Izazovi u liječenju migrene: nove terapijske mogućnosti s djelovanjem na sustav peptida povezanog s kalcitoninskim genom

master's thesis

• Title (english): Challenges in migraine therapy: new therapeutic possibilities with action on the calcitonin gene related peptide system
• Author: Ivana Duić
• Mentor: Lidija Bach-Rojecky (mentor)
• Committee member: Lidija Bach-Rojecky (predsjednik povjerenstva)
• Committee member: Višnja Drinovac (član povjerenstva)
• Committee member: Dubravka Vitali Čepo (član povjerenstva)
• Granter: University of Zagreb; Faculty of Pharmacy and Biochemistry; (Department of pharmacology); Zagreb
• Defense date and country: 2020-07-15, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Pharmacy; Pharmacy

Abstract

Migrena je kronični neurološki poremećaj koji se manifestira napadima umjerene ili jake glavobolje te reverzibilnim
neurološkim i sistemskim simptomima. Procjenjuje se da je ukupna prevalencija migrene u zapadnim zemljama 6-8%
kod muškaraca i 15-25% kod žena.
Patofiziologija migrene je kompleksna, te je i dalje predmet intenzivnih istraživanja. Prema trigeminovaskularnoj
teoriji, vazodilatacija ekstracerebralnih krvnih žila i neurogena upala dure najvažnije su patofiziološke značajke
migrenozne glavobolje.
Farmakološka terapija migrene tradicionalno se dijeli na akutnu i preventivnu. Akutno liječenje namijenjeno je
smanjenju boli i pridruženih simptoma migrene te onesposobljenja bolesnika tijekom samog napadaja. Preventivno
liječenje koristi se u svrhu smanjenja učestalosti i težine očekivanih napada u osoba s intenzivnim i čestim
glavoboljama.
Trenutno se akutni napadi migrene liječe neopioidnim analgeticima, triptanima (agonisti 5-HT1B/1D receptora) ili
nazalnim dihidroergotaminom. Međutim, glavni nedostaci ove terapije su neučinkovitost kod 20-30% pacijenata i
nuspojave. Preventivna terapija je nespecifična i uključuje empirijsku primjenu lijekova iz različitih
farmakoterapijskih skupina te ne postiže zadovoljavajuće učinke kod većine pacijenata.
Cilj ovog rada je dati pregled novih specifičnih lijekova za migrenu koji su razvijeni kako bi se postigla veća
učinkovitost te bolja podnošljivost i sigurnost u odnosu na dosadašnje terapijske opcije, a s konačnim ciljem povećanja
kvalitete života i olakšanja svakodnevnog funkcioniranja pacijenata s migrenom.
Intenzivna istraživanja patofiziologije migrene ukazala su na nove terapijske mete i mogućnost razvoja novih
generacija lijekova. Istraživanjem farmakologije serotonina razvili su se agonisti 5-HT1F receptora, a prvi u skupini
koji je odobren za akutnu migrenu je lasmiditan. Nadalje, rasvjetljavanje važne uloge CGRP sustava u migrenskoj
patofiziologiji dovelo je do razvoja antagonista CGRP receptora, tzv. gepanta i monoklonskih protutijela usmjerenih
na CGRP ligand ili CGRP receptor. Ubrogepant i rimegepant su prva dva odobrena antagonista receptora za akutnu
terapiju migrene, dok su monoklonska protutijela namijenjena uporabi u profilaktičkoj terapiji epizodične i kronične
migrene.

Abstract (english)

Migraine is a chronic neurological disorder that is characterized by an attack of moderate or severe headache and
reversible neurological and systemic symptoms. It is estimated that the overall prevalence of migraine in Western
countries is 6-8% in men and 15-25% in women.
The pathophysiology of migraine is complex and it is still the subject of intensive research. According to the
trigeminovascular theory, vasodilation of extracerebral blood vessels and neurogenic inflammation of the dura are the
most important pathophysiological features of migraine headaches.
Pharmacological therapy of migraine is traditionally divided into acute and preventive. Acute treatment aims to reduce
pain and accompanied symptoms, as well as the disability of patients during a migraine attack. Preventive treatment is
used to reduce the frequency and severity of expected attacks for people with intense and frequent headaches.
Currently, acute migraine attacks are treated with non-opioid analgesics, triptans (5-HT1B/1D receptor agonists), or
nasal dihydroergotamine. However, the main disadvantages of this therapy are ineffectiveness in 20-30% of patients
and side effects. Preventive therapy is non-specific and involves the empirical administration of drugs from different
pharmacotherapeutic groups and does not achieve satisfactory effects in most patients.
This diploma thesis gives an overview of new specific migraine drugs that are developed to achieve better efficiency
and better, tolerability, and safety compared to previous therapeutic options, with the final goal in increasing the
quality of life of patients suffering from migraine. Intensive research on the pathophysiology of migraine has
indicated new therapeutic targets and opportunities for the development of new generations of drugs. Based on the
understanding of serotonin system pharmacology, 5-HT1F receptor agonists were developed, and the first in class for
acute migraine treatment is lasmiditan. Furthermore, clarification of the important role of the CGRP system in
migraine pathophysiology has led to the development of CGRP receptor antagonists, the so-called gepants, and
monoclonal antibodies targeting the CGRP ligand or CGRP receptor. Ubrogepant and rimegepant were the first two
approved receptor antagonists for acute migraine therapy, while monoclonal antibodies are intended for use in the
prophylactic therapy of episodic and chronic migraine.

• Keywords: migrena; patofiziologija migrene; 5-HT1F receptor; CGRP receptor; serotonin; triptani; ditani; gepanti; monoklonska protutijela
• Keywords (english): migraine; pathophysiology of migraine; 5-HT1F receptor; CGRP receptor; serotonin; triptans; ditans; gepants; monoclonal antibodies
• Language: croatian
• URN:NBN: urn:nbn:hr:163:036537
• Study programme: Title: Pharmacy; Study programme type: university; Study level: integrated undergraduate and graduate; Academic / professional title: magistar/magistra farmacije (magistar/magistra farmacije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2021-04-27 12:44:44