The Experts below are selected from a list of 105 Experts worldwide ranked by ideXlab platform
Pk Nguyen - One of the best experts on this subject based on the ideXlab platform.
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Moexipril and left ventricular hypertrophy
Dove Medical Press, 2007Co-Authors: George S Chrysant, Pk NguyenAbstract:George S Chrysant1, PK NguyenUniversity of Oklahoma, 1Director, Advanced Cardiac Imaging, INTEGRIS Heart Hospital, Oklahoma City, OK, USAAbstract: Angiotensin-converting enzyme (ACE) inhibitors today are the standard therapy of patients with myocardial infarction and heart failure due to their proven beneficial effects in left ventricular remodeling and left ventricular function. ACE inhibitors have also been demonstrated to lead to regression of left ventricular hypertrophy (LVH). It is believed that the mechanism of action of LVH regression with ACE inhibitors arises from more than simple blood pressure reduction. LVH is an important risk factor for cardiovascular disease morbidity and mortality independent of blood pressure. Moexipril hydrochloride is a long-acting, non-sulfhydryl ACE inhibitor that can be taken once daily for the treatment of hypertension. Moexipril has now also been demonstrated to have beneficial effects on LVH and can lead to LVH regression.Keywords: Moexipril, ACE inhibitor, cardiovascular disease, left ventricular hypertrop
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Moexipril and left ventricular hypertrophy
Dove Medical Press, 2026Co-Authors: Chrysant, George S, Pk NguyenAbstract:Angiotensin-converting enzyme (ACE) inhibitors today are the standard therapy of patients with myocardial infarction and heart failure due to their proven beneficial effects in left ventricular remodeling and left ventricular function. ACE inhibitors have also been demonstrated to lead to regression of left ventricular hypertrophy (LVH). It is believed that the mechanism of action of LVH regression with ACE inhibitors arises from more than simple blood pressure reduction. LVH is an important risk factor for cardiovascular disease morbidity and mortality independent of blood pressure. Moexipril hydrochloride is a long-acting, non-sulfhydryl ACE inhibitor that can be taken once daily for the treatment of hypertension. Moexipril has now also been demonstrated to have beneficial effects on LVH and can lead to LVH regression
Xinwen Wang - One of the best experts on this subject based on the ideXlab platform.
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ces1 genetic variation affects the activation of angiotensin converting enzyme inhibitors
Pharmacogenomics Journal, 2016Co-Authors: Xinwen Wang, Guangji Wang, Jian Shi, Rinelly Comas, Yan Liang, Hao Jie ZhuAbstract:The aim of the study was to determine the effect of carboxylesterase 1 (CES1) genetic variation on the activation of angiotensin-converting enzyme inhibitor (ACEI) prodrugs. In vitro incubation study of human liver, intestine and kidney s9 fractions demonstrated that the ACEI prodrugs enalapril, ramipril, perindopril, Moexipril and fosinopril are selectively activated by CES1 in the liver. The impact of CES1/CES1VAR and CES1P1/CES1P1VAR genotypes and diplotypes on CES1 expression and activity on enalapril activation was investigated in 102 normal human liver samples. Neither the genotypes nor the diplotypes affected hepatic CES1 expression and activity. Moreover, among several CES1 nonsynonymous variants studied in transfected cell lines, the G143E (rs71647871) was a loss-of-function variant for the activation of all ACEIs tested. The CES1 activity on enalapril activation in human livers with the 143G/E genotype was approximately one-third of that carrying the 143G/G. Thus, some functional CES1 genetic variants (for example, G143E) may impair ACEI activation, and consequently affect therapeutic outcomes of ACEI prodrugs.
Cameron, Ryan T. - One of the best experts on this subject based on the ideXlab platform.
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The role of Hsp20 in Alzheimer's disease
2014Co-Authors: Cameron, Ryan T.Abstract:Alzheimer’s disease is the most common of the degenerative brain diseases and is characterised by impairment of cognitive function. Patients with this disorder lose the ability to encode new memories. Eventually, both declarative and non-declarative memory is significantly impaired, resulting in the capacity for reasoning, abstraction and language becoming progressively reduced. Alzheimer’s disease and other dementias have devastating effects on families and caregivers, and is an increasing burden in an ageing society. It is estimated that 36 million people worldwide are living with dementia and this figure is expected to double every 20 years. The worldwide costs of dementia in 2010 were estimated to be $604 billion, an exorbitant figure that represents 1% of global GDP (World Alzheimer Report 2011). Alzheimer’s disease is the fourth leading cause of death in industrialised nations, preceded by cardiovascular disease, cancer and stroke. As yet there are currently no disease-modifying drugs approved to treat Alzheimer’s disease. The therapeutics that are available only temporarily alleviate symptoms of cognitive impairment, however, they do not halt the inevitable progression of the disease. As such, major scientific efforts are underway in order to develop drugs which can help stabilise the disease. The publication of the “Amyloid Hypothesis” by Dennis Selkoe in 1991 helped to focus research efforts towards a causative protein involved in the disease, the amyloid β protein (Aβ). Aggregation and deposition of the Aβ protein is fundamental in the aetiology of Alzheimer’s disease and its importance has been demonstrated by a number familial heterogeneous mutations in the amyloid precursor protein that promote increased Aβ deposition, resulting in early onset phenotypes. There are several other aspects involved in disease progression such as neuroinflammation and aberrant neuronal signalling, however, therapies targeting amyloid β aggregation have the potential to slow or even halt further neurodegeneration and anti-Aβ therapies are regarded as a logical approach to treating Alzheimer’s disease. Several endogenous pathways exist to prevent protein misfolding and subsequent aggregation following stressful cellular conditions. One pathway includes the amateur chaperones of the small heat-shock protein family, which have recently garnered interest due to their ability to inhibit the aggregation of amyloid-like proteins. In particular, Hsp20 was previously identified as having the ability to inhibit the aggregation of Aβ and could Abstract ii attenuate subsequent toxicity associated with Aβ peptides. Hsp20 was of particular interest to the Baillie group as it has well established cardio-protective functions, which are triggered by the phosphorylation of a serine residue (S16) at a consensus protein kinase A/G site. Hsp20 “activity” can therefore be readily modulated via inhibition of second messenger signal degradation by phosphodiesterases. The first part of this thesis investigated the interaction between Hsp20 and Aβ using Peptide Array technology. This technique allowed rapid characterisation of interacting domains and pinpointed key residues that mediated the protein-protein interaction. Using this approach, I demonstrated that the domain within Hsp20 that interacted with Aβ included the consensus PKA phosphorylation site (R-R-X-S). Upon introduction of a phospho-serine residue or a phospho-mimetic substitution, I was able to show that the binding of Aβ was enhanced. Reciprocal peptide array experiments highlighted that Hsp20 bound to a domain within Aβ, which is key to the aggregation of the Aβ peptide and is required to produce the higher order toxic Aβ species. The Peptide Array data was then verified using full-length recombinant proteins and several Hsp20 mutants were developed including a phospho-mimetic. The phospho-mimetic Hsp20 was shown to outperform the wild-type variant in several assays such as, in vitro pull-down assays, Aβ aggregation measured using nuclear magnetic resonance spectroscopy, and also a novel Aβ aggregation assay which can differentiate between two distinct aggregation pathways, namely fibrillisation and oligomerisation. These data demonstrated for the first time how the interaction between Hsp20 and Aβ may be modulated by cell signalling cascades. I then moved to investigate the cytotoxicity of Aβ in order to investigate whether increasing Hsp20 expression in neuronal-like cells would confer protection against Aβ-mediated toxicity. This was initially carried out using a standard MTT-based cell viability assay, before utilising a real-time cell monitoring device to develop a novel Aβ toxicity assay. In both assays, increasing Hsp20 expression was shown to be cytoprotective. The wild-type variant of Hsp20 was found to be more effective in cell-based assays due to increased levels of phosphorylated Hsp20. The real-time Aβ toxicity monitoring assay also gave me a platform for testing agents with potential neuroprotective properties. Given that increasing levels of phosphorylated Hsp20 could attenuate Aβ-mediated cytotoxicity, I logically was drawn to study ways that this event could be targeted therapeutically. Several drugs that target cAMP- and cGMP-dependent phosphodiesterases have been shown to be effective in alleviating symptoms of Alzheimer’s disease in rodent iii models have also been studied here in cellular systems. These included the “blockbuster” PDE5 inhibitor Viagra® (sildenafil), two novel compounds which selectively inhibit PDE9, which were developed by the pharmaceutical company Lundbeck specifically as Alzheimer’s treatments, and rolipram, a well established cognitive enhancer that was developed originally as an anti-depressant. All of these compounds were shown to “activate” endogenous Hsp20 to varying degrees in neuronal-like cells and the levels of Hsp20 activation was found to correlate with both the level of induced Hsp20/Aβ co-localisation, and subsequent attenuation of Aβ-mediated cytotoxicity. This suggests that this endogenous protection pathway can be targeted by currently available therapeutics in order to reduce the neurotoxic effects of Aβ. Finally, we wanted to develop novel agents of our own that could promote Hsp20 phosphorylation. To do this, in silico docking of all FDA approved drugs against the catalytic domain of PDE4 was undertaken in an attempt to find a novel compound with the potential to reposition as an Alzheimer’s treatment. Using this methodology we discovered an angiotensin converting enzyme inhibitor, Moexipril to be a PDE4 inhibitor in the low micro molar range. Unfortunately, Moexipril works as an ACE inhibitor in the low nano molar range making repositioning unviable. However, Moexipril treatment was more effective than rolipram in reversing Aβ toxicity and I speculate that this may be due to the sub-family selective nature of its (Moexipril) PDE4 inhibition. Furthermore, the lack of emetic side effects associated with Moexipril makes this compound an ideal starting point for the development of isoform selective and/or non-emetic PDE4 inhibitor. In summary, these studies describe a novel endogenous mechanism for combating the toxic effects of the Aβ protein, which underpins the development and progression of Alzheimer’s disease. Given that the interaction between Hsp20 and Aβ can be manipulated via cAMP/cGMP signalling, the interaction could be targeted therapeutically. As there are currently no effective drugs on the market for stabilising Alzheimer’s disease, I believe that the data presented here opens up a potential new avenue that could lead to the development of a new class of AD drugs
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Chemical informatics uncovers a new role for Moexipril as a novel inhibitor of cAMP phosphodiesterase-4 (PDE4)
Elsevier Inc., 2013Co-Authors: Cameron, Ryan T., Coleman, Ryan G., Day, Jon P., Yalla, Krishna C., Houslay, Miles D., Adams, David R., Shoichet, Brian K., Baillie, George S.Abstract:AbstractPDE4 is one of eleven known cyclic nucleotide phosphodiesterase families and plays a pivotal role in mediating hydrolytic degradation of the important cyclic nucleotide second messenger, cyclic 3′5′ adenosine monophosphate (cAMP). PDE4 inhibitors are known to have anti-inflammatory properties, but their use in the clinic has been hampered by mechanism-associated side effects that limit maximally tolerated doses. In an attempt to initiate the development of better-tolerated PDE4 inhibitors we have surveyed existing approved drugs for PDE4-inhibitory activity. With this objective, we utilised a high-throughput computational approach that identified Moexipril, a well tolerated and safe angiotensin-converting enzyme (ACE) inhibitor, as a PDE4 inhibitor. Experimentally we showed that Moexipril and two structurally related analogues acted in the micro molar range to inhibit PDE4 activity. Employing a FRET-based biosensor constructed from the nucleotide binding domain of the type 1 exchange protein activated by cAMP, EPAC1, we demonstrated that Moexipril markedly potentiated the ability of forskolin to increase intracellular cAMP levels. Finally, we demonstrated that the PDE4 inhibitory effect of Moexipril is functionally able to induce phosphorylation of the small heat shock protein, Hsp20, by cAMP dependent protein kinase A. Our data suggest that Moexipril is a bona fide PDE4 inhibitor that may provide the starting point for development of novel PDE4 inhibitors with an improved therapeutic window
Karljiković-rajić Katarina - One of the best experts on this subject based on the ideXlab platform.
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In Vitro modeling of angiotensin-converting enzyme inhibitor's absorption with chromatographic retention data and selected molecular descriptors
'Elsevier BV', 2014Co-Authors: Odović Jadranka, Marković Bojan, Vladimirov Sote, Karljiković-rajić KatarinaAbstract:Set of nine angiotensin-converting enzyme inhibitors (enalapril, quinapril, fosinopril, lisinopril, cilazapril, ramipril, benazepril, perindopril and Moexipril) were studied to evaluate the correlation between their intestinal absorption and salting-out thin-layer chromatography hydrophobicity parameters (R-M(0) or C-0) obtained by ascending technique applying four different salts, (NH4)(2)SO4, NH4NO3, NH4Cl and NaCl as mobile phases. The best correlations between KOWWIN log P and both hydrophobicity parameters, R-M(0) and C-0, (R-2 > 0.850) were observed for NaCl (1.0-3.0 M) while the lowest R-2 was obtained for (NH4)(2)SO4 (0.649 and 0.427, respectively) due to highest salting-out effect of (NH4)(2)SO4. The effect of selected inorganic salts in the salting-out mobile phases, on the solutes solubility and retention was evaluated. The topological polar surface area should be selected as independent variable (only this molecular descriptor showed low correlation with chromatographic hydrophobicity parameters) for multiple linear regression analysis, to obtain reliable correlation between angiotensin-converting enzyme inhibitor's intestinal absorption data and salting-out thin-layer chromatograpic hydrophobicity parameters. These correlations provide R-2 =0.823 for R-M(0) or R-2 =0.799 for C-0 indicating good relationship between predicted and literature available intestinal absorption (ranged from 22% to 70%) of investigated angiotensin-converting enzyme inhibitors. The proposed in vitro model was checked with three in addition experimentally analyzed drugs, zofenopril, trandolapril and captoril. The satisfactory absorption prediction was obtained for zofenopril and trandolapril, while divergence established for captopril resulted from considerably different structure
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Correlation between ultra-high performance liquid chromatography-tandem mass spectrometry and reversed-phase thin-layer chromatography hydrophobicity data for evaluation of angiotensin-converting enzyme inhibitors absorption
'Elsevier BV', 2012Co-Authors: Odović Jadranka, Marković Bojan, Injac Rade, Vladimirov Sote, Karljiković-rajić KatarinaAbstract:In this research seven ACE inhibitors (enalapril, quinapril, fosinopril, lisinopril, cilazapril, ramipril, benazepril) were studied to evaluate the correlation between their absorption and ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS) and reversed-phase thin-layer chromatography (RP-TLC) hydrophobicity data (phi(0) or C-0 parameters, respectively). Their absorption values were in the range of 25-60%, while calculated KOWWIN logP values were from -0.94 to 6.61. Additionally. perindopril (absorption 70%, KOWWIN logP 2.59) and Moexipril (absorption 22%, KOWWIN logP 3.36) were introduced for the theoretical considerations due to their high/low absorption values which were on the opposite sites in comparison with the majority of ACE inhibitors (25-60%). In the theoretical considerations it was shown that the solubility data (logS) must be considered, as independent variable, simultaneously with KOWWIN logP to obtain reliable correlation (r(2) = 0.7208) between absorption and ACE inhibitors lipophilicity. As the main topic of this study, the relationships between literature available and absorption data predicted by multiple linear regression (MLR) using logS values besides chromatographically obtained hydrophobicity parameters C-0 (r(2) = 0.6424) or phi(0) (r(2) = 0.6762) were studied proving that these parameters could be used in ACE inhibitors absorption evaluation. The UHPLC-MS method provides the direct application of experimentally obtained phi(0) values that is the advantage of this method. For better MLR correlation of ACE inhibitors absorption with C-0 parameters (RP-TLC) and logS, mathematical conversion of C-0 parameters to logC(0) values was necessary based on requisite for probability value of regression analysis (P lt 0.05). The accordance and differences between hydrophobicity parameters obtained by UHPLC-MS and RP-TLC were defined
Hao Jie Zhu - One of the best experts on this subject based on the ideXlab platform.
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ces1 genetic variation affects the activation of angiotensin converting enzyme inhibitors
Pharmacogenomics Journal, 2016Co-Authors: Xinwen Wang, Guangji Wang, Jian Shi, Rinelly Comas, Yan Liang, Hao Jie ZhuAbstract:The aim of the study was to determine the effect of carboxylesterase 1 (CES1) genetic variation on the activation of angiotensin-converting enzyme inhibitor (ACEI) prodrugs. In vitro incubation study of human liver, intestine and kidney s9 fractions demonstrated that the ACEI prodrugs enalapril, ramipril, perindopril, Moexipril and fosinopril are selectively activated by CES1 in the liver. The impact of CES1/CES1VAR and CES1P1/CES1P1VAR genotypes and diplotypes on CES1 expression and activity on enalapril activation was investigated in 102 normal human liver samples. Neither the genotypes nor the diplotypes affected hepatic CES1 expression and activity. Moreover, among several CES1 nonsynonymous variants studied in transfected cell lines, the G143E (rs71647871) was a loss-of-function variant for the activation of all ACEIs tested. The CES1 activity on enalapril activation in human livers with the 143G/E genotype was approximately one-third of that carrying the 143G/G. Thus, some functional CES1 genetic variants (for example, G143E) may impair ACEI activation, and consequently affect therapeutic outcomes of ACEI prodrugs.