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Article: Negative pressure ventilation: a special application of expiratory ventilation assistance.

Böttinger, Lena / van der Hoorn, José W A

2019 Volume 7, Issue 1, Page(s) 22

Language	English
Publishing date	2019-05-02
Publishing country	Germany
Document type	Letter
ZDB-ID	2740385-3
ISSN	2197-425X
ISSN	2197-425X
DOI	10.1186/s40635-019-0248-z
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Article ; Online: Flow-controlled ventilation - a new and promising method of ventilation presented with a review of the literature.

Bialka, Szymon / Palaczynski, Piotr / Szuldrzynski, Konstanty / Wichary, Piotr / Kowalski, Denis / van der Hoorn, José W A / Böttinger, Lena / Misiolek, Hanna

Anaesthesiology intensive therapy

2022 Volume 54, Issue 1, Page(s) 62–70

Abstract: Substantial efforts have been undertaken to identify and minimise factors responsible for the development of ventilator-induced lung injury. A novel approach to this problem addresses energy dissipated in lung tissue during the breathing cycle as one of ... ...

Abstract	Substantial efforts have been undertaken to identify and minimise factors responsible for the development of ventilator-induced lung injury. A novel approach to this problem addresses energy dissipated in lung tissue during the breathing cycle as one of the key problems. Flow-controlled ventilation is a new modality of mechanical ventilation based on a constant flow during both inspiration and expiration. This review aims to evaluate the current evidence available regarding flow-controlled ventilation. Lastly, three cases of flow-controlled ventilation application are presented: ventilation with a small lumen tube during tracheal resection, one-lung ventilation during thoracoscopic lobectomy, and ventilation of a critically ill patient with acute respiratory distress syndrome in an intensive care unit setting.
MeSH term(s)	Humans ; Lung ; Respiration ; Respiration, Artificial/methods ; Respiratory Distress Syndrome/therapy ; Ventilator-Induced Lung Injury/prevention & control
Language	English
Publishing date	2022-02-07
Publishing country	Poland
Document type	Journal Article ; Review
ISSN	1731-2531
ISSN (online)	1731-2531
DOI	10.5114/ait.2022.112889
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Article ; Online: Icosabutate Exerts Beneficial Effects Upon Insulin Sensitivity, Hepatic Inflammation, Lipotoxicity, and Fibrosis in Mice.

van den Hoek, Anita M / Pieterman, Elsbet J / van der Hoorn, José W / Iruarrizaga-Lejarreta, Marta / Alonso, Cristina / Verschuren, Lars / Skjæret, Tore / Princen, Hans M G / Fraser, David A

Hepatology communications

2019 Volume 4, Issue 2, Page(s) 193–207

Abstract: Icosabutate is a structurally engineered eicosapentaenoic acid derivative under development for nonalcoholic steatohepatitis (NASH). In this study, we investigated the absorption and distribution properties of icosabutate in relation to liver targeting ... ...

Abstract	Icosabutate is a structurally engineered eicosapentaenoic acid derivative under development for nonalcoholic steatohepatitis (NASH). In this study, we investigated the absorption and distribution properties of icosabutate in relation to liver targeting and used rodents to evaluate the effects of icosabutate on glucose metabolism, insulin resistance, as well as hepatic steatosis, inflammation, lipotoxicity, and fibrosis. The absorption, tissue distribution, and excretion of icosabutate was investigated in rats along with its effects in mouse models of insulin resistance (
Language	English
Publishing date	2019-12-24
Publishing country	United States
Document type	Journal Article
ISSN	2471-254X
ISSN (online)	2471-254X
DOI	10.1002/hep4.1453
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Article ; Online: Innovative pharmaceutical interventions in cardiovascular disease: Focusing on the contribution of non-HDL-C/LDL-C-lowering versus HDL-C-raising: A systematic review and meta-analysis of relevant preclinical studies and clinical trials.

Kühnast, Susan / Fiocco, Marta / van der Hoorn, José W A / Princen, Hans M G / Jukema, J Wouter

European journal of pharmacology

2015 Volume 763, Issue Pt A, Page(s) 48–63

Abstract: Non-HDL-cholesterol is well recognised as a primary causal risk factor in cardiovascular disease. However, despite consistent epidemiological evidence for an inverse association between HDL-C and coronary heart disease, clinical trials aimed at raising ... ...

Abstract	Non-HDL-cholesterol is well recognised as a primary causal risk factor in cardiovascular disease. However, despite consistent epidemiological evidence for an inverse association between HDL-C and coronary heart disease, clinical trials aimed at raising HDL-C (AIM-HIGH, HPS2-THRIVE, dal-OUTCOMES) failed to meet their primary goals. This systematic review and meta-analysis investigated the effects of established and novel treatment strategies, specifically targeting HDL, on inhibition of atherosclerosis in cholesteryl ester transfer protein-expressing animals, and the prevention of clinical events in randomised controlled trials. Linear regression analyses using data from preclinical studies revealed associations for TC and non-HDL-C and lesion area (R(2)=0.258, P=0.045; R(2)=0.760, P<0.001), but not for HDL-C (R(2)=0.030, P=0.556). In clinical trials, non-fatal myocardial infarction risk was significantly less in the treatment group with pooled odd ratios of 0.87 [0.81; 0.94] for all trials and 0.85 [0.78; 0.93] after excluding some trials due to off-target adverse events, whereas all-cause mortality was not affected (OR 1.05 [0.99-1.10]). Meta-regression analyses revealed a trend towards an association between between-group differences in absolute change from baseline in LDL-C and non-fatal myocardial infarction (P=0.066), whereas no correlation was found for HDL-C (P=0.955). We conclude that the protective role of lowering LDL-C and non-HDL-C is well-established. The contribution of raising HDL-C on inhibition of atherosclerosis and the prevention of cardiovascular disease remains undefined and may be dependent on the mode of action of HDL-C-modification. Nonetheless, treatment strategies aimed at improving HDL function and raising apolipoprotein A-I may be worth exploring.
MeSH term(s)	Animals ; Cardiovascular Diseases/drug therapy ; Cardiovascular Diseases/metabolism ; Cholesterol, HDL/metabolism ; Cholesterol, LDL/metabolism ; Drug Evaluation, Preclinical ; Humans ; Randomized Controlled Trials as Topic
Chemical Substances	Cholesterol, HDL ; Cholesterol, LDL
Language	English
Publishing date	2015-09-15
Publishing country	Netherlands
Document type	Journal Article ; Meta-Analysis ; Review
ZDB-ID	80121-5
ISSN	1879-0712 ; 0014-2999
ISSN (online)	1879-0712
ISSN	0014-2999
DOI	10.1016/j.ejphar.2015.03.089
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Zs.A 522: Show issues

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Article ; Online: Dual targeting of hepatic fibrosis and atherogenesis by icosabutate, an engineered eicosapentaenoic acid derivative.

Stokman, Geurt / van den Hoek, Anita M / Denker Thorbekk, Ditte / Pieterman, Elsbet J / Skovgård Veidal, Sanne / Basta, Brittany / Iruarrizaga-Lejarreta, Marta / van der Hoorn, José W / Verschuren, Lars / Berbée, Jimmy F P / Rensen, Patrick C N / Skjaeret, Tore / Alonso, Cristina / Feigh, Michael / Kastelein, John J P / Friedman, Scott L / Princen, Hans M G / Fraser, David A

Liver international : official journal of the International Association for the Study of the Liver

2020 Volume 40, Issue 11, Page(s) 2860–2876

Abstract: Background & aims: While fibrosis stage predicts liver-associated mortality, cardiovascular disease (CVD) is still the major overall cause of mortality in patients with NASH. Novel NASH drugs should thus ideally reduce both liver fibrosis and CVD. ... ...

Abstract	Background & aims: While fibrosis stage predicts liver-associated mortality, cardiovascular disease (CVD) is still the major overall cause of mortality in patients with NASH. Novel NASH drugs should thus ideally reduce both liver fibrosis and CVD. Icosabutate is a semi-synthetic, liver-targeted eicosapentaenoic acid (EPA) derivative in clinical development for NASH. The primary aims of the current studies were to establish both the anti-fibrotic and anti-atherogenic efficacy of icosabutate in conjunction with changes in lipotoxic and atherogenic lipids in liver and plasma respectively. Methods: The effects of icosabutate on fibrosis progression and lipotoxicity were investigated in amylin liver NASH (AMLN) diet (high fat, cholesterol and fructose) fed ob/ob mice with biopsy-confirmed steatohepatitis and fibrosis and compared with the activity of obeticholic acid. APOE3Leiden.CETP mice, a translational model for hyperlipidaemia and atherosclerosis, were used to evaluate the mechanisms underlying the lipid-lowering effect of icosabutate and its effect on atherosclerosis. Results:* In AMLN ob/ob mice, icosabutate significantly reduced hepatic fibrosis and myofibroblast content in association with downregulation of the arachidonic acid cascade and a reduction in both hepatic oxidised phospholipids and apoptosis. In APOE3Leiden.CETP mice, icosabutate reduced plasma cholesterol and TAG levels via increased hepatic uptake, upregulated hepatic lipid metabolism and downregulated inflammation pathways, and effectively decreased atherosclerosis development. Conclusions:* Icosabutate, a structurally engineered EPA derivative, effectively attenuates both hepatic fibrosis and atherogenesis and offers an attractive therapeutic approach to both liver- and CV-related morbidity and mortality in NASH patients.
MeSH term(s)	Animals ; Atherosclerosis/drug therapy ; Atherosclerosis/pathology ; Atherosclerosis/prevention & control ; Butyrates ; Disease Models, Animal ; Eicosapentaenoic Acid/pharmacology ; Humans ; Liver/pathology ; Liver Cirrhosis/drug therapy ; Liver Cirrhosis/pathology ; Mice ; Mice, Inbred C57BL ; Non-alcoholic Fatty Liver Disease/drug therapy ; Non-alcoholic Fatty Liver Disease/pathology
Chemical Substances	Butyrates ; icosabutate ; Eicosapentaenoic Acid (AAN7QOV9EA)
Language	English
Publishing date	2020-08-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2102783-3
ISSN	1478-3231 ; 1478-3223
ISSN (online)	1478-3231
ISSN	1478-3223
DOI	10.1111/liv.14643
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Article ; Online: The AT04A vaccine against proprotein convertase subtilisin/kexin type 9 reduces total cholesterol, vascular inflammation, and atherosclerosis in APOE*3Leiden.CETP mice.

Landlinger, Christine / Pouwer, Marianne G / Juno, Claudia / van der Hoorn, José W A / Pieterman, Elsbet J / Jukema, J Wouter / Staffler, Guenther / Princen, Hans M G / Galabova, Gergana

European heart journal

2017 Volume 38, Issue 32, Page(s) 2499–2507

Abstract: Aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising therapeutic target for the treatment of hypercholesterolaemia and atherosclerosis. PCSK9 binds to the low density lipoprotein receptor and enhances its degradation, ... ...

Abstract	Aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising therapeutic target for the treatment of hypercholesterolaemia and atherosclerosis. PCSK9 binds to the low density lipoprotein receptor and enhances its degradation, which leads to the reduced clearance of low density lipoprotein cholesterol (LDLc) and a higher risk of atherosclerosis. In this study, the AT04A anti-PCSK9 vaccine was evaluated for its therapeutic potential in ameliorating or even preventing coronary heart disease in the atherogenic APOE3Leiden.CETP mouse model. Methods and results:* Control and AT04A vaccine-treated mice were fed western-type diet for 18 weeks. Antibody titres, plasma lipids, and inflammatory markers were monitored by ELISA, FPLC, and multiplexed immunoassay, respectively. The progression of atherosclerosis was evaluated by histological analysis of serial cross-sections from the aortic sinus. The AT04A vaccine induced high and persistent antibody levels against PCSK9, causing a significant reduction in plasma total cholesterol (-53%, P < 0.001) and LDLc compared with controls. Plasma inflammatory markers such as serum amyloid A (SAA), macrophage inflammatory protein-1β (MIP-1β/CCL4), macrophage-derived chemokine (MDC/CCL22), cytokine stem cell factor (SCF), and vascular endothelial growth factor A (VEGF-A) were significantly diminished in AT04A-treated mice. As a consequence, treatment with the AT04A vaccine resulted in a decrease in atherosclerotic lesion area (-64%, P = 0.004) and aortic inflammation as well as in more lesion-free aortic segments (+119%, P = 0.026), compared with control. Conclusions: AT04A vaccine induces an effective immune response against PCSK9 in APOE*3Leiden.CETP mice, leading to a significant reduction of plasma lipids, systemic and vascular inflammation, and atherosclerotic lesions in the aorta.
MeSH term(s)	Animals ; Antibodies/metabolism ; Aortic Diseases/prevention & control ; Apolipoprotein E3/deficiency ; Atherosclerosis/prevention & control ; Biomarkers/metabolism ; Cholesterol, HDL/metabolism ; Coronary Disease/prevention & control ; Disease Models, Animal ; Female ; Hypercholesterolemia/immunology ; Hypercholesterolemia/prevention & control ; Intercellular Adhesion Molecule-1/metabolism ; Mice, Transgenic ; NLR Family, Pyrin Domain-Containing 3 Protein/immunology ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; PCSK9 Inhibitors ; Plaque, Atherosclerotic/prevention & control ; Proprotein Convertase 9/immunology ; Vaccines, Subunit/administration & dosage ; Vaccines, Subunit/immunology ; Vasculitis/immunology ; Vasculitis/prevention & control
Chemical Substances	AT04A vaccine ; Antibodies ; Apolipoprotein E3 ; Biomarkers ; Cholesterol, HDL ; NLR Family, Pyrin Domain-Containing 3 Protein ; Nlrp3 protein, mouse ; PCSK9 Inhibitors ; Vaccines, Subunit ; Intercellular Adhesion Molecule-1 (126547-89-5) ; Pcsk9 protein, mouse (EC 3.4.21.-) ; Proprotein Convertase 9 (EC 3.4.21.-)
Language	English
Publishing date	2017-06-21
Publishing country	England
Document type	Journal Article
ZDB-ID	603098-1
ISSN	1522-9645 ; 0195-668X
ISSN (online)	1522-9645
ISSN	0195-668X
DOI	10.1093/eurheartj/ehx260
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Zs.A 1563: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Feasibility of SPECT-CT Imaging to Study the Pharmacokinetics of Antisense Oligonucleotides in a Mouse Model of Duchenne Muscular Dystrophy.

van de Steeg, Evita / Läppchen, Tilman / Aguilera, Begoña / Jansen, Harm T / Muilwijk, Daan / Vermue, Rick / van der Hoorn, José W / Donato, Katia / Rossin, Raffaella / de Visser, Peter C / Vlaming, Maria L H

Nucleic acid therapeutics

2017 Volume 27, Issue 4, Page(s) 221–231

Abstract: Antisense oligonucleotides (AONs) are promising candidates for treatment of Duchenne muscular dystrophy (DMD), a severe and progressive disease resulting in premature death. However, more knowledge on the pharmacokinetics of new AON drug candidates is ... ...

Abstract	Antisense oligonucleotides (AONs) are promising candidates for treatment of Duchenne muscular dystrophy (DMD), a severe and progressive disease resulting in premature death. However, more knowledge on the pharmacokinetics of new AON drug candidates is desired for effective application in the clinic. We assessed the feasibility of using noninvasive single-photon emission computed tomography-computed tomography (SPECT-CT) imaging to determine AON pharmacokinetics in vivo. To this end, a 2'-O-methyl phosphorothioate AON was radiolabeled with
Language	English
Publishing date	2017-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	2639888-6
ISSN	2159-3345 ; 2159-3337
ISSN (online)	2159-3345
ISSN	2159-3337
DOI	10.1089/nat.2016.0649
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Article: Amlodipine and atorvastatin in atherosclerosis: a review of the potential of combination therapy.

Jukema, J Wouter / van der Hoorn, José W A

Expert opinion on pharmacotherapy

2004 Volume 5, Issue 2, Page(s) 459–468

Abstract: Hypertension and hyperlipidaemia are major risk factors for the development of atherosclerosis. Calcium channel blockers (CCBs) have been used for decades and have established antihypertensive effects. Statins have been extensively used because of their ... ...

Abstract	Hypertension and hyperlipidaemia are major risk factors for the development of atherosclerosis. Calcium channel blockers (CCBs) have been used for decades and have established antihypertensive effects. Statins have been extensively used because of their potent lipid lowering properties. Amongst other factors, inflammation and oxidation are involved in enhanced progression of atherosclerosis and new lesion development. Therefore, research has been initiated focusing on the antioxidant and anti-inflammatory properties of CCBs and statins, beyond their primary effect, in order to evaluate the possible additive effects of combined treatment of CCBs with statins as antiatherosclerotic therapy. Clinical studies (e.g., the International Nifedipine Trial on Antiatherosclerotic Therapy [INTACT]) have demonstrated that the antiatherosclerotic action of CCBs is limited to the attenuation of the first stage of atherosclerogenesis (fatty streak formation or new lesion growth). The lesions that pre-existed at the start of CCB therapy did not demonstrate progression or regression on angiography. However, because the mechanisms of action of lipid-lowering drugs and CCBs, and their role in preventing the progression of atherosclerosis differ, it is conceivable to conclude that these two classes may have an additive or synergic effect, not only on new lesion formation but also on inhibiting the progression of established coronary atherosclerosis. Indeed, this combined effect of lipid-lowering therapy and CCBs on human coronary atherosclerosis has been reported in the Regression Growth Evaluation Statin Study (REGRESS) trial. This beneficial effect of combining CCBs with statins has now been replicated in transgenic atherosclerotic mice, where the combination of amlodipine and atorvastatin produced an additional 60% reduction of atherosclerosis compared with that observed with the statin alone. Serum markers of atherosclerosis and vascular integrity also improved most in the combination group. Synergistic effects of the combination of atorvastatin and amlodipine on acute nitric oxide release/endothelial function, and additive effects of the combination of amlodipine and atorvastatin in the improvement of arterial compliance in hypertensive hyperlipidaemic patients has been demonstrated. Collectively, these studies support the clinical antiatherosclerotic advantages of combination of CCBs and statins and in particular, of atorvastatin with amlodipine beyond their established antihyperlipidaemic and antihypertensive modes of action.
MeSH term(s)	Amlodipine/pharmacology ; Amlodipine/therapeutic use ; Animals ; Arteriosclerosis/drug therapy ; Arteriosclerosis/physiopathology ; Atorvastatin ; Calcium Channel Blockers/pharmacology ; Calcium Channel Blockers/therapeutic use ; Combined Modality Therapy ; Heptanoic Acids/pharmacology ; Heptanoic Acids/therapeutic use ; Humans ; Hypertension/drug therapy ; Hypertension/physiopathology ; Hypolipidemic Agents/pharmacology ; Hypolipidemic Agents/therapeutic use ; Pyrroles/pharmacology ; Pyrroles/therapeutic use
Chemical Substances	Calcium Channel Blockers ; Heptanoic Acids ; Hypolipidemic Agents ; Pyrroles ; Amlodipine (1J444QC288) ; Atorvastatin (A0JWA85V8F)
Language	English
Publishing date	2004-02-04
Publishing country	England
Document type	Evaluation Studies ; Journal Article ; Review
ZDB-ID	2001535-5
ISSN	1465-6566
ISSN	1465-6566
DOI	10.1517/14656566.5.2.459
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Zs.A 5130: Show issues

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Article ; Online: Anacetrapib, but not evacetrapib, impairs endothelial function in CETP-transgenic mice in spite of marked HDL-C increase.

Simic, Branko / Mocharla, Pavani / Crucet, Margot / Osto, Elena / Kratzer, Adelheid / Stivala, Simona / Kühnast, Susan / Speer, Thimoteus / Doycheva, Petia / Princen, Hans M / van der Hoorn, Jose W / Jukema, J Wouter / Giral, Hector / Tailleux, Anne / Landmesser, Ulf / Staels, Bart / Lüscher, Thomas F

Atherosclerosis

2017 Volume 257, Page(s) 186–194

Abstract: Background and aims: High-density lipoprotein cholesterol (HDL-C) is inversely related to cardiovascular risk. HDL-C raising ester transfer protein (CETP) inhibitors, are novel therapeutics. We studied the effects of CETP inhibitors anacetrapib and ... ...

Abstract	Background and aims: High-density lipoprotein cholesterol (HDL-C) is inversely related to cardiovascular risk. HDL-C raising ester transfer protein (CETP) inhibitors, are novel therapeutics. We studied the effects of CETP inhibitors anacetrapib and evacetrapib on triglycerides, cholesterol and lipoproteins, cholesterol efflux, paraoxonase activity (PON-1), reactive oxygen species (ROS), and endothelial function in E3L and E3L.CETP mice. Methods: Triglycerides and cholesterol were measured at weeks 5, 14 and 21 in E3L.CETP mice on high cholesterol diet and treated with anacetrapib (3 mg/kg/day), evacetrapib (3 mg/kg/day) or placebo. Cholesterol efflux was assessed ex-vivo in mice treated with CETP inhibitors for 3 weeks on a normal chow diet. Endothelial function was analyzed at week 21 in isolated aortic rings, and serum lipoproteins assessed by fast-performance liquid chromatography. Results: Anacetrapib and evacetrapib increased HDL-C levels (5- and 3.4-fold, resp.) and reduced triglycerides (-39% vs. placebo, p = 0.0174). Total cholesterol levels were reduced only in anacetrapib-treated mice (-32%, p = 0.0386). Cholesterol efflux and PON-1 activity (+45% and +35% vs. control, p < 0.005, resp.) were increased, while aortic ROS production was reduced with evacetrapib (-49% vs. control, p = 0.020). Anacetrapib, but not evacetrapib, impaired endothelium dependent vasorelaxation (p < 0.05). In contrast, no such effects were observed in E3L mice for all parameters tested. Conclusions: Notwithstanding a marked rise in HDL-C, evacetrapib did not improve endothelial function, while anacetrapib impaired it, suggesting that CETP inhibition does not provide vascular protection. Anacetrapib exerts unfavorable endothelial effects beyond CETP inhibition, which may explain the neutral results of large clinical trials in spite of increased HDL-C.
MeSH term(s)	Animals ; Anticholesteremic Agents/pharmacology ; Anticholesteremic Agents/toxicity ; Apolipoprotein E3/genetics ; Aryldialkylphosphatase/blood ; Benzodiazepines/pharmacology ; Benzodiazepines/toxicity ; Biomarkers/blood ; Cholesterol Ester Transfer Proteins/antagonists & inhibitors ; Cholesterol Ester Transfer Proteins/genetics ; Cholesterol Ester Transfer Proteins/metabolism ; Cholesterol, HDL/blood ; Diet, High-Fat ; Disease Models, Animal ; Dyslipidemias/blood ; Dyslipidemias/drug therapy ; Dyslipidemias/genetics ; Dyslipidemias/physiopathology ; Endothelium, Vascular/drug effects ; Endothelium, Vascular/metabolism ; Endothelium, Vascular/physiopathology ; Female ; Genetic Predisposition to Disease ; Humans ; Mice, Transgenic ; Oxazolidinones/pharmacology ; Oxazolidinones/toxicity ; Phenotype ; Reactive Oxygen Species/metabolism ; Triglycerides/blood ; Up-Regulation ; Vasodilation/drug effects
Chemical Substances	Anticholesteremic Agents ; Apolipoprotein E3 ; Biomarkers ; CETP protein, human ; Cholesterol Ester Transfer Proteins ; Cholesterol, HDL ; Oxazolidinones ; Reactive Oxygen Species ; Triglycerides ; Benzodiazepines (12794-10-4) ; evacetrapib (51XWV9K850) ; Aryldialkylphosphatase (EC 3.1.8.1) ; PON1 protein, mouse (EC 3.1.8.1) ; anacetrapib (P7T269PR6S)
Language	English
Publishing date	2017-02
Publishing country	Ireland
Document type	Comparative Study ; Journal Article
ZDB-ID	80061-2
ISSN	1879-1484 ; 0021-9150
ISSN (online)	1879-1484
ISSN	0021-9150
DOI	10.1016/j.atherosclerosis.2017.01.011
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Article ; Online: PET-CT imaging with [(18)F]-gefitinib to measure Abcb1a/1b (P-gp) and Abcg2 (Bcrp1) mediated drug-drug interactions at the murine blood-brain barrier.

Vlaming, Maria L H / Läppchen, Tilman / Jansen, Harm T / Kivits, Suzanne / van Driel, Andy / van de Steeg, Evita / van der Hoorn, José W / Sio, Charles F / Steinbach, Oliver C / DeGroot, Jeroen

Nuclear medicine and biology

2015 Volume 42, Issue 11, Page(s) 833–841

Abstract: Introduction: The efflux transporters P-glycoprotein (P-gp, ABCB1) and breast cancer resistance protein (BCRP, ABCG2) are expressed at the blood-brain barrier (BBB), and can limit the access of a wide range of drugs to the brain. In this study we ... ...

Abstract	Introduction: The efflux transporters P-glycoprotein (P-gp, ABCB1) and breast cancer resistance protein (BCRP, ABCG2) are expressed at the blood-brain barrier (BBB), and can limit the access of a wide range of drugs to the brain. In this study we developed a PET-CT imaging method for non-invasive, quantitative analysis of the effect of ABCB1 and ABCG2 on brain penetration of the anti-cancer drug gefitinib, and demonstrated the applicability of this method for identification and quantification of potential modulators of ABCB1 and ABCB2 using the dual inhibitor elacridar. Methods: In vitro cellular accumulation studies with [(14)C]-gefitinib were conducted in LLC-PK1, MDCKII, and the corresponding ABCB1/Abcb1a and ABCG2/Abcg2 overexpressing cell lines. Subsequently, in vivo brain penetration of [(18)F]-gefitinib was quantified by PET-CT imaging studies in wild-type, Abcg2(-/-), Abcb1a/1b(-/-), and Abcb1a/1b;Abcg2(-/-) mice. Results: In vitro studies showed that [(14)C]-gefitinib is a substrate of the human ABCB1 and ABCG2 transporters. After i.v. administration of [(18)F]-gefitinib (1mg/kg), PET-CT imaging showed 2.3-fold increased brain levels of [(18)F]-gefitinib in Abcb1a/1b;Abcg2(-/-) mice, compared to wild-type. Levels in single knockout animals were not different from wild-type, showing that Abcb1a/1b and Abcg2 together limit access of [(18)F]-gefitinib to the brain. Furthermore, enhanced brain accumulation of [(18)F]-gefitinib after administration of the ABCB1 and ABCG2 inhibitor elacridar (10 mg/kg) could be quantified with PET-CT imaging. Conclusions: PET-CT imaging with [(18)F]-gefitinib is a powerful tool to non-invasively assess potential ABCB1- and ABCG2-mediated drug-drug interactions (DDIs) in vivo. Advances in knowledge and implications for patient care: This minimally-invasive, [(18)F]-based PET-CT imaging method shows the interplay of ABCB1 and ABCG2 at the BBB in vivo. The method may be applied in the future to assess ABCB1 and ABCG2 activity at the BBB in humans, and for personalized treatment with drugs that are substrates of ABCB1 and/or ABCG2.
MeSH term(s)	ATP Binding Cassette Transporter, Subfamily B/metabolism ; ATP Binding Cassette Transporter, Subfamily G, Member 2 ; ATP-Binding Cassette Transporters/metabolism ; Acridines/pharmacology ; Animals ; Biological Transport/drug effects ; Blood-Brain Barrier/diagnostic imaging ; Blood-Brain Barrier/drug effects ; Blood-Brain Barrier/metabolism ; Cell Line, Tumor ; Drug Interactions ; Fluorine Radioisotopes ; Gefitinib ; Humans ; Male ; Mice ; Positron-Emission Tomography ; Quinazolines/metabolism ; Quinazolines/pharmacokinetics ; Tetrahydroisoquinolines/pharmacology ; Tissue Distribution ; Tomography, X-Ray Computed
Chemical Substances	ATP Binding Cassette Transporter, Subfamily B ; ATP Binding Cassette Transporter, Subfamily G, Member 2 ; ATP-Binding Cassette Transporters ; Abcg2 protein, mouse ; Acridines ; Fluorine Radioisotopes ; Quinazolines ; Tetrahydroisoquinolines ; Abcb1b protein, mouse (EC 7.6.2.2) ; Elacridar (N488540F94) ; Gefitinib (S65743JHBS)
Language	English
Publishing date	2015-07-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1138098-6
ISSN	1872-9614 ; 0883-2897 ; 0969-8051
ISSN (online)	1872-9614
ISSN	0883-2897 ; 0969-8051
DOI	10.1016/j.nucmedbio.2015.07.004
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