Advancing Drug Innovation for Neglected Diseases—Criteria for Lead Progression

Nwaka, Solomon; Ramirez, Bernadette; Brun, Reto; Maes, Louis; Douglas, Frank L.; Ridley, Robert G.

doi:10.1371/journal.pntd.0000440

Cited by 171 publications

(166 citation statements)

References 49 publications

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“…We used the IC 25 of each product as the test dosage. Different authors have claimed that compounds with SI values less than 20-fold those of the reference drug should be discarded as candidates for more advanced leishmanicidal tests due to their poor selectivity against mammalian cells (36). Therefore, we selected the compounds that fulfilled this requirement (compounds 8, 10, 11, 15, 45, and 48 for L. infantum and those compound plus compound 20 for L. braziliensis).…”

mentioning

confidence: 99%

Library of Seleno-Compounds as Novel Agents against Leishmania Species

Martín‐Montes

Plano

Martín‐Escolano

et al. 2017

Antimicrob Agents Chemother

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The in vitro leishmanicidal activities of a series of 48 recently synthesized selenium derivatives against Leishmania infantum and Leishmania braziliensis parasites were tested using promastigotes and intracellular amastigote forms. The cytotoxicity of the tested compounds for J774.2 macrophage cells was also measured in order to establish their selectivity. Six of the tested compounds (compounds 8, 10, 11, 15, 45, and 48) showed selectivity indexes higher than those of the reference drug, meglumine antimonate (Glucantime), for both Leishmania species; in the case of L. braziliensis, compound 20 was also remarkably selective. Moreover, data on infection rates and amastigote numbers per macrophage showed that compounds 8, 10, 11, 15, 45, and 48 were the most active against both Leishmania species studied. The observed changes in the excretion product profile of parasites treated with these six compounds were also consistent with substantial cytoplasmic alterations. On the other hand, the most active compounds were potent inhibitors of Fe superoxide dismutase (Fe-SOD) in the two parasite species considered, whereas their impact on human CuZn-SOD was low. The high activity, low toxicity, stability, low cost of the starting materials, and straightforward synthesis make these compounds appropriate molecules for the development of affordable antileishmanicidal agents.KEYWORDS Leishmania, selenium, superoxide dismutase, glucose metabolism L eishmaniasis, caused by the intracellular protozoan Leishmania, is transmitted by the bite of phlebotomine sand flies and is endemic in 98 countries, with over 350 million people being at risk (1). Environmental, demographic, and human behavioral factors and coinfections contribute to the changing epidemiology of the disease and to its recent worldwide spread. Clinical manifestations are divided into visceral leishmaniasis (VL; or kala-azar) (2) and the forms cutaneous leishmaniasis (CL) and mucocutaneous leishmaniasis (ML). CL remains the most common form of leishmaniasis both in general and in international travelers (3-5).The drugs available for the treatment of VL and severe CL include pentavalent antimonials (SbV), deoxycholate, amphotericin B (AMB), and miltefosine (MIL), all of which have high levels of toxicity and/or require long-duration treatment schedules (5, 6). Moreover, with the exception of MIL, all these drugs must be administered by the parenteral route (7).In the last decade, resistance to SbV has increased mainly due to low rates of compliance with the treatment schedule. In areas where the parasites are resistant to

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confidence: 99%

Library of Seleno-Compounds as Novel Agents against Leishmania Species

Martín‐Montes

Plano

Martín‐Escolano

et al. 2017

Antimicrob Agents Chemother

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“…Este panorama é sensivelmente agravado pela falta de investimentos e inovação em programas de P&D (pesquisa e desenvolvimento) de fármacos, que reflete no número extremamente reduzido de medicamentos que chegaram ao mercado ao longo das últimas décadas. 5 Em dezembro de 2012, um estudo realizado pela Iniciativa de Medicamentos para Doenças Negligenciadas (DNDi, da sigla inglesa para Drugs for Neglected Diseases Initiative) e pela organização Médicos Sem Fronteiras (Doctors Without Borders/Médecins Sans Frontières, MSF) sobre a evolução das ações de P&D para doenças negligenciadas revelou que dos 756 novos fármacos aprovados entre 2000 e 2011, 29 (3,8%) foram indicados para doenças negligenciadas, ainda que a carga global dessas doenças seja superior a 10%. Além disso, apenas quatro eram novas entidades químicas (NCEs, da sigla inglesa para new chemical entities), das quais três foram indicadas para o tratamento da malária e nenhuma para tuberculose ou qualquer das DTNs.…”

Section: A Urgência Por Novos Medicamentosunclassified

Doenças tropicais negligenciadas: uma nova era de desafios e oportunidades

Dias¹,

Dessoy²,

Güido³

et al. 2013

Quím. Nova

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tropical diseases (NTDs) with emphasis on the current challenges and opportunities towards the development and evolution of the field. NTDs leads to illness, long-term disability or death, and has severe social, economic and psychological consequences for millions of men, women, and children worldwide. In most cases, the available treatments are inadequate and extremely limited in terms of efficacy and safety, leading to an urgent demand for new drugs. In addition to the traditional challenges involved in any drug discovery process, it is widely recognized that there is an innovation gap and a lack of investment for research and development (R&D) in the area of NTDs. In the last few decades, methods toward combating, eradication, prevention, and treatment of NTDs have been repeatedly emphasized in the major international agendas. Developments in these strategies and alliances have continued to have an essential impact, particularly in the area of drug discovery, both in Brazil and globally and should be encouraged and supported. Several examples of international activities dedicated to the reduction of the devastating global impact of NTDs can be provided. Despite the beneficial developments in the past 30 years, NTDs continue to devastate poor communities in remote and vulnerable areas, in large part, due to market failures and public policies. Recent studies have shown that among 756 new drugs approved between 2000 and 2011, only four new chemical entities (NCEs) were identified for the treatment of malaria, while none were developed against NTDs or tuberculosis. Furthermore, only 1.4% of approximately 150,000 clinical trials were registered for neglected diseases, with a smaller number of trials for NCEs. Establishment and strengthening of global strategies involving the triad "government-academia-industry" is fundamental to the success in R&D of new drugs for NTDs. National and international public-private initiatives that aim to create, encourage, and invest in R&D projects have been implemented and therefore are of utmost importance to successfully integrate Brazil into this new paradigm. It is essential to lay the foundation for mechanisms that will intensify investments in infrastructure, training, and qualification of personnel with an ultimate strategic vision that foresees continuity. Our research group has made significant contributions to the development of this field with the goal of forging new frontiers while tackling both current and future challenges that include indispensable elements such as innovation and integration.

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“…There are now fewer than 100 drugs being tested in clinical trials for treatment of neglected diseases. 11 New efforts are under way to find ways to provide incentives for for-profit and nonprofit entities to conduct clinical trials once a validated clinical compound has been developed. A number of promising approaches are now being tried, with funding from various foundations and governments.…”

Section: Follow the Moneymentioning

confidence: 99%

Spurring New Research For Neglected Diseases

Anderson

2009

Health Affairs

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A very small proportion of global spending for biomedical research is for neglected diseases. However, neglected diseases account for a sizable percentage of the global burden of disease, especially in low-income countries. For-profit pharmaceutical and biotech companies are unlikely to conduct significant additional research on neglected diseases without financial incentives. This paper examines the benefits of providing a tax credit to encourage companies to conduct preclinical research on neglected diseases in the laboratory or in animals. This strategy could lead to a new generation of treatment options for the people in low-income countries who are susceptible to neglected diseases.

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Advancing Drug Innovation for Neglected Diseases—Criteria for Lead Progression

Cited by 171 publications

References 49 publications

Library of Seleno-Compounds as Novel Agents against Leishmania Species

Library of Seleno-Compounds as Novel Agents against Leishmania Species

Doenças tropicais negligenciadas: uma nova era de desafios e oportunidades

Spurring New Research For Neglected Diseases

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