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Pharmaceuticals: Some General Aspects
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Concerning future prospects of enzyme inhibitors as drugs, there is a never-ending need to develop safe, efficient, and affordable new treatment strategies as alternatives to existing ones. These efforts will be supported by using in vitro systems and in silico models to understand pharmacogenetic causes of variability in drug disposition (Brian et al., 2016). Another important aspect is the further improvement of existing structure-based or ligand-based methods and tools of computer-aided drug design and discovery which increases the hit rate of novel drug compounds due to using a much more targeted search than traditional HTS and combinatorial chemistry (Sliwoski et al., 2014). Furthermore, one of the core areas in drug development should be the neglected diseases The Drugs for Neglected Diseases initiative (DNDi) is a drug research and development (R&D) organization that is developing new treatments for neglected patients.
Clashes between subsidized and private ACT markets
Published in Carine Baxerres, Maurice Cassier, Understanding Drugs Markets, 2021
Carine Baxerres, Jessica Pourraz
The World Health Organization's (WHO) international recommendation to use artemisinin-based combination therapies (ACTs) in the mid-2000s spurred pharmaceutical innovations. Initially driven by two multinational firms based in the West—the Swiss Novartis and the French Sanofi-Aventis—and their partnership with universities and/or transnational actors (WHO and Drugs for Neglected Diseases initiative [DNDi], respectively),1 production of these artemisinin-based combinations has increased both in the Asian countries that produce generics and in Africa. Numerous ACTs, combining different molecules with artemisinin derivatives, the use of which may or may not be recommended by WHO, have been put on the market in a variety of ways in countries affected by malaria. National pharmaceutical regulations for these drugs vary, depending on whether or not they are included in malaria treatment lines in various countries; the criteria for granting Marketing Authorizations (MAs) issued by regulatory authorities; and their actual technical, material, and human resources. Global Health actors working in malaria control, primarily the Global Fund and the President's Malaria Initiative (PMI)2 for the situations we studied, or Chinese development aid for example in others (Sams, 2016), clearly influence trends in these markets by making ACT available in the countries. By supplying specifically from a few pharmaceutical firms, these Global Health programs support the distribution of certain products that have international certifications. To deal with their dominance over the markets, competing companies are organizing themselves to promote their own ACTs as well.
The Renewal of Interest in Nitroaromatic Drugs
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Nicolas Primas, Caroline Ducros, Patrice Vanelle, Pierre Verhaeghe
In 2001, a clinical trial compared three drug combination treatments for second-stage HAT due to T. b. gambiense: melarsoprol (4) with eflornithine (16), melarsoprol (4) with nifurtimox (8), and eflornithine (16) with nifurtimox (8) (Priotto et al. 2006). The existing anti-trypanosomal drugs were combined as a way of reducing the required dosages to avoid the related toxicities and the emergence of drug-resistance. Against all expectations, the trial was interrupted prematurely due to high drug-related mortality in the melarsoprol arms. Fortunately, Nifurtimox-Eflornithine Combination Therapy (NECT) demonstrated good tolerance and sufficient efficacy for further investigations to be performed. Cure rates with the NECT drug-combination (96.5%) were comparable with monotherapy using eflornithine (16), but with lower side-effects. Moreover, it allowed the dose and the duration of the eflornithine (16) infusion to be reduced (Priotto et al. 2009). The Drugs for Neglected Diseases Initiative (DNDi) successfully repositioned nifurtimox (8), originally designed as an antichagasic drug, and prompted the WHO in 2009 to add NECT to the Model Lists of Essential Medicines, as more than 60% of late-stage T. b. gambiense HAT could be treated using this combination. NECT represented a significant achievement, providing the first new drug regimen for HAT in nearly two decades. DNDi is a public-private partnership that focuses on drug discovery and clinical development. It has developed target product profiles (TPPs) and compound progression criteria for trypanosomatid diseases (Don and Ioset 2014). The ideal TPPs focus on new regimens that are active against all strains/subspecies, with good oral bioavailability, short treatment durations, improved safety to efficacy ratios and low cost. Alongside the NECT success, the potential of the old nitroimidazole megazol (7) was rediscovered in combination with suramin (3) and showed to be curative in a stage 2 HAT-infected mouse model (Enanga et al. 1998, Darsaud et al. 2004), although the study was stopped due to the genotoxicity of megazol (7) (Enanga et al. 2003). Drugs used in the combination therapy are shown in Figure 3.
Are patents important indicators of innovation for Chagas disease treatment?
Published in Expert Opinion on Therapeutic Patents, 2023
Andrea Pestana Caroli, Felipe R. P. Mansoldo, Veronica S. Cardoso, Celso Luiz Salgueiro Lage, Flavia L. Carmo, Claudiu T Supuran, Alane Beatriz Vermelho
Compounds containing imidazole rings are studied as candidates for new drugs for CD. These compounds are found in several biomolecules, such as biotin, histidine, and purine bases. Benznidazole, the reference drug for CD, is a bicyclic heteroaromatic compound composed of benzene fused with imidazole [73]. In this sense, imidazole and benznidazole derivatives are described as potent anti-T. cruzi agents. We can cite one of the first studied, the megazol [74] and feximidazol [25]. The patent US20170114068A1 [75] had been deposited, claiming the derivative substituted Imidazo[1,2b]pyridazine compounds for a potential drug for CD treatment. In addition, the patent US10065965B2 [76] describes another imidazole derivative, the imidazole triazine, applied by GlaxoSmithKline. Fexinidazole 5-nitroimidazole was developed by the nonprofit research and development organization the Drugs for Neglected Diseases initiative (DNDi). Derivatives such as sulfoxide and sulfone fexinidazole are more effective in treating mice infected with the T. cruzi Y strain than fexinidazole or benznidazole [26]. The US Food and Drug Administration (FDA) approved 2021 fexinidazole as the first all-oral treatment for both stages of the Trypanosoma brucei gambiense form of sleeping sickness [77].
Anti-trypanosomatid structure-based drug design – lessons learned from targeting the folate pathway
Published in Expert Opinion on Drug Discovery, 2022
Joanna Panecka-Hofman, Ina Poehner, Rebecca C. Wade
Therefore, even in the best-controlled case of sleeping sickness, better treatments, that overcome resistance and have reduced side effects, are needed. Unfortunately, drug design efforts against trypanosomiases are not generally profitable for pharmaceutical companies, since these so-called ‘neglected diseases’ occur mostly in poor regions of the world [21]. However, in recent years, there have been several initiatives to advance drug design against neglected tropical diseases. These include (i) the Drugs for Neglected Diseases initiative (DNDi, https://dndi.org [22]), (ii) the Trypanogen and Trypanogen+ projects funded by AAS/Wellcome under the H3Africa initiative (http://trypanogen.net/ [23]), (iii) two EU-funded projects that focused on targeting specific biochemical pathways of parasites causing the diseases: New Medicines for Trypanosomatidic Infections (NMTrypI [24], https://fp7-nmtrypi.eu/ [25], https://cordis.europa.eu/project/id/603240 [26]) and Parasite-specific cyclic nucleotide phosphodiesterase inhibitors to target Neglected Parasitic Diseases (PDE4NPD, https://cordis.europa.eu/project/id/602666 [27]). One of the focuses of the NMTrypI project, in which the authors of the present article participated, was targeting the parasite folate pathways. We here review recent efforts in anti-trypanosomatid structure-based drug design (SBDD) from this perspective.
Why hasn’t there been more progress in new Chagas disease drug discovery?
Published in Expert Opinion on Drug Discovery, 2020
Alane Beatriz Vermelho, Giseli Capaci Rodrigues, Claudiu T. Supuran
Nowadays, the Drugs for Neglected Diseases initiative (DNDi), a not-for-profit research and development organization, is one of the few major entities focusing on Neglected Diseases and has active programs in Chagas disease in partnership with academies and the pharmaceutical industry. DNDi is trying to improve the treatment of Chagas disease by developing new treatments and drugs, which are safe and effective against the disease in all its phases. DNDi and seven other pharmaceutical companies created a consortium called Neglected Tropical Diseases (NTDs) Drug Discovery Booster.