can medical herbs stimulate regeneration or neuroprotection and …¶der_et_al... · 2019-11-01 ·...

Zurich Open Repository andArchiveUniversity of ZurichMain LibraryStrickhofstrasse 39CH-8057 Zurichwwwzorauzhch

Year 2013

Can medical herbs stimulate regeneration or neuroprotection and treatneuropathic pain in chemotherapy-induced peripheral neuropathy

Schroumlder S Beckmann K Franconi G Meyer-Hamme G Friedemann T Greten H J RostockM Efferth T

DOI httpsdoiorg1011552013423713

Posted at the Zurich Open Repository and Archive University of ZurichZORA URL httpsdoiorg105167uzh-93095Journal ArticlePublished Version

Originally published atSchroumlder S Beckmann K Franconi G Meyer-Hamme G Friedemann T Greten H J Rostock MEfferth T (2013) Can medical herbs stimulate regeneration or neuroprotection and treat neuropathicpain in chemotherapy-induced peripheral neuropathy Evidence-Based Complementary and AlternativeMedicine (423713)1-18DOI httpsdoiorg1011552013423713

Hindawi Publishing CorporationEvidence-Based Complementary and Alternative MedicineVolume 2013 Article ID 423713 18 pageshttpdxdoiorg1011552013423713

Review ArticleCan Medical Herbs Stimulate Regeneration orNeuroprotection and Treat Neuropathic Pain inChemotherapy-Induced Peripheral Neuropathy

Sven Schroumlder12 Kathrin Beckmann1 Giovanna Franconi3 Gesa Meyer-Hamme1

Thomas Friedemann1 Henry Johannes Greten2 Matthias Rostock4 and Thomas Efferth5

1 HanseMerkur Center for Traditional Chinese Medicine at the University Medical Center Hamburg-EppendorfMartinistraszlige 52 20246 Hamburg Germany

2 ICBAS University of Porto Rua de Jorge Viterbo Ferreira No 228 4050-313 Porto Portugal3 Department of Systems Medicine Tor Vergata University 00133 Rome Italy4Hubertus Wald Tumorzentrum University Cancer Center Hamburg University Medical Center Hamburg-EppendorfMartinistraszlige 52 20246 Hamburg Germany

5Department of Pharmaceutical Biology Institute of Pharmacy and Biochemistry Johannes Gutenberg UniversityStaudinger Weg 5 55128 Mainz Germany

Correspondence should be addressed to Sven Schroder schroedertcm-am-ukede

Received 30 April 2013 Accepted 5 June 2013

Academic Editor Yoshiharu Motoo

Copyright copy 2013 Sven Schroder et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Chemotherapy-induced neuropathy (CIPN) has a relevant impact on the quality of life of cancer patients There are no curativeconventional treatments so further options have to be investigated We conducted a systematic review in English and Chineselanguage databases to illuminate the role of medical herbs 26 relevant studies on 5 single herbs one extract one receptor-agonist and 8 combinations of herbs were identified focusing on the single herbs Acorus calamus rhizoma Cannabis sativa fructusChamomilla matricaria Ginkgo biloba Salvia officinalis Sweet bee venom Fritillaria cirrhosae bulbus and the herbal combinationsBu Yang HuanWu modified Bu Yang HuanWu plus Liuwei Di Huang modified Chai Hu Long GuMu LiWan Geranii herba plusAconiti lateralis praeparata radix NiuChe SenQiWan (Goshajinkigan) Gui Zhi Jia Shu FuTang (Keishikajutsubuto)HuangQiWuWu Tang (Ogikeishigomotsuto) and Shao Yao Gan Cao Tang (Shakuyakukanzoto) The knowledge of mechanism of action is stilllimited the quality of clinical trials needs further improvement and studies have not yielded enough evidence to establish a standardpractice but a lot of promising substances have been identified While CIPN has multiple mechanisms of neuronal degeneration acombination of herbs or substances might deal with multiple targets for the aim of neuroprotection or neuroregeneration in CIPN

1 Introduction

Several chemotherapeutic drugs are known to be neurotoxicand can lead to chemotherapy-induced peripheral neuropa-thy (CIPN) It is one of the main dose-limiting toxicitiesin oncologic treatments and a potential reason to terminateor suspend chemotherapy in some cases leading to diseaseprogression [1] CIPN involves damage to the peripheralnervous system and can produce severe neuropathic pain[2 3] sensory deficits or gait impairment [4] and can severelydecrease the patientrsquos quality of life [5] Sensory symptoms

usually develop before motor symptoms because motorneurons are more myelinated [6 7] Distal parts of the axonsare the first affected so sensory symptoms typically startsymmetrically and bilaterally from the tips of the toes and fin-gers and progress proximally in a ldquostocking-gloverdquo distribu-tion [8] The incidence of CIPN can reach levels of up to92 [9]Themajor groups of drugs that induce CIPN includethe antitubulins (paclitaxel docetaxel ixabepilone andvincristine) platinum analogs (cisplatin carboplatin andoxaliplatin) and the proteasome inhibitors bortezomib andthalidomide [1] Patients with a preexisting other cause of

2 Evidence-Based Complementary and Alternative Medicine

peripheral neuropathy develop more severe and persistentCIPN [10ndash12]

The development of CIPN is usually dependent on thecumulative dose and symptoms may progressively aggravate[10] After sustaining therapy symptoms are usually rever-sible but in some cases they may be irreversible [10 13] andsometimes even progress after stoppingmedication especial-ly after treatment with vinca alkaloids (eg vincristine) plat-inum analogues (eg cisplatin and oxaliplatin) and taxanes(eg paclitaxel) [14 15] Mostly the sensory nerve cell bodiesof the dorsal root ganglia are affected or the afferent andefferent distal peripheral axons are damaged [16]

Some differences concerning the mechanisms of CIPNare described for different therapeutic drugs

In platinum compounds the dorsal root ganglia are themain parts of the nervous systems that are injured [17] andapoptosis is induced via structural alterations of DNA andof cell-cycle kinetics [18] triggered by oxidative stress andmitochondrial dysfunction but possibly downregulated by areduction of enzymes like p53 [19ndash22]

The taxanes paxlitaxel and docetaxel are antitubulinsand mainly damage the soma of the sensory neurons andthe nerve axons This is induced by an interference withthe axonal transport which is caused by enhancement ofmicrotubule polymerization [23] Microglial activation inthe spinal cord and high concentration in the dorsal rootganglia tissue induce CIPN [24] Like platinum compoundstaxanes can damage dorsal root ganglia This is inducedby macrophage activation in the dorsal root ganglia butoccurs also in the peripheral nerve [24] Paclitaxel induces amassive polar reconfiguration of axonal microtubules and animpairment of organelle transport [25]

Vinca alkaloids (eg vincristine) prevent tubulin poly-merization from soluble dimers into microtubules [26] Byaffecting the tubulin dimers loss of axonal microtubules andalterations in their length arrangement and orientation areproduced [27 28] This alters the neuronal cytoskeletonleading to abnormalities in axonal transport and axonaldegeneration [28 29] Decreasing affinity for tubulin of thevinca alkaloids explains the different neurotoxicity profilesand the severity of CIPN [30]

Epothilones (eg ixabepilone) are like the taxanes anti-tubulins so there might be similar mechanisms of peripheralneurotoxicity They damage the ganglion soma cells andperipheral axons through disruption of microtubules of themitotic spindle and interfere with the axonal transport inthe neurons [31] and can also induce polymerization oftubulin dimers in microtubules Additionally they stabilizepreformed microtubules against conditions favouring de-polymerization [32 33]

Bortezomib might induce pathological changes inSchwann cells and myelin axonal degeneration and dorsalroot ganglia neuron changes [34 35] as well as chromatolysisof dorsal root ganglial neurons It causes cytoplasmic accu-mulation of eosinophilic material [36] and interferes withthe transcription nuclear processing and transport as wellas with the cytoplasmic translation of messenger RNAs indorsal root ganglions [37] Mitochondrial and endoplasmic

reticulum-mediated calcium dysregulation plays an impor-tant part [38 39] The activation of the mitochondria-basedapoptotic pathway or inhibition of the transcription of thenerve growth factor by interference with the nuclear factor-120581B pathway can lead to disarrangement of the neurotrophinnetwork [39 40] Bortezomib can induce changes in allmajor primary afferent fibres [41]

The structure of thalidomide is characterized by a 3-substituted glutarimide ring and a ph-thalimide ring whichare sensitive to enzymatic or nonenzymatic hydrolysis [42]but despite several studies it has not been possible to identifythe responsible enzymes for the production of neurotoxicmetabolites so its mechanism of peripheral neurotoxicity isstill elusive [43]

Multiple drugs have been testedmainly in animal studiesfor their putative neuroprotective activity in CIPN A fewcomponents which can protect different tissues from toxicagents were clinically tested showing conflicting results Noconclusive reports confirming their effectiveness have beenprovided [44 45] and a reduction of anticancer activity wassuspected [46] Several neurotrophins were tested but therewas no evidence of neuroprotection [47ndash50] Erythropoietina multifunctional trophic factor showed promising results inpreclinical studies [51 52] but has relevant safety problems[53]

Antioxidants have been tested as neuroprotectants [54ndash59] but no conclusive evidence of neuroprotection has yetbeen found

Neuropathic pain is conventionally treated by antiepilep-tic and tricyclic antidepressant drugs but these drugs areineffective for treatment of decreased sensation and cannotinduce neuroprotection or neuroregeneration Other com-pounds with different mechanisms (eg acetyl-L-carnitineglutamate carboxypeptidase II inhibitors calpain inhibitorsa solution of calcium and magnesium) have now beeninvestigated in preclinical stages with unknown value forclinical routine [59ndash63]

Thus specific and effective curative treatments for CIPNare lacking especially those meant for enhancing neurore-generation or neuroprotection [64ndash67] and the evaluation offurther treatment options is of great importance While theeffectiveness of herbal treatment is not well known yet thisreview was done to illuminate the actual and potential futurerole of herbal treatment in CIPN

2 Methods

To review the existing clinical and experimental studies ofherbal treatment in CIPN a systematic literature searchwas performed from the databases from inception up untilJanuary 2013 using MEDLINE Google Scholar CochraneDatabase CINHAL (Cumulative Index toNursing andAlliedHealth Literature) CNKI (ChinaNational Knowledge Infras-tructure) and Wanfang Med Online and ISI Proceedings forconference abstractsThe keywords searched were as follows

(Chinese herbs or herbs or plants or Chinese medicineas MeSH term) AND (neuropathy or chemotherapy) TheCINHAL CNKI and Wanfang Med Online Databases did

Evidence-Based Complementary and Alternative Medicine 3

not allow logical searches with AND so we used simplecombinations of the search words Historical searches ofreference lists of relevant articles were also undertaken

To be included in our review a study had to focus on thetopic CIPN and neuropathy in human and animal modelsirrespective of design Papers with at least an English abstractwere included Study selection was performed by two review-ers (SSch and KB) with disagreement resolved by discussionand adjudication

Listed articles concerning diseases other than CIPN andherbal treatment were excluded while animal products usedin the tradition of herbal medicine were included

3 Results

A total of 3474 (1477 in English and 1997 in Chinese databas-es) articles were retrieved by way of electronic searches andexamination of reference lists of clinical and review articlesAfter screening titles andor abstracts 3376 articles wereexcluded because either the focus was on an interventionother than CIPN and herbal treatment or they were dupli-cated studies or not relevant From a total of 98 articles whichwere retrieved for detailed evaluation 15 were included in thereview focusing on 5 single herbs one extract one receptoragonist and 8 combinations of herbs For a summary of theexperimental and clinical studies see Table 1

31 Single Herbs or Single Herbal Compounds

311 Acorus calamus rhizoma This herb (family Araceae)is traditionally used in the treatment and management ofpain and severe inflammatory in Ayurveda It is commonlyused to relieve the muscle joint vascular and nerve injuryassociated with severe inflammatory and neuropathic pain[68] In a rat model a hydroalcoholic extract of Acoruscalamus rhizoma has been shown to exert beneficial effect onneuropathic pain induced by tibial and sural nerve transec-tion [69] In a further study Acorus calamus rhizoma extractattenuated sciatic nerve chronic constriction injury andinduced ameliorated behavioral (hyperalgesia and allody-nia) biochemical (superoxide anion myeloperoxidase andtotal calcium) and histopathological (axonal degeneration)changes [68] Another study investigated the protective effectof Acorus calamus rhizoma extract in vincristine-inducedpainful neuropathy Hydroalcoholic extracts of Acorus cala-mus rhizoma attenuated vincristine-induced behavioral andbiochemical changes to an extent comparable to pregabalin(positive control) and attenuated vincristine-induced painfulneuropathy which probably may be attributed to its multipleeffects including antioxidative anti-inflammatory and cal-cium inhibitory activity [70]

312 Cannabis sativa Two structurally distinct cannabi-noid CB2 agonistsmdashthe aminoalkylindole (RS)-AM1241((RS)-(2-iodo-5-nitrophenyl)-[1-((1-methyl-piperidin-2ndashyl)methyl)-1H-indol-3-yl]-methanone) and the cannabilac-tone AM1714 (19-dihydroxy-3-(1101584011015840-dimethylheptyl)-6H-benzo[c]chromene-6-one))mdashhad been tested for their

dose related suppression of established paclitaxel-evokedmechanical allodynia in a rat model (R)-AM1241 but not (S)-AM1241 suppressed paclitaxel evoked mechanical allodyniaand AM1714 induced a modest antinociceptive effect Sothe authors suggested that cannabinoid CB2 receptorsmay be important therapeutic targets for the treatment ofchemotherapy-evoked neuropathy [71] Cannabis sativa orCannabis extracts have not been clinically explicitly testedfor CIPN but for other clinical conditions like neuropathicpain in HIV [72] Multiple clinical trials examined the effecton neuropathic pain and found positive effects on centraland peripheral neuropathic pain with different forms ofapplication [73ndash82]

313 Matricaria chamomilla This is a commonly usedherb in western as well as in eastern phytopharmacologicaltradition Flavonoids from Matricaria chamomilla seem tohave an antispasmodic effect and main components such as120572-bisabolol or chamazulene have anti-inflammatory effects[83] En-In-Dicycloether has both antispasmodic and anti-inflammatory effects together [84] In a mouse model it wasshown that Matricaria chamomilla extract-treated mice hada significant reduction of cisplatin-induced peripheral pain[85] Matricaria chamomilla hydroalcoholic extract was ableto decrease cisplatin-induced pain and inflammation betterthan morphine [85]

314 Ginkgo biloba The popular herb from the maidenhairtree that has shown some promising effects as an neuro-protectant The most unique components of the extracts arethe terpene trilactones that is ginkgolides and bilobalide[109] In vitro and ex vivo studies indicate that bilobalide hasmultiple mechanisms of action that may be associated withneuroprotection including its preservation of mitochondrialATP synthesis its inhibition of apoptotic damage induced bystaurosporine or by serum-free medium its suppression ofhypoxia-induced membrane deterioration in the brain andits action in increasing the expression of the mitochondrialDNA-encoded COX III subunit of cytochrome C oxidaseand the ND1 subunit of NADH dehydrogenase [110] Becausemultiple modes of action may apply to bilobalide it couldbe useful in developing therapy for neurodegeneration [109ndash111] Ozturk et al investigatedGinkgo biloba alcoholic extractin cisplatin-induced peripheral neuropathy in mice [86]Development of neuropathy was evaluated with changes insensory nerve conduction velocity (NCV) and Ginkgo bilobaextract prevented reduction in NCV In another study aGinkgo biloba extract prevented some functional and mor-phological deteriorations induced by cisplatin antagonizingthe decrease in the number of migrating cells and in thelength of outgrowing axons [86] Marshall et al investi-gated retrospectively 17 patients with colorectal cancer whoreceived oxaliplatin along with Ginkgo biloba extract butno specification of the extraction method was provided inthe published abstract The researchers found that 11 of the17 patients developed a grade 1 peripheral neuropathy (PN)after the first cycle of oxaliplatin Five of six patients whoreceived Ginkgo biloba after the second cycle of oxaliplatin

4 Evidence-Based Complementary and Alternative MedicineTa

ble1MedicalherbstestedforC

IPN

Sectionno

Medicalherb(s)

Stud

ydesig

nCh

emotherapy

Outcome

Authoryear

Sing

leherbso

rsinglec

ompo

unds

311

Acorus

calamus

rhizom

a(hydroalcoho

licextract)

Ratm

odel

Vincris

tine

Improvem

ento

fneuropathicpain

Muthu

raman

andSing

h2011[70]

312

Cann

abis-Re

ceptor

agon

ists

R-AM1241

andAm-1714

Ratm

odel

Paclitaxel

Allo

dyniaantin

ociceptiv

e

Rahn

etal2008

[71]multip

letrials

forn

europathicpain

notd

ueto

chem

otherapyfor

exam

pleEllis

etal[72]Ka

rstetal[73]W

aree

tal

[74]R

ogetal[75]Blakee

tal[76]

Berm

anetal[77]Wilsey

etal[78]

with

Cannabissativa

313

Matric

ariacham

omilla

(hydroalcoho

licextract)

Mou

semod

elCisplatin

Improvem

ento

fneuropathicpain

Abad

etal2011[85]

314

Ginkgo

biloba

(alcoh

olicextract)

(1)M

ouse

mod

el(2)R

etrospectiv

estudy

(119899=17)

Oxalip

latin

(1)N

europrotectio

n(2)Improvem

ento

fneuropathicpain

(1)O

zturketal2004

[86]

(2)M

arshalletal2004

[87]

315

Salviaoffi

cinalis(hydroalcoho

licextract)

Mou

semod

elVincris

tine

Improvem

ento

fneuropathicpain

Abad

etal2011[88]

316

Sweetb

eevenom

(pharm

acop

uncture)

(1)C

ases

eries(119899=5)

(2)C

ases

eries(119899=11)

Taxolpaclitaxelor

carbop

latin

Injectioninto

acup

oint

(ZusanliSt36)

(1)E

ffecton

pain

andneurop

athy

scales

(2)E

ffecton

VASandHRQ

OLscores

(1)P

arketal2011[89]

(2)Y

oonetal2012

[90]

317

Verticinon

ehydroalcoh

olic

extractedfro

mFritillaria

bulbus

Mou

semod

eland

ratm

odel

Paclitaxel

Inflammatoryandneurop

athicp

ain

dose

depend

entno

tolerance

Xuetal2011[91]

Herbalcom

binatio

ns321

BuYang

Hua

nWulowast1(decoctio

n)Ra

ndom

ized

trial119899=44con

trol=

40Oxalip

latin

Improvem

ento

fclin

icalscales

Sunetal2008

[92]

322

mod

ified

BuYang

Hua

nWuplus

Liuw

eiDiH

uanglowast2(decoctio

n)Ra

ndom

ized

trial119899=32con

trolV

itB1

=32

Different

chem

otherapies

Improvem

ento

fclin

icalscales

DengandZo

u2007

[93]

323

mod

ified

ChaiHuLong

GuMu

LiWanlowast3(decoctio

n)Ra

ndom

ized

trial119899=26con

trol=

22Paclitaxel

neurop

rotection

Panetal2012

[94]

324

Geraniiherbaplus

Acon

itiradix

(granu

le)

(1)R

atmod

el(2)R

ando

mizedprospectiv

etria

l119899=30con

trol=

28

(1)O

xalip

latin

(2)O

xalip

latin

taxol

orcapecitabine

(1)A

llodynia

(2)N

europathicpainparaesthesia

selling

externalwashing

Simaa

ndPan

2009

[95]

325

Goshajin

kigan=NiuCh

eSen

Qi

Wanlowast4(granu

le)

(1)R

atmod

el(2)R

atm

ouse

mod

el(1)P

aclitaxel

(2)O

xalip

latin

(1)N

oneurogeneration

improvem

ent

ofallodynia

(2)Improvem

ento

fneuropathicpain

noneuroregeneration

(1)H

ashimotoetal2004

+2006

[9697]

(2)U

shio

etal2012

[98]

(1)N

oncontrolledstu

dy119899=14

(2)R

etrospectiv

estudy

GJG

=22con

trol=

23(3)R

etrospectiv

estudy

GJG

=45con

trol=

45(4)R

etrospectiv

estudy119899=82

(5)R

ando

mized

prospectives

tudy

Vit

B12=14V

itB12G

JG=15

(1)O

xalip

latin

(2)F

olfoxlowast8

(3)F

olfoxlowast8

(4)P

aclitaxel

(5)P

aclitaxel

carbop

latin

(1)R

educed

acuten

eurotoxicity

(2)N

europrotectio

n(3)N

europrotectio

nNochange

ofantic

ancera

ctivity

(4)N

europrotectio

nbette

rwhen

administered

early

(5)L

essseveren

eurotoxicitybetter

CPTin

GJG

grou

p

(1)S

hind

oetal2008

[99]

(2)N

ishioka

etal2011[100]

(3)K

onoetal2011[101]

(4)Yam

amotoetal2009

[102]

(5)K

akuetal2012

[103]


Table1Con

tinued

Sectionno

Medicalherb(s)

Stud

ydesig

nCh

emotherapy

Outcome

Authoryear

326

Keish

ikaju

tsubu

to=Gui

ZhiJia

ShuFu

Tanglowast5(granu

le)

Uncon

trolledstu

dy119899=15(3

drop

outs)

Folfo

xlowast8

766meanim

provem

ento

nVA

SYamadae

tal2012

[104]

327

Ogikeish

igom

otsuto

=Huang

Qi

WuWuTanglowast6(granu

le)

Case

repo

rt119899=1

Oxalip

latin

neurop

athicp

ain

Tatsum

ietal2009

[105]

328

Shakuyakukan

zoto=Shao

Yao

Gan

CaoTanglowast7(granu

le)

(1)M

ouse

mod

el(2)R

etrospectiv

ecasea

nalysis119899=23

(3)R

etrospectiv

eclin

icalstu

dy

comparis

onGJG

=20SYK

=24

(1)a

nd(2)p

aclitaxel

(3)F

olfoxlowast8

(1)A

llodyniahyperalgesia

(2)E

ffecton

neurop

athicp

ain

(3)5

0respon

sein

Shakuyu-kanzoto

and65in

Goshajin

kiganon

preventio

nof

neurotoxicity

(1)H

idakae

tal2009

[106]

(2)F

ujiietal2004

[107]

(3)H

osokaw

aetal2012

[108]

lowast1Astra

galusm

embranaceusradixA

ngelica

sinensis

radixPrun

uspersica

esem

enPaeoniaerubra

radixLigusticichuanx

iong

rhizom

aLu

mbricu

sterrestr

isSpatholobicaulis

Curcum

aradixCh

aenomele

slagenaria

fructusand

Achyranthesb

identata

lowast2Astra

galusm

embranaceusradixL

igustru

mlucid

umfru

ctusP

aeoniaer

ubra

radixLu

mbricu

sterrestr

isPrun

uspersica

esem

enR

ehmanniae

virid

aeradixCo

rnio

fficin

alisfru

ctusD

ioscorea

oppositaradixand

Alism

atisrhizom

aPoria

albaSpatholobicau

lisS

colopend

raM

orifructusG

lycyrrhizae

Radix

Dipsacifru

ctusL

yciifru

ctusC

oicis

semenA

tractylodisrhizom

aPh

ellodendricortex

ScorpioMoriram

ulusand

Cyathu

laoffi

cinalis

lowast3Pseudoste

llaria

heterophyllaP

inelliaerhizomaGlycyrrhizae

radixScutellariabaica

lensis

radixBu

pleuriradixFossilia

ossis

mastodiadraconis

Ostrae

concha

Rubiae

cordifoliaeradixScutellaria

ebarbataeh

erbaand

Fritillaria

thun

bergiibu

lbiTh

eexternalw

ashing

was

done

with

Astra

galiradixAn

gelicasin

ensis

radixPa

eoniae

rubraradixLu

mbricu

sterrestr

isLigustici

chua

nxiong

rhizom

aPrun

icapersica

esem

enand

Carthamifl

os

lowast4Rehm

anniavirid

eradixA

chyranthisbidentatae

radixCo

rnifructusD

ioscoreaoppositarhizom

ePlantaginissem

enA

lismatisrhizom

aMoutancortexC

innamom

icortexAc

oniti

lateralis

praeparata

tuberand

Poria

alba

lowast5Cinn

amom

icortexAc

oniti

lateralis

praeparata

tuberZingiberisrhizom

aJujubaefructusG

lycyrrhizae

radixandAtracylodism

acrocephalae

rhizom

alowast6Astra

galimem

branaceusradixC

innamom

icortexPa

eoniaalba

radixJujubaefructusand

Zingiberisrhizom

alowast7Pa

eoniaalba

radixandGlycyrrhizae

radix

lowast8Ch

emotherapeuticregimew

ithFO

LFo

linicacid

(leucovorin)FFluo

rouracil(5-FU)andOX

Oxalip

latin

(Eloxatin

)


reported decreased intensity and duration of sensory PN NoGinkgo biloba related side effects have been observed Thedata suggested thatGinkgo biloba extract appears to attenuatethe intensity and duration of acute dysesthesias caused byoxaliplatin and may yield synergistic antitumor activity [87]

315 Salvia officinalis Salvia species and their isolated con-stituents possess significant antioxidant activity in enzyme-dependent and enzyme-independent systems [112ndash115] Theflavonoid apigenin for example has been shown to protectneurons against A120573-induced toxicity [116] In addition toantioxidant activity many salvia species and their isolatedconstituents showed anti-inflammatory properties [117 118]Salvia officinalis extract can have anti-inflammatory and alsoantinociceptive effects on chemical behavioral models ofnociception in mice that involve an opioid mechanism [119]An animal study showed the effects of the Salvia officinalishydroalcoholic extract on vincristine-induced PN in mice incomparison with morphine with a decrease of pain responsesuggesting that Salvia officinalis extract could be useful in thetreatment of vincristine-induced peripheral neuropathic pain[88]

316 Sweet bee venom The venom of honey bees with itsactive peptide Melittin has been tested for injection intothe acupuncture point Zusanli (ST 36) for its effect onCIPN in animal models It showed to alleviate thermalhyperalgesia and mechanical allodynia The results indicatedan association with the activation of the LC noradrenergicsystem and with a reduction in spinal pNR1 [120 121]

In a first case series this was tested in 5 patients in a1-week course of treatment which showed no side effectsand gave evidence of clinical improvement [89] Anotherprospective case series of this procedure analyzed the clinicalobservations made on 11 CIPN patients treated with Sweetbee venom A total of 11 eligible consecutive CIPN patientswere treated for 3 weeks and observed for another 3 weeks Asignificant intraindividual improvement was found for painand neuropathy scales [90]

317 Verticinone from Fritillaria bulbus Verticinone anisosteroidal alkaloid isolated from Fritillaria bulbus wasevaluated inmice for its analgesic activities inmurinemodelsof inflammatory and neuropathic pain It was shown that oraladministration of hydroalcoholic extracted verticinone couldsignificantly inhibit acetic acid-induced writhing responsein a dose-dependent manner superior to acetylsalicyl acidIn the rat model of paclitaxel induced neuropathic pain incontrast to the declined analgesic effect of morphine afterrepeated administration with the same dose a relativelyconstant analgesic effect of verticinone was observed so ver-ticinone is expected to become a potentially novel sedative-analgesic agent without producing tolerance [91]

32 Herbal Combinations

321 Bu Yang Huan Wu (Chin) = Tonify the Yang toRestore Five-Tenths Decoction (Engl) Bu Yang Huan Wu is

a classical combination of Chinese herbs first mentionedin Wang Qing-Renrsquos Yi Lin Gai Cuo (Correcting the Errorsin the Field of Medicine) published in 1830 [122] Thisrecipe contains Astragalus membranaceus radix Angelicasinensis radix Prunus persicae semen Paeoniae rubra radixLigustici chuanxiong rhizoma Lumbricus terrestris Spatholobicaulis Curcuma radix Chaenomeles lagenaria fructus andAchyranthes bidentatae radix

The decoction has been used in a randomized Chinesestudy of 84 patients (treatment group 119899 = 44 control group119899 = 40) after the treatment of oxaliplatin and showed reduceddevelopment of CIPN in the treatment group tested by stand-ardized clinical tests [92]

322 Modified Bu Yang Huan Wu (Chin) = Tonify theYang to Restore Five-Tenths Decoction (Engl) plus Liuwei DiHuang (Chin) = Rokumijiogan (Jap) = Pilula RehmanniaSex Saporum (Lat) = Six Ingredients Pill with Rehmannia(Engl) In another randomized Chinese study a modifiedcombination of two standard recipes Bu Yang Huan Wuand Liuwei Di Huang was tested as a decoction Liuwei DiHuang was first described in the Yozheng Zhijue [123] Themixture of both recipes contains Astragalus membranaceusradix Ligustrum lucidum fructus Paeoniae rubra radix Lum-bricus terrestris Prunus persicae semen Rehmanniae virideradix Corni officinalis fructus Dioscorea opposita radix andAlismatis rhizoma Poria alba Spatholobi caulis ScolopendraMori fructus Glycyrrhizae radix Dipsaci fructus Lycii fruc-tus Coicis semen Atractylodis rhizoma Phellodendri cortexScorpio Mori ramulus and Cyathula officinalis

The remaining dregs of decoction were additionally usedfor washing the lower extremities The treatment was usedon 32 patients with existing CIPN following different chemo-therapies and compared with 32 patients who were treatedorally with vitamin B1 2500 ug plus by intramuscular injec-tion with vitamin B1 100mg Herbal treatment was foundto be significantly more effective to vitamin treatment (119875 lt005) [93]

323 Modified Chai Hu Long Gu Mu Li Wan (Chin) =Modified Saikokaryukotsuboreito (Jap) = Modified Formulabupleurum cum ostrea et Fossilia ossis (Lat) = ModifiedBupleurum Dragon Bone and Oyster Shell Formula (Engl)Chai Hu Long Gu Mu Li Wan is a traditional recipe derivedfrom the Shang Han Lun [124] A modification of thisrecipe was used in a Chinese randomized trial in which48 patients with ovarian cancer were examined parallel tochemotherapy with placitaxel They were divided into atreatment group with paclitaxel alone and a treatment groupwith paclitaxel plus a combination of oral Chinese herbaldecoction treatment and external washing of the feet withChinese herbs

The oral combination of herbs consists of Pseudostellariaheterophylla Pinelliae rhizoma Glycyrrhizae radix Scutel-laria baicalensis radix Bupleuri radix Fossilia ossis mastodiOstreae concha Rubia cordifolia radix Scutellariae barbataeherba and Fritillariae thunbergii bulbi The external washing


was done with Astragali membranaceus radix Angelica sinen-sis radix Paeoniae rubra radix Lumbricus terrestris Ligusticichuanxiong rhizoma Prunus persicae semen and Carthamiflos

The incidence of CIPN was almost half as high in thepatients treated additionally with Chinese herbs as evaluatedby clinical testing (119875 lt 005) [94]

324 Geranii herba plus Aconiti radix External applicationof a combination of Geranii herba and Aconiti radix extracthas been shown to be effective in a rat model of oxali-platin evoked neuropathy Mechanical allodynia and thermalhyperalgesia were alleviated NGF was increased substanceP decreased in the group treated with Geranii herba andAconiti radix extract additionally to oxaliplatin compared tooxaliplatin alone [95]

In the following randomized clinical study 58 patientswith CIPN from oxaliplatin taxol or capecitabine wereassigned prospectively in a controlled randomized trial 30patients were assigned to the study group and 28 were used asa control The clinical study revealed that symptoms of painparaesthesia and swelling were relieved after one week oftherapy and it was concluded that Geranii herba plus Aconitiradix granule can relieve neuropathy and improve the qualityof life Unfortunately the authors did not provide data in thepublished abstract which species of Geranii herba or Aconitiradix they used [95]

325 Goshajinkigan (Jap) = Niu Che Sen Qi Wan (Chin) =Pilula renales plantaginis et achyranthis (Lat) = Life Preserv-ing Kidney Qi Pill (Engl) This formula derives from theJisheng Fang written by Yan Yonghe a little known but highlyregarded physician of the Song Dynasty published in 1253[125] In Japanese Kampomedicine it is called Goshajinkigan(GJG) and is frequently used as a standardized granule It con-tains 10 different herbs (Rehmannia viride radix Achyranthisbidentatae radix Corni fructus Dioscorea opposita rhizomaPlantaginis semen Alismatis rhizoma Moutan cortex Cin-namomi cortex Aconiti lateralis praeparata tuber and Poriaalba) [126] GJG has antioxidant properties [127 128]

GJG was tested for its effect on CIPN in animal studiesIn a rat model of oxaliplatin-induced neuropathy repeatedadministration of GJG prevented the oxaliplatin-inducedcold hyperalgesia but not mechanical allodynia and axonaldegeneration of the rat sciatic nerve A single administrationof GJG reduced both cold hyperalgesia and mechanicalallodynia after the development of neuropathy GJG did notaffect the antitumour effect of oxaliplatin on the tumour cellsor mice implanted with tumour cells [98]

GJG was also tested in a rat model for paclitaxel-inducedperipheral neuropathy but as with oxaliplatin no regenera-tionwas found in histological examination [96] Neverthelessfurther rat animal studies showed a positive effect of GJG oncold allodynia [97]

GJG has been widely used to treat symptoms like numb-ness vibration sensation cold sensation and limb painassociated with diabetic neuropathy [129]

It has been shown to prevent oxaliplatin-induced periph-eral neuropathy in a FOLFOX-regimen (FOL Folinic acid(leucovorin) F Fluorouracil (5-FU) OX Oxaliplatin (Elox-atin)) in clinical studies [99 100] In a noncontrolled study14 patients received GJG every day after the first oxaliplatininfusion GJG seemed to prevent acute oxaliplatin-inducedneurotoxicity [99] In a retrospective analysis of 45 patients22 received GJG during their FOLFOX regimen againstnonresectable or recurrent colorectal cancer while 23 didnot get this additional therapy The incidence of grade 3PN in the GJG group was significantly lower than in thecontrol group (119875 lt 001 log-rank test) The incidenceof grade 3 PN after 10 courses of chemotherapy was 0in the GJG group and 12 in the control group and after20 courses was 33 in the GJG group and 75 in thecontrol group [100] A further retrospective analysis wasperformed in 90 patients who were given a FOLFOX regimenfor metastatic colorectal cancer Two treatment groups werecompared FOLFXOX plus GJG and FOLFOX plus GJGplus Ca2+Mg+ and two control groups FOLFOX withoutadditional therapy and FOLFOX plus Ca2+Mg+ When acumulative dose of oxaliplatin exceeded 500mgm2 theincidence of PN was 91 in the FOLFOX without additionaltherapy group 100 in the FOLFOX group with additionalCa2+Mg+ therapy and 79 in the FOLFOX plus GJG plusCa2+Mg+ therapy group and 50 in the GJG plus FOLFOXgroupThe cumulative oxaliplatin dose when 50 of patientsdeveloped neurotoxicity was 765mgm2 in the GJG plusFOLFOX and 340mgm2 in the FOLFOX plus GJG plusCa2+Mg+ group respectively and 255mgm2 in both controlgroupsThe authors concluded that concomitant administra-tion of GJG reduced the neurotoxicity of oxaliplatin withouthaving a negative influence on the response rate [101] so forfurther validation of these data a concept for a prospectivecontrolled double blinded randomized study was developed[130]

GJG was also tested for paclitaxel-induced neuropathyin breast and gynecological cancer A retrospective study on82 patients found that GJG was possibly effective for thetreatment and the prevention of peripheral neuropathy andseemed to be more effective when administered from thebeginning of chemotherapy using paclitaxel [102]

In a prospective study in paclitaxelcarboplatin treatedpatients with ovarian or endometrial cancer patients wererandomly divided into two groups 14 patients receivedvitamin B12 and 15 patients vitamin B12 plus GJG Theobservation period was 6 weeks following treatment initi-ation A NCI-CTCAE (National Cancer Institute-CommonToxicity criteria) grade 3 of neurotoxicity developed in 2patients (143) after 6 weeks in the vitamin B12 whereasno neurotoxicity was observed in the vitamin B12GJGgroup The change in the frequency of abnormal currentperception threshold (CPT) ratio was significantly lower inthe VB12GJG group in comparison to VitB12 alone (119875 lt005) which suggests that GJG inhibits the progression of PN[103]


326 Keishikajutsubuto (Jap) = Gui Zhi Jia Shu Fu Tang(Chin) = Decoctum ramulorum cassiae cum atractylodismacrocephae et aconiti (Lat) =CinnamonTwigDecoction plusAtractylodes and Aconite (Engl) This formula has its basisfrom the Shang Han Lun andwas further developed as a Japa-nese experimental formula during the Edo period (1603 to1868) It contains Cinamomi cortex Aconiti lateralis praepa-rata tuber Zingiberis rhizoma Jujubae fructus Glycyrrhizaeradix and Atracylodis macrocephalae rhizoma

This herbal combinationwith an increased dose ofAconitilateralis praeparata tuber was used as a granule for 11 patientswith metastatic colorectal cancer receiving FOLFOX in anoncontrolled study Reduction of neuropathy was observedin 5 cases after chemotherapy (455) [104]

The same herbal granule was also used in a study onpostherpetic neuralgia and was found to be effective In threeof 15 patients in this noncontrolled trial continuation of thetreatment with Keishikajutsubuto was not possible due tohot flashes or gastric discomfort The remaining 12 patientsshowed a VAS improvement rate of 765 plusmn 277 (mean plusmnstandard deviation) [131]

327 Ogikeishigomotsuto (Jap) = Huang Qi Wu Wu Tang(Chin) = (Decotum quinque medicamentorum cum astragalo(Lat) = Astragalus and Cinnamon Five Herb Combination(Engl) This classical combination derives from Jin Gui YaoLue (Essential Prescriptions from the Golden Chamber)[132] In Kampo medicine it is called OgikeishigomotsutocontainingAstragalimembranaceus radix Cinnamomi cortexPaeonia alba radix Jujubae fructus and Zingiberis rhizoma Ithas been used in individual cases for neuropathic pain due toANCA-associated vasculitis [133]

In single case report the granule showed a positive effecton neuropathic pain and it allowed the continuation of thesuspended chemotherapy with oxaliplatin [105]

328 Shakuyakukanzoto (Jap) = Shao Yao Gan Cao Tang(Chin) Formula glycyrrhizae et paeonia (Lat) Peony andLicorice Decoction (Engl) This classical formula derivesfrom the ShangHan Lun [124] In Kampomedicine it is calledShakuyakukanzoto and it is a herbal granule of Paeonia albaradix and Glycyrrhizae radix It is used to relieve menstrualpain and muscle spasm as well as muscle pain due to thechemotherapeutic agents paclitaxel and carboplatin [134ndash136] and has also been tested for CIPN A retrospective caseanalysis of 23 patients showed a positive effect on neuropathicpain in CIPN after paclitaxel for ovarian carcinoma [107]

This was supported by animal studies in a mouse modelof paclitaxel-induced pain Shakuyakukanzoto significantlyrelieved the allodynia and hyperalgesia induced by paclitaxel[106] Shakuyakukanzoto has also been tested for prevent-ing neurotoxic side effects of FOLFOX and the effect wasretrospectively compared to the treatment with GJG (seeSection 325) 44 patients with metastatic colorectal cancerreceived FOLFOX and concurrently received either GJG (119899 =20) or Shakuyakukanzoto (119899 = 24)The responsewas 500 inthe GJG and 65 in the Shakuyakkanzoto groupThe authors

concluded that both recipes are able to reduce the FOLFOX-induced neurotoxicity [108]

33 Herbs Tested or Herbal Ingredients for Neuropathic PainNot Specifically Tested to CIPN Capsaicin is the activecomponent of chili peppers which are plants belonging tothe genus Capsicum Topical creams with capsaicin are usedto treat peripheral neuropathic pain Following applicationto the skin capsaicin causes enhanced sensitivity followedby a period with reduced sensitivity and after repeatedapplications persistent desensitisation

Topical capsaicin is used to treat postherpetic neuralgiaand HIV-neuropathy and has been found to be effective inmultiple trialsThere are risks of epidermal innervation uponrepeated application over long periods [137]

Aconiti lateralis praeparata radix is a herb used in manyrecipes for neuropathy like GJG (see Section 325) andKeishikajutsubuto (see Section 326) and is often used forseveral types of persistent pain In a mouse model anal-gesic effects caused by inhibition of astrocytic activationby Aconiti lateralis praeparata radix were mimicked by theintrathecal injection of fluorocitrate The study indicatedthat the activation of spinal astrocytes was responsible forthe late maintenance phase of neuropathic pain so Aconitilateralis praeparata radix could be a therapeutic strategyfor treating neuropathic pain [138] In a rat model Aconitilateralis praeparata radixwas tested against a placebo for allo-dynia and thermal hyperalgesia A dose-dependent effect wasmeasured The effects were inhibited by intraperitoneal andintrathecal nor-binaltorphimine a selective kappa-opioidreceptor antagonist but not by intraperitoneal naloxoneTheauthors concluded that the effect against neuropathic pain isinduced via spinal kappa-opioid receptor mechanisms [139]

Moutan cortex and Coicis semen have been tested posi-tively in two different neuropathic pain mice models In onemodel allodynia was induced by intrathecal administrationof prostaglandin F2alpha (PGF2alpha) and in the secondmodel by selective L5 spinal nerve transectionThe extracts ofMoutan cortex and Coicis semen dose dependently alleviatedthe PGF2alpha-induced allodynia The increase in NADPHdiaphorase activity in the spinal cord associated with neuro-pathic pain was also blocked by these extracts These resultssuggest that Moutan cortex and Coicis semen are substanceseffective in the treatment of neuropathic pain [140]

Nigella sativa and one main compound thymoquinonewere beneficial on histopathological changes of sciatic nervesin streptozotocin (STZ) induced diabetic rats Evaluation ofthe tissues in the diabetic animals showed fewermorphologicalterations and myelin breakdown decreased significantlyafter treatment with Nigella sativa and thymoquinone Theultrastructural features of axons also showed improvement[141]

Ocimum sanctum was investigated in sciatic nerve tran-section induced peripheral neuropathy in rats Axonal degen-eration was assessed histopathologically Paw pressure VonFrey Hair tail cold-hyperalgesia and motor in-coordinationtests were performed to assess the in vivo extent of neuropa-thy Biochemical estimations of thiobarbituric acid reactive


species (TBARS) reduced glutathione (GSH) and totalcalcium levels were also performed Ocimum sanctum atten-uated axonal degeneration rise in TBARS total calciumand decrease in GSH levels in a dose-dependent mannerIn vivo reduction of nociceptive threshold and motor in-coordination was found The authors concluded that anti-oxidant and calcium attenuating actions may be responsiblefor the amelioration [142]

In an another animal study STZ-induced diabetic ratsreceived intraperitoneal injection of this extract of TeucriumpoliumThe treated rats exhibited a lower nociceptive score ascompared to untreated diabetic rats The results may suggesta therapeutic potential of Teucrium polium for the treatmentof hyperalgesia [143]

A hexanic extract from Phyllanthus amarus has beenshown to be effective in a neuropathic model of nociceptionThe antiallodynic effects seemed not to be associated with theimpairment of motor coordination or with the developmentof tolerance Apart from its anti-inflammatory actions whichare probably linked to the presence of lignans another as yetunidentified active principle(s) present in the hexanic extractof Phyllanthus amarus produces pronounced anti-allodynia[144]

An aqueous extract of Sesbania sesbanwas tested in STZ-induced diabetic ratsThe treated group showed an increasedtail flick latency significantly when comparedwith pregabalinand reduced superoxide anion and total calcium levels whichgave evidence of neuroprotective effects [145]

4 Discussion

In spite of intense research in the last decades no conven-tional pharmacological substance has been established as asufficient and safe treatment of CIPN-induced neuroprotec-tion and regeneration [31 43ndash63 65ndash67] Herbal treatment iscommonly used for different kind of therapies where westernmedicine does not offer a sufficient efficacy but the evidenceof the use of herbal treatment is not clear and has to beelucidated

One main problem of doing research on herbs andunderstanding the mechanisms of their action is the factthat herbs contain a number of active compounds and bytradition especially in Asian herbal therapy combinations ofmultiple herbs are common

Classical research mainly focusing on a single activecompound has been done often without regard to historicalknowledge of the therapeutic utility of the plant source[146] This does not reflect the complexity of traditionalAsian herbal recipes while there is some evidence thatsingle components extracted from plants are less potentthan the complete extract [147] and a multitarget approachmight be more effective than a single target approach [148]Pharmacological mixtures can also have the advantage ofpotentiating the action of their multiple bioactive compo-nents and the option of an individualized therapy [149 150]For scientific understanding of the mechanisms of actionthere is still a need for basic research on single herbs andtheir active compounds but research should not stop at

this level but continue with research of multicompoundstheir interactions and increasing or decreasing activity incombinations

The positive effect of a single herb on neuroprotection orregeneration was not found in any clinical study and rarelyfound in animal studies Only the flavonoid apigenin fromSalvia officinalis seems to protect neurons against toxicity[116] andGinkgo biloba as a single herb shows some evidenceof preventing neuronal degeneration and inducing neuralregeneration in CIPN [109ndash111]

Mainly in animal studies only a few single herbs have beentested for treatment of CIPN improving neuropathic painThis effect might be induced by Acorus calamus rhizoma dueto its antioxidative anti-inflammatory and calcium inhibito-ry actions [70] Flavonoids fromMatricaria chamomilla havean antispasmodic and an anti-inflammatory effect [83 84]Salvia officinalis is probably working due to its antioxidantactivity and anti-inflammatory properties [112ndash115] and isalso involved in an opioid mechanism [119] Fritillaria bulbusmight be effective due to its isosteroidal alkaloid verticinone[91]WhileCannabis sativa is effective inmultiple and centralpain syndromes [72ndash78] the fact that two Cannabis agonistshad been shown to be effective in CIPN in a rat model couldbe a hint thatCannabis sativamight be a promising substancefor pain in CIPN in the future

Only Ginkgo biloba extract has been positively testedin a small retrospective clinical study in humans [87] andSweet bee venom had shown positive results by injection intoacupuncture points in a small clinical case series [89 90]Topical capsaicin from chili peppers was found to be effectivein multiple trials to treat pain from postherpetic neuralgiaand HIV-neuropathy but has not been specifically testedagainst pain in CIPN [137]

There are a fewmore single herbs tested in animalmodelsfor the treatment of neuropathic pain in other conditionsthan CIPNMoutan cortex and Coicis semen have been testedpositively in two different neuropathic pain models Bothherbs dose dependently alleviated the PGF2alpha-inducedallodynia and blocked NADPH diaphorase activity in thespinal cord associated with neuropathic pain [140]

Nigella sativa Ocimum sanctum Teucrium polium Phyl-lanthus amarus and Sesbania sesban also have been tested insingle studies to ameliorate neuropathic pain [141ndash145]

Aconiti lateralis praeparata radix in a mouse model ofCIPN had analgesic effects by inhibition of spinal astrocyticactivation [138] and in a rat modelAconiti lateralis praeparataradix had a dose-dependent effect on allodynia and thermalhyperalgesia which was induced via spinal kappa-opioidreceptor mechanisms [139] which confirmed similar ani-mal studies on neuropathic pain in diabetic mice [148]Active components are alkaloids for example aconitine andmesaconitine and have in addition pain-relieving effectscardiotonic and vasodilator actions [151ndash155]

Aconiti lateralis praeparata radix is often used for severaltypes of persistent pain while it is rarely used as a single herbfor CIPN But interestingly Aconiti lateralis praeparata radixis part of many recipes used for CIPN as GJG Shakuyakukan-zoto Keishikajutsubuto and Geranii herba plus Aconiti radixcombination (see Sections 324 325 326 and 328)


Some of the pain-relieving effects of GJG are known to beinduced by aconite [139] and it is considered that the analgesiceffect is exerted by the suppression of pain-transmittingsubstances release by 120581-opioid receptor stimulationmediatedby dynorphin an endogenous opioid substance released byprocessed aconite [148] But on the other hand these effectswere stronger when using of the full recipe in comparison tothe use of Aconiti lateralis praeparata radix alone [155]

GJG is the best tested herbal recipe for CIPN But notall details of its mechanism have been clearly identifiedand for some ingredients the effects are unknown It isconsidered that the analgesic effect is exerted through theimprovement of peripheral nocireceptor sensitivity vasodi-lation and peripheral circulation by the promotion of NOproduction due to the effects of Alismatis rhizoma andDioscorea opposita rhizoma mediated by the bradykinin B2receptor and the muscarinic acetylcholine receptors [148]Another substance from GJG Rehmanniae praeparata radixcould promote the function of learning and memory of MSGrats and its mechanism may be related to the increase ofthe expression of hippocampal c-fos and nerve growth factor(NGF) [156] which can be relevant for regeneration in CIPNas well while NGF exhibits potent biological activities suchas preventing neuronal death promoting neurite outgrowthand supporting synapse formation [157] One further mech-anism of GJG might be its positive effect on improving themicrocirculation which might be helpful for the recovery ofthe nerves in CIPN [158]

Even though the full recipe was clinically positivelytested in a couple of clinical trials most of them wereuncontrolled or retrospective analyses [99ndash102 130] and theonly prospective trial had a limited number of participants[103] So the evidence of a positive effect is still low and needsfurther clinical and experimental confirmation

GJG has also been compared to another herbal recipeShakuyakukanzoto and both were found to be effective inthe treatment of CIPN but there was no negative controlgroup [107] Shakuyakukanzoto was analyzed in a mousemodel [106] and in a retrospective analysis of 23 cases withoutcontrols [108] Since Shakuyakukanzoto contains only twoherbs Paeonia alba radix and Glycyrrhizae radix the futureevaluation of its role for treating CIPN might be easierthan for other herbal recipes While neuronal apoptosiscan be triggered by oxidative stress and mitochondrialdysfunction substances with an antioxidative potency arepossible candidates for treatment of CIPN [19ndash22] so thefact that paeoniflorin as one bioactive component of Paeoniaalba radix has been positively tested as an antioxidant in anonneuronal cell model might be relevant [159] It has alsoneuroprotective effects which are closely correlated to acti-vating the adenosine A1 receptor ameliorating the functionof the cholinergic nerve regulating ion channel homeostasisretarding oxidative stress apoptosis of the neurocytes andpromoting nerve growth [160] Paeonia alba radix was usedin another recipe (see Section 327) and in two recipesPaeonia rubra radix (see Sections 321 and 322) has beenused Paeonia alba radix and Paeonia rubra radix have alot of similarities in their components and paeoniflorin is abioactive compound of both herbs [161]

While the reason for using herbal recipes derives fromhistorical knowledge or transferral of historical concepts tomodern diseases interestingly four of eight herbal recipestested for CIPN contain Glycyrrhizae radix To find thescientific ratio behind this decision analyses of its action inthe context of neural cell damage might be fruitful

Another herb that has been used in four of eight herbalrecipes tested for CIPN is Astragalus membranaceus radixThis might be rational while Astragalus membranaceusradix water extracts caused a marked enhancement of theNGF-mediated neurite outgrowth and the expression ofgrowth-associated protein 43 from PC12 cells in vitro [162]Astragalus membranaceus radix extracts can be a potentialnerve growth-promoting factor being salutary in aiding thegrowth of axons in the peripheral nerve [162] AstragalosideIV (AGS-IV) one bioactive compound of Astragalus mem-branaceus radix is an aldose-reductase inhibitor and a free-radical scavenger which suppressed a decrease in myelinatedfibers promoted an increase in myelinated fiber density andan increase in segmental demyelination in diabetic rats [163]It also increased the activity of glutathione peroxidase innerves depressed the activation of aldose reductase in ery-throcytes decreased the accumulation of advanced glycationend products in both nerves and erythrocytes and elevatedNa+ K+-ATPase activity in both the nerves and erythrocytesof diabetic rats so it is considered to be protective against theprogression of peripheral neuropathy [163]

The herbal recipeBuYangHuan and amodified extensionhave been used in two clinical controlled randomized trials[92 93] (321 and 322 see above) and was found to beeffective in both The formula used is very complex andlittle is known about the mechanism of its compound butherbs like Astragalus membranaceus radix Paeonia rubraradix and Dioscorea opposita rhizoma are part of the herbalcombinationwhere possiblemechanisms are described (321322 325 327 see above) so at least something is knownabout its possible mechanisms of effect

Another study used a modified classical prescriptionnamed Chai Hu Long Gu Mu Li Wan (see Section 323)and found positive results as well [94] Even though it is acontrolled randomized trial the treatment protocol is verycomplicated combining oral intake of medical herbs andexternal washing with other herbs So also with this herbalcombination little is known about the mechanism of itsaction

Two other herbal recipes have been reported for suc-cessful clinical use Keishikajutsubuto = Gui Zhi Jia Shu FuTang (see Section 326) and Ogikeishigomotsuto =Huang QiWu Wu Tang (see Section 327) But these studies are eitheruncontrolled or a case report so the quality of the evidence isvery low

The trials on the single herbs and herbal combinationstested so far do not provide a clear recommendation forclinical use But research on some single herbs as well as oncombinations like GJG is promising even though the level ofknowledge is limited to basic research on the mechanisms ofaction and evidence from clinical trials But it is necessary tocontinue research on this field while treatment concepts forCIPN are lacking


The most used herbs of herbal recipes in clinical trialson CIPN are Aconiti lateralis praeparata radix Rehmanniapraeparata radix Paeonia (alba and rubra) radix Astragalusmembranaceus radix and Glycyrrhizae radix

In Chinese medicine experience Astragalus membrana-ceus radix is supporting theQi whichmeans inwestern termssupporting the general energy level of the body which isusually reduced in CIPN by activating the vegetative nervoussystem Rehmannia praeparata radix is basically supportingtheYin which inwestern terms reflects the structural damageof tissue in the case of CIPN the peripheral nerves Paeoniaalba radix and Paeonia rubra radix promote the flow ofthe Xue which in western terminology has its correlate inenhancing the microcirculation which might be reducedin CIPN promotion of the perfusion might enhance theregeneration

Aconiti lateralis praeparata radix supports in Chinesemedicine theory the Yang A typical symptom of Yang defi-ciency is ice-coldness which is prominent in the extremitiesin some cases of CIPNGlycyrrhizae radix supports the fluidsand has a balancing effect on the whole recipe

So in spite of using different terms Chinese medicinetheory describes physical reactions of the body that can beexplained by western physiology and has found its proof byexperimental studies [138 139 148 151ndash156 159ndash164]

So using these herbs has as rational foundation on thebasis of Chinese medical theory as well as from experimentalstudies but unfortunately still little is known about thecomplex physiological mechanisms of herbal combinationsthe interactions of the substances and the mechanisms ofaction ofmany other substances used in herbalmedicineThechallenge for future research is bringing historical knowledgeand modern scientific analysis together

Due to this limited knowledge on the mechanisms of theaction of herbs we additionally collected data on herbs thatare a putative treatment option for CIPN While oxidativestress and mitochondrial dysfunction promote CIPN sub-stances with an antioxidative potency are possible candidatesfor the treatment of CIPN So in the list below we listherbal antioxidants tested in neuronal cell or disease modelsAdditionally we added herbs for enhancement of nervegrowth as putative treatment options for CIPN NGF exhibitspotent biological activities such as preventing neuronal deathpromoting neurite outgrowth and supporting synapse for-mation [157] which has a relevance for the development ofCIPN [39]

Putative Herbs or Herbal Compounds for the Treatment ofCIPN

(1) Herbal Antioxidants Tested in Neuronal Cell or Dis-ease Models Puerarin (from Pueraria lobata radix)[165 166] Icariin (from Epimedii herba) [167]a fraction of polysaccharides (from Lycium bar-barum) [168] Ginsenoside Rg1 (from Notoginsengpanacis) [169] honokiol and magnolol (from Mag-nolia officinalis) [170] Ginkgolide A B (from Ginkgobiloba) [171] huperzine A (from Huperzia serrata)

[171] Ginseng radix [172] Notoginseng panacisradix [173] 3541015840-tetrahydroxystilbene-2-O-beta-D-glucoside (from Polygonum multiflorum) [174ndash176]celastrol (from Tripterygium wilfordii Hook) [177]Salvianolic acid B (from Salvia miltiorrhiza) [178179] tanshinone IIA (from Salvia miltiorrhizae)[180] Gastrodia elata rhizoma [181 182] Astraga-loside IV (from Astragalus membranaceus radix)[163] Tetramethylpyrazine (from Ligusticum wal-lichi) [183 184] Ziziphus spinosus semen [185]Baicalein (from Scutellaria baicalensis radix Georgi)[186] Uncaria rhynchophylla [164] 67-dihydroxy-2-methoxy-14-phenanthrenedione chrysoeriol 41015840-O-beta-D-glucopyranoside chrysoeriol 7-O-beta-D-glucopyranoside and alternanthin (from Dioscoreaopposita radix) [187]

(2) Herbs or Herbal Compounds That Enhance NerveGrowth Cistanches herba [157 188] Huperzine A(HupA) from Huperzia serrata [189 190] a lipophilicfraction of panax ginseng [191] Astragalus membra-naceus radix [162] Gentiside C a compound of Gen-tiana rigescens radix [191] Rehmanniae praeparataradix [192] Paeoniflorin of Paeonia alba radix [193]

Research with the aim of proving the benefits of promis-ing substances or herbal combinations has to describe themechanism of action for single herbs and single componentsinvestigate the interactions of combinations of substancesand analyse the promoting effects of combinations

From this viewpoint research in this field has not verymuch progressed but if research does not provide these dataherbal combinations will not find acceptance in mainstreamtreatments in non-Asian countries in EuropeNorthAmericaor Australia

This challenge could be taken if more international coop-eration of interested research groups would be organized

5 Conclusion

Experimental and clinical studies have not yielded enoughevidence to establish a standard practice for the treatmentof CIPN but from this literature review a lot of promisingsubstancesmainlyChinesemedical herbswith possible effectinCIPNor a putative influence onmechanisms of CIPN havebeen identified in the last years

The knowledge of themechanisms of action is still limitedand the quality of the clinical trials needs further improve-ment In the future not only the mechanisms of action forsingle herbs and single components have to be described butinteractions of combinations of substances as well as interac-tionswith chemotherapy have to be investigated and analysedin depth While CIPN has multiple possible mechanisms ofneuronal degeneration a combination of components mightbe a promising opportunity focusing on multiple targets ofdegeneration or activating regeneration


References

[1] G Wilkes ldquoPeripheral neuropathy related to chemotherapyrdquoSeminars in Oncology Nursing vol 23 no 3 pp 162ndash173 2007

[2] R B Lipton S C Apfel J P Dutcher et al ldquoTaxol producesa predominantly sensory neuropathyrdquo Neurology vol 39 no 3pp 368ndash373 1989

[3] J M A van Gerven J W B Moll M J van den Bent etal ldquoPaclitaxel (Taxol) induces cumulative mild neurotoxicityrdquoEuropean Journal of Cancer A vol 30 no 8 pp 1074ndash1077 1994

[4] C Visovsky M Collins L Abbott J Aschenbrenner and CHart ldquoPutting evidence into practice evidence-based inter-ventions for chemotherapy-induced peripheral neuropathyrdquoClinical Journal of Oncology Nursing vol 11 no 6 pp 901ndash9132007

[5] J W Hay ldquoQuality of life effects of chemotherapy-induced neu-ropathy in ovarian cancerrdquo Proceedings of the American Societyof Clinical Oncology vol 21 abstract 886 p 222a 2002


[7] F H Hausheer R L Schilsky S Bain E J Berghorn and FLieberman ldquoDiagnosismanagement and evaluation of chemo-therapy-induced peripheral neuropathyrdquo Seminars in Oncologyvol 33 no 1 pp 15ndash49 2006

[8] A M Corse and R W Kunel ldquoPeripheral neuropathyrdquo inPrinciples of AmbulatoryMedicine L R Barker J R Burton andP D Zieve Eds pp 1296ndash1314 Williams ampWilkins BaltimoreMd USA 5th edition 1999

[9] Oxaliplatin Prescribing Information Drugscom HospiraWorldwide 2013 httpwwwdrugscomprooxaliplatinhtml


[11] V Chaudhry M Chaudhry T O Crawford E Simmons-OrsquoBrien and J W Griffin ldquoToxic neuropathy in patients withpre-existing neuropathyrdquoNeurology vol 60 no 2 pp 337ndash3402003

[12] S Mielke K Mross T A Gerds et al ldquoComparative neurotox-icity of weekly non-break paditaxel infusions over 1 versus 3 hrdquoAnti-Cancer Drugs vol 14 no 10 pp 785ndash792 2003

[13] A de Gramont C Boni M Navaro et al ldquoOxaliplatin5FULVin the adjuvant treatment of stage II and stage III colon cancerefficacy results with a medican follow-up of 4 yearsrdquo Journal ofClinical Oncology vol 23 p 16 2005

[14] A Grothey ldquoClinical management of oxaliplatin-associatedneurotoxicityrdquo Clinical Colorectal Cancer vol 5 no 1 pp S38ndashS46 2005

[15] R W Kuncl and E B George ldquoToxic neuropathies andmyopathiesrdquo Current Opinion in Neurology vol 6 no 5 pp695ndash704 1993

[16] S Quasthoff and H P Hartung ldquoChemotherapy-inducedperipheral neuropathyrdquo Journal of Neurology vol 249 no 1 pp9ndash17 2002

[17] R W Gregg J M Molepo V J A Monpetit et al ldquoCisplatinneurotoxicity the relationship between dosage time and plat-inum concentration in neurologic tissues and morphologicevidence of toxicityrdquo Journal of Clinical Oncology vol 10 no5 pp 795ndash803 1992

[18] J S Gill and A J Windebank ldquoCisplatin-induced apoptosis inrat dorsal root ganglion neurons is associated with attemptedentry into the cell cyclerdquo The Journal of Clinical Investigationvol 101 no 12 pp 2842ndash2850 1998

[19] M S Yoon Z Katsarava M Obermann et al ldquoErythropoietinoverrides the triggering effect of DNA platination products ina mouse model of Cisplatin-induced neuropathyrdquo BMC Neuro-science vol 10 article 77 2009

[20] E K Joseph and J D Levine ldquoMitochondrial electron transportinmodels of neuropathic and inflammatory painrdquo Pain vol 121no 1-2 pp 105ndash114 2006

[21] E K Joseph and J D Levine ldquoComparison of oxaliplatin- andCisplatin-induced painful peripheral neuropathy in the ratrdquoTheJournal of Pain vol 10 no 5 pp 534ndash541 2009

[22] E K Joseph X Chen O Bogen and J D Levine ldquoOxaliplatinacts on IB4-positive nociceptors to induce an oxidative stress-dependent acute painful peripheral neuropathyrdquoThe Journal ofPain vol 9 no 5 pp 463ndash472 2008

[23] G Cavaletti G Tredici M Braga and S Tazzari ldquoExperimen-tal peripheral neuropathy induced in adult rats by repeatedintraperitoneal administration of taxolrdquo Experimental Neurol-ogy vol 133 no 1 pp 64ndash72 1995

[24] C M Peters J M Jimenez-Andrade M A Kuskowski J RGhilardi and P W Mantyh ldquoAn evolving cellular pathologyoccurs in dorsal root ganglia peripheral nerve and spinal cordfollowing intravenous administration of paclitaxel in the ratrdquoBrain Research vol 1168 no 1 pp 46ndash59 2007

[25] O A Shemesh and M E Spira ldquoPaclitaxel induces axonalmicrotubules polar reconfiguration and impaired organelletransport implications for the pathogenesis of paclitaxel-induced polyneuropathyrdquoActa Neuropathologica vol 119 no 2pp 235ndash248 2010

[26] L H Weimer ldquoMedication-induced peripheral neuropathyrdquoCurrent Neurology and Neuroscience Reports vol 3 no 1 pp86ndash92 2003

[27] K D Tanner J D Levine and K S Topp ldquoMicrotubule disori-entation and axonal swelling in unmyelinated sensory axonsduring vincristine-induced painful neuropathy in ratrdquo Journalof Comparative Neurology vol 395 pp 481ndash492 1998

[28] K S Topp K D Tanner and J D Levine ldquoDamage to the cyto-skeleton of large diameter sensory neurons and myelinatedaxons in vincristine-induced painful peripheral neuropathy inthe ratrdquo Journal of Comparative Neurology vol 424 no 4 pp563ndash576 2000

[29] Z Sahenk S T Brady and J R Mendell ldquoStudies on the patho-genesis of vincristine-induced neuropathyrdquo Muscle and Nervevol 10 no 1 pp 80ndash84 1987

[30] S Lobert B Vulevic and J-J Correia ldquoInteraction of vincaalkaloids with tubulin a comparison of vinblastine vincristineand vinorelbinerdquo Biochemistry vol 35 no 21 pp 6806ndash68141996

[31] A A Argyriou P Marmiroli G Cavaletti and H P KalofonosldquoEpothilone-induced peripheral neuropathy a review of cur-rent knowledgerdquo Journal of Pain and Symptom Managementvol 42 no 6 pp 931ndash940 2011

[32] R J Kowalski P Giannakakou and E Hamel ldquoActivities of themicrotubule-stabilizing agents epothilones A and B with puri-fied tubulin and in cells resistant to paclitaxel (Taxol)rdquo TheJournal of Biological Chemistry vol 272 no 4 pp 2534ndash25411997


[33] K H Altmann M Wartmann and T OrsquoReilly ldquoEpothilonesand related structuresmdasha new class of microtubule inhibitorswith potent in vivo antitumor activityrdquo Biochimica et BiophysicaActa vol 1470 no 3 pp M79ndashM91 2000

[34] A A Argyriou G Iconomou and H P Kalofonos ldquoBorte-zomib-induced peripheral neuropathy in multiple myeloma acomprehensive review of the literaturerdquoBlood vol 112 no 5 pp1593ndash1599 2008

[35] G Cavaletti and E Nobile-Orazio ldquoBortezomib-induced peri-pheral neurotoxicity still far from a painless gainrdquoHaematolog-ica vol 92 no 10 pp 1308ndash1310 2007

[36] G Cavaletti A Gilardini A Canta et al ldquoBortezomib-inducedperipheral neurotoxicity a neurophysiological and pathologicalstudy in the ratrdquoExperimental Neurology vol 204 no 1 pp 317ndash325 2007

[37] I Casafont M T Berciano and M Lafarga ldquoBortezomibinduces the formation of nuclear poly(A) RNA granulesenriched in Sam68 and PABPN1 in sensory ganglia neuronsrdquoNeurotoxicity Research vol 17 no 2 pp 167ndash178 2010

[38] T H Landowski C J Megli K D Nullmeyer R M Lynchand R T Dorr ldquoMitochondrial-mediated disregulation of Ca2+is a critical determinant of Velcade (PS-341Bortezomib) cyto-toxicity in myeloma cell linesrdquo Cancer Research vol 65 no 9pp 3828ndash3836 2005

[39] C Montagut A Rovira and J Albanell ldquoThe proteasome anovel target for anticancer therapyrdquo Clinical and TranslationalOncology vol 8 no 5 pp 313ndash317 2006

[40] C H Chung J Aulino N J Muldowney et al ldquoNuclear factor-kappa B pathway and response in a phase II trial of bortezomiband docetaxel in patients with recurrent andor metastatic headand neck squamous cell carcinomardquoAnnals of Oncology vol 21no 4 pp 864ndash870 2010

[41] J P Cata H RWeng AW BurtonHVillareal S Giralt and PM Dougherty ldquoQuantitative sensory findings in patients withbortezomib-induced painrdquoThe Journal of Pain vol 8 no 4 pp296ndash306 2007

[42] E R Lepper N F Smith M C Cox C D Scripture and WD Figg ldquoThalidomidemetabolism and hydrolysis mechanismsand implicationsrdquo Current Drug Metabolism vol 7 no 6 pp677ndash685 2006

[43] G Cavaletti and PMarmiroli ldquoChemotherapy-induced periph-eral neurotoxicityrdquo Nature Reviews Neurology vol 6 no 12 pp657ndash666 2010

[44] D H Moore J Donnelly W P McGuire et al ldquoLimited accesstrial using amifostine for protection against Cisplatin- andthree-hour paclitaxel-induced neurotoxicity a phase II study oftheGynecologic OncologyGrouprdquo Journal of Clinical Oncologyvol 21 no 22 pp 4207ndash4213 2003

[45] N Masuda S Negoro F Hausheer et al ldquoPhase I and pharma-cologic study of BNP7787 a novel chemoprotector in patientswith advanced non-small cell lung cancerrdquo Cancer Chemother-apy and Pharmacology vol 67 no 3 pp 533ndash542 2011

[46] D RGandara V JWiebe E A Perez RWMakuch andMWDeGregorio ldquoCisplatin rescue therapy experience with sodiumthiosulfate WR2721 and diethyldithiocarbamaterdquo CriticalReviews in OncologyHematology vol 10 no 4 pp 353ndash3651990

[47] G Tredici M Braga G Nicolini et al ldquoEffect of recombinanthuman nerve growth factor on Cisplatin neurotoxicity in ratsrdquoExperimental Neurology vol 159 no 2 pp 551ndash558 1999

[48] L Aloe L Manni F Properzi S de Santis and M FioreldquoEvidence that nerve growth factor promotes the recovery ofperipheral neuropathy induced inmice byCisplatin behavioralstructural and biochemical analysisrdquo Autonomic Neurosciencevol 86 no 1-2 pp 84ndash93 2000

[49] W Q Gao N Dybdal N Shinsky et al ldquoNeurotrophin-3 reverses experimental Cisplatin-induced peripheral sensoryneuropathyrdquo Annals of Neurology vol 38 no 1 pp 30ndash37 1995

[50] I D Davis L Kiers L MacGregor et al ldquoA randomizeddouble-blinded placebo-controlled phase II trial of recombi-nant human leukemia inhibitory factor (rhuLIF EmfilerminAM424) to prevent chemotherapy-induced peripheral neu-ropathyrdquo Clinical Cancer Research vol 11 no 5 pp 1890ndash18982005

[51] I Cervellini E Bello R Frapolli et al ldquoThe neuroprotectiveeffect of erythropoietin in docetaxel-induced peripheral neu-ropathy causes no reduction of antitumor activity in 13762adenocarcinoma-bearing ratsrdquo Neurotoxicity Research vol 18no 2 pp 151ndash160 2010

[52] R Bianchi A Gilardini V Rodriguez-Menendez et alldquoCisplatin-induced peripheral neuropathy neuroprotection byerythropoietin without affecting tumour growthrdquo EuropeanJournal of Cancer vol 43 no 4 pp 710ndash717 2007

[53] M Dicato and L Plawny ldquoErythropoietin in cancer patientspros and consrdquo Current Opinion in Oncology vol 22 no 4 pp307ndash311 2010

[54] S Cascinu L Cordella E del Ferro M Fronzoni and GCatalano ldquoNeuroprotective effect of reduced glutathione onCisplatin-based chemotherapy in advanced gastric cancer arandomized double-blind placebo- controlled trialrdquo Journal ofClinical Oncology vol 13 no 1 pp 26ndash32 1995

[55] S Cascinu V Catalano L Cordella et al ldquoNeuroprotectiveeffect of reduced glutathione on oxaliplatin-based chemother-apy in advanced colorectal cancer a randomized double-blindplacebo-controlled trialrdquo Journal of Clinical Oncology vol 20no 16 pp 3478ndash3483 2002

[56] L BoveM Picardo VMaresca B Jandolo andA Pace ldquoA pilotstudy on the relation betweenCisplatin neuropathy and vitaminErdquo Journal of Experimental andClinical Cancer Research vol 20no 2 pp 277ndash280 2001

[57] A A Argyriou E Chroni A Koutras et al ldquoVitamin Efor prophylaxis against chemotherapy-induced neuropathy arandomized controlled trialrdquoNeurology vol 64 no 1 pp 26ndash312005

[58] A A Argyriou E Chroni A Koutras et al ldquoPreventingpaclitaxel-induced peripheral neuropathy a phase II trial ofvitamin E supplementationrdquo Journal of Pain and SymptomManagement vol 32 no 3 pp 237ndash244 2006

[59] A Pace D Giannarelli E Galie et al ldquoVitamin E neuro-protection for Cisplatin neuropathy a randomized placebo-controlled trialrdquo Neurology vol 74 no 9 pp 762ndash766 2010

[60] C Pisano G Pratesi D Laccabue et al ldquoPaclitaxel andCisplatin-induced neurotoxicity a protective role of acetyl-L-carnitinerdquoClinical Cancer Research vol 9 no 15 pp 5756ndash57672003

[61] W Boehmerle K Zhang M Sivula et al ldquoChronic exposureto paclitaxel diminishes phosphoinositide signaling by calpain-mediated neuronal calcium sensor-1 degradationrdquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 104 no 26 pp 11103ndash11108 2007


[62] V A Carozzi A Chiorazzi A Canta et al ldquoGlutamate car-boxypeptidase inhibition reduces the severity of chemotherapy-induced peripheral neurotoxicity in ratrdquoNeurotoxicity Researchvol 17 no 4 pp 380ndash391 2010

[63] P C Kurniali L G Luo and A B Weitberg ldquoRole of calciummagnesium infusion in oxaliplatin-based chemotherapy forcolorectal cancer patientsrdquoOncology vol 24 no 3 pp 289ndash2922010

[64] G Cavaletti and PMarmiroli ldquoThe role of growth factors in theprevention and treatment of chemotherapy-induced peripheralneurotoxicityrdquoCurrent Drug Safety vol 1 no 1 pp 35ndash42 2006

[65] J Albers V Chaudhry G Cavaletti and R Donehower ldquoInter-ventions for preventing neuropathy caused by Cisplatin andrelated compoundsrdquo Cochrane Database of Systematic Reviewsvol 1 Article ID CD005228 2007

[66] S Wolf D Barton L Kottschade A Grothey and C LoprinzildquoChemotherapy-induced peripheral neuropathy preventionand treatment strategiesrdquo European Journal of Cancer vol 44no 11 pp 1507ndash1515 2008

[67] G Kannarkat E E Lasher and D Schiff ldquoNeurologic compli-cations of chemotherapy agentsrdquoCurrent Opinion in Neurologyvol 20 no 6 pp 719ndash725 2007

[68] A Muthuraman and N Singh ldquoAttenuating effect of Acoruscalamus extract in chronic constriction injury induced neu-ropathic pain in rats an evidence of anti-oxidative anti-inflammatory neuroprotective and calcium inhibitory effectsrdquoBMC Complementary and Alternative Medicine vol 11 article24 2011

[69] A Muthuraman N Singh and A S Jaggi ldquoEffect of hydroal-coholic extract of Acorus calamus on tibial and sural nervetransection-induced painful neuropathy in ratsrdquo Journal ofNatural Medicines vol 65 no 2 pp 282ndash292 2011

[70] AMuthuraman andN Singh ldquoAttenuating effect of hydroalco-holic extract of Acorus calamus in vincristine-induced painfulneuropathy in ratsrdquo Journal of Natural Medicines vol 65 no 3-4 pp 480ndash487 2011

[71] E J Rahn A M Zvonok G A Thakur A D KhanolkarA Makriyannis and A G Hohmann ldquoSelective activation ofcannabinoid CB

2receptors suppresses neuropathic nocicep-

tion induced by treatment with the chemotherapeutic agentpaclitaxel in ratsrdquo Journal of Pharmacology and ExperimentalTherapeutics vol 327 no 2 pp 584ndash591 2008

[72] R J Ellis W Toperoff F Vaida et al ldquoSmoked medicinalcannabis for neuropathic pain in HIV a randomized crossoverclinical trialrdquoNeuropsychopharmacology vol 34 no 3 pp 672ndash680 2009

[73] M Karst K Salim S Burstein I Conrad L Hoy and USchneider ldquoAnalgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain a randomized controlled trialrdquoJournal of the AmericanMedical Association vol 290 no 13 pp1757ndash1762 2003

[74] M A Ware T Wang S Shapiro et al ldquoSmoked cannabisfor chronic neuropathic pain a randomized controlled trialrdquoCanadianMedical Association Journal vol 182 no 14 pp E694ndashE701 2010

[75] D J Rog T J Nurmikko T Friede and C A Young ldquoRandom-ized controlled trial of cannabis-basedmedicine in central paininmultiple sclerosisrdquoNeurology vol 65 no 6 pp 812ndash819 2005

[76] D R Blake P Robson M Ho R W Jubb and C S McCabeldquoPreliminary assessment of the efficacy tolerability and safety

of a cannabis-based medicine (Sativex) in the treatment of paincaused by rheumatoid arthritisrdquoRheumatology vol 45 no 1 pp50ndash52 2006

[77] J S Berman C Symonds and R Birch ldquoEfficacy of twocannabis based medicinal extracts for relief of central neuro-pathic pain from brachial plexus avulsion results of a ran-domised controlled trialrdquo Pain vol 112 no 3 pp 299ndash3062004

[78] B Wilsey T Marcotte A Tsodikov et al ldquoA randomizedplacebo-controlled crossover trial of cannabis cigarettes inneuropathic painrdquoThe Journal of Pain vol 9 no 6 pp 506ndash5212008

[79] D I Abrams C A Jay S B Shade et al ldquoCannabis in painfulHIV-associated sensory neuropathy a randomized placebo-controlled trialrdquo Neurology vol 68 no 7 pp 515ndash521 2007


[81] J S Berman C Symonds and R Birch ldquoEfficacy of two canna-bis based medicinal extracts for relief of central neuropathicpain from brachial plexus avulsion results of a randomisedcontrolled trialrdquo Pain vol 112 no 3 pp 299ndash306 2004


[83] E T Varro R B Lynn and E R James Pharmacognosy Lea ampFabigen Philadelphia Pa USA 9th edition 1988

[84] G B Norman andWMaxHerbal Drugs and Phytopharmaceu-ticals CRC Press London UK 2nd edition 2001

[85] A N A Abad M H K Nouri A Gharjanie and F TavakolildquoEffect of Matricaria chamomilla hydroalcoholic extract onCisplatin-induced neuropathy in micerdquo Chinese Journal ofNatural Medicines vol 9 no 2 pp 126ndash131 2011

[86] G Ozturk O Anlar ErdoganE M Kosem H Ozbek andA Turker ldquoThe effect of Ginkgo extract EGb761 in Cisplatin-induced peripheral neuropathy inmicerdquoToxicology andAppliedPharmacology vol 196 no 1 pp 169ndash175 2004

[87] J Marshall A Zakari J J Hwang V Papadopoulos A Rosen-berg and C Silver ldquoGinkgo biloba (GB) extract as a neuropro-tective agent in oxaliplatin (Ox)-induced neuropathy AmericanSociety of Clinical Oncologists Annual Meeting ProceedingsrdquoJournal of Clinical Oncology vol 22 supplement 14 abstract3670 2004

[88] A N A Abad M H K Nouri and F Tavakkoli ldquoEffect ofSalvia officinalis hydroalcoholic extract on vincristine-inducedneuropathy in micerdquo Chinese Journal of Natural Medicines vol9 no 5 pp 354ndash358 2011

[89] J W Park J H Jeon J W Yoon et al ldquoEffects of sweetbee venom pharmacopuncture treatment for chemotherapy-induced peripheral neuropathy a case seriesrdquo Integrative Can-cer Therapies vol 11 no 2 pp 166ndash171 2011

[90] J Yoon J H Jeon Y W Lee et al ldquoSweet bee venom pharma-copuncture for chemotherapy-induced peripheral neuropathyrdquoJournal of Acupuncture and Meridian Studies vol 5 no 4 pp156ndash165 2012

[91] F Xu S Xu L Wang et al ldquoAntinociceptive efficacy ofverticinone in murine models of inflammatory pain and pacli-taxel induced neuropathic painrdquo Biological and PharmaceuticalBulletin vol 34 no 9 pp 1377ndash1382 2011


[92] Y Y Sun Y J Jia M N Huang and J Chen ldquoBuyanghuanwu decoction in prevention of peripheral neuropathy afterchemotherapy a clinical observationrdquo Guangming Journal ofChinese Medicine vol 23 no 7 pp 958ndash959 2008

[93] J H Deng and S L Zou ldquoObservation on TCM treatment of 32cases of chemotherapy-induced peripheral neuropathyrdquo Journalof Practical Traditional Chinese Internal Medicine vol 21 no 22007

[94] L Pan H Gao and X R Xing ldquoCombined applica-tion of traditional Chinese medicine prevention of taxolchemotherapy-induced peripheral neuropathy a clinical obser-vationrdquo Neimenggu Zhong Yi Yao vol 3 p 28 2012

[95] L Sima and L Pan ldquoInfluence of Chinese herb on chemo-therapy-induced peripheral neuropathyrdquo Annals of Oncologyvol 20 supplement 3 pp iii45ndashiii46 2009

[96] K Hashimoto Y Sakuma and J Kotani ldquoHistological study ofa paclitaxel-induced peripheral neuropathy model treated withgoshajnkiganrdquo The Journal of Osaka Dental University vol 38no 2 pp 109ndash112 2004

[97] K Hashimoto Y Sakuma and J Kotani ldquoGoshajinkiganimproves paclitaxel-induced peripheral neuropathy in ratsrdquoTheJournal of Osaka Dental University vol 40 no 1 pp 47ndash522006

[98] S Ushio N Egashira H Sada et al ldquoGoshajinkigan reducesoxaliplatin-induced peripheral neuropathy without affectinganti-tumour efficacy in rodentsrdquo European Journal of Cancervol 48 no 9 pp 1407ndash1413 2012

[99] Y Shindo K Tenma H Imano M Hibino K Yoshino and MNakamura ldquoReduction of oxaliplatin-related neurotoxicity byGosha-jinki-ganrdquo Gan to Kagaku Ryoho vol 35 no 5 pp 863ndash865 2008

[100] M Nishioka M Shimada N Kurita et al ldquoThe Kampomedicine Goshajinkigan prevents neuropathy in patientstreated by FOLFOX regimenrdquo International Journal of ClinicalOncology vol 16 no 4 pp 322ndash327 2011

[101] T Kono N Mamiya N Chisato et al ldquoEfficacy of Gosha-jinkigan for peripheral neurotoxicity of oxaliplatin in patientswith advanced or recurrent colorectal cancerrdquo Evidence-BasedComplementary and Alternative Medicine vol 2011 Article ID418481 8 pages 2011

[102] T Yamamoto T Murai M Ueda et al ldquoClinical features ofpaclitaxel-induced peripheral neuropathy and role of Gosya-jinki-ganrdquo Gan to Kagaku Ryoho vol 36 no 1 pp 89ndash92 2009(Japanese)

[103] H Kaku S Kumagai H Onoue et al ldquoObjective evaluation ofthe alleviating effects of Goshajinkigan on peripheral neuropa-thy induced by paclitaxelcarboplatin therapy a multicentercollaborative studyrdquo Experimental and Therapeutic Medicinevol 3 no 1 pp 60ndash65 2012

[104] T Yamada H Kan S Matsumoto et al ldquoReduction in oxali-platin-related neurotoxicity by the administration of Keishika-jutsubuto (TJ-18)and powdered processed aconite rootrdquo Gan toKagaku Ryoho vol 39 no 11 pp 1687ndash1691 2012 (Japanese)

[105] T TatsumiDKishi andTKogure ldquoThe efficacy of ogikeishigo-motsuto on chronic cumulative sensory neuropathy inducedby Oxaliplatinmdashcase report and literature viewrdquo Journal ofTraditional Medicines vol 26 no 3 pp 136ndash140 2009

[106] T Hidaka T Shima K Nagira et al ldquoHerbal medicineShakuyaku-kanzo-to reduces paclitaxel-induced painfulperipheral neuropathy in micerdquo European Journal of Pain vol13 no 1 pp 22ndash27 2009

[107] K Fujii SOkamotoK Saitoh et al ldquoThe efficacy of Shakuyaku-Kanzo-to for peripheral nerve dysfunction in paclitaxel combi-nation chemotherapy for epithelial ovarian carcinomardquo Gan toKagaku Ryoho vol 31 no 10 pp 1537ndash1540 2004

[108] A Hosokawa K Ogawa T Ando et al ldquoPreventive effect oftraditional Japanese medicine on neurotoxicity of FOLFOX formetastatic colorectal cancer a multicenter retrospective studyrdquoAnticancer Research vol 32 no 7 pp 2545ndash2550 2012

[109] F V Defeudis ldquoBilobalide and neuroprotectionrdquo Pharmacolog-ical Research vol 46 no 6 pp 565ndash568 2002

[110] F V DeFeudis V Papadopoulos and K Drieu ldquoGinkgo bilobaextracts and cancer a research area in its infancyrdquo Fundamentaland Clinical Pharmacology vol 17 no 4 pp 405ndash417 2003

[111] B Ahlemeyer and J Krieglstein ldquoPharmacological studiessupporting the therapeutic use of Ginkgo biloba extract forAlzheimerrsquos diseaserdquo Pharmacopsychiatry vol 36 supplement1 pp 8ndash14 2003

[112] H J P Dorman S G Deans R C Noble et al ldquoEvaluation invitro of plant essential oils as natural antioxidantsrdquo Journal ofEssential Oil Research vol 7 no 6 pp 645ndash651 1995

[113] J Hohmann I Zupko D Redei et al ldquoProtective effects of theaerial parts of Salvia officinalisMelissa officinalis andLavandulaangustifolia and their constituents against enzyme-dependentand enzyme-independent lipid peroxidationrdquo Planta Medicavol 65 no 6 pp 576ndash578 1999

[114] D Malencic O Gasic M Popovic and P Boza ldquoScreening forantioxidant properties of Salvia reflexa hornemrdquo PhytotherapyResearch vol 14 no 7 pp 546ndash548 2000

[115] I Zupko J Hohmann D Redei G Falkay G Janicsak andI Mathe ldquoAntioxidant activity of leaves of Salvia species inenzyme-dependent and enzyme-independent systems of lipidperoxidation and their phenolic constituentsrdquo Planta Medicavol 67 no 4 pp 366ndash368 2001

[116] C NWang CW Chi Y L Lin C F Chen and Y J Shiao ldquoTheneuroprotective effects of phytoestrogens on amyloid120573 protein-induced toxicity are mediated by abrogating the activation ofcaspase cascade in rat cortical neuronsrdquoThe Journal of BiologicalChemistry vol 276 no 7 pp 5287ndash5295 2001

[117] M J Howes N S Perry and P J Houghton ldquoPlants withtraditional uses and activities relevant to the management ofAlzheimerrsquos disease and other cognitive disordersrdquo Phytother-apy Research vol 17 no 1 pp 1ndash18 2003

[118] Y A Maklad E A Aboutabl M M El-Sherei and K MMeselhy ldquoBioactivity studies of Salvia transsylvanica (Schur exGriseb) grown in Egyptrdquo Phytotherapy Research vol 13 no 2pp 147ndash150 1999

[119] M R A Rodrigues L K S Kanazawa T L M D Neves etal ldquoAntinociceptive and anti-inflammatory potential of extractand isolated compounds from the leaves of Salvia officinalis inmicerdquo Journal of Ethnopharmacology vol 139 no 2 pp 519ndash5262012

[120] S Y Yoon D H Roh Y B Kwon et al ldquoAcupoint stimulationwith diluted bee venom (apipuncture) potentiates the analgesiceffect of intrathecal clonidine in the rodent formalin test and ina neuropathic painmodelrdquoThe Journal of Pain vol 10 no 3 pp253ndash263 2009

[121] S Y Kang D H Roh S Y Yoon et al ldquoRepetitive treatmentwith diluted bee venom reduces neuropathic pain via poten-tiation of locus coeruleus noradrenergic neuronal activity andmodulation of spinal NR1 phosphorylation in ratsrdquoThe Journalof Pain vol 13 no 2 pp 155ndash166 2012


[122] Q R Wang Yi Lin Gai Cuo Correcting the Errors in the Forestof Medicine Blue Poppy Press Boulder Colo USA 2007

[123] Y Qian Xiaoer Yaozheng Zhijue With coments by X Z Yan JS Guo Peoplersquos Medical Publishing House 2006

[124] Z J Zhang On Cold Damage (Shang Han Lun) Translation ampCommentaries byY FengNWisemanCMitchell andY FengBlue Poppy Press Boulder Colo USA 2000

[125] Y H Yan Jisheng fang first published in 1253 Reprint ShangwuYin Shu Guan Taibei Taiwan 1975

[126] Japan Society for Oriental Medicine Introduction to KampoJapanese Traditional Medicine Elsevier Tokio Japan 2005

[127] Y Niwa and Y Miyachi ldquoAntioxidant action of natural healthproducts and Chinese herbsrdquo Inflammation vol 10 no 1 pp79ndash91 1986

[128] B J Kim J H Kim H P Kim and M Y Heo ldquoBiologicalscreening of 100 plant extracts for cosmetic use (II) anti-oxidative activity and free radical scavenging activityrdquo Interna-tional Journal of Cosmetic Science vol 19 no 6 pp 299ndash3071997

[129] M Tawata A Kurihara K Nitta E Iwase N Gan and TOnaya ldquoThe effects of Goshajinkigan a herbal medicine onsubjective symptoms and vibratory threshold in patients withdiabetic neuropathyrdquo Diabetes Research and Clinical Practicevol 26 no 2 pp 121ndash128 1994

[130] T Kono H Mishima M Shimada S Morita and J SakamotoldquoPreventive effect of Goshajinkigan on peripheral neurotoxicityof FOLFOX therapy a placebo-controlled double-blind ran-domized phase II study (the GONE Study)rdquo Japanese Journalof Clinical Oncology vol 39 no 12 pp 847ndash849 2009

[131] M Nakanishi J Arimitsu M Kageyama et al ldquoEfficacy oftraditional Japanese herbal medicines-Keishikajutsubuto (TJ-18) and Bushi-matsu (TJ-3022)-against postherpetic neuralgiaaggravated by self-reported cold stimulation a case seriesrdquoTheJournal of Alternative and Complementary Medicine vol 18 no7 pp 686ndash692 2012

[132] J Z Zhang Gui Yao Lue (Essential Prescriptions from theGolden Chamber) Translated by Nigel Wiseman ParadigmPublications Taos NM USA 2013

[133] H Hikiami K Yagi S Nakata et al ldquoTwo cases of numbnessand pain of neuropathy due to ANCA-associated vasculitissuccessfully treatedwith ogikeishigomotsutordquoKampoMedicinevol 58 no 3 pp 495ndash501 2007

[134] H Fujiwara T Urabe K Ueda et al ldquoPrevention of arthral-gia and myalgia from paclitaxel and carboplatin combina-tion chemotherapy with Shakuyaku-kanzo-tordquo Gan to KagakuRyoho vol 27 no 7 pp 1061ndash1064 2000

[135] K Hasegawa Y Mizutani H Kuramoto et al ldquoThe effect ofL-Glutamine and Shakuyaku-Kanzo-to for paclitaxel-inducedmyalgiaarthralgiardquo Gan to Kagaku Ryoho vol 29 no 4 pp569ndash574 2002

[136] K Yamamoto H Hoshiai and K Noda ldquoEffects of Shakuyaku-kanzo-to onmuscle pain from combination chemotherapy withpaclitaxel and carboplatinrdquo Gynecologic Oncology vol 81 no 2pp 333ndash334 2001

[137] S Derry A Sven-Rice P Cole et al ldquoTopical capsaicin(high concentration) for chronic neuropathic pain in adultsrdquoCochrane Database of Systematic Reviews vol 2 Article IDCD007393 2013

[138] K Shibata T Sugawara K Fujishita et al ldquoThe astrocyte-targeted therapy by Bushi for the neuropathic pain in micerdquoPLoS ONE vol 6 no 8 Article ID e23510 2011

[139] H Xu H Arita M Hayashida L Zhang H Sekiyama and KHanaoka ldquoPain-relieving effects of processed Aconiti tuber inCCI-neuropathic ratsrdquo Journal of Ethnopharmacology vol 103no 3 pp 392ndash397 2006

[140] S Tatsumi T Mabuchi T Abe L Xu T Minami and SIto ldquoAnalgesic effect of extracts of Chinese medicinal herbsMoutan cortex and Coicis semen on neuropathic pain in micerdquoNeuroscience Letters vol 370 no 2-3 pp 130ndash134 2004

[141] M Kanter ldquoEffects of Nigella sativa and its major constituentthymoquinone on sciatic nerves in experimental diabetic neu-ropathyrdquoNeurochemical Research vol 33 no 1 pp 87ndash96 2008

[142] A Muthuraman V Diwan A S Jaggi N Singh and DSingh ldquoAmeliorative effects ofOcimum sanctum in sciatic nervetransection-induced neuropathy in ratsrdquo Journal of Ethnophar-macology vol 120 no 1 pp 56ndash62 2008

[143] T BaluchnejadmojaradM Roghani and F Roghani-DehkordildquoAntinociceptive effect of Teucrium polium leaf extract in thediabetic rat formalin testrdquo Journal of Ethnopharmacology vol97 no 2 pp 207ndash210 2005

[144] C A L Kassuya A A Silvestre V L G Rehder and J BCalixto ldquoAnti-allodynic and anti-oedematogenic properties ofthe extract and lignans from Phyllanthus amarus in modelsof persistent inflammatory and neuropathic painrdquo EuropeanJournal of Pharmacology vol 478 no 2-3 pp 145ndash153 2003

[145] R B Pandhare B Sangameswaran P B Mohite et al ldquoAttenu-ating effect of Sesbania sesban (L) Merr extract on neuropathicpain in streptozotocin-induced diabetic rats an evidence ofneuroprotective effectsrdquo Phytopharmacology vol 2 no 1 pp190ndash201 2012

[146] D M Eisenberg E S J Harris B A Littlefield et al ldquoDevel-oping a library of authenticated Traditional Chinese Medicinal(TCM) plants for systematic biological evaluation-rationalemethods and preliminary results from a Sino-American collab-orationrdquo Fitoterapia vol 82 no 1 pp 17ndash33 2011

[147] Q Luo Y Cai J YanM Sun andH Corke ldquoHypoglycemic andhypolipidemic effects and antioxidant activity of fruit extractsfrom Lycium barbarumrdquo Life Sciences vol 76 no 2 pp 137ndash1492004

[148] Y Suzuki K Goto A Ishige Y Komatsu and J KameildquoAntinociceptive effect of Gosha-jinki-gan a Kampo medicinein streptozotocin-induced diabetic micerdquo The Japanese Journalof Pharmacology vol 79 no 2 pp 169ndash175 1999

[149] I Raskin and C Ripoll ldquoCan an apple a day keep the doctorawayrdquo Current Pharmaceutical Design vol 10 no 27 pp 3419ndash3429 2004

[150] B M Schmidt D M Ribnicky P E Lipsky and I RaskinldquoRevisiting the ancient concept of botanical therapeuticsrdquoNature Chemical Biology vol 3 no 7 pp 360ndash366 2007

[151] H Shu H Arita M Hayashida H Sekiyama and K HanaokaldquoEffects of processed Aconiti tuber and its ingredient alkaloidson the development of antinociceptive tolerance to morphinerdquoJournal of Ethnopharmacology vol 103 no 3 pp 398ndash405 2006

[152] M Murayama T Mori H Bando and T Amiya ldquoStudies onthe constituents of Aconitum species IX The pharmacologicalproperties of pyro-type aconitine alkaloids components ofprocessed aconite powder lsquokako-bushi-matsursquo analgesic anti-inflammatory and acute toxic activitiesrdquo Journal of Ethnophar-macology vol 35 no 2 pp 159ndash164 1991

[153] K Yamada E Suzuki T Nakaki S Watanabe and S KanbaldquoAconiti tuber increases plasma nitrite and nitrate levels in


humansrdquo Journal of Ethnopharmacology vol 96 no 1-2 pp165ndash169 2005

[154] M Mitamura K Boussery S Horie T Murayama and J vande Voorde ldquoVasorelaxing effect of mesaconitine an alkaloidfrom Aconitum japonicum on rat small gastric artery possibleinvolvement of endothelium-derived hyperpolarizing factorrdquoThe Japanese Journal of Pharmacology vol 89 no 4 pp 380ndash387 2002

[155] Y Suzuki K Goto A Ishige Y Komatsu and J Kamei ldquoEffectsof Gosha-jinki-gan a Kampo medicine on peripheral tissueblood flow in streptozotocin-induced diabetic ratsrdquo Methodsand Findings in Experimental and Clinical Pharmacology vol20 no 4 pp 321ndash328 1998

[156] Y Cui Z Yan S Hou and Z Chang ldquoEffect of radixRehmanniae preparata on the expression of c-fos and NGF inhippocampi and learning and memory in rats with damagedthalamic arcuate nucleusrdquoZhong Yao Cai vol 27 no 8 pp 589ndash592 2004

[157] J G Choi M Moon H U Jeong M C Kim S Y Kim andM S Oh ldquoCistanches Herba enhances learning and memoryby inducing nerve growth factorrdquo Behavioural Brain Researchvol 216 no 2 pp 652ndash658 2011

[158] C Matsumoto T Kojima K Ogawa et al ldquoA proteomicapproach for the diagnosis of lsquoOketsursquo (blood stasis) a patho-physiologic concept of Japanese traditional (Kampo)medicinerdquoEvidence-Based Complementary and Alternative Medicine vol5 no 4 pp 463ndash474 2008

[159] C R Li Z Zhou D Zhu Y N Sun J M Dai and S Q WangldquoProtective effect of paeoniflorin on irradiation-induced celldamage involved in modulation of reactive oxygen species andthe mitogen-activated protein kinasesrdquo International Journal ofBiochemistry and Cell Biology vol 39 no 2 pp 426ndash438 2007

[160] Y Zhu S Dang and Z Hua ldquoAdvanced achievements aboutneuroprotective mechanisms of paeoniflorinrdquo Zhongguo ZhongYao Za Zhi vol 35 no 11 pp 1490ndash1493 2010

[161] H Chunnian P Yong F Yuxiong P Bing W Zhe and XPeigen ldquoQuick comparison of Radix Paeonia Alba RadixPaeonia Rubra and CortexMoutan by high performance liquidchromatography coupled with monolithic columns and theirchemical pattern recognitionrdquo PharmacognosyMagazine vol 8no 31 pp 237ndash243 2012

[162] M C Lu C H Yao S H Wang Y L Lai C C Tsai and Y SChen ldquoEffect of Astragalusmembranaceus in rats on peripheralnerve regeneration in vitro and in vivo studiesrdquo Journal ofTrauma vol 68 no 2 pp 434ndash440 2010

[163] J Yu Y Zhang S Sun et al ldquoInhibitory effects of astragalosideIV on diabetic peripheral neuropathy in ratsrdquoCanadian Journalof Physiology and Pharmacology vol 84 no 6 pp 579ndash5872006

[164] N Y Tang C H Liu S Y Su et al ldquoUncaria rhynchophylla(Miq) Jack plays a role in neuronal protection in kainic acid-treated ratsrdquo American Journal of Chinese Medicine vol 38 no2 pp 251ndash263 2010

[165] H Y Zhang Y H Liu H Q Wang J H Xu and H T HuldquoPuerarin protects PC12 cells against 120573-amyloid-induced cellinjuryrdquo Cell Biology International vol 32 no 10 pp 1230ndash12372008

[166] H Zhang Y Liu M Lao Z Ma and X Yi ldquoPuerarin pro-tects Alzheimerrsquos disease neuronal cybrids from oxidant-stressinduced apoptosis by inhibiting pro-death signaling pathwaysrdquoExperimental Gerontology vol 46 no 1 pp 30ndash37 2011

[167] D Sha L Li L Ye R Liu and Y Xu ldquoIcariin inhibitsneurotoxicity of 120573-amyloid by upregulating cocaine-regulatedand amphetamine-regulated transcriptsrdquo Neuroreport vol 20no 17 pp 1564ndash1567 2009

[168] Y S Ho M S Yu S Y Yik K F So W H Yuen and R CChang ldquoPolysaccharides fromwolfberry antagonizes glutamateexcitotoxicity in rat cortical neuronsrdquo Cellular and MolecularNeurobiology vol 29 no 8 pp 1233ndash1244 2009

[169] Y HWang andGH Du ldquoGinsenoside Rg1 inhibits120573-secretaseactivity in vitro and protects against A120573-induced cytotoxicity inPC12 cellsrdquo Journal of Asian Natural Products Research vol 11no 7 pp 604ndash612 2009

[170] C P Hoi Y P Ho L Baum and A H L Chow ldquoNeuro-protective effect of honokiol and magnolol compounds fromMagnolia officinalis on beta-amyloid-induced toxicity in PC12cellsrdquo Phytotherapy Research vol 24 no 10 pp 1538ndash1542 2010

[171] H W Zhao and X Y Li ldquoGinkgolide A B and huperzineA inhibit nitric oxide-induced neurotoxicityrdquo InternationalImmunopharmacology vol 2 no 11 pp 1551ndash1556 2002

[172] E H Kim M H Jang M C Shin M S Shin and C J KimldquoProtective effect of aqueous extract of Ginseng radix against 1-methyl-4-phenylpyridinium-induced apoptosis in PC12 cellsrdquoBiological and Pharmaceutical Bulletin vol 26 no 12 pp 1668ndash1673 2003

[173] R C Choi Z Jiang H Q Xie et al ldquoAnti-oxidative effects ofthe biennial flower of Panax notoginseng against H

2O2-induced

cytotoxicity in cultured PC12 cellsrdquo Chinese Medicine vol 5article 38 2010

[174] X Li K Matsumoto Y Murakami Y Tezuka Y Wu and SKadota ldquoNeuroprotective effects of Polygonum multiflorum onnigrostriatal dopaminergic degeneration induced by paraquatand maneb in micerdquo Pharmacology Biochemistry and Behaviorvol 82 no 2 pp 345ndash352 2005

[175] WWang andDQWang ldquoProgress of study on brain protectiveeffect and mechanism of Polygonum multiflorumrdquo ZhongguoZhong Xi Yi Jie He Za Zhi vol 25 no 10 pp 955ndash959 2005

[176] X Li Y Li J Chen et al ldquoTetrahydroxystilbene glucosideattenuates MPP+-induced apoptosis in PC12 cells by inhibitingROS generation and modulating JNK activationrdquo NeuroscienceLetters vol 483 no 1 pp 1ndash5 2010

[177] K Faust S Gehrke Y Yang L Yang M F Beal and BLu ldquoNeuroprotective effects of compounds with antioxidantand anti-inflammatory properties in a Drosophila model ofParkinsonrsquos diseaserdquo BMC Neuroscience vol 10 article 1092009

[178] L L Tian X J Wang Y N Sun et al ldquoSalvianolicacid B an antioxidant from Salvia miltiorrhiza prevents 6-hydroxydopamine induced apoptosis in SH-SY5Y cellsrdquo Inter-national Journal of Biochemistry and Cell Biology vol 40 no 3pp 409ndash422 2008

[179] S X Wang L M Hu X M Gao H Guo and GW Fan ldquoAnti-inflammatory activity of salvianolic acid B in microglia con-tributes to its neuroprotective effectrdquo Neurochemical Researchvol 35 no 7 pp 1029ndash1037 2010

[180] W J Xia M Yang T F Fok et al ldquoPartial neuroprotectiveeffect of pretreatmentwith tanshinone IIA onneonatal hypoxia-ischemia brain damagerdquo Pediatric Research vol 58 no 4 pp784ndash790 2005

[181] E J Shin J H Bach T T L Nguyen et al ldquoGastrodia elata blattenuates methamphetamine-induced dopaminergic toxicity


via inhibiting oxidative burdensrdquo Current Neuropharmacologyvol 9 no 1 pp 118ndash121 2011

[182] C L Hsieh C L Chen N Y Tang et al ldquoGastrodia elata BLmediates the suppression of nnos and microglia activation toprotect against neuronal damage in kainic acid-treated ratsrdquoAmerican Journal of Chinese Medicine vol 33 no 4 pp 599ndash611 2005

[183] S Y Li Y H Jia W G Sun et al ldquoStabilization of mitochon-drial function by tetramethylpyrazine protects against kainate-induced oxidative lesions in the rat hippocampusrdquo Free RadicalBiology and Medicine vol 48 no 4 pp 597ndash608 2010

[184] L H Fan K Z Wang B Cheng C S Wang and X QDang ldquoAnti-apoptotic and neuroprotective effects of Tetram-ethylpyrazine following spinal cord ischemia in rabbitsrdquo BMCNeuroscience vol 7 article 48 2006

[185] J H Park H J Lee S B Koh J Y Ban and Y H Seong ldquoPro-tection of NMDA-induced neuronal cell damage by methanolextract of Zizyphi Spinosi Semen in cultured rat cerebellargranule cellsrdquo Journal of Ethnopharmacology vol 95 no 1 pp39ndash45 2004

[186] F Q Li T Wang Z Pei B Liu and J S Hong ldquoInhibition ofmicroglial activation by the herbal flavonoid baicalein atten-uates inflammation-mediated degeneration of dopaminergicneuronsrdquo Journal of Neural Transmission vol 112 no 3 pp 331ndash347 2005

[187] C Ma W Wang Y Y Chen R N Liu R F Wang and L JDu ldquoNeuroprotective and antioxidant activity of compoundsfrom the aerial parts of Dioscorea oppositardquo Journal of NaturalProducts vol 68 no 8 pp 1259ndash1261 2005

[188] B Xue J Jiao L Zhang et al ldquoTriptolide upregulates NGFsynthesis in rat astrocyte culturesrdquoNeurochemical Research vol32 no 7 pp 1113ndash1119 2007

[189] H Y Zhang and X C Tang ldquoNeuroprotective effects ofhuperzine A new therapeutic targets for neurodegenerativediseaserdquo Trends in Pharmacological Sciences vol 27 no 12 pp619ndash625 2006

[190] M S Rafii S Walsh J T Little et al ldquoA phase II trial ofhuperzineA inmild tomoderateAlzheimer diseaserdquoNeurologyvol 76 no 16 pp 1389ndash1394 2011

[191] L Gao L Xiang Y Luo G Wang J Li and J Qi ldquoGentisidesC-K nine new neuritogenic compounds from the traditionalChinese medicine Gentiana rigescens Franchrdquo Bioorganic andMedicinal Chemistry vol 18 no 19 pp 6995ndash7000 2010



Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

International Journal of

EndocrinologyHindawi Publishing Corporationhttpwwwhindawicom

Volume 2014


Disease Markers

BioMed Research International


OncologyJournal of



Oxidative Medicine and Cellular Longevity

PPARRe sea rch


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice

Parkinsonrsquos DiseaseHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Hindawi Publishing CorporationEvidence-Based Complementary and Alternative MedicineVolume 2013 Article ID 423713 18 pageshttpdxdoiorg1011552013423713

Review ArticleCan Medical Herbs Stimulate Regeneration orNeuroprotection and Treat Neuropathic Pain inChemotherapy-Induced Peripheral Neuropathy

Sven Schroumlder12 Kathrin Beckmann1 Giovanna Franconi3 Gesa Meyer-Hamme1

Thomas Friedemann1 Henry Johannes Greten2 Matthias Rostock4 and Thomas Efferth5

1 HanseMerkur Center for Traditional Chinese Medicine at the University Medical Center Hamburg-EppendorfMartinistraszlige 52 20246 Hamburg Germany

2 ICBAS University of Porto Rua de Jorge Viterbo Ferreira No 228 4050-313 Porto Portugal3 Department of Systems Medicine Tor Vergata University 00133 Rome Italy4Hubertus Wald Tumorzentrum University Cancer Center Hamburg University Medical Center Hamburg-EppendorfMartinistraszlige 52 20246 Hamburg Germany

5Department of Pharmaceutical Biology Institute of Pharmacy and Biochemistry Johannes Gutenberg UniversityStaudinger Weg 5 55128 Mainz Germany

Correspondence should be addressed to Sven Schroder schroedertcm-am-ukede

Received 30 April 2013 Accepted 5 June 2013

Academic Editor Yoshiharu Motoo

Copyright copy 2013 Sven Schroder et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Chemotherapy-induced neuropathy (CIPN) has a relevant impact on the quality of life of cancer patients There are no curativeconventional treatments so further options have to be investigated We conducted a systematic review in English and Chineselanguage databases to illuminate the role of medical herbs 26 relevant studies on 5 single herbs one extract one receptor-agonist and 8 combinations of herbs were identified focusing on the single herbs Acorus calamus rhizoma Cannabis sativa fructusChamomilla matricaria Ginkgo biloba Salvia officinalis Sweet bee venom Fritillaria cirrhosae bulbus and the herbal combinationsBu Yang HuanWu modified Bu Yang HuanWu plus Liuwei Di Huang modified Chai Hu Long GuMu LiWan Geranii herba plusAconiti lateralis praeparata radix NiuChe SenQiWan (Goshajinkigan) Gui Zhi Jia Shu FuTang (Keishikajutsubuto)HuangQiWuWu Tang (Ogikeishigomotsuto) and Shao Yao Gan Cao Tang (Shakuyakukanzoto) The knowledge of mechanism of action is stilllimited the quality of clinical trials needs further improvement and studies have not yielded enough evidence to establish a standardpractice but a lot of promising substances have been identified While CIPN has multiple mechanisms of neuronal degeneration acombination of herbs or substances might deal with multiple targets for the aim of neuroprotection or neuroregeneration in CIPN

1 Introduction

Several chemotherapeutic drugs are known to be neurotoxicand can lead to chemotherapy-induced peripheral neuropa-thy (CIPN) It is one of the main dose-limiting toxicitiesin oncologic treatments and a potential reason to terminateor suspend chemotherapy in some cases leading to diseaseprogression [1] CIPN involves damage to the peripheralnervous system and can produce severe neuropathic pain[2 3] sensory deficits or gait impairment [4] and can severelydecrease the patientrsquos quality of life [5] Sensory symptoms

usually develop before motor symptoms because motorneurons are more myelinated [6 7] Distal parts of the axonsare the first affected so sensory symptoms typically startsymmetrically and bilaterally from the tips of the toes and fin-gers and progress proximally in a ldquostocking-gloverdquo distribu-tion [8] The incidence of CIPN can reach levels of up to92 [9]Themajor groups of drugs that induce CIPN includethe antitubulins (paclitaxel docetaxel ixabepilone andvincristine) platinum analogs (cisplatin carboplatin andoxaliplatin) and the proteasome inhibitors bortezomib andthalidomide [1] Patients with a preexisting other cause of
















2 Methods







3 Results










IPN

Sectionno

Medicalherb(s)

Stud

ydesig

nCh

emotherapy

Outcome

Authoryear

Sing

leherbso

rsinglec

ompo

unds

311

Acorus

calamus

rhizom

a(hydroalcoho

licextract)

Ratm

odel

Vincris

tine

Improvem

ento

fneuropathicpain

Muthu

raman

andSing

h2011[70]

312

Cann

abis-Re

ceptor

agon

ists

R-AM1241

andAm-1714

Ratm

odel

Paclitaxel

Allo

dyniaantin

ociceptiv

e

Rahn

etal2008

[71]multip

letrials

forn

europathicpain

notd

ueto

chem

otherapyfor

exam

pleEllis

etal[72]Ka

rstetal[73]W

aree

tal

[74]R

ogetal[75]Blakee

tal[76]

Berm

anetal[77]Wilsey

etal[78]

with

Cannabissativa

313

Matric

ariacham

omilla

(hydroalcoho

licextract)

Mou

semod

elCisplatin

Improvem

ento

fneuropathicpain

Abad

etal2011[85]

314

Ginkgo

biloba

(alcoh

olicextract)

(1)M

ouse

mod

el(2)R

etrospectiv

estudy

(119899=17)

Oxalip

latin

(1)N

europrotectio

n(2)Improvem

ento

fneuropathicpain

(1)O

zturketal2004

[86]

(2)M

arshalletal2004

[87]

315

Salviaoffi

cinalis(hydroalcoho

licextract)

Mou

semod

elVincris

tine

Improvem

ento

fneuropathicpain

Abad

etal2011[88]

316

Sweetb

eevenom

(pharm

acop

uncture)

(1)C

ases

eries(119899=5)

(2)C

ases

eries(119899=11)

Taxolpaclitaxelor

carbop

latin

Injectioninto

acup

oint

(ZusanliSt36)

(1)E

ffecton

pain

andneurop

athy

scales

(2)E

ffecton

VASandHRQ

OLscores

(1)P

arketal2011[89]

(2)Y

oonetal2012

[90]

317

Verticinon

ehydroalcoh

olic

extractedfro

mFritillaria

bulbus

Mou

semod

eland

ratm

odel

Paclitaxel


athicp

ain

dose

depend

entno

tolerance

Xuetal2011[91]

Herbalcom

binatio

ns321

BuYang

Hua

nWulowast1(decoctio

n)Ra

ndom

ized

trial119899=44con

trol=

40Oxalip

latin

Improvem

ento

fclin

icalscales

Sunetal2008

[92]

322

mod

ified

BuYang

Hua

nWuplus

Liuw

eiDiH


n)Ra

ndom

ized

trial119899=32con

trolV

itB1

=32

Different

chem

otherapies

Improvem

ento

fclin

icalscales

DengandZo

u2007

[93]

323

mod

ified

ChaiHuLong

GuMu


n)Ra

ndom

ized

trial119899=26con

trol=

22Paclitaxel

neurop

rotection

Panetal2012

[94]

324

Geraniiherbaplus

Acon

itiradix

(granu

le)

(1)R

atmod

el(2)R

ando

mizedprospectiv

etria

l119899=30con

trol=

28

(1)O

xalip

latin

(2)O

xalip

latin

taxol

orcapecitabine

(1)A

llodynia

(2)N


selling

externalwashing

Simaa

ndPan

2009

[95]

325

Goshajin

kigan=NiuCh

eSen

Qi

Wanlowast4(granu

le)

(1)R

atmod

el(2)R

atm

ouse

mod

el(1)P

aclitaxel

(2)O

xalip

latin

(1)N

oneurogeneration

improvem

ent

ofallodynia

(2)Improvem

ento

fneuropathicpain

noneuroregeneration

(1)H

ashimotoetal2004

+2006

[9697]

(2)U

shio

etal2012

[98]

(1)N

oncontrolledstu

dy119899=14

(2)R

etrospectiv

estudy

GJG

=22con

trol=

23(3)R

etrospectiv

estudy

GJG

=45con

trol=

45(4)R

etrospectiv

estudy119899=82

(5)R

ando

mized

prospectives

tudy

Vit

B12=14V

itB12G

JG=15

(1)O

xalip

latin

(2)F

olfoxlowast8

(3)F

olfoxlowast8

(4)P

aclitaxel

(5)P

aclitaxel

carbop

latin

(1)R

educed

acuten

eurotoxicity

(2)N

europrotectio

n(3)N

europrotectio

nNochange

ofantic

ancera

ctivity

(4)N

europrotectio

nbette

rwhen

administered

early

(5)L

essseveren

eurotoxicitybetter

CPTin

GJG

grou

p

(1)S

hind

oetal2008

[99]

(2)N

ishioka

etal2011[100]

(3)K

onoetal2011[101]

(4)Yam

amotoetal2009

[102]

(5)K

akuetal2012

[103]


Table1Con

tinued

Sectionno

Medicalherb(s)

Stud

ydesig

nCh

emotherapy

Outcome

Authoryear

326

Keish

ikaju

tsubu

to=Gui

ZhiJia

ShuFu

Tanglowast5(granu

le)

Uncon

trolledstu

dy119899=15(3

drop

outs)

Folfo

xlowast8

766meanim

provem

ento

nVA

SYamadae

tal2012

[104]

327

Ogikeish

igom

otsuto

=Huang

Qi


le)

Case

repo

rt119899=1

Oxalip

latin

neurop

athicp

ain

Tatsum

ietal2009

[105]

328

Shakuyakukan

zoto=Shao

Yao

Gan


le)

(1)M

ouse

mod

el(2)R

etrospectiv

ecasea

nalysis119899=23

(3)R

etrospectiv

eclin

icalstu

dy

comparis

onGJG

=20SYK

=24

(1)a

nd(2)p

aclitaxel

(3)F

olfoxlowast8

(1)A


(2)E

ffecton

neurop

athicp

ain

(3)5

0respon

sein

Shakuyu-kanzoto

and65in

Goshajin

kiganon

preventio

nof

neurotoxicity

(1)H

idakae

tal2009

[106]

(2)F

ujiietal2004

[107]

(3)H

osokaw

aetal2012

[108]

lowast1Astra

galusm

embranaceusradixA

ngelica

sinensis

radixPrun

uspersica

esem

enPaeoniaerubra


iong

rhizom

aLu

mbricu

sterrestr

isSpatholobicaulis

Curcum

aradixCh

aenomele

slagenaria

fructusand

Achyranthesb

identata

lowast2Astra

galusm

embranaceusradixL

igustru

mlucid

umfru

ctusP

aeoniaer

ubra

radixLu

mbricu

sterrestr

isPrun

uspersica

esem

enR

ehmanniae

virid

aeradixCo

rnio

fficin

alisfru

ctusD

ioscorea

oppositaradixand

Alism

atisrhizom

aPoria

albaSpatholobicau

lisS

colopend

raM

orifructusG

lycyrrhizae

Radix

Dipsacifru

ctusL

yciifru

ctusC

oicis

semenA

tractylodisrhizom

aPh

ellodendricortex

ScorpioMoriram

ulusand

Cyathu

laoffi

cinalis

lowast3Pseudoste

llaria

heterophyllaP



lensis

radixBu

pleuriradixFossilia

ossis

mastodiadraconis

Ostrae

concha

Rubiae


ebarbataeh

erbaand

Fritillaria

thun

bergiibu

lbiTh

eexternalw

ashing

was

done

with

Astra

galiradixAn

gelicasin

ensis

radixPa

eoniae

rubraradixLu

mbricu

sterrestr

isLigustici

chua

nxiong

rhizom

aPrun

icapersica

esem

enand

Carthamifl

os

lowast4Rehm

anniavirid

eradixA


radixCo

rnifructusD


ePlantaginissem

enA

lismatisrhizom

aMoutancortexC

innamom

icortexAc

oniti

lateralis

praeparata

tuberand

Poria

alba

lowast5Cinn

amom

icortexAc

oniti

lateralis

praeparata


aJujubaefructusG

lycyrrhizae


acrocephalae

rhizom

alowast6Astra

galimem

branaceusradixC

innamom

icortexPa

eoniaalba


Zingiberisrhizom

alowast7Pa

eoniaalba


radix

lowast8Ch


ithFO

LFo

linicacid

(leucovorin)FFluo

rouracil(5-FU)andOX

Oxalip

latin

(Eloxatin

)















































4 Discussion





































5 Conclusion




References























































































































































































2O2-induced





























of





Volume 2014


Disease Markers



OncologyJournal of




PPARRe sea rch




Journal of

ObesityJournal of






























2 Methods







3 Results










IPN

Sectionno

Medicalherb(s)

Stud

ydesig

nCh

emotherapy

Outcome

Authoryear

Sing

leherbso

rsinglec

ompo

unds

311

Acorus

calamus

rhizom

a(hydroalcoho

licextract)

Ratm

odel

Vincris

tine

Improvem

ento

fneuropathicpain

Muthu

raman

andSing

h2011[70]

312

Cann

abis-Re

ceptor

agon

ists

R-AM1241

andAm-1714

Ratm

odel

Paclitaxel

Allo

dyniaantin

ociceptiv

e

Rahn

etal2008

[71]multip

letrials

forn

europathicpain

notd

ueto

chem

otherapyfor

exam

pleEllis

etal[72]Ka

rstetal[73]W

aree

tal

[74]R

ogetal[75]Blakee

tal[76]

Berm

anetal[77]Wilsey

etal[78]

with

Cannabissativa

313

Matric

ariacham

omilla

(hydroalcoho

licextract)

Mou

semod

elCisplatin

Improvem

ento

fneuropathicpain

Abad

etal2011[85]

314

Ginkgo

biloba

(alcoh

olicextract)

(1)M

ouse

mod

el(2)R

etrospectiv

estudy

(119899=17)

Oxalip

latin

(1)N

europrotectio

n(2)Improvem

ento

fneuropathicpain

(1)O

zturketal2004

[86]

(2)M

arshalletal2004

[87]

315

Salviaoffi

cinalis(hydroalcoho

licextract)

Mou

semod

elVincris

tine

Improvem

ento

fneuropathicpain

Abad

etal2011[88]

316

Sweetb

eevenom

(pharm

acop

uncture)

(1)C

ases

eries(119899=5)

(2)C

ases

eries(119899=11)

Taxolpaclitaxelor

carbop

latin

Injectioninto

acup

oint

(ZusanliSt36)

(1)E

ffecton

pain

andneurop

athy

scales

(2)E

ffecton

VASandHRQ

OLscores

(1)P

arketal2011[89]

(2)Y

oonetal2012

[90]

317

Verticinon

ehydroalcoh

olic

extractedfro

mFritillaria

bulbus

Mou

semod

eland

ratm

odel

Paclitaxel


athicp

ain

dose

depend

entno

tolerance

Xuetal2011[91]

Herbalcom

binatio

ns321

BuYang

Hua

nWulowast1(decoctio

n)Ra

ndom

ized

trial119899=44con

trol=

40Oxalip

latin

Improvem

ento

fclin

icalscales

Sunetal2008

[92]

322

mod

ified

BuYang

Hua

nWuplus

Liuw

eiDiH


n)Ra

ndom

ized

trial119899=32con

trolV

itB1

=32

Different

chem

otherapies

Improvem

ento

fclin

icalscales

DengandZo

u2007

[93]

323

mod

ified

ChaiHuLong

GuMu


n)Ra

ndom

ized

trial119899=26con

trol=

22Paclitaxel

neurop

rotection

Panetal2012

[94]

324

Geraniiherbaplus

Acon

itiradix

(granu

le)

(1)R

atmod

el(2)R

ando

mizedprospectiv

etria

l119899=30con

trol=

28

(1)O

xalip

latin

(2)O

xalip

latin

taxol

orcapecitabine

(1)A

llodynia

(2)N


selling

externalwashing

Simaa

ndPan

2009

[95]

325

Goshajin

kigan=NiuCh

eSen

Qi

Wanlowast4(granu

le)

(1)R

atmod

el(2)R

atm

ouse

mod

el(1)P

aclitaxel

(2)O

xalip

latin

(1)N

oneurogeneration

improvem

ent

ofallodynia

(2)Improvem

ento

fneuropathicpain

noneuroregeneration

(1)H

ashimotoetal2004

+2006

[9697]

(2)U

shio

etal2012

[98]

(1)N

oncontrolledstu

dy119899=14

(2)R

etrospectiv

estudy

GJG

=22con

trol=

23(3)R

etrospectiv

estudy

GJG

=45con

trol=

45(4)R

etrospectiv

estudy119899=82

(5)R

ando

mized

prospectives

tudy

Vit

B12=14V

itB12G

JG=15

(1)O

xalip

latin

(2)F

olfoxlowast8

(3)F

olfoxlowast8

(4)P

aclitaxel

(5)P

aclitaxel

carbop

latin

(1)R

educed

acuten

eurotoxicity

(2)N

europrotectio

n(3)N

europrotectio

nNochange

ofantic

ancera

ctivity

(4)N

europrotectio

nbette

rwhen

administered

early

(5)L

essseveren

eurotoxicitybetter

CPTin

GJG

grou

p

(1)S

hind

oetal2008

[99]

(2)N

ishioka

etal2011[100]

(3)K

onoetal2011[101]

(4)Yam

amotoetal2009

[102]

(5)K

akuetal2012

[103]


Table1Con

tinued

Sectionno

Medicalherb(s)

Stud

ydesig

nCh

emotherapy

Outcome

Authoryear

326

Keish

ikaju

tsubu

to=Gui

ZhiJia

ShuFu

Tanglowast5(granu

le)

Uncon

trolledstu

dy119899=15(3

drop

outs)

Folfo

xlowast8

766meanim

provem

ento

nVA

SYamadae

tal2012

[104]

327

Ogikeish

igom

otsuto

=Huang

Qi


le)

Case

repo

rt119899=1

Oxalip

latin

neurop

athicp

ain

Tatsum

ietal2009

[105]

328

Shakuyakukan

zoto=Shao

Yao

Gan


le)

(1)M

ouse

mod

el(2)R

etrospectiv

ecasea

nalysis119899=23

(3)R

etrospectiv

eclin

icalstu

dy

comparis

onGJG

=20SYK

=24

(1)a

nd(2)p

aclitaxel

(3)F

olfoxlowast8

(1)A


(2)E

ffecton

neurop

athicp

ain

(3)5

0respon

sein

Shakuyu-kanzoto

and65in

Goshajin

kiganon

preventio

nof

neurotoxicity

(1)H

idakae

tal2009

[106]

(2)F

ujiietal2004

[107]

(3)H

osokaw

aetal2012

[108]

lowast1Astra

galusm

embranaceusradixA

ngelica

sinensis

radixPrun

uspersica

esem

enPaeoniaerubra


iong

rhizom

aLu

mbricu

sterrestr

isSpatholobicaulis

Curcum

aradixCh

aenomele

slagenaria

fructusand

Achyranthesb

identata

lowast2Astra

galusm

embranaceusradixL

igustru

mlucid

umfru

ctusP

aeoniaer

ubra

radixLu

mbricu

sterrestr

isPrun

uspersica

esem

enR

ehmanniae

virid

aeradixCo

rnio

fficin

alisfru

ctusD

ioscorea

oppositaradixand

Alism

atisrhizom

aPoria

albaSpatholobicau

lisS

colopend

raM

orifructusG

lycyrrhizae

Radix

Dipsacifru

ctusL

yciifru

ctusC

oicis

semenA

tractylodisrhizom

aPh

ellodendricortex

ScorpioMoriram

ulusand

Cyathu

laoffi

cinalis

lowast3Pseudoste

llaria

heterophyllaP



lensis

radixBu

pleuriradixFossilia

ossis

mastodiadraconis

Ostrae

concha

Rubiae


ebarbataeh

erbaand

Fritillaria

thun

bergiibu

lbiTh

eexternalw

ashing

was

done

with

Astra

galiradixAn

gelicasin

ensis

radixPa

eoniae

rubraradixLu

mbricu

sterrestr

isLigustici

chua

nxiong

rhizom

aPrun

icapersica

esem

enand

Carthamifl

os

lowast4Rehm

anniavirid

eradixA


radixCo

rnifructusD


ePlantaginissem

enA

lismatisrhizom

aMoutancortexC

innamom

icortexAc

oniti

lateralis

praeparata

tuberand

Poria

alba

lowast5Cinn

amom

icortexAc

oniti

lateralis

praeparata


aJujubaefructusG

lycyrrhizae


acrocephalae

rhizom

alowast6Astra

galimem

branaceusradixC

innamom

icortexPa

eoniaalba


Zingiberisrhizom

alowast7Pa

eoniaalba


radix

lowast8Ch


ithFO

LFo

linicacid

(leucovorin)FFluo

rouracil(5-FU)andOX

Oxalip

latin

(Eloxatin

)















































4 Discussion





































5 Conclusion




References























































































































































































2O2-induced





























of





Volume 2014


Disease Markers



OncologyJournal of




PPARRe sea rch




Journal of

ObesityJournal of



















3 Results










IPN

Sectionno

Medicalherb(s)

Stud

ydesig

nCh

emotherapy

Outcome

Authoryear

Sing

leherbso

rsinglec

ompo

unds

311

Acorus

calamus

rhizom

a(hydroalcoho

licextract)

Ratm

odel

Vincris

tine

Improvem

ento

fneuropathicpain

Muthu

raman

andSing

h2011[70]

312

Cann

abis-Re

ceptor

agon

ists

R-AM1241

andAm-1714

Ratm

odel

Paclitaxel

Allo

dyniaantin

ociceptiv

e

Rahn

etal2008

[71]multip

letrials

forn

europathicpain

notd

ueto

chem

otherapyfor

exam

pleEllis

etal[72]Ka

rstetal[73]W

aree

tal

[74]R

ogetal[75]Blakee

tal[76]

Berm

anetal[77]Wilsey

etal[78]

with

Cannabissativa

313

Matric

ariacham

omilla

(hydroalcoho

licextract)

Mou

semod

elCisplatin

Improvem

ento

fneuropathicpain

Abad

etal2011[85]

314

Ginkgo

biloba

(alcoh

olicextract)

(1)M

ouse

mod

el(2)R

etrospectiv

estudy

(119899=17)

Oxalip

latin

(1)N

europrotectio

n(2)Improvem

ento

fneuropathicpain

(1)O

zturketal2004

[86]

(2)M

arshalletal2004

[87]

315

Salviaoffi

cinalis(hydroalcoho

licextract)

Mou

semod

elVincris

tine

Improvem

ento

fneuropathicpain

Abad

etal2011[88]

316

Sweetb

eevenom

(pharm

acop

uncture)

(1)C

ases

eries(119899=5)

(2)C

ases

eries(119899=11)

Taxolpaclitaxelor

carbop

latin

Injectioninto

acup

oint

(ZusanliSt36)

(1)E

ffecton

pain

andneurop

athy

scales

(2)E

ffecton

VASandHRQ

OLscores

(1)P

arketal2011[89]

(2)Y

oonetal2012

[90]

317

Verticinon

ehydroalcoh

olic

extractedfro

mFritillaria

bulbus

Mou

semod

eland

ratm

odel

Paclitaxel


athicp

ain

dose

depend

entno

tolerance

Xuetal2011[91]

Herbalcom

binatio

ns321

BuYang

Hua

nWulowast1(decoctio

n)Ra

ndom

ized

trial119899=44con

trol=

40Oxalip

latin

Improvem

ento

fclin

icalscales

Sunetal2008

[92]

322

mod

ified

BuYang

Hua

nWuplus

Liuw

eiDiH


n)Ra

ndom

ized

trial119899=32con

trolV

itB1

=32

Different

chem

otherapies

Improvem

ento

fclin

icalscales

DengandZo

u2007

[93]

323

mod

ified

ChaiHuLong

GuMu


n)Ra

ndom

ized

trial119899=26con

trol=

22Paclitaxel

neurop

rotection

Panetal2012

[94]

324

Geraniiherbaplus

Acon

itiradix

(granu

le)

(1)R

atmod

el(2)R

ando

mizedprospectiv

etria

l119899=30con

trol=

28

(1)O

xalip

latin

(2)O

xalip

latin

taxol

orcapecitabine

(1)A

llodynia

(2)N


selling

externalwashing

Simaa

ndPan

2009

[95]

325

Goshajin

kigan=NiuCh

eSen

Qi

Wanlowast4(granu

le)

(1)R

atmod

el(2)R

atm

ouse

mod

el(1)P

aclitaxel

(2)O

xalip

latin

(1)N

oneurogeneration

improvem

ent

ofallodynia

(2)Improvem

ento

fneuropathicpain

noneuroregeneration

(1)H

ashimotoetal2004

+2006

[9697]

(2)U

shio

etal2012

[98]

(1)N

oncontrolledstu

dy119899=14

(2)R

etrospectiv

estudy

GJG

=22con

trol=

23(3)R

etrospectiv

estudy

GJG

=45con

trol=

45(4)R

etrospectiv

estudy119899=82

(5)R

ando

mized

prospectives

tudy

Vit

B12=14V

itB12G

JG=15

(1)O

xalip

latin

(2)F

olfoxlowast8

(3)F

olfoxlowast8

(4)P

aclitaxel

(5)P

aclitaxel

carbop

latin

(1)R

educed

acuten

eurotoxicity

(2)N

europrotectio

n(3)N

europrotectio

nNochange

ofantic

ancera

ctivity

(4)N

europrotectio

nbette

rwhen

administered

early

(5)L

essseveren

eurotoxicitybetter

CPTin

GJG

grou

p

(1)S

hind

oetal2008

[99]

(2)N

ishioka

etal2011[100]

(3)K

onoetal2011[101]

(4)Yam

amotoetal2009

[102]

(5)K

akuetal2012

[103]


Table1Con

tinued

Sectionno

Medicalherb(s)

Stud

ydesig

nCh

emotherapy

Outcome

Authoryear

326

Keish

ikaju

tsubu

to=Gui

ZhiJia

ShuFu

Tanglowast5(granu

le)

Uncon

trolledstu

dy119899=15(3

drop

outs)

Folfo

xlowast8

766meanim

provem

ento

nVA

SYamadae

tal2012

[104]

327

Ogikeish

igom

otsuto

=Huang

Qi


le)

Case

repo

rt119899=1

Oxalip

latin

neurop

athicp

ain

Tatsum

ietal2009

[105]

328

Shakuyakukan

zoto=Shao

Yao

Gan


le)

(1)M

ouse

mod

el(2)R

etrospectiv

ecasea

nalysis119899=23

(3)R

etrospectiv

eclin

icalstu

dy

comparis

onGJG

=20SYK

=24

(1)a

nd(2)p

aclitaxel

(3)F

olfoxlowast8

(1)A


(2)E

ffecton

neurop

athicp

ain

(3)5

0respon

sein

Shakuyu-kanzoto

and65in

Goshajin

kiganon

preventio

nof

neurotoxicity

(1)H

idakae

tal2009

[106]

(2)F

ujiietal2004

[107]

(3)H

osokaw

aetal2012

[108]

lowast1Astra

galusm

embranaceusradixA

ngelica

sinensis

radixPrun

uspersica

esem

enPaeoniaerubra


iong

rhizom

aLu

mbricu

sterrestr

isSpatholobicaulis

Curcum

aradixCh

aenomele

slagenaria

fructusand

Achyranthesb

identata

lowast2Astra

galusm

embranaceusradixL

igustru

mlucid

umfru

ctusP

aeoniaer

ubra

radixLu

mbricu

sterrestr

isPrun

uspersica

esem

enR

ehmanniae

virid

aeradixCo

rnio

fficin

alisfru

ctusD

ioscorea

oppositaradixand

Alism

atisrhizom

aPoria

albaSpatholobicau

lisS

colopend

raM

orifructusG

lycyrrhizae

Radix

Dipsacifru

ctusL

yciifru

ctusC

oicis

semenA

tractylodisrhizom

aPh

ellodendricortex

ScorpioMoriram

ulusand

Cyathu

laoffi

cinalis

lowast3Pseudoste

llaria

heterophyllaP



lensis

radixBu

pleuriradixFossilia

ossis

mastodiadraconis

Ostrae

concha

Rubiae


ebarbataeh

erbaand

Fritillaria

thun

bergiibu

lbiTh

eexternalw

ashing

was

done

with

Astra

galiradixAn

gelicasin

ensis

radixPa

eoniae

rubraradixLu

mbricu

sterrestr

isLigustici

chua

nxiong

rhizom

aPrun

icapersica

esem

enand

Carthamifl

os

lowast4Rehm

anniavirid

eradixA


radixCo

rnifructusD


ePlantaginissem

enA

lismatisrhizom

aMoutancortexC

innamom

icortexAc

oniti

lateralis

praeparata

tuberand

Poria

alba

lowast5Cinn

amom

icortexAc

oniti

lateralis

praeparata


aJujubaefructusG

lycyrrhizae


acrocephalae

rhizom

alowast6Astra

galimem

branaceusradixC

innamom

icortexPa

eoniaalba


Zingiberisrhizom

alowast7Pa

eoniaalba


radix

lowast8Ch


ithFO

LFo

linicacid

(leucovorin)FFluo

rouracil(5-FU)andOX

Oxalip

latin

(Eloxatin

)















































4 Discussion





































5 Conclusion




References























































































































































































2O2-induced





























of





Volume 2014


Disease Markers



OncologyJournal of




PPARRe sea rch




Journal of

ObesityJournal of

















IPN

Sectionno

Medicalherb(s)

Stud

ydesig

nCh

emotherapy

Outcome

Authoryear

Sing

leherbso

rsinglec

ompo

unds

311

Acorus

calamus

rhizom

a(hydroalcoho

licextract)

Ratm

odel

Vincris

tine

Improvem

ento

fneuropathicpain

Muthu

raman

andSing

h2011[70]

312

Cann

abis-Re

ceptor

agon

ists

R-AM1241

andAm-1714

Ratm

odel

Paclitaxel

Allo

dyniaantin

ociceptiv

e

Rahn

etal2008

[71]multip

letrials

forn

europathicpain

notd

ueto

chem

otherapyfor

exam

pleEllis

etal[72]Ka

rstetal[73]W

aree

tal

[74]R

ogetal[75]Blakee

tal[76]

Berm

anetal[77]Wilsey

etal[78]

with

Cannabissativa

313

Matric

ariacham

omilla

(hydroalcoho

licextract)

Mou

semod

elCisplatin

Improvem

ento

fneuropathicpain

Abad

etal2011[85]

314

Ginkgo

biloba

(alcoh

olicextract)

(1)M

ouse

mod

el(2)R

etrospectiv

estudy

(119899=17)

Oxalip

latin

(1)N

europrotectio

n(2)Improvem

ento

fneuropathicpain

(1)O

zturketal2004

[86]

(2)M

arshalletal2004

[87]

315

Salviaoffi

cinalis(hydroalcoho

licextract)

Mou

semod

elVincris

tine

Improvem

ento

fneuropathicpain

Abad

etal2011[88]

316

Sweetb

eevenom

(pharm

acop

uncture)

(1)C

ases

eries(119899=5)

(2)C

ases

eries(119899=11)

Taxolpaclitaxelor

carbop

latin

Injectioninto

acup

oint

(ZusanliSt36)

(1)E

ffecton

pain

andneurop

athy

scales

(2)E

ffecton

VASandHRQ

OLscores

(1)P

arketal2011[89]

(2)Y

oonetal2012

[90]

317

Verticinon

ehydroalcoh

olic

extractedfro

mFritillaria

bulbus

Mou

semod

eland

ratm

odel

Paclitaxel


athicp

ain

dose

depend

entno

tolerance

Xuetal2011[91]

Herbalcom

binatio

ns321

BuYang

Hua

nWulowast1(decoctio

n)Ra

ndom

ized

trial119899=44con

trol=

40Oxalip

latin

Improvem

ento

fclin

icalscales

Sunetal2008

[92]

322

mod

ified

BuYang

Hua

nWuplus

Liuw

eiDiH


n)Ra

ndom

ized

trial119899=32con

trolV

itB1

=32

Different

chem

otherapies

Improvem

ento

fclin

icalscales

DengandZo

u2007

[93]

323

mod

ified

ChaiHuLong

GuMu


n)Ra

ndom

ized

trial119899=26con

trol=

22Paclitaxel

neurop

rotection

Panetal2012

[94]

324

Geraniiherbaplus

Acon

itiradix

(granu

le)

(1)R

atmod

el(2)R

ando

mizedprospectiv

etria

l119899=30con

trol=

28

(1)O

xalip

latin

(2)O

xalip

latin

taxol

orcapecitabine

(1)A

llodynia

(2)N


selling

externalwashing

Simaa

ndPan

2009

[95]

325

Goshajin

kigan=NiuCh

eSen

Qi

Wanlowast4(granu

le)

(1)R

atmod

el(2)R

atm

ouse

mod

el(1)P

aclitaxel

(2)O

xalip

latin

(1)N

oneurogeneration

improvem

ent

ofallodynia

(2)Improvem

ento

fneuropathicpain

noneuroregeneration

(1)H

ashimotoetal2004

+2006

[9697]

(2)U

shio

etal2012

[98]

(1)N

oncontrolledstu

dy119899=14

(2)R

etrospectiv

estudy

GJG

=22con

trol=

23(3)R

etrospectiv

estudy

GJG

=45con

trol=

45(4)R

etrospectiv

estudy119899=82

(5)R

ando

mized

prospectives

tudy

Vit

B12=14V

itB12G

JG=15

(1)O

xalip

latin

(2)F

olfoxlowast8

(3)F

olfoxlowast8

(4)P

aclitaxel

(5)P

aclitaxel

carbop

latin

(1)R

educed

acuten

eurotoxicity

(2)N

europrotectio

n(3)N

europrotectio

nNochange

ofantic

ancera

ctivity

(4)N

europrotectio

nbette

rwhen

administered

early

(5)L

essseveren

eurotoxicitybetter

CPTin

GJG

grou

p

(1)S

hind

oetal2008

[99]

(2)N

ishioka

etal2011[100]

(3)K

onoetal2011[101]

(4)Yam

amotoetal2009

[102]

(5)K

akuetal2012

[103]


Table1Con

tinued

Sectionno

Medicalherb(s)

Stud

ydesig

nCh

emotherapy

Outcome

Authoryear

326

Keish

ikaju

tsubu

to=Gui

ZhiJia

ShuFu

Tanglowast5(granu

le)

Uncon

trolledstu

dy119899=15(3

drop

outs)

Folfo

xlowast8

766meanim

provem

ento

nVA

SYamadae

tal2012

[104]

327

Ogikeish

igom

otsuto

=Huang

Qi


le)

Case

repo

rt119899=1

Oxalip

latin

neurop

athicp

ain

Tatsum

ietal2009

[105]

328

Shakuyakukan

zoto=Shao

Yao

Gan


le)

(1)M

ouse

mod

el(2)R

etrospectiv

ecasea

nalysis119899=23

(3)R

etrospectiv

eclin

icalstu

dy

comparis

onGJG

=20SYK

=24

(1)a

nd(2)p

aclitaxel

(3)F

olfoxlowast8

(1)A


(2)E

ffecton

neurop

athicp

ain

(3)5

0respon

sein

Shakuyu-kanzoto

and65in

Goshajin

kiganon

preventio

nof

neurotoxicity

(1)H

idakae

tal2009

[106]

(2)F

ujiietal2004

[107]

(3)H

osokaw

aetal2012

[108]

lowast1Astra

galusm

embranaceusradixA

ngelica

sinensis

radixPrun

uspersica

esem

enPaeoniaerubra


iong

rhizom

aLu

mbricu

sterrestr

isSpatholobicaulis

Curcum

aradixCh

aenomele

slagenaria

fructusand

Achyranthesb

identata

lowast2Astra

galusm

embranaceusradixL

igustru

mlucid

umfru

ctusP

aeoniaer

ubra

radixLu

mbricu

sterrestr

isPrun

uspersica

esem

enR

ehmanniae

virid

aeradixCo

rnio

fficin

alisfru

ctusD

ioscorea

oppositaradixand

Alism

atisrhizom

aPoria

albaSpatholobicau

lisS

colopend

raM

orifructusG

lycyrrhizae

Radix

Dipsacifru

ctusL

yciifru

ctusC

oicis

semenA

tractylodisrhizom

aPh

ellodendricortex

ScorpioMoriram

ulusand

Cyathu

laoffi

cinalis

lowast3Pseudoste

llaria

heterophyllaP



lensis

radixBu

pleuriradixFossilia

ossis

mastodiadraconis

Ostrae

concha

Rubiae


ebarbataeh

erbaand

Fritillaria

thun

bergiibu

lbiTh

eexternalw

ashing

was

done

with

Astra

galiradixAn

gelicasin

ensis

radixPa

eoniae

rubraradixLu

mbricu

sterrestr

isLigustici

chua

nxiong

rhizom

aPrun

icapersica

esem

enand

Carthamifl

os

lowast4Rehm

anniavirid

eradixA


radixCo

rnifructusD


ePlantaginissem

enA

lismatisrhizom

aMoutancortexC

innamom

icortexAc

oniti

lateralis

praeparata

tuberand

Poria

alba

lowast5Cinn

amom

icortexAc

oniti

lateralis

praeparata


aJujubaefructusG

lycyrrhizae


acrocephalae

rhizom

alowast6Astra

galimem

branaceusradixC

innamom

icortexPa

eoniaalba


Zingiberisrhizom

alowast7Pa

eoniaalba


radix

lowast8Ch


ithFO

LFo

linicacid

(leucovorin)FFluo

rouracil(5-FU)andOX

Oxalip

latin

(Eloxatin

)















































4 Discussion





































5 Conclusion




References























































































































































































2O2-induced





























of





Volume 2014


Disease Markers



OncologyJournal of




PPARRe sea rch




Journal of

ObesityJournal of
















Table1Con

tinued

Sectionno

Medicalherb(s)

Stud

ydesig

nCh

emotherapy

Outcome

Authoryear

326

Keish

ikaju

tsubu

to=Gui

ZhiJia

ShuFu

Tanglowast5(granu

le)

Uncon

trolledstu

dy119899=15(3

drop

outs)

Folfo

xlowast8

766meanim

provem

ento

nVA

SYamadae

tal2012

[104]

327

Ogikeish

igom

otsuto

=Huang

Qi


le)

Case

repo

rt119899=1

Oxalip

latin

neurop

athicp

ain

Tatsum

ietal2009

[105]

328

Shakuyakukan

zoto=Shao

Yao

Gan


le)

(1)M

ouse

mod

el(2)R

etrospectiv

ecasea

nalysis119899=23

(3)R

etrospectiv

eclin

icalstu

dy

comparis

onGJG

=20SYK

=24

(1)a

nd(2)p

aclitaxel

(3)F

olfoxlowast8

(1)A


(2)E

ffecton

neurop

athicp

ain

(3)5

0respon

sein

Shakuyu-kanzoto

and65in

Goshajin

kiganon

preventio

nof

neurotoxicity

(1)H

idakae

tal2009

[106]

(2)F

ujiietal2004

[107]

(3)H

osokaw

aetal2012

[108]

lowast1Astra

galusm

embranaceusradixA

ngelica

sinensis

radixPrun

uspersica

esem

enPaeoniaerubra


iong

rhizom

aLu

mbricu

sterrestr

isSpatholobicaulis

Curcum

aradixCh

aenomele

slagenaria

fructusand

Achyranthesb

identata

lowast2Astra

galusm

embranaceusradixL

igustru

mlucid

umfru

ctusP

aeoniaer

ubra

radixLu

mbricu

sterrestr

isPrun

uspersica

esem

enR

ehmanniae

virid

aeradixCo

rnio

fficin

alisfru

ctusD

ioscorea

oppositaradixand

Alism

atisrhizom

aPoria

albaSpatholobicau

lisS

colopend

raM

orifructusG

lycyrrhizae

Radix

Dipsacifru

ctusL

yciifru

ctusC

oicis

semenA

tractylodisrhizom

aPh

ellodendricortex

ScorpioMoriram

ulusand

Cyathu

laoffi

cinalis

lowast3Pseudoste

llaria

heterophyllaP



lensis

radixBu

pleuriradixFossilia

ossis

mastodiadraconis

Ostrae

concha

Rubiae


ebarbataeh

erbaand

Fritillaria

thun

bergiibu

lbiTh

eexternalw

ashing

was

done

with

Astra

galiradixAn

gelicasin

ensis

radixPa

eoniae

rubraradixLu

mbricu

sterrestr

isLigustici

chua

nxiong

rhizom

aPrun

icapersica

esem

enand

Carthamifl

os

lowast4Rehm

anniavirid

eradixA


radixCo

rnifructusD


ePlantaginissem

enA

lismatisrhizom

aMoutancortexC

innamom

icortexAc

oniti

lateralis

praeparata

tuberand

Poria

alba

lowast5Cinn

amom

icortexAc

oniti

lateralis

praeparata


aJujubaefructusG

lycyrrhizae


acrocephalae

rhizom

alowast6Astra

galimem

branaceusradixC

innamom

icortexPa

eoniaalba


Zingiberisrhizom

alowast7Pa

eoniaalba


radix

lowast8Ch


ithFO

LFo

linicacid

(leucovorin)FFluo

rouracil(5-FU)andOX

Oxalip

latin

(Eloxatin

)















































4 Discussion





































5 Conclusion




References























































































































































































2O2-induced





























of





Volume 2014


Disease Markers



OncologyJournal of




PPARRe sea rch




Journal of

ObesityJournal of





























































4 Discussion





































5 Conclusion




References























































































































































































2O2-induced





























of





Volume 2014


Disease Markers



OncologyJournal of




PPARRe sea rch




Journal of

ObesityJournal of








































5 Conclusion




References























































































































































































2O2-induced





























of





Volume 2014


Disease Markers



OncologyJournal of




PPARRe sea rch




Journal of

ObesityJournal of
















References























































































































































































2O2-induced





























of





Volume 2014


Disease Markers



OncologyJournal of




PPARRe sea rch




Journal of

ObesityJournal of





































































































































































2O2-induced





























of





Volume 2014


Disease Markers



OncologyJournal of




PPARRe sea rch




Journal of

ObesityJournal of


































of





Volume 2014


Disease Markers



OncologyJournal of




PPARRe sea rch




Journal of

ObesityJournal of















can medical herbs stimulate regeneration or neuroprotection and …¶der_et_al... · 2019-11-01 ·...

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