Progress report of the OCT/macrofil chemotherapy project for 1991/92

WORLD HEALTH ORGANIZATION ORGAI{ISATION MONDIALE DE IJ SANTE ONCHOCERCIASIS CONTROL PROGRAMME IN WEST ATRICA PROGRAT{ME DE LtrIE CONTRE L'ONCHOCERCOSE EN AT".IQUE DE L'OUEST D(PERT ADVISORY COMMITTEE Thlrceenth Sesslon Ouagadougou. June 1992 ocP/EAC]j.6 ENGLISH ONLY PROGRESS REPORT OF T}IE OCTAACROFIL CHEI{OTHERAPY PROJECT FOR 1991/92 SU},TMARY I. Cllnlcal data fron trlals of the Clba Gelgy conpound A.nocarzlne (CGp 6140)belng prepared for subnlsslon to the Srisi-Reglstratlon Authorlty, andcllnlcal crlals agalnst onchocerclasle ln Wesc Afrlca wlll reco*irer,c" or,".efflcacy and safety of the drug ls denonsErated. 2' Ivernectln/Albendazole conblnatlons do noE seetr to show macrofllarlcldal or Pertranenc sterlllzlng effects on Onchocerca fenales, but ftnal analyses are awalted. , are the a a4 A potenclal cllnlcal trlals centre ln Enugu, Nlgerla, wlth assoclatedlaboratorles for pharmacoklnetlc studles.-has bien ldenrlfted. Precllnical work on tl,o potentlally rnacrofllarlcldal drugs, cGI 1g041 and UMF078 conclnues, and phase r trlals nay be lntclared Ln 1992 and 1993respectlvely. Concracc laboratorles for eeveral espects of precllnlca1 developmenE urork havebeen ldenrlfled, and wlll begln work ln 1992. Legal atreemencs rrtch a further chree lnternatlonal pharmaceut,ical companiesfor supply of compounds have been concluded slnce tht lasu EAC meeting. Improvenencs co screenlng centres and screenlng pachuays contlnue co beimplenented. o. ochengl ln cattle has been lniroduced as a neu screening 1od-el, and early reslmthesls of actlve conpounds for screenlng agalnstonchocerca soo ln cattle u111 be a naJor ollectlve of pDDT actlvltles. A sclenclflc worklng grouP neetlng w111 be held ln July 1992 Eo coordlnate chework of chenlsts, pharrnacologlscs and blologlscs lnvolved in the MacrofilProJ ec r . Furcher research proJects to ldentlfy new potenclal pharmacologlcal tartecsfor chemocherapeuclc attack w111 be iougtrc, tncludlni those ,riirr"rr,g .[" nemat,ode Caenorhabdltls elegans. Speciflc studles on Ehe posslblllcy of detecclng lvermectLn reslstance inonchocerclasis are descrlbed, uslni technique" Jf alr.ct biologlcal assay, and 5. 6. ?. 8. 9. 10. 1o/o4t/gz ocP/EAClr.5 -2- of "probes" based on rnolecular blology technology. 11. An lncreased budget for the Macrofll ProJect has been prepared based on the reconmendaELons of EAC and JPC tn 1991, and subrnltted to the CSA and DirecEor OCP for conslderaclon. CT'RRENT STAI'T'S OF MACROFIIARICIDE DEVEI.OPI{ENT 1. Comoounds tn cllnlcal crlals 1.1 Amoearzlne (CGP 6140) - Clba Gele.v A sunmary of the cllnlcal efflcacy and toterablllty of the nacrofilaricldal drug Amocarzlne (CGP 6140) ln onchocerclasLs has been publlshed ln the form of a supplenent to the sclentlfLc Journal Troplcal Medlclne and Parasltology (VoI. 43,Part 3. Supplenent. 157-318). Ttre daca fron these cllnlca1 trlels ln Lacln Amerlca(carrled out by CIba Gelgy), and ln West Afrlca (by OCT), ere currencly beLng collated and analysed by Ciba Gelgy statlstlclans, prlor Eo thelr submlsslon to che Swlss Regulatory Authorlcy (IKS). Ttre conpany and Macrofll are collaboratlng fully on thls subnisslon. A protocol for further cllnlcal trlals of Amocarzlne ln West Afrlca has been prepared, and such trlals w111 be carrled out as soon as the Macrofll, and IJIIO ethlcal conmlttees are satlsfled that the cornpound nay be safely adolnlstered, and the opEltral dose reglmen ls esuabllshed. IE ls hoped the regulatory subnlsslon by Clba Gelgy wtll take place, as planned, durlng L992. 1.2 Comblnatlon therapy : Ivermectln plus Albendazole Cllnical studles on onchocerciasls patlents at the OCRC, Hohoe Hospltal, Ghana, uslng a slngle l5O yg/kg dose of lvermeccln followed one week later by 3 consecutlve days of Ereatment wlth 800 ng/kg of Albendazole, have shown thaE any adverse effects fron the comblnatlon therapy are no greater than those seen with lvermecEin alone. Although flnal analysls of the effects on rrdult lrorms ls noc yet avallable, long-tern trlcrofllarlal counts ln the skln of treated patlenEs lndicace that chere has been lltcle effect on the nlcrofllarial productlon from adult female uorms.A pharma.cokinetio study on the lnteractlon of the two drugs ls nearing comple tion. 1.3 High dose lverurectln treacnents A recenE report fron Letln Amerlca (Duke, B.O.L. et aI. An. J. Trop. Med. Hyg. 43 (6) 657 (1990)) concluded that the scandard dose of lvermectln (150 Fe/kil glven monthly, for one year, to onchocerclasls patlents "nay have a slow actfon of actrltlon only on a certaln group of worms whlch are potenttally susceptlble, perhaps because of lncreased age". However, "lvernectln dld not show a clear-cut, unlversal nacrofllarlcidal effect, such es seen after adequate dosage wlth suramln'. A recent experlnent ln cattle lnfected wlth Onchocerca gibsoni has shown that a slngle oral dose of 5000 ltElkE kllled 45I of adulc female worms and 502 of rnale worns. These results takeri together suggesc that hlgh or repeated doses of lvermectln nlghc have some adultlcldal actlvlcy 1n onchocerclasls, ln addlrion ro the well establlshed nlcrofllaricldal actlon. Merck, Sharp and Dohme have recently allowed experlmental doses of 400 of ivermectin to be glven to llmphatlc fllarlasls patlents every two weeks 5-monch perlod, ln attetrpt to detronstrate Eacrofllarlcldal actlvlty againsc Wuchererta bancroftl. Pe/kefor a }cP/EACt1.6 -1- A protocol has therefore been submlcced to the cotrpany requestlng chaE doses of 400, 600 and 800;.rg/kg should be lnltLaced lnnedlately for onchocerciasis, while awatclng a flnal reiponse frou the cotrpany on hlgher dose levels. 1.4 Alternatlve cllrlca1 Erlals cenEres The OCRC at Hohoe, Ghana, has a flnlte llfetlne. Consequent upon control of dtsease transnlsslon by OCP actlvltles ln the southern areas of Ghana and Togo. Onchocerctasls paElents are addltlonally belng utlllsed co provlde adulc trorms forln vlcro cheootherepeutlc studles ( by noduleccony). Ttre pool of patlents suicablefor cllnlcal trlals of new nacrofllarlcldes ls therefore betng reduced yearly. A Pocenttal cllnlcal trlals slte has been evaluated et che College ofMedlclne, Unlverslty of Nlgerla, Enugu Campus. Patlents are available localIy, and a Protr"nine of lvetmecttn dlscrlbuclon has been conpleted. Ttre Onchocerclasii ProJecc Unlc, headed by Professor P.O. Okonkrro, ls based ln che Department ofPharmacology and Therapeuclcs, and has the capablllty to carry out, pharmacokinetic studies compleuentatT co cllnlcal studles on novel nacrofllaricldes. The group has recelved Research Screngchenlng and Tralnlng trants form TDR over several lears,and could be uclllsed alnost lnnedlacely for ihase II-III cllnlcal rrlals. Thisposslblllcy wl11 be acrlvely pursued by Hacrofll. 2. Comoounds ln orecltnlcal development 2.1 CGI 18041 - Clba Getsy clba Gelgy have almost conpleted the essentlal toxlcologlca1 studles on cGI18041, and flnal rePorcs are antlclpaced ln June Lgg2. prelimLnary lnformartonfrom che conPany Lndicaced that obsenred toxlclcy ln anlnals is slmllar co thacseen wich CGP 6140. - Efftcacy scudles carrted out by Macrofll laboratorles have lndtcared thacsingle oral doses of CGI 18041 are conplecely nacrofllarlcldal agalnsr model anlmallnfeccions of both onchocerclasls and lpphallc fll"rlasls in rodents, prlmaEes andcactle. Pharmacoklneclc scudles and drug necabollsn studles have been lnltlaced incollaboraclon tllch che company, as excenilve netabollsm of che parenc compoundoccurs. If an acceptable therapeuElc raclo ls posslble then phase r cllnical studiesin chen w111 be lnlclaced as soon as posslbie. ciba Gelgy have lndlcared rhar sucha decision can be-made ln August L992, and sultable cablEl formulatlons of che drugare belng prepared. Thls benzlnldazole derlvaclve has prevlously shown good naerofllaricidalaccivity agalnsc^Drugla oahanel ln dogs, both by rhe lnrlamuscular roure (UMF o7g)or orally (tuF 289). RecenE tests -y1:! rhe hydiochlorlde salr (uHF 289) given byche orar rouce, have shoun chac lndlvldual beagle dogs can ""ir"r selzures anddeach following doses of 200 r,B&E and above. Ttrls i"r.r" toxlclry (suscepribiricyEo setzure is a heredrcary tralc in beagre dogs) nay be due to: a) increased oral bloavallablllty of the trater-soluble hydrochlorlde salc; b) anaphylactlc shock due to low pH of the acldlc salt on release from thecapsule formulatlon. oqP/Ef.clr.6 -4- Furcher crlals ln dogs, prlmates and cattle w111 therefore await formulacion studles for presenEatlon by both the orat and lntramuscular routes, and of resulcs fron a pharmacokineclc study ln dogs to determlne conparative bioavailabiliry of the parent drug and lts salt following oral doslng. A furcher 0.. kg of UMF 078 ls belng synEhesised for these studies. Both the chenlcal structure and route of slmthesls of IJMF 078 are novel, and WllO is collaboratlng wlth the Unlverslty of Hlchlgan to parenr rhe compound. Flling of chls pacent ls lumlnent at che tine of wrlcing. Once the patenc ls flIed, Macrofll, ln collaboratlon wlth Ehe ProducE Development Unlc (PDU) of TDR w111 approach a posslble parEner ln rhe pharmaceutlcal lndustry Eo dlscuss Jolnt clevelopnenc of the compound. Depending uPon the results of these dlscusslons, FDU w111 asslst ln drawlng up a developmenrplan, hopefully wlth an lndustrlal parcner, but otherrrlse as a Jolnt OCP/TDRdevelopnent. Cllnlcal trlals of IJMF 078 are not anticLpated before 1993. 2.3 Contract laboratorles for greclinlcal developnent Precllnlcal requlrements, partlcularly wlth compound UMF 078 fron an academic laboratory, has emphaslsed Ehe need for the Macrofll ProJect to have access Eo laboratorles able to carry out precllnlcal work to standards accepcable to incernatlonal regulacory auLhorities. Since the lasc Macrofll Steerlng Commicree meeting, companles Ln thLs fleld have been evaluated and costs ascerEalned. At the March SC neetlng lt uas recorn'nended that laboratorles be contracted for chefollowlng work: (Costs per annum glven Ln parentheses. ) (us$129,300)(us$ 25,000) ( iv)(v)(vi ) (us$ 3,000) Ocher laboracory work w111 be contracted as the need arlses 3. DRUG SCREENING ACTIVITIES 3.1 Availabllity of test compounds. Novel conpounds for in vltro and ln vivo screenl.ng continue to be supplied by Ciba Geigy, Parke-Davls, lJaIEer Reed Arny Instltute, Naclonal Cancer Instituce, and ocher individual companies and chemLsts. Slnce the last EAC neeclng three further companies have slgned legal egreenenEs to supply conpounds for anclfilarlal cescing. These are wellcorne, Rh6ne Poulenc-Rorer and Ell Llrly. Posiclve negotiations contlnue wlch several other companles eg. Merck, Sharp and Dohme, Marion Merrell-Dow, Slmtex, Bayer eEc. As previously noted, legal aBreements for compound tesElng and subsequenE (i)(ii)(iii) Large scale chenlcal slmthesls Synthesls of radlolabelled conpounds Analytical laboratory to monltor quality of nacerlals Drug fornulation Genetlc toxicology Rabblt muscle lrrltancy tests ( (parentersl lnJections) ( ( us$?) us$ 22,500) us$ 46,000)( ocP/EACIr.6 -5- developnent take conslderable tlue and effort to negoclate, and Macrofll proposes,ln collaboratlon wlth PDU of TDR to engete a pert-tlue legal consulcant to undertake thls work. Ic ls antlclpated that the nrrober of conpounds tested u111 lncrease approxlnacely three fold ln the coolng year, and a contracc laboratory has been appolnced to score and shlp cest coDpotrnde to screenlng laboratortes, followlng recelpt frou suppllers. Support for one laboratorT utlllzlng the rodent uodel (Professor H. Zahner,Glessen, Germany) has been t"rilrr.t"d as a result of lotr productlvlty and larerePortlng. Ttrere ls cherefora a need to lncrease the racl of screening ln the cworemalnlng laboracorles, and thls w111 lnvolve tncreased expendlture for techntclansand anlnals at thoge cenCr6a. A eecondary rodent oodel wlth gkln and eye nacrofllarlae reeernbllng those inonchocerclasls (Honaneoa nartlnl ln Leunlsco"!" atrlatus) has been retalned forfurther exanlnatlon of drugc actlve er nacrofilarlcldes in other acreens. A new screenlng uodel uetng onghocerca ochengl ln cattle in Caneroon, hasproved useful ln allowlng sequentlal enalyefs of ttre superflclal nodules found lnthls lnfectlon. Resulte of tcgtlng etandird drugs tn tirtg nodel w111 be comfaredulth those already availablc frou O. slbsonl. It has been suggested Ghet the lntracellular parasltlc nenatode Trlchlnellasolralls ln ulce ulght foto e hlgh-throughput predictlve esaay for porentlal drugsln onchocerclasls. A feasrblllty ?tudy io-lnveerlgate rhls plssrblircy wlll beundercaken lf a laboratory can bL ldentlfled to evil.r"t" ",r"i, a resr syscem.3.3 Br.,g[. *.1":rl t r. ,ltro ..rtlr"clor for d*g ""...r1.g The TDR'Fllarlasls Progron-e recently funded a workshop to traln persons inthe Aslan reglon ln the rec-ntly reported-culcure of B. nalayi fron the L.r(vector) stage to adult torEs proaultng utcrofilarl""Gf,T ;;i;";;-=f3.",n. whenfully characterlsed, uould be l,real foi testlng potentlal nacrofllarlcldes, andresearch proposals ln thls area have been sougirc. 3.4 R""Jrr,th""l" for """o.d.ry ".d t"rti"r? ..1""r ""r"".1.g Professor Baker (unlveraltl of Tennessee) w111 contlnue co resyncheslse smallquantlEles of actlve conPounds for furcher tesclng ln rodencs and dogs. rn cheshort-cerE. Professor Townsend (unlverslty of Hlcf,tgan) wril syncheslse furtherquantltles of IIMF 078 for efflcaey studles ln doge ina-catrie,'ana inlclalfornulatlon studles. However, routine large gcale_s)mcheses to allowDore coopounds to be tesced inthe o' elbsonl or o. ochengl catclc uodels, and to prepare aiig" for precllnlcal '9fk, regulres the use of i contrect lebor"rory abre to "y"ii"!r"e Decerlels roGLPIGHP (Good Laboratory and l{anufacturlng Praltlces) stairdards. Such a laboracoryhas non been ldenrrfled ln the unrted staies of Arnerica. ocP/EAClr.5 6 3.5 Sclentlflc Worklng Group Meetlng of Chenlsts. oharaacologlscs and blologlcal screeners. (July 1992\ fhe PDDT and Hacrofll SC have dlscussed the optlnal pathways to be followed ln antlfllarlal screenlng, and the phatmacological assays needed to decertrlne drug levels, and thus nodify doslng schedules ln experlmental anlnals. Chenlsts have also been made aware of the potentlal drug targets ln fllarLal worms by publlcation of the findlngs of a prevlous Sctentlflc Worklng Group held ln L992. To lmprove lnteractlons between chese constlcuenE percs of the l{acrofll ProJect, and opElmlse lnterchange of naterlale and technlques, all actlve members of the proJects wlIl treet ln Geneva later ln 1992. 4. RESEARCH AREAS REOUIRING FI'RTHER DEVEI.OPMEMT 4.1 Inmunologlcal cechnlques to nonltor death or danage to adult fllarlal worms followlnq chemotheraov The TDR Frleriasig Innunology Sub-Group continues to develop trechods of lnnunodlagnosls of fllarlal lnfecctons, but at thls tlne no essay has been ldentlfied to quantltate nrrmbers of vlable adult worlns in onchocerclasis. Sera fron successful anlnal trlals of nacrofllarlcldes have been stored, and wl11 be nade avallable to collaboretlnt laboratorles. It has been suggested by the Macrofll SC that there nay be a need to flnance a laboratory able to develop sultable lnmunologlcal assays for use ln Macrofll studles. 4.2 Reslstance to lverreccln by Onchocerca volrnrlus Tno laboretorles have now conpleted work on blologlcal assays to determlne the sensitlvlty of O. volrmlus nlcrofllarl.ae to lvernectln IChavasse D.C. and DavLesJ.8., (1990). Trans. R. Soc. Trop. Med. Hyg., &707-8: Townson S. & Tagboto S.K.(f991) Trop. Med. Paraslt. 42 3L-7.1 Baslcally the experinencs lnvolve the shorc Eern .U-l4.gfg, lncubatlon of skln or uterlne nlcrofllarlae ln a dtlucion serles of lverneccln solutlons. Vlabl1lcy of treated mlcrofllarlae ls then determlned by thelr lnJectlon lnco the thorax of adult blackflles, and subsequent evaluatlon of nurubers of lnfectlve L3 larrrae whtch develop. The technlque can utlllze cryopresenred nlcrofllarlae and Slmullrrn spectes other than the normal vector. Basellne data on the lvermectln sensltlvlty of O. volrnrlus mlcrofllariae from sources ln West and CenEraI Afrlca and LaEln Amerlca have been obtalned. However,it would appeer that, as currenEly operated, the tests would not pick up low-levellv*nectln reslsEance, whlch ls the trost llkely to appear lnltlally. A potentlally nore sensltlve technlque ls belng explored by use of 1lvlng nenatode Caenorhabdltls elegans. Recent work on thls laboratory generated lnformatton on the posslble nechanlsn of actlon of lvernectln nenatodes, and on the genetlc basls for the lvermectln reslstance whlch lnduced ln thls organlsm. the free model has on has been Many slngle genes are able to mutete and glve rlse to differenc levels of reslstance ln C. elegans. Generally the leve1 of reslstance produced by a slngle mutatlon ls low (5-20x), but occaslonally nutatlon ln two recesslve genes produce hlgh levet reslstance (100x) ln wotms whlch rematn vlable. Ttre genes responslblefor lvernecttn reslstance are belng cloned, noc only fron C. elegans, but from Parasitlc tasErolntestlnel nenatodes and Onchocerca. Such genes or thefr products, w111 hopefully provlde dlagnostlc cests at the nolecular level to detect the appearance of reslstance. 6P/ELCtr.6 -l- Ttre Princlpel Investltrcor of thlr proJect. Dr C. Johnson, has recencly spenc roae Cluc ulth ProfGsaor J D F Hebbcua. ln Rotterdan, to dtscusg the posslblllty of uslng thc known lncldcncc of tvcrucctl,n rerlatancc tn C.-l9g13e and ln vecerlnary nGaltode3 ruch as Haenonchur. tn thc ONCHOSIH coEputor uodel. ln an attetrpt topredlct che probabtllty of lvcrucctln rcelstancc ln onchocerclasls. Ttrls proJecclt ln lts flrtt ycar, end ulll bc folloued rlth graat lntsregt. 4.3 usc of c. clccans ln devclooncnt of Eacrofllarlcldal drugs Ttrc ncoetodc E-S]$!Eg tr non onc of thc nogt luportent uodels of uodern ooleculer blology, tnd chc .ntlr. tcnoDs her now been cloned, and 70-80I of its nucleotlde scquGncc detcral.ncd. Ar fllerlal uor:us era elco neuatodeg. DNA probes end elmtheclc ollgonuclcoGidc rcgucncce frou C. clegans ero avallable to detect andclonc rclatcd rnolccules fron fllrrleo. Profc--oi Rl Honrltz. a lcadlng worker ln cho c- c198aFs flcld, has bccn eppotnccd to th. Hacrofll Stcartng counltcee, and anoffort ulll bc EsdG ro colhboreri ulrh thc uorkcrr tn thk fleld. 6-4 rtrcr.ascd reg.".ch to tdentlfy ootentral dru, t"rgats In addltlon co chc work on c. cleqans propored abovc, an advartlsetreng wlll beplaced ln thc Wllo and Proferrlonar socrccy il"ril"tt"r", and in research Journals,co scloulaca rGaaarch proporale on ldcntlilcarlon of phamaciroglcal r"ri"ii ro.PocenElal nacrofllarlcldes. HIS _quellcy proporalt. dlr"ct"d at pracrlcal drugdcvclopocnt, tre not belng rccelved et tlrc pr."er.t tlnc. Identlflcatton ofaPcctflc drug cergets ln edult fllerlee ulli ellotr drugt uhtch arc tnhlbltors ofthose^ttrtcts Go be sought frou pherorcGuclcrl coopanl-r. rnd tested for thetrrncl - fllarlal actlvlcy. ADI{INISTRATION AIID FINANCE 5.1 Increasc of budeet for Hacrofil actlvltlcs EAc, durtng lcs Tuelfth Scaelon tn 1991. rocounended that prlorlty be glven cotncreestng fundlng of the Hecroftl ProJect end endorged the suggesrlons uade by rheProJecc l{anagcr to accelGr8tc thc dnrjdevelopaent progra,De. Reprcscntactvcc et JPc-12 ln Rl.yedh eko auggasted an l.ncrease ln rhe budgecfor the l{acrofll ProJecc, and proporld Ghrt thG proJect Danatcr and SEeerlngcouoltccc should eubnlt e rcvlled-budgat ro cSA ior-concl.derftlon. csA-ai igreeaulch thls proposel, and edvtrcd thec in .srlErrlng addlrionii eunarng rhe-uitroftlProJect should bc gulded by thc vteur of thc EAc eg cxpreracd ln paragraph 12 ofthc rcport of irs 12ch Secllon. At 1t3 l{arch -Ecetlnt thc l{acrofll steerlng connlctoc 8pent conslderable clmeon Eh13 toplc, and e revircd budget her_bccn pre-pared along the llnes suggested,end subalttcd to Dlrcctor. ocP end thc CSA fol tirclr consticiatlon. co-devcloPEenG of UHF 078 lr,u bccn accepted by pDU. and wlrh che appolnrmenrof e staff ucnbcr to bc rcrponsl,blc for drug-ievelopoant in t:gg2. resourtes ln pDUulll be avellablc ro proEocl thfu proJcct. e rt has baen egrecd rrlth Dl.rcctor TDR, thet, as in lndustry, snall proJecctrouPs r,lll be scc uP slchln tJllo for lrHF ar78 and CGI 1g041 Go ensure rhac rheseproJects oalnteln DoEentu'r end nect developuent deadrlnes. ocP/F"rclr.6 -8- As noted ln Paragraph 3.1 above, l{acrofll ls also collaboratlng gich pDU ro speed uP PrePeratlon of legal agreenents relaced to patentlng and diug tesclng. 5 3 Annal ntment of onrt-Flna aonsul t.ent t6 aerelrl { e aamrrrr!'atlqaA Aot. basa far results of compound screenlne. Such an appolntnent has been proposed prevlously, but not vlgorously pursued.However, lt has non becoue lmposslble for the ProJ.ct uan"ger co supenrlse- the screenlng ecclvltles of tha PDDT ln addltlon to olher durlis. A JoL descrlpElon,end an adverEleeuant, w111 be prepared for the consultancy, and a candldateactlvely sought. Ttrere w111 be sone resource lnpllcatlon-s to thls appoLntment, wlth a requlreuent for addlclonal office spece and conputer hardsare ln Geneva. Ttre ProJect t{anater, freed fron some of thls rouclne ecclvlcy trlll nake norevtslts to encourage coEpound suppll.ers, and to concrecc laboratories, and will,cherefore, requlre sone addltlonal fundlng of duty cravel. 6. Aooendlces Aooendlx 1 - Research proJects currently funded by Hacrofll. Aooendlx 2 - current nembers of the Macrofil steerlng connlttee. APPENDIX 1 ocP/EACIr.6 -9 - RESFARCT] PRAJEofS CI]RRNWLY N]NDED BY M N997) 7 q,INICAL IRIETS ABIOSE, Professor A. t@ial Dired,or the Natjonal Ele Centre Ott E;press Bye-Pass P.M.B. 2267, IG,dr-tna lligerra "Fjel,d erra]uaEion of caryuterizd yjsual fisnd,ion tests for onchwrciasis"(RP: 970558) AAADZI, Dr K. Onchocercjasjs Ctremotherapy Resea:rch Centne (CE<C) Hohce Hospital P.O. tux 744 Hohre Gtpna "CJ.iniql trjaJ,s of drugs for onchoerciasjs,, (Rp: 85006) EDfiARDS, Dr G. De'pt of Phamacolary e 1herapeutics ?he ttrrjuersity of Livezpol P.O. tux 747 Live4nol, L69 3BX &rired x*@n "The effed, of albttdazole when canbind with irtezmerX.inin the treatment of onchoerciasis,, (Rp: B90J-0) 2. DR(rc SCREEV]'AG CMIIRES e. In Et-ro test systefls b znh a td-Nodt t -Inst i t ut e Aernhard-Nocht-Strasse 74 2000 Hanibum 4 @>areny "In vitro and in vivo dnsg tests of adr:J,t artd lantal O. volwslus and elea,ron microsapic stucy of dn:g effects,, (Rp: BB00G) As at 73.4.,92 Costs (USS) I 539 206 55s 26 780 111 250 Appentlix I ocP/EACIr.5 -10 - zUnilSry Dr S. QB International Institute of parasitology 395A Hatfield Road st .eln^r", Hefr,s AL4 1XU Erited x*@ "Erynrfuterztal denrrtherapy and screer:ing of dnsgs against ( 92 l4l) 'tdto ra in vitro and i-Wjgp,, (Rp: 89001) B. 7n rrirp test syste.rns @PflAN, Prcfessor D.B. Graduate SctrooJ, of TropiaL Veterinary Sciene Jazras Cook University of Nozth Queensland TovtnsviTTe, QLD 4877 eustraJja ubvine scr€en for Ondtoerca gi-bsoni" (Rp.. 89003) I&ALL, Dr J.W. Delpftnent of Parasitolqy Co7\qe of Veterinary /"&dicine Uhirersrty of @orgia Athens, eA 30602 &rited States of Aneria "Dn)g screeningr utiTizing Bnsqia trx.hanqi in the dogr,, @p: 880J-3) rc95lst\L Dr S. CAB International Institute of parasitolqy 395A Hatfleld Road St ALbans, Ilefts AL4 lXUthitd x**n "Discovery and developrsrt of new antifiTarial dntgs,, ( 86 046)(RP: 89012) ?EEES, Dr A.J. & REI;Z, Dr A.Livapol SdlooL of Tropical l@icine & Institut fLr TropmredizirtLiuetpol, L3 sQA University of TUbingut Uhited tcitrydrln D-W-7400 Tlbingut eamny "O. odtengi infeA.ions in cactLe as a tezl.iaryr screen for anti- onchccelrc;.L chetatheraput ic agrents " Costs (USS) 173 433 97 s00 776 777 160 719 19 854 ocP/EACIr.5 -11 - Appendix I C. Resistane to ryezzrBcten lmUl6[I, Dr ^S.AB International Instjcute of parasitolqy 395A Hatfield Road st ALbans, I;F'rts AL4 lxt) &rited Fcfury&/n "Studies on tt:r- sensitiyity of O. raclvutus microfiTariaeto jrerrned.in" (RP: 90003) 3, TER@T IDENTIFIeITICf.,T tuRNEIT, Dr n. D€,pt.t,ntutt of Inwnolqy t,nil,i3rsity of Strathclyde3l TayTor St.reet Glasgow G4 2NR Scrtland "PhosphoryTdtoline-glyan stlirrctur€s of filarialparasites as a targre| for ctenotherapy,, tdcfGaafiL Dr J.H. University of Qlifornia Depaftflent of PathoTqy tux 0506 San Francjsco, CA 94143-0506&rited States of Anrria "Qzsteine proteases of Bruoia and onchoerca as targrets for dtenatherapy 4. S['PPOR?IA6 T,TORK BeXq, Dr D.C. ?he University of fennessee 519 tueiler tIaJ,I I(notcviJ.7e, TN 37996-1600 &rited States of Areria "Reslznthesis and eualuation of antifil,arial. canpunds,, (Rp: ggoog) cosrs (us$) 38 353 87 009 72 073 7 1 No funding provided in L992. o@/EACLr.6 L2 costs (Us$) 129 465 Costs (USS) 46 000 57 321 50 000 47 540 Appendlr 1 - fQ%RAII14II+ Dr V. Diredor, NatjonaJ, Drug Research Cent.re[It:jrersjtj Sa:rs lhlaysia !4inde.n 77800 Pqtatp ,€,J.aysna "Plun'maak-uetics of antifiIarjal, dnrgrs" (Rp: 910336) 7DR/FIL P8ECLTNICAL DRT.I3 DWEINWENT PRA.7EC"S(jncJuded in I4r@<OFIL prqr.anme of rrr:.rk) 8lUIt, Dr O. Iabratoi.ne de Zolqie - yers Mrseum NationaL d,Ifistoi.ze NatureJ,Ie 75237 Paris @)< 05 r)rane "Iubnarlata nartini.. fil,ariasis r+ith &r;ral microfilariae: aninalfi*l ^fo^r- dn-tg trjaLs.' biolqiaI and anatanalntholqiaJ, studies,,(RP: 970337) BE\IIEI?, Prcfessor ./. Delpt of Phanacolay e Toxicolqy Midtigan State CZritersity East Ianshg, W 48824fiited .States of Arcr.ia "fransctrtjcuLar trans4r.tt. in D. rnmitis and Clrtchoera q>p:poterrtjaJ, targ/et for dntg &sign,, ..D[ISCI\I, Dr C.D. President tilanaPhatm, Inc. 565 Sciencre Drire thdison, WI 53777 Elited States of Nrelria "Arrticjpatirg ivenrectin .resistarr@ in O. volvtslus,, f,AK, Dr J.?1. llead, th).aria e FiJ,arjasjs DjyjsjonInstltute for t@,icz.l, Researc} Jalan Paharrg Ruala r+ntrrur 50588 l€,'layrsia "screenrrgr poterrtiaJ. fiJ,aricides against B. malavi infe*.ion inpresbrtis qp." (RP: 910334) learu, Dr J.ll. DepalftE{it of Parasitolqy thircrsity of @orgia At}eas, GA 30602 thited SEates of Atreria "Eqperim=ntal cfiemotherapy of fiIariasis and scneening of fi-tarjcides,,(RPr 9103i2) 78 926 aoCP/EACI,.5 -tt - Append.ix I RInQ.fiD, hfessor B. Head, Derpar,tr;lrtt of Parasitolqy Faanlty of t@icine(.thircrsity of IndonesiaJl Salernba Raya 6 Jakari.a 70430 ftfutesia "Screen:rrgr of yntuttiaL fil,aricjdes against ll. kalinantani inP::esbJtrs s!p." (RP: 970333) ZU3II\ISEI\D, Professor .L.8. Qtaimtan, Interdepa ftrental Prqranin t@icinal Oreaistry Co7\qe of Phantaqr &tirersity of Midtigan Ann Atbr, MI 48709 tfraiterJ States of Anelria "I-ead di.rccteC sJznthesis of ptential frlaricides,, cosrs (us$) 67 450 40 545 APPENDIX 2 ocP/EACIr.6 -u- aAs at 4tril L992 LIST OF Et/PAGOruL SIERZIG CCIMITIW MEMBEF(S 3RD YffiTII.6, 25-27 I"ARCH 7992 Professor (l&s) A. Abiose, t@ial Dired,or, the Natjonal Eye @ntre, Off E:qcness Bye-Pass, P.M.B. 2267, I(u.duta, Nigreria W P. Actd, Qtetatherapy Depftnrutt, Glaxo Grcup Researdr Lilrrrited., Greenford Road, Grcnfott, Middlesex UB6 1IIE, t nited Kingdon (&:r.izman) Dr W.C. Gt@77, reparurcnt of Biolqy, Collqe of Li-rF-ral Arts, Drew Unirmsity, thdison, Irlaru Jersey 07940-4037, Wlited States of Nreria Professor L.L. Fledcqmtein, Co77qe of Ptnnnaqr, 2269 @ad, University of lowa Iowa City, Iowa 52242, Aircd States of Aneria Dr W.E. 6utter:.dgre, I7ead, Ar:tiparasite Qtenatherapy Researci, htellcone Research rabratories, Langley coutt, 8ruckenhan, Kent, ER3 3&s, unitd Kingdon Professor fI. Roberf Hontitz, Deparfrnent of Biologry, Room 56-629, IvlassachusettsInstitute of Tedtnolqy, 77 t"lassadtusetts Ave;lrtt;e-, Anbridge, Irlassachusetts 02739, tlnited States of Aneria Dr G. Jo7lds, Dired,eur Screntifique, Rhlne-poulqtc Sant620, avenue Raynand-Aron, 92765 Antony, f'rane Professor v. Navaratnan, Dired.or, National, Drug.Research Gntre, Unirrersitj Sains lhlaysia, Mindr-n *,npus 77800, putang, thlaysia Dr E.A. Ottesen, Head, Clinical Parasito-l,ogy Sed,ion, NationaL .tnstetute of Atlergy and Infe*ious Diseases, Bt-tilding 4, R@n 726, 9000 RoclariTTe Park, kthesda IhryTand 20892, United States of turerica @d msrDers Dr K. Awadzi, Dired.or, onchoerciasrs d:emotherapy Research Gntre (ffic),Hohe HospitaT, P.O. fux L44, Hohe, @tana Dr E.F. Elslagier, ETsTager Assoc.lates, 4081 rhornoaks Drive, Arn Arbr Midtigan 48704, tJnited States of Aneria (Chaizman PDDT) Dr R. Engle, Eputy Dired.or, Division of Exprinental Theraputics, Walter Reed Army Institute of Researdr, Wasdngton, D.C. 20i07-5700, united States of Arterica Professor B.M. Grene, Dired.or Divisjon of @qraphic t&dicine, Sctrool of t"bdicine/frlPt of l/rudicine, Universit y of Atabara at -Bizminfirratn, Uniyersit y Station, Birminghan, Alabrna 35294, United States of tuneria (etaizman IDR/FIL-SC) Clreners Dr A.D.M. Bryceson, RepresenEatir€ of the Exrezt, Advisory Conmittee (EAC) of theOnchoerciasis Control Prqrarme x2 t/est Afria (@) Dr F. TrautweiTer, Vie-Diredor, R & D, Phamtaeutjcal,s Division, Ci-tu-Ge.igy Li:r.ited, 4002 Basle, Switzerland