ITMI20112433A1 - COMPOSITIONS FOR ADIUVANT ORAL THERAPY OF ANORESSIA INCLUDING ANTIBACTERIALS, ANTIBACTERIALS, GROWTH FACTORS AND CYTOCHINES - Google Patents
COMPOSITIONS FOR ADIUVANT ORAL THERAPY OF ANORESSIA INCLUDING ANTIBACTERIALS, ANTIBACTERIALS, GROWTH FACTORS AND CYTOCHINES Download PDFInfo
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- ITMI20112433A1 ITMI20112433A1 IT002433A ITMI20112433A ITMI20112433A1 IT MI20112433 A1 ITMI20112433 A1 IT MI20112433A1 IT 002433 A IT002433 A IT 002433A IT MI20112433 A ITMI20112433 A IT MI20112433A IT MI20112433 A1 ITMI20112433 A1 IT MI20112433A1
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Description
Descrizione Description
“COMPOSIZIONI PER LA TERAPIA ORALE ADIUVANTE DELL’ANORESSIA COMPRENDENTI ANTICORPI, ANTIBATTERICI, FATTORI DI CRESCITA E CITOCHINE†⠀ œCOMPOSITIONS FOR ADJUVANT ORAL THERAPY FOR ANOREXIA INCLUDING ANTIBODIES, ANTIBACTERIALS, GROWTH FACTORS AND CYTOKINESâ €
La presente invenzione ha per oggetto composizioni per la terapia adiuvante dell’anoressia comprendenti anticorpi, fattori di crescita e citochine, isolati dai tessuti e dai liquidi biologici dei mammiferi. The present invention relates to compositions for the adjuvant therapy of anorexia comprising antibodies, growth factors and cytokines, isolated from the tissues and biological fluids of mammals.
Stato della tecnica State of the art
Una persona à ̈ affetta da Anoressia Nervosa se manifesta tutte e quattro le seguenti caratteristiche: A person has Anorexia Nervosa if they have all four of the following:
- Perdita di peso rilevante (più del 15% del peso considerato normale per età , sesso e altezza); - Significant weight loss (more than 15% of the weight considered normal for age, sex and height);
- Paura intensa di ingrassare anche quando si à ̈ sottopeso; - Intense fear of gaining weight even when you are underweight;
- Alterazione nel modo di vivere il peso, la taglia e le forme corporee; - Scomparsa delle mestruazioni (nelle donne assenza di almeno tre cicli mestruali consecutivi). - Alteration in the way of living weight, size and body shape; - Disappearance of menstruation (absence of at least three consecutive menstrual cycles in women).
Si distinguono due forme di anoressia nervosa: l’anoressia restrittiva, forma in cui il dimagrimento à ̈ causato dal digiuno e dall’intensa attività fisica, e l’anoressia con bulimia, forma in cui la persona mette in atto comportamenti che insieme al digiuno servono a diminuire il peso corporeo (abuso di lassativi e/o diuretici, vomito). There are two forms of anorexia nervosa: restrictive anorexia, a form in which weight loss is caused by fasting and intense physical activity, and anorexia with bulimia, a form in which the person engages in behaviors that together with fasting they serve to decrease body weight (abuse of laxatives and / or diuretics, vomiting).
L’anoressia e i disturbi alimentari in generale sono una vera e propria emergenza sanitaria nei paesi occidentali industrializzati e, secondo molti autori, sono in continuo aumento. In realtà i vari studi effettuati non concordano: se parte di essi tende a evidenziare un preoccupante aumento dei casi, altri sottolineano l’andamento costante, senza alcuna variazione. Uno studio di tipo meta-analitico, che ha esaminato l’evoluzione storica della malattia nel passato (1995), ha dimostrato come negli anni novanta la percentuale di popolazione colpita sia rimasta costante. Anorexia and eating disorders in general are a real health emergency in western industrialized countries and, according to many authors, are constantly increasing. In reality, the various studies carried out do not agree: if some of them tend to highlight a worrying increase in cases, others underline the constant trend, without any variation. A meta-analytical study, which examined the historical evolution of the disease in the past (1995), showed that in the nineties the percentage of the affected population remained constant.
Secondo i dati ricavati dalla letteratura la prevalenza (numero totale dei casi nella popolazione) dell’anoressia si attestava attorno allo 0,3% nel 2003, mentre l’incidenza (numero di nuovi casi nella popolazione in un determinato periodo di tempo) à ̈ di 8 casi per 100.000 soggetti in un anno. La percentuale poi à ̈ stata aggiornata a 0,42% nel 2006 da studi condotti in Italia. In seguito, nel 2007, la prevalenza si sarebbe leggermente alzata, attestandosi attorno allo 0,5% o, come suggerisce più pessimisticamente un altro studio, avrebbe superato il 2%. Per quanto riguarda l’età di esordio, questa si situa fra i 12 e i 25 anni (anche se si sono verificati negli ultimi anni diversi casi che superano i 30 anni), con il momento più critico fra i 15 e i 19 anni. Altri studi hanno trovato picchi di incidenza in corrispondenza dei 14 e 18 anni d’età . La malattia quindi colpisce soprattutto gli adolescenti, anche se ultimamente si stanno sempre più registrando casi negli adulti e anche tra gli anziani. According to the data obtained from the literature, the prevalence (total number of cases in the population) of anorexia was around 0.3% in 2003, while the incidence (number of new cases in the population in a given period of time) It is 8 cases per 100,000 subjects in a year. The percentage was then updated to 0.42% in 2006 by studies conducted in Italy. Thereafter, in 2007, the prevalence would have risen slightly, settling at around 0.5% or, as another study suggests more pessimistically, would have exceeded 2%. As far as the age of onset is concerned, this is between 12 and 25 years (although several cases over 30 years have occurred in recent years), with the most critical moment between 15 and 19 years. Other studies have found incidence peaks at 14 and 18 years of age. The disease therefore affects mainly adolescents, although lately there are more and more cases in adults and also among the elderly.
Altra caratteristica tipica dell’anoressia à ̈ quella di essere un disturbo prettamente femminile: circa il 90% dei casi, infatti, si sviluppa nel sesso femminile. Il problema comunque non riguarda solamente le donne. Anche se gli studi sul sesso maschile sono minori, à ̈ stato stimato che sul totale degli ammalati risultano essere presenti dal 5% al 10% di casi riguardanti ragazzi adolescenti e maschi adulti. Il rapporto uomini-donne secondo alcune ricerche à ̈ di 1:10; altri studi hanno rilevato una differenza minore fra i sessi, arrivando anche a 1:8. La percentuale di maschi anoressici sembra in aumento, ma ciò potrebbe derivare dal semplice fatto che oggi un maggior numero di uomini si rivolgono ad un medico per curare tale disturbo. Another typical characteristic of anorexia is that of being a purely female disorder: about 90% of cases, in fact, develop in the female sex. However, the problem is not just about women. Even if the studies on the male sex are minor, it has been estimated that out of the total number of patients, 5% to 10% of cases involving adolescent boys and adult males are present. According to some research, the male-female ratio is 1:10; other studies have found a smaller difference between the sexes, even reaching 1: 8. The percentage of anorexic males appears to be on the rise, but this could stem from the simple fact that more men are now seeking medical attention to treat this ailment.
Le cause di questa malattia non sono ancora chiare. The causes of this disease are still unclear.
Ricerche effettuate sulle caratteristiche biochimiche dei pazienti affetti da disturbi del comportamento alimentare hanno rilevato che i neurotrasmettitori “serotonina†e “noradrenalina†sono presenti in numero minore in coloro che soffrono di anoressia, caratteristica che li avvicina a coloro che soffrono di depressione. Queste caratteristiche sono confermate da studi che hanno dimostrato che alcuni antidepressivi possono essere utilizzati con successo nella cura di questi disturbi. Persone affette da anoressia tendono spesso ad avere un tasso di “cortisolo†(un ormone prodotto dal cervello in situazioni di stress) e “vasopressina†(un ormone prodotto dal cervello in quantità anormali in pazienti affetti da “disturbo ossessivocompulsivo†) più alto del normale. Researches carried out on the biochemical characteristics of patients suffering from eating disorders have found that the neurotransmitters â € œserotoninâ € and â € œnoradrenalineâ € are present in smaller numbers in those suffering from anorexia, a characteristic that brings them closer to those suffering from depression. These characteristics are confirmed by studies that have shown that some antidepressants can be used successfully in the treatment of these disorders. People with anorexia often tend to have a rate of `` cortisol '' (a hormone produced by the brain in stressful situations) and `` vasopressin '' (a hormone produced by the brain in abnormal quantities in patients with `` obsessive-compulsive disorder '') higher than normal.
Altri scompensi psichici possono accompagnare l’anoressia come il “disturbo ossessivo-compulsivo†, la tendenza all’autolesionismo o i “disturbi bipolari†. Other mental disorders can accompany anorexia such as "obsessive-compulsive disorder", the tendency to self-harm or "bipolar disorders".
In genere i farmaci antidepressivi possono essere efficaci nella cura delle persone affette da anoressia, ma la terapia più efficace si à ̈ rivelata il riuscire a fare raggiungere un peso entro il 10% di quello normale. Anche una psicoterapia individuale a familiare può aiutare. Generally, antidepressant drugs can be effective in treating people with anorexia, but the most effective therapy has been found to be able to achieve a weight within 10% of normal. Individual-to-family psychotherapy can also help.
L’inedia sofferta dagli anoressici può causare danni a organi vitali quali cuore e cervello. The starvation suffered by anorexics can cause damage to vital organs such as the heart and brain.
Il ritmo respiratorio, il battito cardiaco e la pressione sanguigna diminuiscono ed a volte chi soffre di questa patologia à ̈ affetto da aritmie o problemi cardiaci. Un’alimentazione povera causa la decalcificazione delle ossa che diventano fragili e soggette a rotture. Nei casi più gravi gli anoressici possono lasciarsi morire per denutrizione. I disturbi dell’alimentazione presentano il più alto tasso di mortalità tra i disturbi della personalità , annoverando un tasso di mortalità del 6%. La maggior parte degli effetti collaterali si sono rivelati fortunatamente reversibili. Da quanto sopra riportato risulta evidente l’esigenza di disporre di ausili farmacologici, dietetici o alimentari che possano aiutare a risolvere il complesso quadro di questa patologia. The respiratory rate, heart rate and blood pressure decrease and sometimes those suffering from this pathology suffer from arrhythmias or heart problems. A poor diet causes the decalcification of the bones which become brittle and prone to breakage. In severe cases, anorexics can allow themselves to die of malnutrition. Eating disorders have the highest mortality rate among personality disorders, accounting for a death rate of 6%. Fortunately, most of the side effects turned out to be reversible. From the above it is evident the need for pharmacological, dietary or food aids that can help resolve the complex picture of this pathology.
Descrizione dell’invenzione Description of the invention
Secondo la corrente letteratura scientifica, l’azione terapeutica delle cellule staminali può essere riconducibile a due meccanismi: differenziazione delle cellule staminali in cellule residenti e rilascio di fattori trofici rigenerativi da parte delle cellule staminali. I rispettivi contributi di questi due meccanismi rimangono da chiarire, anche se à ̈ stato ipotizzato che non siano le cellule staminali a trasformarsi in cellule mature del tessuto leso, ma che esse trasmettano dei fattori vitali a questo tessuto, che può così tornare a proliferare e a differenziarsi, rigenerandosi (Figura). According to current scientific literature, the therapeutic action of stem cells can be traced back to two mechanisms: differentiation of stem cells into resident cells and release of regenerative trophic factors by stem cells. The respective contributions of these two mechanisms remain to be clarified, even if it has been hypothesized that it is not the stem cells that transform into mature cells of the injured tissue, but that they transmit vital factors to this tissue, which can thus return to proliferate. and to differentiate, regenerating (Figure).
La terapia con cellule staminali presenta molti problemi legati non solo ai costi e a complicazioni tecniche ed applicative, ma anche a scrupoli etici e religiosi. Stem cell therapy presents many problems related not only to costs and technical and application complications, but also to ethical and religious scruples.
La terapia con cellule staminali à ̈ attuabile solo per via iniettiva o, in alcuni casi, topica, e non per via orale. Il sovranatante delle cellule staminali in coltura contiene fattori di crescita, citochine, fattori chemiotattici ecc. che si ritiene siano responsabili dell’effetto benefico della terapia staminale sulla crescita e/o riparazione dei tessuti. Stem cell therapy is feasible only by injection or, in some cases, topically, and not by mouth. The stem cell supernatant in culture contains growth factors, cytokines, chemotactic factors, etc. believed to be responsible for the beneficial effect of stem cell therapy on tissue growth and / or repair.
L’eventuale utilizzo dei fattori vitali isolabili dal sovranatante delle cellule staminali presenta, tuttavia, non solo gli stessi problemi etici dell’uso delle cellule staminali stesse ma anche costi molto elevati. The eventual use of the vital factors that can be isolated from the supernatant of the stem cells presents, however, not only the same ethical problems of the use of the stem cells themselves but also very high costs.
Si à ̈ sorprendentemente scoperto che nei liquidi biologici e in alcuni tessuti dei mammiferi sono presenti gli stessi fattori attivi rilasciati dalle cellule staminali e pertanto presenti nel sovranatante delle colture delle cellule staminali stesse. Le migliori sorgenti di questi fattori sono il siero, la placenta e il colostro dei mammiferi. It was surprisingly found that the same active factors released by stem cells and therefore present in the supernatant of stem cell cultures are present in biological fluids and in some mammalian tissues. The best sources of these factors are mammalian serum, placenta, and colostrum.
La Tabella riporta il confronto qualiquantitativo fra i fattori presenti nel sovranatante delle colture di cellule staminali e i fattori isolati da queste nuove sorgenti da noi denominati POOL OF MATERNAL FACTORS (P.M.F.). The Table reports the qualitative comparison between the factors present in the supernatant of stem cell cultures and the factors isolated from these new sources which we call POOL OF MATERNAL FACTORS (P.M.F.).
Tabella Table
P.M.F. Mesenchymal NÀME (pg/ml) stein ceils (pg/ml) IL 1 ra IL-1 receptor antagonist 29.05 0.0 P.M.F. Mesenchymal Nà € ME (pg / ml) stein ceils (pg / ml) IL 1 ra IL-1 receptor antagonist 29.05 0.0
IL-lb Interleukin - 0.09 0.0 IL-lb Interleukin - 0.09 0.0
IL-2 Interleukin-2 32.05 0.0 IL-2 Interleukin-2 32.05 0.0
IL-4 Interleukin-4 0.17 21.12 IL-4 Interleukin-4 0.17 21.12
IL -6 Interleukin- 6 1.26 293.01 IL-8 Interleukin - 8 0.71 359.56 IL -6 Interleukin- 6 1.26 293.01 IL-8 Interleukin - 8 0.71 359.56
IL-9 Interleu -9 3.66 0.78 IL-9 Interleu -9 3.66 0.78
IL- 10 Interleuk - 10 2.83 0.99 IL- 10 Interleuk - 10 2.83 0.99
IL-12 Interleuk -12 1.73 0.0 IL-12 Interleuk -12 1.73 0.0
IL- 15 Interleukin -15 4.33 0.5 IL- 15 Interleukin -15 4.33 0.5
IL- 17 Interleukin - 17 21.95 0.32 Eotaxin Eotaxin 5.01 0.0 IL- 17 Interleukin - 17 21.95 0.32 Eotaxin Eotaxin 5.01 0.0
INF-γ Gamma -interferon 5.97 11.14 MCP-1 Monocyte chemotactic factor-1 4.12 11.23 INF-γ Gamma -interferon 5.97 11.14 MCP-1 Monocyte chemotactic factor-1 4.12 11.23
PDGF Piatelet derived growth factor 11. 3.08 TNT Tumor necrosis factor 40.00 12.30 PDGF Piatelet derived growth factor 11. 3.08 TNT Tumor necrosis factor 40.00 12.30
endot helial growth 41 .00 208.04 VEGF factor endot helial growth 41 .00 208.04 VEGF factor
HGF Hepatocyte growth factor 52.3 100.74 HGF Hepatocyte growth factor 52.3 100.74
F GF Fibroblast growth factor 180.15 18.21 TGF- 64.00 51.32 beta1 transforming growth factor F GF Fibroblast growth factor 180.15 18.21 TGF- 64.00 51.32 beta1 transforming growth factor
IGF-1 insulin-like growth factor 1.60 0.0 IGF-1 insulin-like growth factor 1.60 0.0
GM- Gramilocyte/moiiocyte-colony 183.85 0.0 CSF stimulating factor GM- Gramilocyte / moiiocyte-colony 183.85 0.0 CSF stimulating factor
LIF leukemia inhibitory factor 15.20 27.32 SCF stelli cell factor 10.55 4.54 SDF- 1 stromal derived factor- 1 41.75 28.8 NGF Nerve growth factor 8.33 0.0 BMP-2 Bone morphogenic protein 25.01 2.65 LIF leukemia inhibitory factor 15.20 27.32 SCF stelli cell factor 10.55 4.54 SDF- 1 stromal derived factor- 1 41.75 28.8 NGF Nerve growth factor 8.33 0.0 BMP-2 Bone morphogenic protein 25.01 2.65
RNÀ 189 ng/ml 48 pg/ml RNà € 189 ng / ml 48 pg / ml
Presenza di fattori di crescita/citochine in P.M.F. (1 mg /ml) e nel surnatan di Cellule Staminali Mesenchimali (1 milione di cellule). Presence of growth factors / cytokines in P.M.F. (1 mg / ml) and in the Mesenchymal Stem Cell supernatant (1 million cells).
È evidente (tabella) la maggior concentrazione di quasi tutti i fattori presenti nel P.M.F. rispetto a quella presente nel sovranatante delle cellule staminali. It is evident (table) the greater concentration of almost all the factors present in the P.M.F. compared to that present in the stem cell supernatant.
È inoltre evidente la possibilità di utilizzare concentrazioni terapeutiche anche molto alte di P.M.F., ad esempio dosi da 0,5/1 g per via topica o iniettiva e dosi fino a 20/30 g per via orale, rispetto alle massime concentrazioni terapeutiche utilizzate di cellule staminali che corrispondono a 1/2 milioni/Kg e pertanto a un massimo di 140 milioni per terapia e, dunque, a valori di fattori sempre dell’ordine dei picogrammi. It is also evident the possibility of using even very high therapeutic concentrations of P.M.F., for example doses of 0.5 / 1 g topically or injected and doses up to 20/30 g orally, compared to the maximum therapeutic concentrations of cells used. stem cells that correspond to 1/2 million / kg and therefore to a maximum of 140 million per therapy and, therefore, to values of factors always of the order of picograms.
L’oggetto dell’invenzione à ̈ quindi un composto (P.M.F.) contenente in altissima concentrazione tutti i fattori attivi presenti nel sovranatante delle cellule staminali ma isolati, con semplici metodiche estrattive, da fonti naturali molto economiche, di facile reperibilità e senza problemi etici. The object of the invention is therefore a compound (PMF) containing in very high concentration all the active factors present in the supernatant of stem cells but isolated, with simple extraction methods, from very cheap natural sources, easily available and without problems. ethical.
Inoltre P.M.F., isolato dai liquidi biologici e dai tessuti di mammiferi, contiene anche fattori antibatterici (transferrina, lisozima, lactoperossidasi, lactoferrina) e anticorpi delle classi IgG e IgA. (P.M.F. Ab). Furthermore P.M.F., isolated from biological fluids and mammalian tissues, also contains antibacterial factors (transferrin, lysozyme, lactoperoxidase, lactoferrin) and antibodies of the IgG and IgA classes. (P.M.F. Ab).
L’assenza di anticorpi e di antibatterici del sovranatante delle cellule staminali à ̈ un’ulteriore ragione per l’utilizzo di P.M.F. Ab in molti usi terapeutici, topici e per via orale. The absence of antibodies and antibacterials of the stem cell supernatant is another reason for the use of P.M.F. Ab in many therapeutic, topical and oral uses.
Il siero presenta il massimo picco dei fattori negli ultimi giorni prima del parto, il colostro nelle prime ore dopo il parto e non oltre la 6° ora. The serum shows the maximum peak of the factors in the last days before the birth, the colostrum in the first hours after the birth and no later than the 6th hour.
Già dopo 12 ore dal parto i fattori diminuiscono notevolmente, a 24 h molti di loro non sono più dosabili. Already after 12 hours from the birth the factors decrease considerably, at 24 hours many of them are no longer measurable.
Questi fattori sono geneticamente molto conservati nelle varie specie e pertanto à ̈ possibile usare sull’uomo fattori isolati da altre specie di mammiferi come i bovini, gli equini, i cammelli, i mammiferi marini ecc. These factors are genetically very conserved in the various species and therefore it is possible to use on humans factors isolated from other mammal species such as cattle, horses, camels, marine mammals, etc.
I fattori sono controllati con metodiche ELISA specifiche per la specie, anche se la cross reazione interspecie à ̈ altissima in quanto i fattori sono filogeneticamente molto conservati e, pertanto, solo qualitativamente sono misurabili anche con ELISA utilizzati per specie diverse (es: uomo-bovino e viceversa). The factors are controlled with specific ELISA methods for the species, even if the interspecies cross reaction is very high as the factors are phylogenetically very conserved and, therefore, they are only qualitatively measurable even with ELISA used for different species (eg: human-bovine and viceversa).
Una prima fonte dei fattori dell’invenzione à ̈ il siero di mammiferi che, negli ultimi giorni (5-15) prima del parto, à ̈ molto ricco dei fattori attivi oggetto dell’invenzione rispetto a mammiferi non gravidi o ai primi mesi di gravidanza. Si descrive di seguito, a titolo di esempio, una metodica di estrazione da siero. A first source of the factors of the invention is the serum of mammals which, in the last days (5-15) before giving birth, is very rich in the active factors object of the invention compared to non-pregnant mammals or in the first months of pregnancy. A serum extraction method is described below, by way of example.
Si preleva 1 litro di sangue in 4 giorni per 4 prelievi complessivi per non danneggiare l’animale, preferibilmente bovino o equino. 1 liter of blood is taken in 4 days for a total of 4 samples in order not to harm the animal, preferably bovine or equine.
Il sangue viene sierato a temperatura ambiente per 24 h e quindi centrifugato per spremere il coagulo. The blood is serumed at room temperature for 24 h and then centrifuged to squeeze the clot.
Si recupera il siero (circa il 30/40% del volume totale) a cui si aggiungono, come agenti antisettici, fenossietanolo al 2,5% e diazolidinil-urea all’1%. Il siero così trattato viene quindi frazionato con i seguenti passaggi. The serum is recovered (about 30/40% of the total volume) to which are added, as antiseptic agents, 2.5% phenoxyethanol and 1% diazolidinyl-urea. The treated serum is then fractionated with the following steps.
Ultrafiltrazione 300'000 Da: Ultrafiltration 300,000 From:
Il campione di siero (congelato a –20°C) ottenuto per coagulazione e centrifugazione da sangue di mammifero viene scongelato a temperatura ambiente e diluito con 2 volumi di acqua demineralizzata. La soluzione ottenuta viene ultrafiltrata su membrana piana a flusso tangenziale Millipore Pellicon Biomax in polyethersulfone da 300'000 Da ad una Pi di 0,5÷1 bar, in camera fredda a 4°C. The serum sample (frozen at â € “20 ° C) obtained by coagulation and centrifugation from mammalian blood is thawed at room temperature and diluted with 2 volumes of demineralized water. The solution obtained is ultrafiltered on a 300'000 Da polyethersulfone Millipore Pellicon Biomax tangential flow flat membrane at a Pi of 0.5à · 1 bar, in a cold room at 4 ° C.
Il retentato e una frazione corrispondente a circa 1:10 del permeato vengono trasferiti in un tubi da dialisi Spectrum Spectrapor in cellulosa rigenerata da 1'000 Da e dializzati contro acqua demineralizzata. The retentate and a fraction corresponding to approximately 1:10 of the permeate are transferred to a 1000 Da regenerated cellulose Spectrum Spectrapor dialysis tube and dialysed against demineralized water.
Ultrafiltrazione 5'000 Da: Ultrafiltration 5'000 From:
Il restante permeato viene ultrafiltrato su membrana da 5000 Da. Il permeato dell’ultrafiltrazione da 300'000 Da viene concentrato su membrana piana a flusso tangenziale Millipore Pellicon Biomax in polyethersulfone da 5000 ad una Pi di 0,5÷1 bar, in camera fredda a 4°C. The remaining permeate is ultrafiltered on a 5000 Da membrane. The 300'000 Da ultrafiltration permeate is concentrated on a Millipore Pellicon Biomax cross flow flat membrane in polyethersulfone of 5000 at a Pi of 0.5à · 1 bar, in the chamber cold to 4 ° C.
Il retentato viene trasferito in un tubo da dialisi Spectrum Spectrapor in cellulosa rigenerata da 1'000 Da e dializzato contro acqua demineralizzata (con questa dialisi si eliminano anche i conservanti). Il composto à ̈ quindi immediatamente liofilizzato. The retentate is transferred to a 1000 Da regenerated cellulose Spectrum Spectrapor dialysis tube and dialyzed against demineralised water (preservatives are also eliminated with this dialysis). The mixture is then immediately freeze-dried.
Una seconda fonte dei fattori dell’invenzione à ̈ la placenta. Si descrive di seguito, a titolo di esempio, una metodica di estrazione. A second source of the factors of the invention is the placenta. An extraction method is described below, by way of example.
Vengono utilizzate preferibilmente placente bovine o equine. Bovine or equine placentas are preferably used.
Omogeneizzazione Homogenization
La placenta (congelata a –20°C) viene scongelata a temperatura ambiente, tagliata in piccoli pezzi, lavata con abbondante soluzione fisiologica (NaCl 0,9%) fredda (4°C) e omogeneizzata tramite cutter Siramm in un buffer di lisi così composto: Tris/HCl 50 mM, EDTA 25mM, triton X-100 0,001% a pH 7,4. Alla sospensione ottenuta viene aggiunto NaCl fino ad una concentrazione dello 0,9%, e i conservanti (fenossietanolo al 2,5% e diazolidinil-urea all’1%). La sospensione viene posta sotto agitazione (agitatore magnetico) per 2 ore e mantenuta statica overnight in camera fredda a 4°C. The placenta (frozen at â € “20 ° C) is thawed at room temperature, cut into small pieces, washed with abundant cold saline (0.9% NaCl) (4 ° C) and homogenized by means of a Siramm cutter in a buffer of lysis composed as follows: 50 mM Tris / HCl, 25mM EDTA, 0.001% triton X-100 at pH 7.4. To the suspension obtained is added NaCl up to a concentration of 0.9%, and the preservatives (phenoxyethanol at 2.5% and diazolidinyl-urea at 1%). The suspension is stirred (magnetic stirrer) for 2 hours and kept static overnight in a cold chamber at 4 ° C.
Centrifugazione Centrifugation
La sospensione viene centrifugata a 13’000 rpm con centrifuga Sorvall RC6 e rotore SLA 15000 per 45 minuti a 4°C. Il surnatante della centrifugazione viene recuperato, prefiltrato sotto vuoto su Dicalite e su filtri in cellulosa rigenerata da 0,45 µm e 0,22 µm. The suspension is centrifuged at 13,000 rpm with a Sorvall RC6 centrifuge and SLA 15000 rotor for 45 minutes at 4 ° C. The supernatant of the centrifugation is recovered, pre-filtered under vacuum on Dicalite and on regenerated cellulose filters of 0.45 µm and 0.22 µm.
Ultrafiltrazione 300'000 Da Ultrafiltration 300'000 Da
Il prodotto filtrato viene ultrafiltrato su membrana piana a flusso tangenziale Millipore Pellicon Biomax in polyethersulfone da 300'000 Da ad una Pi di 0,5 ÷1 bar, in camera fredda a 4°C. The filtered product is ultrafiltered on a 300'000 Da polyethersulfone Millipore Pellicon Biomax tangential flow flat membrane at a Pi of 0.5 à · 1 bar, in a cold room at 4 ° C.
Ultrafiltrazione 5'000 Da Ultrafiltration 5'000 Da
Il permeato dell’ultrafiltrazione da 300'000 Da viene concentrato su membrana piana a flusso tangenziale Millipore Pellicon Biomax in polyethersulfone da 5'000 ad una Pi di 0,5 ÷1 bar, in camera fredda a 4°C. Il retentato viene trasferito in un tubo da dialisi Spectrum Spectrapor in cellulosa rigenerata da 1'000 Da e dializzato contro acqua demineralizzata (si eliminano pertanto anche i conservanti) e quindi immediatamente liofilizzato. The 300'000 Da ultrafiltration permeate is concentrated on a 5'000 cross-flow Millipore Pellicon Biomax polyethersulfone flat membrane at a Pi of 0.5 à · 1 bar, in a cold room at 4 ° C. The retentate is transferred into a 1000 Da regenerated cellulose Spectrum Spectrapor dialysis tube and dialyzed against demineralised water (therefore also the preservatives are eliminated) and then immediately freeze-dried.
Una ulteriore fonte dei fattori dell’invenzione à ̈ il colostro. Si usa preferibilmente colostro bovino per la facilità di approvvigionamento e le quantità disponibili. È particolarmente preferito il colostro da mucche di razza Holstein (Frisona) e Guernsey. È stato provato che tali mucche producono colostro con la maggior concentrazione di fattori attivi. Le mucche sono preferibilmente al secondo o terzo parto. Il colostro à ̈ preferibilmente raccolto fra la 1° e la 6° ora dal parto in quanto, in questo periodo, si assiste alla maggior concentrazione di attivi. Nel colostro a partire dalla sesta ora dal parto i fattori attivi diminuiscono rapidamente (dopo 24 ore ne sono presenti solo il 15%). A further source of the factors of the invention is colostrum. Bovine colostrum is preferably used due to the ease of supply and the quantities available. Colostrum from Holstein (Friesian) and Guernsey cows is particularly preferred. Such cows have been proven to produce colostrum with the highest concentration of active factors. The cows are preferably in the second or third calving. The colostrum is preferably collected between the 1st and the 6th hour from the birth as, in this period, there is the greatest concentration of active ingredients. In colostrum from the sixth hour after birth the active factors decrease rapidly (after 24 hours only 15% are present).
Il colostro raccolto à ̈ sottoposto a test per tubercolosi, citotossicità su culture cellulari, controllo di micoplasmi, prioni e di virus umani e bovini. Collected colostrum is tested for tuberculosis, cytotoxicity on cell cultures, control of mycoplasma, prions and human and bovine viruses.
Il colostro nella cisterna mammaria à ̈ praticamente sterile, ma una volta munto, nonostante ogni precauzione, per l’alta concentrazione di fattori di crescita, la sua carica batterica sale molto rapidamente durante la gelatura e la sgelatura, processi piuttosto lenti data l’alta densità del colostro nelle prime ore. The colostrum in the mammary cistern is practically sterile, but once milked, despite all precautions, due to the high concentration of growth factors, its bacterial load rises very rapidly during freezing and thawing, rather slow processes given the ™ high density of colostrum in the first few hours.
L’utilizzo di raggi γ permette di ottenere un colostro sterile solo se si utilizzano radiazioni superiori a 10 Kgy che tuttavia distruggono gran parte dei fattori attivi, e d’altronde questo metodo non impedisce la formazione di pirogeni il cui utilizzo à ̈ sconsigliabile per via topica e proibito per via parenterale. The use of γ rays allows to obtain a sterile colostrum only if radiations greater than 10 Kgy are used which however destroy most of the active factors, and on the other hand this method does not prevent the formation of pyrogens whose use is inadvisable topically and prohibited injecting.
È stata pertanto messa a punto una filiera di raccolta innovativa, per ottenere un composto anallergico sterile, senza conservanti e senza pirogeni. An innovative collection chain was therefore developed to obtain a sterile hypoallergenic compound, without preservatives and without pyrogens.
Al colostro raccolto in taniche sterili (sterilizzate a vuoto a 25 Kgy) si aggiungono agenti antisettici in quantità tali da garantire la sterilità e l’assenza di pirogeni. Si impiegano preferibilmente fenossietanolo alla concentrazione del 2,5% e diazolidinil-urea a una concentrazione dell’1%. To the colostrum collected in sterile tanks (vacuum sterilized at 25 Kgy) antiseptic agents are added in such quantities as to guarantee sterility and the absence of pyrogens. Phenoxyethanol at a concentration of 2.5% and diazolidinyl urea at a concentration of 1% are preferably used.
Il colostro così trattato può, per brevi periodi (max 30 gg) non essere conservato congelato prima dei processi di estrazione dei fattori attivi, con evidente risparmio dei costi industriali. The colostrum thus treated can, for short periods (max 30 days) not be stored frozen before the extraction processes of the active factors, with evident savings in industrial costs.
I fattori attivi possono essere estratti con i seguenti passaggi: Active factors can be extracted with the following steps:
Centrifugazione Centrifugation
Il colostro bovino viene diluito 1:10 con acqua demineralizzata, si aggiunge NaCl fino ad ottenere una concentrazione dello 0,9%. Bovine colostrum is diluted 1:10 with demineralized water, NaCl is added until a concentration of 0.9% is obtained.
La sospensione viene centrifugata in continuo a 8'000 rpm a temperatura di 20-25°C con una centrifuga Alfa Laval scartando il pellet corrispondente alla parte lipidica. The suspension is centrifuged continuously at 8'000 rpm at a temperature of 20-25 ° C with an Alfa Laval centrifuge, discarding the pellet corresponding to the lipid part.
Ultrafiltrazione ceramica da 300'000 Da 300,000 Da ceramic ultrafiltration
Il prodotto ottenuto dalla centrifugazione viene ultrafiltrato su membrana ceramica con cut-off 300'000 Da ad una temperatura di 20-25°C recuperando il permeato. The product obtained from centrifugation is ultrafiltered on a ceramic membrane with a cut-off of 300,000 Da at a temperature of 20-25 ° C, recovering the permeate.
Ultrafiltrazione su 5000 Da Ultrafiltration on 5000 Da
Il permeato dell’ultrafiltrazione 300'000 Da viene concentrato su membrana a spirale avvolta da 5'000 Da in polyethersulfone ad una temperatura di 20-25°C e dializzato contro acqua demineralizzata fino ad una conducibilità del retentato di circa 600 µs/cm<2>(con questa dialisi si eliminano anche i conservanti). The permeate of the ultrafiltration 300'000 Da is concentrated on a spiral membrane wrapped by 5'000 Da in polyethersulfone at a temperature of 20-25 ° C and dialyzed against demineralized water up to a conductivity of the retentate of about 600 µs / cm <2> (preservatives are also eliminated with this dialysis).
Liofilizzazione Lyophilization
Il retentato dell’ultrafiltrazione da 5000 Da viene filtrato sotto vuoto su filtri Millipore in cellulosa rigenerata da 0,2 µm, congelato a -20°C e liofilizzato. The 5000 Da ultrafiltration retentate is vacuum filtered on 0.2 µm regenerated cellulose Millipore filters, frozen at -20 ° C and freeze-dried.
Il composto, da qualunque sorgente isolato, Ã ̈ stato chiamato P.M.F. Ab e contiene i seguenti fattori: The compound, from any isolated source, was called P.M.F. Ab and contains the following factors:
Immunoglobuline della classe IgG2 e IgA(γ/mg), in proporzione pari a circa il 60% del contenuto di P.M.F. Ab (circa 50% IgG2 e circa 10% IgA), dotate di una specificità naturale contro molti batteri e virus, alcuni dei quali responsabili delle sovrapposizioni infettive dell’anoressia. Immunoglobulins of the IgG2 and IgA class (γ / mg), in a proportion equal to about 60% of the P.M.F. Ab (about 50% IgG2 and about 10% IgA), with a natural specificity against many bacteria and viruses, some of which are responsible for the infectious overlaps of anorexia.
COMPLEMENTO C3/C4: Il complemento à ̈ costituito da proteine circolanti capaci di interagire con le membrane biologiche e con specifici recettori situati sulla superficie di diversi tipi cellulari e che hanno la capacità di indurre reazioni infiammatorie che aiutano a combattere le infezioni. COMPLEMENT C3 / C4: The complement consists of circulating proteins capable of interacting with biological membranes and with specific receptors located on the surface of different cell types and which have the ability to induce inflammatory reactions that help fight infections.
FATTORI ANTIBATTERICI/ANTIVIRALI TRANSFERRINA: rilascia ferro ai globuli rossi e impedisce la chelazione del ferro da parte di batteri e virus. ANTIBACTERIAL / ANTIVIRAL FACTORS TRANSFERRIN: releases iron to red blood cells and prevents iron chelation by bacteria and viruses.
LACTOFERRINA: toglie ai batteri e ai virus il ferro di cui necessitano per crescere. LACTOFERRIN: removes the iron they need to grow from bacteria and viruses.
LISOZIMA: ha effetti antibatterici, dovuti non solo alle sue proprietà enzimatiche, ma anche alle proprietà cationiche ed idrofobiche. LYSOZYME: has antibacterial effects, due not only to its enzymatic properties, but also to its cationic and hydrophobic properties.
LATTOPEROSSIDASI: à ̈ il più potente enzima contenuto nel colostro. Inibisce il metabolismo batterico ossidando i gruppi sulfidrilici di proteine essenziali. LACTOPEROXIDASE: It is the most powerful enzyme contained in colostrum. It inhibits bacterial metabolism by oxidizing the sulfhydryl groups of essential proteins.
FATTORI DI CRESCITA TGF-β1- TRASFORMIG GROWTH FACTOR: stimola la produzione di immunoglobuline della classe A, responsabili delle difese immunitarie a livello mucoso. Modula la proliferazione cellulare e stimola la deposizione di matrice extracellulare. GROWTH FACTORS TGF-β1- TRASFORMIG GROWTH FACTOR: stimulates the production of class A immunoglobulins, responsible for mucosal immune defenses. It modulates cell proliferation and stimulates extracellular matrix deposition.
EGF-EPIDERMAL GROWTH FACTOR: regola lo sviluppo della mucosa. Promuove la formazione di cellule epiteliali. EGF-EPIDERMAL GROWTH FACTOR: regulates the development of the mucosa. Promotes the formation of epithelial cells.
IGF 1- INSULIN-LIKE GROWTH FACTOR: modula la proliferazione, l’adesione e la migrazione cellulare e induce la maturazione delle mucose. IGF 1- INSULIN-LIKE GROWTH FACTOR: modulates cell proliferation, adhesion and migration and induces maturation of the mucous membranes.
VEGF- VASCULAR ENDOTHELIAL GROWTH FACTOR: stimola la produzione di vasi sanguigni. Presenta attività mitogenetica e di attivazione della permeabilità vascolare. VEGF- VASCULAR ENDOTHELIAL GROWTH FACTOR: stimulates the production of blood vessels. It has mitogenetic activity and activation of vascular permeability.
FGF- b- FIBROBLAST GROWTH FACTOR BASIC: stimola la proliferazione delle cellule di origine mesenchimale come fibroblasti, cellule endoteliali, astrociti, cheratinociti. Agisce come fattore chemiotattico e fitogenetico. FGF- b- FIBROBLAST GROWTH FACTOR BASIC: stimulates the proliferation of cells of mesenchymal origin such as fibroblasts, endothelial cells, astrocytes, keratinocytes. It acts as a chemotactic and phytogenetic factor.
GH-GROWTH HORMONE: fattore generale di crescita di ogni tessuto. GH-GROWTH HORMONE: general growth factor of each tissue.
NGF-NERVE GROWTH FACTOR: stimola l’attività e la regolazione della crescita e della differenziazione del sistema simpatico. NGF-NERVE GROWTH FACTOR: stimulates the activity and regulation of the growth and differentiation of the sympathetic system.
SCF- STEM CELL FACTOR: fattore pleiotropico che agisce, in utero e nel neonato, sullo sviluppo delle cellule germinali e neurali e sull’ematopoiesi. SCF- STEM CELL FACTOR: pleiotropic factor that acts, in utero and in the newborn, on the development of germinal and neural cells and on hematopoiesis.
FATTORI CHEMIOTATTICI EOTAXINA: si lega ai recettori delle chemochine per richiamare gli eosinofili nei tessuti infiammati. CHEMOTACTIC FACTORS EOTAXIN: binds to chemokine receptors to call up eosinophils in inflamed tissues.
IP-10-Chemochin ligand 10: indotta dall’interferone gamma aggrega le cellule infiammatorie. IP-10-Chemochin ligand 10: induced by interferon gamma aggregates inflammatory cells.
MCP-1 Monocyte chemotactic factor-1: favorisce l’aggregazione dei monociti ai tessuti infiammati. MCP-1 Monocyte chemotactic factor-1: favors the aggregation of monocytes to inflamed tissues.
CITOCHINE IL1-ra: membro della famiglia dell’interleuchina 1. Modula la risposta immune e antiinfiammatoria. CYTOKIN IL1-ra: member of the interleukin 1 family. It modulates the immune and anti-inflammatory response.
IL-2: induce la proliferazione dei linfociti T. IL-2: induces the proliferation of T lymphocytes.
IL-9: regolatore delle cellule emopoietiche, stimola la proliferazione cellulare e previene l’apoptosi. IL-9: regulator of hematopoietic cells, stimulates cell proliferation and prevents apoptosis.
IL-17: Regola le attività dell’NF-KB e potenzia la produzione di ossido nitrico(NO). IL-17: Regulates the activities of NF-KB and enhances the production of nitric oxide (NO).
IL-10: presenta effetti pleiotropici nell’immunoregolazione e nell’infiammazione. Migliora la sopravvivenza delle cellule β e pertanto la produzione di anticorpi. Studi sui topi knock-out dimostrano che questa proteina à ̈ essenziale nell’immunoregolazione del tratto intestinale. IL-10: has pleiotropic effects in immunoregulation and inflammation. It improves the survival of β cells and therefore the production of antibodies. Studies on knock-out mice show that this protein is essential in the immunoregulation of the intestinal tract.
INTERFERON-gamma: presenta note attività antivirali, antitumorali e immunoregolatorie. È un potente attivatore dei macrofagi. INTERFERON-gamma: has known antiviral, anticancer and immunoregulatory activities. It is a powerful activator of macrophages.
TNF-α-Tumour necrosis factor: stimola la migrazione di neutrofili e monociti nella sede delle infezioni. TNF-Î ± -Tumor necrosis factor: stimulates the migration of neutrophils and monocytes to the site of infections.
La frazione così ottenuta e contenente i fattori sopra elencati à ̈ in grado di fornire un valido effetto terapeutico in tutti i casi di anoressia. La frazione dell’invenzione potrà essere formulata in composizioni adatte alla somministrazione orale per il trattamento dell’anoressia. Il dosaggio per via orale di P.M.F. Ab à ̈ tipicamente compreso fra 20 e 40 g una o due volte al giorno a digiuno. The fraction thus obtained and containing the factors listed above is able to provide a valid therapeutic effect in all cases of anorexia. The fraction of the invention can be formulated in compositions suitable for oral administration for the treatment of anorexia. The oral dosage of P.M.F. Ab is typically between 20 and 40 g once or twice a day on an empty stomach.
RISULTATI TERAPEUTICI THERAPEUTIC RESULTS
Venti pazienti di sesso femminile di età compresa fra i sedici e i trent’anni, affette da anoressia nervosa con perdita di peso compresa tra il 15 e 30% di quello considerato normale per l’età e per la struttura fisica, sono state messe in terapia orale adiuvante con 40 g di P.M.F. Ab con assunzioni giornaliere a digiuno. Twenty female patients aged between sixteen and thirty, suffering from anorexia nervosa with weight loss between 15 and 30% of that considered normal for their age and physical structure, were placed in adjuvant oral therapy with 40 g of P.M.F. Ab with daily intakes on an empty stomach.
Interessante à ̈ notare che tutte le pazienti, nonostante i gravi problemi di alimentazione, hanno accettato di assumere il prodotto in quanto à ̈ stato a loro dimostrato che il prodotto stesso non aumenta la massa grassa ma solo la massa muscolare, influendo positivamente su fenomeni vitali a livello cardiaco, polmonare e celebrale. It is interesting to note that all the patients, despite the serious feeding problems, have accepted to take the product as it has been shown to them that the product itself does not increase fat mass but only muscle mass, positively influencing vital phenomena. in the heart, lungs and brain.
Dopo tre mesi di terapia adiuvante il 50% aveva recuperato più del 30% del peso corporeo con un notevole miglioramento delle capacità fisiche e intellettuali. I parametri ematochimici erano rientrati nella norma. After three months of adjuvant therapy, 50% had regained more than 30% of their body weight with a notable improvement in physical and intellectual abilities. Blood chemistry parameters had returned to normal.
Sorprendentemente il 25% ulteriore di queste paziente ha addirittura ripreso ad alimentarsi normalmente con restitutio ad integrum della massa corporea. Il restante 25% non ha risposto. Surprisingly, a further 25% of these patients even resumed normal nutrition with body mass restitutio ad integrum. The remaining 25% did not respond.
Claims (6)
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| IT002433A ITMI20112433A1 (en) | 2011-12-30 | 2011-12-30 | COMPOSITIONS FOR ADIUVANT ORAL THERAPY OF ANORESSIA INCLUDING ANTIBACTERIALS, ANTIBACTERIALS, GROWTH FACTORS AND CYTOCHINES |
| JP2014549467A JP6139562B2 (en) | 2011-12-30 | 2012-12-27 | Combination of growth factors, cytokines, antibacterial / antiviral factors, stem cell stimulating factors, complement proteins C3A / C4A, immunoglobulins and chemotactic factors |
| EP12816671.7A EP2797609B1 (en) | 2011-12-30 | 2012-12-27 | Combination of growth factors, cytokines, antibacterial/antiviral factors, stem cell stimulating factors, complement proteins c3a/c4a, immunoglobulins and chemotactic factors |
| RU2014128297A RU2642650C2 (en) | 2011-12-30 | 2012-12-27 | Combination of growth factors, cytokines, antibacterial/antiviral factors, stem cells factors, c3a/s4a complement proteins, immunoglobulins and chemotactic factors |
| DK12816671.7T DK2797609T3 (en) | 2011-12-30 | 2012-12-27 | COMBINING growth factors, cytokines, anti-bacterial / ANTIVIRALS FACTORS STEM CELL-STIMULATING FACTORS, complement C3A / C4A, immunoglobulins, and chemotactic factors |
| US14/369,127 US9555084B2 (en) | 2011-12-30 | 2012-12-27 | Combination of growth factors, cytokines, antibacterial/antiviral factors, stem cell stimulating factors, complement proteins C3a/C4a, immunoglobulins and chemotactic factors |
| PCT/EP2012/076962 WO2013098333A1 (en) | 2011-12-30 | 2012-12-27 | Combination of growth factors, cytokines, antibacterial/antiviral factors, stem cell stimulating factors, complement proteins c3a/c4a, immunoglobulins and chemotactic factors |
| ES12816671.7T ES2609352T3 (en) | 2011-12-30 | 2012-12-27 | Combination of growth factors, cytokines, antibacterial / antiviral factors, stem cell stimulating factors, C3a / C4a complement proteins, immunoglobulins and chemotactic factors |
| US15/377,190 US10098927B2 (en) | 2011-12-30 | 2016-12-13 | Combination of growth factors, cytokines, antibacterial/antiviral factors, stem cell stimulating factors, complement proteins C3A/C4A, immunoglobulins and chemotactic factors |
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