Causative drugs for drug-induced cutaneous reactions in central China: a 608-case analysis,

Anais

Brasileiros

de

Dermatologia

www.anaisdedermatologia.org.br

INVESTIGATION

Causative

drugs

for

drug-induced

cutaneous

reactions

in

central

China:

a

608-case

analysis

夽,夽夽

Jun

Zhao

_,

_Lei

_Hu

_,

_Lihua

_Zhang

_,

_Maosong

_Zhou

_,

_Lichen

_Gao

_,

Lin

Cheng

a_{SchoolofOphthalmology&OptometryAffiliatedtoShenzhenUniversity,Shenzhen,China} b_{ShenzhenEyeHospitalAffiliatedtoJinanUniversity,ShenzhenEyeInstitute,Shenzhen,China} c_{DepartmentofPharmacy,PekingUniversityPeople’sHospital,Beijing,China}

d_{DepartmentofClinicalPharmacology,XiangyaHospital,CentralSouthUniversity,Changsha,China}

e_{InstituteofClinicalPharmacology,HunanKeyLaboratoryofPharmacogenetics,CentralSouthUniversity,Changsha,China} f_{DepartmentofDermatology,ChangshaEighthPeople}_{sHospital,Changsha,China}

g_{DepartmentofPharmacy,DepartmentofOncology,CancerInstitute,ChangshaCentralHospital,Changsha,China}

h_{StateKeyLaboratoryofOphthalmology,ZhongshanOphthalmicCenter,SunYat-senUniversity,Guangzhou,China}

i_{ShenzhenEyeisVisualScienceResearchInstitute,Shenzhen,China}

j_{SchoolofOphthalmology&Optometry,EyeHospital,WenzhouMedicalUniversity,Wenzhou,China}

Received21May2018;accepted7January2019

Availableonline26October2019

KEYWORDS Drugeruptions; Drughypersensitivity; Drug-induced cutaneousadverse reactions; Drug-inducedsevere cutaneousadverse reactions; Pharmacovigilance Abstract

Background: Reportsregardingthecausativedrugs ofdrug-inducedcutaneousadverse

reac-tionsinChinaareindistinct,suchthatdifferentregionshavereportedthespectrumofdrugs differssubstantiallyindifferentclinicalconditions.

Objective: Toexplorethecausativedrugsthatledtocutaneousreactions.

Methods: Adversedrug reactionreportsfromcentralChinawerecollectedanddividedinto

cutaneous adverse reactions and severe cutaneous adverse reactions groups. Cases were

reviewedretrospectivelyforcausativedrugs.

Results: The male:female ratio was equal in both cutaneousadverse reactions and severe

cutaneousadversereactions.In cutaneousadversereactions(n=482),thehighestincidence

happenedbetween51and60yearsofageandthetopthreecausativedrugswereantibiotics

(48%),Chinese medicine(16%), andallopurinol (9%).In severe cutaneousadverse reactions

(n=126), the highest incidence happened between 41 and 50 years of age and the top

threecausativedrugsweresedative-hypnoticsandantiepileptics(39%),antibiotics(22%),and allopurinol(15%).Carbamazepinewasthemostfrequentlyusedsingle-drug(16/18)in sedative-hypnoticsandantiepileptics._␤-lactamswerethemostfrequentlyusedantibioticsthatinduced

bothcutaneousadversereactionsandseverecutaneousadversereactions.

夽 _{Howtocitethisarticle:ZhaoJ,HuL,ZhangL,ZhouM,GaoL,ChengL.Causativedrugsfordrug-inducedcutaneousreactionsincentral}

China:a608-caseanalysis.AnBrasDermatol.2019;94:664---70.

夽夽_{StudyconductedattheCentralSouthUniversity,Changsha,China;WenzhouMedicalUniversity,Wenzhou,China.}

∗_{Correspondingauthor.}

E-mail:kjade.cheng@gmail.com(L.Cheng).

https://doi.org/10.1016/j.abd.2019.01.007

0365-0596/©2019PublishedbyElsevierEspa˜na,S.L.U.onbehalfofSociedadeBrasileiradeDermatologia.Thisisanopenaccessarticle

Studylimitations: Thesmallsamplesize,retrospectivedesign,collectionofcutaneousadverse reactionsandseverecutaneousadversereactionsatdifferenttimeframesandlocations,and exclusionofpatientstakingmorethanfivemedicationsarelimitationsofthestudy.

Conclusions: Genderdoesnotaffectcutaneousadversereactionsandseverecutaneousadverse reactions.Thetopthreedrugstoinducecutaneousadversereactionsareantibiotics,Chinese medicine,andallopurinol,whilethosethattriggeredseverecutaneousadversereactionsare sedative-hypnoticsandantiepileptics,antibiotics,andallopurinol.Carbamazepineisthemost frequentsingledrugthatinducesseverecutaneousadversereactions.␤-lactamsarethemost frequentlyusedantibioticsthatinducebothcutaneousadversereactionsandseverecutaneous adversereactions.

©2019PublishedbyElsevierEspa˜na,S.L.U.onbehalfofSociedadeBrasileiradeDermatologia. ThisisanopenaccessarticleundertheCCBYlicense(http://creativecommons.org/licenses/ by/4.0/).

Introduction

Drugeruptionisasymmetriccutaneousreactionthatmay occur when patients are taking medicines. It is known asdrug-induced cutaneousadverse reactions (CARs), drug dermatitis, or dermatitis medicamentosa. Drug eruption is usually mild and may disappear when offending drugs arewithdrawn;however, someseverecasesmaybefatal. According toreports, drug eruptionaffects more than7% of the general population and an estimated 7000 deaths occur.1,2 _{The incidenceof severe cutaneousadverse}

reac-tions(SCARs)isgenerallyverylow.TakingStevens-Johnsons syndrome (SJS) and toxic epidermal necrolysis (TEN) for example,around5.76casesoccuroutofonemillionpeople peryear.3---5 _{Oncesuchreactions occur,thetotalmortality}

couldbeashighas30%,6_38%,7_or32%,8_{asstatedbydifferent}

reports.

Drugs known to induce severe drug eruption are mainly antibiotics,antiepileptic drugs, non-steroidal anti-inflammatorydrugs(NSAIDs),andallopurinol.Datashowed themain causativedrugswere antibiotics(TEN, 40%;SJS, 40%) and painrelievers (TEN, 23%; SJS, 33%), and among antibiotics, sulfa and ␤-lactams were the most common causesofCARs.9,10_{ThespectrumofdrugsthatinduceCARs}

variedsubstantially indifferentclinicalconditions. Identi-fyingthe causative drugs notonly allows early cessation, butalsoimprovestheprognosis.Sincetheepidemiological dataforCARs arelimitedinChinaatpresent, theauthors conducted an analysis in hospitalized patients with drug eruptionincentralChinatoexploretheleadingdrugsthat causeCARsinChinesepopulation.

Methods

Patients

Thestudyisaretrospectiveobservationalstudy.Four hun-dredandeightytwoCARspatientsadmittedtoWuhanNo.1 Hospitalfrom2010and2011and126SCARspatients admit-ted toXiangya Hospital from 2009 to2014 were assessed

(Table 1). The patients’ general information, causative

drugs,clinicalmanifestations,andoutcomeswerecollected and analyzed. The diagnosis of drug eruption was made according to the patient’s history of medication, clinical

manifestations,andlatentperiodbyrulingoutsimilar infec-tiousskin diseases and rashes.Eruptions were diminished or relieved upon withdrawal of the sensitizing drug. The eruptionmanifestationwasatypicalsymmetricaldrug erup-tion,withbrightredcoloranditch.Ifpatientsweretaking multiplemedicines,determiningthesensitizingdrugsmay have been difficult. In this case, the suspected drug was determined by the doctors-in-charge. Only cases showing thedefinite causativedrugs and takingnomore thanfive totaldrugswereincluded.InCARswithprobableorunknown drugs,thecaseswereexcluded.

Clinicalmanifestationclassification

Thisstudy divided drugeruptionsinto twocategories:(1) CARs:fixeddrugeruption,urticarialdrugeruption, measle-like or scarlatina-like drug eruption, eczematous drug eruption,purpura-likedrugeruption,erythemamultiforme, acneiformdrugeruption,photosensitivedrugeruption,etc. (2)SCARs:erythemamultiformemajororSJS,drugrashwith eosinophiliaandsystemicsymptoms(DRESS),TEN, erythro-derma,andexanthematouspustulosis.9,11 _{Onepatientwho}

presentedTENisshowninFig.1.

Drugclassification

The most common drugs that induce drug eruption were divided into the following categories: (1) antibiotics; (2) analgesic-antipyretics, such as aspirin, acetaminophen, etc.; (3) sedative hypnotics and antiepileptic drugs, such asphenobarbitone,phenytoinsodium,carbamazepine,etc.; (4) serum preparations and vaccines, such as tetanus antitoxin,rabiesvaccine, snakeantivenoms,etc.; (5) bio-logical agents. In addition, the anti-hyperuricemia drug allopurinol, antithyroids, and phenothiazines were also included.

Statisticalanalysis

Allthenumericalvariablesinthisarticlewerepresentedas mean±standarderrorofthemean(SEM).Student’st-test

wasusedonnumerical variablesof independentsamples. Thechi-squaredtestwasusedoncategoricalvariables,i.e.,

Table1 Patientinformationfromtwodifferenthospitals.

Hospital Time(years) Cases Patienttype

WuhanNo.1Hospital 2010---2011 482 Patientswithdrugeruptiona,b

XiangyaHospital 2009---2014 126 Patientswithseveredrugeruptiona,b

a_{Unknowndrugsthatinducedrugeruptionwereruledout.}

b _{Patientsintake≤5totaldrugswereanalyzed.}

Fig.1 Dermatologicalmanifestationsofapatientwithtoxicepidermalnecrolysis.

v.13.0 softwarepackage (SPSSInc. --- Chicago,IL, United States).Ap-value<0.05wasconsideredstatistically signifi-cant.

Results

482casesofCARs

Amongthe482CARscasesinWuhanNo.1Hospital,thecases ofmaleandfemale patientswereequal, withno statisti-caldifference(49%,238/482 vs. 51%, 244/482)(p>0.05). Theagedistributionbetweenmaleandfemalewerenot sta-tisticallydifferent(48.71±1.90vs.46.24±1.26yearsold) (p>0.05). The highest CARs incidence occurred between 51 and 60 years old, and the lowest happened between 71and 80,81 and 90,0 and10, and11 and 20years old (Fig.2).Patientsweredividedintothesingle-medicineuse groupand thecombined-medicine use group according to theircausativedrugs.The causativedrugswerethen sub-dividedintosubcategories(Table2).Inthesingle-medicine usegroup,themostfrequent drugswereantibiotics(48%, 201/420),followedbyChinesemedicine(16%,66/420)and allopurinol(9%, 38/420). These werefollowed by NSAIDs, sedativehypnoticantiepilepticdrugs,nitroimidazole, anti-hypertensives and lipid-modifying agents, serums and vaccines, digestive system drugs, biological agents, anti-fungals,antithyroidpreparations,andantiviraldrugs.Other agentsincludedanti-prostatichyperplasiadrugs,pesticides, mango,etc.Inthecombined-medicineusegroup,themost commoncombinationswereantibioticscombinedwithother

81-90 71-80 61-70 51-60 41-50 31-40 21-30 11-20 0-10 0 1 2 3 4 5 6 7 8 9 _{10 11 12 13 14 15 16 17 18 19 20}% Percentage of patients Age r a nge (y ear)

Fig.2 Agedistributionofcutaneousadversereactions(CARs). The chartillustratesthepatient distributionatdifferentage ranges(yearsold).

drugs.Antibioticscombinedwithantibioticsaccountedfor 34% (21/62). Antibiotics combinedwith other drugs, such as serum preparations, antipyretic analgesics, anticoagu-lants,antiviraldrugs,andChinesemedicineaccountedfor 27%(17/62).Thethirdplacewasantibioticscombinedwith nitroimidazole, accounting for 13% (8/62). Subsequently, it was Chinese medicine combined with another Chinese medicine, antiepileptic medicine combined with another antiepileptic medicine,andnitroimidazole combinedwith anothernitroimidazole.

Among those antibiotics (Table 3), ␤-lactams were the most frequently used (46%, 92/201), followed by furan (22%, 44/201), lincomycin(12%, 24/201), quinolone (12%, 24/201), macrolides (4%), and sulfonamides (3%). In␤-lactams,amoxicillinwasthemostfrequentlyused(43%,

Table2 Thecategoriesofcausativedrugsin482casesofcutaneousadversereactions.

Group Ranking Causativedrugs ATCcodes Cases %vs.subtotal %vs.total

Single-medicine use

1 Antibiotics A07AA,C05AB,

D01AA,D06A,

D06AX,G01AA,

J02AA,J04AB,

R02AB,R02AB

201 48%

2 HerbsandChinesemedicine --- 66 16%

3 Allopurinol M04AA01 38 9%

4 NSAIDs M01A,M01AX,

S01BC

30 7%

5 Sedative-hypnoticsand

antiepileptics

N05CandN03 20 5%

6 Nitroimidazole P01AB,P01CA 12 3%

7 Antihypertensivesandlipid

modifyingagents

C02andC10 12 3%

8 Serumandvaccine G03GA03,

J06AA03,J06AA06

andJ07

9 2%

9 Digestivesystemdrugs A09 5 1%

10 Biologicalagents B05A,L03AB,

L03AC,L04AB, etc. 3 1% 11 Antifungals D01 3 1% 12 Antithyroidpreparations H03B 3 1% 13 Antivirals S01AD 1 0% 14 Othersa _{--- 17 4%} Subtotal 420 87% Combined-medicine use

1 Antibiotics+antibiotics S01AA30 21 34%

2 Antibiotics+others S01AA20 17 27%

3 Antibiotics+nitroimidazole --- 8 13% 4 Herb+herb --- 3 5% 5 Antiepileptics+antiepileptics --- 2 3% 6 Nitroimidazole+nitroimidazole --- 1 2% 7 Othersb _{--- 10 16%} Subtotal 62 13% Total 482

TheAnatomicalTherapeuticChemical(ATC)codingsystemdividesdrugsintodifferentgroupsaccordingtotheorganorsystemonwhich

theyact,ortheirtherapeuticandchemicalcharacteristics.

a _{Anti-prostatichyperplasia,pesticides,mango,etc.}

b _{Serumproducts,non-steroidalanti-inflammatorydrugs(NSAIDs),anti-tumormedicine,herbs,etc.}

40/92).Infuranantibiotics,themostcommonwasnifuratel (95%,42/44).

126casesofSCARs

Among the126SCARscasesinXiangya Hospital,wefound 43.50% (385/885) of patients were taking more than five drugs.Tothisend,patientstakingmorethanfivedrugswere excludeddue toitbeingoverlycomplicatedtodetermine theculpritdrugsand/ortoperformstatisticalanalysis.

The ratio of males to females was 1 (43%, 54/126) to 1.33(57%,72/126) (p>0.05).Maleagetofemaleagewas 48.70±2.65vs.43.79±2.30yearsold(p>0.05).Ageranged from2 to86yearsold. Patientsagedunder10 andthose

between 71 and 90 had the lowest incidence rates, with five(4%, 5/126) and ten cases (8%, 10/126), respectively (Fig.3).Thehighestincidenceoccurredattheagebetween 41and50yearsold,withaproportionof16%(20/126).The dermatologicaltypesofSCARsarelistedinTable4.Severe erythemamultiformewasthemostcommontypeofSCARs, accountingfor38% (48/126). The second placewas exan-thematouspustulosis,accountingfor26%(33/126).TENwas rare,accountingfor2%(3/126).

The most common drugs in single-medicine use were sedative-hypnotics and antiepileptics, accounting for 39% (18/46)(Table5).Antibiotics (22%,10/46)and allopurinol (15%,7/46)werethesecondandthirdcategoriesthatinduce SCARs. They were followed by Chinese patent medicine

Table3 Thecategoriesofcausativeantibioticsin482casesofcutaneousadversereactions.

Drugs ATCcodes Cases %

␤-lactams J01C,J01CR,J01D 92 46%

Furan D08AF,J01XE,P01CC 44 22%

Lincomycin J01FF02 24 12%

Quinolone J01M,J01MA,J01MB,S01AE 24 12%

Macrolides J01FA 8 4%

Sulfonamides A07AB,C03BA,C03CA,D06BA,G01AE,S01AB 7 3%

Others --- 2 1% Total 201 100% 81-90 71-80 61-70 51-60 41-50 31-40 21-30 11-20 0-10 0 1 2 3 4 5 6 7 8 9 _{10 11 12 13 14 15 16 17 18 19 20}% Percentage of patients Age r a nge (y ear)

Fig.3 Agedistributionofseverecutaneousadversereactions

(SCARs).Thechartillustratesthepatientdistributionat differ-entageranges(yearsold).

or combined Chinese and drug medicine, nitroimidazole, dapsone, serum and vaccine, and digestive system medicines.Otheragentssuchasfruits,vegetables,anddiet pillswerenotincludedinthesingle-druggroup,sincethey usuallydidnotinduceSCARs.Amongsedative-hypnoticsand antiepileptics,carbamazepinewasthemostfrequentlyused singlemedicine(89%,16/18).␤-lactamswerethemost fre-quentantibioticsthatinduceSCARs.

In combined-medicine use, since drugs were randomly combined,weonlyanalyzedthefrequencyofduplex,triple, quadruple, and quintuple drug combinations (Table 5). Duplexdrugcombinationaccountedfor43%(34/80),triple drugsaccountedfor29%(23/80),quadrupledrugsaccounted for 18% (14/80), and quintuple drugs accounted for 11% (9/80). The medicine combination of SCARs was more complicated than that of CARs, e.g., some patients had antibiotics combinedwithantiviral drugs, serum prepara-tions,andChinesemedicine.

Discussion

In this study, we analyzed 608 cases of drug eruption in Chinesepopulationfromcentral China.482casesof CARs suggestedthatmenandwomenhadequalchancetodevelop CARs,andthosewithagebetween51and60hadthe high-est incidence of CARs. The suspected drugs were mainly inthe following ten categories: (1)antibiotics: ␤-lactams were the most frequently used antibiotics; (2) Chinese medicineorChinesepatentmedicine,orcombinedChinese and drug medicine; (3) allopurinol; (4) NSAIDs; (5) seda-tive hypnotic antiepileptic drugs; (6) nitroimidazole; (7)

antihypertensivesandlipid-modifyingagents;(8)serumand vaccine;(9)digestivesystemdrugs;(10)biologicalagents. This study showed the top three CARs-inducing medicine categories were antibiotics, Chinese medicine,and allop-urinol. In antibiotics, ␤-lactams, furan, and clindamycin werethetopthreeantibioticsubgroupsthatinduceCARs. Consistentwithpreviousreports,␤-lactamswerethemost common antibiotics to induce drug eruption.12---15 _Widely

usedinChina,Chinesemedicine,includingherbs,Chinese patentmedicine,combinedChineseanddrugmedicine,and Chinese medicine injections ranked in the second place to induce CARs in central China. Due to improper use of Chinese medicine, pharmaceutical problems, specific ingredients, complexcomponentsofChinesemedicine,or perhaps interaction withdrugs, drug eruption induced by Chinese medicine wascommonly seen. If the ingredients ofChinesemedicinearenotclear,useofChinesemedicine combinedwithothermedicineshouldbemorecareful, espe-ciallywhenpatientshaveallergyhistoryandmultipledrug usage.Furanwasnotacommoncauseofdrugeruptionand rankedthesecondplaceinantibioticstoinduceCARs.This may due to the nifuratel vaginal suppository, which was extensivelyusedinWuhancity.ItsuggeststhatWuhancity shouldpay aspecialattentiontotheadverse reactions of ␤-lactamssuchasamoxicillinandthegynecological suppos-itorymedicinenifuratelduetotheirhighadversereactions, andconsiderchangingtoanothervendor.

There were 126 cases of SCARs, which showed that SCARsweremostcommonbetween40and70yearsoldof age.WomenhadmorecasesofSCARsthanmen,but with-out statistical significance. The top threecausative drugs to induce SCARs were sedative-hypnotics and antiepilep-tics,antibiotics,andallopurinol.Amongsedative-hypnotics andantiepileptics,carbamazepinewasthemostfrequently used drug, making it the most frequent single-drug that induce SCARs. ␤-lactams were the most frequently used antibiotic that induce SCARs. Allopurinol ranked number three to induce SCARs, which is consistent with previ-ous reports that allopurinol is a common drug to induce SCARs.16---19

Meanwhile,itwasfound thatmostSCARspatientsused amultiple-drugcombinationandhadacomplexmedication history.Theyhadtriple,quadruple,andquintupledruguse. Comparedwiththecombined-medicineusegroupinCARs, SCARs patients had more drug combinations. Despite pri-marydiseases,SCARspatientsusuallyhadmoredrugintake, which greatly enhanced the incidence of SCARs. Avoiding

Table4 Thedermatologicaltypesof126casesofseverecutaneousadversereactions.

SCARstypes Male Female Total %

Severeerythemamultiforme 23 25 48 38%

Exanthematouspustulosis 14 19 33 26%

Stevens-Johnsonssyndrome 0 4 4 3%

Toxicepidermalnecrolysis 2 1 3 2%

Erythroderma 2 0 2 2%

Anotherseveredrugeruption 13 23 36 29%

Total 54 72 126 100%

Table5 Thecategoriesofcausativedrugsin126casesofseverecutaneousadversereactions.

Groups Ranking Causativedrugs ATCcodes Cases %vs.subtotal %vs.total

Single-medicine use

1 Sedative-hypnoticsand

antiepileptics

N05CandN03 18 39%

2 Antibiotics A07AA,C05AB,

D01AA,D06A, D06AX,G01AA, J02AA,J04AB, R02AB,R02AB 10 22% 3 Allopurinol M04AA01 7 15%

4 HerbsandChinesemedicine --- 5 11%

5 Nitroimidazole P01AB,P01CA 2 4%

6 Dapsone J04BA02,D10AX05 2 4%

7 Serumandvaccine G03GA03,

J06AA03,J06AA06

andJ07

1 2%

8 Digestivesystemmedicines A09 1 2%

Subtotal 46 37%

Combined-medicineuse

1 Twodrugcombination --- 34 43%

2 Threedrugcombination --- 23 29%

3 Fourdrugcombination --- 14 18%

4 Fivedrugcombination --- 9 11%

Subtotal 80 63%

Total 126

interaction among different medications is important to lowertheincidenceofSCARs.

Despitethefindingsabove,thisstudyhaslimitations.The smallsamplesizeisoneofthem.This studyonlyanalyzed thepatientswhotooknomorethanfivedrugsinSCARs,since more than five drug intake cases were too sophisticated foreitherdeterminingtheculpritdrugsordoingstatistical analysis.Inthisway,somemeaningfuldatawereeliminated fortheseseverecases.Thisestimationmayunderrepresent SCARsinXiangyaHospital.

Conclusions

IncentralChina,genderdoesnotaffectCARsandSCARs.The highestincidenceofCARsoccursbetween51and60years oldofage.The topthreedrugstoinduceCARsare antibi-otics, Chinese medicine, and allopurinol. Of antibiotics, ␤-lactams, nitrofurans, and lincomycin arethe top three categoriestoinduce CARs.However,SCARsarecommonly

seen between 41 and 50 yearsold of age. The top three drugstoinduceSCARsinsingle-medicineuseare sedative-hypnoticsandantiepileptics,antibiotics,andallopurinol.Of the sedative-hypnotics and antiepileptics, carbamazepine is the most frequently used drug, making carbamazepine the most frequent single medicine to induce SCARs. ␤-lactamsarethemostfrequentlyusedantibioticstoinduce SCARs.Despitethesefindings,thisstudyhaslimitations.The smallsample size, retrospective design, collectionof the non-severeand severe CARs at differenttimeframes and locations,andexclusion ofpatients taking morethanfive medicationsareconsideredthelimitationsofthestudy.

Financial

support

ThisworkwasfundedbygrantfromNationalNaturalScience FoundationofChina(No.81603200).

Author’s

contribution

Jun Zhao, Lei Hu, Lihua Zhang, Maosong Zhou, and LichenGao:obtaining,analyzingandinterpretingthedata; effectiveparticipationinresearchorientation;intellectual participation in propaedeutic and therapeutic conduct of thecasesstudied;criticalreviewoftheliterature.

LinCheng:conceptionandplanningofthestudy; elabora-tionandwritingofthemanuscript;obtaining,analyzingand interpreting the data; effective participation in research orientation;intellectual participationinpropaedeuticand therapeuticconductofthecasesstudied;criticalreviewand finalapprovalofthemanuscript.

Conflicts

of

interest

Nonedeclared.

Acknowledgments

The authors thank Dr. Ji Lifrom the Department of Der-matology, Xiangya Hospital, Central South University, Dr. LimingTianfromWuhanNo.1Hospital,HuazhongUniversity ofScienceandTechnology,andProf. Hong-HaoZhou from theDepartmentofClinicalPharmacology,XiangyaHospital, CentralSouthUniversityforthehelpwithcollectingclinical cases.

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