The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Alan H Fairlamb - One of the best experts on this subject based on the ideXlab platform.
-
Current and Future Prospects of Nitro-compounds as Drugs for Trypanosomiasis and Leishmaniasis.
Current medicinal chemistry, 2019Co-Authors: Stephen Patterson, Alan H FairlambAbstract:Interest in nitroheterocyclic drugs for the treatment of infectious diseases has undergone a resurgence in recent years. Here we review the current status of monocyclic and bicyclic nitroheterocyclic compounds as existing or potential new treatments for visceral leishmaniasis, Chagas' disease and human African trypanosomiasis. Both monocyclic (nifurtimox, benznidazole and Fexinidazole) and bicyclic (pretomanid (PA-824) and delamanid (OPC-67683)) nitro-compounds are prodrugs, requiring enzymatic activation to exert their parasite toxicity. Current understanding of the nitroreductases involved in activation and possible mechanisms by which parasites develop resistance is discussed along with a description of the pharmacokinetic / pharmacodynamic behaviour and chemical structure-activity relationships of drugs and experimental compounds.
-
Fexinidazole for the treatment of human African trypanosomiasis.
Drugs of today (Barcelona Spain : 1998), 2019Co-Authors: Alan H FairlambAbstract:On November 15, 2018, Fexinidazole Winthrop received a positive opinion from the European Medicines Agency (EMA) (under Article 58) for treatment of first-stage (hemolymphatic) and second-stage (meningoencephalitic) human African trypanosomiasis caused by Trypanosoma gambiense (gHAT) in adults and children 6 years and older and weighing 20 or more kg. This is the first oral regimen for gHAT that is effective in treating both disease stages. Although Fexinidazole has potential to simplify current therapies, it does not entirely eliminate the need for disease staging by lumbar puncture because patients with severe stage 2 disease (CSF WBC [cerebrospinal fluid white blood cells] greater than 100 cells/µL) should only be treated with Fexinidazole if no other suitable treatment is available. Nausea and vomiting are a common side effect and the drug must be administered during or after the patient's main meal under direct observation by trained health personnel. Due to late relapses, the EMA recommends follow-up to 24 months after treatment.
-
a role for trypanosomatid aldo keto reductases in methylglyoxal prostaglandin and isoprostane metabolism
Biochemical Journal, 2018Co-Authors: Adam J Roberts, Suzanne Norval, Joanne Dunne, Paul Scullion, Alan H FairlambAbstract:Trypanosomatid parasites are the infectious agents causing Chagas disease, visceral and cutaneous leishmaniasis and human African trypanosomiasis. Recent work of others has implicated an aldo-keto reductase (AKR) in the susceptibility and resistance of Trypanosoma cruzi to benznidazole, a drug used to treat Chagas disease. Here, we show that TcAKR and homologues in the related parasites Trypanosoma brucei and Leishmania donovani do not reductively activate monocyclic (benznidazole, nifurtimox and Fexinidazole) or bicyclic nitro-drugs such as PA-824. Rather, these enzymes metabolise a variety of toxic ketoaldehydes, such as glyoxal and methylglyoxal, suggesting a role in cellular defence against chemical stress. UPLC-QToF/MS analysis of benznidazole bioactivation by T. cruzi cell lysates confirms previous reports identifying numerous drug metabolites, including a dihydro-dihydroxy intermediate that can dissociate to form N-benzyl-2-guanidinoacetamide and glyoxal, a toxic DNA-glycating and cross-linking agent. Thus, we propose that TcAKR contributes to benznidazole resistance by the removal of toxic glyoxal. In addition, three of the four enzymes studied here display activity as prostaglandin F2α synthases, despite the fact that there are no credible cyclooxygenases in these parasites to account for formation of the precursor PGH2 from arachidonic acid. Our studies suggest that arachidonic acid is first converted non-enzymatically in parasite lysates to (PGH2-like) regioisomers by free radical-mediated peroxidation and that AKRs convert these lipid peroxides into isoprostanes, including prostaglandin F2α and 8-iso-prostaglandin F2α.
-
Synthèse et évaluations biologiques de nouvelles 8-nitroquinoléin-2(1H)-ones antiparisitaires.
2018Co-Authors: Julien Pedron, Sandra Bourgeade-delmas, Sébastien Hutter, Clotilde Boudot, Alix Sournia-saquet, Susan Wyllie, Lucie Paloque, A Moreau, Jean-luc Stigliani, Alan H FairlambAbstract:Les kinétoplastidés sont des protozoaires flagellés responsables de maladies tropicales négligées mortelles telles que la leishmaniose viscérale (L. donovani et L. infantum) ou la trypanosomiase africaine (T. brucei), auxquelles plus de 500 millions de personnes sont exposées et pour lesquelles les traitements disponibles sont très limités [1,2]. Depuis quelques années, on observe un regain d’intérêt pour le développement de nitrohétérocycles anti-infectieux tels que le delamanide et le Fexinidazole [3,4]. De récentes études indiquent que l’activité anti-kinétoplastidés de ces dérivés repose sur leur réduction sélective par des nitroréductases parasitaires (NTR1 et NTR2 chez Leishmania, NTR chez Trypanosoma), conduisant à la formation de métabolites cytotoxiques [5-7]. Suite à des travaux préliminaires réalisés dans notre équipe en série 8-nitroquinoléin-2(1H)-ones [8-10], nous présentons ici la synthèse de 60 nouveaux hétérocycles nitro-aromatiques, l’étude de leurs propriétés physico-chimiques (incluant les potentiels de réduction) et pharmacocinétiques in vitro (stabilité microsomale et fixation aux protéines plasmatiques), de leur activité anti-kinétoplastidés in vitro de même que la recherche de leur mécanisme d’action et l’étude de leur cytotoxicité et génotoxicité. Ainsi, ce travail nous a permis d’identifier 3 nouveaux hits (2 anti-kinétoplastidés et 1 sélectif de Trypanosoma), d’observer une corrélation entre les potentiels de réduction et l’activité antileishmanienne, de déterminer que ces molécules sont sélectivement bioactivées par la NTR1 chez L. donovani et qu’elles ne sont pas génotoxiques vis-à-vis de cellules humaines. Dans ce contexte, des études in vivo sur un modèle murin de trypanosomiase sont en cours dans le but de statuer sur le devenir de ces molécules en tant que candidats antiparasitaires humains ou vétérinaires. Références
-
activation of bicyclic nitro drugs by a novel nitroreductase ntr2 in leishmania
PLOS Pathogens, 2016Co-Authors: Susan Wyllie, Stephen Patterson, Suzanne Norval, Kevin D Read, Bernardo J. Foth, Matthew Berriman, Adam J Roberts, Alan H FairlambAbstract:Drug discovery pipelines for the “neglected diseases” are now heavily populated with nitroheterocyclic compounds. Recently, the bicyclic nitro-compounds (R)-PA-824, DNDI-VL-2098 and delamanid have been identified as potential candidates for the treatment of visceral leishmaniasis. Using a combination of quantitative proteomics and whole genome sequencing of susceptible and drug-resistant parasites we identified a putative NAD(P)H oxidase as the activating nitroreductase (NTR2). Whole genome sequencing revealed that deletion of a single cytosine in the gene for NTR2 that is likely to result in the expression of a non-functional truncated protein. Susceptibility of leishmania was restored by reintroduction of the wild-type gene into the resistant line, which was accompanied by the ability to metabolise these compounds. Overexpression of NTR2 in wild-type parasites rendered cells hyper-sensitive to bicyclic nitro-compounds, but only marginally to the monocyclic nitro-drugs, nifurtimox and Fexinidazole sulfone, known to be activated by a mitochondrial oxygen-insensitive nitroreductase (NTR1). Conversely, a double knockout NTR2 null cell line was completely resistant to bicyclic nitro-compounds and only marginally resistant to nifurtimox. Sensitivity was fully restored on expression of NTR2 in the null background. Thus, NTR2 is necessary and sufficient for activation of these bicyclic nitro-drugs. Recombinant NTR2 was capable of reducing bicyclic nitro-compounds in the same rank order as drug sensitivity in vitro. These findings may aid the future development of better, novel anti-leishmanial drugs. Moreover, the discovery of anti-leishmanial nitro-drugs with independent modes of activation and independent mechanisms of resistance alleviates many of the concerns over the continued development of these compound series.
Marcel Kaiser - One of the best experts on this subject based on the ideXlab platform.
-
In Vitro Drug Efficacy Testing Against Trypanosoma brucei.
Methods in molecular biology (Clifton N.J.), 2020Co-Authors: Marcel Kaiser, Pascal MäserAbstract:The recent endorsement of Fexinidazole by the European Medicines Agency for the treatment of human African trypanosomiasis has demonstrated the high predictive value of cell-based assays for parasite chemotherapy. Here we describe three in vitro drug susceptibility tests with Trypanosoma brucei that have served as the basis for the identification of Fexinidazole as a promising lead: (1) a standard assay with end-point measurement to determine drug efficacy; (2) a wash-out assay to test for reversibility and speed of drug action; (3) isothermal microcalorimetry for real-time measurement of onset of drug action and time to kill. Together, these assays allow to estimate pharmacodynamic parameters in vitro and to devise appropriate treatment regimens for subsequent in vivo experiments.
-
New drugs against trypanosomatid parasites : rediscovery of Fexinidazole
2014Co-Authors: Marcel KaiserAbstract:Neglected tropical diseases (NTDs) are a group of communicable diseases mostly affecting people in developing countries. These diseases are responsible for a major part of the global morbidity, mortality and poverty. There is no doubt that the well-being of people in the developing world can only be improved if the NTDs are controlled. An important tool for disease control is the drug treatment. The few available drugs are unsatisfactory because of the limited efficacy, adverse effects and the high price. Chagas disease, leishmaniasis and human African trypanosomiasis belong to this group of NTDs. They are caused by infections with protozoa of the family Trypanosomatidae. For these three diseases new drugs are urgently needed. By definition there is no commercial market for drugs against NTDs. Drug research and development (R&D) for NTDs is mainly driven by the public sector, the so-called product development partnerships (PDPs). Drug R&D is a very long (10-15 years), risky and therefore expensive process. Three different series of compounds (agrochemicals, marketed drugs and nitro-heterocyclic compounds) were tested for their antiparasitic effects, with the aim to identify new lead compounds or even clinical candidates against leishmaniasis, sleeping sickness, and Chagas disease. Agrochemicals are used worldwide on a large scale in food production. They undergo a rigorous toxicological testing prior to launch. Over 600 compounds were screened for their antiparasitic activity. Agrochemicals are not optimized for use in mammals, yet a significant number of molecules were found with good and selective in vitro activity. Some of them showed also efficacy in the corresponding rodent model. These results indicate that agrochemicals can provide very interesting starting structures for drug research against parasitic diseases. Drugs or drug-like compounds are an ideal starting point for antiparasitic drug discovery, because very often pharmacokinetic and toxicological data are available. A number of drugs, including antibiotics, antivirals, antifungals, and anti-psychotics were assayed for antiparasitic activity. Some of the drugs tested showed selective antiparasitic activity. These compounds can be regarded as new lead structures and should be further investigated. Nitroheterocycles belong to a well- known class of compounds with the stigma of being mutagenic or genotoxic. Over 700 compounds, mainly nitroimidazoles, have been systematically tested for their antiparasitic activity, and their pharmacokinetics and mutagenicity was investigated. A number of effective, non-mutagenic and non- genotoxic compounds was identified. So Fexinidazole was rediscovered, a drug that had been in clinical development already in the 70’s as a broad-spectrum antimicrobial drug. Fexinidazole is rapidly metabolized to Fexinidazole-sulfoxide and -sulfone. The parent compound and the two principle metabolites showed in vitro trypanocidal activity against all (sensitive and resistant) tested T. brucei strains (IC50 of 0.2 - 0.9 ug / ml). Fexinidazole cured the first stage mouse model with a 4-day oral treatment of 100 mg/kg/day and the 2nd stage mouse model with a 5-day oral treatment of 200 mg/kg/day. The two metabolites are mainly responsible for the good efficacy in animal models. Both reach very high concentrations in blood and brain tissue. Fexinidazole has successfully completed preclinical development and Phase I clinical trials and is currently in a clinical phase II / III study. With the approach of phenotypic screening of compounds that have been developed for other purposes, new leads for drug R&D against Chagas’ disease, leishmaniasis and human African trypanosomiasis were identified. Fexinidazole is the first drug candidate in clinical Phase II / III trials since decades. It would be the first oral drug for the treatment of stage 1 and 2 of human African sleeping sickness. If Fexinidazole overcomes all obstacles, this would be a major breakthrough in the fight against African sleeping sickness. With a well tolerated, orally active drug like Fexinidazole the elimination of sleeping sickness seems finally tangible.
-
Antiparasitic agents: new drugs on the horizon.
Current opinion in pharmacology, 2012Co-Authors: Pascal Mäser, Marcel Kaiser, Sergio Wittlin, Matthias Rottmann, Tanja Wenzler, Reto BrunAbstract:The need for new drugs against tropical parasites such as Plasmodium falciparum and Trypanosoma brucei is persistent since problems with resistance and toxicity are jeopardizing the currently available medicines. Public-private partnerships aiming to develop new medicines for malaria and sleeping sickness have, over the past 12 years, brought forward several drug candidates that have entered clinical trials. These are the synthetic peroxide OZ439 and the spiroindolone NITD609 against P. falciparum, Fexinidazole and the oxaborole SCYX-7158 against T. brucei. A further class of high chemotherapeutic potential are the diamidines, novel members of which may serve as back-up compounds against trypanosomes and other parasites. Thus, finally, new therapeutic agents against malaria and sleeping sickness are within reach.
-
antitrypanosomal activity of Fexinidazole a new oral nitroimidazole drug candidate for treatment of sleeping sickness
Antimicrobial Agents and Chemotherapy, 2011Co-Authors: Michael A. Bray, Els Torreele, Bernadette Bourdin Trunz, Marcel Kaiser, Reto BrunAbstract:Fexinidazole is a 5-nitroimidazole drug currently in clinical development for the treatment of human sleeping sickness (human African trypanosomiasis [HAT]), caused by infection with species of the protozoan parasite Trypanosoma brucei. The compound and its two principal metabolites, sulfoxide and sulfone, have been assessed for their ability to kill a range of T. brucei parasite strains in vitro and to cure both acute and chronic HAT disease models in the mouse. The parent molecule and both metabolites have shown trypanocidal activity in vitro in the 0.7-to-3.3 μM (0.2-to-0.9 μg/ml) range against all parasite strains tested. In vivo, Fexinidazole is orally effective in curing both acute and chronic diseases in the mouse at doses of 100 mg/kg of body weight/day for 4 days and 200 mg/kg/day for 5 days, respectively. Pharmacokinetic data indicate that it is likely that the sulfoxide and sulfone metabolites provide most, if not all, of the in vivo killing activity. Fexinidazole and its metabolites require up to 48 h exposure in order to induce maximal trypanocidal efficacy in vitro. The parent drug and its metabolites show no in vitro cross-reactivity in terms of trypanocidal activity with either themselves or other known trypanocidal drugs in use in humans. The in vitro and in vivo antitrypanosomal activities of Fexinidazole and its two principal metabolites provide evidence that the compound has the potential to be an effective oral treatment for both the T. b. gambiense and T. b. rhodesiense forms of human sleeping sickness and both stages of the disease.
-
Fexinidazole a new oral nitroimidazole drug candidate entering clinical development for the treatment of sleeping sickness
PLOS Neglected Tropical Diseases, 2010Co-Authors: Els Torreele, Bernadette Bourdin Trunz, David Tweats, Marcel Kaiser, Reto Brun, Guy Mazue, Michael A. BrayAbstract:BACKGROUND: Human African trypanosomiasis (HAT), also known as sleeping sickness, is a fatal parasitic disease caused by trypanosomes. Current treatment options for HAT are scarce, toxic, no longer effective, or very difficult to administer, in particular for the advanced, fatal stage of the disease (stage 2, chronic HAT). New safe, effective and easy-to-use treatments are urgently needed. Here it is shown that Fexinidazole, a 2-substituted 5-nitroimidazole rediscovered by the Drugs for Neglected Diseases initiative (DNDi) after extensive compound mining efforts of more than 700 new and existing nitroheterocycles, could be a short-course, safe and effective oral treatment curing both acute and chronic HAT and that could be implemented at the primary health care level. To complete the preclinical development and meet the regulatory requirements before initiating human trials, the anti-parasitic properties and the pharmacokinetic, metabolic and toxicological profile of Fexinidazole have been assessed. METHODS AND FINDINGS: Standard in vitro and in vivo anti-parasitic activity assays were conducted to assess drug efficacy in experimental models for HAT. In parallel, a full range of preclinical pharmacology and safety studies, as required by international regulatory guidelines before initiating human studies, have been conducted. Fexinidazole is moderately active in vitro against African trypanosomes (IC against laboratory strains and recent clinical isolates ranged between 0.16 and 0.93 microg/mL) and oral administration of Fexinidazole at doses of 100 mg/kg/day for 4 days or 200 mg/kg/day for 5 days cured mice with acute and chronic infection respectively, the latter being a model for the advanced and fatal stage of the disease when parasites have disseminated into the brain. In laboratory animals, Fexinidazole is well absorbed after oral administration and readily distributes throughout the body, including the brain. The absolute bioavailability of oral Fexinidazole was 41% in mice, 30% in rats, and 10% in dogs. Furthermore, Fexinidazole is rapidly metabolised in vivo to at least two biologically active metabolites (a sulfoxide and a sulfone derivative) that likely account for a significant portion of the therapeutic effect. Key pharmacokinetic parameter after oral absorption in mice for Fexinidazole and its sulfoxide and sulfone metabolites are a C(max) of 500, 14171 and 13651 ng/mL respectively, and an AUC of 424, 45031 and 96286 h.ng/mL respectively. Essentially similar PK profiles were observed in rats and dogs. Toxicology studies (including safety pharmacology and 4-weeks repeated-dose toxicokinetics in rat and dog) have shown that Fexinidazole is well tolerated. The No Observed Adverse Event Levels in the 4-weeks repeated dose toxicity studies in rats and dogs was 200 mg/kg/day in both species, with no issues of concern identified for doses up to 800 mg/kg/day. While Fexinidazole, like many nitroheterocycles, is mutagenic in the Ames test due to bacterial specific metabolism, it is not genotoxic to mammalian cells in vitro or in vivo as assessed in an in vitro micronucleus test on human lymphocytes, an in vivo mouse bone marrow micronucleus test, and an ex vivo unscheduled DNA synthesis test in rats. CONCLUSIONS: The results of the preclinical pharmacological and safety studies indicate that Fexinidazole is a safe and effective oral drug candidate with no untoward effects that would preclude evaluation in man. The drug has entered first-in-human phase I studies in September 2009. Fexinidazole is the first new clinical drug candidate with the potential for treating advanced-stage sleeping sickness in thirty years
Susan Wyllie - One of the best experts on this subject based on the ideXlab platform.
-
Synthèse et évaluations biologiques de nouvelles 8-nitroquinoléin-2(1H)-ones antiparisitaires.
2018Co-Authors: Julien Pedron, Sandra Bourgeade-delmas, Sébastien Hutter, Clotilde Boudot, Alix Sournia-saquet, Susan Wyllie, Lucie Paloque, A Moreau, Jean-luc Stigliani, Alan H FairlambAbstract:Les kinétoplastidés sont des protozoaires flagellés responsables de maladies tropicales négligées mortelles telles que la leishmaniose viscérale (L. donovani et L. infantum) ou la trypanosomiase africaine (T. brucei), auxquelles plus de 500 millions de personnes sont exposées et pour lesquelles les traitements disponibles sont très limités [1,2]. Depuis quelques années, on observe un regain d’intérêt pour le développement de nitrohétérocycles anti-infectieux tels que le delamanide et le Fexinidazole [3,4]. De récentes études indiquent que l’activité anti-kinétoplastidés de ces dérivés repose sur leur réduction sélective par des nitroréductases parasitaires (NTR1 et NTR2 chez Leishmania, NTR chez Trypanosoma), conduisant à la formation de métabolites cytotoxiques [5-7]. Suite à des travaux préliminaires réalisés dans notre équipe en série 8-nitroquinoléin-2(1H)-ones [8-10], nous présentons ici la synthèse de 60 nouveaux hétérocycles nitro-aromatiques, l’étude de leurs propriétés physico-chimiques (incluant les potentiels de réduction) et pharmacocinétiques in vitro (stabilité microsomale et fixation aux protéines plasmatiques), de leur activité anti-kinétoplastidés in vitro de même que la recherche de leur mécanisme d’action et l’étude de leur cytotoxicité et génotoxicité. Ainsi, ce travail nous a permis d’identifier 3 nouveaux hits (2 anti-kinétoplastidés et 1 sélectif de Trypanosoma), d’observer une corrélation entre les potentiels de réduction et l’activité antileishmanienne, de déterminer que ces molécules sont sélectivement bioactivées par la NTR1 chez L. donovani et qu’elles ne sont pas génotoxiques vis-à-vis de cellules humaines. Dans ce contexte, des études in vivo sur un modèle murin de trypanosomiase sont en cours dans le but de statuer sur le devenir de ces molécules en tant que candidats antiparasitaires humains ou vétérinaires. Références
-
Snapshot Profiling of the Antileishmanial Potency of Lead Compounds and Drug Candidates against Intracellular Leishmania donovani Amastigotes, with a Focus on Human-Derived Host Cells
Antimicrobial agents and chemotherapy, 2017Co-Authors: Markella Koniordou, Susan Wyllie, Stephen Patterson, Karin SeifertAbstract:This study characterized the in vitro potencies of antileishmanial agents against intracellular Leishmania donovani amastigotes in primary human macrophages, obtained with or without CD14-positive monocyte enrichment, phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1 cells, and mouse peritoneal exudate macrophages (PEMs). Host cell-dependent potency was confirmed for pentavalent and trivalent antimony. Fexinidazole was inactive against intracellular amastigotes across the host cell panel. Fexinidazole sulfone, (R)-PA-824, (S)-PA-824, and VL-2098 displayed similar potency in all of the host cells tested.
-
activation of bicyclic nitro drugs by a novel nitroreductase ntr2 in leishmania
PLOS Pathogens, 2016Co-Authors: Susan Wyllie, Stephen Patterson, Suzanne Norval, Kevin D Read, Bernardo J. Foth, Matthew Berriman, Adam J Roberts, Alan H FairlambAbstract:Drug discovery pipelines for the “neglected diseases” are now heavily populated with nitroheterocyclic compounds. Recently, the bicyclic nitro-compounds (R)-PA-824, DNDI-VL-2098 and delamanid have been identified as potential candidates for the treatment of visceral leishmaniasis. Using a combination of quantitative proteomics and whole genome sequencing of susceptible and drug-resistant parasites we identified a putative NAD(P)H oxidase as the activating nitroreductase (NTR2). Whole genome sequencing revealed that deletion of a single cytosine in the gene for NTR2 that is likely to result in the expression of a non-functional truncated protein. Susceptibility of leishmania was restored by reintroduction of the wild-type gene into the resistant line, which was accompanied by the ability to metabolise these compounds. Overexpression of NTR2 in wild-type parasites rendered cells hyper-sensitive to bicyclic nitro-compounds, but only marginally to the monocyclic nitro-drugs, nifurtimox and Fexinidazole sulfone, known to be activated by a mitochondrial oxygen-insensitive nitroreductase (NTR1). Conversely, a double knockout NTR2 null cell line was completely resistant to bicyclic nitro-compounds and only marginally resistant to nifurtimox. Sensitivity was fully restored on expression of NTR2 in the null background. Thus, NTR2 is necessary and sufficient for activation of these bicyclic nitro-drugs. Recombinant NTR2 was capable of reducing bicyclic nitro-compounds in the same rank order as drug sensitivity in vitro. These findings may aid the future development of better, novel anti-leishmanial drugs. Moreover, the discovery of anti-leishmanial nitro-drugs with independent modes of activation and independent mechanisms of resistance alleviates many of the concerns over the continued development of these compound series.
-
The R enantiomer of the antitubercular drug PA-824 as a potential oral treatment for visceral Leishmaniasis
2016Co-Authors: Stephen Patterson, Susan Wyllie, Laste Stojanovski, Frederick R C Simeons, Suzanne Norval, Kevin D Read, Meghan R. Perry, Maria Osuna-cabello, Manu De Rycker, Alan H FairlambAbstract:The novel nitroimidazopyran agent (S)-PA-824 has potent antibacterial activity againstMycobacterium tuberculosis in vitro and in vivo and is currently in phase II clinical trials for tuberculosis (TB). In contrast toM. tuberculosis, where (R)-PA-824 is inac-tive, we report here that both enantiomers of PA-824 show potent parasiticidal activity against Leishmania donovani, the caus-ative agent of visceral leishmaniasis (VL). In leishmania-infected macrophages, (R)-PA-824 is 6-fold more active than (S)-PA-824. Both des-nitro analogues are inactive, underlining the importance of the nitro group in the mechanism of action. Although the in vitro and in vivo pharmacological profiles of the two enantiomers are similar, (R)-PA-824 is more efficacious in the mu-rine model of VL, with>99 % suppression of parasite burden when administered orally at 100 mg kg of body weight1, twice daily for 5 days. InM. tuberculosis, (S)-PA-824 is a prodrug that is activated by a deazaflavin-dependent nitroreductase (Ddn), an enzyme which is absent in Leishmania spp. Unlike the case with nifurtimox and Fexinidazole, transgenic parasites overex-pressing the leishmania nitroreductase are not hypersensitive to either (R)-PA-824 or (S)-PA-824, indicating that this enzyme is not the primary target of these compounds. Drug combination studies in vitro indicate that Fexinidazole and (R)-PA-824 are additive whereas (S)-PA-824 and (R)-PA-824 showmild antagonistic behavior. Thus, (R)-PA-824 is a promising candidate for late lead optimization for VL andmay have potential for future use in combination therapy with Fexinidazole, currently in phase II clinical trials against VL. Visceral leishmaniasis (VL), caused by the protozoan parasiteLeishmania donovani, is the second largest parasitic killer afte
-
Nitroheterocyclic drug resistance mechanisms in Trypanosoma brucei
The Journal of antimicrobial chemotherapy, 2015Co-Authors: Susan Wyllie, Bernardo J. Foth, Anna Kelner, Antoaneta Y. Sokolova, Matthew Berriman, Alan H FairlambAbstract:Objectives The objective of this study was to identify the mechanisms of resistance to nifurtimox and Fexinidazole in African trypanosomes.
Reto Brun - One of the best experts on this subject based on the ideXlab platform.
-
Antiparasitic agents: new drugs on the horizon.
Current opinion in pharmacology, 2012Co-Authors: Pascal Mäser, Marcel Kaiser, Sergio Wittlin, Matthias Rottmann, Tanja Wenzler, Reto BrunAbstract:The need for new drugs against tropical parasites such as Plasmodium falciparum and Trypanosoma brucei is persistent since problems with resistance and toxicity are jeopardizing the currently available medicines. Public-private partnerships aiming to develop new medicines for malaria and sleeping sickness have, over the past 12 years, brought forward several drug candidates that have entered clinical trials. These are the synthetic peroxide OZ439 and the spiroindolone NITD609 against P. falciparum, Fexinidazole and the oxaborole SCYX-7158 against T. brucei. A further class of high chemotherapeutic potential are the diamidines, novel members of which may serve as back-up compounds against trypanosomes and other parasites. Thus, finally, new therapeutic agents against malaria and sleeping sickness are within reach.
-
antitrypanosomal activity of Fexinidazole a new oral nitroimidazole drug candidate for treatment of sleeping sickness
Antimicrobial Agents and Chemotherapy, 2011Co-Authors: Michael A. Bray, Els Torreele, Bernadette Bourdin Trunz, Marcel Kaiser, Reto BrunAbstract:Fexinidazole is a 5-nitroimidazole drug currently in clinical development for the treatment of human sleeping sickness (human African trypanosomiasis [HAT]), caused by infection with species of the protozoan parasite Trypanosoma brucei. The compound and its two principal metabolites, sulfoxide and sulfone, have been assessed for their ability to kill a range of T. brucei parasite strains in vitro and to cure both acute and chronic HAT disease models in the mouse. The parent molecule and both metabolites have shown trypanocidal activity in vitro in the 0.7-to-3.3 μM (0.2-to-0.9 μg/ml) range against all parasite strains tested. In vivo, Fexinidazole is orally effective in curing both acute and chronic diseases in the mouse at doses of 100 mg/kg of body weight/day for 4 days and 200 mg/kg/day for 5 days, respectively. Pharmacokinetic data indicate that it is likely that the sulfoxide and sulfone metabolites provide most, if not all, of the in vivo killing activity. Fexinidazole and its metabolites require up to 48 h exposure in order to induce maximal trypanocidal efficacy in vitro. The parent drug and its metabolites show no in vitro cross-reactivity in terms of trypanocidal activity with either themselves or other known trypanocidal drugs in use in humans. The in vitro and in vivo antitrypanosomal activities of Fexinidazole and its two principal metabolites provide evidence that the compound has the potential to be an effective oral treatment for both the T. b. gambiense and T. b. rhodesiense forms of human sleeping sickness and both stages of the disease.
-
Development of novel drugs for human African trypanosomiasis.
Future microbiology, 2011Co-Authors: Reto Brun, Robert Don, Robert T. Jacobs, Michael Zhuo Wang, Michael P. BarrettAbstract: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
-
Fexinidazole a new oral nitroimidazole drug candidate entering clinical development for the treatment of sleeping sickness
PLOS Neglected Tropical Diseases, 2010Co-Authors: Els Torreele, Bernadette Bourdin Trunz, David Tweats, Marcel Kaiser, Reto Brun, Guy Mazue, Michael A. BrayAbstract:BACKGROUND: Human African trypanosomiasis (HAT), also known as sleeping sickness, is a fatal parasitic disease caused by trypanosomes. Current treatment options for HAT are scarce, toxic, no longer effective, or very difficult to administer, in particular for the advanced, fatal stage of the disease (stage 2, chronic HAT). New safe, effective and easy-to-use treatments are urgently needed. Here it is shown that Fexinidazole, a 2-substituted 5-nitroimidazole rediscovered by the Drugs for Neglected Diseases initiative (DNDi) after extensive compound mining efforts of more than 700 new and existing nitroheterocycles, could be a short-course, safe and effective oral treatment curing both acute and chronic HAT and that could be implemented at the primary health care level. To complete the preclinical development and meet the regulatory requirements before initiating human trials, the anti-parasitic properties and the pharmacokinetic, metabolic and toxicological profile of Fexinidazole have been assessed. METHODS AND FINDINGS: Standard in vitro and in vivo anti-parasitic activity assays were conducted to assess drug efficacy in experimental models for HAT. In parallel, a full range of preclinical pharmacology and safety studies, as required by international regulatory guidelines before initiating human studies, have been conducted. Fexinidazole is moderately active in vitro against African trypanosomes (IC against laboratory strains and recent clinical isolates ranged between 0.16 and 0.93 microg/mL) and oral administration of Fexinidazole at doses of 100 mg/kg/day for 4 days or 200 mg/kg/day for 5 days cured mice with acute and chronic infection respectively, the latter being a model for the advanced and fatal stage of the disease when parasites have disseminated into the brain. In laboratory animals, Fexinidazole is well absorbed after oral administration and readily distributes throughout the body, including the brain. The absolute bioavailability of oral Fexinidazole was 41% in mice, 30% in rats, and 10% in dogs. Furthermore, Fexinidazole is rapidly metabolised in vivo to at least two biologically active metabolites (a sulfoxide and a sulfone derivative) that likely account for a significant portion of the therapeutic effect. Key pharmacokinetic parameter after oral absorption in mice for Fexinidazole and its sulfoxide and sulfone metabolites are a C(max) of 500, 14171 and 13651 ng/mL respectively, and an AUC of 424, 45031 and 96286 h.ng/mL respectively. Essentially similar PK profiles were observed in rats and dogs. Toxicology studies (including safety pharmacology and 4-weeks repeated-dose toxicokinetics in rat and dog) have shown that Fexinidazole is well tolerated. The No Observed Adverse Event Levels in the 4-weeks repeated dose toxicity studies in rats and dogs was 200 mg/kg/day in both species, with no issues of concern identified for doses up to 800 mg/kg/day. While Fexinidazole, like many nitroheterocycles, is mutagenic in the Ames test due to bacterial specific metabolism, it is not genotoxic to mammalian cells in vitro or in vivo as assessed in an in vitro micronucleus test on human lymphocytes, an in vivo mouse bone marrow micronucleus test, and an ex vivo unscheduled DNA synthesis test in rats. CONCLUSIONS: The results of the preclinical pharmacological and safety studies indicate that Fexinidazole is a safe and effective oral drug candidate with no untoward effects that would preclude evaluation in man. The drug has entered first-in-human phase I studies in September 2009. Fexinidazole is the first new clinical drug candidate with the potential for treating advanced-stage sleeping sickness in thirty years
-
Fexinidazole – A New Oral Nitroimidazole Drug Candidate Entering Clinical Development for the Treatment of Sleeping Sickness
PLoS neglected tropical diseases, 2010Co-Authors: Els Torreele, Michael A. Bray, Bernadette Bourdin Trunz, David Tweats, Marcel Kaiser, Reto Brun, Guy Mazue, Bernard PécoulAbstract:BACKGROUND: Human African trypanosomiasis (HAT), also known as sleeping sickness, is a fatal parasitic disease caused by trypanosomes. Current treatment options for HAT are scarce, toxic, no longer effective, or very difficult to administer, in particular for the advanced, fatal stage of the disease (stage 2, chronic HAT). New safe, effective and easy-to-use treatments are urgently needed. Here it is shown that Fexinidazole, a 2-substituted 5-nitroimidazole rediscovered by the Drugs for Neglected Diseases initiative (DNDi) after extensive compound mining efforts of more than 700 new and existing nitroheterocycles, could be a short-course, safe and effective oral treatment curing both acute and chronic HAT and that could be implemented at the primary health care level. To complete the preclinical development and meet the regulatory requirements before initiating human trials, the anti-parasitic properties and the pharmacokinetic, metabolic and toxicological profile of Fexinidazole have been assessed. METHODS AND FINDINGS: Standard in vitro and in vivo anti-parasitic activity assays were conducted to assess drug efficacy in experimental models for HAT. In parallel, a full range of preclinical pharmacology and safety studies, as required by international regulatory guidelines before initiating human studies, have been conducted. Fexinidazole is moderately active in vitro against African trypanosomes (IC against laboratory strains and recent clinical isolates ranged between 0.16 and 0.93 microg/mL) and oral administration of Fexinidazole at doses of 100 mg/kg/day for 4 days or 200 mg/kg/day for 5 days cured mice with acute and chronic infection respectively, the latter being a model for the advanced and fatal stage of the disease when parasites have disseminated into the brain. In laboratory animals, Fexinidazole is well absorbed after oral administration and readily distributes throughout the body, including the brain. The absolute bioavailability of oral Fexinidazole was 41% in mice, 30% in rats, and 10% in dogs. Furthermore, Fexinidazole is rapidly metabolised in vivo to at least two biologically active metabolites (a sulfoxide and a sulfone derivative) that likely account for a significant portion of the therapeutic effect. Key pharmacokinetic parameter after oral absorption in mice for Fexinidazole and its sulfoxide and sulfone metabolites are a C(max) of 500, 14171 and 13651 ng/mL respectively, and an AUC of 424, 45031 and 96286 h.ng/mL respectively. Essentially similar PK profiles were observed in rats and dogs. Toxicology studies (including safety pharmacology and 4-weeks repeated-dose toxicokinetics in rat and dog) have shown that Fexinidazole is well tolerated. The No Observed Adverse Event Levels in the 4-weeks repeated dose toxicity studies in rats and dogs was 200 mg/kg/day in both species, with no issues of concern identified for doses up to 800 mg/kg/day. While Fexinidazole, like many nitroheterocycles, is mutagenic in the Ames test due to bacterial specific metabolism, it is not genotoxic to mammalian cells in vitro or in vivo as assessed in an in vitro micronucleus test on human lymphocytes, an in vivo mouse bone marrow micronucleus test, and an ex vivo unscheduled DNA synthesis test in rats. CONCLUSIONS: The results of the preclinical pharmacological and safety studies indicate that Fexinidazole is a safe and effective oral drug candidate with no untoward effects that would preclude evaluation in man. The drug has entered first-in-human phase I studies in September 2009. Fexinidazole is the first new clinical drug candidate with the potential for treating advanced-stage sleeping sickness in thirty years
Els Torreele - One of the best experts on this subject based on the ideXlab platform.
-
Fexinidazole: A Potential New Drug Candidate for Chagas Disease
2016Co-Authors: Maria Terezinha Bahia, Els Torreele, Isabel Mayer De Andrade, Fontes Martins, Bourdin Trunz, Isabela RibeiroAbstract:Background: New safe and effective treatments for Chagas disease (CD) are urgently needed. Current chemotherapy options for CD have significant limitations, including failure to uniformly achieve parasitological cure or prevent the chronic phase of CD, and safety and tolerability concerns. Fexinidazole, a 2-subsituted 5-nitroimidazole drug candidate rediscovered following extensive compound mining by the Drugs for Neglected Diseases initiative and currently in Phase I clinical study for the treatment of human African trypanosomiasis, was evaluated in experimental models of acute and chronic CD caused by different strains of Trypanosoma cruzi. Methods and Findings: We investigated the in vivo activity of Fexinidazole against T. cruzi, using mice as hosts. The T. cruzi strains used in the study were previously characterized in murine models as susceptible (CL strain), partially resistant (Y strain), and resistant (Colombian and VL-10 strains) to the drugs currently in clinical use, benznidazole and nifurtimox. Our results demonstrated that Fexinidazole was effective in suppressing parasitemia and preventing death in infected animals for all strains tested. In addition, assessment of definitive parasite clearance (cure) through parasitological, PCR, and serological methods showed cure rates of 80.0 % against CL and Y strains, 88.9 % against VL-10 strain, and 77.8 % against Colombian strain among animals treated during acute phase, and 70 % (VL-10 strain) in those treated in chronic phase. Benznidazole had a similar effect against susceptible and partially resistant T. cruzi strains. Fexinidazole treatment was als
-
ORIGINAL RESEARCH ARTICLE Determination of an Optimal Dosing Regimen for Fexinidazole, a Novel Oral Drug for the Treatment of Human African Trypanosomiasis: First-in-Human Studies
2016Co-Authors: Antoine Tarral, Olaf Valverde Mordt, Michael A. Bray, Els Torreele, Daniela Sassella, Lionel Hovsepian, Virginie Gualano, Mathieu Felices, Nathalie Strub-wourgaftAbstract:The Author(s) 2014. This article is published with open access at Springerlink.com Background and Objectives Fexinidazole is a 5-nitroim-idazole recently included in a clinical efficacy trial as an oral drug for the treatment of human African trypanoso-miasis (HAT). Preclinical studies showed it acts as a pharmacologically active pro-drug with two key active metabolites: sulfoxide and sulfone (the most active metab-olite). The present studies aimed to determine the best dose regimen for the treatment of stage 2 sleeping sickness patients, which could eventually also treat stage 1 patients. Methods Fexinidazole was assessed in 154 healthy adult male subjects of sub-Saharan African origin. Three initial first-in-human studies and two additional studies assessed a single ascending dose and multiple ascending doses (bot
-
Determination of an Optimal Dosing Regimen for Fexinidazole, a Novel Oral Drug for the Treatment of Human African Trypanosomiasis: First-in-Human Studies
Clinical Pharmacokinetics, 2014Co-Authors: Antoine Tarral, Olaf Valverde Mordt, Séverine Blesson, Michael A. Bray, Els Torreele, Daniela Sassella, Lionel Hovsepian, Eric Evène, Virginie Gualano, Mathieu FelicesAbstract:Background and Objectives Fexinidazole is a 5-nitroimidazole recently included in a clinical efficacy trial as an oral drug for the treatment of human African trypanosomiasis (HAT). Preclinical studies showed it acts as a pharmacologically active pro-drug with two key active metabolites: sulfoxide and sulfone (the most active metabolite). The present studies aimed to determine the best dose regimen for the treatment of stage 2 sleeping sickness patients, which could eventually also treat stage 1 patients. Methods Fexinidazole was assessed in 154 healthy adult male subjects of sub-Saharan African origin. Three initial first-in-human studies and two additional studies assessed a single ascending dose and multiple ascending doses (both under fasted conditions), tablet versus suspension formulation and food effect (fasted vs. high-fat meal and field-adapted food), and multiple ascending doses with a loading dose regimen under fed conditions. Results Fexinidazole was well-tolerated in a single dose from 100 to 3,600 mg, with quick absorption of the parent drug and rapid metabolism into sulfoxide [time to maximum concentration ( t _max) 2–5 h] and sulfone ( t _max 18–24 h). The tablet formulation was approximately 25 % less bioavailable than the suspension, and food intake increased drug absorption and plasma concentrations of Fexinidazole and its two metabolites by approximately 200 %. Fourteen-day multiple ascending dosing administered up to 3,600 mg/day in fasted conditions showed that Fexinidazole was generally well-tolerated (mild to moderate, spontaneously reversible drug-related adverse events). Following the high-fat food effect finding, another study was conducted to evaluate the impact of a low-fat regimen closer to that of the target population, showing that the type of meal does not influence Fexinidazole absorption. The last study showed that a loading dose of 1,800 mg/day for 4 days followed by a 1,200 mg/day regimen for 6 days with a normal meal provided the desired exposure of Fexinidazole and its metabolites, particularly sulfone, with good tolerability. Based on preclinical evidence from a chronic infection mouse model, systemic drug concentrations obtained are expected to be clinically effective in stage 2 HAT. Conclusions These studies show that Fexinidazole can be safely assessed in patients as a potential oral cure for both stages of HAT.
-
determination of an optimal dosing regimen for Fexinidazole a novel oral drug for the treatment of human african trypanosomiasis first in human studies
Clinical Pharmacokinectics, 2014Co-Authors: Antoine Tarral, Olaf Valverde Mordt, Séverine Blesson, Michael A. Bray, Els Torreele, Daniela Sassella, Lionel Hovsepian, Eric Evène, Virginie Gualano, Mathieu FelicesAbstract:Background and Objectives Fexinidazole is a 5-nitroimidazole recently included in a clinical efficacy trial as an oral drug for the treatment of human African trypanosomiasis (HAT). Preclinical studies showed it acts as a pharmacologically active pro-drug with two key active metabolites: sulfoxide and sulfone (the most active metabolite). The present studies aimed to determine the best dose regimen for the treatment of stage 2 sleeping sickness patients, which could eventually also treat stage 1 patients.
-
Chemical structure of Fexinidazole and benznidazole.
2013Co-Authors: Maria Terezinha Bahia, Els Torreele, Bernadette Bourdin Trunz, Isabel Mayer De Andrade, Tassiane Assíria Fontes Martins, Lívia De Figueiredo Diniz, Ivo Santana Caldas, André Talvani, Álvaro Fernando Da Silva Do Nascimento, Isabela RibeiroAbstract:Chemical structure of Fexinidazole and benznidazole.