`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
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`
`
`
`
`4 gningesl projections from cat trigeminal ganglia: possible
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`Macor JE, Bukhart JH. Heym JH, et al. 3412 6'
`Tetrehydropyrid-4-yl)pyrrolo[3,2-b] pyrid—5—one: a Ptlltz:
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`"
`Matsubexa T, Moskowitz MA, Byun B. CP—93,129, a Pu
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`and selective 5-HT1B-—receptor agonist blocks maul-33:”?q
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`Nozaki K, Moskowitz MA, Boccalini P. CP-93.129, Sumatfi
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`"
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`
`
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`'
`
`
`
`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.
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`'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
`
`