WORLD HEALTHORGANIZATION

oRGANISAT|ON MONDTALE

DE LA SANTE

I,l

Onchocerciasis control Prograrnme in the vorta River Basin Area

Epidemiological Eval-uation UnitElorking Paper OCP/DPI/7] .11

P. KR.Aiiiffi.

PBESMfT STATUS OF DRUG TRI,Afl/trI]IT OF oNCHoCIRCIASIS

Paper presented. to the ttTqrkshop on onchocerciasis* of thelTest Africarr Coll-ege of Physicians, Accra, Ghana, JuW 77

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The present paper has been written to revlew the present status anrl possibiti-ties of drrrg treatment of onchocerciasis.

The possible objectives of chemotheratry are as follows

- To enhance -bhe results of vector control and contribute to their stabilization.It would probably be inappropriate to talk abor-rt the possibility of shortening vectorcontrol operati-ons, except if eradication of the d.isease is considered feasible.There seems to be, however, general agreanent, that only control of the clisease canbe reasonab\r envisaged. In this case, some sort of vector control will have to be

continued for a long timee and. nass treatment could be used as arr additional stabili-zing factor, lf available.

- The second objective is to red.uce the da4ger of the d.evelopment of onchocercalblindness and severe clinical di-sease in people already heavi\y infected. TreatmentwiLl- have to be selective j.rr this case. It should be made clear, that anti-parasiticactivity is not to be confourrded \,rrith curative effect on eye lesions. l{i1l severeeye leslons improve, when transrnission is cut dovne ? Tii1l they come to a stalrlstill ?

'''/iII they continue to develop on their oya'l account, once initiated, even if theparasite is eliminated by appropriate treatnent ? little is hlown about thesequesti-ons" [wo d.iffer.ent situations may be envi-saged :

- if tranmission is highly reduced or interrupted., even parnial elj-ninatj-on of adultparasi-tes may have a beneflcial effect by cutting off tlre supply of microfilariaeand the danger to the eye may be considerably lessened.. On the other har:d, a.r1y

benefj-ciaI effect of treatment on eye lesion is more likely to be detected andmeasurable l.f no superinfection occurs as in most parts of ocp.

- if transmissj-on contirrues at a sizeable level, all that can be gained eventual\ris a d.elay i-n the onset of blindness or severe eye resions.

An additional objective of dnrg d.evelopment is the availability of a dzug forchemoprophylaxj-s.

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The requilements which relate to these different objectives are not necessarilyidentical. A drug that could be used as afl adjunct to vector control should be abl-e

to b::ilg about parasitological crlre. .Ioxicitl, and tend.ency to reactions should be

very low.

A drug used il ttr.e prevention of onchocercal blindness in infected people shoul6be able to brlng the infectj-on dolrrn to a Iow leye1 not dangerous for the eye. On

the other hand, it should have a proven effect as far as the preventj-on of chalgefrom reversible to irreversibte eye lesi-ons and aggravation of existlng irreversiblelesi-ons is concerned.

$y3amin

Suramin is produced. and nnarketed under a variety of commercj-a} nanes :

Ge:mani:r, Bayer 2O5t Antrypol, Belgaryl, Fourneau lO9, Naganin, Na8anol azrd SoditmNaphuride. Synthetised in 1916, j-t has been large\r used as a Trypanocid.e since1920, and. was first used against Onchocerciasis by van Hoof and coll. (1g+7 ) in whatwas then the Belgian Congo.

Suramin i-s a white powder slow\y dissolving in water. It is accrmul-ated in thubod.y, bound to plasma proteins of al-I kind.s and finally sIow1y etjmj_nated via thekidneys as an intact molecule. By histological rnethod.s it can be shoum, that it istaken u-p as granules by ce11s of the reticuloenclothelial system and by the eptheliimof the proximal convoluted tubules of the kidneys. Suramin may destroy or inhibitma4y different enzJrmes. Its acti-on upon enzymes concerned with DNA metabolim maybe the basis of its anti-parasiti-c action. It is ]m.or,'m also to displace drr:gse e.g.chlorpromazLne or anti-coagulants, from their bind.ing sites. As a result of itsaction upon enzJnnes, it also interferes with complemcnt formation and blood clotti-ng.

Toxicity in Man

Irnmediate reactions may be :

a) Nausea and sometimes vomiting, which can be targely avoided by givi-ng theintravznous injection yery slowly.

b) Collapse with loss of consciousness, shock and profu.se sweating. fhis is bestavoided by giving a test d.ose of 0.1 - 0.2g. in the first instance"

-1-late reactions after 3-24 ltours inclurlc the occurrence of fever, photophobia r.nd

lachrymatlon sometimes with palpebral oedema, abd.omj-nal distension arrd constipation,and cutaneous hyperaesthesia of paLns a.:rd so1es. The phenonenon may be followed by

desquarnat j-on.

T)a ed. late reacti-ons concern an irri_tation of kidneys. The urj-ne should be testcd.for albominurla before each injection of Suramin. A sh-ght cl-oud may be due to inhi-bition of reabsorption of alburnin rather than to irritation of the kidneys. If, how-ever albuminlrria becomes irnportant, casts and,/or red blood cells appear, the treatmentshould be witheld. Polyuria and thirst have also been observed and attributed tokidney irritation.

Other delayed late reactions include ercfoliative dermatitis, stomatitis, jar.mdice,chronic diarrhoea and severe prostration. Ihey seem to be more cornmon among people,who live on a starvati_on diet.

In addition to trr-re toxic reactions, there may be allergic reaetions due to thed.eath of adult wonns or microfilariae. fhese include: urticaria, swelling or tender-ness around adult wonnsi

- itchjJigl swelling, skin inflammation errd papular or vesicular eruptions, r,rhi.ch maybe fol-Iowed W desquamation (due to rleath of rnicrofilariae). Sometjmes painfuljmmobilization of the hip joint or d eep abscess formatlon betweerr muscfe layers az'eobserved. Both are attributed to inflammatory reactions arourrd dying 1/ozrns. Suraminhas been incrjmilated in the causation of adrenal gland lesi-ons and atroplgr aftertreatment with high doses for pemphigusr .As adrenal insufficiency has also beenreported j-n ur:.treated cases of pemphigus, and no reports have been published en simi-lar lesions after treatment for trypanosomi-asis and onchocerciasis, it is not 1ikelythat adrenal damage constitutes a serious rlsk during treatment for onchocerciasis

Action on tr'i-lariae

ltr&len cotton rots irtfected nrith litosomoicles cari-n-ii are treated on five succes-sive days, with 4o@W se., aII adult worrtrs were kilIed, but this occirued. on\y aftera delay of 4 - 5 weeks (r,Anrn1er a1d others, 1971).

In onchocerciasj-s patients treated with the usual d.osa6e of 1g/week, the lvo11ns

begin to die after the fourth or fifth dose. The females are the first to be ki1led;males live longer possib\y because of their l-ess active metabolim.; Apparent\y aplasna concentration of 1o@1oo nI for at least two weeks i-s required to ensure thedeath of all the adult fen"rle woflns (lr_rtu 1968 d)"

Suramin has a certain, but l-jmitcd effect on microfilariae , apart from cutti:rgoff the source of replenj-shment by killing the adult woilns. l,[ost of them, however,

seem to remain alive after treatment and may not di-sappear llntit the end of theirnatural life-span.

Suramin has also a pronounced actiop ep imm3ture worms developing from infectiveIarv:re, if it is given after the ir:fection occurred auad in sufficient dosage ( lut<e

1974 ). It does not seem to be effective if given beforc the infection (I5:nmler &

Ilerzog, 1974).

Dgs_?&e. The usually recormnend.ed dosage for onchocerciasis treatment is 5 - 69 for an

adu1t, corresponding to O.1ilkg. The injections should be gi-ven a.t weekJy intervals.A test d.ose of 0.1 - 0.2g shoukl be given before the full- cor.r-rse to exclude c^n idiogrn-crasy. The solution should be fresh\r preparcd, given slowly c:rd the patient be keptund.er obseryati-on for 24 hor;rs after each injecti_on.

Diet[y]carbemazi:re

Diethylcarbamazine is a derivatlve of piperazine and was discovered by Hewittet 4. in 1947. It is marketed rmder a variety of comrncrcial narnes: Hetrazan, Not6zine,Supatoni:r, Coricide, Carbilazine, Banocide ar:d R,P,3799. Ylhcn dosages are given j11

the literature, these ma;r refer to a specific salt or thc base; usually it can be

assr.aned. that they refer to the cltrate, lrnless otherr-ise stated. This is a rvhitepowder freely soluble in water. It is lrery stable even to autoclaving.

A certain number of d.erivatives of the same baslc molecule have also shorm anti-filarial activlty, but none has so far been i-ntroduced in clinical medicine.

Diethylcarbamazine is rapidly absorbed and metabolised.. The wrchanged drug and

metabolites are excreted mainly by the kld.neys. The pharmacologica.l action of Diet}lyl-carbarnazine is not very u.arked. The on\y effects of clinical value that may occurafter the usual doses are head.ache, sleepiless and. vomiting lvhich may be ascribed toits acti-on on the eentral nervous system errd the stomach. I will not go into detail-sof its anti-inf1amm,atory action, as thj-s aspect is not yet sufficiently r.:nderstood.let us mention only that DEC iras some blacking action on maqy anaphylaetic reactions.Two consequences of i-nterest are the (partial) suppression of skin reactions to fil-arialantigen in patients treated with Diethylcarbamazine and. second\r, its palliative effecton bronchial asthma"

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Action on microfilariae

If diethylcarba-m.azine is injectecl intravenously in people infected with!nI. barrcncfti, BOt'j of the microfil-criae disappear in one minute (i{awking, (iSfo)rcitedafter Havrking ?glA). on the other hard, large doses do not eliminate then completely.A possible explanation is a continuecl supply from outside the circulation, not attaina-b1e by DEC. fn onchocerciasis, this may happen with microfil-ariae fro,l inside thenodules, which are not affected by DEC. Alternative\y the survivirig microfilariae maybe biologically or irornirnologically different.

In contrast with its rapid and powerf\rl action in v-ivo, Diethylcarbamazine ]rasno effect on microfilariae in v-itro. Its mode of action secms to be based on re.movalor destruction of the srl:face coat of microfilariae, thus exposing antigens to anti-bodies circula.ting in the pls,srna. The antigen - antibody - complcx would then attracteosinophils and i:ther phagoceytes and the microfilariae be destroyed (Havukisg 19T6).

I'tobilization of microfilariae

fn the early days of Diethylcarbamazine t::catment,liic"zzotti (1949) worlcing inliiexico, ci-ted after Hawking (lWe) foi;rr.', that after DEC, microfilariae appear moreoften and. in grea"tcr numbers in the urine than normaUy. This findirg he."s beenconfirmed by several other workers over thc last years" likei,riise, it has been esta-bllshed that microfilariae are more commonly foru:cl in the b1ood., the cerebrospinalfluid (lut<e, vincelette and }[oore 1975), the cornea (Anderson and tr\rglsang t 9-fi), tneepidermis (Rougemont 1974), tt e Sputr.rn. ir4obih-zation of nicrofilaricre iirto the cere-brospinal fluid may be clangerous, if they are in excess of J mf/mI, a,:rd provoke Derro-Iogicr."I qrmptoms.

fn bancroftian filariasis, rnobilizatior- of microfilariae mry lead to theirapDeararlcc in the peripheral circulation during the day. This is in contrast with therapicl elimination of mi-crofil-ariae from tl:e circulation when DEC is given at night,The effect has been used to avoid the need of ni5ht bl-ood sul'veys, if on\y a crudeestimation of prevalence is needcd.

Action of Diethylcarbamazine on adul-i; filarie"l \vonns

ffl:ereas t]re adult wofllls of T,oa Ioa, ',Juchereria bsncrofti, Bnrgia i\1ia1ayi and

Dipetalonena streptocerca are kl}led by Dr-r-C, there is no cffect on adult O. volvulusartd perhaps on\y a partial or sterilisiug effect on D,_Ieretar.s. I* onchocerciasispati-eirts treated with DEC a1one, a nerv bu:i-Id-up of microfilarial- charges begilsj:umecliately after treatment.

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The possibility of prophylactic activ-ity of DEC against Onchocerca was j:rvesti-gated. by Duke (tSOe) fu chiropazees ard 2 human voli.urteers, but no such effect cou1d.

be found, in contrast to lvhat has been fourid il loa loa and Brugia malayi.

Reactions to DEC in Onchocerciasis patients

The regularity of a specific reaction of onchocerciasis patients to DEC j-s so

great that it has been usrrrr. as a diagnostic test - the i{Ic.zzotti reaction. It isobv-iously due to the rapid destruction of microfilariae. fl:e first signs - itching -may appear after 15-10 mirrutes. later there rray be swelling and pr.rffiness of the skinrnost prominent around the pelv-ic girdle, rvhere microfil-:riae are usually most abwidant.A fine rash, hyperpyrexia, tacl5rcardia, headachc, glarrdular enlargeurent niay also occur.fhesc signs ancl qnnptoms may persist far up to one v'reek arid then subside after lvhichhigher doses are usually toleratecl. The severity of the reaction scems to be more

proportional to the intensity of infection, than to the i:titial dose.

In hi-gh1y infectecr- patients particulerly in the Y/est African savarr::ah zone, thereaction may be dangerous. tr\rglsarrg and Anderson (t974) reported severe prostration,wrconsciousness and respira,tory clistrcss after 50ng given to heaviJy infected patients.Rougemont et al-. treated 2!O persons in l,liali with d.o,ses of 25mg twice daiJy rising to200mg. Thirty-six hours after the fi-rst d.ose, 20 people tr/ere prostratcd., some of thensemi-conscious, polypnoic and. shocked. Under treatmer:t v'rith Metl:ylprednisolone,holvever, they improvecl in a few hours.

Various drugse malnly a:rtj-histaninics and corticosteroids have been used todanp dovrrn the reaction, Anderson and trL61sang (t975) reconmencled Betarnethasone givenprophylactically, if scvere reacti-ons are to be expected.

Patients in bad general health shor-r.Id probably be

Oonen (1959) reported a fevr d.eaths after DIJC treatnent.had been in a poor condition.

excluded fron treatment.In all cascs, thc patients

Dosage

Hujinaki (tgle), cited e"fter Hawking (Ole) rvorking with ,{. bancrofti, based his1'gs6rrmsnclations on the rel:.tion betwcen doses ancl blood levels strovrn to bc effective.He reconroended 6ng/Waay divided into six tLoses, for two vreeks. Anderson and

Rrglsang (WA) grrve 5Omg citrcte twice on the first day, lOOmg twice on the second.

day a:rd 200mg twice thereafter for ten days. For persons,mder 4O\g dosa.ges vrould

have to be reducecl according to viej-ght. The progresslon of dosage during the firstdays may also have to be handled indj-vi-dua1\y acco::ding to reactions.

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For mass treatment in onchocerciasis, DEC i,s not considcred as appropriate,because of j-ts severe reir.ctions (see above) in patients heavily infected who are most

i-n need. of treatment, and because of its inabillty to kil-l the adult worrns.

In indiviclual patients its ric,in incl.ica.tions are :

1) Treatr:ent of sone acu-be onchocerciasis rnarrifestaitions on thc eye, probablyin conjwrction with the excision of at least aII head nodules if prescnt,

e) fo cl-iminatc the rrricrofilariae, before Suran:.in is given, -bo avoid the sj-de

reactions due to the slor,v cleath of microfilcrj-ae.

The effects of treatment vri_th Suranin and Diethy lcarbamazine on ocular Onchocerciasis

No obserwations are available on the possibilities of prevention of onchocercelbhrliness by treatment of grorlps at risk. Ilowever, Anderson, trbglsa.ng nnd liarshall(lgle) reported. the result. of treatment wittr Suramin and D]jC on ocular oncl:ocerciasisafter an interval of 1-2 years. In the DEC tr!a.-I-, they compared 18 patients receivjnga 1o-1 4days course with a second. group of 21 r,-rrhich vuas given week\r suppresive d-ose

of 1OO-2O0mg after the j:ritial course. A third group of 18 served as controls.

There were severe reactions to the initial DEC course, ocular reactions howevercould be controllcd by beta.:nethasone. The weekly supprcsi-ve d.ose vras not acceptableto the majority of patients in gz'oup 2, on the other har:d arry long term beneficialeffect **s glmost confined to this group, Only '1 patient whose severe iritis hadimproved. during the initial course, could be persuad.ed to terkc -bhe tablets over tvroyeaJs. fhe improvenent concernccl. lc;sions of the anterior segment onlyr posteri-orsegnent lesions were not affcctecl. The observation period was cer-tain\y too short tostate about a possiblc arrest of furthcr development of eye lesions"

In the Suranin tritlr J9 patients (group A) with ocular onchocercj-asis rvcregiven 4-69 Suranin" A seconcl (grotp B) receivcd Sr-rarrrin fol-lowed by a 6-7 day courseof DEC. A third group recei"red_ only placebo injections.

Reactions to Sr-rrarnin werc sevcre. There lvere 1 case of stomatitis, 1 ofexfoliative clermatitis, sevcral of severe prostration, of v,ihj-ch 2 ended fatal1y.(z aeatns in 78 pa-tients trca.ted. vrith Suranin)" cha.nges in ocular lesions j:rch.rded

initiai aggravation of p'.inctate ancl sclcrosi-ng kerati-tj-s and anterior uveitj-s. Therewas also a possibility of arr advcrse effect on the optic disc. Thc authors commentthat it rlight have been bettcr to clininate the rnicrofilarJ-ae by DEC prior to Suraraj-n.

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After 5 months and thereafter, the cyes lverc generally quj-eter tharr beforetreatnent. Again, benefit of treatmcnt vras lilited to the anterior segrnent.

14 out of 27 lesions improved. in group A arrcl 19 out of 53 in group B. There rvas no

improvement in the control group.

It is evident frorc the forcgoing, tha.t importanb efforts vril1 he.ve to bc made

to a.rrive at the developrnent of more satj-sfiictory drugs. 1\,[y scopc r,vas to depict thepresent situation. In the tliseussion, this picture may be completed by other aspccts,particularJy cument efforts in drr.6 development.

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