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1.
Environ Sci Technol ; 55(21): 14844-14853, 2021 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-34674525

RESUMO

The presence of dissolved organic matter (DOM) is known to inhibit the degradation of trace organic contaminants (TrOCs) in SO4•--based advanced oxidation processes (AOPs) due to filtering of the photochemically active light and radical scavenging effects. This study revealed an unexpected contribution for DOM in the degradation of nitroimidazoles (NZs) in the UV/persulfate AOP. The apparent second-order rate constants of NZs with SO4•- increased by 2.05 to 4.77 times in the presence of different DOMs. The increments were linearly related to the total electron capacity of DOM. Quinone and polyphenol moieties were found to play a dominant role. The reactive species generated from SO4•-'s oxidation of DOM, including semiquinone radical (SQ•-) and superoxide (O2•-), were found to react with NZs via Michael addition and O2•- addition. The second-order rate constants of tinidazole with SQ•- is determined to be (5.69 ± 0.59) × 106 M-1 s-1 by laser flash photolysis. Reactive species potentially generated from DOM may be considered in designing processes for the abatement of different types of TrOCs.


Assuntos
Nitroimidazóis , Poluentes Químicos da Água , Oxirredução , Poluentes Químicos da Água/análise
2.
Parasitol Res ; 120(9): 3307-3317, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34370070

RESUMO

The aim of this study was to synthesize several small molecules of the type 5-nitroimidazole-sulfanyl and evaluate biological properties against the main Leishmania species that cause cutaneous leishmaniasis in Venezuela. Final compounds 4-7 were generated through simple nucleophilic substitution of 1-(2-chloroethyl)-2-methyl-5-nitroimidazole 3 with 2-mercaptoethanol, 1-methyl-2-mercaptoethanol, and 2-thyolacetic acid derivative. Compound 8 was synthesized via a coupling reaction between 7 and (S)-Methyl 2-amino-4-methylpentanoate hydrochloride. The inhibitory concentrations of (3, 4, 7, 8) against Leishmania (L.) mexicana and (V.) braziliensis in promastigotes and experimentally infected macrophages were determined by in vitro activity assays. Compounds 7 and 8 shown high activity against both species of Leishmania and were selected for the in vivo evaluation. Animals were infected with promastigotes of the two species and divided into four groups of ten (10) animals and a control group. Intralesional injection way was used for the treatment. The parasitological diagnostic after treatment was obtained by PCR using species specific oligonucleotides. The two Leishmania species were susceptible to compounds 7 and 8 in vivo assays. The results indicated that both compounds reduce significantly (96%) the size of the lesion and cure 63% of the mice infected with L (L) mexicana or L (V) braziliensis as was determined by PCR. The results are indicating that both compounds may represent an alternative treatment for these two Leishmania species.


Assuntos
Antiprotozoários , Leishmania braziliensis , Leishmania mexicana , Leishmaniose Cutânea , Nitroimidazóis , Animais , Antiprotozoários/farmacologia , Leishmania braziliensis/efeitos dos fármacos , Leishmania mexicana/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Camundongos , Nitroimidazóis/farmacologia
3.
Am J Trop Med Hyg ; 105(3): 643-650, 2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34398818

RESUMO

This cross-sectional study evaluated epidemiologic characteristics of persons living with HIV (PWH) coinfected with Trypanosoma cruzi in Cochabamba, Bolivia, and estimated T. cruzi parasitemia by real-time quantitative polymerase chain reaction (qPCR) in patients with and without evidence of reactivation by direct microscopy. Thirty-two of the 116 HIV patients evaluated had positive serology for T. cruzi indicative of chronic Chagas disease (27.6%). Sixteen of the 32 (50%) patients with positive serology were positive by quantitative polymerase chain reaction (qPCR), and four of the 32 (12.5%) were positive by direct microscopy. The median parasite load by qPCR in those with CD4+ < 200 was 168 parasites/mL (73-9951) compared with 28.5 parasites/mL (15-1,528) in those with CD4+ ≥ 200 (P = 0.89). There was a significant inverse relationship between the degree of parasitemia estimated by qPCR from blood clot and CD4+ count on the logarithmic scale (rsBC= -0.70, P = 0.007). The correlation between T. cruzi estimated by qPCR+ blood clot and HIV viral load was statistically significant with rsBC = 0.61, P = 0.047. Given the significant mortality of PWH and Chagas reactivation and that 57% of our patients with CD4+ counts < 200 cells/mm3 showed evidence of reactivation, we propose that screening for chronic Chagas disease be considered in PWH in regions endemic for Chagas disease and in the immigrant populations in nonendemic regions. Additionally, our study showed that PWH with advancing immunosuppression have higher levels of estimated parasitemia measured by qPCR and suggests a role for active surveillance for Chagas reactivation with consideration of treatment with antitrypanosomal therapy until immune reconstitution can be achieved.


Assuntos
Doença de Chagas/sangue , Infecções por HIV/sangue , Infecção Latente/sangue , Parasitemia/sangue , Adulto , Anticorpos Antiprotozoários/imunologia , Bolívia , Contagem de Linfócito CD4 , Doença de Chagas/complicações , Doença de Chagas/diagnóstico , Doença de Chagas/tratamento farmacológico , Coinfecção , Estudos Transversais , Feminino , Infecções por HIV/complicações , Humanos , Infecção Latente/complicações , Infecção Latente/diagnóstico , Infecção Latente/tratamento farmacológico , Masculino , Microscopia , Pessoa de Meia-Idade , Nitroimidazóis/uso terapêutico , Carga Parasitária , Parasitemia/complicações , Parasitemia/diagnóstico , Parasitemia/tratamento farmacológico , Reação em Cadeia da Polimerase em Tempo Real/métodos , Tripanossomicidas/uso terapêutico , Trypanosoma cruzi , Carga Viral
4.
Curr Med Chem ; 28(36): 7513-7528, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34365936

RESUMO

Chagas Disease, also known as American trypanosomiasis, is a Neglected Tropical Disease that affects around seven million people, especially in Latin America. Noteworthy, there has been an increase in the numbers of case reports in non-endemic areas, such as North America, Europe, Japan, and Australia. The disease is a vector-borne disease caused by the pathogen Trypanosoma cruzi being transmitted by infected bugs. It is known that about forty percent of infected patients develop cardiac, digestive, or neurological alterations. There are only two drugs currently used for treatment, benznidazole and nifurtimox. However, both therapeutic regimens present several limitations, such as toxicity, mutagenicity and low efficiency during the chronic phase. Some reports in the literature point to the occurrence of parasite resistance. To overcome these limitations, the bioprospection of novel molecules as alternatives is one of the major goals to improve therapeutic success in this chronic disease. Bioprospecting active metabolites from natural resources might bring new hopes for disease control and parasite elimination. Here we summarize the most recent advances to identify and test Algae, Bacteria and Fungi-derived bioactive compounds with trypanocidal activity using experimental models, in vitro testing and in silico approaches.


Assuntos
Doença de Chagas , Nitroimidazóis , Tripanossomicidas , Trypanosoma cruzi , Bactérias , Doença de Chagas/tratamento farmacológico , Fungos , Humanos , Nifurtimox/uso terapêutico , Nitroimidazóis/uso terapêutico , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêutico
5.
PLoS Negl Trop Dis ; 15(8): e0009680, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34388146

RESUMO

American trypanosomiasis (Chagas disease, CD) affects circa 7 million persons worldwide. While of those persons present the asymptomatic, indeterminate chronic form (ICF), many will eventually progress to cardiac or digestive disorders. We studied a nonconcurrent (retrospective) cohort of patients attending an outpatient CD clinic in Southeastern Brazil, who were admitted while presenting the ICF in the period from 1998 through 2018 and followed until 2019. The outcomes of interest were the progression to cardiac or digestive CD forms. We were also interested in analyzing the impact of Benznidazole therapy on the progression of the disease. Extensive review of medical charts and laboratory files was conducted, collecting data up to year 2019. Demographics (upon inclusion), body mass index, comorbidities (including the Charlson index) and use of Benznidazole were recorded. The outcomes were defined by abnormalities in those test that could not be attributed to other causes. Statistical analysis included univariate and multivariable Cox regression models. Among 379 subjects included in the study, 87 (22.9%) and 100 (26.4%) progressed to cardiac and digestive forms, respectively. In the final multivariable model, cardiac disorders were positively associated with previous coronary syndrome (Hazzard Ratio [HR], 2.42; 95% Confidence Interval [CI], 1.53-3.81) and negatively associated with Benznidazole therapy (HR, 0.26; 95%CI, 0.11-0.60). On the other hand, female gender was the only independent predictor of progression to digestive forms (HR, 1.56; 95%CI, 1.03-2.38). Our results point to the impact of comorbidities on progression do cardiac CD, with possible benefit of the use of Benznidazole.


Assuntos
Doença de Chagas/complicações , Doenças do Sistema Digestório/etiologia , Cardiopatias/etiologia , Adulto , Antiprotozoários/administração & dosagem , Brasil/epidemiologia , Doença de Chagas/tratamento farmacológico , Doença de Chagas/epidemiologia , Doença de Chagas/parasitologia , Doença Crônica/epidemiologia , Doença Crônica/terapia , Doenças do Sistema Digestório/epidemiologia , Doenças do Sistema Digestório/mortalidade , Feminino , Cardiopatias/epidemiologia , Cardiopatias/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Nitroimidazóis/administração & dosagem , Estudos Retrospectivos , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/fisiologia
6.
Front Cell Infect Microbiol ; 11: 692655, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34381739

RESUMO

Chronic Chagas cardiomyopathy (CCC) is the most frequent and severe form of Chagas disease, a neglected tropical illness caused by the protozoan Trypanosoma cruzi, and the main cause of morbimortality from cardiovascular problems in endemic areas. Although efforts have been made to understand the signaling pathways and molecular mechanisms underlying CCC, the immunological signaling pathways regulated by the etiological treatment with benznidazole (Bz) has not been reported. In experimental CCC, Bz combined with the hemorheological and immunoregulatory agent pentoxifylline (PTX) has beneficial effects on CCC. To explore the molecular mechanisms of Bz or Bz+PTX therapeutic strategies, C57BL/6 mice chronically infected with the T. cruzi Colombian strain (discrete typing unit TcI) and showing electrocardiographic abnormalities were submitted to suboptimal dose of Bz or Bz+PTX from 120 to 150 days postinfection. Electrocardiographic alterations, such as prolonged corrected QT interval and heart parasite load, were beneficially impacted by Bz and Bz+PTX. RT-qPCR TaqMan array was used to evaluate the expression of 92 genes related to the immune response in RNA extracted from heart tissues. In comparison with non-infected mice, 30 genes were upregulated, and 31 were downregulated in infected mice. Particularly, infection upregulated the cytokines IFN-γ, IL-12b, and IL-2 (126-, 44-, and 18-fold change, respectively) and the T-cell chemoattractants CCL3 and CCL5 (23- and 16-fold change, respectively). Bz therapy restored the expression of genes related to inflammatory response, cellular development, growth, and proliferation, and tissue development pathways, most probably linked to the cardiac remodeling processes inherent to CCC, thus mitigating the Th1-driven response found in vehicle-treated infected mice. The combined Bz+PTX therapy revealed pathways related to the modulation of cell death and survival, and organismal survival, supporting that this strategy may mitigate the progression of CCC. Altogether, our results contribute to the better understanding of the molecular mechanisms of the immune response in the heart tissue in chronic Chagas disease and reinforce that parasite persistence and dysregulated immune response underpin CCC severity. Therefore, Bz and Bz+PTX chemotherapies emerge as tools to interfere in these pathways aiming to improve CCC prognosis.


Assuntos
Cardiomiopatia Chagásica , Doença de Chagas , Trypanosoma cruzi , Animais , Cardiomiopatia Chagásica/tratamento farmacológico , Imunidade , Camundongos , Camundongos Endogâmicos C57BL , Nitroimidazóis
7.
Molecules ; 26(12)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207619

RESUMO

Trypanosoma cruzi is the etiologic agent for Chagas disease, which affects 6-7 million people worldwide. The biological diversity of the parasite reflects on inefficiency of benznidazole, which is a first choice chemotherapy, on chronic patients. ABC transporters that extrude xenobiotics, metabolites, and mediators are overexpressed in resistant cells and contribute to chemotherapy failure. An ABCC-like transport was identified in the Y strain and extrudes thiol-conjugated compounds. As thiols represent a line of defense towards reactive species, we aimed to verify whether ABCC-like transport could participate in the regulation of responses to stressor stimuli. In order to achieve this, ABCC-like activity was measured by flow cytometry using fluorescent substrates. The present study reveals the participation of glutathione and ceramides on ABCC-like transport, which are both implicated in stress. Hemin modulated the ABCC-like efflux which suggests that this protein might be involved in cellular detoxification. Additionally, all strains evaluated exhibited ABCC-like activity, while no ABCB1-like activity was detected. Results suggest that ABCC-like efflux is not associated with natural resistance to benznidazole, since sensitive strains showed higher activity than the resistant ones. Although benznidazole is not a direct substrate, ABCC-like efflux increased after prolonged drug exposure and this indicates that the ABCC-like efflux mediated protection against cell stress depends on the glutathione biosynthesis pathway.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Doença de Chagas/tratamento farmacológico , Glutationa/metabolismo , Nitroimidazóis/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Transporte Biológico , Doença de Chagas/parasitologia , Resistência a Medicamentos , Estresse Oxidativo/fisiologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/metabolismo
8.
Parasitol Res ; 120(8): 2905-2918, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34195872

RESUMO

Current treatments for Chagas disease have a limited impact during the chronic stage and trigger severe side effects. Treatments target Trypanosoma cruzi, the etiological agent of the disease. The aims of this study were to evaluate the trypanocidal activity of four 2-phenylbenzothiazole derivatives (BZT1-4) in vitro by using the infectious and non-infectious forms of T. cruzi (trypomastigotes and epimastigotes, respectively) and to test the most promising compound (BZT4) in vivo in mice. Additionally, the toxicological profile and possible neuronal damage were examined. In relation to trypomastigotes, BZT4 was more selective and effective than the reference drug (benznidazole) during this infective stage, apparently due to the synergistic action of the CF3 and COOH substituents in the molecule. During the first few hours post-administration of BZT4, parasitemia decreased by 40% in an in vivo model of short-term treatment, but parasite levels later returned to the basal state. In the long-term assessment, the compound did not produce a significant antiparasitic effect, only attaining a 30% reduction in parasitemia by day 20 with the dose of 16 mg/kg. The toxicity test was based on repeated dosing of BZT4 (administered orally) during 21 days, which did not cause liver damage. However, the compound altered the concentration of proteins and the proteinic profile of neuronal cells in vitro, perhaps leading to an effect on the central nervous system. Further research on the low trypanocidal activity in vivo compared to the better in vitro effect could possibly facilitate molecular redesign to improve trypanocidal activity.


Assuntos
Doença de Chagas , Nitroimidazóis , Tiazóis , Tripanossomicidas , Trypanosoma cruzi , Animais , Doença de Chagas/tratamento farmacológico , Camundongos , Nitroimidazóis/uso terapêutico , Nitroimidazóis/toxicidade , Tiazóis/uso terapêutico , Tiazóis/toxicidade , Testes de Toxicidade , Tripanossomicidas/uso terapêutico , Tripanossomicidas/toxicidade , Trypanosoma cruzi/efeitos dos fármacos
9.
Acta Trop ; 222: 106050, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34302770

RESUMO

This study compared the serological and electrocardiographic evolution among patients with chronic T. cruzi infection treated during childhood or left untreated. A retrospective cohort study was conducted during a mean follow-up period of 25 years in 82 patients: half of them underwent treatment (nifurtimox 8, benznidazole 33) before being 15 years old, whereas the other half remained untreated. During the follow-up, negative seroconversion occurred in 92.7% of the treated children, while all the untreated ones remained positive for conventional serology. At baseline, 2 patients from each group had electrocardiographic abnormalities. During the study period, 4/41 (9.75%) and 9/41 (21.95%) of treated and untreated patients displayed an altered electrocardiogram, respectively. In multivariate analyses, the probability of developing electrocardiographic abnormalities was significantly reduced among treated patients (OR = 0.18, 95% CI = 0.04-0.79; p = 0.023). Electrocardiographic abnormalities attributable to Chagas cardiomyopathy were seen in 3 patients from the untreated group (complete right bundle branch block + left anterior fascicular block, frequent ventricular extrasystole, and left anterior fascicular block). The remarkable seronegativization seen in Benznidazole and Nifurtimox recipients underlines the parasiticidal effect of both compounds. Such demonstration along with the fact that CCC-related alterations were only present in the untreated group, reinforces the view of trypanocidal treatment in chronically T. cruzi-infected children as decreasing the risk for cardiomyopathy development.


Assuntos
Doença de Chagas , Nifurtimox , Nitroimidazóis , Tripanossomicidas , Adolescente , Cardiomiopatia Chagásica/epidemiologia , Doença de Chagas/tratamento farmacológico , Criança , Seguimentos , Humanos , Nifurtimox/uso terapêutico , Nitroimidazóis/uso terapêutico , Estudos Retrospectivos , Tripanossomicidas/uso terapêutico , Trypanosoma cruzi
10.
J Glob Antimicrob Resist ; 26: 241-248, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34214699

RESUMO

OBJECTIVES: The new antituberculous drugs delamanid and bedaquiline form the last line of defence against drug-resistant tuberculosis (TB). Understanding the background prevalence of resistance to new drugs can help predict the lifetime of these drugs' effectiveness and inform regimen design. METHODS: Mycobacterium tuberculosis without prior exposure to novel anti-TB drugs were analysed retrospectively. Drug susceptibility testing for bedaquiline, delamanid, linezolid, clofazimine and widely used first- and second-line anti-TB drugs was performed. All TB isolates with resistance to new or repurposed drugs were subjected to whole-genome sequencing to explore the molecular characteristics of resistance and to perform phylogenetic analysis. RESULTS: Overall, resistance to delamanid, bedaquiline, linezolid and clofazimine was observed in 0.7% (11/1603), 0.4% (6/1603), 0.4% (7/1603) and 0.4% (6/1603) of TB isolates, respectively. Moreover, 1.0% (1/102), 2.9% (3/102), 3.9% (4/102) and 1.0% (1/102) of multidrug-resistant TB (MDR-TB) were resistant to bedaquiline, delamanid, linezolid and clofazimine, respectively. Whereas 22.2% (2/9) of extensively-drug resistant tuberculosis (XDR-TB) isolates were resistant to both delamanid and linezolid, and none was resistant to bedaquiline or clofazimine. Phylogenetic analysis showed that recent transmission occurred in two XDR-TB with additional resistance to delamanid and linezolid. None known gene mutation associated with delamanid resistance was detected. All four isolates with cross-resistance to bedaquiline and clofazimine had a detected gene mutation in Rv0678. Three of five strains with linezolid resistance had a detected gene mutation in rplC. CONCLUSION: Detection of resistance to new anti-TB drugs emphasises the pressing need for intensive surveillance for such resistance before their wide usage.


Assuntos
Mycobacterium tuberculosis , China/epidemiologia , Diarilquinolinas , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/genética , Nitroimidazóis , Oxazóis , Filogenia , Prevalência , Estudos Retrospectivos
11.
Exp Parasitol ; 228: 108136, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34280400

RESUMO

Strains of Trypanosoma cruzi, etiological agent of Chagas disease, are classified into different discrete typing units that may present distinct dynamics of infection and susceptibility to benznidazole (BZ) treatment. Mice that were orally inoculated with T. cruzi IV strains exhibited a more intense course of infection compared with intraperitoneally inoculated mice, reflected by higher parasite loads. We evaluated the efficacy of BZ treatment in Swiss mice that were inoculated with T. cruzi IV strains from the Western Brazilian Amazon. The mice were orally (OR) or intraperitoneally (IP) inoculated with 2 × 106 culture-derived metacyclic trypomastigotes of the AM14, AM16, AM64, and AM69 strains of T. cruzi that were obtained from two outbreaks of orally acquired acute Chagas disease in the state of Amazonas, Brazil. The animals were treated with BZ (100 mg/kg/day for 20 days). Fresh blood examination, hemoculture, conventional and quantitative real-time polymerase chain reaction were performed to monitor the therapeutic effects of BZ. Significant reductions in five of 24 parameters of parasitemia and parasite load were found in different tissues in the OR group, indicating worse response to BZ treatment compared with the IP group, in which significant reductions in nine of those 24 parameters were observed. The cure rates in the OR groups ranged from 18.2% (1/11) to 75.0% (9/12) and in the IP groups from 58.3% (7/12) to 91.7% (11/12), for the AM14 and AM69 strains, respectively. These findings indicate that treatment with BZ had fewer beneficial effects with regard to reducing parasitemia and parasite load in different tissues of mice that were OR inoculated with four TcIV strains compared with IP inoculation. Therefore, the route of infection with T. cruzi should be considered when evaluating the therapeutic efficacy of BZ in patients with Chagas disease.


Assuntos
Doença de Chagas/parasitologia , Nitroimidazóis/uso terapêutico , Tripanossomicidas/uso terapêutico , Trypanosoma cruzi/classificação , Parede Abdominal/parasitologia , Animais , Brasil/epidemiologia , Doença de Chagas/tratamento farmacológico , Doença de Chagas/epidemiologia , Esôfago/parasitologia , Coração/parasitologia , Camundongos , Nitroimidazóis/farmacologia , Carga Parasitária , Parasitemia/tratamento farmacológico , Parasitemia/epidemiologia , Parasitemia/parasitologia , Estômago/parasitologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos
14.
J Am Assoc Lab Anim Sci ; 60(5): 587-591, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34325772

RESUMO

Tinidazole is a second-generation nitroimidazole compound that is used as an antimicrobial to treat anaerobic bacterial and protozoal infections in humans and, less frequently, in veterinary medicine. However, metronidazole, another secondgeneration nitroimidazole, is more commonly used. Nonetheless, tinidazole has proven to be a superior therapy for parasitic infections in humans, particularly in the treatment of giardiasis. Furthermore, in chinchillas, metronidazole has been shown to cause a clinically relevant reduction in food intake after oral administration at published dosages. This study's objective was to evaluate the effect of orally administered tinidazole on food intake in healthy chinchillas. In 2 randomized, placebocontrolled, blinded, crossover studies, tinidazole was evaluated at 2 single high doses (100 mg/kg and 200 mg/kg PO, n = 9) and a repeated dosing schedule at a lower dose (20 mg/kg PO q12h for 10 doses, n = 12). Food intake was measured over 24-h periods before and after drug administration. The single-dose treatment groups both displayed significantly reduced food intake (200 mg/kg: -26 ± 21%; 100 mg/kg: -9 ± 21%, P < 0.01) as compared with the control group during the first 24 h after drug administration. Food intake returned to pretreatment values within 4-5 d. Repeated administration at 20 mg/kg q12h was not associated with any significant changes in food intake. No other adverse effects were noted during this study. Tinidazole administration at single higher doses resulted in an acute self-limiting reduction in food intake. In comparison, repeated administration of lower doses (20 mg/kg PO q12h) had no significant effects on food intake in healthy chinchillas. Therefore, tinidazole may be a more suitable drug for treating Giardia and anaerobic bacterial infections in this species than the more commonly used metronidazole.


Assuntos
Nitroimidazóis , Tinidazol , Animais , Chinchila , Ingestão de Alimentos , Humanos , Metronidazol
15.
Eur J Pharm Sci ; 164: 105912, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34133985

RESUMO

Benznidazole (BZ) is a first-line drug for the treatment of Chagas disease; however, it presents several disadvantages that could hamper its therapeutic success. Multiparticulate drug delivery systems (MDDS) are promising carriers to improve the performance of drugs. We developed BZ-loaded MDDS intended for improving Chagas disease therapy. To assess their efficacy and safety, Trypanosoma (T) cruzi infected BALB/c mice were orally treated with free BZ or BZ-MDDS at different regimens (doses of 50 and 100 mg/kg/day, administered daily or at 2- or 5-days intervals) and compared with infected non-treated (INT) mice. At 100 mg/kg/day, independent of the administration regimen, both treatments were able to override the parasitemia, and at 50 mg/kg/day significantly reduced it compared to INT mice. BZ-MDDS at a dose of 100 mg/kg/day administered every 5 days (BZ-MDDS 100-13d) induced the lowest cardiac parasite load, indicating an improved efficacy with lower total dose of BZ when loaded to the MDDS. Reactive oxygen species produced by leukocytes were higher in INT and mice treated with BZ at 50 mg/kg/day compared to 100 mg/kg/day, likely because of persistent infection. BZ-MDDS treatments markedly reduced heart and liver injury markers compared to INT mice and those receiving the standard treatment. Therefore, BZ-MDDS exhibited enhanced activity against T. cruzi infection even at lower doses and reduced administration frequency compared to free BZ while increasing the treatment safety. They likely avoid undesired side effects of BZ by keeping a sustained concentration, avoiding plasmatic drug peaks. BZ-MDDS evidenced significant improvements in experimental Chagas disease treatment and can be considered as a potential improved therapeutic alternative against this illness.


Assuntos
Doença de Chagas , Nitroimidazóis , Tripanossomicidas , Trypanosoma cruzi , Animais , Doença de Chagas/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Parasitemia/tratamento farmacológico
16.
Antimicrob Agents Chemother ; 65(8): e0257120, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34097484

RESUMO

Delamanid has been studied extensively and approved for the treatment of pulmonary multidrug-resistant tuberculosis; however, its potential in the treatment of extrapulmonary tuberculosis remains unknown. We previously reported that, in rats, delamanid was broadly distributed to various tissues in addition to the lungs. In this study, we simulated human plasma concentration-time courses (pharmacokinetic profile) of delamanid, which has a unique property of metabolism by albumin, using two different approaches (steady-state concentration of plasma-mean residence time [Css-MRT] and physiologically based pharmacokinetic [PBPK] modeling). In Css-MRT, allometric scaling predicted the distribution volume at steady state based on data from mice, rats, and dogs. Total clearance was predicted by in vitro-in vivo extrapolation using a scaled albumin amount. A simulated human pharmacokinetic profile using a combination of human-predicted Css and MRT was almost identical to the observed profile after single oral administration, which suggests that the pharmacokinetic profile of delamanid could be predicted by allometric scaling from these animals and metabolic capacity in vitro. The PBPK model was constructed on the assumption that delamanid was metabolized by albumin in circulating plasma and tissues, to which the simulated pharmacokinetic profile was consistent. Moreover, the PBPK modeling approach demonstrated that the simulated concentrations of delamanid at steady state in the lung, brain, liver, and heart were higher than the in vivo effective concentration for Mycobacterium tuberculosis. These results indicate that delamanid may achieve similar concentrations in various organs to that of the lung and may have the potential to treat extrapulmonary tuberculosis.


Assuntos
Nitroimidazóis , Tuberculose , Animais , Antituberculosos/uso terapêutico , Cães , Humanos , Camundongos , Modelos Biológicos , Oxazóis , Ratos , Tuberculose/tratamento farmacológico
17.
Lancet Glob Health ; 9(7): e999-e1008, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34143998

RESUMO

BACKGROUND: Staging and treatment of human African trypanosomiasis caused by Trypanosoma brucei gambiense (g-HAT) required lumbar puncture to assess cerebrospinal fluid (CSF) and intravenous drugs that cross the blood-brain barrier for late-stage infection. These procedures are inconvenient in rural health systems of disease-endemic countries. A pivotal study established fexinidazole as the first oral monotherapy to be effective against non-severe stage 2 g-HAT. We aimed to assess the safety and efficacy of fexinidazole in early g-HAT. METHODS: In this prospective, multicentre, open-label, single-arm cohort study, patients with stage 1 or early stage 2 g-HAT were recruited from eight treatment centres in the Democratic Republic of the Congo. Primary inclusion criteria included being older than 15 years, being able to ingest at least one complete meal per day (or at least one sachet of Plumpy'Nut®), a Karnofsky score higher than 50, evidence of trypanosomes in the blood or lymph but no evidence of trypanosomes in the CSF, willingness to be admitted to hospital to receive treatment, having a permanent address, and being able to comply with the follow-up visit schedule. Exclusion criteria included severe malnutrition, inability to take medication orally, pregnant or breastfeeding women, any clinically important medical condition that could jeopardise patient safety or participation in the study, severely deteriorated general status, any contraindication to imidazole drugs, HAT treatment in the past 2 years, previous enrolment in the study or previous intake of fexinidazole, abnormalities on electrocardiogram that did not return to normal in pretreatment repeated assessments or were considered clinically important, QT interval corrected using Fridericia's formula of at least 450 ms, and patients not tested for malaria or not having received appropriate treatment for malaria or for soil-transmitted helminthiasis. Patients were classified into stage 1 or early stage 2 g-HAT groups following evidence of trypanosomes in the blood, lymph, and absence in CSF, and using white-blood-cell count in CSF. Patients received 1800 mg fexinidazole once per day on days 1-4 then 1200 mg fexinidazole on days 5-10. Patients were observed for approximately 19 months in total. Study participants were followed up on day 5 and day 8 during treatment, at end of treatment on day 11, at end of hospitalisation on days 11-18, at week 9 for a subset of patients, and after 6 months, 12 months, and 18 months. The primary endpoint was treatment success at 12 months. Safety was assessed through routine monitoring. Analyses were done in the intention-to-treat population. The acceptable success rate was defined as treatment efficacy in more than 80% of patients. This study is completed and registered with ClinicalTrials.gov (NCT02169557). FINDINGS: Patients were enrolled between April 30, 2014, and April 25, 2017. 238 patients were recruited: 195 (82%) patients with stage 1 g-HAT and 43 (18%) with early stage 2 g-HAT. 189 (97%) of 195 patients with stage 1 g-HAT and 41 (95%) of 43 patients with early stage 2 g-HAT were finally included and completed the 10 day treatment period. Three patients with stage 1 g-HAT died after the 10 day treatment period and before the 12 month primary follow-up visit, considered as treatment failure and were withdrawn from the study. Treatment was effective at 12 months for 227 (99%) of 230 patients (95% CI 96·2-99·7): 186 (98%) of 189 patients (95·4-99·7) with stage 1 and 41 (100%) of 41 patients (91·4-100·0) with early stage 2, indicating that the primary study endpoint was met. No new safety issues were observed. The most frequent adverse events were headache and vomiting. In total, 214 (93%) of 230 patients had treatment-emergent adverse events, mainly common-terminology criteria for adverse events grades 1 to 3. None led to treatment discontinuation. INTERPRETATION: Fexinidazole is a valuable first-line treatment option in the early stages of g-HAT. FUNDING: Through the Drugs for Neglected Diseases initiative: the Bill & Melinda Gates Foundation, the Republic and Canton of Geneva (Switzerland), the Dutch Ministry of Foreign Affairs (also known as DGIS; Netherlands), the Norwegian Agency for Development Cooperation (also known as Norad; Norway), the Federal Ministry of Education and Research (also known as BMBF) through KfW (Germany), the Brian Mercer Charitable Trust (UK), and other private foundations and individuals from the HAT campaign. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.


Assuntos
Nitroimidazóis/administração & dosagem , Trypanosoma brucei gambiense , Tripanossomíase Africana/tratamento farmacológico , Administração Oral , Adolescente , Adulto , Idoso , República Democrática do Congo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto Jovem
18.
Molecules ; 26(9)2021 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-34063264

RESUMO

The present work aims to examine the worrying problem of antibiotic resistance and the emergence of multidrug-resistant bacterial strains, which have now become really common in hospitals and risk hindering the global control of infectious diseases. After a careful examination of these phenomena and multiple mechanisms that make certain bacteria resistant to specific antibiotics that were originally effective in the treatment of infections caused by the same pathogens, possible strategies to stem antibiotic resistance are analyzed. This paper, therefore, focuses on the most promising new chemical compounds in the current pipeline active against multidrug-resistant organisms that are innovative compared to traditional antibiotics: Firstly, the main antibacterial agents in clinical development (Phase III) from 2017 to 2020 are listed (with special attention on the treatment of infections caused by the pathogens Neisseria gonorrhoeae, including multidrug-resistant isolates, and Clostridium difficile), and then the paper moves on to the new agents of pharmacological interest that have been approved during the same period. They include tetracycline derivatives (eravacycline), fourth generation fluoroquinolones (delafloxacin), new combinations between one ß-lactam and one ß-lactamase inhibitor (meropenem and vaborbactam), siderophore cephalosporins (cefiderocol), new aminoglycosides (plazomicin), and agents in development for treating drug-resistant TB (pretomanid). It concludes with the advantages that can result from the use of these compounds, also mentioning other approaches, still poorly developed, for combating antibiotic resistance: Nanoparticles delivery systems for antibiotics.


Assuntos
Antibacterianos/farmacologia , Desenho de Fármacos , Farmacorresistência Bacteriana Múltipla , Animais , Ácidos Borônicos/farmacologia , Cefalosporinas/farmacologia , Química Farmacêutica/tendências , Clostridioides difficile , Infecções por Clostridium/tratamento farmacológico , Fluoroquinolonas/farmacologia , Gonorreia/tratamento farmacológico , Humanos , Meropeném/farmacologia , Neisseria gonorrhoeae , Nitroimidazóis/farmacologia , Sisomicina/análogos & derivados , Sisomicina/farmacologia , Tetraciclinas/farmacologia , Inibidores de beta-Lactamases/farmacologia
19.
Antimicrob Agents Chemother ; 65(9): e0095621, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34152815

RESUMO

Mycobacterium tuberculosis, the causative agent of human tuberculosis, harbors a branched electron transport chain, preventing the bactericidal action of cytochrome bc1 inhibitors (e.g., TB47). Here, we investigated, using luminescent mycobacterial strains, the in vitro combination activity of cytochrome bc1 inhibitors and nitric oxide (NO) donors including pretomanid (PMD) and explored the mechanisms of combination activity. The TB47 and PMD combination quickly abolished the light emission of luminescent bacilli, as was the case for the combination of TB47 and aurachin D, a putative cytochrome bd inhibitor. The TB47 and PMD combination inhibited M. tuberculosis oxygen consumption, decreased ATP levels, and had a delayed bactericidal effect. The NO scavenger carboxy-PTIO prevented the bactericidal activity of the drug combination, suggesting the requirement for NO. In addition, cytochrome bc1 inhibitors were largely bactericidal when administered with DETA NONOate, another NO donor. Proteomic analysis revealed that the cotreated bacilli had a compromised expression of the dormancy regulon proteins, PE/PPE proteins, and proteins required for the biosynthesis of several cofactors, including mycofactocin. Some of these proteomic changes, e.g., the impaired dormancy regulon induction, were attributed to PMD. In conclusion, combination of cytochrome bc1 inhibitors with PMD inhibited M. tuberculosis respiration and killed the bacilli. The activity of cytochrome bc1 inhibitors can be greatly enhanced by NO donors. Monitoring of luminescence may be further exploited to screen cytochrome bd inhibitors.


Assuntos
Mycobacterium tuberculosis , Citocromos , Transporte de Elétrons , Complexo III da Cadeia de Transporte de Elétrons , Humanos , Óxido Nítrico , Nitroimidazóis , Proteômica
20.
Clin Infect Dis ; 73(8): 1517-1523, 2021 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-34115100

RESUMO

BACKGROUND: Giardiasis failing nitroimidazole first-line treatment is an emerging problem in returning European travelers. We present data on the efficacy and tolerability of 2 second-line treatment regimens. METHODS: This prospective, open-label, multicenter study assessed the efficacy and tolerability of quinacrine monotherapy (100 mg 3 times per day for 5 days) and albendazole plus chloroquine combination therapy (400 mg twice daily plus 155 mg twice daily for 5 days) in nitroimidazole-refractory giardiasis. The defined end points were the clinical outcome, assessed at week 5 after treatment and the parasitological outcome, assessed using microscopy of 2 stool samples, ≥2 to ≤5 weeks after treatment. RESULTS: A total of 106 patients were included in the study. Quinacrine achieved clinical and parasitological cure in 81% (59/73) and 100% (56/56), respectively. Albendazole plus chloroquine achieved clinical and parasitological cure in 36% (12/33) and 48% (12/25), respectively. All patients (9/9) who clinically and parasitologically failed albendazole plus chloroquine treatment and opted for retreatment with quinacrine achieved clinical cure. Mild to moderate treatment-related adverse events were reported by 45% and 30% of patients treated with quinacrine and albendazole plus chloroquine, respectively. One patient treated with quinacrine developed severe neuropsychiatric side effects. The majority of nitroimidazole-refractory Giardia infections (57%) were acquired in India. CONCLUSIONS: Quinacrine was a highly effective treatment in nitroimidazole-refractory giardiasis, but patients should be cautioned on the low risk of severe neuropsychiatric adverse event. Albendazole plus chloroquine had a low cure rate in nitroimidazole-refractory giardiasis. Nitroimidazole-refractory giardiasis was primarily seen in travelers returning from India.


Assuntos
Antiprotozoários , Giardia lamblia , Giardíase , Nitroimidazóis , Albendazol/efeitos adversos , Antiprotozoários/efeitos adversos , Cloroquina/efeitos adversos , Giardíase/tratamento farmacológico , Humanos , Nitroimidazóis/efeitos adversos , Estudos Prospectivos , Quinacrina/efeitos adversos
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