new investigational drugs for the treatment of neuropathic pain
TRANSCRIPT
1. Introduction
2. Drug targets for the treatment
of NP
3. Expert opinion
Review
New investigational drugs for thetreatment of neuropathic painKinga Sałat, Paula Kowalczyk, Beata Gryzło, Anna Jakubowska &Katarzyna Kulig†
†Jagiellonian University, Department of Physicochemical Drug Analysis, Faculty of Pharmacy,
Krakow, Poland
Introduction: Neuropathic pain (NP) is a chronic condition that arises from a
lesion or dysfunction of the somatosensory nervous system. However, there
are several new targets and novel technologies in the pipeline to address
this unmet medical need.
Areas covered: In this review, the authors briefly discuss a direction of the
development of agents that could be potentially used in NP treatment. Spe-
cial attention is paid to 1.7-selective voltage-gated sodium channels, N-type
voltage-gated calcium channels, angiotensin II (Ang II) AT2 receptors and
nerve growth factor (NGF) as promising targets for new drugs. Furthermore,
the article also presents and discusses, in detail, the results of Phase II clinical
studies with the AT2 receptor antagonist - EMA401 in NP (the results of
Phase II clinical trials of other described compounds are not available, yet).
Expert opinion: There is a real hope that new drugs for NP may be available
soon. This hope is based on advancing methods of genomics, developing
new targets and more efficient drug screening. Some forms of direct influ-
ence on voltage-gated ion channels have a place in the treatment of NP, while
the development of entirely novel Ang II AT2 receptor antagonists or NGF
inhibitors may be available for many chronic pain sufferers in the foreseeable
future.
Keywords: angiotensin II AT2 receptor antagonists, inhibitors of Nav1.7 channels,
neuropathic pain, N-type calcium channel antagonists, Phase II clinical studies, tanezumab
Expert Opin. Investig. Drugs [Early Online]
1. Introduction
1.1 What is neuropathic pain?Neuropathic pain (NP) affects between 3 and 8% of the world’s population, withunpleasant consequences on the patients’ quality of life, general mood and occupa-tional functioning [1,2]. The International Association for the Study of Pain definespain as an unpleasant sensory and emotional experience associated with actual orpotential somatic or visceral tissue damage generated by noxious or potentiallyinjurious stimulus, or described in terms of such damage [3,4]. In this context, NPis a chronic disease that stems from a primary lesion or dysfunction of the centralor peripheral nervous system [4,5]. Numerous factors, inter alia nerve trauma, viralinfections caused by Herpes or HIV viruses, cancer or its treatment with drugs,such as platinum-based drugs (cisplatin, oxaliplatin), vincristine and paclitaxel areresponsible for the development of NP [6,7]. NeuPSIG treatment guidelines specifythe first-line therapy for NP as tricyclic antidepressants (desipramine, nortriptyline),dual serotonin and noradrenaline re-uptake inhibitors (duloxetine, venlafaxine) anda2d ligands of voltage-gated calcium channels (VGCCs) (pregabalin, gabapentin),while classical analgesics, such as opioids, are used only in certain clinicalconditions, for example, in cancer-related NP [8,9].
10.1517/13543784.2014.916688 © 2014 Informa UK, Ltd. ISSN 1354-3784, e-ISSN 1744-7658 1All rights reserved: reproduction in whole or in part not permitted
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Typically NP is featured by allodynia, that is, pain that arisesin response to innocuous stimuli (e.g., light touch), andhyperalgesia -- a decrease in pain threshold resulting in anincreased pain sensation in response to a normally painful stim-ulus. Both these phenomena are due to excessive excitabilityand pain sensitization that may occur peripherally (‘peripheralsensitization of pain’ -- the release of cytokines, growth factorsand other nociceptive mediators, the activation of G-protein-coupled receptors [GPCRs], ion channels and tyrosine kinasereceptors) or centrally (‘central sensitization’ -- synapticplasticity and an increased synaptic transmission via increasedsensitivity of the secondary neurons in the dorsal horn of thespinal cord). Thus, sensitization arises from the functionalalteration of molecules involved in pain perception, nociceptivetransduction or transmission or from structural neuroplasticitywithin the spinal cord [5,10].
1.2 Peripheral sensitization of painNumerous mechanisms are implicated in pain sensitization atthe periphery. All of them cause an increased responsivenessof peripheral primary afferent neurons. In this process, theactivation of protein kinases by GPCRs (due to the activationof, e.g., purinergic P2Y receptors or bradykinin B2 receptors)catalyzes phosphorylation of downstream targets. Thephosphorylation of voltage-gated ion channels increases theirinward currents, while the activation of downstream enzymesactivates the inflammatory signaling cascade. When activated,
peripheral receptors also stimulate the release of neuropepti-des (e.g., substance P -- SP, and cholecystokinin), whilethe release of neurotrophic factors and the activation ofsecond messenger systems can alter the expression of variouscomponents of nociceptive signaling pathways. Both thereduction of inhibitory pathway components andthe increases in excitatory pathway components underlie thedevelopment of peripheral sensitization of pain [5,11,12].
1.3 Central sensitization of painCentral (secondary) sensitization of pain occurs within thedorsal horn of the spinal cord. At the central level, the synap-tic transmission is modulated by rapid ligand-gated ion chan-nels (glutamate ionotropic receptors: AMPA, NMDA),metabotropic receptors (glutamate metabotropic receptors)and other slow modulatory pathways (SP, calcitonin gene-related peptide [CGRP], neurotrophic factors: brain-derivedneurotrophic factor [BDNF], nerve growth factor [NGF])which downstream activate other signaling pathways, inducethe phosphorylation of NMDA receptors and its conforma-tional change with the dissociation of magnesium ions andcalcium influx. The latter leads to the activation of extracellu-lar signal-related protein kinase (ERK is known as MAPK1),stimulation of neuronal nitric oxide synthase, activation ofneuronal cyclooxygenase and calcium-sensitive transcriptionfactors. This subsequently results in glial cells activation,production of inflammatory cytokines, generation of reactiveoxygen species and a structural remodeling at the spinalcord level [4,8].
2. Drug targets for the treatment of NP
The pharmacotherapy of NP remains an important compo-nent of multimodal, multidisciplinary pain management.Despite recent progress in the understanding of pathophysio-logical mechanisms, diagnosis and the treatment of NP, manypatients (40 -- 50%) remain refractory to, or intolerant of, theexisting pharmacological treatment. A complex cascade ofevents implicated in peripheral and central sensitization ofNP makes its treatment very difficult and at present notentirely satisfactory. There is still a research effort that aimsat the improvement of our understanding of the etiology ofNP and its mechanisms [13]. Despite this, NP remains oftenintractable [14,15] and its management is still a challengingendeavor. On the other hand, novel molecules that havebeen discovered as factors underlying the development ofNP are potential therapeutic targets for new analgesic drugs.These include [16-27]:
. Voltage-gated ion channels selectively permeable forsodium, calcium or potassium ions
. Non-selective and cation-permeable channels, such asTransient Receptor Potential channels
. Ionotropic receptors (N-methyl-D-aspartate,GABAergic receptors)
Article highlights.
. Neuropathic pain (NP) causes suffering and disability formany patients, and is an important public healthproblem, so there is a significant need to search for newclasses of analgesics and explore novel drug targets.
. The Nav1.7-selective inhibitors demonstrate analgesicefficacy without causing unwanted adverse effectstypical for classical non-selective sodium channelinhibitors.
. Efforts have been made to develop a new, systemicsmall-molecule N-type calcium channel antagonist forNP. Although this agent was generally safe andwell-tolerated, it did not meet the primary end point inthe Phase II clinical trial, so the program wasdiscontinued.
. The comparison of angiotensin II AT2 receptorantagonist with available analgesics shows that thiscompound is clinically efficacious and might be a newtreatment option.
. Tanezumab, a first-in-class recombinant humanizedanti-nerve growth factor (NGF) antibody in Phase IIclinical trials in osteoarthritic pain and chronic lowerback pain, demonstrates good efficacy and a goodsafety profile, so it also appears to be particularly wellsuited for targeting chronic pain actions of NGF and itsreceptor system.
This box summarizes key points contained in the article.
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. GPCRs (histaminergic H3, Ang II AT2 receptors)
. Receptor chaperones (sigma-1 receptors)
. Transporters for neurotransmitters: serotonin,dopamine, noradrenaline
. Systems: endocannabinoid, purinergic signaling systems
. Hormones (erythropoietin)
. Cytokines (TNFa, IL1b, IL-6, IL-17, IFNg)
. Neurotrophins (NGF and BDNF)
. Enzymes (MAPK)
In the recent years, much attention has been paid to therole of voltage-gated sodium (Nav) channels and VGCCs, aswell as the renin-angiotensin system (RAS) beyond thecirculatory system. Also, the role of NGF in NP is discussed.Available data indicate that they might be regarded as poten-tial drug targets for novel analgesic active drug candidates forthe treatment of NP. At present, some of these compoundsare tested in Phase II clinical trials in neuropathic patients.Below the current state of the art regarding their analgesicactivity is discussed.
2.1 Ion channels
2.1.1 Nav channelsThe therapeutic potential of targeting Nav channels to treatpain is well known with abundant evidence demonstrating acritical role for these structures in pain transmission. Nav areheteromultimers of a large pore-forming a-subunit andsmaller auxiliary b-subunits [28]. The a-subunit has fourdomains, each consisting of six transmembrane segmentsthat are connected by intra- and extracellular linkers.b-subunits are type I membrane proteins, each with a singletransmembrane segment and a larger extracellular domain.Based on nine different a-subunits encoded by distinct genes(SCN1A-5A, SCN8A-11A), nine sodium channels aredistinguished [28]. These channels are essential for theinitiation and propagation of action potentials and thereforeneuronal conduction. Importantly, following transduction oftissue-damaging and chemical stimuli, the transmission ofpain depends on sodium channels, thus pointing to thesemolecules as important targets in nociception resulting fromtissue damage [13,18,19,29-35]. Up to date, these nine sodiumchannel subtypes are postulated to have an impact on sensoryneuronal effect.
Nav1.1 and 1.6 -- 1.9 are expressed at high levels in the dor-sal root ganglia (DRG) and hence they are relevant forprimary afferent transmission. Of these, the Nav1.7 -- 1.9channels are of particular interest, since they are preferentiallyexpressed on peripheral nerve endings being linked to chronicinflammatory and NP conditions. Nav1.8 and Nav1.9 arelimited to sensory and myenteric neurons, while Nav1.7 chan-nels are expressed in sensory, sympathetic and myenteric neu-rons [28]. Recent human studies demonstrated that SCN9A, agene encoding Nav1.7 channel, is implicated in some humanpain syndromes, including dominantly inherited gain-of-function mutations in erythromelalgia, whose treatment
with classical sodium channel blockers (lidocaine, mexiletine)is not satisfactory [28].
At present, numerous drugs possessing sodium channelblocking properties are used for the treatment of NP. Theseinclude tricyclic antidepressants (amitriptyline, nortriptyline),local anesthetics (mexiletine, lidocaine) and anticonvulsants(carbamazepine, lamotrigine, phenytoin). Unfortunately, insome patients they provide only a partial relief from NP.Moreover, some of these drugs (e.g., tricyclic antidepressants)are featured by a narrow therapeutic window, and they possesscardiovascular- and CNS-associated adverse effects. This is atleast in part due to the lack of specificity for sodium channelisoforms [29]. In view of this, several novel strategies are beingexplored in the search for better sodium channel blockers.Novel compounds targeting at sodium channel isoforms(i.e., compounds with increased isoform selectivity) preferen-tially expressed in peripheral sensory neurons involved in paintransduction and transmission, novel techniques for limitingthe effects of sodium channel ligands to the periphery ordesign of compounds that target specific patterns of sodiumchannel activity associated with pain are a leading researchdirection [28,29]. Among these agents, only Nav1.7 modulatorsare in the Phase II clinical studies now [13,18,19,29-35].
2.1.1.1 Nav1.7-selective inhibitorsThe Nav1.7 channels, solely expressed in the nociceptive andsympathetic nervous system, have been proposed as an inter-esting drug target for pain caused by impairments of sensoryperception or noxious peripheral stimuli. The clinical geneticinvestigations indicated that these sodium channels havepotential to become one of the most important targets forthe treatment of all types of pain. The Nav1.7-selectiveinhibitors in contrast to inhibitors of other Nav channelsthat are expressed in the heart and the CNS demonstrateclinical analgesic efficacy without causing unwanted adverseeffects [33,34,36,37].
PF-05089771 (Figure 1) is a sulfonamide derivative thatexhibits 1000-fold selectivity for Nav1.7 (IC50 = 11.0 nM)versus tetrodotoxin (TTX)-resistant Nav1.5 and Nav1.8 chan-nels (IC50 > 10 mM) and a range of selectivity overTTX-sensitive Nav1.2, Nav1.3 and Nav1.4 (10-foldNav1.2 -- 900-fold for Nav1.3 and Nav1.4). It is worth tonote this compound displays also a 1000-fold selectivitytoward the Nav1.7 channel versus other ion channel classes,such as cardiac calcium and potassium channels. To date, inthe Phase I of clinical studies, PF-05089771 was found tobe safe and well tolerated at systematic exposures reachingunprecedented high multiples of in vitro potency.PF-05089771 is currently being evaluated as a new paintherapy in the Phase II clinical trial entitled ‘A randomized,double blind third party open placebo-controlled exploratorystudy to evaluate the efficacy and safety of single doses ofPF-05089771 in patients with primary (inherited) eryth-romelalgia’ in which the efficacy and safety of two singleoral doses (each 1600 mg) of PF-05089771 against placebo
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in the treatment of pain in patients aged 18 -- 78 years withinherited erythromelalgia are assessed [38].CNV1014802 (Figure 1) is a peripherally and centrally
acting sodium channel inhibitor that shows selectivity forthe Nav1.7 over other subtypes tested (Nav1.1, Nav1.2,Nav1.5 and Nav1.6). This compound is also a selective andreversible inhibitor of the monoamine oxidase isoenzyme B(MAO-B) with no effect on MAO-A. One hundred percentinhibition of MAO-B was achieved with doses of 75 mg andabove in clinical studies [39,40]. CNV1014802 has successfullycompleted the Phase I studies with single and repeated dosesin 166 healthy volunteers. Currently, this new Nav1.7 blockeris a subject of further studies aiming at the evaluation of itsefficacy in trigeminal neuralgia. The final results of this trialare expected in the first half of 2014 [40].Another Nav1.7-selective agent is a neutral spiro-indole
derivative from XEN402 (IC50 80 nM), which has effectivelytreated pain in patients with congenital erythromelalgia, anNP disorder due to point mutations in the TTX-sensitivechannel Nav1.7 [41]. In the Phase I healthy volunteer studies,XEN402 (Figure 1) was found to be safe and welltolerated. The Phase II clinical studies of this compoundversus placebo were performed in a small group of patientsand for the short dosing period (2 days). However, significantimprovements were observed in the time taken to inducepain, the magnitude of induced pain and/or reductionsin the amount of pain experienced in the 2 h afterinduction [42-44].
2.1.2 Voltage-gated calcium channelsVGCCs are macromolecular protein assemblies consisting ofa pore-forming a-subunit and auxiliary a2d, b and g subu-nits. Based on a combination of biophysical and physiologicalstudies, VGCCs are classified into five different types: L, N,P/Q, R and T. It was found that VGCCs play a significant
role in the transmission of painful signals toward the higherlevels of the CNS, being localized abundantly at the dorsalhorn of the spinal cord level, where the activity of N-typechannels (Cav2.2 channels) modulates neurotransmitterrelease [19,22,24,26,45,46].
2.1.2.1 N-type calcium channels antagonistsPharmacological studies on the role of N-type calcium chan-nels in the therapy of pain were based on the finding thatw-conotoxins isolated from a marine snail Conus geographusreduced pain behavior and the activity of the dorsal horn ofthe spinal cord in response to evoked noxious and non-noxious stimuli. It was found that spinally administeredantagonists of these channels block nerve injury-induced tac-tile allodynia and DRG responses [45]. Ziconotide is a syn-thetic form of w-conotoxin that is licensed for the treatmentof intractable pain, but its use is limited by significant nervoussystem, sympathetic and cardiac adverse effects, narrow thera-peutic window and the intrathecal delivery [33].
To overcome these limitations, efforts have been under-taken to develop systemic small-molecule N-type (Cav2.2)VGCC inhibitors [33,46].
Z160 (Figure 1) is an oral N-type calcium channel blockerthat has advanced to clinical trials. This compound blocksnative and recombinant N-type calcium channel currents inan irreversible, dose-dependent manner with sub-micromolarpotency and 25- -- 100-fold selectivity over P/Q- and L-typecalcium channels. Recently, Z160 has been evaluated as anew pain therapy in Phase II clinical studies toward its efficacyin lumbosacral radiculopathy (LSR) and postherpetic neural-gia (PHN) [24,30,47-50]. Z160 did not meet the primary endpoint in either of the Phase II studies in patients with NP.It was not able to cause a change in weekly average of dailypain scores in patients with LSR and did not induce a signif-icant change from baseline to week 6 in the weekly average
CNV1014802 XEN402 PF-05089771
Z160
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Figure 1. Structures of Nav and calcium channel blockers: PF-05089771, CNV1014802, XEN402, Z160 and Z944.Nav: Voltage-gated sodium.
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pain score based on Pain Intensity-Numeric Rating Scalein patients with PHN. In view of this, althoughZ160 was generally safe and well-tolerated with no drug-related serious adverse effects, the Z160 program was discon-tinued. The precise description of study results is still notavailable.
2.1.2.2 T-type calcium channels antagonistsIt is postulated that T-type calcium channels situated in noci-ceptive sensory neurons are important for controlling cellularexcitability. Thus, compounds that modulate their functionmay affect both peripheral and central sensitization of neu-rons in the pain pathway [51].
Z944 (Figure 1) is a novel, oral, state-dependent, selectiveT-type calcium channel modulator that has demonstratedefficacy in multiple preclinical pain models. The Phase Ibstudy was conducted in a single center in Germany utilizingLaser-Evoked-Potentials model to provide both objectiveand subjective assessments of the activity of Z944 in inducedpain states. The results of those studies showed that Z944 wasgenerally well tolerated with dose-dependent CNS side effectsand no serious adverse events [52-54]. The clinical Phase IIstudy of Z944 is scheduled to 2014.
2.2 Renin-angiotensin systemAng II is an octapeptide that regulates blood pressure andfluid balance via two GPCRs (AT1 and AT2) that mediateits biological functions [55-57]. Both AT1 and AT2 receptorsbelong to the G protein-coupled receptor family, also knownas seven-transmembrane domain receptors. Molecular studies
revealed that AT1 and AT2 receptors share ~ 30% amino acidsequence similarity [55].
In the RAS, renin converts angiotensinogen toangiotensin I, which in turn is cleaved by the angiotensin con-verting enzyme (ACE) to Ang II (Figure 2). It is assumed thatmost of the physiological effects of Ang II, contraction ofsmooth muscles leading to vasoconstriction and increase inblood pressure, increase in water and sodium intake, renalsodium retention and secretion of vasopressin and aldoste-rone, are mediated by the stimulation of AT1 receptors, whilethe role of AT2 receptors is not so well understood. It is sug-gested that the stimulation of AT2 receptors may oppose thebiological effects mediated by AT1 receptors -- in particulartheir effects on cell growth, blood pressure and fluid intake.AT2 receptor stimulation suppresses cellular growth, inducesneuronal differentiation and stimulates apoptosis [58].
Apart from the role as an important component of the cir-culatory RAS, Ang II is a neurohormone and a neuromodula-tor [58] in the local RAS present in various organs, includingthe brain [56,58] and the spinal cord [55]. In these local systems,Ang II controls numerous sensory modalities, includingnociception [57].
2.2.1 Ang II AT1 and AT2 receptors in the pain
pathwayThere is evidence that Ang II through its receptors participatesin the central and peripheral regulation of sensory informa-tion, nociception, taste and vision [56]. In mammalian organ-isms, the expression of receptors for Ang II was demonstratedinter alia in the spinal cord and the DRG [55,56]. AT1 [56] and
Angiotensinogen
Angiotensini
Angiotensini II
Analgesics for neuropathic painAntihypertensive drug
AT1receptor
AT2receptor
D R V Y I H P F H H N COOH
COOH
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Renin
ACE
L
D R V Y I H P F
COOHH2N D
LosartanPD123319 (EMA 200)
EMA 300EMA 400EMA 401
R V Y I H P F
H L
V I
Figure 2. Components of the RAS.RAS: Renin-angiotensin system.
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AT2 receptors [59] have been found in rat and human DRG,trigeminal ganglia, dorsal horn of the spinal cord and in thesciatic nerve, indicating for the existence of an intrinsic angio-tensinergic system there [56,59,60]. In addition, both the expres-sion of AT1 receptors and the conversion of Ang II -- III inneurons of the CNS are involved in the descending painmodulation [56].It was shown [55,56] that AT1 receptors are present in high
density in the lumbar superficial dorsal horn (laminae I andII) in rats and mice. Furthermore, it was demonstrated thatin humans and rats Ang II co-localizes with SP and CGRPin the neurons of DRG, which suggests that Ang II mightplay a role in pain transmission [55].In rodents, a marked hyperalgesia after systemic adminis-
tration of Ang II was shown in the chronic constriction injurymodel (CCI) using von Frey test and thermal methods. Thiseffect was attenuated by losartan - the AT1 receptor antago-nist, indicating that the activation of AT1 receptors is pivotalfor the perception of NP, and that these receptors play a keyrole in the injury of large-diameter neurons of DRG, as wellas in the activation of satellite glial cells surrounding the pri-mary sensory neurons of the DRG [57].It was also demonstrated that the phosphorylation of spinal
p38 MAPK but not of the other MAPKs is involved in AngII-related nociception via non-transcriptional mechanisms,plausibly through posttranscriptional modifications of kin-ases, ion channels and receptors [55]. Losartan (AT1 receptorantagonist) inhibited p38 MAPK phosphorylation in the dor-sal horn of the spinal cord, while no effect was observed in thecase of PD123319 (EMA200), an antagonist of AT2 receptor.Thus, it was hypothesized that AT1 receptors play multiplefunctions in controlling sensory neurotransmission and theyregulate the activity of motor neurons [55,56].Abundant distribution of AT2 receptors was demonstrated
in the brain and viscera of adult mice and on small- tomedium-sized DRG neurons in adult rats and humans. Inhumans, AT2 receptors are expressed on peripheral nervefibers, in the skin, urinary bladder and bowel [61]. Ang IImay act as a neurotransmitter on upregulated AT2 receptorsin sensory neurons by autocrine, paracrine and systemicmechanisms [61]. In cultured neuronal cells, Ang II inducedneuronal excitability and neurite outgrowth and these effectswere blocked by selective small-molecule AT2 receptor antag-onists: PD 123319 (EMA200) and EMA401 [61,62]. Hence, itis thought that AT2 receptors also play a role in nociceptionand neuronal regeneration [59].
2.2.2 RAS as a drug target for NPThe inhibition of Ang II formation by ACE inhibitors is oneof the leading methods to treat hypertension. Similar effectscan be achieved by a selective blockade of AT1 receptors.Recent evidence showing the co-localization of Ang II withSP, NGF and CGRP in DRG neurons indicates for a roleof this octapeptide in nociception [59,61].
In rodents, repeated oral administrations of AT1 receptorantagonist, losartan and ACE inhibitors exert antinociceptiveeffects in the hot plate test, whereas the intrathecal adminis-tration of losartan produces antinociception in the formalintest [55,63].
On the other hand, numerous data indicate that AT2 recep-tor antagonists are efficacious in NP models in rodents, aswell [64,65]. AT2 receptors partly co-localize withTRPV1 channels, and Ang II is able to enhance capsaicinresponses in DRG neurons in the rat [66]. The distributionof AT2 receptors in human DRG nociceptors along with theirco-localization with TRPV1 suggests that AT2 receptor antag-onists may inhibit pain perception in clinical disorders [66]. Invitro Ang II signaling via AT2 receptors induces phosphoryla-tion of tyrosine kinase-A receptor (TrkA) receptors indepen-dently of NGF action to produce sustained activation ofp44/p42 MAPK and neurite overgrowth [61].
2.2.3 Ang II AT2 receptor antagonists in animal
models of NPIn view of aforementioned data, several AT2 receptor antago-nists with > 1000-fold selectivity over AT1 receptor have beendeveloped as potential novel analgesics for alleviation of NP(Figures 3 and 4): EMA200 (also referred to as PD 123319),EMA300 (PD 121981), EMA400 (PD 126055) andEMA401 ((S)-enantiomer of EMA400) [61,62].
Their analgesic efficacy was proven in several nonclinicalmodels of NP [61,64] and inflammatory pain [65]. For instance,in rats that underwent CCI of the sciatic nerve these com-pounds produced a dose-dependent analgesia [61,62] with thefollowing analgesic potency rank order: EMA400 >EMA300 > EMA200 [62].
In CCI rats, single i.p. bolus doses (0.003 -- 0.03 mg/kg) ofEMA400 produced a strong antiallodynic effect with a rapidonset and mean peak analgesia between 30 and 75 min afteradministration. At doses tested, EMA400 did not induce seri-ous adverse effects. In CCI rats, its ED50 value was 0.013(0.008 -- 0.021) mg/kg showing that EMA400 was~ 250-fold more potent than EMA200 and almost 60-foldmore potent than EMA300 for the attenuation of mechanicalallodynia [62].
In cultured rat and human DRG neurons, EMA401reduced neurite length and was able to inhibit capsaicinresponses with IC50 = 10 nmol/l. In rodent models of NP,EMA401 was also efficacious [64,65]. Other studies demon-strated that it did not cause neurite vesiculation or disintegra-tion indicating that it was not neurotoxic [66]. NGF-inducedneurite outgrowth in rDRG cultures was not affected byEMA401, while sharing features in common with anti-NGFantibodies, so it was concluded that this compound mightprovide a safer therapy as compared to anti-NGF therapy,and AT2 receptor antagonists might be useful in chronicpain and hypersensitivity associated with abnormal nervesprouting [66].
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2.2.4 EMA401 -- the lead compound and the first-in-
class orally bioavailable AT2 receptor antagonist for
the treatment of patients with PHNThe aforementioned high analgesic potency without signifi-cant CNS distribution, along with no serious CNS-relatedadverse effects shown in rats treated with 1000 mg/kg (oral),the superior pharmacokinetics of EMA400 and its S-enantio-mer EMA401 in rats compared to EMA200 and EMA300,as well as high binding selectivity for the AT2 receptorunderpinned EMA401 as a lead compound for furtherinvestigations on its antinociceptive efficacy.
Recently, EMA401 (Figure 3) has been tested in Phase IIprogram in humans as a novel analgesic drug for thetreatment of NP [62,67]. Its activity and bioavailability after
oral administration was evaluated in patients suffering frompain related to PHN [59,67]. In a 4-week, double-blind,randomized, placebo-controlled clinical study, EMA401produced significant analgesia compared to placebo and waswell tolerated. EMA401 did not cross the blood--brain barrierand was devoid of CNS-associated adverse effects [62].
In August 2012, these positive results from the Phase IIclinical trial of EMA401, a potential first-in-class orallyavailable AT2 receptor antagonist in patients with PHNwithout causing central nervous system side effects, wereannounced. The official title of this trial was: ‘A double-blind,placebo-controlled, randomized trial to prove the therapeuticconcept and to determine the safety, tolerability, pharmacoki-netic profile and efficacy of EMA401 (Ang II type 2 receptor
EMA300EMA200
EMA401 EMA402EMA400
O N
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Figure 3. Ang II AT2 receptor antagonists with antiallodynic properties in NP models in rodents.Ang II: Angiotensin II; NP: Neuropathic pain.
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AT2 receptor (rat) AT1 receptor (rat)
Figure 4. Radioligand binding affinities at AT2 and AT1 receptors (rats) of small molecule Ang II AT2 receptor antagonists [63].Ang II: Angiotensin II.
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antagonist) administered orally in patients with PHN.’ Thisstudy enrolled 183 patients (92 patients received EMA401,while other 91 received placebo) and was recruited in sixcountries [67].
2.2.4.1 Phase II clinical development of EMA401The primary objective of this Phase II clinical trial was todetermine the efficacy of EMA401 after oral administrationtwice daily (100 mg b.i.d) in patients suffering from PHN,as assessed by the difference in their mean pain intensity scorecompared to placebo. Patients were allowed to continuetaking only one drug approved for NP treatment; however,they had severe or moderate pain when they entered the study.The clinical trial achieved its primary end point, that is, the
reduction in mean daily pain intensity score versus placebo(using the 11-point numerical rating scale/Likert scale)between baseline and the last week of dosing (Days22 -- 28). The patients who were included were randomlydivided to receive either 100 mg EMA401 or placebo twicedaily orally for 28 consecutive days with the final dose onthe morning of Day 29 for the establishment ofpharmacokinetic parameters.In EMA401 group, the mean pain intensity reduction from
baseline after 4 weeks of treatment was -2.34, and in placebo-treated group -1.64. This difference was statistically significantat p = 0.006. The secondary end point, that is, the proportionof patients achieving a ‡ 30% reduction in mean pain intensityscore compared to baseline (i.e., responder rate) was also met(placebo group: 34.1%, EMA401 group: 56.5%; p = 0.003).The second of the secondary end points, that is, the onsetand maintenance of the effect as defined by pattern of changein the mean pain intensity score over the entire TreatmentPeriod is currently being statistically evaluated.In this trial, EMA401 was generally safe and well tolerated
without causing any serious adverse events. The number ofpatients reporting at least one treatment-emergent adverseevent was 32 (34.8%) in the EMA401 group versus29 (31.8%) in the placebo one. Headache was prevalent inthe EMA401 group in six patients (7%). The other adverseeffects observed in the EMA401 group were nausea, pharyngi-tis and allergic dermatitis in three patients (3%) and upperabdominal pain in one of them (1%) [67]. Interestingly,although available literature pointed out to an importantrole of AT2 receptors in the cardiovascular and renal system,no significant changes occurred during this study. Thisabsence of EMA401-induced adverse effects suggests the pos-sibility of the use of doses higher than 100 mg twice daily infuture trials [67].To conclude, existing therapies for PHN-associated pain
comprise orally administered tricyclic antidepressants,opioids, anticonvulsants, as well as topical therapies contain-ing lidocaine and capsaicin. These therapies are efficaciousfor between every second and ninth patient treated [67].Available results from the Phase II clinical trial indicate thatin patients with PHN EMA401 has analgesic efficacy that is
at least comparable to other approved orally administeredtreatments using pregabalin at doses 300 and 600 mg or gaba-pentin at 1200 mg. By contrast with these current therapies,the lack of treatment-emergent adverse effects related toEMA401 at the dose tested suggests the further need tooptimize its use in neuropathic patients [67].
The Phase II clinical study on EMA401 demonstrated thatthis compound administered orally at the dose of 100 mgtwice daily resulted in the relief of PHN-associated pain,which was evident by the third week of treatment andEMA401 provided superior analgesia when compared to pla-cebo. This pain relief was observed when EMA401 was usedeither alone or in combination with available analgesics forPHN, so EMA401 might be regarded as a new and promisingtreatment option. It should be however noted that this onlyone 4-week study is a main limitation and further studiesare necessary [67]. Good tolerance of EMA401 encouragessuch further clinical trials aiming at the assessment of theefficacy of doses higher than 100 mg and longer term treat-ment to establish both the efficacy and possible adverse effectsof such treatment regimens. The efficacy of EMA401 in otherNP syndromes should be also assessed in patients with NPfollowing peripheral nerve injury and in patients withchemotherapy-induced peripheral neuropathy [68].
2.3 Nerve growth factorNGF was discovered more than a half century ago and is thefirst neurotrophic factor that was identified, purified and bio-chemically characterized. NGF is a 13 kDa polypeptidesecreted as a dimer from target cells of sympathetic andsensory neurons, and is involved in the growth, signalingand survival of neurons. In the developing nervous system,the primary role of NGF is the control of neuronal survival,while in adults its role shifts to a more protective one, atorganismal level by mediating pain from noxiousstimuli [69,70].
NGF is a target-derived neurotrophin and upon its releaseit binds to a receptor complex located on the distal ends ofaxons that innervate the target in which NGF is produced.The effect of NGF is mediated by its binding to this receptorcomplex that consists of the TrkA and the p75 neurotrophinreceptor (p75NTR) [69,70].
In humans, the levels of NGF are elevated in a variety ofacute and chronic pain states, including rheumatoid arthritisand spondyloarthritis, neurogenic overactive bladder andinterstitial cystitis, cancer-induced pain, prostatitis, endome-triosis and in patients with degenerative intervertebral discdisease. The evidence that NGF is important in the mediationand potentiation of pain has led to the development of NGFantagonists as potential analgesics and antihyperalgesics [71,72].
Of the pharmacological agents developed to date, antibod-ies that block the interaction of NGF with its receptors haveshown the most promising therapeutic potential. A numberof clinical trials focusing on the use of anti-NGF antibodies
K. Sałat et al.
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have been run for tanezumab, fulranumab, REGN 475, PG110 and MEDI 578 [70,71].
Among these compounds, tanezumab is in the mostadvanced phases of clinical studies. It is a humanized IgG2
antibody that blocks the interaction of NGF with its receptorsTrkA and p75NTR, and the complex obtained has a half-lifelonger than 100 h.
In order to evaluate its clinical efficacy in the treatment ofchronic pain syndromes, tanezumab was studied in patientswith painful diabetic neuropathy, lower back pain (LBP; amixed pain type with an NP component) and other chronicpain states, such as inflammatory pain (osteoarthritis),urological chronic pelvic pain syndromes and cancer pain [73].
In patients suffering from chronic LBP, tanezumab wastested for its efficacy in a Phase II trial and its efficacy wascompared to naproxen and placebo. The patients received asingle intravenous dose (200 µg/kg) of tanezumab, naproxen(500 mg twice a day) or placebo in a 2: 2: 1 ratio and wereobserved for 12 weeks. The results of this study proved thesuperior effect of tanezumab compared to both naproxenand placebo at weeks 4 -- 12 with a higher proportion ofpatients showing over 30% reduction in LBP intensivityscore [73].
The experiments carried out on cynomolgus monkeyspharmacokinetic and toxicological studies of tanezumab didnot show any adverse events or any histological abnormalitiesin the brain, spinal cord, nerves or ganglia [73], but some of thevery recent studies [74] raise concerns about the safety of anti-NGF monoclonal antibodies that may cause or worsen periph-eral neuropathies. These issues require further confirmation.
3. Expert opinion
Many therapies have been proposed for the management ofNP. However, the lack of high-quality studies indicates thatresults obtained for different neuropathic disorders understudy did not recommend any particular drug treatment.Additionally, the patients’ needs for a more effective painrelief without unwanted side effects are currently being devel-oped by the introduction of new targets for these drugs or bythe search for new and more selective agents with a knownmechanism of action. Hence, the application of geneticapproaches and biochemical assays leading to a deeper under-standing of molecular mechanisms of action of known andinvestigated drugs enables the progress in NP treatment.
Currently, 1.7-selective VGSC, NGF and Ang II AT2 recep-tors seem to be the most promising targets for new drugsused in NP treatment.
The results of the Phase II clinical trial regarding theanalgesic activity of the first-in-class orally bioavailablecompound EMA401 in patients with PHN are very promis-ing. A reduction of pain intensity in EMA401 group comparedto placebo, together with a beneficial pharmacokineticsdemonstrated in Phase I studies, and good human safety is ofparticular relevance. Results of next planned clinical trialsmay confirm the effectiveness of EMA401 in other types ofNP syndromes.
It is worth noting that EMA401 represents a novel group ofpotential analgesics for patients with PHN, which act on anovel analgesic drug target, that is, Ang II AT2 receptors.Hence, it could be a valuable therapeutic option for NP inthe future. It is extremely important as currently used analge-sic drugs for NP are effective only in some patients, whileothers do not respond to analgesic therapy or suffer fromanalgesic drug-related and dose-limiting adverse effects.Importantly, the research on a highly selective for Ang IIAT2 receptors compound EMA401 as a pharmacologicaltool would also help to elucidate the role of these receptorsin nociceptive, inflammatory and NP.
The investigation on EMA401 seems to be a major step inthe search for novel therapeutic options for NP. Thiscompound is featured by placebo-like CNS adverse effects,few drug-drug interactions and convenient dosage regimen(twice daily dosing as tablets or capsules). These featuresmay be extremely important for patients suffering from NP,in particular PHN. We are looking forward to seeing furtherevidence for the efficacy of EMA401 in patients with PHN,chemotherapy-induced NP or painful diabetic neuropathy,as well as other pain states (nociceptive pain, inflammatorypain).
Declaration of interest
The authors have no relevant affiliations or financial involve-ment with any organization or entity with a financial interestin or financial conflict with the subject matter or materialsdiscussed in the manuscript. This includes employment,consultancies, honoraria, stock ownership or options, experttestimony, grants or patents received or pending, or royalties.
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BibliographyPapers of special note have been highlighted as
either of interest (�) or of considerable interest(��) to readers.
1. Jensen TS, Baron R, Haanpaa M, et al.
A new definition of neuropathic pain.
Pain 2011;152:2204-5
2. Haanpaa M, Attal N, Backonja M, et al.
NeuPSIG guidelines on neuropathic pain
assessment. Pain 2011;152:14-27
3. Haanpaa M. The assessment of
neuropathic pain patients. Pain Manag
2013;3:59-65
4. Backonja MM. Defining neuropathic
pain. Anesth Analg 2003;97:785-90
5. Babos MB, Grady B, Wisnoff W, et al.
Pathophysiology of pain. Dis Mon
2013;59:330-58
6. Fallon MT. Neuropathic pain in cancer.
Br J Anaesth 2013;111:105-11
7. Gilron I, Max MB. Combination
pharmacotherapy for neuropathic pain:
current evidence and future directions.
Expert Rev Neurother 2005;5:823-30
8. Namaka M, Gramlich CR, Ruhlen D,
et al. A treatment algorithm for
neuropathic pain. Clin Ther
2004;26:951-79
9. Backonja M, Woolf CJ. Future
directions in neuropathic pain therapy:
closing the translational loop. Oncologist
2010;15(Suppl 2):24-9
10. Mick G, Baron R, Finnerup NB. What
is localized neuropathic pain? A first
proposal to characterize and define a
widely used term. Pain Manag
2012;2:71-7
. A summary of several guidelines for
neuropathic pain (NP) treatment.
11. Hartrick CT. Noradrenergic reuptake
inhibition in the treatment of pain.
Expert Opin Investig Drugs
2012;21:1827-34
12. Richards N, McMahon SB. Targeting
novel peripheral mediators for the
treatment of chronic pain. Br J Anaesth
2013;111:46-51
13. L€otsch J, Doehring A, Mogil JS, et al.
Functional genomics of pain in analgesic
drug development and therapy.
Pharmacol Ther 2013;139:60-70
.. A review of genomic research aiming at
better understanding of NP.
14. Finnerup NB, Otto M, McQuay HJ,
et al. Algorithm for neuropathic pain
treatment: an evidence based proposal.
Pain 2005;118:289-305
15. Gagnon B, Almahrezi A, Schreier G.
Methadone in the treatment of
neuropathic pain. Pain Res Manag
2003;8:149-54
16. Burgess G, Williams D. The discovery
and development of analgesics: new
mechanisms, new modalities.
J Clin Invest 2010;120:3753-9
17. Sałat K, Moniczewski A, Librowski T.
Transient receptor potential channels -
emerging novel drug targets for the
treatment of pain. Curr Med Chem
2013;20(11):1409-36
18. Bhattacharya A, Wickenden AD,
Chaplan SR. Sodium channel blockers
for the treatment of neuropathic pain.
Neurotherapeutics 2009;6:663-78
19. Colombo E, Francisconi S, Faravelli L,
et al. Ion channel blockers for the
treatment of neuropathic pain.
Future Med Chem 2010;2:803-42
.. A very comprehensive review on
general properties and pharmacological
significance of voltage-gated ion
channels in NP.
20. Clark AK, Old EA, Malcangio M.
Neuropathic pain and cytokines: current
perspectives. J Pain Res 2013;21:803-14
21. Papoiu AD, Yosipovitch G. Topical
capsaicin. The fire of a ’hot’ medicine is
reignited. Expert Opin Pharmacother
2010;11:1359-71
22. Choi KH. The design and discovery of
T-type calcium channel inhibitors for the
treatment of central nervous system
disorders. Expert Opin Drug Discov
2013;8:919-31
23. Szallasi A, Sheta M. Targeting
TRPV1 for pain relief: limits, losers and
laurels. Expert Opin Investig Drugs
2012;21:1351-69
24. Pexton T, Moeller-Bertram T,
Schilling JM, et al. Targeting voltage-
gated calcium channels for the treatment
of neuropathic pain: a review of drug
development. Expert Opin
Investig Drugs 2011;20:1277-84
25. Todorovic SM, Jevtovic-Todorovic V.
T-type voltage-gated calcium channels as
targets for the development of novel pain
therapies. Br J Pharmacol
2011;163:484-95
26. Yang P, Wang L, Xie XQ. Latest
advances in novel cannabinoid
CB2 ligands for drug abuse and their
therapeutic potential. Future Med Chem
2012;4:187-204
27. Gether U, Andersen PH, Larsson OM,
et al. Neurotransmitter transporters:
molecular function of important drug
targets. Trends Pharmacol Sci
2006;27:375-83
28. Dib-Hajj SD, Binshtok AM,
Cummins TR, et al. Voltage-gated
sodium channels in pain states: Role
pathophysiology and target for treatment.
Brain Res Rev 2009;60:65-83
29. Theile JW, Cummins TR. Recent
developments regarding voltage-gated
sodium channel blockers for the
treatment of inherited and acquired
neuropathic pain syndromes.
Front Pharmacol 2011;2:1-54
. A key reference providing an overview
of the recent development regarding
voltage-gated sodium channel blockers.
30. Zhang XF, Shieh CC, Chapman ML,
et al. A-887826 is a structurally novel,
potent and voltage-dependent
Nav1.8 sodium channel blocker that
attenuates neuropathic tactile allodynia in
rats. Neuropharmacology 2010;59:201-7
31. Nanayakkara B, Phillips D, Russell M.
The molecular pathogenesis of primary
erythromelalgia, a painful inherited
syndrome -- An update. MSJA
2012;4:33-8
32. Mantegazza M, Curia G, Biagini G,
et al. Voltage-gated sodium channels as
therapeutic targets in epilepsy and other
neurological disorders. Lancet Neurol
2010;9:413-24
33. Rahman W, Dickenson AH. Voltage
gated sodium and calcium channel
blockers for the treatment of chronic
inflammatory pain. Neurosci Lett
2013;557:19-26
34. Eijkelkamp N, Linley JE, Baker MD,
et al. Neurological perspectives on
voltage-gated sodium channels. Brain
2012;35:2585-612
35. Wickenden A. Ion channel drug
discovery: challenges and future
directions. Future Med Chem
2012;4:661-79
36. Ali Z, Palmer JE, Goli V. Anticonvulsant
clinical. In: McMahon S,
Koltzenburg M, Tracey I, Turk D,
K. Sałat et al.
10 Expert Opin. Investig. Drugs (2014) 23(8)
Exp
ert O
pin.
Inv
estig
. Dru
gs D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y K
arol
insk
a In
stitu
tet U
nive
rsity
Lib
rary
on
06/1
7/14
For
pers
onal
use
onl
y.
editors. Wall and Melzack’s texbook of
pain. Elsevier; Barcelona: 2006
37. Chapman ML, Printzenhoff D, Lin Z,
et al. Characterization of a novel
subtype-selective inhibitor of human
Nav1.7 voltage-dependent sodium
channels, 140.06/C25,
2012 Neuroscience Meeting Planner.
Society for Neuroscience; New Orleans,
LA: 2012. Online
38. Evaluation of the efficacy and safety of
single doses of PF-05089771 in patients
with primary (inherited) erythromelalgia
(IEM). Available from: http://
clinicaltrials.gov/ct2/show/
NCT01769274?term=PF-
05089771&rank=7
39. Lotsch J, Geisslinger G.
Pharmacogenetics of new analgesics.
Br J Pharmacol 2011;163:447-60
40. Zakrzewska JM, Palmer J, Ettlin DA,
et al. Novel design for a phase IIa
placebo-controlled, double-blind
randomized withdrawal study to evaluate
the safety and efficacy of
CNV1014802 in patients with trigeminal
neuralgia. Trials 2013;14:402
41. Campbell JN, Meyer RA. Mechanisms of
neuropathic pain. Neuron
2006;52(1):77-92
42. Goldberg YP, Price N, Namdari R, et al.
Treatment of Na(v)1.7-mediated pain in
inherited erythromelalgia using a novel
sodium channel blocker. Pain
2012;153:80-5
43. Goldberg YP, Pimstone SN, Namdari R,
et al. Human Mendelian pain disorders:
a key to discovery and validation of
novel analgesics. Clin Genet
2012;82:367-73
44. Crow M, Denk F, McMahon SB. Genes
and epigenetic processes as prospective
pain targets. Genome Med 2013;5:12
45. Perret D, Luo ZD. Targeting voltage-
gated calcium channels for neuropathic
pain management. Neurotherapeutics
2009;6:679-92
46. Vink S, Alewood PF. Targeting voltage-
gated calcium channels: developments in
peptide and small-molecule inhibitors for
trearment of neuropathic pain.
Br J Pharmacol 2012;167:970-89
47. Corrigan MHN. Calcium channel treats
chronic pain. Drug Discovery and
Development. 2012. Available from:
www.dddmag.com/articles/2012/05/
calcium-channel-treats-chronic-pain
48. Lee M, Snutch T. Z160: a potent and
state-dependent, small molecule blocker
of N-type calcium channels effective in
nonclinical models of neuropathic pain.
J Pain 2013;14:S71
49. Phase 2 Efficacy Trial of Z160 in
Lumbosacral Radiculopathy. Available
from: http://clinicaltrials.gov/ct2/show/
NCT01655849?term=Z160&rank=1
50. Efficacy and Safety Study of Z160 in
Subjects With Postherpetic Neuralgia
(PHN). Available from: http://
clinicaltrials.gov/ct2/show/
NCT01757873?term=Z160&rank=2
51. Jacus MO, Uebele VN, Renger JJ,
Todorovic SM. Presynaptic CaV channels
regulate excitatory neurotransmission in
nociceptive dorsal horn neurons.
J Neurosci 2012;32:9374-81
52. Tringham E, Powell KL, Cain SM, et al.
T-type calcium channel blockers that
attenuate thalamic buers firing and
suppress absence seizures. Sci Transl Med
2012;4:1-13
53. Short G, Lee M, Snutch T. Z944: a first
in-class T-type calcium channel blocker
effective in nonclinical models of acute
and inflammatory pain J Pain.
2013;14:S71
54. Hassan P, Ramesh K, Yanbing D, et al.
N-piperidinyl acetamide derivatives as
calcium channel blockers. US patent
US8569344; 2013
55. Nemoto W, Nakagawasai O, Yaoita F,
et al. Angiotensin II produces nociceptive
behavior through spinal AT1 receptor-
mediated p38 mitogen-activated protein
kinase activation in mice. Mol Pain
2013;9:38
56. Pavel J, Tang H, Brimijoin S, et al.
Expression and transport of Angiotensin
II AT1 receptors in spinal cord, dorsal
root ganglia and sciatic nerve of the rat.
Brain Res 2008;1246:111-22
57. Pavel J, Oroszova Z, Hricova L, et al.
Effect of subpressor dose of angiotensin
II on pain-related behavior in relation
with neuronal injury and activation of
satellite glial cells in the rat dorsal root
ganglia. Cell Mol Neurobiol
2013;33:681-8
58. Saavedra JM, Ando H, Armando I, et al.
Anti-stress and anti-anxiety effects of
centrally acting angiotensin II
AT1 receptor antagonists. Regul Pept
2005;128:227-38
59. Anand U, Facer P, Yiangou Y, et al.
Angiotensin II type 2 receptor (AT2R)
localization and antagonist-mediated
inhibition of capsaicin responses and
neurite outgrowth in human and rat
sensory neurons. Eur J Pain
2013;17:1012-26
60. Gallinat S, Yu M, Dorst A, et al. Sciatic
nerve transection evokes lasting
up-regulation of angiotensin AT2 and
AT1 receptor mRNA in adult rat dorsal
root ganglia and sciatic nerves. Brain Res
Mol Brain Res 1998;57:111-22
61. Tan YH, Li K, Chen XY, et al.
Activation of Src family kinases in spinal
microglia contributes to formalin-induced
persistent pain state through
p38 pathway. J Pain 2012;13:1008-15
62. Smith MT, Woodruff TM, Wyse BD,
et al. A small molecule angiotensin II
type 2 receptor (AT2R) antagonist
produces analgesia in a rat model of
neuropathic pain by inhibition of p38
mitogen-activated protein kinase
(MAPK) and p44/p42 MAPK activation
in the dorsal root ganglia. Pain Med
2013;14:1557-68
63. Smith MT, Wyse BD, Edwards SR,
et al. Small molecule angiotensin II
type 2 receptor (AT2R) antagonists as
novel analgesics for neuropathic pain:
comparative pharmacokinetics,
radioligand binding, and efficacy in rats.
Pain Med 2013;14:692-705
64. Smith MT, Wyse BD. Method of
treatment or prophylaxis. US patent
US7795275; 2010
65. Smith MT. Method of treatment or
prophylaxis inflammatory pain. Patent
EP1996183; 2008
66. Takai S, Song K, Tanaka T, et al.
Antinociceptive effects of angiotensin-
converting enzyme inhibitors and an
angiotensin II receptor antagonist in
mice. Life Sci 1996;59:PL331-6
67. Rice ASC, Dworkin RH, McCarthy TD,
et al. EMA401, an orally administrated
highly selective angiotensin II
type 2 receptor antagonist, as novel
treatment for postherpetic neuralgia:
a randomized, double-blind, placebo-
controlled phase 2 clinical trial. Lancet
2014; Epub ahead of print
.. The article summarizes the available
results of clinical tests on EMA401 in
patients with PHN.
68. Available from: www.anzctr.org
New investigational drugs for the treatment of neuropathic pain
Expert Opin. Investig. Drugs (2014) 23(8) 11
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ert O
pin.
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. Dru
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oade
d fr
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ahea
lthca
re.c
om b
y K
arol
insk
a In
stitu
tet U
nive
rsity
Lib
rary
on
06/1
7/14
For
pers
onal
use
onl
y.
69. Kumar V, Mahal BA. NGF - the
TrkA to successful pain treatment.
J Pain Res 2012;5:279-87
70. Seidel MF, Wise BL, Lane NE. Nerve
growth factor: an update on the science
and therapy. Osteoarthritis Cartilage
2013;21:1223-8
71. McKelvey L, Shorten GD,
O’Keeffe GW. Nerve growth factor-
mediated regulation of pain signalling
and proposed new intervention strategies
in clinical pain management.
J Neurochem 2013;124:276-89
72. Watson JJ, Allen SJ, Dawbarn D.
Targeting nerve growth factor in pain:
what is the therapeutic potential?
BioDrugs 2008;22:349-59
. An interesting review on the
therapeutic potential of nerve growth
factor inhibitors in NP.
73. Sanga P, Katz N, Polverejan E, et al.
Efficacy, safety, and tolerability of
fulranumab, an anti-nerve growth factor
antibody, in the treatment of patients
with moderate to severe osteoarthritis
pain. Pain 2013;154:1910-19
74. Bannwarth B, Kostine M. Targeting
Nerve Growth Factor (NGF) for pain
management: what does the future hold
for NGF antagonists? Drugs
2014; Epub ahead of print
AffiliationKinga Sałat1, Paula Kowalczyk2, Beata Gryzło2,
Anna Jakubowska2 & Katarzyna Kulig†2
†Author for correspondence1Chair of Pharmacodynamics,
Jagiellonian University, Faculty of Pharmacy,
Medyczna 9 St., 30-688 Krakow, Poland2Chair of Pharmaceutical Chemistry,
Jagiellonian University, Department of
Physicochemical Drug Analysis, Faculty of
Pharmacy, Medyczna 9 St., 30-688 Krakow,
Poland
E-mail: [email protected]
K. Sałat et al.
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