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Anaphylaxis is a potentially life-threatening multi-system allergic reaction to a biological trigger resulting in the release of potent inflammatory mediators from mast cells and basophils and causing symptoms in at least two organ systems that generally include skin, lungs, heart, or gastrointestinal tract in any combination. One exception is profound hypotension as an isolated symptom. There are two types of triggers of anaphylaxis: immunologic and non-Immunologic. Immunologic anaphylaxis is initiated when a foreign antigen directly binds to IgE expressed on mast cells or basophils and induces the release of histamine and other inflammatory substances resulting in vasodilation, vascular leakage, decreased peripheral vascular resistance, and heart muscle depression. If left untreated, death by shock (profound hypotension) or asphyxiation (airway obstruction) can occur. The non-immunologic pathway, on the other hand, can be initiated in many ways. A foreign substance can directly bind to receptors of mast cells and basophils leading to degranulation. There can be immune complex activation of the classical complement cascade with the release of anaphylatoxins C3a and C5a with subsequent recruitment of mast cells and basophils. Finally, hyperosmolar contrast agents can cause blood cell lysis, enzyme release, and complement activation, resulting in anaphylactoid (anaphylactic-like) symptoms. In this report we emphasize the recruitment of the bradykinin-forming cascade in mast cell dependent anaphylactic reactions as a potential mediator of severe hypotension, or airway compromise (asthma, laryngeal edema). We also consider airway obstruction due to inhibition of angiotensin converting enzyme with a diminished rate of endogenous bradykinin metabolism, leading not only to laryngeal edema, but massive tongue swelling with aspiration of secretions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Ghebrehiwet, Joseph and Kaplan.)

Hereditary angioedema (HAE) is a rare autosomal-dominant disorder; most cases are characterized by low plasma levels of C1 esterase inhibitor (C1-INH). Clinical manifestations of HAE due to C1-INH deficiency include unpredictable, acute, recurrent episodes of nonpruritic swelling that can affect the face, trunk, limbs, and the respiratory, gastrointestinal, and genitourinary tracts. Attacks can be disfiguring, disabling, painful, and even life-threatening if laryngeal swelling occurs. Symptoms of HAE generally manifest in childhood. Effective medications are available and approved to treat HAE in children. However, evidence informing use of these medications in pediatric clinical practice is limited. Hereditary angioedema management plans are critical to optimize outcomes and should address on-demand treatment for acute attacks and plans to prevent potentially fatal laryngeal attacks. The plan should also comprise a holistic approach to address nonclinical aspects of HAE, including quality of life (QoL) and psychological issues. This article provides an overview of HAE management principles that health care providers can apply to treat pediatric patients to improve their QoL.

Human high molecular weight kininogen (HK) is the substrate from which bradykinin is released as a result of activation of the plasma "contact" system, a cascade that includes the intrinsic coagulation pathway, and a fibrinolytic pathway leading to the conversion of plasminogen to plasmin. Its distinction from low molecular weight kininogen (LK) was first made clear in studies of bovine plasma. While early studies did suggest two kininogens in human plasma also, their distinction became clear when plasma deficient in HK or both HK and LK were discovered. The light chain of HK is distinct and has the site of interaction with negatively charged surfaces (domain 5) plus a 6th domain that binds either prekallikrein or factor XI. HK is a cofactor for multiple enzymatic reactions that relate to the light chain binding properties. It augments the rate of conversion of prekallikrein to kallikrein and is essential for the activation of factor XI. It indirectly augments the "feedback" activation of factor XII by plasma kallikrein. Thus, HK deficiency has abnormalities of intrinsic coagulation and fibrinolysis akin to that of factor XII deficiency in addition to the inability to produce bradykinin by factor XII-dependent reactions. The contact cascade binds to vascular endothelial cells and HK is a critical binding factor with binding sites within domains 3 and 5. Prekallikrein (or factor XI) is attached to HK and is brought to the surface. The endothelial cell also secretes proteins that interact with the HK-prekallikrein complex resulting in kallikrein formation. These have been identified to be heat shock protein 90 (HSP 90) and prolylcarboxypeptidase. Cell release of urokinase plasminogen activator stimulates fibrinolysis. There are now 6 types of HAE with normal C1 inhibitors. One of them has a mutated kininogen but the mechanism for overproduction (presumed) of bradykinin has not yet been determined. A second has a mutation involving sulfation of proteoglycans which may lead to augmented bradykinin formation employing the cell surface reactions noted above., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kaplan, Joseph and Ghebrehiwet.)

Hereditary angioedema (HAE) is a rare and disabling disease for which early diagnosis and effective therapy are critical. This revision and update of the global WAO/EAACI guideline on the diagnosis and management of HAE provides up-to-date guidance for the management of HAE. For this update and revision of the guideline, an international panel of experts reviewed the existing evidence, developed 28 recommendations, and established consensus by an online DELPHI process. The goal of these recommendations and guideline is to help physicians and their patients in making rational decisions in the management of HAE with deficient C1 inhibitor (type 1) and HAE with dysfunctional C1 inhibitor (type 2), by providing guidance on common and important clinical issues, such as: (1) How should HAE be diagnosed? (2) When should HAE patients receive prophylactic on top of on-demand treatment and what treatments should be used? (3) What are the goals of treatment? (4) Should HAE management be different for special HAE patient groups such as children or pregnant/breast-feeding women? and (5) How should HAE patients monitor their disease activity, impact, and control? It is also the intention of this guideline to help establish global standards for the management of HAE and to encourage and facilitate the use of recommended diagnostics and therapies for all patients., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Hereditary Angioedema (HAE) is a rare and disabling disease for which early diagnosis and effective therapy are critical. This revision and update of the global WAO/EAACI guideline on the diagnosis and management of HAE provides up-to-date guidance for the management of HAE. For this update and revision of the guideline, an international panel of experts reviewed the existing evidence, developed 28 recommendations, and established consensus by an online DELPHI process. The goal of these recommendations and guideline is to help physicians and their patients in making rational decisions in the management of HAE with deficient C1-inhibitor (type 1) and HAE with dysfunctional C1-inhibitor (type 2), by providing guidance on common and important clinical issues, such as: 1) How should HAE be diagnosed? 2) When should HAE patients receive prophylactic on top of on-demand treatment and what treatments should be used? 3) What are the goals of treatment? 4) Should HAE management be different for special HAE patient groups such as children or pregnant/breast feeding women? 5) How should HAE patients monitor their disease activity, impact, and control? It is also the intention of this guideline to help establish global standards for the management of HAE and to encourage and facilitate the use of recommended diagnostics and therapies for all patients., Competing Interests: Dr. Maurer reports personal fees from Alnylam, grants and personal fees from BioCryst, grants from Centogene, grants and personal fees from CSL Behring, grants from Dyax, grants and personal fees from Kalvista, grants from Pharming, personal fees from Pharvaris, grants and personal fees from Shire/Takeda, outside the submitted work. Dr. Magerl reports personal fees and non-financial support from Shire/Takeda, personal fees and non-financial support from CSL Behring, personal fees from Pharming, personal fees and non-financial support from Biocryst, during the conduct of the study; personal fees and non-financial support from Shire/Takeda, personal fees and non-financial support from CSL Behring, personal fees from Pharming, personal fees and non-financial support from Biocryst, personal fees from Kalvista, personal fees from Octapharma, personal fees from Novartis, outside the submitted work. Dr Betschel has received fees for advisory boards, presentations and research from CSL and Takeda. Advisor fees from Biocryst and Kalvista, Octapharma, Pharming, outside of the submitted work. Dr. Aberer has nothing to disclose. Dr. Ansotegui has nothing to disclose. Dr. Aygören-Pürsün reports personal fees from Biocryst, personal fees from Biomarin, personal fees from Centogene, grants and personal fees from CSL Behring, personal fees from Kalvista, personal fees from Pharming, personal fees from Pharvaris, grants and personal fees from Shire/Takeda, outside the submitted work. Dr. Banerji reports grants from Takeda, Biocryst, other from Takeda, Biocryst, Pharming, CSL, Kalvista, Pharvaris, outside the submitted work. Dr. Bara reports personal fees from commercial sponsor, outside the submitted work. Dr. Boccon-gibod reports grants, personal fees and non-financial support from Takeda, grants, personal fees and non-financial support from Biocryst Pharmaceutical, non-financial support from Pharming, outside the submitted work. Dr. Bork reports grants and personal fees from CSL Behring, personal fees from Shire/Takeda, personal fees from Pharvaris, outside the submitted work. Dr. Bouillet reports grants and personal fees from Takeda, Biocryst, Novartis, and GSK. H. B. Boysen has nothing to disclose. Dr. Brodski has nothing relevant to disclose. Dr. Busse reports grants and personal fees from CSL Behring, BioCryst, Takeda; personal fees from Medscape, CVS Health, Novartis, Regeneron Dr. Bygum reports grants and personal fees from CSL Behring, grants from BioCryst, personal fees from Takeda/Shire outside the submitted work. Dr. Caballero reports grants, personal fees and other from CSL-BEHRING, grants, personal fees and other from TAKEDA, personal fees and other from PHARMING NV, personal fees from OCTAPHARMA, personal fees and other from BIOCRYST, personal fees and other from NOVARTIS, outside the submitted work. Dr. Cancian reports and has received grant research support and/or speaker/consultancy fees from BioCryst, CSL Behring, Kalvista, Pharming, Shire (a Takeda company) and SOBI; has received funding to attend conferences/educational events from CSL Behring, Menarini, MSD, Novartis, Pharming and Shire; is/has been a clinical trial/registry investigator for BioCryst, CSL Behring, Kalvista, Novartis, Pharming, Shire and UCB. Dr. Castaldo has nothing to disclose. Dr. Cohn reports personal fees from CSL Behring, personal fees from Shire/Takeda, personal fees from Ionis Pharmaceuticals, Inc, personal fees from KalVista, personal fees from BioCryst, personal fees from Pharming, personal fees from Pharvaris, personal fees from Sanofi/Genzyme Europe, outside the submitted work. Dr. Csuka has nothing to disclose. Dr. Farkas reports grants and personal fees from CSL Behring, grants and personal fees from Shire/Takeda, grants and personal fees from Pharming Group NV, personal fees from Biocryst Pharmaceuticals, personal fees from Kalvista, personal fees from ONO Pharmaceuticals, outside the submitted work. Dr. Gompels reports fee for CSL and conference attendance support, member of the immunology clinical reference group, clinical trial work for Novartis, BioCryst. Dr. Gower reports Industry funded research/investigator: BioCryst, Kalvista, Pharming, Pharvaris, Takeda/Shire/Dyax Consultant: BioCryst, CSL Behring, Fresenius Kabi, Pharming, Takeda/Shire/Dyax Speakers Bureau, Faculty, Peer Reviewer: BioCryst, Pharming, Takeda/Shire/Dyax Advisory Committee/Board: BioCryst, CSL Behring, Fresenius Kabi, Pharming, Takeda/Shire/Dyax. Dr Grumach reports grants from Shire/Takeda and personal fees from CSL Behring, Takeda, and Catalyst for educative programs and consulting. Dr. Guidos-Fogelbach has nothing to disclose. Dr Hide reports personal fees from BioCryst, CSL Behring, Takeda and Torii. Dr. Kang has nothing to disclose. Dr. Kaplan has nothing to disclose. Dr Katelaris reports grants from CSL Behring, personal fees from CSL Behring, personal fees from Takeda, during the conduct of the study. Dr. Kiani-Alikhan reports personal fees from BioCryst, personal fees from CSL Behring, personal fees from Takeda, outside the submitted work. Dr. Lei has nothing to disclose. Dr. Lockey has nothing to disclose. Dr. Longhurst has consulted for, acted as speaker for or collaborated in research with the following: Adverum, BioCryst, CSL Behring, GSK, Intellia, Ionis, Kalivista, Pharming, Pharvaris, and Takeda. Dr. Lumry has consulted for, acted as speaker for or collaborated in research with the following: Adverum, Astra Zeneca, BioCryst, Biomarin, CSL Behring, Fresenius Kabi, GSK, Intellia, Ionis, Kalivista, Pharming, Pharvaris, Sanofi Regeneron, Takeda and Teva. Dr. MacGinnitie reports personal fees from Biocryst, during the conduct of the study. Dr. Malbran has nothing to disclose. Inmaculada Martinez Saguer has received research grant support and/or speaker/consultancy fees from BioCryst, CSL Behring, KalVista, Pharming, and Takeda. Dr. Matta has nothing to disclose. Dr. Nast has no conflict of interest in relation to this manuscript. Dr. Nguyen has nothing to disclose. Dr. Nieto-Martinez has nothing to disclose. Dr. Pawankar declares no conflicts of interest in relation to this manuscript. Dr. Peter has nothing to disclose. Dr. Porebski is or recently was a speaker and/or advisor for CSL Behring, Takeda, Pharming, and has served as an investigator for clinical trials sponsored by BioCryst Pharmaceuticals. Dr. Prior reports receipt of research grant support and/or speaker/consultancy fees from CSL Behring, Pharming, and Shire (currently Takeda). Dr. Reshef Received research grants, speakers and consulting honoraria from CSL Behring, Stallergens, Teva, Pharming, BioCryst, Pharvaris, Takeda (Shire) - not related to the article. Dr. Marc Riedl has received research grants from BioCryst, CSL Behring, Ionis, Kalvista, Pharvaris, and Takeda outside the submitted work; consultancy fees from Astria, BioCryst, Biomarin, CSL Behring, Cycle Pharma, Fresenius-Kabi, Ipsen, Kalvista, Ono Pharma, Pfizer, Pharming, Pharvaris, RegenexBio, and Takeda outside the submitted work. Dr. Bruce Ritchie has received Research grants from CSL-Behring, and has participated in clinical trials with Biocrist, CSL-Behring, Ionis, Kalvista, Pharvaris, and Takeda. The University of Alberta has received donations in lieu of consultancy fees to Dr. Ritchie from CSL Behring, Takeda. Dr. Sheikh reports other from Takeda, grants from CSL Behring, outside the submitted work. Dr. Smith reports other from BioCryst, during the conduct of the study; personal fees from Takeda/Shire, personal fees from CSL Behring, outside the submitted work. Dr. Späth reports other from CSL Ltd, outside the submitted work; and Expert in an ongoing litigation. Dr. Stobiecki reports other from Takeda, Biocryst, Pharming, Kalvista, fees from CSL Behring, Takeda, Biocryst, outside the submitted work. Dr. Toubi has no conflict of interest in relation to this manuscript. Dr. Varga has no conflict of interest in relation to this manuscript. Dr. Weller reports personal fees from Biocryst, CSL Behring, MOXIE and Pharvaris as well as grants and personal fees from Shire/Takeda, all outside the submitted work. Dr. Zanichelli has no conflict of interest in relation to this manuscript. Dr. Zhi has nothing to disclose. Dr. Zuraw has been a paid consultant for Biomarin, CSL Behring, Cycle Pharma, Fresenius-Kabi, and Takeda. He serves on adjudication boards for Novartis and Genentech. Dr. Craig does research for CSL Behring, Ionis, Takeda, Kalvista, Pharvaris, BioMarin, and Biocryst. He speaks for CSL Behring, Takeda and Grifols. He has a grant to support education from Takeda. He consults with Spark, CSL Behring, Takeda, BioMarin, Pharming and Biocryst., (© 2022 The Author(s).)

Angioedema is characterized by swelling of the skin or mucous membranes. Overproduction of the vasodilator bradykinin (BK) is an important contributor to the disease pathology, which causes rapid increase in vascular permeability. BK formation on endothelial cells results from high molecular weight kininogen (HK) interacting with gC1qR, the receptor for the globular heads of C1q, the first component of the classical pathway of complement. Endothelial cells are sensitive to blood-flow-induced shear stress and it has been shown that shear stress can modulate gC1qR expression. This study aimed to determine the following: (1) how BK or angioedema patients' (HAE) plasma affected endothelial cell permeability and gC1qR expression under shear stress, and (2) if monoclonal antibody (mAb) 74.5.2, which recognizes the HK binding site on gC1qR, had an inhibitory effect in HK binding to endothelial cells. Human dermal microvascular endothelial cells (HDMECs) grown on Transwell inserts were exposed to shear stress in the presence of HAE patients' plasma. Endothelial cell permeability was measured using FITC-conjugated bovine serum albumin. gC1qR expression and HK binding to endothelial cell surface was measured using solid-phase ELISA. Cell morphology was quantified using immunofluorescence microscopy. The results demonstrated that BK at 1 µg/mL, but not HAE patients' plasma and/or shear stress, caused significant increases in HDMEC permeability. The mAb 74.5.2 could effectively inhibit HK binding to recombinant gC1qR, and reduce HAE patients' plasma-induced HDMEC permeability change. These results suggested that monoclonal antibody to gC1qR, i.e., 74.5.2, could be potentially used as an effective therapeutic reagent to prevent angioedema., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Infection with SARS-CoV-2 triggers the simultaneous activation of innate inflammatory pathways including the complement system and the kallikrein-kinin system (KKS) generating in the process potent vasoactive peptides that contribute to severe acute respiratory syndrome (SARS) and multi-organ failure. The genome of SARS-CoV-2 encodes four major structural proteins - the spike (S) protein, nucleocapsid (N) protein, membrane (M) protein, and the envelope (E) protein. However, the role of these proteins in either binding to or activation of the complement system and/or the KKS is still incompletely understood. In these studies, we used: solid phase ELISA, hemolytic assay and surface plasmon resonance (SPR) techniques to examine if recombinant proteins corresponding to S1, N, M and E: (a) bind to C1q, gC1qR, FXII and high molecular weight kininogen (HK), and (b) activate complement and/or the KKS. Our data show that the viral proteins: (a) bind C1q and activate the classical pathway of complement, (b) bind FXII and HK, and activate the KKS in normal human plasma to generate bradykinin and (c) bind to gC1qR, the receptor for the globular heads of C1q (gC1q) which in turn could serve as a platform for the activation of both the complement system and KKS. Collectively, our data indicate that the SARS-CoV-2 viral particle can independently activate major innate inflammatory pathways for maximal damage and efficiency. Therefore, if efficient therapeutic modalities for the treatment of COVID-19 are to be designed, a strategy that includes blockade of the four major structural proteins may provide the best option., Competing Interests: BG and EP receive royalties from the sale of anti-gC1qR mAbs and gC1qR detection assay kit. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2021 Savitt, Manimala, White, Fandaros, Yin, Duan, Xu, Geisbrecht, Rubenstein, Kaplan, Peerschke and Ghebrehiwet.)

The plasma contact system is the initiator of the intrinsic pathway of coagulation and the main producer of the inflammatory peptide bradykinin. When plasma is exposed to a negatively charged surface the two enzymes factor XII (FXII) and plasma prekallikrein (PK) bind to the surface alongside the co-factor high molecular weight kininogen (HK), where PK is non-covalently bound to. Here, FXII and PK undergo a reciprocal activation feedback loop that leads to full contact system activity in a matter of seconds. Although naturally occurring negatively charged surfaces have shown to be involved in the role of the contact system in thrombosis, such surfaces are elusive in the pathogenesis of bradykinin-driven hereditary angioedema (HAE). In this review, we will explore the molecular mechanisms behind contact system activation, their assembly on the endothelial surface, and their role in the HAE pathophysiology., (© 2021. The Author(s).)

Chronic spontaneous urticaria is characterized by a perivascular non-necrotizing cellular infiltrate around small venules of the skin. It consists primarily of CD4(+) lymphocytes, a prominence of the T helper (Th)2 subtype but also Th1 cells, with Th17 cell-derived cytokines elevated in plasma. There are also neutrophils, eosinophils, basophils, and monocytes. Chemokines derived from mast cells and activated endothelial cells drive the process. Although the role of the cellular infiltrate has not previously been addressed, each constituent can contribute to the overall pathogenesis. It is of interest that CSU responds to corticosteroid, yet, short-term steroids do not affect autoimmunity or degranulation of mast cells, and act on margination of cells along the endothelium and chemotaxis to enter the surrounding dermis. In this review, we address each cell's contribution to the overall inflammatory response, as it is currently understood, with a view toward development of therapeutic options that impede the function of critical cells and/or their secretory products., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Guidelines for the treatment of chronic spontaneous urticaria (CSU) recommend the use of the IgE-targeted biologic omalizumab in patients with antihistamine-refractory disease. The rationale for this is supported by the key role of IgE and its high-affinity receptor, FcεRI, in the degranulation of skin mast cells that drives the development of the signs and symptoms of CSU, itchy wheals, and angioedema. Here, we review the current understanding of the pathogenesis of CSU and its autoimmune endotypes. We describe the mechanisms of action of omalizumab, the only biologic currently approved for CSU, its efficacy and ways to improve it, biomarkers for treatment response, and strategies for its discontinuation. We provide information on the effects of the off-label use, in CSU, of biologics licensed for the treatment of other diseases, including dupilumab, benralizumab, mepolizumab, reslizumab, and secukinumab. Finally, we discuss targets for novel biologics and where we stand with their clinical development. These include IgE/ligelizumab, IgE/GI-310, thymic stromal lymphopoietin/tezepelumab, C5a receptor/avdoralimab, sialic acid-binding Ig-like lectin 8/lirentelimab, CD200R/LY3454738, and KIT/CDX-0159. Our aim is to provide updated information and guidance on the use of biologics in the treatment of patients with CSU, now and in the near future., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The future therapies for hereditary angioedema will likely involve the development of oral agents as alternatives to parenteral administration of drugs, specific targeting of proteins and/or enzymes that are not yet possible (e.g., factor XIIa), new agents that target the β₂ receptor with sustained action properties, testing of products to determine whether the β 1 receptor contributes significantly to attacks of angioedema, disrupting protein synthesis by using RNA technology as an alternative to enzyme inhibition, and, finally, gene therapy to attempt to cure the disease. Complete inhibition of attacks may well require sustained blood levels of C1 inhibitor that exceed 85% of normal, and it may be possible to delete the prekallikrein gene (analogous to familial prekallikrein deficiency), which is the one factor that might alleviate bradykinin formation, even by factor XII-independent initiating mechanisms, with the possible exception of Mannose Associated Serine Protease 1 (MASP-1) cleavage of high molecular weight kininogen (HK). Deletion of the light chain of high-molecular-weight kininogen would eliminate all possibilities for bradykinin formation, except tissue kallikrein cleavage of low-molecular-weight kininogen to support normal physiologic function to at least 50%.

A strategy to conformationally restrain a series of GlyT1 inhibitors identified potent analogs that exhibited slowly interconverting rotational isomers. Further studies to address this concern led to a series of azetidine-based inhibitors. Compound 26 was able to elevate CSF glycine levels in vivo and demonstrated potency comparable to Bitopertin in an in vivo rat receptor occupancy study. Compound 26 was subsequently shown to enhance memory in a Novel Object Recognition (NOR) behavioral study after a single dose of 0.03 mg/kg, and in a contextual fear conditioning (cFC) study after four QD doses of 0.01-0.03 mg/kg., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Hereditary angioedema (HAE) is caused by deficiency or dysfunction in the C1 inhibitor (C1-INH) protein. C1-INH replacement therapy is used to treat patients with HAE to restore the missing or dysfunctional protein. In vitro studies showed that C1-INH inhibits prekallikrein activation and bradykinin formation in a dose-dependent manner when added to the plasma of patients with HAE. HAE is highly variable in clinical presentation, and early studies suggested that there was not a clear relationship between functional C1-INH levels and disease activity. Later, a threshold of approximately 40% functional C1-INH was identified, above which patients' risk of an attack was diminished. Long-term prophylaxis with plasma-derived C1-INH effectively reduces attack frequency and severity. Pharmacokinetic modeling shows that functional C1-INH levels are associated with the relative risk of having an attack. Subcutaneous administration of C1-INH results in consistently high levels of functional C1-INH activity, whereas intravenous administration results in periods of low trough functional C1-INH activity before the next scheduled dose, increasing the risk of an angioedema attack. These studies suggest that measurement of functional C1-INH activity may be useful as a biomarker of the risk of an attack in patients with HAE who are receiving long-term prophylaxis with plasma-derived C1-INH., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Prekallikrein (PK) is the precursor of the trypsin-like plasma protease kallikrein (PKa), which cleaves kininogens to release bradykinin and converts the protease precursor factor XII (FXII) to the enzyme FXIIa. PK and FXII undergo reciprocal conversion to their active forms (PKa and FXIIa) by a process that is accelerated by a variety of biological and artificial surfaces. The surface-mediated process is referred to as contact activation. Previously, we showed that FXII expresses a low level of proteolytic activity (independently of FXIIa) that may initiate reciprocal activation with PK. The current study was undertaken to determine whether PK expresses similar activity. Recombinant PK that cannot be converted to PKa was prepared by replacing Arg371 with alanine at the activation cleavage site (PK-R371A, or single-chain PK). Despite being constrained to the single-chain precursor form, PK-R371A cleaves high-molecular-weight kininogen (HK) to release bradykinin with a catalytic efficiency ∼1500-fold lower than that of kallikrein cleavage of HK. In the presence of a surface, PK-R371A converts FXII to FXIIa with a specific activity ∼4 orders of magnitude lower than for PKa cleavage of FXII. These results support the notion that activity intrinsic to PK and FXII can initiate reciprocal activation of FXII and PK in solution or on a surface. The findings are consistent with the hypothesis that the putative zymogens of many trypsin-like proteases are actually active proteases, explaining their capacity to undergo processes such as autoactivation and to initiate enzyme cascades., (© 2020 by The American Society of Hematology.)

Purpose of Review: This manuscript describes the recommended therapy of chronic spontaneous urticaria based on our understanding of the pathogenesis of hive formation. Thus, the mechanism of action of each medication is elaborated in addition to a discussion of clinical utility., Recent Findings: The main drugs are antihistamines, omalizumab, and cyclosporine with a success rate of 40-55, 65-80, and 70-80%, respectively. Used in sequence, over 90% of patients can be successfully treated. The addition of omalizumab represents a major advance because of its efficacy, easy utility, and favorable side-effect profile. The interaction with IgE eliminates any reaction with antigens to which it might be directed, down regulates IgE receptors on mast cells and basophils, and leads to down-regulation of mast cell functions with amelioration of hives., Summary: The use of antihistamines in high dosage (at least four times a day) is effective in close to half the patients with CSU. For antihistamine resistance, the use of omalizumab has revolutionized therapy of antihistamine-resistant cases because of its efficacy and excellent side-effect profile. If the response is insufficient, cyclosporine is the next choice. Patients should be monitored regarding any adverse effects on blood pressure or renal function. All these are far safer than extended use of corticosteroid.

We report here the identification and optimization of a novel series of potent GlyT1 inhibitors. A ligand design campaign that utilized known GlyT1 inhibitors as starting points led to the identification of a novel series of pyrrolo[3,4- c]pyrazoles amides (21-50) with good in vitro potency. Subsequent optimization of physicochemical and in vitro ADME properties produced several compounds with promising pharmacokinetic profiles. In vivo inhibition of GlyT1 was demonstrated for select compounds within this series by measuring the elevation of glycine in the cerebrospinal fluid (CSF) of rats after a single oral dose of 10 mg/kg. Ultimately, an optimized lead, compound 46, demonstrated in vivo efficacy in a rat novel object recognition (NOR) assay after oral dosing at 0.1, 1, and 3 mg/kg.

Chronic urticaria is defined as the presence of urticaria for a period exceeding 6 weeks, assuming symptoms for most days of the week. It is divided into chronic inducible urticarias and chronic spontaneous urticaria, previously termed chronic idiopathic urticaria. The latter designation emphasizes that patients can experience urticaria independent of any exogenous stimulus even if one can define circumstances that may worsen symptoms. A search for such an external "cause" is fruitless because the underlying abnormality is "intrinsic," whether it is autoimmune, or some unknown process. Approximately 40% of patients with chronic spontaneous urticaria report accompanying episodes of angioedema, whereas 10% have angioedema as their primary manifestation. In most cases, it is a self-limiting disorder, persisting for 2 to 5 years in most cases, although 20% of patients suffer for more than 5 years. The treatment that has evolved is largely empiric, based on double-blind, placebo-controlled studies whenever possible, but is not yet targeted to any particular pathogenic mechanism. In this article, we review the current status regarding pathogenesis, discuss the diagnostic workup, and update the approach to treatment including consideration of published guidelines, our own experience, and guideline updates that are being prepared., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Chronic Spontaneous Urticaria (CSU) is an endogenous disorder that is strongly associated with autoimmunity, particularly with immunoglobulin G (IgG) antibody to the alpha subunit of the IgE receptor seen in 35-40% of patients. Basophils and cutaneous mast cells can be activated and lead to a late-phase-like perivascular infiltration about small venules and hive formation., Methods: Review of current literature., Results: Antibody to thyroid antigens are seen in 25% of patients; a small fraction of these may be clinically hypothyroid (Hashimoto's Thyroiditis). Forty percent of patients have angioedema, but not laryngeal edema. Therapy typically begins with second-generation antihistamines (H1 receptor blockers) up to four times a day. The failure rate is substantial, and estimates vary from 25% to 50%. The drug of choice for antihistamine resistant cases is omalizumab, at 300 mg/month, which is effective in 70% of patients. H-2-antagonists and leucotriene antagonists are no longer recommended because the literature does not support additional efficacy beyond blockage of H-1 receptors. For patients unresponsive to antihistamines and omalizumab, cyclosporine is recommended next. This is similarly effective in 65-70% of patients; however, assessment of blood pressure and renal function need to be followed every 4-6 weeks. Corticosteroid should not be employed chronically; however, a brief course of 3-10 days can be used acutely for severe exacerbations. Other agents, such as dapsone, sulfasalazine, or hydroxychloroquin, can be tried when the aforementioned medications fail, but the results are unpredictable because they have not been shown to have efficacy beyond the placebo effect (25-30%), and have not been studied in patients for whom the aforementioned approach i.e. antihistamines, omalizumab, and cyclosporine has failed., Conclusion: High dose antihistamines, omalizumab and cyclosporine (in that order) are effective and recommended for therapy of CUS, an inflammatory skin disorder associated with autoimmunity in 45% of patients.

Initial work in Drosophila and mice demonstrated that the transcription factor cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) is a master control gene for memory formation. The relationship between CREB and memory has also been found to be true in other species, including aplysia and rats. It is thus well-established that CREB activation plays a central role in memory enhancement and that CREB is activated during memory formation. On the basis of these findings, a phenotypic high-throughput screening campaign utilizing a CRE-luciferase (CRE-Luci) SK-N-MC cell line was performed to identify compounds that enhance transcriptional activation of the CRE promoter with a suboptimal dose of forskolin. A number of small-molecule hits of unknown mechanisms of action were identified in the screening campaign, including HT-0411. Follow-up studies suggested that the CREB activation by HT-0411 is attributed to its specific and selective inhibition of monoamine oxidase B (MAO-B). Further, HT-0411 was shown to improve 24 h memory in rodents in a contextual fear conditioning model. This report describes the lead optimization of a series of 5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl) thiophene-2-carboxamides that were identified as novel, potent, and selective inhibitors of MAO-B. Extensive SAR studies and in vivo behavioral evaluations of this and other related analogue series identified a number of potential clinical development candidates; ultimately, compound 8f was identified as a candidate molecule with high selectivity toward MAO-B (29-56 nM) over MAO-A (19% inhibition at a screening concentration of 50 μM), an excellent profile against a panel of other enzymes and receptors, good pharmacokinetic properties in rodents and dogs, and efficacy in multiple rodent memory models.

The unpredictable nature of attacks of tissue swelling in hereditary angioedema requires the identification of reliable biomarkers to monitor disease activity as well as response to therapy. At present, one can assess a C4 level (by ELISA) to assist in diagnosis but neither C4 nor C1 inhibitor levels reflect clinical course or prognosis. We will here review a collection of plasma proteins involved in blood coagulation, fibrinolysis, and innate immunity (Figure 1). A main focus is those proteins that are key to the formation of bradykinin (BK); namely, factor XII, plasma prekallikrein/kallikrein, high-molecular weight kininogen, and BK itself since overproduction of BK is key to the disease. Considerations include new approaches to measurement of active enzymes, ELISA methods that may supersede SDS gel analysis of bond cleavages, and examples of changes outside the BK cascade that may reflect when, where, and how an attack of swelling is initiated. We will discuss their usefulness as biomarker candidates, with pros and cons, and compare the analytical methods that are being developed to measure their levels or activity.

The treatment of chronic spontaneous urticaria begins with antihistamines; however, the dose required typically exceeds that recommended for allergic rhinitis. Second-generation, relatively non-sedating H₁-receptor blockers are typically employed up to 4 times a day. First-generation antihistamines, such as hydroxyzine or diphenhydramine (Atarax or Benadryl), were employed similarly in the past. Should high-dose antihistamines fail to control symptoms (at least 50%), omalizumab at 300 mg/month is the next step. This is effective in 70% of antihistamine-refractory patients. H₂-receptor blockers and leukotriene antagonists are no longer recommended; they add little and the literature does not support significant efficacy. For those patients who are unresponsive to both antihistamines and omalizumab, cyclosporine is recommended next. This is similarly effective in 65%-70% of patients; however, care is needed regarding possible side-effects on blood pressure and renal function. Corticosteroids should not be employed chronically due to cumulative toxicity that is dose and time dependent. Brief courses of steroid e.g., 3-10 days can be employed for severe exacerbations, but should be an infrequent occurrence. Finally, other agents, such as dapsone or sulfasalazine, can be tried for those patients unresponsive to antihistamines, omalizumab, and cyclosporine., Competing Interests: There are no financial or other issues that might lead to conflict of interest., (Copyright © 2017 The Korean Academy of Asthma, Allergy and Clinical Immunology · The Korean Academy of Pediatric Allergy and Respiratory Disease.)

Background: Chronic spontaneous/idiopathic urticaria (CSU/CIU) has substantial detrimental effects on health-related quality of life (HRQoL) with an effect comparable to or worse than many other skin diseases., Objective: To assess the effect of omalizumab on CSU patients' HRQoL, measured by the Dermatology Life Quality Index (DLQI) in three phase III studies ASTERIA I, ASTERIA II and GLACIAL., Methods: A post hoc analysis examined changes in DLQI scores, distribution of patients across DLQI bands and the proportion reaching minimal clinically important difference (MCID) following omalizumab vs. placebo., Results: Omalizumab 300 mg significantly improved total DLQI scores vs. placebo, with a mean decrease from baseline to week 12 of -10.3 vs. -6.1 (P < 0.0001) in ASTERIA I, -10.2 vs. -6.1 (P = 0.0004) in ASTERIA II and -9.7 vs. -5.1 (P < 0.0001) in GLACIAL. A significant shift from high disease impact on life at baseline towards less impact at week 12 was seen with omalizumab 300 mg vs. placebo (P < 0.001; all studies). The proportion of patients where change in mean total DLQI score from baseline to week 12 reached an MCID of ≥4 was 74.1%, 76.0% and 77.2% in ASTERIA I, II and GLACIAL, respectively (P < 0.01; all studies)., Limitations: Maximum duration of omalizumab treatment was 24 weeks., Conclusion: This additional analysis assessed the impact of CSU and benefit of treatment with omalizumab by exploring different facets of DLQI data by treatment arm at multiple assessment points. The original aspects of analysis included applying the concept of the recently validated score for the MCID of the DLQI, changes in DLQI domain scores and in the distribution of subjects based on validated total DLQI score bands. It showed consistently that omalizumab provides significant and clinically relevant improvements in many aspects of HRQoL that are important to patients with CSU. These results contribute to a better understanding of the impact of CSU and its treatment on patients and can support clinical decision-making in routine medical practice., (© 2017 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Hereditary angioedema (HAE) is an autosomal-dominant disorder owing to mutations in the C1 inhibitor gene. Type I is characterized by a low C1 inhibitor protein level and diminished functional activity, whereas type II has a normal (or elevated) protein level but diminished function. When functional levels drop beyond 40% of normal, attacks of swelling are likely to occur due to overproduction of bradykinin. Angioedema can be peripheral, abdominal, or laryngeal. The typical duration of episodes is 3 days. Therapies include C1 inhibitor replacement for prophylaxis or acute therapy, whereas inhibition of kallikrein or blockade at the bradykinin receptor level can interrupt acute episodes of swelling., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: When the prekallikrein-high molecular weight kininogen complex is bound to endothelial cells, prekallikrein is stoichiometrically converted to kallikrein because of release of heat shock protein-90 (Hsp90). Although bradykinin formation is typically initiated by factor XII autoactivation, it is also possible to activate factor XII either by kallikrein, thus formed, or by plasmin., Objective: Because attacks of hereditary angioedema can be related to infection and/or exposure to estrogen, we questioned whether estrogen or cytokine stimulation of endothelial cells could augment release of Hsp90 and prekallikrein activation. We also tested release of profibrinolytic enzymes, urokinase, and tissue plasminogen activator (TPA) as a source for plasmin formation., Methods: Cells were stimulated with agonists, and secretion of Hsp90, urokinase, and TPA was measured in the culture supernatants by ELISA. Activation of the prekallikrein-HK complex was measured by using pro-phe-arg-p-nitroanilide reflecting kallikrein formation., Results: Hsp90 release was stimulated with optimal doses of estradiol, IL-1, and TNF-α (10 ng/mL) from 15 minutes to 120 minutes. TPA release was not augmented by any of the agonists tested but urokinase was released by IL-1, TNF-α, and thrombin (positive control), but not estrogen. Augmented activation of the prekallikrein-HK complex to generate kallikrein was seen with each agonist that releases Hsp90. Addition of 0.1% factor XII relative to prekallikrein-HK leads to rapid formation of kallikrein; factor XII alone does not autoactivate., Conclusions: IL-1, TNF-α, and estrogen stimulate release of Hsp90 and augment activation of the prekallikrein-HK complex to generate kallikrein and bradykinin. IL-1 and TNF-α stimulate release of urokinase, which can convert plasminogen to plasmin and represents a possible source for plasmin generation in all types of hereditary angioedema, but particularly hereditary angioedema with normal C1 inhibitor with a factor XII mutation. Both kallikrein and plasmin activate factor XII; kallikrein is 20 times more potent on a molar basis., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Chronic urticaria (CU) has a major effect on patients' quality of life. While there have been progressive advances regarding its pathogenesis and treatment, much remains to be done. Registries of other chronic non-communicable diseases have shown many benefits, such as additional basic knowledge and management approaches to diabetes mellitus. Standards of care as well as diagnostic approaches can be elaborated and compared from different sites, using validated instruments. Registries in allergic diseases are also becoming well recognized, and the first registry on CU, accessible from SLaai's webpage, includes parameters for identification, evaluation and management. In our vision, informatics strategies have the potential to improve care for chronic illnesses such as CU. The registry represents a valid instrument from which to obtain a sufficient sample size for epidemiological studies and/or clinical research planning, including feasibility and potential enrollment. It can also provide invaluable data for adapting guidelines to local populations, as well as diagnostic approaches and cost-effective interventions in the context of organizational efforts to improve patient care.

The monoclonal anti-immunoglobulin E (IgE) antibody, omalizumab, was the first drug approved for use in patients with chronic idiopathic/spontaneous urticaria (CIU/CSU) who remain symptomatic despite H 1 -antihistamine treatment. Omalizumab binds to free IgE, which lowers free IgE levels and causes FcεRI receptors on basophils and mast cells to be downregulated. It has been shown to improve symptoms of CIU/CSU, but its mechanism of action is not currently understood. Potential mechanisms in CIU/CSU include reducing mast cell releasability, reversing basopenia and improving basophil IgE receptor function, reducing activity of IgG autoantibodies against FcεRI and IgE, reducing activity of IgE autoantibodies against an antigen or autoantigen that has yet to be definitively identified, reducing the activity of intrinsically 'abnormal' IgE, and decreasing in vitro coagulation abnormalities associated with disease activity. However, none of these theories alone or in combination fully account for the pattern of symptom improvement seen with omalizumab therapy, and therefore, no one mechanism is likely to be the definitive mechanism of action. Additional research is needed to further clarify the involvement of omalizumab in relieving symptoms associated with the complex, multifactorial pathogenesis of CIU/CSU., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The blood plasma contains four biologically important proteolytic cascades, which probably evolved from the same ancestral gene. This in part may explain why each cascade has very similar "initiating trigger" followed by sequential and cascade-like downstream enzymatic activation pattern. The four cascades are: the complement system, the blood clotting cascade, the fibrinolytic system, and the kallikrein-kinin system. Although much has been written about the interplay between all these enzymatic cascades, the cross-talk between the complement and the kinin generating systems has become particularly relevant as this interaction results in the generation of nascent molecules that have significant impact in various inflammatory diseases including angioedema and cancer. In this review, we will focus on the consequences of the interplay between the two systems by highlighting the role of a novel molecular link called gC1qR. Although this protein was first identified as a receptor for C1q, it is now recognized as a multiligand binding cellular protein, which serves not only as C1q receptor, but also as high affinity (K D  ≤ 0.8 nM) binding site for both high molecular weight kininogen (HK) and factor XII (FXII). At inflammatory sites, where atherogenic factors such as immune complexes and/or pathogens can activate the endothelial cell into a procoagulant and proinflammatory surface, the two pathways are activated to generate vasoactive peptides that contribute in various ways to the inflammatory processes associated with numerous diseases. More importantly, since recent observations strongly suggest an important role for both pathways in cancer, we will focus on how a growing tumor cluster can employ the byproducts derived from the two activation systems to ensure not only its survival and growth, but also its escape into distal sites of colonization., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Plasma of patients with types I and II hereditary angioedema is unstable if incubated in a plastic (i.e., inert) vessel at 37 °C manifested by progressively increasing formation of bradykinin. There is also a persistent low level of C4 in 95 % of patients even when they are symptomatic. These phenomena are due to the properties of the C1r subcomponent of C1, factor XII, and the bimolecular complex of prekallikrein with high molecular weight kininogen (HK). Purified C1r auto-activates in physiologic buffers, activates C1s, which in turn depletes C4. This occurs when C1 inhibitor is deficient. The complex of prekallikrein-HK acquires an inducible active site not present in prekallikrein which in Tris-type buffers cleaves HK stoichiometrically to release bradykinin, or in phosphate buffer auto-activates to generate kallikrein and bradykinin. Thus immunologic depletion of C1 inhibitor from factor XII-deficient plasma (phosphate is the natural buffer) auto-activates on incubation to release bradykinin. Normal C1 inhibitor prevents this from occurring. During attacks of angioedema, if factor XII auto-activates on surfaces, the initial factor XIIa formed converts prekallikrein to kallikrein, and kallikrein cleaves HK to release bradykinin. Kallikrein also rapidly activates most remaining factor XII to factor XIIa. Additional cleavages convert factor XIIa to factor XIIf and factor XIIf activates C1r enzymatically so that C4 levels approach zero, and C2 is depleted. There is also a possibility that kallikrein is generated first as a result of activation of the prekallikrein-HK complex by heat shock protein 90 released from endothelial cells, followed by kallikrein activation of factor XII.

Background: Hereditary angioedema with normal C1 inhibitor levels (HAE-N) is associated with a Factor XII mutation in 30% of subjects; however, the role of this mutation in the pathogenesis of angioedema is unclear., Objective: We sought evidence of abnormalities in the pathways of bradykinin formation and bradykinin degradation in the plasma of patients with HAE-N both with and without the mutation., Methods: Bradykinin was added to plasma, and its rate of degradation was measured by using ELISA. Plasma autoactivation was assessed by using a chromogenic assay of kallikrein formation. Plasminogen activator inhibitors (PAIs) 1 and 2 were also measured by means of ELISA., Results: PAI-1 levels varied from 0.1 to 4.5 ng/mL (mean, 2.4 ng/mL) in 23 control subjects, from 0.0 to 2 ng/mL (mean, 0.54 ng/mL) in patients with HAE-N with a Factor XII mutation (12 samples), and from 0.0 to 3.7 ng/mL (mean, 1.03 ng/mL) in patients with HAE-N without a Factor XII mutation (11 samples). PAI-2 levels varied from 25 to 87 ng/mL (mean, 53.8 ng/mL) in control subjects and were 0 to 25 ng/mL (mean, 4.3 ng/mL) in patients with HAE-N with or without the Factor XII mutation. Autoactivation at a 1:2 dilution was abnormally high in 8 of 17 patients with HAE-N (4 in each subcategory) and could be corrected by supplemental C1 inhibitor in 4 of them. Bradykinin degradation was markedly abnormal in 1 of 23 patients with HAE-N and normal in the remaining 22 patients., Conclusions: Bradykinin degradation was normal in all but 1 of 23 patients with HAE-N studied. By contrast, there was a marked abnormality in PAI-2 levels in patients with HAE-N that is not seen in patients with C1 inhibitor deficiency. PAI-1 levels varied considerably, but a statistically significant difference was not seen. A link between excessive fibrinolysis and bradykinin generation that is estrogen dependent is suggested., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Data from the 3 omalizumab pivotal trials in patients with chronic idiopathic urticaria/chronic spontaneous urticaria (CIU/CSU) represent the largest database of patients reported to date with refractory disease (omalizumab, n = 733; placebo, n = 242)., Objective: The objective of this study was to compare results from ASTERIA I and II, which included only approved doses of H1-antihistamine as background therapy based on regulatory authority requirements, to those from GLACIAL, which permitted higher doses of H1-antihistamines as well as other types of background therapy, in a post hoc analysis., Methods: Efficacy data from the placebo, omalizumab 150-mg, and omalizumab 300-mg treatment arms of ASTERIA I and II were pooled and analyzed (n = 162 and n = 160, respectively). The 300-mg treatment arm analyses were compared with the analysis of data from GLACIAL (n = 252) using analysis of covariance models. The key efficacy endpoint was change from baseline to week 12 in mean weekly itch severity score (ISS); other endpoints were also evaluated. Safety data were pooled from all 3 studies., Results: Mean ISS was significantly reduced from baseline at week 12 in the pooled ASTERIA I and II omalizumab 150- and 300-mg treatment arms and in the GLACIAL omalizumab 300-mg arm. The weekly ISS reduction magnitude at week 12 was similar between the omalizumab 300-mg groups in the ASTERIA I and II pooled and GLACIAL studies. Similar treatment effect sizes were observed across multiple endpoints. Omalizumab was well tolerated and the adverse-event profile was similar regardless of background therapy for CIU/CSU. The overall safety profile was generally consistent with omalizumab therapy in allergic asthma., Conclusion: Omalizumab 300 mg was safe and effective in reducing CIU/CSU symptoms regardless of background therapy., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Angiotensin-converting enzyme (ACE) inhibitors cause angioedema due to diminished degradation of bradykinin. Angiotensin receptor blockers may occasionally cause angioedema but the mechanism is unknown, and are generally considered safe, even in those who have reacted to ACE inhibitors. We determined whether aliskiren, a renin inhibitor, has an effect on the rate of bradykinin degradation., Methods: The ability of renin to metabolize bradykinin was studied and the rate of bradykinin degradation compared in the presence or absence of aliskiren. Enalapril, a known ACE inhibitor that causes angioedema served as positive control., Results: Renin was unable to digest bradykinin, indicating that a renin inhibitor is unlikely to affect the rate of bradykinin degradation. In a plasma system, aliskiren had no effect on the rate of bradykinin degradation while enalapril inhibited it appreciably. An inhibitory effect of aliskiren on the rate of bradykinin degradation by human pulmonary endothelial cells was observed, estimated to be about 5% of that of enalapril., Conclusion: Aliskiren has no effect upon the rate of bradykinin degradation in plasma and a minimal effect employing vascular endothelial cells. The latter suggests inhibition of a non-renin enzyme that is a minor contributor to bradykinin degradation., (© The Author(s) 2013.)

Activation of the high-affinity nerve growth factor (NGF) receptor Trk occurs through multiple processes consisted of translocation and clustering within the plasma membrane lipid rafts, dimerization and autophosphorylation. Here we found that a nonprotein extract of inflamed rabbit skin inoculated with vaccinia virus (Neurotropin(®)) enhanced efficiency of NGF signaling. In rat pheochromocytoma PC12 cells overexpressing Trk (PCtrk cells), Neurotropin augmented insufficient neurite outgrowth observed at suboptimal concentration of NGF (2ng/mL) in a manner depending on Trk kinase activity. Cellular exposure to Neurotropin resulted in an accumulation of Trk-GM1 complexes without affecting dimerization or phosphorylation states of Trk. Following NGF stimulation, Neurotropin significantly facilitated the time course of NGF-induced Trk autophosphorylation. These observations provide a unique mechanism controlling efficiency of NGF signaling, and raise the therapeutic potential of Neurotropin for various neurological conditions associated with neurotrophin dysfunction., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Hereditary angioedema types I and II are caused by a functional deficiency of C1 inhibitor (C1-INH), leading to overproduction of bradykinin. The current functional diagnostic assays employ inhibition of activated C1s; however, an alternative, more physiologic method is desirable., Methods: ELISAs were developed using biotinylated activated factor XII (factor XIIa) or biotinylated kallikrein bound to avidin-coated plates. Incubation with plasma was followed by detection of bound C1-INH., Results: After standard curves were developed for quantification of C1-INH, serial dilutions of normal plasma were employed to validate the ability to detect known concentration of C1-INH in the plasma as a percent of normal. Hereditary angioedema (HAE) types I and II were then tested. The level of functional C1-INH in all HAE types I and II plasma tested was less than 40% of our normal control. This was evident regardless of whether we measured factor XIIa-C1-INH or kallikrein-C1-INH complexes, and the two assays were in close agreement. By contrast, testing the same samples utilizing the commercial method (complex ELISA, Quidel Corp.) revealed the levels of C1-INH between 0 and 57% of normal (mean, 38%), and 42 samples were considered equivocal (four controls and 38 patients)., Conclusions: Diagnosis of HAE types I and II can be ascertained by inhibition of enzymes of the bradykinin-forming cascade, namely factor XIIa and kallikrein. Either method yields functional C1-INH levels in patients with HAE (types I and II) that are clearly abnormal with less variance or uncertainty than the commercial method., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)