BE1028307B9 - Complementary animal feeds including GABA, 5-HTP and targeted cofactors - Google Patents

Abstract

The present invention relates to a formulation in the form of complementary foods for animals, in the form of cachets, capsules, granules, liquid (to be diluted or ready-to-use drink) or supplemented foods, comprising GABA and/or associated with 5-HTP in addition to the cofactors: Arginine, Magnesium and Vitamin B6, an aroma that is palatable for the species of destination and containing technical excipients such as a sugar, a binder or any other technical excipient useful for its integrity. The compounds GABA and cofactors, and 5-HTP and cofactors are presented separately, but can be administered simultaneously in order to treat animal behavioral disorders.

Description

] "Complementary feedstuffs comprising GABA, 5-HTP and target cofactors" Technical Field The present invention relates to a composition comprising GABA, Arginine, Magnesium and Vitamin Be.

The present invention relates to a composition comprising 5-HTP, Arginine, Magnesium and Vitamin B6.

The present invention relates to a formulation in the form of complementary feed for animals, in the form of cachets, capsules, granules, liquid or supplemented feed.

The present invention relates to a composition containing GABA or 5-HTP whatever their mode of production: synthetic, natural fermentation from plant or animal amino acid or any other manufacturing process.

The present invention also relates to a composition containing technical excipients such as a sugar, a binder or any other technical excipient useful for its integrity.

The present invention relates to a composition intended for animals.

The present invention also relates to a composition containing an appetizing aroma suitable for the target animals, which may be different for each species.

Technological background of the invention In a first aspect, the present invention relates to two compositions associated in a protocol for the treatment of behavioral disorders in animals.

Containing GABA, Arginine, Magnesium and Vitamin Be for one.

5-HTP, Arginine, Magnesium and Vitamin B6 for the second.

STATE OF THE ART 1) GABA (γ-aminobutyric acid, chemical formula C4AH9NO2) is the main inhibitory neurotransmitter of the mature central nervous system in mammals and birds. It therefore has the effect of slowing down and/or calming the excitation pathways. By increasing its production, administering or stimulating its receptors, an anxiolytic, magnetizing or antiepileptic clinical effect is obtained.

Barrett et al. have shown that certain strains of probiotics secrete this neurotransmitter in the presence of glutamate and/or glutamine (Barrett E, Ross RP, O'Toole PW, et al. y-Aminobutyric acid production by culturable bacteria from the human intestine.

J Appl Microbiol. 2012 Aug;113(2):411-7. doi: 10.1111/.1365-2672.2012.05344x. PubMed PMID: 22612585). Additionally, the presence of GABA receptors in the digestive system has been demonstrated (Auteri M, Zizzo MG, Serio R. GABA and GABA receptors in the gastrointestinal tract: from motility to inflammation. Pharmacol Res. 2015 Mar;93:11-21 .doi:10.1016/.phrs.2014.12.001.Epub 2014 Dec 17.Review.PubMed PMID:25526825.).

Although GABA does not pass the BBB (blood-brain barrier) but is recaptured by the blood vessels, oral intake is functional. Oral GABA has an indirect effect on neuronal chemistry via the vagus nerve, as demonstrated by Bravo JA and co-workers in a study of mice given the probiotic Lactobacillus rnamnosus (JB- 1) GABA producer. The latter had greater expression of enteric GABA receptors and less anxious behavior (Bravo JA, Forsythe P, Chew MV, et al. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Nail Acad Sci US A. 2011 Sep 20:108(38}:16050-5. doi:

10.1073/pnas.1102999108. PubMed PMID: 21876150; PubMed Central PMCID:). These effects disappeared after vagotomy, which supports the thesis of an indirect effect via the vagus nerve (Auteri M, Zizzo MG, Serio R. GABA and GABA receptors in the gastrointestinal tract: from motility to inflammation. Pharmacol Res. 2015 Mar;93:11-21. doi: 10.1016/j.phrs.2014.12.001. Epub 2014 Dec 17. Review. PubMed PMID: 25526825).

Taking GABA per os therefore has an anxiolytic and soothing action corresponding to various pathologies, because it has the ability to regulate neuronal activity by slowing down or calming overstimulated excitation pathways.

In addition, the inhibitory effects of GABA counteract the excitatory effects of glutamate.

An imbalance between these two neurotransmitters is, among other things, involved in epilepsy and cerebral ischemia.

Since glutamate is very widely used in industrial animal feed, it is possible that an imbalance is the cause of certain behavioral disorders in domestic animals.

All the more reason to consider using GABA to rebalance animals' neural chemistry and return it to normal.

Unfortunately, the use of GABA itself, well known from the scientific literature for use on humans, has never been adapted for animal use.

However, this would correspond very well to all mammals and birds, since GABA plays the same role in their brains.

On the other hand, it was found that the use of GABA alone presented irregular effects over time on dogs.

In addition, the use of allopathic products acting on GABA (benzodiazepines) has the same disadvantages with animals as with humans: dependence and strong and rapid habituation. There is therefore a need in the art to formulate a product suitable for animal use using GABA and whose effects would be stable in order to treat various behavioral disorders with fewer, if any, side effects. 2) 5-HTP (5-hydroxytryptophan, C11 H12 N2 O3), (not to be confused with tryptophan) found in the plant Griffonia simplifia as well as in the bodies of mammals in their natural state, is one of the precursors of serotonin and represents a key in the natural treatment of conditions that involve the synthesis and release of serotonin in the CNS (central nervous system). The advantage is that it is much less invasive and causes fewer or milder side effects in the long term, compared to the allopathic SSRIs currently used in the treatment of certain canine, feline or equine pathologies.

These are generally animals with aggressive, fearful or hyperactive tendencies.

The presence of serotonin itself in the bloodstream is irrelevant, as it does not cross the blood-brain barrier (BBB). 5-HTP can and is easily transported through the BBB by means of a transport mechanism known from the scientific literature.

Serotonin synthesis begins with the hydroxylation of tryptophan to 5-HTP by means of 5-tryptophan-hydroxylase, which is the rate-limiting enzyme in the serotonin synthesis pathway.

Other compounds, such as proteins and niacin, are also synthesized from tryptophan with different enzymatic pathways: it is therefore more judicious to work with 5-HTP, in this way one avoids going through an additional reaction involving a limiting factor, competition and adding delay.

5HTP is then converted into serotonin by an aromatic amino acid decarboxylase (AAAD) having the coenzyme pyridoxine found in vitamin B6 (JH Juhl, "Fibromyalgia and the Serotonin Pathway”, Altem Med Rev 1998; 3 5L. 365-375) The amount of tryptophan transformed into serotonin is between 2 and 10% of the total tryptophan present.

Excess tryptophan induces a pyrrolase enzyme that diverts tryptophan onto the kynurenine pathway leading to the synthesis of niacin, kynurenines and picolinic acid (l.

p.

Rabbit, Developments in Tryptophan and Serotonin Metabolism Epilepsia, 22:257 1981). Due to these peculiarities in the synthesis of serotonin, it is essential that 5-HTP be administered in quantities that would avoid overloading the serotonin conversion pathway, thus avoiding that surpluses (in this case 5 -HTP) are used inefficiently for serotonin synthesis, leading to undesirable metabolic outcome such as massive release of tryptophan in the gastrointestinal tract.

It is known that high concentrations of 5-HTP cause undesirable side effects such as nausea and/or heartburn (EP 1637185B1).

On the other hand, to obtain a rapid and effective therapeutic response, it is essential to provide an adequate quantity of serotonin precursors in a rapid manner without overloading the enzymatic conversion steps.

All of this information is known to the world of human dietary supplements.

There are also many uses of allopathic products acting on the serotonergic and phytotherapeutic system for human uses diverted to the benefit of animals.

Unfortunately, the problems encountered by these products are a large number of side effects for allopathic products.

Unsatisfactory effects for phytotherapeutic products.

The use of 5-HTP has not yet been adapted for animal use to date.

In view of the benefits and advantages it represents compared to allopathic products, there is therefore a general need to have a product containing 5-HTP suitable for animal use.

It has been shown that a large part of the behavioral problems encountered today in our pets is due to a part of predisposing genetics.

Another part, much less, is attributed to education, respect for the needs and socialization of the animal.

It is possible to reduce this genetic part thanks to the aforementioned products.

SUMMARY OF THE INVENTION Other characteristics, details and advantages of the invention will emerge from the description given below, without limitation.

In its preferred embodiment, according to the present invention, GABA and its targeted cofactors for animal use: Arginine (L-form or not), Magnesium (in any suitable form), Pyridoxine (provided by Vitamin Bó or under n any other form) are presented separately in the form of palatable tablets (for the target species) that can be cut in half, but can be administered simultaneously.

A composition, according to the present invention, in which the mass of GABA is between 250 mg and 900 mg/gr. preferably between 350 mg and 750 mg/gr and even more preferably between 450 mg and 550 mg/gr.

Advantageously, the composition according to the present invention, 5-HTP and its targeted cofactors for animal use: Arginine (L form or not) and Pyridoxine (provided by vitamin B6 or in any other form) are presented separately in in the form of palatable tablets (for the target species) that can be split in two, but can be administered simultaneously.

A composition, according to the present invention, in which the mass of 5-HTP is between 250 mg and 900 mg/gr. preferably between 350 mg and 750 mg/gr and even more preferably between 450 mg and 550 mg/gr.

In another embodiment, according to the present invention, GABA and its targeted cofactors (Arginine (L-form or not}, Magnesium (in any suitable form}, Pyridoxine (provided by vitamin Bó or in any any other form) and 5-HTP and its targeted cofactors (Arginine (L-form or not), Magnesium (in any suitable form}, Pyridoxine (provided by vitamin B6 or in any other form) can be presented, always separately and for animal use, in the form of palatable unscored tablets (for the species of destination] or not, capsules (vegetable or animal whose envelope may or may not be flavored with a product that is palatable for the species of destination), palatable powder (for the target species) or not, granules, or palatable liquid (for the target species) or not, dry or moist biscuits palatable (for the target species) or not , or food (dry or wet) supplemented, or soft drinks supplemented.

In another variant, GABA and its targeted cofactors (Arginine (L-form or not), Magnesium (in any suitable form), Pyridoxine (provided by vitamin B6 or in any other form), and 5-HTP and its targeted cofactors (Arginine [L-form or not), Magnesium (in any suitable form), Pyridoxine (provided by vitamin Bó or in any other form), can be presented within the same product for animal use, in the form of unscored tablets that are palatable (for the target species) or not, capsules [vegetable or animal whose envelope may be flavored with a product that is palatable for the target species or no), granules, palatable powder (for the target species) or not, or palatable liquid (for the target species) or not, biscuits (dry or wet) palatable (for the target species) or not, or supplemented food (dry or wet), or supplemented drinks.

Other embodiments of the administration formula are indicated in the appended claims.

Description of the invention OBJECT 1 A first object of this invention is the design of a complex of cofactors aimed at stabilizing the effects of GABA over the long term in cats and dogs. It has been observed, empirically, when using GABA alone on dogs and cats that the animal showed symptoms similar to before the treatment after one month of it.

A first solution consists in increasing the dose, but once the theoretical maximum dose has been reached, the symptoms reappeared after a few weeks, to a lesser extent than before the treatment, but the results were not satisfactory.

This is why we have chosen another approach: that of using cofactors allowing better penetration of GABA via the _ enterocytes and subsequently the vagus nerve, to the brain, in order to improve its effectiveness, but also to stabilize the effects.

List of cofactors used L-Arginine: α-amino acid whose L enantiomer is one of the 22 proteinogenic amino acids (raw formula: CeH14N402). According to work provided by Shyamala Devi N, Jayakumar AR, Sujatha R, et al (Brain Res Bull. 2002 Jan 15:57(2):231-6. Evidence that nitric oxide production increases gamma-amino buiyric acid permeability of blood- brain barrier.

Shyamaladevi Ni, Jayakumar AR, Sujatha R, Paul V, Subramanian EH) in rats, the consumption of exogenous GABA (660 mg/kg) increases its concentration in the brain by 33%.

Consumption of arginine, on the other hand, increases the concentration of GABA by 65%. By combining the two, we observe a cerebral increase in GABA of 383.3%. nitric oxide, which promotes its penetration into the brain.

Pyridoxine: Active substance of vitamin B6. (raw formula CaHi1NO3) In the brain, the major pathway for the synthesis of endogenous GABA is the conversion of glutamate to GABA by GAD, an enzyme requiring pyridoxal-P. GABA is degraded by two enzymatic steps, the first of which is carried out by another enzyme requiring pyridoxal-P, GABA:2-oxoglutarate transaminase (GABA-T). Pyridoxine administration significantly increases the expression of glutamic acid decarboxylase 67 in the hippocampus (Role of pyridoxine in GABA synthesis and degradation in the hippocampus

An imbalance between GABA and glutamate is associated with neuronal hyperexcitability characteristic of pathological angiogenesis The role of GABA in anxiety disorders.Lydiard RB,Clin Psychiatry. 2003; 64 Suppl 3:21-7.) One inhibits, the other excites. According to the postulate made above that glutamate is widely used in industrial animal feed, it was essential to consider reducing the share of glutamate present in the brain in favor of GABA, otherwise the intake of exogenous GABA would be less efficient. That's why we added Pyridoxine.

Magnesium: mineral (Mg) Magnesium increases the availability of GABA by decreasing the release of presynaptic glutamate (Papadopol V., Nechifor M. Magnesium in Neuroses and Neuroticism. In: Vink R., Nechifor M., editors. Magnesium and the Central Nervous System. University of Adelaide Press; Adelaide, Australia: 2011.) It therefore regulates upstream glutamate intake. In this variant of the invention, we have chosen Mg citrate but other forms of this mineral can be used subsequently.

We have therefore associated the intake of GABA, L-arginine in order to improve cerebral penetration, magnesium in order to limit the release of presynaptic glutamate, as well as pyridoxine in order to promote the transformation of glutamate into GABA in order to to double the intake of exogenous GABA with an endogenous intake. Thanks to this formula, we were able to increase the effects of our active ingredient (GABA) significantly and reduce the dosage of pure GABA to its minimum, namely between 0.05 and 0.1 gram kilo of live weight per day.

Of course, we have limited the cofactor intakes to the recommended daily intakes, taking into account the fact that some of them are already provided by the industrial diet.

OBJECT 2 The second object of this invention relates to the use of 5-HTP administered in addition to the first product in the event of a deficiency in the serotonin production cycle in animals.

In dogs and cats, this deficiency is particularly noticeable in cases of so-called distancing behavior, in which case the reduction of anxiety via the supply of GABA, although essential to the treatment, is not sufficient to reduce the behavior of significantly.

Since no phytotherapeutic product acting directly on the serotoninergic system exists on the market for animals, we have designed it, suitable for animals, in order to supplement the supply of GABA.

It has been found that dogs exhibiting so-called distancing behaviors are more anxious and this is one of the most common causes of aggression.

We also supplemented 5-HTP with L-Arginine and pyridoxine for the same reasons as mentioned above: to increase the permeability of GABA in the brain and to promote the transformation of glutamate into GABA.

Pyridoxine also plays an important role in the production of serotonin in the brain.

By also supplementing the tablet with 5-HTP, we avoid competition between the transformation of glutamate and GABA and the transformation of 5-HTP into serotonin.

The mixing and compression procedures to obtain the above tablets are those commonly known in the art and used for production purposes.

According to the invention, the active principles (GABA and 5-HTP) and cofactors (magnesium, L-Arginine and pyridoxine) of the tablets can be synthetic or natural (plant or animal extracts, plant or animal fermentation).

They can also be combined with excipients commonly used in the preparation of food supplements or complementary foods.

The tablets are also both supplemented with an aroma that is palatable for the target animals (dogs and cats initially, but the formula can be adapted to other pets or not). No side effects were observed with this synergy of active ingredients and cofactors, unlike the administration of the active ingredient GABA alone, which shows a regression in behavior after one month.

Therefore, another object of the present invention is the use of the complexes described, in the treatment of pathologies linked to the synthesis and release of GABA and serotonin in the central nervous system, such as animal behavior disorders associated with fearful behavior, aggressiveness and hyperactivity.

The compositions associated with the present invention can be used for the preparation of complementary foods or supplemented foods and can also contain vitamins, minerals, amino acids, fatty acids, antioxidants, sugars, other nutrients , fats and proteins or any other useful technical excipient.

OBJECT 3 A third object of this invention is the use and adaptation of object 1 and 2 for animal use.

The present invention is illustrated by the following non-limiting examples which do not include the technical excipients which may vary according to the mode of administration chosen:

OBJECT 1 Type of material Ingredient details Galenic dosage en | % mg Functional ingredient | GABA (Y-76.8 Aminobutyric Acid) 7.6 Magnesium Citrate eee [oo qe qe

CC ZOO ps | Je qe PURPOSE 2 Type of material Ingredient details Galenic dosage in mg Griffonia Simplicifolia | 500 90.8 {5-HTP) ae [oee qe qe vene [eea Jon CN i | qe wa Other characteristics, details and advantages of the invention will emerge from the description given below, without limitation. It is understood that the present invention is in no way limited to the embodiments described above and that many modifications can be made thereto without departing from the scope of the appended claims.

REFERENCES CITED IN THE DESCRIPTION

1. Barrett E, Ross RP, O'Toole PW, et al. y-Aminobutyric acid production by culturable bacteria from the human intestine. J Appl Microbiol. 2012 Aug:113(2):411-7. doi: 10.1111/j.1365-2672.2012.05344.x. PubMed PM ID: 22612585

2. Auteri M, Zizzo MG, Serio R. GABA and GABA receptors in the gastrointestinal tract: from motility to inflammation. Pharmacol Res. 2015 Mar;93:11-21. doi: 10.1016/j.phrs.2014.12.001. Epub 2014 Dec 17. Review.

PubMed PM ID: 25526825.

3. Bravo JA, Forsythe P, Chew MV, et al. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci U S A. 2011 Sep 20:108(38):16050-5. doi: 10.1073/pnas.1102999108. PubMed PMID: 21876150; PubMed Central PMCID:

4. Auteri M, Zizzo MG, Serio R. GABA and GABA receptors in the gastrointestinal tract: from motility to inflammation. Pharmacol Res. 2015 Mar:93:11-21. doi:10.1016/j.phrs.2014.12.001. Epub 2014 Dec 17. Review. PubMed PM ID: 25526825

5. J H Juhl, "Fibromylagia and the Serotonin Pathway', Altern Med Rev 1998; 35L. 365-375

6. |. P. Lapin, Developments in Tryptophan and Serotonin Metabolism Epilepsia, 22:257 1981

7. Brain Res Bull. 2002 Jan 15;57(2):231-6. Evidence that nitric oxide production increases gamma-amino butyric acid permeability of blood-brain barmier. Shyamaladevi Nl, Jayakumar AR, Sujatha R, Paul V, Subramanian EH.

8. Role of pyridoxine in GABA synthesis and degradation in the hippocampus, YoungJungalHyun JungKwonb1WoosukKimcSung MinNamdJong WhiKimaKyu RiHahnaDae YoungYooeYeo SungYoonaSoo YoungChoicDae WonKimbin KooHwangc

9. The role of GABA in anxiety disorders. Lydiard RB, Clin Psychiatry. 2003; 64 Suppl 3:21-7.

10. Papadopol V., Nechifor M. Magnesium in Neuroses and Neuroticism. In: Vink R. Nechifor M., editors. Magnesium and the Central Nervous System. University of Adelaide Press; Adelaide, Australia: 201 1.

11. Patent EP 1 637 185 B1 Clinical evaluation of the products and their combinations A clinical evaluation of the therapeutic efficacy of the tablets of the present invention, which were prepared as explained, was carried out. The evaluation was made according to a behavioral evaluation grid evaluating the set of behavioral criteria relevant to our object. The points highlighted were first selected according to an ad libitum sampling while keeping in mind the previous knowledge concerning the efhogram of the cat and the dog. Once the observation criteria had been chosen, we drew up a grid. It is obvious that not all the animals exhibited all the behaviors highlighted. To avoid any observation bias, we filled in the grid in accordance with the daily observations of the owner of the animal and the observations of the behaviorist during weekly meetings. 16 dogs and cats received a protocol in 3 phases extended over 3 months using an observation grid rated from 0 to 10. O meaning that no improvement was observed, 10 that the improvement is more than remarkable.

To illustrate how the behaviors were assessed, here is an example of the assessment grid for one of the animals tested: eee Tempe in weeks [EE [B [AEG [7 een en le LS RITES fear, aggression} relax) Corine des emotions face 8 noumiure esciion [0 |? [2267 Fe [9 OO aggression} ee [9 19 RENE previously | Behavior of fote/inhieitien dan [© [B [ojoj5|5| Copocié de concentration: altenif our requests [0 [1 [0jojs|5| in a rn eene A OIS excitement, aggression) "Demonstration of affection towards humans of the family— | | | Bvtaied in exchanges between animals or with humans | | men a TO TEE healthy exploratory behavior

CI RE D EE | Biééohpieerog obsessive behavior | 11110 oreert ee RE LE in a strong emotions recessie OT TT [Recoidié momentum [LL [LL [| | Copacted & confronting his little by cufeste (© | [O[O[5 [5 gese OO Awiéédesépaaion KE EN ReéducatondeTryperaachemen (© [8 SI Reduction deseicisde shock (Deadlock) [LL [| Terios LL Aggressors/ distancing abolations (decrease) | © [2 [iis] In order to reduce observation bias, we deliberately chose to mix the behaviors linked to the 3 pathologies with which we wanted to observe: fear, hyperactivity and aggressiveness.

Protocol in 3 phases over 3 months On day 1, we do a complete behavioral assessment of each animal. After which each animal received: Phase 1: GABA alone for 1 month (between 100 and 300 mg/kg body weight). Phase 2: GABA + cofactors for 1 month (between 50 and 100 mg of Gaba / kg of live weight). Phase 3: GABA + cofactors + 5-HTP (between 50 and 100 mg of Gaba / kg of body weight and between 50 and 100 mg of 5-HTP / kg of body weight) As illustrated in the example table, we have assessed changes in behavior at weeks 1, 2, 4, 6, 8, and 12. Full sample mean Here are the means (all numbers rounded to the nearest hundredth) at weeks 2, 4, 8, and 12: Mean Standard Deviation After 2 weeks GABA alone 2.48 1.18; After 1 month GABA alone 1.36 0.99 After 1 month GABA + cofactors 457 1.75 | After 1 month GABA + cofactors + 5-HTP 4.76 1.00 We see directly that after an improvement at week 2, there is a noticeable regression in the results at week 4. We can conclude that the animal sees its behavior improved after 2 weeks of GABA alone but that it declines after a month of treatment, even if we increase the doses to the theoretical maximum.

We also notice that the standard deviations are high. This is explained by the splitting of our study population into 2. As explained above, some of the animals obtained good results with only the GABA+cofactor complex, others need supplementation with 5- HTP to achieve equivalent results. We found that some animals had nearly identical means at week 8 (GABA+cofactors) and 12 (GABA+cofactors + 5-HTP). This clearly means that the addition of 5-HTP in these individuals does not add value.

We were able to separate our sample into 2 groups, here are the results:

té GROUP 1: Dogs with similar means at week 8 (GABA+cofactors) and 12 (GABA+cofactors + 5-HTP) { Mean Standard deviation After 2 weeks alone 2.53 0.88 After 1 month GABA alone 1.38 1.38 After | months GABA + cofactors 4.95 0.33 After | months GABA + cofactors + 5-HTP { 5.01 0.37 { GROUP 2: Dogs with a delta between the means at week 8 (GABA+cofactors) and 12 (GABA+cofactors + 5-HTP) a Mean Standard deviation After 2 weeks alone 1.71 0.918 | After ! month GABA alone 0.66 0.38 After 1 month GABA + cofactors 3.23 0.81 After 1 month GABA + cofactors + 5-HTP 4.99 0.2 We notice several very important things.

Firstly, the standard deviations have normalized by passing below the 0.5 mark, our dispersion is therefore normal, except for the figures for GABA alone after 2 weeks in individuals with averages close to week 8 (GABA+cofactors ) and 12 (GABA+cofactors + 5-HTP). This therefore means that the animals did not react regularly to this treatment (GABA alone) in the two groups.

On the other hand, the regression of behaviors after 4 weeks is much more disparate in group 1 than in group 2. This means that whatever the result after 2 weeks of GABA alone, the animal will see its behavior regress in all the case.

It was therefore absolutely necessary to stabilize the effects of GABA.

Second, there is a 17.2% difference between Group 1 and 2 results at week 8 (GABA+cofactors). This difference is reduced to 0.2% when 5-HTP is added.

The Average of group 2 catches up with that of group 1, which remains almost unchanged.

This shows that dogs in group 2 need a 5-HTP supplement to achieve results equivalent to group 1.

Third, the standard deviations at term for each treatment show satisfactory and stable results: week 8 (GABA+cofactors) for group 1 and week 12 (GABA+cofactors + 5-HTP) for group 2, are significantly lower and well below 0.5. It can be concluded that the effects are stabilized and that the statistical confidence index is high. An important element remains to be determined for the use of one or both tablets: according to what criteria does the animal need a 5-HTP supplement. It was easy to isolate the behaviors appearing in the individuals of group 2 and not in group 1. These are all fear behaviors combined with aggression, in short everything that relates to distancing behaviors: barking / growls / growls / distancing aggressions. Animals showing only fear behaviors or only aggressive behaviors reacted satisfactorily to GABA+cofactors, the addition of 5-HTP did not improve their results. Note that we also recorded 2 marginal or even aberrant values: one animal did not respond satisfactorily to the treatment with an average of 1.21 at week 8 as at week 12. Another animal presented extremely high values with an average of 9.3 at week 8. We deemed it unnecessary to give him the additional 5-HTP, and his average remained unchanged at week 12. Side effects No unknown side effects were reported. We have identified those already known from the literature for human use. For GABA+cofactors

1. Short breath:

1. A case has been declared, after an accidental overdose on the part of its owner.

2. A case was declared during a summer heat wave. Since the symptom disappeared as soon as warmer weather returned, we believe the dog was hyperthermic.

2. Skin tingling: difficult to observe in animals.

1. A dog exhibiting itching may be related to treatment.

For 5-HTP

1. Enteric disorders: none reported.

2. Belching / heartburn: None reported.

We can conclude that the doses administered were optimal to obtain a significant improvement in behavior without suffering side effects.

In summary, we therefore observe a 50% improvement in behavioral disorders related to aggressiveness, fears and hyperactivity, with strong statistical significance in 87.5% of individuals subjected to the protocol including GABA + cofactors, and/or by adding a dose of 5-HTP.

On the other hand, the protocol including only GABA alone shows unsatisfactory results with an improvement of only 10% in behavior and a statistical significance that is weaker although satisfactory on 100% of the animals.

Claims (7)

“Claim” ]l. A composition, according to the present invention, containing GABA and at least one of the following compounds: Arginine (L-form or not), Magnesium (in any suitable form), Pyridoxine (provided by vitamin B6 or in any what other form). 2. A composition according to the present invention, containing GABA regardless of the mode of production: synthetic, natural fermentation from plant or animal amino acid or any other manufacturing process. 3. A composition, according to the present invention, containing 5 HTP and at least one of the following compounds: Arginine (L-form or not), Magnesium (in any suitable form), Pyridoxine (provided by vitamin B6 or in any other shape). 4. A composition according to, according to the present invention, containing 5-HTP regardless of the mode of production: synthetic, plant extract or any other manufacturing process. 5. A composition, according to the present invention, containing technical excipients such as a sugar, a binder (eg acacia gum) or any other technical excipient useful for its integrity. 6. A composition, according to the present invention, containing an appetizing flavor and suitable for the target animals, which may be different for each species. 7. A composition, according to the present invention, intended for animals, all species included.