Natural products as starting points for future anti-malarial therapies: going back to our roots?

Abstract Background The discovery and development of new anti-malarials are at a crossroads. Fixed dose artemisinin combination therapy is now being used to treat a hundred million children each year, with a cost as low as 30 cents per child, with cure rates of over 95%. However, as with all anti-infective strategies, this triumph brings with it the seeds of its own downfall, the emergence of resistance. It takes ten years to develop a new medicine. New classes of medicines to combat malaria, as a result of infection by Plasmodium falciparum and Plasmodium vivax are urgently needed. Results Natural product scaffolds have been the basis of the majority of current anti-malarial medicines. Molecules such as quinine, lapachol and artemisinin were originally isolated from herbal medicinal products. After improvement with medicinal chemistry and formulation technologies, and combination with other active ingredients, they now make up the current armamentarium of medicines. In recent years advances in screening technologies have allowed testing of millions of compounds from pharmaceutical diversity for anti-malarial activity in cellular assays. These initiatives have resulted in thousands of new sub-micromolar active compounds – starting points for new drug discovery programmes. Against this backdrop, the paucity of potent natural products identified has been disappointing. Now is a good time to reflect on the current approach to screening herbal medicinal products and suggest revisions. Nearly sixty years ago, the Chinese doctor Chen Guofu, suggested natural products should be approached by dao-xing-ni-shi or ‘acting in the reversed order’, starting with observational clinical studies. Natural products based on herbal remedies are in use in the community, and have the potential unique advantage that clinical observational data exist, or can be generated. The first step should be the confirmation and definition of the clinical activity of herbal medicinal products already used by the community. This first step forms a solid basis of observations, before moving to in vivo pharmacological characterization and ultimately identifying the active ingredient. A large part of the population uses herbal medicinal products despite limited numbers of well-controlled clinical studies. Increased awareness by the regulators and public health bodies of the need for safety information on herbal medicinal products also lends support to obtaining more clinical data on such products. Conclusions The relative paucity of new herbal medicinal product scaffolds active against malaria results discovered in recent years suggest it is time to re-evaluate the ‘smash and grab’ approach of randomly testing purified natural products and replace it with a patient-data led approach. This will require a change of perspective form many in the field. It will require an investment in standardisation in several areas, including: the ethnopharmacology and design and reporting of clinical observation studies, systems for characterizing anti-malarial activity of patient plasma samples ex vivo followed by chemical and pharmacological characterisation of extracts from promising sources. Such work falls outside of the core mandate of the product development partnerships, such as MMV, and so will require additional support. This call is timely, given the strong interest from researchers in disease endemic countries to support the research arm of a malaria eradication agenda. Para-national institutions such as the African Network for Drugs and Diagnostics Innovation (ANDi) will play a major role in facilitating the development of their natural products patrimony and possibly clinical best practice to bring forward new therapeutics. As in the past, with quinine, lapinone and artemisinin, once the activity of herbal medicinal products in humans is characterised, it can be used to identify new molecular scaffolds which will form the basis of the next generation of anti-malarial therapies.</p

Factors influencing transfusion-associated HLA sensitization in patients bridged to heart transplantation using ventricular assist device.

BackgroundBridging heart failure patients with mechanical ventricular assist devices (VAD) enables access to transplantation. However, VAD is associated with increased risk for anti-HLA antibodies associated with rejection of subsequent allografts. Factors determining alloantibody formation in these patients remain undefined.MethodsWe performed a single-center retrospective cohort study of 164 patients undergoing heart transplantation from 2014 to 2017. Medical records including use of VAD, transfused blood products, anti-HLA antibody testing, crossmatch, and time to transplant were evaluated.ResultsPatients received an average of 13.8 red blood cell and 1.9 single-donor platelet units associated with VAD. There was a 28.7% increase in the incidence of anti-HLA antibodies after VAD. Development of anti-HLA antibodies did not correlate with volume or type of blood products, but with pre-VAD HLA sensitization status; relative risk of new alloantibodies in patients with pre-VAD antibodies was 3.5-fold higher than those without prior antibodies (P = .008). Development of new anti-HLA antibodies was associated with an increased time to transplant (169 vs 330 days, P = .013).ConclusionsOur findings indicate that the presence of anti-HLA antibodies pre-VAD was the most significant risk factor for developing additional antibodies post-VAD, suggesting that a subset of patients may be predisposed to alloantibody formation

Accelerating vaccine development and deployment: report of a Royal Society satellite meeting.

The Royal Society convened a meeting on the 17th and 18th November 2010 to review the current ways in which vaccines are developed and deployed, and to make recommendations as to how each of these processes might be accelerated. The meeting brought together academics, industry representatives, research sponsors, regulators, government advisors and representatives of international public health agencies from a broad geographical background. Discussions were held under Chatham House rules. High-throughput screening of new vaccine antigens and candidates was seen as a driving force for vaccine discovery. Multi-stakeholder, small-scale manufacturing facilities capable of rapid production of clinical grade vaccines are currently too few and need to be expanded. In both the human and veterinary areas, there is a need for tiered regulatory standards, differentially tailored for experimental and commercial vaccines, to allow accelerated vaccine efficacy testing. Improved cross-fertilization of knowledge between industry and academia, and between human and veterinary vaccine developers, could lead to more rapid application of promising approaches and technologies to new product development. Identification of best-practices and development of checklists for product development plans and implementation programmes were seen as low-cost opportunities to shorten the timeline for vaccine progression from the laboratory bench to the people who need it

A review of evidence on non-invasive prenatal diagnosis (NIPD) : tests for fetal RHD genotype

This report concentrates on three main areas. First and foremost, we set the background context for RhD NIPD in prenatal care. While the methodology chapter describes how the literature review was carried out and how additional information was collected, the second chapter provides an overview of the key issues associated with pregnancy of RhD negative women. We present background information based on publications from 1997 to 2006 which describe the genetic condition and its prevalence (RhD negativity) in populations, as well as the frequency of cases of sensitisation and HDN (haemolytic disease of the newborn). We also discuss current service provision for RhD negative women in a number of European countries and look at how the NIPD test might be set within current service contexts

Commercialisation of research results – cooperation between science and business

When analysing the term commercialisation one should answer the crucial question: what mechanisms govern commercialisation of knowledge and technology as well as which resources and sources determine it. The article presents a theoretical deliberation concerning the development of issues related to the commercialisation of research results in the last century. A review of literature precedes the section on sources for the commercialisation of knowledge and technologies when considering research results and technology providers. The author claims that analysis of technological resources also determines the possibilities for the cooperation between science and business. It is important for the selection of the commercialisation strategy to describe technological resources and their complementarity. Strong technological resources and their market availability ensures independent technological development. However, a lack of technological resources or the chance to acquire them encourages an innovative organisation to pass know-how or technologies to another, capable organisation which is willing to commercialise this knowledge on the market. Frequently however when commercialising research results, organisations establish cooperation on the market in order to build resources to implement research results. This article, ‘Commercialisation of research results – cooperation between science and business’, is concluded with an example depicting the cooperation between scientists and business people in a new spin-off company set up in order to build technological resources and the market implementation of a device for measuring the structure of soft material surfaces.Article has been prepared based on Polish National Scientific Agency project - DEC-2011/01/B/HS4/05200. (Powstanie artykuł zostało sfinansowane ze środków Narodowego Centrum Nauki przyznanych na podstawie decyzji numer DEC-2011/01/B/HS4/05200”) Preparation and printing funded by the National Agency for Research and Development under project “Kreator Innowacyjności – wparcie dla Przedsiębiorczości akademickiej

Two research contributions in 64-bit computing: Testing and Applications

Following the release of Windows 64-bit and Redhat Linux 64-bit operating systems (OS) in late April 2005, this is the one of the first 64-bit OS research project completed in a British university. The objective is to investigate (1) the increase/decrease in performance compared to 32-bit computing; (2) the techniques used to develop 64-bit applications; and (3) how 64-bit computing should be used in IT and research organizations to improve their work. This paper summarizes research discoveries for this investigation, including two major research contributions in (1) testing and (2) application development. The first contribution includes performance, stress, application, multiplatform, JDK and compatibility testing for AMD and Intel models. Comprehensive testing results reveal that 64-bit computing has a better performance in application performance, system performance and stress testing, but a worse performance in compatibility testing than the traditional 32-bit computing. A 64-bit dual-core processor has been tested and the results show that it performs better than a 64-bit single-core processor, but only in application that requires very high demands of CPU and memory consumption. The second contribution is .NET 1.1 64-bit implementations. Without additional troubleshooting, .NET 1.1 does not work on 64-bit Windows operating systems in stable ways. After stabilizing .NET environment, the next step is the application development, which is a dynamic repository with functions such as registration, download, login-logout, product submissions, database storage and statistical reports. The technology is based on Visual Studio .NET 2003, .NET 1.1 Framework with Service Pack 1, SQL Server 2000 with Service Pack 4 and IIS Server 6.0 on the Windows Server 2003 Enterprise x64 platform with Service Pack 1

Human anti-D immunoglobulin preparations: potency standardisation milestones

Human anti-D immunoglobulin preparations derived from human immune plasma are much needed and highly effective for specific anti-D prevention of perinatal complications and treatment of primary immune thrombocytopenia. The effectiveness of immune suppression is a direct function of the active ingredient dose received with the medicinal product. To improve the accuracy of anti-D antibody quantification, it is recommended to use certified reference materials with values assigned in international units (IUs). The aim of this study was to analyse the main stages in the development of the international standards (ISs) for human anti-D immunoglobulin potency testing and to substantiate the need for a national standard for anti-Rho(anti-D) antibody quantification. The article describes the creation of the first and subsequent ISs, the procedure for establishing the IU equivalent for the anti-Rho(anti-D) antibody concentration, the characteristics of the raw materials and preparations used, and the anti-Rho(anti-D) antibody assay methods applied to certify the ISs. According to the study conclusions, it is necessary to develop and certify a national standard for the content of anti-Rho(anti-D) antibodies that will meet the requirements of the corresponding Russian regulations

Socially-marketed rapid diagnostic tests and ACT in the private sector: ten years of experience in Cambodia.

Whilst some populations have recently experienced dramatic declines in malaria, the majority of those most at risk of Plasmodium falciparum malaria still lack access to effective treatment with artemisinin combination therapy (ACT) and others are already facing parasites resistant to artemisinins.In this context, there is a crucial need to improve both access to and targeting of ACT through greater availability of good quality ACT and parasitological diagnosis. This is an issue of increasing urgency notably in the private commercial sector, which, in many countries, plays an important role in the provision of malaria treatment. The Affordable Medicines Facility for malaria (AMFm) is a recent initiative that aims to increase the provision of affordable ACT in public, private and NGO sectors through a manufacturer-level subsidy. However, to date, there is little documented experience in the programmatic implementation of subsidized ACT in the private sector. Cambodia is in the unique position of having more than 10 years of experience not only in implementing subsidized ACT, but also rapid diagnostic tests (RDT) as part of a nationwide social marketing programme. The programme includes behaviour change communication and the training of private providers as well as the sale and distribution of Malarine, the recommended ACT, and Malacheck, the RDT. This paper describes and evaluates this experience by drawing on the results of household and provider surveys conducted since the start of the programme. The available evidence suggests that providers' and consumers' awareness of Malarine increased rapidly, but that of Malacheck much less so. In addition, improvements in ACT and RDT availability and uptake were relatively slow, particularly in more remote areas.The lack of standardization in the survey methods and the gaps in the data highlight the importance of establishing a clear system for monitoring and evaluation for similar initiatives. Despite these limitations, a number of important lessons can still be learnt. These include the importance of a comprehensive communications strategy and of a sustained and reliable supply of products, with attention to the geographical reach of both. Other important challenges relate to the difficulty in incentivising providers and consumers not only to choose the recommended drug, but to precede this with a confirmatory blood test and ensure that providers adhere to the test results and patients to the treatment regime. In Cambodia, this is particularly complicated due to problems inherent to the drug itself and the emergence of artemisinin resistance

Nanotechnology Oversight: An Agenda for the New Administration

Identifies how current laws can be applied or modified to provide needed oversight of nanotechnology and materials for public health and environmental protection. Calls for more funding for risk research, coordinated regulation, and public involvement

Recombinant factorVIII Fc fusion protein for the prevention and treatment of bleeding in children with severe hemophilia A

This work was supported by funding from Biogen, including funding for the editorial and writing support in the the development of this paper