Platelet Aggregation Unchanged by Lipoprotein-Associated Phospholipase A2 Inhibition: Results from an In Vitro Study and Two Randomized Phase I Trials

Shaddinger, Bonnie C.; Xu, Yanjun; Roger, James; Macphee, Colin H.; Händel, M.; Baidoo, Charlotte A.; Magee, Mindy; Lepore, John J.; Sprecher, Dennis L.

doi:10.1371/journal.pone.0083094

Cited by 22 publications

(15 citation statements)

References 30 publications

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“…The inhibition of phospholipase A2 is reported as the main mechanism of action for Rilapladib ( SB‐659032 developed by GlaxoSmithKline) . The clinical research in AD patients was completed in 2015, but the results are not yet available.…”

Section: Current Strategies Of Ad Drug Developmentmentioning

confidence: 99%

Drugs in Clinical Trials for Alzheimer's Disease: The Major Trends

Бачурин

Bovina

Ustyugov

2017

Medicinal Research Reviews

272

164

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Alzheimer's disease (AD) is characterized by a chronic and progressive neurodegenerative process resulting from the intracellular and extracellular accumulation of fibrillary proteins: beta-amyloid and hyperphosphorylated Tau. Overaccumulation of these aggregates leads to synaptic dysfunction and subsequent neuronal loss. The precise molecular mechanisms of AD are still not fully understood but it is clear that AD is a multifactorial disorder and that advanced age is the main risk factor. Over the last decade, more than 50 drug candidates have successfully passed phase II clinical trials, but none has passed phase III. Here, we summarize data on current "anti-Alzheimer's" agents currently in clinical trials based on findings available in the Thomson Reuters «Integrity» database, on the public website www.clinicaltrials.gov, and on database of the website Alzforum.org. As a result, it was possible to outline some major trends in AD drug discovery: (i) the development of compounds acting on the main stages of the pathogenesis of the disease (the so-called "disease-modifying agents") - these drugs could potentially slow the development of structural and functional abnormalities in the central nervous system providing sustainable improvements of cognitive functions, which persist even after drug withdrawal; (ii) focused design of multitargeted drugs acting on multiple molecular targets involved in the pathogenesis of the disease; (3) finally, the repositioning of old drugs for new (anti-Alzheimer's) application offers a very attractive approach to facilitate the completion of clinical trials.

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Section: Current Strategies Of Ad Drug Developmentmentioning

confidence: 99%

Drugs in Clinical Trials for Alzheimer's Disease: The Major Trends

Бачурин

Bovina

Ustyugov

2017

Medicinal Research Reviews

272

164

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“…Furthermore, both darapladib and rilapladib were well tolerated with no major side effects observed. Both had no influence on platelet aggregation and displayed a good correlation of PD and PK effects . Subsequently, both compounds have been under assessment in further clinical trials to evaluate the possibility of Lp‐PLA2 as a therapeutic target for various diseases.…”

Section: Identification Of Small‐molecule Inhibitors Of Lp‐pla2mentioning

confidence: 99%

Lipoprotein‐associated phospholipase A2: The story continues

Huang

Wang

Shen

2019

Medicinal Research Reviews

131

140

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Inflammation is thought to play an important role in the pathogenesis of vascular diseases. Lipoprotein‐associated phospholipase A2 (Lp‐PLA2) mediates vascular inflammation through the regulation of lipid metabolism in blood, thus, it has been extensively investigated to identify its role in vascular inflammation‐related diseases, mainly atherosclerosis. Although darapladib, the most advanced Lp‐PLA2 inhibitor, failed to meet the primary endpoints of two large phase III trials in atherosclerosis patients cotreated with standard medical care, the research on Lp‐PLA2 has not been terminated. Novel pathogenic, epidemiologic, genetic, and crystallographic studies regarding Lp‐PLA2 have been reported recently, while novel inhibitors were identified through a fragment‐based lead discovery strategy. More strikingly, recent clinical and preclinical studies revealed that Lp‐PLA2 inhibition showed promising therapeutic effects in diabetic macular edema and Alzheimer's disease. In this review, we not only summarized the knowledge of Lp‐PLA2 established in the past decades but also emphasized new findings in recent years. We hope this review could be valuable for helping researchers acquire a much deeper insight into the nature of Lp‐PLA2, identify more potent and selective Lp‐PLA2 inhibitors, and discover the potential indications of Lp‐PLA2 inhibitors.

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“…[144][145][146][147] La señal vascular cuantitativa de PET FDG ha sido ampliamente utilizada como un objetivo subrogado para probar los efectos de drogas antiinflamatorias en los estudios clínicos. [148][149][150][151][152][153][154][155] La PET con FDG se está usando activamente como un objetivo subrogado en muchos estudios en curso de ateroesclerosis. Más recientemente, otros agentes de imágenes novedosos dirigidos se han utilizado con PET para caracterizar la inflamación 134,156-160 y otros aspectos de la biología de la placa que incluyen la neoangiogénesis 161 y microcalcificación, 162 y también en complicaciones de la ateroesclerosis 163 en animales experimentales y seres humanos.…”

Section: Imágenes De Infarto De Miocardiounclassified

The Future of Cardiovascular Imaging

2016

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O ver the past 2 decades, we have witnessed an explosive expansion in the armamentarium of noninvasive and invasive imaging technologies capable of providing detailed information about the structure and function of the heart and vasculature. Many of these technologies are integrative (eg, positron emission tomography and computed tomography, positron emission tomography and MRI), thereby compounding the unique strengths of the component technologies to achieve unprecedented improvements to our ability to diagnose disease, improve patient care, and advance biomedical research. In addition, the miniaturization of imaging devices with dramatic increases in sensitivity and spatial resolution, coupled with the development of quantitative molecular imaging approaches for evaluating physiology and pathobiology at the cellular and molecular levels, provides a unique platform for a new era in diagnostic imaging. The crucial role of imaging in early phenotyping of disease, risk assessment, and management guidance is expanding rapidly in ways previously thought unrealistic.Along with clinical, molecular, and genomewide association studies, structural and functional quantitative imaging already plays a critical role in phenotyping cardiovascular disease. Unique strengths of imaging phenotyping include its ability to provide precise, organ-specific anatomic localization and quantification of disease traits, to demonstrate and quantify involvement of other organs in cardiac disease, to provide an opportunity to investigate the time course of disease-specific molecular events in vivo, and to track their response to therapy. In so doing, quantitative structural and functional imaging can provide a nuanced description of disease burden (eg, atherosclerosis, myocarditis), disease subtypes (eg, amyloidosis), and, importantly, the relationship between the specific phenotype and outcomes, thereby informing treatment strategies and allowing more personalized approaches to patient management.Our objectives for this article are to (1) provide a viewpoint regarding the evolving role of cardiovascular imaging in biomedical research and clinical practice, (2) discuss the challenges associated with clinical translation of imaging innovations and the opportunities for multimodality imaging in the changing paradigm of value-based medicine, and (3) briefly outline future challenges and opportunities including the requirements for training future generations of imaging scientists and clinical specialists. Unlike traditional reviews that provide a detailed discussion of the role of 1 or more imaging modalities in cardiovascular (CV) disease, our discussion will focus on the potential role of imaging in what we believe are key areas of the translational highway with specific examples on how structural and functional imaging may contribute to scientific discovery, diagnosis, risk stratification, and patient management in each of those areas. Redefining the Role of Imaging Across the Continuum of Biomedical Research and Clinical Practice Translati...

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Platelet Aggregation Unchanged by Lipoprotein-Associated Phospholipase A2 Inhibition: Results from an In Vitro Study and Two Randomized Phase I Trials

Cited by 22 publications

References 30 publications

Drugs in Clinical Trials for Alzheimer's Disease: The Major Trends

Drugs in Clinical Trials for Alzheimer's Disease: The Major Trends

Lipoprotein‐associated phospholipase A2: The story continues

The Future of Cardiovascular Imaging

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