New WHO guidelines for treatment of gambiense human African trypanosomiasis including fexinidazole: substantial changes for clinical practice

Lindner, Andreas; Lejon, Veerle; Chappuis, François; Seixas, Jorge; Kazumba, Léon; Barrett, Michael P.; Mwamba, Erick; Erphas, Olema; Akl, Elie A.; Villanueva, Gemma; Bergman, Hanna; Simarro, Pere P.; Ebeja, Augustin Kadima; Priotto, Gérardo; Franco, José R.

doi:10.1016/s1473-3099(19)30612-7

Cited by 112 publications

(99 citation statements)

References 33 publications

(40 reference statements)

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“…The most important limitation of fexinidazole, however, seems to be a relatively low curative rate of 86.9% for the patients with the most severe meningoencephalitic HAT (defined as > 100 white blood cells/ml CSF) [1,182]. Thus, for these patients NECT remains the best option [182,184].…”

Section: Nifurtimoxmentioning

confidence: 99%

“…The number of patients, particularly with gambiense HAT, is in steep decline, human-to-human transmission is low, possibly at an all-time low, and we have in hand first-stage treatments that have stood the no-resistance test of time (pentamidine, suramin), and a combination therapy for late stage that is safer than we ever had. The introduction of fexinidazole [181][182][183][184] and potentially acoziborole [2,3], safe oral drugs that are active against both stages of the disease, is finally eliminating the need for risky lumbar punctures for determining the disease stage. The fact that there are finally multiple treatment options would allow clinicians to rotate treatments, should the need arise, but as long as continued vigilance keeps transmission very low, resistance is much less likely to develop.…”

Section: A Perspective On Drug Resistance In African Trypanosomiasismentioning

confidence: 99%

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The Drugs of Sleeping Sickness: Their Mechanisms of Action and Resistance, and a Brief History

Koning

2020

TropicalMed

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With the incidence of sleeping sickness in decline and genuine progress being made towards the WHO goal of eliminating sleeping sickness as a major public health concern, this is a good moment to evaluate the drugs that ‘got the job done’: their development, their limitations and the resistance that the parasites developed against them. This retrospective looks back on the remarkable story of chemotherapy against trypanosomiasis, a story that goes back to the very origins and conception of chemotherapy in the first years of the 20 century and is still not finished today.

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Section: Nifurtimoxmentioning

confidence: 99%

Section: A Perspective On Drug Resistance In African Trypanosomiasismentioning

confidence: 99%

The Drugs of Sleeping Sickness: Their Mechanisms of Action and Resistance, and a Brief History

Koning

2020

TropicalMed

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“…gambiense HAT with fewer than 100 cerebrospinal fluid white blood cells per μL. These recommendations cannot be applied for the treatment of patients younger than 6 years or with a bodyweight less than 20 kg [31,32]. One more new oral compound developed for treatment of all stages of T.b.…”

Section: Introductionmentioning

confidence: 99%

“…One more new oral compound developed for treatment of all stages of T.b. gambiense HAT is acoziborole being at late Phase II/III of clinical trials [31].…”

Section: Introductionmentioning

confidence: 99%

Thiazolidinone-Related Heterocyclic Compounds as Potential Antitrypanosomal Agents

Kryshchyshyn¹,

Kaminskyy²,

Grellier³

et al. 2021

Azoles - Synthesis, Properties, Applications and Perspectives

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Human African trypanosomiasis (HAT) and Chagas disease are neglected tropical diseases (NTDs) due to parasite protists from the Trypanosoma genus transmitted by insect vectors. Trypanosomiases affect mostly poor populations in the developing countries, and the development of new antitrypanosomal drugs is underinvested by governments and the pharmaceutical industry. In this chapter, we described the development of 4-thiazolidinone and thiazole derivatives with heterocyclic fragments which exhibit good inhibition of trypanosome growth and might constitute potential candidates for the development of new drugs against trypanosomiasis. Antitrypanosomal design, mainly within structure-based design, led to the synthesis of 5-ene-4-thiazolidinone-3-alkanecarboxylic acids; 2,3-disubstituted 4-thiazolidinones; thiazolidinone-pyrazoline, phenylindole-thiazolidinone, and imidazothiadiazole-thiazolidinone hybrids; as well as 4-thiazolidinone-based fused heterocycles, especially thiopyrano[2,3-d]thiazoles, and non-thiazolidinone compounds-namely, isothiocoumarine derivatives. Moreover, antitrypanosomal 4-thiazolidinones are of special interest in the search for new antimalarial and antileishmanial agents. Also many active anticancer agents among the abovementioned 4-thiazolidinones have been discovered.

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“…Synthesized as early as 1917, the compound suramin (originally Bayer 205 and later sold as Germanin) was first used therapeutically to treat African trypanosomiasis in the 1920s [11][12][13] . It is one of only a few drugs (including pentamidine, melarsoprol, eflornithine, nifirtimox, and fexinidazole) 12,13 available to counter the disease and is only effective in the early stages of infection, before the parasite has entered the central nervous system (as suramin cannot effectively penetrate the blood-brain barrier 14 ). It has also been used prophylactically 15 and is on the World Health Organization's List of Essential Medicines 16 .…”

Section: Introductionmentioning

confidence: 99%

A Parasite Coat Protein Binds Suramin to Confer Drug Resistance

Zeelen

Straaten

Verdi

et al. 2020

Preprint

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Suramin has been a primary early-stage treatment for African trypanosomiasis for nearly one hundred years. Recent studies revealed that trypanosome strains that express the Variant Surface Glycoprotein VSGsur possess heightened resistance to suramin. We show here that VSGsur binds tightly to suramin, other VSGs do not, and that together with VSG13 it defines a structurally divergent subgroup of these coat proteins. The co-crystal structure of VSGsur with suramin reveals that the chemically symmetric drug binds within a large cavity in the VSG homodimer asymmetrically, primarily through contacts of its central benzene rings. Structure-based, loss-of-contact mutations in VSGsur significantly decrease the affinity to suramin and lead to a loss of the resistance phenotype. Altogether, these data show that the resistance phenotype is dependent on the binding of suramin to VSGsur, establishing that the VSG proteins can possess functionality beyond their role in antigenic variation.

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New WHO guidelines for treatment of gambiense human African trypanosomiasis including fexinidazole: substantial changes for clinical practice

Abstract: JR. New WHO guidelines for treatment of gambiense human African trypanosomiasis including fexinidazole: fundamental changes for clinical practice.

Cited by 112 publications

References 33 publications

The Drugs of Sleeping Sickness: Their Mechanisms of Action and Resistance, and a Brief History

The Drugs of Sleeping Sickness: Their Mechanisms of Action and Resistance, and a Brief History

Thiazolidinone-Related Heterocyclic Compounds as Potential Antitrypanosomal Agents

A Parasite Coat Protein Binds Suramin to Confer Drug Resistance

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