ITRM20120285A1 - ORMONE ANTI-MULLERIANO. - Google Patents
ORMONE ANTI-MULLERIANO. Download PDFInfo
- Publication number
- ITRM20120285A1 ITRM20120285A1 IT000285A ITRM20120285A ITRM20120285A1 IT RM20120285 A1 ITRM20120285 A1 IT RM20120285A1 IT 000285 A IT000285 A IT 000285A IT RM20120285 A ITRM20120285 A IT RM20120285A IT RM20120285 A1 ITRM20120285 A1 IT RM20120285A1
- Authority
- IT
- Italy
- Prior art keywords
- hormone
- endometriosis
- treatment
- amh
- müllerian
- Prior art date
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Endocrinology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Reproductive Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Description
"ORMONE ANTI-MULLERIANO†"ANTI-MULLERIAN HORMONE⠀
DESCRIZIONE DESCRIPTION
La presente descrizione riguarda l’ormone anti-mulleriano o una sua forma biologicamente attiva per uso nel trattamento e/o rallentamento dell’endometriosi, come anche composizioni farmaceutiche comprendenti detto ormone e/o una sua forma biologicamente attiva per uso nel trattamento e/o rallentamento dell’endometriosi. The present description relates to the anti-Müllerian hormone or a biologically active form thereof for use in the treatment and / or slowing of endometriosis, as well as pharmaceutical compositions comprising said hormone and / or a biologically active form thereof for use in the treatment and / or slowing of endometriosis.
STATO DELLA TECNICA ANTERIORE STATE OF THE PRIOR ART
L’endometriosi si definisce come un disordine ginecologico ricorrente e benigno caratterizzato dalla presenza di tessuto endometriale (ghiandole e stroma) presente al di fuori della cavità uterina. Il tessuto endometriosico, più comunemente, si reperta sulla superficie peritoneale all’interno della pelvi femminile, sulle ovaie, nel setto retto-vaginale, e più raramente nel pericardio, nella pleura e perfino nel cervello (Giudice LC , and Kao LC: Endometriosis. The Lancet, 364: 1789-1799, 2004). Endometriosis is defined as a recurrent and benign gynecological disorder characterized by the presence of endometrial tissue (glands and stroma) present outside the uterine cavity. Endometriotic tissue, most commonly, is found on the peritoneal surface inside the female pelvis, on the ovaries, in the recto-vaginal septum, and more rarely in the pericardium, in the pleura and even in the brain (Judge LC, and Kao LC: Endometriosis . The Lancet, 364: 1789-1799, 2004).
Attualmente la diagnosi di certezza per l’endometriosi può essere formulata solo attraverso pratiche chirurgiche e ciò rende difficile la valutazione esatta della sua prevalenza nella popolazione femminile. Stime recenti indicano una prevalenza del 6-10%; tuttavia in pazienti con dolore e/o infertilità tale prevalenza sale al 35-60% (Houston DE: Evidence for the risk of pelvic endometriosis by age, race, and socioeconomic status. Epidemiol Rev, 6: 167-191, 1984). In effetti, l’endometriosi à ̈ generalmente associata a infertilità e dolori pelvici, come ad esempio dismenorrea, dolori addominali e pelvici inter-mestruali, dolore di schiena, disuria e dispareunia (Giudice LC , and Kao LC: Endometriosis. The Lancet, 364: 1789-1799, 2004). La malattia à ̈ stata individuata come entità nosologica a se stante fin dal 1860 dal patologo austriaco von Rokitansky (Von Rokitansky C: Ueber uterusdrusen-neubildung in uterus and ovarilsarcomen. Z Ges Aertze Wein, 37: 577-593, 1860). Nonostante il fatto che sia molto comune nel sesso femminile e che sia conosciuta da circa 150 anni, spesso viene misconosciuta, i meccanismi patogenetici sono poco chiari e le strategie diagnostiche e terapeutiche sono ancora inadeguate. Currently, the diagnosis of certainty for endometriosis can only be formulated through surgical procedures and this makes it difficult to accurately assess its prevalence in the female population. Recent estimates indicate a prevalence of 6-10%; however, in patients with pain and / or infertility this prevalence rises to 35-60% (Houston DE: Evidence for the risk of pelvic endometriosis by age, race, and socioeconomic status. Epidemiol Rev, 6: 167-191, 1984). Indeed, endometriosis is generally associated with infertility and pelvic pain, such as dysmenorrhea, inter-menstrual abdominal and pelvic pain, back pain, dysuria and dyspareunia (Judge LC, and Kao LC: Endometriosis. The Lancet, 364: 1789-1799, 2004). The disease has been identified as a nosological entity in its own right since 1860 by the Austrian pathologist von Rokitansky (Von Rokitansky C: Ueber uterusdrusen-neubildung in uterus and ovarilsarcomen. Z Ges Aertze Wein, 37: 577-593, 1860). Despite the fact that it is very common in women and has been known for about 150 years, it is often misunderstood, the pathogenetic mechanisms are unclear and diagnostic and therapeutic strategies are still inadequate.
L’ormone anti-mulleriano (AMH) à ̈ una glicoproteina dimerica appartenente alla superfamiglia del “Transforming Growth Factor-beta†(TGF-beta). L’AMH à ̈ prodotto dalle cellule del Sertoli nel feto maschile ed à ̈ responsabile della regressione dei dotti del Muller (La Marca A et al.: Anti-Mullerian hormone (AMH): what do we still need to know? Hum Reproduct, 24: 2264-2275, 2009). Nel feto femminile, l’AMH comincia ad essere espresso a partire dalla trentaduesima settimana di gestazione nelle cellule della granulosa dei follicoli. L’espressione di AMH nei follicoli ovarici si mantiene per tutta la vita fertile della donna, per poi decadere nella menopausa e i livelli di AMH sono considerati degli indicatori della riserva ovarica attiva (Lee MM et al.: Mullerian inhibiting substance in humans: normal levels from infancy to adulthood. J Clin Endocrinol Metab, 81: 571-576, 1996). E†̃ una sostanza presente nell’organismo femminile umano ed à ̈ aumentato nel siero di donne affette da policistosi ovarica non determinando il suo aumento alcun effetto organico o biologico negativo sugli organi femminili. Inoltre, à ̈ stato proposto un’azione anti-cancro per l’AMH nei tumori epiteliali dell’ovaio e diverse evidenze sperimentali sembrano supportare l’effetto citotossico su cellule tumorali (La Marca A., Volpe A: The anti-Mullerian Hormone and ovarian cancer. Hum Reproduct., 13: 265-273, 2007). The anti-Müllerian hormone (AMH) is a dimeric glycoprotein belonging to the superfamily of the â € œTransforming Growth Factor-betaâ € (TGF-beta). AMH is produced by the Sertoli cells in the male fetus and is responsible for the regression of the Muller ducts (La Marca A et al .: Anti-Mullerian hormone (AMH): what do we still need to know? Hum Reproduct , 24: 2264-2275, 2009). In the female fetus, AMH begins to be expressed from the thirty-second week of gestation in the granulosa cells of the follicles. The expression of AMH in the ovarian follicles is maintained throughout the fertile life of the woman, and then decays in the menopause and the levels of AMH are considered indicators of the active ovarian reserve (Lee MM et al .: Mullerian inhibiting substance in humans: normal levels from infancy to adulthood. J Clin Endocrinol Metab, 81: 571-576, 1996). It is a substance present in the human female organism and it is increased in the serum of women suffering from ovarian polycystosis, not causing its increase any organic or biological negative effect on the female organs. Furthermore, an anti-cancer action has been proposed for AMH in epithelial tumors of the ovary and several experimental evidences seem to support the cytotoxic effect on tumor cells (La Marca A., Volpe A: The anti -Mullerian Hormone and ovarian cancer. Hum Reproduct., 13: 265-273, 2007).
Considerando la bassissima tossicità di tale sostanza nel corpo umano, la possibilità di utilizzo come farmaco anti-cancro à ̈ di grande interesse clinico. Considering the very low toxicity of this substance in the human body, the possibility of its use as an anti-cancer drug is of great clinical interest.
Studi recenti hanno dimostrato che l’AMH, così come un suo recettore (MISRII), sono espressi nella donna adulta anche a livello dell’endometrio, dove probabilmente esplicano una funzione di tipo paracrino. Recent studies have shown that AMH, as well as its receptor (MISRII), are also expressed in the adult woman at the level of the endometrium, where they probably perform a paracrine function.
L'endometriosi à ̈ ancora oggi una malattia per la quale l’unica strategia terapeutica efficace à ̈ la rimozione chirurgica delle lesioni endometriosiche: non esiste nessuna terapia farmacologica in grado di eliminare o ridurre le lesioni endometriosiche e gli unici trattamenti farmacologici utilizzati dalla comunità medicoscientifica sono in grado solo di agire sui sintomi, mitigandoli. Endometriosis is still today a disease for which the only effective therapeutic strategy is the surgical removal of endometriotic lesions: there is no drug therapy capable of eliminating or reducing endometriotic lesions and the only pharmacological treatments used by the community. medicoscientifica are only able to act on the symptoms, mitigating them.
E’ quindi estremamente sentita nello stato della tecnica nota la necessità di individuare una nuova strategia terapeutica che consenta di trattare in maniera radicale l’endometriosi agendo tutte direttamente sulle lesioni endometriosiche a livello cellulare, e in maniera differente dalla chirurgia che, non solo à ̈ una metodica invasiva, ma permette di intervenire solo sulle lesioni visibili e non su quelle microscopiche. It is therefore extremely felt in the state of the art the need to identify a new therapeutic strategy that allows to radically treat endometriosis by acting directly on the endometriotic lesions at the cellular level, and in a different way from surgery which, not only It is an invasive method, but it allows to intervene only on visible lesions and not on microscopic ones.
SOMMARIO DELL'INVENZIONE SUMMARY OF THE INVENTION
La presente descrizione riguarda l’utilizzo dell’ormone anti-mulleriano (AMH) e/o di una sua forma biologicamente attivo nel trattamento e/o rallentamento dell’endometriosi in un soggetto che lo necessiti. The present description relates to the use of the anti-Müllerian hormone (AMH) and / or its biologically active form in the treatment and / or slowing down of endometriosis in a subject who needs it.
Nella presente invenzione per rallentamento dell’endometriosi s’intende la diminuzione o la non variazione nel tempo del numero di lesioni endometriosiche osservate ed identificate dal clinico in un soggetto affetto da endometriosi. Per trattamento dell’endometriosi s’intende, invece, l’eliminazione nel tempo di tutte le lesioni endometriosiche presenti in un soggetto affetto da endometriosi, quindi, in altri termini, s’intende nella presente descrizione l’eradicazione nel tempo dell’endometriosi stessa nel soggetto sottoposto a terapia con l’AMH. In the present invention, slowing down of endometriosis means the decrease or non-variation over time in the number of endometriotic lesions observed and identified by the clinician in a subject affected by endometriosis. By treatment of endometriosis, on the other hand, we mean the elimination over time of all endometriotic lesions present in a subject affected by endometriosis, therefore, in other words, in this description we mean the eradication in the time of endometriosis itself in the subject undergoing therapy with AMH.
L’invenzione oggetto della presente descrizione si base sull’osservazione, effettuata dagli stessi inventori che, il trattamento di cellule endometriiosiche, siano esse ottenute dalla componente ghiandolare o stromale della lesione endometriosica, con l’ormone anti-mulleriano determina da un lato il blocco delle cellule trattate nella fase G1/G2 del ciclo cellulare, con conseguente diminuzione della fase S del ciclo stesso, e dall’altra l’aumento della morte cellulare indotta per apoptosi. In particolare, quindi, gli inventori della presente invenzione hanno dimostrato per la prima volta che, à ̈ possibile rallentare la crescita o indurre apoptosi delle cellule endometriosiche mediante il trattamento con l’ormone anti-mulleriano. Di conseguenza, l’ormone antimulleriano può essere vantaggiosamente impiegato per rallentare lo sviluppo delle lesioni endometriosiche già presenti nel paziente e/o per trattare in maniera radicale tale patologia senza la necessità di ricorre alla rimozione delle lesioni endometriosiche mediante chirurgia. The invention object of the present description is based on the observation, carried out by the inventors themselves, that the treatment of endometriosis cells, whether obtained from the glandular or stromal component of the endometriotic lesion, with the anti-Müllerian hormone determines from a on the other hand, the block of the cells treated in the G1 / G2 phase of the cell cycle, with a consequent decrease in the S phase of the cycle itself, and on the other hand the increase in cell death induced by apoptosis. In particular, therefore, the inventors of the present invention have shown for the first time that it is possible to slow down the growth or induce apoptosis of endometriotic cells by treatment with the anti-Müllerian hormone. Consequently, the anti-Müllerian hormone can be advantageously used to slow down the development of endometriotic lesions already present in the patient and / or to radically treat this pathology without the need to resort to the removal of endometriotic lesions by surgery.
Il vantaggio principale, quindi, associato all’invenzione oggetto della presente invenzione à ̈ l’aver identificato per la prima volta nell’ormone antimulleriano uno strumento farmacologico estremamente efficace nel trattamento non invasivo dell’endometriosi, trattamento che, come già detto nella sezione precedente relativa alla stato della tecnica nota, era possibile solo mediante intervento chirurgico. The main advantage, therefore, associated with the invention object of the present invention is having identified for the first time in the anti-Müllerian hormone an extremely effective pharmacological tool in the non-invasive treatment of endometriosis, a treatment which, as already said in the previous section relating to the state of the known art, it was only possible by means of surgical intervention.
Formano pertanto oggetti della presente domanda: Therefore, the objects of this application form:
-ormone anti-mulleriano o sua forma biologicamente attiva per uso nel trattamento e/o rallentamento dell’endometriosi in un soggetto che lo necessiti; - anti-Müllerian hormone or its biologically active form for use in the treatment and / or slowing down of endometriosis in a person who needs it;
- una composizione farmaceutica comprendente ormone anti-mulleriano e/o una sua forma biologicamente attiva e almeno un eccipiente farmaceuticamente accettabile per uso nel trattamento e/o rallentamento dell’endometriosi in un soggetto che lo necessiti; - a pharmaceutical composition comprising anti-Müllerian hormone and / or a biologically active form thereof and at least one pharmaceutically acceptable excipient for use in the treatment and / or slowing down of endometriosis in a subject who needs it;
- Kit comprendente aliquote per uso sequenziale o contemporaneo delle componenti della composizione come precedentemente definita per uso nel trattamento e/o rallentamento dell’endometriosi. - Kit including aliquots for sequential or simultaneous use of the components of the composition as previously defined for use in the treatment and / or slowing down of endometriosis.
Ulteriori vantaggi, così come le caratteristiche e le modalità di impiego della presente invenzione risulteranno evidenti dalla seguente descrizione dettagliata di alcune forme di realizzazione preferite, presentate a scopo meramente esemplificativo e non limitativo. Further advantages, as well as the characteristics and methods of use of the present invention, will become evident from the following detailed description of some preferred embodiments, presented for purely illustrative and non-limiting purposes.
DESCRIZIONE DETTAGLIATA DELLE FIGURE DETAILED DESCRIPTION OF THE FIGURES
La figura 1 mostra l’effetto dell’ormone anti-mulleriano sulle diverse fasi del ciclo cellulare in cellule trattate. Figure 1 shows the effect of the anti-Müllerian hormone on the different phases of the cell cycle in treated cells.
La figura 2 mostra nel tempo il grado di apoptosi indotto in cellule enometriosiche dopo trattamento con l’ormone anti-mulleriano. Figure 2 shows over time the degree of apoptosis induced in enometriotic cells after treatment with anti-Müllerian hormone.
La figura 3 mostra come il recettore per l'omone anti-mulleriano MISRII sia effettivamente espresso a livello di RNA nelle cellule endometriosiche Figure 3 shows how the MISRII anti-Mullerian homone receptor is effectively expressed at the RNA level in endometriotic cells
DESCRIZIONE DETTAGLIATA DELL'INVENZIONE DETAILED DESCRIPTION OF THE INVENTION
La presente invenzione riguarda l’ormone antimulleriano (AMH) o una sua forma biologicamente attiva per uso nel trattamento e/o rallentamento dell’endometriosi in un soggetto. The present invention relates to the anti-Müllerian hormone (AMH) or a biologically active form thereof for use in the treatment and / or slowing down of endometriosis in a subject.
L’ormone antimulleriano à ̈ una proteina glicosilata di 140 kDa omodimerica presentante ponti disolfuro appartenente alla superfamiglia del “Transforming Growth Factor-beta†(TGF-beta). La sequenza nucleotidica e la sequenza amminoacidica codificante per l’AMH di origine sia umana che bovina sono descritte nello stato della tecnica nota e ad esempio riportate nel brevetto US5047336. The anti-Müllerian hormone is a glycosylated homodimeric 140 kDa protein presenting disulfide bridges belonging to the superfamily of the â € œTransforming Growth Factor-betaâ € (TGF-beta). The nucleotide sequence and the amino acid sequence coding for the AMH of both human and bovine origin are described in the state of the art and for example reported in the patent US5047336.
Ai fini della presente invenzione, l’AMH può essere ottenuto mediante tecniche di DNA ricombinante ovvero mediante clonaggio della sequenza nucleotidica d’interesse in un vettore di clonazione, trasformazione di una cellula ospite con detto vettore, espressione della proteina d’interesse in detta cellula ospite, purificazione della proteina ricombinate ottenuta. Le tecniche per ottenere la proteine ricombinanti sono ampiamente note e descritte in diversi manuali di laboratorio come, ad esempio in Maniatis et al.( Maniatis et al. Molecular Cloning: A laboratori Manual, Cold Spring Harbor, NY) pertanto nella presente descrizione non à ̈ necessario approfondire le tecniche mediante le quali à ̈ possibile ottenete l’AMH in forma di proteina ricombinante. Inoltre, il brevetto US5047336 qui incorporato come referenza descrive nel dettaglio un metodo per produrre AMH ricombinante a partire sia da sequenze nucleotidiche di origine umana che bovina. Il tecnico del settore potrà quindi sintetizzare l’AMH secondo una qualsiasi tecnica convenzionale o addirittura commissionando, se desiderato, la sintesi a compagnie che offrono tra i loro servizi sintesi di proteine d’interesse. For the purposes of the present invention, AMH can be obtained by recombinant DNA techniques or by cloning the nucleotide sequence of interest in a cloning vector, transformation of a host cell with said vector, expression of the protein of interest in said host cell, purification of the obtained recombinant protein. The techniques for obtaining recombinant proteins are widely known and described in various laboratory manuals such as, for example in Maniatis et al. (Maniatis et al. Molecular Cloning: A Laboratories Manual, Cold Spring Harbor, NY) therefore in the present description there is no It is necessary to deepen the techniques by which it is possible to obtain AMH in the form of recombinant protein. Furthermore, US patent 5047336 incorporated herein by reference describes in detail a method for producing recombinant AMH starting from both human and bovine nucleotide sequences. The person skilled in the art will then be able to synthesize AMH according to any conventional technique or even by commissioning, if desired, the synthesis to companies that offer among their services synthesis of proteins of interest.
Alternativamente, l’ormone AMH può essere isolato e purificato a partire da un idoneo campione biologico di un animale in cui la proteina antimulleriana à ̈ espressa. A titolo meramente esemplificativo e non limitante, il campione biologico può essere sangue o plasma e detto animale può essere un mammifero come ad esempio l’uomo oppure bovini, suini, equini, cani, gatti, conigli. Quindi, in generale, l’ormone antimulleriano utile per il trattamento e/o rallentamento dell’endometriosi può essere di qualsiasi origine, come anche sopra indicato, ed ottenuto mediante tecniche di ingegneria genetica o mediante purificazione a partire da idonei campioni biologici. Preferibilmente detto ormone à ̈ di origine umana o bovina. Alternatively, the AMH hormone can be isolated and purified starting from a suitable biological sample of an animal in which the anti-Müllerian protein is expressed. By way of non-limiting example, the biological sample can be blood or plasma and said animal can be a mammal such as man or cattle, pigs, horses, dogs, cats, rabbits. Therefore, in general, the anti-Müllerian hormone useful for the treatment and / or slowing down of endometriosis can be of any origin, as also indicated above, and obtained by genetic engineering techniques or by purification starting from suitable biological samples. Preferably said hormone is of human or bovine origin.
Per forma biologicamente attiva s’intende, nella presente descrizione, una forma modificata della proteina d’interesse che si caratterizza per la capacità di indurre gli stessi effetti biologici della proteina nella sua forma selvatica (wild type) dal momento che, la sua azione biologica sarà indotta mediante lo stesso meccanismo molecolare stimolato dalla forma selvatica. Quindi, a titolo esemplificativo ma non limitante, forme biologicamente attive dell’ormone antimulleriano sono proteine che rispetto alla forma wild type presentano delezioni, inserzioni, mutazioni puntiformi oppure sostituzioni di un amminoacido con un amminoacido dello stesso tipo/gruppo (ad esempio aspartato con glutammato, arginina con lisina ecc), oppure sequenze aggiuntive per la rilevazione/purificazione/stabilità . By biologically active form is meant, in the present description, a modified form of the protein of interest which is characterized by the ability to induce the same biological effects of the protein in its wild type since its biological action will be induced by the same molecular mechanism stimulated by the wild form. Therefore, by way of example but not limiting, biologically active forms of the anti-Müllerian hormone are proteins that, compared to the wild type form, have deletions, insertions, point mutations or substitutions of an amino acid with an amino acid of the same type / group (for example aspartate with glutamate, arginine with lysine, etc.), or additional sequences for detection / purification / stability.
In una forma di realizzazione preferita dell’invenzione, tale forma biologicamente attiva comprende o consiste nella porzione C-terminale (carbossi terminale) dell’AMH. La porzione carbossi terminale dell’AMH corrisponde ad un frammento di 12.5 kDa (circa 25kDa in condizioni non riducenti quindi in condizioni favorevoli all’esistenza della forma dimerica) ottenuto per taglio proteolitico al residuo 427 della sequenza amminoacidica di 535 aa dell’AMH monomerica umana (sequenza amminoacidica AMH monomerica umana: numero identificativo P03971 nella banca UniProtKB/Swiss-Prot, versione 133, ultima modifica 16 maggio 2012; http://www.uniprot.org/) . Il residuo in corrispondenza del quale avviene il taglio proteolitico à ̈ invece il 443 della proteina bovina di 551 aa (sequenza amminoacidica dell’AMH bovino: numero identificativo P03972 nella banca UniProtKB/Swiss-Prot, versione 91, ultima modifica 16 maggio 2012; http://www.uniprot.org/). In a preferred embodiment of the invention, this biologically active form comprises or consists of the C-terminal (terminal carboxy) portion of the AMH. The terminal carboxy portion of AMH corresponds to a fragment of 12.5 kDa (about 25kDa in non-reducing conditions therefore in conditions favorable to the existence of the dimeric form) obtained by proteolytic cutting at residue 427 of the 535 aa amino acid sequence of Human monomeric AMH (human monomeric AMH amino acid sequence: identification number P03971 in the UniProtKB / Swiss-Prot bank, version 133, last modified May 16, 2012; http://www.uniprot.org/). The residue at which the proteolytic cut occurs is instead 443 of the bovine protein of 551 aa (amino acid sequence of bovine AMH: identification number P03972 in the UniProtKB / Swiss-Prot bank, version 91, last modification 16 May 2012; http://www.uniprot.org/).
Analogamente a quanto sopra descritto, anche la porzione C-terminale può essere ottenuta mediante tecniche di ingegneria genetica o isolate e purificata da un campione biologico di un animale. Alternativamente, può essere semplicemente ottenuta per taglio proteolitico, ad esempio utilizzando l’enzima plasmina, dalla corrispondente forma selvatica della sequenza amminoacidica dell’AMH. Inoltre, ai fini della presente invenzione, la porzione carbossi terminale può essere a sua volta utilizzata in una sua forma modificata biologicamente attiva, come sopra precedentemente descritto per l’AMH wild type. Similarly to what has been described above, the C-terminal portion can also be obtained by genetic engineering techniques or isolated and purified from a biological sample of an animal. Alternatively, it can be simply obtained by proteolytic cleavage, for example using the enzyme plasmin, from the corresponding wild form of the amino acid sequence of AMH. Furthermore, for the purposes of the present invention, the terminal carboxy portion can in turn be used in a modified biologically active form thereof, as previously described above for wild type AMH.
La presente invenzione si riferisce all’uso di detto ormone antimulleriano o di detta sua forma biologicamente attiva per il trattamento e/o il rallentamento dell’endometriosi in un soggetto che lo necessiti. In altri termini, l’AMH può essere usato vantaggiosamente per diminuire, eliminare, oppure mantenere invariato nel tempo il numero di lesioni endometriosiche in un soggetto affetto da endometriosi. Per “soggetto effetto endometriosi†à ̈ da intendersi qualsiasi soggetto animale in cui à ̈ possibile diagnosticare e/o evidenziare lesioni endometriosiche, come ad esempio, un essere umano o un cavallo. The present invention relates to the use of said anti-Müllerian hormone or of said biologically active form thereof for the treatment and / or slowing down of endometriosis in a subject who needs it. In other words, AMH can be used advantageously to reduce, eliminate, or keep the number of endometriotic lesions unchanged over time in a subject with endometriosis. By â € œsubject with endometriosis effectâ € is meant any animal in which it is possible to diagnose and / or highlight endometriotic lesions, such as, for example, a human being or a horse.
L’ormone antimulleriano per uso secondo quanto qui descritto à ̈ preferibilmente usato ad una quantità efficace ai fini del trattamento e/o rallentamento dell’endometriosi. Il quantitativo efficace di AMH o di una sua forma biologicamente attiva da somministrare può essere prestabilito in dosi unitarie giornaliere, o ad intervalli di più giorni o di settimane, o può essere valutato dallo staff medico secondo lo stato di malattia del paziente, il peso, il sesso e l’età . The anti-Müllerian hormone for use as described herein is preferably used in an effective amount for the treatment and / or slowing of endometriosis. The effective amount of AMH or one of its biologically active form to be administered can be predetermined in unit doses per day, or at intervals of several days or weeks, or can be evaluated by the medical staff according to the patient's disease status, weight, sex and age.
Per quantità efficace o terapeuticamente efficace s’intende una dose che consenta al ricercatore o al medico di osservare l’effetto terapeutico desiderato nel paziente trattato. Nel caso specifico, una dose terapeuticamente efficace sarà una dose (somministrata in uno o più dosaggi unitari nell’arco del tempo) che porti ad una riduzione, eliminazione o non variazione del numero delle lesioni endometriosiche osservate rispetto al tempo t=0 ovvero prima dell’inizio della terapia con AMH o sua forma biologicamente attiva. By effective or therapeutically effective quantity we mean a dose that allows the researcher or doctor to observe the desired therapeutic effect in the patient being treated. In the specific case, a therapeutically effective dose will be a dose (administered in one or more unit doses over time) that leads to a reduction, elimination or non-variation in the number of endometriotic lesions observed with respect to time t = 0 or before initiation of therapy with AMH or its biologically active form.
A livello molecolare, l’effetto biologico osservato nel paziente trattato ovverro la capacità dell’ormone anti-mulleriano di agire direttamene sulla lesione endometriosica à ̈ dovuta alla presenza dei recettori per l'omone AMHMISRII nelle cellule endometriosiche. Infatti, i dati sperimentali sotto riportati dimostrano anche che le cellule endometriosiche esprimono il recettore MISRII specifico per l'ormone antimulleriano e, quindi, che tali cellule sono un bersaglio ideale per tale ormone.Inoltre, à ̈ riportato in letteratura che la saturazione del recettore MISRII avviene a concentrazioni di 75-100 nmol/L e che la costante di dissociazione varia in un range di 6-12 nmol/L (Masiakos PT, MacLaughlin DT, Maheswaran S, Teixeira J, Fuller AF Jr, Shah PC, et al. Human ovarian cancer, cell lines, and primary ascites cells express the human Mullerian inhibiting substance (MIS) type II receptor, bind, and are responsive to MIS. Clin Cancer Res 1999; 5: 3488-99). At the molecular level, the biological effect observed in the treated patient, ie the ability of the anti-Müllerian hormone to act directly on the endometriotic lesion, is due to the presence of receptors for the AMHMISRII homone in endometriotic cells. In fact, the experimental data reported below also demonstrate that endometriotic cells express the MISRII receptor specific for the anti-Müllerian hormone and, therefore, that these cells are an ideal target for this hormone. MISRII occurs at concentrations of 75-100 nmol / L and that the dissociation constant varies in a range of 6-12 nmol / L (Masiakos PT, MacLaughlin DT, Maheswaran S, Teixeira J, Fuller AF Jr, Shah PC, et al . Human ovarian cancer, cell lines, and primary ascites cells express the human Mullerian inhibiting substance (MIS) type II receptor, bind, and are responsive to MIS. Clin Cancer Res 1999; 5: 3488-99).
Comunque, la dose efficace dipenderà essenzialmente da come sarà farmacologicamente definita la sostanza, considerando anche che l'AMH esercita probabilmente un'azione paracrina sui tessuti bersaglio, e che sarà probabilmente necessario modificare la molecola in maniera da ottenere concentrazioni elevate proprio nei siti bersaglio. However, the effective dose will essentially depend on how the substance will be pharmacologically defined, also considering that AMH probably exerts a paracrine action on target tissues, and that it will probably be necessary to modify the molecule in order to obtain high concentrations precisely in the target sites.
In particolare, i dati sperimentali sotto riportati dimostrano come in cellule endometriosiche trattate con AMH si osserva un blocco del ciclo cellulare in fase G1/G2 con conseguente diminuzione della fase S del ciclo stesso, e un aumento della morte cellulare per apoptosi. Tali dati consento di sostenere la capacità dell’AMH o di una sua forma biologicamente attiva nel rallentare o trattare l’endometriosi. (spostato nel capoverso precedente). In particular, the experimental data reported below demonstrate how in endometriotic cells treated with AMH there is a blockage of the cell cycle in the G1 / G2 phase with a consequent decrease in the S phase of the cycle itself, and an increase in cell death due to apoptosis. These data allow us to support the ability of AMH or one of its biologically active forms to slow down or treat endometriosis. (moved to the previous paragraph).
La presente invenzione riguarda anche una composizione farmaceutica comprendente l’ormone anti-mulleriano e/o una sua forma biologicamente attiva e almeno un eccipiente farmaceuticamente accettabile per uso nel trattamento e/o rallentamento dell’endometriosi in un soggetto che lo necessiti. The present invention also relates to a pharmaceutical composition comprising the anti-Müllerian hormone and / or a biologically active form thereof and at least one pharmaceutically acceptable excipient for use in the treatment and / or slowing down of endometriosis in a subject who needs it.
In una forma di realizzazione preferita delle composizioni qui descritte, la forma biologicamente attiva à ̈ una forma che comprende la porzione C-terminale di detto ormone, come sopra definita. In a preferred embodiment of the compositions described herein, the biologically active form is a form which comprises the C-terminal portion of said hormone, as defined above.
L’ormone o la sua forma modificata, in accordo a quanto precedentemente descritto, unitamente ad un eccipiente, adiuvante, veicolante, diluente convenzionalmente utilizzato nelle preparazione/composizioni per uso farmaceutico, può essere posto nella composizione stessa in qualsiasi tipo di dosaggio ritenuto idoneo ai fini della presente invenzione quindi, ad esempio, in dosaggi di tipo unitario. The hormone or its modified form, according to what previously described, together with an excipient, adjuvant, carrier, diluent conventionally used in the preparation / compositions for pharmaceutical use, can be placed in the composition itself in any type of dosage considered suitable for the purposes of the present invention therefore, for example, in unitary-type dosages.
Per dosaggio unitario s’intende la dose idonea a raggiungere la quantità terapeuticamente efficace come sopra definito, e viene normalmente stabilito anche in base all’età , al peso, al sesso e allo stato di salute del paziente da trattare. By unit dosage we mean the dose suitable to reach the therapeutically effective quantity as defined above, and it is normally established also on the basis of the age, weight, sex and state of health of the patient to be treated.
Il dosaggio unitario potrà variare in funzione del regime di somministrazione scelto dal medico ed à ̈ evidente che il regime di somministrazione dovrà essere idoneo a raggiungere l’effetto desiderato, terapeutico e/o di rallentamento dell’endometriosi che sia, che sarà tipicamente determinato da un medico, alla luce delle circostanze rilevanti, inclusa li sito di insorgenza della malattia, la via di somministrazione scelta, l’età , il peso e la risposta del paziente individuale, la severità dei sintomi del paziente e simili. The unit dosage may vary according to the administration regimen chosen by the doctor and it is evident that the administration regimen must be suitable for achieving the desired effect, therapeutic and / or slowing down of endometriosis which is, which will typically be determined by a physician, in light of the relevant circumstances, including the site of disease onset, the chosen route of administration, the individual patient's age, weight and response, the severity of the patient's symptoms and the like.
Come descritto sopra, le composizioni farmaceuticamente della presente invenzione, inoltre, comprendono un eccipiente farmaceuticamente accettabile, adiuvante e/o veicolo che, come qui utilizzato, include qualsiasi e tutti i solventi, diluenti o altri veicoli liquidi, ausili per dispersione o sospensione, agenti attivi in superficie, agenti isotonici, agenti addensanti o emulsionanti, conservanti, leganti solidi, lubrificanti e simili, come idonei per la particolare forma di dosaggio desiderata. Il Remington's Pharmaceutical Sciences, sedicesima edizione, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) descrive vari veicolanti utilizzati nella formulazione di composizioni farmaceuticamente accettabili e le tecniche note per la loro preparazione. As described above, the pharmaceutically compositions of the present invention further comprise a pharmaceutically acceptable excipient, adjuvant and / or carrier which, as used herein, includes any and all solvents, diluents or other liquid carriers, dispersion or suspension aids, agents surface actives, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suitable for the particular dosage form desired. Remington's Pharmaceutical Sciences, 16th edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) describes various carriers used in the formulation of pharmaceutically acceptable compositions and known techniques for their preparation.
Alcuni materiali esemplificativi che possono servire come veicolanti farmaceuticamente accettabili includono, ma non sono limitati a, scambiatori ionici, alluminio, stearato di alluminio, lecitina, proteine di siero quali siero albumina umana, sostanze tampone (fosfato, acido sorbico o sorbato di potassio), miscele parziali di gliceridi di acidi grassi saturi vegetali, acqua, sale o elettroliti quali solfato di protammina, fosfato di disodio idrogeno, fosfato di potassio idrogeno, cloruro di sodio, sali di zinco, silice colloidale, trisilicato di magnesio, polivinil pirrolidone, poliacrilati, cere, tessuto grasso, zuccheri quali lattosio, glucosio e saccarosio; amidi quali amido di mais e amido di patata; cellulosa e suoi derivati quali sodio carbossimetil cellulosa, etil cellulosa e acetato di cellulosa; polvere di tragacanto; malto; gelatina; talco; eccipienti quali burro di cacao e cera per supposte, oli quali olio di arachidi, olio di semi di cotone, olio di girasole, olio di sesamo, olio di oliva, olio di mais e olio di soia; glicoli quali propilenglicole o polietilglicole; esteri quali etil oleato e etil laurato; agar; agenti tamponanti quali idrossido di magnesio e idrossido di alluminio, acido alginico, acqua priva di pirogeno, soluzione salina isotonica, soluzione di Ringer; alcol etilico e soluzioni saline tamponate con fosfato così come altri lubrificanti compatibili non tossici quali sodio laurilsolfato e stearato di magnesio, così come agenti coloranti, agenti rilascianti, agenti di rivestimento, dolcificanti, aromi ed agenti profumanti, conservanti ed antiossidanti possono essere anch’essi presenti nella composizione secondo il giudizio di chi prepara la formulazione. Some exemplary materials that may serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, whey proteins such as human serum albumin, buffers (phosphate, sorbic acid or potassium sorbate), partial mixtures of glycerides of vegetable saturated fatty acids, water, salt or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, fatty tissue, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; tragacanthus powder; malt; jelly; talc; excipients such as cocoa butter and suppository wax, oils such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol or polyethylglycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution; ethyl alcohol and phosphate buffered saline solutions as well as other compatible non-toxic lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweeteners, flavorings and perfuming agents, preservatives and antioxidants can also be € ™ they are present in the composition according to the judgment of the person preparing the formulation.
Le composizioni farmaceutiche qui descritte, possono anche comprendere almeno un principio attivo diverso dall’AMH e noto essere utile nel trattamento dell’endometriosi A titolo meramente esemplificativo si indicano di seguito alcuni principi attivi, alcuni dei quali già utilizzati nel trattamento dell'endometriosi, che possono essere utilizzati in combinazione con AMH. The pharmaceutical compositions described here may also include at least one active principle other than AMH and known to be useful in the treatment of endometriosis. By way of example, some active principles are indicated below, some of which are already used in the treatment of endometriosis. , which can be used in conjunction with AMH.
Preferibilmente, detto almeno un principio attivo à ̈ scelto nel gruppo comprendente le seguenti classi di composti: Preferably, said at least one active principle is selected from the group comprising the following classes of compounds:
a) antiflogistici non steroidei come : antiinfiammatori arilacidici, antiinfiammatori non acidici, antielmintici, composti sulfridici, inibitori delle proteasi, antimalarici di sintesi, sali di oro, griseofulvina, sostanze varie e blanda azione antiflogistica quali la glucosamina, i lisati di organo, la SAMe, l'eparina, gli eparinoidi, i derivati azulenici, i flavonoidi, le cumarine, l'escina, la calcitonina, il D-glicofuranoside, gli enzimi proteolitici, gli antifibrinolitici, il bametan, la bufenina, il salbutamolo, l'acido glicirrizzinico, gli immunodepressori; a) non-steroidal anti-inflammatory drugs such as: arylacid anti-inflammatory, non-acidic anti-inflammatory, anthelmintic, sulphride compounds, protease inhibitors, synthetic antimalarials, gold salts, griseofulvin, various substances and mild anti-inflammatory action such as glucosamine, organ lysates, SAMe , heparin, heparinoids, azulenic derivatives, flavonoids, coumarins, aescin, calcitonin, D-glycofuranoside, proteolytic enzymes, antifibrinolytics, bametan, bufenin, salbutamol, glycyrrhizinic acid , immunosuppressants;
b) antiflogistici steroidei (glucorticoidi naturali e di sintesi); b) steroidal anti-inflammatory drugs (natural and synthetic glucorticoids);
c) ormoni follicoloidi o estrogeni e loro inibitori (naturali e di sintesi); c) follicoloid or estrogen hormones and their inhibitors (natural and synthetic);
d) ormoni luteoidi o progestinici e loro inibitori (naturali e di sintesi); d) luteoid or progestin hormones and their inhibitors (natural and synthetic);
e) associazioni di estroprogestinici (naturali e di sintesi); e) combinations of estrogen-progestins (natural and synthetic);
f) ormone testicolare (testosterone) e suoi inibitori (naturali e di sintesi); f) testicular hormone (testosterone) and its inhibitors (natural and synthetic);
g) agonisti e antagonisti del GHRH (ormone liberante le gonadotropine), GH-IH (somatostatina), CRH (ormone liberante l'ACTH), PIH e PRH (ormoni inibente e liberante la prolattina rispettivamente), MIH e MRH (ormoni inibente e liberante l'MSH rispettivamente, LH-RH e FSH-RH (ormoni stimolanti il rilascio di LH e FSH rispettivamente), tutti naturali e di sintesi; g) agonists and antagonists of GHRH (gonadotropin releasing hormone), GH-IH (somatostatin), CRH (ACTH releasing hormone), PIH and PRH (inhibiting and releasing hormones respectively), MIH and MRH (inhibiting and releasing MSH respectively, LH-RH and FSH-RH (hormones stimulating the release of LH and FSH respectively), all natural and synthetic;
h) agonisti e antagonisti del STH (ormone somatotropo) (naturali e di sintesi); agonisti e antagonisti del ACTH (ormone corticotropo) (naturali e di sintesi); agonisti e antagonisti del TRH (ormone tireotropo) (naturali e di sintesi); agonisti e antagonisti di FSH e LH (ormoni gonadotropi) (naturali e di sintesi); agonisti e antagonisti di MSH (ormoni melanofori) (naturali e di sintesi); agonisti e antagonisti di vasopressina e ossitocina (naturali e di sintesi); h) agonists and antagonists of STH (somatotropic hormone) (natural and synthetic); ACTH (corticotropic hormone) agonists and antagonists (natural and synthetic); TRH agonists and antagonists (thyrotropic hormone) (natural and synthetic); agonists and antagonists of FSH and LH (gonadotropic hormones) (natural and synthetic); agonists and antagonists of MSH (melanophoric hormones) (natural and synthetic); vasopressin and oxytocin agonists and antagonists (natural and synthetic);
l) inibitori delle aromatasi (naturali e di sintesi); l) aromatase inhibitors (natural and synthetic);
m) farmaci antineoplastici come ad esempio alchilanti, antimetaboliti, antibiotici, mitostatici ricavati da piante, enzimatici, ormoni, immunogeni, e vari quali il nocodazolo, il razoxano, l'acido azelaico; m) antineoplastic drugs such as alkylating agents, antimetabolites, antibiotics, mitostats derived from plants, enzymatic, hormones, immunogens, and various such as nocodazole, razoxane, azelaic acid;
n) farmaci antineoplastici biologici come ad esempio farmaci appartenenti alle due famiglie dei -MAB e degli -INIB; n) biological antineoplastic drugs such as drugs belonging to the two families of -MAB and -INIB;
o) antibiotici come ad esempio presulfonamidici, sulfonamidici, post-sulfonamidici, penicilline, cefalosporine, macrolidi, lincosamidi, novobiocina, fosfomicina, rifampicine, ristocetina, vancomicina, acifdo fusidico, streptopgramine, cloramfenicolo, tiamfenicolo, tetracicline, aminoglucosidici, polipetidi ciclici, albomicina e monomicina, antimicobatterici, antimicotici, antiluetici, antiamebici, antimalarici, antitripanosomiasici, antibilharziosici, antiparassitari locali o) antibiotics such as presulfonamides, sulfonamides, post-sulfonamides, penicillins, cephalosporins, macrolides, lincosamides, novobiocin, phosphomycin, rifampicins, ristocetin, vancomycin, fusus acyphus, streptopgramins, chloramphenicol, tiamiphenicylline and tiamphenicolins monomycin, antimicobacterials, antifungals, antiluetics, antiamebics, antimalarials, antitripanosomiasics, antibilharziosics, local pesticides
p) coagulanti e anticoagulanti p) coagulants and anticoagulants
q) antianemici e anemizzanti; piastrinogenetici e piastrinopenizzanti q) anti-anemic and anemic; platelet-genetics and platelet-suppressants
r) vasocostrittori, antiipertensivi-ipotensivi r) vasoconstrictors, antihypertensive-hypotensive
s) cardiotrofici, stimolanti il cuore come ad esempio digitalici, canforici, xantine metilate, adrenalinici, antiaritmici s) cardiotrophic, heart stimulants such as digitalis, camphorics, methylated xanthines, adrenaline, antiarrhythmic
t) diuretici e antidiuretici t) diuretics and antidiuretics
u) sostanze organiche ed inorganiche utilizzate come traccianti nella diagnostica e nella terapia con mezzi fisici, quali a titolo esemplificativo raggi x,onde magnetiche, ultrasuoni, pet, ecc. u) organic and inorganic substances used as tracers in diagnostics and therapy with physical means, such as x-rays, magnetic waves, ultrasounds, pet, etc.
v) immunostimolatori, immunosoppressori ed immuno modulatori. v) immunostimulators, immunosuppressants and immuno modulators.
La concentrazione degli ulteriori uno o più principi attivi nella composizione potranno essere facilmente stabilite dagli esperti del settore sulla base delle concentrazioni normalmente utilizzate. The concentration of the additional one or more active ingredients in the composition can be easily established by experts in the field on the basis of the concentrations normally used.
Le composizioni farmaceuticamente possono essere somministrate per via orale, parenterale, endovenosa, aerosol, rettale, transdermica, sottocutanea, intracisternale, intramuscolare, vaginale, intraperitoneale, topica, perlinguale e intranasale e secondo tutte le vie di somministrazione note al tecnico del settore ed idonee ai fini della presente invenzione. The compositions can be pharmaceutically administered orally, parenteral, intravenous, aerosol, rectal, transdermal, subcutaneous, intracisternal, intramuscular, vaginal, intraperitoneal, topical, perlingual and intranasal and according to all the routes of administration known to the skilled in the art and suitable for purposes of the present invention.
Le composizioni per somministrazione orale possono prendere la forma di soluzioni o sospensioni liquide o polveri. Le composizioni potranno essere presentate in forma di dosaggio unitario in modo da facilitare il dosaggio. The compositions for oral administration can take the form of liquid or powder solutions or suspensions. The compositions may be presented in unit dosage form in order to facilitate the dosage.
Il termine "forma di dosaggio unitario" si riferisce ad un’unità fisica discreta idonea a dosaggi unitari per soggetti umani, ciascuna dose unitaria contenendo una quantità di materiale attivo predeterminata calcolata per produrre l’effetto terapeutico desiderato, in associazione con un eccipiente farmaceutico idoneo. Tipiche forme di dosaggio unitario includono fiale o siringhe, della composizione liquida, o pillole, compresse, capsule o simili nel caso di composizioni solide e cerotti trans. The term "unit dosage form" refers to a discrete physical unit suitable for unit dosages for human subjects, each unit dose containing a predetermined amount of active material calculated to produce the desired therapeutic effect, in association with an excipient suitable pharmaceutical. Typical unit dosage forms include vials or syringes, of the liquid composition, or pills, tablets, capsules or the like in the case of solid compositions and trans patches.
Forme liquide idonee alla somministrazione orale includono, ma non sono limitate a, emulsioni, gel, microemulsioni, soluzioni, sospensioni, sciroppi ed elisir farmaceuticamente accettabili e potranno contenere diluenti comunemente utilizzati nello stato della tecnica. Le forme liquide orali possono quindi includere un idoneo veicolo acquoso o non acquoso con tamponi, agenti sospendenti e disperdenti, emulsionanti, solventi, coloranti, aromi e simili. Liquid forms suitable for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, gels, microemulsions, solutions, suspensions, syrups and elixirs and may contain diluents commonly used in the state of the art. The oral liquid forms may therefore include a suitable aqueous or non-aqueous vehicle with buffers, suspending and dispersing agents, emulsifiers, solvents, dyes, flavors and the like.
Ad esempio, potranno includere acqua o altri solventi, agenti solubilizzanti ed emulsionanti quali alcol etilico, alcol isopropilico, etil carbonato, etil acetato, alcol benzilico, benzil benzoato, propilenglicole, 1,3-butilenglicole, dimetilformammide, oli (in particolare oli di semi di cotone, di noci di terra, di mais, di germe, di olive di casto e di sesamo), glicerolo, alcol tetraidrofurfurilico, polietilenglicoli ed esteri di acidi grassi di sorbitano e loro miscele. Oltre a diluenti inerti, le composizioni orali potranno includere anche adiuvanti come agenti umettanti, agenti emulsionanti e sospendenti, agenti dolcificanti, aromatizzanti e profumanti. For example, they may include water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially seed oils of cotton, earthen nuts, corn, germ, chaste and sesame olives), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and esters of sorbitan fatty acids and their mixtures. In addition to inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
Le forme liquide potranno essere anche preparazioni iniettabili, ad esempio, sospensioni acquose o oleaginose sterili iniettabili e potranno essere formulate secondo la tecnica nota utilizzando agenti disperdenti, umettanti e sospendenti idonei. Le preparazioni iniettabili sterili potranno essere anche una soluzione, sospensione o emulsione sterile iniettabile in un diluente o solvente parenteralmente accettabile atossico, ad esempio, come soluzione in 1,3-butandiolo. Tra i veicoli e solventi accettabili che possono essere utilizzati vi sono acqua, soluzione di Ringer, U.S.P. e soluzione di cloruro di sodio isotonica. Inoltre, sono convenzionalmente utilizzati come mezzi solventi o di sospensione oli fissati sterili. Inoltre, acidi grassi come l’acido oleico sono utilizzati nelle preparazioni iniettabili. The liquid forms may also be injectable preparations, for example, sterile injectable aqueous or oil-based suspensions and may be formulated according to the known art using suitable dispersing, wetting and suspending agents. The sterile injectable preparations may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Acceptable carriers and solvents that may be used include water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvent or suspension media. In addition, fatty acids such as oleic acid are used in injectable preparations.
Potranno anche essere presenti conservanti ed altri additivi quali antimicrobici, antiossidanti, agenti chelanti e gas inerti (Mack (1982) Remington's Pharmaceutical Sciences, 16ma Edizione). Preservatives and other additives such as antimicrobials, antioxidants, chelating agents and inert gases may also be present (Mack (1982) Remington's Pharmaceutical Sciences, 16th Edition).
Le formulazioni iniettabili potranno essere sterilizzate, ad esempio, mediante filtrazione attraverso un filtro che trattiene i batteri o incorporando agenti sterilizzanti sotto forma di composizioni sterili solide che possono essere sciolte o disperse in acqua sterile o altri mezzi sterili iniettabili prima dell’uso. The injectable formulations can be sterilized, for example, by filtration through a filter that retains bacteria or by incorporating sterilizing agents in the form of solid sterile compositions that can be dissolved or dispersed in sterile water or other sterile injectable media before use.
Forme iniettabili a rilascio rallentato si possono realizzare anche formando matrici microincapsulate del o dei principi attivi in polimeri biodegradabili quali polilattide-poliglicolide. Secondo il rapporto principio/i attivo/i-polimero e secondo la natura del particolare polimero impiegato, la velocità di rilascio può essere controllata. Esempi di altri polimeri biodegradabili includono poli(ortoesteri) e poli(anidridi). Formulazioni a rilascio rallentato iniettabili si possono preparare anche intrappolando il o i principi attivi in liposomi o microemulsioni compatibili con tessuti corporei. Slow-release injectable forms can also be achieved by forming microencapsulated matrices of the active ingredient (s) in biodegradable polymers such as polylactide-polyglycolide. According to the active principle / s / polymer ratio and according to the nature of the particular polymer used, the release speed can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Injectable slow-release formulations can also be prepared by trapping the active ingredient (s) in liposomes or microemulsions compatible with body tissues.
Formulazioni semiliquide (cerose). Le composizioni per somministrazione rettale o vaginale sono preferibilmente supposte che possono essere preparate mischiando i composti di questa invenzione con eccipienti o veicolanti non irritanti idonei quali burro di cacao, polietilene glicole o una cera per supposte che à ̈ solida a temperatura ambiente ma liquida a temperatura corporea e si scioglie quindi nel retto o nella cavità vaginale rilasciando il composto attivo. Semi-liquid (waxy) formulations. The compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which is solid at room temperature but liquid at temperature. body and then dissolves in the rectum or vaginal cavity releasing the active compound.
Forme di dosaggio solido per somministrazione orale includono capsule, compresse, pillole polveri e granuli. In tali forme solide il o i principi attivi sono miscelati con almeno un eccipiente o veicolante inerte farmaceuticamente accettabile come, ad esempio citrato di sodio o di calcio fosfato e/o riempitivi o estensivi (quali amidi, lattosio, saccarosio, glucosio, mannitolo, e acido silicico) leganti; (quali, ad esempio, carbossimetilcellulosa, alginati, gelatina, polivinilpirrolidone, saccarosio); umettanti (es, glicerolo); agenti disintegranti (quali agar-agar, carbonato di calcio, amido di patate o tapioca, acido alginico, certi silicati e carbonato di sodio); agenti ritardanti (es. paraffina) acceleratori di assorbimento (quali composti di ammonio quaternario); agenti umidificanti (quali, ad esempio, acido cetilico e monostearato di glicerolo); assorbenti (quali caolino e argilla di bentonite); lubrificanti (quali talco, stearato di calcio, stearato di magnesio, polietilenglicoli solidi, sodio laurilsolfato) e loro miscele. Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid forms, the active ingredient (s) are mixed with at least one pharmaceutically acceptable inert excipient or carrier such as, for example, sodium citrate or calcium phosphate and / or fillers or extenders (such as starches, lactose, sucrose, glucose, mannitol, and acid silica) binders; (such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose); humectants (eg, glycerol); disintegrating agents (such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate); retarding agents (eg paraffin) absorption accelerators (such as quaternary ammonium compounds); wetting agents (such as, for example, cetyl acid and glycerol monostearate); absorbents (such as kaolin and bentonite clay); lubricants (such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate) and their mixtures.
Nel caso di capsule, compresse e pillole, la forma di dosaggio potrà comprendere anche agenti tamponanti. In the case of capsules, tablets and pills, the dosage form may also include buffering agents.
Le composizioni solide come sopra indicate possono essere anche impiegate per riempire capsule di gelatina rigida o morbida utilizzando eccipienti come lattosio o zucchero di latte come anche polietilenglicoli di alto peso molecolare e simili. Le forme a dosaggio solido di compresse, confetti, capsule, pillole, e granuli si possono preparare con rivestimenti quali rivestimenti enterici ed altri agenti di rivestimento noti nella tecnica delle formulazioni farmaceutiche. Potranno opzionalmente essere formulate in modo da rilasciare l’ingrediente attivo o gli ingredienti attivi solamente o preferenzialmente in certe parti del tratto intestinale, opzionalmente in maniera ritardata. The solid compositions as indicated above can also be used to fill hard or soft gelatin capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings such as enteric coatings and other coating agents known in the art of pharmaceutical formulations. They can optionally be formulated to release the active ingredient or ingredients only or preferentially in certain parts of the intestinal tract, optionally in a delayed manner.
Le composizioni della presente invenzione potranno essere formulate anche per somministrazione topica in forma di unguenti, paste, lozioni, gel, polveri, soluzioni, spray, inalanti, gocce oftalmiche o auricolari, o cerotti. Il componente attivo (o i componenti) à ̈ mescolato in condizioni sterili con un veicolante farmaceuticamente accettabile e qualsiasi conservante o tampone necessario secondo la necessità . The compositions of the present invention can also be formulated for topical administration in the form of ointments, pastes, lotions, gels, powders, solutions, sprays, inhalants, ophthalmic or ear drops, or patches. The active component (s) are mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers as needed.
I cerotti transdermici potranno essere utilizzati per fornire un rilascio controllato. Potranno anche essere utilizzati esaltatori di assorbimento per aumentare il flusso del composto attraverso la pelle. La velocità di rilascio potrà essere controllata fornendo una membrana a controllo di velocità o disperdendo il composto in una matrice polimerica o in un gel. Come indicato sopra quindi, la composizione comprendente l’ormone anti-mulleriano e/o una sua forma biologicamente attiva può ulteriormente contenere uno o più ulteriori principi attivi, può essere somministrata anche in forme a rilascio prolungato o con sistemi di somministrazione di farmaci a rilascio prolungato. Una descrizione di materiali per tale forma di realizzazione si può anche trovare nei materiali incorporati in Remington's Pharmaceutical Sciences. The transdermal patches can be used to provide controlled release. Absorption enhancers may also be used to increase the flow of the compound through the skin. The release rate can be controlled by providing a speed controlled membrane or by dispersing the compound into a polymer matrix or gel. As indicated above, therefore, the composition comprising the anti-Müllerian hormone and / or one of its biologically active form may further contain one or more further active ingredients, it can also be administered in prolonged-release forms or with drug delivery systems. prolonged release. A description of materials for such an embodiment can also be found in the materials incorporated into Remington's Pharmaceutical Sciences.
Le componenti sopra descritte per composizioni per somministrazione orale o iniettabili sono meramente rappresentative. Ulteriori materiali così come tecniche di processamento e simili sono mostrate nella parte 8 del Remington's Pharmaceutical Sciences, 17esima edizione, 1985, Marck Publishing Company, Easton, Pennsilvania, che à ̈ qui incorporato per riferimento. The components described above for compositions for oral or injectable administration are merely representative. Additional materials as well as processing techniques and the like are shown in part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Marck Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.
I componenti della composizioni come l’AMH e/o la sua forma biologicamente attiva e/o altri principi attivi presenti possono essere liofilizzati per la conservazione e ricostituiti in un veicolante idoneo prima dell’uso. Per questa forma di realizzazione possono essere utilizzate tecniche di liofilizzazione e ricostituzione note nello stato della tecnica. The components of the compositions such as AMH and / or its biologically active form and / or other active ingredients present can be freeze-dried for storage and reconstituted in a suitable carrier before use. For this embodiment, lyophilization and reconstitution techniques known in the state of the art can be used.
Per quanto osservato e dimostrato dagli inventori della presente invenzione relativamente all’efficacia dell’ormone anti-mulleriano nella eliminazione e/o riduzione delle lesione endometriosiche, l’AMH può essere anche utilizzato in un metodo per il trattamento e/o rallentamento dell’endometriosi comprendente il passaggio di: As observed and demonstrated by the inventors of the present invention regarding the efficacy of the anti-Müllerian hormone in the elimination and / or reduction of endometriotic lesions, AMH can also be used in a method for the treatment and / or slowing endometriosis including the passage of:
e) somministrare quantitativi efficaci di ormone anti-mulleriano o una composizione che lo comprende, come definito nella presente descrizione, ad un paziente che lo necessiti. e) administering effective amounts of anti-Müllerian hormone or a composition comprising it, as defined in the present disclosure, to a patient in need.
La presente invenzione comprende anche un kit farmaceutico per somministrazione concomitante o sequenziale delle diverse componenti comprese nella composizione farmaceutica, come sopra definite, e presenti nel kit in forma di aliquote. Quindi, a titolo esemplificativo quando la composizione comprende come principi attivi l’AMH e una sua forma biologicamente attiva, il kit può comprendere uno o più aliquote separate per detto AMH e di detta forma. Ciascuna aliquota del kit qui descritto potrà ulteriormente comprendere uno o più tra veicolanti farmaceuticamente accettabili, adiuvanti o veicoli che, come qui utilizzato, includono qualsiasi e tutti i solventi, diluenti o altri veicoli liquidi, ausili per dispersione o sospensione, agenti attivi in superficie, agenti isotonici, agenti addensanti o emulsionanti, conservanti, leganti solidi, lubrificanti e simili, come idonei per la particolare forma di dosaggio desiderata. The present invention also comprises a pharmaceutical kit for concomitant or sequential administration of the various components included in the pharmaceutical composition, as defined above, and present in the kit in the form of aliquots. Therefore, by way of example, when the composition includes AMH and a biologically active form thereof as active ingredients, the kit can comprise one or more separate aliquots for said AMH and said form. Each aliquot of the kit described herein may further comprise one or more of pharmaceutically acceptable carriers, adjuvants or vehicles which, as used herein, include any and all solvents, diluents or other liquid carriers, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suitable for the particular dosage form desired.
Il kit potrà essere formulato in modo da poter somministrare dette aliquote per uso orale, parenterale, endovenoso, aerosol, rettale, transdermico, sottocutaneo, intracisternale, intramuscolare, vaginale, intraperitoneale, topica, perlinguale e intranasale. The kit may be formulated so as to be able to administer said aliquots for oral, parenteral, intravenous, aerosol, rectal, transdermal, subcutaneous, intracisternal, intramuscular, vaginal, intraperitoneal, topical, perlingual and intranasal use.
Il kit farmaceutico come descritto potrà essere utilizzato nel trattamento e/o rallentamento dell’endometriosi in un soggetto. The pharmaceutical kit as described can be used in the treatment and / or slowdown of endometriosis in a subject.
La successiva sezione ha lo scopo di illustrare i dati ottenuti sull'ormone antimulleriano e le attività osservate su quest'ultimo ed ha quindi lo scopo di chiarire l’invenzione senza ovviamente essere limitativa della stessa. The following section has the purpose of illustrating the data obtained on the anti-Müllerian hormone and the activities observed on the latter and therefore has the purpose of clarifying the invention without obviously limiting it.
ESEMPI EXAMPLES
Esempio 1: efficacia dell’AMH nel bloccare la crescita delle cellule endometriosiche. Example 1: efficacy of AMH in blocking the growth of endometriotic cells.
Colture primarie di cellule endometriosiche immortalizzate sia della componente ghiandolare che di quella stromale, precedentemente definite e caratterizzate dal come descritto in Boccellino et al (Boccellino et al: In vitro model of stromal and epithelial immortalized endometriotic cells. Journal of Cellular Biochemistry, doi: 10.1002/jcb.24000. [Epub ahead of print])sono state utilizzate come modello cellulare in vitro per testare l’efficacia farmacologica dell’ormone anti-mulleriano. Primary cultures of endometriotic cells immortalized both of the glandular and stromal components, previously defined and characterized by the as described in Boccellino et al (Boccellino et al: In vitro model of stromal and epithelial immortalized endometriotic cells. Journal of Cellular Biochemistry, doi: 10.1002 /jcb.24000. [Epub ahead of print]) were used as an in vitro cell model to test the pharmacological efficacy of the anti-Müllerian hormone.
Le linee cellulari immortalizzate ESC Epiteliali e Stromali sono state risospese in mezzo di coltura DMEM/F12 arricchito con 10% di FBS (FetalSerum Bovine), 100 IU/ mL di penicillina, 100 µg/mL di streptomicina, 0,25 µg/mL di amfotericina e 200 mM di L-Glutammina. Sono state piastrate nelle fiasche T-25 della Corning in presenza di Puromicina (concentrazione finale 500 ng/mL) ed incubate a 37°C in una atmosfera di 5% CO2. Successivamente le linee cellulari sono state tripsinizzate e trasferite in multiwell da 6 pozzetti ad una densità di circa 100.000 cellule per pozzetto ed incubate a 37°C in una atmosfera di 5% CO2. Dopo 24 ore il m ezzo à ̈ stato aspirato, le cellule sono state lavate con PBS 1x sterile e solo tre pozzetti sono stati indotti con Recombinant Human MIS/AMH della R&D system, # di catalogo 1737-MS (ricostituito a 10 ug/ mL in PBS sterile contenente 0,1% BSA) per 72 ore a tre diverse concentrazioni finali (10-100-1000 ng). Dopo 24 ore, altri tre pozzetti sono stati indotti con Recombinant Human MIS/AMH alle tre differenti concentrazioni. Dopo altre 24 ore sono stati indotti ulteriori tre pozzetti con le stesse indicazioni. Al termine delle 72 ore, à ̈ stato aspirato il mezzo, le cellule sono state lavate con PBS 1x sterile, tripsinizzate, trasferite nei tubi specifici per la lettura al citofluorimetro FACS e centrifugate a 1000 rpm per 5 mina 4°C; il pellet o ttenuto à ̈ stato sottoposto all’analisi del ciclo cellulare e dell’apoptosi. Ogni pellet cellulare ottenuto dopo il trattamento con Recombinant Human MIS/AMH per 72, 48 e 24 ore a diverse concentrazioni à ̈ stato risospeso e lisato in circa 500 µL di Buffer ipotonico (contenente Na citrato 0,1%, NP-40 0,1%, Propidio ioduro (PI) 50 µg/mL). Le cellule sono state incubate al buio e a temperatura ambiente per circa 30 minuti. Successivamente, si à ̈ proceduto con l’acquisizione dei campioni al citofluorimetro FACS-Calibur usando il software Cell Quest (Becton Dickinson). I campioni sono stati analizzati con le procedure standard usando i software Cell Quest e il ModFit versione 3 (Verity). Immortalized ESC Epithelial and Stromal cell lines were resuspended in DMEM / F12 culture medium enriched with 10% FBS (FetalSerum Bovine), 100 IU / mL penicillin, 100 µg / mL streptomycin, 0.25 µg / mL of amphotericin and 200 mM of L-Glutamine. They were plated in Corning T-25 flasks in the presence of Puromycin (final concentration 500 ng / mL) and incubated at 37 ° C in an atmosphere of 5% CO2. The cell lines were then trypsinized and transferred to 6-well multiwells at a density of approximately 100,000 cells per well and incubated at 37 ° C in an atmosphere of 5% CO2. After 24 hours the medium was aspirated, the cells were washed with sterile 1x PBS and only three wells were induced with the R&D system Recombinant Human MIS / AMH, catalog # 1737-MS (reconstituted at 10 ug / mL in sterile PBS containing 0.1% BSA) for 72 hours at three different final concentrations (10-100-1000 ng). After 24 hours, three more wells were induced with Recombinant Human MIS / AMH at the three different concentrations. After a further 24 hours, a further three wells were induced with the same indications. At the end of 72 hours, the medium was aspirated, the cells were washed with sterile 1x PBS, trypsinized, transferred to the specific tubes for reading on the FACS flow cytometer and centrifuged at 1000 rpm for 5 min 4 ° C; the pellet or content was subjected to cell cycle and apoptosis analysis. Each cell pellet obtained after treatment with Recombinant Human MIS / AMH for 72, 48 and 24 hours at different concentrations was resuspended and lysed in approximately 500 µL of Hypotonic Buffer (containing 0.1% Na citrate, NP-40 0, 1%, Propidium iodide (PI) 50 µg / mL). The cells were incubated in the dark and at room temperature for approximately 30 minutes. Subsequently, we proceeded with the acquisition of the samples on the FACS-Calibur flow cytometer using the Cell Quest software (Becton Dickinson). Samples were analyzed with standard procedures using Cell Quest software and ModFit version 3 (Verity).
Come evidente dalla figura 1, indipendentemente dalla concentrazioni di AMH, utilizzato, il trattamento causa a 48 ore un significativo blocco del ciclo cellulare in G1 con conseguente diminuzione della fase S; tale blocco diventa poi significativamente a carico di G2 a 48 ore, con una conseguente diminuzione della fase S. As evident from figure 1, regardless of the AMH concentration used, the treatment causes a significant block of the cell cycle in G1 at 48 hours with a consequent decrease in the S phase; this block then becomes significantly dependent on G2 at 48 hours, with a consequent decrease in the S phase.
Inoltre, l’analisi dell'entità dell'apoptosi in tali cellule, ha dimostrato come evidente nella in figura 2, che il numero di cellule apoptotiche aumenta rispetto al controllo già a partire dalle 24 ore, raggiungendo i valori più elevati a 72 ore per il trattamento con 1000 ng/mL. Furthermore, the analysis of the extent of apoptosis in these cells has shown, as evident in figure 2, that the number of apoptotic cells increases compared to the control already starting from 24 hours, reaching the highest values at 72 hours. for treatment with 1000 ng / mL.
Esempio 2: espressione del gene MISRII, recettore dell'AMH, nelle cellule endometriosiche. Example 2: expression of the MISRII gene, AMH receptor, in endometriotic cells.
Dalla linea ESC Epiteliale ed ESC Stromale à ̈ stato estratto l’RNA totale usando il reagente Trizol secondo il protocollo Invitrogen. L’RNA ottenuto à ̈ stato retrotrascrittonel DNA complementare (cDNA) usando il kitSuperScript Vilo (Invitrogen) secondo le istruzioni del produttore. Il cDNA risultante assieme ai primers sintetizzati MISRII (1) e (2) à ̈ stato analizzato attraverso PCR. Total RNA was extracted from the Epithelial ESC and Stromal ESC lines using the Trizol reagent according to the Invitrogen protocol. The obtained RNA was reverse transcribed into complementary DNA (cDNA) using the SuperScript Vilo kit (Invitrogen) according to the manufacturer's instructions. The resulting cDNA together with the MISRII synthesized primers (1) and (2) were analyzed by PCR.
La reazione di PCR Ã ̈ avvenuta secondo il protocollo EuroClone (EuroTaq; 100 mMdATP- dTTP- dCTP- dGTP ; 10x Reaction Buffer Magnesium Free; 50 mM MgCl2; 10 µM Oligont Reverse eForward) alle condizioni: The PCR reaction took place according to the EuroClone protocol (EuroTaq; 100 mMdATP- dTTP- dCTP- dGTP; 10x Reaction Buffer Magnesium Free; 50 mM MgCl2; 10 µM Oligont Reverse eForward) under the following conditions:
1) 94°C per 10min; 94°C per 30 sec; 59°C per 30 sec ; 72°C per 30 sec; ripetuto per 35 cicli. 1) 94 ° C for 10min; 94 ° C for 30 sec; 59 ° C for 30 sec; 72 ° C for 30 sec; repeated for 35 cycles.
2) 94°C per 10min; 94°C per 30 sec; 62°C per 30 sec ; 72°C per 30 sec; ripetuto per 40 cicli 2) 94 ° C for 10min; 94 ° C for 30 sec; 62 ° C for 30 sec; 72 ° C for 30 sec; repeated for 40 cycles
I prodotti di PCR sono stati successivamente visualizzati mediante corsa elettroforetica su gel d’agarosio all’1% contenente bromuro di etidio. The PCR products were subsequently visualized by electrophoretic run on 1% agarose gel containing ethidium bromide.
I primers sono stati disegnati usando il software Primer3Plus. Le sequenze sono le seguenti: The primers were designed using Primer3Plus software. The sequences are as follows:
per il recettore MISRII (1) Forward-5’CCC TGC TAC AGC GAA AGA AC 3’; Reverse-5’ATG GCA ACC AGT TTT CCT TG 3’. Per il recettore MISRII(2)Forward- 5’AAC TGG CCT ATG AGG CAG AA 3’; Reverse- 5’GGT CTG CAT CCC AAC AGT CT 3’. Per il gene GAPDH Forward- 5’GGT GTC AAC GGA TTT GGT CG 3’; Reverse- 5’CTT CCC GTT CTC AGC CTT GA 3’. for the MISRII receptor (1) Forward-5â € ™ CCC TGC TAC AGC GAA AGA AC 3â € ™; Reverse-5â € ™ ATG GCA ACC AGT TTT CCT TG 3â € ™. For the MISRII receptor (2) Forward- 5â € ™ AAC TGG CCT ATG AGG CAG AA 3â € ™; Reverse- 5â € ™ GGT CTG CAT CCC AAC AGT CT 3â € ™. For the GAPDH Forward gene - 5â € ™ GGT GTC AAC GGA TTT GGT CG 3â € ™; Reverse- 5â € ™ CTT CCC GTT CTC AGC CTT GA 3â € ™.
In figura 3 Ã ̈ riportata la visualizzazione su gel d'agarosio dei prodotti di amplificazione genica per MISRII e per GAPDH, usato come controllo, in cellule endometriosiche Figure 3 shows the visualization on agarose gel of the gene amplification products for MISRII and for GAPDH, used as control, in endometriotic cells
BIBLIOGRAFIA BIBLIOGRAPHY
1. Giudice LC , and Kao LC: Endometriosis. The Lancet, 364: 1789-1799, 2004. 1. Judge LC, and Kao LC: Endometriosis. The Lancet, 364: 1789-1799, 2004.
2. Houston DE: Evidence for the risk of pelvic endometriosis by age, race, and socioeconomic status. Epidemiol Rev, 6: 167-191, 1984. 2. Houston DE: Evidence for the risk of pelvic endometriosis by age, race, and socioeconomic status. Epidemiol Rev, 6: 167-191, 1984.
3. Von Rokitansky C: Ueber uterusdrusen-neubildung in uterus and ovarilsarcomen. Z Ges Aertze Wein, 37: 577-593, 1860. 3. Von Rokitansky C: Ueber uterusdrusen-neubildung in uterus and ovarilsarcomen. Z Ges Aertze Wein, 37: 577-593, 1860.
4. La Marca A et al.: Anti-Mullerian hormone (AMH): what do we still need to know? Hum Reproduct, 24: 2264-2275, 2009. 4. La Marca A et al .: Anti-Mullerian hormone (AMH): what do we still need to know? Hum Reproduct, 24: 2264-2275, 2009.
5. Lee MM et al.: Mullerian inhibiting substance in humans: normal levels from infancy to adulthood. J Clin Endocrinol Metab, 81: 571-576, 1996. 5. Lee MM et al .: Mullerian inhibiting substance in humans: normal levels from infancy to adulthood. J Clin Endocrinol Metab, 81: 571-576, 1996.
6. La Marca A., Volpe A: The anti-Mullerian Hormone and ovarian cancer. Hum Reproduct., 13: 265-273, 2007. 6. La Marca A., Volpe A: The anti-Mullerian Hormone and ovarian cancer. Hum Reproduct., 13: 265-273, 2007.
7. Masiakos PT, MacLaughlin DT, Maheswaran S, Teixeira J, Fuller AF Jr, Shah PC, et al. Human ovarian cancer, cell lines, and primary ascites cells express the human Mullerian inhibiting substance (MIS) type II receptor, bind, and are responsive to MIS. Clin Cancer Res 1999; 5: 3488-99 7. Masiakos PT, MacLaughlin DT, Maheswaran S, Teixeira J, Fuller AF Jr, Shah PC, et al. Human ovarian cancer, cell lines, and primary ascites cells express the human Mullerian inhibiting substance (MIS) type II receptor, bind, and are responsive to MIS. Clin Cancer Res 1999; 5: 3488-99
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DATABASE EMBASE [online] ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL; November 2009 (2009-11-01), SHEBL O ET AL: "Anti muellerian hormone serum levels in women with endometriosis: A case-control study", XP002688432, Database accession no. EMB-2009560016 * |
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