Efficacy and safety of dimeticones in the treatment of epidermal parasitic skin diseases with special emphasis on tungiasis: an evidence-based critical review

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w w w . e l s e v ie r . c o m / l o c a t e / b j i d

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

Review

article

Efﬁcacy

and

safety

of

dimeticones

in

the

treatment

of

epidermal

parasitic

skin

diseases

with

special

emphasis

on

tungiasis:

an

evidence-based

critical

review

夽

Hollman

Miller

a,1

_,

_Julián

_{Trujillo-Trujillo}

b,∗,1

_,

_Francis

_Mutebi

c,1

_,

Hermann

Feldmeier

d,1

a_Secretaría_de_Salud_de_Vaupés,_Mitú,_Colombia

b_Ministry_of_Health_and_Social_Protection,_Bogota,_Colombia

c_Makerere_University,_Animal_Resources_and_Biosecurity,_College_of_Veterinary_Medicine,_Kampala,_Uganda d_Charité_University_Medicine,_Institute_of_Microbiology_and_Infection_Immunology,_Berlin,_Germany

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received4October2019 Accepted27January2020 Availableonline24February2020

Keywords:

Tungiasis

Pediculosistreatment Sandﬂeadisease Dimeticone

Indigenouspopulations Indigenouspopulationsdiseases

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b

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Epidermalparasiticskindiseasesencompassscabies,pediculosis,cutaneouslarvamigrans, myiasis,andtungiasis.TungiasisisprobablythemostneglectedofallNeglectedTropical Diseases(NTD).ItoccursinSouthAmerica,theCaribbeanandSub-SaharanAfricaand affectsmarginalizedpopulationswherepeopleliveinextremepoverty.Inendemic com-munitiestheprevalencecanbeupto30%ingeneralpopulationand85%inchildren.Over time,chronicpathologydevelopscharacterizedbyhyperkeratosis,edemaaroundthenail rim,ﬁssures,ulcers,deformationandlossofnails.Thisleadstoapatternofdisabilities, eventuallyresultinginimpairmentofmobility.

Dimeticonesareafamilyofsiliconoilswithapotentialtokillparasiteslocatedontop orinsidetheepidermisbyaphysicalmodeofaction.Theyareconsideredthetreatmentof choiceforpediculosiscapitisandpediculosispubis.Withregardtotungiasis,thesocalled rearabdominalconeoftheparasiteshasbeenidentifiedasa targetfortreatmentwith dimeticones.NYDA®,amixtureoftwodimeticoneswithdifferentviscosity,istheonly dimeticoneproductforwhichdataonthemodeofaction,efficacyandsafetywithregardto tungiasisexists.Theproducthasbeenshownhighlyeffectiveagainstembeddedsandfleas, eveninveryintenseinfectionwithmorethan500parasitessituatedontopofeachother.A randomizedcontrolledtrialshowedthatsevendaysafteratargetedapplicationofNYDA® 97%(95%CI94–99%)oftheembeddedsandfleashadlostallsignsofviability.

夽_The_ﬁnancing_of_this_work_was_done_by_the_Charité_University_of_Berlin. ∗ _{Corresponding}_author.

E-mailaddress:trujillotrujillojulian@gmail.com(J.Trujillo-Trujillo).

1 _All_authors_contributed_equally_to_the_review_of_the_literature,_to_the_writing_and_critical_review_of_the_manuscript. https://doi.org/10.1016/j.bjid.2020.01.004

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Comprehensive toxicological investigations on the dimeticones contained in NYDA® showedthatthereispracticallynoriskofembryotoxicity,fetotoxicity,teratogenicity,and othertoxicity.Thesafetyofdimeticoneswasalsodemonstratedinclinicaltrialswithatotal of106participantswithtungiasis,inwhichnotasingleadverseeventwasobserved.

Introduction

Tungiasis(sandﬂeadisease)isaparasiticskindiseasewith originsintheAmericas.Amultitudeoflocaldesignations indi-catethattungiasisoriginallyoccurredinmostcountriesand populationsoftheAmericas.1_In_some_areas_tungiasis_is_still

socommonthatitbecamepartofthelocalfolklore(Fig.1). DataongeographicaldiseaseoccurrenceintheAmericasis scanty,butindicatethattungiasisexistsinMexico,Honduras,2

Venezuela, Colombia,3 _Ecuador, _Peru, _Paraguay, _Argentina,

Haiti,Barbados,andTrinidad.3,4_In_Brazil_tungiasis_is_reported

fromAmazoniaStateintheNorthtoRioGrandedoSulState intheSouth.5_Several_{community-based}_studies_performed_in

Brazil,HaitiandTrinidad-Tobagoshowedastoundinglyhigh prevalencein resource-poorrural and urbancommunities.

Fig.1–NameplateofacoffeeshopinPopayan,Southwest Colombia,reﬂectingthattungiasiswascommoninthe town.NiguaisapopularnameinSpanishforthesandﬂea.

Prevalencerangedfrom10.6to82.6%inthegeneral popula-tion.

Tungiasis seems to be frequent in Amerindian popu-lations in the Amazon/Orinoco lowlands of Colombia and Venezuela. In Amerindian populations, tungiasis is asso-ciated with severe morbidity potentially leading to death (Heukelbach, unpublished observation, 2012; Grundmann, unpublishedobservations,2010;Roger,unpublished observa-tion,2017).Eveninchildren≤1yeartheprevalencewas2%.3

Howintensetransmissioncanbeinaresource-poorsetting isdemonstratedbyastudyinafavelainFortaleza,Northeast Brazil.Allindividualswhoenteredthecommunityafterbeing outoftheendemicareaforsometimebecameinfectedwithin threeweeks.Inthissettingtheaverageattackratewas15ﬂeas perpersonperweek.6

Usually, transmission occurs peri-domiciliary. When housesdonothaveasolidﬂoor,anddomesticanimalscan roaminanout,intra-domiciliarytransmissionisfrequent.7–9

InAmerindiancommunities,commonlythewholelifecycle oftheparasiteiscompletedinsidethehouse.10

Morbidityistriggeredbyanintenseinﬂammatoryresponse around embedded female sand ﬂeas11 _leading _to _pain

and intense itching. Bacterial super-infection of lesions is almost constant and intensiﬁes the inﬂammation.12

In non-immunized individuals, tetanus is a known fatal complication.13_Over_time,_with_constant_{re-infection,}_chronic

pathology developscharacterizedbyhyperkeratosis,edema aroundthenailrim,ﬁssures,ulcers,deformationandlossof nails.Thisleadstoapatternofdisabilitiesﬁnallyresultingin partialortotalimmobility.14_Children,_persons_with

disabili-tiesandtheelderlybearthehighestdiseaseburden.11,15

Theaimofthisreviewistocriticallyevaluatetheefﬁcacy andsafetyofdimeticonesinthetreatmentoftungiasis.

Methodology

Studydesign

Initialsearchesrevealedthatpublishedstudiesonthe treat-mentoftungiasisvariedconsiderablyintermsofintervention types,outcomemeasures,durationoftreatmentandlength offollow-up,makingameta-analysisorasystematicreview unfeasible. Hence, a narrative-style review ofpublications, usingsystematicdatasearches,wasperformed.

Searchstrategies

Studiesevaluatingtheefﬁcacyoftreatmentsagainsttungiasis werecollectedfromasetofdatabasesusingthespeciﬁcsearch

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terms‘tungiasis’,‘Tunga*’,‘Tungapenetrans’,‘sandﬂeadisease’, ‘efﬁcacy’and‘safety’.Thedatabasessearchedincluded MED-LINE, PubMed,SciELO and Lilacs.Databaseswere searched frominceptionto31December2018.

To identify studies not indexed in the databases listed above,greyliteraturewassearchedinOpenGreyandPQDT Global(ProQuestDissertations&ThesesGlobal).

Studyselection

Duetothesmallnumberofpublications,allstudies investi-gatingtheefﬁcacyandsafetyofdimeticonesinthetreatment ofepidermalparasiticskindiseaseswereincluded,regardless ofstudy population, intervention type,outcome measures, durationoffollow-up,andlanguage.

Results

Variousinsecticides andanti-helminthicshave beentested regardingtheiractivity againstembeddedsand ﬂeas,using systemicortopicalapplication. Inarandomizedcontrolled trial,theefﬁcacyofthetopicalapplicationofivermectinlotion (0.8% w/v), metrifonate (trichlorfon) lotion (0.2% w/v), thi-abendazole lotion (0.2% w/v), thiabendazole ointment (5% w/v)were comparedtoplacebo lotion.16 _The_study_showed

alighteffectofivermectinlotion,metrifonatelotionand thi-abendazolelotion.Arandomizedcontrolledstudywithoral ivermectindidnotshowanyeffectatall.17

Hitherto,onlyforonecommerciallyavailabledimeticone productdata onmode ofaction, efﬁcacy against ectopara-sitesand safety isavailable. NYDA® (Pohl-BoskampGmbH &Co. KG,Hohenlockstedt,Germany) contains amixtureof twodimeticones differing inviscosity and volatility,which accountforthespecialcreepingandspreadingpropertiesof NYDA®.Thehigh-andthelow-viscousdimeticonesarethe functionalcomponentsresponsibleforthephysicalmodeof action.18,19_{NYDA® is}_a_certiﬁed_medical_device_according_to

MedicalDeviceDirectiveinEurope.Itisregisteredforthe treat-mentofpediculosiscapitisinover30countriesworldwide.

NYDA® entersopenings as small as 10␮m and rapidly coversmicroscopicsurfaces.20 _The_dimeticone_with_the_low

viscosityevaporatesand thedimeticone withthehigh vis-cosityformsanoilﬁlmwhichclosestheopeningsandseals microscopicsurfaces.

NYDA® also contains medium-chain triglycerides and jojobaoil.Themedium-chaintriglyceridesandthejojobaoil are addedas hairand skinnourishingcomponents and to increasethecosmeticperformanceoftheformula.Theydo nothaveaneffectonectoparasites.18,19_{NYDA® does}_not

con-tainanycomponentwithaneurotoxicmodeofaction.

Modeofactionofdimeticones

Dimeticones(synonyms:polydimethylsiloxanes;siliconeoils) consist of fully methylated linear siloxane polymers con-taining repeating units of the formula [(CH3)2SiO] with trimethylsiloxyend-blockingunitsoftheformula.21_They_are

translucent,almostodorlessﬂuids.22

Fig.2–Sectionofafemalesandﬂeainstage3.The parasiteisalmostcompletelyembeddedintheskin.Itis obviousthattheparasiteisdifﬁculttotarget.

The mode ofaction ofdimeticones was investigatedin headlice(Pediculushumanuscapitis)andhousecrickets(Acheta

domestica). WhenNYDA® wasappliedontheabdomenand thoraxoftheinsects,thedimeticonerapidlyspreadoverthe chitinouscuticleoftheinsects,producingaclosedoillayer, and within1min,enteredtherespiratorytract throughthe 14stigmata(theentriestothetrachealsystem,locatedatthe lateralsideoftheinsect).20

Inhousecrickets,theinsect’sheadtracheawascompletely ﬁlledwithNYDA® withinlessthan1min;inheadlicethe ﬁll-ing oftheentiretrachealsystemoccurredwithin3.5min.20

Thisresultedinblockingtheoxygensupplytothebrain. Since the cuticle of the blood-sucking insects becomes completely coveredwith aﬁlmofthe high-viscous dimeti-cone,theyareunabletoeliminatethewatertheyhavetaken upwithabloodmeal,eventuallyleadingtodisruptionofthe intestine.18 _Either_mode_of_action_is_purely_physical._Similar

observationsweremadeinpiglice,parasitesthataremuch largerthanhumanlice17_(Mutebi_F_and_Feldmeier_H,

unpub-lishedobservation).

Itisdifﬁculttoenvisagehowaninsectcandevelop resis-tanceagainstacompoundwhichhasapurelyphysicalmode ofaction,particularlyiftheparasitesarekilledwithinavery shorttime.

Rationalefortheuseofdimeticonesintungiasis

Onceafemalesandﬂeahasbecomeembeddedintheskin (Fig.2),itremainsincontactwiththeenvironmentthrough atinyopeninginthecorneallayer(Figs.3and4).Inthe so-calledrearabdominalconewhichprotrudesabovetheskin, anumberofvitalorgansbegin/end,namelytherespiratory tract,theintestinaltractandthegenitaltract.Thediameter oftheopeningsoftherespectivetractsisnotpreciselyknown

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Fig.3–Scanningelectronmicroscopyoftherearabdominal coneofanembeddedfemalesandﬂeaprotrudingabove theskin.Heretherespiratorytractbeginsandtheintestinal andthegenitaltractend.

Fig.4–PigidialareaandrespiratoryspiraclesofTunga Penetrans.

butisconsiderablylessthan20␮m.Onlyﬂuidswithnosurface tensioncanpenetrateintosuchsmallopenings.

ToconfirmthephysicalmodeofactionofNYDA® against embeddedsandfleas,astudyinnaturallyinfectedpigswas performedinUganda(MutebiFandFeldmeierH,unpublished observation).Fivedropsweretargetedtotherearabdominal coneofan embeddedsand flea.Theembeddedsand fleas wereremovedsurgicallyand wereexaminedusinga hand-heldlightmicroscopetoestablishifthedimeticonehascrept into the rear abdominal cone. In all cases the abdominal coneofembeddedsandfleaswassealedbythehighviscous dimeticoneandthephysicalmodeofactionofdimeticoneson embeddedsandfleaswasconfirmed(MutebiandFeldmeier, unpublishedobservation).

Efﬁcacy

of

dimeticones

Efﬁcacyinthetreatmentofpediculosis

Arandomized,controlled,observer-blindedclinicaltrialwas performedinapoorneighborhoodinBrazil.23_Children_aged

5–15yearswithahighintensityofinfestationwithheadlice weretreatedtwicewithNYDA® sevendaysapart.NYDA® was comparedtopermethrin1%,thelocalstandardtreatment.The scalpandthehairwerewettedwithNYDA® accordingtothe instructionsofthe producer.After8hthehairwaswashed withacommercialshampoonotcontainingdimeticones.A normalcombwasusedtospreadtheliquidsevenly.Overall curerateswere:day2(afterﬁrsttreatment)–dimeticone94.5% (95%CI:86.6–98.5%)andpermethrin66.7%(95%CI:54.6–77.3%;

p<0.0001);day9(aftersecondtreatment)–dimeticone97.2% (95%CI:90.3–99.7%)[p<0.0001]andpermethrin67.6%(95%CI: 55.4–78.2%)[p<0.0001].

In twoin vitro studies the efﬁcacy ofNYDA® on killing headliceembryoswasinvestigatedusingaHairTuft Bioas-say.Afteranimmersionofviableheadliceeggsfor30minin NYDA®,noeggshatched.Iftheapplicationtimewasreduced to10min,5–8%oftheembryossurvivedanddevelopedinto adults.When9–11daysoldheadliceeggsweretreatedwith NYDA®,the efﬁcacyofkillinglice embryoswasreducedto 97%.24,25

Anecdotal observations suggest that pubic lice are also highlysusceptibletotreatmentwithNYDA®.26

Efﬁcacyinthetreatmentoftungiasis

The efﬁcacy of NYDA® in the treatment of tungiasis was investigatedintworandomizedcontrolledstudiesperformed inKenyaandUganda,andinacaseseriesinpatientswith extremelyseveretungiasisinColombia.

Thetopicalapplication ofNYDA® tothewhole footfor 10minwascomparedtobathingthefootinKMnO4for10min

withsubsequentapplicationofpetroleumjelly.Thelatteris thestandardtreatmentrecommendedbytheMoHofKenya.15

Patients were monitored every second day for a total of 7 days.Outcome measures were disappearance ofviability signs (expulsion of eggs, excretion of fecal thread, excre-tionoffecalliquidorpulsations/contractionsoftheparasite) assessedthrough adigital handheldmicroscope,abnormal developmentregardingthelifestagesdefinedintheFortaleza classification11_and_assessment_of_a_local_{inflammation}_score.

Sevendaysaftertreatment,inthedimeticonegroup78% (95%CI67–86%)oftheparasiteshadlostallsignsofviability comparedto39%(95%CI28–52%) inthe KMnO4-petroleum

jellygroup(p<0.001).In thedimeticone group90%(95% CI 80–95%) ofthe penetrated sand ﬂeas showed anabnormal developmentalreadyafterﬁvedays,comparedto53%(95%CI 40–66%;p<0.001)intheKMnO4-petroleumjellygroup.Seven

days after treatment, signs of local inﬂammationhad sig-niﬁcantly decreasedinthe dimeticonegroup(p<0.001),but not in the KMnO4-petroleum jelly group. The little effect

observedafterbathingthefootinKMnO4 wasattributedto

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liquidandmayhavepartiallysealedtheabdominalconewhen KMnO4haddied.

The finding that the local inflammation rapidly disap-peared when the parasite had died in situ showed that inflammationiscausallyrelatedtothepresenceofaviable parasite. In practice, this means that there is no need to surgicallyremoveembeddedparasitesaftertreatmentwith NYDA®: the deadparasites are eliminatedbynatural skin repairmechanismwithoutdelay(H.Feldmeier,unpublished observation,2016).

In astudy in rural Uganda, the efﬁcacy oftwo distinct modesofapplicationofNYDA® werecompared:onetargeted applicationtotheareawheretheparasiteprotrudesthrough theskinandonecomprehensiveapplicationtothewholefoot, identical tothe oneused inthe proof-of-principle-study.26

Wholefoottreatmentmeantthatdimeticonewasappliedto theskinofthefootuptotheankle.Targetedtreatmentmeant that dimeticonewas aspired into a 5-mLsyringe towhich aﬂexible tube was mounted.Three drops were applied to theareawheretheparasite’srearabdominalconeprotruded throughtheskin. Onedropcorrespondedtoapproximately 50␮Lofdimeticone.Thisprocedurewasrepeatedthreetimes within10mintoensurethatamaximumamountof dimeti-coneentered the rear abdominalcone ofthe parasite and sealedit.

Atthefirstfollow-up,twodaysaftertreatment,thenumber ofviableparasitesdecreasedsignificantlyinbothgroups.The lossofviabilitywashigherinthetargetedtreatmentgroup (p<0.001).Atthesecondfollow-up,afterfivedays,thelossof viabilitywasstillhigherinthetargetedtreatmentgroup com-paredtothewholefoottreatmentgroup(p<0.02).Afterseven days,thereductionofthenumberofviablesandfleaswas similarinbothgroups:95%(95%CI92–99%)oftheparasitesin thewholefoottreatmentgrouphadlostallsignsofviability and97%(95%CI94–99%)inthetargetedtreatmentgroup.The authorsconcludedthatthetargetedapplicationkilled embed-dedsand fleas morerapidly compared towhen the whole footwascovered.Besides,substantiallylessdimeticonewas needed.26

In a case series of patients with very severe tungiasis in Vaupés Department, Colombia, five patients being in a life-threateningconditionwereidentifiedinAmerindian com-munities.All patientsshowedhundreds(uptoathousand) embedded sand fleas and presented ectopic localizations ofembedded sand fleas suchas at the ankles, the knees, the elbows,the fingersand around the anus.Atthe soles, embedded sand fleas were laying in multiple layers on top of each other.10 _All _affected _body _areas _with

embed-ded sand ﬂeas were intensely wetted with NYDA® and treatment was repeated after 12–24h. All patients recov-ered rapidly. After three to four days, inﬂammation of the skin had regressed considerably, and patients could place their feet on the ground without feeling pain. After one week all lesions had developed into crusts and heal-ing of the skin had started.10 No adverse events were observed.10

Animportant ﬁnding ofthe three studies was that the fewparasiteswhichremainedviabledidnotexpeleggs.This suggeststhatasystematicapplicationofNYDA® onthe com-munitylevelmayresultinatotaldisruptionoftheoff-host

cycle–providedthatthereisnoanimalreservoirinvolvedin maintenanceofthecycle.

Takentogetherthethreestudiesprovideevidencethat: • NYDA® killsup to97% ofembeddedsandﬂeas within5

days;

• Atargetedapplicationactsmorerapidlythanwettingthe wholefoot andneeds considerablyless dimeticone.This makesthetargetedapplicationmorecost-effectiveif the totalnumberoflesionsis<40orifpenetratedsandﬂeasare locatedinclusters;

• NYDA® is effective in infections with several hundred embeddedsandﬂeassituatedinexcessivehyper-keratotic skinandlocatedontopofeachother.Inthesecases,the affectedskinhastobewettedintensivelyandrepeatedly withNYDA®.

Otherectoparasites

During a study on scabies in indigenous communities in the Amazon lowlandofColombia,several individuals were identiﬁedhavingmyiasiscausedbyDermatobiahominis.The infectionwassuccessfullytreatedbythetopicalapplication ofNYDA® (HollmanMiller,unpublishedobservation,2018).

Safety

of

dimeticones

Generalaspects

Dimeticonesarewidelyusedincosmeticsandindustrialfood preparation.Dimeticonesareusedinurology,ophthalmology anddermatology.27_In_the_European_Union_(EU),_high-viscous

dimeticonesareapprovedasantifoamingfoodadditive‘E900’ atamaximumlevelof10mg/kginsolidfoodstuffsand10mg/L inliquids.Theacceptabledailyintakeis1.5mg/kgof body-weight.

NYDA® isaCEmarkedclassIIamedicaldeviceregistered fortreatmentofectoparasites.NYDA® fallsinEUregulatory classIIaaccordingtoRule4,AnnexIXoftheCouncil Direc-tive93/42/EECof14June1993concerningmedicaldevices,as amendedbyDirective2007/47/EC.NYDA® isavailableonthe marketsince2006.19

High-viscousdimeticones

High-viscous dimeticones are of well-established use in humansregardingtopicalandoraladministration(suchasin cosmeticsanddrugs,particularlyindrugstotreatﬂatulence) indosesexceedinglargerthanthoseappliedinNYDA® forthe treatmentofpediculosiscapitis.

In2011,theEuropeanCentreforEcotoxicologyand Toxicol-ogyofChemicalsJointAssessmentofCommodityChemicals (JACC)27 _concluded _that _humans _may _be _exposed _to

high-viscousdimeticonesviaoralordermalcontactwithoutany healthrisk(IASONConsulting,2016,unpublisheddocument). Inlaboratoryanimals,thesubstancesshowedalowpotential forabsorptionbytheseroutes.Sincedimeticonesare metabol-ically inert, following ingestion, they are rapidly excreted unchangedinthefeces.27

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Inrabbits,noteratogeniceffectswerefoundafter implan-tation as well as after oral administration. None of the reproductiveand developmental toxicitystudiesperformed using rats and rabbits gaveevidence ofany adverse effect ofhigh-viscous dimeticones on fertility, gestation,peri- or post-natal development after oral, dermal or implantation exposure.27

Insummary,animal studydataaswellasclinical expe-rienceinhumansshowedthathigh-viscousdimeticonesare highlyunlikelytobeabsorbedatsigniﬁcantamountsbythe humanbodyirrespectiveoftherouteofapplication(dermal, oral,inhalation).Theriskofembryotoxicity,fetotoxicity, ter-atogenicity,oranysystemictoxicityinthefetus,breast-fed babyorchildren≤2yearsofageisjudgedasvirtually non-existent(IASONConsulting,2016,unpublisheddocument).

Takentogether,fromthetoxicologicalpointofview,there arenoobjectionstousehigh-viscousdimeticonesforthe topi-caltreatmentofectoparasitesinpregnantorlactatingwomen aswellasinchildren≤2yearsofage(IASONConsulting,2016, unpublisheddocument).

Low-viscousdimeticones

Low-viscousdimeticonesarehighlyvolatilesubstancesthat are potentially absorbed afterinhalationbut pass the skin onlyatlowamounts.Animaltoxicitydataonthelow-viscous dimeticonesoctamethyltrisiloxane,decamethyltetrasiloxane and hexadimethylsiloxane revealed no evidence of any detrimental effect on reproductive or developmental per-formance up to the highest doses tested after inhalation exposure (IASON Consulting, 2016, unpublished). As these low-viscousdimeticones aretransferredinto humanbreast milkonly at trace amounts, the risk of adverse effects to thebreast-fedbabycanalsobeconsiderednegligiblylow.A toxicologicalreview concludedthat the risk of embryotox-icity, fetotoxicity,teratogenicity,orany systemictoxicity in the fetus, breast-fedbaby or children≤2 years ofage can bejudgedasverylow(IASONConsulting,2016,unpublished document).

Inﬂammability

Since dimeticones contain oxygen, they are potentially inflammable. Their inflammability depends on the chain length of the molecule. Dimeticones with a short chain, havealowviscosityand ahighvolatilityandthereforeare inflammableatratherlowtemperatures.Incontrast, dimeti-coneswithmediumtolongchainarenotvolatileandneed hightemperaturestogetignited.

Experiments performed under standardized conditions showedthathumanhairimpregnatedwithNYDA® cannot beeasilyignitedbutneedsadirectcontacttoanakedflame. AssumingthatscalphaircoveredwithNYDA® mightfunction asawickenhancingtheinflammability,andfurthermorehair increasesthesurfaceincontactwithoxygen,therisktocatch fireonhumanskinwasconsideredverylow.Nonetheless,it isrecommendedbytheproducerthataftertopicaltreatment withNYDA® directcontacttonakedflamesisavoidedfor2h (Pohl-Boskamp,unpublisheddocument,2012).

Clinicalstudies

SafetyofNYDA® inthetreatmentofheadliceinfestation

Arandomizedcontrolledtrialinchildrenwithheadlice infes-tationsshowedthatNYDA® canbeconsideredasverysafe. ExceptintwocasesinwhichNYDA® accidentallycamein touchwiththeeyeandresultedinatemporaryirritationof theconjunctiva,noadverseeventsoccurred.23

SafetyofNYDA® inthetreatmentoftungiasis

In contrast to ectoparasites such as lice and other siphonaptera species, sand fleas are embedded almost completely in the epidermis. To determine whether topi-cally applied dimeticone can penetrate into the skin next toa lesion,aseriesofexperiments wasperformedin nat-urally infected pigs in rural Uganda (Mutebi et al., 2018, unpublished). Five drops of NYDA® were applied on the rear abdominal cone of the embedded sand fleas on the digitsofthepigs.Aftertreatment,embeddedsandfleaswere surgically removed and were examined using a handheld light microscope to establish if the dimeticone had crept betweenthecuticleoftheparasiteandthehosttissues.After treatmentwithNYDA® nodimeticonewasdetectedonthe outersurfaceoftheembeddedsandfleasandintheadjacent host tissue. The outer surface of the intersegmental skin remainedwhitishasitisnormallythecase.

Intworandomizedcontrolledtrialswithatotalof106 par-ticipants,notasingleadverseeventwasobserved,evenwhen thewholefootwasrepeatedlycoveredwithNYDA®.15,26

More-over,patientslikedtheapplicationofthedimeticone,because itsoftenedroughanddryskinandgaveitanappealingshine.15

Discussion

Dimeticonesarepolymersiliconeoilsandhaveapure phys-ical mode of action on ectoparasites. Due to the physical modeofactiondevelopmentofresistanceishighlyunlikely. Althoughwedonotrestrictthedocumentsanalyzedbystudy population, type ofintervention, outcome measures, dura-tionoffollow-upandlanguage,wefoundalimitednumber ofpublicationsandgrayliteratureonefﬁcacy andsafetyof dimeticonesforthetreatmentofparasiticskindiseasesinour search.However,withtheavailableevidence,wecanconclude thatdimeticonesareverysafemoleculesandcanbeused top-icallyeveninsmallchildrenandpregnantwomen.NYDA®, amixtureoftwodimeticoneswithadifferentviscosityand volatility,hasbeenshowntobeeffectiveinpediculosiscapitis, pediculosispubis,tungiasis,andmyiasis.

Dimeticones are promising tools for the treatment of parasites residing on top or inside the skin, provided the dimeticoneisabletotargettheAchillesheelofthe respec-tiveparasite,suchastherespiratorytractinliceandtherear abdominalconeinsandﬂeas.

Tungiasis,likeotherparasiticskindiseases,continuesto affect the quality of life of many people, especially those fromruralareas,withlimitedaccesstohealthservicesand lowincome.Thedevelopmentofresearchonprevalence, dis-easeburden,complicationsassociatedwithhighinfestation andbadtherapeuticpracticesinthecommunity,toxicityor

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adverse effects when dimeticones and NYDA are used on bleedingskinorskinthathaslacerationsaswellasthe devel-opmentofnewtreatmentsandtheevaluationoftheefﬁcacy andsafetyofthosealreadyavailable,isawayof contribut-ingtothereductionofunfairinequalitiesinhealththatexist betweenthesepopulationsandthemajoritysocieties. There-fore, their study and dissemination ofthe resultsthrough scientiﬁcpublicationsshouldbepartoftheresearchand pub-lichealthagendasofthegovernmentsofendemiccountries andcollaboratingcenters.

Conﬂicts

of

interest

Theauthorsdeclarenoconﬂictsofinterest.

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