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1.
Int J Mol Sci ; 22(11)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34205228

RESUMO

BACKGROUND: Artemether-lumefantrine is a highly effective artemisinin-based combination therapy that was adopted in Mali as first-line treatment for uncomplicated Plasmodium falciparum malaria. This study was designed to measure the efficacy of artemether-lumefantrine and to assess the selection of the P. falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multi-drug resistance 1 (pfmdr1) genotypes that have been associated with drug resistance. METHODS: A 28-day follow-up efficacy trial of artemether-lumefantrine was conducted in patients aged 6 months and older suffering from uncomplicated falciparum malaria in four different Malian areas during the 2009 malaria transmission season. The polymorphic genetic markers MSP2, MSP1, and Ca1 were used to distinguish between recrudescence and reinfection. Reinfection and recrudescence were then grouped as recurrent infections and analyzed together by PCR-restriction fragment length polymorphism (RFLP) to identify candidate markers for artemether-lumefantrine tolerance in the P. falciparum chloroquine resistance transporter (pfcrt) gene and the P. falciparum multi-drug resistance 1 (pfmdr1) gene. RESULTS: Clinical outcomes in 326 patients (96.7%) were analyzed and the 28-day uncorrected adequate clinical and parasitological response (ACPR) rate was 73.9%. The total PCR-corrected 28-day ACPR was 97.2%. The pfcrt 76T and pfmdr1 86Y population prevalence decreased from 49.3% and 11.0% at baseline (n = 337) to 38.8% and 0% in patients with recurrent infection (n = 85); p = 0.001), respectively. CONCLUSION: Parasite populations exposed to artemether-lumefantrine in this study were selected toward chloroquine-sensitivity and showed a promising trend that may warrant future targeted reintroduction of chloroquine or/and amodiaquine.


Assuntos
Combinação Arteméter e Lumefantrina/administração & dosagem , Malária Falciparum/tratamento farmacológico , Proteínas de Membrana Transportadoras/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas de Protozoários/genética , Alelos , Combinação Arteméter e Lumefantrina/efeitos adversos , Artemisininas/administração & dosagem , Artemisininas/efeitos adversos , Criança , Pré-Escolar , Cloroquina/administração & dosagem , Cloroquina/efeitos adversos , Resistência a Medicamentos/genética , Feminino , Humanos , Malária Falciparum/genética , Malária Falciparum/parasitologia , Malária Falciparum/patologia , Masculino , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/patogenicidade
2.
Int J Mol Sci ; 22(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207256

RESUMO

ATP-binding cassette (ABC) transporter proteins are a gene super-family in plants and play vital roles in growth, development, and response to abiotic and biotic stresses. The ABC transporters have been identified in crop plants such as rice and buckwheat, but little is known about them in soybean. Soybean is an important oil crop and is one of the five major crops in the world. In this study, 255 ABC genes that putatively encode ABC transporters were identified from soybean through bioinformatics and then categorized into eight subfamilies, including 7 ABCAs, 52 ABCBs, 48 ABCCs, 5 ABCDs, 1 ABCEs, 10 ABCFs, 111 ABCGs, and 21 ABCIs. Their phylogenetic relationships, gene structure, and gene expression profiles were characterized. Segmental duplication was the main reason for the expansion of the GmABC genes. Ka/Ks analysis suggested that intense purifying selection was accompanied by the evolution of GmABC genes. The genome-wide collinearity of soybean with other species showed that GmABCs were relatively conserved and that collinear ABCs between species may have originated from the same ancestor. Gene expression analysis of GmABCs revealed the distinct expression pattern in different tissues and diverse developmental stages. The candidate genes GmABCB23, GmABCB25, GmABCB48, GmABCB52, GmABCI1, GmABCI5, and GmABCI13 were responsive to Al toxicity. This work on the GmABC gene family provides useful information for future studies on ABC transporters in soybean and potential targets for the cultivation of new germplasm resources of aluminum-tolerant soybean.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Alumínio/toxicidade , Proteínas de Plantas/metabolismo , Soja/genética , Transportadores de Cassetes de Ligação de ATP/genética , Resistência a Medicamentos/genética , Proteínas de Plantas/genética , Soja/efeitos dos fármacos , Soja/metabolismo
3.
Rev Bras Parasitol Vet ; 30(2): e005021, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34133616

RESUMO

The aim of this study was to characterize the anthelmintic resistance (AR) of a sheep gastrointestinal nematode population, named Caucaia, from northeastern Brazil. Phenotypic tests performed were: egg hatch (EHT), larval development (LDT) and fecal egg count reduction (FECRT). Benzimidazoles (BZs) genotypic evaluation was by frequency of single nucleotide polymorphisms (SNPs) F200Y, F167Y and E198A, and for levamisole (LEV), by frequency of resistance alleles of Hco-acr-8 gene. The primers were designed specifically for Haemonchus contortus. Effective concentrations 50% (EC50) for BZs (EHT), and for macrocyclic lactones (MLs) and LEV (LDT) were 1.02 µg/mL, 1.81 ng/mL and 0.04 µg/mL, respectively. Resistance ratios for MLs and LEV were 0.91 and 3.07, respectively. FECRT efficacies of BZs, MLs, monepantel (MPTL) and LEV were 52.4; 87.0; 94.5 and 99.6%, respectively. qPCR for BZs demonstrated resistance allele frequencies of 0%, 26.24% and 69.08% for SNPs E198A, F200Y and F167Y, respectively. For LEV, 54.37% of resistance alleles were found. There was agreement between EHT, FECRT and qPCR for BZs, and agreement between LDT and qPCR for LEV. Thus, based on higher sensitivity of qPCR, and phenotypic evaluation, the Caucaia population was considered resistant to BZs, MLs, LEV and suspect for MPTL.


Assuntos
Anti-Helmínticos , Haemonchus , Nematoides , Doenças dos Ovinos , Animais , Anti-Helmínticos/farmacologia , Anti-Helmínticos/uso terapêutico , Brasil , Resistência a Medicamentos/genética , Fezes , Contagem de Ovos de Parasitas/veterinária , Ovinos , Doenças dos Ovinos/diagnóstico , Doenças dos Ovinos/tratamento farmacológico
4.
Medicine (Baltimore) ; 100(25): e26308, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34160394

RESUMO

INTRODUCTION: Mechanical circulatory support such as the left ventricular assist device (LVAD) has become widely implemented in the treatment of end-stage heart failure, whether as bridge-to-transplant or as destination therapy. The hemodynamic effects of arrhythmia on LVADs and its management are significant in determining the long-term outcome of these patients. Both atrial arrhythmia and ventricular arrhythmia are commonly seen after implantation of the device. There are no strict guidelines, however, on the need for intensive management of arrhythmias in LVAD. In this case report, we present a patient with new onset atrial fibrillation after LVAD implantation which leads to acute decompensating heart failure. The patient was treated with catheter ablation. The intervention demonstrated positive outcomes for this patient. PATIENT CONCERNS: The patient was a Korean male, who presented with dyspnea, fatigue and generalized edema after persistent atrial fibrillation precipitated by implantation of the left ventricular assist device. DIAGNOSIS: The patient was diagnosed with acute decompensating heart failure that was aggravated by recurrent atrial arrhythmia. INTERVENTION: We attempted to relieve symptoms of right ventricular dysfunction by method of strict rhythm control in this patient. The patient underwent radiofrequency catheter ablation for recurrent atrial fibrillation. OUTCOME: The patient showed improved clinical symptoms, BNP levels, and echocardiogram parameters immediately after the procedure as well as during long term outpatient follow up. CONCLUSION: In this case report, we present the first successful case in Korea of atrial fibrillation in LVAD treated with catheter ablation. This case suggests setting catheter ablation as a routine first-line treatment for atrial arrhythmia in LVAD patients, especially when the arrhythmia predisposes the patient at risk for decompensating heart failure.


Assuntos
Fibrilação Atrial/terapia , Cardiomiopatia Dilatada/cirurgia , Ablação por Cateter , Insuficiência Cardíaca/terapia , Coração Auxiliar/efeitos adversos , Idoso , Antiarrítmicos/administração & dosagem , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/etiologia , Cardiomiopatia Dilatada/complicações , Resistência a Medicamentos , Ecocardiografia , Eletrocardiografia , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/etiologia , Humanos , Masculino , Recidiva , Resultado do Tratamento
5.
Korean J Intern Med ; 36(4): 888-897, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34092048

RESUMO

BACKGROUND/AIMS: To examine the prevalence and clinical characteristics of apparent treatment-resistant hypertension among ambulatory hypertensive patients. METHODS: We enrolled adult ambulatory hypertensive patients at 13 well-qualified general hospitals in Korea from January to June 2012. Apparent resistant hypertension was defined as an elevated blood pressure > 140/90 mmHg with the use of three antihypertensive agents, including diuretics, or ≥ 4 antihypertensives, regardless of the blood pressure. Controlled hypertension was defined as a blood pressure within the target using three antihypertensives, including diuretics. RESULTS: Among 16,915 hypertensive patients, 1,172 (6.9%) had controlled hypertension, and 1,514 (8.9%) had apparent treatment-resistant hypertension. Patients with apparent treatment-resistant hypertension had an earlier onset of hypertension (56.8 years vs. 58.8 years, p = 0.007) and higher body mass index (26.3 kg/m2 vs. 24.9 kg/m2, p < 0.001) than those with controlled hypertension. Drug compliance did not differ between groups. In the multivariable analysis, earlier onset of hypertension (odds ratio [OR], 0.98; 95% confidence interval [CI], 0.97 to 0.99; p < 0.001) and the presence of comorbidities (OR, 2.06; 95% CI, 1.27 to 3.35; p < 0.001), such as diabetes mellitus, ischemic heart disease, heart failure, and chronic kidney disease, were independent predictors. Among the patients with apparent treatment-resistant hypertension, only 5.2% were receiving ≥ 2 antihypertensives at maximally tolerated doses. CONCLUSION: Apparent treatment-resistant hypertension prevalence is 8.9% among ambulatory hypertensive patients in Korea. An earlier onset of hypertension and the presence of comorbidities are independent predictors. Optimization of medical treatment may reduce the rate of apparent treatment-resistant hypertension.


Assuntos
Hospitais Gerais , Hipertensão , Adulto , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea , Estudos Transversais , Resistência a Medicamentos , Humanos , Hipertensão/diagnóstico , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Prevalência , República da Coreia/epidemiologia
6.
Emerg Infect Dis ; 27(7): 1902-1908, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34152946

RESUMO

The spread of drug resistance to antimalarial treatments poses a serious public health risk globally. To combat this risk, molecular surveillance of drug resistance is imperative. We report the prevalence of mutations in the Plasmodium falciparum kelch 13 propeller domain associated with partial artemisinin resistance, which we determined by using Sanger sequencing samples from patients enrolled in therapeutic efficacy studies from 9 sub-Saharan countries during 2014-2018. Of the 2,865 samples successfully sequenced before treatment (day of enrollment) and on the day of treatment failure, 29 (1.0%) samples contained 11 unique nonsynonymous mutations and 83 (2.9%) samples contained 27 unique synonymous mutations. Two samples from Kenya contained the S522C mutation, which has been associated with delayed parasite clearance; however, no samples contained validated or candidate artemisinin-resistance mutations.


Assuntos
Antimaláricos , Malária Falciparum , Antimaláricos/uso terapêutico , Resistência a Medicamentos , Humanos , Quênia , Malária Falciparum/tratamento farmacológico , Mutação , Plasmodium falciparum , Proteínas de Protozoários/genética
7.
Nat Commun ; 12(1): 3483, 2021 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-34108481

RESUMO

The hexameric AAA-ATPase Drg1 is a key factor in eukaryotic ribosome biogenesis and initiates cytoplasmic maturation of the large ribosomal subunit by releasing the shuttling maturation factor Rlp24. Drg1 monomers contain two AAA-domains (D1 and D2) that act in a concerted manner. Rlp24 release is inhibited by the drug diazaborine which blocks ATP hydrolysis in D2. The mode of inhibition was unknown. Here we show the first cryo-EM structure of Drg1 revealing the inhibitory mechanism. Diazaborine forms a covalent bond to the 2'-OH of the nucleotide in D2, explaining its specificity for this site. As a consequence, the D2 domain is locked in a rigid, inactive state, stalling the whole Drg1 hexamer. Resistance mechanisms identified include abolished drug binding and altered positioning of the nucleotide. Our results suggest nucleotide-modifying compounds as potential novel inhibitors for AAA-ATPases.


Assuntos
ATPases Associadas a Diversas Atividades Celulares/química , Adenosina Trifosfatases/química , Compostos de Boro/química , Proteínas de Saccharomyces cerevisiae/química , Domínio AAA , ATPases Associadas a Diversas Atividades Celulares/antagonistas & inibidores , ATPases Associadas a Diversas Atividades Celulares/genética , ATPases Associadas a Diversas Atividades Celulares/metabolismo , Adenosina Trifosfatases/antagonistas & inibidores , Adenosina Trifosfatases/genética , Adenosina Trifosfatases/metabolismo , Sítios de Ligação , Compostos de Boro/farmacologia , Resistência a Medicamentos/genética , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/genética , Mutação , Nucleotídeos/química , Proteínas de Saccharomyces cerevisiae/antagonistas & inibidores , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo
8.
Hematology ; 26(1): 447-452, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34165031

RESUMO

BACKGROUND: Diabetes mellitus is a major factor in clopidogrel resistance (CR), and the glucokinase (GCK) gene plays a pivotal role in glucose homeostasis. This study investigated the contribution of GCK polymorphisms to CR risk. METHODS: Two hundred SCAD patients were recruited, and their platelet functions were detected by the Verify-Now P2Y12 assay. The polymorphisms of GCK were tested based on the methods of polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). We investigated the associations of GCK polymorphisms and CR. Multivariate logistic regression was performed to analyse the correlations between GCK polymorphisms and clinical values. RESULTS: Our study found that the SNPs rs4607517 and rs6975024 were associated with CR. Additionally, patients with the G allele of rs4607517had a greater CR risk, but the C allele of rs6975024 might be a protective factor. Finally, logistic regression revealed that CC + TC (rs6975024) as well as the values of albumin were correlated with a decreased risk of CR, and higher levels of uric acid (UA) may be positively associated with CR. CONCLUSION: The GCK gene polymorphisms might increase the CR risk in SCAD patients. Meanwhile, higher albumin levels and lower UA values might decrease the risk.


Assuntos
Clopidogrel/uso terapêutico , Doença da Artéria Coronariana/tratamento farmacológico , Resistência a Medicamentos , Glucoquinase/genética , Inibidores da Agregação Plaquetária/uso terapêutico , Polimorfismo de Nucleotídeo Único , Idoso , Clopidogrel/farmacologia , Doença da Artéria Coronariana/genética , Humanos , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/farmacologia
9.
Turkiye Parazitol Derg ; 45(2): 83-87, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34103282

RESUMO

Objective: The relationship between drug resistance and the expression of hexokinase (HK) has been indicated in leishmaniasis. According to the prolonged treatment period in cutaneous leishmaniasis (CL) patients co-infected with Crithidia in Iran, this study aims to investigate the expression of HK in the proteome of Leishmania major and Crithidia using a proteomic approach. Methods: A total of 205 samples were removed from the lesions of patients in Fars province, Iran, for the characterization of L. major and Crithidia using polymerase chain reaction (PCR). After protein extraction, two-dimensional gel electrophoresis was employed for protein separation. Several spots were isolated for HK determination in the proteomes of L. major and Crithidia using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI TOF/TOF MS). Results: The PCR results showed 5 positive cases for Crithidia and 96 positive cases for L. major. MALDI TOF/TOF MS indicated HK as a common protein in the proteome of L. major and Crithidia. HK was up-regulated in the Crithidia proteome in comparison with the L. major proteome. Conclusion: Since a relationship between HK expression and drug resistance has been indicated in leishmaniasis, the overexpression of HK in Crithidia might be related to the increased duration of the treatment period in CL patients co-infected with Crithidia.


Assuntos
Crithidia/metabolismo , Hexoquinase/metabolismo , Leishmania major/metabolismo , Proteoma/metabolismo , Coinfecção/tratamento farmacológico , Coinfecção/parasitologia , Crithidia/enzimologia , Crithidia/isolamento & purificação , Resistência a Medicamentos , Infecções por Euglenozoa/tratamento farmacológico , Infecções por Euglenozoa/parasitologia , Humanos , Irã (Geográfico) , Leishmania major/enzimologia , Leishmania major/isolamento & purificação , Proteômica
10.
Parasite ; 28: 50, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34114948

RESUMO

Anthelmintic overuse and failure to implement methods preventing the development and spread of anthelmintic resistance (AR) have led to an alarming increase of resistant ovine trichostrongylids worldwide. The aim of the present study was to determine whether the routine anthelmintic treatment strategy was effective, to obtain insights into the frequency of AR in trichostrongylids of sheep in Austria, and to determine the presence of different trichostrongylid genera. On 30 sheep farms, the faecal egg count reduction test (FECRT) was performed with the Mini-FLOTAC technique in two consecutive studies. In study 1, only fenbendazole and moxidectin were tested, while different compounds and products were used in study 2. Overall, 33 treatment groups were formed: 11 groups were treated with benzimidazoles (fenbendazole and albendazole), 2 groups with avermectins (ivermectin, doramectin), 18 groups with moxidectin, and two groups with monepantel. Reduced efficacy was detected in 64%, 100%, 28% and 50% of these groups, respectively. The most frequently detected genus in larval cultures was Haemonchus, which had been barely detected in Austria previously, followed by Trichostrongylus. Multispecific resistance of trichostrongylids in Austria seems to be on the rise and H. contortus was detected unexpectedly frequently in comparison to previous studies. There is an urgent need to develop efficient communication strategies aimed at improving the engagement of farmers and veterinarians in sustainable parasite control.


Assuntos
Anti-Helmínticos , Haemonchus , Doenças dos Ovinos , Animais , Anti-Helmínticos/farmacologia , Anti-Helmínticos/uso terapêutico , Áustria/epidemiologia , Resistência a Medicamentos , Fezes , Ivermectina , Contagem de Ovos de Parasitas/veterinária , Ovinos , Doenças dos Ovinos/tratamento farmacológico , Doenças dos Ovinos/epidemiologia , Doenças dos Ovinos/prevenção & controle
11.
Front Cell Infect Microbiol ; 11: 691121, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34178727

RESUMO

Parasites of the phylum Apicomplexa impact humans in nearly all parts of the world, causing diseases including to toxoplasmosis, cryptosporidiosis, babesiosis, and malaria. Apicomplexan parasites have complex life cycles comprised of one or more stages characterized by rapid replication and biomass amplification, which enables accelerated evolutionary adaptation to environmental changes, including to drug pressure. The emergence of drug resistant pathogens is a major looming and/or active threat for current frontline chemotherapies, especially for widely used antimalarial drugs. In fact, resistant parasites have been reported against all modern antimalarial drugs within 15 years of clinical introduction, including the current frontline artemisinin-based combination therapies. Chemotherapeutics are a major tool in the public health arsenal for combatting the onset and spread of apicomplexan diseases. All currently approved antimalarial drugs have been discovered either through chemical modification of natural products or through large-scale screening of chemical libraries for parasite death phenotypes, and so far, none have been developed through a gene-to-drug pipeline. However, the limited duration of efficacy of these drugs in the field underscores the need for new and innovative approaches to discover drugs that can counter rapid resistance evolution. This review details both historical and current antimalarial drug discovery approaches. We also highlight new strategies that may be employed to discover resistance-resistant drug targets and chemotherapies in order to circumvent the rapid evolution of resistance in apicomplexan parasites.


Assuntos
Antimaláricos , Malária , Parasitos , Animais , Antimaláricos/farmacologia , Descoberta de Drogas , Resistência a Medicamentos , Humanos , Malária/tratamento farmacológico , Plasmodium falciparum
12.
FEBS Lett ; 595(12): 1696-1707, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33960401

RESUMO

The transcriptional regulators of arsenic-induced gene expression remain largely unknown. Sulfur assimilation is tightly linked with arsenic detoxification. Here, we report that mutant alleles in the SLIM1 transcription factor are substantially more sensitive to arsenic than cadmium. Arsenic treatment caused high levels of oxidative stress in the slim1 mutants, and slim1 alleles were impaired in both thiol accumulation and sulfate accumulation. We further found enhanced arsenic accumulation in roots of slim1 mutants. Transcriptome analyses indicate an important role for SLIM1 in arsenic-induced tolerance mechanisms. The present study identifies the SLIM1 transcription factor as an essential component in arsenic tolerance and arsenic-induced gene expression. Our results suggest that the severe arsenic sensitivity of the slim1 mutants is caused by altered redox status.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Arsênio , Proteínas de Ligação a DNA , Resistência a Medicamentos , Estresse Oxidativo/efeitos dos fármacos , Raízes de Plantas , Fatores de Transcrição , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Arsênio/metabolismo , Arsênio/farmacologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Raízes de Plantas/genética , Raízes de Plantas/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
13.
Nat Commun ; 12(1): 3160, 2021 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-34039976

RESUMO

Despite the high burden of Plasmodium vivax malaria in South Asian countries, the genetic diversity of circulating parasite populations is not well described. Determinants of antimalarial drug susceptibility for P. vivax in the region have not been characterised. Our genomic analysis of global P. vivax (n = 558) establishes South Asian isolates (n = 92) as a distinct subpopulation, which shares ancestry with some East African and South East Asian parasites. Signals of positive selection are linked to drug resistance-associated loci including pvkelch10, pvmrp1, pvdhfr and pvdhps, and two loci linked to P. vivax invasion of reticulocytes, pvrbp1a and pvrbp1b. Significant identity-by-descent was found in extended chromosome regions common to P. vivax from India and Ethiopia, including the pvdbp gene associated with Duffy blood group binding. Our investigation provides new understanding of global P. vivax population structure and genomic diversity, and genetic evidence of recent directional selection in this important human pathogen.


Assuntos
Genes de Protozoários , Malária Vivax/parasitologia , Plasmodium vivax/genética , Seleção Genética , África Oriental , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Ásia , Resistência a Medicamentos/genética , Sistema do Grupo Sanguíneo Duffy , Loci Gênicos , Humanos , Malária Vivax/sangue , Malária Vivax/tratamento farmacológico , Filogenia , Filogeografia , Plasmodium vivax/efeitos dos fármacos , Plasmodium vivax/patogenicidade , Polimorfismo de Nucleotídeo Único , Proteínas de Protozoários/genética , Reticulócitos/parasitologia
14.
Rev Bras Parasitol Vet ; 30(2): e025120, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33950148

RESUMO

This study evaluated the resistance status of Haemonchus contortus from sheep flocks in the state of São Paulo, Brazil, through comparison between the fecal egg count reduction test (FECRT) and the larval development test (LDT). For the FECRT, 35 sheep were selected in each of five flocks and divided into groups treated with: benzimidazole, levamisole, ivermectin, monepantel and control. Feces were collected for EPG and fecal cultures. The LDT was performed using thiabendazole (TBZ), levamisole (LEV), ivermectin aglycone (IVM-A) and Zolvix (ZLV). Resistance to all drugs was detected using FECRT in 100% of the flocks, except in relation to ZLV (40% resistant and 20% suspected of resistance). LDT indicated resistance to TBZ and IVM-A in all flocks, to LEV in 80% of flocks and to ZLV in 10%. Total agreement was obtained between the two tests for TBZ and IVM (k = 1.0), while for LEV (k = 0.8) and ZLV (k = 0.9), substantial and almost perfect agreement were obtained, respectively. The concordance between the tests was significant, thus showing that it is possible to use the outcome of the LDT to predict the FECRT, and hence validating the former as a fast diagnostic test for use by sheep farmers in Brazil.


Assuntos
Anti-Helmínticos , Hemoncose , Haemonchus , Doenças dos Ovinos , Animais , Anti-Helmínticos/farmacologia , Anti-Helmínticos/uso terapêutico , Brasil , Resistência a Medicamentos , Fezes , Hemoncose/diagnóstico , Hemoncose/tratamento farmacológico , Hemoncose/veterinária , Ivermectina/uso terapêutico , Contagem de Ovos de Parasitas/veterinária , Ovinos , Doenças dos Ovinos/diagnóstico , Doenças dos Ovinos/tratamento farmacológico
16.
Medicine (Baltimore) ; 100(20): e25831, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34011048

RESUMO

BACKGROUND: : The gene mutation of coding sodium channel is one of the most important mechanisms in the pathogenesis of epilepsy. There exists a large inter-individual variation in the efficacy of valproic acid (VPA) against epilepsy. What are the genetic polymorphism influences of sodium channels on VPA response is still under discussion. In this study, a meta-analysis was used to further explore the effects of SCN1A and SCN2A gene polymorphism on VPA response in children with epilepsy. METHODS: : The PubMed, EMBASE, Web of Science, Chinese National Knowledge Infrastructure, Chinese Science and Technique Journals Database, China Biology Medicine disc, and Wan Fang Database were searched up to April 2021 for appropriate studies regarding the association between SCN1A and SCN2A gene polymorphism on VPA response in children suffering from epilepsy. The meta-analysis was conducted by Review Manager 5.3 software. RESULTS: : The results of this meta-analysis will be submitted to a peer-reviewed journal for publication. CONCLUSION: : This meta-analysis will summarize the effects of SCN1A and SCN2A gene polymorphisms on VPA response in children with epilepsy. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/N2786.


Assuntos
Anticonvulsivantes/farmacologia , Epilepsia/tratamento farmacológico , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Canal de Sódio Disparado por Voltagem NAV1.2/genética , Ácido Valproico/farmacologia , Anticonvulsivantes/uso terapêutico , Criança , Resistência a Medicamentos/genética , Eletroencefalografia , Epilepsia/diagnóstico , Epilepsia/genética , Humanos , Metanálise como Assunto , Polimorfismo de Nucleotídeo Único , Revisões Sistemáticas como Assunto , Resultado do Tratamento , Ácido Valproico/uso terapêutico
17.
J Med Chem ; 64(10): 6608-6620, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-33974434

RESUMO

Trichomonas vaginalis causes the most common, nonviral sexually transmitted infection. Only metronidazole (Mz) and tinidazole are approved for treating trichomoniasis, yet resistance is a clinical problem. The gold(I) complex, auranofin, is active against T. vaginalis and other protozoa but has significant human toxicity. In a systematic structure-activity exploration, we show here that diversification of gold(I) complexes, particularly as halides with simple C1-C3 trialkyl phosphines or as bistrialkyl phosphine complexes, can markedly improve potency against T. vaginalis and selectivity over human cells compared to that of the existing antirheumatic gold(I) drugs. All gold(I) complexes inhibited the two most abundant isoforms of the presumed target enzyme, thioredoxin reductase, but a subset of compounds were markedly more active against live T. vaginalis than the enzyme, suggesting that alternative targets exist. Furthermore, all tested gold(I) complexes acted independently of Mz and were able to overcome Mz resistance, making them candidates for the treatment of Mz-refractory trichomoniasis.


Assuntos
Antiprotozoários/química , Complexos de Coordenação/química , Ouro/química , Fosfinas/química , Animais , Antiprotozoários/metabolismo , Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/metabolismo , Complexos de Coordenação/farmacologia , Complexos de Coordenação/uso terapêutico , Modelos Animais de Doenças , Resistência a Medicamentos/efeitos dos fármacos , Feminino , Células HeLa , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Parasitária , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Relação Estrutura-Atividade , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Tiorredoxina Dissulfeto Redutase/metabolismo , Tricomoníase/tratamento farmacológico , Tricomoníase/parasitologia , Trichomonas vaginalis/efeitos dos fármacos , Trofozoítos/efeitos dos fármacos
18.
Front Public Health ; 9: 663974, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33968888

RESUMO

Setting: Programmatic management of drug-resistant tuberculosis in Ningbo, China. Objective: To assess whether data-driven genetic determinants of drug resistance patterns could outperform phenotypic drug susceptibility testing in predicting clinical meaningful outcomes among patients with multidrug-resistant tuberculosis (MDR-TB). Design: We conducted a prospective cohort study of 104 MDR-TB patients. All MDR-TB isolates underwent drug susceptibility testing and genotyping for mutations that could cause drug resistance. Study outcomes were time to sputum smear conversion and probability of treatment success, as well as time to culture conversion within 6 months. Data were analyzed using latent class analysis, Kaplan-Meier curves, and Cox regression models. Results: We report that latent class analysis of data identified two latent classes that predicted sputum smear conversion with P = 0.001 and area under receiver-operating characteristic curve of 0.73. The predicted latent class memberships were associated with superior capability in predicting sputum culture conversion at 6 months and overall treatment success compared to phenotypic drug susceptibility profiling using boosted logistic regression models. Conclusion: These results suggest that genetic determinants of drug resistance in combination with phenotypic drug-resistant tests could serve as useful biomarkers in predicting treatment prognosis in MDR-TB.


Assuntos
Mycobacterium tuberculosis , Preparações Farmacêuticas , Antituberculosos/uso terapêutico , China/epidemiologia , Resistência a Medicamentos , Humanos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/genética , Estudos Prospectivos
19.
ACS Infect Dis ; 7(6): 1752-1764, 2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-33974405

RESUMO

Trichomoniasis is the most common nonviral sexually transmitted disease in humans, but treatment options are limited. Here, we report a resorufin-based drug sensitivity assay for high-throughput microplate-based screening under hypoxic conditions. A 5203-compound enamine kinase library and several specialized compound series were tested for the inhibition of Trichomonas growth at 10 µM with Z' values of >0.5. Hits were rescreened in serial dilution to establish an IC50 concentration. A series of 7-substituted 7-deazaadenosine analogues emerged as highly potent anti-T. vaginalis agents, with EC50 values in the low double digit nanomolar range. These analogues exhibited excellent selectivity indices. Follow-up medicinal chemistry efforts identified an optimal ribofuranose and C7 substituent. Several nucleosides rapidly cleared cultures of T. vaginalis at a concentrations of just 2 × EC50. Preliminary in vivo evaluation in a murine trichomoniasis model (Tritrichomonas foetus) revealed promising activity upon topical administration, validating purine nucleoside analogues as a new class of antitrichomonal agents.


Assuntos
Doenças Sexualmente Transmissíveis , Trichomonas vaginalis , Animais , Resistência a Medicamentos , Ensaios de Triagem em Larga Escala , Humanos , Camundongos , Nucleosídeos/farmacologia
20.
Parasitol Res ; 120(6): 2233-2241, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34002261

RESUMO

Reports on metronidazole resistance of Trichomonas vaginalis strains have been on the increase. This study investigated the in vitro metronidazole resistance patterns in T. vaginalis isolates obtained from South African pregnant women and the genotypes of these isolates. This study included 362 pregnant women recruited from a hospital in Durban, South Africa. The women provided self-collected vaginal swabs for the detection of T. vaginalis by culture in Diamonds media. Cultured isolates were then subjected to anaerobic susceptibility assays to metronidazole. For the genotyping assays, the actin gene was digested by HindII, MseI, and RsaI. The banding patterns obtained after digestion was used to determine the genotypes. A total of 21/362 (5.8%) pregnant women tested positive for T. vaginalis infection. Of the 21 T. vaginalis isolates tested for metronidazole susceptibility, 9.5% (2/21) had a minimum inhibitory concentration (MIC) of 4 µg/ml (resistant), 38.1% (8/21) had a MIC of 2 µg/ml (intermediate), and 52.4% (11/21) had a MIC ≤ 1 µg/ml (susceptible). The dominant genotype that was identified across the isolates was genotype G. There was no correlation between genotype harboured and metronidazole susceptibility patterns. In this study, resistance to metronidazole was observed in clinical isolates of T. vaginalis. This study did not find a correlation between genotype harboured and metronidazole susceptibility patterns. Despite the lack of association, our study provides data on an area of research that is currently lacking in our setting.


Assuntos
Antitricômonas/farmacologia , Metronidazol/farmacologia , Vaginite por Trichomonas/parasitologia , Trichomonas vaginalis/efeitos dos fármacos , Actinas/genética , Adulto , Estudos Transversais , Resistência a Medicamentos , Feminino , Genótipo , Humanos , Testes de Sensibilidade Microbiana , Gravidez , África do Sul , Trichomonas vaginalis/isolamento & purificação
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