Assessment of OMT-28, a synthetic analog of omega-3 epoxyeicosanoids, in patients with persistent atrial fibrillation: Rationale and design of the PROMISE-AF phase II study

Berlin, Sarah; Goette, Andreas; Summo, Luciana; Lossie, Janine; Gebauer, Alexander; Al-Saady, N.; Calò, Leonardo; Naccarelli, Gerald V.; Schunck, Wolf Hagen; Fischer, Robert; Dobrev, Dobromir

doi:10.1016/j.ijcha.2020.100573

Cited by 5 publications

(6 citation statements)

References 44 publications

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“…Polyunsaturated omega‐3 fatty acid (PUFA) supplementation exerts anti‐inflammatory effects but has yet to demonstrate a consistent benefit in patients with AF. The potential mechanism of action includes the reduction of pro‐inflammatory signaling 22 . PROMISE‐AF, a dose‐finding, phase II study on OMT‐28, a synthetic analog of 17,18‐epoxyeicosatetraenoic acid will hopefully clarify any potential benefit of PUFA supplementation in patients with persistent AF.…”

Section: Methodsmentioning

confidence: 99%

The role of inflammation in the pathogenesis and treatment of arrhythmias

et al. 2022

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The pathogenesis of arrhythmias is complex and multifactorial. The role of inflammation in the pathogenesis of both atrial and ventricular arrhythmias (VA) has been explored. However, developing successful pharmacotherapy regimens based on those pathways has proven more of a challenge. This narrative review provides an overview of five common arrhythmias impacted by inflammation, including atrial fibrillation (AF), myocardial infarction, arrhythmogenic cardiomyopathy, cardiac sarcoidosis, and QT prolongation, and the potential role for anti‐inflammatory therapy in their management. We identified arrhythmias and arrhythmogenic disease states with the most evidence linking pathogenesis to inflammation and conducted comprehensive searches of United States National Library of Medicine MEDLINE® and PubMed databases. Although a variety of agents have been studied for the management of AF, primarily in an effort to reduce postoperative AF following cardiac surgery, no standard anti‐inflammatory agents are used in clinical practice at this time. Although inflammation following myocardial infarction may contribute to the development of VA, there is no clear benefit with the use of anti‐inflammatory agents at this time. Similarly, although inflammation is clearly linked to the development of arrhythmias in arrhythmogenic cardiomyopathy, data demonstrating a benefit with anti‐inflammatory agents are limited. Cardiac sarcoidosis, an infiltrative disease eliciting an immune response, is primarily treated by immunosuppressive therapy and steroids, despite a lack of primary literature to support such regimens. In this case, anti‐inflammatory agents are frequently used in clinical practice. The pathophysiology of arrhythmias is complex, and inflammation likely plays a role in both onset and duration, however, for most arrhythmias the role of pharmacotherapy targeting inflammation remains unclear.

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Section: Methodsmentioning

confidence: 99%

The role of inflammation in the pathogenesis and treatment of arrhythmias

et al. 2022

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“…More recently, there is growing interest in ω-3 EpFAs, namely Eicosapentaenoic acid (EPA, 20:5)-derived Epoxyeicosatetraenoic acids (EEQs) and Docosahexaenoic acid (DHA, 22:6)derived Epoxydocosapentaenoic acids (EDPs), and their synthetic analogues. [29][30][31] Thus, as a possible next step, the alkoxy-mimics of these EpFAs could also be examined, especially since EEQs and EDPs have in fact proven to be more potent than EETs in certain disease models. 32,33 26 Finally, activity of individual regioisomers within the most promising series could potentially be explored, with particular emphasis being placed on molecules with functional groups positioned at the terminal olefin, since these have generally proven to be the most biologically relevant within each of the three EpFA series.…”

Section: Discussionmentioning

confidence: 99%

“…More recently, there is growing interest in ω-3-EpFAs, namely, eicosapentaenoic acid (EPA, 20:5)-derived epoxyeicosatetraenoic acids (EEQs) and docosahexaenoic acid (DHA, 22:6)-derived epoxydocosapentaenoic acids (EDPs), and their synthetic analogues. − Thus, as a next step, the alkoxy- analogues of these EpFAs could also be examined, especially since EEQs and EDPs are more potent than EETs in certain disease models. , Moreover, activity of individual regioisomers within the most promising series should eventually be explored.…”

Section: Discussionmentioning

confidence: 99%

New Alkoxy- Analogues of Epoxyeicosatrienoic Acids Attenuate Cisplatin Nephrotoxicity In Vitro via Reduction of Mitochondrial Dysfunction, Oxidative Stress, Mitogen-Activated Protein Kinase Signaling, and Caspase Activation

Singh

Vik

Lybrand

et al. 2021

Chem. Res. Toxicol.

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Application of cisplatin, a widely used and highly potent chemotherapeutic, is limited by its severe nephrotoxicity. Arachidonic acid (ARA)-derived epoxyeicosatrienoic acids (EETs), as well as soluble epoxide hydrolase (sEH) inhibitors, are promising therapeutics that can ameliorate this dose-limiting side effect, but both approaches have certain limitations. EET analogues are an alternative approach with distinct benefits, but the structural aspects of the current series of mimics have faced criticisms. Hence, in this study, regioisomer mixtures of four new ARA alkoxides were synthesized, characterized, and assessed as EET mimics against varying cisplatin doses and exposure durations in proximal tubular epithelial cells. All four ether groups displayed bioisostere activity, ranging from marginal for methoxy-, good for n-propoxy-, and excellent for ethoxy-and ipropoxy-. Cell protective potency of the ethoxy-and ipropoxymimics was comparable to that of EETs against high, acute exposures, but surpassed it against low to moderate, chronic exposures. The ethoxy-and ipropoxy-mimics exhibited their therapeutic effects through stabilization of the mitochondrial transmembrane potential and attenuation of reactive oxygen species generation, leading to reduced phosphorylation of mitogen-activated protein kinases p38 and JNK and decreased activation of caspase-9 and -3.The study elucidates linear ethers as potent and more metabolically stable bioisostere alternatives to the epoxide group within EETs, that concurrently enable ARA backbone preservation and sEH independent activity. It also illustrates the potential of alkoxy-mimics of EETs and other epoxy fatty acids to be promising nephroprotective agents to tackle the clinically relevant side effect of cisplatin.

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“…One of the first analogs was already successfully used to attenuate laser-induced choroidal neovascularization in mice (25). Currently, 17,18-EEQ analogs are under further clinical development (30) by the OMEICOS Therapeutics GmbH (https://omeicos.com/).…”

Section: Introductionmentioning

confidence: 99%

Amelioration of Endotoxemia by a Synthetic Analog of Omega-3 Epoxyeicosanoids

et al. 2022

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Sepsis, a systemic inflammatory response to pathogenic factors, is a difficult to treat life-threatening condition associated with cytokine and eicosanoid storms and multi-organ damage. Omega-3 polyunsaturated fatty acids, such as eicosapentaenoic (EPA) and docosahexaenoic acid, are the precursors of potent anti-inflammatory lipid mediators, including 17,18-epoxyeicosatetraenoic acid (17,18-EEQ), the main metabolite of EPA generated by cytochrome P450 epoxygenases. Searching for novel therapeutic or preventative agents in sepsis, we tested a metabolically robust synthetic analog of 17,18-EEQ (EEQ-A) for its ability to reduce mortality, organ damage, and pro-inflammatory cytokine transcript level in a mouse model of lipopolysaccharide (LPS)-induced endotoxemia, which is closely related to sepsis. Overall survival significantly improved following preventative EEQ-A administration along with decreased transcript level of pro-inflammatory cytokines. On the other hand, the therapeutic protocol was effective in improving survival at 48 hours but insignificant at 72 hours. Histopathological analyses showed significant reductions in hemorrhagic and necrotic damage and infiltration in the liver. In vitro studies with THP-1 and U937 cells showed EEQ-A mediated repression of LPS-induced M1 polarization and enhancement of IL-4-induced M2 polarization of macrophages. Moreover, EEQ-A attenuated the LPS-induced decline of mitochondrial function in THP-1 cells, as indicated by increased basal respiration and ATP production as well as reduction of the metabolic shift to glycolysis. Taken together, these data demonstrate that EEQ-A has potent anti-inflammatory and immunomodulatory properties that may support therapeutic strategies for ameliorating the endotoxemia.

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Assessment of OMT-28, a synthetic analog of omega-3 epoxyeicosanoids, in patients with persistent atrial fibrillation: Rationale and design of the PROMISE-AF phase II study

Cited by 5 publications

References 44 publications

The role of inflammation in the pathogenesis and treatment of arrhythmias

The role of inflammation in the pathogenesis and treatment of arrhythmias

New Alkoxy- Analogues of Epoxyeicosatrienoic Acids Attenuate Cisplatin Nephrotoxicity In Vitro via Reduction of Mitochondrial Dysfunction, Oxidative Stress, Mitogen-Activated Protein Kinase Signaling, and Caspase Activation

Amelioration of Endotoxemia by a Synthetic Analog of Omega-3 Epoxyeicosanoids

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