Asunto(s)
Enfermedad de Chagas , Nifurtimox , Tripanocidas , Humanos , Nifurtimox/uso terapéutico , Nifurtimox/efectos adversos , Nifurtimox/administración & dosificación , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/diagnóstico , Tripanocidas/uso terapéutico , Tripanocidas/efectos adversos , Trypanosoma cruzi/efectos de los fármacos , Animales , Resultado del TratamientoRESUMEN
Chagas disease is a chronic, systemic parasitic infection caused by the protozoan Trypanosoma cruzi. The primary mode of transmission to humans is by the Reduviid insect, endemic to South America. Recent migration of the vector has led to increased cases in the southern United States and has prompted increased surveillance and blood donation screening. It is unusual to diagnose and treat individuals with Chagas disease in the northern United States. This case describes an immigrant female from El Salvador that was informed she had Chagas disease from a blood bank screening. Confirmation and treatment of the disease were performed by her South Dakota primary care provider thus demonstrating the importance of identifying Chagas disease in the immigrant population in regions where Chagas disease infection is uncommon.
Asunto(s)
Enfermedad de Chagas , Humanos , Femenino , Enfermedad de Chagas/diagnóstico , Enfermedad de Chagas/epidemiología , Enfermedad de Chagas/terapia , Enfermedad de Chagas/tratamiento farmacológico , South Dakota , Tripanocidas/uso terapéutico , El Salvador , Adulto , Emigrantes e Inmigrantes , Nifurtimox/uso terapéuticoRESUMEN
Chagas disease (CD), caused by the flagellated protozoan Trypanosoma cruzi (T. cruzi), affects approximately 7 million people worldwide and is endemic in Latin America, especially among socioeconomically disadvantaged populations. Since the 1960s, only two drugs have been commercially available for treating this illness: nifurtimox (NFX) and benznidazole (BZN). Although these drugs are effective in the acute phase (AP) of the disease, in which parasitemia is usually high, their cure rates in the chronic phase (CP) are low and often associated with several side effects. The CP is characterized by a subpatent parasitaemia and absence of clinical symptoms in the great majority of infected individuals. However, at least 30 % of the individuals will develop potentially lethal symptomatic forms, including cardiac and digestive manifestations. For such reason, in the CP the treatment is usually symptomatic and typically focuses on managing complications such as arrhythmias, heart failure, or digestive problems. Therefore, the need for new drugs or therapeutic approaches using BZN or NFX is extremely urgent. This review presents the main clinical trials, especially in the CP, which involve BZN and NFX in different treatment regimens. Additionally, other therapies using combinations of these drugs with other substances such as allopurinol, itraconazole, ravuconazole, ketoconazole, posaconazole and amiodarone are also reported. The importance of early diagnosis, especially in pediatric patients, is also discussed, emphasizing the need to identify the disease in its early stages to improve the chances of successful treatment.
Asunto(s)
Enfermedad de Chagas , Nifurtimox , Nitroimidazoles , Tripanocidas , Trypanosoma cruzi , Enfermedad de Chagas/tratamiento farmacológico , Humanos , Nitroimidazoles/uso terapéutico , Trypanosoma cruzi/efectos de los fármacos , Tripanocidas/uso terapéutico , Nifurtimox/uso terapéutico , Enfermedad CrónicaRESUMEN
Considering the health relevance of Chagas' disease, recent research efforts have focused on developing more efficient drug delivery systems containing nifurtimox (NFX). This paper comprehensively investigates NFX through conformational analysis and spectroscopic characterization. Using a conformer-rotamer ensemble sampling tool (CREST-xtb), five distinct conformers of NFX were sampled within a 3.0 kcal mol-1 relative energy window. Subsequently, such structures were used as inputs for geometry optimization by density functional theory (DFT) at B3LYP-def2-TZVP level of theory. Notably, harmonic vibrational frequencies were calculated to establish an in-depth comparison with experimental results and existing literature for the NFX or similar molecules and functional groups, thereby achieving a widely reasoned assignment of the mid-infrared band absorptions for the first time. Moreover, UV-VIS spectra of NFX were obtained in several solvents, enabling the determination of the molar absorptivity coefficient for the two electronic transitions observed for NFX. Among the aprotic solvents, a bathochromic effect was observed in the function of the dielectric constants. Furthermore, a hypochromic effect was observed when the drug was dissolved in protic solvents. These findings offer crucial support for new drug delivery systems containing NFX while demonstrating the potential of spectrophotometric studies in establishing quality control assays for NFX drug products.
Asunto(s)
Enfermedad de Chagas , Conformación Molecular , Nifurtimox , Enfermedad de Chagas/tratamiento farmacológico , Nifurtimox/química , Espectrofotometría Ultravioleta , Tripanocidas/química , Modelos Moleculares , Teoría Funcional de la Densidad , Trypanosoma cruzi/efectos de los fármacos , Solventes/químicaRESUMEN
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.
Asunto(s)
Enfermedad de Chagas , Nitroimidazoles , Tripanocidas , Trypanosoma cruzi , Lactante , Niño , Recién Nacido , Humanos , Femenino , Masculino , Estudios Retrospectivos , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/prevención & control , Nifurtimox/uso terapéutico , Nitroimidazoles/uso terapéutico , Tripanocidas/uso terapéuticoRESUMEN
BACKGROUND: More than six million people worldwide, particularly in vulnerable communities in Latin America, are infected with Trypanosoma cruzi, the causative agent of Chagas disease. Only a small portion have access to diagnosis and treatment. Both drugs used to treat this chronic, neglected infection, benznidazole and nifurtimox, were developed more than 50 years ago, and adverse drug reactions during treatment pose a major barrier, causing 20% of patients to discontinue therapy. Fexinidazole proved efficacious in an earlier, interrupted clinical trial, but the doses evaluated were not well tolerated. The present study evaluated fexinidazole at lower doses and for shorter treatment durations. METHODS: In this randomised, double-blind, phase 2 trial, we included adult patients (18-60 years old) with confirmed T cruzi infection by serology and PCR and without signs of organ involvement. We evaluated three regimens of fexinidazole-600 mg once daily for 10 days (6·0 g total dose), 1200 mg daily for 3 days (3·6 g), and 600 mg daily for 3 days followed by 1200 mg daily for 4 days (6·6 g)-and compared them with a historical placebo control group (n=47). The primary endpoint was sustained negative results by PCR at end of treatment and on each visit up to four months of follow-up. This study is registered with ClinicalTrials.gov, NCT03587766, and EudraCT, 2016-004905-15. FINDINGS: Between Oct 16, 2017, and Aug 7, 2018, we enrolled 45 patients (n=15 for each group), of whom 43 completed the study. Eight (19%) of 43 fexinidazole-treated patients reached the primary endpoint, compared with six (13%) of 46 in the historical control group. Mean parasite load decreased sharply following treatment but rebounded beginning 10 weeks after treatment. Five participants had seven grade 3 adverse events: carpal tunnel, sciatica, device infection, pneumonia, staphylococcal infection, and joint and device dislocation. Two participants discontinued treatment due to adverse events unrelated to fexinidazole. INTERPRETATION: The fexinidazole regimens in this study had an acceptable safety profile but did not prove effective against T cruzi infection. Development of fexinidazole monotherapy for treating T cruzi infection has been stopped. FUNDING: The Drugs for Neglected Diseases initiative.
Asunto(s)
Enfermedad de Chagas , Nitroimidazoles , Trypanosoma cruzi , Adulto , Humanos , Adolescente , Adulto Joven , Persona de Mediana Edad , Resultado del Tratamiento , Enfermedad de Chagas/tratamiento farmacológico , Nifurtimox/efectos adversos , Método Doble CiegoRESUMEN
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.
Asunto(s)
Nifurtimox , Nitrofuranos , Nifurtimox/metabolismo , Nifurtimox/uso terapéutico , Cristalización , Dióxido de Nitrógeno , Preparaciones FarmacéuticasRESUMEN
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.
Asunto(s)
Enfermedad de Chagas , Nanocápsulas , Nitroimidazoles , Tripanocidas , Trypanosoma cruzi , Animales , Ratones , Nifurtimox/uso terapéutico , Nitroimidazoles/farmacología , Nitroimidazoles/uso terapéutico , Enfermedad de Chagas/tratamiento farmacológico , Poliésteres/farmacología , Poliésteres/uso terapéutico , Tripanocidas/farmacología , Tripanocidas/uso terapéuticoRESUMEN
BACKGROUND: Nifurtimox is an effective treatment for patients with Chagas disease, but knowledge of its biotransformation and excretion is limited. OBJECTIVE: This study aimed to better understand the fate of oral nifurtimox in vivo. METHODS: We investigated the exposure and excretion pathways of [14C]-labeled nifurtimox and its metabolites in rats. We then quantified the prominent metabolites and nifurtimox in the urine and plasma of patients receiving nifurtimox using LC-HRMS with reference standards and quantified these compounds in rat plasma after a single, high dose of nifurtimox. We also investigated potential drug-drug interactions (DDIs) of these compounds in vitro. RESULTS: In rats, orally administered nifurtimox was rapidly absorbed (tmax 0.5 h) and eliminated (t½ 1.4 h). Metabolism of nifurtimox yielded six predominant metabolites (M-1 to M-6) in urine and plasma, and the dose was excreted equally via the renal and fecal routes with only traces of unchanged nifurtimox detectable due to its instability in excreta. In patients with Chagas disease, only M-6 and M-4 achieved relevant exposure levels, and the total amount of excreted metabolites in urine was higher in fed versus fasted patients, consistent with the higher systemic exposure. For nifurtimox, M-6, and M-4, no potential perpetrator pharmacokinetic DDIs with the main cytochrome P- 450 enzymes and drug transporters were identified in vitro. CONCLUSION: This contemporary analysis of the complex metabolite profile and associated exposures emerging after oral dosing of nifurtimox in rats and humans, together with the expected low risk for clinically relevant DDIs, expands the understanding of this important anti-trypanosomal drug.
Asunto(s)
Enfermedad de Chagas , Nifurtimox , Humanos , Ratas , Animales , Interacciones Farmacológicas , Biotransformación , Sistema Enzimático del Citocromo P-450 , Enfermedad de Chagas/tratamiento farmacológico , Administración OralRESUMEN
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.
Asunto(s)
Enfermedad de Chagas , Tripanocidas , Humanos , Niño , Nifurtimox/uso terapéutico , Tripanocidas/uso terapéutico , Ensayo de Inmunoadsorción Enzimática , Enfermedad de Chagas/diagnóstico , Enfermedad de Chagas/tratamiento farmacológico , Anticuerpos Antiprotozoarios , BiomarcadoresRESUMEN
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.
Asunto(s)
Neoplasias Cerebelosas , Meduloblastoma , Neuroblastoma , Niño , Humanos , Topotecan/efectos adversos , Nifurtimox/uso terapéutico , Meduloblastoma/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/etiología , Ciclofosfamida , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
Nifurtimox is recommended for the treatment of Chagas disease; however, long-term follow-up data are scarce. This prolonged follow-up phase of the prospective, historically controlled, CHICO clinical trial evaluated seronegative conversion in pediatric patients aged <18 years with Chagas disease who were followed for 4 years after nifurtimox treatment. Patients were randomly assigned 2:1 to nifurtimox 60-day or 30-day regimens comprising 10 to 20 mg/kg/day for patients aged <12 years and body weight <40 kg, and 8 to 10 mg/kg/day for those aged ≥12 years and body weight ≥40 kg. Anti-Trypanosoma cruzi antibodies decreased during the study period, achieving seronegative conversion in 16 (8.12%) and 8 (8.16%) patients in the 60-day and 30-day nifurtimox regimens, respectively, with corresponding incidence rates per 100 patients/year of seronegative conversion of 2.12 (95% confidence interval [CI]: 1.21 to 3.45) and 2.11 (95% CI: 0.91 to 4.16). Superiority of the 60-day nifurtimox regimen was confirmed by the lower limit of the 95% CI being higher than that (0%) in a historical placebo control group. Children aged <2 years at baseline were more likely to reach seronegative conversion during the 4-year follow-up than older children. At any annual follow-up visit, >90% of evaluable patients had persistently negative quantitative PCR results for T. cruzi DNA. No adverse events potentially related to treatment or caused by protocol-required procedures were documented for either treatment regimen. This study confirms the effectiveness and safety of a pediatric formulation of nifurtimox administered in an age- and weight-adjusted regimen for 60 days to treat children with Chagas disease.
Asunto(s)
Enfermedad de Chagas , Nitroimidazoles , Tripanocidas , Humanos , Niño , Adolescente , Nifurtimox/efectos adversos , Tripanocidas/efectos adversos , Estudios de Seguimiento , Estudios Prospectivos , Estudio Históricamente Controlado , Resultado del Tratamiento , Enfermedad de Chagas/tratamiento farmacológico , Peso Corporal , Nitroimidazoles/efectos adversosRESUMEN
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.
Asunto(s)
Enfermedad de Chagas , Emigrantes e Inmigrantes , Trasplante de Órganos , Trypanosoma cruzi , Humanos , Estados Unidos , Enfermedad de Chagas/diagnóstico , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/epidemiología , Nifurtimox/uso terapéuticoRESUMEN
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.
Asunto(s)
Enfermedad de Chagas , Farmacia , Humanos , Nifurtimox/química , Nifurtimox/farmacología , Nifurtimox/uso terapéutico , Enfermedad de Chagas/tratamiento farmacológico , Preparaciones FarmacéuticasRESUMEN
Nifurtimox (NFX) is a nitrofuran derivative used to treat Chagas disease, a neglected disease caused by the protozoan Trypanosoma cruzi. The drug is very sparingly soluble in aqueous media and no other solid phases of NFX have been reported to date. The preparation of the amorphous mode of NFX is reported, as well as its characterization by hot stage microscopy, thermal (differential scanning calorimetry and thermogravimetric analysis), spectroscopic (solid state nuclear magnetic resonance, mid-infrared, and near-infrared), diffractometric and functional (powder dissolution rate) means. The stability of the new phase was investigated. This was characterized using thermal, spectroscopic, and diffractometric methods, finding out its spontaneous reversion to the crystalline state, as sign of instability. In addition, the amorphous material proved to be sensitive to temperature, pressure, and mechanical stress, all of which accelerated phase conversion. However, it was able to remain stable in a model polymeric amorphous solid dispersion with PEG 4000 for more than one month. An approach for monitoring the conversion of the amorphous phase to its crystalline counterpart under thermal stress by chemometric analysis of mid-infrared spectra at different temperatures is also disclosed.
Asunto(s)
Nifurtimox , Estabilidad de Medicamentos , Cristalización , Rastreo Diferencial de Calorimetría , Temperatura , Solubilidad , Difracción de Rayos X , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
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.
Asunto(s)
Enfermedad de Chagas , Nitroimidazoles , Tripanocidas , Trypanosoma cruzi , Humanos , Trypanosoma cruzi/genética , Enfermedad de Chagas/tratamiento farmacológico , Nitroimidazoles/uso terapéutico , Resultado del Tratamiento , Linfocitos B , Nifurtimox/uso terapéutico , Infección Persistente , Tripanocidas/uso terapéutico , Enfermedad CrónicaRESUMEN
BACKGROUND: Human African trypanosomiasis caused by Trypanosoma brucei gambiense (gambiense HAT) in patients with late-stage disease requires hospital admission to receive nifurtimox-eflornithine combination therapy (NECT). Fexinidazole, the latest treatment that has been recommended by WHO, also requires systematic admission to hospital, which is problematic in areas with few health-care resources. We aim to assess the safety and efficacy of acoziborole in adult and adolescent patients with gambiense HAT. METHODS: This multicentre, prospective, open-label, single-arm, phase 2/3 study recruited patients aged 15 years or older with confirmed gambiense HAT infection from ten hospitals in the Democratic Republic of the Congo and Guinea. Inclusion criteria included a Karnofsky score greater than 50, ability to swallow tablets, a permanent address or traceability, ability to comply with follow-up visits and study requirements, and agreement to hospital admission during treatment. Oral acoziborole was administered as a single 960 mg dose (3 × 320 mg tablets) to fasted patients. Patients were observed in hospital until day 15 after treatment administration then for 18 months as outpatients with visits at 3, 6, 12, and 18 months. The primary efficacy endpoint was the success rate of acoziborole treatment at 18 months in patients with late-stage gambiense HAT (modified intention-to-treat [mITT] population), based on modified WHO criteria. A complementary post-hoc analysis comparing the 18-month success rates for acoziborole and NECT (using historical data) was performed. This study is registered at ClinicalTrials.gov, NCT03087955. FINDINGS: Between Oct 11, 2016, and March 25, 2019, 260 patients were screened, of whom 52 were ineligible and 208 were enrolled (167 with late-stage and 41 with early-stage or intermediate-stage gambiense HAT; primary efficacy analysis set). All 41 (100%) patients with early-stage or intermediate-stage and 160 (96%) of 167 with late-stage disease completed the last 18-month follow-up visit. The mean age of participants was 34·0 years (SD 12·4), including 117 (56%) men and 91 (44%) women. Treatment success rate at 18 months was 95·2% (95% CI 91·2-97·7) reached in 159 of 167 patients with late-stage gambiense HAT (mITT population) and 98·1% (95·1-99·5) reached in 159 of 162 patients (evaluable population). Overall, 155 (75%) of 208 patients had 600 treatment-emergent adverse events. A total of 38 drug-related treatment-emergent adverse events occurred in 29 (14%) patients; all were mild or moderate and most common were pyrexia and asthenia. Four deaths occurred during the study; none were considered treatment related. The post-hoc analysis showed similar results to the estimated historical success rate for NECT of 94%. INTERPRETATION: Given the high efficacy and favourable safety profile, acoziborole holds promise in the efforts to reach the WHO goal of interrupting HAT transmission by 2030. FUNDING: Bill & Melinda Gates Foundation, UK Aid, Federal Ministry of Education and Research, Swiss Agency for Development and Cooperation, Médecins Sans Frontières, Dutch Ministry of Foreign Affairs, Norwegian Agency for Development Cooperation, Norwegian Ministry of Foreign Affairs, the Stavros Niarchos Foundation, Spanish Agency for International Development Cooperation, and the Banco Bilbao Vizcaya Argentaria Foundation. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.
Asunto(s)
Antiprotozoarios , Tripanosomiasis Africana , Adolescente , Adulto , Animales , Femenino , Humanos , Masculino , Antiprotozoarios/uso terapéutico , Quimioterapia Combinada , Eflornitina/efectos adversos , Nifurtimox/efectos adversos , Estudios Prospectivos , Trypanosoma brucei gambiense , Tripanosomiasis Africana/tratamiento farmacológicoRESUMEN
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.
Asunto(s)
Enfermedad de Chagas , Tripanocidas , Trypanosoma cruzi , Humanos , Tripanocidas/química , Enfermedad de Chagas/tratamiento farmacológico , Nifurtimox/farmacología , Nifurtimox/uso terapéutico , Descubrimiento de DrogasRESUMEN
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 (Qâ¢-) and hydroquinone (QH2) suggest that all quinones have negative ΔG for the formation of Qâ¢-. 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.
Asunto(s)
Enfermedad de Chagas , Tripanocidas , Trypanosoma cruzi , Humanos , Nifurtimox/uso terapéutico , Quinonas/farmacología , Enfermedad de Chagas/tratamiento farmacológico , Oxidación-Reducción , Simulación por Computador , Tripanocidas/farmacología , Tripanocidas/uso terapéuticoRESUMEN
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.