Title: New Targets in Migraine Therapy
Other Titles: Nieuwe Behandelingstrategieën voor Migraine
Authors: Van der Schueren, Bart
Issue Date: 2-Jun-2009
Abstract: Migraine is a common neurovascular disorder which ranks among the world’ s most disabling medical conditions and has been estimated to be the mos t costly neurological disease in the European Community. Although knowle dge of the main molecular players is still incomplete, intensive researc h during the last decade has led to conceptual changes in our understand ing of migraine headache (Chapter 1). Current acute and prophylactic treatment options are far from optimal and consequently improved treatme nts based on the new insights in the pathophysiology of migraine are des perately needed. In the present thesis, a number of clinical pharmacological experimental methods are used to evaluate emerging new targets for the treatment of migraine in vivo in humans (Chapter 2). The main aim is to link fi ndings from basic science to their clinical applications quickly, exempl ifying the relevance of clinical pharmacology and its contribution to tr anslational medicine and the explorative phase of clinical drug developm ent. Our research focuses on three promising new treatment strategies: ( 1) calcitonin gene-related peptide (CGRP) receptor antagonism (Part I)</ >, (2) nitric oxide synthase (NOS) inhibition (Part II) and (3) inter vention in the endocannabinoid system (Part III). In Part I of the thesis, we translate a non-invasive pharmacodynamic model used in animals to allow rapid evaluation of CGRP receptor antagon ists into an in vivo human model. As the selectivity of CGRP receptor antagonists is known to differ between species this translational step is crucial for investigating proof-of-mechanism of CGRP antagonists in h umans. The model uses topical application of capsaicin to the skin of he althy volunteers to provoke CGRP release leading to an increase in derma l blood flow (DBF) which can be measured by Laser Doppler perfusion imag ing. In a first exploratory study in 12 healthy men, we identify the dos e of capsaicin needed to produce a robust and reproducible dermal blood flow (DBF) response measured by Laser Doppler perfusion imaging after to pical application to the human forearm (Chapter 3). Simultaneously, t he influence of the forearm location on the capsaicin response is assess ed. In the proximal forearm of healthy volunteers a 1000 µg capsaicin do se elicits a reproducible response in both proximal sites at the 30-minu tes time point. Subsequently, a reproducibility study is performed in 21 healthy men to assess the within-subject arm-to-arm and period-to-perio d reproducibility of the forearm DBF response to capsaicin using the 100 0 µg capsaicin dose and the proximal forearm locations. In this second s tudy, the data of 11 subjects with an increase in forearm blood flow fro m baseline &#8805; 100 % (i.e. responders) during both study visits are included in a reproducibility analysis. The arm-to-arm reproducibility o f the DBF after capsaicin application is almost perfect and based on the within-subject standard deviation the sample-size needed to detect diff erences in capsaicin-induced DBF increase between arms are calculated. Subsequently, we characterize and indentify the mediators involved in th e dermal vasodilation induced by capsaicin application to the human skin (Chapter 4). To assess the involvement of CGRP, the CGRP receptor an tagonist CGRP8-37 is infused into the brachial artery of one arm. In thi s way, the non-infused arm is not treated and serves as the control arm. The involvement of nitric oxide (NO) and prostaglandins in capsaicin-in duced DBF increase are evaluated in a similar way by infusing the non-se lective NO synthase inhibitor, NG-monomethyl-L-arginine monoacetate (L-N MMA), and the cyclo-oxygenase inhibitor indomethacin, respectively. To a ssess to involvement of substance P (SP) the potent SP antagonist aprepi tant is given orally, and capsaicin-induced vasodilation is measured pre dose on the left arm and postdose (Tmax) on the right arm. The main find ing from this study is that capsaicin-induced vasodilation in the human skin is to a large extent antagonized by CGRP8-37, but not by L-NMMA, ap repitant or indomethacin. Therefore CGRP seems to be the major mediator involved in this vasodilatory response to capsaicin. In addition, CGRP8- 37 does not affect resting DBF, indicating that CGRP does not play a rol e in maintaining basal DBF. The proposed model allows the assessment of the pharmacodynamic efficacy of CGRP receptor antagonists in a small gro up of healthy subjects and may guide the finding of a clinical effective dose. In Part I of the thesis, we also use tools from clinical pharmacology to assess the vascular effects and safety of CGRP receptor antagonists. Data in animals suggest that administration of nitroglycerin (NTG), whi ch is widely used in the treatment of cardiac ischemic pain (i.e. angina pectoris), causes release of CGRP in the cardiovascular system resultin g in coronary artery vasodilatation. We therefore want to investigate th e effect of CGRP receptor antagonism on response to NTG in vivo in hu mans (Chapter 5). We conduct a study in 22 healthy men and assessed v ascular changes using non-invasive techniques, including ultrasound meas urement of the brachial artery diameter and systolic pulse contour analy sis. By administering NTG following a high clinical dose of the potent C GRP receptor antagonist, telcagepant, we demonstrate that CGRP antagonis m has no clinically relevant effect on NTG-induced hemodynamic changes i n healthy men. Nor is there a measurable vasoconstrictor effect of telca gepant as such in both the central and peripheral vascular beds. These r esults support the favourable cardiovascular safety profile of CGRP rece ptor antagonists, especially when compared to triptans. In Part II of the thesis, the involvement of NO synthase activity in the pathogenesis of migraine is investigated by measuring associated bio markers of systemic NO production. In clinical pharmacology, the measure ment of biomarkers is used to identify potential treatment targets. Late r, the same biomarkers can often be used as “surrogates” to evaluate pre liminary clinical efficacy of newly developed compounds. There is abunda nt evidence for the involvement of NO in the pathogenesis of migraine. N O induces delayed headaches in migraineurs which resemble the characteri stics of spontaneous migraine attacks and the non-selective NO synthase inhibitor L-NMMA provides pain relief to patients experiencing a spontan eous migraine headache. In a first study, we assess whether migraine patients display a chronic NOS hyperactivity (Chapter 6). Based on the results of a reproducibil ity study in 12 healthy volunteers, we set up a study to compare NO prod uction before and following a loading dose of L-arginine between 20 migr aine patients, outside of a migraine attack, and 20 healthy volunteers b y measuring biomarkers associated with the L-arginine/NO conversion (i.e . nasal and exhaled NO, plasma L-citrulline and L-ariginine and urinary excretion of nitrates and cyclic guanosine monophosphate (cGMP)). The re sults of this study do not support the idea of a generalized increase in NOS activity in migraine patients outside of a migraine attack. On the contrary, following L-arginine infusion, the increase in plasma L-citrul line levels and urinary excretion of nitrite/nitrate and cGMP is smaller in migraine patients compared to healthy volunteers. The latter might i ndicate dysfunction of endothelial NOS in migraine patients and adds to the ongoing discussion about migraine being an endotheliopathy leading t o decreased endothelial NOS. The second study in Part II of the thesis investigates the pharmacoki netic and pharmacodynamic properties of GW273629, a potent inducible NOS (iNOS) inhibitor, in 15 migraine patients both during and outside of an acute migraine attack (Chapter 7). As in the first study, systemic N O production is evaluated by measuring biomarkers associated with the L- arginine/NO pathway (i.e. nasal and exhaled NO, plasma nitrate and plasm a 3-nitrotyrosine). This allows to assess the effect of migraine headach e and selective inducible NO synthase inhibition upon systemic NO produc tion. Although the early absorption of orally administered GW273629 is d elayed during a migraine attack, the time-course of iNOS inhibition, as assessed by nasal and exhaled NO, is similar during and outside of a mig raine attack. So while migraine headache changes the pharmacokinetic pro perties of GW273629, its pharmacodynamic profile remains unaffected . Re sults from this study suggest that migraine headache might be associated with excess systemic NO production, but strong iNOS inhibition by GW273 629 has no beneficial effect in this small open label study. Recent larg e clinical trials have also failed to show any efficacy of potent iNOS i nhibitors, both in the acute and the prophylactic treatment of a migrain e headache. In Part III of the thesis, we use recent advances in neuroimaging to evaluate putative changes in the endocannabinoid system associated with migraine. In vivo investigation of the type 1 cannabinoid receptor (CB1R ) has become possible with the development of positron emission tomograp hy (PET) radioligands. We compare cerebral CB1R availability between 20 female migraineurs outside the acute phase of a migraine attack and 18 h ealthy women. Migraine patients present an increase in CB1R availability in all brain regions, especially in the cingulo-frontal cortex and the limbic system which presumably exert top-down influences to modulate pai n. This is in accordance with recent findings suggesting that a failure of the endogenous endocannabinoid system might play a role in the pathop hysiology of migraine and its tendency to progress to chronic migraine. This study is another illustration of how clinical pharmacology uses a l arge variety of tools to identify potential treatment targets. Our findi ng that there exists a dysregulation in the endocannabinoid system in mi graine patients should encourage further investigation into cannabinoid signalling and might ultimately lead to pharmacological advances in the treatment of migraine. General conclusion This thesis presents a number of tools from clinical pharmacology which allow to both identify and facilitate clinical development of new pharma cological migraine treatments. Whereas preclinical research remains esse ntial in the quest for more efficient and safer migraine therapy, our re sults clearly underline the need for human models as there seems to be l arge variability with regard to the mediators involved in the pathophysi ological processes associated with the development of a migraine headach e. In addition, the mere nature of migraine renders the development of a nimal research models difficult and therefore their validity remains unc ertain. Whereas CGRP receptor antagonists for migraine treatment will soon appea r on the market, the future of NOS inhibition and modulation of the endo cannabinoid system remains uncertain. Non-selective NOS inhibition is ef fective in the treatment of migraine but unattractive because of cardiov ascular safety concerns. Our results favour the involvement of nNOS in t he pathogenesis of migraine above iNOS and eNOS but clinical data are la cking at this moment. Finally, therapeutic intervention in the endocanna binoid system does seem attractive, but the recent withdrawal from the m arket of cannabinoid receptor antagonists clearly illustrates that cauti on is warranted with regard to central nervous system side effects.
Publication status: published
KU Leuven publication type: TH
Appears in Collections:Clinical Pharmacology Centre (-)
Clinical and Experimental Endocrinology

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