- |||||||||| Lampit (nifurtimox) / Bayer
Journal: New Insights into the Role of the Trypanosoma cruzi Aldo-Keto Reductase TcAKR. (Pubmed Central) - Jan 22, 2023
Only two drugs are currently approved for the treatment, Benznidazole and Nifurtimox, and both have to be activated by reducing the nitro-group...Structural analysis showed that TcAKR contains a catalytic tetrad conserved in the AKR superfamily. Finally, we found that TcAKR is also involved in Nfx metabolization.
- |||||||||| Lampit (nifurtimox) / Bayer
Preclinical, Journal: Effect of B-NIPOx in Experimental Trypanosoma cruzi Infection in Mice. (Pubmed Central) - Jan 9, 2023
We then evaluated the trypanocidal activity of B-NIPOx in vitro and in vivo and its effect in the intestine of T. cruzi-infected mice. We found that B-NIPOx had higher trypanocidal activity on epimastigotes and trypomastigotes than Benznidazole and Nifurtimox, that it was more effective to reduce blood parasitemia and amastigote nests in infected mice, and that, in contrast to the reference drugs, it prevented the development of Chagasic enteropathy.
- |||||||||| Lampit (nifurtimox) / Bayer
Trial completion, Trial completion date: Study of Nifurtimox to Treat Refractory or Relapsed Neuroblastoma or Medulloblastoma (clinicaltrials.gov) - Dec 29, 2022
P2, N=112, Completed,
We found that B-NIPOx had higher trypanocidal activity on epimastigotes and trypomastigotes than Benznidazole and Nifurtimox, that it was more effective to reduce blood parasitemia and amastigote nests in infected mice, and that, in contrast to the reference drugs, it prevented the development of Chagasic enteropathy. Active, not recruiting --> Completed | Trial completion date: Dec 2023 --> Oct 2022
- |||||||||| Lampit (nifurtimox) / Bayer
Journal: Mode of action of p-quinone derivatives with trypanocidal activity studied by experimental and in silico models. (Pubmed Central) - Dec 13, 2022
All the compounds, except for a furanequinone (EC38 μM), proved to be similarly or even more potent (EC = 0.5-5.5 μM) than the clinical drug nifurtimox (EC = 5.3 μM)...DFT calculations on the oxidized quinone (Q), semiquinone (Q) and hydroquinone (QH) suggest that all quinones have negative ΔG for the formation of Q. Qualitative and quantitative structure-activity relationship analyses in two or three dimensions of different electronic and biophysical descriptors of quinones and their corresponding bioactivities (killing potency and oxidative capacity) were performed...QSAR analysis also highlighted that both bromine substitution in the p-quinone ring and a bulky phenyl group attached to the furane and thiazole rings (which generates a negative charge due to the π electron system polarized by the nearby heteroatoms) are favorable for activity. By combining experimental and in silico procedures, this study disclosed important information about p-quinones that may help to rationally tune their electronic properties and biological activities.
- |||||||||| Lampit (nifurtimox) / Bayer
Preclinical, Journal: Effect of benznidazole on cerebral microcirculation during acute Trypanosoma cruzi infection in mice. (Pubmed Central) - Dec 7, 2022
Only benznidazole and nifurtimox are available for clinical treatment, they have an efficiency of 80% in the acute phase and less than 20% in chronic phase...Early treatment with benznidazole at 100 mg/kg/day and 50 mg/kg/day prevented the occurrence of the alterations mentioned. Here, we show that BZ is able to protect the microcirculation and reduced brain inflammation in acute experimental Chagas disease.
- |||||||||| Lampit (nifurtimox) / Bayer
Preclinical, Journal: Phenotypic Evaluation of Nucleoside Analogues against Trypanosoma cruzi Infection: In Vitro and In Vivo Approaches. (Pubmed Central) - Nov 27, 2022
Current treatment is restricted to two drugs, benznidazole and nifurtimox, displaying serious efficacy and safety drawbacks...Given orally, the compounds did not induce noticeable mouse toxicity (50 mg/kg), suppressed the parasitemia of T. cruzi-infected Swiss mice (25 mg/kg, 5 days) and presented DNA amplification below the limit of detection. These findings justify further studies with longer treatment regimens, as well as evaluations in combination with nitro drugs, aiming to identify more effective and safer therapies for Chagas disease.
- |||||||||| Fexinidazole Winthrop (fexinidazole) / Sanofi, Lampit (nifurtimox) / Bayer, Germanin (suramin) / Optimum Therap
Review, Journal: Recent progress in diagnosis and treatment of Human African Trypanosomiasis has made the elimination of this disease a realistic target by 2030. (Pubmed Central) - Nov 22, 2022
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...Here, a combination therapy of eflornithine and nifurtimox (NECT) has been the choice of treatment since 2009...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.
- |||||||||| Lampit (nifurtimox) / Bayer, Nailin (fosravuconazole) / DNDi, Eisai, Sato Pharma, Noxafil (posaconazole) / Merck (MSD)
Review, Journal, Monotherapy: Monotherapy and combination chemotherapy for Chagas disease treatment: A systematic review of clinical efficacy and safety based on randomized controlled trials. (Pubmed Central) - Nov 15, 2022
Benznidazole (BNZ), nifurtimox, fosravuconazole, posaconazole, allopurinol and thioctic acid were the identified drugs. No abstract available
- |||||||||| Lampit (nifurtimox) / Bayer
Journal: Discovery of novel drugs for Chagas disease: is carbonic anhydrase a target for antiprotozoal drugs? (Pubmed Central) - Nov 5, 2022
Benznidazole and Nifurtimox have been used for Chagas disease treatment for 60 years despite all efforts done for obtaining more efficient treatments, acting in the acute and chronic phases of illness, with fewer side effects and resistance induction...Several studied inhibitors were active against Trypanosoma cruzi, but their penetration and toxicity problems emerged. New approaches are in progress to obtain inhibitors with desired properties, allowing further steps such as tests using an adequate animal model and subsequent developments for the preclinical testing.
- |||||||||| Lampit (nifurtimox) / Bayer
Journal: Trypanosoma cruzi nitroreductase: Structural features and interaction with biological membranes. (Pubmed Central) - Nov 3, 2022
Benznidazole and nifurtimox are currently the only drugs available for CD...For the first time, the interaction of TcNTR with membranes was demonstrated, with a preference for those containing cardiolipin, a unique dimeric phospholipid that exists almost exclusively in the inner mitochondrial membrane in eukaryotic cells. Prediction of TcNTR's 3D structure suggests that a 23-residue long insertion (199 to 222), absent in the homologous bacterial protein and identified as conserved in protozoan sequences, mediates enzyme specificity, and is involved in protein-membrane interaction.
- |||||||||| Fexinidazole Winthrop (fexinidazole) / Sanofi, Lampit (nifurtimox) / Bayer
Retrospective data, Review, Journal: Systematic Review and Meta-Analysis on Human African Trypanocide Resistance. (Pubmed Central) - Oct 28, 2022
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.
- |||||||||| Lampit (nifurtimox) / Bayer
Journal: Disruption of multiple copies of the Prostaglandin F2alpha synthase gene affects oxidative stress response and infectivity in Trypanosoma cruzi. (Pubmed Central) - Oct 26, 2022
Chagas disease, caused by the protozoan Trypanosoma cruzi, is a serious chronic parasitic disease, currently treated with Nifurtimox (NFX) and Benznidazole (BZ)...Interestingly, NTR-1 transcripts were shown to be upregulated in ΔPGFS mutants. Furthermore, the ΔPGFS parasites were 1.6 to 1.7-fold less tolerant to oxidative stress generated by menadione, presented lower levels of lipid bodies than the control parasites during the stationary phase, and were less infective than control parasites.
- |||||||||| Lampit (nifurtimox) / Bayer
Review, Journal: Chagas Disease in Oklahoma. (Pubmed Central) - Oct 25, 2022
There are several reported cases of locally-acquired Chagas disease in the United States, but there is a paucity of information in Oklahoma. We present a brief summary of the available data of Chagas disease in Oklahoma to raise awareness and serve as a foundation for future research.
- |||||||||| Lampit (nifurtimox) / Bayer
Journal: Structural and Mechanistic Investigation of the Unusual Metabolism of Nifurtimox. (Pubmed Central) - Oct 11, 2022
Overall, we determined that the metabolism of nifurtimox is almost certainly not mediated by typical hepatic and renal drug-metabolizing enzymes, and instead is rapidly metabolized mainly by reduction or nucleophilic attack, with some evidence of oxidation. Knowledge of the most abundant metabolites of nifurtimox affords the possibility of future studies to investigate levels of exposure and possible drug-drug interactions.
- |||||||||| Lampit (nifurtimox) / Bayer
Standardization of High-content (HC) phenotype imaging and validations for novel drug discovery against intracellular Trypanosoma cruzi (Convention Center - Hall 4A (4th Floor); In-Person-Only) - Oct 9, 2022 - Abstract #ASTMH2022ASTMH_715;
With only two clinically accepted drug treatments, nifurtimox and benznidazole, which have well reported toxic side effects, and the ongoing spread of the disease to non-endemic areas, there is an urgency to identify new treatments against the clinically relevant form of T. cruzi -the intracellular amastigote...Using Image-Express PICO, we can determine the true efficacy of test compounds following this HC phenotype screening protocol. As part of the validation of HC method, we have identified an FDA approved Epigallocatechin gallate (EGCG) as a lead natural compound specific to parasite GAPDH, with binding energy of -10.6 kcal/mol and an IC50 of 46.5µM against epimastigotes, and cytotoxicity levels below Amphotericin B. Additional experiments are underway to expand validations using T. cruzi brazil strain expressing luciferase reporter gene.
- |||||||||| Lampit (nifurtimox) / Bayer
Journal: Solid Nanomedicines of Nifurtimox and Benznidazole for the Oral Treatment of Chagas Disease. (Pubmed Central) - Sep 24, 2022
NFX-BNZ-SNEDDS demonstrated nanomolar efficacy in epimastigotes and amastigotes of T. cruzi with acceptable selectivity indexes and demonstrated enhanced survival and reduced parasitaemia in acute murine experimental models of CD. Thus, the results presented here illustrate the ability for an easily scalable and personalised combination oral therapy prepared from GRAS excipients, enabling treatment access worldwide for the treatment of CD.
- |||||||||| Lampit (nifurtimox) / Bayer
Journal: Broadening the spectrum of ivermectin: Its effect on Trypanosoma cruzi and related trypanosomatids. (Pubmed Central) - Aug 16, 2022
The current therapies, benznidazole (BZN) and nifurtimox (NFX), show limited efficacy and multiple side effects...The putative IMPα genes (with 76% similarity) showed conserved Armadillo domains but lacked the canonical IMPβ binding sequence. These results allowed us to propose a novel molecular target in T. cruzi and suggest IVM as a good candidate for drug repurposing in the Chagas disease context.
- |||||||||| Lampit (nifurtimox) / Bayer, Noxafil (posaconazole) / Merck (MSD)
Journal: Transplantation for chagas' disease: closing the knowledge gap. (Pubmed Central) - Aug 10, 2022
These results allowed us to propose a novel molecular target in T. cruzi and suggest IVM as a good candidate for drug repurposing in the Chagas disease context. Patients with chronic T. cruzi infection can be safely transplanted and be noncardiac organ donors.
- |||||||||| Lampit (nifurtimox) / Bayer
Journal: The Use of AlphaFold for In Silico Exploration of Drug Targets in the Parasite Trypanosoma cruzi. (Pubmed Central) - Aug 3, 2022
The two anti-parasitic drugs available, nifurtimox and benznidazole, have a good efficacy against the acute stage of the infection...The best receptors (targets) for the most promising ligands were analyzed in detail to address molecular interactions and potential drugs' mode of action. The results provide insight into the mechanisms of action of the compounds and their targets, and pave the way for new strategies to finding novel compounds or optimize already existing ones.
- |||||||||| Lampit (nifurtimox) / Bayer
Review, Journal: Diagnosis and Clinical Management of Chagas Disease: An Increasing Challenge in Non-Endemic Areas. (Pubmed Central) - Aug 2, 2022
Treatment with benznidazole or nifurtimox is most effective in the acute phase and prevents progression to chronic phase when given to children...The involvement of patients and their communities is central and key for success and must be sought early and actively. This review proposes strategies to address challenges faced by non-endemic countries.
- |||||||||| Lampit (nifurtimox) / Bayer
Journal: Pharmaceutical agents for the treatment of Chagas disease: patenting trends in 2016-2021 period. (Pubmed Central) - Jul 31, 2022
American trypanosomiasis is a neglected tropical disease and an endemic problem in 21 Latin American countries, whose treatment relies on only two US FDA-approved drugs: benznidazole and nifurtimox...A total of 50 patent families were collected and grouped as 'small molecules', 'pharmaceutical compositions of known compounds' and vaccines. From the results and interpretation, it can be concluded that the treatment of Chagas disease receives little attention in the field of patents and that the upward trend is minimal.
- |||||||||| Lampit (nifurtimox) / Bayer
Journal: Imidazole and nitroimidazole derivatives as NADH-fumarate reductase inhibitors: Density functional theory studies, homology modeling, and molecular docking. (Pubmed Central) - Jul 29, 2022
Benznidazole and nifurtimox are drugs used for its therapy; nevertheless, they have collateral effects...The main hydrogen-binding interactions for FUM were identified in NADH, Lys172, and Arg89; while hydrophobic interactions in Phe479, Thr174, Met63. The molecules S3-8, S2-8, and S1-8 could be inhibitors of NADH-FUM reductase.
- |||||||||| Lampit (nifurtimox) / Bayer
Review, Journal: Potential of sulfur-selenium isosteric replacement as a strategy for the development of new anti-chagasic drugs. (Pubmed Central) - Jul 15, 2022
Current treatment for Chagas disease is based on only two drugs: benznidazole and nifurtimox...Therefore, we have investigated S compounds described in the literature tested against T. cruzi. We focused on those tested in vivo that allowed isosteric replacement to propose their Se counterparts as promising compounds for the future development of new drugs against Chagas disease.
- |||||||||| Lampit (nifurtimox) / Bayer
Journal: New antiparasitic derivatives of the furoquinoline alkaloids kokusaginine and flindersiamine. (Pubmed Central) - May 6, 2022
In addition, both compounds were not cytotoxic activity against the three human cell lines K562 (erytroleukimia), LM2 (breast cancer) and HaCat (keratinocyte). Interestingly, when evaluated against intracellular amastigotes, compound 1c was able to significantly reduce the number of this parasite form, compared to the negative control.
- |||||||||| Lampit (nifurtimox) / Bayer
Journal: Study of the dynamic behavior of the cruzain enzyme in free and complexed forms with competitive and noncovalent benzimidazole inhibitors. (Pubmed Central) - Apr 28, 2022
There are only two drugs for the treatment of Chagas disease, namely, nifurtimox and benznidazole, that can cause several adverse effects...As expected, we also observed a correlation between the inhibitory activity of each inhibitor and their respective binding-free energies, reinforcing that the affinity of the complexes seems to be a relevant factor for enzymatic inhibition. Hence, the results presented in this work contribute to a better understanding of the cruzain enzyme inhibition mechanism through competitive and non-covalent inhibitors.Communicated by Ramaswamy H. Sarma.
- |||||||||| Lampit (nifurtimox) / Bayer
PK/PD data, Journal: Population Pharmacokinetics of Nifurtimox in Adult and Pediatric Patients with Chagas' Disease. (Pubmed Central) - Apr 24, 2022
No hints of dose-nonlinearity were observed in a dose range of 30 to 240 mg single dose in adults and 15 to 300 mg 3 times daily (8 to 20 mg/kg) in children. Altogether, this study retroactively showed that the current mg/kg dosing regimen in children reached similar exposure as in adults receiving an 8 mg/kg total daily dose.
- |||||||||| Lampit (nifurtimox) / Bayer
Trial completion date, Trial primary completion date: Study of Nifurtimox to Treat Refractory or Relapsed Neuroblastoma or Medulloblastoma (clinicaltrials.gov) - Feb 18, 2022
P2, N=112, Active, not recruiting,
Whether longer duration treatments may eliminate all parasites remains to be explored. Trial completion date: Dec 2021 --> Dec 2023 | Trial primary completion date: Oct 2021 --> Oct 2022
- |||||||||| Lampit (nifurtimox) / Bayer
Biomarker, Enrollment closed, Trial completion date, Trial primary completion date: TESEO: New Therapies and Biomarkers for Chagas Infection (clinicaltrials.gov) - Jun 30, 2021
P2, N=450, Active, not recruiting,
Active, not recruiting --> Completed Recruiting --> Active, not recruiting | Trial completion date: Jul 2023 --> Jul 2024 | Trial primary completion date: May 2021 --> May 2024
- |||||||||| Lampit (nifurtimox) / Bayer
Biomarker, Trial primary completion date: TESEO: New Therapies and Biomarkers for Chagas Infection (clinicaltrials.gov) - Apr 22, 2021
P2, N=450, Recruiting,
Trial primary completion date: May 2021 --> Oct 2021 Trial primary completion date: Dec 2020 --> May 2021
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