IT202000029459A1 - THERAPY OF EMOTIONAL DISORDERS - Google Patents
THERAPY OF EMOTIONAL DISORDERS Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
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- C07K2317/00—Immunoglobulins specific features
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Description
Domanda di Brevetto per invenzione industriale dal titolo Patent application for industrial invention entitled
TERAPIA DEI DISTURBI EMOTIVI THERAPY OF EMOTIONAL DISORDERS
DESCRIZIONE DESCRIPTION
CAMPO DELL?INVENZIONE FIELD OF THE INVENTION
La presente invenzione si riferisce al campo dei farmaci per la terapia dei disturbi emotivi. The present invention relates to the field of drugs for the therapy of emotional disorders.
STATO DELL?ARTE STATE OF ART
I disturbi emotivi rappresentano una frequente patologia psichiatrica che interessa pazienti sia in et? adulta che evolutiva. I pi? frequenti disturbi emotivi sono rappresentati dai disturbi d'ansia, stati depressivi, attacchi di panico, disturbi del sonno, disturbi ossessivi-compulsivi, fobie, disturbi da stress postraumatico, disturbi somatoformi, disturbi dell?alimentazione inclusa l?anoressia nervosa. Tra i disturbi emotivi si annoverano anche quelle condizioni di anticipazione dello stress quali l?aversione a determinate condizioni che causano malessere o pericolo per l?individuo. Un classico esempio di disturbo emotivo anticipatorio ? l?ansia da prestazione o la nausea nei soggetti che dovranno sottoporsi a chemioterapia. Dato il grave impatto sociale di questi disturbi e la loro condizione di cronicit?, sono stati compiuti molti studi volti ad identificarne le cause neurobiologiche e neurochimiche. Oggi sappiamo che la patogenesi dei disturbi emotivi ? estremamente complessa e coinvolge numerosi distretti del sistema nervoso centrale cos? come altrettanto numerose vie neurotrasmettitoriali. Tra queste ultime rivestono un ruolo fondamentale le vie serotoninergiche, noradrenergiche, dopaminergiche e gabaergiche. In linea con questi dati neurochimici, farmaci in grado di modificare le funzioni dei neurotrasmettitori sopra menzionati hanno una indubbia efficacia nei disturbi emotivi e rappresentano oggi un validissimo strumento di terapia. Purtroppo, per?, i pazienti che beneficiano di tali farmaci molto spesso vanno in contro ad una perdita di efficacia nel tempo. Esistono poi pazienti con disturbi emotivi che o non risultano sensibili all?azione dei farmaci attualmente disponibili o non possono assumerli a causa di controindicazioni assolute o relative. Emotional disturbances are a frequent psychiatric pathology affecting patients in both age and adult and developmental. The most? frequent emotional disorders are represented by anxiety disorders, depressive states, panic attacks, sleep disorders, obsessive-compulsive disorders, phobias, post-traumatic stress disorders, somatoform disorders, eating disorders including anorexia nervosa. Emotional disorders also include those conditions of anticipation of stress such as aversion to certain conditions that cause discomfort or danger for the individual. A classic example of anticipatory emotional disorder? performance anxiety or nausea in people who will have to undergo chemotherapy. Given the serious social impact of these disorders and their chronic condition, many studies have been carried out to identify the neurobiological and neurochemical causes. Today we know that the pathogenesis of emotional disorders ? extremely complex and involves numerous districts of the central nervous system as well as as well as numerous neurotransmitter pathways. Among the latter, the serotonergic, noradrenergic, dopaminergic and gabaergic pathways play a fundamental role. In line with these neurochemical data, drugs capable of modifying the functions of the neurotransmitters mentioned above have undoubted efficacy in emotional disorders and today represent a very valid therapeutic tool. Unfortunately, however, patients who benefit from these drugs very often experience a loss of efficacy over time. There are also patients with emotional disorders who either are not sensitive to the action of currently available drugs or cannot take them due to absolute or relative contraindications.
Il problema da risolvere ? pertanto quello di identificare nuovi farmaci per i disturbi emotivi con meccanismo di azione innovativo e ottimo profilo di tollerabilit?. The problem to solve? therefore that of identifying new drugs for emotional disorders with an innovative mechanism of action and an excellent tolerability profile.
Un campo in larga parte inesplorato neH?ambito della neurochimica dei disturbi emotivi ? quello dei neuropeptidi. Si tratta di molecole di natura proteica di piccole dimensioni (in genere 10-40 aminoacidi) che svolgono una miriade di funzioni neuronali e neuroendocrine. Tipicamente i neuropeptidi vengono rilasciati dalla presinapsi attraverso il classico apparato vescicolare ma, a differenza dei neurotrasmettitori tipo acetilcolina, sertonina o noradrenalina, non danno vita ad una segnalazione postsinaptica ultraveloce. Al contrario, una volta rilasciati nello spazio intersinaptico i neuropeptidi attivano vie di segnalazione che presentano cinetiche di disattivazione medio-lunghe e che spesso portano a modificazioni significative del profilo di espressione genica nei neuroni che esprimono i recettori relativi. Alto importate aspetto che caratterizza la neurotrasmissione peptidergica ? la capacit? di quest?ultima di interessare neuroni a significativa distanza dalla sede di rilascio determinando pertanto quella che viene definita ?volume transmission?. Nel complesso quindi i neurotrasmettitori sostengono vie di segnalazione che durano pi? a lungo e si estendono in aree pi? ampie rispetto ai classici neurotrasmettitori veloci. Tra le varie implicazioni neurobiologiche ne deriva che la trasmissione peptidergica riveste un ruolo chiave ne regolare uno stato di attivazione/inibizione di alcuni circuiti neuronali che saranno poi sottoposti ad una pi? veloce e fasica regolazione da parte dei trasmettitori veloci. Tale funzione suggerisce che la neurotrasmissione peptidergica svolge un ruolo chiave nella regolazione degli stati emotivi. A largely unexplored field in the neurochemistry of emotional disorders is that of neuropeptides. These are small protein molecules (generally 10-40 amino acids) that perform a myriad of neuronal and neuroendocrine functions. Typically, neuropeptides are released from the presynaptic via the classic vesicular apparatus but, unlike neurotransmitters such as acetylcholine, sertonin or norepinephrine, they do not initiate ultrafast postsynaptic signaling. Conversely, once released into the intersynaptic space, neuropeptides activate signaling pathways that exhibit medium-long deactivation kinetics and often lead to significant modifications of the gene expression profile in neurons expressing the related receptors. Another important aspect that characterizes peptidergic neurotransmission? the capacity? of the latter to affect neurons at a significant distance from the site of release thus determining what is defined as ?volume transmission?. Overall, therefore, neurotransmitters support signaling pathways that last longer. long and extend into areas pi? large compared to the classic fast neurotransmitters. Among the various neurobiological implications it follows that the peptidergic transmission plays a key role in regulating a state of activation / inhibition of some neuronal circuits which will then be subjected to a more? fast and phasic regulation by fast transmitters. This function suggests that peptidergic neurotransmission plays a key role in the regulation of emotional states.
Tra i vari neuropeptidi che recentemente sono stati oggetto di notevoli studi si annovera il peptide correlato al gene della calcitonina (calcitonin gene related peptide, CGRP). Si tratta di un peptide di 37 aa che svolge ruoli non ancora ben identificati sia nel sistema nervoso centrale che periferico. Per quanto riguarda le funzioni del CGRP nel sistema nervoso centrale ? importante sottolineare che, sebbene il peptide si ampiamente rappresentato nelle varie arre cerebrali, al momento sussistono ancora numerose incertezze circa le sue funzioni neurotrasmettitoriali. Esistono per? degli studi sperimentali nel topo che dimostrano un ruolo chiave del CGRP nel regolare le funzioni emotive quali le risposte allo stress e agli stimoli aversivi. In particolare ? stato dimostrato grazie all?utilizzo di moderne tecniche con vettori virali che il rilascio di CGRP in specifici nuclei dell?amigdala promuove l?aversione al cibo, lo stress, la paura e la memoria del pericolo (Trends Neurosci. 2018;41:280-293). Al momento per? non sono noti farmaci in grado di modulare le funzioni centrali del CGRP e pertanto non ? possibile contrastare i suoi effetti di promozione e mantenimento delle patologie sopra elencate. Among the various neuropeptides that have recently been the subject of considerable study is the calcitonin gene related peptide (CGRP). It is a 37 aa peptide that plays as yet unidentified roles in both the central and peripheral nervous systems. What about the functions of CGRP in the central nervous system? It is important to underline that, although the peptide is widely represented in the various brain areas, at the moment there are still many uncertainties about its neurotransmitter functions. Do they exist for? of experimental studies in mice demonstrating a key role of CGRP in regulating emotional functions such as responses to stress and aversive stimuli. Particularly ? Thanks to the use of modern techniques with viral vectors, it has been demonstrated that the release of CGRP in specific nuclei of the amygdala promotes food aversion, stress, fear and memory of danger (Trends Neurosci. 2018;41:280- 293). At the moment for? are not known drugs capable of modulating the central functions of the CGRP and therefore not? possible to counteract its effects of promotion and maintenance of the pathologies listed above.
Recentemente sono stati sviluppati degli anticorpi monoclonali anti-CGRP quali fremanezumab, galcanezumab, eptinezumab e erenumab che hanno dimostrato efficacia nella terapia di profilassi dell?emicrania. A causa dell?impermeabilit? della barriera ematoencefalica agli anticorpi, l?azione antiemicranica degli anticorpi anti-CGRP ? stata ascritta alla loro azione periferica, in particolare alla capacit? di bloccare la nocicezione sostenuta dal CGRP a livello delle terminazioni trigeminovascolari delle meningi (Nat. Rev. Neurol. 2018;14:338-350; CNS Neurol. Disord. Drug. Targets. 2020;19:344-359). La letteratura insegna infatti che gli anticorpi anti-GCGRP non penetrano nel cervello dei roditori e che svolgono le loro azioni farmacodinamiche solo in periferia (J Neurosci. 2019;39:6001-6011; Cephalalgia 2020;40:229-240; Cephalalgia. 2020;40:924-934). Pertanto, l?esperto del settore non trova alcun insegnamento nello stato dell?arte che gli anticorpi anti-CGRP possano avere una azione a livello del sistema nervoso centrale. Allo stesso modo, l?esperto del settore non trova alcun insegnamento nello stato dell?arte che gli anticorpi anti-CGPR siano in grado di ridurre disturbi emotivi quali ansia, risposta allo stress, paure o aversione al cibo e disturbi dell?alimentazione. Il problema da risolvere ? pertanto quello di identificare molecole capaci di inibire le azioni del CGRP a livello del sistema nervoso centrale al fine di ottenere un rimedio farmacologico innovativo capace di ridurre lo stress, l?aversione al cibo, la paura e l?ansia negli individui che soffrono di disturbi emotivi. Anti-CGRP monoclonal antibodies such as fremanezumab, galcanezumab, eptinezumab and erenumab have recently been developed and have demonstrated efficacy in the prophylactic therapy of migraine. Because of? impermeabilit? of the blood brain barrier to antibodies, the antimigraine action of anti-CGRP antibodies ? been ascribed to their peripheral action, in particular to the capacity? to block the nociception supported by the CGRP at the level of the trigeminovascular endings of the meninges (Nat. Rev. Neurol. 2018;14:338-350; CNS Neurol. Disord. Drug. Targets. 2020;19:344-359). In fact, the literature teaches that anti-GCGRP antibodies do not penetrate the rodent brain and that they perform their pharmacodynamic actions only in the periphery (J Neurosci. 2019;39:6001-6011; Cephalalgia 2020;40:229-240; Cephalalgia. 2020 ;40:924-934). Therefore, the expert in the field does not find any teaching in the state of the art that the anti-CGRP antibodies can have an action at the level of the central nervous system. Similarly, the expert in the field finds no teaching in the state of the art that anti-CGPR antibodies are able to reduce emotional disorders such as anxiety, response to stress, fears or aversion to food and eating disorders. The problem to solve? therefore that of identifying molecules capable of inhibiting the actions of CGRP at the level of the central nervous system in order to obtain an innovative pharmacological remedy capable of reducing stress, food aversion, fear and anxiety in individuals suffering from emotional disorders .
DESCRIZIONE DELL?INVENZIONE DESCRIPTION OF THE INVENTION
Abbiamo ora inaspettatamente trovato che il trattamento sottocutaneo con anticorpi anti-CGRP fremanezumab, galcanezumab, eptinezumab ed erenumab causa una riduzione nel ratto e nel topo di comportamenti correlati ai vari disturbi emotivi. We have now unexpectedly found that subcutaneous treatment with anti-CGRP antibodies fremanezumab, galcanezumab, eptinezumab and erenumab causes a reduction in rats and mice of behaviors related to various emotional disturbances.
Nello specifico abbiamo inaspettatamente trovato che la somministrazione sottocutanea di fremanezumab galcanezumab, eptinezumab o erenumab alla dose di 30 mg/kg riduce l?aversione al cibo. Nello specifico abbiamo utilizzato un classico test di aversione al gusto cha si basa sulla induzione per tre giorni consecutivi (fase di training) di nausea tramite iniezione di LiCI subito dopo l?assunzione di acqua zuccherata. Questo protocollo causa aversione verso l?acqua zuccherata che si quantizza, dopo il training, valutando se il topo preferisce l?acqua normale o zuccherata quando gli viene data la possibilit? di scegliere. Come mostrato nella Figura 1, la somministrazione sottocute di fremanezumab, galcanezumab, eptinezumab e erenumab previene lo sviluppo dell?aversione all?acqua zuccherata. Specifically, we unexpectedly found that subcutaneous administration of fremanezumab galcanezumab, eptinezumab, or erenumab at a dose of 30 mg/kg reduced food aversion. Specifically, we used a classic taste aversion test based on the induction of nausea for three consecutive days (training phase) by injection of LiCI immediately after the intake of sugared water. This protocol causes aversion to sugar water which is quantified, after training, by assessing whether the rat prefers regular or sugar water when given the option. to choose. As shown in Figure 1, subcutaneous administration of fremanezumab, galcanezumab, eptinezumab, and erenumab prevented the development of aversion to sugar water.
Abbiamo inoltre inaspettatamente trovato che la somministrazione sottocutanea di fremanezumab, galcanezumab, eptinezumab ed erenumab nel topo riduce la risposta emotiva al pericolo in un modello di condizionamento alla paura. Nello specifico abbiamo misurato la risposta al pericolo e la memoria del pericolo valutando il tempo di immobilit? (freezing) in un classico modello di condizionamento alla paura. Gli animali sono stati esposti a una scossa elettrica di basso amperaggio (0.5 mA) per 2 secondi. Il giorno seguente l?animale ? stato reintrodotto nello stesso ambiente nel quale ha subito la scossa (senza riceverla nuovamente) e abbiamo valutato la risposta di freezing (immobilit?) come indice di memoria del pericolo indotto da un ambiente ostile. Come mostrato in Figura 2, la somministrazione sottocutanea di fremanezumab, galcanezumab, eptinezumab o erenumab riduce la durata del tempo di freezing, indice di una ridotta risposta emotiva al pericolo. We also unexpectedly found that subcutaneous administration of fremanezumab, galcanezumab, eptinezumab and erenumab in mice reduced the emotional response to danger in a fear conditioning model. Specifically, we measured the response to danger and the memory of danger by evaluating the time of immobility? (freezing) in a classic model of fear conditioning. The animals were exposed to a low amperage (0.5 mA) electric shock for 2 seconds. The following day the animal? was reintroduced in the same environment in which he was shocked (without receiving it again) and we evaluated the freezing response (immobile) as an index of memory of the danger induced by a hostile environment. As shown in Figure 2, subcutaneous administration of fremanezumab, galcanezumab, eptinezumab, or erenumab reduces the duration of freezing time, indicating a reduced emotional response to danger.
Abbiamo inoltre inaspettatamente trovato che la somministrazione sottocutanea di fremanezumab, galcanezumab, eptinezumab ed erenumab nel topo riduce la risposta di evitamento sociale in un modello sperimentale di disturbo da stress post-traumatico (PTSD). Nello specifico abbiamo misurato la tendenza all?interazione sociale con un topo aggressivo di riferimento (opponente) in topi stressati mediante precedente trattamento con ripetute scosse elettriche a basso voltaggio (0.5 mA). Come mostrato in Figura 3 la somministrazione sottocutanea di fremanezumab, galcanezumab, eptinezumab ed erenumab aumenta l?interazione sociale nei topi con disturbo da stress post-traumatico. We also unexpectedly found that subcutaneous administration of fremanezumab, galcanezumab, eptinezumab and erenumab to mice reduced the social avoidance response in an experimental model of post-traumatic stress disorder (PTSD). Specifically, we measured the tendency for social interaction with an aggressive reference mouse (opponent) in stressed mice by prior treatment with repeated low-voltage (0.5 mA) electric shocks. As shown in Figure 3, subcutaneous administration of fremanezumab, galcanezumab, eptinezumab, and erenumab increased social interaction in mice with PTSD.
Abbiamo inoltre inaspettatamente trovato che la somministrazione sottocutanea di fremanezumab, galcanezumab, eptinezumab ed erenumab nel topo riduce l?ansia post-traumatica. Nello specifico abbiamo utilizzato il classico test dell?ansia ?plus maze?, valutando quanto tempo i topi precedentemente stressati con ripetute scosse elettriche a basso voltaggio (0.5 mA) passano nei bracci non riparati (aperti) dell?apparato plus maze rispetto al tempo speso nei bracci riparati (chiusi). Come mostrato nella Figura 4, la somministrazione sottocutanea di fremanezumab, galcanezumab, eptinezumab e erenumab nei topi aumenta il tempo che questi ultimi passano nei bracci aperti del plus maze, classico indice di un effetto ansiolitico. We also unexpectedly found that subcutaneous administration of fremanezumab, galcanezumab, eptinezumab and erenumab in mice reduced post-traumatic anxiety. Specifically, we used the classic ?plus maze? anxiety test, evaluating how much time mice previously stressed with repeated low-voltage (0.5 mA) electric shocks spend in the unrepaired (open) arms of the plus maze apparatus compared to the time spent in the sheltered (closed) arms. As shown in Figure 4, subcutaneous administration of fremanezumab, galcanezumab, eptinezumab and erenumab to mice increases the time that the latter spend in the open arms of the plus maze, a classic index of an anxiolytic effect.
Secondo l'invenzione gli anticorpi anti-CGRP possono essere formulati e somministrati per via endovenosa, endoarteriosa, intramuscolare e sottocutanea. Le quantit? di principio attivo da somministrare sono quelle gi? comunemente impiegate per questo tipo di farmaci, ad esempio 10-3000 mg/die. According to the invention the anti-CGRP antibodies can be formulated and administered by the intravenous, intra-arterial, intramuscular and subcutaneous routes. The quantities? of the active ingredient to be administered are those already? commonly used for this type of drug, for example 10-3000 mg/day.
BREVE DESCRIZIONE DELLE FIGURE BRIEF DESCRIPTION OF THE FIGURES
Figura 1. Effetto di fremanezumab, galcanezumab, eptinezumab ed erenumab sull?aversione al gusto nel ratto come modello di anoressia. La figura mostra come i ratti con aversione indotta al sapore dolce (ottenuta associando la somministrazione di LiCI 120 mg/kg i.p. ogni volta che assumono l?acqua zuccherata) prediligano l?acqua non zuccherata. Tale aversione al dolce viene completamente revertita nei ratti che sono stati trattati con fremanezumab, galcanezumab, eptinezumab o erenumab (30 mg/kg sottocute) una settimana prima dell?induzione dell?aversione. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 vs Water, ANOVA and Tukeys post hoc test. Figure 1. Effect of fremanezumab, galcanezumab, eptinezumab and erenumab on taste aversion in the rat model of anorexia. The figure shows how rats with induced aversion to sweet tastes (obtained by associating the administration of LiCI 120 mg/kg i.p. every time they drink sugared water) prefer unsweetened water. This aversion to sweets was completely reversed in rats that were treated with fremanezumab, galcanezumab, eptinezumab, or erenumab (30 mg/kg subcutaneously) one week before induction of the aversion. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 vs Water, ANOVA and Tukeys post hoc test.
Figura 2. Effetto di fremanezumab, galcanezumab, eptinezumab ed erenumab sulla paura e memoria del pericolo. La figura mostra come i topi che subiscono una scossa (0.5 mA per 2 sec) alle zampe tramite apposita griglia elettrificata manifestano una risposta di freezing (somma cumulativa dei periodi di immobilit?) se dopo 24 ore vengono reintrodotti per 5 min sulla stessa griglia in assenza di stimolo elettrico, indice di paura e memoria del pericolo. Il pretrattamento di una settimana con fremanezumab, galcanezumab, eptinezumab o erenumab (30 mg/kg sottocute) riduce il tempo di freezing indice di una ridotta risposta emotiva al pericolo. *p<0.05, **p<0.01 vs Control, ANOVA and Tukeys post hoc test. Figure 2. Effect of fremanezumab, galcanezumab, eptinezumab and erenumab on fear and memory of danger. The figure shows how mice that receive a shock (0.5 mA for 2 sec) to their paws via a special electrified grid show a freezing response (cumulative sum of periods of immobility) if after 24 hours they are reintroduced for 5 min on the same grid in absence of electrical stimulus, index of fear and memory of danger. One week of pre-treatment with fremanezumab, galcanezumab, eptinezumab or erenumab (30 mg/kg subcutaneously) reduces freezing time indicative of a reduced emotional response to danger. *p<0.05, **p<0.01 vs Control, ANOVA and Tukeys post hoc test.
Figura 3. Effetto di fremanezumab, galcanezumab, eptinezumab ed erenumab sull?evitamento sociale in un modello di stress post-traumatico. La figura mostra la somma dei tempi che topi stressati 24 h prima con ripetute scosse elettriche a basso voltaggio (0.5 mA/2 sec due volte al minuto per 5 min) dedicano all?interazione con un nuovo topo (opponente) introdotto per 5 min nella gabbia. Il pretrattamento di una settimana con fremanezumab, galcanezumab, eptinezumab o erenumab (30 mg/kg sottocute) aumenta significativamente il tempo di interazione sociale dei topi. *p<0.05 vs Control, ANOVA and Tukeys post hoc test. Figure 3. Effect of fremanezumab, galcanezumab, eptinezumab and erenumab on social avoidance in a post-traumatic stress model. The figure shows the sum of the times that mice stressed 24 h previously with repeated low voltage electric shocks (0.5 mA/2 sec twice a minute for 5 min) spend interacting with a new (opponent) mouse introduced for 5 min into the cage. One-week pretreatment with fremanezumab, galcanezumab, eptinezumab, or erenumab (30 mg/kg subcutaneously) significantly increased the social interaction time of the mice. *p<0.05 vs Control, ANOVA and Tukeys post hoc test.
Figura 4. Effetto di fremanezumab, galcanezumab, eptinezumab ed erenumab nel plus-maze test come modello di ansia post-traumatica. La figura mostra come durante i 5 min del test i topi stressati 24 h prima con ripetute scosse elettriche a basso voltaggio (0.5 mA/2 sec due volte al minuto per 5 min) passino poco tempo ad esplorare i bracci aperti (non protetti da pareti) rispetto a quello impiegato per esplorare i bracci coperti (protetti da pareti) dell?apparato plus-maze test, indicando pertanto una condizione di ansia. Il pretrattamento di una settimana con fremanezumab, galcanezumab, eptinezumab o erenumab (30 mg/kg sottocute) aumenta significativamente il tempo che i topi impiegano ad esplorare i bracci aperti indicando pertanto un effetto ansiolitico. *p<0.05 vs Control, ANOVA and Tukeys post hoc test. Figure 4. Effect of fremanezumab, galcanezumab, eptinezumab and erenumab in the plus-maze test as a model of post-traumatic anxiety disorder. The figure shows how during the 5 min of the test the mice stressed 24 h previously with repeated low voltage electric shocks (0.5 mA/2 sec twice a minute for 5 min) spend little time exploring the open arms (not protected by walls ) than that used to explore the covered arms (protected by walls) of the plus-maze test apparatus, thus indicating a condition of anxiety. One week's pretreatment with fremanezumab, galcanezumab, eptinezumab or erenumab (30 mg/kg subcutaneously) significantly increased the time the mice spent exploring the open arms thereby indicating an anxiolytic effect. *p<0.05 vs Control, ANOVA and Tukeys post hoc test.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024057352A1 (en) * | 2022-09-14 | 2024-03-21 | Chiarugi Alberto | Cgrp receptor antagonists for treating chemotherapy-induced nausea and vomiting (cinv) |
| WO2024057351A1 (en) * | 2022-09-14 | 2024-03-21 | Chiarugi Alberto | Modulators of nausea and vomiting |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007054809A2 (en) * | 2005-11-14 | 2007-05-18 | Rinat Neuroscience Corp. | Antagonist antibodies directed against calcitonin gene-related peptide and methods using same |
| US20170342141A1 (en) * | 2011-05-20 | 2017-11-30 | Alderbio Holdings Llc | Use of anti-cgrp antibodies and antibody fragments to prevent or inhibit photophobia or light aversion in subjects in need thereof, especially migraine sufferers |
| WO2020150703A1 (en) * | 2019-01-20 | 2020-07-23 | Biohaven Pharmaceutical Holding Company Ltd. | Cgrp antagonists for treating migraine breakthrough |
| WO2021005494A1 (en) * | 2019-07-05 | 2021-01-14 | Allergan Pharmaceuticals International Limited | Cgrp antagonists and clostridial derivatives for the treatment of neuropsychiatric and neurological disorders |
-
2020
- 2020-12-03 IT IT102020000029459A patent/IT202000029459A1/en unknown
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007054809A2 (en) * | 2005-11-14 | 2007-05-18 | Rinat Neuroscience Corp. | Antagonist antibodies directed against calcitonin gene-related peptide and methods using same |
| US20170342141A1 (en) * | 2011-05-20 | 2017-11-30 | Alderbio Holdings Llc | Use of anti-cgrp antibodies and antibody fragments to prevent or inhibit photophobia or light aversion in subjects in need thereof, especially migraine sufferers |
| WO2020150703A1 (en) * | 2019-01-20 | 2020-07-23 | Biohaven Pharmaceutical Holding Company Ltd. | Cgrp antagonists for treating migraine breakthrough |
| WO2021005494A1 (en) * | 2019-07-05 | 2021-01-14 | Allergan Pharmaceuticals International Limited | Cgrp antagonists and clostridial derivatives for the treatment of neuropsychiatric and neurological disorders |
Non-Patent Citations (9)
| Title |
|---|
| CEPHALALGIA, vol. 40, 2020, pages 924 - 934 |
| CHEN JANE Y. ET AL: "Parabrachial CGRP Neurons Establish and Sustain Aversive Taste Memories", NEURON, vol. 100, no. 4, 1 November 2018 (2018-11-01), US, pages 891 - 899.e5, XP055831526, ISSN: 0896-6273, Retrieved from the Internet <URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6250580/pdf/nihms-1508479.pdf> DOI: 10.1016/j.neuron.2018.09.032 * |
| CNS NEUROL. DISORD. DRUG. TARGETS., vol. 19, 2020, pages 344 - 359 |
| HASHIKAWA-HOBARA NARUMI ET AL: "Calcitonin gene-related peptide pre-administration acts as a novel antidepressant in stressed mice", SCIENTIFIC REPORTS, NATURE PUBLISHING GROUP, US, vol. 5, 7 August 2015 (2015-08-07), pages 12559 - 14, XP009522656, ISSN: 2045-2322, DOI: 10.1038/SREP12559 * |
| J NEUROSCI., vol. 39, 2019, pages 6001 - 6011 |
| JAN LEWIS BRANDES ET AL: "Effects of fremanezumab on the use of acute headache medication and associated symptoms of migraine in patients with episodic migraine", CEPHALALGIA, vol. 40, no. 5, 21 November 2019 (2019-11-21), GB, pages 470 - 477, XP055759202, ISSN: 0333-1024, DOI: 10.1177/0333102419885905 * |
| NAT. REV. NEUROL., vol. 14, 2018, pages 338 - 350 |
| SINK K. S. ET AL: "Calcitonin Gene-Related Peptide in the Bed Nucleus of the Stria Terminalis Produces an Anxiety-Like Pattern of Behavior and Increases Neural Activation in Anxiety-Related Structures", THE JOURNAL OF NEUROSCIENCE, vol. 31, no. 5, 2 February 2011 (2011-02-02), US, pages 1802 - 1810, XP055827326, ISSN: 0270-6474, DOI: 10.1523/JNEUROSCI.5274-10.2011 * |
| TRENDS NEUROSCI., vol. 41, 2018, pages 280 - 293 |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024057352A1 (en) * | 2022-09-14 | 2024-03-21 | Chiarugi Alberto | Cgrp receptor antagonists for treating chemotherapy-induced nausea and vomiting (cinv) |
| WO2024057351A1 (en) * | 2022-09-14 | 2024-03-21 | Chiarugi Alberto | Modulators of nausea and vomiting |
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