Publications by authors named "Jennifer Keiser"

336 Publications

, , and ADME evaluation of SF-containing -diarylureas as antischistosomal agents.

Antimicrob Agents Chemother 2021 Jul 26:AAC0061521. Epub 2021 Jul 26.

Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia i Ciències de l'Alimentació, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Barcelona, Spain.

In recent years, -diarylureas have emerged as a promising chemotype for the treatment of schistosomiasis, a disease that poses a considerable health burden to millions of people worldwide. Here, we report a novel series of -diarylureas featuring the scarcely explored pentafluorosulfanyl group. Low IC values for newly transformed schistosomula (0.6 - 7.7 μM) and adult worms (0.1 - 1.6 μM) were observed. Four selected compounds, highly active in presence of albumin (>70% at 10 μM), endowed with decent cytotoxicity profile (SI against L6 cells >8.5) and good microsomal hepatic stability (>62.5% of drug remaining after 60 min), were tested in infected mice. Despite the promising worm killing potency, none of them showed significant activity . Pharmacokinetic data showed a slow absorption, with maximal drug concentrations reached after 24 h of exposure. Finally, no direct correlation between drug exposure and activity was found. Thus, further investigations are needed to better understand the underlying mechanisms of SF-containing -diarylureas.
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http://dx.doi.org/10.1128/AAC.00615-21DOI Listing
July 2021

Characterization of the Population Pharmacokinetics of Moxidectin in Adults Infected with Strongyloides Stercoralis: Support for a Fixed-Dose Treatment Regimen.

Clin Pharmacokinet 2021 Jul 23. Epub 2021 Jul 23.

Pediatric Pharmacology and Pharmacometrics Research, University of Basel Children's Hospital (UKBB), Spitalstrasse 33, 4056, Basel, Switzerland.

Background: Moxidectin has recently attracted attention as a novel candidate for the treatment of helminth infections, including Strongyloides stercoralis. This study aims to characterize the population pharmacokinetics (PPK) of moxidectin in S. stercoralis-infected adults using a pharmacometric approach, and to perform model-based simulations to explore different drug dosing strategies.

Methods: A PPK study embedded in a dose-escalation phase IIa trial was conducted in NamBak, Laos. Eight micro blood samples were collected from each of 96 S. stercoralis-infected adults following a moxidectin dose-ranging study, from 2 to 12 mg. A PPK model was developed using nonlinear mixed-effects modeling, and dosing strategies were explored using simulations in S. stercoralis-infected subjects with varying age and body weight (n = 5000 per dosing strategy).

Results: A two-compartment model including delayed absorption with lag-time best described the available PK data. Allometric scaling was applied to account for the influence of body weight. High clearance was found in the infected adults (4.47 L/h [95% confidence interval 3.63-5.39] for a 70 kg individual) compared with that previously reported for healthy adults. Model-based simulations indicated similar variability in mean ± standard deviation area under the curve from time zero to infinity of 1907 ± 1552 and 2175 ± 1670 ng × h/mL in the 60-70 kg weight group, after 8 mg fixed- or weight-based dosing, respectively.

Conclusion: We describe the first PPK model for moxidectin in adults with S. stercoralis infection. Equivalent exposures after fixed-dose and weight-dependent dosing strategies support the use of a simple fixed-dose approach, particularly in large-scale treatment programs.

Trial Registration: Registered at ClinicalTrials.gov (NCT04056325).
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http://dx.doi.org/10.1007/s40262-021-01048-4DOI Listing
July 2021

Development of emodepside as a possible adulticidal treatment for human onchocerciasis-The fruit of a successful industrial-academic collaboration.

PLoS Pathog 2021 Jul 22;17(7):e1009682. Epub 2021 Jul 22.

Department of Biomedical Sciences, Iowa State University, Ames, Iowa, United States of America.

Current mass drug administration (MDA) programs for the treatment of human river blindness (onchocerciasis) caused by the filarial worm Onchocerca volvulus rely on ivermectin, an anthelmintic originally developed for animal health. These treatments are primarily directed against migrating microfilariae and also suppress fecundity for several months, but fail to eliminate adult O. volvulus. Therefore, elimination programs need time frames of decades, well exceeding the life span of adult worms. The situation is worsened by decreased ivermectin efficacy after long-term therapy. To improve treatment options against onchocerciasis, a drug development candidate should ideally kill or irreversibly sterilize adult worms. Emodepside is a broad-spectrum anthelmintic used for the treatment of parasitic nematodes in cats and dogs (Profender and Procox). Our current knowledge of the pharmacology of emodepside is the result of more than 2 decades of intensive collaborative research between academia and the pharmaceutical industry. Emodepside has a novel mode of action with a broad spectrum of activity, including against extraintestinal nematode stages such as migrating larvae or macrofilariae. Therefore, emodepside is considered to be among the most promising candidates for evaluation as an adulticide treatment against onchocerciasis. Consequently, in 2014, Bayer and the Drugs for Neglected Diseases initiative (DNDi) started a collaboration to develop emodepside for the treatment of patients suffering from the disease. Macrofilaricidal activity has been demonstrated in various models, including Onchocerca ochengi in cattle, the parasite most closely related to O. volvulus. Emodepside has now successfully passed Phase I clinical trials, and a Phase II study is planned. This Bayer-DNDi partnership is an outstanding example of "One World Health," in which experience gained in veterinary science and drug development is translated to human health and leads to improved tools to combat neglected tropical diseases (NTDs) and shorten development pathways and timelines in an otherwise neglected area.
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http://dx.doi.org/10.1371/journal.ppat.1009682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8297762PMC
July 2021

Long-term outcomes of ivermectin-albendazole versus albendazole alone against soil-transmitted helminths: Results from randomized controlled trials in Lao PDR and Pemba Island, Tanzania.

PLoS Negl Trop Dis 2021 Jun 30;15(6):e0009561. Epub 2021 Jun 30.

Medical Parasitology and Infection Biology, Helminth Drug Development Unit, Swiss Tropical and Public Health Institute, Basel, Switzerland.

Background: Preventive chemotherapy is the cornerstone of soil-transmitted helminth (STH) control. Long-term outcomes and adequate treatment frequency of the recently recommended albendazole-ivermectin have not been studied to date.

Methodology/principal Findings: Double-blind randomized controlled trials were conducted in Lao PDR, Pemba Island, Tanzania and Côte d'Ivoire between 2018 and 2020 to evaluate the efficacy and safety of ivermectin-albendazole versus albendazole-placebo in Trichuris trichiura-infected individuals aged 6 to 60. In the framework of this study, in Lao PDR 466 and 413 participants and on Pemba Island, 558 and 515 participants were followed-up six and 12 months post-treatment, respectively. From each participant at least one stool sample was processed for Kato-Katz diagnosis and cure rates (CRs), egg reduction rates (ERRs) and apparent reinfection rates were calculated. If found helminth-positive at six months, participants were re-treated according to their allocated treatment. Long-term outcomes against T. trichiura based on CRs and ERRs of ivermectin-albendazole compared to albendazole were significantly higher at six months in Lao PDR (CR, 65.8 vs 13.4%, difference; 52.4; 95% CI 45.0-60.0; ERRs, 99.0 vs 79.6, difference 19.4; 95% CI 14.4-24.4) and Pemba Island (CR, 17.8 vs 1.4%, difference; 16.4; 95% CI 11.6-21.0; ERRs, 84.9 vs 21.2, difference 63.8; 95% CI 50.6-76.9) and also at 12 months in Lao PDR (CR, 74.0 vs 23.4%, difference; 50.6; 95% CI 42.6-61.0; ERRs, 99.6 vs 91.3, difference 8.3; 95% CI 5.7-10.8) and Pemba Island (CR, 19.5 vs 3.4%, difference; 16.1; 95% CI 10.7-21.5; ERRs, 92.9 vs 53.6, difference 39.3; 95% CI 31.2-47.4) respectively. Apparent reinfection rates with T. trichiura were considerably higher on Pemba Island (100.0%, 95% CI, 29.2-100.0) than in Lao PDR (10.0%, 95% CI, 0.2-44.5) at 12 months post-treatment for participants treated with albendazole alone.

Conclusions/significance: The long-term outcomes against T. trichiura of ivermectin-albendazole are superior to albendazole in terms of CRs and ERRs and in reducing infection intensities. Our results will help to guide decisions on how to best use ivermectin-albendazole in the context of large-scale PC programs tailored to the local context to sustainably control STH infections.

Trial Registration: ClinicalTrials.gov registered with clinicaltrials.gov, reference: NCT03527732, date assigned: 17 May 2018.
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http://dx.doi.org/10.1371/journal.pntd.0009561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277064PMC
June 2021

Evaluation of two communication tools, slideshow and theater, to improve participants' understanding of a clinical trial in the informed consent procedure on Pemba Island, Tanzania.

PLoS Negl Trop Dis 2021 05 14;15(5):e0009409. Epub 2021 May 14.

Swiss Tropical and Public Health Institute, Basel, Switzerland.

Background: Clinical trial participants are required to sign an informed consent form (ICF). However, information is lacking on the most effective methods to convey trial relevant information prior to inviting participants to sign the ICF, being particularly pertinent in low-income countries. A previous study on Pemba Island, Tanzania, found that a verbal information session (IS) was significantly better than providing an ICF alone. However, knowledge gaps remained. Building on these findings, we investigated the effect of adding a slideshow or a theater to the IS in the informed consent procedure of an anthelminthic clinical trial.

Methodology/principal Findings: A total of 604 caregivers were randomized into the control group that only received an ICF (n = 150) or an ICF plus one of three intervention strategies: (i) verbal IS (n = 135), (ii) verbal IS with a slideshow (n = 174) or (iii) verbal IS followed by a theater (n = 145). All modes of information covered the same key messages. Participants' understanding was assessed using a semi-structured questionnaire. The mean score of caregivers in the control group (ICF only) was 4.41 (standard deviation = 1.47). Caregivers attending the IS alone were more knowledgeable than those in the control group (estimated difference in mean scores: 2.40, 95% confidence interval (CI) 1.95 to 2.86, p < 0.01). However, there was no evidence of an improvement compared to the IS only when participants attended a slideshow (0.09, 95% CI -0.53 to 0.35, p = 0.68) or a theater (0.28, 95% CI -0.27 to 0.82, p = 0.32). Three out of 10 key messages remained largely misunderstood, regardless of the mode of information group.

Conclusions/significance: Our study confirmed that, in this setting, an ICF alone was not sufficient to convey clinical trial-related information. An IS was beneficial, however, additional theater and slideshows did not further improve understanding. Future research should explore methods to improve communication between study teams and participants for different key messages, study types and settings.
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http://dx.doi.org/10.1371/journal.pntd.0009409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8153490PMC
May 2021

Preclinical and Clinical Characteristics of the Trichuricidal Drug Oxantel Pamoate and Clinical Development Plans: A Review.

Drugs 2021 Jun 30;81(8):907-921. Epub 2021 Apr 30.

Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, P.O. Box, 4002, Basel, Switzerland.

Soil-transmitted helminths (Ascaris lumbricoides, hookworm and Trichuris trichiura) infect about one-fifth of the world's population. The currently available drugs are all highly efficacious against A. lumbricoides. However, they are only moderately efficacious against hookworm and poorly efficacious against T. trichiura. Oxantel, a tetrahydropyrimidine derivative discovered in the 1970s, has recently been brought back to our attention given its high efficacy against T. trichiura infections (estimated 76% cure rate and 85% egg reduction rate at a 20 mg/kg dose). This review summarizes the current knowledge on oxantel pamoate and its use against T. trichiura infections in humans. Oxantel pamoate acts locally in the human gastrointestinal tract and binds to the parasite's nicotinic acetylcholine receptor (nAChR), leading to a spastic paralysis of the worm and subsequent expulsion. The drug is metabolically stable, shows low permeability and low systemic bioavailability after oral use. Oxantel pamoate was found to be safe in humans, with only a few mild adverse events reported. Several clinical trials have investigated the efficacy of this drug against T. trichiura and suggest that oxantel pamoate is more efficacious against T. trichiura than the currently recommended drugs, which makes it a strong asset to the depleted drug armamentarium and could help delay or even prevent the development of resistance to existing drugs. We highlight existing data to support the use of oxantel pamoate against T. trichiura infections.
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http://dx.doi.org/10.1007/s40265-021-01505-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144136PMC
June 2021

Efficacy and safety of ascending doses of moxidectin against Strongyloides stercoralis infections in adults: a randomised, parallel-group, single-blinded, placebo-controlled, dose-ranging, phase 2a trial.

Lancet Infect Dis 2021 08 30;21(8):1151-1160. Epub 2021 Mar 30.

Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland; University of Basel, Basel, Switzerland. Electronic address:

Background: Strongyloidiasis represents a major public health issue, particularly in resource-limited countries. Preliminary studies suggest that moxidectin might serve as an alternative to the only available treatment option, ivermectin. We aimed to evaluate the efficacy and safety of ascending doses of moxidectin in Strongyloides stercoralis-infected patients.

Methods: We did a randomised, parallel-group, single-blinded, placebo-controlled, dose-ranging, phase 2a trial in four villages in northern Laos. Eligible adults (aged 18-65 years) with S stercoralis infection intensities of at least 0·4 larvae per g of stool in at least two stool samples were randomly assigned (1:1:1:1:1:1:1) by use of computerised, stratified, block randomisation into seven treatment groups: 2 mg of moxidectin, 4 mg of moxidectin, 6 mg of moxidectin, 8 mg of moxidectin, 10 mg of moxidectin, 12 mg of moxidectin, or placebo. Participants and primary outcome assessors were masked to treatment allocation, but study site investigators were not. Participants received a single oral dose of their allocated dose of moxidectin in 2 mg tablets, or four placebo tablets. Three stool samples were collected at baseline and two stool samples were collected 28 days after treatment from each participant. A Baermann assay was used to quantify S stercoralis infection and Kato-Katz thick smears were used to qualitatively identify coinfections with additional helminths species. The primary endpoint was cure rate against S stercoralis and was analysed in an available case analysis set, defined as all randomly assigned participants with primary endpoint data. Predicted cure rates and associated CIs were estimated with hyperbolic E models. Safety was evaluated in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT04056325, and is complete.

Findings: Between Nov 27, 2019, and March 15, 2020, 785 adults were screened for trial eligibility. Of these, 223 participants were randomly assigned to treatment groups and 209 completed the study and were analysed for the primary outcome. 2 mg of moxidectin had a predicted cure rate of 75% (95% CI 59-87; 22 [73%] of 30 cured) against S stercoralis compared with a predicted cure rate of 14% (5-31; four [14%] of 29 cured) for placebo. With escalating doses, the probability of cure increased from 83% (95% CI 76-88; 26 [90%] of 29 cured) at 4 mg to 86% (79-90; 27 [84%] of 32 cured) at 6 mg, and to 87% (80-92; 24 [83%] of 29 cured) at 8 mg, levelling off at 88% (80-93; 29 [97%] of 30 cured) at 10 mg and 88% (80-93; 26 [87%] of 30 cured) at 12 mg. Moxidectin was well tolerated across all treatment groups, with no serious adverse events being recorded and all reported symptoms being classified as mild.

Interpretation: 4-12 mg of moxidectin showed promising tolerability and efficacy profiles in the treatment of S stercoralis infections in adults. Because 8 mg of moxidectin is used for the treatment of onchocerciasis and has been evaluated for other helminth infections, we recommend this dose for phase 2b and phase 3 trials of strongyloidiasis therapy.

Funding: Fondazione Adiuvare.
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http://dx.doi.org/10.1016/S1473-3099(20)30691-5DOI Listing
August 2021

Structural Requirements for Dihydrobenzoxazepinone Anthelmintics: Actions against Medically Important and Model Parasites: , , , and .

ACS Infect Dis 2021 05 2;7(5):1260-1274. Epub 2021 Apr 2.

Centre for Respiratory Biology, UCL Respiratory, Division of Medicine, University College London, London WC1E 6JF, United Kingdom.

Nine hundred million people are infected with the soil-transmitted helminths (roundworm), hookworm, and (whipworm). However, low single-dose cure rates of the benzimidazole drugs, the mainstay of preventative chemotherapy for whipworm, together with parasite drug resistance, mean that current approaches may not be able to eliminate morbidity from trichuriasis. We are seeking to develop new anthelmintic drugs specifically with activity against whipworm as a priority and previously identified a hit series of dihydrobenzoxazepinone (DHB) compounds that block motility of Here, we report a systematic investigation of the structure-activity relationship of the anthelmintic activity of DHB compounds. We synthesized 47 analogues, which allowed us to define features of the molecules essential for anthelmintic action as well as broadening the chemotype by identification of dihydrobenzoquinolinones (DBQs) with anthelmintic activity. We investigated the activity of these compounds against other parasitic nematodes, identifying DHB compounds with activity against and . We also demonstrated activity of DHB compounds against the trematode a parasite that causes schistosomiasis. These results demonstrate the potential of DHB and DBQ compounds for further development as broad-spectrum anthelmintics.
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http://dx.doi.org/10.1021/acsinfecdis.1c00025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154432PMC
May 2021

Validation of a human-serum-based in vitro growth method for drug screening on juvenile development stages of Schistosoma mansoni.

PLoS Negl Trop Dis 2021 03 30;15(3):e0009313. Epub 2021 Mar 30.

Swiss Tropical and Public Health Institute, Basel, Switzerland.

Background: Schistosomiasis affects over 200 million people worldwide but only praziquantel is available for treatment and control. Drug discovery is often based on phenotypic drug screening, involving different parasite stages retrieved from infected mice. Aiming to reduce animal use, we validated an in vitro growth method for juvenile Schistosoma mansoni for the purpose of drug sensitivity assays.

Methodology/principal Findings: We compared inter-batch variability of serum, worm size and organ development, gender distribution, and drug sensitivity between in vitro and in vivo grown worms over different life stages. In vitro developed S. mansoni in Hybridoma medium supplemented with 20% human serum were similar in size as in vivo worms until 28 days of incubation (males 1.4 ± 0.2 mm, females 1.1 ± 0.5 mm long). qPCR analysis revealed similar gender distribution both on newly transformed schistosomula and worms grown for 21 days. Worms developed in vitro and in vivo were similarly sensitive to praziquantel from 7 to 35 days of development with the exception of 21 days of development, where a slightly lower activity was observed for the in vitro grown worms (IC50: 0.54 μM in vitro, 0.14 μM in vivo 72 hours post-incubation). The evaluation of five additional drugs revealed a similar sensitivity on worms developed for 21 days, with the exception of mefloquine, where we observed a 10-fold lower sensitivity on in vitro developed schistosomes when compared to in vivo grown (IC50: 4.43 μM in vitro, 0.48 μM in vivo).

Conclusion: A large number of juvenile S. mansoni worms can be grown in vitro, which show similar drug sensitivity, gender distribution, size and morphology as the worms recovered from rodents, supporting the use of this method in drug screening efforts.
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http://dx.doi.org/10.1371/journal.pntd.0009313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034724PMC
March 2021

A systematic review and an individual patient data meta-analysis of ivermectin use in children weighing less than fifteen kilograms: Is it time to reconsider the current contraindication?

PLoS Negl Trop Dis 2021 03 17;15(3):e0009144. Epub 2021 Mar 17.

WorldWide Antimalarial Resistance Network (WWARN), Oxford, United Kingdom.

Background: Oral ivermectin is a safe broad spectrum anthelminthic used for treating several neglected tropical diseases (NTDs). Currently, ivermectin use is contraindicated in children weighing less than 15 kg, restricting access to this drug for the treatment of NTDs. Here we provide an updated systematic review of the literature and we conducted an individual-level patient data (IPD) meta-analysis describing the safety of ivermectin in children weighing less than 15 kg.

Methodology/principal Findings: A systematic review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) for IPD guidelines by searching MEDLINE via PubMed, Web of Science, Ovid Embase, LILACS, Cochrane Database of Systematic Reviews, TOXLINE for all clinical trials, case series, case reports, and database entries for reports on the use of ivermectin in children weighing less than 15 kg that were published between 1 January 1980 to 25 October 2019. The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO): CRD42017056515. A total of 3,730 publications were identified, 97 were selected for potential inclusion, but only 17 sources describing 15 studies met the minimum criteria which consisted of known weights of children less than 15 kg linked to possible adverse events, and provided comprehensive IPD. A total of 1,088 children weighing less than 15 kg were administered oral ivermectin for one of the following indications: scabies, mass drug administration for scabies control, crusted scabies, cutaneous larva migrans, myiasis, pthiriasis, strongyloidiasis, trichuriasis, and parasitic disease of unknown origin. Overall a total of 1.4% (15/1,088) of children experienced 18 adverse events all of which were mild and self-limiting. No serious adverse events were reported.

Conclusions/significance: Existing limited data suggest that oral ivermectin in children weighing less than 15 kilograms is safe. Data from well-designed clinical trials are needed to provide further assurance.
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http://dx.doi.org/10.1371/journal.pntd.0009144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968658PMC
March 2021

Assessment of fecal calprotectin and fecal occult blood as point-of-care markers for soil-transmitted helminth attributable intestinal morbidity in a case-control substudy conducted in Côte d'Ivoire, Lao PDR and Pemba Island, Tanzania.

EClinicalMedicine 2021 Feb 30;32:100724. Epub 2021 Jan 30.

Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland.

Background: Infections with soil-transmitted helminths (STHs) may result in chronic inflammatory disorders affecting the human host. The objective of this study was to evaluate Fecal Calprotectin (FC) and Fecal Occult Blood (FOB) in individuals infected and non-infected with STHs to identify potential intestinal morbidity markers.

Methods: Stool from participants diagnosed positive for and concomitant STH infections from three countries was used to perform FC and FOB point-of-care assays. Simultaneously, identified STH negative participants underwent FC and FOB testing as controls. Potential associations between test results and determinants were analyzed using multivariable logistic regression.

Findings: In total, 1034 infected cases (mostly light infections) and 157 STH negative controls were tested for FC and FOB. Among all participants tested, 18·5% had ≥ 50 µg/g FC concentration, while 14 (1·2%) were positive for FOB. No statistically significant association was found between infection or co-infection and FC concentration, while an inverse association (odds ratio (OR): 0·45, 95% credible intervals (CrI): 0·26, 0·75) was found between hookworm co-infection and FC concentration. In Lao PDR, the proportion of participants in the ≥ 50 µg/g FC category was significantly higher in the oldest age category compared to the 5-11 years group (OR: 3·31, 95% CrI: 1·62, 7·24). Too few participants were found positive for FOB to derive any conclusions.

Interpretation: Studies are needed to better understand the relationship between intestinal morbidity and STH infections. Suitable, standardized, low-cost markers of STH attributable morbidity to better monitor the impact of STH control interventions are necessary.

Funding: BMGF (OPP1153928).
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http://dx.doi.org/10.1016/j.eclinm.2021.100724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851339PMC
February 2021

Development and validation of an LC-MS/MS method for the quantification of the anthelmintic drug moxidectin in a volumetric absorptive microsample, blood, and plasma: Application to a pharmacokinetic study of adults infected with Strongyloides stercoralis in Laos.

J Chromatogr B Analyt Technol Biomed Life Sci 2021 Mar 20;1166:122556. Epub 2021 Jan 20.

Swiss Tropical and Public Health Institute, University of Basel, Basel, Switzerland; University of Basel, Basel, Switzerland. Electronic address:

Moxidectin is a promising candidate for addition to the lean repertoire of drugs against neglected tropical diseases (NTD) including strongyloidiasis. Pharmacokinetic (PK) and -dynamic studies are required to support its clinical development. Microsampling approaches enable PK studies in the challenging environments where NTDs are most prevalent, due to simplified collection and processing. We developed a liquid chromatography tandem mass spectrometry method for the sensitive quantification of moxidectin in human blood obtained by capillary sampling with the microsampling device Mitra® compared to blood and plasma obtained by venous sampling. Sample preparation consisted of protein precipitation, evaporation and reconstitution and also included phospholipid filtration for blood and plasma. Moxidectin was detected by multiple reaction monitoring (640.4 → 528.5 m/z) using a Luna C8(2) (30 × 2.0 mm, 3 µm particle size, 100 Å) analytical column with a gradient program of 6 min duration. Validation was performed with respect to accuracy, precision, sensitivity, selectivity, linearity, stability, recovery, and haematocrit influence with a limit of quantification of 0.5 and 2.5 ng/mL, for venous and capillary blood respectively. Moxidectin was stable up to 2 months at storage condition (blood and plasma: -20 °C, microsamples: room temperature), 3 cycles of temperature shift, for at least 4 h on the bench-top and 24 h in the autosampler (4 °C). Deviations of inter- and intra-assay accuracy and precision were smaller than 12.6% and recoveries were in the range of 80.7-111.2%. The method was applied to samples obtained from nine Strongyloides stercoralis-infected adults from northern Laos. A good agreement in the time-concentration profiles of moxidectin and a high consistency in PK parameters was found between the different matrixes and sampling strategies: e.g. identical time to reach maximal concentration of 4.0 h and a similar maximal concentration of 83.9-88.5 ng/mL of moxidectin. The simple and practical capillary procedure using Mitra® microsampling has been demonstrated to be suitable for PK studies of moxidectin and will pave the way for future PK studies.
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http://dx.doi.org/10.1016/j.jchromb.2021.122556DOI Listing
March 2021

Optimization of Benzothiazole and Thiazole Hydrazones as Inhibitors of Schistosome BCL-2.

ACS Infect Dis 2021 05 1;7(5):1143-1163. Epub 2021 Feb 1.

The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.

Limited therapeutic options are available for the treatment of human schistosomiasis caused by the parasitic Schistosoma flatworm. The B cell lymphoma-2 (BCL-2)-regulated apoptotic cell death pathway in schistosomes was recently characterized and shown to share similarities with the intrinsic apoptosis pathway in humans. Here, we exploit structural differences in the human and schistosome BCL-2 (sBCL-2) pro-survival proteins toward a novel treatment strategy for schistosomiasis. The benzothiazole hydrazone scaffold previously employed to target human BCL-XL was repurposed as a starting point to target sBCL-2. We utilized X-ray structural data to inform optimization and then applied a scaffold-hop strategy to identify the 5-carboxamide thiazole hydrazone scaffold () with potent sBCL-2 activity (IC 30 nM). Human BCL-XL potency (IC 13 nM) was inadvertently preserved during the optimization process. The lead analogues from this study exhibit on-target activity in model fibroblast cell lines dependent on either sBCL-2 or human BCL-XL for survival. Further optimization of the thiazole hydrazone class is required to exhibit activity in schistosomes and enhance the potential of this strategy for treating schistosomiasis.
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http://dx.doi.org/10.1021/acsinfecdis.0c00700DOI Listing
May 2021

Insights gained from conducting a randomised controlled trial on Ivermectin-Albendazole against Trichuris trichiura in Côte d'Ivoire, Lao PDR and Pemba Island.

Adv Parasitol 2021 19;111:253-276. Epub 2020 Dec 19.

Swiss Tropical and Public Health Institute, Basel, Switzerland; University of Basel, Basel, Switzerland. Electronic address:

There is only limited scientific literature on trial methodology, trial procedures and mitigation strategies to overcome challenges faced during clinical research taking place in resource constrained healthcare environments. Organisational, cultural, infrastructural and ethical challenges may vary between settings although conduct of clinical trials for the same disease (in our case soil-transmitted helminth (STH) infections) share similar risks for implementation. We use the example of a phase III randomised controlled trial, conducted between 2018 and 2020 in Côte d'Ivoire, Lao PDR and Pemba Island (Tanzania), to share challenges faced and mitigation strategies to guide future planning of studies in similar settings. We describe the planning, screening, enrolment and implementation phases in each of the three settings. Our findings indicate that involvement of local staff and close collaboration are essential factors for successful trial preparation and implementation. A strategic plan adapted to each setting with a distinct focus on community engagement and workforce is crucial to proceed efficiently. Mutual trust between the trial population and the trial team is of utmost importance and allows for early reaction and adaption to emerging issues.
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http://dx.doi.org/10.1016/bs.apar.2020.11.001DOI Listing
September 2021

Diagnosis of soil-transmitted helminths using the Kato-Katz technique: What is the influence of stirring, storage time and storage temperature on stool sample egg counts?

PLoS Negl Trop Dis 2021 01 22;15(1):e0009032. Epub 2021 Jan 22.

Swiss Tropical and Public Health Institute, Basel, Switzerland.

Background: Soil-transmitted helminths infect about one fifth of the world's population and have a negative impact on health. The Kato-Katz technique is the recommended method to detect soil-transmitted helminth eggs in stool samples, particularly in programmatic settings. However, some questions in its procedure remain. Our study aimed to investigate the effect of storage time, storage temperature and stirring of stool samples on fecal egg counts (FECs).

Methodology/principal Findings: In the framework of a clinical trial on Pemba Island, United Republic of Tanzania, 488 stool samples were collected from schoolchildren. These samples were evaluated in three experiments. In the first experiment (n = 92), two Kato-Katz slides were prepared from the same stool sample, one was stored at room temperature, the other in a refrigerator for 50 hours, and each slide was analyzed at nine time points (20, 50, 80, 110, 140 minutes, 18, 26, 42 and 50 hours). In the second experiment (n = 340), whole stool samples were split into two, one part was stored at room temperature, and the other part was put in a refrigerator for 48 hours. From each part one Kato-Katz slide was prepared and analyzed at three time points over two days (0, 24 and 48 hours). In the third experiment (n = 56), whole stool samples where stirred for 15 seconds six times and at each time point a Kato-Katz slide was prepared and analyzed. Mean hookworm FECs of Kato-Katz slides stored at room temperature steadily decreased following slide preparation. After two hours, mean hookworm FECs decreased from 22 to 16, whereas no reduction was observed if Kato-Katz slides were stored in the refrigerator (19 vs 21). The time x storage interaction effect was statistically significant (coefficient 0.26, 95% CI: 0.17 to 0.35, p < 0.0001). After 24 hours mean hookworm FECs dropped close to zero, irrespective of the storage condition. Whole stool samples stored at room temperature for one day resulted in a mean hookworm FEC decrease of 23% (p < 0.0001), compared to a 13% reduction (p < 0.0001) if samples were stored in the refrigerator. Fecal egg counts of A. lumbricoides and T. trichiura remained stable over time regardless of storage temperature of whole stool samples. Finally, we found a significant reduction of the variation of hookworm and T. trichiura eggs with increasing rounds of stirring the sample, but not for A. lumbricoides. For hookworm we observed a simultaneous decrease in mean FECs, making it difficult to draw recommendations on stirring samples.

Conclusions/significance: Our findings suggest that stool samples (i) should be analyzed on the day of collection and (ii) should be analyzed between 20-30 minutes after slide preparation; if that is not possible, Kato-Katz slides can be stored in a refrigerator for a maximum of 110 minutes.
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http://dx.doi.org/10.1371/journal.pntd.0009032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857572PMC
January 2021

Evaluation of Commercially Available Anthelminthics in Laboratory Models of Human Intestinal Nematode Infections.

ACS Infect Dis 2021 05 7;7(5):1177-1185. Epub 2021 Jan 7.

Swiss Tropical and Public Health Institute, Socinstrasse 57, CH-4051 Basel, Switzerland.

Drug repurposing from veterinary to human medicine has been the main strategy to develop the four recommended human anthelminthics, albendazole, mebendazole, levamisole, and pyrantel pamoate, 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. studies were performed on L1 larval stage and adults, as well as , , , and L3 larvae and adults. The benzimidazoles showed pronounced differences against larval and adult stages, with low activity against larvae and the highest activity observed against adult (IC of flubendazole 1.1 μM). The macrocyclic lactones, on the other hand, revealed a higher activity on the larval stages, with the lowest IC values observed against L3 (IC values of 0.03-3 μM). studies were performed in the and mice models, with moxidectin and milbemycin oxime showing the highest activity against (ED values of 0.009 and 0.006 mg/kg, respectively) and moxidectin and abamectin being the most effective drugs against (ED values of 0.2 and 0.5 mg/kg, respectively). 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.
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http://dx.doi.org/10.1021/acsinfecdis.0c00719DOI Listing
May 2021

Identification of Adult spp. Using Matrix-Assisted Laser/Desorption Ionization Time-of-Flight (MALDI-TOF) Mass Spectrometry.

Microorganisms 2020 Dec 31;9(1). Epub 2020 Dec 31.

Institute of Medical Microbiology and Hygiene, Saarland University, 66421 Homburg/Saar, Germany.

Fascioliasis is a neglected trematode infection caused by and . Routine diagnosis of fascioliasis relies on macroscopic identification of adult worms in liver tissue of slaughtered animals, and microscopic detection of eggs in fecal samples of animals and humans. However, the diagnostic accuracy of morphological techniques and stool microscopy is low. Molecular diagnostics (e.g., polymerase chain reaction (PCR)) are more reliable, but these techniques are not routinely available in clinical microbiology laboratories. Matrix-assisted laser/desorption ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) is a widely-used technique for identification of bacteria and fungi; yet, standardized protocols and databases for parasite detection need to be developed. The purpose of this study was to develop and validate an in-house database for species-specific identification. To achieve this goal, the posterior parts of seven adult and one adult were processed and subjected to MALDI-TOF MS to create main spectra profiles (MSPs). Repeatability and reproducibility tests were performed to develop the database. A principal component analysis revealed significant differences between the spectra of and . Subsequently, 78 samples were analyzed by MALDI-TOF MS using the previously developed database, out of which 98.7% (n = 74) and 100% (n = 3) were correctly identified as and , respectively. Log score values ranged between 1.73 and 2.23, thus indicating a reliable identification. We conclude that MALDI-TOF MS can provide species-specific identification of medically relevant liver flukes.
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http://dx.doi.org/10.3390/microorganisms9010082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823262PMC
December 2020

Antischistosomal, antionchocercal and antitrypanosomal potentials of some Ghanaian traditional medicines and their constituents.

PLoS Negl Trop Dis 2020 12 31;14(12):e0008919. Epub 2020 Dec 31.

Department of Chemistry, University of Ghana, Accra, Ghana.

Background: Ghana is endemic for some neglected tropical diseases (NTDs) including schistosomiasis, onchocerciasis and lymphatic filariasis. The major intervention for these diseases is mass drug administration of a few repeatedly recycled drugs which is a cause for major concern due to reduced efficacy of the drugs and the emergence of drug resistance. Evidently, new treatments are needed urgently. Medicinal plants, on the other hand, have a reputable history as important sources of potent therapeutic agents in the treatment of various diseases among African populations, Ghana inclusively, and provide very useful starting points for the discovery of much-needed new or alternative drugs.

Methodology/principal Findings: In this study, extracts of fifteen traditional medicines used for treating various NTDs in local communities were screened in vitro for efficacy against schistosomiasis, onchocerciasis and African trypanosomiasis. Two extracts, NTD-B4-DCM and NTD-B7-DCM, prepared from traditional medicines used to treat schistosomiasis, displayed the highest activity (IC50 = 30.5 μg/mL and 30.8 μg/mL, respectively) against Schistosoma mansoni adult worms. NTD-B2-DCM, also obtained from an antischistosomal remedy, was the most active against female and male adult Onchocera ochengi worms (IC50 = 76.2 μg/mL and 76.7 μg/mL, respectively). Antitrypanosomal assay of the extracts against Trypanosoma brucei brucei gave the most promising results (IC50 = 5.63 μg/mL to 18.71 μg/mL). Incidentally, NTD-B4-DCM and NTD-B2-DCM, also exhibited the greatest antitrypanosomal activities (IC50 = 5.63 μg/mL and 7.12 μg/mL, respectively). Following the favourable outcome of the antitrypanosomal screening, this assay was selected for bioactivity-guided fractionation. NTD-B4-DCM, the most active extract, was fractionated and subsequent isolation of bioactive constituents led to an eupatoriochromene-rich oil (42.6%) which was 1.3-fold (IC50 <0.0977 μg/mL) more active than the standard antitrypanosomal drug, diminazene aceturate (IC50 = 0.13 μg/mL).

Conclusion/significance: These findings justify the use of traditional medicines and demonstrate their prospects towards NTDs drug discovery.
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http://dx.doi.org/10.1371/journal.pntd.0008919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810346PMC
December 2020

Activities of Quinoxaline, Nitroquinoxaline, and [1,2,4]Triazolo[4,3-a]quinoxaline Analogs of MMV007204 against Schistosoma mansoni.

Antimicrob Agents Chemother 2021 02 17;65(3). Epub 2021 Feb 17.

Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland

The reliance on one drug, praziquantel, to treat the parasitic disease schistosomiasis in millions of people a year shows the need to further develop a pipeline of new drugs to treat this disease. Recently, an antimalarial quinoxaline derivative (MMV007204) from the Medicines for Malaria Venture (MMV) Malaria Box demonstrated promise against In this study, 47 synthesized compounds containing quinoxaline moieties were first assayed against the larval stage of this parasite, newly transformed schistosomula (NTS); of these, 16 killed over 70% NTS at 10 µM. Further testing against NTS and adult yielded three compounds with 50% inhibitory concentrations (ICs) of ≤0.31 µM against adult and selectivity indices of ≥8.9. Administration of these compounds as a single oral dose of 400 mg/kg of body weight to infected mice yielded only moderate worm burden reduction (WBR) (9.3% to 46.3%). The discrepancy between these compounds' good activities and their poor activities indicates that optimization of their pharmacokinetic properties may yield compounds with greater bioavailabilities and better antischistosomiasis activities .
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http://dx.doi.org/10.1128/AAC.01370-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092513PMC
February 2021

A cross-sectional survey on parasitic infections in schoolchildren in a rural Tanzanian community.

Acta Trop 2021 Jan 4;213:105737. Epub 2020 Nov 4.

Swiss Tropical and Public Health Institute, P.O. Box, CH-4002 Basel, Switzerland; University of Basel, P.O. Box, CH-4003 Basel, Switzerland. Electronic address:

Infectious diseases remain the leading cause of death in children in low- and middle-income countries. Infection with helminths and intestinal protozoa cause considerable morbidity. The aim of this study was to assess the health status of schoolchildren in nine villages of the Kilombero district in Tanzania. We conducted a cross-sectional survey and subjected 427 children aged 6-12 years to standardized diagnostic tests. We found that 15% of children were infected with Entamoeba histolytica/Entamoeba dispar/Entamoeba moshkovskii, 12% with Schistosoma mansoni, and 5% with Plasmodium falciparum. The most common soil-transmitted helminth species was Trichuris trichiura (7%). Strongyloides stercoralis, Schistosoma haematobium, Giardia intestinalis and lymphatic filariasis were rare. Having a latrine inside the house was associated with a lower odds of parasite infections (odds ratio (OR) 0.51, 95% confidence interval (CI) 0.27-0.96, p = 0.04). Children from households with goats were at higher odds of E. histolytica/E. dispar/E. moshkovskii infection (OR 3.03, 95%%CI 1.29-7.10, p = 0.01).When compared to a cross-sectional survey conducted in the same district in the 1980s, there seems to have been a substantial reduction in the prevalence and intensity of parasitic infections, except for T. trichiura, which showed a similar prevalence. Our data suggest that the general development, coupled with infectious disease control programmes improved children's health markedly. However, continued efforts to control parasitic diseases, including new approaches of drug combinations, stronger intersectoral collaboration, rigorous surveillance and public health responses tailored to the local settings are needed to move from control to elimination.
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http://dx.doi.org/10.1016/j.actatropica.2020.105737DOI Listing
January 2021

Efficacy, safety and acceptability of a new chewable formulation the solid tablet of mebendazole against hookworm infections in children: An open-label, randomized controlled trial.

EClinicalMedicine 2020 Oct 20;27:100556. Epub 2020 Sep 20.

Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, and University of Basel, P.O. Box, CH-4002, Basel, Switzerland.

Background: Soil-transmitted helminths (STHs) infect almost 1·5 billion people worldwide. The control of STH infections is based on preventive chemotherapy using either albendazole or mebendazole. Before being widely used, a sufficient body of evidence on efficacy, safety and acceptability is warranted for the new chewable child-friendly formulation of mebendazole that was recently developed.

Methods: We conducted a randomised controlled superiority trial in four primary schools and kindergartens on Pemba Island, Tanzania. We considered eligible children aged 3 to 12 years with a hookworm infection intensity of at least 50 eggs per gram (EPG) of stool and no chronic diseases. Participants were allocated to treatment arms (ratio 1:1) using a computer generated random sequence. Our primary outcome was geometric mean based egg reduction rate (ERR) against hookworm assessed 14-21 days post-treatment. This trial complete and is registered with ClinicalTrials.gov, number NCT03995680 (June 24, 2019).

Findings: 397 children were eligible and randomised into the solid (198) or chewable (199) tablet arms, of whom 393 were analysed. We found no significant difference between both formulations in terms of ERR (solid 70·8% chewable 68·5%, difference in ERR 2·3%-points, 95% CI -7·8 to 12·6,  = 0.65) and CR (11·2 12·7%, 95% CI -4·9 to 7·9,  = 0.65) against hookworm infections. Adverse events were mild in both treatment arms.

Interpretations: Though we could not demonstrate superiority in terms of efficacy of the new formulation, the difference between arms was small and therefore, the chewable formulation could be safely used as an alternative to swallowable tablets, in particular in young children who may have swallowing difficulties. This might help increase compliance and, consequently, enhance the effect of preventive chemotherapy.
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http://dx.doi.org/10.1016/j.eclinm.2020.100556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599302PMC
October 2020

Population Pharmacokinetics and Exposure-Response Analysis of Tribendimidine To Improve Treatment for Children with Hookworm Infection.

Antimicrob Agents Chemother 2021 01 20;65(2). Epub 2021 Jan 20.

Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland

Tribendimidine has been successful in treating hookworm infections and may serve as an alternative to albendazole should resistance arise. Our aims were to (i) characterize the pharmacokinetics (PK) of tribendimidine's primary metabolite, deacetylated amidantel (dADT), and secondary metabolite, acetylated derivative of amidantel (adADT), in school-aged children and adolescents, (ii) link exposure to efficacy against hookworm, and (iii) evaluate whether tribendimidine pharmacotherapy in children could be further improved. First, a population PK model was developed based on dried-blood-spot samples collected from 155 school-aged children and adolescents with hookworm infections, following tribendimidine doses ranging from 100 to 400 mg. Second, an exposure-response analysis was conducted to link the active metabolite dADT to cure rates (CRs) and egg reduction rates (ERRs). Third, simulations were performed to identify a treatment strategy associated with >90% CRs. A two-compartmental model with transit compartments describing observed delay in absorption adequately described PK data of dADT and adADT. Allometric scaling was included to account for growth and development. The absorption rate was 56% lower with 200-mg tablets than with 50-mg tablets, while the extent of absorption remained unaffected. The identified models linking dADT exposure to ERRs and CRs showed shallow curves, as increasing exposure led to marginal efficacy increase. Combination therapy should be considered, as a 12-fold-higher dose would be needed to achieve 95% ERRs and CRs >90% with tribendimidine alone. Further studies are warranted to evaluate safety of higher tribendimidine doses and combination therapies with other anthelmintic agents to improve treatment strategy for children with hookworm infection.
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http://dx.doi.org/10.1128/AAC.01778-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848977PMC
January 2021

Pharmacometric Analysis of Tribendimidine Monotherapy and Combination Therapies To Achieve High Cure Rates in Patients with Hookworm Infections.

Antimicrob Agents Chemother 2021 01 20;65(2). Epub 2021 Jan 20.

Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland

In the treatment of hookworm infections, pharmacotherapy has been only moderately successful and drug resistance is a threat. Therefore, novel treatment options including combination therapies should be considered, in which tribendimidine could play a role. Our aims were to (i) characterize the pharmacokinetics of tribendimidine's metabolites in adolescents receiving tribendimidine monotherapy or in combination with ivermectin or oxantel pamoate, (ii) evaluate possible drug-drug interactions (DDI), (iii) link exposure to response, and (iv) identify a treatment strategy associated with high efficacy, i.e., >90% cure rates (CRs), utilizing model-based simulations. A population pharmacokinetic model was developed for tribendimidine's primary and secondary metabolites, dADT and adADT, in 54 hookworm-positive adolescents, with combination therapy evaluated as a possible covariate. Subsequently, an exposure-response analysis was performed utilizing CRs as response markers. Simulations were performed to identify a treatment strategy to achieve >90% CRs. A two-compartmental model best described metabolite disposition. No pharmacokinetic DDI was identified with ivermectin or oxantel pamoate. All participants receiving tribendimidine plus ivermectin were cured. For the monotherapy arm and the arm including the combination with oxantel pamoate, models adequately described the correlation between dADT exposure and probability of being cured, with required exposures to achieve 50% of maximum effect of 39.6 and 15.6 nmol/ml·h, respectively. Based on our simulations, an unrealistically high monotherapy tribendimidine dose would be necessary to achieve CRs of >90%, while combination therapy with ivermectin would meet this desired target product profile. Further clinical studies should be launched to develop this combination for the treatment of hookworm and other helminth infections.
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http://dx.doi.org/10.1128/AAC.00714-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849000PMC
January 2021

Evaluation of Human Liver Microtissues for Drug Screening on Schistosomula.

ACS Infect Dis 2021 07 26;7(7):1894-1900. Epub 2020 Oct 26.

Swiss Tropical and Public Health Institute, Socinstrasse 57, CH-4002 Basel, Switzerland.

Schistosomiasis is a major neglected tropical disease with more than 200 million infections annually. Despite only one drug, praziquantel, being available, the drug pipeline against schistosomiasis is empty, and drug screening tools have limitations. We evaluated the potential of human liver microtissues (hLiMTs) in antischistosomal drug discovery. Because hLiMTs express all human P450 enzymes, they are an excellent tool to evaluate compounds' bioinactivation, bioactivation, and toxicity. To validate the metabolic conversion capacity of hLiMTs, we first quantified ()- and ()-praziquantel and the main metabolite -OH-praziquantel following incubation with 0.032-50 μM (0.01-15.62 μg/mL) praziquantel for up to 72 h by a validated LC-MS/MS method. We cocultured hLiMTs with newly transformed schistosomula (NTS) and evaluated the antischistosomal activity and cytotoxicity of three prodrugs terfenadine, tamoxifen citrate, and flutamide. HLiMTs converted 300-350 ng ()-praziquantel within 24 h into -OH-praziquantel. We observed changes in the IC values for terfenadine, flutamide, and tamoxifen citrate in comparison to the standard NTS assay Cytotoxicity was observed at high concentrations of flutamide and tamoxifen citrate. An platform containing hLiMTs could serve as an advanced drug screening tool for , providing information on reduced or increased activity and toxicity.
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http://dx.doi.org/10.1021/acsinfecdis.0c00614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611177PMC
July 2021

Performance of the Kato-Katz method and real time polymerase chain reaction for the diagnosis of soil-transmitted helminthiasis in the framework of a randomised controlled trial: treatment efficacy and day-to-day variation.

Parasit Vectors 2020 Oct 15;13(1):517. Epub 2020 Oct 15.

Swiss Tropical and Public Health Institute, Socinstrasse 57, 4051, Basel, Switzerland.

Background: Accurate, scalable and sensitive diagnostic tools are crucial in determining prevalence of soil-transmitted helminths (STH), assessing infection intensities and monitoring treatment efficacy. However, assessments on treatment efficacy comparing traditional microscopic to newly emerging molecular approaches such as quantitative Polymerase Chain Reaction (qPCR) are scarce and hampered partly by lack of an established diagnostic gold standard.

Methods: We compared the performance of the copromicroscopic Kato-Katz method to qPCR in the framework of a randomized controlled trial on Pemba Island, Tanzania, evaluating treatment efficacy based on cure rates of albendazole monotherapy versus ivermectin-albendazole against Trichuris trichiura and concomitant STH infections. Day-to-day variability of both diagnostic methods was assessed to elucidate reproducibility of test results by analysing two stool samples before and two stool samples after treatment of 160 T. trichiura Kato-Katz positive participants, partially co-infected with Ascaris lumbricoides and hookworm, per treatment arm (n = 320). As negative controls, two faecal samples of 180 Kato-Katz helminth negative participants were analysed.

Results: Fair to moderate correlation between microscopic egg count and DNA copy number for the different STH species was observed at baseline and follow-up. Results indicated higher sensitivity of qPCR for all three STH species across all time points; however, we found lower test result reproducibility compared to Kato-Katz. When assessed with two samples from consecutive days by qPCR, cure rates were significantly lower for T. trichiura (23.2 vs 46.8%), A. lumbricoides (75.3 vs 100%) and hookworm (52.4 vs 78.3%) in the ivermectin-albendazole treatment arm, when compared to Kato-Katz.

Conclusions: qPCR diagnosis showed lower reproducibility of test results compared to Kato-Katz, hence multiple samples per participant should be analysed to achieve a reliable diagnosis of STH infection. Our study confirms that cure rates are overestimated using Kato-Katz alone. Our findings emphasize that standardized and accurate molecular diagnostic tools are urgently needed for future monitoring within STH control and/or elimination programmes.
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http://dx.doi.org/10.1186/s13071-020-04401-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7558729PMC
October 2020

Comparison of real-time PCR and the Kato-Katz method for the diagnosis of soil-transmitted helminthiasis and assessment of cure in a randomized controlled trial.

BMC Microbiol 2020 10 2;20(1):298. Epub 2020 Oct 2.

Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002, Basel, Switzerland.

Background: Diagnosis of soil-transmitted helminths (STHs) in developing countries is commonly based on microscopic detection of eggs in stool samples, using the Kato-Katz (KK) method, which has a poor sensitivity for detecting light intensity infections. We compared the performance of the KK method and real-time PCR in the framework of a randomized trial, which evaluated four novel treatments against Trichuris trichiura and concomitant STH infections.

Results: Two stool samples obtained from 320 participants were examined at baseline and follow-up with quadruplicate KK and PCR analyses of one of the two samples using "bead-beating" for DNA extraction. At follow-up, 80 samples were negative according to both PCR and KK and 173 were positive with both methods for any of the STHs. Relative to PCR, the calculated sensitivity of KK at follow-up was 83.6%, 43.0% and 53.8% for T. trichiura, for hookworm and for Ascaris lumbricoides, respectively. The sensitivity of PCR compared with KK at this time point was 89.1% for T. trichiura, 72.7% for hookworm and 87.5% for A. lumbricoides. Cure rates (CRs) for T. trichiura and A. lumbricoides were slightly lower with the PCR method. For hookworm CRs with KK were mostly significantly lower, namely 36.7%, 91.1%, 72.2% and 77.8% for moxidectin, moxidectin in combination with tribendimidine, moxidectin in combination with albendazole and albendazole in combination with oxantel pamoate, respectively, whereas with PCR the CRs were 8.3%, 82.6%, 37.1% and 57.1%, respectively.

Conclusions: In conclusion, a single real-time PCR is as sensitive as quadruplicate KK for T. trichiura and A. lumbricoides detection but more sensitive for hookworm, which has an influence on the estimated treatment efficacy. PCR method with DNA extraction using the "bead-beating protocol" should be further promoted in endemic areas and laboratories that can afford the needed equipment. The study is registered at ISRCTN (no. 20398469).
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http://dx.doi.org/10.1186/s12866-020-01963-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7531123PMC
October 2020

Characterization of Moxidectin against : In Vitro and In Vivo Activity and Pharmacokinetics in the Rat Model.

ACS Infect Dis 2021 05 8;7(5):1069-1076. Epub 2020 Oct 8.

Swiss Tropical and Public Health Institute, Socinstrasse 57, P.O. Box, CH-4002 Basel, Switzerland.

is a soil-transmitted helminth affecting an estimated 30-100 million people. Since the infection may be severe and life-threatening, accessible and effective treatment is pivotal. Currently, ivermectin is the drug of choice but has limitations. Moxidectin, a veterinary anthelminthic approved for use in human onchocerciasis, is a promising drug alternative against strongyloidiasis. In this study, we evaluated the in vitro activity of moxidectin on larvae (L) and adult females and the activity as well as the pharmacokinetics of moxidectin in infected rats. In vitro, moxidectin had an activity that was similar to that of ivermectin, with median lethal concentration values for L and adults in the range of 0.08-1.44 μM, after 72 h of exposure. In vivo, doses of 250, 500, and 750 μg/kg of moxidectin resulted in a reduction of the worm burden ranging from 48.5 to 75%. At the highest dose (750 μg/kg) we observed a maximal blood concentration of 50.3 ng/mL and an area under the curve of 895.2 ng × h/mL. The half-life in rats was 9 h, and moxidectin was cleared to undetectable blood levels within 7 d (<10 ng/mL). No exposure-response relationship was observed. This work contributes to the characterization of moxidectin in the treatment of as a model of . and, as such, supports moving moxidectin further along the drug development pipeline in the treatment of human strongyloidiasis.
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http://dx.doi.org/10.1021/acsinfecdis.0c00435DOI Listing
May 2021

An in-depth report of quality control on Kato-Katz and data entry in four clinical trials evaluating the efficacy of albendazole against soil-transmitted helminth infections.

PLoS Negl Trop Dis 2020 09 21;14(9):e0008625. Epub 2020 Sep 21.

Department of Virology, Parasitology and Immunology, Ghent University, Merelbeke, Belgium.

Background: Efforts to control soil-transmitted helminth (STH) infections have intensified over the past decade. Field-survey data on STH prevalence, infection intensity and drug efficacy is necessary to guide the implementation of control programs and should be of the best possible quality.

Methodology: During four clinical trials designed to evaluate the efficacy of albendazole against STHs in Brazil, Ethiopia, Lao PDR and Tanzania, quality control (QC) was performed on the duplicate Kato-Katz thick smears and the data entry. We analyzed datasets following QC on both fecal egg counts (FECs) and data entry, and compared the prevalence of any STH infection and moderate-to-heavy intensity (MHI) infections and the drug efficacy against STH infections.

Results: Across the four study sites, a total of 450 out of 4,830 (9.3%) Kato-Katz thick smears were re-examined. Discrepancies in FECs varied from ~3% (hookworms) to ~6.5% (Ascaris lumbricoides and Trichuris trichiura). The difference in STH prevalence and prevalence of MHI infections using the datasets with and without QC of the FECs did not exceed 0.3%, except for hookworm infections in Tanzania, where we noted a 2.2 percentage point increase in MHI infections (pre-QC: 1.6% vs. post-QC: 3.8%). There was a 100% agreement in the classification of drug efficacy of albendazole against STH between the two datasets. In total, 201 of the 28,980 (0.65%) data entries that were made to digitize the FECs were different between both data-entry clerks. Nevertheless, the overall prevalence of STH, the prevalence of MHI infections and the classification of drug efficacy remained largely unaffected.

Conclusion/significance: In these trials, where staff was informed that QC would take place, minimal changes in study outcomes were reported following QC on FECs or data entry. Nevertheless, imposing QC did reduce the number of errors. Therefore, application of QC together with proper training of the personnel and the availability of clear standard operating procedures is expected to support higher data quality.
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http://dx.doi.org/10.1371/journal.pntd.0008625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549791PMC
September 2020

Multidisciplinary Preclinical Investigations on Three Oxamniquine Analogues as New Drug Candidates for Schistosomiasis*.

Chemistry 2020 Nov 22;26(66):15232-15241. Epub 2020 Oct 22.

Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory of Inorganic Chemical Biology, 75005, Paris, France.

Schistosomiasis is a disease of poverty affecting millions of people. Praziquantel (PZQ), with its strengths and weaknesses, is the only treatment available. We previously reported findings on three lead compounds derived from oxamniquine (OXA), an old antischistosomal drug: ferrocene-containing (Fc-CH -OXA), ruthenocene-containing (Rc-CH -OXA) and benzene-containing (Ph-CH -OXA) OXA derivatives. These derivatives showed excellent in vitro activity against both Schistosoma mansoni larvae and adult worms and S. haematobium adult worms, and were also active in vivo against adult S. mansoni. Encouraged by these promising results, we conducted additional in-depth preclinical studies and report in this investigation on metabolic stability studies, in vivo studies on S. haematobium and juvenile S. mansoni, computational simulations, and formulation development. Molecular dynamics simulations supported the in vitro results on the target protein. Though all three compounds were poorly stable within an acidic environment, they were only slightly cleared in the in vitro liver model. This is likely the reason why the promising in vitro activity did not translate into in vivo activity on S. haematobium. This limitation could not be overcome by the formulation of lipid nanocapsules as a way to improve the in vivo activity. Further studies should focus on increasing the compound's bioavailability, to reach an active concentration in the microenvironment of the parasite.
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http://dx.doi.org/10.1002/chem.202002856DOI Listing
November 2020

Expanding the Activity Profile of Pyrido[1,2-]benzimidazoles: Synthesis and Evaluation of Novel -1-Phenylethanamine Derivatives against .

ACS Infect Dis 2021 05 18;7(5):1032-1043. Epub 2020 Aug 18.

Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.

Praziquantel is the only widely available drug to treat schistosomiasis. With very few candidates currently in the drug development pipeline, there is an urgent need to discover and develop novel antischistosomal drugs. In this regard, the pyrido[1,2-]benzimidazole (PBI) scaffold has emerged as a promising chemotype in hit-to-lead efforts. Here, we report a novel series of antischistosomal PBIs with potent activity (IC values of 0.08-1.43 μM) against newly transformed schistosomula and adult worms. Moreover, the current PBIs demonstrated good hepatic microsomal stability (>70% of drug remaining after 30 min) and were nontoxic to the Chinese hamster ovarian and human liver HepG2 cells, though toxicity (selectivity index, SI < 10) against the rat L6 myoblast cell line was observed. The compounds showed a small therapeutic window but were efficacious , exhibiting moderate to high worm burden reductions of 35.8-89.6% in -infected mice.
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http://dx.doi.org/10.1021/acsinfecdis.0c00278DOI Listing
May 2021
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