Efficacy of short-course treatment for prevention of congenital transmission of Chagas disease: A retrospective cohort study.

BACKGROUND: In regions with controlled vector transmission of T. cruzi, congenital transmission is the most frequent route of infection. Treatment with benznidazole (BZ) or nifurtimox (NF) for 60 days in girls and women of childbearing age showed to be effective in preventing mother to child transmission of this disease. Reports on short-course treatment (≤30 days) are scarce. METHODS: Retrospective cohort study. Offspring of women with Chagas disease who received short-course treatment (≤30 days) with BZ or NF, attended between 2003 and 2022, were evaluated. Parasitemia (microhaematocrit and/or PCR) was performed at <8 months of age, and serology (ELISA and IHA) at ≥8 months to rule out congenital infection. RESULTS: A total of 27 women receiving ≤30 days of treatment and their children were included in this study. NF was prescribed in 17/27 (63%) women, and BZ in 10/27 (37%). The mean duration of treatment was 29.2 days. None of the women experienced serious adverse events during treatment, and no laboratory abnormalities were observed. Forty infants born to these 27 treated women were included. All newborns were full term, with appropriate weight for their gestational age. No perinatal infectious diseases or complications were observed. DISCUSSION: Several studies have shown that treatment of infected girls and women of childbearing age for 60 days is an effective practice to prevent transplacental transmission of T. cruzi. Our study demonstrated that short-duration treatment (≤30 days) is effective and beneficial in preventing transplacental transmission of Chagas disease.

Melt crystallization and thermal degradation profile of the antichagasic drug nifurtimox.

Despite nifurtimox (NFX) being a traditional drug for treating Chagas disease, some of its physicochemical properties are still unknown, especially its thermal behavior, which brings important outcomes regarding stability and compatibility. In this work, a comprehensive study of NFX's thermal properties was conducted to assist incremental innovations that can improve the efficacy of this drug in novel pharmaceutical products. For this purpose, thermal analyses associated with spectroscopy and spectrometry techniques were used. DSC analyses revealed that the melt crystallization of the NFX led to its amorphous form with the possible formation of a minor fraction of a different crystalline phase. Coats-Redfern method using TGA results indicated the activation energy of NFX non-isothermal degradation as 348.8 ± 8.2 kJ mol-1, which coincides with the C-NO2 bond dissociation energy of the 2-nitrofuran. Investigation of the isothermal degradation kinetics using FTIR 2D COS showed the possible detachment of radical NO2 and ethylene from the NFX structure, which could affect its mechanism of action. A preliminary mechanism for the thermal degradation of this drug was also proposed. The results enhanced the understanding of NFX's thermal properties, providing valuable insights, especially for developing NFX-based pharmaceutical products that involve thermal processing.

Lychnopholide loaded in surface modified polylactide nanocapsules (LYC-PLA-PEG-NC) cure mice infected by Trypanosoma cruzi strain a prototype of resistance to benznidazole and nifurtimox: First insights of its mechanism of action.

Chagas disease (CD) remains neglected and causes high morbidity and mortality. The great difficulty is the lack of effective treatment. The current drugs cause side effects and have limited therapeutic efficacy in the chronic phase. This study aims to fulfil some gaps in studies of the natural substance lychnopholide nanoencapsulated LYC-PLA-PEG-NC (LYC-NC) and free (Free-LYC): the activity in epimastigotes and amastigotes to determine its selectivity index (SI), the therapeutic efficacy in mice infected with Colombian Trypanosoma cruzi strain and insight of the mechanism of LYC-NC action on T. cruzi. The SI was obtained by calculation of the ratio between the IC50 value toward H9c2 cells divided by the IC50 value in the anti-T. cruzi test. Infected Swiss mice were treated with 2 and 12 mg/kg/day via intravenous and oral, respectively, and the therapeutic efficacy was determined. The IC50 of LYC-NC and Free-LYC for epimastigotes of T. cruzi were similar. Both were active against amastigotes in cell culture, particularly Free-LYC. The SI of LYC-NC and Free-LYC were 45.38 and 32.11, respectively. LYC-NC 2 and 12 mg/kg/day cured parasitologically, 62.5% and 80% of the animals, respectively, infected with a strain resistant to treatment. The fluorescent NC was distributed in the cardiomyocyte cytoplasm, infected or not, and interacted with the trypomastigotes. Together, these results represent advances in demonstrating LYC as a potent new therapeutic option for treating CD.

ELISA F29 -A therapeutic efficacy biomarker in Chagas disease: Evaluation in pediatric patients treated with nifurtimox and followed for 4 years post-treatment.

BACKGROUND: Measurement of the success of antitrypanosomal treatment for Chagas disease is difficult, particularly in the chronic phase of the disease, because anti-Trypanosoma cruzi antibodies persist in serum for prolonged periods. We studied the effects of nifurtimox administered by two different treatment regimens on the T. cruzi calcium-binding flagellar protein F29 in children diagnosed with Chagas disease measured using an enzyme-linked immunosorbent assay (ELISA) technique (ELISA F29). METHODS AND PRINCIPAL FINDINGS: In a phase 3, randomized, double-blind, parallel-group, historically controlled study (ClinicalTrials.gov NCT02625974), blood samples obtained from children diagnosed with Chagas disease and treated with nifurtimox for either 60 days or 30 days were analyzed using an ELISA with an F29 recombinant protein as the antigen, as well as conventional serological tests (recombinant ELISA and indirect hemagglutination assay). In an exploratory approach, serological response to nifurtimox treatment was evaluated for 4 years post-treatment. In both treatment groups, the number of patients with negative ELISA F29 values increased over the period of observation. The incidence rate of negative seroconversion using ELISA F29 was 22.94% (95% CI: 19.65%, 26.63%) in the 60-day treatment group and 21.64% (95% CI: 17.21%, 26.86%) in the 30-day treatment group. In the subpopulation of patients who tested seropositive for F29 before nifurtimox treatment, 88 patients (67.7%) in the 60-day regimen and 39 patients (59.1%) in the 30-day regimen were F29 seronegative at 4 years post-treatment. All patients who had a positive ELISA F29 test at baseline and seroconverted to negative measured by conventional serology reached seronegativity in ELISA F29 earlier than in conventional serology. CONCLUSIONS: The results demonstrate a serological response to treatment with nifurtimox measured by the ELISA F29 test in children diagnosed with Chagas disease. The F29-based ELISA can be considered a potential early marker of response to antitrypanosomal therapy for Chagas disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT02625974.

A phase II trial of nifurtimox combined with topotecan and cyclophosphamide for refractory or relapsed neuroblastoma and medulloblastoma.

Children with relapsed/refractory (R/R) neuroblastoma (NB) and medulloblastoma (MB) have poor outcomes. We evaluated the efficacy of nifurtimox (Nfx) in a clinical trial for children with R/R NB and MB. Subjects were divided into three strata: first relapse NB, multiply R/R NB, and R/R MB. All patients received Nfx (30 mg/kg/day divided TID daily), Topotecan (0.75 mg/m2 /dose, days 1-5) and Cyclophosphamide (250 mg/m2 /dose, days 1-5) every 3 weeks. Response was assessed after every two courses using International Neuroblastoma Response Criteria and Response Evaluation Criteria in Solid Tumors (RECIST) criteria. One hundred and twelve eligible patients were enrolled with 110 evaluable for safety and 76 evaluable for response. In stratum 1, there was a 53.9% response rate (CR + PR), and a 69.3% total benefit rate (CR + PR + SD), with an average time on therapy of 165.2 days. In stratum 2, there was a 16.3% response rate, and a 72.1% total benefit rate, and an average time on study of 158.4 days. In stratum 3, there was a 20% response rate and a 65% total benefit rate, an average time on therapy of 105.0 days. The most common side effects included bone marrow suppression and reversible neurologic complications. The combination of Nfx, topotecan and cyclophosphamide was tolerated, and the objective response rate plus SD of 69.8% in these heavily pretreated populations suggests that this combination is an effective option for patients with R/R NB and MB. Although few objective responses were observed, the high percentage of stabilization of disease and prolonged response rate in patients with multiply relapsed disease shows this combination therapy warrants further testing.

Selected Aspects of the Analytical and Pharmaceutical Profiles of Nifurtimox.

Nifurtimox is a nitroheterocyclic drug employed for treatment of trypanosomiases (Chagas disease and West African sleeping sickness); its use for certain cancers has also been assessed. Despite having been in the market for over 50 years, knowledge of nifurtimox is still fragmentary and incomplete. Relevant aspects of the chemistry and biology of nifurtimox are reviewed to summarize the current knowledge of this drug. These comprise its chemical synthesis and the preparation of some analogues, as well as its chemical degradation. Selected physical data and physicochemical properties are also listed, along with different approaches toward the analytical characterization of the drug, including electrochemical (polarography, cyclic voltammetry), spectroscopic (ultraviolet-visible, nuclear magnetic resonance, electron spin resonance), and single crystal X-ray diffractometry. The array of polarographic, ultraviolet-visible spectroscopic, and chromatographic methods available for the analytical determination of nifurtimox (in bulk drug, pharmaceutical formulations, and biological samples), are also presented and discussed, along with chiral chromatographic and electrophoretic alternatives for the separation of the enantiomers of the drug. Aspects of the drug likeliness of nifurtimox, its classification in the Biopharmaceutical Classification System, and available pharmaceutical formulations are detailed, whereas pharmacological, chemical, and biological aspects of its metabolism and disposition are discussed.

Chagas Disease.

Chagas disease, which is caused by infection with the parasite Trypanosoma cruzi, is a leading neglected tropical disease in the United States. An estimated 240 000 to 350 000 persons in the United States are infected, primarily immigrants from Mexico, Central America, and South America, where the disease is endemic. The parasite is transmitted by the triatomine bug but can also be passed through blood transfusion, via organ transplant, or congenitally. Approximately 30% of infected persons later develop cardiac and/or gastrointestinal complications. Health care providers should consider screening at-risk patients with serologic testing. Early diagnosis and treatment with benznidazole or nifurtimox can help prevent complications.

Mode of action of p-quinone derivatives with trypanocidal activity studied by experimental and in silico models.

Quinones are attractive pharmacological scaffolds for developing new agents for the treatment of different transmissible and non-transmissible human diseases due to their capacity to alter the cell redox homeostasis. The bioactivity and potential mode of action of 19 p-quinone derivatives fused to different aromatic rings (carbo or heterocycles) and harboring distinct substituents were investigated in infective Trypanosoma brucei brucei. All the compounds, except for a furanequinone (EC50=38 µM), proved to be similarly or even more potent (EC50 = 0.5-5.5 µM) than the clinical drug nifurtimox (EC50 = 5.3 µM). Three furanequinones and one thiazolequinone displayed a higher selectivity than nifurtimox. Two of these selective hits resulted potent inhibitors of T. cruzi proliferation (EC50=0.8-1.1 µM) but proved inactive against Leishmania infantum amastigotes. Most of the p-quinones induced a rapid and marked intracellular oxidation in T. b. brucei. DFT calculations on the oxidized quinone (Q), semiquinone (Q•-) and hydroquinone (QH2) 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. Charge distribution over the quinone ring carbons of Q and Q.- and the frontier orbitals energies of SUMO (Q.-) and LUMO (Q) correlate with their oxidative and trypanocidal activity. 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.

The Potential of Secondary Metabolites from Plants as Drugs or Leads against Trypanosoma cruzi-An Update from 2012 to 2021.

BACKGROUND: Chagas disease (American Trypanosomiasis) is classified by the World Health Organization (WHO) as one of the seventeen neglected tropical diseases (NTD), affecting, mainly, several regions of Latin America. INTRODUCTION: However, immigration has expanded the range of this disease to other continents. Thousands of patients with Chagas disease die annually, yet no new therapeutics for Chagas disease have been approved, with only nifurtimox and benznidazole available. Treatment with these drugs presents several challenges, including protozoan resistance, toxicity, and low efficacy. Natural products, including the secondary metabolites found in plants, offer a myriad of complex structures that can be sourced directly or optimized for drug discovery. METHODS: Therefore, this review aims to assess the literature from the last 10 years (2012-2021) and present the anti-T. cruzi compounds isolated from plants in this period, as well as briefly discuss computational approaches and challenges in natural product drug discovery. Using this approach, more than 350 different metabolites were divided based on their biosynthetic pathway alkaloids, terpenoids, flavonoids, polyketides, and phenylpropanoids which displayed activity against different forms of this parasite epimastigote, trypomastigote and more important, the intracellular form, amastigote. CONCLUSION: In this aspect, there are several compounds with high potential which could be considered as a scaffold for the development of new drugs for the treatment of Chagas disease-for this, more advanced studies must be performed including pharmacokinetics (PK) and pharmacodynamics (PD) analysis as well as conduction of in vivo assays, these being important limitations in the discovery of new anti-T. cruzi compounds.

B-Cell Responses in Chronic Chagas Disease: Waning of Trypanosoma cruzi-Specific Antibody-Secreting Cells Following Successful Etiological Treatment.

BACKGROUND: A drawback in the treatment of chronic Chagas disease (American trypanosomiasis) is the long time required to achieve complete loss of serological reactivity, the standard for determining treatment efficacy. METHODS: Antibody-secreting cells and memory B cells specific for Trypanosoma cruzi and their degree of differentiation were evaluated in adult and pediatric study participants with chronic Chagas disease before and after etiological treatment. RESULTS: T. cruzi-specific antibody-secreting cells disappeared from the circulation in benznidazole or nifurtimox-treated participants with declining parasite-specific antibody levels after treatment, whereas B cells in most participants with unaltered antibody levels were low before treatment and did not change after treatment. The timing of the decay in parasite-specific antibody-secreting B cells was similar to that in parasite-specific antibodies, as measured by a Luminex-based assay, but preceded the decay in antibody levels detected by conventional serology. The phenotype of total B cells returned to a noninfection profile after successful treatment. CONCLUSIONS: T. cruzi-specific antibodies in the circulation of chronically T. cruzi-infected study participants likely derive from both antigen-driven plasmablasts, which disappear after successful treatment, and long-lived plasma cells, which persist and account for the low frequency and long course to complete seronegative conversion in successfully treated participants.

Long-term cardiology outcomes in children after early treatment for Chagas disease, an observational study.

BACKGROUND: Parasite persistence after acute infection with Trypanosoma cruzi is an important factor in the development of Chagas disease (CD) cardiomyopathy. Few studies have investigated the clinical effectiveness of CD treatment through the evaluation of cardiological events by long term follow-up of treated children. Cardiological evaluation in children is challenging since features that would be diagnosed as abnormal in an adult's ECG may be normal, age-related findings in a pediatric ECG trace. The objective was to evaluate cardiac involvement in patients with Chagas disease with a minimum follow-up of 6 years post-treatment. METHODOLOGY: A descriptive study of a cohort of pediatric patients with CD treated with benznidazole (Bz) or nifurtimox (Nf) was conducted. Children (N = 234) with at least 6 years post CD treatment followed at the Parasitology and Chagas Service, Buenos Aires Children's Hospital (Argentina) were enrolled. By convenience sampling, children who attended a clinical visit between August 2015 and November 2019 were also invited to participate for additional cardiovascular studies like 24-hour Holter monitoring and speckle-tracking 2D echocardiogram (STE). Benznidazole was prescribed in 171 patients and nifurtimox in 63 patients. Baseline parasitemia data was available for 168/234 patients. During the follow-up period, alterations in routine ECG were observed in 11/234 (4.7%, 95% CI [2-7.4%]) patients. In only four patients, with complete right bundle branch block (cRBBB) and left anterior fascicular block (LAFB), ECG alterations were considered probably related to CD. During follow-up, 129/130 (99%) treated patients achieved persistent negative parasitemia by qPCR. Also decrease in T.cruzi antibodies titers was observed in all patients and negative seroconversion occurred in 123/234 (52%) patients. CONCLUSIONS: A low incidence of cardiological lesions related to CD was observed in patients treated early for pediatric CD. This suggests a protective effect of parasiticidal treatment on the development of cardiological lesions and highlights the importance of early treatment of infected children. TRIAL REGISTRATION: ClinicalTrials.gov NCT04090489.

Disruption of multiple copies of the Prostaglandin F2alpha synthase gene affects oxidative stress response and infectivity in Trypanosoma cruzi.

Chagas disease, caused by the protozoan Trypanosoma cruzi, is a serious chronic parasitic disease, currently treated with Nifurtimox (NFX) and Benznidazole (BZ). In addition to high toxicity, these drugs have low healing efficacy, especially in the chronic phase of the disease. The existence of drug-resistant T. cruzi strains and the occurrence of cross-resistance between BZ and NFX have also been described. In this context, it is urgent to study the metabolism of these drugs in T. cruzi, to better understand the mechanisms of resistance. Prostaglandin F2α synthase (PGFS) is an enzyme that has been correlated with parasite resistance to BZ, but the mechanism by which resistance occurs is still unclear. Our results show that the genome of the CL Brener clone of T. cruzi, contains five PGFS sequences and three potential pseudogenes. Using CRISPR/Cas9 we generated knockout cell lines in which all PGFS sequences were disrupted, as shown by PCR and western blotting analyses. The PGFS deletion did not alter the growth of the parasites or their susceptibility to BZ and NFX when compared to wild-type (WT) parasites. 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.

Trypanosoma cruzi nitroreductase: Structural features and interaction with biological membranes.

Due to its severe burden and geographic distribution, Chagas disease (CD) has a significant social and economic impact on low-income countries. Benznidazole and nifurtimox are currently the only drugs available for CD. These are prodrugs activated by reducing the nitro group, a reaction catalyzed by nitroreductase type I enzyme from Trypanosoma cruzi (TcNTR), with no homolog in the human host. The three-dimensional structure of TcNTR, and the molecular and chemical bases of the selective activation of nitro drugs, are still unknown. To understand the role of TcNTR in the basic parasite biology, investigate its potential as a drug target, and contribute to the fight against neglected tropical diseases, a combined approach using multiple biophysical and biochemical methods together with in silico studies was employed in the characterization of TcNTR. 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.

Nifurtimox for Treatment of Chagas Disease in Pediatric Patients: the Challenges of Applying Pharmacokinetic-Pharmacodynamic Principles to Dose Finding.

The antiparasitic drug nifurtimox was approved in the USA in 2020 for the treatment of patients with Chagas disease aged less than 18 years and weighing at least 2.5 kg, based on outcomes from the phase 3 CHICO study. Accordingly, pediatric patients with Chagas disease take nifurtimox thrice daily with food at one of two body weight-adjusted dose ranges. We investigated possible relationships between pharmacokinetic (PK) data, and pharmacodynamic efficacy and safety data collected in an analysis population of 111 participants in CHICO, using a published population PK model to estimate nifurtimox exposure at the patient level. Pediatric exposure to nifurtimox was benchmarked against levels of nifurtimox exposure known to be effective in adults with Chagas disease. Given the complex dosing regimen for nifurtimox, we also modeled nifurtimox exposure associated with simpler dosing strategies. We found no relationship between exposure to nifurtimox and efficacy measures (e.g., serological response to treatment), or between exposure and safety outcomes (including typical adverse events, e.g., headache, decreased appetite, nausea/vomiting). The analysis population appeared to represent the overall CHICO population based on the similarity of their baseline characteristics and the profiles of adverse events in the two groups. Modeled exposure based on the dosing regimen in CHICO was within the reference range derived from phase 1 data in adults. The relationship between nifurtimox exposure and cure is complex; a simplified pediatric dosing regimen is unlikely to be beneficial.

Pharmaceutical agents for the treatment of Chagas disease: patenting trends in the 2016-2021 period.

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. Patent literature reveals vital information on new trends in therapies for various diseases, including Chagas disease. The authors used the patent databases of the world's major patent offices to generate an overview of patent trends related to the treatment of Chagas disease. 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.

Effectiveness of Nifurtimox in the Treatment of Chagas Disease: a Long-Term Retrospective Cohort Study in Children and Adults.

Chagas disease (ChD), caused by Trypanosoma cruzi, has a global prevalence due to patient migration. However, despite its worldwide distribution, long-term follow-up efficacy studies with nifurtimox (NF) are scarce and have been conducted with only small numbers of patients. A retrospective study of a large cohort of ChD treated children and adults with NF. Treatment response was evaluated by clinical, parasitological, and serological after-treatment evaluation. A total of 289 patients were enrolled, of which 199 were children and 90 adults. At diagnosis, 89.6% of patients were asymptomatic. Overall, all symptomatic patients showed clinical improvement. At baseline, parasitemia was positive in 130 of 260 (50%) patients. All but one adult patient had cleared their parasitemia by the end of treatment. That patient was considered a treatment failure. Median follow-up time for children was 37.7 months, with an interquartile range of (IQR25-75 12.2 to 85.3), and for adults was 14.2 months (IQR25-75, 1.9 to 33.8). After treatment, a decrease of T. cruzi antibodies and seroconversion were observed in 34.6% of patients. The seroconversion profile showed that, the younger the patient, the higher the rate of seroconversion (log rank test; P value, <0.01). At least 20% seroreduction at 1 year follow-up was observed in 33.2% of patients. Nifurtimox was highly effective for ChD treatment. Patients had excellent treatment responses with fully resolved symptoms related to acute T. cruzi infection. Clearance of parasitemia and a decrease in T. cruzi antibodies were observed as markers of treatment response. This study reinforces the importance of treating patients during childhood since the treatment response was more marked in younger subjects. (This protocol was registered at ClinicalTrials.gov under registration number NCT04274101).

Population Pharmacokinetics of Nifurtimox in Adult and Pediatric Patients With Chagas Disease.

Nifurtimox (LAMPIT) has been used for decades for the treatment of Chagas disease, a chronic and potentially life-threatening disease caused by the parasite Trypanosoma cruzi. The pharmacokinetic (PK) information on nifurtimox in humans derived from controlled clinical studies is very limited. The objective was to investigate and compare the population PK of nifurtimox in adult and pediatric patients with Chagas disease to confirm the clinical dosing regimen in children, which was based on allometric approaches using the concept that a dose-equivalent exposure would reach equivalent antiparasitic efficacy as in adults. The resulting adult model adequately described the PK in adults. Significant predictors of the availability in PK were food intake, tablet formulation (fast- vs slow-dissolution tablet), study, and body weight. As the resulting adult model could not adequately predict the sparse sampled pediatric patient data, these data were analyzed separately to derive exposure estimates for comparison with adult exposure. In the population PK model for pediatric patients, significant covariates were body weight and age. As compared to adults, children aged >2 years were estimated to have 50.6% higher apparent clearance. 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 (8-20 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.

Characteristics and Adverse Events of Patients for Whom Nifurtimox Was Released Through CDC-Sponsored Investigational New Drug Program for Treatment of Chagas Disease - United States, 2001-2021.

Chagas disease, or American trypanosomiasis, is caused by the parasite Trypanosoma cruzi. Chagas disease is endemic in rural areas of Latin America, but T. cruzi, triatomine vectors, infected mammalian reservoir hosts, and rare cases of autochthonous vector borne transmission have been reported in the United States (1). Possible modes of transmission include the following: vector borne via skin or mucosal contact with feces of infected triatomine bugs, congenital, blood transfusion, organ transplantation, or laboratory accident. Chagas disease can be treated with benznidazole (commercially available since May 14, 2018) or nifurtimox (2). Before January 25, 2021, nifurtimox (Lampit) had been exclusively available through CDC under an Institutional Review Board-approved Investigational New Drug (IND) treatment protocol, at which time it became reasonably accessible to health care providers outside of the program. This report summarizes CDC Drug Service reports for selected characteristics of and adverse events reported by 336 patients for whom nifurtimox was requested under the CDC IND program during January 1, 2001-January 25, 2021. Of the 336 patients, 34.2% resided in California. Median age of patients was 37 years (range = 1-78 years). Most patients were aged ≥18 (91.8%; 305 of 332) and Hispanic (93.2%; 290 of 311). Among the patients with available information, 91.4% (222 of 243) reported an adverse event. Among those with information about the severity of their adverse events, 20.5% reported a severe event. On August 7, 2020, the Food and Drug Administration (FDA) announced approval of a nifurtimox product, Lampit (Bayer), for treatment of Chagas disease in patients aged <18 years weighing ≥5.5 lbs (≥2.5 kg). Lampit became commercially available during October 2020. Physicians should take frequency of adverse events into consideration when prescribing nifurtimox and counseling patients.

Population Pharmacodynamic Modeling of Eflornithine-Based Treatments Against Late-Stage Gambiense Human African Trypanosomiasis and Efficacy Predictions of L-eflornithine-Based Therapy.

Eflornithine is a recommended treatment against late-stage gambiense human African trypanosomiasis, a neglected tropical disease. Standard dosing of eflornithine consists of repeated intravenous infusions of a racemic mixture of L- and D-eflornithine. Data from three clinical studies, (i) eflornithine intravenous monotherapy, (ii) nifurtimox-eflornithine combination therapy, and (iii) eflornithine oral monotherapy, were pooled and analyzed using a time-to-event pharmacodynamic modeling approach, supported by in vitro activity data of the individual enantiomers. Our aim was to assess (i) the efficacy of the eflornithine regimens in a time-to-event analysis and (ii) the feasibility of an L-eflornithine-based therapy integrating clinical and preclinical data. A pharmacodynamic time-to-event model was used to estimate the total dose of eflornithine, associated with 50% reduction in baseline hazard, when administered as monotherapy or in the nifurtimox-eflornithine combination therapy. The estimated total doses were 159, 60 and 291 g for intravenous eflornithine monotherapy, nifurtimox-eflornithine combination therapy and oral eflornithine monotherapy, respectively. Simulations suggested that L-eflornithine achieves a higher predicted median survival, compared to when racemate is administered, as treatment against late-stage gambiense human African trypanosomiasis. Our findings showed that oral L-eflornithine-based monotherapy would not result in adequate efficacy, even at high dose, and warrants further investigations to assess the potential of oral L-eflornithine-based treatment in combination with other treatments such as nifurtimox. An all-oral eflornithine-based regimen would provide easier access to treatment and reduce burden on patients and healthcare systems in gambiense human African trypanosomiasis endemic areas. Graphical abstract.

Pediatric Chagas disease in the non-endemic area of Madrid: A fifteen-year review (2004-2018).

BACKGROUND: Chagas disease (CD) has become an emerging global health problem in association with the immigration of individuals from endemic areas (in LatinAmerica) to other countries.Spain is the country in Europe with the highest number of CD cases. Concerning pediatric CD, treatment is not only better tolerated by younger children but also has greater cure possibilities. The aim of this study was to describe clinical and epidemiological aspects of CD in a pediatric population diagnosed of 10 hospitals in the Community of Madrid during the 2004-2018 period, as well as the safety and efficacy of CD treatment on this population. METHODOLOGY/PRINCIPAL FINDINGS: A multicenter, retrospective, descriptive study was conducted. The studied population included all identified children under the age of 18 with a diagnosis of CD. Diagnosis was performed with a positive parasitological test (with subsequent confirmation) or confirmed persistence of positive serology beyond 9 months, for children younger than one year-old, and with two different positive serological tests, for children older than one. Fifty-one children were included (59% male; 50.9% born in Spain). All mothers were from Latin America. The median age at diagnosis was 0.7 months for those under one year of age, and 11.08 years for those older than one year-old. Only one case presented a symptomatic course (hydrops faetalis, haemodynamic instability at birth, ascites, anaemia). For 94% treatment was completed. Considering patients who received benznidazole (47), AE were recorded in 48,9%. Among the 32 patients older than one year-old treated with benznidazole, 18 (56.25%) had adverse events whereas in the 15 under one year, 5(33,3%) did. Eigtheen (78.2%) of the patients with benznidazole AE were older than one year-old(median age 11.4 years). Of the patients treated with nifurtimox (9), AE were reported in 3 cases (33,3%). Cure was confirmed in 80% of the children under one year-old vs 4.3% in those older (p<0.001). Loss to follow- up occurred in 35.3% of patients. CONCLUSIONS/SIGNIFICANCES: Screening programs of CD since birth allow early diagnosis and treatment, with a significantly higher cure rate in children treated before one year of age, with lower incidence of adverse events. The high proportion of patients lost to follow-up in this vulnerable population is of concern.