Icatibant as acute treatment for hereditary angioedema in adults

Farkas, Henriette

doi:10.1080/17512433.2016.1182425

Cited by 18 publications

(8 citation statements)

References 78 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The safety and tolerability of icatibant are good, although transient local injection site reactions (erythema, wheal, pruritus, and burning sensation) occur. Allergic reactions have not been reported We recommend that all patients have sufficient medication for on‐demand treatment of two attacks and carry on‐demand medication at all times.Evidence grade: D, strength of recommendation: Strong.…”

Section: Therapymentioning

confidence: 99%

The international WAO/EAACI guideline for the management of hereditary angioedema—The 2017 revision and update

Maurer

Magerl

Ansotegui

et al. 2018

Allergy

430

911

View full text Add to dashboard Cite

Hereditary Angioedema (HAE) is a rare and disabling disease. Early diagnosis and appropriate therapy are essential. This update and revision of the global guideline for HAE provides up‐to‐date consensus recommendations for the management of HAE. In the development of this update and revision of the guideline, an international expert panel reviewed the existing evidence and developed 20 recommendations that were discussed, finalized and consented during the guideline consensus conference in June 2016 in Vienna. The final version of this update and revision of the guideline incorporates the contributions of a board of expert reviewers and the endorsing societies. The goal of this guideline update and revision is to provide clinicians and their patients with guidance that will assist them in making rational decisions in the management of HAE with deficient C1‐inhibitor (type 1) and HAE with dysfunctional C1‐inhibitor (type 2). The key clinical questions covered by these recommendations are: (1) How should HAE‐1/2 be defined and classified?, (2) How should HAE‐1/2 be diagnosed?, (3) Should HAE‐1/2 patients receive prophylactic and/or on‐demand treatment and what treatment options should be used?, (4) Should HAE‐1/2 management be different for special HAE‐1/2 patient groups such as pregnant/lactating women or children?, and (5) Should HAE‐1/2 management incorporate self‐administration of therapies and patient support measures?

show abstract

Section: Therapymentioning

confidence: 99%

The international WAO/EAACI guideline for the management of hereditary angioedema—The 2017 revision and update

Maurer

Magerl

Ansotegui

et al. 2018

Allergy

430

911

View full text Add to dashboard Cite

show abstract

“…Underestimated system complexity and few results translated from animal models to humans led to the failure of B1 inhibitors in the clinic. Only Icatibant (B2 antagonist) has been approved for the acute treatment of hereditary angioedema (HAE) [ 30 ]. An improved understanding of the mechanism of action of B1 inhibitors and their biological effects would be crucial for the development of antagonists able to successfully proceed in clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Binding Mode Exploration of B1 Receptor Antagonists’ by the Use of Molecular Dynamics and Docking Simulation—How Different Target Engagement Can Determine Different Biological Effects

Gemei

Talarico

Brandolini

et al. 2020

IJMS

View full text Add to dashboard Cite

The kinin B1 receptor plays a critical role in the chronic phase of pain and inflammation. The development of B1 antagonists peaked in recent years but almost all promising molecules failed in clinical trials. Little is known about these molecules’ mechanisms of action and additional information will be necessary to exploit the potential of the B1 receptor. With the aim of contributing to the available knowledge of the pharmacology of B1 receptors, we designed and characterized a novel class of allosteric non-peptidic inhibitors with peculiar binding characteristics. Here, we report the binding mode analysis and pharmacological characterization of a new allosteric B1 antagonist, DFL20656. We analyzed the binding of DFL20656 by single point mutagenesis and radioligand binding assays and we further characterized its pharmacology in terms of IC50, B1 receptor internalization and in vivo activity in comparison with different known B1 antagonists. We highlighted how different binding modes of DFL20656 and a Merck compound (compound 14) within the same molecular pocket can affect the biological and pharmacological properties of B1 inhibitors. DFL20656, by its peculiar binding mode, involving tight interactions with N114, efficiently induced B1 receptor internalization and evoked a long-lasting effect in an in vivo model of neuropathic pain. The pharmacological characterization of different B1 antagonists highlighted the effects of their binding modes on activity, receptor occupancy and internalization. Our results suggest that part of the failure of most B1 inhibitors could be ascribed to a lack of knowledge about target function and engagement.

show abstract

“…One of the most interesting findings of our transcriptome analysis was that rMASP-1 treatment significantly up-regulated the expression of bradykinin receptor B2R, which mediates the edematogenic effect of bradykinin. Bradykinin—proteolytically produced mainly by kallikrein—is known as the key edematogenic factor in the pathomechanism of HAE (39). However, we have recently shown that MASP-1 can also produce bradykinin by cleaving high-molecular-weight kininogen (11).…”

Section: Discussionmentioning

confidence: 99%

MASP-1 Increases Endothelial Permeability

et al. 2019

View full text Add to dashboard Cite

Pathologically increased vascular permeability is an important dysfunction in the pathomechanism of life-threatening conditions, such as sepsis, ischemia/reperfusion, or hereditary angioedema (HAE), diseases accompanied by uncontrolled activation of the complement system. HAE for example is caused by the deficiency of C1-inhibitor (the main regulator of early complement activation), which leads to edematous attacks threatening with circulatory collapse. We have previously reported that endothelial cells become activated during HAE attacks. A natural target of C1-inhibitor is mannan-binding lectin-associated serine protease-1 (MASP-1), a multifunctional serine protease, which plays a key role in the activation of complement lectin pathway. We have previously shown that MASP-1 induces the pro-inflammatory activation of endothelial cells and in this study we investigated whether MASP-1 can directly affect endothelial permeability. All experiments were performed on human umbilical vein endothelial cells (HUVECs). Real-time micro electric sensing revealed that MASP-1 decreases the impedance of HUVEC monolayers and in a recently developed permeability test (XperT), MASP-1 dose-dependently increased endothelial paracellular transport. We show that protease activated receptor-1 mediated intracellular Ca 2+ -mobilization, Rho-kinase activation dependent myosin light chain (MLC) phosphorylation, cytoskeletal actin rearrangement, and disruption of interendothelial junctions are underlying this phenomenon. Furthermore, in a whole-transcriptome microarray analysis MASP-1 significantly changed the expression of 25 permeability-related genes in HUVECs—for example it up-regulated bradykinin B2 receptor expression. According to our results, MASP-1 has potent permeability increasing effects. During infections or injuries MASP-1 may help eliminate the microbes and/or tissue debris by enhancing the extravasation of soluble and cellular components of the immune system, however, it may also play a role in the pathomechanism of diseases, where edema formation and complement lectin pathway activation are simultaneously present. Our findings also raise the possibility that MASP-1 may be a promising target of anti-edema drug development.

show abstract

Icatibant as acute treatment for hereditary angioedema in adults

Cited by 18 publications

References 78 publications

The international WAO/EAACI guideline for the management of hereditary angioedema—The 2017 revision and update

The international WAO/EAACI guideline for the management of hereditary angioedema—The 2017 revision and update

Binding Mode Exploration of B1 Receptor Antagonists’ by the Use of Molecular Dynamics and Docking Simulation—How Different Target Engagement Can Determine Different Biological Effects

MASP-1 Increases Endothelial Permeability

Contact Info

Product

Resources

About