Dataset Information

Oral, ultra-long-lasting drug delivery: Application toward malaria elimination goals.

ABSTRACT: Efforts at elimination of scourges, such as malaria, are limited by the logistic challenges of reaching large rural populations and ensuring patient adherence to adequate pharmacologic treatment. We have developed an oral, ultra-long-acting capsule that dissolves in the stomach and deploys a star-shaped dosage form that releases drug while assuming a geometry that prevents passage through the pylorus yet allows passage of food, enabling prolonged gastric residence. This gastric-resident, drug delivery dosage form releases small-molecule drugs for days to weeks and potentially longer. Upon dissolution of the macrostructure, the components can safely pass through the gastrointestinal tract. Clinical, radiographic, and endoscopic evaluation of a swine large-animal model that received these dosage forms showed no evidence of gastrointestinal obstruction or mucosal injury. We generated long-acting formulations for controlled release of ivermectin, a drug that targets malaria-transmitting mosquitoes, in the gastric environment and incorporated these into our dosage form, which then delivered a sustained therapeutic dose of ivermectin for up to 14 days in our swine model. Further, by using mathematical models of malaria transmission that incorporate the lethal effect of ivermectin against malaria-transmitting mosquitoes, we demonstrated that this system will boost the efficacy of mass drug administration toward malaria elimination goals. Encapsulated, gastric-resident dosage forms for ultra-long-acting drug delivery have the potential to revolutionize treatment options for malaria and other diseases that affect large populations around the globe for which treatment adherence is essential for efficacy.

SUBMITTER: Bellinger AM

PROVIDER: S-EPMC5264553 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Oral, ultra-long-lasting drug delivery: Application toward malaria elimination goals.

Bellinger Andrew M AM Jafari Mousa M Grant Tyler M TM Zhang Shiyi S Slater Hannah C HC Wenger Edward A EA Mo Stacy S Lee Young-Ah Lucy YL Mazdiyasni Hormoz H Kogan Lawrence L Barman Ross R Cleveland Cody C Booth Lucas L Bensel Taylor T Minahan Daniel D Hurowitz Haley M HM Tai Tammy T Daily Johanna J Nikolic Boris B Wood Lowell L Eckhoff Philip A PA Langer Robert R Traverso Giovanni G

Science translational medicine 20161101 365

Efforts at elimination of scourges, such as malaria, are limited by the logistic challenges of reaching large rural populations and ensuring patient adherence to adequate pharmacologic treatment. We have developed an oral, ultra-long-acting capsule that dissolves in the stomach and deploys a star-shaped dosage form that releases drug while assuming a geometry that prevents passage through the pylorus yet allows passage of food, enabling prolonged gastric residence. This gastric-resident, drug de ...[more]

PMID: 27856796

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Project description:BackgroundMalaria causes more than 200 million cases of illness and 400,000 deaths each year across 90 countries. The World Health Organization (WHO) set a goal for 35 countries to eliminate malaria by 2030, with an intermediate milestone of 10 countries by 2020. In 2017, the WHO established the Elimination-2020 (E-2020) initiative to help countries achieve their malaria elimination goals and included 21 countries with the potential to eliminate malaria by 2020.MethodsAcross its three levels of activity (country, region and global), the WHO developed normative and implementation guidance on strategies and activities to eliminate malaria; provided technical support and subnational operational assistance; convened national malaria programme managers at three global meetings to share innovations and best practices; advised countries on strengthening their strategy to prevent re-establishment and preparing for WHO malaria certification; and contributed to maintaining momentum towards elimination through periodic evaluations, monitoring and oversight of progress in the E-2020 countries. Changes in the number of indigenous cases in E-2020 countries between 2016 and 2020 are reported, along with the number of countries that eliminated malaria and received WHO certification.ResultsThe median number of indigenous cases in the E-2020 countries declined from 165.5 (interquartile range [IQR] 14.25-563.75) in 2016 to 78 (IQR 0-356) in 2020; 12 (57%) countries reported reductions in indigenous cases over that period, of which 7 (33%) interrupted malaria transmission and maintained a malaria-free status through 2020 and 4 (19%) were certified malaria-free by the WHO. Two countries experienced outbreaks of malaria in 2020 and 2021 attributed, in part, to the COVID-19 pandemic.ConclusionsAlthough the E-2020 countries contributed to the achievement of the 2020 global elimination milestone, the initiative highlights the difficulties countries face to interrupt malaria transmission, even when numbers of cases are very low. The 2025 global elimination milestone is now approaching, and the lessons learned, experience gained, and updated guidance developed during the E-2020 initiative will help serve the countries seeking to eliminate malaria by 2025.

Project description:In 2000, 189 member states of the United Nations (UN) developed a plan for peace and development, which resulted in eight actionable goals known as the Millennium Development Goals (MDGs). Since their inception, the MDGs have been considered the international standard for measuring development progress and have provided a blueprint for global health policy and programming. However, emphasis upon the achievement of priority benchmarks around the "big three" diseases--namely HIV, tuberculosis (TB), and malaria--has influenced global health entities to disproportionately allocate resources. Meanwhile, several tropical diseases that almost exclusively impact the poorest of the poor continue to be neglected, despite the existence of cost-effective and feasible methods of control or elimination. One such Neglected Tropical Disease (NTD), onchocerciasis, more commonly known as river blindness, is a debilitating and stigmatizing disease primarily affecting individuals living in remote and impoverished areas. Onchocerciasis control is considered to be one of the most successful and cost-effective public health campaigns ever launched. In addition to improving the health and well-being of millions of individuals, these programs also lead to improvements in education, agricultural production, and economic development in affected communities. Perhaps most pertinent to the global health community, though, is the demonstrated effectiveness of facilitating community engagement by allowing communities considerable ownership with regard to drug delivery. This paper reviews the contributions that such concentrated efforts to control and eliminate onchocerciasis make to achieving select MDGs. The authors hope to draw the attention of public policymakers and global health funders to the importance of the struggle against onchocerciasis as a model for community-directed interventions to advance health and development, and to advocate for NTDs inclusion in the post 2015 agenda.

Project description:BackgroundSince malaria is one of the foremost public health problems in Iran, a malaria elimination phase has been initiated and application of long-lasting insecticidal nets (LLINs) is an important strategy for control. Success and effectiveness of this community based strategy largely dependent on proper use of LLINs. In this context, to determine the community's knowledge and practices about malaria and LLINs, a study was conducted in Rudan County, one of the important malaria endemic areas in southeast of Iran.MethodsIn this cross-sectional study, 400 households in four villages were selected by cluster randomly sampling method. Community knowledge and practices about malaria and LLINs including symptoms and transmission of malaria and washing, drying and using of bed nets were investigated using pre-tested structured questionnaires. The data were analysed using SPSS.16 software.ResultsIn this study nearly 89% of the respondents knew at least one symptom of malaria and 86.8% considered malaria as an important disease. The majority of respondents (77.8%) believed that malaria transmits through mosquito bite and 72.5% mentioned stagnated water as a potential mosquito breeding place. About 46% of respondents mentioned the community health worker as the main source of their information about malaria. Approximately 44.8% of studied population washed the LLINs once in six months and 92% of them mentioned that they dry the bed nets in direct sunlight. While 94% of households reported they received one or more LLINs by government and 60.8% of respondents mentioned that LLINs were the main protective measure against malaria, only 18.5% of households slept under bed nets the night before the survey, this use rate is lower than the targeted coverage (80%) which is recommended by World Health Organization.ConclusionAlthough, majority of studied population were aware of the symptoms and cause of malaria, a majority had misconceptions about LLINs. Therefore, appropriate educational intervention by trained health workers should be developed for a behaviour change and motivating people to use LLINs which would improve malaria elimination programme.

Project description:A majority of nanoencapsulated drugs that have shown promise in cancer chemotherapy are administered intravenously. Development of effective oral nanoformulations presents a very challenging medical goal. Here, we describe successful applications of innovative polymeric nanogels in the form of conjugates with activated nucleoside analogs for oral administration in cancer chemotherapy. Previously, we reported the synthesis of amphiphilic polyvinyl alcohol and dextrin-based nanogel conjugates with the phosphorylated 5-FU nucleoside Floxuridine and demonstrated their enhanced activity against regular and drug-resistant cancers (T.H. Senanayake, G. Warren, S.V. Vinogradov, Novel anticancer polymeric conjugates of activated nucleoside analogs, Bioconjug. Chem. 22 (2011) 1983-1993). In this study, we synthesized and evaluated oral applications of nanogel conjugates of a protected Gemcitabine, the drug never used in oral therapies. These conjugates were able to quickly release an active form of the drug (Gemcitabine 5'-mono-, di- and triphosphates) by specific enzymatic activities, or slowly during hydrolysis. Gemcitabine conjugates demonstrated up to 127 times higher in vitro efficacy than the free drug against various cancer cells, including the lines resistant to nucleoside analogs. Surprisingly, these nanogel-drug conjugates were relatively stable in gastric conditions and able to actively penetrate through the gastrointestinal barrier based on permeability studies in Caco-2 cell model. In tumor xenograft models of several drug-resistant human cancers, we observed an efficient inhibition of tumor growth and extended the life-span of the animals by 3 times that of the control with orally treated Gemcitabine- or Floxuridine-nanogel conjugates. Thus, we have demonstrated a potential of therapeutic nanogel conjugates with the activated and stabilized Gemcitabine as a successful oral drug form against Gemcitabine-resistant and other drug-resistant tumors.

Project description:Leaders in the Asia-Pacific have endorsed an ambitious target to eliminate malaria in the region by 2030. The emergence and spread of artemisinin drug resistance in the Greater Mekong Subregion makes elimination urgent and strategic for the global goal of malaria eradication. Mathematical modelling is a useful tool for assessing and comparing different elimination strategies and scenarios to inform policymakers. Mathematical models are especially relevant in this context because of the wide heterogeneity of regional, country and local settings, which means that different strategies are needed to eliminate malaria. However, models and their predictions can be seen as highly technical, limiting their use for decision making. Simplified applications of models are needed to allow policy makers to benefit from these valuable tools. This paper describes a method for communicating complex model results with a user-friendly and intuitive framework. Using open-source technologies, we designed and developed an interactive application to disseminate the modelling results for malaria elimination. The design was iteratively improved while the application was being piloted and extensively tested by a diverse range of researchers and decision makers. This application allows several target audiences to explore, navigate and visualise complex datasets and models generated in the context of malaria elimination. It allows widespread access, use of and interpretation of models, generated at great effort and expense as well as enabling them to remain relevant for a longer period of time. It has long been acknowledged that scientific results need to be repackaged for larger audiences. We demonstrate that modellers can include applications as part of the dissemination strategy of their findings. We highlight that there is a need for additional research in order to provide guidelines and direction for designing and developing effective applications for disseminating models.

Project description:BackgroundWhile bed nets and insecticide spraying have had significant impact on malaria burden in many endemic regions, outdoor vector feeding and insecticide resistance may ultimately limit their contribution to elimination and control campaigns. Complementary vector control methods such as endectocides or systemic insecticides, where humans or animals are treated with drugs that kill mosquitoes upon ingestion via blood meal, are therefore generating much interest. This work explores the conditions under which long-lasting systemic insecticides would have a substantial impact on transmission and burden.MethodsHypothetical long-lasting systemic insecticides with effective durations ranging from 14 to 90 days are simulated using an individual-based mathematical model of malaria transmission. The impact of systemic insecticides when used to complement existing vector control and drug campaigns is evaluated in three settings-a highly seasonal high-transmission setting, a near-elimination setting with seasonal travel to a high-risk area, and a near-elimination setting in southern Africa.ResultsAt 60% coverage, a single round of long-lasting systemic insecticide with effective duration of at least 60 days, distributed at the start of the season alongside a seasonal malaria chemoprevention campaign in a high-transmission setting, results in further burden reduction of 30-90% depending on the sub-populations targeted. In a near-elimination setting where transmission is sustained by seasonal travel to a high-risk area, targeting high-risk travellers with systemic insecticide with effective duration of at least 30 days can result in likely elimination even if intervention coverage is as low as 50%. In near-elimination settings with robust vector control, the addition of a 14-day systemic insecticide alongside an anti-malarial in mass drug administration (MDA) campaigns can decrease the necessary MDA coverage from about 85% to the more easily achievable 65%.ConclusionsWhile further research into the safety profile of systemic insecticides is necessary before deployment, models predict that long-lasting systemic insecticides can play a critical role in reducing burden or eliminating malaria in a range of contexts with different target populations, existing malaria control methods, and transmission intensities. Continued investment in lengthening the duration of systemic insecticides and improving their safety profile is needed for this intervention to achieve its fullest potential.

Dataset Information

Oral, ultra-long-lasting drug delivery: Application toward malaria elimination goals.

Publications

Oral, ultra-long-lasting drug delivery: Application toward malaria elimination goals.

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