Basic biochemical investigations as rationale for the design of original antimalarial drugs. An example of phospholipid metabolism

The future of antimalarial chemotherapy is particulary alarming in view of the spread of parasite cross-resistances to drugs that are not even structurally related. Only the availability of new pharmacological models will make it possible to select molecules with novel mechanisms of action, thus delaving resistance and allowing the development of new chemotherapeutic strategies. We reached this objective in mice. Our approach is hunged on fundamental and applied research begun in 1980 to investigate to phospholipid (PL) metabolism of intraerythrocytic Plasmodium. This metabolism is abundant, specific and indispensable for the production of Plasmodium membranes. Any drug to interfere with this metabolism blocks parasitic development. The most effective interference yet found involves blockage of the choline transporter, which supplies Plasmodium with choline for the synthesis of phosphatidylcholine, its major PL, this is a limiting step in the pathway. The drug sensitivity thereshold is much lower for the parasite, which is more dependent on this metabolism than host cells. The compounds show in vitro activity against P. falciparum at 1 to 10 nM. They show a very low toxicity against a lymphblastoid cell line, demonstrating a total abscence of correlation between growth inhibition of parasites and lymphoblastoid cells. They show antimalarial activity in vivo, in the P. berghei or P. chabaudi/mouse system, at doses 20-to 100-fold lower than their in acute toxicity limit. The bioavailability of a radiolabeled form of the product seemed to be advantageous (slow blood clearance and no significant concentration in tissues). Lastly, the compounds are inexpensive to produce. They are stable and water-soluble

Structural readiness to implement community-wide mass drug administration programs for soil-transmitted helminth elimination: results from a three-country hybrid study

BACKGROUND: Current soil-transmitted helminth (STH) control programs target pre-school and school-age children with mass drug administration (MDA) of deworming medications, reducing morbidity without interrupting ongoing transmission. However, evidence suggests that STH elimination may be possible if MDA is delivered to all community members. Such a change to the STH standard-of-care would require substantial systems redesign. We measured baseline structural readiness to launch community-wide MDA for STH in Benin, India, and Malawi. METHODS: After field piloting and adaptation, the structural readiness survey included two constructs: Organizational Readiness for Implementing Change and Organizational Capacity for Change. Sub-constructs of organizational readiness include change commitment and change efficacy. Sub-constructs of organizational capacity include flexibility, organizational structure, and demonstrated capacity. Survey items were also separately organized into seven implementation domains. Surveys were administered to policymakers, mid-level managers, and implementers in each country using a five-point Likert scale. Item, sub-construct, construct, and domain-level medians and interquartile ranges were calculated for each stakeholder level within each country. RESULTS: Median organizational readiness for change scores were highest in Malawi (5.0 for all stakeholder groups). In India, scores were 5.0, 4.0, and 5.0 while in Benin, scores were 4.0, 3.0, and 4.0 for policymakers, mid-level managers, and implementers, respectively. Median change commitment was equal to or higher than median change efficacy across all countries and stakeholder groups. Median organizational capacity for change was highest in India, with a median of 4.5 for policymakers and mid-level managers and 5.0 for implementers. In Malawi, the median capacity was 4.0 for policymakers and implementers, and 3.5 for mid-level managers. In Benin, the median capacity was 4.0 for policymakers and 3.0 for mid-level managers and implementers. Median sub-construct scores varied by stakeholder and country. Across countries, items reflective of the implementation domain 'policy environment' were highest while items reflective of the 'human resource' domain were consistently lower. CONCLUSION: Across all countries, stakeholders valued community-wide MDA for STH but had less confidence in their collective ability to effectively implement it. Perceived capacity varied by stakeholder group, highlighting the importance of accounting for multi-level stakeholder perspectives when determining organizational preparedness to launch new public health initiatives. TRIAL REGISTRATION: NCT03014167

Evaluation of opportunities to implement community-wide mass drug administration for interrupting transmission of soil-transmitted helminths infections in India.

BackgroundThe World Health Organization Neglected Tropical Disease (NTD) guidelines recommend control of soil transmitted helminth (STH)-associated morbidity with targeted deworming of preschool and school-aged children who are disproportionately affected by STH-associated morbidity. However, this strategy leaves many adults untreated and reinfection within communities perpetuates transmission even when mass drug administration (MDA) coverage of children is high. Evidence suggests that it may be possible to interrupt STH transmission by expanding MDA to a community-wide MDA (cMDA).MethodsThis multi-methods study of organizational readiness survey, key informant interviews, and program mapping, were conducted with government stakeholders in three Indian states, Goa, Sikkim, and Odisha, to assess readiness of the states for transitioning from school-based MDA to cMDA and identify opportunities to leverage existing infrastructure from other NTD programs like lymphatic filariasis (LF) for STH cMDA.Principal findingsOverall, all three states indicated a highly favorable policy environment, effective leadership structure, adequate material resources, demonstrated technical capacity, and adequate community infrastructure needed to launch a STH cMDA program. The findings indicated a high-level of health system readiness to implement provided human resources and financial resources to deliver cMDA is strengthened. Areas with a significant overlap between LF and STH MDA platforms, particularly at the community-level, may be best primed for transitioning. Immunization, maternal child health, and non-communicable disease control programs were the other programs for possible integration of cMDA. States indicated having effective leadership structures in place at the state-level, however, engaging local leaders and community groups were considered crucial for successful implementation of cMDA. In-migration was a perceived challenge for estimating drug requirement and preventing possible stockouts.ConclusionsFindings from this study are intended to proactively support government decision making, prioritization, and program planning across heterogenous implementation contexts in India to speed the translation of research findings into practice.Clinical trial registrationNCT03014167; ClinicalTrials.gov

Policy stakeholder perspectives on barriers and facilitators to launching a community-wide mass drug administration program for soil-transmitted helminths

Abstract Background Recent evidence suggests that soil-transmitted helminth (STH) transmission interruption may be feasible through community-wide mass drug administration (cMDA) that deworms community members of all ages. A change from school-based deworming to cMDA will require reconfiguring of STH programs in endemic countries. We conducted formative qualitative research in Benin, India, and Malawi to identify barriers and facilitators to successfully launching a cMDA program from the policy-stakeholder perspective. Methods We conducted 40 key informant interviews with policy stakeholders identified as critical change agents at national, state/district, and sub-district levels. Participants included World Health Organization country office staff, implementing partners, and national and sub-national government officials. We used the Consolidated Framework for Implementation Research to guide data collection, coding, and analysis. Heat maps were used to organize coded data and differentiate perceived facilitators and barriers to launching cMDA by stakeholder. Results Key facilitators to launching a cMDA program included availability of high-quality, tailored sensitization materials, and human and material resources that could be leveraged from previous MDA campaigns. Key barriers included the potential to overburden existing health workers, uncertainty of external funding to sustain a cMDA program, and concerns about weak intragovernmental coordination to implement cMDA. Cross-cutting themes included the need for rigorous trial evidence on STH transmission interruption to gain confidence in cMDA, and implementation evidence to effectively operationalize cMDA. Importantly, if policy stakeholders anticipate a cMDA program cannot be sustained due to cost and human resource barriers in the long term they may be less likely to support the launch of a program in the short term. Conclusions Overall, policy stakeholders were optimistic about implementing cMDA primarily because they believe that the tools necessary to successfully implement cMDA are already available. Policy stakeholders in this study were cautiously optimistic about launching cMDA to achieve STH transmission interruption and believe that it is feasible to implement. However, launching cMDA as an alternative policy to school-based deworming will require addressing key resource and evidence barriers. Trial registration This study was registered in the U.S. National Library of Medicine Clinical Trials registry (NCT03014167)

Identifying opportunities to optimize mass drug administration for soil-transmitted helminths: A visualization and descriptive analysis using process mapping.

BackgroundThe control of soil-transmitted helminths (STH) is achieved through mass drug administration (MDA) with deworming medications targeting children and other high-risk groups. Recent evidence suggests that it may be possible to interrupt STH transmission by deworming individuals of all ages via community-wide MDA (cMDA). However, a change in delivery platforms will require altering implementation processes.MethodsWe used process mapping, an operational research methodology, to describe the activities required for effective implementation of school-based and cMDA in 18 heterogenous areas and over three years in Benin, India, and Malawi. Planned activities were identified during workshops prior to initiation of a large cMDA trial (the DeWorm3 trial). The process maps were updated annually post-implementation, including adding or removing activities (e.g., adaptations) and determining whether activities occurred according to plan. Descriptive analyses were performed to quantify differences and similarities at baseline and over three implementation years. Comparative analyses were also conducted between study sites and areas implementing school-based vs. cMDA. Digitized process maps were developed to provide a visualization of MDA processes and inspected to identify implementation bottlenecks and inefficient activity flows.ResultsAcross three years and all clusters, implementation of cMDA required an average of 13 additional distinct activities and was adapted more often (5.2 adaptations per year) than school-based MDA. An average of 41% of activities across both MDA platforms did not occur according to planned timelines; however, deviations were often purposeful to improve implementation efficiency or effectiveness. Visualized process maps demonstrated that receipt of drugs at the local level may be an implementation bottleneck. Many activities rely on the effective setting of MDA dates and estimating quantity of drugs, suggesting that the timing of these activities is important to meet planned programmatic outcomes.ConclusionImplementation processes were heterogenous across settings, suggesting that MDA is highly context and resource dependent and that there are many viable ways to implement MDA. Process mapping could be deployed to support a transition from a school-based control program to community-wide STH transmission interruption program and potentially to enable integration with other community-based campaigns.Trial registrationNCT03014167

Regulatory T cells in the treatment of disease

International audienceRegulatory T (Treg) cells suppress inflammation and regulate immune system activity. In patients with systemic or organ-specific autoimmune diseases or those receiving transplanted organs, Treg cells are compromised. Approaches to strengthen Treg cell function, either by expanding them ex vivo and reinfusing them or by increasing the number or capacity of existing Treg cells, have entered clinical trials. Unlike the situation in autoimmunity, in patients with cancer, Treg cells limit the antitumour immune response and promote angiogenesis and tumour growth. Their immunosuppressive function may, in part, explain the failure of many immunotherapies in cancer. Strategies to reduce the function and/or number of Treg cells specifically in tumour sites are being investigated to promote antitumour immunity and regression. Here, we describe the current progress in modulating Treg cells in autoimmune disorders, transplantation and cancer