Innovative drug development for headache disorders

240 Pages·2008·1.223 MB·English

by  Jes Olesen, Nabih Ramadan

Innovative Drug
Development for
Headache Disorders
Frontiers in Headache Research
Volume 16
FRONTIERS IN HEADACHE RESEARCH SERIES
Published by Lippincott-Raven
Volume 1:Migraine and Other Headaches: The Vascular Mechanisms
J.Olesen,editor;1991
Volume 2:5-Hydroxytryptamine Mechanisms in Primary Headaches
J.Olesen and P.R.Saxena,editors;1992
Volume 3:Tension-Type headache: Classification,Mechanisms and Treatment
J.Olesen and J.Schoenen,editors;1993
Volume 4:Headache Classification and Epidemiology
J.Olesen,editor;1994
Volume 5:Experimental Headache Models
J.Olesen and M.A.Moskowitz,editors;1995
Volume 6:Headache Treatment: Trial Methodology and New Drugs
J.Olesen and P.Tfelt-Hansen,editors;1995
Volume 7:Headache Pathogenesis: Monoamines,Neuropeptides,Purines and Nitric Oxide
J.Olesen and L.Edvinsson,editors;1997
Volume 8:Genetics ofHeadache Disorders
J.Olesen,editors;1998
Published by Oxford University Press
Volume 9:Cluster Headache and Related Conditions
J.Olesen and P.Goadsby,editors;1999
Volume 10:The Triptans: Novel Drugs for Migraine
P.Humphrey,M Ferrari,and J.Olesen,editors;2001
Volume 11:Reducing the Burden ofHeadache
J.Olesen,T.J.Steiner,and R.Lipton,editors;2003
Volume 12:Preventive Pharmacotherapy ofHeadache Disorders
J.Olesen,S.D.Silberstein,and P.Tfelt-Hansen,editors;2004
Volume 13:The Classification and Diagnosis ofHeadache Disorders
J.Olesen,editor;2005
Volume 14:From Basic Pain Mechanisms to Headache
J.Olesen and T.S.Jensen,editors;2006
Volume 15:Headache Clinics: Organization,Patients and Treatment
R.Jensen,H-C.Diener,and J.Olesen,editors;2007
Volume 16:Innovative Drug Development for Headache Disorders
J.Olesen and N.Ramadan,editors;2008
Innovative Drug
Development for
Headache Disorders
Frontiers in Headache Research
Volume 16
Edited by
Jes Olesen
Department of Neurology and
Danish Headache Centre, Glostrup Hospital,
University of Copenhagen,
Denmark
Nabih Ramadan
Diamond Headache Clinic
Chicago, Illinois, USA
1
1
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Contents
Preface viii
Contributors ix
Session I Screening models
1 The human γ-aminobutyric acid transporter GAT-2:from cloning to
high throughput screening 3
Bolette Christiansen,Trine Kvist,Anders A.Jensen,and Hans Bräuner-Osborne
2 Low throughput preclinical models for headache 17
Peter J.Goadsby
3 Human models:screening models 25
Messoud Ashina
Session II Trials methodology
4 Stricter success criteria,qualitative and quantitative
end-points:acute versus prevention trials 31
Peer Tfelt-Hansen
5 Health-related quality oflife and similar end-points 43
Carl G.H.Dahlöf
6 Clinically relevant designs and outcome measures for
acute migraine trials 57
Michel D.Ferrari and Hille Koppen
7 Effectiveness ofdifferent steroid dosage in Tolosa–Hunt
syndrome with different phenotypes:some critical
points about the new International Headache
Society classification 59
E.Marchioni,S.Colnaghi,M.Versino,A.Pichiecchio,
E.Tavazzi,and G.Nappi
8 Discussion summary:Trials methodology 63
Jes Olesen
Session III Nitric oxide and spreading depression modulators
9 Inducible nitric oxide synthase and development ofnew
migraine treatments 67
Boris A.Chizh
vi CONTENTS
10 Mechanisms ofcortical spreading depression as targets for
migraine therapy 73
Kevin C.Brennan and Andrew C.Charles
11 Tonabersat 85
Peter R.Blower and Paul C.Sharpe
12 Discussion summary:Nitric oxide and spreading
depression modulators 95
Nabih Ramadan
Session IV Calcitonin gene-related peptide and
5-hydroxytryptamine modulators
13 Calcitonin gene-related peptide:relevance for
migraine 99
Jes Olesen and Inger Jansen-Olesen
14 New 5-hydroxytryptamine-related drug targets 109
Pramod R.Saxena
15 Effect oftwo novel calcitonin gene-related
peptide-binding compounds in a closed
cranial window rat model 115
Louise Juhl,Lars Edvinsson,Jes Olesen,
and Inger Jansen-Olesen
16 Vasoactive intestinal polypeptide is unlikely
to be a target for headache and
migraine treatment 121
Jakob Møller Hansen,Alexandra Maria Rahmann,
Jes Olesen,and Messoud Ashina
17 Discussion summary:Calcitonin gene-related
peptide and 5-hydroxytryptamine
modulators 129
Rigmor Jensen
Session V Ion channel modulators and antiepileptics
18 Migraine:from genes to pathophysiology – transgenic
mouse models ofmigraine 133
Arn M.J.M.van den Maagdenberg
19 K channels and migraine 143
ATP
Inger Jansen-Olesen and Kenneth Beri Ploug
20 Antiepileptic drugs and migraine 153
Michael A.Rogawski
CONTENTS vii
21 Discussion summary:Ion channel modulators
and antiepileptics 179
Pramod R.Saxena
Session VI Other future targets for headache therapy
22 Innovative drug development for headache
disorders:glutamate 185
Kirk W.Johnson,Eric S.Nisenbaum,Michael P.Johnson,
Donna K.Dieckman,Amy Clemens-Smith,Edward R.Siuda,Colin P.Dell,
Veronique Dehlinger,Kevin J.Hudziak,Sandra A.Filla,Paul L.Ornstein,
Nabih M.Ramadan,and David Bleakman
23 The modulation ofTRPV1 channels by cannabinoid
1
receptors 195
Beatriz Fioravanti and Todd W.Vanderah
24 Future targets for headache therapy:prostanoids 205
Christian Waeber
25 Role ofanandamide in the modulation of
nitroglycerin-induced hyperalgesia:
a study in the rat 219
Cristina Tassorelli,Rosaria Greco,Armando Perrotta,
Simona Buscone,Giorgio Sandrini,and Giuseppe Nappi
Index 223
Preface
Migraine treatment was very much improved with the advent of the triptans in the
1990s.While previous drugs have had efficacy,compounds such as ergotamine,had
bothersome side-effects and their overuse could lead to severe complications.The trip-
tans were the first class ofdrugs with high receptor specificity and disease specificity.In
the early days ofthe triptans,it was widely presumed that migraine was no longer a treat-
ment problem.However,it has gradually been recognized that a significant proportion of
patients are not responsive to triptans or do not tolerate them.Furthermore,the success
criteria in the triptan trials were quite relaxed.With more strict success criteria,particu-
larly the sustained pain-free response,one-third ofthe patients or lower respond.It is
now clear that,even with effective attack treatment,patients with frequent attacks are not
treated well exclusively with acute medications.This is partly because patients are still
bothered by the attacks and partly because frequent intake of acute medication may
result in medication overuse headache.These problems have led to a renewed interest in
preventive migraine drugs.In relation to the other major primary headache disorder,
chronic tension-type headache,there has not been much progress.Amitriptyline is still
the mainstay oftreatment but recently mirtazapine has also proven to be ofvalue.There
is a great need for preventive drugs for chronic tension-type headache.
Recent European data have shown that research funding ofthe migraine in Europe is
the lowest ofall of12 major brain disorders studied.Research support to other types of
headache could not be identified at all.The combined headache field probably receives
less than 10% ofthe funding ofepilepsy or movement disorders but costs society four
times more.How can therapeutic progress then be expected? The happy message is that
despite the gloomy figures on research support,there have been significant advances in
migraine research over recent years.As demonstrated in this volume,there are several
promising new avenues for the development of future drugs for migraine.The main
principles with proof of concept,but not yet in full clinical development,are cortical
spreading depression inhibition,nitric oxide synthase inhibition,and calcitonin gene-
related peptide receptor antagonism.The present book presents frontline knowledge as
far as it is available in the public domain.Hopefully,readers and their patients will find it
exciting to learn about all the novel possibilities,and hopefully the impressive research
advances in migraine will lead to increased funding,not only of migraine but also of
other types ofheadache.Only then can we fully exploit all the academic advances for the
benefit ofour patients.
Contributors
Ashina,Messoud Chizh,Boris A.
Danish Headache Center and Department GlaxoSmithKline,Addenbrooke’s
ofNeurology,Glostrup Hospital, Centre for Clinical Investigation,
University ofCopenhagen, Addenbrooke’s Hospital,
Glostrup,Denmark Cambridge,UK
Bleakman,David Christiansen,Bolette
Lilly Research Laboratories,Lilly Department ofMedical Chemistry,
Corporate Center, Faculty ofPharmaceutical Sciences,
Indianapolis,USA University ofCopenhagen,
Copenhagen,Denmark
Blower,Peter R.
Minster Pharmaceuticals plc., Clemens-Smith,Amy
Audley End Business Centre, Lilly Research Laboratories,Lilly
The Old Forge,Saffron Walden, Corporate Center,
Essex,UK Indianapolis,USA
Bräuner-Osborne,Hans Colnaghi,S.
Department ofMedical Chemistry, Laboratory ofOcular Movements,
Faculty ofPharmaceutical Sciences, Foundation IRCCS ‘C.Mondino’,
University ofCopenhagen, Pavia,Italy
Copenhagen,Denmark
Dahlöf,Carl G.H.
Brennan,Kevin C. Institute ofNeuroscience and Physiology,
Headache Research and Treatment Department ofClinical Neuroscience
Program,Department ofNeurology, and Rehabilitation,
David Geffen School ofMedicine at Sahlgrenska University Hospital,
UCLA,Los Angeles,California,USA Göteborg,Sweden
Buscone,Simona Dehlinger,Veronique
University Centre for the Study of Eli Lilly and Co.Ltd.,Lilly Research
Adaptive Disorder and Headache, Centre,Erl Wood Manor,
University ofPavia,Italy Windlesham,
Surrey,UK
Charles,Andrew C.
Headache Research and Treatment Dell,Colin P.
Program,Department ofNeurology, Eli Lilly and Co.Ltd.,Lilly Research
David Geffen School ofMedicine at Centre,Erl Wood Manor,
UCLA,Los Angeles,USA Windlesham
Surrey,UK