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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] Endereço: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] Título: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] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo: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] Termos MeSH primário: Avaliação Pré-Clínica de Medicamentos/métodos
Hepatócitos/efeitos dos fármacos
Lipidoses/induzido quimicamente
Fosfolipídeos/metabolismo
Pele/citologia
Células-Tronco/citologia
[Mh] Termos MeSH secundário: Amiodarona/toxicidade
Diferenciação Celular/efeitos dos fármacos
Células Cultivadas
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos
Citometria de Fluxo
Expressão Gênica/efeitos dos fármacos
Células Hep G2
Hepatócitos/ultraestrutura
Seres Humanos
Lipidoses/genética
Lisossomos/efeitos dos fármacos
Lisossomos/metabolismo
Masculino
Fosfolipídeos/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Phospholipids); N3RQ532IUT (Amiodarone)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180221
[Lr] Data última revisão:
180221
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171218
[St] Status:MEDLINE


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[PMID]:28512733
[Au] Autor:García-Cañaveras JC; Peris-Díaz MD; Alcoriza-Balaguer MI; Cerdán-Calero M; Donato MT; Lahoz A
[Ad] Endereço:Unidad de Biomarcadores y Medicina de Precisión, Unidad Analítica, Instituto de Investigación Sanitaria, Fundación Hospital La Fe, Spain.
[Ti] Título:A lipidomic cell-based assay for studying drug-induced phospholipidosis and steatosis.
[So] Source:Electrophoresis;38(18):2331-2340, 2017 09.
[Is] ISSN:1522-2683
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Phospholipidosis and steatosis are two toxic effects, which course with overaccumulation of different classes of lipids in the liver. MS-based lipidomics has become a powerful tool for the comprehensive determination of lipids. LC-MS lipid profiling of HepG2 cells is proposed as an in vitro assay to study and anticipate phospholipidosis and steatosis. Cells with and without preincubation with a mixture of free fatty acids (FFA; i.e. oleic and palmitic) were exposed to a set of well-known steatogenic and phospholipidogenic compounds. The use of FFA preloading accelerated the accumulation of phospholipids, thus leading to a better discrimination of phospholipidosis, and magnified the lipidomic alterations induced by steatogenic drugs. Phospholipidosis was characterized by increased levels of phosphatidylcholines, phosphatidylethanolamines, phosphatidylserines, and phosphatidylinositols, while steatosis induced alterations in FA oxidation and triacylglyceride (TG) synthesis pathways (with changes in the levels of FFA, acylcarnitines, monoacylglycerides, diacylglycerides, and TG). Interestingly, palmitic and oleic acids incorporation into lipids differed. A characteristic pattern was observed in the fold of change of particular TG species in the case of steatosis (TG(54:3) > TG(52:2) > TG(50:1) > TG(48:0)). Based on the levels of those lipids containing only palmitic and/or oleic acid moieties a partial least squares-discriminant analysis model was built, which showed good discrimination among nontoxic, phospholipidogenic and steatogenic compounds. In conclusion, it has been shown that the use of FFA preincubation together with intracellular LC-MS based lipid profiling could be a useful approach to identify the potential of drug candidates to induce phospholipidosis and/or steatosis.
[Mh] Termos MeSH primário: Doença Hepática Induzida por Substâncias e Drogas/metabolismo
Fígado Gorduroso/metabolismo
Lipidoses/metabolismo
Fosfolipídeos/análise
[Mh] Termos MeSH secundário: Cromatografia Líquida
Biologia Computacional
Células Hep G2
Seres Humanos
Análise dos Mínimos Quadrados
Espectrometria de Massas
Modelos Biológicos
Fosfolipídeos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Phospholipids)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170518
[St] Status:MEDLINE
[do] DOI:10.1002/elps.201700079


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[PMID]:28398727
[Au] Autor:Ceccarelli M; Wagner B; Alvarez-Sánchez R; Cruciani G; Goracci L
[Ad] Endereço:Laboratory for Chemoinformatics and Molecular Modelling, Department of Chemistry, Biology and Biotechnology, University of Perugia , via Elce di Sotto 8, 06123 Perugia, Italy.
[Ti] Título:Use of the Distribution Coefficient in Brain Polar Lipids for the Assessment of Drug-Induced Phospholipidosis Risk.
[So] Source:Chem Res Toxicol;30(5):1145-1156, 2017 May 15.
[Is] ISSN:1520-5010
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In vitro safety assessment in early drug discovery represents an important step to detect potential safety-related liabilities. It reduces late stage attrition and allows candidate optimization. In this study, we report on the use of the LogD assay (a recently published assay for the determination of drug distribution coefficients between an aqueous phase and porcine brain polar lipids extract) for phospholipidosis (PLD) risk evaluation. The LogD parameter was first compared to the effective permeability in the parallel artificial membrane permeability assay (PAMPA), previously reported as correlating with PLD risk. Subsequently, the LogD for a set of 234 drugs with known PLD effect was measured, representing the largest data set of LogD data published so far, and the correlation with phospholipid accumulation was further investigated. In addition, a comparison with other in silico methods based on physicochemical parameters is reported. Results showed that LogD is an efficient descriptor to assess PLD risk, especially when corrected using the pK value of compounds, being superior to the distribution coefficient in octanol, LogD , and the effective permeability in the PAMPA assay. A multivariate statistical analysis approach was finally used to better define the intrinsic features of LogD , whose effect proved to be highly similar to that of volume of distribution in silico when used to predict brain distribution and PLD.
[Mh] Termos MeSH primário: Encéfalo/metabolismo
Lipidoses/induzido quimicamente
Fosfolipídeos/metabolismo
[Mh] Termos MeSH secundário: Animais
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos
Preparações Farmacêuticas/classificação
Análise de Componente Principal
Suínos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Pharmaceutical Preparations); 0 (Phospholipids)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170626
[Lr] Data última revisão:
170626
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170412
[St] Status:MEDLINE
[do] DOI:10.1021/acs.chemrestox.6b00459


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[PMID]:28285021
[Au] Autor:Okamoto H; Hamaguchi R; Kuroda Y
[Ad] Endereço:School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women's University, 11-68, Koshien Kyuban-cho, Nishinomiya, Hyogo, 663-8179, Japan.
[Ti] Título:Hydrophilic interaction chromatography with a focus on the drug-phosphate interaction in drug screening to determine the phospholipidosis induction risk.
[So] Source:J Chromatogr B Analyt Technol Biomed Life Sci;1051:33-40, 2017 Apr 15.
[Is] ISSN:1873-376X
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Cationic amphiphilic drugs (CADs) can induce the hyperaccumulation of phospholipids in cells and tissues. This side effect, which is known as drug-induced phospholipidosis, is sometimes problematic in the development and clinical use of CADs. It is known that CADs generally interact with phospholipids via both hydrophobic and acid-base interactions, and CADs with the larger affinity to phospholipid exhibit the larger induction risk. To develop a chromatographic assay system to predict the phospholipidosis-inducing potential with considering the acid-base interaction between CAD and phosphate group of phospholipid, hydrophilic interaction chromatographic (HILIC) methods were tested in this study. First, a PC HILIC column with phosphocholine groups on a packed material was used. The acid-base or other hydrophilic interactions to the stationary phase differed among basic drugs, and retention to the PC HILIC column did not accurately reflect the induction potential of phospholipidosis. As an alternative HILIC approach, the elution of CADs with the phosphate buffer from an amide column was tested. The elution effect, which is expressed as ratio of retention factors between different phosphate content in the mobile phase, closely correlated with the induction potential. Using the elution effect and retention factor to a reversed-phase HPLC column, the phospholipidosis-inducing drugs were clearly discriminated from the non-inducers. These results suggest that the proposed chromatographic approach can screen phospholipidosis-inducing drugs.
[Mh] Termos MeSH primário: Cromatografia Líquida de Alta Pressão/métodos
Avaliação Pré-Clínica de Medicamentos/métodos
Lipidoses/induzido quimicamente
Preparações Farmacêuticas/metabolismo
Fosfatos/metabolismo
Fosfolipídeos/metabolismo
[Mh] Termos MeSH secundário: Seres Humanos
Interações Hidrofóbicas e Hidrofílicas
Lipidoses/metabolismo
Preparações Farmacêuticas/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Pharmaceutical Preparations); 0 (Phosphates); 0 (Phospholipids)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170601
[Lr] Data última revisão:
170601
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170313
[St] Status:MEDLINE


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[PMID]:27793708
[Au] Autor:Domingues N; Estronca LM; Silva J; Encarnação MR; Mateus R; Silva D; Santarino IB; Saraiva M; Soares MI; Pinho E Melo TM; Jacinto A; Vaz WL; Vieira OV
[Ad] Endereço:CEDOC, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, 1169-056 Lisboa, Portugal. Electronic address: neuzadomingues16@gmail.com.
[Ti] Título:Cholesteryl hemiesters alter lysosome structure and function and induce proinflammatory cytokine production in macrophages.
[So] Source:Biochim Biophys Acta;1862(2):210-220, 2017 02.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:RATIONALE: Cholesteryl hemiesters are oxidation products of polyunsaturated fatty acid esters of cholesterol. Their oxo-ester precursors have been identified as important components of the "core aldehydes" of human atheromata and in oxidized lipoproteins (Ox-LDL). We had previously shown, for the first time, that a single compound of this family, cholesteryl hemisuccinate (ChS), is sufficient to cause irreversible lysosomal lipid accumulation (lipidosis), and is toxic to macrophages. These features, coupled to others such as inflammation, are typically seen in atherosclerosis. OBJECTIVE: To obtain insights into the mechanism of cholesteryl hemiester-induced pathological changes in lysosome function and induction of inflammation in vitro and assess their impact in vivo. METHODS AND RESULTS: We have examined the effects of ChS on macrophages (murine cell lines and primary cultures) in detail. Specifically, lysosomal morphology, pH, and proteolytic capacity were examined. Exposure of macrophages to sub-toxic ChS concentrations caused enlargement of the lysosomes, changes in their luminal pH, and accumulation of cargo in them. In primary mouse bone marrow-derived macrophages (BMDM), ChS-exposure increased the secretion of IL-1ß, TNF-α and IL-6. In zebrafish larvae (wild-type AB and PU.1:EGFP), fed with a ChS-enriched diet, we observed lipid accumulation, myeloid cell-infiltration in their vasculature and decrease in larval survival. Under the same conditions the effects of ChS were more profound than the effects of free cholesterol (FC). CONCLUSIONS: Our data strongly suggest that cholesteryl hemiesters are pro-atherogenic lipids able to mimic features of Ox-LDL both in vitro and in vivo.
[Mh] Termos MeSH primário: Colesterol/metabolismo
Inflamação/metabolismo
Interleucina-1beta/metabolismo
Interleucina-6/metabolismo
Lisossomos/metabolismo
Macrófagos/metabolismo
Fator de Necrose Tumoral alfa/metabolismo
[Mh] Termos MeSH secundário: Animais
Aterosclerose/metabolismo
Linhagem Celular
Ésteres do Colesterol/metabolismo
Ésteres/metabolismo
Seres Humanos
Concentração de Íons de Hidrogênio
Larva/metabolismo
Lipidoses/metabolismo
Camundongos
Células RAW 264.7
Peixe-Zebra
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cholesterol Esters); 0 (Esters); 0 (Interleukin-1beta); 0 (Interleukin-6); 0 (Tumor Necrosis Factor-alpha); 97C5T2UQ7J (Cholesterol); T3J4KS4201 (cholesteryl succinate)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161031
[St] Status:MEDLINE


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[PMID]:27785616
[Au] Autor:Semakova J; Hyrossová P; Méndez-Lucas A; Cutz E; Bermudez J; Burgess S; Alcántara S; Perales JC
[Ad] Endereço:Department of Physiological Sciences, Faculty of Medicine, University of Barcelona, L'Hospitalet del Llobregat, Barcelona, Spain.
[Ti] Título:PEPCK-C reexpression in the liver counters neonatal hypoglycemia in Pck1 mice, unmasking role in non-gluconeogenic tissues.
[So] Source:J Physiol Biochem;73(1):89-98, 2017 Feb.
[Is] ISSN:1877-8755
[Cp] País de publicação:Spain
[La] Idioma:eng
[Ab] Resumo:Whole body cytosolic phosphoenolpyruvate carboxykinase knockout (PEPCK-C KO) mice die early after birth with profound hypoglycemia therefore masking the role of PEPCK-C in adult, non-gluconeogenic tissues where it is expressed. To investigate whether PEPCK-C deletion in the liver was critically responsible for the hypoglycemic phenotype, we reexpress this enzyme in the liver of PEPCK-C KO pups by early postnatal administration of PEPCK-C-expressing adenovirus. This maneuver was sufficient to partially rescue hypoglycemia and allow the pups to survive and identifies the liver as a critical organ, and hypoglycemia as the critical pathomechanism, leading to early postnatal death in the whole-body PEPCK-C knockout mice. Pathology assessment of survivors also suggest a possible role for PEPCK-C in lung maturation and muscle metabolism.
[Mh] Termos MeSH primário: Erros Inatos do Metabolismo dos Carboidratos/veterinária
Hipoglicemia/prevenção & controle
Hepatopatias/veterinária
Fígado/enzimologia
Pulmão/metabolismo
Músculo Esquelético/metabolismo
Fosfoenolpiruvato Carboxiquinase (GTP)/deficiência
Fosfoenolpiruvato Carboxiquinase (GTP)/metabolismo
[Mh] Termos MeSH secundário: Animais
Animais Recém-Nascidos
Encéfalo/enzimologia
Encéfalo/metabolismo
Encéfalo/patologia
Erros Inatos do Metabolismo dos Carboidratos/enzimologia
Erros Inatos do Metabolismo dos Carboidratos/fisiopatologia
Erros Inatos do Metabolismo dos Carboidratos/terapia
Cruzamentos Genéticos
Técnicas de Transferência de Genes
Gluconeogênese
Heterozigoto
Hipoglicemia/etiologia
Hipoglicemia/metabolismo
Hipoglicemia/patologia
Gotículas Lipídicas/metabolismo
Gotículas Lipídicas/patologia
Metabolismo dos Lipídeos
Lipidoses/etiologia
Fígado/metabolismo
Fígado/patologia
Hepatopatias/enzimologia
Hepatopatias/fisiopatologia
Hepatopatias/terapia
Pulmão/enzimologia
Pulmão/patologia
Camundongos Endogâmicos C57BL
Camundongos Knockout
Músculo Esquelético/enzimologia
Músculo Esquelético/patologia
Neurônios/enzimologia
Neurônios/metabolismo
Neurônios/patologia
Fosfoenolpiruvato Carboxiquinase (GTP)/genética
Fosfoenolpiruvato Carboxiquinase (GTP)/uso terapêutico
Proteínas Recombinantes/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Recombinant Proteins); EC 4.1.1.32 (Phosphoenolpyruvate Carboxykinase (GTP))
[Em] Mês de entrada:1703
[Cu] Atualização por classe:171111
[Lr] Data última revisão:
171111
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161028
[St] Status:MEDLINE
[do] DOI:10.1007/s13105-016-0528-y


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[PMID]:27960019
[Au] Autor:Feriozzi S
[Ti] Título:[Glomerular lipidosis].
[Ti] Título:Lipidosi glomerulari..
[So] Source:G Ital Nefrol;33(S68), 2016 Malattie Metaboliche e Rene.
[Is] ISSN:1724-5990
[Cp] País de publicação:Italy
[La] Idioma:ita
[Ab] Resumo:Lipidoses occur for an abnormal storage parenchymal deposition of lipids and products of their metabolism in large amounts or sometimes, involving only some particular tissue structures. The lipid storage is usually due to an inborn error causing an enzyme absence /deficiency in the primary lipidoses and to a complex metabolism alterations in the secondary forms. However, histologically all lipid depositions look very similar, and immunohistochemical investigation, clinical pictures knowledge and genetic tests need to make a correct diagnosis. Lipid deposition causes parenchymal structural changes especially of glomeruli resulting in renal function impairment and proteinuria and haematuria appearance. This manuscript gathers clinical and histological features present in these storage pathologies. Renal involvement is described in Anderson-Fabry disease, in hyperlipoproteinemias, in lecithin-cholesterol acyltransferase deficiency, in Gaucher disease and finally in secondary lipidoses features such as nephrotic syndrome, Alagille disease, and toxic or ischemic renal damage. Recently the replacement enzymatic therapy availability is substantially modifying the clinical picture and the outcome in some lipidoses such as Anderson-Fabry and Gaucher diseases. Therefore, it is import to be aware of these disorders, not only for making a correct diagnosis but also for starting, when it is possible, an effective therapy.
[Mh] Termos MeSH primário: Nefropatias
Glomérulos Renais
Lipidoses
[Mh] Termos MeSH secundário: Doença de Fabry/diagnóstico
Doença de Fabry/terapia
Seres Humanos
Nefropatias/diagnóstico
Nefropatias/terapia
Lipidoses/diagnóstico
Lipidoses/terapia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161214
[St] Status:MEDLINE


  8 / 2576 MEDLINE  
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[PMID]:27715138
[Au] Autor:Todd M
[Ad] Endereço:Clinical Nurse Specialist in Lymphoedema, Glasgow Specialist Lymphoedema Service, Glasgow, Scotland.
[Ti] Título:Diagnosis and management of lipoedema in the community.
[So] Source:Br J Community Nurs;21(Suppl 10):S6-S12, 2016 Oct.
[Is] ISSN:1462-4753
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Lipoedema is a chronic progressive adipose disorder that affects mainly women and presents as symmetrical enlargement of the buttocks and legs. It is commonly misdiagnosed as obesity or lymphoedema, but careful assessment will reveal a disproportionate enlargement below the waist which is resistant to dieting, sparing of the feet, legs are tender or painful to touch and bruise easily, there is occasional orthostatic oedema, and there is often significant psychological morbidity. Lipoedema is a oestrogen-regulated condition with onset around puberty in 78% of women, and there is often a strong family history. The condition is exacerbated by weight gain and there is increasing anecdotal evidence that women who are obese are seeking a diagnosis of lipoedema, either to procure NHS funded manual lymphatic drainage, or to medicalise their obesity and avoid acknowledging that the responsibility for their weight gain is lifestyle orientated. Management of lipoedema consists of accurate diagnosis, psychological care, management of orthostatic oedema, and prevention of progression through skin care and weight management.
[Mh] Termos MeSH primário: Edema/enfermagem
Lipidoses/enfermagem
[Mh] Termos MeSH secundário: Enfermagem em Saúde Comunitária
Edema/diagnóstico
Edema/terapia
Seres Humanos
Perna (Membro)
Lipidoses/diagnóstico
Lipidoses/terapia
Processo de Enfermagem
Meias de Compressão
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1701
[Cu] Atualização por classe:170113
[Lr] Data última revisão:
170113
[Sb] Subgrupo de revista:N
[Da] Data de entrada para processamento:161008
[St] Status:MEDLINE


  9 / 2576 MEDLINE  
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[PMID]:27221059
[Au] Autor:Glock M; Muehlbacher M; Hurtig H; Tripal P; Kornhuber J
[Ad] Endereço:Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany.
[Ti] Título:Drug-induced phospholipidosis caused by combinations of common drugs in vitro.
[So] Source:Toxicol In Vitro;35:139-48, 2016 Sep.
[Is] ISSN:1879-3177
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Drug-induced phospholipidosis (DIPLD), characterized by the accumulation of phospholipids within lysosomes, is suspected to impair lysosomal function and considered an adverse side effect of the administered medication. The increasing use of polypharmacy and the resultant elevated risks of adverse drug reactions raise the need to explore the effects of drug combinations with respect to their influence on side effects, such as DIPLD. In this study, we utilized an in vitro assay to investigate DIPLD that was caused by 24 commonly used drugs applied alone and in binary combinations with each other. Moreover, we attempted to predict the extent of DIPLD resulting from the combinations using a simple additive approach based on the increase in phospholipid levels caused by the single drugs. The results suggest that DIPLD, which was caused by combinations of drugs, occurs in an additive manner, depending on total drug concentration. Furthermore, we show that the extent of DIPLD can be predicted from the DIPLD caused by the single drugs. Thus, the simultaneous use of multiple drugs with PLD-inducing properties increases the event risk, as well as the severity of drug-induced phospholipidosis. The findings underline the importance of considering the DIPLD-inducing properties of drugs, especially in the context of polypharmacy.
[Mh] Termos MeSH primário: Combinação de Medicamentos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos
Lipidoses/induzido quimicamente
Fosfolipídeos/metabolismo
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Interações Medicamentosas
Seres Humanos
Lipidoses/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Drug Combinations); 0 (Phospholipids)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170404
[Lr] Data última revisão:
170404
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160526
[St] Status:MEDLINE


  10 / 2576 MEDLINE  
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[PMID]:26961617
[Au] Autor:Haranosono Y; Nemoto S; Kurata M; Sakaki H
[Ad] Endereço:Senju Pharmaceutical Co. Ltd., Pharmacokinetics & Toxicology Research Laboratories.
[Ti] Título:Establishment of an in silico phospholipidosis prediction method using descriptors related to molecular interactions causing phospholipid-compound complex formation.
[So] Source:J Toxicol Sci;41(2):321-8, 2016 Apr.
[Is] ISSN:1880-3989
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:Although phospholipidosis (PLD) often affects drug development, there is no convenient in vitro or in vivo test system for PLD detection. In this study, we developed an in silico PLD prediction method based on the PLD-inducing mechanism. We focused on phospholipid (PL)-compound complex formation, which inhibits PL degradation by phospholipase. Thus, we used some molecular interactions, such as electrostatic interactions, hydrophobic interactions, and intermolecular forces, between PL and compounds as descriptors. First, we performed descriptor screening for intermolecular force and then developed a new in silico PLD prediction using descriptors related to molecular interactions. Based on the screening, we identified molecular refraction (MR) as a descriptor of intermolecular force. It is known that ClogP and most-basic pKa can be used for PLD prediction. Thereby, we developed an in silico prediction method using ClogP, most-basic pKa, and MR, which were related to hydrophobic interactions, electrostatic interactions, and intermolecular forces. In addition, a resampling method was used to determine the cut-off values for each descriptor. We obtained good results for 77 compounds as follows: sensitivity = 95.8%, specificity = 75.9%, and concordance = 88.3%. Although there is a concern regarding false-negative compounds for pKa calculations, this predictive ability will be adequate for PLD screening. In conclusion, the mechanism-based in silico PLD prediction method provided good prediction ability, and this method will be useful for evaluating the potential of drugs to cause PLD, particularly in the early stage of drug development, because this method only requires knowledge of the chemical structure.
[Mh] Termos MeSH primário: Simulação por Computador
Descoberta de Drogas
Previsões/métodos
Interações Hidrofóbicas e Hidrofílicas
Lipidoses/diagnóstico
Lipidoses/metabolismo
Fosfolipídeos/metabolismo
Eletricidade Estática
[Mh] Termos MeSH secundário: Ensaios de Triagem em Larga Escala
Lipidoses/induzido quimicamente
Fosfolipases/metabolismo
Curva ROC
Tensoativos/efeitos adversos
Tensoativos/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Phospholipids); 0 (Surface-Active Agents); EC 3.1.- (Phospholipases)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:161230
[Lr] Data última revisão:
161230
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160311
[St] Status:MEDLINE
[do] DOI:10.2131/jts.41.321



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