ITPD20060014A1 - METHOD FOR FEEDING THE EFFLUSSO FROM THE NERVOUS SYSTEM OF AMYLOID PEPTIDES - Google Patents
METHOD FOR FEEDING THE EFFLUSSO FROM THE NERVOUS SYSTEM OF AMYLOID PEPTIDES Download PDFInfo
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- ITPD20060014A1 ITPD20060014A1 ITPD20060014A ITPD20060014A1 IT PD20060014 A1 ITPD20060014 A1 IT PD20060014A1 IT PD20060014 A ITPD20060014 A IT PD20060014A IT PD20060014 A1 ITPD20060014 A1 IT PD20060014A1
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Description
DESCRIZIONE DESCRIPTION
Campo di applicazione Field of application
La presente invenzione si riferisce all’applicazione in campo farmacologico di molecole di struttura diidropiridinica, come ad esempio: nicardipina, felodipina, niguldipina, nifedipina, lercanidipina, amlodipina, clinidipina, efonidipina, benidipina, oxodipina, darodipina, isradipina, manidipina, lacidipina, mepirodipina, nimodipina, nisoldipina, pranidipina e ryodipina. La Richiedente ha, infatti, sorprendentemente scoperto che questi composti sono in grado, dopo somministrazione, non solo di inibire il processamento della proteina beta-amiloide ma anche di aumentare l’efflusso di questa proteina dal sistema nervoso centrale e di aumentare la sua concentrazione nel plasma favorendo così una riduzione dei depositi di beta-amiloide e trovando quindi applicazione nella cura o nella prevenzione di tutti quegli stati in cui si manifesta un aumento delle deposizione di peptide beta-amiloide come nel caso del morbo di Alzheimer, di traumi cranici, dell’angiopatia cerebrale amiloidogenica, nell’encefalite spongiforme o nello scrapie. The present invention relates to the application in the pharmacological field of molecules with a dihydropyridine structure, such as: nicardipine, felodipine, niguldipine, nifedipine, lercanidipine, amlodipine, clinidipine, ephonidipine, benidipine, oxodipine, darodipine, isradipine, lacidipine, lacidipine , nimodipine, nisoldipine, pranidipine and ryodipine. The Applicant has, in fact, surprisingly discovered that these compounds are able, after administration, not only to inhibit the processing of the beta-amyloid protein but also to increase the efflux of this protein from the central nervous system and to increase its concentration in the plasma thus favoring a reduction of beta-amyloid deposits and therefore finding application in the treatment or prevention of all those states in which an increase in the deposition of beta-amyloid peptide occurs as in the case of Alzheimer's disease, head trauma, amyloidogenic cerebral angiopathy, in spongiform encephalitis or scrapie.
STATO DELL’ARTE STATE OF THE ART
La malattia di Alzheimer è una patologia neurodegenerativa che risulta essere la causa più frequente di demenza senile. Stime recenti indicano che nel mondo circa 18 milioni di persone sono affette da demenza, circa 700 mila in Italia. Da pochi anni sono disponibili farmaci (donepezil, galantamina, rivastigmina, ecc.) la cui efficacia è stata dimostrata in studi clinici e che sono in grado di migliorare temporaneamente la sintomatologia negli stadi iniziali della malattia. Tuttavia non esistono attualmente terapie in grado di arrestare la progressione della malattia. La comparsa di placche senili nel parenchima cerebrale è una caratteristica alterazione nella malattia di Alzheimer. Le placche senili sono costituite da materiale proteinaceo depositato in sede extracellulare. Il peptide beta-amiloide oltre a formare depositi insolubili, esercita un effetto neurotossico, sia direttamente, mediante interazioni con specifici recettori di membrana, che indirettamente, mediante l’interazione con cellule non neuronali, quali la microglia, stimolandone la produzione di radicali liberi, eccitotossine e citochine. Le variabili che influenzano la citopatologia associata a beta-amiloide sono numerose e comprendono: 1) la lunghezza del peptide; 2) la quantità di peptide che si accumula; 3) il suo stato chimico-fisico e l’aggregazione in fibrille; 4) l’interazione con altre proteine. Numerose evidenze indicano che strategie farmacologiche volte alla riduzione della produzione e/o accumulo di beta amiloide potrebbero quindi prevenire, ritardare o revertire la progressione della malattia di Alzheimer (passate in rassegna da Hardy and Selkoe, 2002) Alzheimer's disease is a neurodegenerative disease which is the most frequent cause of senile dementia. Recent estimates indicate that around 18 million people in the world are affected by dementia, about 700,000 in Italy. For a few years, drugs have been available (donepezil, galantamine, rivastigmine, etc.) whose efficacy has been demonstrated in clinical studies and which are able to temporarily improve symptoms in the initial stages of the disease. However, there are currently no therapies capable of halting the progression of the disease. The appearance of senile plaques in the brain parenchyma is a characteristic alteration in Alzheimer's disease. The senile plaques are made up of proteinaceous material deposited in the extracellular area. The beta-amyloid peptide in addition to forming insoluble deposits, exerts a neurotoxic effect, both directly, through interactions with specific membrane receptors, and indirectly, through interaction with non-neuronal cells, such as microglia, stimulating the production of free radicals, excitotoxins and cytokines. The variables that influence the cytopathology associated with beta-amyloid are numerous and include: 1) the length of the peptide; 2) the amount of peptide that accumulates; 3) its chemical-physical state and aggregation into fibrils; 4) interaction with other proteins. Numerous evidences indicate that pharmacological strategies aimed at reducing the production and / or accumulation of beta amyloid could therefore prevent, delay or reverse the progression of Alzheimer's disease (reviewed by Hardy and Selkoe, 2002)
L'identificazione della proteina precursore di beta-amiloide (APP), la cui proteolisi dà origine a beta-amiloide, ha permesso di fare interessanti osservazioni sul suo metabolismo. Fondamentale è la scoperta che il peptide beta-amiloide viene costitutivamente prodotto e secreto come peptide solubile durante il normale metabolismo cellulare. Esperimenti condotti su cellule modificate geneticamente hanno dimostrato che l’espressione di forme di APP recanti mutazioni associate a forme familiari della malattia di Alzheimer causa un aumento della secrezione di frammenti amiloidogenici del peptide beta-amiloideo, in particolare la forma 1-42. Secondo uno schema ancora non completamente definito, la proteina APP è oggetto dell’azione proteolitica sequenziale di due enzimi, descritti con il nome di beta e gamma-secretasi che tagliando APP in due siti distinti producono 3 frammenti di APP incluso il peptide beta-amiloide. E’ stato inoltre identificata una metallo-protease detta alfa-secretasi, la cui azione si oppone alla formazione di frammenti amiloidogenici poiché l’azione proteolitica è diretta verso un sito interno alla sequenza del peptide beta-amiloide. The identification of the beta-amyloid precursor protein (APP), whose proteolysis gives rise to beta-amyloid, has allowed us to make interesting observations on its metabolism. Fundamental is the discovery that beta-amyloid peptide is constitutively produced and secreted as a soluble peptide during normal cellular metabolism. Experiments conducted on genetically modified cells have shown that the expression of forms of APP bearing mutations associated with familial forms of Alzheimer's disease causes an increase in the secretion of amyloidogenic fragments of the beta-amyloid peptide, in particular the 1-42 form. According to a still not fully defined scheme, the APP protein is the object of the sequential proteolytic action of two enzymes, described with the name of beta and gamma-secretase which by cutting APP in two distinct sites produce 3 fragments of APP including the beta-amyloid peptide . A metallo-protease called alpha-secretase has also been identified, whose action opposes the formation of amyloidogenic fragments since the proteolytic action is directed towards a site within the beta-amyloid peptide sequence.
II metabolismo di APP e la formazione di beta-amiloide possono essere modulati farmacologicamente; ad esempio è stato dimostrato che inibitori degli enzimi betae gamma-secretasi, riducono la formazione di beta-amiloide mentre l’attivazione della protein-chinasi-C, un importante enzima fosforante, aumenta la secrezione di APP solubile e riduce la formazione di beta-amiloide. Queste osservazioni hanno dato avvio ad una serie di studi sull’effetto di modulatori fisiologici e/o di farmaci sul metabolismo di APP e sulla formazione di beta-amiloide, allo scopo di disegnare possibili interventi terapeutici centrati sull’inibizione dei meccanismi di produzione e accumulo di beta-amiloide (Selkoe, 2002). Recentemente è stato riportato che sorprendentemente alcuni farmaci antinfiammatori non steroidei (FANS) sono in grado di diminuire piu’ o meno selettivamente la formazione di beta-amiloide 1-42 senza alterare sostanzialmente la formazione di altre isoforme (1-38, 1-40) del peptide stesso (Eriksen et al., 2003). E’ interessante notare che l’effetto di quei FANS in grado di inibire la produzione di beta-ami Ioide (flurbiprofene, indometacina, ibuprofene) non è riconducibile alle loro proprietà antinfiammatorie (Eriksen et al., 2003). Studi recenti indicherebbero invece chetali farmaci agiscono come modulatori allosterici dell’attività gamma-secretasica, l’enzima direttamente responsabile della formazione del peptide beta-amiloide. Inoltre, esistono altri diversi approcci terapeutici che vedono coinvolto il metabolismo e/o deposito di beta-amiloide quali ad esempio la vaccinazione, l’utilizzo di sostanze in grado di interferire con la i depositi di questa proteina e l’utilizzo di sostanze in grado di aumentare l'efflusso di beta amiloide dal sistema nervoso centrale. The metabolism of APP and the formation of beta-amyloid can be pharmacologically modulated; for example, it has been shown that inhibitors of betae gamma-secretase enzymes reduce the formation of beta-amyloid while the activation of protein kinase-C, an important phosphorating enzyme, increases the secretion of soluble APP and reduces the formation of beta- amyloid. These observations have initiated a series of studies on the effect of physiological modulators and / or drugs on the metabolism of APP and on the formation of beta-amyloid, in order to design possible therapeutic interventions centered on the inhibition of the mechanisms of production and accumulation. of beta-amyloid (Selkoe, 2002). Recently it has been reported that surprisingly some non-steroidal anti-inflammatory drugs (NSAIDs) are able to more or less selectively decrease the formation of beta-amyloid 1-42 without substantially altering the formation of other isoforms (1-38, 1-40) of the peptide itself (Eriksen et al., 2003). It is interesting to note that the effect of those NSAIDs capable of inhibiting the production of beta-ami ioide (flurbiprofen, indomethacin, ibuprofen) is not attributable to their anti-inflammatory properties (Eriksen et al., 2003). Recent studies, on the other hand, indicate that ketal drugs act as allosteric modulators of gamma-secretase activity, the enzyme directly responsible for the formation of the beta-amyloid peptide. Furthermore, there are other different therapeutic approaches that involve the metabolism and / or deposition of beta-amyloid such as vaccination, the use of substances capable of interfering with the deposits of this protein and the use of substances capable of to increase the efflux of beta amyloid from the central nervous system.
SOMMARIO SUMMARY
La presente invenzione si riferisce all’applicazione farmacologica delie molecole oggetto della presente invenzione per aumentare l’efflusso dal sistema nervoso centrale di proteina amiloide al fine di prevenire, ritardare o revertire la progressione del morbo di Alzheimer o altre patologie caratterizzate da anormale deposizione di proteine amiloidee (ad es. traumi cranici, angiopatia cerebrale amiloidogenica, encefalite spongiforme, scrapie). La Richiedente ha infatti sorprendente scoperto che certe molecole a struttura diidropiridinica sebbene siano in grado di inibire (Benjannet, rif. citato) a livello cellulare la produzione/secrezione del peptide beta-amiloide, dopo somministrazione in vivo, sono in grado di aumentarne significativamente i livelli plasmatici mediante l’aumento dell’efflusso di questa proteina dal sistema nervoso centrale. Tali esperimenti sono stati condotti sia in vitro che in vivo. In vitro, impiegando cellule di neuroglioma o di neuroblastoma umano (H4) transfettate stabilmente con il gene APP umano recante mutazioni associate alia malattia di Alzheimer (cellule H4/APP), abbiamo osservato che in colture cellulari H4/APP le diidropiridine oggetto del presente brevetto alle concentrazioni di 10 e 30 μΜ, inducono una drammatica e significativa inibizione dose-dipendente della secrezione delle varie isoforme del peptide beta-amiloide, misurate mediante tecnica ELISA (Tab 1 e Tab. 2). Inoltre i due stereoisomeri (+)niguldipine e (-)niguldipine, pur avendo un profilo farmacologico molto diverso come calcio antagonisti, hanno il medesimo effetto inibitorio sulla secrezione del peptide beta-amiloide Al contrario, la diidropiridina BayK 8644 non ha un effetto apprezzabile sulla secrezione di betaamiloide come del resto anche altri calcio antagonisti (vedi di seguito). È riportato in letteratura che calcio antagonisti non diidropiridinici, quali esempio il diltiazem e metossiverapamil, non mostrano un effetto significativo sulla secrezione di betaamiolide per concentrazioni comprese tra 3 e 30 μΜ (Facchinetti et al., 2005). L’effetto sul rilascio di beta-amiloide delle diidropiridine oggetto della presente invenzione non è quindi riconducibile al loro noto effetto farmacologico di antagonismo all’influsso di calcio in quanto non tutti i calcio-antagonisti, inclusi alcuni diidropiridinici, hanno un effetto inibitorio sulla secrezione di beta-amiloide a livello cellualre. Infine, esperimenti in vivo, condotti dalla Richiedente, su topi transgenici TG2576 sovraesprimenti la proteina APP umana mutata hanno dimostrato che la somministrazione delle molecole oggetto della presente invenzione è in grado di aumentare l’efflusso di proteina amiloide dal sistema nervoso centrale al circolo sistemico inducendo una rimozione di beta amiloide da questi tessuti. The present invention relates to the pharmacological application of the molecules object of the present invention to increase the efflux from the central nervous system of amyloid protein in order to prevent, delay or reverse the progression of Alzheimer's disease or other pathologies characterized by abnormal protein deposition amyloid (e.g. head trauma, amyloidogenic cerebral angiopathy, spongiform encephalitis, scrapie). The Applicant has indeed surprisingly discovered that certain molecules with a dihydropyridine structure, although they are able to inhibit (Benjannet, ref. Cited) at the cellular level the production / secretion of the beta-amyloid peptide, after in vivo administration, are able to significantly increase its plasma levels by increasing the efflux of this protein from the central nervous system. These experiments were conducted both in vitro and in vivo. In vitro, using human neuroglioma or neuroblastoma (H4) cells stably transfected with the human APP gene bearing mutations associated with Alzheimer's disease (H4 / APP cells), we observed that in H4 / APP cell cultures the dihydropyridines object of this patent at concentrations of 10 and 30 μΜ, they induce a dramatic and significant dose-dependent inhibition of the secretion of the various isoforms of the beta-amyloid peptide, measured by ELISA technique (Tab 1 and Tab. 2). Furthermore, the two stereoisomers (+) niguldipine and (-) niguldipine, despite having a very different pharmacological profile as calcium antagonists, have the same inhibitory effect on the secretion of the beta-amyloid peptide.In contrast, BayK 8644 dihydropyridine does not have an appreciable effect on secretion of betaamyloid as well as other calcium antagonists (see below). It is reported in the literature that non-dihydropyridine calcium antagonists, such as diltiazem and methoxyiverapamil, do not show a significant effect on betaamiolide secretion for concentrations between 3 and 30 μΜ (Facchinetti et al., 2005). The effect on beta-amyloid release of the dihydropyridines object of the present invention is therefore not attributable to their known pharmacological effect of antagonism to the calcium influx since not all calcium channel blockers, including some dihydropyridines, have an inhibitory effect on secretion of beta-amyloid at the cellular level. Finally, in vivo experiments, conducted by the Applicant, on TG2576 transgenic mice overexpressing the mutated human APP protein have shown that the administration of the molecules object of the present invention is able to increase the efflux of amyloid protein from the central nervous system to the systemic circulation, inducing a removal of beta amyloid from these tissues.
Più specificamente la presente invenzione individua delle molecole appartenenti alla classe delle diidropiridine, quali ad esempio la nicardipina, la felodipina la niguldipina e la manidipina in grado di ridurre prevalentemente i depositi del peptide beta-amiloide aumentandone l'efflusso dal sistema nervoso centrale. More specifically, the present invention identifies molecules belonging to the class of dihydropyridines, such as for example nicardipine, felodipine, niguldipine and manidipine capable of mainly reducing the deposits of the beta-amyloid peptide by increasing its efflux from the central nervous system.
E’ quindi oggetto della presente invenzione l’impiego di composti diidropiridinici in grado di modulare il processo amiloidogenico e di indurre reflusso di beta-amiloide dal sistema nervoso centrale e quindi utili nella cura o prevenzione del morbo di Alzheimer o di altre patologie come ad esempio traumi cranici, angiopatia cerebrale amiloidogenica, encefalite spongiforme, scrapie. La presente invenzione si riferisce ai composti citati sia nelle loro forme stereoattive pure che nella forma di miscela racemica. L’invenzione inoltre fornisce composizioni dei sovracitati agenti in associazione con agenti farmacologici quali antiossidanti, antinfiammatori, inibitori delle proteasi, e inibitori delle coline esterasi. The object of the present invention is therefore the use of dihydropyridine compounds capable of modulating the amyloidogenic process and inducing reflux of beta-amyloid from the central nervous system and therefore useful in the treatment or prevention of Alzheimer's disease or other pathologies such as for example head trauma, amyloidogenic cerebral angiopathy, spongiform encephalitis, scrapie. The present invention relates to the compounds mentioned both in their pure stereoactive forms and in the form of racemic mixture. The invention also provides compositions of the aforementioned agents in association with pharmacological agents such as antioxidants, anti-inflammatories, protease inhibitors, and choline esterase inhibitors.
DESCRIZIONE DETTAGLIATA DELL’INVENZIONE DETAILED DESCRIPTION OF THE INVENTION
Gli scopi ed i vantaggi dell'impiego medico terapeutico o paramedico di certe diidropiridine, oggetto della presente invenzione, in stati patologici caratterizzati da un abnorme deposizione extraceilulare di proteina amiloide saranno meglio compresi nel corso della seguente descrizione dettagliata. La Richiedente ha infatti trovato che, il trattamento con i composti dell’invenzione, contrariamente ad altri derivati diidropiridinici (es. BayK 8644), induce una significativa riduzione della secrezione costitutiva della proteina beta-amiloide in una linea cellulare di origine umana ingegnerizzata che esprime costitutivamente un isoforma del gene APP695 associata al morbo di Alzheimer. Tale effetto è probabilmente imputabile ad una modulazione allosterica dell’azione proteasica della gamma secretasi e non è riconducibile agli effetti farmacologici noti di tali molecole (inibizione dei canali al calcio voltaggio-dipendenti). In questa invenzione riportiamo per la prima volta dati che mostrano come le molecole diidropiridiniche oggetto della presente invenzione, siano efficaci nel ridurre la secrezione del peptide beta-amiloide in cellule umane in coltura. The objects and advantages of the medical, therapeutic or paramedical use of certain dihydropyridines, object of the present invention, in pathological states characterized by an abnormal extraceilular deposition of amyloid protein will be better understood in the course of the following detailed description. The Applicant has in fact found that, the treatment with the compounds of the invention, contrary to other dihydropyridine derivatives (eg BayK 8644), induces a significant reduction of the constitutive secretion of the beta-amyloid protein in a cell line of human engineered origin which expresses constitutively an isoform of the APP695 gene associated with Alzheimer's disease. This effect is probably attributable to an allosteric modulation of the protease action of gamma secretase and is not attributable to the known pharmacological effects of these molecules (inhibition of voltage-gated calcium channels). In this invention we report for the first time data showing how the dihydropyridine molecules object of the present invention are effective in reducing the secretion of the beta-amyloid peptide in human cells in culture.
Inoltre la richiedente ha trovato che, il trattamento sistemico di animali transgenici TG2576 con gli stessi composti oggetto della presente invenzione induce già atre ore un aumento significativo dei livelli plasmatici della proteina beta-amiloide indicando un aumentato efflusso di questa proteina dal sistema nervoso dove è noto accumularsi in differenti stati patologici. Furthermore, the Applicant has found that the systemic treatment of TG2576 transgenic animals with the same compounds object of the present invention already induces a significant increase in plasma levels of the beta-amyloid protein for three hours, indicating an increased efflux of this protein from the nervous system where it is known. accumulate in different pathological states.
Esempio 1: Sono state usate colture cellulari di neuroglioma umano (H4) stabilmente transfettate con un gene codificante per la forma umana della proteina APP695 recante mutazioni associate al morbo di Alzheimer e sotto il controllo di un promotore costitutivamente attivo. Le cellule sono coltivate in un mezzo di coltura composto da OPTI-MEM contenente 10% siero bovino fetale, igromicina (0.2 mg/ml) e blasticidina (0.002 mg/ml). Il peptide beta-amiloide viene prodotto dall’intervento sequenziale delle proteasi beta- e gamma-secretasi e viene secreto dalle cellule nel mezzo extracellulare. La concentrazione di peptide nel mezzo cellulare viene misurato mediante metodo immu noenzimatico (ELISA) grazie all’uso di anticorpi selettivi anti beta-amiloide. I risultati ottenuti con le diverse diidropiridine sono riportati in tabella 1. Example 1: Cell cultures of human neuroglioma (H4) stably transfected with a gene encoding the human form of the APP695 protein bearing mutations associated with Alzheimer's disease and under the control of a constitutively active promoter were used. Cells are cultured in a culture medium consisting of OPTI-MEM containing 10% fetal bovine serum, hygromycin (0.2 mg / ml) and blasticidin (0.002 mg / ml). The beta-amyloid peptide is produced by the sequential intervention of the beta- and gamma-secretase proteases and is secreted by the cells in the extracellular medium. The concentration of peptide in the cell medium is measured by an immunoenzymatic method (ELISA) thanks to the use of selective antibodies to beta-amyloid. The results obtained with the different dihydropyridines are reported in table 1.
Gli effetti inibitori sul rilascio di beta-amiloide di tali molecole non sono imputabile ad un aspecifico effetto citotossico in quanto il saggio di vitalità cellulare (MTT) indica che questo parametro non viene alterato dal trattamento con diidropiridine. Sono stati anche esaminati gli effetti sulla secrezione di beta-amiloide delle 2 forme enantiomeriche della niguldipina (vedi tab. 1). Va qui rilevato che la (-)niguldipina è l’enantiomero inattivo per quanto riguarda l’effetto calcio antagonista. Tuttavia, come evidenziato nella tabella 1, entrambi le forme enentiomeriche, (-)niguldipina e (+) niguldipina, hanno un effetto inibitorio sulla secrezione di beta-amiloide. The inhibitory effects on beta-amyloid release of these molecules are not attributable to a non-specific cytotoxic effect as the cell viability assay (MTT) indicates that this parameter is not altered by treatment with dihydropyridines. The effects on beta-amyloid secretion of the 2 enantiomeric forms of niguldipine were also examined (see table 1). It should be noted here that (-) niguldipine is the inactive enantiomer as regards the calcium antagonist effect. However, as shown in Table 1, both enentiomeric forms, (-) niguldipine and (+) niguldipine, have an inhibitory effect on beta-amyloid secretion.
La diidropiridina BayK8644, al contrario delie altre diidropiridine non sortisce alcun effetto sulla secrezione di beta-amiloide nelle cellule H4/APP (tab. 1). Dihydropyridine BayK8644, unlike other dihydropyridines, has no effect on the secretion of beta-amyloid in H4 / APP cells (table 1).
Esemplo 2. 1 derivati nimodipina, nicardipina, sono stati somministrati via iniezione intraperitoneale alla dose di 10 mg/kg in animali TG2576. Prima del trattamento e dopo tre ore, da ogni animale è stato fatto un prelievo di sangue sul quale è stata determinata la concentrazione mediante un metodo immunoenzimatico (ELISA) che sfrutta anticorpi selettivi anti beta-amiloide. I risultati ottenuti (Tab. 2) indicano che la somministrazione di questi derivati è in grado di aumentare l’efflusso di beta-amiloide dal sistema nervoso centrale come riflesso dal vistoso aumento della concentrazione piasmatica di beta-amiloide indotto da questi derivati. Example 2. The nimodipine derivatives, nicardipine, were administered via intraperitoneal injection at a dose of 10 mg / kg in TG2576 animals. Before the treatment and after three hours, a blood sample was taken from each animal on which the concentration was determined by an immunoenzymatic method (ELISA) which exploits selective antibodies against beta-amyloid. The results obtained (Table 2) indicate that the administration of these derivatives is able to increase the efflux of beta-amyloid from the central nervous system as reflected by the marked increase in the piasmatic concentration of beta-amyloid induced by these derivatives.
I composti oggetto della presente invenzione possono quindi essere utilmente impiegabili per la preparazione di composizioni farmaceutiche per il trattamento terapeutico, da soli o in associazione con altri agenti terapeutici di elezione per lo stato patologico specifico, come ad esempio antiossidanti, antinfiammatori, inibitori delle proteasi, inibitori delle coline esterasi, antiepilettici, neurolettici, neurolettici atipici, antidepressivi, dopaminergici, dopamino-agonisti, gaba-agonisti, per il miglioramento della memoria, antinfiammatori/antidolorifici (es. oppiodi, salicilati, pirazolici, indolici, arilantranilici, arilpropionici, arilacetici, oxicami, piranocarbossilici, glucocorticoidi, anti-cox2, nimesulide e acetaminofene). The compounds object of the present invention can therefore be usefully employed for the preparation of pharmaceutical compositions for the therapeutic treatment, alone or in association with other therapeutic agents of choice for the specific pathological state, such as for example antioxidants, anti-inflammatories, protease inhibitors, choline esterase inhibitors, antiepileptics, neuroleptics, atypical neuroleptics, antidepressants, dopaminergics, dopamine agonists, gaba agonists, for memory enhancement, anti-inflammatory / pain relievers (e.g. opioids, salicylates, pyrazolics, indoles, arylanthrionics, arylpropionics, arylpropionics, oxicams, pyranocarboxyls, glucocorticoids, anti-cox2, nimesulide and acetaminophen).
Le vie di somministrazione che possono essere usate per il trattamento preventivo o terapeutico degli stati patologici secondo la presente invenzione possono essere la via orale, parenterale, intramuscolare, sottocutanea, endovenosa, topica, transdermica, rettale, sublinguale e nasale. I composti oggetto della presente invenzione possono essere somministrati in composizioni farmaceutiche in combinazione con eccipienti, disperdenti e diluenti noti o nuovi compatibili con gli impieghi farmaceutici, al fine di ottenere una migliore veicolazione del principio attivo al sito d’azione e di ottenere un effetto rapido, sostenuto o ritardato nel tempo. Allo scopo quindi possono essere impiegate forme farmaceutiche a fast, sustained o slowrelease. I dosaggi sono dipendenti dalla gravità della patologia e della via di somministrazione scelta, come pure dallo stato (età, peso corporeo, condizioni generali di salute) del paziente ed a scopo illustrativo ma non limitativo della presente invenzione, possono essere compresi tra 0.1 mo/Κg di peso corporeo e 50 mg/Kg di peso corporeo in somministrazioni giornaliere ripetute per un periodo compreso tra 2 e 16 settimane. Per la somministrazione orale possono essere adatte composizioni sotto forma di polveri disperdibili, compresse, confetti, capsule di gelatina molle o rigida, sospensioni; per la somministrazione parenterale intramuscolo, sottocutanea, endovena o peridurale possono essere adatte composizioni sotto forma di soluzioni acquose tamponate, sospensioni oleose o polveri liofilizzate disperdibili in opportuno solvente al momento della somministrazione; per la somministrazione topica transdermica, rettale, nasale o sublinguale possono essere adatte composizioni in opportuni eccipienti o disperdenti sotto forma di cerotti, supposte, ovuli, candelette, aereosol o spray. The routes of administration that can be used for the preventive or therapeutic treatment of the pathological states according to the present invention can be the oral, parenteral, intramuscular, subcutaneous, intravenous, topical, transdermal, rectal, sublingual and nasal routes. The compounds object of the present invention can be administered in pharmaceutical compositions in combination with known or new excipients, dispersants and diluents compatible with pharmaceutical uses, in order to obtain a better delivery of the active principle to the site of action and to obtain a rapid effect. , sustained or delayed over time. For this purpose, fast, sustained or slowrelease pharmaceutical forms can be used. The dosages depend on the severity of the pathology and the chosen route of administration, as well as on the state (age, body weight, general health conditions) of the patient and for illustrative but not limitative purposes of the present invention, they can be included between 0.1 m or / Κg of body weight and 50 mg / kg of body weight in repeated daily administrations for a period of between 2 and 16 weeks. For oral administration, compositions in the form of dispersible powders, tablets, dragees, soft or hard gelatin capsules, suspensions, may be suitable; for intramuscular, subcutaneous, intravenous or epidural parenteral administration, compositions in the form of buffered aqueous solutions, oily suspensions or lyophilized powders dispersible in a suitable solvent at the time of administration may be suitable; for topical transdermal, rectal, nasal or sublingual administration, compositions in suitable excipients or dispersants in the form of patches, suppositories, ovules, candles, aerosols or sprays may be suitable.
Claims (7)
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITPD20060014 ITPD20060014A1 (en) | 2006-01-19 | 2006-01-19 | METHOD FOR FEEDING THE EFFLUSSO FROM THE NERVOUS SYSTEM OF AMYLOID PEPTIDES |
| PT06727482T PT1874311E (en) | 2005-04-15 | 2006-04-14 | A method for preventing, delaying or reverting abnormal amyloid deposition |
| EP06727482A EP1874311B1 (en) | 2005-04-15 | 2006-04-14 | A method for preventing, delaying or reverting abnormal amyloid deposition |
| ES06727482T ES2374716T3 (en) | 2005-04-15 | 2006-04-14 | METHOD TO PREVENT, DELAY OR REVERT THE ABNORMAL AMILOID DEPOSITION. |
| AT06727482T ATE526965T1 (en) | 2005-04-15 | 2006-04-14 | METHOD FOR PREVENTING, DELAYING OR REVERSING ABNORMAL AMYLOID DEPOSIT |
| PCT/IB2006/000886 WO2006109164A2 (en) | 2005-04-15 | 2006-04-14 | A method for preventing, delaying or reverting abnormal amyloid deposition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITPD20060014 ITPD20060014A1 (en) | 2006-01-19 | 2006-01-19 | METHOD FOR FEEDING THE EFFLUSSO FROM THE NERVOUS SYSTEM OF AMYLOID PEPTIDES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ITPD20060014A1 true ITPD20060014A1 (en) | 2007-07-19 |
Family
ID=40260668
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ITPD20060014 ITPD20060014A1 (en) | 2005-04-15 | 2006-01-19 | METHOD FOR FEEDING THE EFFLUSSO FROM THE NERVOUS SYSTEM OF AMYLOID PEPTIDES |
Country Status (1)
| Country | Link |
|---|---|
| IT (1) | ITPD20060014A1 (en) |
-
2006
- 2006-01-19 IT ITPD20060014 patent/ITPD20060014A1/en unknown
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