Challenges in drug discovery targeting TriTryp diseases with an emphasis on leishmaniasis

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Term Occurence Count Dictionary
Chagas disease 9 infectiousdiseases
cryptosporidiosis 1 infectiousdiseases
eflornithine 7 infectiousdiseasesdrugs
giardiasis 1 infectiousdiseases
pentamidine 2 infectiousdiseasesdrugs
visceral leishmaniasis 1 infectiousdiseases
cutaneous leishmaniasis 2 infectiousdiseases
infectious disease 1 infectiousdiseases
malaria 1 infectiousdiseases
mucocutaneous leishmaniasis 1 infectiousdiseases
paromomycin 10 infectiousdiseasesdrugs
sleeping sickness 4 infectiousdiseases
trypanosomiasis 4 infectiousdiseases

Graph of close proximity drug and disease terms (within 200 characters).

Note: If this graph is empty, then there are no terms that meet the proximity constraint.

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Select Drug Character Offset Drug Term Instance
eflornithine 3760 Amphotericin B, miltefosine and paromomycinBenznidazole and nifurtimoxSuramin, pentamidine, melarsoprol, eflornithine , and nifurtimox-eflornithine combinationDisadvantages of chemotherapyToxicity, severe side effects,
eflornithine 3789 paromomycinBenznidazole and nifurtimoxSuramin, pentamidine, melarsoprol, eflornithine, and nifurtimox- eflornithine combinationDisadvantages of chemotherapyToxicity, severe side effects, hospitalization requirement and
eflornithine 10416 therapy to reduce resistance in pathogenic organisms ([48]; [1]). It has been shown that nifurtimox- eflornithine combination therapy (NECT) can be safely used as first-line treatment for the second-stage of Human
eflornithine 10757 randomized clinical trial conducted in Uganda showed that NECT schemes are shorter and less expensive than eflornithine monotherapy. It is worth pointing out that this clinical trial was funded from a partnership between
eflornithine 12726 repurposed, such as antibiotics (paromomycin), antifungals (Amphotericin B) and anti-cancer agents ( eflornithine , miltefosine and nifurtimox).Bottlenecks in drug discovery against Leishmania4Non-scientific challenges4.1Primarily,
eflornithine 14028 evaluate the repositioning of pozaconazole for Chagas' disease (Box 1). One combination (nifurtimox+ eflornithine ) was approved for sleeping sickness treatment during the same period. Clinical trials registered in
eflornithine 19255 fexinidazole and acoziborole against T. brucei;(iv)implementation: access to combinatory therapy of eflornithine and oral nifurtimox for human African trypanosomiasis treatment, new benznidazole formulation for children
paromomycin 3687 coordination, somnolence, comaCurrent treatmentsPentavalent antimonials, Amphotericin B, miltefosine and paromomycin Benznidazole and nifurtimoxSuramin, pentamidine, melarsoprol, eflornithine, and nifurtimox-eflornithine
paromomycin 6641 (Fungizone® – salt formulation and Ambisome® - liposomal formulation), miltefosine (Impavido™) and paromomycin (Humatin®) are classically used for the treatment of leishmaniasis; however, these drugs present a
paromomycin 11066 Government of Uganda ([43]). VL’ clinical studies using Amphotericin B in combination with miltefosine or paromomycin have also shown promising results: both combinations were well tolerated and safe, with cure ratios
paromomycin 12659 the TriTryp diseases as several commercial drugs in use were indeed repurposed, such as antibiotics ( paromomycin ), antifungals (Amphotericin B) and anti-cancer agents (eflornithine, miltefosine and nifurtimox).Bottlenecks
paromomycin 13744 disease. Regarding leishmaniasis, two new alternatives were approved for treatment, miltefosine and paromomycin , both repurposed drugs. For Chagas disease, only a new formulation of benznidazole designed for paediatric
paromomycin 19421 treatment, new benznidazole formulation for children with Chagas disease and sodium stibogluconate+ paromomycin scheme for leishmaniasis in East Africa.Table 2List of compounds on current DNDi pipeline.Table 2CompoundTarget
paromomycin 39699 antimonial, Amphotericin B deoxycholate, miltefosine, Amphotericin B lipid-associated formulations, paromomycin , pentamidine or sitamaquine ([13]). Indeed, all DNDi clinical trials that are ongoing are with reference
paromomycin 40476 5IdentifierCountryPhaseTreatmentGoalProject start:NCT03129646Ethiopia, Kenya, Sudan, UgandaIIISSGa+ paromomycin , paromomycin+miltefosineAssess the efficacy and safety of two combination regimens for the treatment
paromomycin 40489 5IdentifierCountryPhaseTreatmentGoalProject start:NCT03129646Ethiopia, Kenya, Sudan, UgandaIIISSGa+paromomycin, paromomycin +miltefosineAssess the efficacy and safety of two combination regimens for the treatment of primary VL
paromomycin 40737 2018CTRI/2017/04/008421; NCT03399955India, Bangladesh, SudanIIAmBisome®b, AmBisome®+miltefosine, paromomycin +miltefosineDetermine safety and efficacy profiles of two treatment regimens for patients with PKDL.March
pentamidine 3734 treatmentsPentavalent antimonials, Amphotericin B, miltefosine and paromomycinBenznidazole and nifurtimoxSuramin, pentamidine , melarsoprol, eflornithine, and nifurtimox-eflornithine combinationDisadvantages of chemotherapyToxicity,
pentamidine 39712 Amphotericin B deoxycholate, miltefosine, Amphotericin B lipid-associated formulations, paromomycin, pentamidine or sitamaquine ([13]). Indeed, all DNDi clinical trials that are ongoing are with reference drugs (Table
Select Disease Character Offset Disease Term Instance
Chagas disease 2106 Trypanosoma brucei subspecies are the causative agents of leishmaniasis, American trypanosomiasis ( Chagas disease ) and Human African trypanosomiasis (sleeping sickness), respectively. Together, these protozoal infections
Chagas disease 2888 regimens (Table 1) ([59]; [82]).Table 1TriTryp diseases.Table 1LeishmaniasisAmerican Trypanosomiasis ( Chagas disease )Human African Trypanosomiasis (sleeping sickness)Causative agentLeishmania species (Leishmania and Viannia
Chagas disease 13784 new alternatives were approved for treatment, miltefosine and paromomycin, both repurposed drugs. For Chagas disease , only a new formulation of benznidazole designed for paediatric use was developed, despite recent clinical
Chagas disease 14611 broad-spectrum second-generation triazole with antifungal activity, has emerged as a possible drug candidate to Chagas disease treatment. However, anti-T. cruzi activity of posaconazole in animal models failed to predict drug effectiveness
Chagas disease 15133 results in the murine model and human trials is that the former represents the early stage of chronic Chagas disease in which the response of the drugs can be overestimated. Besides that, it has been suggested that in
Chagas disease 17654 Discovery Unit (DDU, University of Dundee) and Wellcome Trust to discover new candidate drugs for VL and Chagas disease ([27]). Willie and collaborators have recently reported a potential drug candidate (DDD853651/GSK3186899)
Chagas disease 18558 different stages (Fig. 2B), being the majority focused on leishmaniasis (21 projects), followed by Chagas disease (9 projects) and sleeping sickness (4 projects). The activities’ portfolio currently consists on:(i)research:
Chagas disease 19380 nifurtimox for human African trypanosomiasis treatment, new benznidazole formulation for children with Chagas disease and sodium stibogluconate+paromomycin scheme for leishmaniasis in East Africa.Table 2List of compounds
Chagas disease 21719 2014 has been granted accelerated approval ([31]) and in 2017 benznidazole also received a PRV for Chagas disease paediatric treatment ([30]). The Pros of this program are the release of the review result by FDA in
cryptosporidiosis 13528 Additionally, the development of new chemical entities was focused on malaria and diarrhoeal diseases ( cryptosporidiosis and giardiasis). During the period of study, no new compound was registered targeting a neglected disease.
cutaneous leishmaniasis 5853 virulence of different species/strains ([56]). Clinical manifestations range from cutaneous lesions ( cutaneous leishmaniasis , CL) and mucous ulcers (mucocutaneous leishmaniasis, MCL) to systemic visceral damage (visceral leishmaniasis,
cutaneous leishmaniasis 5905 Clinical manifestations range from cutaneous lesions (cutaneous leishmaniasis, CL) and mucous ulcers (muco cutaneous leishmaniasis , MCL) to systemic visceral damage (visceral leishmaniasis, VL). VL is the most severe form of the disease
giardiasis 13550 development of new chemical entities was focused on malaria and diarrhoeal diseases (cryptosporidiosis and giardiasis ). During the period of study, no new compound was registered targeting a neglected disease. Regarding
infectious disease 41697 poor housing, and illiteracy. Being responsible for the ninth largest disease burden among individual infectious disease s, leishmaniasis should not be ignored in discussions of tropical disease priorities. The combination
malaria 13495 and 4 new chemical entities. Additionally, the development of new chemical entities was focused on malaria and diarrhoeal diseases (cryptosporidiosis and giardiasis). During the period of study, no new compound
mucocutaneous leishmaniasis 5901 Clinical manifestations range from cutaneous lesions (cutaneous leishmaniasis, CL) and mucous ulcers ( mucocutaneous leishmaniasis , MCL) to systemic visceral damage (visceral leishmaniasis, VL). VL is the most severe form of the disease
sleeping sickness 2157 agents of leishmaniasis, American trypanosomiasis (Chagas disease) and Human African trypanosomiasis ( sleeping sickness ), respectively. Together, these protozoal infections are known as TriTryp diseases. They represent a
sleeping sickness 2934 diseases.Table 1LeishmaniasisAmerican Trypanosomiasis (Chagas disease)Human African Trypanosomiasis ( sleeping sickness )Causative agentLeishmania species (Leishmania and Viannia subgenera)Trypanosoma cruziTrypanosoma brucei
sleeping sickness 14059 pozaconazole for Chagas' disease (Box 1). One combination (nifurtimox+eflornithine) was approved for sleeping sickness treatment during the same period. Clinical trials registered in WHO and NIH databases showed that the
sleeping sickness 18590 being the majority focused on leishmaniasis (21 projects), followed by Chagas disease (9 projects) and sleeping sickness (4 projects). The activities’ portfolio currently consists on:(i)research: library screenings and
trypanosomiasis 2089 Trypanosoma cruzi and Trypanosoma brucei subspecies are the causative agents of leishmaniasis, American trypanosomiasis (Chagas disease) and Human African trypanosomiasis (sleeping sickness), respectively. Together, these
trypanosomiasis 2140 the causative agents of leishmaniasis, American trypanosomiasis (Chagas disease) and Human African trypanosomiasis (sleeping sickness), respectively. Together, these protozoal infections are known as TriTryp diseases.
trypanosomiasis 9967 identification and optimization ([67]; [16]). Drug combination has been explored in leishmaniasis and trypanosomiasis treatment/clinical trials in order to increase drug efficacy, shorten the course of treatment and potentially
trypanosomiasis 19306 brucei;(iv)implementation: access to combinatory therapy of eflornithine and oral nifurtimox for human African trypanosomiasis treatment, new benznidazole formulation for children with Chagas disease and sodium stibogluconate+paromomycin
visceral leishmaniasis 5964 leishmaniasis, CL) and mucous ulcers (mucocutaneous leishmaniasis, MCL) to systemic visceral damage ( visceral leishmaniasis , VL). VL is the most severe form of the disease and is potentially fatal if untreated ([68]). Bangladesh,

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