EX2297
`Eli Lilly & Co. v. Teva Pharms. Int'l GMBH
`IPR2018-01710
`
`1
`
`

`

`I: degranulation as seen in the loss of normal
`' .l'IItm-ial properties, ultrastructural disintegration
`‘IiIl'Ilasma membrane, and loss of electron-dense
`{lethal within cytoplasmic granules. Following a
`| I-uIIinute stimulation period, frank degranulation
`q'ame ev1dent 20 minutes later. All of these
`depended on the presence of small, un-
`'I'."11'nated fibers and were not noted after gan-
`
`
`"
`iC stimulation in animals treated with cap-
`
`,_ n as neonates.
`""ensitization and hyperalgesia. In migraine,
`[III-bus triggers, which remain to be identified, ini-
`
`"
`a complex cascade of events within the me-
`
`.
`5 that cause both pain through depolarization
`2.11me afferents and long-lasting enhancement
`'flgiceptor activity that leads to sensitization and
`i.
`" -."gq-a1gesia.3'15116 Neither event, of course, is
`I Filing to the meninges or to migraine, and both
`'
`'I' within the skin, joints, and eye, as well as in
`1
`.jm'Tmrjnary and respiratory tracts.”19 Important
`Iain-ital mediators that modulate sensory trans-
`.5';I_ '011 in affected tissue include potassium, sero-
`.= I'n (5-HT), bradykinin, histamine, prosta-
`
`': “n“.dins, leukotrienes, substance P, and CGRP.20
`
`I
`} njured tissue—or tissue threatened with
`-'
`,Ej.l _y-#the extracellular concentrations of these
`I'gmicals increase by release from local cells
`
`". assium, histamine, 5-HT), local synthesis
`'- .I,.'.'staglandins, leukotrienes, bradykinin), or
`
`'ase from sensory axons (neuropeptides).
`
`eralgesia and pain occur as a consequence of
`
`initial trigger and the cellular response to neu-
`-
`i
`.
`'c inflammation.
`
`
`
`
`
`
`
`king neurogenic plasma protein extrava-
`
`on. Pharmacologic observations that 5-HT1
`
`'ts with some selectivity for the D-type recep-
`
`__ luck inflammation selectively Within the dura
`'ii-I'r, support the belief that neurogenic inflam-
`
`. Jon is especially relevant to vascular head-
`2713:1531 Vasoconstriction mediated by 5-HT1D
`
`
`more on vascular smooth muscle plays a minor
`'“l- if any.
`'
`__. "fporzse to sumatriptan and related compounds.
`
`'
`853 have shown that neurogenic plasma pro-
`Extravasation from blood vessels in the dura
`
`can be significantly reduced by drugs such
`J-llnatriptan, 5-carboxamidotryptamine (5-CT),
`
`.Nl'flergotamine (DHE), ergotamine tartrate,
`'III'..'.,m9thysergide. The dosage of sumatriptan
`-' puffed to block extravasation is similar to that
`" fired to treat acute migraine in humans“)22
`:17. - e reSponse to these agents has been most con-
`3'23“} With an effect mediated by 5-HT1D receptors
`.35" a1030115 5-HT-lB receptors in rats. Some no-
`_te exCeptions were found, however. Pre-
`
`.
`fimenf with the 5-HTl antagonist metergoline
`
`partially reversed the response to sumatrip-
`
`i. $35 methiothepine did not reverse the
`“lithe at all. The effect of 5-CT was not blocked
`it -. er antagonist, and serotonin itself appears
`in" we in this model. Pretreatment with 5-HT2
`
`antagonists (pizotifen, ketanserin) or 5-HT3 antago-
`nists (MDL 7222, 108 205-930) did not affect leak-
`age, which is consistent with a 5-HT1 receptor-
`mediated response.
`However, the rank order of effective dosages, or
`threshold concentrations of 5-HT1D selective com-
`pounds, does not correlate with affinities for the
`same drugs at the 5-HT1D receptor binding site
`determined by ligand binding in vitro. Hence,
`emerging pharmacology suggests that a receptor
`subtype other than 5-HT1D may mediate the
`antineurogenic inflammatory effects of sumatrip-
`tan and DHE. This receptor is present only in
`intracranial tissue innervated by the trigeminal
`nerve; the equivalent or higher concentrations of
`sumatriptan or ergot alkaloid do not block plasma
`protein extravasation in extracranial cephalic tis-
`sue.
`
`Prejunctional mechanisms and inhibited neu-
`ropeptide release. Several lines of evidence support
`the conclusion that 5-HT heteroreceptors are locat-
`ed on neuropeptide-containing unmyelinated C
`fibers. Prejunctional mechanisms and inhibited
`neuropeptide release mediate drug blockade of
`plasma leakage within the dura mater. First,
`sumatriptan and DHE are inactive when tested
`against concentrations of substance P or neu-
`rokinin A, which cause plasma leakage. Later
`experiments have found sumatriptan, also, to be
`inactive against leakage caused by a-methyl 5-HT,
`a 5-HT2 agonist that stimulated endothelial cell
`leakage directly. Extravasation caused by a-methyl
`5-HT was blocked by pretreatment With the 5-HT2
`antagonist pimozide. Second, DHE and, to a lesser
`extent, sumatriptan attenuated the increase in
`immunoreactive CGRP within sagittal sinus blood
`(venous effluent) during electrical stimulation of
`the trigeminal ganglion.23 This presumably reflects
`the inhibition of neuropeptide release. Third,
`sumatriptan and DHE pretreatment block platelet
`aggregation, endothelial vesicle formation within
`postcapillary venules, mast cell secretion, and
`degranulation in the dura mater.24
`These findings are difficult to reconcile with a
`mechanism based on activation of postjunctional
`receptors on vascular smooth muscle, endothelial
`cells, or sympathetic fibers. Sympathetic fibers
`were in fact ruled out as a possible mediator by
`direct experiments showing that sumatriptan
`inhibits neurogenic plasma extravasation in sym-
`pathectomized animals.
`Recently, in situ hybridization studies have
`demonstrated that the 5-HT1D,B gene is expresed
`Within trigeminal ganglia.25 Moreover, the ex-
`pressed gene has been amplified using the poly-
`merase chain reaction and oligonucleotide probes
`complementary to the cDNA prepared from the
`5-HT1D receptor message (unpublished data).
`Role of 5-HT1 receptors. Studies involving suma-
`triptan and endopeptidase 24.11 (enkephalinase),
`an enzyme that degrades substance P and CGRP,
`suggest a coupling between the 5-HT1 receptor and
`
`2
`
`June 1993 NEUROLOGY 43 (Suppl 3) $17
`
`2
`
`

`

`the blockade of neuropeptide release. When admin-
`istered after stimulation, the two agents were
`found to exhibit nearly identical time-dependent
`effects. They blocked plasma extravasation, even
`when administered 60 minutes after the 5—minute
`
`stimulation period. After terminating the stimulus
`in our model, neuropeptide release from sensory
`fibers appeared to continue for some time.
`Blockade of neuropeptide release from sensory
`fibers was consistent with the role of 5-HT1D recep-
`tors as inhibitors of presynaptic neurotransmitter
`release Within brain and perivascular sympathetic
`nerve fibers.24'26 More recent data indicate that a2,
`H3, propioid, and somatostatin receptors may also
`be located on trigeminovascular fibers and may
`block neurogenic plasma extravasation.27
`
`C-fos expression. C-fos protein, a nuclear phos-
`phoprotein that regulates the transcription rate of
`target genes, may play a role in the long-term
`alteration of cellular function.”31 This phosphopro-
`tein can be induced in neurons in the dorsal horn of
`the spinal cord by noxious and non-noxious
`stimuli.”34 Noxious stimuli increase the number of
`
`cells expressing c-fos protein within Rexed’s lami-
`nae (I and 110), where unmyelinated C fibers termi-
`nate and spinothalamic projecting neurons predom—
`inate.3‘*'36
`
`Continuous or prolonged stimulation evokes the
`most robust response, and the number of cells con-
`taining c-fos protein correlates with stimulus inten-
`sity. In the same way, the number of positive cells
`decreases after analgesic administration. For
`example, the number of positive cells in the dorsal
`horn has been correlated with the nociceptive
`behavioral response observed in rats after formalin
`has been injected into the hind paw. In the forma-
`lin experiments, the number of expressing cells
`decreased after morphine administration in a dose-
`dependent, naloxone-sensitive manner.”36 C—fos
`expression provides both spatial and temporal
`markers of neuronal activation following sensory
`stimulation.
`
`The trigeminal nucleus caudalis. We have re-
`cently studied c-fos expression within the trigemi-
`nal nucleus caudalis after instilling autologous
`blood into the subarachnoid space of rats.37 The
`trigeminal nucleus caudalis receives the major
`synaptic input from the trigeminal nerve and con-
`tains neurons that discharge when the meninges
`are stimulated.38
`
`When placed in the subarachnoid space, blood is
`noxious, as evidenced by the development of severe
`headache, nausea and vomiting, photophobia, and
`vasoconstriction in humans. In our model, the
`injection of blood increased the number of cells
`expressing the c-fos protein within laminae I and
`Ho. The number of expressing cells corresponded to
`the amount of blood injected, and the number of
`responding cells was maximal 2 hours after injec-
`tion. After surgical or chemical denervation, the
`number of expressing cells was reduced by 50% or
`
`SIS NEUROLOGY 43 (Suppl 3) June 1993
`
`3
`
`I.
`
`more. In our model, inhibition of c-fos ex
`Presgh .l
`was probably also related to the developme
`analgesia because pretreatment with morplig? '
`decreased the number of expressing cells,
`5’12;
`Pretreatment With 5-HT1 agonists With 8
`selectivity for the B- and D-subtype rem-2pm.S [0W '5
`morphine) reduced the number of c-fos_p03i§'-I[."
`cells caused by instilling blood. CP-93 12939401? -.
`selective 5-HTIB agonist, sumatriptan, or dihYdrg- '2
`ergotamine decreased the number of positiVe 06';
`significantly in laminae I and Ho, compared Witt“
`those in vehicle-treated animals,41 Sumatliptan' .
`.m-
`not block c-fos expression in the trigeminal 1111le
`caudalis following formalin application to the
`' ‘1
`mucosa. This means that sumatriptan is fimfl‘ .l
`mentally different from such analgesics as 11'1qu
`phine.
`|_
`Inhibiting c-fos expression. Drug-induced 131--
`ade of c-fos expression may well be mediated"‘--
`receptors on primary afferent (trigeminovasc :f'.
`
`fibers. Consistent with this conclusion, we fa "1'
`that chemical or surgical denervation, as well-3'
`drugs such as CP-93 129, sumatriptan, and DIE-“f"
`caused a similar pattern of c-fos inhibition wi' 3'11}
`the brain stem. This was seen in the reduced it
`ber of expressing cells in the caudalis but not in" 1
`nucleus of the solitary tract or area postrema§fri
`Administering CP-93 129 did not decrease flit
`number of expressing cells below the 50% in ‘f
`tion in chemically denervated animals, suggesh
`the importance of extracerebral sites to drug activrii lI
`I.
`ty.
`
`f
`'
`
`If the inhibition of c-fos expression within laflilj‘;
`nae I and Ho correlates with the amelioration if
`pain, we can infer that constricted blood vessels 81?
`not required to alleviate pain by sumatriptan 33E]
`DHE and, furthermore, that dilation may n0t"_|_3§
`the pain stimulus, or trigger, in vascular head-i2
`aches. Blood vessel constriction, which occurs 8%
`blood enters the subarachnoid space, provides filly '
`ther evidence that 5-HTm-receptor—mediated V359;
`constriction may not be necessary for 1’.hte:1"dl'“*ut='l
`effect.
`_
`.-'
`We recently demonstrated that recuTr‘F-n.
`spreading depression induces c-fos expression W1 '
`
`
`in lamina I, 110 trigeminal nucleus caudallfii' it
`does the intracisternal administration 0f
`‘-.
`rageenan, a proinflammatory agent.42 C-fOS exp
`
`_..
`sion following spreading depression (SD) W3?
`
`blocked by prior sectioning of trigeminal 311811.111...”
`afferents. Sumatriptan did not affect the ablhwfifi.
`the brain tissue to initiate andfor propagatte S -_
`Quite remarkably, sumatriptan suppressed. ”11m!
`expression in both instances, raising the p055“? w!
`that 5-HT1D agonists may alleviate pain 3550615, "'
`with a wide variety of conditions, including bi"c
`'
`'
`al and viral meningitis and head injury.
`.5
`3.
`Based on the results of these experimeflfi'
`suggest that under certain circumstances {gut-._.: i
`graine), the cortical mantle releases nocicepli
`molecules and generates the pain SM!” "1’
`migraine. The released molecules collect 1n
`'
`
`i
`
`!
`
`'
`
`3
`
`

`

`
`
`I,.acellular and perivascular space and within
`.ervated draining veins leading to discharge and
`
`"-- ation of trigeminovascular fibers. The chal-
`
`Vie for the decade ahead is to identify those neu-
`“haysiological and metabolic brain events which
`
`"- 'ipate and provoke the pain of migrane.
`
`
`
`. 11clusion. Our data support the formulation
`
`5;". the actions of sumatriptan and DHE are con-
`
`led to at least two important events that may
`.
`ifljsh pain and sensitization in patients with
`
`rular headache. Sumatriptan and DHE block
`
`transmission within trigeminovascular
`
`3 and, by so doing, gene expression within
`
`itsynaptic brain stem neurons. At the same time,
`I5. block the neuroinflammatory response follow-
`
`' fferent fiber stimulation. The therapeutic
`fifications of these compounds to other conditions
`
`" ‘ated with meningeal irritation merit further
`fideration.
`
`"The occurance of c-fos within ipsilateral trigemi-
`.‘nucleus caudalis after recurrent spreading
`
`fission suggests that the brain can indeed pro-
`
`' .original research published in the past 10
`"
`1-3,12-16,21-24,37,38,40,41,43
`
`oskowitz MA, Reinhard JF Jr, Romero J, et al. Neu-
`_- __transmitters and the fifih cranial nerve: is there a relation
`
`
`
`
`
`4 gningesl projections from cat trigeminal ganglia: possible
`ilkthway for vascular headaches in man. Science 1981;
`:11 3:228-230.
`
`*1}: 'kflwitac MA. The neurobiology of vascular head pain. Ann
`
`J Enrol 1984;16:157-168.
`rdebo JE. The involvement of trigeminal substance P
`limos in cluster headache. An hypothesis. Headache
`‘ 24:294-304.
`
`_
`_
`-.
`'b€€k
`F, Holzer P. Substance P as neurogenic mediator
`
`-" 'flntldromic vasodilation and neurogenic plasma extrava-
`
`Mien. Naunyn Schmiedebergs Arch Pharmacol 1979;
`,II.
`.
`.- 10:175-183.
`
`A, Gamse R, Lundberg JM, et al. Coexistence of
`
`rilahykinins and calcitonin gene-related peptide in sensory
`
`
`-
`93 in relation to neurogenic inflammation. In: Hakanson
`its
`
`.Qndler F, eds. Tachykinin antagonists. New York:
`:1]
`|-.;_-Ea:"'18r Science Publishing, 1985.
`a A, Gamse R, Petermann J, et a1. Simultaneous release
`gf. Rape
`Ilium ral tachykinins and calcitonin gene-related. peptide
`191. “it Spinal cord slices. Neurosci Lett 1986;63:310-314.
`' an SD, Williams TJ. Tippins JR, et al.Calcitonin gene-
`t‘efi Peptide is a potent vasodilator. Nature 1985;313:54-
`
`
`
`
`
`I:
`' i‘komtz S, Saito K, Moskowitz MA. Neurogenically medi-
`theakage of plasma protein occurs from blood vessels in
`
`.; by Elgater but not brain. J Neurosci 1987;7:4129-4136.
`'
`:Ei
`.
`- Wolff HG. Experimental studies on headache: pain-
`
`""1131? Structures of the head and their significance in
`,. [MC 9- Arch Surg 1940;41:813-856.
`. {In-d
`3
`, Von During M, Muszynslci K, et al. Nerve fibres
`
`their t0I‘minals of the dura mater encephali of the rat.
`
`12.
`
`13.
`
`14.
`
`15.
`
`16.
`
`17.
`
`18.
`
`19.
`
`20.
`
`21.
`
`22.
`
`23.
`
`24.
`
`25.
`
`26.
`
`27.
`
`28.
`
`29.
`
`30.
`
`31.
`
`32.
`
`33.
`4
`
`Anat Embryol (Berl) 1987;175:289-301.
`Steiger HJ, Tew JM Jr, Keller JT. The sensory representa-
`tion of the dura mater in the trigeminal ganglion of the cat.
`Neurosci Lett 1982;31:231-236.
`Mayberg MR, Zervas NT, Moskowitz MA. Trigeminal projec-
`tions to supratentorial pial and dural blood vessels in cats
`demonstrated by horseradish peroxidase histochemistry. J
`Comp Neurol 1984;223:46-56.
`Dimitriadou V, Buzzi MG, Moskowitz MA, et al. Trigeminal
`sensory fiber stimulation induces morphological changes
`reflecting secretion in rat dura mater mast cells. Neu-
`roscience 1991;44:97-112.
`Buzzi MG, Moskowitz MA. The antimigraine drug, suma-
`triptan (GR43175), selectively blocks neurogenic plasma
`extravasation from blood vessels in dura mater. Br J Phar-
`macol 1990;99:202-206.
`Moskowitz MA. The visceral organ brain: implications for
`the pathophysiology of vascular head pain. Neurology 1991;
`41:182-186.
`Lembeck F. Sir Thomas Lewis’s nocifensor system, his-
`tamine and substance-P—containing primary afferent
`nerves. TINS 1983;6:106-108.
`Saria A, Lundberg JM, Skofitsch G, et a1. Vascular protein
`leakage in various tissues induced by substance P, cap-
`saicin, bradykinin, serotonin, histamine and by antigen
`challenge. Naunyn Schmiedebergs Arch Pharmacol 1983;
`324:212-218.
`Levine JD, Clark R, Devor M, et al. Intraneuronal substance
`P contributes to the severity of experimental arthritis.
`Science 1984;226:547-568.
`Fields HL. Pain. New York: McGraw-Hill Book Co, 1987:13-
`40.
`Buzzi MG, Moskowitz MA, Peroutka SJ, et al. Further char-
`acterization of the putative 5-HT receptor which mediates
`blockade of neurogenic plasma extravasation in rat dura
`mater. Br J Pharmacol 1991;103:1421-1428.
`Doenicke A, Brand J, Perrin VL. Possible benefit of
`GR43175, a novel 5-HT1-like receptor agonist, for the acute
`treatment of severe migraine. Lancet 1988;1z1309—1311.
`Buzzi MG, Carter WE, Shimizu T, et al. Dihydroergotamine
`and sumatriptan attenuate the levels of CGRP in plasma in
`rat superior sagittal sinus during electrical stimulation of
`the trigeminal ganglion. Neuropharmacology 1991;30:1193-
`1200.
`Buzzi MG, Dimitriadou V, Theoharides T, et a1. 5-Hydrox-
`ytryptamine receptor agonists for the abortive treatment of
`vascular headaches block mast cell, endothelial, and platelet
`activation within the rat dura mater after trigeminal stimu-
`lation. Brain Res 1992;583:137-149.
`Bruinvels AT, Landwehrmeyer B, Moskowitz MA, et al.
`Evidence for presence of 5-HT“, receptor messenger RNA in
`neurons of the rat trigeminal gangila. Eur J Pharmacol
`1992;227:357-359.
`Sleight AJ, Cervenka A, Peroutka SJ. In vivo effects of
`sumatriptan (GR43175) on extracellular levels of 5-HT in
`guinea pig. Neuropharmacology 1990;29:511-513.
`Matsubara T, Moskowitz MA, Huang Z. UK-14, 304, R(-)-a-
`methyl—histamine and octreotide (SMSZOl-995) block plas-
`ma protein within dura mater by prejunctional mechanisms.
`Eur J Pharmacol 1992;224:145-150.
`Morgan JI, Curran T. Stimulus-transcription coupling in
`neurons: role of cellular immediate-early genes. TINS
`1989;12(11):459-462.
`Sambucetii LC, Curran T. Expression of c-fos protein in
`brain: metabolic mapping at the cellular level. Science
`1988;240:1328-1331.
`Sheng M, Greenberg ME. The regulation and function of
`c-fos and other immediate early genes in the nervous sys-
`tem. Neuron 1990;4z477-485.
`Curran T, Morgan JI. Supei‘induction of c-fos by nerve
`growth factor in the presence of peripherally active benzodi—
`azepines. Science 1985;229:1265-1268.
`Hunt SP, Pini A, Evan G. Induction of c-fos—like protein in
`spinal cord neurons following sensory stimulation. Nature
`1987 ;328:632-634.
`Anton F, Herdegen T, Peppel P, et al. C—fos—like immunore-
`
`June 1993 NEUROLOGY 43 (Suppl 3) S19
`
`4
`
`

`

`34.
`
`35.
`
`36.
`
`37.
`
`38.
`
`activity in rat brainstem neurons following noxious chemical
`stimulation of the nasal mucosa. Neuroscience 1991;
`41:629-641.
`Bullitt E. Expression of c—fos—like protein as a marker for
`neuronal activity following noxious stimulation in the rat. J
`Comp Neurol 1990;296:517-530.
`Presley RW, Menétrey D, Levine JD, et al. Systemic mor-
`phine suppresses noxious stimulus-evoked fos protein—like
`immunoreactivity in the rat spinal cord. J Neurosci 1990;
`10:323-335.
`
`Gogas KR, Presley RW, Levine JD, et al. The antinociceptive
`action of supraspinal opioids results from an increase in
`descending inhibitory control: correlation of nociceptive
`behavior and c-fos expression. Neuroscience 1991;42:617-
`628.
`
`Nozaki K, Boccalini P, Moskowitz MA. Expression of
`c—fos—like immunoreactivity in brain stem after meningeal
`irritation by blood in the subarachnoid space. Neuroscience
`1992;49:669-680.
`Strassman A, Mason P, Moskowitz M, et al. Response of
`brainstem trigeminal neurons to electrical stimulation of the
`dura. Brain Res 1986;379:242-250.
`
`39.
`
`40.
`
`41.
`
`42.
`
`43.
`
`Macor JE, Bukhart JH. Heym JH, et al. 3412 6'
`Tetrehydropyrid-4-yl)pyrrolo[3,2-b] pyrid—5—one: a Ptlltz:
`and selective serotonin (5-HT1B) agonist and mtation ll
`restricted phenolic analogue of 5-methy1-3-(1,2.5.6-1—,etm1|-IJ-
`dropyrid-4-yl) indole. J Med Chem 1990;33:1087—1093,
`"
`Matsubexa T, Moskowitz MA, Byun B. CP—93,129, a Pu
`_
`and selective 5-HT1B-—receptor agonist blocks maul-33:”?q
`plasma extravasstion within rat but not guinea—pig dull“-
`mater [special report]. Br J Pharmacol 1991;104:34.
`’!
`Nozaki K, Moskowitz MA, Boccalini P. CP-93.129, Sumatfi
`tan, dihydroergotsmine block c—f‘os expression Within P4
`tz-igeminal nucleus caudalis caused by chemical stiuiulaé:i
`of the meninges. Br J Phs-rmaco] 1992;196:409-415.
`Moskowitz MA, Nozaki K, Kraig RP. Noncorticai 313%
`depression provokes the expression of c-fos Pmteimli},
`immunoreactivity within trigeminal nucleus caudalis 75!
`trigeminovascular mechanisms. J Neurosci 1993;13:11313
`1177.
`"
`
`
`
`
`
`
`Moskowitz MA. Neurogenic vs vascular mechanisms or
`sumatriptan and ergot alkaloids in migraine. Treud's
`Pharmacol Sci 1992;13:307-311.
`'
`
`
`
`s20 NEUROLOGY 43 (Suppl 3) June 1993
`
`5
`
`5
`
`

`

`
`
`This supplement to Neurology was produced by the Health Care Projects division of
`Advanstar Communications Inc., under an educational grant from
`CerenexTM Pharmaceuticals, division of Glaxo Inc., Research Triangle Park, NO.
`The views and opinions expressed in this supplement are those of the participants and authors
`and do not necessarily reflect the views of the editors, Advanstar Communications Inc., or
`CerenexTM Pharmaceuticals.
`‘
`
`Copyright © 1993 Advanstar Communications Inc. All rights reserved.
`
`Q _
`ADVANST
`
`Bernard J. Rogers
`Jeffrey M. Preston
`Eric Gulley
`Kristi Thomsen
`
`President/ Group Publisher
`Vice President /Director
`Associate Director
`Editor
`
`Janice Weaver Managing Editor
`David C. Smith
`Associate Editor
`
`Sandra Houghton
`Andrea Junker
`Bonnie Ling
`
`Editorial Assistant
`Production Manager
`Production Director
`
`Editorial Offices: 7500 Old Oak Blvd., Cleveland, OH 44130. Telephone: (216) 891-2757
`Publishing Offices: 270 Madison Ave., New York, NY 10016. Telephone: (212) 951-6633
`
`Printed in USA
`
`@-
`
`This publication is printed
`on recycled paper using soy-based ink.
`
`6
`
`

`

`'ilJUNE1993 * VOLUME 43 - NUMBER 6 ' SUPPLEMENT 3
`||.
`i
`
`.r'E'fifi‘p
`
`E“-
`43:3"Cifilllfllll1%
`
`
`
`Advances in '
`biology and pharmacOIOgy
`of headache
`
`_
`
`SSIEE‘QE
`UniversityofWisconsin
`
`,-
`5
`a
`m
`[M
`
`HEALTH
`
`Offitzial Journal of the American Academy of Neurology
`
`James W. Lance, MD
`Supplement Editor
`
`'
`
`g
`9-3
`
`5 1305LindenDriveMadison,WI53706
`
`JUN1
`
`7
`
`