Current Mass Drug Administration Research Articles

Single nucleotide polymorphisms in the β-tubulin gene family of Ascaris lumbricoides and their potential role in benzimidazole resistance: a systematic review

IntroductionThe most common soil-transmitted helminthic infection is caused by Ascaris lumbricoides (A. lumbricoides). Approximately 4 billion people are at risk of infection globally. The World Health Organisation recommends the administration of benzimidazole- containing deworming drugs (Albendazole and Mebendazole) to all susceptible populations. Due to this high drug pressure, these parasites may develop resistance to current benzimidazole drugs. The β-tubulin gene family is the target gene for benzimidazole deworming drugs. This systematic review aimed to highlight work that explored the genetic mutations in the β-tubulin gene family of A. lumbricoides that are associated with potential benzimidazole resistance.MethodsAn electronic search of several online databases was used to extract eligible articles using specific keywords related to the topic of interest.ResultsThe majority of ascariasis infections occur in the subtropical and tropical regions of sub-Saharan Africa, the Americas and East Asia, although not enough studies were done to extensively cover this geographical range. In the β-tubulin gene family of A. lumbricoides the mutations at codons F200Y (TTC/Phenylalanine to TAC/Tyrosine), E198A (GAG, GAA/Glutamic acid to GCG, GCA/Alanine) and F167Y (TTC, TTT/Phenylalanine to TAC, TAT/Tyrosine) were associated with potential benzimidazole resistance.DiscussionResistant mutations were found in A. lumbricoides samples at codon F167Y from Haiti, Kenya and Panama. The first evidence of the mutation at codon F200Y was observed in Brazil. The codon E198A mutation was the least prevalent and most undetected.ConclusionThere is a serious shortage of studies investigating the prevalence of β-tubulin gene family mutations in A. lumbricoides populations from endemic areas; this is a serious concern as resistance will negatively impact current mass drug administration programmes.

The anthelmintic meclonazepam activates a schistosome transient receptor potential channel

Parasitic flatworms cause various clinical and veterinary infections that impart a huge burden worldwide. The most clinically impactful infection is schistosomiasis, a neglected tropical disease caused by parasitic blood flukes. Schistosomiasis is treated with praziquantel (PZQ), an old drug introduced over 40 years ago. New drugs are urgently needed, as while PZQ is broadly effective it suffers from several limitations including poor efficacy against juvenile worms which may prevent it from being completely curative. An old compound that retains efficacy against juvenile worms is the benzodiazepine meclonazepam (MCLZ). However, host side effects caused by benzodiazepines preclude development of MCLZ as a drug, and MCLZ lacks an identified parasite target to catalyze rational drug design for engineering out human host activity. Here, we identify a transient receptor potential ion channel of the melastatin subfamily, named TRPMMCLZ, as a parasite target of MCLZ. MCLZ potently activates Schistosoma mansoni TRPMMCLZ through engagement of a binding pocket within the voltage-sensor like domain of the ion channel to cause worm paralysis, tissue depolarization and surface damage. TRPMMCLZ reproduces all known features of MCLZ action on schistosomes, including a lower activity versus Schistosoma japonicum which is explained by a polymorphism within this VSLD binding pocket. TRPMMCLZ is distinct from the TRP channel targeted by PZQ (TRPMPZQ), with both anthelmintic chemotypes targeting unique parasite TRPM paralogs. This advances TRPMMCLZ as a novel druggable target that could circumvent target-based resistance emerging in response to current mass drug administration campaigns centered around PZQ.

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

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.

Efficacy of subcutaneous doses and a new oral amorphous solid dispersion formulation of flubendazole on male jirds (Meriones unguiculatus) infected with the filarial nematode Brugia pahangi.

River blindness and lymphatic filariasis are two filarial diseases that globally affect millions of people mostly in impoverished countries. Current mass drug administration programs rely on drugs that primarily target the microfilariae, which are released from adult female worms. The female worms can live for several years, releasing millions of microfilariae throughout the course of infection. Thus, to stop transmission of infection and shorten the time to elimination of these diseases, a safe and effective drug that kills the adult stage is needed. The benzimidazole anthelmintic flubendazole (FBZ) is 100% efficacious as a macrofilaricide in experimental filarial rodent models but it must be administered subcutaneously (SC) due to its low oral bioavailability. Studies were undertaken to assess the efficacy of a new oral amorphous solid dispersion (ASD) formulation of FBZ on Brugia pahangi infected jirds (Meriones unguiculatus) and compare it to a single or multiple doses of FBZ given subcutaneously. Results showed that worm burden was not significantly decreased in animals given oral doses of ASD FBZ (0.2–15 mg/kg). Regardless, doses as low as 1.5 mg/kg caused extensive ultrastructural damage to developing embryos and microfilariae (mf). SC injections of FBZ in suspension (10 mg/kg) given for 5 days however, eliminated all worms in all animals, and a single SC injection reduced worm burden by 63% compared to the control group. In summary, oral doses of ASD formulated FBZ did not significantly reduce total worm burden but longer treatments, extended takedown times or a second dosing regimen, may decrease female fecundity and the number of mf shed by female worms.

One hundred years of neglect in paediatric schistosomiasis.

Early in the history of schistosomiasis research, children under 5 years of age were known to be infected. Although this problem was recognized over 100 years ago, insufficient action has been taken to address this issue. Under current policy, such infected children only receive their first antiparasitic treatment (praziquantel - PZQ) upon entry into primary school as current mass drug administration programmes typically target school-aged children. For many infected children, they will wait up to 6 years before receiving their first medication and significant schistosomiasis-related morbidity may have already established. This inequity would not be accepted for other diseases. To unveil some of the reasons behind this neglect, it is paramount to understand the intricate historical relationship between schistosomiasis and British Imperial medicine, to underline its lasting influence on today's public health priorities. This review presents a perspective on the historical neglect of paediatric schistosomiasis, focusing on important gaps that persist from the early days after discovery of this parasite. Looking to end this inequity, we address several issues that need to be overcome to move forward towards the lasting success of schistosomiasis control and elimination efforts.

Expanding Praziquantel (PZQ) Access beyond Mass Drug Administration Programs: Paving a Way Forward for a Pediatric PZQ Formulation for Schistosomiasis.

Treating preschool age children (PSAC) with schistosomiasis remains a challenge. Without a pediatric praziquantel (PZQ) formulation, the inclusion of this age group in control programs is limited, and general access to treatment in routine care settings is severely bottlenecked. There are, however, current platforms that target PSAC in primary health care such as the integrated management of childhood illnesses (IMCI), which could integrate PZQ in their portfolio and deliver a pediatric PZQ formulation when available. In addition, other age groups such as school-aged children (SAC) could also benefit from the IMCI’s successful strategy and be treated in health centers using a similar approach. This Viewpoint article reports a summary of a symposium held at the American Society of Tropical Medicine and Hygiene national meeting in 2014 that brought together six experts in different areas in the field of pediatric schistosomiasis to form a working group that could provide recommendations for the inclusion of PSAC in the IMCI and other existing preschool outreach programs. This was to develop and adapt methodologies to fill existing gaps left by current mass drug administration (MDA) programs and synergize efforts for schistosomiasis control more broadly. Foremost, this includes a better definition of subclinical disease in young children to integrate into ICMI guidelines and further demonstration of the benefit of expanded access of treatment to children of all ages by encouraging universal access.

Bayesian calibration of simulation models for supporting management of the elimination of the macroparasitic disease, Lymphatic Filariasis.

BackgroundMathematical models of parasite transmission can help integrate a large body of information into a consistent framework, which can then be used for gaining mechanistic insights and making predictions. However, uncertainty, spatial variability and complexity, can hamper the use of such models for decision making in parasite management programs.MethodsWe have adapted a Bayesian melding framework for calibrating simulation models to address the need for robust modelling tools that can effectively support management of lymphatic filariasis (LF) elimination in diverse endemic settings. We applied this methodology to LF infection and vector biting data from sites across the major LF endemic regions in order to quantify model parameters, and generate reliable predictions of infection dynamics along with credible intervals for modelled output variables. We used the locally calibrated models to estimate breakpoint values for various indicators of parasite transmission, and simulate timelines to parasite extinction as a function of local variations in infection dynamics and breakpoints, and effects of various currently applied and proposed LF intervention strategies.ResultsWe demonstrate that as a result of parameter constraining by local data, breakpoint values for all the major indicators of LF transmission varied significantly between the sites investigated. Intervention simulations using the fitted models showed that as a result of heterogeneity in local transmission and extinction dynamics, timelines to parasite elimination in response to the current Mass Drug Administration (MDA) and various proposed MDA with vector control strategies also varied significantly between the study sites. Including vector control, however, markedly reduced the duration of interventions required to achieve elimination as well as decreased the risk of recrudescence following stopping of MDA.ConclusionsWe have demonstrated how a Bayesian data-model assimilation framework can enhance the use of transmission models for supporting reliable decision making in the management of LF elimination. Extending this framework for delivering predictions in settings either lacking or with only sparse data to inform the modelling process, however, will require development of procedures to estimate and use spatio-temporal variations in model parameters and inputs directly, and forms the next stage of the work reported here.Electronic supplementary materialThe online version of this article (doi:10.1186/s13071-015-1132-7) contains supplementary material, which is available to authorized users.

Knowledge, attitude, and practices towards schistosomiasis among rural population in Yemen.

BackgroundSchistosomiasis is highly prevalent in Yemen, with an estimated 3 million cases, particularly among rural communities. This community-based study aims to evaluate the knowledge, attitude and practices (KAP) on schistosomiasis among rural communities in Yemen.MethodsA cross-sectional study was carried out among 250 households from ten rural districts in Yemen. Overall, 400 children were screened for urogenital and intestinal schistosomiasis. Moreover, parents were interviewed using a pre-tested questionnaire to collect information about the demographic and socioeconomic information and their KAP concerning schistosomiasis.ResultsA total of 127 (31.8 %) children were found to be excreting schistosome eggs in either their urine or faeces (22.5 % S. haematobium and 8.0 % S. mansoni). Although 92.4 % of the respondents had heard about schistosomiasis, 49.8 %, 68.0 % and 47.2 % had knowledge concerning the transmission, signs and symptoms, and prevention, respectively. In addition, 77.1 % considered schistosomiasis as harmful while 48.5 % believed that schistosomiasis could be prevented, albeit their practices to prevent infections were still inadequate. Significant associations between the KAP and age, education, employment status and household monthly income were reported (P < 0.05). Moreover, a significantly higher level of knowledge was reported among the respondents who had infected children compared to those with no infected family members (P < 0.05). Multiple logistic regression analysis revealed that the level of education and the history of schistosomiasis were the most important factors associated with the KAP concerning schistosomiasis among this population.ConclusionThis study reveals that knowledge about the cause, transmission, symptoms and prevention of schistosomiasis among the rural population in Yemen was inadequate, and that this could be a challenging obstacle to the elimination of schistosomiasis in these communities. Besides the current mass drug administration, school and community-based health education regarding schistosomiasis is imperative among these communities to significantly reduce the transmission and morbidity of schistosomiasis.

It's time to dispel the myth of "asymptomatic" schistosomiasis.

It's time to dispel the myth of "asymptomatic" schistosomiasis.

Schistosomiasis Elimination Strategies and Potential Role of a Vaccine in Achieving Global Health Goals

In March 2013, the National Institute of Allergy and Infectious Diseases and the Bill and Melinda Gates Foundation co-sponsored a meeting entitled "Schistosomiasis Elimination Strategy and Potential Role of a Vaccine in Achieving Global Health Goals" to discuss the potential role of schistosomiasis vaccines and other tools in the context of schistosomiasis control and elimination strategies. It was concluded that although schistosomiasis elimination in some focal areas may be achievable through current mass drug administration programs, global control and elimination will face several significant scientific and operational challenges, and will require an integrated approach with other, additional interventions. These challenges include vector (snail) control; environmental modification; water, sanitation, and hygiene; and other future innovative tools such as vaccines. Defining a clear product development plan that reflects a vaccine strategy as complementary to the existing control programs to combat different forms of schistosomiasis will be important to develop a vaccine effectively.

Praziquantel: mechanisms of action, resistance and new derivatives for schistosomiasis

Praziquantel (PZQ) is the only drug being used to treat human schistosomiasis on a large scale. This review focuses on current knowledge about the mechanisms of action of PZQ, prospects for PZQ resistance, possible future alternative drugs and on exhortations that control of schistosomiasis and other so-called neglected tropical diseases becomes more integrated. Schistosome calcium ion (Ca2+) channels are the only moiety so far identified as the molecular target of PZQ, but the evidence remains indirect. In the presence of cytochalasin D worms survive high concentrations of PZQ and experiments with cytochalasin D also indicated that PZQ induced worm death and Ca2+ influx are not correlated. Despite PZQ being widely used, there is no clinically relevant evidence for resistance to date, but worryingly low-cure rates have been recorded in some studies in Africa. Artemisinins and the related 1,2,4-trioxolanes are new promising antischistosomal compounds, as are inhibitors of a schistosome-specific bifunctional enzyme, thioredoxin-glutathione reductase. Use of PZQ will increase in the foreseeable future, whether given alone or coadministered with other anthelminthics in integrated control programmes. PZQ resistance remains a threat and its prevention requires adequate monitoring of current mass drug administration programmes and development of new schistosomicides.