause involution of the mammary gland in ruminants, thereby avoiding infections or inflammations of the mammary gland.

Moreover, it is interesting to note that such intramammary administration of the compositions of the present invention allows for improved bioavailability of cabergoline in ruminants, allowing for a lower dose of cabergoline to be administered compared to intramuscular administration while obtaining similar results and/or efficacy, or allowing for a dose of cabergoline to be administered similar to the dose of cabergoline administered intramuscularly while obtaining higher results and/or efficacy.

Moreover, the inventors note with surprise that the veterinary composition containing cabergoline, which is administered into the mammary gland, also allows to prevent or reduce hypocalcemia in ruminants during the dry period, especially during the first 24 hours after cessation of milking, compared to cabergoline administered IM.

If the said compositions are administered into the mammary gland of ruminants during the dry period, they allow to maintain the calcium concentration in the blood of ruminants higher than or equal to 2.1 mmol/l or preferably 2.2 mmol/l, even without any specific diet and more particularly even without any feeding regimen aimed at maintaining a satisfactory calcium concentration in the blood of ruminants (for example, feeding with an appropriate amount of magnesium and a balance of these feeding regimens to obtain DCAD). Thus, the compositions used according to the present invention prevent the development of hypocalcemia or reduce the risk of developing hypocalcemia, especially during the first 24 hours after starting, i.e., if the risk of developing hypocalcemia is high when using cabergoline by IM.

The present invention also relates to a method for reducing milk production in dairy ruminants, which comprises administering veterinary compositions to the ruminant animal in accordance with an effective therapeutic regimen, preferably during the dry period, into the mammary gland.

Preferably, said veterinary compositions are administered to dairy cows.

The veterinary compositions for use according to the present invention are administered into the mammary gland, more particularly during the start-up after the last milking. In a particular embodiment, the veterinary compositions are administered into the mammary gland, preferably after the last milking and more preferably during the first 5, first 4 or first 2 hours after the last milking, preferably during the first 30 minutes (for example 15-20 minutes) after the last milking.

The veterinary compositions and methods according to the present invention are attractive to farmers because their use is simple to implement, which allows for rapid cessation of milk production in the mammary glands without causing an increase in the udder. They can also maintain a satisfactory concentration of calcium in the blood, without causing concern about a specific increase in the concentration of calcium in the blood compared to the concentration when using cabergoline IM. The treatment according to the present invention leads to simplification of herd management and savings in the cost of treating diseases when lactation is resumed. Thus, the administration of the compositions according to the present invention allows for better management of feeding programs during the dry period.

Cabergoline, whose chemical name is N-[3-(dimethylamino)propyl]-N-[(ethylamino)carbonyl]-6-(2-propenyl)-8g-ergoline-8-carboxamide, is an antiprolactin compound-agonist specific for D2 dopamine receptors. Specifically, it is described in U.S. Patent No. 4,526,892. Its chemical structural formula is as follows:

Cabergoline is the active ingredient in the medicinal products for human use sold under the names Dostinex ^® and Cabaser ^® . In addition, it is the main active ingredient in the veterinary compositions sold under the name Galastop ^® , for females prone to lactation in pseudopregnancy. Neither of these cabergoline-based compositions, Dostinex ^® or Galastop ^® , are administered into the mammary gland.

Effective amounts or therapeutic doses of cabergoline administered according to the present invention may vary depending on the species of ruminant animals to be treated. Dosages, also referred to as therapeutic regimens, can be readily determined by systematic testing based on the examples below and are within the capabilities of those skilled in the art. According to a specific embodiment of the present invention, effective therapeutic doses according to the present invention are from 1 to 50 μg/kg, or from 5 to 50 μg/kg, preferably from 5 to 11 μg/kg, and more preferably from 6 to 9 μg/kg.

More preferably, the amount of cabergoline administered into the mammary gland is from 0.25 to 7 mg, preferably from 0.3 to 6 mg, and more preferably 1-6 mg per lactating ruminant.

More preferably, the amount of cabergoline administered into the mammary gland is from 2 to 7 mg, preferably from 3 to 6 mg, and more preferably 5-6 mg per dairy cow.

According to a specific embodiment, the amount of cabergoline administered into the mammary gland is from 2 to 4 mg, preferably from 3 to 3.5 mg per dairy ruminant, and preferably per dairy cow.

According to the present invention, the term "ruminant animals" refers to herbivorous mammals such as, for example, cattle, sheep, goats, camelids or bovids. The compositions according to the present invention are administered to milk-producing (or dairy) ruminant mammals, preferably such as dairy cows, sheep and goats, and more preferably dairy cows.

It is an advantage that the veterinary compositions of the present invention can be administered together with standard means for the treatment and/or prevention of inflammations of the mammary gland and infections of the mammary gland (such as mastitis) in ruminants. Examples of standard therapeutic or prophylactic compositions for mastitis are local disinfectants for the udder, antibiotics such as penicillins, cephalosporins, gentamicin or teat sealants.

As mentioned above, hypocalcemia is caused by a temporary deficiency of calcium in the blood, which usually occurs during parturition when lactation is resumed, but can also occur at other times, especially during the first 48 hours, and more often during the first 24 hours, after the start of ruminant mammals producing milk, after the administration of cabergoline by the IM route. According to a particular embodiment of the present invention, the prevention and/or reduction of hypocalcemia in a dairy ruminant animal refers to a treatment in which the ruminant animal presents or achieves a satisfactory concentration of calcium in the blood, which is greater than or equal to 2.1 mmol/l, preferably 2.2 mmol/l.

Veterinary compositions are administered by administration into the mammary glands. For this purpose, the veterinary composition is administered into one or more quarters of the mammary glands by administering the composition by infusion, implantation, injection or a combination thereof. Administration is usually carried out through the teat canal by infusion into the mammary gland. Implantation can be in the form of a solid, paste, gel or suspension. The infusion or injection described in the present invention can be carried out by bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage form, for example, in ampoules or in multi-dose containers with an optionally added preservative. The compositions can be suspensions, solutions or emulsions in oily or aqueous carrier media.

Preferably, the composition is administered to one or more, preferably all, quarters of the mammary gland of a ruminant animal. For example, in a dairy cow, it is administered to 1, 2, 3 or 4 quarters, preferably all 4 quarters of the udder.

Depending on the compositions of the compositions used, they may additionally include ingredients commonly used in pharmacy for the preparation of liquid or solid compositions for administration into the mammary gland.

Also, the compositions according to the present invention may contain, depending on the type of formulations, a solvent, a glidant, a lubricant and any auxiliary substance of suitable mass, such as lactose, cellulose or starch. Stearic acid, magnesium stearate, L-leucine or, for example, glycerol tribehenate may be used as a lubricant. Sodium carboxymethylamidon, cross-linked sodium carboxymethylcellulose or cross-linked polyvinylpyrrolidone may be used as a disintegrant. Pure silicon dioxide or colloidal silicon dioxide may be used as glidants. Solid oral forms may be in the form of coated tablets.

The injectable preparations are prepared by mixing an effective therapeutic amount of at least one antiprolactin compound as described above with a solvent, a pH adjuster, a buffering agent, a suspending agent, a solubilizing agent, a stabilizer, a tonicity adjuster and/or a preservative, and converting the mixture into a subcutaneous or intramuscular injection according to a conventional method. As the solvent, dimethyl sulfoxide (DMSO), oily solvents such as medium-chain triglycerides, or a mixture of capric acid, caprylic acid and triglycerides sold under the name ^Mygliol® 812 can be mentioned. If necessary, the injectable preparations can be lyophilized according to a conventional method. Examples of suspending agents include methylcellulose, polysorbate 80, hydroxyethylcellulose, xanthan gum, sodium carboxymethylcellulose and polyethoxylated sorbitan monolaurate. Examples of solubilizing agents include polyoxyethylene hardened castor oil, polysorbate 80, nicotinamide, polyethoxylated sorbitan monolaurate, macrogol, and ethyl ester of castor oil fatty acid. In addition, stabilizers include sodium sulfite, sodium metasulfite, and ether, while preservatives include methyl para-hydroxybenzoate, ethyl para-hydroxybenzoate, sorbic acid, benzyl alcohol, phenol, cresol, and chlorocresol. An example of a tonicity regulator is mannitol.

The present invention further relates to a kit for veterinary use, more particularly for reducing milk production in dairy ruminants. The kits according to the present invention comprise at least one compartment for optionally sterile packaging, which comprises an effective therapeutic amount of cabergoline, as described above, for administration into the mammary gland of ruminants. The kit may also comprise means for administering the composition by administration into the mammary gland, and/or instructions regarding the method and time of administration of the veterinary compositions or drugs according to the present invention.

All embodiments described above for the composition and use of said composition are also applicable to the kit and method of the present invention.

Examples are provided below. These examples are illustrative and in no way limiting.

EXAMPLES

Example 1: Effect of intramammary (IMM) administration of cabergoline on milk production in a dairy cow (continued milking context)

The cabergoline composition is a solution containing cabergoline with dimethyl sulfoxide and medium chain triglyceride as excipients. It corresponds to the product named Velactis™ (cabergoline 1.12 mg/ml).

The study included 5 lactating cows of the Prim'holstein breed with the following characteristics:

- Multiple pregnancy: parity from 2 to 4,

- Daily milk yield (l): 17.4+/- 2.8,

- Days with milk (s): 251+/-51,

- Body weight (kg): 686+/-29.

Cabergoline was administered as an oily solution as described above into the mammary gland using a catheter inserted into the teat canal and fitted onto the tip of a syringe containing the solution. A volume of 10 ml was directly injected into the udder cistern of each quarter. Velactis™ (cabergoline 1.12 mg/ml) was diluted with the excipient immediately before administration according to the dose to be studied.

The cows were milked twice a day, in the morning and in the evening, at approximately 07:00 and 05:00 pm, respectively.

Milk production (morning milking) was measured during the day before (baseline) and after treatment. In the D0 study, 3/5 cows were treated with adjuvant only and it was shown that the adjuvant had no effect on milk production.

The 5 cows were treated with a dose of 1.34 mg/quarter in all 4 quarters (total dose 5.4 mg/cow, corresponding to ~7.5 μg/kg based on kg body weight) after the evening milking (D4), i.e., 15-20 minutes after the end of milking.

At the next morning milking (D5), all 5 cows showed a sharp decrease in milk production by an average of minus 6 l, which represents an average decrease of -54% (sd=10, min-38%, max-62%) compared to the initial milk production value (from D2 to D4). Then, during the following days, milk production gradually increased (about -15% of the initial value 3 days after treatment), see Fig. 1.

These results obtained by the IMM route compared favourably with the IM (intramuscular) route results obtained from another study conducted previously. This previous study tested different IM doses to establish a dose-response relationship of cabergoline on the reduction of milk production. The results obtained are presented below:

Extrapolation of the dose-response relationship with an IM dose of 7.5 μg/kg yielded the predicted effect of reducing milk production by -43%. This result was confirmed by another study (field study, n=106) where a reduction in milk production of approximately -40% was found for treated cows compared to negative control cows.

Thus, it was concluded that cabergoline administered by the IMM route at a dose of 1.34 mg/quarter in all four quarters exhibited a superior effect on reducing milk production compared to a similar total dose of 5.6 mg/cow (i.e., ~75 mcg/kg) administered by the IM route, which is the licensed dose for Velactis™. This superior effect was similar to that observed with the higher IM dose of cabergoline (12 mcg/kg). However, such a high dose (12 mcg/kg) by the IM route has not actually been used in ruminants. This conclusion was also supported by the pharmacokinetic results obtained in the study described below, which demonstrated a proportionality of the effect on reducing milk production depending on the systemic exposure of cabergoline (see Example 2.2). Moreover, the reduction in milk production obtained by IMM was more reliable and reproducible, as the sd, min and max values were less scattered compared to those obtained by IM.

Example 2. Pharmacokinetics of cabergoline by IMM and effects on udder enlargement and blood calcium concentrations during start-up in dairy cows

Ten lactating cows (9 Prim'holstein and 1 Brown Swiss) were included in this study. The cows were divided into two groups:

- Negative control group (n=5): no treatment at D0 start,

- Test group (n=5): IMM cabergoline treatment at D0 start after last milking (1.34 mg/quarter in all 4 quarters - same methods as in example 1).

There were no feed restrictions during the 3 weeks preceding and following D0 start. Animals had free access to water and hay throughout the study. Each cow was fed 7 kg/day of antibiotic-free lactating cow concentrate feed prior to D0 start. After start-up, each cow was fed 7 kg/day of antibiotic-free growth concentrate. The concentrate composition is as follows:

When D0 was launched, milking was abruptly stopped.

Interteatal perimeter (ITP) was considered as an index of udder volume and gain and was measured before udder treatment, before and after milking, and then uniformly after treatment up to 9 days post-treatment.

Blood was drawn and cabergoline and calcium concentrations were assessed at various time points: before treatment and no earlier than 6 days after treatment for cabergoline, and no earlier than 3 days after treatment for calcium.

2.1 Effect on ITP (udder enlargement):

As shown in Fig. 2, the ITP of treated cows increased less than that of the control group during the first 48 hours after treatment and was always lower than that of the control group during the post-start observation.

The results are also clear when expressed as the difference in ITP (AITP), i.e., calculated by subtracting the ITP value after milking on D0 from the ITP value at each time point after run-in, as shown in Fig. 3.

Such ITP delta results obtained by IMM are in the same efficiency range or slightly better than those obtained by IM.

In another study with the same total dose by IM route and under similar experimental conditions, the delta ITP results obtained can be compared with the IMM results as follows:

2.2 Cabergoline blood concentrations

Following intramammary (IMM) administration of 5.4 mg/udder cabergoline, the mean and sd plasma concentration-time profiles of cabergoline were shown in Fig. 4.

In a comparative study, cabergoline (Velactis™, 1.12 mg/mL) administered intramuscularly at an equivalent dose (5.6 mg/cow) showed plasma concentration-time profiles as shown in Fig. 5 (comparative study).

The pharmacokinetic parameters of both studies were compared in the following table:

AUCo-inf: area under the plasma drug concentration versus time curve from zero to infinity;

Cmax: observed maximum concentration of drug;

Tmax: time at which St was observed;

MRT: mean residence time of the drug in the plasma compartment;

Sd: standard deviation;

It can be concluded that at an equivalent dose of 5.4 mg/cow (~7.5 μg/kg), the bioavailability of cabergoline in blood is higher when administered IMM than by the IM route, as determined by the ratio AUC _{IMM route} /AUC _{IM route} of approximately 1.9.

It is interesting to note that in the dose-response study as described in Example 1, the AUCo-inf are as follows:

Together, these RC results showed good linear proportionality between cabergoline doses (ranging from 1.33 to 12 μg/kg) and their AUC, and hence between AUC and the effect of cabergoline on reducing milk production. The dose effect of 7 to 8 μg/kg by the IMM route was also shown to be equivalent to that of 12 μg/kg by the IM route, and accounted for the superior observed effect compared with 7 to 8 μg/kg by the IM route.

It was concluded that IMM routes represent a way to improve the efficacy of cabergoline compared to the parenteral (IM) route.

2.3 Blood calcium concentration

Compared to cows in the control group (i.e., without cabergoline treatment, see animal characteristics, example 2), cows treated with cabergoline via IMM showed only a slight decrease in blood calcium concentration (-0.2 mmol/l on average) and this was limited to the +6 hour time point only. No decrease was observed at the time point before (+3 h) or after (+12 h, +24 h and beyond).

Figures 6A-6B show the time course of blood calcium concentrations in both groups. These results are unexpected when compared with the blood calcium concentrations following cabergoline treatment by the IM route at the same total dose (5.6 mg/cow), and in addition, the IMM route resulted in higher systemic exposure than the IM route, as explained above (Note 2.2).

In studies previously conducted using a dose of 5.6 mg/dose of cabergoline IM, a more significant reduction in blood calcium levels in time and degree was observed. These studies were conducted in comparison with a negative control group, and the reduction in blood calcium levels was monitored and clearly detected: A reduction in calcium levels was observed as early as 2-3 hours after treatment, a maximum of 6-12 hours, and it returned to normal after 24 hours.

Figure 7 shows the difference in mean blood calcium levels relative to baseline values before treatment as a function of time between the IMM study (upper curve), as described in detail above, and the IM studies (2 lower curves, called IM studies 1 and 2 in the legend to Fig. 7).

It is important to note that the benefit in terms of a smaller decrease in blood calcium concentration was obtained in the Example 2 study despite the lower amount of dietary calcium compared with the IM studies 1 and 2. In these latter 2 IM studies, 150 g calcium/day/cow was provided in a total or part mixed ration, whereas in the IMM study of Example 2 only 50 g calcium was supplied via concentrate (7 kg/day/cow at 0.7% Ca) and the remainder via hay, which was given ad libitum. Although the exact amount of Ca supplied by the hay was unknown, it was certainly less than in the 2 IM studies because

i) the calcium content of hay is usually lower than that of concentrates, typically around 0.3%,

ii) the actual dry matter intake of hay can be estimated at approximately 13-15 kg for the cows included in Example 2.

The amount of calcium supplied can be estimated at 100 g/s/cow in Example 2, which is clearly less than the 150 g calcium in the two IM studies (the two lower curves, labeled IM studies 1 and 2 in Fig. 7).

Administration of cabergoline via the IMM route had a surprising ability to disrupt calcium homeostasis less in dairy cows compared to the IM route at the same dose, and even in the context of less stringent dietary calcium recommendations.

Therefore, administration of cabergoline by the IMM route has a better safety profile with regard to the risk of cow recumbency due to any hypocalcemia associated with cabergoline treatment, while maintaining the same or better efficacy compared to the IM route (according to the IMM dose chosen for administration) for starter dairy cows.

In conclusion, the IMM route represents a way to improve the safety and efficacy of cabergoline for starting dairy cows compared to the known IM route for this indication. IMM administration of cabergoline allows for a more effective reduction in milk production than the IM route, which is explained by the higher bioavailability of cabergoline in the blood. IMM administration of cabergoline also allows for the prevention of hypocalcemia in ruminants during the dry period, and more specifically immediately after starting (particularly during the first 24 hours after the last milking).

Claims (10)

1. A method for reducing milk production in dairy ruminants, comprising administering a veterinary composition containing cabergoline into the mammary gland of said dairy ruminant. 2. The method according to item 1, characterized in that the said composition is introduced during the dry period. 3. The method according to claim 1, characterized in that said composition is introduced during start-up, after the last milking, preferably during the first 5, first 4 or first 2 hours after the last milking. 4. The method according to any one of paragraphs. 1-3, characterized in that the therapeutic dose of cabergoline is from 1 to 50 mcg/kg or from 5 to 50 mcg/kg, from 5 to 11 mcg/kg or more, from 6 to 9 mcg/kg. 5. The method according to any one of paragraphs 1-4, characterized in that said administration is carried out into one or more quarters of the mammary gland by means of infusion, implantation, injection or a combination thereof. 6. The method according to any one of paragraphs 1-5, characterized in that the said composition is administered into all quarters of the mammary gland of a ruminant animal. 7. The method according to any one of claims 1 to 6, characterized in that the amount of cabergoline that is administered into the mammary gland is from 0.25 to 7 mg, from 0.3 to 6 mg, and more particularly 1 to 6 mg per dairy ruminant. 8. The method according to any one of claims 1 to 7, characterized in that the amount of cabergoline that is administered into the mammary gland is from 2 to 7 mg, from 3 to 6 mg, and more specifically from 5 to 6 mg per dairy cow. 9. The method according to any one of paragraphs 1-8, characterized in that the ruminants are herbivorous mammals selected from cattle, sheep, goats, camels or bovids. 10. The method according to any one of claims 1 to 9, characterized in that the ruminants are ruminant mammals that produce milk, preferably dairy cows, sheep or goats, and more preferably dairy cows.