Antoinette Maassen VanDenBrink

Consensus Statement: Cardiovascular Safety Profile of Triptans (5-HT1B/1D Agonists) in the Acute Treatment of Migraine

Background.—Health care providers frequently cite concerns about cardiovascular safety of the triptans as a barrier to their use. In 2002, the American Headache Society convened the Triptan Cardiovascular Safety Expert Panel to evaluate the evidence on triptan‐associated cardiovascular risk and to formulate consensus recommendations for making informed decisions for their use in patients with migraine.

Migraine headache is not associated with cerebral or meningeal vasodilatation—a 3T magnetic resonance angiography study

Sir, with great interest, we read the article by Schoonman et al. (2008), who claim that ‘in contrast to widespread belief, migraine attacks are not associated with vasodilatation of cerebral or meningeal blood vessels’ and, therefore, ‘future anti-migraine agents may not require vasoconstrictor action’. Whereas the methodology used in this investigation is elegant, we disagree with their claim for the following reasons. First, it may be noted that Schoonman et al. (2008) did observe vasodilatation during nitroglycerin (NTG; 0.5 mg/kg/min over 20 min) infusion in all blood vessels investigated (middle meningeal, internal and external carotid, middle cerebral, basilar and posterior cerebral arteries), but not during the migraine-like headache provoked 1.5–5.5 h after cessation of NTG infusion. However, these initial vasodilator changes can trigger a chain of events leading to headache. Cranial vasodilatation leads to enhanced blood volume following each cardiac stroke with consequent augmentation of vascular pulsations, which may be sensed by stretch receptors in the vessel wall; the resultant increase in perivascular (trigeminal) sensory nerve activity can provoke headache and other migraine symptoms (Fig. 2; Villalón et al., 2003). Admittedly, the magnitude of vasodilatation did not significantly differ between the 20 subjects later developing a migraine-like attack after NTG and the 7 subjects who did not or between the two sides in case of unilateral headache. This may, however, be due to differences in headache threshold. Second, Schoonman et al. (2008) measured diameter changes in the proximal (extracranial) conducting section of the meningeal artery, while the distal intracranial regions could not be studied due to technical reasons. The authors submit that ‘it seems likely that there were also no changes in the intracranial resistance microvasculature during migraine attacks, [because] basilar and internal carotid artery blood flows, . . . which are dependent on cardiac output, arterial calibre and vasomotor tone in small resistance vessels, . . . did also not change during migraine attacks’. It should be obvious that basilar and internal carotid artery blood flows do not directly relate to diameter changes in the middle meningeal artery, which originates from the external carotid artery. Moreover, there may be regional differences in the innervation of the meningeal artery (O’Connor and van der Kooy, 1986; Strassman et al., 2004), which illustrates that it is an oversimplification to consider the large extracranial section of the meningeal artery as an accurate representative of its smaller, intracranial portion. Indeed, as described for the coronary circulation in detail (for a review, see Tiefenbacher and Chilian, 1998), pharmacological responses to vasoactive compounds may differ between proximal and distal regions of the meningeal artery. For example, we demonstrated that large ‘conducting’ portions of the porcine-isolated meningeal artery are insensitive to the 5-HT1B/1D receptor agonist sumatriptan (Mehrotra et al., 2006), while others observed contractions when the whole meningeal arterial bed, including resistance vessels, was perfused (Bou et al., 2000). In addition, there is at least some evidence for the dilatation of cranial extracerebral arteriovenous anastomoses in migraine (Heyck, 1969) and these shunt vessels, which were not studied here, selectively and strongly constrict in response to ergot alkaloids as well as triptans in experimental animals (Saxena and Tfelt-Hansen, 2006). Finally, one must keep in mind that this investigation concerns NTG-provoked (not spontaneous) migraine headaches and lacks measurements at the beginning of such headaches. To their credit, Schoonman et al. (2008) have acknowledged these potential limitations. doi:10.1093/brain/awn259 Brain 2009: 132; 1–2 | e112

Interictal cortical hyperexcitability in migraine patients demonstrated with transcranial magnetic stimulation

Cortical excitability to magnetic stimulation was investigated interictally in 10 patients with migraine with aura, 10 with migraine without aura and in 10 healthy volunteers. Thresholds, latencies and amplitudes of the magnetic-evoked potentials (MEPs) were measured from threshold to 100% stimulus intensity in 10% steps. Compound motor action potentials (CMAPs) evoked with supramaximal electrical stimulation of the ulnar nerve were used to calculate MEP/CMAP amplitude ratios. Thresholds and latencies of MEPs did not differ between patients and controls. MEP/CMAP amplitude ratios were significantly increased at all intensities in patients with migraine with aura (RM-ANOVA, p < 0.01) and without aura (p < 0.05) compared with controls. In migraine patients, MEP amplitudes and MEP/CMAP amplitude ratios were positively related to the frequency of migraine attacks (Spearmans r = 0.47, p < 0.01 and r = 0.56, p < 0.002, respectively). MEP parameters were not related to the side of the headache nor the aura, in either type of migraine, implying that both hemispheres are equally involved in migraine. Migraine with aura and, to a lesser extent, migraine without aura, are associated with increased interictal cortical excitability.

Chromosomal localization of the 5-HT1F receptor gene: no evidence for involvement in response to sumatriptan in migraine patients.

The 5-HT1F receptor, which is present in both human vascular and neuronal tissue, may mediate the therapeutic effect and/or side-effects of sumatriptan. We investigated the chromosomal localization of the 5-HT1F receptor gene and the relation between eventually existing polymorphisms and the clinical response to sumatriptan in migraine patients. The 5-HT1F receptor gene was localized using a monochromosomal mapping panel, followed by a radiation-reduced hybrid mapping and fluorescent in situ hybridization. The results of these techniques show that the 5-HT1F receptor gene is localized at 3p12. We investigated the presence of polymorphisms by single strand conformation polymorphism analysis in 14 migraine patients who consistently responded well to sumatriptan, 12 patients who consistently experienced recurrence of the headache after initial relief, 12 patients with no response to sumatriptan, and in 13 patients who consistently experienced chest symptoms after use of sumatriptan. No polymorphisms were detected in any of the patients. We therefore conclude that genetic diversity of the 5-HT1F receptor gene is most probably not responsible for the variable clinical response to sumatriptan.

Effects of avitriptan, a new 5-HT 1B/1D receptor agonist, in experimental models predictive of antimigraine activity and coronary side-effect potential

Abstract Several acutely acting antimigraine drugs, including ergotamine and sumatriptan, have the ability to constrict porcine arteriovenous anastomoses as well as the human isolated coronary artery. These two experimental models seem to serve as indicators, respectively, for the therapeutic and coronary side-effect potential of the compounds. Using these two models, we have now investigated the effects of avitriptan (BMS-180048; 3-[3-[4-(5-methoxy-4-pyrimidinyl)-1-piperazinyl]propyl]-N-methyl-1H-indole-5-methanesulfonamide monofumarate), a new 5-HT1B/1D receptor agonist. In anaesthetized pigs, avitriptan (10, 30, 100 and 300 μg·kg–1) decreased the total carotid blood flow by exclusively decreasing arteriovenous anastomotic blood flow; capillary blood flow was increased. The mean ± SEM i.v. dose of avitriptan eliciting a 50% decrease (ED50) in the porcine carotid arteriovenous anastomotic blood flow was calculated to be 76 ± 23 μg·kg–1 (132 ± 40 nmol·kg–1) and the highest dose (300 μg·kg–1) produced a 72 ± 4% reduction. In recent comparative experiments (DeVries et al. 1996), the mean ± SEM ED50 (i.v.) of sumatriptan in decreasing carotid arteriovenous anastomotic blood flow was 63 ± 17 μg·kg–1 (158 ± 43 nmol·kg–1), with a reduction of 76 ± 4% by 300 μg·kg–1, i.v. Both avitriptan (pD2: 7.39 ± 0.09; Emax: 13.0 ± 4.5% of the contraction to 100 mM K+) and sumatriptan (pD2: 6.33 ± 0.09; Emax: 15.5 ± 2.3% of the contraction to 100 mM K+) contracted the human isolated coronary artery. The above results suggest that avitriptan should be able to abort migraine headaches in patients, but may exhibit sumatriptan-like effects on coronary arteries. Initial clinical studies have demonstrated the therapeutic action of the drug in acute migraine.

Activation of 5-hydroxytryptamine1B/1D/1F receptors as a mechanism of action of antimigraine drugs

Introduction: The introduction of the triptans (5-hydroxytryptamine (5-HT)1B/1D receptor agonists) was a great improvement in the acute treatment of migraine. However, shortcomings of the triptans have prompted research on novel serotonergic targets for the treatment of migraine. Areas covered: In this review the different types of antimigraine drugs acting at 5-HT receptors, their discovery and development are discussed. The first specific antimigraine drugs were the ergot alkaloids, consisting of ergotamine, dihydroergotamine and methysergide, which are agonists at 5-HT receptors, but can also bind α-adrenoceptors and dopamine receptors. In the 1990s, the triptans became available on the market. They are 5-HT1B/1D receptor agonists, showing fewer side effects due to their receptor specificity. In the last years, compounds that bind specifically to 5-HT1D, 5-HT1F and 5-HT7 receptors have been explored for their antimigraine potential. Furthermore, the serotonergic system seems to act in tight connection with the glutamatergic as well as the CGRP-ergic systems, which may open novel therapeutic avenues. Expert opinion: Although the triptans are very effective in treating migraine attacks, their shortcomings have stimulated the search for novel drugs. Currently, the focus is on 5-HT1F receptor agonists, which seem devoid of vascular side effects. Moreover, novel compounds that affect multiple transmitter and/or neuropeptide systems that are involved in migraine could be of therapeutic relevance.

The 5-HT1 receptors inhibiting the rat vasodepressor sensory CGRPergic outflow: Further involvement of 5-HT1F, but not 5-HT1A or 5-HT1D, subtypes

We have previously shown that 5-HT(1B) receptors inhibit prejunctionally the rat vasodepressor CGRPergic sensory outflow. Since 5-HT(1) receptors comprise 5-HT(1A), 5-HT(1B), 5-HT(1D) and 5-HT(1F) functional subtypes, this study has further investigated the role of 5-HT(1A), 5-HT(1D) and 5-HT(1F) receptor subtypes in the inhibition of the above vasodepressor sensory outflow. Pithed rats were pretreated with i.v. continuous infusions of hexamethonium and methoxamine, followed by 5-HT(1) receptor agonists. Then electrical spinal stimulation (T(9)-T(12)) or i.v. bolus injections of exogenous α-CGRP produced frequency-dependent or dose-dependent vasodepressor responses. The electrically-induced vasodepressor responses remained unchanged during infusions of the 5-HT(1A) receptor agonists 8-OH-DPAT and NN-DP-5-CT. In contrast, these responses were inhibited by the agonists sumatriptan (5-HT(1A/1B/1D/1F)), indorenate (5-HT(1A)), PNU-142633 (5-HT(1D)) or LY344864 (5-HT(1F)), which did not affect the vasodepressor responses to exogenous CGRP (implying a prejunctional sensory-inhibition). When analysing the effects of antagonists: (i) 310 μg/kg (but not 100 μg/kg) GR127935 (5-HT(1A/1B/1D/1F)) abolished the inhibition to sumatriptan, indorenate, PNU-142633 or LY344864; (ii) 310 μg/kg SB224289 (5-HT(1B)) or BRL15572 (5-HT(1D)) failed to block the inhibition to sumatriptan or PNU-142633, whereas SB224289+BRL15572 partly blocked the inhibition to sumatriptan; and (iii) 10 μg/kg WAY100635 (5-HT(1A)) failed to block the inhibition to indorenate. These results suggest that 5-HT(1F), but not 5-HT(1A) or 5-HT(1D), receptor subtypes inhibit the vasodepressor sensory CGRPergic outflow although, admittedly, no selective 5-HT(1F) receptor agonist is available yet. The pharmacological profile of these receptors resembles that shown in rat dorsal root ganglia by molecular biology techniques.

Effects of Female Sex Hormones on Responses to CGRP, Acetylcholine, and 5‐HT in Rat Isolated Arteries

Background.—Female sex hormones are implicated in the modulation of reactivity of a wide range of blood vessels under physiological as well as pathological conditions. Migraine, a neurovascular syndrome, is 3 times more prevalent in women during their reproductive period than in men.

The Role of 5-Hydroxytryptamine in the Pathophysiology of Migraine and its Relevance to the Design of Novel Treatments

BACKGROUND Migraine is a highly prevalent neurovascular disorder. OBJECTIVE Of the many factors that have been implicated over the years, 5-hydroxytryptamine (5-HT; serotonin) has long been involved in the pathophysiology of migraine. Certainly, some lines of evidence suggest: (i) a 5-HT depletion from blood platelets resulting in cranial extracerebral vasodilatation; and (ii) the effectiveness of an intravenous (i.v.) infusion of 5-HT to abort migraine in some patients. More direct evidence comes from some drugs that influence 5-HT release and/or interact (as agonists or antagonists) with 5-HT receptors to treat this disorder. Indeed, the development of sumatriptan and second generation triptans in the 1990s led to discover that these drugs produce selective cranial extracerebral vasoconstriction (via 5-HT1B receptors) and inhibition of the trigeminovascular system responses implicated in migraine (via 5-HT1D/5-HT1F receptors). Although the triptans represent the current mainstay of acute antimigraine treatment, a number of patients do not respond well to the triptans and are contraindicated in patients with cardiovascular pathologies. CONCLUSION This mini-review outlines further developments in the design of novel (non-vasoconstrictor) antimigraine treatments acting via 5-HT receptors, including selective agonists at 5-HT1D and 5-HT1F receptors, agonists at 5-HT1B/1D receptors combined with other properties as well as antagonists at 5-HT2B/2C, 5-HT3 and 5-HT7 receptors. It also touches upon the recent development of antagonists and antibodies at calcitonin gene-related peptide (CGRP) and its receptors, which produce a direct blockade of the CGRPergic vasodilator mechanisms involved in migraine. These alternative pharmacological approaches will hopefully lead to less side-effects.

Reproducibility and agreement of different non-invasive methods of endothelial function assessment

Flow-mediated dilatation (FMD) is an established, but investigator-demanding method, used to non-invasively determine nitric oxide (NO)-dependent endothelial function in humans. Local thermal hyperemia (LTH) or post-occlusive reactive hyperemia (PORH) of the skin measured with a laser Doppler flow imager may be a less demanding alternative of FMD. We investigated the reproducibility of the different measures of vascular function, their interrelationship and the NO-dependency of LTH. Measurements were performed twice in 27 healthy men (8 smokers), one week apart. Local application of NG-monomethyl-l-arginine (L-NMMA) by means of iontophoresis was used to determine the NO-dependency of LTH. Using L-NMMA, the peak and plateau responses of LTH were reduced by 31% (p < .001) and 65% (<0.001), respectively. For all measurements the coefficient of variation (CV) was higher in smokers than in non-smokers. For non-smokers the CV of FMD was 12%, of LTH peak response 17%, of LTH plateau response 12%, of PORH peak response 14% and of PORH area under the curve response 11%. FMD correlated weakly with the PORH peak and area under the curve response (r = 0.39 and 0.43, p < .05), whereas the LTH-plateau response correlated with the PORH peak response (r = 0.68, p < .01) in non-smokers, but FMD and LTH peak or plateau responses were unrelated. In conclusion, the LTH plateau response is for two-third NO-dependent, but unrelated to FMD. Furthermore, despite easy to perform the LTH responses are not more reproducible than FMD. Given the weak associations, the different methods of vascular function assessment are not interchangeable.