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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
Phase II/III study results published in 2017 confirmed that fexinidazole (11) is safe and effective and presents significant advantages over NECT for HAT disease. In fact, it eliminates both the need for a lumbar puncture and systematic patient hospitalization (Mesu et al. 2018). Fexinidazole (11) received a positive scientific opinion by the European Medicines Agency’s Committee in November 2018 and was registered in the Democratic Republic of Congo in December 2018. Fexinidazole is indicated as a 10-day once-a-day oral treatment for T. b. gambiense sleeping sickness that works both for two stages of the disease. A phase IIIb (clinical trial NCT03025789) study is currently underway, aiming to provide additional information on the efficacy and safety of fexinidazole and to assess its use under conditions as close as possible to real life, ideally allowing patients to take their medication at home, the results are expected by 2020 (Pollastri 2018). A new Phase II/III study is also being prepared in Malawi to assess fexinidazole (11) to treat HAT caused by T. b. rhodesiense, the other subspecies of the parasite that causes a more virulent strain of the disease. The study should start in mid-2019 (DNDi 2019a).
Flies (Biting)
Published in Gail Miriam Moraru, Jerome Goddard, The Goddard Guide to Arthropods of Medical Importance, Seventh Edition, 2019
Gail Miriam Moraru, Jerome Goddard
There are over 20 species of flies in the genus Glossina that are called tsetse flies (see box). Most of the species are vectors of trypanosomes of people and animals (Figure 19.23); however, at least six species are of primary importance as vectors of human African trypanosomiasis (HAT), caused by subspecies of the protozoan Trypanosoma brucei (Figure 19.24). HAT is sometimes called sleeping sickness because meningoencephalitis associated with the disease causes apathy, fatigability, confusion, and somnolence. The patient may gradually become more and more difficult to arouse and finally becomes comatose. In 1998, the WHO estimated that at least 300,000 cases of African trypanosmiasis were undiagnosed and untreated; however, intensive tsetse fly trapping and control, as well as case surveillance/treatment, brought the number of cases in 2009 to below 10,000 for the first time in 50 years.36 Fortunately, case numbers continue to decline, with only about 3000 reported in 2015.37 Countries affected the most include the Democratic Republic of Congo, Angola, and Sudan (Figure 19.25). Unfortunately, there is rising resistance to melarsoprol, the only widely available drug for CNS involvement in African trypanosomiasis. Researchers are now exploring the use of fexinidazole as a viable alternative treatment. Nash38 and Willet39 provided very good reviews of the complicated African trypanosomiasis problem. Briefly, the chief vectors of Trypanosoma brucei gambiense, the cause of the Gambian form of sleeping sickness, are Glossina palpalis, G. fuscipes, and G. tachinoides. Cases of Gambian sleeping sickness occur in western and central Africa and are usually more chronic. In eastern Africa, the Rhodesian (or eastern) form, which is virulent and rapidly progressive, is caused by T. brucei rhodesiense. The primary vectors of the Rhodesian form are G. morsitans, G. swynnertoni, and G. pallidipes. The eastern form is commonly contracted by travelers on game safaris or eco vacations. Other than the possibility for sleeping sickness transmission, the bites of tsetse flies are of minor consequence; however, some individuals become sensitized to the saliva, and subsequent bites produce welts.
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].
Oxidative stress implications for therapeutic vaccine development against Chagas disease
Published in Expert Review of Vaccines, 2021
Subhadip Choudhuri, Lizette Rios, Juan Carlos Vázquez-Chagoyán, Nisha Jain Garg
The currently available benznidazole and nifurtimox drug therapies are effective against acute T. cruzi infection [14–16], and are recommended for the treatment of all infected children under 15 years of age and adults with recent infection [17]. While effective in parasite clearance in children, these drugs exhibit therapeutic failure and/or adverse events in adults and are not always recommended for patients with chronic infection [18–20]. Thus, new therapies to cure, eliminate, and eradicate T. cruzi are needed. However, clinical trials testing new chemotherapeutics against T. cruzi have not been very successful in identifying replacements for benznidazole and nifurtimox. Several drugs, such as ravuconazole and posaconazole exhibited promising, parasite-specific effects in pre-clinical studies but failed to surpass the efficacy of benznidazole in clinical studies. Fexinidazole, a drug in the same class as benznidazole and nifurtimox, has completed phase II clinical trial (clinical trial identifier NCT03587766). This drug has shown promise for treating the indeterminate phase of CD in experimental studies but currently outcomes of the clinical trial are publicly documented [21–25].
Emerging agents for the treatment of Chagas disease: what is in the preclinical and clinical development pipeline?
Published in Expert Opinion on Investigational Drugs, 2020
Nieves Martínez-Peinado, Nuria Cortes-Serra, Irene Losada-Galvan, Cristina Alonso-Vega, Julio A. Urbina, Ana Rodríguez, John L. VandeBerg, Maria-Jesus Pinazo, Joaquim Gascon, Julio Alonso-Padilla
Finally, two trials have evaluated the efficacy of fexinidazole: DNDi-promoted FEXI-001 [70] and FEXI-12 [72]. According to available information in public clinical trials repository, FEXI-001 evaluated anti-parasitic efficacy by measuring parasite clearance at 6 months after the end of treatment. Fexinidazole arms included: 1,800 mg during 2 weeks; 1,800 mg during 4 weeks; 1,800 mg during 8 weeks; 1,200 mg during 2 weeks; 1,200 mg during 4 weeks; and 1200 mg during 8 weeks [70]. All of them were compared against a placebo control group. After recruiting 47 subjects, recruitment was halted due to safety and tolerability issues [111]. However, since the results from FEXI-001 showed sustained parasite clearance even at the lowest dose tested (1,200 mg for 2 weeks), including subjects that received treatment for less than 3 days, a subsequent FEXI-12 trial was designed to evaluate the efficacy of lower fexinidazole doses and shorter treatment durations: 600 mg during 10 days; 1,200 mg during 3 days; and 600 mg during 3 days followed by 1,200 mg during another 4 days [72].