RESUMO
Introduction: Chagas disease, caused by the Trypanosoma cruzi parasite infection, is a potentially life-threatening neglected tropical disease with a worldwide distribution. During the chronic phase of the disease, there exists a fragile balance between the host immune response and parasite replication that keeps patients in a clinically-silent asymptomatic stage for years or even decades. However, in 40% of patients, the disease progresses to clinical manifestations mainly affecting and compromising the cardiac system. Treatment is recommended in the chronic phase, although there are no early markers of its effectiveness. The aim of this study is to identify differential expression changes in genes involved in the immune response in antigen-restimulated PBMC from chronic patients with Chagas disease due to benznidazole treatment. Methods: Thus, high-throughput real-time qPCR analysis has been performed to simultaneously determine global changes in the expression of 106 genes involved in the immune response in asymptomatic (IND) and early cardiac manifestations (CCC I) Chagas disease patients pre- and post-treatment with benznidazole. Results and discussion: The results revealed that 7 out of the 106 analyzed genes were differentially expressed (4 up- and 3 downregulated) after treatment in IND patients and 15 out of 106 (3 up- and 12 downregulated) after treatment of early cardiac Chagas disease patients. Particularly in CCC I patients, regulation of the expression level of some of these genes towards a level similar to that of healthy subjects suggests a beneficial effect of treatment and supports recommendation of benznidazole administration to early cardiac Chagas disease patients. The data obtained also demonstrated that both in asymptomatic patients and in early cardiac chronic patients, after treatment with benznidazole there is a negative regulation of the proinflammatory and cytotoxic responses triggered as a consequence of T. cruzi infection and the persistence of the parasite. This downregulation of the immune response likely prevents marked tissue damage and healing in early cardiac patients, suggesting its positive effect in controlling the pathology.
Assuntos
Doença de Chagas , Nitroimidazóis , Trypanosoma cruzi , Humanos , Nitroimidazóis/uso terapêutico , Doença de Chagas/tratamento farmacológico , Doença de Chagas/imunologia , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/genética , Adulto , Masculino , Feminino , Pessoa de Meia-Idade , Tripanossomicidas/uso terapêutico , Tripanossomicidas/farmacologia , Leucócitos Mononucleares/imunologia , Doença Crônica , Perfilação da Expressão Gênica , Voluntários Saudáveis , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Objective: To explore the characteristics of adverse drug reactions during the 24-week therapy with delamanid-containing regimen for patients with multidrug-resistant and rifampicin-resistant pulmonary tuberculosis (MDR/RR-PTB). Methods: The prospective multicenter study was conducted from June 2020 to June 2023. A total of 608 eligible patients with MDR/RR-PTB were enrolled in 26 tuberculosis medical institutions in China including 364 males and 79 females, aged 39.6(19.0-68.0) years. Patients were treated with chemotherapy regimens containing delamanid. Patients were closely supervised during treatment of medication, and all adverse reactions occurring during treatment were monitored and recorded. The clinical characteristics of adverse reactions were evaluated by descriptive analysis. Chi-square test and multivariate logistic regression were used to analyze the related factors of QTcF interval prolongation (QT corrected with Fridericia's formula). Results: Of the 608 patients enrolled in this study, 325 patients (53.5%) reported 710 adverse events within 24 weeks of treatment. The top 6 most common complications were hematological abnormalities (143 patients, 23.5%), QT prolongation (114 patients, 18.8%), liver toxicity (85 patients, 14.0%), gastrointestinal reaction (41 patients, 6.7%), peripheral neuropathy (25 patients, 4.1%) and mental disorders (21 patients, 3.5%). The prolongation of QT interval mostly occurred in the 12th week after the first dose of medication. Serious adverse reactions occurred in 21 patients (3.5%). There were 7 patients (1.2%) with mental disorders, including 2 patients (0.3%) with severe mental disorders. Conclusions: The safety of dalamanid-based regimen in the staged treatment of MDR/RR-PTB patients was generally good, and the incidence of adverse reactions was similar to that reported in foreign studies. This study found that the incidence of QT interval prolongation in Chinese patients was higher than that reported overseas, suggesting that the monitoring of electrocardiogram should be strengthened when using drugs containing delamanid that may cause QT interval prolongation.
Assuntos
Antituberculosos , Nitroimidazóis , Oxazóis , Rifampina , Tuberculose Resistente a Múltiplos Medicamentos , Tuberculose Pulmonar , Humanos , Masculino , Feminino , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Adulto , Estudos Prospectivos , Rifampina/efeitos adversos , Pessoa de Meia-Idade , Oxazóis/efeitos adversos , Oxazóis/uso terapêutico , Oxazóis/administração & dosagem , Antituberculosos/efeitos adversos , Tuberculose Pulmonar/tratamento farmacológico , Nitroimidazóis/efeitos adversos , Nitroimidazóis/uso terapêutico , Nitroimidazóis/administração & dosagem , Idoso , China , Adulto Jovem , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologiaRESUMO
Rising cases of drug resistance of mycobacterium species are one of the biggest concerns when the goal is to eradicate TB (Tuberculosis) from the world by the year 2030. A limited number of treatment options as MTB (Mycobacterium tuberculosis) is getting resistant to anti-mycobacterial drugs either due to a patient's non-compliance towards treatment regimen or if a patient is infected by drug-resistant species of MTB. This review aims to assess the effectiveness of pretomanid, a recently approved drug for the treatment of extensively drug-resistant TB. A thorough search of databases like PubMed, Cochrane library, CDC, Research Gate, and Google scholar was used in order to find case reports and clinical trials providing data on the efficacy of pretomanid in different drug regimens. According to research trials conducted, the drug appears to be efficacious, safe, and well-tolerable. Only headache was the most frequently observed adverse drug event, and a high dose-related increase in serum creatinine level was seen, which came to normal after the drug was discontinued.
Assuntos
Antituberculosos , Tuberculose Extensivamente Resistente a Medicamentos , Humanos , Antituberculosos/uso terapêutico , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Nitroimidazóis/uso terapêutico , Resultado do Tratamento , Mycobacterium tuberculosis/efeitos dos fármacosRESUMO
The treatment of multidrug-resistant tracheobronchial tuberculosis poses challenges, and research investigating the efficacy of bedaquiline or delamanid as treatment for this condition is limited. This retrospective cohort study was conducted from 2017 to 2021. The study extracted data of patients with multidrug-resistant tracheobronchial tuberculosis from medical records and followed up on prognoses. Participants were divided into three groups: the bedaquiline, delamanid, and control group. Clinical outcomes and the risk factors associated with early culture conversion were analyzed. This study included 101 patients, with 32, 25, and 44 patients in the bedaquiline, delamanid, and control groups respectively. The differences in the treatment success rates among the three groups did not show statistical significance. Both the bedaquiline and delamanid groups had significantly higher culture conversion rates compared to the control after 2 or 6 months of treatment, with significantly shorter median times to culture conversion (bedaquiline group: 2 weeks, delamanid group: 2 weeks, control group: 12 weeks, P < 0.001). Treatment with bedaquiline or delamanid were identified as independent predictors of culture conversion at 2 months (bedaquiline group: aOR = 13.417, 95% CI 4.067-44.260, delamanid group: aOR = 9.333, 95% CI 2.498-34.878) or 6 months (bedaquiline group: aOR = 13.333, 95% CI 3.379-52.610, delamanid group: aOR = 5.000, 95% CI 1.357-18.426) of treatment through multivariable logistic regression analyses. The delamanid group showed better improvement in lumen stenosis compared to bedaquiline. Regimens containing bedaquiline or delamanid may accelerate the culture conversion during the early treatment phase in multidrug-resistant tracheobronchial tuberculosis, and delamanid appears to have the potential to effectively improve airway stenosis.
Assuntos
Antituberculosos , Diarilquinolinas , Nitroimidazóis , Oxazóis , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Feminino , Masculino , Nitroimidazóis/uso terapêutico , Nitroimidazóis/administração & dosagem , Antituberculosos/uso terapêutico , Pessoa de Meia-Idade , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Estudos Retrospectivos , Oxazóis/uso terapêutico , Adulto , Diarilquinolinas/uso terapêutico , Resultado do Tratamento , IdosoRESUMO
BACKGROUND: Bedaquiline is one of the core drugs used to treat multidrug-resistant TB (MDR-TB). Delamanid is one of the companion drugs in group C which is used to complete the treatment regimen when drugs in groups A and B can not be used. This study was conducted to analyze the efficacy and safety between individual regimens containing bedaquiline with delamanid and bedaquiline without delamanid. METHODS: This was an observational analytic study with a retrospective design in MDR-TB patients treated with individual regimens containing bedaquiline with delamanid (bedaquiline-delamanid group) and bedaquiline without delamanid (bedaquiline group). Efficacy was measured according to the time to Acid Fast Bacilli (AFB) conversion and Mycobacterium tuberculosis culture conversion, while safety was measured specifically on QTc interval prolongation. RESULTS: The median (range) time to AFB conversion in bedaquiline-delamanid group was faster than bedaquiline group, although there was no significant difference (1.5 (1-4) months vs. 1 (1-6) months, P=0.429), the median time to culture conversion in bedaquiline-delamanid group also faster than bedaquiline group, although there was no significant difference (1 (1-6) months vs. 2 (1-6) months, P=0.089). The incidence of QTc interval prolongation in bedaquiline-delamanid group was less than bedaquiline group, although there was no significant difference (26.9% vs. 40.3%, P=0.223). CONCLUSIONS: Individual regimens containing bedaquiline with delamanid was proven to provide similar efficacy and safety profiles with individual regimens containing bedaquiline without delamanid. Delamanid should be preferred when selecting drugs to complete the treatment regimen when drugs in groups A and B can not be used.
Assuntos
Antituberculosos , Diarilquinolinas , Quimioterapia Combinada , Nitroimidazóis , Oxazóis , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Nitroimidazóis/uso terapêutico , Nitroimidazóis/efeitos adversos , Nitroimidazóis/administração & dosagem , Diarilquinolinas/uso terapêutico , Diarilquinolinas/administração & dosagem , Oxazóis/uso terapêutico , Oxazóis/administração & dosagem , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Antituberculosos/uso terapêutico , Antituberculosos/administração & dosagem , Antituberculosos/efeitos adversos , Estudos Retrospectivos , Feminino , Adulto , Masculino , Pessoa de Meia-Idade , Indonésia , Resultado do Tratamento , Adulto Jovem , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Adolescente , IdosoAssuntos
Antituberculosos , Diarilquinolinas , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Europa (Continente) , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Diarilquinolinas/uso terapêutico , Diarilquinolinas/farmacologia , Linezolida/farmacologia , Linezolida/uso terapêutico , Testes de Sensibilidade Microbiana , Fluoroquinolonas/farmacologia , Fluoroquinolonas/uso terapêutico , Rifampina/farmacologia , Rifampina/uso terapêutico , Moxifloxacina/uso terapêutico , Moxifloxacina/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Nitroimidazóis/uso terapêutico , Nitroimidazóis/farmacologia , OxazóisRESUMO
Chagasic chronic cardiomyopathy (CCC) is the primary clinical manifestation of Chagas disease (CD), caused by Trypanosoma cruzi. Current therapeutic options for CD are limited to benznidazole (Bz) and nifurtimox. Amiodarone (AMD) has emerged as most effective drug for treating the arrhythmic form of CCC. To address the effects of Bz and AMD we used a preclinical model of CCC. Female C57BL/6 mice were infected with T. cruzi and subjected to oral treatment for 30 consecutive days, either as monotherapy or in combination. AMD in monotherapy decreased the prolonged QTc interval, the incidence of atrioventricular conduction disorders and cardiac hypertrophy. However, AMD monotherapy did not impact parasitemia, parasite load, TNF concentration and production of reactive oxygen species (ROS) in cardiac tissue. Alike Bz therapy, the combination of Bz and AMD (Bz/AMD), improved cardiac electric abnormalities detected T. cruzi-infected mice such as decrease in heart rates, enlargement of PR and QTc intervals and increased incidence of atrioventricular block and sinus arrhythmia. Further, Bz/AMD therapy ameliorated the ventricular function and reduced parasite burden in the cardiac tissue and parasitemia to a degree comparable to Bz monotherapy. Importantly, Bz/AMD treatment efficiently reduced TNF concentration in the cardiac tissue and plasma and had beneficial effects on immunological abnormalities. Moreover, in the cardiac tissue Bz/AMD therapy reduced fibronectin and collagen deposition, mitochondrial damage and production of ROS, and improved sarcomeric and gap junction integrity. Our study underlines the potential of the Bz/AMD therapy, as we have shown that combination increased efficacy in the treatment of CCC.
Assuntos
Amiodarona , Cardiomiopatia Chagásica , Modelos Animais de Doenças , Quimioterapia Combinada , Camundongos Endogâmicos C57BL , Nitroimidazóis , Tripanossomicidas , Trypanosoma cruzi , Animais , Nitroimidazóis/farmacologia , Nitroimidazóis/administração & dosagem , Nitroimidazóis/uso terapêutico , Feminino , Trypanosoma cruzi/efeitos dos fármacos , Amiodarona/farmacologia , Amiodarona/administração & dosagem , Cardiomiopatia Chagásica/tratamento farmacológico , Cardiomiopatia Chagásica/parasitologia , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêutico , Camundongos , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Espécies Reativas de Oxigênio/metabolismo , Doença Crônica , Parasitemia/tratamento farmacológico , Parasitemia/parasitologia , Fator de Necrose Tumoral alfa/metabolismo , Carga ParasitáriaRESUMO
BACKGROUND: Delamanid (DLM) is a relatively new drug for drug-resistant tuberculosis (DR-TB) that has been used in Indonesia since 2019 despite its limited safety data. DLM is known to inhibit hERG potassium channel with the potential to cause QT prolongation which eventually leads to Torsades de pointes (TdP). OBJECTIVE: This study aims to analyse the changes of QTc interval in DR-TB patients on DLM regimen compared to shorter treatment regimens (STR). METHODS: A retrospective cohort was implemented on secondary data obtained from two participating hospitals. The QTc interval and the changes in QTc interval from baseline (ΔQTc) were assessed every 4 weeks for 24 weeks. RESULTS: The maximum increased of QTc interval and ΔQTc interval were smaller in the DLM group with mean difference of 18,6 (95%CI 0.3 to 37.5) and 31.6 milliseconds (95%CI 14.1 to 49.1) respectively. The proportion of QTc interval prolongation in DLM group were smaller than STR group (RR=0.62; 95%CI 0.42 to 0.93). CONCLUSION: This study has shown that DLM regimens are less likely to increase QTc interval compared to STR. However, close monitoring of the risk of QT interval prolongation needs to be carried out upon the use of QT interval prolonging antituberculoid drugs.
Assuntos
Antituberculosos , Eletrocardiografia , Síndrome do QT Longo , Nitroimidazóis , Oxazóis , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Estudos Retrospectivos , Masculino , Feminino , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Adulto , Antituberculosos/efeitos adversos , Antituberculosos/administração & dosagem , Antituberculosos/uso terapêutico , Síndrome do QT Longo/induzido quimicamente , Nitroimidazóis/efeitos adversos , Nitroimidazóis/uso terapêutico , Nitroimidazóis/administração & dosagem , Oxazóis/efeitos adversos , Oxazóis/uso terapêutico , Oxazóis/administração & dosagem , Pessoa de Meia-Idade , Indonésia , Torsades de Pointes/induzido quimicamenteRESUMO
Phenothiazines inhibit antioxidant enzymes in trypanosomatids. However, potential interferences with host cell antioxidant defenses are central concerns in using these drugs to treat Trypanosoma cruzi-induced infectious myocarditis. Thus, the interaction of thioridazine (TDZ) with T. cruzi and cardiomyocytes antioxidant enzymes, and its impact on cardiomyocytes and cardiac infection was investigated in vitro and in vivo. Cardiomyocytes and trypomastigotes in culture, and mice treated with TDZ and benznidazole (Bz, reference antiparasitic drug) were submitted to microstructural, biochemical and molecular analyses. TDZ was more cytotoxic and less selective against T. cruzi than Bz in vitro. TDZ-pretreated cardiomyocytes developed increased infection rate, reactive oxygen species (ROS) production, lipid and protein oxidation; similar catalase (CAT) and superoxide dismutase (SOD) activity, and reduced glutathione's (peroxidase - GPx, S-transferase - GST, and reductase - GR) activity than infected untreated cells. TDZ attenuated trypanothione reductase activity in T. cruzi, and protein antioxidant capacity in cardiomyocytes, making these cells more susceptible to H2O2-based oxidative challenge. In vivo, TDZ potentiated heart parasitism, total ROS production, myocarditis, lipid and protein oxidation; as well as reduced GPx, GR, and GST activities compared to untreated mice. Benznidazole decreased heart parasitism, total ROS production, heart inflammation, lipid and protein oxidation in T. cruzi-infected mice. Our findings indicate that TDZ simultaneously interact with enzymatic antioxidant targets in cardiomyocytes and T. cruzi, potentiating the infection by inducing antioxidant fragility and increasing cardiomyocytes and heart susceptibility to parasitism, inflammation and oxidative damage.
Assuntos
Antioxidantes , Cardiomiopatia Chagásica , Miócitos Cardíacos , Espécies Reativas de Oxigênio , Tioridazina , Trypanosoma cruzi , Animais , Miócitos Cardíacos/parasitologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Trypanosoma cruzi/efeitos dos fármacos , Camundongos , Antioxidantes/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Tioridazina/farmacologia , Cardiomiopatia Chagásica/tratamento farmacológico , Cardiomiopatia Chagásica/parasitologia , Cardiomiopatia Chagásica/metabolismo , Cardiomiopatia Chagásica/patologia , Miocardite/parasitologia , Miocardite/tratamento farmacológico , Miocardite/metabolismo , Miocardite/patologia , Nitroimidazóis/farmacologia , Nitroimidazóis/uso terapêutico , Masculino , Tripanossomicidas/farmacologia , Superóxido Dismutase/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Doença de Chagas/metabolismo , Doença de Chagas/patologia , Catalase/metabolismo , Ratos , NADH NADPH Oxirredutases/metabolismoRESUMO
Sputum culture reversion after conversion is an indicator of tuberculosis (TB) treatment failure. We analyze data from the endTB multi-country prospective observational cohort (NCT03259269) to estimate the frequency (primary endpoint) among individuals receiving a longer (18-to-20 month) regimen for multidrug- or rifampicin-resistant (MDR/RR) TB who experienced culture conversion. We also conduct Cox proportional hazard regression analyses to identify factors associated with reversion, including comorbidities, previous treatment, cavitary disease at conversion, low body mass index (BMI) at conversion, time to conversion, and number of likely-effective drugs. Of 1,286 patients, 54 (4.2%) experienced reversion, a median of 173 days (97-306) after conversion. Cavitary disease, BMI < 18.5, hepatitis C, prior treatment with second-line drugs, and longer time to initial culture conversion were positively associated with reversion. Reversion was uncommon. Those with cavitary disease, low BMI, hepatitis C, prior treatment with second-line drugs, and in whom culture conversion is delayed may benefit from close monitoring following conversion.
Assuntos
Antituberculosos , Diarilquinolinas , Nitroimidazóis , Oxazóis , Escarro , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Antituberculosos/uso terapêutico , Antituberculosos/farmacologia , Escarro/microbiologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Diarilquinolinas/uso terapêutico , Diarilquinolinas/farmacologia , Masculino , Feminino , Oxazóis/uso terapêutico , Adulto , Nitroimidazóis/uso terapêutico , Nitroimidazóis/farmacologia , Pessoa de Meia-Idade , Estudos Prospectivos , Mycobacterium tuberculosis/efeitos dos fármacos , Reposicionamento de MedicamentosRESUMO
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.
Assuntos
Doença de Chagas , Nifurtimox , Nitroimidazóis , Tripanossomicidas , Trypanosoma cruzi , Doença de Chagas/tratamento farmacológico , Humanos , Nitroimidazóis/uso terapêutico , Trypanosoma cruzi/efeitos dos fármacos , Tripanossomicidas/uso terapêutico , Nifurtimox/uso terapêutico , Doença CrônicaRESUMO
BACKGROUND: The current tuberculosis (TB) drug development pipeline is being re-populated with candidates, including nitroimidazoles such as pretomanid, that exhibit a potential to shorten TB therapy by exerting a bactericidal effect on non-replicating bacilli. Based on results from preclinical and early clinical studies, a four-drug combination of bedaquiline, pretomanid, moxifloxacin, and pyrazinamide (BPaMZ) regimen was identified with treatment-shortening potential for both drug-susceptible (DS) and drug-resistant (DR) TB. This trial aimed to determine the safety and efficacy of BPaMZ. We compared 4 months of BPaMZ to the standard 6 months of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE) in DS-TB. 6 months of BPaMZ was assessed in DR-TB. METHODS: SimpliciTB was a partially randomised, phase 2c, open-label, clinical trial, recruiting participants at 26 sites in eight countries. Participants aged 18 years or older with pulmonary TB who were sputum smear positive for acid-fast bacilli were eligible for enrolment. Participants with DS-TB had Mycobacterium tuberculosis with sensitivity to rifampicin and isoniazid. Participants with DR-TB had M tuberculosis with resistance to rifampicin, isoniazid, or both. Participants with DS-TB were randomly allocated in a 1:1 ratio, stratified by HIV status and cavitation on chest radiograph, using balanced block randomisation with a fixed block size of four. The primary efficacy endpoint was time to sputum culture-negative status by 8 weeks; the key secondary endpoint was unfavourable outcome at week 52. A non-inferiority margin of 12% was chosen for the key secondary outcome. Safety and tolerability outcomes are presented as descriptive analyses. The efficacy analysis population contained patients who received at least one dose of medication and who had efficacy data available and had no major protocol violations. The safety population contained patients who received at least one dose of medication. This study is registered with ClinicalTrials.gov (NCT03338621) and is completed. FINDINGS: Between July 30, 2018, and March 2, 2020, 455 participants were enrolled and received at least one dose of study treatment. 324 (71%) participants were male and 131 (29%) participants were female. 303 participants with DS-TB were randomly assigned to 4 months of BPaMZ (n=150) or HRZE (n=153). In a modified intention-to-treat (mITT) analysis, by week 8, 122 (84%) of 145 and 70 (47%) of 148 participants were culture-negative on 4 months of BPaMZ and HRZE, respectively, with a hazard ratio for earlier negative status of 2·93 (95% CI 2·17-3·96; p<0·0001). Median time to negative culture (TTN) was 6 weeks (IQR 4-8) on 4 months of BPaMZ and 11 weeks (6-12) on HRZE. 86% of participants with DR-TB receiving 6 months of BPaMZ (n=152) reached culture-negative status by week 8, with a median TTN of 5 weeks (IQR 3-7). At week 52, 120 (83%) of 144, 134 (93%) of 144, and 111 (83%) of 133 on 4 months of BPaMZ, HRZE, and 6 months of BPaMZ had favourable outcomes, respectively. Despite bacteriological efficacy, 4 months of BPaMZ did not meet the non-inferiority margin for the key secondary endpoint in the pre-defined mITT population due to higher withdrawal rates for adverse hepatic events. Non-inferiority was demonstrated in the per-protocol population confirming the effect of withdrawals with 4 months of BPaMZ. At least one liver-related treatment-emergent adverse effect (TEAE) occurred among 45 (30%) participants on 4 months of BPaMZ, 38 (25%) on HRZE, and 33 (22%) on 6 months of BPaMZ. Serious liver-related TEAEs were reported by 20 participants overall; 11 (7%) among those on 4 months of BPaMZ, one (1%) on HRZE, and eight (5%) on 6 months of BPaMZ. The most common reasons for discontinuation of trial treatment were hepatotoxicity (ten participants [2%]), increased hepatic enzymes (nine participants [2%]), QTcF prolongation (three participants [1%]), and hypersensitivity (two participants [<1%]). INTERPRETATION: For DS-TB, BPaMZ successfully met the primary efficacy endpoint of sputum culture conversion. The regimen did not meet the key secondary efficacy endpoint due to adverse events resulting in treatment withdrawal. Our study demonstrated the potential for treatment-shortening efficacy of the BPaMZ regimen for DS-TB and DR-TB, providing clinical validation of a murine model widely used to identify such regimens. It also highlights that novel, treatment-shortening TB treatment regimens require an acceptable toxicity and tolerability profile with minimal monitoring in low-resource and high-burden settings. The increased risk of unpredictable severe hepatic adverse events with 4 months of BPaMZ would be a considerable obstacle to implementation of this regimen in settings with high burdens of TB with limited infrastructure for close surveillance of liver biochemistry. Future research should focus on improving the preclinical and early clinical detection and mitigation of safety issues together and further efforts to optimise shorter treatments. FUNDING: TB Alliance.
Assuntos
Antituberculosos , Diarilquinolinas , Moxifloxacina , Nitroimidazóis , Pirazinamida , Tuberculose Pulmonar , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Antituberculosos/uso terapêutico , Antituberculosos/efeitos adversos , Diarilquinolinas/uso terapêutico , Quimioterapia Combinada , Etambutol/uso terapêutico , Isoniazida/uso terapêutico , Moxifloxacina/uso terapêutico , Moxifloxacina/administração & dosagem , Mycobacterium tuberculosis/efeitos dos fármacos , Nitroimidazóis/uso terapêutico , Nitroimidazóis/efeitos adversos , Pirazinamida/uso terapêutico , Rifampina/uso terapêutico , Resultado do Tratamento , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/microbiologiaAssuntos
Antituberculosos , Diarilquinolinas , Fluoroquinolonas , Moxifloxacina , Pirazinamida , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Moxifloxacina/uso terapêutico , Antituberculosos/uso terapêutico , Diarilquinolinas/uso terapêutico , Pirazinamida/uso terapêutico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Fluoroquinolonas/uso terapêutico , Fluoroquinolonas/farmacologia , Nitroimidazóis/uso terapêutico , Quimioterapia Combinada , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose/tratamento farmacológicoRESUMO
Digestive Chagas disease (DCD) is an enteric neuropathy caused by Trypanosoma cruzi infection. There is a lack of evidence on the mechanism of pathogenesis and rationales for treatment. We used a female C3H/HeN mouse model that recapitulates key clinical manifestations to study how infection dynamics shape DCD pathology and the impact of treatment with the front-line, anti-parasitic drug benznidazole. Curative treatment 6 weeks post-infection resulted in sustained recovery of gastrointestinal transit function, whereas treatment failure led to infection relapse and gradual return of DCD symptoms. Neuro/immune gene expression patterns shifted from chronic inflammation to a tissue repair profile after cure, accompanied by increased cellular proliferation, glial cell marker expression and recovery of neuronal density in the myenteric plexus. Delaying treatment until 24 weeks post-infection led to partial reversal of DCD, suggesting the accumulation of permanent tissue damage over the course of chronic infection. Our study shows that murine DCD pathogenesis is sustained by chronic T. cruzi infection and is not an inevitable consequence of acute stage denervation. The risk of irreversible enteric neuromuscular tissue damage and dysfunction developing highlights the importance of prompt diagnosis and treatment. These findings support the concept of treating asymptomatic, T. cruzi-infected individuals with benznidazole to prevent DCD development.
Assuntos
Doença de Chagas , Modelos Animais de Doenças , Sistema Nervoso Entérico , Camundongos Endogâmicos C3H , Nitroimidazóis , Tripanossomicidas , Trypanosoma cruzi , Animais , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Feminino , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêutico , Nitroimidazóis/farmacologia , Nitroimidazóis/uso terapêutico , Trypanosoma cruzi/efeitos dos fármacos , Camundongos , Sistema Nervoso Entérico/efeitos dos fármacos , Regeneração Nervosa/efeitos dos fármacosRESUMO
The BPaLM regimen (bedaquiline, pretomanid, linezolid and moxifloxacin) recently recommended by the World Health Organization offers short, safe, and effective treatment for multidrug-resistant/rifampicin-resistant tuberculosis (TB). In a survey with national TB focal points in 18 central and western European countries to explore barriers for the implementation of BPaLM, only three reported full availability of pretomanid, a necessary component of this regimen. Implementation barriers included financing and procurement. Solutions on national and supranational level are needed to guarantee universal access.
Assuntos
Antituberculosos , Linezolida , Rifampina , Tuberculose Resistente a Múltiplos Medicamentos , Organização Mundial da Saúde , Humanos , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Antituberculosos/uso terapêutico , Europa (Continente) , Linezolida/uso terapêutico , Rifampina/uso terapêutico , Moxifloxacina/uso terapêutico , Diarilquinolinas/uso terapêutico , Nitroimidazóis/uso terapêutico , Mycobacterium tuberculosis/efeitos dos fármacos , Acessibilidade aos Serviços de SaúdeRESUMO
Trypanosoma cruzi infection in dogs can cause heart failure and sudden death with few treatment options available. A litter of 4 dogs living in a T cruzi endemic area were randomized to prophylaxis and nonprophylaxis groups as part of a study evaluating a modified benznidazole dosing regimen administered twice weekly to prevent T cruzi infection during a vector transmission season. The 2 dogs that received prophylaxis remained healthy without T cruzi infection or cardiac disease for >2 years. One dog that did not receive prophylaxis died unexpectedly with acute T cruzi-induced pancarditis, and the second dog tested positive for T cruzi and developed complex arrhythmias with markedly increased cardiac troponin I and improved with a higher benznidazole treatment dose. Although the small sample size precludes definitive conclusions, we describe the potential clinical benefit of prophylactic and early treatment with modified benznidazole dosing regimens for dogs with T cruzi infection.
Assuntos
Doença de Chagas , Doenças do Cão , Nitroimidazóis , Tripanossomicidas , Trypanosoma cruzi , Cães , Animais , Nitroimidazóis/uso terapêutico , Nitroimidazóis/administração & dosagem , Doenças do Cão/tratamento farmacológico , Doença de Chagas/veterinária , Doença de Chagas/tratamento farmacológico , Trypanosoma cruzi/efeitos dos fármacos , Tripanossomicidas/uso terapêutico , Tripanossomicidas/administração & dosagem , Feminino , MasculinoRESUMO
A major challenge for tuberculosis (TB) drug development is to prioritize promising combination regimens from a large and growing number of possibilities. This includes demonstrating individual drug contributions to the activity of higher-order combinations. A BALB/c mouse TB infection model was used to evaluate the contributions of each drug and pairwise combination in the clinically relevant Nix-TB regimen [bedaquiline-pretomanid-linezolid (BPaL)] during the first 3 weeks of treatment at human equivalent doses. The rRNA synthesis (RS) ratio, an exploratory pharmacodynamic (PD) marker of ongoing Mycobacterium tuberculosis rRNA synthesis, together with solid culture CFU counts and liquid culture time to positivity (TTP) were used as PD markers of treatment response in lung tissue; and their time-course profiles were mathematically modeled using rate equations with pharmacologically interpretable parameters. Antimicrobial interactions were quantified using Bliss independence and Isserlis formulas. Subadditive (or antagonistic) and additive effects on bacillary load, assessed by CFU and TTP, were found for bedaquiline-pretomanid and linezolid-containing pairs, respectively. In contrast, subadditive and additive effects on rRNA synthesis were found for pretomanid-linezolid and bedaquiline-containing pairs, respectively. Additionally, accurate predictions of the response to BPaL for all three PD markers were made using only the single-drug and pairwise effects together with an assumption of negligible three-way drug interactions. The results represent an experimental and PD modeling approach aimed at reducing combinatorial complexity and improving the cost-effectiveness of in vivo systems for preclinical TB regimen development.
Assuntos
Antituberculosos , Diarilquinolinas , Modelos Animais de Doenças , Linezolida , Camundongos Endogâmicos BALB C , Mycobacterium tuberculosis , Animais , Antituberculosos/farmacologia , Antituberculosos/farmacocinética , Antituberculosos/uso terapêutico , Linezolida/farmacologia , Linezolida/farmacocinética , Diarilquinolinas/farmacologia , Diarilquinolinas/farmacocinética , Camundongos , Mycobacterium tuberculosis/efeitos dos fármacos , Feminino , Nitroimidazóis/farmacologia , Nitroimidazóis/farmacocinética , Nitroimidazóis/uso terapêutico , Quimioterapia Combinada , Pulmão/microbiologia , Pulmão/efeitos dos fármacos , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia , Testes de Sensibilidade Microbiana , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/microbiologiaRESUMO
OBJECTIVES: Multidrug-resistant/rifampicin-resistant tuberculosis is a major obstacle to successful tuberculosis control. The recommendation by the WHO to use bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaL(M)) for 6 months, based on results of two trials with high efficacy and low toxicity, has revolutionized treatment options. METHODS: In this study, representatives of the Tuberculosis Network European Trials group in 44 of 54 countries of the WHO Europe region documented the availability of the medicines and drug susceptibility testing (DST) of the BPaL(M) regimen through a structured questionnaire between September and November 2023. RESULTS: In total, 24 of 44 (54.5%), 42 of 44 (95.5%), 43 of 44 (97.7%), and 43 of 44 (97.7%) countries had access to pretomanid, bedaquiline, linezolid, and moxifloxacin, respectively. Overall, 23 of 44 (52.3%) countries had access to all the drugs composing the BPaL(M) regimen. In total, 21 of 44 (47.7%), 37 of 44 (84.1%), 40 of 44 (90.9%), and 41 of 44 (93.2%) countries had access to DST for pretomanid, bedaquiline, linezolid, and moxifloxacin, respectively. Overall, DST was available for all medicines composing the BPaL(M) regimen in 21 of 44 (47.7%) countries, including countries where pretomanid DST was available at specialized laboratories. The availability of DST for the drugs the countries had access to, varied from 87.5% to 95.3% (pretomanid 21 of 24 (87.5%), bedaquiline 37 of 42 (88.1%), linezolid 40 of 43 (93.1%) and moxifloxacin 41 of 43 (95.3%)). DISCUSSION: In only about half of the countries participating in the survey, clinicians had access to all the BPaL(M) regimen drugs. A complete DST for the BPaL(M) medicines was possible in less than half of the countries, because of the low accessibility of DST for pretomanid. Equal access to new regimens is urgently needed in Europe and a rapid scale up of DST, especially for pretomanid, is important to prevent unnoticed spread of drug resistance.
Assuntos
Antituberculosos , Diarilquinolinas , Linezolida , Testes de Sensibilidade Microbiana , Moxifloxacina , Tuberculose Resistente a Múltiplos Medicamentos , Linezolida/farmacologia , Linezolida/uso terapêutico , Europa (Continente) , Humanos , Moxifloxacina/uso terapêutico , Diarilquinolinas/uso terapêutico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Antituberculosos/uso terapêutico , Antituberculosos/farmacologia , Rifampina/uso terapêutico , Rifampina/farmacologia , Nitroimidazóis/uso terapêutico , Nitroimidazóis/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Inquéritos e QuestionáriosRESUMO
Delamanid, bedaquiline, and pretomanid have been recently added in the anti-tuberculosis (anti-TB) treatment regimens and have emerged as potential solutions for combating drug-resistant TB. These drugs have proven to be effective in treating drug-resistant TB when used in combination. However, concerns have been raised about the eventual loss of these drugs due to evolving resistance mechanisms and certain adverse effects such as prolonged QT period, gastrointestinal problems, hepatotoxicity, and renal disorders. This Perspective emphasizes the properties of these first-in-class drugs, including their mechanism of action, pharmacokinetics/pharmacodynamics profiles, clinical studies, adverse events, and underlying resistance mechanisms. A brief coverage of efforts toward the generation of best-in-class leads in each class is also provided. The ongoing clinical trials of new combinations of these drugs are discussed, thus providing a better insight into the use of these drugs while designing an effective treatment regimen for resistant TB cases.
Assuntos
Diarilquinolinas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Mycobacterium tuberculosis , Nitroimidazóis , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Antituberculosos/efeitos adversos , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Nitroimidazóis/farmacologia , Nitroimidazóis/uso terapêutico , Oxazóis/farmacologia , Oxazóis/uso terapêutico , Resistência a MedicamentosRESUMO
BACKGROUND: Trypanosoma cruzi and HIV coinfection can evolve with depression of cellular immunity and increased parasitemia. We applied quantitative PCR (qPCR) as a marker for preemptive antiparasitic treatment to avoid fatal Chagas disease reactivation and analyzed the outcome of treated cases. METHODOLOGY: This mixed cross-sectional and longitudinal study included 171 Chagas disease patients, 60 coinfected with HIV. Of these 60 patients, ten showed Chagas disease reactivation, confirmed by parasites identified in the blood, cerebrospinal fluid, or tissues, 12 exhibited high parasitemia without reactivation, and 38 had low parasitemia and no reactivation. RESULTS: We showed, for the first time, the success of the timely introduction of benznidazole in the non-reactivated group with high levels of parasitemia detected by qPCR and the absence of parasites in reactivated cases with at least 58 days of benznidazole. All HIV+ patients with or without reactivation had a 4.0-5.1 higher chance of having parasitemia than HIV seronegative cases. A positive correlation was found between parasites and viral loads. Remarkably, treated T. cruzi/HIV-coinfected patients had 77.3% conversion from positive to negative parasitemia compared to 19.1% of untreated patients. Additionally, untreated patients showed ~13.6 times higher Odds Ratio of having positive parasitemia in the follow-up period compared with treated patients. Treated and untreated patients showed no differences regarding the evolution of Chagas disease. The main factors associated with all-cause mortality were higher parasitemia, lower CD4 counts/µL, higher viral load, and absence of antiretroviral therapy. CONCLUSION: We recommend qPCR prospective monitoring of T. cruzi parasitemia in HIV+ coinfected patients and point out the value of pre-emptive therapy for those with high parasitemia. In parallel, early antiretroviral therapy introduction is advisable, aiming at viral load control, immune response restoration, and increasing survival. We also suggest an early antiparasitic treatment for all coinfected patients, followed by effectiveness analysis alongside antiretroviral therapy.