Use of non-therapeutic Anti-inflammatory molecules in pigs

Abstract

Disclosed is the non-therapeutic use of an anti-inflammatory compound in healthy, mastitis-free sows, for healthy piglets to gain weight when they are not affected by at least one of the symptoms consisting of pain, fever and inflammation.

Description

Use of anti-inflammatory molecules for non-therapeutic purposes in pigs

[0001] The present invention is in the field of livestock farming and is aimed more particularly at pig farming and relates, more specifically, to a method for improving the rearing conditions of pigs during their first months of life, after giving birth. State of the art [2]In pig farming, the weight heterogeneity of piglets in the same litter at weaning is detrimental to farm productivity, since heterogeneity in weaning weights translates into heterogeneity in weight at slaughter age. It is therefore necessary to feed piglets weaned at a low weight for a longer period to achieve their ideal weight at slaughter, or to slaughter them at a weight below their ideal weight, which impacts the performance of production farms. [3] It is known that the weight gain of each piglet is related to the position of the teat suckled by the piglet, the said piglet generally always suckling from the same teat until weaning, as recalled in the document cited as reference [1]. Piglets suckling from one of the posterior teats, also called the caudal teat, and more particularly the 6th and 7th pairs of teats, have a lower average weight than piglets suckling from one of the anterior teats, also called the cranial teats, as described in particular in reference [2]. In reference [5], studies aimed at showing that the quantity of milk produced is related to the position of the teat have shown lower milk production for pairs 6 and 7. Blood flow differs depending on the position of the teat, and caudal teats are smaller than cranial teats, which could explain the differences in weight gain. [4] Furthermore, the lack of uniformity in terms of weight gain is more pronounced in piglets born to primiparous sows, i.e., those nursing their first litter, than in other sows that have already farrowed several times, referred to as multiparous. This phenomenon appears to be observed worldwide in all pig breeds. The incidence of the number of farrowings The heterogeneity of piglet litter weights in sows is described, notably in reference [2]. The document cited in reference [3] describes greater milk production from the fore udders compared to the hind udders, particularly for sows having their first litter. Reference [4] studies the decline in milk production over time for sows giving birth for the first time, referred to as primiparous sows, compared to other sows that have given birth previously, referred to as multiparous sows. [5] On the other hand, the use of compounds with anti-inflammatory activity is known to treat mastitis in sows. Mastitis is an infection of the udder by bacteria that enter through the teat sphincter. This infection triggers an inflammatory reaction associated with an influx of white blood cells (or leukocytes) into the udder, which increases the number of somatic cells in the milk. This is a natural defense reaction against bacterial attack. The main bacteria involved are thought to be coliforms (Escherichia coli, Klebsiella sp., Enterobacer, and Citrobacter) and bacteria of the genera Staphylococcus and Streptococcus. [6] The use of a non-steroidal anti-inflammatory drug (NSAID), particularly tolfenamic acid, for the treatment of the condition known as mastitis, metritis and agalactia (MMA), which can occur during farrowing in sows and until weaning of piglets, is well known. MMA is often associated with syndromes known as Postpartum Dysgalactia Syndrome (PDS), which are described in connection with MMA in the referenced review [6]. Description of the invention [7] Definitions: [8]In the context of the present invention the term "primiparous" refers to sows giving birth for the first time. [9]The term “multiparous” describes sows that have already given birth one or more times previously, and that have a new litter of piglets.

[0010] The term "weight gain" describes the weight gain of an individual within a population of piglets over time.

[0011] The term "weaning period" refers to a time during which an individual begins to diversify their diet, that is, is no longer fed exclusively on sow's milk until the complete cessation of breastfeeding, which marks the end of the weaning period. In pigs, the end of the weaning period is defined as 28 days after birth according to European Directive 2008 / 120 / EC: this definition is chosen for the purposes of the present invention.

[0012] The acronym "GMD" is the abbreviation for average daily gain and corresponds to the weight gain in kilograms over a 24-hour period.

[0013] The term "caudal udder" refers to the pair of udders in the sow positioned closest to the animal's tail.

[0014] The term "cranial udder" refers to the pair of udders in the sow positioned closest to the animal's head.

[0015] The term "non-steroidal anti-inflammatory drugs" (NSAIDs) refers to medications with analgesic, antipyretic, and anti-inflammatory properties. Their known therapeutic indications in human and animal health aim to reduce pain, fever, and inflammation. The term "non-steroidal" is used to distinguish these anti-inflammatories from other anti-inflammatories known as steroids, such as glucocorticoids, commonly called corticosteroids, which belong to the class of molecules classified as steroids.

[0016] The term "intramammary" defines the introduction of a substance through the udder, into one or more teats, after emptying the udder and disinfecting the teat.

[0017] The term "transdermal" defines the delivery of a substance through the skin.

[0018] The present invention relates to a non-therapeutic use of an anti-inflammatory compound in healthy sows, not affected by mastitis, to promote weight gain in healthy piglets, not affected by at least one symptom among pain, fever, and inflammation.

[0019] The inventors have shown that administering an anti-inflammatory compound to multiparous and primiparous sows increases piglet weight gain, as measured by average daily gain (ADG), based on data collected and categorized according to the piglet's udder position (cranial or caudal). The data studied by the inventors also highlight a homogeneity of piglet weight from litter to weaning. The inventors demonstrated that not only were weight differences between piglets in the same litter reduced through the use of the anti-inflammatory drug, but also that the weight difference between piglets suckling in a caudal position and those suckling in a cranial position was significantly reduced, even becoming negligible. Thus, thanks to the use of an anti-inflammatory drug, regardless of the position of the udder used by the piglets, weight gain and final weaning weight were observed to be virtually identical across an entire litter.

[0020] Advantageously, the anti-inflammatory compound is a non-steroidal anti-inflammatory.

[0021] Advantageously, the anti-inflammatory compound is selected from at least one of the following molecules: tolfenamic acid, meloxicam, ketoprofen, flunixin and its meglumine salt, preferably the anti-inflammatory is tolfenamic acid (AT).

[0022] Tolfenamic acid (CAS number: 13710-19-5) is a contracyclic acid derivative belonging to the NSAID group, its chemical formula being:

[0023] Meloxicam (CAS number: 71125-38-7) is also an NSAID, its chemical formula being:

[0024] Ketoprofen (CAS number: 22071-15-4; racemic) is also an NSAID, its chemical formula being:

[0025] Flunixin (CAS number: 38677-85-9) is also an NSAID, its chemical formula being:

[0026] Alternatively, or in combination with the foregoing within the scope of the present invention, the anti-inflammatory compound advantageously has the following formula: in which the Ri and R2 groups are selected from a hydrogen and an alkyl, preferably a hydrogen; the R3, R4, Rs and Re groups are selected from a hydrogen; an alkyl, optionally substituted by, preferably a group selected from a methyl and an ethyl; and a halogen, preferably a chlorine; and in which the X group is a heteroatom, preferably a nitrogen.

[0027] The anti-inflammatory drug is preferably chosen from among those recommended for the treatment of mastitis, preferably mastitis present in the udders of a lactating sow. Even more preferably, the anti-inflammatory drug is an anti-inflammatory compound recommended for the treatment of mastitis, metritis, and agalactia (MMA).

[0028] Advantageously, the quantity of the anti-inflammatory, preferably tolfenamic acid, is greater than 0.5 mg per 20 kg of sow body mass, and preferably the quantity is 5 to 75 mg, advantageously it is 10 to 70 mg, more advantageously 20 to 60 mg, or even 30 to 50 mg per 20 kg of sow body mass.

[0029] The anti-inflammatory is preferably given to the healthy pregnant sow or the healthy lactating sow that is nursing the aforementioned piglets after farrowing in order to promote their weight gain.

[0030] Preferably, the anti-inflammatory compound is given for the weight gain of piglets suckling at least one teat in the caudal position of the sow nursing said piglets.

[0031] Advantageously, the anti-inflammatory compound is given for the weight gain of piglets at an early stage of their development, preferably intended for piglets over a period from the farrowing of said piglets to the end of the weaning period, and advantageously from the beginning of the weaning period to the end of the weaning period.

[0032] Advantageously, the anti-inflammatory compound is intended to be given by at least one route chosen from the oral, intramammary, injectable, or transdermal route; preferably the anti-inflammatory compound is given intramuscularly or transdermally. Experimental Results

[0033] The inventors unexpectedly noted that tolfenamic acid or AT (Tolfine® / Tolfedine®CS), along with three other anti-inflammatory compounds, used in postpartum sows of piglets, with the aim of treating suspected or confirmed PDS / MMA, had a positive effect on weight uniformity within the litter of piglets at weaning time.

[0034] To demonstrate the relevance of the observed effects, the inventors conducted tests under the experimental conditions described below.

[0035] Blinded, randomized trials were conducted in a modern pig farm, across several farrowing series. The compound was injected intravenously or intramuscularly into the sow more than 12 hours after farrowing. The quantities injected into a sow, based on a 20 kg body mass index, were: - 40 mg per 20 kg of body mass for tolfenamic acid; - 08 mg per 20 kg of body mass for meloxicam; - 60 mg per 20 kg of body mass for Ketoprofen.

[0036] Sows of all parities (primiparous, multiparous, and gilts) and body condition scores were randomly assigned to one group or the other. Piglets were individually identified using ear tags. The control group consisted of 20 multiparous sows, 20 primiparous sows, and 458 piglets, while the tolfenamic acid-treated group consisted of 21 multiparous sows, 20 primiparous sows, and 472 piglets. General farm management and routines were not altered. Given the large number of multiparous and primiparous sows and the batch management of the farm, cohorts were repeated weekly over a period of two and a half months. [371 METHOD]

[0038] The effect of the treatment on the number of piglets alive 2 days after farrowing, and then at weaning, was analyzed with the Mann-Whitney Wilcoxon test.

[0039] The effect of the treatment on the weight of piglets at weaning and the average daily weight gain was analyzed using a linear mixed model with treatment group, sex (male or female), maternal parity (primiparous or multiparous).

[0040] The critical probability known as "p-value" was set at 0.05 for all tests and models. [411RESULTS OBTAINED ACCORDING TO THE SUCKING POSITION OF THE PIGGETS

[0042] Average daily gain (ADG) is an indicator of animal growth used in animal husbandry; it represents the growth rate of an animal. animal. It is used in particular for monitoring performance in animal nutrition, mainly in livestock farms.

[0043] It is measured by operating as follows: the mass of the animal is recorded at the beginning, md, and at the end, mf (expressed in kg), over a period t (expressed in days); the ADG is then calculated:

[0044] The results on the measurement of ADG are obtained according to the groups, and also considering the position of suckling on the udder.

[0045] Position 1: anterior (cranial) nipple, position 2: posterior (caudal) nipple, all of these results are reported in Table 1. [461 Table 1 . : AT: tolfenamic acid; PS: Weaning weight; GMD: Average daily gain; N being the number of piglets; Std. Dev. being the statistical deviation between the lowest and highest values.

[0047] Results: The treated group achieved significantly higher weaned weights in both position 1 (p = 0.0337) and position 2 (p = 0.0008).

[0048] For piglets in position 1, the effect of the treatment on ADG is not significant (p = 0.6138) (comparison of values ​​(a) and (b)).

[0049] In contrast, for piglets in position 2, the ADG of the treated group was significantly better (p = 0.0051) (comparison of values ​​(c) and (d)).

[0050] No difference in GMQ was found between the two positions in the treated groups (p = 0.1050) (comparison of values ​​(b) and (d).

[0051] In contrast, in the control group, the GMQs in position 1 were significantly higher (p = 0.0458) compared to those in position 2 (comparison of values ​​((a) and (c).

[0052] Results :

[0053] Average daily gain (ADG) was significantly higher in piglets from sows treated with tolfenamic acid (p < 0.0001). Weaned weights, in absolute value, were also significantly higher in the treated group (on average 800g more).

[0054] Average daily gain (ADG) as a function of breastfeeding position:

[0055] In the group treated with AT, no significant difference was observed among piglets suckling on anterior teats compared to posterior teats (p = 0.1050).

[0056] In the control group, significant differences were found depending on their breastfeeding position.

[0057] Furthermore, when comparing the AT-treated group and the control group, the piglets' weaning weight gain was higher in both suckling positions in the AT-treated group compared to the control group. However, no statistically significant difference was observed in average daily gain (ADG) compared to the previous suckling positions of either group. References

[0058] The following list details the references cited earlier in the text:

[0001] Franci O. et al., Italian Journal Animal Science, 2002, 21:4, 281 -290 [2], Dyck, G.W, Can. J.Anim. Sci. 1987, 67, 929-939 [3], Fraser D. et al. Canadian Journal of Animal Science, 1986, 66, (1), https: / / cdnsciencepub.com / doi / 10.4141 / cjas86-005 [4] Craig, JR, 2019, Animais 9, 35 [5] Milligan BN, Livestock Production Science, 2002, 76(1), 181 -191 [6] Martineau G. P et al., Journal of Swine Health and Production, 2013, 21 (2), 85-93

Claims

DEMANDS 1. Non-therapeutic use of an anti-inflammatory compound in healthy sows, not affected by mastitis, for the weight gain of healthy piglets, not affected by at least one symptom among pain, fever, and inflammation.

2. Use according to claim 1, wherein the anti-inflammatory compound is a non-steroidal anti-inflammatory.

3. Use according to any one of claims 1 or 2, wherein the anti-inflammatory compound is selected from at least one of the following molecules: tolfenamic acid, meloxicam, ketoprofen, flunixin and its meglumine salt, preferably the anti-inflammatory is tolfenamic acid (AT).

4. Use according to claim 1 or 2, wherein the anti-inflammatory compound has the following formula: in which the Ri and R2 groups are selected from a hydrogen and an alkyl, preferably a hydrogen; the R3, R4, Rs and Re groups are selected from a hydrogen; an alkyl, optionally substituted by, preferably a group selected from a methyl and an ethyl; and a halogen, preferably a chlorine; and in which the X group is a heteroatom, preferably a nitrogen.

5. Use according to any one of claims 1 to 4, wherein the quantity of the anti-inflammatory is greater than 0.5 per 20 kg of sow body mass.

6. Use according to any one of claims 1 to 5, wherein the anti-inflammatory compound is given to the healthy pregnant sow or the healthy lactating sow that is nursing said piglets.

7. Use according to any one of claims 1 to 6, for the weight gain of piglets suckling at least one teat in the caudal position of the sow nursing said piglets.

8. Use according to any one of claims 1 to 7, for the weight gain of piglets over a period from the farrowing of said piglets to the end of the weaning period, and advantageously from the beginning of the weaning period to the end of the weaning period.

9. Non-therapeutic use according to any one of claims 1 to 9, wherein the anti-inflammatory compound is intended to be administered by at least one route selected from the oral, intramammary, injectable or transdermal route.

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