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`
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`
`ELSEVIER
`
`Vascular Pharmacology 43 (2005) 176 – 187
`
`Vascular
`Pharmacology
`
`www.elsevier.com/locate/vph
`
`Migraine: Current concepts and emerging therapies
`
`D.K. Arulmozhi a,b,*, A. Veeranjaneyulu a, S.L. Bodhankar b
`
`aNew Chemical Entity Research, Lupin Research Park, Village Nande, Taluk Mulshi, Pune 411 042, Maharashtra, India
`bDepartment of Pharmacology, Bharati Vidyapeeth, Poona College of Pharmacy, Pune 411 038, Maharashtra, India
`
`Received 23 April 2005; received in revised form 17 June 2005; accepted 11 July 2005
`
`Abstract
`
`Migraine is a recurrent incapacitating neurovascular disorder characterized by attacks of debilitating pain associated with photophobia,
`phonophobia, nausea and vomiting. Migraine affects a substantial fraction of world population and is a major cause of disability in the
`work place. Though the pathophysiology of migraine is still unclear three major theories proposed with regard to the mechanisms of
`migraine are vascular (due to cerebral vasodilatation), neurological (abnormal neurological firing which causes the spreading depression
`and migraine) and neurogenic dural
`inflammation (release of
`inflammatory neuropeptides). The modern understanding of
`the
`pathogenesis of migraine is based on the concept that it is a neurovascular disorder. The drugs used in the treatment of migraine either
`F
`_
`abolish the acute migraine headache or aim its prevention. The last decade has witnessed the advent of Sumatriptan and the
`triptan
`class of 5-HT1B/1D receptor agonists which have well established efficacy in treating migraine. Currently prophylactic treatments for
`migraine include calcium channel blockers, 5-HT2 receptor antagonists, beta adrenoceptor blockers and g-amino butyric acid (GABA)
`agonists. Unfortunately, many of these treatments are non specific and not always effective. Despite such progress, in view of the
`complexity of the etiology of migraine, it still remains undiagnosed and available therapies are underused. In this article, the diverse
`pieces of evidence that have linked the different theories of migraine with its pathophysiology are reviewed. Furthermore, the present
`therapeutic targets and futuristic approaches for the acute and prophylactic treatment of migraine, with a special emphasis to calcitonin
`gene-related peptide, are critically evaluated.
`D 2005 Published by Elsevier Inc.
`
`Keywords: Migraine; CGRP; Serotonin; Triptan
`
`1. Introduction
`
`Migraine is a chronic, often debilitating disease that
`affects 12% of the general population. This episodic brain
`disorder is characterized by unilateral throbbing headache
`lasting from 4 h to 3 days. Associated symptoms include
`nausea vomiting and sensitivity to light, sound and head
`movements (Silberstein, 2004). A working definition of
`migraine is benign recurring headache and/or neurological
`dysfunction usually attended by pain-free interludes and
`often provoked by stereotyped stimuli. Migraine is more
`common in females, with a hereditary predisposition
`
`* Corresponding author. Department of Pharmacology, New Chemical
`Entity Research, Lupin Research Park, Village Nande, Taluk Mulshi, Pune
`411 042, Maharashtra, India. Tel.: +91 20 2512 6161; fax: +91 20 2512 6298.
`E-mail address: adk_bits@yahoo.com (D.K. Arulmozhi).
`
`1537-1891/$ - see front matter D 2005 Published by Elsevier Inc.
`doi:10.1016/j.vph.2005.07.001
`
`towards attacks and the cranial circulatory phenomenon
`appears to be secondary to a primary central nervous system
`disorder.
`The Headache Classification Committee of the Interna-
`tional Headache Society (IHS) published the classification
`and diagnostic criteria for headache disorders (International
`F
`_
`Headache Society, 2004). The terms
`common migraine
`F
`_
`F
`and
`classical migraine
`have been replaced by
`migraine
`_
`F
`_
`without aura
`and
`migraine with aura
`respectively. These
`operational criteria have been validated by different
`approaches and have enabled to distinguish different head-
`ache entities in a reliable manner.
`Migraine apparently a global disorder, occurring in all
`races, cultures and geographical locations. Current figures
`suggest that 18% of women and six percent of men suffer
`from migraine and those numbers are increasing. The Center
`for Disease Control reported a 60% increase in the disease
`
`

`

`D.K. Arulmozhi et al. / Vascular Pharmacology 43 (2005) 176 – 187
`
`177
`
`incidence of migraine
`from 1980 to 1989. The highest
`occurs between the ages of 20 and 35 and often associated
`with a positive family history of the disease (Liption and
`Bigal, 2005).
`Migraine has an enormous impact on society. Recent
`studies have evaluated the indirect and direct costs of
`migraine. Indirect costs include the aggregate effects of
`migraine on productivity at work (paid employment), in
`performance of household work and in other roles. It was
`estimated that productivity losses due to migraine cost
`American employers $13 billion per year (Lipton et al.,
`2003).
`In the present review, the modern theories of migraine
`with respect
`to its diverse etiology as well
`the present
`therapeutic targets and futuristic approaches for the acute
`and prophylactic treatment of migraine are critically
`evaluated.
`
`2. Pathophysiology of migraine
`
`2.1. Clinical manifestations
`
`Migraine is characterized by episodes of head pain that is
`often throbbing and frequently unilateral and may be severe.
`In migraine without aura (previously known as common
`migraine) attacks are usually associated with nausea,
`vomiting, or sensitivity to light, sound, or movement and
`when treated, the attacks typically last 4 to 72 h (Olesen and
`Lipton, 1994; Michel et al., 1993). A combination of
`features is required for the diagnosis, but not all features are
`present in every attack or in every patient (Tables 1 and 2).
`These symptoms do distinguish migraine from tension type
`headache, the most common form of primary headache,
`which is characterized by the lack of associated features
`(Silberstein, 2004). Any severe and recurrent headache is
`most likely a form of migraine and should be responsive to
`antimigraine therapy (Lance, 2000). In 15% of patients
`migraine attacks are usually preceded or accompanied by
`transient focal neurotic symptoms, which are usually visual;
`such patients have migraine with aura (previously known as
`classic migraine) (Rasmussen et al., 1992; Rasmussen and
`Olesen, 1992). In a recent, large population-based study,
`64% of patients with migraine had only migraine without
`aura, 18% had only migraine with aura and 13% had both
`types of migraine (the remaining 5% had aura without
`headache). Thus, up to 31% of patients with migraine have
`aura on some occasions (Launer et al., 1999), but clinicians
`who rely on the presence of aura for the diagnosis of
`migraine will miss many cases.
`A recent survey by the World Health Organization
`(WHO), rates severe migraine, along with quadriplegia,
`psychosis, and dementia, as one of the most disabling
`chronic disorders (Menken et al., 2000). This ranking
`suggests that in the judgment of WHO, a day with severe
`migraine is a disabling as a day with quadriplegia.
`
`Table 1
`Diagnostic criteria of migraine
`
`Migraine without aura
`A. At least 5 attacks fulfilling B – D
`B. Headache attacks, lasting 4 – 72 h (untreated or unsuccessfully treated)
`C. Headache has at least two of the following characteristics
`1. Unilateral localization
`2. Pulsating quality
`3. Moderate to severe intensity
`4. Aggravation by walking stairs or similar routine physical activity
`D. During headache at least one of the following
`1. Nausea and/or vomiting
`2. Photophobia and phonophobia
`E. At least one of the following
`1. History, physical- and neurological examinations do not suggest
`association with head trauma, vascular or non-vascular disorders,
`use of or withdrawal from noxious substances, non-cephalic
`infections, metabolic disorders or disorder or cranial or facial
`structures
`2. History and/or physical- and/or neurological examinations do suggest
`such disorder, but it is ruled out by appropriate investigations
`3. Such disorder is present, but migraine attacks do not occur for the
`first time in close temporal relation with the disorder
`
`Migraine with aura
`A. At least 2 attacks fulfilling B
`B. Migraine aura fulfills criteria for typical aura, hemiplegic aura, or
`basilar-type aura
`C. Not attributed to another disorder
`
`Typical aura
`1. Fully reversible visual, sensory, or speech symptoms (or any
`combination) but no motor weakness
`2. Homonymous or bilateral visual symptoms including positive features
`(eg. Flicking of lights, spots, lines) or negative features (e.g. Loss of
`vision), or unilateral sensory symptoms including positive features (e.g.
`Visual loss, pins and needles) or negative features (e.g. Numbness), or
`any combination
`3. At least one of
`a. At least one symptom develops gradually over a minimum of 5 min
`or different symptoms occur in succession or both
`b. Each symptom lasts for at least 5 min and for no longer than 60 min
`4. Headache that meets criteria for migraine without aura begins during
`the aura or follows aura within 60 min
`
`2.2. Genetics of migraine
`
`Migraine is best understood as primary disorder of pain
`(Silberstein, 2004). It is a form of neurovascular headache:
`a disorder in which neural events result in the dilation of
`blood vessels, which in turn, results in pain and further
`nerve activation (Goadsby, 2001). Migraine is not caused
`by primary vascular event. Migraine attacks are episodic
`and vary within and among the individuals. The variability
`is best explained by considering the biologic problem in
`migraine to be the dysfunction of an ion channel in the
`aminergic brain stem nuclei
`that normally modulates
`sensory input and exerts neural
`influences on cranial
`vessels (Silberstein, 2004). There is thus ample evidence
`for genetic liability of migraine. Missense mutations in
`CACNA1A gene, coding for
`the alpha subunit of a
`neuronal P/Q type Ca2+ channel were discovered in patients
`
`

`

`178
`
`D.K. Arulmozhi et al. / Vascular Pharmacology 43 (2005) 176 – 187
`
`Table 3
`Drugs for acute migraine attacks
`
`with familial hemiplegic migraine (Montagna, 2004; Oph-
`off et al., 1996). It
`is possible that other ion-channel
`mutations contribute to migraine without aura, since it is
`primarily consist patients of migraine with aura who have
`been linked to the familial hemiplegic migraine locus
`(Terwindt et al., 2001).
`The second gene responsible for familial hemeplegic
`migraine was discovered to consist of the alpha 2 subunit of
`the Na/K pump gene linked to chromosome 1q23. The
`sodium-potassium pump catalyses the energy dependent
`transport of Na+ and K+ across the cell membrane and is a
`heterodimer, composed of a catalytic and a glycoprotein
`subunit. Two mechanisms were hypothesized to account for
`an altered excitability of the memebrane in mutated cells; an
`increase in extra cellular K+ because of impaired clearance
`of K+ might induce cortical depolarization and facilitate a
`spreading depression (Montagna, 2004).
`
`3. Theories of migraine
`
`3.1. Vascular theory
`
`In the late 1930’s, Harold Wolff became the first
`researcher to place migraine on a scientific basis, Wolf
`measured the diameter of
`the extracranial
`(temporal)
`arteries in patients suffering migraine attacks and found
`them to be dilated. These patients were treated with
`vasoconstrictors (ergotamine) which relieved the pain
`(Tables 2 and 3) and decreased the arterial dilation
`(Graham and Wolf, 1938).
`Although subsequent events leading to headache (and
`associated symptoms) are not completely understood, the
`increased vascular pulsation may activate stretch receptors.
`This would, in turn increase the activity of neuropeptide
`containing (mainly calcitonin gene-related peptide (CGRP)
`perivascular nerves which may ultimately cause pain and
`other associated symptoms (De Vries et al., 1999; Willems
`et al., 2003).
`In line with the finding that carotid arteriovenous
`anastomoses dilatation play a role in the pathogenesis of
`migraine, it is reasonable to believe that compounds which
`produce a cranioselective vasoconstriction may have a
`potential therapeutic use in the treatment of migraine. In
`anaesthetized dogs and pigs acutely acting antimigraine
`drugs, ergot alkaloids (ergotamine and dihydroergotamine)
`and triptans (sumatriptan and second generation triptans)
`produced potent vasoconstriction in the canine and porcine
`
`Table 2
`Migraine treatment strategies
`
`Suppressing initiation and perpetuation of cortical spreading depression
`Inhibiting mechanism of neurovascular coupling neurogenic inflammation
`Inhibiting nociceptor activation
`Enhancing descending modulation
`Blocking peripheral and central sensitization
`
`Acute antimigraine
`agents
`
`Acetaminophen
`Aspirin
`
`Nonsteroidal
`anti-inflammatory
`drugs
`Butalbital, Caffeine,
`and analgesics
`Caffeine adjuvant
`Isomethheptene
`
`Opioids
`
`Neuroleptics
`
`Dihydroergotamine
`
`inj and intranasal}Coronary artery disease,
`
`Ergotamine
`Triptans
`
`peripheral vascular disease,
`uncontrolled hypertension
`
`Contraindications
`
`Indication
`
`Liver disease
`Kidney disease, ulcer
`disease, peptic ulcer
`disease
`Kidney disease, peptic ulcer
`disease, gastritis
`
`Pregnancy
`Coronary artery
`disease, transient
`ischeamic attack
`Arthritis
`
`Use of other sedative, history
`of medication overuse
`Sensitivity to caffeine
`Uncontrolled hypertension,
`coronary artery disease,
`peripheral vascular disease
`Drug or substance misuse
`
`Parkinsons disease,
`prolonged QTc
`
`Pregnancy, rescue
`medication
`Nausea, vomiting,
`pregnancy
`Prominent nausea
`or vomiting
`
`carotid vasculature (De Vries et al., 1996). Further studies
`demonstrated that mainly 5-HT1B receptors mediate suma-
`triptan-induced cranial vasoconstriction, involving carotid
`arteriovenous anastomoses and temporal and middle menin-
`geal arteries (De Vries et al., 1998).
`
`3.2. Neurological theory
`
`A second theory of migraine is the neurological theory of
`migraine. This theory suggests that migraine arises as a
`result of abnormal neuronal firing and neurotransmitter
`release in brain neurons. This theory focuses on an
`explanation for certain symptoms, such as premonitory
`symptoms occurring prior to an attack (prodrome), which
`are difficult to explain based on the vascular hypothesis. The
`fact
`that migraine headaches begin and develop slowly
`coupled to the fact that external factors, such as stress, and
`hunger can precipitate migraine attacks to pathologies
`arising in the neuronal system, thus supporting a neuro-
`logical basis of migraine (Pearce, 1984). Cortical spreading
`depression, an expanding depolarization of cortical neurons
`which is well characterized in many species but not in man
`is often suggested to underlie the aura or prodrome
`associated with initiation of migraine attack. During spread-
`ing depression, cortical function is disrupted subsequent to
`neuronal depolarization and increased extracellular potas-
`sium. These cortical changes are thought to be the cause of
`the transient sensory or motor impairments that frequently
`precede the painful period of a migraine attack.
`Many investigators hypothesize that neuronal activation in
`migraine may be mediated by cortical spreading depression
`(CSD). In brief, CSD is a phenomenon of neuronal activation
`
`

`

`D.K. Arulmozhi et al. / Vascular Pharmacology 43 (2005) 176 – 187
`
`179
`
`followed by suppression, which progresses over the cortical
`surface and spreads down into the depth of the sulci at a rate
`of 2 – 8 mm/min. Coupled with this electrical phenomenon
`are cerebral blood flow changes that manifest as initial
`hyperemia followed by spreading oligemia. Experimentally,
`CSD can be triggered by trauma and by chemicals such as
`hydrogen ions, potassium, and glutamate. The coupling
`between CSD and activation of the vascular nociceptives is
`not fully elucidated. Potential culprits include release of nitric
`oxide (NO) and atrionatriuretic factor (ANP), spread of
`astrocytic calcium waves to pial arachnoid cells with
`subsequent activation of intradural nociceptives, descending
`activation of noradrenergic pathways, changes in blood flow,
`and vascular dilatation with nociceptive sensitization (Lash-
`ley, 1941; Lashley et al., 1981; Olesen et al., 1981).
`Several inconsistencies exist with the neurological theory
`of migraine. In part, these are related to the fact that the
`brain itself does not contain pain sensory fibers although
`pain fibers are located in the meninges. Furthermore,
`although stress may precipitate migraine, the actual occur-
`rence of the headache pain generally prevails after, rather
`than during the stressful circumstance.
`
`3.3. Neurogenic theory
`
`Lance et al. (1983) demonstrated that blood flow changes
`similar to those known to occur in migraine could be
`produced by electrically stimulating brain stem structures.
`This finding led to the neurogenic theory. Stimulation studies
`investigated the relationship between the trigeminal nerve
`and the cranial vasculature. Moskowitz (1992) showed that
`trigeminovascular axons from blood vessels of the pia mater
`and dura mater release vasoactive peptides producing a sterile
`inflammatory reaction with pain. During this neurogenic
`inflammation, the trigeminal ganglion is stimulated and this
`induces neurogenic protein extravasation. Vasodilatory pep-
`tides then released, including calcitonin gene related peptide
`(CGRP), substance P (SP) and neurokinin A.
`Neurogenic theory is an attempt to reconcile the vascular
`changes in the neuronal dysfunction that may occur in
`migraine headache and proposes that migraine pain is
`associated with inflammation and dilation of the meninges,
`particularly the dura, a membrane surrounding the brain.
`Neurogenic dural inflammation is thought to result from the
`actions of inflammatory neuropeptides released from the
`primary sensory nerve terminals innervating the dural blood
`vessels. In fact, the dural membrane surrounding the brain is
`the source for the majority of intracranial pain afferents and
`dural stimulation produces headache like pain in human
`(Moskowitz, 1992, 1993). Stimulation or inflammation of
`sensory fibers release the inflammatory neuropeptides,
`substance P and calcitonin gene-related peptide onto dural
`tissue, where these peptides produce a local response called
`neurogenic inflammation. Neurogenic inflammation may
`lower
`the nociceptive threshold required to stimulate
`meningial sensory fibers (Moskowitz, 1990). According to
`
`neurogenic dural inflammation theory of migraine, release
`of these inflammatory neuropeptides in the dura mater
`during migraine can act on vascular
`tissues to cause
`vasodilatation, plasma protein extravasation in the surround-
`ing area, endothelial changes, platelet aggregation and
`subsequent release of serotonin and other mediators, white
`cell adhesion and subsequent inflammation (Dimitriadou et
`al., 1991, 1992). CGRP plays a facilitatory role in this
`process (Brain and Williams, 1985). Whereas substance P
`induces extravasation via activation of NK1 receptors,
`release of CGRP enhances the effects of substance P by
`increasing dural blood flow and by inhibiting an extrac-
`ellular enzyme that normally can metabolize substance P.
`Therefore, these two sensory neuropeptides act in concert to
`produce painful dural inflammation. Although not reliably
`demonstrated,
`increased cranial venous concentration of
`CGRP have been observed during a migraine attack and the
`elevated concentrations of CGRP have returned to normal
`following treatment of the migraine in the serotonergic
`agonists (Arulmani et al., 2004).
`This theory is in consistent with the proposal that sero-
`tonergic agonist alleviate the acute pain of migraine by
`inhibiting the release of substance P and CGRP from trige-
`minal sensory afferent neurons surrounding the meninges.
`
`4. Pain mechanisms in migraine
`
`The pathogenesis of pain in migraine is not completely
`understood so far, but three key factors merit consider-
`ations are:
`the cranial blood vessels,
`the trigeminal
`innervation of the vessels, and the reflex connection of
`the trigeminal system in the cranial parasympathetic
`outflow. The substance of the brain is largely insensate;
`pain can be generated by large cranial vessels, proximal
`intracranial vessels or by the dura mater (Martin et al.,
`1993; Feindel et al., 1960). These vessels are innervated
`by branches of the ophthalmic division of the trigeminal
`nerve, whereas the structures of the posterior fossa are
`innervated by branches of the C2 nerve roots. In non-
`human primates, stimulation of vascular afferents leads to
`the activation of neurons in the superficial layers of the
`trigeminal nucleus caudalis in the region of the craniome-
`dullary junction and the superficial
`layers of the dorsal
`horns C1 and C2 levels of the spinal cord trigeminocer-
`vical complex (Hoskin et al., 1999; Goadsby and Hoskin,
`1997). Similarly, stimulation of branches of C2 activates
`neurons in the same regions of the brain (Kerr, 1960). The
`involvement of ophthalmic division of the trigeminal nerve
`and the overlap with structures innervated by C2 explain
`the common distribution of migraine pain over the frontal
`and temporal regions, as well as involvement of parietal,
`occipital and high cervical regions by what is, in essence,
`referred pain.
`Peripheral trigeminal activation in migraine is evidenced
`by release of CGRP, a vasodilator (Goadsby et al., 1990),
`
`

`

`180
`
`D.K. Arulmozhi et al. / Vascular Pharmacology 43 (2005) 176 – 187
`
`but the mechanism of generation of pain is not clear. Studies
`in animals suggest that the pain may be caused by a sterile
`neurogenic inflammatory process in the dura mater (Mos-
`kowitz and Cutrer, 1993), but this mechanism has not been
`clearly demonstrated to correlate in humans (May et al.,
`1998). The pain may be a combination of an altered percep-
`tion — as a result of peripheral or central sterilization of
`craniovascular input that is not usually painful (Burstein et
`al., 2000) and the activation of feed-forward neurovascular
`dilator mechanism that is functionally specific for the first
`(ophthalmic) division of the trigeminal nerve (May et al.,
`2001).
`
`5.1. 5-HT1B/1D receptors
`
`The antimigraine gold standard sumatriptan was origi-
`nally identified and developed based on the vasodilatory
`theory of migraine and the hypothesis that constriction of
`the cerebral vascular smooth muscle would minimize the
`pain associated with migraine headache. Since the discovery
`of sumatriptan, intensive research in this area has led to
`several second generation compounds (Tables 4 and 5).
`These second generation triptans, though not much different
`from sumatriptan in their pharmacodynamics, have
`improved pharmacokinetics, higher oral bioavailability and
`in some cases, longer plasma half-life (Slassi et al., 2001).
`
`5. Serotonergic receptors and other pharmacological
`targets for potential antimigraine agents
`
`5.2. 5-HT1F receptors
`
`Since long, it was observed that administration of 5-HT
`could abort migraine attacks. Further evidence that 5-HT is
`involved in the pathophysiology of migraine was provided
`by the observation that 5-HT metabolism in migraine
`patients is disturbed, interictal systemic 5-HT levels are
`reduced and raised during migraine attacks, possibly a
`(failing) self-defense response (Ferrari et al., 1990). These
`observations prompted the development of sumatriptan; the
`first migraine drug for which a specific molecular basis of
`action is known (Humphrey et al., 1990). Sumatriptan was
`designed to act selectively as a vasoconstrictor at 5-HT1
`receptors in cranial blood vessels, but the drug also acts on
`5-HT1 receptors located in peripheral human blood vessels.
`The exact mode of action of sumatriptan is still under debate.
`Three distinct modes of action have been suggested
`(Ophoff et al., 2001; Ahn and Basbaum, 2005) are 1.
`Vasoconstriction of meningial, dural, cerebral or pial vessels,
`mediated via stimulation of vascular 5-HT1B receptors. 2.
`Inhibition of dural neurogenic inflammation, most probably
`mediated by presynaptic stimulation of 5-HT1D and/or 5-HT1F
`receptors. 3. Central inhibition of pain transmission: inhibition
`of trigeminal neurons in the brain stems and upper spinal cord,
`mediated by 5-HT1B, 5-HT1D or 5-HT1F receptors.
`
`their antimigraine
`Though the triptans partly exert
`efficacy at
`least partly through cerebral vasoconstrictor
`effects (5-HT1B receptor mediated effect),
`triptans also
`inhibit neurotransmitter release from trigeminal nociceptive
`neurons (Table 7). Several triptans have modest to significant
`agonist activity 5-HT1F receptors. The ability of serotonergic
`receptor agonists to inhibit plasma protein extravasation in
`guinea pigs is correlated with their affinity to 5-HT1F
`receptors. In laboratory studies and preliminary clinical
`studies the 5-HT1F receptor agonist LY334370 found to be
`efficacious in acute migraine without associated vasocon-
`strictor effects observed with triptans, however subsequently
`the development of LY334370 has been discontinued due to
`poor efficacy in large trials. Further studies are warranted in
`order to better understand the link between 5-HT1F receptor
`and migraine with respect to clinical response to potential
`antimigraine therapies (Ramadan et al., 2003; Johnson et al.,
`1998).
`
`5.3. 5-HT2B receptors
`
`Recent observations suggested that nitric oxide gener-
`ation and subsequent release of inflammatory neuropeptides
`(CGRP and substance P) from the trigeminal sensory nerve
`
`Table 4
`5-HT1B/1D receptor agonists as antimigraine agents
`
`Company
`
`Novartis
`Glaxo Wellcome
`
`AstraZeneca
`Merck
`
`Pfizer
`
`Vanguard
`Pharmacia
`Janssen
`Bristol-Myers Squibb
`
`Code name
`
`Generic name
`
`–
`GR-43175
`GR-85548
`BW-311C-90
`L705126/MK-462
`
`UK-116044
`SB-209509
`VML-251
`LAS-31416
`R-91274
`BMS-180048
`
`Dihydroergotamine
`Sumatriptan
`Naratriptan
`Zolmitriptan
`Rizatriptan
`
`Eletriptan
`
`Frovatriptan
`Almotriptan
`Alniditan
`Avitriptan
`
`Trade name
`\
`Migranal
`\
`Imitrex
`Imigrain
`\
`\
`/Amerge
`Naramig
`\
`Zomig
`\
`Maxalt
`Maxalt melt
`–
`
`–
`–
`–
`–
`
`Formulation
`
`Nasal spray
`Nasal spray suppository
`Oral
`Oral
`Oral
`Oral lysophilate
`Oral
`
`Oral
`Oral, sc
`Sc
`–
`
`

`

`D.K. Arulmozhi et al. / Vascular Pharmacology 43 (2005) 176 – 187
`
`181
`
`Table 5
`Selected pharmacologic characteristic of oral triptans
`
`Agent
`
`Tmax during
`migraine
`
`Bioavailability(%)
`
`Route of metabolism Plasma half
`life (h)
`
`Drug interactions/precautions
`
`Naratriptan
`
`3 – 4
`
`70
`
`CYP450 isoenzymes
`
`6
`
`Rizatriptan
`
`1.0 – 1.5
`
`45
`
`MAO-A
`
`2 – 3
`
`Sumatriptan
`
`2.5
`
`Zolmitriptan
`
`2.5
`
`15
`
`40
`
`2.5
`
`CYP1A2/MAO-A
`
`3
`
`No change in efficacy or adverse events when used with
`beta-blockers; efficacy not affected when used with oral
`contraceptives (OCs); observe patients when given with
`SSRIs; not contraindicated with MAO inhibitors
`Concomitant use with propranolol increases triptan plasma
`levels and requires dose adjustment; no change in efficacy or
`adverse events when used with metoprolol, nadolol or OCs;
`observe patients when given with SSRIs; contraindicated with
`MAO inhibitors
`Efficacy not affected when used with beta-blockers; observe
`patient when given with SSRIs; contraindicated with selective
`MAO-A and nonselective MAO inhibitors; not contraindicated
`with selective MAO-B inhibitors
`Concomitant use with propranolol increases plasma levels;
`no change in efficacy or adverse events when used with
`propranolol; observe patient when given with SSRIs;
`contraindicated with selective MAO-A and nonselective MAO
`inhibitors; not contraindicated with selective MAO-B inhibitors
`
`may be associated with the initiation of migraine (Johnson
`et al., 1998). Furthermore, the 5-HT2B receptors on vascular
`endothelial cell have been linked to NO release (Schmuck et
`al., 1996). These observations coupled to the marked
`correlation between pharmacologically active doses of
`anti-migraine drugs and their potency at
`the human
`5-HT2B receptor (Kalkman, 1994; Fozard and Kalkman,
`1994; Fozard, 1995). It has been reported that 5-HT2B
`receptors in certain vascular endothelial beds can enhance
`nitric oxide release, which may diffuse from the endothelial
`cell to induce vasodilation and neuropeptide release. Thus
`the selective antagonism of 5-HT2B receptors would be
`effective in migraine prophylaxis (Johnson et al., 1998).
`
`5.4. 5-HT7 receptors
`
`Increasing data supports the concept that 5-HT7 receptor
`activation is responsible for the initial dilation of cerebral
`vessels and the subsequent activation of sensory pathways,
`consequent to neurogenic inflammation around the menin-
`gial vessels, neural sensitization and activation of pain.
`Potential implications of the 5-HT7 receptor in cerebrovas-
`cular dilation, hyperalgesia and neurogenic inflammation
`might pave the way for new research efforts towards the
`understanding of migraine pathophysiological mechanism
`and drug development. The putative involvement of this
`receptor
`in the vascular and neurogenic alteration of
`migraine is consistent
`in the concept
`that
`the condition
`may result from massive release of 5-HT after abnormal
`activation of brainstem that is secondary to the hypothala-
`mic dysfunctions (Fozard and Kalkman, 1994; Fozard,
`1995) and the disease arises primarily from the neuro-
`vascular interaction (May and Goadsby, 1999). Admitting,
`despite the fact that the correlation analysis suggest the
`for migraine prophylactic
`5-HT7 receptor be a target
`
`compounds, interpretation of their antimigraine effect in
`terms of blockade at
`this site is at present speculative.
`Clinical trials with selective 5-HT7 receptor antagonists, will
`be awaited with interest so the potential involvement of the
`5-HT7 receptor in migraine pathogenesis and preventive
`treatment is elucidated (Terron, 2002).
`
`5.5. a-adrenoceptors
`
`It is believed that a-adrenoceptors could be involved in
`the vascular tone of carotid circulation, which may provide
`a potential avenue for the development of new antimi-
`graine agents. It has been well established that several
`acutely acting antimigraine agents,
`including the ergots
`(ergotamine and dihydroergotamine) produce potent vaso-
`constriction in the canine and porcine carotid vasculature
`(De Vries et al., 1999). The canine carotid vasoconstrictor
`responses of these ergot alkaloids are mediated by 5-HT1B/
`1D and a2-adrenoceptors (Villalon et al., 1999). It has been
`suggested that,
`the high affinity of ergotamine and
`dihydroergotamine at a-adrenoceptors could be the possi-
`ble reason for their therapeutic applications (Tfelt-Hansen
`et al., 2000).
`
`5.6. b-adrenergic receptors
`
`h-adrenoceptor blockers, the most widely used class of
`drugs in prophylactic migraine treatment, are 60 – 80%
`effective in producing a > 50% reduction attack frequency.
`The mechanism of action of h-adrenergic blockers is not
`certain, but it appears that their anti-migraine effect is due to
`the inhibition of h
`1-mediated mechanisms (Hieble, 2000).
`h-blockade results in inhibition of norepinephrine release by
`blocking prejunctinonal h receptors. In addition, it results in
`a delayed reduction in tyrosine hydroxylase activity, the
`
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`182
`
`D.K. Arulmozhi et al. / Vascular Pharmacology 43 (2005) 176 – 187
`
`in the
`rate-limiting step in norepinephrine synthesis,
`superior cervical ganglia. In the rat brain stem, a delayed
`reduction of the locus ceruleus neuronal firing rate has been
`demonstrated after propranolol administration (Hieble,
`2000). This could explain the delay in the prophylactic
`effects of the h-blocker.
`The action of h-blockers is probably central and could be
`mediated by: (i) inhibiting central h receptors interfering
`with vigilance-enhancing adrenergic pathway, (ii) interac-
`tion with 5-HT receptors (but not all h-blockers bind to 5-
`HT receptors), and (iii) cross-modulation of serotonin
`system (Ablad and Dahlof, 1986; Koella, 1985).
`
`5.7. Calcium channels
`
`The complex nature of the genetics of the common
`types of migraine has, however hampered the identification
`of an underlying genetic factor. The migraine spectra
`comprises the common types of migraine (with and
`without aura) as well as rate autosomal dominant variants
`of migraine with aura, associated with a transient hemi-
`paresis or hemiplegia (one sided weakness or paralysis of
`the body) in addition to other aura symptoms. In some
`families, symptoms of familial hemiplegic migraine are
`also associated with (progressive) permanent ataxia (dis-
`turbance of co-ordination of movements). The symptoms
`of headache and aura phase of
`familial hemiplegic
`migraine and normal migraine attacks are very similar
`and both types may alternate within individuals and co-
`occur within families. These observations suggest strongly
`that familial hemiplegic migraine is part of the migraine
`spectrum and that familial hemiplegic migraine can be
`used as a model to study the complex genetics of common
`types of migraine. Importantly, familial hemiplegic mi-
`graine exhibi