ITFI20090005A1 - Formulazioni farmaceutiche per indurre immunosoppressione attraverso l'inibizione del fenomeno dell'epitope spreading e loro uso. - Google Patents
Formulazioni farmaceutiche per indurre immunosoppressione attraverso l'inibizione del fenomeno dell'epitope spreading e loro uso. Download PDFInfo
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- ITFI20090005A1 ITFI20090005A1 IT000005A ITFI20090005A ITFI20090005A1 IT FI20090005 A1 ITFI20090005 A1 IT FI20090005A1 IT 000005 A IT000005 A IT 000005A IT FI20090005 A ITFI20090005 A IT FI20090005A IT FI20090005 A1 ITFI20090005 A1 IT FI20090005A1
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- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- Epidemiology (AREA)
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- General Health & Medical Sciences (AREA)
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Description
Formulazioni farmaceutiche per indurre immunosoppressione attraverso l'inibizione del fenomeno dell’epitope spreading e loro uso
Campo dell’invenzione
La presente invenzione si riferisce al campo della immunofarmacologia in particolare al trattamento delle patologie immunitarie.
Stato dell’arte
I risultati conseguiti dalla ricerca scientifica negli ultimi anni hanno cambiato le strategie terapeutiche dei disordini immunitari. In particolare è stato dimostrato che in seguito alla risposta immunitaria scatenata da un determinato antigene primario si susseguono ulteriori risposte specifiche per antigeni secondari che si sono liberati a causa della risposta primaria. Tale fenomeno prende il nome di “epitope spreading" (ES). La risposta immune deve quindi essere vista come il susseguirsi di risposte consecutive verso antigeni differenti causate dal fenomeno dell’ES. Questa visone patogenetica è particolarmente applicabile alle malattie autoimmunitarie croniche. Su queste basi patogenetiche si capisce come la sia destinata a fallire la terapia che un tempo si riteneva efficace e che si prefiggeva di regolare la risposta immunitaria riducendo la risposta contro uno specifico antigene causante la risposta iniziale.
Alla base dell’ES si trovano le cellule presentanti l’antigene ( antigen presenting cells, APC) di cui le cellule dendritiche (DC) rappresentano un sottogruppo di fondamentale importanza. Tali cellule sono infatti specializzate nel captare gli antigeni, processarli e riesporli in maniera opportuna ai linfociti in modo da stimolarne la proliferazione e la risposta immune verso l’antigene esposto.
Le APC sono alla base dell’ES proprio grazie alla loro capacità di captare gli antigeni che si sono liberati durante la risposta immunitaria primaria inducendo una nuova risposta immune contro di essi.
Affinché la presentazione dell’antigene da parte delle APC sia ottimale e attivi la risposta linfocitaria occorre che alcune molecole di membrana, i cosiddetti “antigeni di costimolazione” (tra cui CD40, CD80 e CD86), vengano esposti dalle APC stesse e riconosciuti dai linfociti. In altre parole un linfocita specifico per un determinato antigene si attiva solo quando una APC gli presenta sulla sua membrana l’antigene opportunamente processato insieme agli antigeni di costimolazione. Al contrario, l’assenza della costimolazione rende il linfocita anergico verso l’antigene presentato. In questo caso le APC presentanti l’antigene processato ma non le molecole di costimolazione vengono definite APC tolerogeniche, vale a dire cellule che rendono l’organismo tollerante verso l’antigene processato. Ne deriva che la presenza o meno delle molecole di costimolazione sia un determinante chiave della risposta immune, essendo capace di rendere un organismo immunologicamente attivo o anergico verso un antigene.
E’ stato recentemente trovato, dallo stesso Richiedente, che l’enzima denominato poli(ADP-ribosio) polimerasi (PARP) svolge un ruolo fondamentale nella regolazione dell’espressione delle molecole di costimolazione da parte delle APC. In particolare la PARP promuove l’espressione delle molecole mentre farmaci inibitori della sua attività enzimatica la riducono. In accordo con il ruolo funzionale delle molecole di costimolazione, tali farmaci sono in grado di inibire la proliferazione linfocitaria da parte delle APC.
Descrizione dettagliata dell’invenzione
E’ stato ora inaspettatamente trovato che è possibile bloccare il fenomeno dell’ES inibendo la PARP a livello delle APC. Tale strategia farmacologica permette l’inibizione della risposta immunitaria verso nuovi antigeni e la prevenzione della cronicizzazione della patologia immunitaria.
Per inibitori della PARP si intendono ad esempio composti scelti fra: nicotinamidi, benzamidi, isochinolinoni, diidroisochinolinoni, benzimidazoli, indoli, ftalazin-1 (2H)-oni, chinozolinoni, isoindolinoni, fenantridine, benzopironi, salicilamidi, derivati insaturi dell'acido idrossimico, caffeina, teofillina, timidina, 3-[2-fluoro-5-(4-oxo-3,4-diidro-ftalazin-l-ilmetil)-fenil]-5-metil-imidazolina-2,4-dione; 3-[3-(5,8-difluoro-4-oxo-3,4-diidro-fta!azin-l-ilmetil)-feni!]-5-metil-imidazolina-2,4-ione; 5-cloro-2-{l-[3-([1 ,4]diazepano-1 -carbonil)-4-fluoro-fenil]-etossi}-benzamide; 2-{3-[2-fluoro-5-(4-OXO-3, 4-diidro-ftalazin-l-ilmetil)-fenil]-5-metil-2,4-dioxo-midazolidin-l-il} acetamide; 4-[3-(4-ciclopropanocarbonil-piperazina-1-carbonil)-4-fluoro-benzil]-2H-ftalazin-1 -one; 3-[2-fluoro-5-(4-oxo-3,4,diidro-ftalazin-1 -ilmetil)-fenil]-5,5-dimetil-1 -[2-(4-metil-piperazin-l-il)-2-oxo-etil]-imidazolina-2,4-dione; 8-fluoro-2- (4metilaminometill-fenil)-l,3,4,5-tetraidro-azepino[5,4,3-cd]indol-6-one, INO-1 001 , AG-0014699, BSI-201 , BSI-401 and BSI-101 ; nonché analoghi e derivati.
Secondo l’invenzione gli inibitori della PARP possono essere utilizzati per brevi cicli di trattamento solo in corrispondenza della recrudescenza della malattia (che corrisponde alla risposta verso un nuovo antigene) al fine di bloccare il fenomeno dell’ES, rendere l’individuo tollerante verso gli antigeni che altrimenti causerebbero una nuova ricaduta e, nel complesso, la cronicizzazione della patologia immune. Quindi, secondo l’invenzione, in corso di patologia immune cronicizzata o potenzialmente cronicizzante non è più necessario il trattamento cronico con inibitori delle PARP, al contrario è sufficiente un trattamento di pochi giorni in corrispondenza della ricaduta e peggioramento dei sintomi. E’ infatti in questo momento che l’inibizione della PARP permette di ridurre l’espressione delle molecole di costimolazione da parte delle APC, bloccando il fenomeno dell’ES e trasformando le APC stesse in cellule tolerogeniche. Inoltre, tale trattamento è mirato a colpire specificamente il fenomeno dell’ES e non è basato su meccanismi cellulari non specifici come precedentemente proposto.
Tra le patologie che possono trarre vantaggio da questo trattamento sono comprese: sclerosi multipla, neuropatie autoimmuni centrali e periferiche, diabete mellito di l° tipo, miastenia gravis, rigetto di trapianto d’organo, graft versus host disease, piatrinopenie autoimmuni, Porpora trombocitopenica idiopatica, Porpora trombotica trombocitopenia, glomerulonefriti, malattia di Chron, colite ulcerosa, morbo celiaco, Artrite reumatoide, Spondilite anchilosante, Artrite psoriasica, Idrartro intermittente, Lupus Eritematoso Sistemico, indotto da farmaci e discoide fisso, Sclerosi sistemica e circoscritta, Sindrome eosinofilia/mialgia, Polimiosite/dermatomiosite, Sindrome di Sjògren, Connettivite mista, Cirrosi biliare primitiva, Vasculiti, Arterite di Takayasu, Arterite gigantocellulare di Horton, Panarterite nodosa, Granulomatosi di Wegener, Crioglobulinemia mista essenziale, Malattia di Beh^et, Malattia di Kawasaki, Sindrome da anticorpi antifosfolipidi, Polimialgia reumatica, Eritema nodoso, Panniculiti, Policondriti, Artrite postinfettiva, Reumatismo articolare acuto, Gotta, Artrosi primaria, Artrosi secondaria, sindrome di goodpasture, tiroidite di Hashimoto, uveite, morbo di Addison, gastrite atrofica, infertilità maschile, connettiviti, anemia perniciosa, Anemia emolitica, Angioedema, Eczema, Epatite, Pemfigo.
Le quantità di principi attivo da somministrare sono quelle già comunemente impiegate per questo tipo di farmaci, ad esempio 10-1000 mg/die e anche le formulazioni farmaceutiche sono quelle comunemente in uso in particolare per la somministrazione per via endovenosa, intramuscolare, orale, rettale, trans dermica e oculare.
Fa parte della presente invenzione anche la possibilità di stimolare in vitro le APC di un animale in presenza di inibitori della PARP e di particolari antigeni, al fine di rendere le cellule stesse capaci di indurre tolleranza una volta reintrodotte nell’organismo.
A supporto della presente invenzione, esperimenti condotti dal richiedente in un modello di encefalite allergica sperimentale di tipo relapsing-remitting dimostrano che gli inibitori della PARP se somministrati solo acutamente (6-7 gg) dopo la prima fase di paralisi acuta sono in grado di ridurre la frequenza e la severità delle ricadute. Dato che le ricadute sono legate al verificarsi dell’ES, ne deriva che un trattamento acuto con inibitori della PARP risulta in grado di bloccare, contenendo il fenomeno di ES in vivo, una patologia immunitaria cronica. Questo strategia terapeutica si discosta da quanto prima ipotizzato in quanto è stato fin ora proposto che la terapia antiinfiammatoria con inibitori della PARP debba essere condotta per lunghi periodi (sub-cronica).
Claims (6)
- RIVENDICAZIONI 1. Uso di composti in grado di inibire l’ES per la preparazione di formulazioni farmaceutiche atte a ridurre la funzione immunostimolante delle APC.
- 2. Uso secondo la rivendicazione 1 in cui detti composti in grado di inibire l'ES sono composti capaci di inibire la PARP.
- 3. Uso secondo la rivendicazione 2 in cui detti composti capaci di inibire la PARP sono scelti fra: nicotinamidi, benzamidi, isochinolinoni, diidroisochinolinoni, 4H-tieno[2,3-c] isoquinolin-5-oni, benzimidazoli, indoli, ftalazin-1(2H)-oni, chinozolinoni, isoindolinoni, fenantridine, benzopironi, salicilamidi, derivati insaturi dell’acido idrossimico, caffeina, teofillina, timidina, 3-[2-fluoro-5-(4-oxo-3,4-diidroftalazin-l-ilmetil)-fenil]-5-metil-imidazolina-2,4-dione; 3-[3-(5,8-difluoro-4-oxo-3,4-diidro-ftalazin-l-ilmetil)-fenil]-5-metil-imidazolina-2,4-ione; 5-cloro-2-{l-[3-([1 ,4]diazepano-1 -carbonil)-4-fluoro-fenil]-etossi}-benzamide; 2-{3-[2-fluoro-5-(4-OXO-3, 4-diidro-ftalazin-l-ilmetil)-fenil]-5-metil-2,4-dioxo-midazolidin-l-il} acetamide; 4-[3-(4-ciclopropanocarbonil-piperazina-1-carbonil)-4-fluoro-benzil]-2H-ftalazin-1-one; 3-[2-fluoro-5-(4-oxo-3,4,diidro-ftalazin-1-ilmetil)-fenil]-5,5-dimetil-1-[2-(4-metil-piperazin-l-il)-2-oxo-etil]-imidazolina-2,4-dione; 8-fluoro-2- (4-metilaminometill-fenil)-l,3,4,5-tetraidro-azepino[5,4,3-cd]indol-6-one, INO-1001 , AG-0014699, BSI-201, BSI-401 and BSI-101; nonché analoghi e derivati.
- 4. Metodo per indurre immunosoppressione in cui si somministrano al paziente inibitori delle PARP in corrispondenza della ricaduta e peggioramento dei sintomi.
- 5. Metodo secondo la rivendicazione 4 per il trattamento di patologie quali: sclerosi multipla, neuropatie autoimmuni centrali e periferiche, diabete mellito di l° tipo, miastenia gravis, rigetto di trapianto d’organo, graft versus host disease, piatrinopenie autoimmuni, Porpora trombocitopenica idiopatica, Porpora trombotica trombocitopenia, glomerulonefriti, malattia di Chron, colite ulcerosa, morbo celiaco, Artrite reumatoide, Spondilite anchilosante, Artrite psoriasica, Idrartro intermittente, Lupus Eritematoso Sistemico, indotto da farmaci e discoide fisso, Sclerosi sistemica e circoscritta, Sindrome eosinofilia/mialgia, Polimiosite/dermatomiosite, Sindrome di Sjògren, Connettivite mista, Cirrosi biliare primitiva, Vasculiti, Aderite di Takayasu, Aderite gigantocellulare di Hodon, Panaderite nodosa, Granulomatosi di Wegener, Crioglobulinemia mista essenziale, Malattia di Behget, Malattia di Kawasaki, Sindrome da anticerpi antifosfolipidi, Polimialgia reumatica, Eritema nodoso, Panniculiti, Policondriti, Artrite postinfettiva, Reumatismo articolare acuto, Gotta, Artrosi primaria, Artrosi secondaria, sindrome di goodpasture, tiroidite di Hashimoto, uveite, morbo di Addison, gastrite atrofica, infertilità maschile, connettiviti, anemia perniciosa, Anemia emolitica, Angioedema, Eczema, Epatite, Pemfigo.
- 6. Metodo per indurre tolleranza in un animale stimolando in vitro le sue APC in presenza di inibitori della PARP e degli antigeni verso cui si vuole indurre tolleranza prima di reintrodurle neH’organismo.
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