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Angina pectoris in the elderly
Published in Wilbert S. Aronow, Jerome L. Fleg, Michael W. Rich, Tresch and Aronow’s Cardiovascular Disease in the Elderly, 2019
Wilbert S. Aronow, William H. Frishman
Patients with unstable angina pectoris do not benefit from treatment with the oral selective inhibitor of the Lp-PLA2 enzyme darapladib (91). Patients with unstable angina pectoris also do not benefit from treatment with the oral sPLA2 inhibitor varespladib (92).
Preclinical Models
Published in George C. Kagadis, Nancy L. Ford, Dimitrios N. Karnabatidis, George K. Loudos, Handbook of Small Animal Imaging, 2018
Irene Cuadrado, Jesús Egido, Jose Luis Zamorano, Carlos Zaragoza
Currently, there is no single and golden standard animal model of vulnerable plaque, but pig models are probably the best way to recreate human plaque instability. The combination of diabetes and hypercholesterolemia constitute a good model of accelerated atherosclerosis (Gerrity et al. 2001) and it was relevant to study the role of certain biomarkers, such as the Lp-PLA2, since these animals share a similar plasma lipoprotein profile to humans. In this regard, the selective inhibition of Lp-PLA2 by darapladib decreased progression to advanced coronary atherosclerotic lesions and confirmed a crucial role of vascular inflammation not associated to hypercholesterolemia, in the development of lesions implicated in the pathogenesis of myocardial infarction (MI) and stroke (Wilensky et al. 2008).
Translational personalized medicine: Molecular profiling, druggable targets, and clinical genomic medicine
Published in Priya Hays, Advancing Healthcare Through Personalized Medicine, 2017
Colley et al. (2011) have identified serum markers of inflammation that lead to inflammation and atherosclerosis. They discovered that lipoprotein-associated phospholipase A2 (Lp-PLA2) emerged as a marker of cardiovascular risk, supported by epidemiologic studies. They also report the development of a drug therapy, darapladib, that inhibits Lp-PLA2, which might reduce the progression of coronary artery plaques. They conclude, “The growing body of evidence points to an important role and utility for Lp-PLA2 testing in preventive and personalized clinical medicine” (Colley et al., 2011, 27).
Current and emerging drugs for the treatment of atherosclerosis: the evidence to date
Published in Expert Review of Cardiovascular Therapy, 2022
Ali A. Rizvi, Djordje S. Popovic, Nikolaos Papanas, Anca Pantea Stoian, Wael Al mahmeed, Amirhossein Sahebkar, Andrej Janez, Manfredi Rizzo
Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY) was a randomized, double-blind, placebo-controlled trial, analyzing the efficacy and safety of darapladib (LpPLA2 inhibitor) in patients with stable coronary heart disease [85]. It enrolled 15,828 patients assigned to receive either darapladib (160 mg daily) or placebo. The primary endpoint was a composite of cardiovascular death, myocardial infarction, or stroke. The occurrence of the primary endpoint was not significantly different between darapladib and placebo groups [85]. Stabilization of Plaque Using Darapladib-Thrombolysis in Myocardial Infarction 52 (SOLID-TIMI 52) was a multinational, double-blind, placebo-controlled trial assessing the efficacy and safety of darapladib in patients after an acute coronary syndrome event [86]. It included 13,026 patients within thirty days of hospitalization with an acute coronary syndrome (NSTEMI or STEMI) randomized to receive either darapladib (160 mg daily) or a matching placebo. The primary endpoint was the composite of coronary heart disease death, myocardial infarction, or urgent coronary revascularization for myocardial ischemia. The incidence of occurrence of the primary endpoint was similar between the two groups, while patients taking darapladib more often experienced odor-related concerns and diarrhea [86].
Anti-inflammatory strategies for atherosclerotic artery disease
Published in Expert Opinion on Drug Safety, 2022
Federica Agnello, Davide Capodanno
Several mediators of atherogenesis have been targeted by novel anti-inflammatory drugswith no convicing demonstration of clinical benefit so far. Darapladib is a selective inhibitor of the lipoprotein-associated phospholipase A2 (Lp-PLA2), which has been specifically developed for the treatment of atherosclerosis. Preclinical and clinical tests of this drug produced conflicting results. Indeed, the inhibition of this enzyme, which is known to generate inflammatory mediators [93,94], produced promising result in diabetic and hypercholesterolemic swines, reducing the development of advanced coronary atherosclerosis, but showed no clinical benefit in two large phase 3 trials in humans, namely the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial, recruiting stable CAD patients, and the SOLID-TIMI 52 (Stabilization Of pLaques usIng Darapladib-Thrombolysis In Myocardial Infarction 52), recruiting ACS patients [93–97]. Some authors speculate about the possibility of beneficial effects from this treatment only in subjects with higher baseline levels of Lp-PLA2. However, the available evidence suggests that the Lp-PLA2 activity could predict cardiovascular events only in individuals with stable CAD, advocating a role as inflammation biomarker without a causal role; furthermore, loss-of-function mutations of gene encoding for Lp-PLA2 do not support a cardiovascular protective effect [98].
The design and discovery of phospholipase A2 inhibitors for the treatment of inflammatory diseases
Published in Expert Opinion on Drug Discovery, 2021
Charikleia S. Batsika, Anna-Dimitra D. Gerogiannopoulou, Christiana Mantzourani, Sofia Vasilakaki, George Kokotos
Darapladib, although a highly potent inhibitor of Lp-PLA2, did not reduce the risk of major coronary events as compared to placebo in two phase III studies (STABILITY and SOLID-TIMI 52) [125]. These studies suggested that Lp-PLA2 may be a biomarker of vascular inflammation rather than a causal pathway of cardiovascular diseases. Varespladib, a potent inhibitor of GIIA sPLA2, has entered clinical trials initially against sepsis, and later for the treatment of cardiovascular diseases. In both cases, it failed to exhibit the required efficiency. Currently, varespladib, alone or combined with another inhibitor, is under investigation as a treatment of snakebite envenoming. In the case of GIVA cPLA2, inhibitors, like giripladib, studied for osteoarthritis; however, they presented gastrointestinal side effects. It seems that GIVA cPLA2 inhibitors might be useful for topical application, for example against atopic dermatitis (ZPL-5,212,372) or psoriasis (AVX001).