Scientific articles by institution members of the HELP Consortium
Evaluation of commercially available anthelminthics in laboratory models of human intestinal nematode infections
by Keiser J, Häberli C. ACS Infectious Diseases 2021. doi: 10.1021/acsinfecdis.0c00719
Summary: Drug repurposing from veterinary to human medicine has been the main strategy to develop the four recommended human anthelminthics for the treatment of soil-transmitted helminthiasis. A systematic, head-to-head comparison of the anthelminthic activity profile of derivatives of these drugs and other anthelminthics developed in succession has not been conducted to date. We studied eight benzimidazoles, five macrocyclic lactones, tribendimidine, levamisole, and pyrantel pamoate in laboratory models of human intestinal nematode infections. Laboratory models for soil-transmitted helminthiasis can assist characterizing potential drug candidates. Drugs should be evaluated against different species, and both the adult and larval stages as activities could differ considerably.
Oxfendazole mediates macrofilaricidal efficacy against the filarial nematode Litomosoides sigmodontis in vivo and inhibits Onchocerca spec. motility in vitro
by Hübner MP, Martin C, Specht S, Koschel M, Dubben B, Frohberger SJ, Ehrens A, Fendler M, Struever D, Mitre E, Vallarino-Lhermitte N, Gokool S, Lustigman S, Schneider M, Townson S, Hoerauf A, Scandale I. PLOS Neglected Tropical Diseases 2020;14(7): e0008427. doi: 10.1371/journal.pntd.0008427
Summary: Current efforts to eliminate onchocerciasis and lymphatic filariasis are hampered by the lack of short-course drugs that kill adult worms or regimens that are proven to be safe for both diseases. The authors investigated the efficacy of anthelmintic drug oxfendazole, used in veterinary medicine, in an animal model of filariasis. Oxfendazole caused complete clearance of adult worms but was not directly active against juvenile worms, suggesting that drug-induced serious adverse events due to microfilariae clearance are unlikely. Based on these results, the predicted human dose is within a range already been shown to be safe in phase 1 clinical trials. Oxfendazole is a promising drug candidate for the treatment of human filarial diseases.
Designing antifilarial drug trials using clinical trial simulators
by Walker M, Hamley JID, Milton P, Monnot F, Pédrique B, Basanez M-G. Nature Communications 2020, 11: 2685. doi: 10.1038/s41467-020-16442-y
Summary: The treatments used in mass drug administration for Lymphatic filariasis and onchocerciasis are predominantly active against the microfilarial progeny of adult worms. New treatments are needed, and several therapies and regimens are currently in (pre-)clinical testing. Clinical trial simulators have not been widely applied to neglected tropical diseases, where their resource-saving payoffs could be highly beneficial. The authors use an individual-based onchocerciasis transmission model that projects trial outcomes of a hypothetical drug that kills adult worms. They identify key design decisions that influence the power of clinical trials and discuss how clinical trial simulators help to inform target product profiles.
Onchocerciasis elimination: What’s left to do?
by Specht S, Monnot F. Bulletin of the Netherlands Society for Tropical Medicine and International Health 2020: 13-14.
Summary: This review explains that years of experience show that current mass drug administration with ivermectin has severe shortcomings in onchocerciasis control. New approaches are needed, such as development of macrofilarial drugs, to supplement current mass drug administration in order to meet the sustainable development goals.
Solubility and stability enhanced oral formulations for the anti-infective corallopyronin A.
by Krome AK, Becker T, Kehraus S, Schiefer A, Steinebach C, Aden T, Frohberger SJ, López Mármol Á, Kapote D, Jansen R, Chaverra-Muñoz L, Hübner MP, Pfarr K, Hesterkamp T, Stadler M, Gütschow M, König GM, Hoerauf A, Wagner KG. Pharmaceutics 2020; 12(11):1105.
Summary: Novel-antibiotics are urgently needed to combat an increase in morbidity and mortality due to resistant bacteria. The preclinical candidate corallopyronin A (CorA) is a potent antibiotic against Gram-positive and some Gram-negative pathogens for which a solid oral formulation was needed for further preclinical testing of the active pharmaceutical ingredient (API). The neat API CorA is poorly water-soluble and instable at room temperature, both crucial characteristics to be addressed and overcome for use as an oral antibiotic. Therefore, amorphous solid dispersion (ASD) was chosen as formulation principle. The results demonstrated that the ASD formulation principle is a suitable stability- and solubility-enhancing oral formulation strategy for the API CorA to be used in preclinical and clinical trials and as a potential market product.
Whipworm and roundworm infections
by Else KJ, Keiser J, Holland CV, Grencis RK, Sattelle DB, Fujiwara RT, Bueno LL, Asaolu SO, Sowemimo OA, Cooper PJ. Nature Reviews Diseases Primers 2020, 6:44. doi: 10.1038/s41572-020-0171-3
Summary: Trichuriasis and ascariasis are neglected tropical diseases caused by the gastrointestinal dwelling nematodes Trichuris trichiura (a whipworm) and Ascaris lumbricoides (a roundworm), respectively. Both parasites are staggeringly prevalent, particularly in tropical and subtropical areas, and are associated with substantial morbidity. Infection is initiated by ingestion of infective eggs, which hatch in the intestine. Thereafter, T. trichiura larvae moult within intestinal epithelial cells, with adult worms embedded in a partially intracellular niche in the large intestine, whereas A. lumbricoides larvae penetrate the gut mucosa and migrate through the liver and lungs before returning to the lumen of the small intestine, where adult worms dwell. Both species elicit type 2 anti-parasite immunity. Diagnosis is typically based on clinical presentation (gastrointestinal symptoms and inflammation) and the detection of eggs or parasite DNA in the faeces. Prevention and treatment strategies rely on periodic mass drug administration (generally with albendazole or mebendazole) to at-risk populations and improvements in water, sanitation and hygiene. The effectiveness of drug treatment is very high for A. lumbricoides infections, whereas cure rates for T. trichiura infections are low. Novel anthelminthic drugs are needed, together with vaccine development and tools for diagnosis and assessment of parasite control in the field.