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[PMID]: 28468677
[Au] Autor:Andrade-Campos M; Alfonso P; Irun P; Armstrong J; Calvo C; Dalmau J; Domingo MR; Barbera JL; Cano H; Fernandez-Galán MA; Franco R; Gracia I; Gracia-Antequera M; Ibañez A; Lendinez F; Madruga M; Martin-Hernández E; O'Callaghan MDM; Del Soto AP; Del Prado YR; Sancho-Val I; Sanjurjo P; Pocovi M; Giraldo P
[Ad] Address:Haematology Department, Miguel Servet University Hospital, Zaragoza, Spain.
[Ti] Title:Diagnosis features of pediatric Gaucher disease patients in the era of enzymatic therapy, a national-base study from the Spanish Registry of Gaucher Disease.
[So] Source:Orphanet J Rare Dis;12(1):84, 2017 May 03.
[Is] ISSN:1750-1172
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:BACKGROUND: The enzymatic replacement therapy (ERT) availability for Gaucher disease (GD) has changed the landscape of the disease, several countries have screening programs. These actions have promoted the early diagnosis and avoided many complications in pediatric patients. In Spain ERT has been available since 1993 and 386 patients have been included in the Spanish Registry of Gaucher Disease (SpRGD). The aim of this study is to analyze the impact of ERT on the characteristics at time of diagnosis and initial complications in pediatric Gaucher disease patients. AIM: To analyze the impact of ERT on the characteristics at time of diagnosis and initial complications in pediatric Gaucher disease patients. METHODS: A review of data in SpRGD from patients' diagnosed before 18 years old was performed. The cohort was split according the year of diagnosis (≤1994, cohort A; ≥1995, cohort B). RESULTS: A total of 98 pediatric patients were included, GD1: 80, GD3: 18; mean age: 7.2 (0.17-16.5) years, 58 (59.2%) males and 40 (40.8%) females. Forty-five were diagnosed ≤ 1994 and 53 ≥ 1995. Genotype: N370S/N370S: 2 (2.0%), N370S/L444P: 27 (27.5%), N370S/other: 47 (48%), L444P/L444P: 7 (7.1%), L444P/D409H: 2 (2.0%), L444P/other: 3 (6.2%), other/other: 10 (10.2%). The mean age at diagnosis was earlier in patients diagnosed after 1995 (p < 0.001) and different between the subtypes, GD1: 8.2 (0.2-16.5) years and GD3: 2.8 (0.17-10.2) years (p < 0.001). There were more severe patients in the group diagnosed before 1994 (p = 0.045) carrying L444P (2), D409H (2), G377S (1), G195W (1) or the recombinant mutation. The patients' diagnosed ≤1994 showed worse cytopenias, higher chance of bone vascular complications at diagnosis and previous spleen removal. The patients started ERT at a median time after diagnosis of 5.2 years [cohort A] and 1.6 years [cohort B] (p < 0.001). CONCLUSIONS: The early diagnosis of Gaucher disease in the era of ERT availability has permitted to reduce the incidence of severe and irreversible initial complication in pediatric patients, and this has permitted better development of these patients. This is the largest pediatric cohort from a national registry.
[Mh] MeSH terms primary: Enzyme Replacement Therapy
Gaucher Disease/diagnosis
[Mh] MeSH terms secundary: Adolescent
Child
Child, Preschool
Enzyme Replacement Therapy/statistics & numerical data
Female
Gaucher Disease/drug therapy
Gaucher Disease/epidemiology
Humans
Infant
Male
Registries
Spain/epidemiology
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180228
[Lr] Last revision date:180228
[Js] Journal subset:IM
[Da] Date of entry for processing:170505
[St] Status:MEDLINE
[do] DOI:10.1186/s13023-017-0627-z

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[PMID]: 29248575
[Au] Autor:Natale A; Boeckmans J; Desmae T; De Boe V; De Kock J; Vanhaecke T; Rogiers V; Rodrigues RM
[Ad] Address:Department of In Vitro Toxicology & Dermato-Cosmetology (IVTD), Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium. Electronic address: alessandra.natale@vub.be.
[Ti] Title:Hepatic cells derived from human skin progenitors show a typical phospholipidotic response upon exposure to amiodarone.
[So] Source:Toxicol Lett;284:184-194, 2018 Mar 01.
[Is] ISSN:1879-3169
[Cp] Country of publication:Netherlands
[La] Language:eng
[Ab] Abstract:Phospholipidosis is a metabolic disorder characterized by intracellular accumulation of phospholipids. It can be caused by short-term or chronic exposure to cationic amphiphilic drugs (CADs). These compounds bind to phospholipids, leading to inhibition of their degradation and consequently to their accumulation in lysosomes. Drug-induced phospholipidosis (DIPL) is frequently at the basis of discontinuation of drug development and post-market drug withdrawal. Therefore, reliable human-relevant in vitro models must be developed to speed up the identification of compounds that are potential inducers of phospholipidosis. Here, hepatic cells derived from human skin (hSKP-HPC) were evaluated as an in vitro model for DIPL. These cells were exposed over time to amiodarone, a CAD known to induce phospholipidosis in humans. Transmission electron microscopy revealed the formation of the typical lamellar inclusions in the cell cytoplasm. Increase of phospholipids was already detected after 24 h exposure to amiodarone, whereas a significant increase of neutral lipid vesicles could be observed after 72 h. At the transcriptional level, the modulation of genes involved in DIPL was detected. These results provide a valuable indication of the applicability of hSKP-HPC for the quick assessment of drug-induced phospholipidosis in vitro, early in the drug development process.
[Mh] MeSH terms primary: Drug Evaluation, Preclinical/methods
Hepatocytes/drug effects
Lipidoses/chemically induced
Phospholipids/metabolism
Skin/cytology
Stem Cells/cytology
[Mh] MeSH terms secundary: Amiodarone/toxicity
Cell Differentiation/drug effects
Cells, Cultured
Drug-Related Side Effects and Adverse Reactions
Flow Cytometry
Gene Expression/drug effects
Hep G2 Cells
Hepatocytes/ultrastructure
Humans
Lipidoses/genetics
Lysosomes/drug effects
Lysosomes/metabolism
Male
Phospholipids/genetics
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (Phospholipids); N3RQ532IUT (Amiodarone)
[Em] Entry month:1802
[Cu] Class update date: 180221
[Lr] Last revision date:180221
[Js] Journal subset:IM
[Da] Date of entry for processing:171218
[St] Status:MEDLINE

  3 / 6528 MEDLINE  
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[PMID]: 29290526
[Au] Autor:Voorink-Moret M; Goorden SMI; van Kuilenburg ABP; Wijburg FA; Ghauharali-van der Vlugt JMM; Beers-Stet FS; Zoetekouw A; Kulik W; Hollak CEM; Vaz FM
[Ad] Address:Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, The Netherlands. Electronic address: m.voorinkmoret@amc.uva.nl.
[Ti] Title:Rapid screening for lipid storage disorders using biochemical markers. Expert center data and review of the literature.
[So] Source:Mol Genet Metab;123(2):76-84, 2018 Feb.
[Is] ISSN:1096-7206
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:BACKGROUND: In patients suspected of a lipid storage disorder (sphingolipidoses, lipidoses), confirmation of the diagnosis relies predominantly on the measurement of specific enzymatic activities and genetic studies. New UPLC-MS/MS methods have been developed to measure lysosphingolipids and oxysterols, which, combined with chitotriosidase activity may represent a rapid first tier screening for lipid storage disorders. MATERIAL AND METHODS: A lysosphingolipid panel consisting of lysoglobotriaosylceramide (LysoGb3), lysohexosylceramide (LysoHexCer: both lysoglucosylceramide and lysogalactosylceramide), lysosphingomyelin (LysoSM) and its carboxylated analogue lysosphingomyelin-509 (LysoSM-509) was measured in control subjects and plasma samples of predominantly untreated patients affected with lipid storage disorders (n=74). In addition, the oxysterols cholestane-3ß,5α,6ß-triol and 7-ketocholesterol were measured in a subset of these patients (n=36) as well as chitotriosidase activity (n=43). A systematic review of the literature was performed to assess the usefulness of these biochemical markers. RESULTS: Specific elevations of metabolites, i.e. without overlap between controls and other lipid storage disorders, were found for several lysosomal storage diseases: increased LysoSM levels in acid sphingomyelinase deficiency (Niemann-Pick disease type A/B), LysoGb3 levels in males with classical phenotype Fabry disease and LysoHexCer (i.e. lysoglucosylceramide/lysogalactosylceramide) in Gaucher and Krabbe diseases. While elevated levels of LysoSM-509 and cholestane-3ß,5α,6ß-triol did not discriminate between Niemann Pick disease type C and acid sphingomyelinase deficiency, LysoSM-509/LysoSM ratio was specifically elevated in Niemann-Pick disease type C. In Gaucher disease type I, mild increases in several lysosphingolipids were found including LysoGb3 with levels in the range of non-classical Fabry males and females. Chitotriosidase showed specific elevations in symptomatic Gaucher disease, and was mildly elevated in all other lipid storage disorders. Review of the literature identified 44 publications. Most findings were in line with our cohort. Several moderate elevations of biochemical markers were found across a wide range of other, mainly inherited metabolic, diseases. CONCLUSION: Measurement in plasma of LysoSLs and oxysterols by UPLC-MS/MS in combination with activity of chitotriosidase provides a useful first tier screening of patients suspected of lipid storage disease. The LysoSM-509/LysoSM ratio is a promising parameter in Niemann-Pick disease type C. Further studies in larger groups of untreated patients and controls are needed to improve the specificity of the findings.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1801
[Cu] Class update date: 180211
[Lr] Last revision date:180211
[St] Status:In-Data-Review

  4 / 6528 MEDLINE  
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[PMID]: 29227082
[Au] Autor:Olkhovych NV
[Ti] Title:Chitotriosidase activity as additional biomarker in the diagnosis of lysosomal storage diseases.
[So] Source:Ukr Biochem J;88(1):69-78, 2016 Jan-Feb.
[Is] ISSN:2409-4943
[Cp] Country of publication:Ukraine
[La] Language:eng
[Ab] Abstract:To date, several genetic variants that lead to a deficiency of chitotriosidase activity have been described. The duplication of 24 bp (dup24bp) in exon 10 of the CHIT1 gene, which causes a complete loss of enzymatic activity of the gene product, is the most common among the European population. The aim of the study was to evaluate the possibility of using chitotriosidase activity as an additional biomarker in diagnosis of lysosomal storage diseases (LSDs) in Ukraine, to determine this parameter in blood plasma of the patients with various lysosomal diseases and to assess the effect of the presence of dup24bp in the CHIT1 gene on this parameter. It has been shown that chitotriosidase activity in blood plasma is a convenient additional biochemical marker in the diagnosis of some LSDs, namely Gaucher disease, Niemann-Pick disease A, B, C and GM1-gangliosidosis. Reference ranges of the normal chitotriosidase activity were determined in blood plasma of Ukrainian population and found to be 8.0-53.1 nmol 4-methylumbelliferone/h·ml of plasma. The total allele frequency of the dup24bp in the CHIT1 gene in Ukrainian population was determined, which amounted to 0.26 (323/1244) that is higher than in European population. It was indicated that moleculargenetic screening of dup24bp in the CHIT1 gene is a necessary stage in a protocol for the laboratory diagnosis of Gaucher disease, Niemann-Pick disease A, B, C as well as GM1-gangliosidosis to avoid incorrect diagnosis.
[Mh] MeSH terms primary: Gangliosidosis, GM1/genetics
Gaucher Disease/genetics
Gene Frequency
Hexosaminidases/genetics
Niemann-Pick Diseases/genetics
[Mh] MeSH terms secundary: Adult
Alleles
Biomarkers/metabolism
Case-Control Studies
Exons
Female
Gangliosidosis, GM1/classification
Gangliosidosis, GM1/diagnosis
Gangliosidosis, GM1/pathology
Gaucher Disease/diagnosis
Gaucher Disease/pathology
Gene Duplication
Gene Expression
Genetic Testing
Hexosaminidases/blood
Hexosaminidases/deficiency
Humans
Hymecromone/blood
Male
Niemann-Pick Diseases/classification
Niemann-Pick Diseases/diagnosis
Niemann-Pick Diseases/pathology
Ukraine
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (Biomarkers); 3T5NG4Q468 (Hymecromone); EC 3.2.1.- (Hexosaminidases); EC 3.2.1.- (chitotriosidase)
[Em] Entry month:1801
[Cu] Class update date: 180116
[Lr] Last revision date:180116
[Js] Journal subset:IM
[Da] Date of entry for processing:171212
[St] Status:MEDLINE
[do] DOI:10.15407/ubj88.01.069

  5 / 6528 MEDLINE  
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[PMID]: 28450571
[Au] Autor:Weinreb NJ
[Ad] Address:UNIVERSITY OF MIAMI.
[Ti] Title:Encore! Oral therapy for type 1 Gaucher disease.
[So] Source:Blood;129(17):2337-2338, 2017 04 27.
[Is] ISSN:1528-0020
[Cp] Country of publication:United States
[La] Language:eng
[Mh] MeSH terms primary: Gaucher Disease
Glucosylceramidase
[Mh] MeSH terms secundary: Enzyme Replacement Therapy
Humans
[Pt] Publication type:JOURNAL ARTICLE; COMMENT
[Nm] Name of substance:EC 3.2.1.45 (Glucosylceramidase)
[Em] Entry month:1801
[Cu] Class update date: 180116
[Lr] Last revision date:180116
[Js] Journal subset:AIM; IM
[Da] Date of entry for processing:170429
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2017-02-769034

  6 / 6528 MEDLINE  
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[PMID]: 28453301
[Au] Autor:Najarian DR; Hilton K; McCauley T; Qiu Y
[Ad] Address:Bioanalytical & Biomarker Development, 300 Shire Way, Lexington, MA 02421, USA.
[Ti] Title:A comparison study of bioanalytical methods for detection and characterization of anti-velaglucerase alfa antibodies.
[So] Source:Bioanalysis;9(10):775-786, 2017 May.
[Is] ISSN:1757-6199
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:AIM: To provide more efficient and timely immunogenicity testing service to support routine patient care, the original complex testing algorithm for evaluation of anti-velaglucerase alfa antibodies has been simplified and individual methods (screen, confirm, titer, neutralizing antibody [NAb] and IgE) have been redeveloped/optimized and validated. RESULTS: To compare the performance of different methods, 50 velaglucerase alfa-treated patient samples were analyzed using both old and new methods for the presence of antidrug antibodies (ADAs) and 31 ADA-positive samples were analyzed for neutralizing capacity. The ADA and NAb statuses are almost identical from both methods and both ADA and NAb titer results are highly correlated with a Spearman's correlation of 0.96 and 0.86, respectively. CONCLUSION: The original and new testing methods can be considered interchangeable for the measurement of total and neutralizing anti-velaglucerase alfa antibodies.
[Mh] MeSH terms primary: Antibodies, Neutralizing/blood
Antibodies, Neutralizing/immunology
Blood Chemical Analysis/methods
Glucosylceramidase/immunology
[Mh] MeSH terms secundary: Gaucher Disease/drug therapy
Gaucher Disease/enzymology
Glucosylceramidase/therapeutic use
Humans
[Pt] Publication type:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Name of substance:0 (Antibodies, Neutralizing); EC 3.2.1.45 (Glucosylceramidase); EC 3.2.1.45 (Velaglucerase alfa, human)
[Em] Entry month:1712
[Cu] Class update date: 171225
[Lr] Last revision date:171225
[Js] Journal subset:IM
[Da] Date of entry for processing:170429
[St] Status:MEDLINE
[do] DOI:10.4155/bio-2016-0274

  7 / 6528 MEDLINE  
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[PMID]: 29146892
[Au] Autor:Liao H; Wan S; Zhang X; Shi D; Zhu X; Chen X
[Ad] Address:Department of Cardiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China (mainland).
[Ti] Title:Intermedin Ameliorates Atherosclerosis by Increasing Cholesterol Efflux Through the cAMP-PKA Pathway in Macrophage RAW264.7 Cell Line.
[So] Source:Med Sci Monit;23:5462-5471, 2017 Nov 17.
[Is] ISSN:1643-3750
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:BACKGROUND The aim of this study was to explore the role of intermedin and its mechanism in cholesterol efflux of macrophage THP-1 and RAW264.7 cell lines in atherosclerosis (AS). MATERIAL AND METHODS ApoE-/- mice were fed with a high-fat diet, and the concentrations of total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were measured. The lipidoses of the aortic sinus were analyzed by hematoxylin and eosin staining, and the cAMP level was detected by enzyme-linked immunosorbent assay (ELISA). The expressions of ATP-binding cassette transporter (ABCA1) were tested by real-time PCR and Western blot analysis. RESULTS IMD decreased serum TC and LDL-C, and increased serum HDL-C level in apoE-/- mice and attenuated AS plaque areas. In vitro, IMD increased intracellular cAMP concentration in a dose-dependent manner in THP-1 and RAW264.7 cell lines, which enhanced the expression of ABCA1 and increased cholesterol efflux rate. However, this effect was inhibited by PKAI in the RAW 264.7 cell line but not in the THP-1 cell line. CONCLUSIONS IMD can ameliorate the development of AS in ApoE-/- mice and regulate cholesterol balance in the RAW264.7 cell line through the cAMP-PKA pathway.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1711
[Cu] Class update date: 171117
[Lr] Last revision date:171117
[St] Status:In-Process

  8 / 6528 MEDLINE  
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[PMID]: 28857617
[Au] Autor:Arenz C
[Ad] Address:Institute for Chemistry, Humboldt Universität zu Berlin, Brook-Taylor-Str. 2, 12489 Berlin, Germany.
[Ti] Title:Recent advances and novel treatments for sphingolipidoses.
[So] Source:Future Med Chem;9(14):1685-1698, 2017 Sep.
[Is] ISSN:1756-8927
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Sphingolipidoses are genetically inherited diseases in which genetic mutations lead to functional deficiencies in the enzymes needed for lysosomal degradation of sphingolipid substrates. As a consequence, nondegradable lipids enrich in the lysosomes and lead to fatal pathological phenotypes in affected individuals. In this review, different drug-based treatment strategies including enzyme replacement therapy and substrate reduction therapy are discussed. A special focus is on the concept of pharmacological chaperones, one of which recently acquired clinical approval within the EU. On the basis of the different limitations for each approach, possible future directions of research are discussed.
[Mh] MeSH terms primary: Enzymes/therapeutic use
Sphingolipidoses/drug therapy
[Mh] MeSH terms secundary: Enzyme Replacement Therapy
Enzymes/genetics
Enzymes/metabolism
Fabry Disease/drug therapy
Gaucher Disease/drug therapy
Glucosylceramidase/genetics
Glucosylceramidase/metabolism
Glucosylceramidase/therapeutic use
Humans
Lysosomes/metabolism
Recombinant Proteins/biosynthesis
Recombinant Proteins/isolation & purification
Recombinant Proteins/therapeutic use
Sphingolipidoses/genetics
Sphingolipidoses/pathology
Sphingolipids/metabolism
alpha-Galactosidase/genetics
alpha-Galactosidase/metabolism
alpha-Galactosidase/therapeutic use
[Pt] Publication type:JOURNAL ARTICLE; REVIEW
[Nm] Name of substance:0 (Enzymes); 0 (Recombinant Proteins); 0 (Sphingolipids); EC 3.2.1.22 (alpha-Galactosidase); EC 3.2.1.45 (Glucosylceramidase)
[Em] Entry month:1710
[Cu] Class update date: 171025
[Lr] Last revision date:171025
[Js] Journal subset:IM
[Da] Date of entry for processing:170901
[St] Status:MEDLINE
[do] DOI:10.4155/fmc-2017-0065

  9 / 6528 MEDLINE  
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[PMID]: 28762527
[Au] Autor:Mistry PK; Lukina E; Ben Turkia H; Shankar SP; Baris H; Ghosn M; Mehta A; Packman S; Pastores G; Petakov M; Assouline S; Balwani M; Danda S; Hadjiev E; Ortega A; Gaemers SJM; Tayag R; Peterschmitt MJ
[Ad] Address:Department of Internal Medicine and Pediatrics, Yale University School of Medicine, New Haven, CT, USA.
[Ti] Title:Outcomes after 18 months of eliglustat therapy in treatment-naïve adults with Gaucher disease type 1: The phase 3 ENGAGE trial.
[So] Source:Am J Hematol;92(11):1170-1176, 2017 Nov.
[Is] ISSN:1096-8652
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Eliglustat, an oral substrate reduction therapy, is a first-line treatment for adults with Gaucher disease type 1 (GD1) who are poor, intermediate, or extensive CYP2D6 metabolizers (>90% of patients). In the primary analysis of the Phase 3 ENGAGE trial (NCT00891202), eliglustat treatment for 9 months resulted in significant reductions in spleen and liver volumes and increases in hemoglobin concentration and platelet count compared with placebo. We report 18-month outcomes of patients who entered the trial extension period, in which all patients received eliglustat. Of 40 trial patients, 39 entered the extension period, and 38 completed 18 months. Absolute values and percent change over time were determined for spleen and liver volume, hemoglobin concentration, platelet count, bone mineral density, bone marrow burden, and Gaucher disease biomarkers. For patients randomized to eliglustat in the double-blind period, continuing treatment with eliglustat for 9 more months resulted in incremental improvement of all disease parameters. For patients randomized to placebo in the double-blind period, eliglustat treatment during the 9-month, open-label period resulted in significant decrease of spleen and liver volumes and significant increase of hemoglobin and platelets, with a similar rate of change to patients who had received eliglustat in the double-blind period. Eliglustat treatment was also associated with improvement in bone marrow burden score, bone mineral density, and established biomarkers of Gaucher disease, including reduction of the bioactive lipid, glucosylsphingosine. These findings underscore the efficacy of eliglustat in treatment-naïve patients. Eliglustat was well-tolerated, and there were no new safety concerns with longer-term exposure.
[Mh] MeSH terms primary: Enzyme Inhibitors/therapeutic use
Enzyme Replacement Therapy
Gaucher Disease/drug therapy
Pyrrolidines/therapeutic use
[Mh] MeSH terms secundary: Enzyme Inhibitors/administration & dosage
Enzyme Inhibitors/adverse effects
Follow-Up Studies
Gaucher Disease/diagnosis
Gaucher Disease/enzymology
Glucosylceramidase/antagonists & inhibitors
Humans
Liver/pathology
Organ Size
Pyrrolidines/administration & dosage
Pyrrolidines/adverse effects
Spleen/pathology
Treatment Outcome
[Pt] Publication type:CLINICAL TRIAL, PHASE III; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Name of substance:0 (Enzyme Inhibitors); 0 (Pyrrolidines); DR40J4WA67 (eliglustat); EC 3.2.1.45 (Glucosylceramidase)
[Em] Entry month:1710
[Cu] Class update date: 171103
[Lr] Last revision date:171103
[Js] Journal subset:IM
[Da] Date of entry for processing:170802
[St] Status:MEDLINE
[do] DOI:10.1002/ajh.24877

  10 / 6528 MEDLINE  
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[PMID]: 28617219
[Au] Autor:Lee YH; Choi H; Park S; Lee B; Yi GS
[Ad] Address:Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, South Korea.
[Ti] Title:Drug repositioning for enzyme modulator based on human metabolite-likeness.
[So] Source:BMC Bioinformatics;18(Suppl 7):226, 2017 May 31.
[Is] ISSN:1471-2105
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:BACKGROUND: Recently, the metabolite-likeness of the drug space has emerged and has opened a new possibility for exploring human metabolite-like candidates in drug discovery. However, the applicability of metabolite-likeness in drug discovery has been largely unexplored. Moreover, there are no reports on its applications for the repositioning of drugs to possible enzyme modulators, although enzyme-drug relations could be directly inferred from the similarity relationships between enzyme's metabolites and drugs. METHODS: We constructed a drug-metabolite structural similarity matrix, which contains 1,861 FDA-approved drugs and 1,110 human intermediary metabolites scored with the Tanimoto similarity. To verify the metabolite-likeness measure for drug repositioning, we analyzed 17 known antimetabolite drugs that resemble the innate metabolites of their eleven target enzymes as the gold standard positives. Highly scored drugs were selected as possible modulators of enzymes for their corresponding metabolites. Then, we assessed the performance of metabolite-likeness with a receiver operating characteristic analysis and compared it with other drug-target prediction methods. We set the similarity threshold for drug repositioning candidates of new enzyme modulators based on maximization of the Youden's index. We also carried out literature surveys for supporting the drug repositioning results based on the metabolite-likeness. RESULTS: In this paper, we applied metabolite-likeness to repurpose FDA-approved drugs to disease-associated enzyme modulators that resemble human innate metabolites. All antimetabolite drugs were mapped with their known 11 target enzymes with statistically significant similarity values to the corresponding metabolites. The comparison with other drug-target prediction methods showed the higher performance of metabolite-likeness for predicting enzyme modulators. After that, the drugs scored higher than similarity score of 0.654 were selected as possible modulators of enzymes for their corresponding metabolites. In addition, we showed that drug repositioning results of 10 enzymes were concordant with the literature evidence. CONCLUSIONS: This study introduced a method to predict the repositioning of known drugs to possible modulators of disease associated enzymes using human metabolite-likeness. We demonstrated that this approach works correctly with known antimetabolite drugs and showed that the proposed method has better performance compared to other drug target prediction methods in terms of enzyme modulators prediction. This study as a proof-of-concept showed how to apply metabolite-likeness to drug repositioning as well as potential in further expansion as we acquire more disease associated metabolite-target protein relations.
[Mh] MeSH terms primary: Drug Repositioning
Enzymes/metabolism
[Mh] MeSH terms secundary: Antimetabolites/metabolism
Area Under Curve
Databases, Factual
Enzymes/chemistry
Gaucher Disease/drug therapy
Gaucher Disease/enzymology
Gaucher Disease/pathology
Glucosylceramidase/therapeutic use
Humans
ROC Curve
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (Antimetabolites); 0 (Enzymes); EC 3.2.1.45 (Glucosylceramidase)
[Em] Entry month:1711
[Cu] Class update date: 171102
[Lr] Last revision date:171102
[Js] Journal subset:IM
[Da] Date of entry for processing:170616
[St] Status:MEDLINE
[do] DOI:10.1186/s12859-017-1637-5


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