Progress and challenges in the discovery of macrofilaricidal drugs

References

• Ottesen EA, Hooper PJ, Bradley M, Biswas G. The Global Programme to Eliminate Lymphatic Filariasis: health impact after 8 years. PLoS Negl. Trop. Dis.2, e317 (2008).
   PubMed Web of Science ®Google Scholar
• Boatin BA, Richards FO Jr. Control of onchocerciasis. Adv. Parasitol.61, 349–394 (2006).
   PubMed Web of Science ®Google Scholar
• Thylefors B. The Mectizan Donation Program. Ann. Trop. Med. Parasitol.102(Suppl. 1), 39–44 (2008).
   PubMed Web of Science ®Google Scholar
• McCall JW, Genchi C, Kramer LH, Guerrero J, Venco L. Heartworm disease in animals and humans. Adv. Parasitol.66, 193–285 (2008).
   PubMed Web of Science ®Google Scholar
• Bowman DD, Atkins CE. Heartworm biology, treatment and control. Vet. Clin. North Am. Small Animal Pract.39, 1127–1158 (2009).
   PubMed Web of Science ®Google Scholar
• Geary TG. Ivermectin 20 years on: maturation of a wonder drug. Trends Parasitol.21, 530–532 (2005).
   PubMed Web of Science ®Google Scholar
• Schaeffer JM, Haines HW. Avermectin binding in Caenorhabditis elegans. A two-state model for the avermectin binding site. Biochem. Pharmacol.38, 2329–2338 (1989).
   PubMed Web of Science ®Google Scholar
• Cheeseman CL, Delany NS, Woods DJ, Wolstenholme AJ. High-affinity ivermectin binding to recombinant subunits of the Haemonchus contortus glutamate-gated chloride channel. Mol. Biochem. Parasitol.114(2), 161–168 (2001).
   PubMed Web of Science ®Google Scholar
• Geary TG, Moreno Y. Macrocyclic lactone anthelmintics: spectrum of activity and mechanism of action. Curr. Pharmaceut. Biotech. (2011) (In Press).
   Google Scholar
• Dadzie Y, Neira M, Hopkins D. Final report of the Conference on the Eradicability of Onchocerciasis. Filaria J.2, 2 (2003).
   PubMedGoogle Scholar
• Bockarie MJ, Deb RM. Elimination of lymphatic filariasis: do we have the drugs to complete the job? Curr. Opin. Infect. Dis.23, 617–620 (2010).
   PubMed Web of Science ®Google Scholar
• Cupp EW, Sauerbrey M, Richards F. Elimination of human onchocerciasis: history of progress and current feasibility using ivermectin (Mectizan) monotherapy. Acta Trop. DOI: 10.1016/j.actatropica.2010.08.009 (2010) (Epub ahead of print).
   PubMedGoogle Scholar
• Maizels RM, Denham DA. Diethylcarbamazine (DEC): immunopharmacological interactions of an anti-filarial drug. Parasitology105(Suppl.), S49–S60 (1992).
   PubMed Web of Science ®Google Scholar
• Mackenzie CD, Geary TG, Gerlach JA. Possible pathogenic pathways in the adverse clinical events seen following ivermectin administration to onchocerciasis patients. Filaria J.2(Suppl. 1), S5 (2003).
   PubMedGoogle Scholar
• Moreno Y, Nabhan JF, Solomon J, Mackenzie CD, Geary TG. Ivermectin disrupts the function of the excretory-secretory apparatus in microfilariae of Brugia malayi. Proc. Natl Acad. Sci. USA107, 20120–20125 (2010).
   PubMed Web of Science ®Google Scholar
• Geary TG, Woo K, McCarthy JS et al. Unresolved issues in anthelmintic pharmacology for helminthiases of humans. Int. J. Parasitol.40, 1–13 (2010).
   PubMed Web of Science ®Google Scholar
• Dreyer G, Coutinho A, Miranda D et al. Treatment of bancroftian filariasis in Recife, Brazil: a two-year comparative study of the efficacy of single treatments with ivermectin or diethylcarbamazine. Trans. R. Soc. Trop. Med. Hyg.89, 98–102 (1995).
   PubMed Web of Science ®Google Scholar
• Dreyer G, Addiss D, Noroes J, Amaral F, Rocha A, Coutinho A. Ultrasonographic assessment of the adulticidal efficacy of repeat high-dose ivermectin in bancroftian filariasis. Trop. Med. Int. Heath1(4), 427–432 (1996).
   PubMed Web of Science ®Google Scholar
• Duke BOL, Pacqué MC, Muñoz B, Greene BM, Taylor H.R. Viability of adult Onchocerca volvulus after six 2-weekly doses of ivermectin. Bull. World Health Organ.69, 163–168 (1991).
   PubMed Web of Science ®Google Scholar
• Pfarr KM, Hoerauf AM. Antibiotics which target the Wolbachia symbionts of filarial parasites – a new strategy for control of filariasis and amelioration of pathology. Mini Rev. Med. Chem.6, 203–210 (2006).
   PubMed Web of Science ®Google Scholar
• Boussinesq M, Gardon J, Gardon-Wendel N, Chippaux JP. Clinical picture, epidemiology and outcome of Loa-associated serious adverse events related to mass ivermectin treatment of onchocerciasis in Cameroon. Filaria J.2(Suppl. 1), S4 (2003).
   PubMedGoogle Scholar
• Twum-Danso NA. Loa loa encephalopathy temporally related to ivermectin administration reported from onchocerciasis mass treatment programs from 1989–2001: implications for the future. Filaria J.2(Suppl. 1), S7 (2003).
   PubMedGoogle Scholar
• Bourguinat C, Kamgno J, Boussinesq M, Mackenzie C, Prichard R, Geary T. Analysis of the mdr-1 gene in patients co-infected with Onchocerca volvulus and Loa loa who experienced a post-ivermectin serious adverse event. Am. J. Trop. Med. Hyg.83, 28–32 (2010).
   PubMedGoogle Scholar
• Osei-Atweneboana MY, Eng JK, Boakye DA, Gyapong JO, Prichard RK. Prevalence and intensity of Onchocerca volvulus infection and efficacy of ivermectin in endemic communities in Ghana: a two-phase epidemiological study. Lancet369, 2021–2029 (2007).
   PubMed Web of Science ®Google Scholar
• Churcher TS, Pion SD, Osei-Atweneboana MY et al. Identifying suboptimal responses to ivermectin in the treatment of River Blindness. Proc. Natl Acad. Sci. USA106, 16716–16721 (2009).
   PubMed Web of Science ®Google Scholar
• Bourguinat C, Ardelli BF, Pion SD et al. P-glycoprotein-like protein, a possible genetic marker for ivermectin resistance selection in Onchocerca volvulus. Mol. Biochem. Parasitol.158, 101–111 (2008).
   PubMed Web of Science ®Google Scholar
• Hampshire VA. Evaluation of efficacy of heartworm preventive products at the FDA. Vet. Parasitol.133, 191–195 (2005).
   PubMed Web of Science ®Google Scholar
• Bourguinat C, Keller K, Blagburn B, Schenker R, Geary TG, Prichard RK. Correlation between loss of efficacy of macrocyclic lactone heartworm preventatives and P-glycoprotein genotype. Vet. Parasitol.176, 374–381 (2011).
   PubMed Web of Science ®Google Scholar
• Orme M, Awadzi K, Edwards G, Breckenridge AM. Drug treatment of onchocerciasis. Quart. J. Med.66, 195–201 (1988).
   PubMedGoogle Scholar
• Awadzi K. Clinical picture and outcome of Serious Adverse Events in the treatment of onchocerciasis. Filaria J.2(Suppl. 1), S6 (2003).
   PubMedGoogle Scholar
• Hoerauf A. Filariasis: new drugs and new opportunities for lymphatic filariasis and onchocerciasis. Curr. Opin. Infect. Dis.21, 673–681 (2008).
   PubMed Web of Science ®Google Scholar
• Turner JD, Tendongfor N, Esum M et al. Macrofilaricidal activity after doxycycline only treatment of Onchocerca volvulus in an area of Loa loa co-endemicity: a randomized controlled trial. PLoS Negl. Trop. Dis.4, e660 (2010).
   PubMed Web of Science ®Google Scholar
• Bazzochi C, Mortarino M, Grandi G et al. Combined ivermectin and doxycycline treatment has microfilaricidal and adulticidal activity against Dirofilaria immitis in experimentally infected dogs. Int. J. Parasitol.38, 1401–1410 (2008).
   PubMed Web of Science ®Google Scholar
• Grandi G, Quintavalla C, Mavropoulou A et al. A combination of doxycycline and ivermectin is adulticidal in dogs with naturally acquired heartworm disease (Dirofilaria immitis). Vet. Parasitol.169, 347–351 (2010).
   PubMed Web of Science ®Google Scholar
• Wanji S, Tendongfor N, Nji N et al. Community-directed delivery of doxycycline for the treatment of onchocerciasis in areas of co-endemicity with loaisis in Cameroon. Parasit. Vectors2, 39 (2009).
   PubMed Web of Science ®Google Scholar
• McCall JW. The safety-net story about macrocyclic lactone heartworm preventatives: a review, an update and recommendations. Vet. Parasitol.133, 197–206 (2005).
   PubMed Web of Science ®Google Scholar
• Gyapong JO, Kumaraswami V, Biswas G, Ottesen EA. Treatment strategies underpinning the global programme to eliminate lymphatic filariasis. Expert Opin. Pharmacother.6, 179–200 (2005).
   PubMed Web of Science ®Google Scholar
• Taylor MJ, Hoerauf A, Bockarie M. Lymphatic filariasis and onchocerciasis. Lancet376, 1175–1185 (2010).
   PubMed Web of Science ®Google Scholar
• Supali T, Djuardi Y, Pfarr KM et al. Doxycycline treatment of Brugia malayi-infected persons reduces microfilaremia and adverse reactions after diethylcarbamazine and albendazole treatment. Clin. Infect. Dis.46, 1385–1393 (2008).
   PubMed Web of Science ®Google Scholar
• McCall JW, Genchi C, Kramer L et al. Heartworm and Wolbachia: therapeutic implications. Vet. Parasitol.158, 204–214 (2008).
   PubMed Web of Science ®Google Scholar
• Cotreau MM, Warren S, Ryan JL et al. The antiparasitic moxidectin: safety, tolerability, and pharmacokinetics in humans. J. Clin. Pharmacol.43, 1108–1115 (2003).
   PubMed Web of Science ®Google Scholar
• Lespine A, Martin S, Dupuy J et al. Interaction of macrocyclic lactones with P-glycoprotein: structure-affinity relationship. Eur. J. Pharm. Sci.30, 84–94 (2007).
   PubMed Web of Science ®Google Scholar
• Bronsvoort BM, Renz A, Tchakouté V, Tanya VN, Ekale D, Trees AJ. Repeated high doses of avermectins cause prolonged sterilisation, but do not kill, Onchocerca ochengi adult worms in African cattle. Filaria J.4, 4–8 (2005).
   PubMedGoogle Scholar
• Conder GA, Campbell WC. Chemotherapy of nematode infections of veterinary importance, with special reference to drug resistance. Adv. Parasitol.35, 1–84 (1995).
   PubMed Web of Science ®Google Scholar
• Banks BJ, Bishop BF, Evans NA et al. Avermectins and flea control: structure-activity relationships and the selection of selamectin for development as an endectocide for companion animals. Bioorg. Med. Chem.8, 2017–2025 (2000).
   PubMed Web of Science ®Google Scholar
• Scherkenback J, Jeschke J, Harder A. PF1022A and related cyclodepsipeptides – a novel class of anthelmintics. Curr. Top. Med. Chem.2, 759–777 (2002).
   PubMedGoogle Scholar
• Harder A, Schmitt-Wrede H-P, Krücken J et al. Cyclooctadepsipeptides – an anthelmintically active class of compounds exhibiting a novel mode of action. Int. J. Antimicrob. Agents22, 318–331 (2003).
   PubMed Web of Science ®Google Scholar
• von Samson-Himmelstjerna G, Harder A, Sangster NC, Coles GC. Efficacy of two cyclooctadepsipeptides, PF1022A and emodepside, against anthelmintic-resistant nematodes in sheep and cattle. Parasitology130, 343–347 (2005).
   PubMed Web of Science ®Google Scholar
• Jeschke P, Iinuma K, Harder A, Schindler M, Mirakami T. Influence of the cyclooctadepsipeptides PF1022A and PF1022E natural products on the design of semi-synthetic anthelmintics such as emodepside. Parasitol. Res.97(Suppl. 1), S11–S16 (2005).
   PubMedGoogle Scholar
• Zahner H, Taubert A, Harder A, von Samson-Himmelstjerna G. Filaricidal efficacy of anthelmintically active cyclodepsipeptides. Int. J. Parasitol.31, 1515–1522 (2001).
   PubMed Web of Science ®Google Scholar
• Townson S, Freeman A, Harris A, Harder A. Activity of the cyclooctadepsipeptide emodepside against Onchocerca gutturosa, Onchocerca lienalis and Brugia pahangi. Am. J. Trop. Med. Hyg.73(Suppl.), 93 (2005).
   Google Scholar
• Guest M, Bull K, Walker RJ et al. The calcium-activated potassium channel, SLO-1, is required for the action of the novel cyclo-octadepsipeptide anthelmintic, emodepside, in Caenorhabditis elegans. Int. J. Parasitol.37, 1577–1588 (2007).
   PubMed Web of Science ®Google Scholar
• Horton J. Albendazole: a broad spectrum anthelminthic for treatment of individuals and populations. Curr. Opin. Infect. Dis.15, 599–608 (2002).
   PubMed Web of Science ®Google Scholar
• Mackenzie CD, Geary TG. Flubendazole, a potentially valuable macrofilaricide for lymphatic filariasis and onchocerciasis field programs. Expert Rev. Anti Infect. Ther.9(5), 497–501(2011).
   PubMed Web of Science ®Google Scholar
• Dominguez-Vasquez A, Taylor HR, Greene BM et al. Comparison of flubendazole and diethylcarbamazine in treatment of onchocerciasis. Lancet1(8317), 139–143 (1983).
   PubMed Web of Science ®Google Scholar
• Ceballos L, Elissondo M, Bruni SS, Denegri G, Alvarez L, Lanusse C. Flubendazole in cystic echinococcosis therapy: pharmaco-parasitological evaluation in mice. Parasitol. Int.58, 354–358 (2009).
   PubMed Web of Science ®Google Scholar
• Nianjun H, Cerepnalkoski L, Nwankwo JO et al. Induction of chromosomal aberrations, cytotoxicity, and morphological transformation in mammalian cells by the antiparasitic drug flubendazole and the antineoplastic drug harringtonine. Fund. Appl. Toxicol.22, 304–313 (1994).
   PubMedGoogle Scholar
• Yoshimura H. Effect of oral dosing vehicles on the developmental toxicity of flubendazole in rats. Reprod. Toxicol.17, 377–385 (2003).
   PubMed Web of Science ®Google Scholar
• Spagnuolo PA, Hu, J, Hurren R et al. The antihelmintic flubendazole inhibits microtubule function through a mechanism distinct from Vinca alkaloids and displays preclinical activity in leukemia and myeloma. Blood115, 4824–4833 (2010).
   PubMed Web of Science ®Google Scholar
• Bronsvoort BM, Makepeace BL, Renz A et al. UMF-078: a modified flubendazole with potent macrofilaricidal activity against Onchocerca ochengi in African cattle. Parasit. Vectors1, 18 (2008).
   PubMedGoogle Scholar
• Tellez-Giron E, Ramos MC, Dufour L et al. Treatment of neurocysticercosis with flubendazole. Am. J. Trop. Med. Hyg.33, 427–431 (1984).
   Google Scholar
• Gavidia CM, Gonzalez AE, Barron EA et al. Evaluation of oxfendazole, praziquantel and albendazole against cystic echinococcosis: a randomized clinical trial in naturally infected sheep. PLoS Negl. Trop. Dis4, e616 (2010).
   PubMed Web of Science ®Google Scholar
• Anderson VR, Curram MP. Nitazoxanide: a review of its use in the treatment of gastrointestinal infections. Drugs67, 1947–1967 (2007).
   PubMed Web of Science ®Google Scholar
• Bacon JA, Ulrich RG, Davis JP et al. Comparative in vitro effects of closantel and selected β-ketoamide anthelmintics on a gastrointestinal nematode and vertebrate liver cells. J. Vet. Pharmacol. Ther.21, 190–198 (1998).
   PubMed Web of Science ®Google Scholar
• Rao RU, Huang Y, Fischer K, Fischer PU, Weil GJ. Brugia malayi: effects of nitazoxanide and tizoxanide on adult worms and microfilariae of filarial nematodes. Exp. Parasitol.121(1), 38–45 (2009).
   PubMed Web of Science ®Google Scholar
• Kaminsky R, Ducray P, Jung M et al. A new class of anthelmintics effective against drug-resistant nematodes. Nature452, 176–180 (2008).
   PubMed Web of Science ®Google Scholar
• Hosking BC, Kaminsky R, Sager H, Rolfe PF, Seewald W. A pooled analysis of the efficacy of monepantel, an amino-acetonitrile derivative, against gastrointestinal nematodes of sheep. Parasitol. Res.106, 529–532 (2010).
   PubMed Web of Science ®Google Scholar
• Rufener L, Keiser J, Kaminsky R, Mäser P, Nilsson D. Phylogenomics of ligand-gated ion channels predicts monepantel effect. PLoS-Pathogens9, e1001091 (2010).
   Google Scholar
• Lee BH, Clothier MF, Dutton FE et al. Marcfortine and paraherquamide class of anthelmintics: discovery of PNU-141962. Curr. Top. Med. Chem.2, 779–793 (2002).
   PubMedGoogle Scholar
• Little PR, Hodges A, Watson TG, Seed JA, Maeder SJ. Field efficacy and safety of an oral formulation of the novel combination anthelmintic, derquantel-abamectin, in sheep in New Zealand. NZ Vet. J.58, 121–129 (2010).
   PubMed Web of Science ®Google Scholar
• Xiao SH, Hui-Ming W, Tanner M, Utzinger J, Chong W. Tribendimidine: a promising, safe and broad-spectrum anthelmintic from China. Acta Trop.94, 1–14 (2005).
   PubMed Web of Science ®Google Scholar
• Hu Y, Xiao S-H, Aroian RF. The new anthelmintic tribendimidine is an L-type (levamisole and pyrantel) nicotinic acetylcholine receptor agonist. PLoS Negl. Trop. Dis.3, e499 (2009).
   PubMed Web of Science ®Google Scholar
• Xue J, Xiao S-H, Xu LL, Qiang HQ. The effect of tribendimidine and its metabolites against Necator americanus in golden hamsters and Nippostrongylus brasiliensis in rats. Parasitol. Res.106, 775–781 (2010).
   PubMed Web of Science ®Google Scholar
• Tripathi RP, Katiyar D, Dwivedi N, Singh BK, Pandey J. Recent development in search of antifilarial agents. Curr. Med. Chem.13, 3319–3334 (2006).
   PubMed Web of Science ®Google Scholar
• Singh PK, Ajay A, Kushwaha S, Tripathi RP, Misra-Bhattacharya S. Towards novel antifilarial drugs: challenges and recent developments. Fut. Med. Chem.2, 251–283 (2010).
   PubMed Web of Science ®Google Scholar
• Woods DJ, Williams TM. The challenges of developing novel antiparasitic drugs. Inv. Neurosci.7, 245–250 (2007).
   PubMedGoogle Scholar
• Townson S, Ramirez B, Fakorede F, Mouries M-A, Nwaka S. Challenges in drug discovery for novel antifilarials. Expert Opin. Drug. Discov.2(Suppl. 1), S63–S73 (2007).
   PubMed Web of Science ®Google Scholar
• Thompson DP, Klein RD, Geary TG. Prospects for rational approaches to anthelmintic discovery. Parasitol.113, S217–S238 (1996).
   PubMed Web of Science ®Google Scholar
• Geary TG, Thompson DP, Klein RD. Mechanism-based screening: discovery of the next generation of anthelmintics depends upon more basic research. Int. J. Parasitol.29, 105–112 (1999).
   PubMed Web of Science ®Google Scholar
• Geary TG, Thompson DP. Caenorhabditis elegans: how good a model for veterinary parasites? Vet. Parasitol.101, 371–386 (2001).
   PubMed Web of Science ®Google Scholar
• Burns AR, Wallace IM, Wildenhain J et al. A predictive model for drug bioaccumulation and bioactivity in Caenorhabditis elegans. Nat. Chem. Biol.6, 549–557 (2010).
   PubMed Web of Science ®Google Scholar
• Ruiz-Lancheros E, Viau C, Walter TN, Francis, A, Geary TG. Activity of novel nicotinic anthelmintics in cut preparations of Caenorhabditis elegans. Int. J. Parasitol.41, 455–461 (2011).
   PubMed Web of Science ®Google Scholar
• Woods DJ, Lauret C, Geary TG. Anthelmintic discovery and development in the animal health industry. Expert Opin. Drug. Discov.2(Suppl. 1), S25–S33 (2007).
   PubMed Web of Science ®Google Scholar
• Geary TG, Woods DJ, Williams T, Nwaka S. Target identification and mechanism-based screening for anthelmintics: application of veterinary antiparasitic research programmes to search for new antiparasitic drugs for human indications. In: Drug Discovery in Infectious Diseases. Selzer PM (Ed.). Wiley-VCH, Weinheim, Germany, 1–16 (2009).
   Google Scholar
• McCarter JP. Genome filtering: an approach to discovering novel antiparasitics. Trends Parasitol.20, 462–468 (2004).
   PubMed Web of Science ®Google Scholar
• Kumar S, Chaudhary K, Foster JM et al. Mining predicted essential genes of Brugia malayi for nematode drug targets. PLoS ONE11, e1189 (2007).
   Google Scholar
• Agüero F, Al-Lazikani, B, Aslett M et al. Genomic-scale prioritization of drug targets: the TDR Targets database. Nat. Rev. Drug Discov.7, 900–907 (2008).
   PubMed Web of Science ®Google Scholar
• Crowther GJ, Shanmugam D, Carmona SJ et al. Identification of attractive drug targets in neglected-disease pathogens using an in silico approach. PLoS Negl. Trop. Dis.4, e804 (2010).
   PubMedGoogle Scholar
• Behm CA, Bendig MM, McCarter JP, Sluder AE. RNAi-based discovery and validation of new drug targets in filarial nematodes. Trends Parasitol.21, 97–100 (2005).
   PubMed Web of Science ®Google Scholar
• Knox DP, Geldhof P, Visser A, Britton C. RNA interference in parasitic nematodes of animals: a reality check. Trends Parasitol.23, 105–107 (2007).
   PubMed Web of Science ®Google Scholar
• Eberhard ML, Dickerson JW, Tsang VCW et al. Onchocerca volvulus: parasitological and serological responses in experimentally infected chimpanzees and mangabey monkeys. Exp. Parasitol.80, 454–462 (1995).
   PubMed Web of Science ®Google Scholar
• Dube A, Murthy PK, Puri SK, Misra-Bhattacharya S. Presbytis entellus: a primate model for parasitic disease research. Trends Parasitol.20, 358–360 (2004).
   PubMed Web of Science ®Google Scholar
• Allen JE, Adjei O, Bain O et al. Of mice, cattle, and humans: the immunology and treatment of river blindness. PLoS Negl. Trop. Dis.2, e217 (2008).
   PubMedGoogle Scholar
• Hewitson JP, Harcus YM, Curwen RS et al. The secretome of the filarial parasite, Brugia malayi: proteomic profile of adult excretory-secretory products. Mol. Biochem. Parasitol.160, 8–21 (2008).
   PubMed Web of Science ®Google Scholar
• Moreno Y, Geary TG. Stage- and gender-specific proteomic analysis of Brugia malayi excretory-secretory products. PLoS Negl. Trop. Dis.2, e326 (2008).
   PubMedGoogle Scholar
• Bennuru S, Semnani R, Meng Z, Ribeiro JM, Veenstra TD, Nutman TB. Brugia malayi excreted/secreted proteins at the host/parasite interface: stage- and gender-specific proteomic profiling. PLoS Negl. Trop. Dis.3, e410 (2009).
   PubMedGoogle Scholar
• Nwaka S, Hudson A. Innovative lead discovery strategies for tropical diseases. Nature Drug Disc.5, 941–955 (2006).
   PubMed Web of Science ®Google Scholar
• Hudson A, Nwaka S. The concept paper on the Helminth Drug Initiative. Onchocerciasis/lymphatic filariasis and schistosomiasis: opportunities and challenges for the discovery of new drugs/diagnostics. Exp. Opin. Drug Discov.2(Suppl. 1), S3–S7 (2007).
   PubMed Web of Science ®Google Scholar
• Nwaka S, Ramirez B, Brun R, Maes L, Douglas F, Ridley R. Advancing drug innovation for neglected diseases – criteria for lead progression. PLoS Negl. Trop. Dis.3, e440 (2009).
   PubMed Web of Science ®Google Scholar