Genotoxicity profile of fexinidazole—a drug candidate in clinical development for human African trypanomiasis (sleeping sickness)

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 201

Inquiry, engagement, and literacy in science: a retrospective, cross-national analysis of PISA 2006

In this study, we examine patterns of students’ literacy and engagement in science associated with different levels of ‘inquiry-oriented’ learning reported by students in Australia, Canada, and New Zealand. To achieve this we analysed data from the Organisation for Economic Co-operation and Development’s (OECD) 2006 Programme for International Student Assessment (PISA) which had science as its focus. Consistently, our findings show that science students who report experiencing low levels of inquiry-oriented learning activities are found to have above average levels of science literacy, but below average levels of interest in science, and below average levels on six variables that reflect students’ engagement in science. Our findings show that the corollary is also true. Across the three countries, students who report high levels of inquiry-oriented learning activities in science are observed to have below average levels of science literacy, but above average levels of interest in learning science, and above average engagement in science. These findings appear to run counter to science education orthodoxy that the more students experience inquiry-oriented teaching and learning, the more likely they are to have stronger science literacy, as well as more positive affect towards science. We discuss the implications of these findings for science educators and researchers

Elevated ethyl methanesulfonate (EMS) in nelfinavir mesylate (Viracept®, Roche): overview

Roche's protease inhibitor nelfinavir mesylate (Viracept®) produced between March 2007-June 2007 was found to contain elevated levels of ethyl methanesulfonate (EMS), a known mutagen (alkylator) – leading to a global recall of the drug. EMS levels in a daily dose (2,500 mg Viracept/day) were predicted not to exceed a dose of ~2.75 mg/day (~0.055 mg/kg/day based on 50 kg patient). As existing toxicology data on EMS did not permit an adequate patient risk assessment, a comprehensive animal toxicology evaluation of EMS was conducted. General toxicity of EMS was investigated in rats over 28 days. Two studies for DNA damage were performed in mice; chromosomal damage was assessed using a micronucleus assay and gene mutations were detected using the MutaMouse transgenic model. In addition, experiments designed to extrapolate animal exposure to humans were undertaken. A general toxicity study showed that the toxicity of EMS occurred only at doses ≥ 60 mg/kg/day, which is far above that received by patients. Studies for chromosomal damage and mutations in mice demonstrated a clear threshold effect with EMS at 25 mg/kg/day, under chronic dosing conditions. Exposure analysis (Cmax) demonstrated that ~370-fold higher levels of EMS than that ingested by patients, are needed to saturate known, highly conserved, error-free, mammalian DNA repair mechanisms for alkylation. In summary, animal studies suggested that patients who took nelfinavir mesylate with elevated levels of EMS are at no increased risk for carcinogenicity or teratogenicity over their background risk, since mutations are prerequisites for such downstream events. These findings are potentially relevant to >40 marketed drugs that are mesylate salts

Overcoming the challenges and complexities of researching a vulnerable population within a palliative care context

While previous studies have investigated sleep issues in chronic illness and the effectiveness of Cognitive Behavioral Therapy for Insomnia (CBT-I), this has not been examined within palliative care. High rates of sleep difficulties have been found in patients receiving palliative care. We aimed to explore the practical feasibility of implementing CBT-I among palliative patients using techniques such as stimulus control therapy, progressive muscle relaxation and guided imagery/thought blocking. However, issues such as the intervention protocols being relatively labor intensive and time consuming for participants that were receiving palliative care, involving completion of daily diaries and quantitative outcome measures, led to high non-completion rates among participants. Consequently, a shift in methodology was required and a qualitative approach was adopted to explore participants’ experiences of sleep disturbance within palliative care. The aim was to gain an in-depth understanding of the specific issues and challenges within palliative care that impacted on sleep. Focus groups were conducted with patients, informal carers and hospice staff who all described how they experienced sleep difficulties. This provided a broader understanding of insomnia from multiple perspectives within palliative care. Furthermore, it helped inform how we will go about designing future studies in CBT-I in palliative care; having illuminated the appropriate adaptions required to current protocols. This case study will discuss the complexities and ethical issues we faced at each stage of the research process and how adopting both quantitative and qualitative approaches helped provide useful insights that will inform future research

Current and Future Prospects of Nitro-compounds as Drugs for Trypanosomiasis and Leishmaniasis

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.</p

Antikinetoplastid SAR study in 3-nitroimidazopyridine series:identification of a novel non-genotoxic and potent anti-T. b. brucei hit-compound with improved pharmacokinetic properties.

International audienceTo study the antikinetoplastid 3-nitroimidazo[1,2-a]pyridine pharmacophore, a structure-activity relationship study was conducted through the synthesis of 26 original derivatives and their in vitro evaluation on both Leishmania spp and Trypanosoma brucei brucei. This SAR study showed that the antitrypanosomal pharmacophore was less restrictive than the antileishmanial one and highlighted positions 2, 6 and 8 of the imidazopyridine ring as key modulation points. None of the synthesized compounds allowed improvement in antileishmanial activity, compared to previous hit molecules in the series. Nevertheless, compound 8, the best antitrypanosomal molecule in this series (EC50 = 17 nM, SI = 2650 & E° = −0.6 V), was not only more active than all reference drugs and previous hit molecules in the series but also displayed improved aqueous solubility and better in vitro pharmacokinetic characteristics: good microsomal stability (T1/2 > 40 min), moderate albumin binding (77%) and moderate permeability across the blood brain barrier according to a PAMPA assay. Moreover, both micronucleus and comet assays showed that nitroaromatic molecule 8 was not genotoxic in vitro. It was evidenced that bioactivation of molecule 8 was operated by T. b. brucei type 1 nitroreductase, in the same manner as fexinidazole. Finally, a mouse pharmacokinetic study showed that 8 displayed good systemic exposure after both single and repeated oral administrations at 100 mg/kg (NOAEL) and satisfying plasmatic half-life (T1/2 = 7.7 h). Thus, molecule 8 appears as a good candidate for initiating a hit to lead drug discovery program