Far émis par | 224-4L56A9 ,., r. ù et L'Bqttipe nationale de I'onchocercosc Ir{inistère de la Santé publique de la Population et des Affaires sociales Kankal République de Guinée Olls GUIIIEE CoHâHRv â4->â4 18/lL/96 14:86 Pg: 1 PROGRAMMB DB LUTTB CONTRE UONCIIOCBRCOSB EN AFRIQUE DE I,,'OUEST 01 BP 549 - Tél.(nG) 30.23.12 - lblex 5241P.F / oUAGADOUGOU 01 - BURKINA FASO .,/ / Bquipe nationale dc l'ouchocercosc Ministère de la Snnté publiquc de la Population e( des Affirires sociales Kankarl Républiquc dc Guinéc l)ossier N«r. : 08/181/79'D Datc :11/11/96 No. d'Irnputation : OU ICP CTD 426 ON 96 834 strRvrctr§ TBCHNIOUBS - I,Jl't'rRF |)'ACCOBD Aux fins de I'institutionrtalisation du traitement cotnnruuarrtaire à l'ive.rmectine à grande écehelle en Guinée, dans les villagcs dcs préfecturcs sanitaires sur les bassins. L Organisation mondiale de la Santé, Progranurre clc lutte c()ntre I'onchocercose ci- après dénornuréc "I'OMS/ONCHO* d'une part, ,4" i'i' -1'r/ t- b, ilt\rt(,aoci-après déuommée "I'INSTITUTION" d'autre part, ONT CONVBNU BT AT(RBTE CB OUI SUIT: 1. TRAVAUX A trXECUTtrR FATSANT T/OBJDT DU PRD,SDNT ACCORD I.-orntatiotr des infirmiers des centres de santé ct dirccteurs préfcctoranx dc santé A. Bassin de Kolenté Forrrtal,ion dc 08 infirrniers chefs dc p()ste des centrcs de sarrté, deux clirecteurs préfcctoraux dc santé clc l(india cl Forécariah ct l'inspcctcur régional de la sar:té clu 20 at 24 xrvcnrl>rc 1996 incltrs, soit 05 jorrr's. Lieu de la forrnation : Kindia. . I I t I t». R F q'tt I tltilrI t"i' i' l" 'l r'ax émis par i 7,24-415AA9 OI'IS GUIIIEE COHâNBY Ê4->â4 t8/LL/96 L4iA6 Pg: 2 ) B 2 Bassin§..du Niandan.Nieer et MafqU Formation de 19 infirnricrs des centres de santé, deur directcurs préfectoraux de santé et deux irtspccteurs régionaux des préfectures de Kissidougou, F'aranah, Kourotrssa et Kankan du 2 au 6 décçmbre 1996 inclus, soit 5 jours. Ueu de fomatlon : Faranah. [æ programme «le travail faisant l'objet du présent accord peut en cours d'exécution subir des modifications de la part de IOMS/ONCHO après discrrssions avec les responsables sanitaires des préfectures ou régionâux et l'équipe uâtionâle. , 2, MODALIîES DE TRAVAIL Formation des iufirnriers dcs ccntrcs clc santé et cles rnéclccirt^s-chcfs dcs préfcctnrcs dc Kindia, Forcécariah, Kissidougou, Kouroussa, Kankan et Faranah snr Ies bassins : Kole-nté, Niandan, Niger et Mafou. L'équipe nationale (le coordonnatertr rtational etf ot Ie médecin épidémiologisrc «le I'équipe d'évaluation et 2 techniciens nationaux) en collaboration avec nn agent PII'I'/OC)' procè«leront à la formation des infirrniêrs des centres de santé des préfeclures de Kindia, Forécariah, Kankan, Kissidorrgou, Konronssa et Faranah. I-es médecins-chefs des préfectures ci-dessus rnentionés scror)l dcs facilitatcurs pour coordonner la mise en oeuvre du traitenrent commttnarttaire par chacuu dtrus sa préfecture. Cette fornration conrprendra : - une formation théorique sur les procédures de formation des distribnteurs villagcois, Ics nressages d'IEC à transr:tcttrc aux Ç()rnr)runautés villagc.«liscs ; tune microplanification par chaqtte infinnier pour son aire de santé. II sera chargé de fonner les distributeurs villageois et la supervjsion du traitcntcnt dans sa zone ; Pcndant la nricroplanification chaque infirrnicr doit avoir à sa disp«rsition Iç nonrbrc dc villages à traiter dans sa zone, et leur populatiorr respective. Il doit établir un calendrier de f<rrtnation cles distributeurs commut)autaircs dc scs villages, Il irrtégrera les formations et Ic suivi dcs c()r»rnunarrtés dans les activités de santé au rriveau dc sa zone. Après cette fofmatiou et microplauification, l'ivermectine- seta rernis r) cha<pre infirurie.r ert fottctiotr du nonrbre de village à traiter dans sa zone. De rctour à son p<lstc, srrr Ia base «le son microl>lan préalablelnent discuté avec Ie nrêrlecin-chef cle la 1>réfecture, il doit utiliser les moyens dont il dispose dans sou centre pour les villages de sa zone d'action en : scnsil>ilisant lcs cornrnunautés à clroisir lc livrerrr et le distritruteur forruant Ce§ agents contrr'tunautaircs. A la fin de Ia forrnation rrne listc clc villagcs doit être étatrlie ; cette liste cJ«rit comprenclre le nont dtr village, la population rcÇcnsée, le dispcnsairc ct la préfccturc concerttée, les dates du premier et dernier traitements à I'jvernlectine et le nonr du bassin, I Fax érnis par = 224-4l5AA9 olls GUIITEE CollâImY â4->â4 l8/LL/96 1.4:e6 Ps: 3 3 3. OBLIGATIONS DE I'OMS/ONCHO 3.1. Indemnités de dÉplacement; Voir annexe 1 Il scra versé à la partie natiorralc des indemnités de déplacernerrt et des frais de transport dcs infirmiers des Çentrcs dc santé et des directerrrs préfcctoraux de santé an lien dc Ia fonnation pour un montant total de 4.010.600 FG (quatrc rnilliorrs dix milte six cenr francs guinéens). Iæs indenultés de déplacement à payer ne doivcnt corrcerner qrre les jours de participation effcctive pour la formation, le nonrbre de ces jours pouvant etrc inféricur à celui 1>révu dans Ia lættre d'Accord. 3.2. Frais de fonctionnemqnt Carburant Iæ carburant nécessairc pour les véhicules utilisés pour la formalion sera disltonible au sectettr ONCHO/Kankan et Faranah, Guinée soit uu total dc l3ùl litrcs de gas-oil répartis cornrne strit : Forrnation A : Kankan-Kinclia-Karrkan 273,5litrcs x 4 véhicules : total 854 litres. Formation ts : Kankan-Faranah-Kankan I I7,5 litres x 4 véhiculcs : total 470 litres. Petiles dépenses LJne sorttrtrc dc 30.000 I.'G 1>ar fornration sera misc i) la disposition de la partie nationalc pour diverses autres pctitcs dépcnscs durant Ia fornration soit au t<ltal 60.000 FG (30.000 FG x 2). 3.3. Moyeus de locourotion Véhictrles I'OMS/ONCHO fottrnira pour les séarrces de formation énumérées ci-dcssus : 4 vélricules 4x4. 3.4. Matériel de burçau et autres Urt lot dc rnatériel de bttreart nécessaire et Ie modtrlc de forrnation sera foumi par I'OMS/ONCHO. l,c(s) participant(s) of lcs nrcmbr«;s dc Ia coordinatiou ue bénéficicront quc tlc la nroitié des indemrrités dc déplacomcn( au cas or) la forrnation À Iieu à tcur résidcncc. fln jorrr d'irrdemnité dc déplaconrcnl (pour le voyrg,e) esL accordé aux pnrlicipants por.u rejoindrc Ie licu do la fornration et permeLtre aux ntcrrbrss dc la coordination naLionalc dc mctlrc cn place les disposi[ifs rtéocssaircs avnnt le début dc la formation. e D ,:I Fax élnis pan i 2.24-41-5t/lïg oI'tS GUII{EE COIIâHBÿ â4->â4 L8/1,1/96 L4.86 Pg: 4 4 4, CONTRIITUflON DE L'INSIITUTION I-llnstitution, en accord avcc son Gonvernemer)t, fottrnira pour chaque formation le personnel chargé de l'exécution tlc la mise en oeuvre du traitenreul comntrnautaire. Ce Per§onnel comPrend : A. FormalLiql Préfecturqs Kin«lia et Ë'orécadÂlt - Infirnricrs - Médecins (DPS) - Inspecteur régional - Coordonnateur national - Médçcin épi. Equtpe nat. - Techniciens nationaux - Chauffeurs Total 19 agcnts B. Fornrqtion Préfectrlres de F-aranah. Kissiclougou, K@ - lnfirmiers - N,Iédecins (DPS) - Inspecteur régional - Médecin épi, Eguil>e nat - Techniciens nat. - Chauffetrrs Total 30 agcnts [æ G<luvernement de l'Institution pren«lra er) chargc Ics frais de location cles salles pour toutes les formatlons dans les préfectures et Ics pauscs-café. 5. D[IREIC COUVERTE PAR L'ACCORD [æ présent accord couvrira une périorle cle 10 jours ré1>arlis comrne suit : A. I'réfectures «le Kinclia et Forécqfjah - du 20 av 24 novembre 1996 inclus soit 5 jours. B. Préfectures de Kissidougou. K4nkan. Faranah et Kourorrssa - du 2 au 6 déccrubrç 1996 inclus soit 5 jours. 8 2 1 I 1 2 : 19 ? 2 1 2 : ,) t; Fax énis par : 224-4L5;O8i9 OllS GUIHEE COHâHRY â4->â4 18,/LL/96 L4iA6 Ps: 5 5 6. IICITEANCDS, MODALTTES ET CONDITION§ DE PAIEMENî 6.1. I-e montant total des dépenses pré\rucs par I'accord s'élève à 4 865 000 FG (quatre millions lruit cent soixante cinq mille fraucs guinéerx). 6.2. Cette somme sera payée dès gue cet accord sera dilment signé par les deux parties et Ie document retourné à I'OMS/ONCHO à Ouagadorrgou. 6.3. I-es doctrnrenls conrptables justificatifs des dépenscs cffcctuécs cloivcnt égalcrncnt êtrc transmis à la flrt de chaque fornration à l'adrcssc suivante: Directeur clu Progranrme { Attention: Admfnistrateur du Budget et des Finances . oMs/oNcHo 01 BP 549 Ouqgaçlqugqu 01 Burkina I?aso * 6.4. Un rapport tcchnique sur les fornrations, la liste des villages déservis par chaquc infirnriet plus une cartc ds diurcnsion A4 des zoncs çoncernées par les préfectures et les bassiru cloivcnt parvenir au Chcf dc l'rruité Plarrification, Evaluation et Transfcrt à I'adrcssc suivante: Directeur du Programrne Attention: Chef PBT oMS/oNCHO 01 BP 549 OrrAgadouSou 01 Burkina Faso 6.5. L.e montant intégral de tout solde positif dégagé pour une raison quclconquc à la fin de Ia période couverte par le présent accord sera déduit ;>ar Ia suite du r:rorrtarrt des déperuses que I'OMS/ONCHO aura à prendre en charge dans le caclre cl'urt évenluel proclrain accord avcc I'hrstitution, Ân cas or) il n'y arrrait pltrs de lettre tl'accord, ce .soklc positlf serait rembonrsé par chèque à I'OMS-ONCI{O. 7. DtSt,OSrl'IONS JURIDIQUES : Il est bicn entendu que la présente lçttre d'accord rt'institue pas de relations d'cmploycrrr à cmployé cutrc I'OMS/ONCIIO ct les agenLs de l'Institution évoluant dans le cadrc du pr«rjet. Aussl I'OMS/ONCIIO nc saurait assrrnler auculle re-sponsabilité pour toute. pcrte, tout accident, tout dotnmagc ou toutc blessure que l'Iu^stitution ou torrte autre personne agissant en son norn pourralt srrbir flu corrrs ou en raison de l'exécution d'trn travail ou de quelque autre manière. Tout différend relatif à l'interprétation ou à I'exécution clu présent accord qui n'aurait pu être résolu à I'amiable sera reglé par conciliation. Si toutefois la conciliation devait échorrer, Ie différend sera réglé parnn arbitrage dont les nrodalités seront cortver)ues entre lcs partics ou, à défarrt, confornrcs au règlcrrrcttl dc conciliation et d'arbitrage dc la Chambrc dc Ck»mmerca lutcrnationalc. Iæs partics rccouuaisscnt qu'cllcs scront définitivement liées par la sentence arbitrale. a * I'our faciliter la comnrurricatlon, vouilloz rcsPoctor la scc(ion 6,4 ci-dossus. I ) l I :l I t Fax ênris pan i 224-4158lA9 OllS GUIIIEE COIIâI(RV â4->â4 1g/Ll/96 L4i86 Ps: 6 6 Si vous scceptez cette ptoposition, nous vous scrions reconnaissarts de bien voulair fairc signer les quatre o(emplaires du présent Accord p{rr «letrx autorités responsables de I'exécution des travaux et nous cn rctounler lrois (3) elqnlplaires revêtus des signatnrcs dcs personnes autorisées en nous indiquant l'adresse «le la banguc à. laquelle «levront être effcctués les différents versements ci-dcssus mentionnés. signataireg l, 9M§/ONCHO Signataites Instilutip,n 1- Dr Boakye A. Boatin Chcf PET 1, Norh, Fonçtion P.B sN.ojli Ip. u...r.9.I{rgt8a..}r A LI,o - Signature »"t.'..{,k i,.:.!,.:..!S 2. Dr. K. Yankum ï)adzie Directeur du Prograr)rrne l<.!)*tw Signature o ut",.. !. 3..,. !.1.,:..2b COORDONMItsI]R NÀ1I ONAT Signaturc Date .1d/11/1996 2. Nom, Fonction P.I.:,I91 Il l§1, . .§.Y..{'.t*. ., ... SECRIÎîÂIM GENSRÀI Signal.ure D at e:.,rfl /, I 1 /. i.99.6........ d6"'- c * I c §ectdrclr.c (' (o Crrl te d c \ Fax énis par : 224-4158,A9 olls GUIIIEE Col{AI{Rv â4->44 t8/LL/96 L4:A6 Pg: ?1 7 AI{NEXB 1 Irormation des inflrmiers des postes rnédicaux (centre cle santé) pour ls mise en place clu traitenrent commuuautaire en Guinée). A. Bassin de Kolenté Préfecture dc Kindia et de Forécariah I-ieu de la fornration : Kindia Indemnltéuûe déplacemcnt lnfirmiers «les centres 6 jours x 11 500 FG x 8 = 552 000 FG Médccirr (DPS) 5 jours x 10 750 FG x | = 53 75q FG Médecin (DPS) 6 jorrrs x 21 500 FG x 1 -- 129 000 FG Médccin (IRS) 3 jours x 10 750 FG x | : 32 250 FG Médecin epi. Equipc Nat, 7 jours x 21 500 I;G x t = 150 500 FG Coordonnateur national 7 jours x 25 800 FG x 1 - 180 600 I'-G Tcclrnicicns natioltaux 7 jours x 11 500 FG x 2 = 161 000 FG Chauffeurs 7jotrrsx6500FGx4 = 182000trG So*s total = r 441 100 FG 'Iiansporl 1>our 9 1>articipants au lieu de la formatlon = 116 000 FG Tbtal = I..§§![AAJ§ Carlrtrrant Kankau-Klndia-Kankan : 213,5 litres x 4 véhicules soit 854 litres de gas-oil. B. Bap"s,in-du Niandan et du Nrger Mafou a .l I I I il I I I I i { ,l i I { ,l ,I I I I I I i t I ,l ,l Préfectures de Kissicloltgolr Kouroussa et Faralrall Lieu cle formation : Faranah IrXlcmnltés tlc dénlacement Infirmicrs des postes médicaux 6 jotrrs x 11 500 FG x L9 = Médecin (DPS) 6 jours x 21 500 Gl'x 2 = Médecin (DPS) 5 jotrs x 10 750 FG x I = Médccirr (IRS) 3 jotrrs x 21 500 FG x | = Médecin (IRS) 3 jours x 10 750 FG x t = Médecin epl. B«pripe nat. 6 jours x 21 500 FG x J = Tcchniciens nationaux 6 jours x 11 500 FG x 2 : chauffcurs 6joursx6500FGx4 = Sorrs total = Trarrsport pour 22 participants = Total = 1 311 000 I?G 258 000 FG 53 750 FG 64 500 FG 32 250 FG 129 000 FG 138 000 IlG 156 000 FG 2 I42 500 FG 311 000 FG el§rllg-E§, Fax ênis par : ZZ4-4L5,AA9 olls GUIIIEE COIIÊIffiY â{->â4 L8/LL/96 L4i8,6 Pg: I 8 Carburant pour Ies 4 véhicule§ : Kankan-Faranah-Kankan . tl7,5litres x 4 véhicules = 470 litres de gas-oil.. RECAPITUIÂlTON .t" 1ç ', 'i i it 1 .l I |l Indemnités de déplacemenr Frais de liansport I>etites «lépenses ou/961ot1268 oule6/ott272 II oulso/ollzs5 L-._. _ = 3 583 600 FG = 427 O00 FG = 60 000 I?G = 794 400 FG = 4 86i 000 FG l I I I I I I I I I _t Carburant : t324litres de gas-oil x 600 FG GRAND TOTAL " OUtgSl ol129IL___ _.._l I I I t I i 1
African Programme for onchocerciasis Control Programme africain de lutte contre I'onchocercose JOINT ACTION FORUM Office of the Chairman FORUM D'ACTION COMMUNE Bureau du Pr6sident JAF. JPC FAC. CCP JOINT SESSION / SESSION CONJOINTE Ouagadougou, Burkina Faso,4 December 2002 MACROFIL / FILARIASIS R&D Onchocerciasis Control Programme in West Africa Programme de lutte contre l'onchocercose en Afrique de l,Ouest JOINT PROGRAMME COMMITTEE Office of the Chairman COMITE CONJOINT DU PROGRAMME Bureau du Pr6sident JAF8/JPC23-INF/DOC.I I I it. i MACROFIL / F'ILARIASIS R&D Clinical studies 1. A survey carried out in two onchocerciasis endemic foci in Ghana (Asubende in the Pru River basin and Bui in the lower part of the Black Volta) 1997 by the OCP Revealed individuals with persistent, significant microfilaridermia. Both foci had been under prolonged vector control and had received multiple treatments with ivermectin. As a working definition, individuals with : or > l0 mf/snip after 9 or more treatments with ivermectin were labelled as "non-responders"; individuals who were skin snip negative after similar exposure were termed "responders". The pathogenesis of non-response could be failure or inadequate drug intake, sub optimal drug exposure, adverse interactions, patient factors, parasite resistance and possibly other factors. An open, case control study was set up to investigate the phenomenon. This involved the OCRC at Hohoe, The Division of Oncho Control of the Ministry of Health Ghana, The Noguchi Memorial Institute for Medical Research of the University of Ghana. The aims of the study were to investigate whether the microfilaria and /or the adult female worrns of Onchocerca volvulus in non responders to multiple treatments have developed resistance to ivermectin and provide characterised parasite material to aid the development of tools to detect such resistance. 2. The individuals were studied at the OCRC History of drug intake was confirmed and reclassified on the basis of skin snip findings Underlying disease or adverse interaction with other drugs excluded Re challenged with ivermectin and a pharmacokinetic study conducted Determined the sensitivity of microfilariae at day 8 (% reduction on initial counts, vector mf uptake and development on fly feeding) Determined the sensitivity of adult worms at days 90 and or 364 (embryograms, skin microfi lariae, fly feeding) Parasite material saved for future probing for markers of ivermectin resistance. 3. From the OCP data base l6 cases ("non responders") were matched with l2 responders from the same foci and 14 individuals from an area (Todzi basin) without previous ivermectin distribution ("ivermectin naive") or vector control. After re examination of the cases and the responders there were 2l cases and 7 responders 4. rJ,.*^- ^L^*^^^r.:- cafafrr qnA a€finomr cf..rliao nf ^1L^-,1--^l + irzpmanfin / nF(- combinations. Due to the fact that the LF elimination programme could be viewed in some areas as a coordinated programme with the Onchocerciasis Control Programs, it was recognised that additional clinical studies addressing the PK, safety and efficacy of ivermectin or DEC + albendazole were warranted. 3 studies were initiated: i) Albendazole + ivermectin safety, efficacy in LF and intestinal helminthes study in Pemba Island (Dr. M. Dahoma). 1000 subjects including LF positive. The treatment phase of this study has been completed. The data analysis is ongoing and results are expected by December 2002. ii) Albendazole * DEC, pharmacokinetics, safety study (Dr. K. Shenoy) This study has been terminated and has provided PK data indicating that there are no drug interactions between albendazole + DEC. I 2iii) Alb + DEC safety, efficacy and PK (Dr. N. Kshirsagar) 1400 subjects from a LF endemic region in India have been treated, the I year follow up (night mf, scrotal and ICE card test evaluation) has been concluded. The study was extended to study the effect of a second treatment and is expected to be finalized (two year follow-up) in September 2002. Moxidectin 5. Moxidectin is a veterinarian product that TDR scientists investigated for its effect on filarial worrns showing that it has a beffer profile than ivermectin. The pharmaceutical company WYETH has conducted clinical, technical and regulatory activities to define if moxidectin can be assessed in Onchocerca volvulus patients. The results from the studies that WYETH has conducted have allowed defining the dose range to be used in future efficacy and safety studies. The consultations with UK and French drug regulatory authorities regarding the suitability to evaluate moxidectin in patients as well as the suitability of the clinical development strategy was welcomed and endorsed. Current activities have been focused on the strategy and design of the Phase II study to be conducted in OCRC, this was finalized during a recent meeting at WYETH (August 20-21,2002). For this study to be implemented a "Clinical Transfer Agreement" must be negotiated between WYETH and WHO, it is expected that this agreement will be finalized by 3'o quarter 2002 and the study could be initiated in October-November 2002. It will include 193 patients with different levels of microfiladermia and eye disease, will compare several doses of ivermectin against several doses of moxidectin addressing safety and efficacy with a follow-up of 18 months. The results of this study will serve as the Go/noGo for future phase III studies that will have to be conducted at several sites / countries. The search for these sites was initiated during a recent meeting of APOC with the National Onchocerciasis Coordinators in Abuja, Nigeria. Pre-clinical research activities Ivermectin resistance detection tool 6. In June 1999 a WHO sponsored meeting entitled "Ivermectin Resistance in Onchocerca volvulus: Tools To Detect It" was held at APOC/OCP headquarters, Ouagadougou. This workshop concluded that it was feasible to develop a PCR-based assay to detect ivermectin resistance or shifts in the allele frequencies at loci that may serve as markers for ivermectin resistance in O. vohulus. Two focused teams were formed, one in West Africa undertaking fieldwork and one international group (The Product Development Team) undertaking laboratory sfudies. 7. During the first year of the project the identification of ivermectin resistance candidate genes associated with ivermectin resistance in Haemonchus contortus and C. elegans was completed in order to identify genes likely to be associated with ivermectin resistance in O. volvulus. In the second year, candidate O. volvulus genes, based on experience in H. contortus and C. elegans, from "unselected" (untreated areas) and "IVM exposed" populations were examined for polymorphism and a short list of marker genes and their alleles were determined. The IVM exposed Onchocerca came from people who had received at least 6 treatments with IVM. In addition to the examination of candidate IVM-resistance genes, the Onchocerca EST database was examined for all sequences in which there was evidence of polymorphism and a number of polymorphic ESTs were identified. In the past year, analysis of differences in polymorphism between the unselected and IVM exposed worrns for both the candidate resistance genes and ESTs that showed polymorphism Jcontinued. Three candidate genes had significantly different polymorphism between the unselected and IVM treated worms. Nodules have been collected from more regions, so that it can be determined whether differences in polymorphism can be attributed to treatment history or to geographical source of collection. This analysis of polymorphism in the identified genes, using the material collected from a wider range of regions has continued. At the same time, two rapid PCR based assays have been developed for monitoring the frequency of resistance-associated alleles of one of the identified marker genes in O. volvulus. Other genes showing polymorphic differences, between untreated and treated populations of O. volvulus, will be further evaluated and if shown to be reliable markers of ivermectin resistance in all regions from which worms have been collected, they will be developed into PCR based assays to detect ivermectin resistance. So far one of the marker genes shows a strong positive correlation between the frequency of a particular allele and microfilaria count after ivermectin treatment. At the end of the fourth year a robust PCR assay to detect allelic changes in O. volvulus candidate genes in microfilaria will have been completed and assessed on a large number of O. volvulus samples from several regions in Africa. At this stage the assay should be ready for surveillance monitoring in the field. This project will contribute to the sustained control of O. volvulus through development of an assay to detect ivermectin resistance before resistance genes become widespread in the parasite population. Early warning of resistance development will allow alternative control measures to be introduced to eliminate the resistance genes before they spread. Optimization of DEC skin patch test 8. Based on discussions with LTS Lohman Therapie-Systems AG, a German Company with expertise in transdermal drug delivery systems their expertise was assessed and an agreement to perform work (APW) was established. This work has yielded 3 patch prototypes. On the basis of the results of a short term stability study one of the formulations that were prepared have been selected. The selected formulation is the most stable one, but nevertheless there was seen a slight decrease of the drug content over the time. This decrease is very likely because some of the drug evaporated out of the edges of the patches into the pouch material (the citrate has to be converted into the free base in situ during the manufacturing process and that the free base is a liquid at room temperature). Degradation products which could explain the loss of drug have not been seen and in aged patches higher drug concentrations were found in the center of the patch compared to the peripheral rim. In order to minimize the losses, during the production of the clinical samples a more inert primary packaging material will be used. The anticipated production date is the second week in September 2002, whereby the patches can be released until middle of November. At this point the clinical studies could be initiated. Drug discovery activities 9. For the identification of new drug leads for Filariases the group of TDR Drug Discovery addresses filariases in the context of a multi-parasite drug discovery approach. 10. Grant renewals. Two key research grants in the drug discovery are currently being supported through MACROFIL a) M. Kron (Michigan State University, USA) is using a rational, target-based approach to search for inhibitors of B. malayi asparagine tRNA synthetase. Sixteen hits from a high- throughput screen of a large diverse library are being followed up by synthesis and testing of analogues. Two of six tested hits were toxic to cultured adult worms at 25 micromolar 4concentration, but structure optimisation and analogue selection, based on the enzyme's three-dimensional structure, are expected to improve this activity. In addition, a unique lysyl tRNA synthetase from Wolbachia has been expressed, in preparation for a high-throughput screen on this new potential drug target. b) C. Behm (Australian National University) used RNA interference (RNAi) to validate trehalose-6-phosphate synthase and two trehalase isoforms as potential new drug targets in C. elegans. Other enzymes are now being investigated as potential targets. I l. Comoound evaluation a) Tibotec. Screening of about 9000 compounds in Tibotec's T. colubriformis in vitro larval development test produced about 60 confirmed hits. All of these except 8 are from BioSPECS. Compounds that are available in sufficient amount and whose structures are promising will be sent to S. Townson for further evaluation against O. gutturosa. b) S. Townson, Detailed study of many available antibiotics by S. Townson (Northwick Park Institute for Medical Research; London, UK) suggested that minocycline was the most promising candidate for further progression. An agreement for evaluation of a large series of novel tetracyclines is under negotiation with Paratek (Boston, MA, USA). Also, about 800 non-antibiotic compounds (mostly from GSK, selected around pharmacophores with known or likely anti-filarial activity) were evaluated for activity against adult O. gutturosa worms in culture. About 30 were further evaluated for activity against microfilaria in mice. Analogues of the most promising active compounds have been requested for further studies including antibiotics, pharmacophore-selected compounds from GSK, and potentially teracyclines. c) A focused collection of 220 additional compounds, selected around pharmacophores with known or likely anti-filarial activity, has been purchased from Olivia (Princeton, NJ, USA) and is now being evaluated by S. Townson. d) A diverse compound library of over 10000 compounds will be screened for activity against C. elegans in two assay systems that are being developed by Cambria Biosciences (Bedford, MA, USA): one assay detects changes in nematode nuclear functions, and the other targets enzymes in the worm's protein secretion pathway.