Social representation of "music" in young adults: a cross-cultural study.

Int J Audiol. 2016 Sep 9;:1-9

Authors: Manchaiah V, Zhao F, Widén S, Auzenne J, Beukes EW, Ahmadi T, Tomé D, Mahadeva D, Krishna R, Germundsson P

Abstract
OBJECTIVE: This study was aimed to explore perceptions of and reactions to music in young adults (18-25 years) using the theory of social representations (TSR).
DESIGN: The study used a cross-sectional survey design and included participants from India, Iran, Portugal, USA and UK. Data were analysed using various qualitative and quantitative methods.
STUDY SAMPLE: The study sample included 534 young adults.
RESULTS: The Chi-square analysis showed significant differences between the countries regarding the informants' perception of music. The most positive connotations about music were found in the responses obtained from Iranian participants (82.2%), followed by Portuguese participants (80.6%), while the most negative connotations about music were found in the responses obtained from Indian participants (18.2%), followed by Iranian participants (7.3%). The participants' responses fell into 19 main categories based on their meaning; however, not all categories were found in all five countries. The co-occurrence analysis results generally indicate that the category "positive emotions or actions" was the most frequent category occurring in all five countries.
CONCLUSIONS: The results indicate that music is generally considered to bring positive emotions for people within these societies, although a small percentage of responses indicate some negative consequences of music.

PMID: 27609441 [PubMed - as supplied by publisher]

10 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("orphan disease" OR "rare disease" OR "orphan diseases" OR "rare diseases")

These pubmed results were generated on 2016/09/09

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Repositioning of bromocriptine for treatment of acute myeloid leukemia.

J Transl Med. 2016;14:261

Authors: Lara-Castillo MC, Cornet-Masana JM, Etxabe A, Banús-Mulet A, Torrente MÁ, Nomdedeu M, Díaz-Beyá M, Esteve J, Risueño RM

Abstract
BACKGROUND: Treatment for acute myeloid leukemia (AML) has not significantly changed in the last decades and new therapeutic approaches are needed to achieve prolonged survival rates. Leukemia stem cells (LSC) are responsible for the initiation and maintenance of AML due to their stem-cell properties. Differentiation therapies aim to abrogate the self-renewal capacity and diminish blast lifespan.
METHODS: An in silico screening was designed to search for FDA-approved small molecules that potentially induce differentiation of AML cells. Bromocriptine was identified and validated in an in vitro screening. Bromocriptine is an approved drug originally indicated for Parkinson's disease, acromegaly, hyperprolactinemia and galactorrhoea, and recently repositioned for diabetes mellitus.
RESULTS: Treatment with bromocriptine reduced cell viability of AML cells by activation of the apoptosis program and induction of myeloid differentiation. Moreover, the LSC-enriched primitive AML cell fraction was more sensitive to the presence of bromocriptine. In fact, bromocriptine decreased the clonogenic capacity of AML cells. Interestingly, a negligible effect is observed in healthy blood cells and hematopoietic stem/progenitor cells.
CONCLUSIONS: Our results support the use of bromocriptine as an anti-AML drug in a repositioning setting and the further clinical validation of this preclinical study.

PMID: 27604463 [PubMed - in process]

Multiple sclerosis: Repurposing dopaminergic drugs for MS--the evidence mounts.

Nat Rev Neurol. 2016 Apr;12(4):191-2

Authors: Marino F, Cosentino M

PMID: 27020558 [PubMed - indexed for MEDLINE]

Clinical Utility of Combinatorial Pharmacogenomics-Guided Antidepressant Therapy: Evidence from Three Clinical Studies.

Mol Neuropsychiatry. 2015 Oct;1(3):145-55

Authors: Altar CA, Carhart J, Allen JD, Hall-Flavin D, Winner J, Dechairo B

Abstract
DNA of 258 patients with treatment-resistant depression was collected in three 8-10 week, two-arm, prospective clinical trials. Forty-four allelic variations were measured in genes for the cytochrome P450 (CYP) enzymes CYP2D6, CYPC19, and CYP1A2, the serotonin transporter (SLC6A4), and the 5-HT2A receptor (HTR2A). The combinatorial pharmacogenomic (CPGx™) GeneSight test results were provided to clinicians to support medication changes from baseline (guided arm), or they were provided at the end of each study to clinicians of unguided patients who were treated as usual (TAU). TAU subjects who at baseline were prescribed medications genetically discordant for them showed only a 12% symptom improvement, far less than the 32.5% or 28.5% improvements of the TAU subjects on yellow-category ('use with caution'; p = 0.002) or green-category medications ('use as recommended'; p = 0.02), respectively. The odds of a clinical response were increased 2.3-fold among all GeneSight-guided compared to all TAU subjects (p = 0.004), and overall, the guided group had a 53% greater improvement in depressive symptoms (p = 0.0002), a 1.7-fold relative improvement in response (p = 0.01), and a number needed to treat for one clinical response above that seen in the TAU group of 6.07.

PMID: 27606312 [PubMed]

VA Evidence-based Synthesis Program Evidence Briefs

Book. 2011

Authors:

Abstract
In January, 2015, the White House identified Veterans Affairs (VA) as a participating agency in the Precision Medicine Initiative, an effort to “enable a new era of medicine through research, technology, and policies that empower patients, researchers, and providers to work together toward development of individualized care” that takes into account individual differences in people's genes, environments, and lifestyles.5 To inform this initiative, the VA Office of Research and Development (ORD) is developing a clinical study to implement precision medicine in mental health (PMH). This study will supplement the Million Veteran Program's (MVP) capabilities to (1) understand the lifestyle, genomics and pharmacogenomics of depression in Veterans, (2) develop individualized approaches to treat depression in Veterans, and (3) develop and implement a responsible and efficient process of returning genetic data to providers and patients to determine how to use genetic findings in the clinical setting.6 The PMH planning committee identified depression as a relevant focus because of its high prevalence, the continuing need for better treatment strategies, and the growing use of genetic testing for decision making. As funding for this study is arranged for FY17, ORD is convening a planning committee meeting for April 2016 to discuss study development. To inform their meeting, ORD commissioned the Evidence-based Synthesis Program Coordinating Center (ESP CC) to conduct an evidence brief on the comparative effectiveness, harms, and cost-effectiveness of pharmacogenomics-guided antidepressant treatment versus usual care for major depressive disorder.

PMID: 27606389

A secondary benefit: the reproductive impact of carrier results from newborn screening for cystic fibrosis.

Genet Med. 2016 Sep 8;

Authors: Bombard Y, Miller FA, Barg CJ, Patton SJ, Carroll JC, Chakraborty P, Potter BK, Tam K, Taylor L, Kerr E, Davies C, Milburn J, Ratjen F, Guttmann A, Hayeems RZ

Abstract
PURPOSE: Newborn screening (NBS) for cystic fibrosis (CF) can identify carriers, which is considered a benefit that enables reproductive planning. We examined the reproductive impact of carrier result disclosure of NBS for CF.
METHODS: We surveyed mothers of carrier infants after NBS (Time 1) and 1 year later (Time 2) to ascertain intended and reported communication of their infants' carrier results to relatives, carrier testing for themselves/other children, and reproductive decisions. A sub-sample of mothers was also interviewed at Time 1 and Time 2.
RESULTS: The response rate was 54%. A little more than half (55%) of mothers underwent carrier testing at Time 1; another 40% of those who intended to undergo testing at Time 1 underwent testing at Time 2. Carrier result communication to relatives was high (92%), but a majority of participants did not expect the results to influence family planning (65%). All interviewed mothers valued learning their infants' carrier results. Some underwent carrier testing and then shared results with family. Others did not use the results or used them in unintended ways.
CONCLUSION: Although mothers valued learning carrier results from NBS, they reported moderate uptake of carrier testing and limited influence on family planning. Our study highlights the secondary nature of the benefit of disclosing carrier results of NBS.Genet Med advance online publication 08 September 2016Genetics in Medicine (2016); doi:10.1038/gim.2016.125.

PMID: 27608173 [PubMed - as supplied by publisher]

Long-term Rasamsonia argillacea complex species colonization revealed by rep-PCR in cystic fibrosis patients.

J Clin Microbiol. 2016 Sep 7;

Authors: Mouhajir A, Matray O, Giraud S, Mély L, Marguet C, Sermet-Gaudelus I, Le Gal S, Labbé F, Person C, Troussier F, Ballet JJ, Gargala G, Zouhair R, Bougnoux ME, Bouchara JP, Favennec L

Abstract
The aim of this work was to document molecular epidemiology of Rasamsonia argillacea species complex isolates from cystic fibrosis (CF) patients. In this work, 116 isolates belonging to this species complex and collected from 26 CF patients and one patient with chronic granulomatous disease were characterized using PCR amplification assays of repetitive DNA sequences, and electrophoretic separation of amplicons (rep-PCR). Data revealed a clustering consistent with molecular species identification. A single species was recovered from most patients. Rasamsonia aegroticola was the most common species, followed by R. argillacea stricto sensu and R. piperina, while R. eburnea was not identified. Of 29 genotypes, 7 were shared by distinct patients, while 22 were patient-specific. In each clinical sample, most isolates exhibited an identical genotype. Genotyping of isolates recovered from sequential samples from the same patient confirmed the capability of R. aegroticola and R. argillacea isolates to chronically colonize the airways. A unique genotype was recovered from two siblings during a 6-month period. In the other cases, a largely dominant genotype was detected. Present results which support the use of rep-PCR for both identification and genotyping for the R. argillacea species complex, provide the first molecular evidence of chronic airway colonization by these fungi in CF patients.

PMID: 27605712 [PubMed - as supplied by publisher]

A systems biology approach for elucidating the interaction of curcumin with Fanconi anemia FANC G protein and the key disease targets of leukemia.

J Recept Signal Transduct Res. 2016 Sep 8;:1-7

Authors: Mahato D, Samanta D, Mukhopadhyay SS, Krishnaraj RN

Abstract
Fanconi anemia (FA) is an autosomal recessive disorder with a high risk of malignancies including acute myeloid leukemia and squamous cell carcinoma. There is a constant search out of new potential therapeutic molecule to combat this disorder. In most cases, patients with FA develop haematological malignancies with acute myeloid leukemia and acute lymphoblastic leukemia. Identifying drugs which can efficiently block the pathways of both these disorders can be an ideal and novel strategy to treat FA. The curcumin, a natural compound obtained from turmeric is an interesting therapeutic molecule as it has been reported in the literature to combat both FA as well as leukemia. However, its complete mechanism is not elucidated. Herein, a systems biology approach for elucidating the therapeutic potential of curcumin against FA and leukemia is investigated by analyzing the computational molecular interactions of curcumin ligand with FANC G of FA and seven other key disease targets of leukemia. The proteins namely DOT1L, farnesyl transferase (FDPS), histone decetylase (EP3000), Polo-like kinase (PLK-2), aurora-like kinase (AUKRB), tyrosine kinase (ABL1), and retinoic acid receptor alpha (RARA) were chosen as disease targets for leukemia and modeled structure of FANC G protein as the disease target for FA. The docking investigations showed that curcumin had a very high binding affinity of -8.1 kcal/mol with FANC G protein. The key disease targets of leukemia namely tyrosine kinase (ABL1), aurora-like kinase (AUKRB), and polo-like kinase (PLK-2) showed that they had the comparable binding affinities of -9.7 k cal/mol, -8.7 k cal/mol, and -8.6 k cal/mol, respectively with curcumin. Further, the percentage similarity scores obtained from PAM50 using EMBOSS MATCHER was shown to provide a clue to understand the structural relationships to an extent and to predict the binding affinity. This investigation shows that curcumin effectively interacts with the disease targets of both FA and leukemia.

PMID: 27608133 [PubMed - as supplied by publisher]

Systems Perspective of Morbillivirus Replication.

J Mol Microbiol Biotechnol. 2016 Sep 9;26(6):389-400

Authors: Kumar N, Barua S, Thachamvally R, Tripathi BN

Abstract
Systems biology refers to system-wide changes in biological components such as RNA/DNA (genomics), protein (proteomics) and lipids (lipidomics). In this review, we provide comprehensive information about morbillivirus replication. Besides discussing the role of individual viral/host proteins in virus replication, we also discuss how systems-level analyses could improve our understanding of morbillivirus replication, host-pathogen interaction, immune response and disease resistance. Finally, we discuss how viroinformatics is likely to provide important insights for understanding genome-genome, genome-protein and protein-protein interactions.

PMID: 27607146 [PubMed - as supplied by publisher]

41st FEBS Congress, Molecular and Systems Biology for a Better Life, Ephesus/Kuşadasi, Turkey, September 3-8, 2016.

FEBS J. 2016 Sep;283 Suppl 1:2-427

Authors:

PMID: 27604825 [PubMed - in process]

Role of Systems Biology in Brain Injury Biomarker Discovery: Neuroproteomics Application.

Methods Mol Biol. 2016;1462:157-74

Authors: Jaber Z, Aouad P, Al Medawar M, Bahmad H, Abou-Abbass H, Ghandour H, Mondello S, Kobeissy F

Abstract
Years of research in the field of neurotrauma have led to the concept of applying systems biology as a tool for biomarker discovery in traumatic brain injury (TBI). Biomarkers may lead to understanding mechanisms of injury and recovery in TBI and can be potential targets for wound healing, recovery, and increased survival with enhanced quality of life. The literature available on neurotrauma studies from both animal and clinical studies has provided rich insight on the molecular pathways and complex networks of TBI, elucidating the proteomics of this disease for the discovery of biomarkers. With such a plethora of information available, the data from the studies require databases with tools to analyze and infer new patterns and associations. The role of different systems biology tools and their use in biomarker discovery in TBI are discussed in this chapter.

PMID: 27604718 [PubMed - in process]

Application of Systems Biology to Neuroproteomics: The Path to Enhanced Theranostics in Traumatic Brain Injury.

Methods Mol Biol. 2016;1462:139-55

Authors: Jaber Z, Aouad P, Al Medawar M, Bahmad H, Abou-Abbass H, Kobeissy F

Abstract
The application of systems biology tools in analyzing heterogeneous data from multiple sources has become a necessity, especially in biomarker discovery. Such tools were developed with several approaches to address different types of research questions and hypotheses. In the field of neurotrauma and traumatic brain injury (TBI), three distinct approaches have been used so far as systems biology tools, namely functional group categorization, pathway analysis, and protein-protein interaction (PPI) networks. The databases allow for query of the system to identify candidate targets which can be further studied to elucidate potential downstream biomarkers indicative of disease progression, severity, and improvement. The various systems biology tools, databases, and strategies that can be implemented on available TBI data in neuroproteomic studies are discussed in this chapter.

PMID: 27604717 [PubMed - in process]

Genome-wide protein-protein interactions and protein function exploration in cyanobacteria.

Sci Rep. 2015;5:15519

Authors: Lv Q, Ma W, Liu H, Li J, Wang H, Lu F, Zhao C, Shi T

Abstract
Genome-wide network analysis is well implemented to study proteins of unknown function. Here, we effectively explored protein functions and the biological mechanism based on inferred high confident protein-protein interaction (PPI) network in cyanobacteria. We integrated data from seven different sources and predicted 1,997 PPIs, which were evaluated by experiments in molecular mechanism, text mining of literatures in proved direct/indirect evidences, and "interologs" in conservation. Combined the predicted PPIs with known PPIs, we obtained 4,715 no-redundant PPIs (involving 3,231 proteins covering over 90% of genome) to generate the PPI network. Based on the PPI network, terms in Gene ontology (GO) were assigned to function-unknown proteins. Functional modules were identified by dissecting the PPI network into sub-networks and analyzing pathway enrichment, with which we investigated novel function of underlying proteins in protein complexes and pathways. Examples of photosynthesis and DNA repair indicate that the network approach is a powerful tool in protein function analysis. Overall, this systems biology approach provides a new insight into posterior functional analysis of PPIs in cyanobacteria.

PMID: 26490033 [PubMed - indexed for MEDLINE]

The burden of severe asthma in childhood and adolescence: results from the paediatric U-BIOPRED cohorts.

Eur Respir J. 2015 Nov;46(5):1322-33

Authors: Fleming L, Murray C, Bansal AT, Hashimoto S, Bisgaard H, Bush A, Frey U, Hedlin G, Singer F, van Aalderen WM, Vissing NH, Zolkipli Z, Selby A, Fowler S, Shaw D, Chung KF, Sousa AR, Wagers S, Corfield J, Pandis I, Rowe A, Formaggio E, Sterk PJ, Roberts G, U-BIOPRED Study Group

Abstract
U-BIOPRED aims to characterise paediatric and adult severe asthma using conventional and innovative systems biology approaches. A total of 99 school-age children with severe asthma and 81 preschoolers with severe wheeze were compared with 49 school-age children with mild/moderate asthma and 53 preschoolers with mild/moderate wheeze in a cross-sectional study. Despite high-dose treatment, the severe cohorts had more severe exacerbations compared with the mild/moderate ones (annual medians: school-aged 3.0 versus 1.1, preschool 3.9 versus 1.8; p<0.001). Exhaled tobacco exposure was common in the severe wheeze cohort. Almost all participants in each cohort were atopic and had a normal body mass index. Asthma-related quality of life, as assessed by the Paediatric Asthma Quality of Life Questionnaire (PAQLQ) and the Paediatric Asthma Caregiver's Quality of Life Questionnaire (PACQLQ), was worse in the severe cohorts (mean±se school-age PAQLQ: 4.77±0.15 versus 5.80±0.19; preschool PACQLQ: 4.27±0.18 versus 6.04±0.18; both p≤0.001); however, mild/moderate cohorts also had significant morbidity. Impaired quality of life was associated with poor control and airway obstruction. Otherwise, the severe and mild/moderate cohorts were clinically very similar. Children with severe preschool wheeze or severe asthma are usually atopic and have impaired quality of life that is associated with poor control and airflow limitation: a very different phenotype from adult severe asthma. In-depth phenotyping of these children, integrating clinical data with high-dimensional biomarkers, may help to improve and tailor their clinical management.

PMID: 26405287 [PubMed - indexed for MEDLINE]

Clinical and inflammatory characteristics of the European U-BIOPRED adult severe asthma cohort.

Eur Respir J. 2015 Nov;46(5):1308-21

Authors: Shaw DE, Sousa AR, Fowler SJ, Fleming LJ, Roberts G, Corfield J, Pandis I, Bansal AT, Bel EH, Auffray C, Compton CH, Bisgaard H, Bucchioni E, Caruso M, Chanez P, Dahlén B, Dahlen SE, Dyson K, Frey U, Geiser T, Gerhardsson de Verdier M, Gibeon D, Guo YK, Hashimoto S, Hedlin G, Jeyasingham E, Hekking PP, Higenbottam T, Horváth I, Knox AJ, Krug N, Erpenbeck VJ, Larsson LX, Lazarinis N, Matthews JG, Middelveld R, Montuschi P, Musial J, Myles D, Pahus L, Sandström T, Seibold W, Singer F, Strandberg K, Vestbo J, Vissing N, von Garnier C, Adcock IM, Wagers S, Rowe A, Howarth P, Wagener AH, Djukanovic R, Sterk PJ, Chung KF, U-BIOPRED Study Group

Abstract
U-BIOPRED is a European Union consortium of 20 academic institutions, 11 pharmaceutical companies and six patient organisations with the objective of improving the understanding of asthma disease mechanisms using a systems biology approach.This cross-sectional assessment of adults with severe asthma, mild/moderate asthma and healthy controls from 11 European countries consisted of analyses of patient-reported outcomes, lung function, blood and airway inflammatory measurements.Patients with severe asthma (nonsmokers, n=311; smokers/ex-smokers, n=110) had more symptoms and exacerbations compared to patients with mild/moderate disease (n=88) (2.5 exacerbations versus 0.4 in the preceding 12 months; p<0.001), with worse quality of life, and higher levels of anxiety and depression. They also had a higher incidence of nasal polyps and gastro-oesophageal reflux with lower lung function. Sputum eosinophil count was higher in severe asthma compared to mild/moderate asthma (median count 2.99% versus 1.05%; p=0.004) despite treatment with higher doses of inhaled and/or oral corticosteroids.Consistent with other severe asthma cohorts, U-BIOPRED is characterised by poor symptom control, increased comorbidity and airway inflammation, despite high levels of treatment. It is well suited to identify asthma phenotypes using the array of "omic" datasets that are at the core of this systems medicine approach.

PMID: 26357963 [PubMed - indexed for MEDLINE]

Nos3-/- iPSCs model concordant signatures of in utero cardiac pathogenesis.

J Mol Cell Cardiol. 2015 Oct;87:228-36

Authors: Campbell KA, Li X, Biendarra SM, Terzic A, Nelson TJ

Abstract
BACKGROUND: Through genome-wide transcriptional comparisons, this study interrogates the capacity of in vitro differentiation of induced pluripotent stem cells (iPSCs) to accurately model pathogenic signatures of developmental cardiac defects.
METHODS AND RESULTS: Herein, we studied the molecular etiology of cardiac defects in Nos3(-/-) mice via transcriptional analysis of stage-matched embryonic tissues and iPSC-derived cells. In vitro comparisons of differentiated cells were calibrated to in utero benchmarks of health and disease. Integrated systems biology analysis of WT and Nos3(-/-) transcriptional profiles revealed 50% concordant expression patterns between in utero embryonic tissues and ex vivo iPSC-derived cells. In particular, up-regulation of glucose metabolism (p-value=3.95×10(-12)) and down-regulation of fatty acid metabolism (p-value=6.71×10(-12)) highlight a bioenergetic signature of early Nos3 deficiency during cardiogenesis that can be recapitulated in iPSC-derived differentiated cells.
CONCLUSIONS: The in vitro concordance of early Nos3(-/-) disease signatures supports the utility of iPSCs as a cellular model of developmental heart defects. Moreover, this study supports the use of iPSCs as a platform to pinpoint initial stages of congenital cardiac pathogenesis.

PMID: 26344701 [PubMed - indexed for MEDLINE]

Genome-wide protein-protein interactions and protein function exploration in cyanobacteria.

Sci Rep. 2015;5:15519

Authors: Lv Q, Ma W, Liu H, Li J, Wang H, Lu F, Zhao C, Shi T

Abstract
Genome-wide network analysis is well implemented to study proteins of unknown function. Here, we effectively explored protein functions and the biological mechanism based on inferred high confident protein-protein interaction (PPI) network in cyanobacteria. We integrated data from seven different sources and predicted 1,997 PPIs, which were evaluated by experiments in molecular mechanism, text mining of literatures in proved direct/indirect evidences, and "interologs" in conservation. Combined the predicted PPIs with known PPIs, we obtained 4,715 no-redundant PPIs (involving 3,231 proteins covering over 90% of genome) to generate the PPI network. Based on the PPI network, terms in Gene ontology (GO) were assigned to function-unknown proteins. Functional modules were identified by dissecting the PPI network into sub-networks and analyzing pathway enrichment, with which we investigated novel function of underlying proteins in protein complexes and pathways. Examples of photosynthesis and DNA repair indicate that the network approach is a powerful tool in protein function analysis. Overall, this systems biology approach provides a new insight into posterior functional analysis of PPIs in cyanobacteria.

PMID: 26490033 [PubMed - indexed for MEDLINE]

21 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("orphan disease" OR "rare disease" OR "orphan diseases" OR "rare diseases")

These pubmed results were generated on 2016/09/08

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Antileishmanial activity of ezetimibe: inhibition of sterol biosynthesis, in vitro synergy with azoles and efficacious in experimental cutaneous leishmaniasis.

Antimicrob Agents Chemother. 2016 Sep 6;

Authors: Andrade-Neto VV, Cunha-Júnior EF, Canto-Cavalheiro MM, Atella GC, Fernandes TA, Costa PR, Torres-Santos EC

Abstract
Leishmaniasis affects mainly low-income populations in tropical regions. Radical innovation in drug discovery is time- and money-consuming, causing severe restrictions to launch new chemical entities to treat neglected diseases. Drug repositioning is an attractive strategy to attend a specific demand more easily. In this project, we have evaluated the antileishmanial activity of 30 drugs currently in clinical usage for different morbidities. Ezetimibe, clinically used to reduce intestinal cholesterol absorption in dyslipidemic patients, killed promastigotes of L. amazonensis, with an IC50 of 30 μM. Morphological analysis revealed that ezetimibe caused the parasites to become rounded with multiple nuclei and flagellae. Analysis by GC/MS showed that promastigotes treated with ezetimibe had a lower amount of C14-demethylated sterols and accumulated cholesterol and lanosterol. Then, we evaluated the combination of ezetimibe with well-known antileishmanial azoles. The Fractional Inhibitory Concentration Index (FICI) indicated synergy when ezetimibe is associated with ketoconazole or miconazole. Ezetimibe activity was confirmed against intracellular amastigotes, with an IC50 of 20 μM, and reduced the IC90 of ketoconazole and miconazole from 11.3 and 11.5 μM to 4.14 and 8.25 μM, respectively. Following, ezetimibe confirmed its activity in vivo, decreasing the lesion development and parasite load in murine cutaneous leishmaniasis. We concluded that ezetimibe has promising antileishmanial activity and should be considered in association with azoles in further preclinical and clinical studies.

PMID: 27600041 [PubMed - as supplied by publisher]