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PLoS Neglected Tropical Diseases Jan 2024Little attention has been paid to neglected tropical diseases (NTDs) in high-income countries and no literature provides an overview of NTDs in Japan. This scoping... (Review)
Review
Little attention has been paid to neglected tropical diseases (NTDs) in high-income countries and no literature provides an overview of NTDs in Japan. This scoping review aims to synthesize the latest evidence and information to understand epidemiology of and public health response to NTDs in Japan. Using three academic databases, we retrieved articles that mentioned NTDs in Japan, written in English or Japanese, and published between 2010 and 2020. Websites of key public health institutions and medical societies were also explored. From these sources of information, we extracted data that were relevant to answering our research questions. Our findings revealed the transmission of alveolar echinococcosis, Buruli ulcer, Chagas disease, dengue, foodborne trematodiases, mycetoma, scabies, and soil-transmitted helminthiasis as well as occurrence of snakebites within Japan. Other NTDs, such as chikungunya, cystic echinococcosis, cysticercosis, leishmaniasis, leprosy, lymphatic filariasis, rabies, and schistosomiasis, have been imported into the country. Government agencies tend to organize surveillance and control programs only for the NTDs targeted by the Infectious Disease Control Law, namely, echinococcosis, rabies, dengue, and chikungunya. At least one laboratory offers diagnostic testing for each NTD except for dracunculiasis, human African trypanosomiasis, onchocerciasis, and yaws. No medicine is approved for treatment of Chagas disease and fascioliasis and only off-label use drugs are available for cysticercosis, opisthorchiasis, human African trypanosomiasis, onchocerciasis, schistosomiasis, and yaws. Based on these findings, we developed disease-specific recommendations. In addition, three policy issues are discussed, such as lack of legal frameworks to organize responses to some NTDs, overreliance on researchers to procure some NTD products, and unaffordability of unapproved NTD medicines. Japan should recognize the presence of NTDs within the country and need to address them as a national effort. The implications of our findings extend beyond Japan, emphasizing the need to study, recognize, and address NTDs even in high-income countries.
Topics: Animals; Humans; Japan; Onchocerciasis; Trypanosomiasis, African; Neglected Diseases; Rabies; Chikungunya Fever; Yaws; Tropical Medicine; Schistosomiasis; Chagas Disease; Cysticercosis; Dengue
PubMed: 38166156
DOI: 10.1371/journal.pntd.0011854 -
Parasitology Research Dec 2023Suramin was the first drug developed using the approach of medicinal chemistry by the German Bayer company in the 1910s for the treatment of human African sleeping... (Review)
Review
Suramin was the first drug developed using the approach of medicinal chemistry by the German Bayer company in the 1910s for the treatment of human African sleeping sickness caused by the two subspecies Trypanosoma brucei gambiense and Trypanosoma brucei rhodesienese. However, the drug was politically instrumentalized by the German government in the 1920s in an attempt to regain possession of its former African colonies lost after the First World War. For this reason, the formula of suramin was kept secret for more than 10 years. Eventually, the French pharmacist Ernest Fourneau uncovered the chemical structure of suramin by reverse engineering and published the formula of the drug in 1924. During the Nazi period, suramin became the subject of colonial revisionism, and the development of the drug was portrayed in books and films to promote national socialist propaganda. Ever since its discovery, suramin has also been tested for bioactivity against numerous other infections and diseases. However, sleeping sickness caused by Trypanosoma brucei rhodesiense is the only human disease for which treatment with suramin is currently approved.
Topics: Animals; Humans; Suramin; Trypanosomiasis, African; Trypanosoma brucei rhodesiense; Trypanosoma brucei brucei
PubMed: 38057659
DOI: 10.1007/s00436-023-08027-7 -
Bulletin of the World Health... Aug 2023Rhodesiense human African trypanosomiasis is a lethal parasitic infection caused by and transmitted by tsetse flies in eastern and southern Africa. It accounts for...
Rhodesiense human African trypanosomiasis is a lethal parasitic infection caused by and transmitted by tsetse flies in eastern and southern Africa. It accounts for around 5% of all cases of human African trypanosomiasis. Currently, there is no simple serological test for rhodesiense human African trypanosomiasis and diagnosis relies on microscopic confirmation of trypanosomes in samples of blood or other tissues. The availability of a simple and accurate diagnostic test would aid the control, surveillance and treatment of the disease. A subcommittee of the World Health Organization's Neglected Tropical Diseases Diagnostics Technical Advisory Group has developed a target product profile for a diagnostic tool to identify infection. The optimum tool would have a sensitivity and specificity above 99% for detecting but be simple enough for use by minimally trained health-care workers in unsophisticated peripheral health facilities or mobile teams in villages. The test should yield a qualitative result that can be easily observed and can be used to determine treatment. An antigen test would be preferable, with blood collected by finger-prick. Ideally, there should be no need for a cold chain, instrumentation or precision liquid handling. The test should be usable between 10 °C and 40 °C and between 10% and 88% relative humidity. Basic training should take under 2 hours and the test should involve fewer than five steps. The unit cost should be less than 1 United States dollar.
Topics: Animals; Humans; Trypanosoma brucei rhodesiense; Trypanosomiasis, African; Africa, Southern; Sensitivity and Specificity; Diagnostic Tests, Routine
PubMed: 37529024
DOI: 10.2471/BLT.23.290173 -
PLoS Neglected Tropical Diseases May 2024
Topics: Humans; Trypanosomiasis, African; Disease Eradication; Animals; Africa; Neglected Diseases
PubMed: 38691551
DOI: 10.1371/journal.pntd.0012091 -
Antimicrobial Agents and Chemotherapy Jan 2024The intestinal parasites and are major causes of morbidity and mortality associated with diarrheal diseases. Metronidazole is the most common drug used to treat...
The intestinal parasites and are major causes of morbidity and mortality associated with diarrheal diseases. Metronidazole is the most common drug used to treat giardiasis and amebiasis. Despite its efficacy, treatment failures in giardiasis occur in up to 5%-40% of cases. Potential resistance of to metronidazole is an increasing concern. Therefore, it is critical to search for more effective drugs to treat giardiasis and amebiasis. We identified antigiardial and antiamebic activities of the rediscovered nitroimidazole compound, fexinidazole, and its sulfone and sulfoxide metabolites. Fexinidazole is equally active against and trophozoites, and both metabolites were 3- to 18-fold more active than the parent drug. Fexinidazole and its metabolites were also active against a metronidazole-resistant strain of . and cell extracts exhibited decreased residual nitroreductase activity when metabolites were used as substrates, indicating nitroreductase may be central to the mechanism of action of fexinidazole. In a cell invasion model, fexinidazole and its metabolites significantly reduced the invasiveness of trophozoites through basement membrane matrix. A q.d. oral dose of fexinidazole and its metabolites at 10 mg/kg for 3 days reduced infection significantly in mice compared to control. The newly discovered antigiardial and antiamebic activities of fexinidazole, combined with its FDA-approval and inclusion in the WHO Model List of Essential Medicines for the treatment of human African trypanosomiasis, offer decreased risk and a shortened development timeline toward clinical use of fexinidazole for treatment of giardiasis or amebiasis.
Topics: Mice; Animals; Humans; Giardiasis; Metronidazole; Nitroimidazoles; Amebiasis; Giardia lamblia; Entamoeba histolytica; Nitroreductases
PubMed: 38063401
DOI: 10.1128/aac.00731-23 -
Pharmaceuticals (Basel, Switzerland) Jul 2023Neglected diseases, primarily found in tropical regions of the world, present a significant challenge for impoverished populations. Currently, there are 20 diseases... (Review)
Review
Neglected diseases, primarily found in tropical regions of the world, present a significant challenge for impoverished populations. Currently, there are 20 diseases considered neglected, which greatly impact the health of affected populations and result in difficult-to-control social and economic consequences. Unfortunately, for the majority of these diseases, there are few or no drugs available for patient treatment, and the few drugs that do exist often lack adequate safety and efficacy. As a result, there is a pressing need to discover and design new drugs to address these neglected diseases. This requires the identification of different targets and interactions to be studied. In recent years, there has been a growing focus on studying enzyme covalent inhibitors as a potential treatment for neglected diseases. In this review, we will explore examples of how these inhibitors have been used to target Human African Trypanosomiasis, Chagas disease, and Malaria, highlighting some of the most promising results so far. Ultimately, this review aims to inspire medicinal chemists to pursue the development of new drug candidates for these neglected diseases, and to encourage greater investment in research in this area.
PubMed: 37513939
DOI: 10.3390/ph16071028 -
ACS Omega Nov 2023African trypanosomiasis is a vector-borne disease of animals and humans in the tsetse fly belt of Africa. ("nagana") is the most pathogenic trypanosome in livestock and...
African trypanosomiasis is a vector-borne disease of animals and humans in the tsetse fly belt of Africa. ("nagana") is the most pathogenic trypanosome in livestock and causes high morbidity and mortality rates among cattle. In the absence of effective preventative vaccines, the management of trypanosomiasis relies on chemoprophylaxis and/or -therapy. However, the trypanocides in clinical use exhibit poor oral bioavailability and toxicity, and therapeutic failures occur because of resistant strains. Because nitrofurantoin displayed, in addition to its clinical use, promising antiparasitic activity, the current study was conducted to evaluate the trypanocidal activity and preliminary treatment efficacy of previously synthesized nitrofuranylazines. The trypanocidal activity of these nitrofuran derivatives varied among the evaluated trypanosome species; however, strain IL3000 was more susceptible than other animal and human trypanosomes. The nitrofurylazines (IC 0.04 μM; SI > 7761) and (IC 0.03 μM; SI > 9542) as well as the nitrothienylazine (IC 0.04 μM; SI 232), with nanomolar IC values, were revealed as early antitrypanosomal leads. Although these derivatives showed strong trypanocidal activity , no treatment efficacy was observed in IL3000 infected mice after both oral and intraperitoneal administration in a preliminary study. This was attributed to the poor solubility of the test compounds in the testing media. Indeed, a challenge in drug discovery is finding a balance between the physicochemical properties of a drug candidate, particularly lipophilicity and water solubility, and maintaining adequate potency to provide an effective dose. Hence, future chemical modifications may be required to generate lead-like to lead-like nitrofuranylazines that possess optimal physicochemical and pharmacokinetic properties while retaining and, ultimately, trypanocidal efficacy.
PubMed: 38024678
DOI: 10.1021/acsomega.3c06508 -
Parasites & Vectors Oct 2023In its 'Road map for neglected tropical diseases 2021-2030', the World Health Organization outlined its targets for control and elimination of neglected tropical... (Review)
Review
In its 'Road map for neglected tropical diseases 2021-2030', the World Health Organization outlined its targets for control and elimination of neglected tropical diseases (NTDs) and research needed to achieve them. For many NTDs, this includes research for new treatment options for case management and/or preventive chemotherapy. Our review of small-molecule anti-infective drugs recently approved by a stringent regulatory authority (SRA) or in at least Phase 2 clinical development for regulatory approval showed that this pipeline cannot deliver all new treatments needed. WHO guidelines and country policies show that drugs may be recommended for control and elimination for NTDs for which they are not SRA approved (i.e. for 'off-label' use) if efficacy and safety data for the relevant NTD are considered sufficient by WHO and country authorities. Here, we are providing an overview of clinical research in the past 10 years evaluating the anti-infective efficacy of oral small-molecule drugs for NTD(s) for which they are neither SRA approved, nor included in current WHO strategies nor, considering the research sponsors, likely to be registered with a SRA for that NTD, if found to be effective and safe. No such research has been done for yaws, guinea worm, Trypanosoma brucei gambiense human African trypanosomiasis (HAT), rabies, trachoma, visceral leishmaniasis, mycetoma, T. b. rhodesiense HAT, echinococcosis, taeniasis/cysticercosis or scabies. Oral drugs evaluated include sparfloxacin and acedapsone for leprosy; rifampicin, rifapentin and moxifloxacin for onchocerciasis; imatinib and levamisole for loiasis; itraconazole, fluconazole, ketoconazole, posaconazole, ravuconazole and disulfiram for Chagas disease, doxycycline and rifampicin for lymphatic filariasis; arterolane, piperaquine, artesunate, artemether, lumefantrine and mefloquine for schistosomiasis; ivermectin, tribendimidine, pyrantel, oxantel and nitazoxanide for soil-transmitted helminths including strongyloidiasis; chloroquine, ivermectin, balapiravir, ribavirin, celgosivir, UV-4B, ivermectin and doxycycline for dengue; streptomycin, amoxicillin, clavulanate for Buruli ulcer; fluconazole and isavuconazonium for mycoses; clarithromycin and dapsone for cutaneous leishmaniasis; and tribendimidine, albendazole, mebendazole and nitazoxanide for foodborne trematodiasis. Additional paths to identification of new treatment options are needed. One promising path is exploitation of the worldwide experience with 'off-label' treatment of diseases with insufficient treatment options as pursued by the 'CURE ID' initiative.
Topics: Humans; Ivermectin; Rifampin; Doxycycline; Fluconazole; Off-Label Use; Anti-Infective Agents; Drug Combinations; Neglected Diseases
PubMed: 37907954
DOI: 10.1186/s13071-023-05909-8 -
Heliyon Jan 2024Kinetoplastids are the causative agents for a spectrum of vector-borne diseases including Leishmaniasis, Chagas disease and Trypanosomiasis that affect millions of... (Review)
Review
Kinetoplastids are the causative agents for a spectrum of vector-borne diseases including Leishmaniasis, Chagas disease and Trypanosomiasis that affect millions of people worldwide. In the absence of safe and effective vaccines, chemotherapy, in conjunction with vector control, remain the most significant control approach for kinetoplastid diseases. However, commercially available treatment for these neglected tropical diseases frequently ends up with toxic side effects and increasing resistance. To meet the rising need for innovative medications, alternative chemotherapeutic agents are required. Moreover, insights into target-based mode of action of chemotherapeutic agents are required if novel drugs that may outwit resistance to commercially available drugs are to be developed. Tryptophan has been implicated in a variety of diseases and disorders due to its fundamental role as a precursor to several bioactive metabolites, as well as its importance in the improvement of health and nutrition, diagnostics, and therapeutics. The regulation of tryptophan metabolism plays a fundamental role in the growth of kinetoplastids. Moreover, the levels of tryptophan may serve as a biomarker to distinguish between the stages of kinetoplastids making it an important amino acid to explore for drug targets. The main aim of this review is thus to provide a comprehensive literature synthesis of tryptophan derivatives to explore as potential anti-kinetoplastids. Here we highlight the role of tryptophan derivatives as chemotherapeutic agents against kinetoplastids. The reviewed compounds provide insights into potential new drug interventions that may combat the increasing problem of anti-kinetoplastid resistance.
PubMed: 38187297
DOI: 10.1016/j.heliyon.2023.e23895 -
Scientific Reports Nov 2023African animal trypanosomiasis (AAT) is one of the major constraints to animal health and production in sub-Saharan Africa. To inform AAT control in Uganda and help...
African animal trypanosomiasis (AAT) is one of the major constraints to animal health and production in sub-Saharan Africa. To inform AAT control in Uganda and help advance along the progressive control pathway (PCP), we characterized AAT prevalence among eight host species in Uganda and explored factors that influence the prevalence variation between studies. We retrieved AAT prevalence publications (n = 2232) for Uganda (1980-2022) from five life sciences databases, focusing on studies specifying AAT detection methods, sample size, and the number of trypanosome-positive animals. Following PRISMA guidelines, we included 56 publications, and evaluated publication bias by the Luis Furuya-Kanamori (LFK) index. National AAT prevalence under DNA diagnostic methods for cattle, sheep and goats was 22.15%, 8.51% and 13.88%, respectively. Under DNA diagnostic methods, T. vivax was the most common Trypanosoma sp. in cattle (6.15%, 95% CI: 2.91-10.45) while T. brucei was most common among small ruminants (goats: 8.78%, 95% CI: 1.90-19.88, and sheep: 8.23%, 95% CI: 4.74-12.50, respectively). Northern and Eastern regions accounted for the highest AAT prevalence. Despite the limitations of this study (i.e., quality of reviewed studies, underrepresentation of districts/regions), we provide insights that could be used for better control of AAT in Uganda and identify knowledge gaps that need to be addressed to support the progressive control of AAT at country level and other regional endemic countries with similar AAT eco-epidemiology.
Topics: Animals; Cattle; Sheep; Animals, Domestic; Livestock; Prevalence; Uganda; Trypanosomiasis, African; Trypanosoma; Ruminants; Goats; DNA; Tsetse Flies
PubMed: 37990067
DOI: 10.1038/s41598-023-47141-5