IT202100001067A1 - NUTRACEUTICAL COMPOSITION FOR THE TREATMENT OF PATHOLOGIES RELATED TO CHEMOTHERAPY - Google Patents
NUTRACEUTICAL COMPOSITION FOR THE TREATMENT OF PATHOLOGIES RELATED TO CHEMOTHERAPY Download PDFInfo
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- IT202100001067A1 IT202100001067A1 IT102021000001067A IT202100001067A IT202100001067A1 IT 202100001067 A1 IT202100001067 A1 IT 202100001067A1 IT 102021000001067 A IT102021000001067 A IT 102021000001067A IT 202100001067 A IT202100001067 A IT 202100001067A IT 202100001067 A1 IT202100001067 A1 IT 202100001067A1
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Description
TITOLO DELL?INVENZIONE TITLE OF THE INVENTION
?COMPOSIZIONE NUTRACEUTICA PER IL TRATTAMENTO DI PATOLOGIE COLLEGATE A CHEMIOTERAPIA? ?NUTRACEUTIC COMPOSITION FOR THE TREATMENT OF PATHOLOGIES RELATED TO CHEMOTHERAPY?
CAMPO DELL?INVENZIONE FIELD OF THE INVENTION
La presente invenzione riguarda una composizione nutraceutica, da utilizzarsi in combinazione con un trattamento con un agente chemioterapico per il trattamento delle patologie collegate a chemioterapia. The present invention relates to a nutraceutical composition, to be used in combination with a treatment with a chemotherapeutic agent for the treatment of pathologies linked to chemotherapy.
STATO DELLA TECNICA STATE OF THE ART
Nel 2018, nel mondo, sono stati diagnosticati oltre 18 milioni di casi di tumore, una cifra destinata ad aumentare di circa il 60% entro il 2040 a causa dell?invecchiamento e dell?aumento della popolazione mondiale. Sono alcuni dei dati pubblicati nella terza edizione del ?Cancer Atlas?, frutto della collaborazione tra la American Cancer Society (ACS), l?Unione internazionale per il controllo del cancro (UICC) e l?Agenzia internazionale per la ricerca sul cancro (IARC). In 2018, more than 18 million cases of cancer were diagnosed worldwide, a figure set to increase by around 60% by 2040 due to the aging and increasing population of the world. These are some of the data published in the third edition of the ?Cancer Atlas?, the result of a collaboration between the American Cancer Society (ACS), the International Union for Control of Cancer (UICC) and the International Agency for Research on Cancer (IARC) .
In Europa, nel 2018, si sono verificati 3,9 milioni di nuovi casi di cancro e 1,9 milioni di decessi. La met? dei casi ? rappresentata da quattro tipi di tumore: seno (523 mila nuovi casi, il 13% del totale), colon-retto (500 mila, 13%), prostata (470 mila, 12%) e polmoni (450 mila, 12%). Per quanto riguarda la mortalit?, nel 2018 il 20% dei decessi per cancro era dovuto al tumore dei polmoni (388.000 morti), il 13% al colon-retto (242.000 morti) e il 7% al seno (138.000 morti). Per gli uomini si osserva una predominanza di tumori alla prostata nei Paesi occidentali e ai polmoni in quelli orientali, mentre per le donne il cancro al seno rappresenta il principale tumore in tutto il continente. In Italia la casistica rispecchia il quadro europeo: tra le donne il tumore pi? diffuso ? quello al seno (responsabile anche del maggior numero di decessi), mentre tra gli uomini quello alla prostata (il numero pi? alto di decessi ? invece dovuto al tumore del polmone). In Europe, in 2018, there were 3.9 million new cases of cancer and 1.9 million deaths. half any cases? represented by four types of cancer: breast (523,000 new cases, 13% of the total), colorectal (500,000, 13%), prostate (470,000, 12%) and lungs (450,000, 12%). As for mortality, in 2018 20% of cancer deaths were due to lung cancer (388,000 deaths), 13% to colorectal cancer (242,000 deaths) and 7% to breast cancer (138,000 deaths). For men, there is a predominance of prostate cancer in Western countries and lung cancer in Eastern ones, while for women, breast cancer is the leading cancer across the continent. In Italy, the case study reflects the European picture: among women, the most common cancer? widespread ? that of the breast (also responsible for the highest number of deaths), while among men that of the prostate (the highest number of deaths is instead due to lung cancer).
Il cancro del pancreas ? uno tra i pi? letali cancri al mondo classificandosi al quarto posto con circa 200.000 decessi per anno solo in nord America ed Europa. Nel 2020 il cancro del pancreas ? stimato diventare la seconda causa di morte cancro correlata in quanto ad oggi non vi ? alcun approccio terapeutico realmente efficace perch? non presentando sintomi specifici viene quasi sempre diagnosticato in fase tardiva e soprattutto perch? caratterizzato da un?estrema chemioresistenza. Terapie attualmente note per la cura dei tumori, specificatamente il tumore al pancreas, prevedono trattamenti con agenti chemioterapici, tra cui agenti nucleosidici analogici come la Gemcitabina, un agente antitumorale ampiamente utilizzato nei trattamenti farmacologici di diverse tipologie di tumore. Pancreatic cancer ? one of the most deadliest cancers in the world ranking fourth with approximately 200,000 deaths per year in North America and Europe alone. Pancreatic cancer in 2020? estimated to become the second leading cause of cancer-related death as of today there is no ? any therapeutic approach really effective why? not presenting specific symptoms it is almost always diagnosed in the late phase and above all because? characterized by extreme chemoresistance. Currently known therapies for the treatment of tumors, specifically pancreatic cancer, involve treatments with chemotherapeutic agents, including nucleoside analog agents such as Gemcitabine, an anticancer agent widely used in the pharmacological treatments of various types of tumors.
Tuttavia questi trattamenti chemioterapici noti, presentano indubbi svantaggi ed effetti collaterali sul paziente. However, these known chemotherapeutic treatments have undoubted disadvantages and side effects on the patient.
Tra i numerosi effetti collaterali riscontrati dai pazienti, oltre alla nota perdita di capelli, anemia, stanchezza, nausea, vomito, sono da enumerarsi la cachessia, una condizione caratterizzata da atrofia muscolare e perdita di massa magra accompagnata da uno stato di infiammazione sistemico, e gli effetti collaterali legati al microbiota intestinale. Among the numerous side effects experienced by patients, in addition to the well-known hair loss, anemia, fatigue, nausea, vomiting, cachexia should be enumerated, a condition characterized by muscle atrophy and loss of lean body mass accompanied by a state of systemic inflammation, and side effects related to the intestinal microbiota.
Quest?ultimo influenza largamente i processi carcinogenetici, la progressione tumorale e la risposta alle terapie anticancro. The latter largely influences carcinogenic processes, tumor progression and response to anticancer therapies.
Il microbiota intestinale ? costituito da oltre cento trilioni di microorganismi che vivono in simbiosi con il corpo umano, pu? raggiungere il peso di circa 1,8 kg, ed ? spesso definito come l?organo ?nascosto? o dimenticato? anche per via della sua capacit? di modulare il metabolismo, l?infiammazione e l?immunit?. Il microbiota svolge un ruolo importante nella genesi e nella progressione di diversi tipi di tumore nonch? nel determinarne la risposta alle terapie. Recenti ricerche pubblicate da laboratori nazionali ed internazionali hanno dimostrato che trattamenti chemioterapici causano sostanziali modifiche al microbiota intestinale in modelli in vivo favorendo un profilo batterico pro-infiammatorio. Quest?ultimo ? responsabile non solo della mucosite gastrointestinale e degli effetti collaterali spesso osservati in pazienti soggetti a chemioterapia ma anche dell?esacerbazione dello stato infiammatorio che ? un fattore critico nell?alimentazione del cancro. The intestinal microbiota? made up of over one hundred trillion microorganisms that live in symbiosis with the human body, can reach the weight of about 1.8 kg, and ? often referred to as the ?hidden? organ? or forgot? also because of its ability? to modulate metabolism, inflammation and immunity. The microbiota plays an important role in the genesis and progression of different types of cancer as well as in determining their response to therapy. Recent research published by national and international laboratories has shown that chemotherapy treatments cause substantial changes to the intestinal microbiota in in vivo models favoring a pro-inflammatory bacterial profile. The latter ? responsible not only for gastrointestinal mucositis and the side effects often observed in patients undergoing chemotherapy but also for the exacerbation of the inflammatory state which is a critical factor in cancer nutrition.
In particolare, nel tumore al pancreas ? stato osservato che il trattamento con l?agente chemioterapico Gemcitabina, induce disbiosi intestinale in topi modello di cancro del pancreas. Nello specifico, in topi trattati con l?agente chemioterapico Gemcitabina rispetto a topi controllo ? stato riscontrato un notevole incremento di patogeni quali Escherichia coli e Peptoclostridum difficile, un complessivo aumento di batteri associati all?infiammazione (es. Proteobatteri) ed una parallela diminuzione di batteri produttori di butirrato e acidi grassi a corta catena con funzione antiinfiammatoria (es. Lachnospiraceae e Rumicoccocaceae). In merito all?aumento di Escherichia coli (che appartiene alla classe dei gammaproteobatteri), ? interessante notare che in un recente studio ( , ?Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine?, Science, 2017, 357, 6356, 1156-1160) ? stato dimostrato che i gamma-proteobatteri esprimono un?isoforma dell?enzima citidina deaminasi che metabolizza l?agente chemioterapico Gemcitabina nella sua forma inattiva suggerendo un ruolo nella farmacoresistenza per questa classe di microorganismi. In particular, in pancreatic cancer ? Treatment with the chemotherapeutic agent gemcitabine was observed to induce intestinal dysbiosis in pancreatic cancer mouse models. Specifically, in mice treated with the chemotherapeutic agent gemcitabine compared with control mice ? A significant increase in pathogens such as Escherichia coli and Peptoclostridum difficile was found, an overall increase in bacteria associated with inflammation (e.g. Proteobacteria) and a parallel decrease in bacteria producing butyrate and short-chain fatty acids with an anti-inflammatory function (e.g. Lachnospiraceae and Rumicoccocaceae). Regarding the increase in Escherichia coli (which belongs to the class of gammaproteobacteria), ? Interestingly, in a recent study ( ? Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine?, Science, 2017, 357, 6356, 1156-1160) ? Gamma Proteobacteria have been shown to express an isoform of the enzyme cytidine deaminase which metabolises the chemotherapeutic agent gemcitabine to its inactive form suggesting a role in drug resistance for this class of microorganisms.
Un ulteriore approccio per ridurre le vie metaboliche dell?infiammazione e al contempo ritardare la progressione tumorale ? stato proposto sottoforma di dieta basata su carboidrati resistenti che aumentava la proliferazione di microorganismi produttori di SCFA (acidi grassi a catena corta). Another approach to reduce the metabolic pathways of inflammation and at the same time delay tumor progression? was proposed in the form of a diet based on resistant carbohydrates which increased the proliferation of SCFA-producing microorganisms (short-chain fatty acids).
Tuttavia, la sola dieta non ? sufficiente a ristabilire tutti i microorganismi del microbiota intestinale e ridurre la disbiosi intestinale da Gemcitabina. However, diet alone is not sufficient to restore all microorganisms of the intestinal microbiota and reduce intestinal dysbiosis by Gemcitabine.
Pertanto, alla luce di queste problematiche, che non solo inficiano la compliance del paziente sottoposto a trattamenti chemioterapici gi? invasivi, ma ne impediscono spesso la continuazione, aumentando pertanto la mortalit?, ? tuttora sentita l?esigenza di una composizione che possa essere utilizzata come adiuvante naturale e non tossico alla chemioterapia, limitando, se non addirittura proteggendo dagli effetti collaterali a livello di microbiota intestinale e pertanto migliorando la qualit? della vita del paziente e l?efficacia della terapia mediante il completamento dei protocolli farmacologici. Therefore, in the light of these problems, which not only affect the compliance of the patient undergoing chemotherapy treatments already? invasive, but often prevent the continuation, thus increasing mortality?,? The need is still felt for a composition that can be used as a natural and non-toxic adjuvant to chemotherapy, limiting, if not even protecting from side effects at the intestinal microbiota level and therefore improving the quality of the product. of the patient's life and the effectiveness of the therapy by completing the pharmacological protocols.
SOMMARIO DELL?INVENZIONE SUMMARY OF THE INVENTION
Senza essere legati ad alcuna teoria, gli inventori hanno sorprendentemente scoperto che mediante la combinazione di almeno un ceppo batterico del genere Bifidobacterium, almeno un ceppo batterico del genere Lactobacillus, almeno un prebiotico e una transferrina scelta dal gruppo consistente in lattoferrina, ovotransferrina, e loro miscele, era possibile modulare i profili del microbiota intestinale, ridurre l?infiammazione indotta da farmaci chemioterapici e pertanto trattare patologie collegate a chemioterapia, migliorando quindi lo stato di salute del paziente in modo che i protocolli terapeutici siano portati a compimento con successo e si possano cos? trattare pi? efficacemente le neoplasie. Without being bound by any theory, the inventors surprisingly discovered that by combining at least one bacterial strain of the genus Bifidobacterium, at least one bacterial strain of the genus Lactobacillus, at least one prebiotic, and a transferrin selected from the group consisting of lactoferrin, ovotransferrin, and their mixtures, it was possible to modulate the intestinal microbiota profiles, reduce the inflammation induced by chemotherapy drugs and therefore treat pathologies related to chemotherapy, thus improving the patient?s state of health so that the therapeutic protocols are successfully completed and can be what? treat more neoplasms effectively.
Pertanto, scopo della presente invenzione ? quello di fornire una composizione nutraceutica comprendente almeno un ceppo batterico del genere Bifidobacterium, almeno un ceppo batterico del genere Lactobacillus, almeno un prebiotico e una transferrina scelta dal gruppo consistente in lattoferrina, ovotransferrina, e loro miscele, per l?uso nel trattamento di patologie collegate a chemioterapia. Therefore, the purpose of the present invention ? that of providing a nutraceutical composition comprising at least one bacterial strain of the genus Bifidobacterium, at least one bacterial strain of the genus Lactobacillus, at least one prebiotic and a transferrin selected from the group consisting of lactoferrin, ovotransferrin, and mixtures thereof, for use in the treatment of pathologies related to chemotherapy.
La presente invenzione riguarda altres? una composizione nutraceutica consistente in 20 * 10<9 >CFU/g di Bifidobacterium breve, 20 * 10<9 >CFU/g di Bifidobacterium bifidum, 15 * 10<9 >CFU/g di Lactobacillus kefiri, 15 * 10<9 >CFU/g di Lactobacillus plantarum, 15 * 10<9 >CFU/g di Lactobacillus salivarius, 15 * 10<9 >CFU/g di Lactobacillus reuteri, 449 mg di inulina, 100 mg di lattoferrina, per l?uso come adiuvante nel trattamento di tumore al pancreas. The present invention also relates a nutraceutical composition consisting of 20 * 10<9 >CFU/g of Bifidobacterium breve, 20 * 10<9 >CFU/g of Bifidobacterium bifidum, 15 * 10<9 >CFU/g of Lactobacillus kefiri, 15 * 10<9 > Lactobacillus plantarum CFU/g, Lactobacillus salivarius 15 * 10<9 >CFU/g, Lactobacillus reuteri 15 * 10<9 >CFU/g, inulin 449 mg, lactoferrin 100 mg, for use as an adjuvant in treatment of pancreatic cancer.
Oggetto della presente invenzione ? anche un metodo di trattamento di patologie legate a chemioterapia mediante somministrazione quotidiana, ad un paziente sottoposto a chemioterapia, di una composizione nutraceutica secondo la presente invenzione fino al completamento del trattamento chemioterapico. Object of the present invention ? also a method of treating pathologies linked to chemotherapy by daily administration, to a patient undergoing chemotherapy, of a nutraceutical composition according to the present invention until completion of the chemotherapy treatment.
Ulteriore oggetto della presente invenzione ? un metodo di trattamento di un tumore, specificatamente del tumore al pancreas, consistente nella somministrazione quotidiana, ad un paziente sottoposto a chemioterapia, di una composizione nutraceutica secondo la presente invenzione fino al completamento del trattamento chemioterapico, come adiuvante/sinergico nell?inibizione della crescita del cancro del pancreas. Further object of the present invention ? a method of treating a tumour, specifically pancreatic cancer, consisting in the daily administration, to a patient undergoing chemotherapy, of a nutraceutical composition according to the present invention until the completion of the chemotherapy treatment, as an adjuvant/synergist in growth inhibition of pancreatic cancer.
DESCRIZIONE DETTAGLIATA DELLE FIGURE DETAILED DESCRIPTION OF THE FIGURES
Figura 1: Schema del protocollo sperimentale. Figure 1: Scheme of the experimental protocol.
Figura 2: Progressione tumorale dei 4 gruppi sperimentali: volume tumorale degli xenograft misurati ad ogni settimana sperimentale. Figure 2: Tumor progression of the 4 experimental groups: tumor volume of the xenografts measured at each experimental week.
Figura 3: Sezioni istologiche di tumori xenograft prelevate da animali appartenenti ai 4 gruppi sperimentali. Immagini ottenute mediante colorazioni HE (Ematossilina/Eosina per colorazione base) e con i seguenti anticorpi: CD31 (marker di angiogenesi), Ki67 (marker di proliferazione cellulare). Figure 3: Histological sections of xenograft tumors taken from animals belonging to the 4 experimental groups. Images obtained by HE staining (Hematoxylin/Eosin for basic staining) and with the following antibodies: CD31 (marker of angiogenesis), Ki67 (marker of cell proliferation).
Figura 4: Sezioni istologiche di tumori xenograft prelevate da animali appartenenti ai 4 gruppi sperimentali. Immagini ottenute mediante colorazioni: Masson Trichrome (colorante che differenzia le cellule muscolari dal collagene), Psicrosirius Red (evidenzia la porzione del collagene nei tessuti) e con i seguenti anticorpi: E-Cadherin e N-Cadherin (indice della transizione epiteliale-mesenchimale ?EMT?). Figura 5: Dosaggi mediante immunoblot di proteine coinvolte nella transizione epitelio mesenchimale: E-caderina, N-caderina, Snail, Slug e Vimentin, proteine di adesione il cui profilo di espressione ? legato alla transizione epiteliomesenchimale. Rappresentazione grafica mediante grafico radar. Figure 4: Histological sections of xenograft tumors taken from animals belonging to the 4 experimental groups. Images obtained by staining: Masson Trichrome (dye that differentiates muscle cells from collagen), Psicosirius Red (highlights the portion of collagen in the tissues) and with the following antibodies: E-Cadherin and N-Cadherin (epithelial-mesenchymal transition index ? EMTs?). Figure 5: Immunoblot assays of proteins involved in epithelial-to-mesenchymal transition: E-cadherin, N-cadherin, Snail, Slug and Vimentin, adhesion proteins whose expression profile is ? related to the epitheliomesenchymal transition. Graphical representation by radar chart.
Figura 6: Sezioni istologiche di epitelio intestinale. Immagine ottenute con diverse colorazioni, HE (Eosina/Ematossilina per colorazione base), Ki67 (marker di proliferazione cellulare) e Alcian Blue/PAS (colorante con affinit? ai mucopolisaccaridi). Figure 6: Histological sections of intestinal epithelium. Images obtained with different stains, HE (Eosin/Hematoxylin for basic staining), Ki67 (marker of cell proliferation) and Alcian Blue/PAS (dye with affinity to mucopolysaccharides).
DESCRIZIONE DETTAGLIATA DELL?INVENZIONE DETAILED DESCRIPTION OF THE INVENTION
Scopo della presente invenzione ? quello di fornire una composizione nutraceutica comprendente almeno un ceppo batterico del genere Bifidobacterium, almeno un ceppo batterico del genere Lactobacillus, almeno un prebiotico e una transferrina scelta dal gruppo consistente in lattoferrina, ovotransferrina, e loro miscele, per l?uso nel trattamento di patologie collegate a chemioterapia. Purpose of the present invention? that of providing a nutraceutical composition comprising at least one bacterial strain of the genus Bifidobacterium, at least one bacterial strain of the genus Lactobacillus, at least one prebiotic and a transferrin selected from the group consisting of lactoferrin, ovotransferrin, and mixtures thereof, for use in the treatment of pathologies related to chemotherapy.
Senza essere legati ad alcuna teoria, gli inventori hanno sorprendentemente scoperto che miscelando in una composizione nutraceutica almeno un ceppo batterico del genere Bifidobacterium, almeno un ceppo batterico del genere Lactobacillus, almeno un prebiotico e una transferrina scelta dal gruppo consistente in lattoferrina, ovotransferrina, era possibile trattare gli effetti collaterali delle terapie chemioterapiche, specificatamente le patologie collegate a chemioterapia. Without being tied to any theory, the inventors have surprisingly discovered that by mixing in a nutraceutical composition at least one bacterial strain of the genus Bifidobacterium, at least one bacterial strain of the genus Lactobacillus, at least one prebiotic and a transferrin selected from the group consisting of lactoferrin, ovotransferrin, it was It is possible to treat the side effects of chemotherapy therapies, specifically diseases related to chemotherapy.
Nella presente invenzione coi termini: In the present invention with the terms:
- ?patologie collegate a chemioterapia? si intende qualsiasi effetto collaterale o patologia sviluppata in concomitanza e/o a seguito di trattamento chemioterapico in un paziente sottoposto a chemioterapia. - ?diseases related to chemotherapy? means any side effect or pathology developed concomitantly and/or following chemotherapy treatment in a patient undergoing chemotherapy.
In un primo aspetto dunque, l?invenzione concerne una composizione nutraceutica comprendente almeno un ceppo batterico del genere Bifidobacterium, almeno un ceppo batterico del genere Lactobacillus, almeno un prebiotico e una transferrina scelta dal gruppo consistente in lattoferrina, ovotransferrina, e loro miscele, per l?uso nel trattamento di patologie collegate a chemioterapia. In a first aspect, therefore, the invention concerns a nutraceutical composition comprising at least one bacterial strain of the genus Bifidobacterium, at least one bacterial strain of the genus Lactobacillus, at least one prebiotic and a transferrin selected from the group consisting of lactoferrin, ovotransferrin, and mixtures thereof, for use in the treatment of diseases related to chemotherapy.
Preferibilmente detto almeno un ceppo batterico del genere Bifidobacterium ? scelto dal gruppo comprendente Bifidobacterium breve, Bifidobacterium bifidum, Bifidobacterium adolescentis reuter, Bifidobacterium animalis, Bifidobacterium bombi, Bifidobacterium catenulatum, Bifidobacterium denticolens, Bifidobacterium dentium, Bifidobacterium gallicum, Bifidobacterium gallinarum, Bifidobacterium globosum, Bifidobacterium longum, Bifidobacterium pseudocatenulatum, Bifidobacterium pseudolongum, e loro miscela. Preferably said at least one bacterial strain of the genus Bifidobacterium ? selected from the group comprising Bifidobacterium breve, Bifidobacterium bifidum, Bifidobacterium folletos reuter, Bifidobacterium animalis, Bifidobacterium bombi, Bifidobacterium catenulatum, Bifidobacterium denticolens, Bifidobacterium dentium, Bifidobacterium gallicum, Bifidobacterium gallinarum, Bifidobacterium globosum, Bifidobacterium longum, Bifidobacterium pseudocatenulatum, Bifi dobacterium pseudolongum, and a mixture thereof .
Pi? preferibilmente, detto almeno un ceppo batterico del genere Bifidobacterium ? in una quantit? compresa nell?intervallo da 14 a 140 * 10<9 >CFU/g, preferibilmente 10 a 100 * 10<9 >CFU/g. Pi? preferably, said at least one bacterial strain of the genus Bifidobacterium ? in a quantity comprised in the range from 14 to 140 * 10<9 >CFU/g, preferably 10 to 100 * 10<9 >CFU/g.
In una forma di realizzazione, quando la composizione nutraceutica per l?uso secondo la presente invenzione comprende Bifidobacterium breve, esso ha funzione di produttore di acidi grassi a corta catena ed ? scelto dal gruppo consistente in B.breve SGB 01, B.breve Reuter ATCC 15700, B.breve BR03 (DSM 16604), B.breve B632 (DSM 24706), B.breve Bbr8 (BCCM: LMG P-17501), B. breve DSM24732-BB02, B. breve W25, BB-G95. In one embodiment, when the nutraceutical composition for use according to the present invention comprises Bifidobacterium breve, it has the function of producer of short-chain fatty acids and ? chosen from the group consisting of B.short SGB 01, B.short Reuter ATCC 15700, B.short BR03 (DSM 16604), B.short B632 (DSM 24706), B.short Bbr8 (BCCM: LMG P-17501), B short DSM24732-BB02, B. short W25, BB-G95.
In un?altra forma di realizzazione, quando la composizione nutraceutica per l?uso secondo la presente invenzione comprende Bifidobacterium bifidum, esso ha funzione di produttore di acidi grassi a corta catena ed ? scelto dal gruppo consistente in B. bifidum SGB 02, B.bifidum ATCC 29521, B.bifidum BB 06/MB 107, B.bifidum BB01 (DSM 22892), B.bifidum BB01 (DSM 19818), B.bifidum MB109 (DSM 23731), B.bifidum BB06 (DSM 24688), B. bifidum W23 - W28, BB-G90. La composizione nutraceutica per l?uso secondo l?invenzione comprende almeno un ceppo batterico del genere Lactobacillus. In another embodiment, when the nutraceutical composition for use according to the present invention comprises Bifidobacterium bifidum, it has the function of producer of short-chain fatty acids and ? selected from the group consisting of B.bifidum SGB 02, B.bifidum ATCC 29521, B.bifidum BB 06/MB 107, B.bifidum BB01 (DSM 22892), B.bifidum BB01 (DSM 19818), B.bifidum MB109 (DSM 23731), B. bifidum BB06 (DSM 24688), B. bifidum W23 - W28, BB-G90. The nutraceutical composition for use according to the invention comprises at least one bacterial strain of the genus Lactobacillus.
Preferibilmente detto almeno un ceppo batterico del genere Lactobacillus ? scelto dal gruppo comprendente Lactobacillus kefiri, Lactobacillus plantarum, Lactobacillus salivarius, Lactobacillus reuteri, Lactobacillus acidophilus, Lactobacillus agilis, Lactobacillus alimentarius, Lactobacillus amylolyticus, Lactobacillus amylovorus, Lactobacillus animalis, Lactobacillus apinorum, Lactobacillus apis, Lactobacillus aviaries, Lactobacillus bombi, Lactobacillus bombicola, Lactobacillus brevis, Lactobacillus buchneri, Lactobacillus bulgaricus, Lactobacillus casei, Lactobacillus cellobiosus, Lactobacillus collinoides, Lactobacillus coryniformis, Lactobacillus crispatus, Lactobacillus curvatus, Lactobacillus diolivorans, Lactobacillus farciminis, Lactobacillus fermentum, Lactobacillus gallinarum, Lactobacillus gasseri, Lactobacillus helveticus, Lactobacillus jensenii, Lactobacillus johnsonii, Lactobacillus kefiranofaciens, Lactobacillus kefirgranum, Lactobacillus kefiri, Lactobacillus kimchicus, Lactobacillus kimchiensis, Lactobacillus kimchi, Lactobacillus kisonensis, Lactobacillus kitasatonis, Lactobacillus koreensis, Lactobacillus kosoi, Lactobacillus kullabergensis, Lactobacillus kunkeei, Lactobacillus mellifer, Lactobacillus mellis, Lactobacillus melliventris, Lactobacillus mucosae, Lactobacillus oris, Lactobacillus oryzae, Lactobacillus panis, Lactobacillus parabuchneri, Lactobacillus paracasei, Lactobacillus paraplantarum, Lactobacillus pentosus, Lactobacillus plantarum, Lactobacillus pontis, Lactobacillus sakei, Lactobacillus salivarius, Lactobacillus sanfranciscensis, e loro miscele. Preferably said at least one bacterial strain of the genus Lactobacillus ? selected from the group comprising Lactobacillus kefiri, Lactobacillus plantarum, Lactobacillus salivarius, Lactobacillus reuteri, Lactobacillus acidophilus, Lactobacillus agilis, Lactobacillus Alimentarius, Lactobacillus amylolyticus, Lactobacillus amylovorus, Lactobacillus animalis, Lactobacillus apinorum, Lactobaci llus apis, Lactobacillus aviaries, Lactobacillus bombi, Lactobacillus bombicola, Lactobacillus brevis, Lactobacillus buchneri, Lactobacillus bulgaricus, Lactobacillus casei, Lactobacillus cellobiosus, Lactobacillus collinoides, Lactobacillus coryniformis, Lactobacillus crispatus, Lactobacillus curvatus, Lactobacillus diolivorans, Lactobacillus farciminis, Lactobacillus fermentum, Lactobaci llus gallinarum, Lactobacillus gasseri, Lactobacillus helveticus, Lactobacillus jensenii, Lactobacillus johnsonii, Lactobacillus kefiranofaciens, Lactobacillus kefirgranum, Lactobacillus kefiri, Lactobacillus kimchicus, Lactobacillus kimchiensis, Lactobacillus kimchi, Lactobacillus kisonensis, Lactobacillus kitasatonis, Lactobacillus koreensis, Lactobacillus kosoi, Lactobacillus kullaberg ensis, Lactobacillus kunkeei, Lactobacillus mellifer, Lactobacillus mellis, Lactobacillus melliventris, Lactobacillus mucosae, Lactobacillus oris , Lactobacillus oryzae, Lactobacillus panis, Lactobacillus parabuchneri, Lactobacillus paracasei, Lactobacillus paraplantarum, Lactobacillus pentosus, Lactobacillus plantarum, Lactobacillus pontis, Lactobacillus sakei, Lactobacillus salivarius, Lactobacillus sanfranciscensis, and mixtures thereof.
Pi? preferibilmente, detto almeno un ceppo batterico del genere Lactobacillus ? in una quantit? compresa nell?intervallo da 14 a 140 * 10<9 >CFU/g, preferibilmente 10 a 100 * 10<9 >CFU/g. Pi? preferably, called at least one bacterial strain of the genus Lactobacillus ? in a quantity comprised in the range from 14 to 140 * 10<9 >CFU/g, preferably 10 to 100 * 10<9 >CFU/g.
In una forma di realizzazione, quando la composizione nutraceutica per l?uso secondo la presente invenzione comprende Lactobacillus kefiri, esso ha azione antiinfiammatoria e anti-tumorale ed ? scelto dal gruppo consistente in L.kefiri SGL 13, L.kefiri ATCC 35411, L.kefiri LKF01 (DSM 32079), L.kefiri LKF02 (DSM 32080). In un?altra forma di realizzazione preferita dell?invenzione, quando la composizione nutraceutica per l?uso secondo la presente invenzione comprende Lactobacillus plantarum, esso ha funzione di inibitore di Escherichia Coli ed ? scelto dal gruppo consistente in L.plantarum SGL 07, L.plantarum ATCC 14917, L.plantarum LP02 (LMG P-21020), L.plantarum LP01 (LMG P-21021), L.plantarum LP09 (DSM 25710), L. plantarum W62 - W21- W57, L.plantarum Lp-115, L.plantarum DSM24730 -BP06, L. plantarum P17630, LP-G18. In one embodiment, when the nutraceutical composition for use according to the present invention comprises Lactobacillus kefiri, it has anti-inflammatory and anti-tumor action and is ? selected from the group consisting of L.kefiri SGL 13, L.kefiri ATCC 35411, L.kefiri LKF01 (DSM 32079), L.kefiri LKF02 (DSM 32080). In another preferred embodiment of the invention, when the nutraceutical composition for use according to the present invention comprises Lactobacillus plantarum, it has the function of inhibitor of Escherichia Coli and ? selected from the group consisting of L.plantarum SGL 07, L.plantarum ATCC 14917, L.plantarum LP02 (LMG P-21020), L.plantarum LP01 (LMG P-21021), L.plantarum LP09 (DSM 25710), L. plantarum W62 - W21- W57, L.plantarum Lp-115, L.plantarum DSM24730 -BP06, L. plantarum P17630, LP-G18.
In un?ulteriore forma di realizzazione vantaggiosa dell?invenzione, quando la composizione nutraceutica per l?uso secondo la presente invenzione comprende Lactobacillus salivarius, esso ha funzione di inibitore di Escherichia Coli ed ? scelto dal gruppo consistente in L.salivarius SGL 03, L.salivarius ATCC 11741, L.salivarius CRL 1328, L.salivarius LS01 (DSM 22775), L.salivarius LS03 (DSM 22776), L.salivarius W24, L.salivarius CECT 5713, L.salivarius UCC118, L.salivarius I1794, L.salivarius LS-G60. In a further advantageous embodiment of the invention, when the nutraceutical composition for use according to the present invention comprises Lactobacillus salivarius, it has the function of inhibitor of Escherichia Coli and ? selected from the group consisting of L.salivarius SGL 03, L.salivarius ATCC 11741, L.salivarius CRL 1328, L.salivarius LS01 (DSM 22775), L.salivarius LS03 (DSM 22776), L.salivarius W24, L.salivarius CECT 5713, L.salivarius UCC118, L.salivarius I1794, L.salivarius LS-G60.
In un?ulteriore forma di realizzazione preferita dell?invenzione, quando la composizione nutraceutica per l?uso secondo la presente invenzione comprende Lactobacillus reuteri esso ha funzione di tonificante muscolare ai fini dell?inibizione della cachessia ed ? scelto dal gruppo consistente in L.reuteri SGL 01, L.reuteri ATCC 23272/DSM 20016, L.reuteri LRE02 (DSM 23878), L.reuteri LRE03 (DSM 23879), L.reuteri DSM17938, L.reuteri ATCC55730, L.reuteri CRL1098, L.reuteri LR-G100. In a further preferred embodiment of the invention, when the nutraceutical composition for use according to the present invention comprises Lactobacillus reuteri it has the function of muscle toning for the purpose of inhibition of cachexia and ? selected from the group consisting of L.reuteri SGL 01, L.reuteri ATCC 23272/DSM 20016, L.reuteri LRE02 (DSM 23878), L.reuteri LRE03 (DSM 23879), L.reuteri DSM17938, L.reuteri ATCC55730, L. reuteri CRL1098, L.reuteri LR-G100.
La composizione nutraceutica per l?uso secondo l?invenzione comprende almeno un prebiotico. The nutraceutical composition for use according to the invention comprises at least one prebiotic.
Preferibilmente, detto almeno un prebiotico ha funzione di bifidogeno della flora autoctona ed ? scelto dal gruppo consistente in galatto-oligosaccaridi (GOS), fruttooligosaccaridi (FOS), fibre vegetali, preferibilmente fibra di acacia, fibra di guar, fibra di mela, fibra di limone e loro miscele. Preferably, said at least one prebiotic has the function of bifidogenic of the autochthonous flora and is selected from the group consisting of galacto-oligosaccharides (GOS), fructooligosaccharides (FOS), vegetable fibers, preferably acacia fiber, guar fiber, apple fiber, lemon fiber and mixtures thereof.
Pi? preferibilmente, detto almeno un prebiotico ? in una quantit? compresa nell?intervallo da 350 a 1400 mg, preferibilmente da 250 a 1000 mg. Pi? preferably, said at least a prebiotic ? in a quantity comprised in the range from 350 to 1400 mg, preferably from 250 to 1000 mg.
La composizione nutraceutica per l?uso secondo l?invenzione comprende almeno una transferrina scelta dal gruppo consistente in lattoferrina, ovotransferrina, e loro miscele. The nutraceutical composition for use according to the invention comprises at least one transferrin selected from the group consisting of lactoferrin, ovotransferrin, and mixtures thereof.
Preferibilmente, detta almeno una transferrina scelta dal gruppo consistente di lattoferrina, ovotransferrina, e loro miscele hanno funzione di inibitrici dei patogeni intestinali ? in una quantit? compresa nell?intervallo da 70 a 280 mg, preferibilmente da 50 a 200 mg. Preferably, does said at least one transferrin selected from the group consisting of lactoferrin, ovotransferrin, and mixtures thereof have the function of inhibitors of intestinal pathogens? in a quantity comprised in the range from 70 to 280 mg, preferably from 50 to 200 mg.
La composizione nutraceutica secondo l?invenzione ? utilizzata nel trattamento di patologie collegate a chemioterapia. The nutraceutical composition according to the invention? used in the treatment of diseases related to chemotherapy.
Preferibilmente, dette patologie collegate a chemioterapia sono scelte dal gruppo consistente in mucosite gastrointestinale, disbiosi intestinale, cachessia, incremento di Escherichia Coli e Peptoclostidrium difficile, il cui incremento ? responsabile rispettivamente di crampi addominali, nausea, vomito, diarrea anche emorragica, infezioni delle vie urinarie, gastroenteriti e coliti pseudomembranose, febbre, perdita dell?appetito, infiammazioni ulcerative a carico del colon, riduzione di Lachnospiraceae e Rumicoccocaceae, la cui riduzione causa di infiammazione e/o infezione anche ulcerativa dell?intestino tenue. Preferably, said pathologies linked to chemotherapy are selected from the group consisting of gastrointestinal mucositis, intestinal dysbiosis, cachexia, increase in Escherichia Coli and Peptoclostidrium difficile, the increase of which is ? respectively responsible for abdominal cramps, nausea, vomiting, diarrhea including hemorrhagic, urinary tract infections, gastroenteritis and pseudomembranous colitis, fever, loss of appetite, ulcerative inflammation of the colon, reduction of Lachnospiraceae and Rumicoccocaceae, the reduction of which causes inflammation and/or infection, including ulcerative, of the small intestine.
In una forma particolarmente preferita e vantaggiosa dell?invenzione, la composizione nutraceutica per l?uso consiste in 20 * 10<9 >CFU/g di Bifidobacterium breve, 20 * 10<9 >CFU/g di Bifidobacterium bifidum, 15 * 10<9 >CFU/g di Lactobacillus kefiri, 15 * 10<9 >CFU/g di Lactobacillus plantarum, 15 * 10<9 >CFU/g di Lactobacillus salivarius, 15 * 10<9 >CFU/g di Lactobacillus reuteri, 449 mg di inulina, 100 mg di lattoferrina. In a particularly preferred and advantageous form of the invention, the nutraceutical composition for use consists of 20 * 10<9 >CFU/g of Bifidobacterium breve, 20 * 10<9 >CFU/g of Bifidobacterium bifidum, 15 * 10< 9 >CFU/g of Lactobacillus kefiri, 15 * 10<9 >CFU/g of Lactobacillus plantarum, 15 * 10<9 >CFU/g of Lactobacillus salivarius, 15 * 10<9 >CFU/g of Lactobacillus reuteri, 449 mg of inulin, 100 mg of lactoferrin.
Vantaggiosamente la composizione nutraceutica per l?uso secondo l?invenzione ha un dosaggio giornaliero compreso nell?intervallo da 420 a 1680 mg, preferibilmente da 300 a 1200 mg, pi? preferibilmente ? di 1000 mg. Advantageously, the nutraceutical composition for use according to the invention has a daily dosage ranging from 420 to 1680 mg, preferably from 300 to 1200 mg, plus? preferably ? of 1000 mg.
Preferibilmente detta composizione ? somministrata per via orale. Preferably said composition ? administered orally.
Ancora preferibilmente detta composizione ? in forma solida di una compressa, capsula, polvere, granuli, crema o gel orale, caramella, pillola o striscia solubile, gomma da masticare, pastiglia da sciogliere in bocca o polvere o in forma liquida di sospensione, emulsione, soluzione, spray orale. Still preferably said composition ? in the solid form of a tablet, capsule, powder, granule, cream or oral gel, candy, soluble pill or strip, chewing gum, lozenge or powder or in the liquid form of a suspension, emulsion, solution, oral spray.
In un altro aspetto l?invenzione concerne altres? una composizione nutraceutica consistente in 20 * 10<9 >CFU/g di Bifidobacterium breve, 20 * 10<9 >CFU/g di Bifidobacterium bifidum, 15 * 10<9 >CFU/g di Lactobacillus kefiri, 15 * 10<9 >CFU/g di Lactobacillus plantarum, 15 * 10<9 >CFU/g di Lactobacillus salivarius, 15 * 10<9 >CFU/g di Lactobacillus reuteri, 449 mg di inulina, 100 mg di lattoferrina, per l?uso come adiuvante nel trattamento di tumore al pancreas. In another aspect does the invention also concern a nutraceutical composition consisting of 20 * 10<9 >CFU/g of Bifidobacterium breve, 20 * 10<9 >CFU/g of Bifidobacterium bifidum, 15 * 10<9 >CFU/g of Lactobacillus kefiri, 15 * 10<9 > Lactobacillus plantarum CFU/g, Lactobacillus salivarius 15 * 10<9 >CFU/g, Lactobacillus reuteri 15 * 10<9 >CFU/g, inulin 449 mg, lactoferrin 100 mg, for use as an adjuvant in treatment of pancreatic cancer.
Oggetto della presente invenzione ? anche un metodo di trattamento di patologie legate a chemioterapia mediante somministrazione quotidiana, ad un paziente sottoposto a chemioterapia, di una composizione nutraceutica secondo la presente invenzione fino al completamento del trattamento chemioterapico. Object of the present invention ? also a method of treating pathologies linked to chemotherapy by daily administration, to a patient undergoing chemotherapy, of a nutraceutical composition according to the present invention until completion of the chemotherapy treatment.
Ulteriore oggetto della presente invenzione ? un metodo di trattamento di un tumore, specificatamente del tumore al pancreas, consistente nella somministrazione quotidiana, ad un paziente sottoposto a chemioterapia, di una composizione nutraceutica secondo la presente invenzione fino al completamento del trattamento chemioterapico, come adiuvante nell?inibizione della crescita del cancro del pancreas. L?invenzione sar? ulteriormente dettagliata con la seguente parte sperimentale, che riporta esempi e prove sulla composizione dell?invenzione. Further object of the present invention ? a method of treating a tumour, specifically pancreatic cancer, consisting in the daily administration, to a patient undergoing chemotherapy, of a nutraceutical composition according to the present invention until the completion of the chemotherapy treatment, as an adjuvant in the inhibition of cancer growth of the pancreas. The invention will be further detailed with the following experimental part, which reports examples and tests on the composition of the invention.
PARTE SPERIMENTALE EXPERIMENTAL PART
Esempio 1 Example 1
Preparazione della composizione nutraceutica dell?invenzione Preparation of the nutraceutical composition of the invention
La composizione nutraceutica dell?invenzione ? stata ottenuta miscelando gli ingredienti secondo la Tabella 1a. La composizione nutraceutica dell?invenzione pertanto contiene: The nutraceutical composition of the invention ? was obtained by mixing the ingredients according to Table 1a. The nutraceutical composition of the invention therefore contains:
Tabella 1a Table 1a
Mediante equazioni (I) e (II), di seguito riportate, ? stata calcolata la quantit? di composizione nutraceutica dell?invenzione da somministrare ai topi xenograft per le successive analisi: By means of equations (I) and (II), shown below, ? been calculated the amount? of nutraceutical composition of the invention to be administered to xenograft mice for subsequent analyses:
(Quantit? da somministrare a uomo / 60 kg) * 12.3 = Quantit? topo (mg/kg) (I) (Quantit? topo (mg/kg))/1000 * 25 g = Quantit? da somministrare al topo (mg) (II), in cui nella equazione (I) 12.3 ? il fattore di conversione Uomo/topo. (Quantity to be administered to man / 60 kg) * 12.3 = Quantity? mouse (mg/kg) (I) (Amount mouse (mg/kg))/1000 * 25 g = Amount to be administered to the mouse (mg) (II), where in equation (I) 12.3 ? the Human/Mouse conversion factor.
La composizione nutraceutica dell?invenzione somministrata ai topi pertanto contiene: The nutraceutical composition of the invention administered to mice therefore contains:
Tabella 1b Table 1b
Come indicato in descrizione, la composizione pu? contenere anche altri ceppi di Bifidobacterium e Lactobacillus. As indicated in the description, the composition can? also contain other strains of Bifidobacterium and Lactobacillus.
Esempio 2 Example 2
Analisi della progressione tumorale Analysis of tumor progression
La composizione nutraceutica dell?invenzione secondo l?Esempio 1 ? stata testata su modello animale murino, un modello in vivo secondo la procedura riportata in Panebianco C. et al. ?Influence of gemcitabine chemotherapy on the microbiota of pancreatic cancer xenografted mice?, Cancer Chemother Pharmacol. 2018, 81 (4), 773-782, che consiste in 32 topi nu/nu con iniezione subcutanea di linee cellulari tumorali di Bx-PC3 per lo sviluppo di tumore al pancreas xenograft. The nutraceutical composition of the invention according to Example 1? been tested on a murine animal model, an in vivo model according to the procedure reported in Panebianco C. et al. ?Influence of gemcitabine chemotherapy on the microbiota of pancreatic cancer xenografted mice?, Cancer Chemother Pharmacol. 2018, 81 (4), 773-782 , which consists of 32 nu/nu mice subcutaneously injected with Bx-PC3 tumor cell lines for pancreatic tumor xenograft development.
Gli arruolati sono stati randomizzati in 4 gruppi di studio: Enrollees were randomized into 4 study groups:
- 8 topi xenograft per tumore al pancreas (BxPC3 cells) (controllo), - 8 pancreatic tumor xenograft mice (BxPC3 cells) (control),
- 8 topi xenograft BxPC3 Composizione nutraceutica dell?invenzione, - 8 BxPC3 xenograft mice Nutraceutical composition of the invention,
- 8 topi xenograft BxPC3 con Gemcitabina, - 8 BxPC3 xenograft mice with Gemcitabine,
- 8 topi xenograft con Gemcitabina Composizione nutraceutica dell?invenzione. I topi con normale alimentazione (controllo) sono stati confrontati con quelli a cui ? stata somministrata la composizione nutraceutica dell?invenzione secondo l?Esempio 1 ed ? stata valutata la progressione di crescita del volume tumorale. Lo schema del protocollo sperimentale ? schematizzato in Figura 1. - 8 mice xenograft with Gemcitabine Nutraceutical composition of the invention. Were the normally fed (control) mice compared with those that ? was the nutraceutical composition of the invention administered according to Example 1 and? tumor volume growth progression was evaluated. The outline of the experimental protocol? schematized in Figure 1.
Nel corso della sperimentazione, ? stato valutato il volume del tumore, mediante misurazioni con il calibro (Digital Caliper MITUTOYO) I valori misurati sulla media dei topi dei gruppi ? stata raffigurata con deviazione standard in Figura 2. Il grafico di Figura 2 mostra con evidenza che i gruppi trattati hanno un minor volume tumorale rispetto al controllo non trattato. Specificatamente, il gruppo trattato con la sola composizione dell?invenzione secondo l?Esempio 1 e il gruppo trattato con la combinazione della composizione dell?invenzione secondo l?Esempio 1 e il farmaco chemioterapico Gemcitabina, sono caratterizzati da un rallentamento della progressione tumorale in termini di volume. During the experimentation, ? the volume of the tumor was evaluated, by means of measurements with the caliper (Digital Caliper MITUTOYO) The values measured on the average of the mice of the groups ? was depicted with standard deviation in Figure 2. The graph in Figure 2 clearly shows that the treated groups have a smaller tumor volume than the untreated control. Specifically, the group treated with the sole composition of the invention according to Example 1 and the group treated with the combination of the composition of the invention according to Example 1 and the chemotherapeutic drug Gemcitabine, are characterized by a slowing down of tumor progression in terms of volume.
Esempio 3 Example 3
Analisi dei profili ematologici: emocromo, parametri epatici e renali su prelievi di sangue Analysis of hematological profiles: blood count, liver and kidney parameters on blood samples
La composizione nutraceutica dell?invenzione secondo l?Esempio 1 ? stata testata su modello animale murino, un modello in vivo secondo la procedura riportata in Panebianco C. et al. ?Influence of gemcitabine chemotherapy on the microbiota of pancreatic cancer xenografted mice?, Cancer Chemother Pharmacol. 2018, 81 (4), 773-782, che consiste in 32 topi nu/nu con iniezione subcutanea di linee cellulari tumorali di Bx-PC3 per lo sviluppo di tumore al pancreas xenograft. The nutraceutical composition of the invention according to Example 1? been tested on a murine animal model, an in vivo model according to the procedure reported in Panebianco C. et al. ?Influence of gemcitabine chemotherapy on the microbiota of pancreatic cancer xenografted mice?, Cancer Chemother Pharmacol. 2018, 81 (4), 773-782 , which consists of 32 nu/nu mice subcutaneously injected with Bx-PC3 tumor cell lines for pancreatic tumor xenograft development.
Gli arruolati sono stati randomizzati in 4 gruppi di studio: Enrollees were randomized into 4 study groups:
- 8 topi xenograft per tumore al pancreas (BxPC3 cells) (controllo), - 8 pancreatic tumor xenograft mice (BxPC3 cells) (control),
- 8 topi xenograft BxPC3 Composizione nutraceutica dell?invenzione, - 8 BxPC3 xenograft mice Nutraceutical composition of the invention,
- 8 topi xenograft BxPC3 con Gemcitabina, - 8 BxPC3 xenograft mice with Gemcitabine,
- 8 topi xenograft con Gemcitabina Composizione nutraceutica dell?invenzione. I topi con normale alimentazione (controllo) sono stati confrontati con quelli a cui ? stata somministrata la composizione nutraceutica dell?invenzione secondo l?Esempio 1. - 8 mice xenograft with Gemcitabine Nutraceutical composition of the invention. Were the normally fed (control) mice compared with those that ? the nutraceutical composition of the invention was administered according to Example 1.
Lo schema del protocollo sperimentale ? schematizzato in Figura 1. The outline of the experimental protocol? schematized in Figure 1.
Al sacrificio, sono stati raccolti i campioni di sangue e su questi ? stata condotta la misurazione dei parametri riportati nella tabelle: emocromo e funzionalit? epatica e renale. At the sacrifice, blood samples were collected and on these ? was the measurement of the parameters shown in the tables carried out: blood count and functionality? hepatic and renal.
La tabella 2 riporta i valori medi per gruppo dei parametri dell?emocromo dei 4 gruppi sperimentali, dopo sacrificio, con le loro deviazioni standard. Table 2 reports the mean values per group of the blood count parameters of the 4 experimental groups, after sacrifice, with their standard deviations.
Tabella 2 Table 2
In Tabella 2 sono rappresentati gli emocromo dei 4 gruppi sperimentali dopo il sacrificio. Table 2 shows the blood counts of the 4 experimental groups after the sacrifice.
Sono evidenziati in grigio i seguenti parametri: conta dei globuli rossi (RBC), conta dei globuli bianchi (WBC) e il numero di piastrine (PLT). The following parameters are highlighted in gray: red blood cell count (RBC), white blood cell count (WBC) and platelet count (PLT).
Questi parametri evidenziati sono risultati significativamente rinormalizzati grazie al trattamento con la composizione nutraceutica dell?invenzione secondo l?Esempio 1 e hanno mostrato un?attivit? sinergica della composizione nutraceutica dell?invenzione quando somministrata con l?agente chemioterapico Gemcitabina. In particolare, l?effetto dell?agente chemioterapico Gemcitabina su questi parametri, quando somministrato da solo, ? gi? elevato. Si ? osservato infatti un abbassamento del numero di globuli rossi (RBC) rispetto al controllo (da 8.8 a 7.58 x 10<+6 >U/l), un numero elevato pressoch? inalterato di globuli bianchi rispetto al controllo (WBC 7.77 e 7.05 x 10<+3 >U/l) e una importante riduzione del numero di piastrine rispetto al controllo (PLT, da 854 a 485 x 10<+3 >U/l). These highlighted parameters resulted to be significantly renormalized thanks to the treatment with the nutraceutical composition of the invention according to Example 1 and showed an activity? synergistic of the nutraceutical composition of the invention when administered with the chemotherapeutic agent Gemcitabine. In particular, the effect of the chemotherapeutic agent gemcitabine on these parameters, when given alone, was ? already high. Yes ? observed in fact a lowering of the number of red blood cells (RBC) compared to the control (from 8.8 to 7.58 x 10<+6 >U/l), a high number almost? unchanged white blood cells compared to the control (WBC 7.77 and 7.05 x 10<+3 >U/l) and an important reduction in the number of platelets compared to the control (PLT, from 854 to 485 x 10<+3 >U/l) .
Questi valori, quando compromessi, provocano l?interruzione del protocollo farmacologico causando una riduzione dell?efficacia dell?intero protocollo e di conseguenza una riduzione della sopravvivenza dei pazienti. These values, when compromised, cause the interruption of the pharmacological protocol causing a reduction in the effectiveness of the entire protocol and consequently a reduction in patient survival.
Il trattamento con la composizione nutraceutica dell?invenzione in combinazione con l?agente chemioterapico Gemcitabina, ha mostrato di rinormalizzare i parametri sora descritti. Treatment with the nutraceutical composition of the invention in combination with the chemotherapeutic agent Gemcitabine has shown to renormalize the parameters described above.
I valori dei globuli rossi (RBC) sono tornati ad aumentare fino a valori di 9.36 x 10<+6 >U/l, i valori dei globuli bianchi (WBC) si sono abbassati fino al valore di 6.18 x 10<+3 >U/l e le piastrine (PLT) eccezionalmente sono ritornate a valori normali (819,80 x 10<+3 >U/l). Red blood cell (RBC) values increased again to values of 9.36 x 10<+6 >U/l, white blood cell (WBC) values decreased to 6.18 x 10<+3 >U /l and platelets (PLT) exceptionally returned to normal values (819.80 x 10<+3 >U/l).
Successivamente sono stati valutati i parametri epatici e renali. Subsequently, hepatic and renal parameters were evaluated.
La tabella 3 riporta i valori medi per gruppo dei parametri epatici e renali dei 4 gruppi sperimentali, dopo sacrificio, con le loro deviazioni standard. Table 3 reports the mean values per group of the hepatic and renal parameters of the 4 experimental groups, after sacrifice, with their standard deviations.
Tabella 3 Table 3
In Tabella 3 sono rappresentati i valori epatici e renali dei 4 gruppi sperimentali dopo il sacrificio. Table 3 shows the hepatic and renal values of the 4 experimental groups after the sacrifice.
Sono evidenziati in grigio i seguenti parametri: transaminasi (AST) e gammaglutamil transferasi (GGT). The following parameters are highlighted in gray: transaminase (AST) and gammaglutamyl transferase (GGT).
Anche un aumento di questi parametri, che evidenziano un aumento del danno renale, porterebbe ad una interruzione del trattamento farmacologico, o comunque ad una deviazione dello schema classico, causando una riduzione dell?efficacia del trattamento stesso. Pertanto il loro controllo e la loro riduzione ? un fattore da considerare. Even an increase in these parameters, which show an increase in renal damage, would lead to an interruption of the pharmacological treatment, or in any case to a deviation from the classic scheme, causing a reduction in the effectiveness of the treatment itself. Therefore their control and their reduction? a factor to consider.
Questi parametri evidenziati sono risultati significativamente rinormalizzati grazie al trattamento con la composizione nutraceutica dell?invenzione secondo l?Esempio 1 e hanno mostrato un?attivit? sinergica della composizione nutraceutica dell?invenzione quando somministrata con l?agente chemioterapico Gemcitabina. Si ? osservato che i valori delle transaminasi (AST) sono stati rinormalizzati rispetto al controllo che aveva un valore di 153.33 U/l, che ? aumentato a seguito del trattamento con l?agente chemioterapico Gemcitabina fino a 185.00 U/l ed ? stato invece rinormalizzato con il trattamento con la composizione nutraceutica dell?invenzione secondo l?Esempio 1 fino a 164.00 U/l da sola e fino a 150.75 U/l dopo trattamento con la composizione nutraceutica dell?invenzione in combinazione con l?agente chemioterapico Gemcitabina. Questi valori mostrano l?efficacia della composizione nutraceutica secondo l?invenzione da sola e la sinergia della sua azione in presenza dell?agente chemioterapico Gemcitabina. These highlighted parameters resulted to be significantly renormalized thanks to the treatment with the nutraceutical composition of the invention according to Example 1 and showed an activity? synergistic of the nutraceutical composition of the invention when administered with the chemotherapeutic agent Gemcitabine. Yes ? observed that the values of transaminases (AST) have been renormalized with respect to the control which had a value of 153.33 U/l, which ? increased following treatment with the chemotherapeutic agent Gemcitabine up to 185.00 U/l and ? was instead renormalized with treatment with the nutraceutical composition of the invention according to Example 1 up to 164.00 U/l alone and up to 150.75 U/l after treatment with the nutraceutical composition of the invention in combination with the chemotherapeutic agent Gemcitabine . These values show the efficacy of the nutraceutical composition according to the invention alone and the synergy of its action in the presence of the chemotherapeutic agent Gemcitabine.
La gamma-glutamil transferasi (GGT) ? un enzima che si trova principalmente nel rene, nel fegato e nelle cellule pancreatiche, normalmente ? bassa nel circolo sanguigno mentre in caso di disfunzioni organiche tende ad aumentare. Gamma-glutamyl transferase (GGT) ? an enzyme found primarily in kidney, liver and pancreatic cells, normally ? low in the bloodstream while in case of organic dysfunctions it tends to increase.
Infatti da un valore di 28.00 U/l presentato dal controllo, ? stato riscontrato un aumento fino al valore di 35.25 U/l dopo trattamento con il solo agente chemioterapico Gemcitabina ed ? stato invece rinormalizzato fino ad un valore di 26.20 U/l con il trattamento con la composizione nutraceutica dell?invenzione in combinazione con l?agente chemioterapico Gemcitabina. Questi valori mostrano l?efficacia della composizione nutraceutica secondo l?invenzione da sola e la sinergia della sua azione in presenza dell?agente chemioterapico Gemcitabina. In fact, from a value of 28.00 U/l presented by the control, ? been found an increase up to the value of 35.25 U / l after treatment with the only chemotherapeutic agent Gemcitabine and ? instead, it was renormalized up to a value of 26.20 U/l with treatment with the nutraceutical composition of the invention in combination with the chemotherapeutic agent Gemcitabine. These values show the efficacy of the nutraceutical composition according to the invention alone and the synergy of its action in the presence of the chemotherapeutic agent Gemcitabine.
Esempio 4 Example 4
Valutazione degli istologici post mortem di tessuto tumorale intestinale Post-mortem histological evaluation of intestinal tumor tissue
La composizione nutraceutica dell?invenzione secondo l?Esempio 1 ? stata testata su modello animale murino, un modello in vivo secondo la procedura riportata in Panebianco C. et al. ?Influence of gemcitabine chemotherapy on the microbiota of pancreatic cancer xenografted mice?, Cancer Chemother Pharmacol. 2018, 81 (4), 773-782, che consiste in 32 topi nu/nu con iniezione subcutanea di linee cellulari tumorali di Bx-PC3 per lo sviluppo di tumore al pancreas xenograft. The nutraceutical composition of the invention according to Example 1? been tested on a murine animal model, an in vivo model according to the procedure reported in Panebianco C. et al. ?Influence of gemcitabine chemotherapy on the microbiota of pancreatic cancer xenografted mice?, Cancer Chemother Pharmacol. 2018, 81 (4), 773-782 , which consists of 32 nu/nu mice subcutaneously injected with Bx-PC3 tumor cell lines for pancreatic tumor xenograft development.
Gli arruolati sono stati randomizzati in 4 gruppi di studio: Enrollees were randomized into 4 study groups:
- 8 topi xenograft per tumore al pancreas (BxPC3 cells) (controllo) - 8 pancreatic tumor xenograft mice (BxPC3 cells) (control)
- 8 topi xenograft BxPC3 Composizione nutraceutica dell?invenzione, - 8 BxPC3 xenograft mice Nutraceutical composition of the invention,
- 8 topi xenograft BxPC3 con Gemcitabina, - 8 BxPC3 xenograft mice with Gemcitabine,
- 8 topi xenograft con Gemcitabina Composizione nutraceutica dell?invenzione. I topi con normale alimentazione (controllo) sono stati confrontati con quelli a cui ? stata somministrata la composizione nutraceutica dell?invenzione secondo l?Esempio 1. - 8 mice xenograft with Gemcitabine Nutraceutical composition of the invention. Were the normally fed (control) mice compared with those that ? the nutraceutical composition of the invention was administered according to Example 1.
Lo schema del protocollo sperimentale ? schematizzato in Figura 1. The outline of the experimental protocol? schematized in Figure 1.
Al sacrificio sono stati raccolti i campioni di tessuti tumorali intestinali dei 4 gruppi di studio. Samples of intestinal tumor tissue from the 4 study groups were collected at sacrifice.
In Figura 3 sono mostrate le immagini delle sezioni istologiche di tumori xenograft prelevate da animali appartenenti ai 4 gruppi sperimentali, ottenute mediante colorazioni HE (Ematossilina/Eosina per colorazione base) e con i seguenti anticorpi: CD31 (marker di angiogenesi), Ki67 (marker di proliferazione cellulare). In Figura 4 sono mostrate le immagini delle sezioni istologiche di tumori xenograft prelevate da animali appartenenti ai 4 gruppi sperimentali, ottenute mediante colorazioni: Masson Trichrome (colorante che differenzia le cellule muscolari dal collagene), Psicrosirius Red (evidenzia la porzione del collagene nei tessuti) e con i seguenti anticorpi: E-Cadherin e N-Cadherin (indice della transizione epitelialemesenchimale ?EMT?). Figure 3 shows the images of the histological sections of xenograft tumors taken from animals belonging to the 4 experimental groups, obtained by means of HE stains (Hematoxylin/Eosin for basic staining) and with the following antibodies: CD31 (marker of angiogenesis), Ki67 (marker of cell proliferation). Figure 4 shows the images of the histological sections of xenograft tumors taken from animals belonging to the 4 experimental groups, obtained by staining: Masson Trichrome (dye that differentiates muscle cells from collagen), Psicosirius Red (highlights the portion of collagen in the tissues) and with the following antibodies: E-Cadherin and N-Cadherin (epithelial-mesenchymal transition index ?EMT?).
Il campione Controllo (39952 Ctr) ha mostrato, come si evince dalla Figura 3, una neoplasia epiteliale di alto grado con un alto grado di pleiomorfismo costituito da cellule con morfologia prismatica che si mescolano a cellule a forma di fuso. Si ? osservata un'alta frequenza di aree apoptotiche. The Control sample (39952 Ctr) showed, as can be seen from Figure 3, a high-grade epithelial neoplasm with a high degree of pleomorphism consisting of cells with prismatic morphology intermingling with spindle-shaped cells. Yes ? observed a high frequency of apoptotic areas.
Il colorante Ki-67 rivela in Figura 3 una frazione proliferativa di circa il 30% nel gruppo di controllo (39952 Ctr). The Ki-67 dye reveals in Figure 3 a proliferative fraction of about 30% in the control group (39952 Ctr).
Mediante colorazione Masson Trichrome e Picrosirius si sono evidenziati in Figura 4 i fasci stromali che delineano nidi epiteliali e sono caratterizzati da una densa deposizione collagenica. La E-caderina mostra una colorazione diffusa ma variamente intensa, le aree marcate con N-caderina sono densamente popolate da cellule a forma di fuso. By means of Masson Trichrome and Picrosirius staining, Figure 4 highlighted the stromal bundles that outline epithelial nests and are characterized by a dense collagen deposition. E-cadherin shows diffuse but varyingly intense staining, N-cadherin-labelled areas are densely populated with spindle-shaped cells.
Dopo il trattamento con il solo agente chemioterapico Gemcitabina (39958 Gem), la morfologia delle cellule tumorali ? meno pleiomorfa con una predominanza di elementi a forma di fuso. I fasci stromali mostrano in Figura 3 una disposizione pi? libera di fibre di collagene con vasi colorati di CD31 che mostrano una parete meno strutturata. After treatment with the chemotherapeutic agent Gemcitabine (39958 Gem) alone, the morphology of the tumor cells ? less pleomorphic with a predominance of spindle-shaped elements. The stromal bundles show in Figure 3 a more? free of collagen fibers with CD31 stained vessels showing a less structured wall.
La colorazione con E-caderina in Figura 4 ? meno diffusa e densa e la colorazione con N-caderina ? mostra come essa sia indotta multifocalmente, supportando un'espressione inferiore di un fenotipo epiteliale coerente con il cambiamento morfologico osservato su H&E. Non si osserva per? alcuna riduzione significativa dell'indice proliferativo (25/30%). The E-cadherin stain in Figure 4 ? less widespread and dense and the staining with N-cadherin ? shows that it is multifocally induced, supporting a lower expression of an epithelial phenotype consistent with the morphological change observed on H&E. Do you observe for? no significant reduction in the proliferative index (25/30%).
Nei campioni trattati con la sola composizione nutraceutica dell?invenzione secondo l?Esempio 1 (39947 Pro) la morfologia ? simile al controllo con un relativo arricchimento in cellule con forma prismatica e giunzioni intercellulari strette, come evidente dalla Figura 3. Si osservano in Figura 3 frequenti aree apoptotiche e lacune vascolari. In the samples treated with only the nutraceutical composition of the invention according to Example 1 (39947 Pro) the morphology ? similar to the control with relative enrichment in cells with prismatic shape and tight intercellular junctions, as evident from Figure 3. Frequent apoptotic areas and vascular lacunae are observed in Figure 3.
In Figura 3, il Ki-67 evidenzia una leggera riduzione della frazione complessiva di cellule proliferanti (15/20%), una caratteristica che pu? essere correlata con transizione epitelio- mesenchimale. In Figure 3, Ki-67 shows a slight reduction in the overall fraction of proliferating cells (15/20%), a characteristic that can be correlated with epithelial-mesenchymal transition.
In Figura 4 si osserva, per i campioni trattati con la sola composizione nutraceutica dell?invenzione secondo l?Esempio 1 (39955 Pro) una riduzione complessiva della densit? della deposizione di matrice extracellulare associata alla stromatogenesi del cancro, valutata da Picrosirius e dal Trichrome di Masson. La E-caderina mostra costantemente una colorazione forte e diffusa e la N-caderina ? sotto modulata a livello globale. Figure 4 shows, for the samples treated with only the nutraceutical composition of the invention according to Example 1 (39955 Pro) an overall reduction of the density of extracellular matrix deposition associated with cancer stromatogenesis, assessed by Picrosirius and Masson's Trichrome. E-cadherin consistently exhibits strong and diffuse staining and N-cadherin ? under-modulated globally.
Analogamente a quanto osservato nei campioni del gruppo trattato con il solo agente chemioterapico Gemcitabina, nel trattamento combinato (Gemcitabina composizione nutraceutica dell?invenzione) (399545 Pro+Gem) la morfologia delle cellule maligne ? meno pleiomorfa a causa di una predominanza di elementi a forma di fuso, come evidente dalla Figura 4. La reazione stromale ? simile a quella del campione di controllo (colorazioni Picrosirius e Trichrome di Masson); la colorazione E-caderina mostra in Figura 4 la riduzione di fuochi con una morfologia di transizione epitelio-stromale ridotta, e una riduzione dei fuochi con immunoreattiva per N-caderina. L?espressione Ki-67 ? paragonabile a quello del campione Controllo. Similarly to what was observed in the samples of the group treated with the single chemotherapeutic agent Gemcitabine, in the combined treatment (Gemcitabine nutraceutical composition of the invention) (399545 Pro+Gem) the morphology of the malignant cells ? less pleomorphic due to a predominance of spindle-shaped elements, as evident from Figure 4. The stromal reaction ? similar to that of the control sample (Masson's Picrosirius and Trichrome stains); E-cadherin staining shows in Figure 4 the reduction of foci with reduced epithelial-stromal transition morphology, and a reduction of foci with N-cadherin immunoreactive. The expression Ki-67 ? comparable to that of the control sample.
Da queste immagini ? possibile confermare l?efficacia della composizione nutraceutica secondo l?invenzione somministrata da sola e la sinergia della sua azione in presenza dell?agente chemioterapico Gemcitabina. From these images? It is possible to confirm the efficacy of the nutraceutical composition according to the invention administered alone and the synergy of its action in the presence of the chemotherapeutic agent Gemcitabine.
Esempio 5 Example 5
Esperimenti di immunoblotting Immunoblotting experiments
Al fine di verificare ulteriormente le osservazioni istologiche, su estratto proteico di tessuto tumorale, sono state quantificate le proteine il cui profilo di espressione ? legato alla transizione epitelio-mesenchimale mediante esperimenti di immunoblotting. Come mostrato nel grafico Figura 5, sebbene la E-Cadherina sia sotto-espressa (marcatore epiteliale) anche tutte le altre proteine coinvolte nell?EMT, ossia N-caderina, Snail, Slug e Vimentin, risultano tutte sotto espresse nel gruppo trattato con la formula. Dai valori assoluti si pu? anche evincere nel grafico a radar, riportato in Figura 5, una sinergia del trattamento combinato con l?agente chemioterapico Gemcitabina e la composizione nutraceutica dell?invenzione secondo l?Esempio 1 rispetto ai trattamenti coi singoli composti. In order to further verify the histological observations, the proteins whose expression profile ? linked to epithelial-mesenchymal transition by immunoblotting experiments. As shown in the graph Figure 5, although E-Cadherin is underexpressed (epithelial marker) all the other proteins involved in EMT, i.e. N-cadherin, Snail, Slug and Vimentin, are also all underexpressed in the group treated with EMT. formula. From the absolute values you can? also deduce in the radar graph, shown in Figure 5, a synergy of the combined treatment with the chemotherapeutic agent Gemcitabine and the nutraceutical composition of the invention according to Example 1 with respect to the treatments with the single compounds.
Esempio 6 Example 6
Valutazione degli istologici dei tessuti intestinali nei topi con cancro del pancreas (soggetti a chemio e nutraceutico) Evaluation of intestinal tissue histologics in mice with pancreatic cancer (subject to chemo and nutraceutical)
La composizione nutraceutica dell?invenzione secondo l?Esempio 1 ? stata testata su modello animale murino, un modello in vivo secondo la procedura riportata in Panebianco C. et al. ?Influence of gemcitabine chemotherapy on the microbiota of pancreatic cancer xenografted mice?, Cancer Chemother Pharmacol. 2018, 81 (4), 773-782, che consiste in 32 topi nu/nu con iniezione subcutanea di linee cellulari tumorali di Bx-PC3 per lo sviluppo di tumore al pancreas xenograft. The nutraceutical composition of the invention according to Example 1? been tested on a murine animal model, an in vivo model according to the procedure reported in Panebianco C. et al. ?Influence of gemcitabine chemotherapy on the microbiota of pancreatic cancer xenografted mice?, Cancer Chemother Pharmacol. 2018, 81 (4), 773-782 , which consists of 32 nu/nu mice subcutaneously injected with Bx-PC3 tumor cell lines for pancreatic tumor xenograft development.
Gli arruolati sono stati randomizzati in 4 gruppi di studio: Enrollees were randomized into 4 study groups:
- 8 topi xenograft per tumore al pancreas (BxPC3 cells) (controllo) - 8 pancreatic tumor xenograft mice (BxPC3 cells) (control)
- 8 topi xenograft BxPC3 Composizione nutraceutica dell?invenzione, - 8 BxPC3 xenograft mice Nutraceutical composition of the invention,
- 8 topi xenograft BxPC3 con Gemcitabina, - 8 BxPC3 xenograft mice with Gemcitabine,
- 8 topi xenograft con Gemcitabina Composizione nutraceutica dell?invenzione. I topi con normale alimentazione (controllo) sono stati confrontati con quelli a cui ? stata somministrata la composizione nutraceutica dell?invenzione secondo l?Esempio 1. - 8 mice xenograft with Gemcitabine Nutraceutical composition of the invention. Were the normally fed (control) mice compared with those that ? the nutraceutical composition of the invention was administered according to Example 1.
Lo schema del protocollo sperimentale ? schematizzato in Figura 1. The outline of the experimental protocol? schematized in Figure 1.
Al sacrificio, sono stati raccolti i campioni di tessuti intestinali dei 4 gruppi di studio. At sacrifice, intestinal tissue samples from the 4 study groups were collected.
In Figura 6 si osserva che la mucosa intestinale degli animali controllo (39952 Ctr) ? caratterizzata da cripte ghiandolari regolarmente distanziate con sintesi di muco conservato, come evidenziato dalla colorazione Alcian Blue ed ? presente una lamina propria normalmente popolata. I pochi elementi proliferanti sono normalmente localizzati all'interno delle cripte, coerentemente con una condizione omeostatica. In Figure 6 it is observed that the intestinal mucosa of the control animals (39952 Ctr) ? characterized by regularly spaced glandular crypts with preserved mucus synthesis as evidenced by Alcian Blue staining and ? a normally populated lamina propria is present. The few proliferating elements are normally located inside the crypts, consistently with a homeostatic condition.
In Figura 6, il campione trattato col solo agente chemioterapico Gemcitabina (39958 Gem) mostra una riduzione globale della sintesi di muco da parte delle cellule epiteliali che rivestono le cripte. Queste cellule mostrano morfologia nucleare irregolare e cromasia alterata e lo stroma circostante della lamina propria mostra segni di edema e un leggero e focale aumento dell'infiltrazione cellulare infiammatoria, nonch? una struttura dei villi intestinali compromessa. In Figure 6, the sample treated with the chemotherapeutic agent Gemcitabine alone (39958 Gem) shows a global reduction of mucus synthesis by the epithelial cells lining the crypts. These cells show irregular nuclear morphology and altered chromasia, and the surrounding stroma of the lamina propria shows signs of edema and a slight and focal increase in inflammatory cellular infiltration, as well as an impaired intestinal villous structure.
In Figura 6, Il Ki-67 sottolinea una riduzione complessiva della frazione di elementi proliferanti suggerendo che l'alterazione della funzione ghiandolare non sia associata alla rigenerazione epiteliale. In Figure 6, Ki-67 underlines an overall reduction of the fraction of proliferating elements suggesting that the alteration of the glandular function is not associated with epithelial regeneration.
I campioni trattati con la sola composizione nutraceutica dell?invenzione secondo l?Esempio 1 (39955 Pro) sono caratterizzati da una lieve diminuzione della sintesi di muco da parte delle cellule epiteliali rispetto ai campioni trattati col solo agente chemioterapico Gemcitabina (39958 Gem). La lamina propria presenta segni di edema focale e aumento focale della densit? cellulare infiammatoria. L'attivit? proliferativa delle cellule epiteliali nei campioni trattati con la sola composizione nutraceutica dell?invenzione secondo l?Esempio 1 (39955 Pro) risulta significativamente aumentata rispetto ai campioni controllo (39952 Ctr) e rispetto a quelli trattati con il solo agente chemioterapico Gemcitabina (39958 Gem). Questa evidenza, insieme alla diminuzione della secrezione di muco, suggerisce cambiamenti rigenerativi. The samples treated only with the nutraceutical composition of the invention according to Example 1 (39955 Pro) are characterized by a slight decrease in mucus synthesis by the epithelial cells compared to the samples treated only with the chemotherapeutic agent Gemcitabine (39958 Gem). Does the lamina propria show signs of focal edema and focal increase in density? inflammatory cell. The activity? proliferation of epithelial cells in the samples treated only with the nutraceutical composition of the invention according to Example 1 (39955 Pro) is significantly increased compared to the control samples (39952 Ctr) and compared to those treated only with the chemotherapeutic agent Gemcitabine (39958 Gem) . This evidence, together with decreased mucus secretion, suggests regenerative changes.
A seguito del trattamento combinato (Gemcitabina composizione nutraceutica secondo l?invenzione) (399545 Pro+Gem), l'architettura epiteliale e stromale complessiva risulta meglio preservata rispetto a quella mostrata dopo trattamento con il solo agente chemioterapico Gemcitabina (39958 Gem). Le cellule epiteliali mostrano una morfologia pi? regolare e un contenuto di muco parzialmente conservato, nonch? viene ripristinata parzialmente l?integrit? dei villi, fortemente compromessa nei topi trattati con il solo chemioterapico. Following the combined treatment (Gemcitabine nutraceutical composition according to the invention) (399545 Pro+Gem), the overall epithelial and stromal architecture is better preserved than that shown after treatment with the single chemotherapeutic agent Gemcitabine (39958 Gem). Epithelial cells show a more regular and a partially preserved mucus content, as well as? is the integrity partially restored? of the villi, strongly impaired in mice treated with chemotherapy alone.
In Figura 6, Il Ki-67 ? risultato pi? alto di quello di una mucosa quiescente (39952 Ctr) e la localizzazione delle cellule proliferanti ? risultata coerente con il loro tentativo di rigenerazione. In Figure 6, the Ki-67 ? result more? higher than that of a quiescent mucosa (39952 Ctr) and the localization of proliferating cells ? found to be consistent with their attempted regeneration.
Da queste immagini ? possibile confermare l?efficacia della composizione nutraceutica secondo l?invenzione somministrata da sola e la sinergia della sua azione in presenza dell?agente chemioterapico Gemcitabina. From these images? It is possible to confirm the efficacy of the nutraceutical composition according to the invention administered alone and the synergy of its action in the presence of the chemotherapeutic agent Gemcitabine.
Esperimento 7 Experiment 7
Valutazione dei profili microbici del microbiota intestinale dalle feci Evaluation of microbial profiles of the intestinal microbiota from feces
La composizione nutraceutica dell?invenzione secondo l?Esempio 1 ? stata testata su modello animale murino, un modello in vivo secondo la procedura riportata in Panebianco C. et al. ?Influence of gemcitabine chemotherapy on the microbiota of pancreatic cancer xenografted mice?, Cancer Chemother Pharmacol. 2018, 81 (4), 773-782, che consiste in 32 topi nu/nu con iniezione subcutanea di linee cellulari tumorali di Bx-PC3 per lo sviluppo di tumore al pancreas xenograft. The nutraceutical composition of the invention according to Example 1? been tested on a murine animal model, an in vivo model according to the procedure reported in Panebianco C. et al. ?Influence of gemcitabine chemotherapy on the microbiota of pancreatic cancer xenografted mice?, Cancer Chemother Pharmacol. 2018, 81 (4), 773-782 , which consists of 32 nu/nu mice subcutaneously injected with Bx-PC3 tumor cell lines for pancreatic tumor xenograft development.
Gli arruolati sono stati randomizzati in 4 gruppi di studio: Enrollees were randomized into 4 study groups:
- 8 topi xenograft per tumore al pancreas (BxPC3 cells) (controllo), - 8 pancreatic tumor xenograft mice (BxPC3 cells) (control),
- 8 topi xenograft BxPC3 Composizione nutraceutica dell?invenzione, - 8 BxPC3 xenograft mice Nutraceutical composition of the invention,
- 8 topi xenograft BxPC3 con Gemcitabina, - 8 BxPC3 xenograft mice with Gemcitabine,
- 8 topi xenograft con Gemcitabina Composizione nutraceutica dell?invenzione. I topi con normale alimentazione (controllo) sono stati confrontati con quelli a cui ? stata somministrata la composizione nutraceutica dell?invenzione secondo l?Esempio 1. - 8 mice xenograft with Gemcitabine Nutraceutical composition of the invention. Were the normally fed (control) mice compared with those that ? the nutraceutical composition of the invention was administered according to Example 1.
Lo schema del protocollo sperimentale ? schematizzato in Figura 1. The outline of the experimental protocol? schematized in Figure 1.
Sono state prelevate le feci di ciascuno dei 4 gruppi di studio. Stools from each of the 4 study groups were collected.
In Tabella 4 sono rappresentati i profili dei gruppi microbici rappresentativi del microbiota intestinale, estratto dalle feci dei 4 gruppi sperimentali. Table 4 shows the profiles of the microbial groups representative of the intestinal microbiota, extracted from the faeces of the 4 experimental groups.
Tabella 4 Table 4
* Significativo vs Controllo, # Significativo vs Gemcitabina, ? Significativo vs Composizione nutraceutica dell?invenzione . * Significant vs Control, # Significant vs Gemcitabine, ? Significant vs Nutraceutical composition of the invention .
Come riportato in Tabella 4, le Defluviitaleaceae sono presenti solo nei gruppi trattanti con la composizione nutraceutica dell?invenzione secondo l?Esempio 1. Le Defluviitaleaceae, sono importanti in quanto producono butirrato, acido grasso a corta catena la cui funzione benefica sulla mucosa intestinale ? pi? che documentata. As reported in Table 4, the Defluviitaleaceae are present only in the groups treating with the nutraceutical composition of the invention according to Example 1. The Defluviitaleaceae are important as they produce butyrate, a short-chain fatty acid whose beneficial function on the intestinal mucosa is? more that documented.
La famiglia delle Eubacteriaceae ? molto frequentemente rappresentata nell?intestino di controlli sani, rispetto a chi soffre di infiammazioni intestinali, per cui se una sintomatologia infiammatoria si attenua, questa famiglia tende ad incrementare. Anche a questa famiglia sono ascrivibili microrganismi che producono butirrato, e si ? osservato che uno degli effetti delle radioterapie ? quello di andare a ridurne il numero. The Eubacteriaceae family? very frequently represented in the intestine of healthy controls, compared to those suffering from intestinal inflammation, so that if an inflammatory symptomatology subsides, this family tends to increase. Microorganisms that produce butyrate can also be ascribed to this family, and yes? observed that one of the effects of radiotherapy ? that of going to reduce their number.
Le Halomonadaceae risultano significativamente diminuite nei gruppi trattati con la composizione nutraceutica dell?invenzione secondo l?Esempio 1 rispetto ai valori del gruppo di controllo. The Halomonadaceae are significantly decreased in the groups treated with the nutraceutical composition of the invention according to Example 1 compared to the values of the control group.
Questi batteri sono stati identificati come marker di un ambiente intestinale anormale, in quanto potenziali agenti patogeni nell'uomo. These bacteria have been identified as markers of an abnormal intestinal environment, as they are potential pathogens in humans.
Il genere Clostridium, ? significativamente diminuito nel gruppo trattato con la combinazione della composizione nutraceutica dell?invenzione con la Gemcitabina, rispetto al gruppo sottoposto solo a terapia con Gemcitabina. The genus Clostridium, ? significantly decreased in the group treated with the combination of the nutraceutical composition of the invention with Gemcitabine, compared to the group subjected only to Gemcitabine therapy.
Questi valori sono rilevanti, poich? al genere Clostridium appartengono tra i batteri pi? tossigenici esistenti. These values are relevant, since? to the genus Clostridium belong among the bacteria pi? existing toxigens.
Il Faecalibacterium ? un genere anch?esso produttore di butirrato, sebbene non significativamente. Il trattamento con la sola Gemcitabina ne provoca una diminuzione di tre volte della sua abbondanza. The Faecalibacterium? a genus that also produces butyrate, although not significantly. Treatment with gemcitabine alone causes a three-fold decrease in its abundance.
A seguito del trattamento con la sola composizione nutraceutica dell?invenzione si assiste gi? all?aumento di Faecalibacterium rispetto al gruppo di controllo. Following the treatment with only the nutraceutical composition of the invention, one already witnesses to the increase in Faecalibacterium compared to the control group.
A seguito del trattamento con la combinazione della composizione nutraceutica dell?invenzione con la Gemcitabina, l?abbondanza di Faecalibacterium viene completamente ristabilita. Following treatment with the combination of the nutraceutical composition of the invention with Gemcitabine, the abundance of Faecalibacterium is completely restored.
La specie Flintibacter butyricus, ? stata recentemente identificata come uno dei maggiori produttori di butirrato a livello del microbiota intestinale. Questo batterio risulta presente esclusivamente nei due gruppi a seguito del trattamento con la composizione nutraceutica dell?invenzione da sola o in combinazione con Gemcitabina. Questi valori dimostrano l?efficacia della composizione nutraceutica dell?invenzione da sola, e la sua sinergia quando somministrata con Gemcitabina. Anche la specie Stomatobaculum longum, appartenendo alla famiglia delle Lachnospiraceae, risulta importante poich? produttrice di butirrato. Essa risulta significativamente arricchita nel gruppo trattato con la composizione nutraceutica dell?invenzione, rispetto a quello trattato con il solo agente chemioterapico Gemcitabina, dimostrando anche in questo caso un effetto benefico della composizione nutraceutica dell?invenzione. The species Flintibacter butyricus, ? has recently been identified as one of the major producers of butyrate at the intestinal microbiota level. This bacterium is present exclusively in the two groups following treatment with the nutraceutical composition of the invention alone or in combination with Gemcitabine. These values demonstrate the efficacy of the nutraceutical composition of the invention alone, and its synergy when administered with Gemcitabine. Also the species Stomatobaculum longum, belonging to the Lachnospiraceae family, is important since it butyrate producer. It is significantly enriched in the group treated with the nutraceutical composition of the invention, compared to that treated with the chemotherapeutic agent only Gemcitabine, demonstrating also in this case a beneficial effect of the nutraceutical composition of the invention.
Claims (14)
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| EP22705461.6A EP4281092A1 (en) | 2021-01-21 | 2022-01-21 | A nutraceutical composition for use as an adjuvant in a cancer therapy |
| PCT/IB2022/050532 WO2022157697A1 (en) | 2021-01-21 | 2022-01-21 | A nutraceutical composition for use as an adjuvant in a cancer therapy |
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| WO2010081126A2 (en) * | 2009-01-12 | 2010-07-15 | Wyeth Llc | Compositions comprising probiotic and prebiotic components and mineral salts, with lactoferrin |
| AU2016203744A1 (en) * | 2009-01-12 | 2016-06-23 | Pfizer Italia S.R.L.. | Compositions comprising probiotic and prebiotic components and mineral salts, with lactoferrin |
| CN110754656A (en) * | 2019-11-07 | 2020-02-07 | 上海奥医高科技实业有限公司 | Special clinical nutrition formula for lymphoma function and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2010081126A2 (en) * | 2009-01-12 | 2010-07-15 | Wyeth Llc | Compositions comprising probiotic and prebiotic components and mineral salts, with lactoferrin |
| AU2016203744A1 (en) * | 2009-01-12 | 2016-06-23 | Pfizer Italia S.R.L.. | Compositions comprising probiotic and prebiotic components and mineral salts, with lactoferrin |
| CN110754656A (en) * | 2019-11-07 | 2020-02-07 | 上海奥医高科技实业有限公司 | Special clinical nutrition formula for lymphoma function and preparation method thereof |
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| PANEBIANCO C. ET AL.: "Influence of gemcitabine chemotherapy on the microbiota of pancreatic cancer xenografted mice", CANCER CHEMOTHER PHARMACOL, vol. 81, no. 4, 2018, pages 773 - 782, XP036458085, DOI: 10.1007/s00280-018-3549-0 |
| ROLLER MONIKA ET AL: "Intestinal immunity of rats with colon cancer is modulated by oligofructose-enriched inulin combined with Lactobacillus rhamnosus and Bifidobacterium lactis", BRITISH JOURNAL OF NUTRITION,, vol. 92, no. 6, 1 December 2004 (2004-12-01), pages 931 - 938, XP009117214, ISSN: 0007-1145, DOI: 10.1079/BJN20041289 * |
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