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

Abstract

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

Description

Title of the invention: Use of anti-inflammatory molecules for non-therapeutic purposes in pigs

[0001] The present invention is in the field of livestock breeding and is aimed more particularly at pig breeding and relates, more particularly, to a method intended to improve the breeding conditions of pigs during their first months of life, after farrowing. State of the art

[0002] In pig farms, the heterogeneity in the weight of piglets from the same litter on the day of servitude is detrimental to the performance of a breeding operation, since the heterogeneity in weaning weights translates into heterogeneity in weight at slaughter age. It is therefore necessary to feed weaned piglets at a low weight for longer to obtain their ideal weight at the time of slaughter or to slaughter them at a weight lower than the ideal weight, which impacts the performance of production farms.

[0003] It is known that the weight gain of each piglet is related to the position of the udder suckled by the piglet, said piglet generally always suckling the same udder until weaning, as recalled in the document cited as reference [1]. Piglets suckling one of the posterior udders, also called the caudal udder, and more particularly the 6th and 7th pairs of udders, have a lower average weight than piglets suckling one of the anterior udders, also called the cranial udder, as described in particular in reference [2]. In reference [5], studies aimed at showing that the quantity of milk produced is linked to the position of the udder have shown lower milk production for pairs 6 and 7. Blood flow is different depending on the position of the udder and the caudal udders are smaller than the cranial udders, which could explain the differences in weight gain.

[0004] Furthermore, the lack of homogeneity 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 given birth several times, referred to as multiparous. Such a phenomenon seems to be observed everywhere on the planet in all pig breeds. The impact of the number of farrowings per sow on the heterogeneity of the weight of piglet litters is described, in particular in reference [2]. The document cited in reference [3] describes a higher milk production from the anterior udders in comparison with the posterior udders, in particular for sows having their first litter. Reference [4] studies the decline in milk production over time for sows giving birth for the first time, called primiparous sows, in comparison with other sows that have given birth, called multiparous.

[0005] 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 aggression by bacteria. The main bacteria involved are thought to be coliforms (Escherischia coli, Klebsiella sp. Enterobacer and Citrobacter) and bacteria of the genera Staphylococcus and Streptococcus.

[0006] The use of a nonsteroidal anti-inflammatory drug (NSAID), in particular tolfenamic acid, for the treatment of the pathology called mastitis, metritis and agalactia (MMA) which can occur during the farrowing of sows and until the weaning of piglets, is known. MMA is often associated with syndromes called Postpartum Dysgalactia Syndrom (PDS) which are described in connection with MMA in the review in reference [6]. Description of the invention

[0007] Definitions:

[0008] In the context of the present invention, the term “primiparous” describes sows giving birth for the first time.

[0009] The term "multiparous" describes sows that have already given birth one or more times previously, and who have a new litter of piglets.

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

[0011] The term "weaning period" describes a period during which an individual begins to diversify its diet, i.e. is no longer fed solely on sow's milk, until the total interruption of breastfeeding which marks the end of the weaning period. In pigs, the end of the weaning period is defined as being at the age of 28 days after birth according to European Directive 2008 / 120 / EC: in the context of the present invention, this definition is chosen.

[0012] The acronym “GMQ” 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" corresponds to the pair of udders in the sow positioned closest to the animal's tail.

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

[0015] The term "nonsteroidal anti-inflammatory drugs" (NSAIDs) describes drugs 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 "nonsteroidal" is used to distinguish these anti-inflammatories from other so-called steroidal anti-inflammatories, namely glucocorticoids, commonly called corticosteroids, which belong to the chemistry of molecules called steroids.

[0016] The term "intramammary" defines the supply 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 suffering from mastitis, to promote the weight gain of healthy piglets, not suffering from at least one symptom among pain, fever, and inflammation.

[0019] The inventors have shown that the administration of an anti-inflammatory compound to multiparous and primiparous sows increases the weight gain of the piglets, measured by the average daily gain (ADG) from data recorded and classified according to the position of the udder used by the piglet (cranial or caudal). The data studied by the inventors also highlight a homogeneity of weight of the piglets from the litter to weaning. The inventors have demonstrated that not only were the differences in weight between the different piglets of the same litter attenuated thanks to the use of the anti-inflammatory, but also that the difference in weight between the piglets which suckle the udders in the caudal position and those which suckle the udders in the cranial position were greatly attenuated, or could even be considered non-existent.Thus, thanks to the use of an anti-inflammatory, regardless of the position of the udder used by the piglets, it was possible to observe a weight gain and a final weight at weaning which was almost 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 (TA).

[0022] Tolfenamic acid (CAS number: 13710-19-5) is a derivative of contracyclic acid which belongs to the group of NSAIDs, 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 above within the scope of the present invention, the anti-inflammatory compound advantageously has the formula:

[0027] wherein the groups R1 and R2 are selected from hydrogen and alkyl, preferably hydrogen; the groups R3, R4, R5 and R6 are selected from hydrogen; alkyl, optionally substituted by, preferably a group selected from methyl and ethyl; and halogen, preferably chlorine; and in which the group X is a heteroatom, preferably nitrogen.

[0028] The anti-inflammatory is preferably chosen from anti-inflammatories recommended in the treatment of mastitis, preferably mastitis present on the udders of a lactating sow. More preferably, the anti-inflammatory is an anti-inflammatory compound recommended in the treatment of mastitis of the mastitis, metritis and agalactia (MMA) type.

[0029] Advantageously, the amount of the anti-inflammatory, preferably for tolfenamic acid, is greater than 0.5 mg per 20 kg of body mass of the sow, and preferably the amount 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 body mass of the sow.

[0030] the anti-inflammatory is preferably given to the healthy pregnant sow or the healthy lactating sow which is suckling the above-mentioned piglets following farrowing with a view to their weight gain.

[0031] Preferably, the anti-inflammatory compound is given for the weight growth of piglets suckling at least one udder in the caudal position of the sow which is suckling said piglets.

[0032] 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 ranging from the farrowing of said piglets to the end of the weaning period, and advantageously ranging from the start of the weaning period to the end of the weaning period.

[0033] Advantageously, the anti-inflammatory compound is intended to be given by at least one method chosen from oral, intramammary, injectable, or transdermal routes, preferably the anti-inflammatory compound is given intramuscularly or transdermally. Experimental Results

[0034] The inventors unexpectedly noted that tolfenamic acid or AT (Tolfine® / Tolfedine®CS), along with three other anti-inflammatory compounds, when used in mothers of postpartum piglets, with the aim of treating suspected or confirmed PDS / MMA, had a positive effect on weight uniformity within the litter of weaning piglets.

[0035] To demonstrate the relevance of the observed effects, the inventors conducted tests under the experimental conditions described below.

[0036] Blinded and randomized trials were carried out in a modern breeding facility, on several series of farrowings. The compound is injected intravenously or intramuscularly, into the sow more than 12 hours after farrowing. The quantities injected into a sow, taking as reference 20 kg body mass slices for the sow are: - 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.

[0037] Sows of all parities (primiparous and multiparous and gilts) and all body indices were randomly assigned to one or the other group. 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. The management and general routine of the farm were not changed. Given the large number of multiparous dams and primiparous sows, and the batch management of the farm, the cohorts were repeated weekly, over a period of two and a half months.

[0038] METHOD

[0039] The effect of treatment on the number of live piglets 2 days after farrowing, then at weaning, was analyzed with the Mann-Whitney Wilcoxon test.

[0040] The effect of treatment on piglet weight at weaning and average daily weight gain was analyzed using a linear mixed model with treatment group, sex (male or female), maternal parity (primiparous or multiparous).

[0041] The critical probability known as "p-value" was set at 0.05 for all tests and models.

[0042] RESULTS OBTAINED AS A FUNCTION OF THE PIGLETS' NURSING POSITION

[0043] Average daily gain or GMQ is an indicator of animal growth used in zootechnics, it is translated from the Anglo-Saxon expression "average daily growth" or ADG. It represents the growth rate of an animal. It is used in particular to the monitoring of animal nutrition performance, mainly in livestock farms.

[0044] It is measured by operating in the following manner: the mass of the animal is recorded at the beginning, md, and at the end, mf (expressed in kg), of a period t (expressed in days); the GMQ is then calculated: GMQ =

[0045] The results on the GMQ measurement are obtained according to the groups, and also considering the position of the suckling on the breast.

[0046] Position 1: anterior nipple (cranial), position 2: posterior nipple (caudal), all of these results are reported in table 1.

[0047] Table 1, : Position AT Number of piglets Measurement carried out N value obtained in kilograms Std Dev Minimum Maximum Cranial(l) control 19 PS GMQ 19 19 5.6105263 0.1997915(3) 0.6785399 0.0437027 4.8000000 0.1223077 6.8000000 0.2694737 treated 20 PS GMQ 18 18 6.5044444 0.2125410(b) 1.1135857 0.0533209 5.0000000 0.1075000 9.4000000 0.3011111 Caudal(2) control 21 PS GMQ 20 20 5.3655000 0.1729155(0) 0.7513180 0.0473211 3.8200000 0.0569231 6.5000000 0.2533333 treated 20 PS GMQ 16 16 6.7625000 0.2391685(3) 1.0097359 0.0493209 5.2200000 0.1500000 8.4400000 0.3136842 AT: tolfenamic acid; PS: weaning weight; GMQ: average daily gain; N being the number of piglets; Std. Dev. being the statistical deviation between the lowest and highest values.

[0048]

[0049] Results: The treated group obtained significantly higher weaned weights both in position 1 (p = 0.0337) and in position 2 (p = 0.0008).

[0050] For piglets in position 1, the effect of treatment on GMQ is not significant (p = 0.6138) (comparison of values ​​(a) and (b)).

[0051] On the other hand, for piglets in position 2, the GMQ of the treated group was significantly better (p = 0.0051) (comparison of values ​​(c) and (d)).

[0052] No difference in GMQ was found between the two positions in the treated groups (p = 0.1050) (comparison of values ​​(b) and (d).

[0053] In contrast, in the control group, GMQs in position 1 were significantly higher (p = 0.0458) compared to those in position 2 (comparison of values ​​((a) and (c).

[0054] Results:

[0055] The GMQ is significantly higher in piglets from mothers treated with tolfenamic acid (p <0.0001). Weaned weights, in absolute value, are also significantly higher in the treated group (on average 800g more).

[0056] GMQ as a function of the feeding position:

[0057] In the AT-treated group, no significant difference was observed among piglets suckling on the anterior teats compared to the posterior teats (p = 0.1050).

[0058] In the control group, significant differences were found depending on their feeding position.

[0059] Furthermore, when comparing the AT-treated group and the control group, the evolution of the weaned weight of the piglets was higher in both suckling positions in the AT-treated group compared to the control group. However, no statistical difference was observed on the GMQ compared to the previous positions of the two groups. References

[0060] The following list details the references cited previously in the text: [1] Franci O. et al., Italian Journal Animal Science, 2002, 21:4, 281-290

[0061] [2], Dyck, G. W„ Can. J. Anim. Sci. 1987,67,929-939

[0062] [3].Fraser D. et al. Canadian Journal of Animal Science, 1986, 66, (1), https: / / cdnsciencepub.com / doi / 10.4141 / cjas86-005

[0063] [4] Craig, J. R., 2019, Animais 9, 35

[0064] [5] Milligan B. N., Livestock Production Science, 2002, 76(1), 181-191

[0065] [6] Martineau G.P et al., Journal ofSwine Health and Production, 2013, 21(2), 85-93

[0066]

[0067]

Claims

Claims

1. Non-therapeutic use of tolfenamic acid in healthy sows, not suffering from mastitis, for the weight gain of healthy piglets, not suffering from at least one symptom among pain, fever, and inflammation.

2. Use according to claim 1, wherein the amount of tolfenamic acid is greater than 0.5 per 20 kg of body weight of the sow.

3. Use according to one of claims 1 or 2, wherein the tolfenamic acid is given to the healthy pregnant sow or the healthy lactating sow which is suckling said piglets.

4. Use according to one of claims 1 to 3, for the weight growth of piglets suckling at least one udder in the caudal position of the sow which suckles said piglets.

5. Use according to one of claims 1 to 4, for the weight growth of piglets over a period extending from the farrowing of said piglets to the end of the weaning period, and advantageously extending from the start of the weaning period to the end of the weaning period.

6. Non-therapeutic use according to one of claims 1 to 5, in which the tolfenamic acid is intended to be given by at least one route chosen from oral, intramammary, injectable or transdermal.