An Update on African Trypanocide Pharmaceutics and Resistance

Kasozi, Keneth Iceland; MacLeod, Ewan T.; Ntulume, Ibrahim; Welburn, Susan C.

doi:10.3389/fvets.2022.828111

Cited by 53 publications

(47 citation statements)

References 167 publications

(211 reference statements)

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“…It is effective for the treatment of both the blood-stage and non-severe second-stage gambiense-HAT, making invasive procedures of stage determination unnecessary in most cases ( 98 , 99 ). An update on trypanocidal pharmaceuticals and their resistances was recently published by Kasozi et al ( 100 ), while all current treatment protocols and guidelines for HAT interventions are available through the WHO ( 101 ). To date, fexinidazole treatment is not yet approved for rhodesiense-HAT, but preparations for this application are underway ( 102 ).…”

Section: Advances In the Treatment Of Human African Trypanosomiasismentioning

confidence: 99%

Recent progress in diagnosis and treatment of Human African Trypanosomiasis has made the elimination of this disease a realistic target by 2030

et al. 2022

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Human African Trypanosomiasis (HAT) is caused by unicellular flagellated protozoan parasites of the genus Trypanosoma brucei. The subspecies T. b. gambiense is mainly responsible for mostly chronic anthroponotic infections in West- and Central Africa, accounting for roughly 95% of all HAT cases. Trypanosoma b. rhodesiense results in more acute zoonotic infections in East-Africa. Because HAT has a two-stage pathogenesis, treatment depends on clinical assessment of patients and the determination whether or not parasites have crossed the blood brain barrier. Today, ultimate confirmation of parasitemia is still done by microscopy analysis. However, the introduction of diagnostic lateral flow devices has been a major contributor to the recent dramatic drop in T. b. gambiense HAT. Other techniques such as loop mediated isothermal amplification (LAMP) and recombinant polymerase amplification (RPA)-based tests have been published but are still not widely used in the field. Most recently, CRISPR-Cas technology has been proposed to improve the intrinsic diagnostic characteristics of molecular approaches. This will become crucial in the near future, as preventing the resurgence of HAT will be a priority and will require tools with extreme high positive and negative predicted values, as well as excellent sensitivity and specificity. As for treatment, pentamidine and suramin have historically been the drugs of choice for the treatment of blood-stage gambiense-HAT and rhodesiense-HAT, respectively. For treatment of second-stage infections, drugs that pass the blood brain barrier are needed, and melarsoprol has been effectively used for both forms of HAT in the past. However, due to the high occurrence of post-treatment encephalopathy, the drug is not recommended for use in T. b. gambiense HAT. Here, a combination therapy of eflornithine and nifurtimox (NECT) has been the choice of treatment since 2009. As this treatment requires IV perfusion of eflornithine, efforts were launched in 2003 by the drugs for neglected disease initiative (DNDi) to find an oral-only therapy solution, suitable for rural sub-Saharan Africa treatment conditions. In 2019 this resulted in the introduction of fexinidazole, with a treatment regimen suitable for both the blood-stage and non-severe second-stage T. b. gambiense infections. Experimental treatment of T. b. rhodesiense HAT has now been initiated as well.

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Section: Advances In the Treatment Of Human African Trypanosomiasismentioning

confidence: 99%

Recent progress in diagnosis and treatment of Human African Trypanosomiasis has made the elimination of this disease a realistic target by 2030

et al. 2022

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“…The clinical symptoms are usually general in this stage making the diagnosis difficult ( Fall et al., 2022 ). Without prompt treatment the disease can evolve to the second stage, in which the parasites cross the blood–brain barrier causing severe neurological damage and death if untreated ( Fall et al., 2022 ; Kasozi et al, 2022 ). Currently, there are four approved drugs for treating HAT.…”

Section: Introductionmentioning

confidence: 99%

“…The high cost, low oral bioavailability, toxicity, lack of efficacy, and prolonged treatment are the major issues associated with these therapies. The emergence of resistant parasite species for practically all chemically related trypanocidal drugs is also an obstacle to be considered ( Kasozi et al., 2022 ).…”

Section: Introductionmentioning

confidence: 99%

The endoplasmic reticulum of trypanosomatids: An unrevealed road for chemotherapy

Sandes

Figueiredo²

2022

Front. Cell. Infect. Microbiol.

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The endoplasmic reticulum (ER) of higher eukaryotic cells forms an intricate membranous network that serves as the main processing facility for folding and assembling of secreted and membrane proteins. The ER is a highly dynamic organelle that interacts with other intracellular structures, as well as endosymbiotic pathogenic and non-pathogenic microorganisms. A strict ER quality control (ERQC) must work to ensure that proteins entering the ER are folded and processed correctly. Unfolded or misfolded proteins are usually identified, selected, and addressed to Endoplasmic Reticulum-Associated Degradation (ERAD) complex. Conversely, when there is a large demand for secreted proteins or ER imbalance, the accumulation of unfolded or misfolded proteins activates the Unfold Protein Response (UPR) to restore the ER homeostasis or, in the case of persistent ER stress, induces the cell death. Pathogenic trypanosomatids, such as Trypanosoma cruzi, Trypanosoma brucei and Leishmania spp are the etiological agents of important neglected diseases. These protozoans have a complex life cycle alternating between vertebrate and invertebrate hosts. The ER of trypanosomatids, like those found in higher eukaryotes, is also specialized for secretion, and depends on the ERAD and non-canonical UPR to deal with the ER stress. Here, we reviewed the basic aspects of ER biology, organization, and quality control in trypanosomatids. We also focused on the unusual way by which T. cruzi, T. brucei, and Leishmania spp. respond to ER stress, emphasizing how these parasites’ ER-unrevealed roads might be an attractive target for chemotherapy.

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“…The World Health Organization (WHO) has set 2030 as a target for the elimination of human African trypanosomiasis (HAT) [ 1 ]; however, the development of drug-resistant phenotypes (see [ 2 ] on trypanocide resistance) in resource-poor countries affected by HAT presents a major challenge for HAT control. In Africa, HAT is caused by Trypanosoma brucei gambiense (TBG, chronic variant) and T. b. rhodesiense (TBR, acute variant), also referred to as gHAT and rHAT, respectively.…”

Section: Introductionmentioning

confidence: 99%

“…Globally, six major drugs are available for treatment of HAT depending on the stage of the infection: pentamidine, suramin, melarsoprol, eflornithine, nifurtimox/eflornithine combination therapy (NECT), and fexinidazole (see [ 2 ] on HAT pharmaceutics and limitations of current approved therapies). The emergence of human African trypanocide resistance (HATr) has undermined the use of monotherapy for HAT treatment.…”

Section: Introductionmentioning

confidence: 99%

Systematic Review and Meta-Analysis on Human African Trypanocide Resistance

2022

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Background Human African trypanocide resistance (HATr) is a challenge for the eradication of Human African Trypansomiaisis (HAT) following the widespread emergence of increased monotherapy drug treatment failures against Trypanosoma brucei gambiense and T. b. rhodesiense that are associated with changes in pathogen receptors. Methods: Electronic searches of 12 databases and 3 Google search websites for human African trypanocide resistance were performed using a keyword search criterion applied to both laboratory and clinical studies. Fifty-one publications were identified and included in this study using the PRISMA checklist. Data were analyzed using RevMan and random effect sizes were computed for the statistics at the 95% confidence interval. Results: Pentamidine/melarsoprol/nifurtimox cross-resistance is associated with loss of the T. brucei adenosine transporter 1/purine 2 gene (TbAT1/P2), aquaglyceroporins (TbAQP) 2 and 3, followed by the high affinity pentamidine melarsoprol transporter (HAPT) 1. In addition, the loss of the amino acid transporter (AAT) 6 is associated with eflornithine resistance. Nifurtimox/eflornithine combination therapy resistance is associated with AAT6 and nitroreductase loss, and high resistance and parasite regrowth is responsible for treatment relapse. In clinical studies, the TbAT1 proportion of total random effects was 68% (95% CI: 38.0–91.6); I2 = 96.99% (95% CI: 94.6–98.3). Treatment failure rates were highest with melarsoprol followed by eflornithine at 41.49% (95% CI: 24.94–59.09) and 6.56% (3.06–11.25) respectively. HATr-resistant phenotypes used in most laboratory experiments demonstrated significantly higher pentamidine resistance than other trypanocides. Conclusion: The emergence of drug resistance across the spectrum of trypanocidal agents that are used to treat HAT is a major threat to the global WHO target to eliminate HAT by 2030. T. brucei strains were largely resistant to diamidines and the use of high trypanocide concentrations in clinical studies have proved fatal in humans. Studies to develop novel chemotherapeutical agents and identify alternative protein targets could help to reduce the emergence and spread of HATr.

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An Update on African Trypanocide Pharmaceutics and Resistance

Cited by 53 publications

References 167 publications

Recent progress in diagnosis and treatment of Human African Trypanosomiasis has made the elimination of this disease a realistic target by 2030

Recent progress in diagnosis and treatment of Human African Trypanosomiasis has made the elimination of this disease a realistic target by 2030

The endoplasmic reticulum of trypanosomatids: An unrevealed road for chemotherapy

Systematic Review and Meta-Analysis on Human African Trypanocide Resistance

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