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International Journal of Molecular... Aug 2023Human African trypanosomiasis is a neglected tropical disease caused by the extracellular protozoan parasite , and targeted for eradication by 2030. The COVID-19... (Review)
Review
Human African trypanosomiasis is a neglected tropical disease caused by the extracellular protozoan parasite , and targeted for eradication by 2030. The COVID-19 pandemic contributed to the lengthening of the proposed time frame for eliminating human African trypanosomiasis as control programs were interrupted. Armed with extensive antigenic variation and the depletion of the B cell population during an infectious cycle, attempts to develop a vaccine have remained unachievable. With the absence of a vaccine, control of the disease has relied heavily on intensive screening measures and the use of drugs. The chemotherapeutics previously available for disease management were plagued by issues such as toxicity, resistance, and difficulty in administration. The approval of the latest and first oral drug, fexinidazole, is a major chemotherapeutic achievement for the treatment of human African trypanosomiasis in the past few decades. Timely and accurate diagnosis is essential for effective treatment, while poor compliance and resistance remain outstanding challenges. Drug discovery is on-going, and herein we review the recent advances in anti-trypanosomal drug discovery, including novel potential drug targets. The numerous challenges associated with disease eradication will also be addressed.
Topics: Animals; Humans; Trypanosomiasis, African; Pandemics; COVID-19; Trypanosoma brucei brucei; Trypanosoma
PubMed: 37569903
DOI: 10.3390/ijms241512529 -
The American Journal of Tropical... May 2022In this article, the authors show the strategy used to streamline the introduction of fexinidazole, the first all oral treatment of human African trypanosomiasis (HAT)...
In this article, the authors show the strategy used to streamline the introduction of fexinidazole, the first all oral treatment of human African trypanosomiasis (HAT) caused by Trypanosoma brucei gambiense. The dose range was determined in phase 1 studies and a significant food effect was observed, which was tested with field-adapted meals. The pharmacokinetic profile required definition of a higher loading dosage for the first 4 days and administration of the daily dose together with a typical local meal to optimize product absorption and rapidly achieve drug steady state. This allowed for a combined phase II/III pivotal study directly after phase I trials. Partnerships with highly engaged actors from endemic country control programs and international research institutions started early through the HAT platform, building on an agreed target product profile (TPP), establishing a regulatory plan early and transparently including endemic countries in the research and data flow. A key element that enabled a quick start to access activities was preparing for World Health Organization guidelines early and starting the process prior to registration. Distribution plans were identified and supply was established from the start, by taking advantage of the existing supply agreement between the producers of all HAT drugs (Sanofi and Bayer) and the WHO. Pharmacovigilance and phase 4 studies were nested into wider implementation activities. Targeted sequential introduction into national programs was prioritized, based on medical need and epidemiologically updated information.
Topics: Animals; Humans; Trypanosomiasis, African; Nitroimidazoles; Trypanosoma brucei gambiense; Administration, Oral
PubMed: 35292581
DOI: 10.4269/ajtmh.21-1176 -
Trends in Parasitology Mar 2018Trypanosoma brucei gambiense causes human African trypanosomiasis (HAT). Between 1990 and 2015, almost 440000 cases were reported. Large-scale screening of populations... (Review)
Review
Trypanosoma brucei gambiense causes human African trypanosomiasis (HAT). Between 1990 and 2015, almost 440000 cases were reported. Large-scale screening of populations at risk, drug donations, and efforts by national and international stakeholders have brought the epidemic under control with <2200 cases in 2016. The World Health Organization (WHO) has set the goals of gambiense-HAT elimination as a public health problem for 2020, and of interruption of transmission to humans for 2030. Latent human infections and possible animal reservoirs may challenge these goals. It remains largely unknown whether, and to what extend, they have an impact on gambiense-HAT transmission. We argue that a better understanding of the contribution of human and putative animal reservoirs to gambiense-HAT epidemiology is mandatory to inform elimination strategies.
Topics: Animals; Disease Eradication; Disease Reservoirs; Humans; Risk Factors; Trypanosoma brucei gambiense; Trypanosomiasis, African
PubMed: 29396200
DOI: 10.1016/j.pt.2017.11.008 -
Journal of Neurology Sep 2019Human African trypanosomiasis (HAT), also known as sleeping sickness, is one of the Africa's 'neglected diseases' and is caused by infection with protozoan parasites of... (Review)
Review
Human African trypanosomiasis (HAT), also known as sleeping sickness, is one of the Africa's 'neglected diseases' and is caused by infection with protozoan parasites of the Trypanosoma genus. Transmitted by the bite of the tsetse fly, it puts 70 million people at risk throughout sub-Saharan Africa and is usually fatal if untreated or inadequately treated. In this brief overview, some important recent developments in this disease are outlined. These cover various aspects including a reduction in disease incidence, newly recognised parasite reservoir sites in humans, disease outcome, novel diagnostic methods, new and improved treatment, and disease neuropathogenesis.
Topics: Animals; Benzamides; Boron Compounds; Humans; Neglected Diseases; Trypanosoma brucei gambiense; Trypanosoma brucei rhodesiense; Trypanosomiasis, African
PubMed: 31209574
DOI: 10.1007/s00415-019-09425-7 -
Tropical Medicine & International... Jun 2015To review current and emerging tools for Gambiense HAT control and elimination, and propose strategies that integrate these tools with epidemiological evidence. (Review)
Review
OBJECTIVES
To review current and emerging tools for Gambiense HAT control and elimination, and propose strategies that integrate these tools with epidemiological evidence.
METHODS
We reviewed the scientific literature to identify contemporary and emerging tools and strategies for controlling and eliminating Gambiense HAT. Through an iterative process involving key stakeholders, we then developed comprehensive scenarios leading to elimination, considering both established and new tools for diagnosis, case treatment and vector control.
RESULTS
Core components of all scenarios include detecting and treating cases with established or emerging techniques. Relatively more intensive scenarios incorporate vector control. New tools considered include tiny targets for tsetse fly control, use of rapid diagnostic tests and oral treatment with fexinidazole or oxaboroles. Scenarios consider the time when critical new tools are expected to become ready for deployment by national control programmes. Based on a review of the latest epidemiological data, we estimate the various interventions to cover 1,380,600 km(2) and 56,986,000 people.
CONCLUSIONS
A number of new tools will fill critical gaps in the current armamentarium for diagnosing and treating Gambiense HAT. Deploying these tools in endemic areas will facilitate the comprehensive and sustainable control of the disease considerably and contribute to the ultimate goal of elimination.
Topics: Africa; Animals; Disease Eradication; Humans; Insect Vectors; Neglected Diseases; Public Health; Trypanosoma brucei gambiense; Trypanosomiasis, African; Tsetse Flies
PubMed: 25694261
DOI: 10.1111/tmi.12483 -
Journal of Cellular Physiology Jun 2022African trypanosomes are early branching protists that cause human and animal diseases, termed trypanosomiases. They have been under intensive study for more than 100... (Review)
Review
African trypanosomes are early branching protists that cause human and animal diseases, termed trypanosomiases. They have been under intensive study for more than 100 years and have contributed significantly to our understanding of eukaryotic biology. The combination of conserved and parasite-specific features mean that their flagellum has gained particular attention. Here, we discuss the different structural features of the flagellum and their role in transmission and virulence. We highlight the possibilities of targeting flagellar function to cure trypanosome infections and help in the fight to eliminate trypanosomiases.
Topics: Animals; Flagella; Trypanosoma; Trypanosomiasis; Trypanosomiasis, African; Virulence
PubMed: 35616248
DOI: 10.1002/jcp.30778 -
Parasitology Aug 2020Human African trypanosomiasis (HAT) is caused by Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense and caused devastating epidemics during the 20th... (Review)
Review
Human African trypanosomiasis (HAT) is caused by Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense and caused devastating epidemics during the 20th century. Due to effective control programs implemented in the last two decades, the number of reported cases has fallen to a historically low level. Although fewer than 977 cases were reported in 2018 in endemic countries, HAT is still a public health problem in endemic regions until it is completely eliminated. In addition, almost 150 confirmed HAT cases were reported in non-endemic countries in the last three decades. The majority of non-endemic HAT cases were reported in Europe, USA and South Africa, due to historical alliances, economic links or geographic proximity to disease-endemic countries. Furthermore, with the implementation of the 'Belt and Road' project, sporadic imported HAT cases have been reported in China as a warning sign of tropical diseases prevention. In this paper, we explore and interpret the data on HAT incidence and find no positive correlation between the number of HAT cases from endemic and non-endemic countries. This data will provide useful information for better understanding the imported cases of HAT globally in the post-elimination phase.
Topics: Communicable Diseases, Imported; Endemic Diseases; Humans; Incidence; Trypanosomiasis, African
PubMed: 32338232
DOI: 10.1017/S0031182020000645 -
BMC Public Health Dec 2022Human African trypanosomiasis (HAT) is one of the world's classical neglected tropical diseases representing a major public health threat in sub-Saharan Africa. Although...
BACKGROUND
Human African trypanosomiasis (HAT) is one of the world's classical neglected tropical diseases representing a major public health threat in sub-Saharan Africa. Although the parasitic disease is in decline in the Republic of Congo, the better understanding of the epidemiological situation of active foci is required to reduce the risk of disease resurgence which could impede progress registered so far. The aim of this study was to determine the prevalence of HAT and the associated risk factors in individuals living in remote areas of the Republic of Congo.
METHODS
A cross-sectional survey was carried out in volunteers living in rural settings from June 2020 to January 2021. Socio-demographic and Clinical parameters of the participants were recorded. The presence of HAT-specific antibodies was assessed in whole blood, and then confirmed in serial diluted plasma samples using Card-Agglutination Trypanosomiasis Test (CATT)/T.b. gambiense CATT. The Capillary Tube Centrifugation (CTC) and Lymph nodes (LN) examination were done for detecting trypanosome parasites in CATT-serum positive cases. The staging of positive participants was determined by cerebrospinal fluid (CSF) examination.
RESULTS
Out of 8556 enrolled participants, 48.5% were more than 15 years old, 57.7% were unschooled and 67.2% practiced peasant activities. The prevalence of HAT infection was 0.3% with the predominance of patients at stage 1 of the disease (84.0%). The districts of Mindouli (OR: 25.9 (5.2-468); p = 0.0016) and Mpouya (OR: 13.3 (2.5-246); p = 0.0140) was revealed as the foci of high risk of HAT infection. Several factors were associated with an increased risk of HAT infection mainly including the non-schooling (OR: 5.1 (1.2-21.9); p = 0.0268), the life in couple or married (OR: 3.3 (1.0-11.3); p = 0.0545) and the practice of peasant activities (OR: 6.9 (2.4-29.3); p = 0.0017).
CONCLUSION
This study highlights the need of revising and strengthening the strategies of HAT control in Republic of Congo, using an approach which will take into account the education level, the marital status and the occupation of the population at risk.
Topics: Animals; Humans; Adolescent; Trypanosomiasis, African; Trypanosoma brucei gambiense; Cross-Sectional Studies; Agglutination Tests; Risk Factors
PubMed: 36510162
DOI: 10.1186/s12889-022-14577-9 -
Parasite Immunology 2004Human African trypanosomiasis or sleeping sickness is caused by infection with two subspecies of the tsetse-fly-vectored haemoflagellate parasite Trypanosoma brucei.... (Review)
Review
Human African trypanosomiasis or sleeping sickness is caused by infection with two subspecies of the tsetse-fly-vectored haemoflagellate parasite Trypanosoma brucei. Historically, epidemic sleeping sickness has caused massive loss of life, and related animal diseases have had a crucial impact on development in sub-Saharan Africa. After a period of moderately successful control during the mid-part of the 20th century, sleeping sickness incidence is currently rising, and control is hampered by a combination of factors, including civil unrest and the possible development of drug resistance by the parasites. The prevailing view is that the disease is invariably fatal without anti-trypanosomal drug treatment. However, there have also been intriguing reports of wide variations in disease severity as well as evidence of asymptomatic carriers of trypanosomes. These differences in the presentation of the disease will be discussed in the context of our knowledge of the immunology of trypanosomiasis. The impact of dysregulated inflammatory responses in both systemic and CNS pathology will be examined and the potential for host genotype variation in disease severity and control will be discussed.
Topics: Animals; Humans; Severity of Illness Index; Trypanosoma brucei gambiense; Trypanosoma brucei rhodesiense; Trypanosomiasis, African; Tsetse Flies
PubMed: 15771682
DOI: 10.1111/j.0141-9838.2004.00731.x -
Chemical Derivatization and Characterization of Novel Antitrypanosomals for African Trypanosomiasis.Molecules (Basel, Switzerland) Jul 2021The search for novel antitrypanosomals and the investigation into their mode of action remain crucial due to the toxicity and resistance of commercially available...
The search for novel antitrypanosomals and the investigation into their mode of action remain crucial due to the toxicity and resistance of commercially available antitrypanosomal drugs. In this study, two novel antitrypanosomals, tortodofuordioxamide (compound ) and tortodofuorpyramide (compound ), were chemically derived from the natural N-alkylamide tortozanthoxylamide (compound ) through structural modification. The chemical structures of these compounds were confirmed through spectrometric and spectroscopic analysis, and their in vitro efficacy and possible mechanisms of action were, subsequently, investigated in () one of the causative species of African trypanosomiasis (AT). The novel compounds and displayed significant antitrypanosomal potencies in terms of half-maximal effective concentrations (EC) and selectivity indices (SI) (compound , EC = 7.3 μM, SI = 29.5; compound , EC = 3.2 μM, SI = 91.3; compound , EC = 4.5 μM, SI = 69.9). Microscopic analysis indicated that at the EC values, the compounds resulted in the coiling and clumping of parasite subpopulations without significantly affecting the normal ratio of nuclei to kinetoplasts. In contrast to the animal antitrypanosomal drug diminazene, compounds , and exhibited antioxidant absorbance properties comparable to the standard antioxidant Trolox (Trolox, 0.11 A; diminazene, 0.50 A; compound , 0.10 A; compound , 0.09 A; compound , 0.11 A). The analysis of growth kinetics suggested that the compounds exhibited a relatively gradual but consistent growth inhibition of at different concentrations. The results suggest that further pharmacological optimization of compounds and may facilitate their development into novel AT chemotherapy.
Topics: Animals; Mice; RAW 264.7 Cells; Trypanocidal Agents; Trypanosoma brucei brucei; Trypanosomiasis, African
PubMed: 34361641
DOI: 10.3390/molecules26154488