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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).
Snakebite-associated thrombotic microangiopathy: a spotlight on pharmaceutical interventions
Published in Expert Review of Clinical Pharmacology, 2023
Tina Noutsos, Geoffrey K Isbister
The newest emerging therapeutic approaches to snakebite, mostly in preclinical phase of development, include recombinant monoclonal antibodies and small molecule toxin inhibitors which target major pathogenic protein family toxins (SVMP, phospholipase A2 [PLA2] etc.) of differing snake species [105]. One such example is varespladib, a small synthetic toxin-specific potent inhibitor of secreted PLA2 venom toxins [106]. Venom PLA2 are present in over 95% of venomous snake species globally, with a wide spectrum of toxicities, including but not limited to hemotoxicity. In addition, PLA2s play a role as catalysts for other venom toxin families, including SVMPs [106]. Multiple preclinical studies have shown that varespladib minimizes toxic effects, including neutralizing coagulopathic toxicities (most notably in restoring normal coagulation in anticoagulant and procoagulant snake PLA2 toxins) in in vitro and envenomed animal studies, including in E. carinatus, E. ocellatus, D. russelii, and B. arietans species [107].
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).
Anti-inflammatory strategies for atherosclerotic artery disease
Published in Expert Opinion on Drug Safety, 2022
Federica Agnello, Davide Capodanno
Compared with the positive CANTOS, these studies were different in many ways, which contributes to explain their reasons for failure. The study population of CANTOS was characterized by high residual inflammatory risk, as shown by the median baseline hs-CPR value of 4.2.mg/L, which is higher than the median hs-CRP value of 1.5 mg/L of CIRT. Moreover, low-dose methotrexate showed no impact on hs-CRP and its upstream biomarkers. The same observation applies to losmapimod, which in the LATITUDE (Losmapimod To Inhibit p38 MAP kinase as a TherapeUtic Target and Modify Outcomes After an Acute Coronary Syndrome) – TIMI 60 trial actually impacted on hs-CRP, but not sufficiently to result into a significant clinical benefit. Someone suggests that the tested dose was inadequate, but further preclinical research highlighted that the potential benefit of losmapimod is counteracted by the apoptosis induced by p38 mitogen-activated protein kinase inhibition. Varespladib is an inhibitor of different isoforms of secreted phospholipase A2 (sPLA2) (i.e. groups II, V, and X), which showed reduction of atherosclerosis development in animal models; subsequently, it showed significant reductions of LDL and hs-CRP compared to placebo in a phase 2b trial. That finding prompted the investigation of varespladib on cardiovascular outcomes in patients with ACS on a phase 3 trial, named VISTA-16 (The Vascular Inflammation Suppression to Treat Acute Coronary Syndrome for 16 Weeks). This study was early discontinued for futility and possible harm of the drug, since it was associated to a greater risk of MI compared to placebo [99–101]. Animal models of mice deficient of sPLA2 group X isoform gene presented advanced and accelerated atherosclerosis, suggesting the presence of sPLA2 pro-atherogenic isoforms (group II and V) and sPLA2 anti-atherogenic (group X) isoforms; therefore, the broad and nonspecific action of varespladib may be the reason of its failure in clinical trials [102].