WO2014029924A1 - Novel uses of lactoferrin and pharmaceutical and nutraceutical compositions - Google Patents

Abstract

The present invention relates to novel nutritional and nutraceutical therapeutic uses of lactoferrin in psychiatric or non-degenerative neurological diseases.

Description

New applications of lactoferrin and pharmaceutical and nutraceutical compositions

The present invention relates to compositions for regulating iron metabolism in patients with restless legs syndrome and other iron deficiency neurological or neuropsychiatric syndrome, such as Tourette's syndrome, attention deficit and nocturnal myoclonus. The present invention also relates to novel applications and uses of lactoferrin.

Lactoferrin compositions used as a dietary supplement or as a treatment against Willis-Ekbom syndrome (restless leg syndrome) and other neurological and neuropsychiatric conditions are part of the present invention.

Lactoferrin according to the invention relates to a protein extracted and purified from mammalian milk or obtained from the expression of recombinant cells such as eukaryotic cells or bacteria expressing the gene for human lactoferrin, ovine, bovine or buffalo preferentially as well as any fragment of this purified protein having retained its iron chelating properties and its functional properties of attachment to its specific cell receptors. Lactoferrin can also be produced by transgenic animals expressing the gene encoding this protein. Lactoferrin may be composed of a mixture of this protein from different species (human and animal or animal only) or a mixture of proteins extracted and purified milk and recombinant proteins or fragments thereof . Included as "lactoferrin" in the present invention are the fragments of this protein described in paragraph 31 of US2009 / 0156484 A1 published on June 18, 2009.

Iron is essential for the functioning of many cellular mechanisms, primarily the fixation of oxygen by hemoglobin and myoglobin. However, the pro-inflammatory nature of iron (via interleukin-6 and / or the onset of NF-κΒ pathway - Int J Colorectal Dis. May 2006; 21 (4): 381-7. Epub 2005 Aug 23. Exacerbation of dextran sulfate sodium-induced colitis by dietary iron supplementation: role of NF-kappaB. JC Carrier, Aghdassi E, Jeejeebhoy K, JP Allard), its tendency to form toxic oxygen radicals, to see to precipitate if its concentration is locally too high have forced the higher organisms to set up a cellular and systemic engineering responsible for ensuring to the good economy of iron in the body. The challenge for the body is, in fact, to provide for the needs of all cells iron, while avoiding iron saturation in different fluid compartments and especially in the bloodstream. This involves, on the one hand, the creation of entities responsible for the transport of iron (ferritin / transferrin) and, on the other hand, the establishment of a system for storing iron in specific cell types, foremost among which are hepatocytes. , enterocytes and macrophages and at the pregnant woman syncitiotrophoblasts. For all these cell types, regulation is under the control of two chemical entities:

^• On the one hand ferroportin (transmembrane protein present at the blood / cell junction) which is the only known protein capable of exporting iron from the intracellular medium to the blood. Its role is crucial to ensure the provision of iron in the bloodstream. It needs to be associated with a ferroxidase in order to allow the export of iron to the extracellular medium, at the same time as its oxidation of Fe (II) to Fe (III).

^• On the other hand, hepcidin (circulating peptide hormone secreted by hepatocytes). Active hepcidin, which is derived from a precursor (prohepcidin) of 84 amino acids; contains 25 amino acids.

Hepcidin regulates the storage of iron in the cells listed above, not its interaction with ferroportin. In fact, hepcidin has the capacity to bind to ferroportin, to induce its phosphorylation, its internalization and its degradation in the lysosome. Since ferroportin is the only known protein able to export iron from the cells of the reserve organs in the blood, hepcidin (circulating hormone) has an antagonistic function of ferroportin by hindering the release of iron in the general circulation and its export to other body cells (Annu Rev Nutr 2006, 26: 323-42, Regulation of iron metabolism by hepcidin, Nemeth E, Ganz T). Schematically, when hepcidin levels are low, the rate of transmembrane ferroportin is high and the iron is exported to the general circulation. Conversely, when the level of hepcidin is high, the rate of transmembrane ferroportin is low, and the iron remains trapped in the cytosol of cells in general complexed with intracellular ferritin (Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, DM Ward, Ganz T, Kaplan J. Science, 2004 Dec 17, 306 (5704): 2090-3, and Regulation of iron acquisition and iron distribution in mammals. Ganz T, Nemeth E.Biochim Biophys Acta, Jul 2006: 1763 (7): 690-9). Restless legs syndrome is a disease for which no pathophysiological abnormality is clearly identified. This disease is manifested by "impatience" in the legs mainly at the end of the day and during the night, forcing the person to get up and walk to get through the disorder. This condition has a significant impact on patients' sleep quality and has a major impact on their lifestyle. In this condition, the part respectively attributable to the central nervous system and the peripheral nervous system is still subject to discussion (The restless legs syndrome, Barrier G, Cazalets JR, Bioulac B, Tison F, Ghorayeb I. Prog Neurobiol, 2005 Oct; (3): 139-65).

Objectively, no lesions of dopaminergic structure have been revealed in restless legs syndrome (in particular, no pathological study has been able to show neuronal loss either at the level of the substantia nigra or at the level of hypothalamic dopaminergic region Ail) (Restless legs syndrome: Revisiting the dopamine hypothesis from the spinal cord perspective, Clemens S, Rye D, Hochman S. Neurology, 2006 Jul 11, 67 (1): 125-30). However, the marked improvement of the symptoms during the administration of dopaminergic agonists and, conversely, the exacerbation of the symptoms when taking dopaminergic (neuroleptic) antagonists underline the importance of the dopaminergic system (s) in the clinical manifestations of the Dopamine agonists for restless legs syndrome, Scholz H, Trenkwalder C, Kohnen R, Riemann D, Kriston L, Hornyak M. Cochrane Database Syst Rev. 2011 Mar 16; (3): CD006009).

The classical therapeutic approach (based essentially on clinically obtained data) therefore consists in the administration of Levodopa or agonists of the dopamine (such as ropinirole, pramipexole, rotigotine and cabergoline), which by a non-specific action on abnormal movements contribute to the reduction of annoying symptoms (impatience) and to the well-being of the patient. a number of side effects and gives rise after a few months to phenomena of rebound, tolerance or increase in the syndrome requiring the patient to increase doses to maintain a sufficient benefit justifying the continuation of treatment with Dopaminergic agonists (Ondo W, Romanyshyn J, Vuong KD, Lai D. Arch Neurol, 2004 Sep; 61 (9): 1393-7 and Progressive development of increase during long-term Hogl B, Garcia-Borreguero D, Kohnen R, Ferini-Strambi L, G Hadjigeorgiou, Hornyak M, Weerd A, Ha S, Stiasny-Kolster K, Gschliesser V, Egatz R, Frauscher B, Benes H, Trenkwalder C, Hening WA, Allen RP. J Neurol. 2010 Feb; 257 (2): 230-7). In the event of failure or contraindication of treatment with dopaminergic agonists, the alternatives are essentially benzodiazepines, some antiepileptics (such as gabapentin), codeine derivatives, morphine derivatives. Combinations of some of these products with dopaminergic agonists may sometimes be used for particularly severe cases (A Randomized, Double-Blind, Placebo-Controlled, Dose-Response Study to Assess the Pharmacokinetics, Efficacy, and Safety of Gabapentin Enacarbil in Subjects With Restless Legs Syndrome, Lal R, Ellenbogen A, Chen D, Zomorodi K, Atluri H, Luo W, Tovera J, Hurt J, Bonzo D, Lassauzet ML, Vu A, Cundy KC Clin Neuropharmacol, 2012 Jun 1).

To date, there is no targeted therapeutic response for the management of restless legs syndrome. The classic dopaminergic response provides only temporary phenotypic relief and only partially addresses the etiology of the disease. The same goes for other therapeutic approaches, which anesthetize the patient more than they care for him. As a result, the community of patients and neurologists are still looking for an effective, safe and well-tolerated cure for this pathology, which is estimated to be between 0.01 and 18.3% of the general adult population (Epidemiology of Restless Legacy Syndrome). Black Sea coast of Turkey: A door-to-door study in a rural area.Tasdemir M, Erdogan H, UT Boni, Dilaver E, Kumas A.Sleep Med. 2010 Jan; ll (l): 82-6 and Restless legs syndrome: relationship between prevalence and latitude. Koo BB. Sleep Breath. 2011 Dec 31).

In some patients with restless legs syndrome, abnormalities in the iron concentration of body fluids have been observed (Dopamine and iron in the pathophysiology of restless legs syndrome (RLS) .Allen R.Sleep Med. 2004 Jul; 4): 385-91). This martial anomaly has been confirmed epidemiologically. Indeed, it has long been recognized that restless legs syndrome is triggered preferentially in individuals undergoing martial stress (with abnormally low iron levels) such as people giving their blood frequently, pregnant women and renal dialysis patients. (Balendran J, D Champion, Jaaniste T, Welsh A.Aust NZJ Obstet Gynaecol 2011 Jun; 51 (3): 262-4 and Restless Legs Syndrome (A common sleep disorder in pregnancy in patients' dialysis: a comparison between hemodialysis and continuous ambulatory peritoneal dialysis: Merlino G, Lorenzut S, Romano G, Sommaro M, Fontana A, Montanaro D, Valente M, Gigli GL, Neurol Sci., 2012 Jan 22). Conversely, the ethnic group where restless legs syndrome is the rarest is the Japanese population with a rate of restless legs syndrome ten times lower than the western average (0.46% for older men) (Prevalence of restless legs syndrome in a Japanese elderly population, Tsuboi Y, Imamura A, Sugimura M, Nakano S, Shirakawa S, Yamada T.

Parkinsonism Relat Disord. 2009 Sep; 15 (8): 598-601). This is partly because of a diet very rich in iron (algae consumed in Japan are known nutrients rich in iron with a rate of up to 200mg of iron per 100g). However, the lack of iron in patients with restless legs syndrome does not necessarily lead to anemia characterized.

This anomaly in iron levels was found during biopsies performed on brains of people with restless legs syndrome where abnormally low iron levels were confirmed (MRI-determined regional brain iron concentrations in early and late-onset restless legs syndrome, Earley CJ, B Barker P, Horska A, Allen RP, Sleep Med, 2006 Aug; 7 (5): 458-61). However, the link between falling iron level and restless leg syndrome is not established. In this article, it is assumed that the Defective dopamine synthesis is explained by the fact that the tyrosine hydroxylase involved in the synthesis of dopamine has the cofactor iron. But the results on tyrosine hydroxylase are in contradiction with the observations made in Parkinson's disease, where unlike restless legs syndrome, the intracerebral iron level is higher than normal (Potential sources of increased iron in the Substantial nigra of parkinsonian patients, Gerlach M, Double KL, Youdim MB, Riederer J Neural Transm Suppl 2006 (70): 133-42. Consequently, no objective element of the prior art makes it possible to bind the concentration of available iron and iron sequestered in the cells with a dopaminergic disease. However, circulating iron is not a good marker of iron deficiency because it is always maintained, via a systemic regulation process, at a concentration of less than 10 ¹⁸ M in physiological fluids. This regulation imposed by the potential toxicity of iron in the form of free Fe ³⁺ ions (Fe (III)) involves a number of circulating proteins acting as iron chelating agents. The two main proteins involved in this process are transferrin and ferritin, two secreted proteins found in serum and cerebrospinal fluid. Transferrin has the capacity to fix two iron atoms while ferritin has the capacity to fix 4500. This imbalance in the chelation capacities of these two proteins is found in their respective concentrations in physiological fluids (the concentration of Serum transferrin amounts to 2.5 g / L while the concentration of serum ferritin is between 50 and 100 μg / L in adults). The extremely high affinity of ferritin for iron makes it a good recognized physiological marker of iron homeostasis.

This central role of ferritin as a marker of available iron storage has been confirmed in the case of restless legs syndrome by several studies. Not only is the concentration of ferritin in the cerebrospinal fluid abnormally low in the majority of patients with restless legs syndrome (Ferritin subunits in CSF are decreased in restless legs syndrome.) Clardy SL, Earley CJ, Allen RP, Beard JL, Connor JR, J Lab Clin Med), but also in serum (The Seriousness of Restless Behavior Syndrome (RLS) and a prospective patient cohort: association with ferritin levels, Frauscher B, Gschliesser V, Brandauer E, El-Demerdash E, Kaneider M, Rücker L, Poewe W, Hôgl B. Sleep Med 2009 Jun; 10 (6): 611-5). This agreement between the parameters of the two physiological fluids is moreover confirmed by the analysis of the endothelial tissue of the blood-brain barrier. Other studies have shown that ferritin levels in cerebrospinal fluid are directly correlated with serum ferritin levels. This importance of serum ferritin as a biomarker of restless leg syndrome has been confirmed in severe forms of the syndrome where there is a negative linear correlation between the intensity of the disease and serum ferritin level. syndrome is associated with low ferritin. Trenkwalder C, Hôgl B, Benes H, Kohnen R. Sleep Med. 2008 Jul; 9 (5): 572-4). This indicator is particularly interesting during worsening of the syndrome because in these cases, a collapse of the serum ferritin level is observed.

Other neurological diseases present an iron deficiency without a nutraceutical or pharmaceutical solution being considered or allows obtaining a biological rebalancing. In fact, similar to restless legs syndrome, other neurological or psychiatric disorders show abnormalities in metabolism and iron and more particularly an abnormal fall in ferritin levels. These are Attention Deficit Disorder (ADHD), nocturnal myoclonus and Gilles de la Tourette Syndrome. Patients with Attention Deficit Disorder (ADHD) have a frequent comorbidity with restless legs syndrome whether in infantile or adult forms. In children, some child psychiatrists even think that ADHD is the juvenile expression of restless legs syndrome. The similarity between the two diseases was confirmed from a pathophysiological point of view, with in both cases an iron anomaly. Like restless legs syndrome, patients with ADHD have statistically lower levels of iron and ferritin than normal. However, the link between iron levels and ADHD has been shown only for cognitive aspects and does not relate to the physical aspects of the disease (Relation of ferritin levels with symptom ratings and cognitive performance in children with attention deficit-hyperactivity disorder. Oner 0, Alkar OY, Oner P. Pediatr Int 2008 Feb, 50 (1): 40-4). This martial deficiency resulted in clinical trials, where was tested iron supplementation in ADHD patients (Konofal E, Lecendreux M, Deron J, Marchand M, Cortese S, Zaïm M, Mouren MC, Arnulf I. Pediatr Neurol 2008). January; 38 (l): 20-6). The other argument in favor of a similarity between the two syndromes concerns the family and genetic aspects of the two diseases:

- restless legs syndrome is more commonly found in parents of children with ADHD than in the general population

Studies in molecular biology have confirmed epidemiological studies and reported several loci statistically found in both pathologies. In particular, the BTBD9 locus, which would not only be common to RLS and ADHD, but is linked to iron metabolism (Exploring the genetic link between RLS and ADHD, Schimmelmann BG, Friedel S, Nguyen TT, Sauer S, Ganz Vogel CI, Konrad K, Wilhelm C, Sinzig J, Renner TJ, Romanos M, Palmason H, Dempfle A, Walitza S, Freitag C, Meyer J, Linder M, Schfer H, Warnke A, Lesch KP, Herpertz-Dahlman B, Hinney A, Hebebrand J Psychiatr Res 2009 Jul 43 (10): 941-5).

Myoclonus, or Periodic Limb Movement Disorder (PLMD), is very similar in symptomatology to restless legs syndrome, with the difference that this syndrome only occurs during sleep, and that it is not in itself painful or embarrassing, apart from the fact that it induces untimely awakenings during the night. It is often observed that nocturnal myoclonus precedes in patients' history a diagnosis of restless leg syndrome and that there is a strong statistical link between these two pathologies. This link is found at a family level, where children with nocturnal myoclonus often have parents with restless leg syndrome (Pediatric restless legs syndrome and periodic limb movement disorder.) - Picchietti DL, Rajendran RR, Wilson MP, Picchietti MA Sleep Med 2009 Sep; 10 (8): 925-31).

In the same way as for restless legs syndrome, abnormalities in iron metabolism are frequently observed, with an abnormally low rate Ferritin (Iron deficiency and chronicle movement disorder of sleep, Gozal D, Kheirandish-Gozal L. Sleep Med 2009 Feb; 10 (2): 265).

Gilles de la Tourette's syndrome is characterized by a number of tics, including facial movements, blinking, guttural scrapings that are associated with the involuntary oral expression of obscenities (coprolalia).

The role of iron, as for restless legs syndrome and ADHD, has been highlighted in the case of Tourette syndrome. There is also an abnormally low intracranial iron and ferritin level in patients with this syndrome (Gorman DA, Zhu H, Anderson GM, Davies M, Peterson BS, Am. J Psychiatry, 2006 Jul, 163 (7): 1264-72). From a genetic point of view, abnormalities observed at the BTBD9 locus, in other neurological pathologies linked to an anomaly of iron metabolism are also found in the syndrome of Gilles de la Tourette (Attention-deficit / hyperactivity disorder, Tourette's Syndrome, and Restless Behavior Syndrome: The Iron Hypothesis: Cortese S, Lecendreux M, Bernardina BD, Mouren MC, Sbarbati A, Konofal E. Med Assumptions, 2008; 70 (6): 1128-32).

Therefore, for these diseases in which abnormalities of iron metabolism are implicated, the measurement of serum ferritin level is a quantitative marker described in the literature of the pathology and its intensity. Acting on serum ferritin levels to increase it is a good way to normalize iron homeostasis in patients to reduce annoying symptoms and improve their quality of life. In the prior art, the low limit of the blood ferritin level is 50 g / L, its maximum limit is 300 μg / L (hemochromatoses, pathologies in which the ferritin level is in excess are at a ferritin level serum 1000 g / L). The margin of increase of ferritin is therefore important and it is very unlikely to reach the maximum of the serum level.

The technical problem to be solved is to bring a new solution to the supply of iron in neurological and psychiatric disorders deficient in iron. The definition of compositions, having the capacity to raise the rate of iron and more particularly the rate of ferritin in patients with restless legs syndrome without inducing undesirable side effects while stabilizing the Biological concentration towards normality, is the object of the present invention as well as the new use of lactoferrin to reduce the symptoms of neurological diseases such as restless leg syndrome or psychiatric such as ADHD. To act on plasma ferritin and to compensate for a supposed iron deficit in patients with restless legs syndrome, it has been proposed to increase iron intake massively with the disadvantage of leading to iron sequestration in iron. the intracellular space, either by oral supplementation or by intravenous injections (essentially iron sucrose, iron dextran). These approaches have resulted in several clinical trials, in which the criteria (objective and subjective) defined to measure the potential benefit of these therapeutic approaches are mainly:

• the serum ferritin level

^• periodic movements of the legs during sleep (periodic leg movement in sleep-PLMS)

^• sleep time (total sleep time)

^• the evolution of pain according to the international scale of severity of the syndrome of the legs without the rest (International RLS severity rating scale - IRLS)

The results of these studies show a variable response in recruited patients. With a rate of responders (partial or total improvement of the syndrome) which vary between 20 and 60% according to the age, the sex, the general state of the patients.

In general, the results, with oral supplementation were rather disappointing, and did not lead to any therapeutic recommendations (Mohri I, Kato-Nishimura K, agitani-Shimono K, Kimura-Ohba S, Ozono K, Tachibana N, Taniike M. Sleep Med 2012 Apr; 13 (4): 429-32). Intravenous iron injections (which are more difficult to handle and more restrictive in the long term) have not given the expected results in the case of iron sucrose (A randomized, double-blind, placebo-controlled trial of intravenous iron Sucrose in Restless Behavior, Earley CJ, Horska A, Mohamed MA, Barker PB, Beard JL, Allen RP, Sleep Med 2009 Feb; 10 (2): 206-ll), and iron dextran (The treatment of restless legacy syndrome with intravenous iron dextran Earley CJ, Heckler D, Allen KP. Sieep Med. 2O04 May; 5 (3): 231-5). The use of these approaches based on a massive addition of iron can be dangerous because of the accumulation of iron in cells including nerve cells. It should also be noted that in a number of cases, massive iron intake has given rise to allergies.

These phenomena of massive iron intakes are to be compared with the fact that supplementation-err iron has a number of risks and undesirable side effects that can sometimes be dangerous such as:

• microbial proliferation

 Inflammation (Iron overload odd pro-inflammatory cytokine responses by Kupfferreils, Olynyk JK, Clarke SL, Gastroenterol Hepatol, 2001 Apr; 16 (4): 438-44]

 • cancers

 • hepatitis

 · Digestive problems

(diarrhea / nausea / vomiting / bloating / constipation induced by the low bioavailability of inorganic iron and the need to administer massive doses). A prospective LA Wool, Bentley E, Chandrasoma P. Dig Dis Sci 1988 Feb; 33 (2): 172-7).

Moreover AFFSAPS has issued negative recommendations on iron supplementation, which should be reserved for particular situations (Article du Monde of Friday, September 30, 2011 - The 56 drugs particularly monitored - pl2, Paul Benkimoun)). In conclusion, clinical trials, the results of which are available, show that massive iron supplementation is not a satisfactory solution in the long-term management of patients with restless legs syndrome.

Thus in the case of restless legs syndrome, a massive iron supplementation will force the body to put in place an immediate response to avoid excess iron in the bloodstream. Excess iron will induce the increase circulating proinflammatory interi uki-ns, such as interleukin-6. The latter promotes the transcription of the hepcidin gene in the hepatocytes, by means of the intermediate-the fixaliun of STAT3 ^~ sui eque that promoter of the gene.

This will initially induce a sharp rise in the blood hepcidine level which will lead to the elimination of ferroportin from the cell surface. This disappearance of transmembrane ferroportin will have the effect of sequestering iron in the intracellular compartments. This decrease in available iron will induce iron deficiency and a decrease in ferritin in other fluid compartments and especially in cerebrospinal fluid. This result is not very surprising when we know that if iron is quantitatively the most imfwrftarrt metal in the human corp {about 5g of iron in an adult man of 70 Kg), the daily intake of iron in the A normal diet is sufficient to compensate for iron losses that average one thousandth of the total mass of iron present in the body (between 5 and 10 mg approximately). This is explained by the capacity of the body to recycle the heme iron (hemoglobin mainly) during the destruction of red blood cells (normal hemolysis). Only very special situations such as pregnancy warrant an increase in daily intake of iron in the adult individual.

The low rate of circulating iron in adults and children is not necessarily due to a lack of quantitative iron in the body but rather to its sequestration in the cells of the intestinal mucosa and in macrophages by the Hepcidin-ferroportin system game. (Hepcidin and iron homeostasis, Ganz T, Nemeth E. Biochem Biophys Acta, 2012 Jan 26 and The molecular mechanism of hepcidin-mediated ferroportin down-regulation, De Domenico I, DM Ward, Langelier C, Vaughn MB, Nemeth E, Sundquist WI , Ganz T, Musci G, Kaplan Mol Mol. Cell 2007 Jul; 18 (7): 2569-78). The direct and massive supply of iron is therefore not the appropriate answer to solve the technical problem mentioned above.

Other solutions have been proposed in the prior art, such as those of using blood transferrins. Blood transferrins are a family of globular proteins, conserved during evolution, involved in the provision of iron. They may have an action (positive or negative) on the serum ferritin level, and intervening on the transfer ines could be a way to raise the rate of ferritin.

The transferriye family consists of four proteins: - Sartguihe transferrin (or serotransferrin)

 - natural lactoferrin (blood)

 - ovotransferrinet

 - melanotransferrin

For blood transferrins, the results reported in the literature suggest that there is no clear link between these two parameters, even in pathological situations [64].

This decorrelation is confirmed by the differences in these two parameters during the circadian cycle. While ferritin is the most stable blood protein parameter with variations during the day considered insignificant, transferrin levels can vary over a single day by 70%. (Sennels HP, J0rgensen HL, Hansen AL, JP Goetze, Fahrenkrug J. Scand J Clin Lab Invest, Nov. 2011; 71 (7): 532-41 (Diurnal variation of hematology parameters in healthy young men: the Bispebjerg study of diurnal variations. and Diurnal variation of iron serum, iron-binding capacity, transferrin saturation, and ferritin levels, Dale B, MF Burritt, Zinsmeister AR, Am J Clin Pathol, 2002 May, 117 (5): 802-8). Trying to act on serum ferritin levels via serum transferrin is therefore not a good approach and could induce biochemical disorders.

We can therefore conclude that the serum ferritin level is independent of the serum levels of all transferrins. Acting on serum transferrins does not provide a satisfactory answer to the technical problem.

Blood lactoferrin is also present mainly at the tissue level and at very low concentrations in the bloodstream. She can not have action Direct on ferritin (Diurnal variation of iron serum, iron-binding capacity, transferrin saturation, and ferritin levels, Dale JC, Burritt MF, Zinsmeister AR, Am J Clin Pathol, 2002 May, 117 (5): 802-8), and has never been cited as a therapeutic or nutraceutical molecule in restless leg disease and other neurological diseases related to iron deficiency.

Ovotransferrin is a protein found in egg white that is absent in humans (Evidence for the expression of lactotransferrin receptors in the human intestine, Cox TM, Mazurier J, Spik G, Montreuil, Peters TJ Biochem Biophys Acta, 1979 Nov 15, 588 (1): 120-8).

Melanotransferrin, a predominantly cellular or tissue protein, is catabolized very rapidly by the liver in its serum form, which prevents it from reaching the brain (The transferrin homologue, melanotransferrin (p97), is rapidly catabolized by the liver of the rat Richardson DR, Morgan EH, Biochim Biophys Acta, 2004 Oct 14, 1690 (2): 124-33).

Certain biochemical characteristics of lactoferrin, independent of its presence in the blood and its possible drug transporter activity, led surprisingly despite the absence of a link in the scientific literature to be considered in the present invention a new use of the Bovine lactoferrin for the treatment of restless legs syndrome and other neurological conditions in which an abnormally low level of ferritin circulating in the blood has been noted.

Bovine and human blood and non-blood lactoferrin is a cationic globular glycoprotein of the transferrin family that has a molecular weight of 80 kilo daltons. Its affinity for iron is 300 times greater than that of serum transferrin. It is present in all mammals with a high stability during the evolution (Bioinformatics analysis of lactoferrin gene for several species) Kang JF, Li XL, Zhou RY, Li LH, Feng FJ, Guo XL Biochem Genet 2008 Jun ; 46 (5-6): 312-22). It is produced by all the mucous cells in different body fluids and has the ability (like transferrin) to bind to two iron atoms (it is called holo-lactoferrin in its chelated form and apo-lactoferrin in its non-chelated form). It participates in the tissues to maintain a correct concentration of iron and prevents inflammation. Mammalian milk is the biological fluid in which its rate is highest. In human milk, the concentration of lactoferrin is 1.5g / L

The type of lactoferrin that can be used is either bovine lactoferrin, which is biologically active in humans (assuming the mode of extraction / purification is not denaturing) or recombinant human lactoferrin, as long as it is a biologically active form (correctly glycosylated). (Bovine lactoferrin can be taken up by the intestinal human lactoferrin receptor and exert bioactivities.Lonnerdal B, Jiang R, Du X. Pediatr Gastroenterol Nutr Nu 2011 Dec; 53 (6): 606-14).

In contrast to most proteins, human bovine lactoferrin is one of the few biologically active proteins that has retained its therapeutic properties when administered orally. It has the particularity of resisting digestion and preserving its biological activity in the digestive tract in adults and children (Lactoferrin, a bird's eye view.Vogel HJ Biochem Cell Biol 2012 Jun; 90 (3): 233-44 and Lactoferrin - 50 years on, Brock JH, Biochem Cell Biol 2012 Jun, 90 (3): 245-51).

There are receptors specific to lactoferrin on the villi of duodenal mucosa cells in humans, which allow the cell incorporation of lactoferrin. The specificity of these receptors is such that other members of the family of transferrins (ovotransferrins, transferrins) yet structurally very close do not bind to this receptor of bovine or human lactoferrin and are therefore not absorbed.

Thus it has been demonstrated in pigs that bovine lactoferrin, which is naturally active until its arrival in the small intestine, is transported by transcytosis from the lumen of the digestive tract to the endothelial cells at the level of the villi; and endothelial cells to the bloodstream through the lymphatic system to the portal vein (Persorption of bovine lactoferrin from the intestinal lumen into the systemic circulation via the portal vein and the mesenteric lymphatics in growing pigs, Kitagawa H, Yoshizawa Y, Yokoyama T, Takeuchi T, Talukder MJ, Shimizu H, Ando K, Harada EJ Vet Med Sci 2003 May, 65 (5): 567-72). In the context of the present invention, lactoferrin administered orally is chosen, because of the martial etiology of neurological pathologies inventoried (restless leg syndrome, ADHD, nocturnal myoclonus, Tourette's syndrome) for its ability to normalize the circulating iron concentration by a tissue action at the level of the cells of the digestive tract.

Clinical studies have been conducted to compare the effects of iron supplementation versus oral lactoferrin intake on the different proteins involved in iron metabolism (particularly ferritin) (Lactoferrin efficacy versus ferrous sulfate in curing iron). Paesano R, Berlutti F, Pietropaoli M, Goolsbee W, Pacifici E, Valenti P. Int J Immunopathol Pharmacol 2010 Apr-Jun; 23 (2): 577-87). The results were obtained clinically with ferrous sulfate-type oral supplementation versus lactoferrin 20% saturated.

Nothing in these previous works suggests that human or bovine lactoferrin administered orally can also be used to treat diseases of neurological types or to compensate for nutritional imbalance in these patients. Oral lactoferrin can be used as a systemic therapeutic agent to act on the rise of ferritin levels in patients with restless legs syndrome, with the advantage of not disrupting systemic iron homeostasis and avoiding any inflammatory risk or undesirable side effect.

Even if they share an abnormally low level of ferritin, the subjects concerned by the invention (restless leg disease and other neurological or neuropsychiatric disorders) are in very different pathological situations and have symptoms that have nothing to do with it. in common with the patients described in the articles (Paesano R, Berlutti F, Pietropaoli M, Pantanella F, Pacifici E, Goolsbee W, Valenti P. Biometals, Lactoferrin efficacy versus ferrous sulfate in iron deficiency and iron deficiency anemia. 2010 Jun; 23 (3): 411-7 and Lactoferrin efficacy versus ferrous sulfate in curing iron and non-pregnant women. Paesano R, Berlutti F, Pietropaoli M, Goolsbee W, Pacifici E, Valenti P. Int J Immunopathol Pharmacol 2010 Apr-Jun; 23 (2): 577-87) (anemia of pregnant women or of childbearing age). The results described in the two articles cited above (2010 Paesano et al., Supra) do not make it possible to transfer the solution of the therapeutic choice to administer lactoferrin, especially orally, in order to compensate for and compensate for the symptoms associated with neurological diseases ( Restless legs syndrome, nocturnal myoclonus, Gilles de la Tourette syndrome) and corresponding neuropsychiatric (ADHD). These diseases have nothing to do with the situation of a non-pathological pregnancy, examples are the results of which have been published. This is therefore a very different technical field from that of the present invention.

In the present invention, human or bovine lactoferrin (natural molecules extracted or obtained by expression in genetic recombination systems retaining the natural glycosylations of the molecule obtained) was selected from the proteins belonging to the transferrin family as the active ingredient of a pharmaceutical composition and / or dietary or nutraceutical supplements for regulating and providing a serum concentration of suitable and sufficient iron to patients with iron deficiency or iron sequestration in tissues associated with non-specific treatment.

To avoid the inconveniences associated with a massive iron supplementation and to raise the ferritin level without inducing the triggering of a pro-inflammatory response and an intracellular sequestration of iron, lactoferrin (bovine or human) meets the characteristics of a molecule useful for regulating, orally, the level of iron in the tissues and in the blood.

The present invention therefore consists of compositions containing, as active principle, lactoferrin, the active principle alone, or in combination with other active ingredients, for use in a preparation:

- a pharmaceutical preparation

 - a dietary supplement

 - or as a nutraceutical component in an agri-food product.

This composition according to the invention aims to modulate the martial metabolism with a view to normalizing iron and the associated protein parameters in order to limit to eliminate the causes and symptoms of restless legs syndrome and other neurological or neuropsychiatric diseases related to iron deficiency, such as Gilles de Fa Tourette's syndrome, attention deficit disorder and nocturnal myoclonus. ¾

For neurological diseases, only those which are not neurodegenerative, are concerned with a pharmaceutical treatment consisting of a composition consisting wholly or in part of pure or purified lactoferrin or a nutraceutical food supplementation consisting wholly or in part at least by lactoferrin according to the present invention. The proportion of lactoferrin associated with other components or active products is between 10% to 90% total dry weight or total volume in case of liquid form of the composition in question.

In the context of this invention, it is not the ability of lactoferrin to bring iron via the hematoencephalic barrier to the cerebrospinal fluid, it is its ability to provide iron to blood proteins and especially to ferritin, which will improve the patient's symptomatology and the level of iron available and biologically useful for the human body.

The present invention relates to a pharmaceutical composition for treating non-degenerative neurological diseases selected from: restless leg syndrome, attention deficit, nocturnal myoclonus and Gilles de la Tourette syndrome and associated with iron deficiency, characterized in that it comprises lactoferrin.

It also relates to a pharmaceutical composition for treating psychiatric diseases associated with iron deficiency, characterized in that it comprises lactoferrin.

The present invention includes purified lactoferrin for treating nutritional deficits in patients with neurological diseases. . we degenerative o - psychiatric diseases and to treat symptoms of non-degenerative neurological disease or psychiatric illness.

 The present invention relates to dietary supplements or a nutraceutical composition characterized in that they comprise lactoferrin for treating restless leg syndromes, attention deficit, nocturnal rhyoconia and Tourette's syndrome and to treat iron deficiency in patients with the same syndromes. The invention relates to a combined composition for daily or delayed use for treating iron deficiency in adults and children, or a pathology associated with anemia characterized in that it comprises an active compound of lactoferrin administered. orally, combined with compounds allowing the oral use of said active compound.

The invention in its variants comprises a pharmaceutical composition characterized in that the concentration of lactoferrin is between 10 and

90 percent preferably between 25 and 45% by dry weight of said composition.

The invention relates to a pharmaceutical composition for treating psychiatric diseases or non-degenerative neurological diseases characterized in that it contains at least one of the compounds chosen from an excipient and / or a binder and / or an anticaking agent and / or at least one of the following compounds: ferrous or ferric salts, sialic acid and omega-3.

The present invention relates to a novel use of lactoferrin for the manufacture of an active pharmaceutical composition for treating non-degenerative or psychiatric neurological diseases or for the manufacture of a veterinary composition.

The invention relates to veterinary compositions containing at least one of the compounds selected from an excipient and / or a binder and / or an anti-caking agent and / or at least one of the following compounds: ferrous or ferric salts, sialic acid and omega And also comprising lactoferrin for the treatment of iron deficiency in animals. The invention relates to a process for the preparation of food supplements or nutraceutical composition comprising adding to a foodstuff bovine lactoferrin or extracted from milk or its derivatives or from human lactoferrin.

In order to illustrate the effects obtained in vivo in patients having signed an informed consent form in accordance with the legal provisions, the compositions according to the invention containing lactoferrin were administered as dietary supplements in the context of a clinical study. In the study, the nanaceutical compositions contained as active ingredient purified lactoferrin.

 The clinical study was conducted for 3 months to evaluate in vivo the interest of lactoferrin in patients with restless legs syndrome also known as RLS. It was carried out on two sites: in Strasbourg and in

Lille University Hospital.

Objectives of the study

 The main objective is to compare the situation of patients with restless leg syndrome with moderate iron deficiency preexisting to the clinical study (before treatment with bovine lactoferrin) with the possible effect observed on the evolution of this deficiency. iron after treatment with bovine lactoferrin. The purpose of the study is also to measure the benefits obtained on patients' iron deficiency by measuring a biomarker involved in iron metabolism (circulating ferritin level). The secondary objective is to compare the symptomatology of the same patients with restless legs syndrome with the possible effect observed on the evolution of this symptomatology after treatment with bovine lactoferrin.

The research therefore investigates the potential benefits on the symptoms of restless legs syndrome and anemia in patients taking lactoferrin in standard doses of 200mg per day.

 Main objective of the study: improvement of the circulating ferritin level

 During the clinical study, the main objective was to measure the evolution of the blood ferritin level of the patients included in the study.

Secondary objective: significant improvement of the RLS score To measure the severity of the syndrome, it has been established at an international level, a standardized and globally recognized questionnaire (IRLS International Remains ^" Legs Syndrome Rating Scale" written by the International Restless Legs Syndrom Study Group, in French: Questionnaire of severity of the syndrome Restless Legs) to assess and quantify the discomfort caused by the disease.This questionnaire includes 1Θ questions, which assess the degree of incorruption caused by the disease.The patient is asked to answer each of the questions by giving a our between us 0 and 4 (the score 0 corresponding to the absence of disorder and the note 4 to a ^" or -e-eele-maximum fading). At the end of the questionnaires, the 10 values obtained are summed up and lead to the elaboration of a final score (included between 0 "and 40) which makes it possible to evaluate the degree of severity of the syndrome (appreciating in particular, the frequency of crises, their duration, their consequences on the quality of sleep as well as their impact on mood and social life (your patients):

^• Score between 0 and 10: light restless leg syndrome

^• Score between 11 and 20: moderate restless leg syndrome

^• Score between 21 and 30: severe restless leg syndrome

^• Score between 31 and 40: very severe restless leg syndrome.

 During the course of the study, secondary objective was to have the patients recruited in the trial complete the questionnaire before and after treatment, in order to evaluate the impact of taking lactoferrin in terms of benefit and comfort of life. for the patient.

 Description of the studied population

 The population studied is patients with restless legs syndrome whose disorder has been clearly diagnosed. Since the disease appears at very different ages and exists in both sexes, there has been no elimination criteria, depending on the age or sex of the patient, as long as the person is of age.

To ensure a better intrinsic appreciation of the treatment, patients with restless legs syndrome excluding other sleep disorders (sleep apnea, for example) have been included unless these disorders are treated and stabilized (by a drug or medical device) for a period of at least three months prior to recruitment into the study.

In addition, people with major co-morbidities (heart, kidney, liver, etc.) were also excluded from the study.

Having previously been treated for restless legs syndrome with a product other than lactoferrin did not constitute an obstacle to inclusion, since treatment had been stopped for a period of at least one month, stabilized for a period of at least two months, and that it would not result in modifications during the trial.

Inclusion criteria

 The criteria for inclusion of patients were:

• Person diagnosed with Restless Leg Syndrome

 • Moderate iron deficiency: Serum ferritin level <90ng / l (less than or equal to 90 ng / l) in the absence of inflammatory syndrome

 • Major, free of his consent

 • No treatment of restless legs syndrome for one month or stable treatment for at least 2 months, unmodified during the trial

• Intensity of moderate to very severe syndrome IRLS> 15

 • Normal CRP and sedimentation rate

 • Affiliation to a social security scheme

Criteria of non-inclusion

The criteria for non-inclusion were:

 • Pregnant woman

 • Allergy known to dairy products *

^• Comorbidity with a disorder affecting sleep not stabilized by treatment for at least 2 months

 · Major comorbidity

 • Serum ferritin level> 90ng / l

 • Concomitant participation in another clinical trial

^• Alteration of the long-term treatment for Restless Leg Syndrome in the last 2 months prior to inclusion or during the trial

 · Patients already receiving treatment containing iron (wash-out period of one month prior to inclusion)

^• Sufficient linguistic and cognitive capacity to complete the questionnaire

^• Being under legal safeguards or guardianship * Although they exist, allergies to lactoferrin are rare, and generally unknown to the patient. The most common allergies to dairy products are lactose or large milk proteins (casein, albumin). As far as the test is concerned, it is safe to opt for a systematic exclusion of people with any allergy to dairy products.

Evaluation criteria

Main criterion

The main endpoint is the significant increase in ferritinemia. Traditionally, the blood ferritin level is considered normal for values between 50 and 300ng / l. These values were calculated on the basis of hematological parameters. The values of normal ferritinemia are giving rise to more and more discussion within the community of neurologists specializing in restless legs syndrome. And, in the context of this pathology, it appears that the low limit of the rate is probably insufficient and that the normality would be (according to the ethnic groups) rather between 75 and 300 ng / 1. serum ferritin in an incident dialysis patient cohort Int Urol Nephrol 2012 Dec; 44 (6): 1825-31 Kutner NG, Zhang R, Huang Y, Bliwise DLJ.

 In addition, patients with restless legs syndrome and mild iron deficiency may have very variable blood ferritin levels between 10 and 90 ng / l.

 Consequently, the statistical parameter chosen to estimate the impact of the treatment on the ferritin level was the measurement of a rise in the ferritin level by calculating the difference between the value of the ferritin level before the administration of lactoferrin and after the study. This rise is considered significant, since the rate increase is greater than or equal to 20ng / l.

 Secondary criterion

The secondary criterion consists in the improvement of the symptomatology: score obtained on the questionnaire of severity of the syndrome of the legs without rest before inclusion ( ₀ ) and at the end of the treatment (T ₃ ).

 Progress of the research

 As part of this research, 24 major patients were recruited for a period of 3 months, during which they took, blindly, twice a day, before the lunch and evening meal, 100mg of bovine lactoferrin.

 Statistical model

Description of statistical methods planned

 The statistical study protocol will be established as follows:

 • Unique analysis, no intermediate analysis

^• The subjects are matched, for each subject, compare the measurement before (at To) with the measure after (at T ₃ ).

^• The test is multicentric (2 centers), the analyzes will be adjusted on the center.

^• 1 single main criterion: response to ferritin, a blood biomarker. This is a continuous quantitative data.

^• Secondary criteria not influencing the calculation of the number of subjects required: simplified score resulting from the IRLS questionnaire.

^• Descriptive analysis of data and analysis of missing data

^• Variance analysis of the main criterion adjusted to the center

^• Analysis of variance of the secondary criterion adjusted on the center • The tests are all done bilaterally.

 • Significance test performed for an alpha risk of 5%

Expected number of people to be included in the research, with its statistical justification The expected number of people in the research is justified by the following data:

• Measures studied:

o Difference between the value at T ₀ and at T ₃ (3 months) of the blood biomarker

(rated Delta (To, T ₃ )

 o Secondary criterion does not influence the calculation of the number of subjects required: score resulting from the IRLS questionnaire

 • Bilateral comparison test:

o Null hypothesis: The Delta average (To, T ₃ ) is zero. No effect of the treatment.

o Alternative hypothesis: The Delta average (To, T ₃ ) is non-zero. Treatment has a positive or negative effect,

 o Alpha risk = 5%

 o Power = 90%

o Minimum gap to detect between To and T ₃ = 20

o Standard deviation of the difference between To and T ₃ = 25

 o Number of subjects needed = 17

^• expected degree of statistical significance;

 o Alpha risk = 5%, there is one main criterion and no intermediate analysis.

Recruitment is increased by 41% to account for potential loss of power due to missing data.

Choice of people included in the analyzes.

 All enrolled patients who meet the inclusion criteria and who do not have any protocol violations were included in the analysis. The analysis was conducted in intent to treat.

 Result of the study

The results are summarized in Table 1:

The results are summarized in Table 1:

 The results are summarized in Table 1:

The results are summarized in Table 1:

 Table 1: Summary of data obtained patient by patient

Materials and methods

 The data was provided from a spreadsheet file. All data processing was done with the R software.

 Patient LIL56 was removed from the study for non-compliance with inclusion criteria. Thus, the statistical study covers only 23 subjects, 13 from Strasbourg (identifier beginning with STR) and 10 from Lille (identifier beginning with LIL). Patient STR62 with a T3 ferritin level <5 was retained in the study at a rate arbitrarily set at 5.

 The statistical tests performed in the descriptive analysis part of the data and aimed at comparing the centers are the Student's test for quantitative variables and the Chi-2 test or the Fisher test (if the Chi-square test is not applicable) for qualitative variables.

Age distribution of subjects in both centers

 Age has a strong dispersion of values with a minimum of 20 years and a maximum of 80 years and a standard deviation of nearly 18 years. 50% of the subjects are over 60 years old and 25% are over 68.5 years old. The average age of the sample is 57 (56.78).

In view of the statistical indicators, it would seem that the sample from Strasbourg is younger (average, median and quartiles 25% and 75% lower than those of Lille), however the statistical test does not conclude to a significant difference between 2 centers (probability of Student's test = 0.33> 5%). The dispersions are very close (standard deviations = 17.91 and 17.39). Conclusion

 The samples recruited from the two centers are quite comparable at the time of recruitment. Table 2 provides a summary of the descriptive analysis of each variable. Moreover, the order of inclusion does not seem to have created a bias in the data.

 The data therefore seems entirely correct for the analysis of the clinical trial.

Global Lille Strasbourg P *

Age. Average (Min-Max) "56.8 (20-80) 61 (20-80) 53.5 (20-80) 0.33

Sex M / F, N (%) 6/17 (26.1 / 73.9) 1/0 (10/90) 5/8 (38.5 / 61.5) o. is

Baseline Yes / No, {%) 16/7 (69.6 / 30.4) 8/2 (80/20) 8/5 (61.5 / 38.5) 0.41

RLS score at TO.

28.5 (17-38) 28.2 (17-35) 28.7 (20-38) 0.86

Ferritin at TO, Average (Min-Max) 36.5 (7-8S) 41 (16-88) 33.1 (7-69) 0.36

 Table 2: Summary of descriptive analysis of variables at To * p is the probability of the comparison test in both centers

Analysis of the clinical trial

2 criteria are éttKrrés ^~ "fe-scoreda RLS questionnaire and rate Ferritin

 RLS questionnaire score

Figure 1 and Table 3 represent the distribution of the evolution of the RLS questionnaire score between T ₀ and T ₃ (delta corresponding to the T ₃ score - To score). Distribution is plotted by center and all centers combined.

Figure 1 represents comparative box plots for the evolution of the RLS questionnaire score

 - Lines A, C, E represent the maximum values of the sample

 Lines B, D, F represent the minimum values of the sample - Lines G, H, 1 represent the median of the data (the value that divides the sample into two groups of equal numbers)

 - The ends of the boxes Ql represent the first quartile

The ends of the Q3 boxes represent the third quartile Min Q. 25% 1 Median Mean Q, 75% 1Vl x Standard deviation N

Lille -17.00 -1 1.50 -5.00 -5.00 2.00 5.00 7.86 10

Strasbourg -15-00 -8.00 -3.00 -3.85 -1.00 8.00 5.74 13

Strasbourg + Lille -17.00 -8.50 -3.00 -4.35 -0.50 8.00 6.60 23

Table 3: Statistical indicators of the evolution of the RLS questionnaire score (Delta =

 T3-T0)

 Overall, the score decreases between T0 and T3 since 75% of the subjects in the overall sample have a negative delta corresponding to a positive effect (ie a medium to high improvement) of lactoferrin treatment. On average, the score decreases by 4.35 points on the overall sample. The effect is stronger for Lille with a reduction of 5 points of the score against only 3.85 for Strasbourg. The standard deviations are not negligible because they all exceed the observed averages (in absolute value). There is therefore a significant disparity in the evolution of the score between the subjects, the disparity is greater in the center of Lille.

 Model results: After defining the best configuration of the random effect, we test the fixed effects (center effect, sex effect, background treatment effect, treatment effect tested). From all these results, we deduce that:

- The center effect is not significant (p = 0.7218). It is still kept in the model as an adjustment factor.

 - Sex and treatment effects have no significant effect (p = 1 and p = 0.434, respectively).

 They are not included in the model testing the treatment effect.

- The effect of treatment with lactoferrin is very significant (p = 0.003302), it significantly reduces the score.

We then proceed to the Student test because the data follow a normal distribution. The probability of the test confirms that the mean delta is significantly different from 0 (probability of the test = 0.004563 <5%). The results converge well with those of modeling.

Conclusion: There is a significant effect of the treatment in terms of improvement of the symptomatology of the patients. On average, the gain in score is 4.35 points.

Ferritin levels Figure 2 and Table 4 show the evolution of Ferritin levels between T0 and T3 (T3 rate - TO level). Figure 2 represents comparative boxes of the rate of ferritin

Min Q, 25% Median Mean Q. 75% Max Standard Deviation N

Lille -23.00 -4.75 -1.50 Î .90 14.00 22.00 14.25 10

Strasbourg -14.00 -6.00 -2.00 -0.23 6.00 24.00 10.30 13

Strasbourg -Lille -23.00 -6.00 -2.00 0.70 7.00 24.00 1 1.92 23

Table 4: Statistical indicators of the evolution of the ferritin level (Delta = T3-T0) One observes a very great dispersion in the results. There is a minimum at -23 and a maximum at 24, which is 47. Standard deviations are all well above average. There is therefore a great deal of variability between subjects. The variability is greater in the sample from Lille. The medians by center and all centers are very close together and the value 0. The average of the delta of Lille is the highest at 1.9.

 Model results: After defining the best configuration of the random effect, we test the fixed effects (center effect, sex effect, stable background treatment effect, tested treatment effect). From all these results, we deduce that:

 From all these results, we deduce that:

- The sex effect is significant (p = 0.008148). Women have a lower Ferritin level overall than men. This effect is therefore included in the model that tests the treatment effect.

 - The center effect is significant in the model including the sex effect (p = 0.01572). Strasbourg subjects tend to have a lower rate.

- The background treatment effect (yes / no) is at the limit of significance (p = 0.06224). Taking a background treatment may have a tendency to increase the level of Ferritin. This effect is included in the model that tests the treatment effect.

- The treatment effect with lactoferrin is not significant (p = 0.6821) on the ferritin level.

The modeling has shown a significant effect of the center and sex, it is not recommended to conduct a simple analysis that does not take into account (Student-type test).

Conclusion: Treatment with lactoferrin has no significant effect on the level of Ferritin.

General conclusion The treatment has a significant effect on the 3-month evolution of the RLS questionnaire score. On average, the score is reduced by 4.35 points. There is a strong disparity in the evolution of the scores

between the subjects (25% of the subjects have an improvement of the score of 8.5 points whereas 25% of the subjects have a score which has hardly changed or increased (delta> -0.5)).

On the other hand, the statistical analysis does not allow to conclude to a significant effect of the treatment on the Ferritin level.

 The intake of lactoferrin to patients included in the clinical study statistically shows an improvement of the symptomatology in 75% of the cases with a dose of 200 mg per day.

A preferred dosage of 200 to 800 mg / day of lactoferrin is recommended in patients to modulate the severity effects of the EPIRB and as a function of the duration of this treatment.

It is found that the ferritin level, as such, which is known to be a marker of anemia when it is low, can not be considered as a reliable (causal) marker of the EPIRB.

Iron intake by lactoferrin has not shown a significant effect and should not be considered as the only active treatment for anemia in patients with non-neurodegenerative neurological diseases.

A. EXAMPLES

 Example No. 1: Pharmaceutical Composition

The lactoferrin composition to be administered orally comprises:

- The active ingredient which is freeze-dried lactoferrin (or fragments of lactoferrin having retained their therapeutic properties) extracted from purified recombinant human milk or lactoferrin (25 to 45% of the dry weight) with a degree of iron saturation between 0 and 90 %, preferably between 0 and 50% and optionally at least one of the following: an excipient, a binder and an anti-caking agent. If necessary, a dye and a delivery medium such as capsule or cachet. Optionally, these compositions may also contain the following elements: ferrous or ferric salts, the concentration of which represents a ratio of between 0.1% and 10% of the total weight of the composition, as well as, optionally, sialic acid in a ratio of between 0.1% and 10% of the total weight of the composition, polyunsaturated fatty acids, for example omega-3 in a ratio of between 0.1% and 10% of the total weight of the composition, and omega In a ratio of between 0.1% and 10% of the total weight of the composition.

By way of example, a pharmaceutical presentation according to the invention will comprise, in a capsule-type carrier, freeze-dried lactoferrin (100 mg) and starch such as corn starch (450 mg). By way of example, this composition is used at a daily dosage of the active principle of between 100 and 400 mg / day for a subject of 70 kg in one or more doses:

 - As a therapeutic treatment in Restless Legs Syndrome (Willis-Ekbom's Disease), Tourette's syndrome, Attention Deficit Disorder (ADHD) and nocturnal myoclonus.

 - As a dietary supplement in Restless Legs Syndrome (Willis-Ekbom's Disease), Tourette's syndrome, Attention Deficit Disorder (ADHD) and nocturnal myoclonus.

In the context of a therapeutic use, the composition must be administered taking into account the following elements:

^• The appropriate dosage is based on age and patient profile between 50 and 400mg / day, ideally in two doses

^• The duration of the treatment extends over a minimum period of one month without limit of duration

· There are no known interactions of lactoferrin with other compounds. Lactoferrin can therefore be used alone or in combination with other treatments. • Lactoferrin is given orally twice daily before meals (lactoferrin is degraded by excess stomach acid).

• The optional realization of a preliminary diagnostic test to evaluate serum ferritin

 · Vigilance is needed for people allergic to dairy products, although the most common allergy is lactose

EXAMPLE 2 Nutraceutical Composition A nutraceutical composition containing lactoferrin extracted from cow's milk or whey is constituted by:

Lactoferrin according to the invention (or lactoferrin fragments having retained their therapeutic properties) is at an iron saturation level of between 0 and 90%, preferably between 0 and 50%, representing between 0.1 and 10 g. for 100 kcal. Optionally, lactoferrin is associated with the following elements: ferrous or ferric salts, the concentration of which represents a ratio of between 0.1% and 10% of the total weight of the composition, as well as, optionally, sialic acid in a ratio between 0.1% and 10% of the total weight of the composition, polyunsaturated fatty acids such as omega-3 in a ratio of between 0.1% and 10% of the total weight of the composition, and omega-6 in a ratio of between 0.1% and 10% of the total weight of the composition. The composition may also, as an alternative, contain only purified lactoferrin according to the invention.

 - The said nutraceutical composition can be used in the manufacture of a food, a food for animals such as livestock, pet food, a nutritional formulation, a drink, a food additive for the adult or the child

 This composition can also be a source of proteins, lipids, carbohydrates.

This composition contains lactoferrin in dry form, such as a lyophilizate, which is a stabilized form. This composition is used daily:

 - As a supplement in the diet to improve the symptoms of patients with Restless Legs Syndrome (Willis-Ekbom's Disease), Tourette's Syndrome, Attention Deficit Disorder (ADHD) and nocturnal myoclonus.

As an indication, the composition comprises 0.2 ml of purified bovine lactoferrin per 100 ml of milk drink. Milks sterilized by Ultra High Temperature (UHT) (above 70 ° C) are depleted or lack lactoferrin. The addition of purified or bovine recombinant human lactoferrin or sterile extract to these commercially produced milk, makes it possible to compensate for the very low residual lactoferrin and to constitute a nutraceutical composition useful for adults and children with iron deficiency. This composition comprises per liter of UHT milk 10 to 100 mg of lactoferrin per 100 ml of milk.

Example 3: Dietary supplement

An edible composition based on lactoferrin extracted from cow's milk or whey used as a dietary supplement contains:

 Lactoferrin (or fragments of lactoferrin which have retained their therapeutic properties) at an iron saturation level of between 0 and 90%, preferably between 0 and 50%, represents between 0.1 and 25 g for 100 kcal, and optionally ferrous or ferric salts, the concentration of which represents a ratio of between 0.1% and 10% of the total weight of the composition, as well as, optionally, sialic acid in a ratio of between 0.1% and 10%. % of the total weight of the composition, omega-3 in a ratio of between 0.1% and 10% of the total weight of the composition, and omega-6 in a ratio of between 0.1% and 10% by weight. total of the composition.

- The composition may be used in the manufacture of a food for human use or an animal feed (such as livestock, horses, pets such as cats or dogs), a drink, a food additive or in a nutritional formulation. - Possibly a diluent or solvent such as liquid (water or milk for example aromatized or not) allowing the suspension or the production of a solution of lactoferrin or lactoferrin containing.

 The said composition may also be a source of proteins, lipids, carbohydrates, which have been selected according to need.

 - Lactoferrin can be added in the form of powder, lyophilisate, solution.

This composition may be used daily or in a delayed form on a weekly basis, for example:

- as a dietary supplement to improve the symptoms of patients with Restless Legs Syndrome (Willis-Ekbom's Disease), Tourette's Syndrome, Attention Deficit Disorder (ADHD) and nocturnal myoclonus and other neurological and psychiatric pathologies. A list of bibliographic references is included in order to illustrate the prior art existing prior to the design and implementation of the present invention without limiting the variants thereof.

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Claims

claims

1. Pharmaceutical composition for treating non-degenerative neurological diseases selected from: restless legs syndrome, attention deficit, nocturnal myoclonus and Gilles de la Tourette syndrome characterized in that it comprises lactoferrin.

 2. Pharmaceutical composition according to claim 1 for treating non-degenerative neurological diseases selected from restless leg syndrome, attention deficit, nocturnal myoclonus and Tourette's syndrome and associated with iron deficiency.

 3. A pharmaceutical composition for treating psychiatric diseases characterized in that it comprises lactoferrin.

 4. Pharmaceutical composition according to claim 3 for treating psychiatric diseases associated with iron deficiency

 5. Purified lactoferrin to treat nutritional deficits in patients with non-degenerative or psychiatric neurological conditions and to treat symptoms of non-degenerative or psychiatric neurological conditions.

 6. Dietary supplement characterized in that it comprises lactoferrin according to claim 5 for treating restless leg syndromes, attention deficit, nocturnal myoclonus and Tourette's syndrome and to treat iron deficiency in patients with the same syndromes.

7. Combination composition for daily or delayed use according to one of claims 1 to 6 for the treatment of iron deficiency in adults and children or a pathology associated with anemia characterized in that it comprises as an active compound lactoferrin administered orally, combined with compounds allowing the oral use of said active compound.

8. Composition according to one of claims 1 to 4 characterized in that the lactoferrin concentration is between 10 and 90% by dry weight of said composition

 9. Composition according to one of claims 1 to 4 and according to claim 8 characterized in that the concentration of lactoferrin is between 25 and

45% by dry weight of said composition.

 10. Composition according to one of claims 1 to 4 and according to claims 8 or 9 characterized in that it contains at least one of the compounds selected from an excipient and / or a binder and / or an anti-caking agent and / or at least one of the following compounds: ferrous or ferric salts, sialic acid and omega-3.

11. Use of lactoferrin for the manufacture of an active pharmaceutical composition for treating non-degenerative neurological diseases or psychiatric diseases or for the manufacture of a veterinary composition.

Veterinary compositions containing the composition according to at least one of claims 7, 8, 9 or 10 and comprising lactoferrin for the treatment of iron deficiency in animals.

13. Process for the preparation of food supplements or nutraceutical composition consisting of adding bovine lactoferrin to a food or extracted from milk or its derivatives or from human lactoferrin.