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New Mollecules in Migraine Treatment FARMACIA, 2015, Vol. 63, 4 REVIEW NEW MOLLECULES IN MIGRAINE TREATMENT ADINA ROCEANU1, FLORINA ANTOCHI1*, OVIDIU BAJENARU1,2 1University Emergency Hospital Bucharest, Neurology Department 2“Carol Davila” University of Medicine and Pharmacy Bucharest, Romania *corresponding author: [email protected] Manuscript received: November 2014 Abstract In the 1990s, serotonin receptor agonist 5-HT1B/1D (the triptans) became available on the market for migraine treatment. Although the triptans are highly effective in aborting migraine attacks, the vasoconstrictor effect in cerebral and coronary territory limits their use. In the “post-triptans” era, new molecules, without vasoactive components are about to expand migraine treatment armamentarium, such as: serotonin 5-HT1F receptor agonists, calcitonin gene related peptide (CGRP) receptor antagonists (olcegepant, telcagepant) and monoclonal antibodies (mAbs) targeting the CGRP, glutamate receptor (AMPA/kainate) antagonists, transient receptor potential vanilloid (TRV1) antagonists, nitric oxide (NO) synthesis inhibitors, prostanoid E4 receptor antagonists. Rezumat În anii 1990, au apărut pe piaţa farmaceutică agoniștii receptorilor serotoninei 5-HT1B/1D (triptanii) pentru tratamentul atacurilor migrenoase. Deşi triptanii sunt foarte eficienţi în atacurile migrenoase, folosirea lor este limitată de efectul vasoconstrictor din teritoriul cerebral şi coronarian. În era „post-triptani”, noi molecule, fără componente vasoactive, sunt pe cale să completeze armamentarium-ul pentru tratamentul migrenei, precum: agoniştii de receptori 5-HT1F, antagoniştii receptorilor CGRP şi anticorpii monoclonali anti-CGRP, antagoniştii receptorilor de glutamat (AMPA/kainate), antagonişti ai TRV1, inhibitori ai sintezei de NO, antagonişti ai receptorilor prostanoid E3. Keywords: migraine, triptans, new molecules, neural targets Introduction and onabotulinumtoxin A are the two drugs recommended in chronic migraine. Frequently, Migraine is highly prevalent worldwide, affecting chronic migraine is associated with medication- 11 % of the population, being a public health overuse-headache. problem [2]. Migraine is a brain disorder, with a complex neurobiology, and so research must be Current therapies for migraine oriented to find new neural targets and new molecules for its treatment. For acute migraine treatment, current guidelines Migraine is characterized by recurrent episodes of recommend non-specific molecules such as severe unilateral throbbing headache, associated NSAIDs (non-steroidal anti-inflammatory drugs), with autonomic nervous system dysfunction acetaminophen and aspirin, in patients with mild to (nausea, vomiting) and with sensitivity to light, moderate attacks. They are effective in some sound and head movement (migraine without aura) patients, but with the cost of gastrointestinal effects [1]. About one third of migraineurs experience fully [3]. NSAIDs must be used with caution, the regular reversible neurological symptoms. The aura is intake of one or more NSAIDs on ≥ 15 days per characterized by transitory visual or sensory-motor month, for > 3 months can induce medication- dysfunction that precedes or accompanies the overuse headache (MOH) [1]. headache (migraine with aura) [1]. Chronic Antiemetic drugs (metoclopramide, domperidone) migraine - a new concept introduced by the may be associated to NSAIDs to treat vegetative International Classification of Headache Disorders symptoms (nausea, vomiting) associated to the 3rd edition, is defined as headache on more than 15 headache and also to improve analgesics resorption [3]. days per month, for at least 3 consecutive months, Due to their addictive potential and the risk of the headache having the clinical features of medication overuse headache, opioids must be used migraine without aura for at least 8 days per month only in selective cases [3]. [1]. Chronic migraine produces an important Specific anti-migraine drugs (ergot alkaloids, disability to the patients, its treatment being more triptans) are indicated to abort moderate-to severe challenging than for episodic migraine. Topiramate headache attacks [3]. 475 FARMACIA, 2015, Vol. 63, 4 If there is a high frequency or a great severity of and severe headache attacks, or in the case of migraine attacks, un-responsivity to acute drug headache recurrence after triptans (exploiting their treatment, or long and disabling auras, there is need long half-time and low headache recurrence rate) [3]. for a prophylactic treatment of migraine. According For these old drugs, a new device for the delivery to the guidelines, molecules used in migraine of DHE by oral inhalation (in order to increase the preventive treatment are beta-blockers (metoprolol, pulmonary distribution and systemic absorption) propranolol), calcium-channel blockers (flunarizine was recently approved by FDA (Levadex®). – in familial hemiplegic migraine), anti-epileptic In the early 1990s, a new class of anti-migraine drugs (valproic acid, topiramate), and drugs - selective 5-HT1B and 5-HT1D receptors antidepressants (tricyclic – amitriptyline, selective agonists (triptans) for the acute treatment of serotonin reuptake inhibitors (SSRIs) – fluoxetine) [3]. migraine was developed. Migraine may be comorbid with other neurological Migraine’s headache might be due to sterile, and psychiatric disorders, including stroke, epilepsy, neurogenic inflammation in the cranial arterial depression and anxiety disorders, treatment must be walls. The trigeminal-vascular system concept selected also according to these aspects. referred to the pain-producing intracranial ♦ Serotonin receptor agonists structures (large cerebral vessels, pial vessels, large Serotonin (5-Hydroxytriptamine, 5-HT) is a basic venous sinuses and dura mater) that are surrounded amine derived from tryptophan, which is involved by unmyelinated fibres that arise from the in migraine pathogenesis. During migraine attacks trigeminal ganglion. there is an increased urinary excretion of the 5- The pain information from cranial structures is hydroxyindoleacetic acid (5-HIAA - the main directed orthodromic from vessels walls to metabolite of serotonin) [4] and in the meantime a trigeminal nucleus caudalis, ascends centrally in the drop of the platelet 5-HT [5]. So, in migraineurss, quinto-talamic tract, than synapse in contralateral there are increased plasma 5-HT levels during the thalamus and then projects to the cortex. attack and reduced interictal levels [6, 7]. There is also an antidromic pathway, namely 5-HT receptors have different molecular structures: neurons from the trigeminal ganglion release guanine nucleotide G protein-coupled receptors, substance P, calcitonin-gene-related peptide (CGRP), ligand-gated ion channels and transporters. In that are conducted by trigeminal nerve fibres humans, there are at least five 5-HT1 receptor towards arterial wall. These molecules determine subtypes: 5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, 5-HT1E, vasodilatation, plasma extravasation and enhance and 5-HT1F. neurogenic inflammation from cranial vessels [8]. Humphrey et al [6, 7] clarified the 5-HT receptors The inflammation from the vessel wall sends pain responsible for selective cranial vasoconstriction. information back to the trigeminal ganglion, which The small meningeal vessels contain mainly 5-HT1B releases inflammatory molecules (antidromic receptors, whereas the trigeminal ganglion and free CGRP, substance P). trigeminal nerve fibres contain mainly 5-HT1D In time, this vicious cycle determines central receptors. 5-HT1B receptors mediate vasoconstriction sensitization of the trigeminal ganglion, having the in cerebral and coronary arteries, whereas 5-HT1D clinical correspondent of cutaneous allodynia receptors are involved in neurogenic inflammation (abnormal perception of pain from a normally non- of the dura mater. painful mechanical or thermal stimulus) in Ergot alkaloids (ergotamine, dihidroergotamine - “transformed” migraine. DHE) represent the first class of specific anti- Triptans act by inhibiting the peripheral migraine drugs. They act as 5-HT receptors trigeminovascular neurons and also act centrally agonists, but they also bind α-adrenoceptors and along the trigeminal nociceptive pathways. dopamine receptors. They have low oral The first molecule of this class of drugs was bioavailability and many side effects (nausea, sumatriptan. Other triptans emerged immediately vomiting, paraesthesia, ergotism), causing also after, rising a SO CALLED „triptan war”: vasoconstriction at the coronary, cerebral and zolmitriptan, rizatriptan, naratriptan, eletriptan, peripheral level. almotriptan, frovatriptan. Ergot alkaloids are contraindicated in cardio- In case of headache recurrence (worsening of vascular, cerebrovascular diseases, Reynaud’s headache after pain free state achieved with a drug syndrome, pregnancy, uncontrolled arterial within 24 hours), a second dose of triptan is hypertension, renal and liver failure. Ergotamine - effective in most cases. If one triptan fails in acute overuse headache may appear in the case of regular migraine attack, another must be tried. Early intake for ≥ 10 days per month, for > 3 months [1]. triptan treatment in migraineurs may prevent the Ergot alkaloids use decreased after triptans central sensitization. appearance, but they are still indicated in very long The general contraindications for the use of triptans are: arterial hypertension (untreated), coronary 476 FARMACIA, 2015, Vol. 63, 4 heart disease, cerebrovascular disease, Raynaud’s ♦ CGRP
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