Mears E.R.,University of Swansea |
Mears E.R.,University of Auckland |
Modabber F.,Drugs for Neglected Diseases initiative |
Modabber F.,Tehran University of Medical Sciences |
And 2 more authors.
PLoS Neglected Tropical Diseases | Year: 2015
The current in vivo models for the utility and discovery of new potential anti-leishmanial drugs targeting Cutaneous Leishmaniasis (CL) differ vastly in their immunological responses to the disease and clinical presentation of symptoms. Animal models that show similarities to the human form of CL after infection with Leishmania should be more representative as to the effect of the parasite within a human. Thus, these models are used to evaluate the efficacy of new anti-leishmanial compounds before human clinical trials. Current animal models aim to investigate (i) host–parasite interactions, (ii) pathogenesis, (iii) biochemical changes/pathways, (iv) in vivo maintenance of parasites, and (v) clinical evaluation of drug candidates. This review focuses on the trends of infection observed between Leishmania parasites, the predictability of different strains, and the determination of parasite load. These factors were used to investigate the overall effectiveness of the current animal models. The main aim was to assess the efficacy and limitations of the various CL models and their potential for drug discovery and evaluation. In conclusion, we found that the following models are the most suitable for the assessment of anti-leishmanial drugs: L. major–C57BL/6 mice (or–vervet monkey, or–rhesus monkeys), L. tropica–CsS-16 mice, L. amazonensis–CBA mice, L. braziliensis–golden hamster (or–rhesus monkey). We also provide in-depth guidance for which models are not suitable for these investigations. © 2015 Mears et al.
Tweats D.,Drugs for Neglected Diseases Initiative |
Tweats D.,University of Swansea |
Trunz B.B.,Drugs for Neglected Diseases Initiative |
Torreele E.,Drugs for Neglected Diseases Initiative
Mutagenesis | Year: 2012
The parasitic disease human African trypanomiasis (HAT), also known as sleeping sickness, is a highly neglected fatal condition endemic in sub-Saharan Africa, which is poorly treated with medicines that are toxic, no longer effective or very difficult to administer. New, safe, effective and easy-to-use treatments are urgently needed. Many nitroimidazoles possess antibacterial and antiprotozoal activity and examples such as tinidazole are used to treat trichomoniasis and guardiasis, but concerns about toxicity including genotoxicity limit their usefulness. Fexinidazole, a 2-substituted 5-nitroimidazole rediscovered by the Drugs for Neglected Diseases initiative (DNDi) after extensive compound mining of public and pharmaceutical company databases, has the potential to become a short-course, safe and effective oral treatment, curing both acute and chronic HAT. This paper describes the genotoxicity profile of fexinidazole and its two active metabolites, the sulfoxide and sulfone derivatives. All the three compounds are mutagenic in the Salmonella/Ames test; however, mutagenicity is either attenuated or lost in Ames Salmonella strains that lack one or more nitroreductase(s). It is known that these enzymes can nitroreduce compounds with low redox potentials, whereas their mammalian cell counterparts cannot, under normal conditions. Fexinidazole and its metabolites have low redox potentials and all mammalian cell assays to detect genetic toxicity, conducted for this study either in vitro (micronucleus test in human lymphocytes) or in vivo (ex vivo unscheduled DNA synthesis in rats; bone marrow micronucleus test in mice), were negative. Thus, fexinidazole does not pose a genotoxic hazard to patients and represents a promising drug candidate for HAT. Fexinidazole is expected to enter Phase II clinical trials in 2012. © The Author 2012.
Francisco A.F.,London School of Hygiene and Tropical Medicine |
Lewis M.D.,London School of Hygiene and Tropical Medicine |
Lewis M.D.,National Institute of Allergy and Infectious Diseases |
Jayawardhana S.,London School of Hygiene and Tropical Medicine |
And 3 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2015
The antifungal drug posaconazole has shown significant activity against Trypanosoma cruzi in vitro and in experimental murine models. Despite this, in a recent clinical trial it displayed limited curative potential. Drug testing is problematic in experimental Chagas disease because of difficulties in demonstrating sterile cure, particularly during the chronic stage of infection when parasite burden is extremely low and tissue distribution is ill defined. To better assess posaconazole efficacy against acute and chronic Chagas disease, we have exploited a highly sensitive bioluminescence imaging system which generates data with greater accuracy than other methods, including PCR-based approaches. Mice inoculated with bioluminescent T. cruzi were assessed by in vivo and ex vivo imaging, with cyclophosphamide-induced immunosuppression used to enhance the detection of relapse. Posaconazole was found to be significantly inferior to benznidazole as a treatment for both acute and chronic T. cruzi infections. Whereas 20 days treatment with benznidazole was 100% successful in achieving sterile cure, posaconazole failed in almost all cases. Treatment of chronic infections with posaconazole did however significantly reduce infection-induced splenomegaly, even in the absence of parasitological cure. The imaging-based screening system also revealed that adipose tissue is a major site of recrudescence in mice treated with posaconazole in the acute, but not the chronic stage of infection. This in vivo screening model for Chagas disease is predictive, reproducible and adaptable to diverse treatment schedules. It should provide greater assurance that drugs are not advanced prematurely into clinical trial. Copyright © 2015, Francisco et al.
News Article | December 12, 2016
The Association of Strategic Alliance Professionals (ASAP), the world’s leading professional association dedicated to the practice of alliance management, partnering, and business collaboration, announced 10 nominees vying for four annual Alliance Excellence Awards: Individual Alliance Excellence, Innovative Best Alliance Practice, Alliance Program Excellence, and Alliance for Corporate Social Responsibility. The winners will be announced at the upcoming 2017 ASAP Global Alliance Summit, “Profit, Innovation, and Value for the Part¬nering Enterprise,” Feb. 28–March 2, at the San Diego Marriott Mission Valley, San Diego, California. “These companies have proven track records demonstrating significant leadership value in alliance management,” said Michael Leonetti, president & CEO of ASAP. “Our awards committee reviewed a number of outstanding nominees this year from a range of industries. We selected candidates that were going above and beyond in their practices and can serve as models for the ASAP community. They hail from industries such as consumer credit reporting, audit, tax, and advisory services, IT, utilities, healthcare, consulting, and biopharma, and the projects span the globe, including the Kruger National Park in South Africa,” he added. “I especially appreciate the submissions for Social Corporate Responsibility,” added Norma Watenpaugh, CSAP, chair of the 2017 Alliance Excellence Awards committee and founder/CEO of Phoenix Consulting Group. “We had three worthy finalists for that category this year. It’s always great to see the contributions companies are making to make the world a better place.” Past winners received awards for significant contributions through partnering that increased revenues, provided society with creative business models and problem solving, enhanced products/services/technologies, advanced the profession, etc. Additional value is placed on leadership practices that result in high levels of productivity, effort, achievement, and innovation. Past winners share three key achievements: The Individual Alliance Excellence Award is given to a partnership that has instituted practices, tools, and methodologies in support of successful formation and management for a single alliance. The alliance may be an emerging alliance or comprised of two or more companies. The three finalists are: Bayer-Evotec: This strategic research alliance hopes to identify three small molecule clinical candidates for the treatment of endometriosis. Bayer and Evotec have joint responsibility in early research and preclinical characterization of potential candidates, with Bayer responsible for subsequent clinical development and commercialization. To date the alliance team has delivered five preclinical candidates, exceeding the initial goals of the collaboration. Loonaangifeketen-UWV-CBS- Belastingdienst : After a disastrous start, this unique partnership of three government agencies managing tax revenues in The Netherlands—Belastingdienst (Dutch IRA), UWV (Dutch National Social Security Administration), and CBS (Statistics Netherlands)—became highly effective by applying alliance management best practices, such as development of governance, trust building, and extensive attention to team meetings. National Grid-EnergySage: The alliance provides a marketplace for solar energy to Rhode Island residents by leveraging existing programs that provide an energy efficiency assessment with a solar assessment. The multi-level value creation is designed to meet the state’s carbon reduction goals and create jobs in alternative energy, while providing a one-stop website for all services, and where dozens of local solar installers provide quotes and choices. This year’s Innovative Best Alliance Practice Award will be presented to one of two companies for the use of new alliance management tools or processes that have an immediate and powerful impact on the organization and/or discipline of alliance management. The tools or processes are additions to existing practices that address specific elements of alliance management, such as measurement, training, conflict resolution, general communication across the partner ecosystem, or similar facets of the discipline. The two finalists are: KPMG-UK: This KPMG-powered enterprise branding combines the company’s knowledge of back-office transformation with leading cloud technology providers, such as Oracle, Workday, ServiceNow, and Coupa. The innovation in branding and bundling technology helps accountants easily grasp the business value and significantly increase the win rate in competitive situations. NetApp: While many companies still try to manage partnering processes through spreadsheets, NetApp has invested in technology and governance of its rigorous alliance co-selling program to ensure trackable processes that produce results. The processes engage NetApp and partner representatives proactively in account mapping, account planning, and pipeline management with exemplary execution of the most difficult aspects of go-to-market alliances. The Alliance Program Excellence Award is presented to a single, specific company and its partnering program, not to an alliance. The company exceeds expectations with scalable practices, tools, and methodologies to support successful formation and management of alliance portfolios over time. They are repeatable and have led to consistent alliance performance across multiple alliances. Winners build programs on efficiency, creativity, and an integrated suite of tools, processes, professional development/alliance professional certification, and other elements. The two finalists are: Equifax: Equifax has built an exemplary partnering program in an industry where partnership and alliance business models are still at the budding stages. Internal governance structures enabled management across a highly matrixed enterprise and impacted results on multiple levels, such as revenue, the ability to enter new markets, the launch of new products, and changes to organizational culture. STC Solutions: This highly innovative, consolidated, and centralized alliance and partnership management framework spans different divisions and functional groups throughout the organization and business relationships—from supply side to customer side. The framework develops and promotes an extremely effective corporate-wide collaborative culture that includes supplier, tactical alliances, technology partners, cloud/IoT channel partners, and strategic alliances. The Alliances for Corporate Social Responsibility Award is for partnerships making a profound, measurable, and positive social impact. The principal objective of the alliance is social impact, not profit—although profit, especially if used to fund program expansion, is not discouraged. The three partnering finalists are: Bayer and Drugs for Neglected Diseases Initiative (DNDi): The focus of this alliance is to develop a drug to dramatically reduce treatment time and increase effectiveness for River Blindness, a disease affecting 25 million people in 31 African countries. Current treatments only affect young worms and must be repeated to target adult worms over their 17-year lifespan. Bayer has contracted with non-profit DNDi to provide the new drug at an affordable price for national disease control programs. Dimension Data and Cisco Systems, Inc.: South Africa is home to 70 percent of the remaining rhinos in the world. Cisco Systems and Dimension Data collaborated in the Connected Conservation initiative to apply Internet of Things (IoT) solutions to prevent and reduce the number of rhinos being poached in South Africa’s Kruger National Park. The alliance developed new technology for tracking rhinos without needing to tranquilize them, which can be extremely dangerous to the animals. The technology also creates tight physical security within the preserve to track staff, suppliers, contractors, security, and visitors. The technology and alliance can be replicated to conserve other endangered species. The Synergist-Sanofi: This multiparty alliance incorporates an ecosystem approach to address Dengue fever that includes the general public, government and health agencies, industry, academics, and healthcare professionals aimed at co-creating solutions. “Break Dengue” uses information sharing and crowd sourcing through social media, online chats, case tracking worldwide, and public access to toolkits that reduce risk of infection. The Synergist framework and innovative governance structure provides a systematic approach to manage a diverse ecosystem. The platform is extendible to other diseases, such as Zika. Held Feb. 28-March 2, “Profit, Innovation, and Value for the Partnering Enterprise,” will take place at the San Diego Marriott Mission Valley, San Diego, California, USA. The annual ASAP Global Alliance Summit is the world’s largest gathering of alliance, partnering, and business collaboration professionals. Early Bird discount pricing is available until January 13, 2017. For more information or to register for the 2017 summit, visit http://www.asapweb.org/summit. The Association of Strategic Alliance Professionals (ASAP) is the only professional association dedicated to elevating and promoting the profession of alliance management, partnerships, and collaboration. Founded in 1998, the organization provides professional development, networking, and resources for cultivating the skills and toolsets needed to manage successful business partnerships. ASAP’s professional certifications include the Certificate of Achievement-Alliance Management (CA-AM) and Certified Strategic Alliance Professional (CSAP). Active global members include Astellas, AstraZeneca, Bayer, Capgemini, Cisco, Citrix, Covance, Dell, Eli Lilly and Company, HealthCore, Huawei, IBM, INC Research, Janssen—Pharmaceutical Companies of Johnson & Johnson, Merck, Mission Pharmacal, NetApp, Novartis, Plantronics, Sanofi, SAS, Schneider Electric, Takeda, The Warren Company, and Xerox. A complete list of global members is available at http://www.strategic-alliances.org.
News Article | November 10, 2016
Chagas disease (Trypanosoma cruzi infection) is a parasitic infection that can lead to fatal cardiac disease. While Latin America is known as an endemic area, there have been relatively few studies investigating the prevalence of Chagas disease in the Rio Grande Valley of Texas. A paper published in PLOS Neglected Diseases led by researchers at the National School of Tropical Medicine at Baylor College of Medicine suggests that the disease burden in southern Texas is much higher than previously thought. Considering up to 30% of people infected with Trypanosoma cruzi can develop fatal cardiomyopathy, this study's findings carry important implications to the health of the population of south Texas. "Kissing bugs", (triatominae) who feed on both humans and animals, are the vectors primarily responsible for the transmission of Chagas disease. The disease is predominantly found in impoverished regions where substandard living conditions can lead to increased exposure to the parasitic kissing bugs. In order to assess the infection status of vectors and seroprevalence among human and mammal populations living in in the lower Rio Grande Valley, Dr. Melissa Nolan Garcia, instructor of pediatrics at Baylor who is also with Texas Children's Hospital, and colleagues tested kissing bug vectors and retrospectively analyzed previously collected sera from coyotes, stray dogs, and human participants. Out of 841 human sera samples, 3 people (0,4%) tested positive for T. cruzi, while 8% of coyotes and 3.8% of stray dogs were found to be infected. Among the insects sampled, 56.5% were found to be T. cruzi carriers. Based on the findings of the study, the authors estimate that around 4,600 people in the Rio Grande Valley are currently infected with Chagas disease, and of those, an estimated 1,300 are at risk for developing cardiomyopathy. These results not only confirm the risk for disease transmission in south Texas, but indicate that the regional burden of Chagas disease is 23 times higher than previously estimated. The study does have limitations, as the authors acknowledge that the specimens were originally collected for other studies, and they are now conducting larger, more extensive surveillance studies targeting Chagas risk in this region. Overall, the findings point to a greater need for attention to Chagas disease in United States, particularly the identification of high risk groups. The authors assert that, "with up to 30% of infected individuals developing a potentially fatal cardiac disease, it is imperative that we identify and treat patients before heart disease occurs." Please contact firstname.lastname@example.org if you would like more information about our content and specific topics of interest. All works published in PLOS Neglected Tropical Diseases are open access, which means that everything is immediately and freely available. Use this URL in your coverage to provide readers access to the paper upon publication: http://dx. (Link goes live upon article publication) Funding: This study was supported in part by MD000170 P20 funded from the National Center on Minority Health and Health Disparities, the Centers for Translational Science Award 1U54RR023417-01 from the National Center for Research Resources and the Centers for Disease Control Award RO1 DP000210-01, the United States Department of Defense, Army (W81XWH-04-2-0035), the Drugs for Neglected Diseases Initiative (DNDi), and NIH/NIAID 1R21AI114877-01A1. TPF and RP are supported by the NIH grant 5R25GM100866-02 564 awarded to Robert K. Dearth and Jason G. Parsons. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist.
Planer J.D.,University of Washington |
Hulverson M.A.,University of Washington |
Arif J.A.,University of Washington |
Ranade R.M.,University of Washington |
And 2 more authors.
PLoS Neglected Tropical Diseases | Year: 2014
An estimated 8 million persons, mainly in Latin America, are infected with Trypanosoma cruzi, the etiologic agent of Chagas disease. Existing antiparasitic drugs for Chagas disease have significant toxicities and suboptimal effectiveness, hence new therapeutic strategies need to be devised to address this neglected tropical disease. Due to the high research and development costs of bringing new chemical entities to the clinic, we and others have investigated the strategy of repurposing existing drugs for Chagas disease. Screens of FDA-approved drugs (described in this paper) have revealed a variety of chemical classes that have growth inhibitory activity against mammalian stage Trypanosoma cruzi parasites. Aside from azole antifungal drugs that have low or sub-nanomolar activity, most of the active compounds revealed in these screens have effective concentrations causing 50% inhibition (EC50's) in the low micromolar or high nanomolar range. For example, we have identified an antihistamine (clemastine, EC50 of 0.4 μM), a selective serotonin reuptake inhibitor (fluoxetine, EC50 of 4.4 μM), and an antifolate drug (pyrimethamine, EC50 of 3.8 μM) and others. When tested alone in the murine model of Trypanosoma cruzi infection, most compounds had insufficient efficacy to lower parasitemia thus we investigated using combinations of compounds for additive or synergistic activity. Twenty-four active compounds were screened in vitro in all possible combinations. Follow up isobologram studies showed at least 8 drug pairs to have synergistic activity on T. cruzi growth. The combination of the calcium channel blocker, amlodipine, plus the antifungal drug, posaconazole, was found to be more effective at lowering parasitemia in mice than either drug alone, as was the combination of clemastine and posaconazole. Using combinations of FDA-approved drugs is a promising strategy for developing new treatments for Chagas disease. © 2014 Planer et al.
Don R.,Drugs for Neglected Diseases initiative |
Ioset J.-R.,Drugs for Neglected Diseases initiative
Parasitology | Year: 2014
SUMMARY The Drugs for Neglected Diseases initiative (DNDi) has defined and implemented an early discovery strategy over the last few years, in fitting with its virtual R&D business model. This strategy relies on a medium- to high-throughput phenotypic assay platform to expedite the screening of compound libraries accessed through its collaborations with partners from the pharmaceutical industry. We review the pragmatic approaches used to select compound libraries for screening against kinetoplastids, taking into account screening capacity. The advantages, limitations and current achievements in identifying new quality series for further development into preclinical candidates are critically discussed, together with attractive new approaches currently under investigation. © Cambridge University Press 2013.
van Griensven J.,Institute of Tropical Medicine |
Balasegaram M.,Drugs for Neglected Diseases initiative |
Meheus F.,Institute of Tropical Medicine |
Alvar J.,World Health Organization |
And 2 more authors.
The Lancet Infectious Diseases | Year: 2010
Combination therapy for the treatment of visceral leishmaniasis has increasingly been advocated as a way to increase treatment efficacy and tolerance, reduce treatment duration and cost, and limit the emergence of drug resistance. We reviewed the evidence and potential for combination therapy, and the criteria for the choice of drugs in such regimens. The first phase 2 results of combination regimens are promising, and have identified effective and safe regimens as short as 8 days. Several phase 3 trials are underway or planned in the Indian subcontinent and east Africa. The limited data available suggest that combination therapy is more cost-effective and reduces indirect costs for patients. Additional advantages are reduced treatment duration (8-17 days), with potentially better patient compliance and lesser burden on the health system. Only limited data are available on how best to prevent acquired resistance. Patients who are coinfected with visceral leishmaniasis and HIV could be a reservoir for development and spread of drug-resistant strains, calling for special precautions. The identification of a short, cheap, well-tolerated combination regimen that can be given in ambulatory care and needs minimal clinical monitoring will most likely have important public health implications. Effective monitoring systems and close regulations and policy will be needed to ensure effective implementation. Whether combination therapy could indeed help delay resistance, and how this is best achieved, will only be known in the long term. © 2010 Elsevier Ltd. All rights reserved.
Burrows J.N.,Medicines for Malaria Venture |
Elliott R.L.,Bill and Melinda Gates Foundation |
Kaneko T.,Global Alliance for TB Drug Development |
Mowbray C.E.,Drugs for Neglected Diseases Initiative |
Waterson D.,Medicines for Malaria Venture
MedChemComm | Year: 2014
Neglected and tropical diseases affect a large proportion of the world's population and impose a huge economic and health burden on developing countries. Despite this, there is a dearth of safe, effective, suitable medications for treatment of these diseases, largely as a result of an underinvestment in developing new drugs against these diseases by the majority of research-based pharmaceutical companies. In the past 12 years, the situation has begun to improve with the emergence of public-private product development partnerships (PDPs), which foster a collaborative approach to drug discovery and have established strong drug development pipelines for neglected and tropical diseases. Some large pharmaceutical companies have also now established dedicated research sites for developing world diseases and are working closely with PDPs on drug development activities. However, drug discovery in this field is still hampered by a lack of sufficient funding and technological investment, and there is a shortage of the tools, assays, and well-validated targets needed to ensure strong drug development pipelines in the future. The availability of high-quality chemically diverse compound libraries to enable lead discovery remains one of the critical bottlenecks. The pharmaceutical industry has much that it can share in terms of drug discovery capacity, know-how, and expertise, and in some cases has been moving towards new paradigms of collaborative pre-competitive research with the PDPs and partners. The future of drug discovery for neglected and tropical diseases will depend on the ability of those working in the area to collaborate together and will require sustained resourcing and focus. © 2014 the Partner Organisations.
Brun R.,Swiss Tropical and Public Health Institute |
Don R.,Drugs for Neglected Diseases initiative |
Jacobs R.T.,SCYNEXIS |
Wang M.Z.,University of North Carolina at Chapel Hill |
Barrett M.P.,University of Glasgow
Future Microbiology | Year: 2011
Human African trypanosomiasis (HAT) or 'sleeping sickness' is a neglected tropical disease caused by the parasite Trypanosoma brucei. Novel models for funding pharmaceutical development against HAT are beginning to yield results. The Drugs for Neglected Diseases initiative (DNDi) rediscovered a nitroimidazole, fexinidazole, which is currently in Phase I clinical trials. Novel benzoxaboroles, discovered by Anacor, Scynexis and DNDi, have good pharmacokinetic properties in plasma and in the brain and are curative in a murine model of stage two HAT with brain infection. The Consortium for Parasitic Drug Development (CPDD) has identified a series of dicationic compounds that can cure a monkey model of stage two HAT. With other screening programs yielding hits, the pipeline for new HAT drugs might finally begin to fill. © 2011 Future Medicine Ltd.