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Search results for: Anti-B1 Bradykinin Receptor Antibody


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#33993830   2021/07/06 To Up

The importance of recognizing and managing a rare form of angioedema: hereditary angioedema due to C1-inhibitor deficiency.

The majority of angioedema cases encountered in clinical practice are histamine-mediated (allergic); however, some cases are bradykinin-related (non-allergic) and do not respond to standard anti-allergy medications. Among bradykinin-related angioedema, hereditary angioedema (HAE) is a rare, but chronic and debilitating condition. The majority of HAE is caused by deficiency (type 1) or abnormal function (type 2) of the naturally occurring protein, C1-inhibitor (C1-INH)-a major inhibitor of proteases in the contact (kallikrein-bradykinin cascade), fibrinolytic pathway, and complement systems. Failure to recognize HAE and initiate appropriate intervention can lead to years of pain, disability, impaired quality of life (QoL) and, in cases of laryngeal involvement, it can be life-threatening. HAE must be considered in the differential diagnosis of non-urticarial angioedema, particularly for patients with a history of recurrent angioedema attacks, family history of HAE, symptom onset in childhood/adolescence, prodromal signs/symptoms before swellings, recurrent/painful abdominal symptoms, and upper airway edema. Management strategies for HAE include on-demand treatment for acute attacks, short-term prophylaxis prior to attack-triggering events/procedures, and long-term or routine prophylaxis for attack prevention. Patients should be evaluated at least annually to assess need for routine prophylaxis. HAE specific medications like plasma-derived and recombinant C1-INH products, kallikrein inhibitors, and bradykinin B2 receptor antagonists, have improved management of HAE. While the introduction of intravenous C1-INH represented a major breakthrough in routine HAE prophylaxis, some patients fail to achieve adequate control and others have psychological barriers or experience complications related to intravenous administration. Subcutaneous (SC) C1-INH, SC monoclonal antibody (mAb)-based therapies, and an oral kallikrein inhibitor offer effective alternatives for HAE attack prevention and may facilitate self-administration. HAE management should be individualized, with QoL improvement being a key goal. This can be achieved with broader availability of existing options for routine prophylaxis, including greater global availability of C1-INH(SC), mAb-based therapy, oral treatments, and multiple on-demand therapies.
Joshua Jacobs, Teresa Neeno

1444 related Products with: The importance of recognizing and managing a rare form of angioedema: hereditary angioedema due to C1-inhibitor deficiency.

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#33832694   // To Up

Non-IgE-mediated anaphylaxis.

Anaphylaxis is a rapidly evolving, acute, life-threatening reaction that occurs rapidly on contact with a trigger. Anaphylaxis is classically defined as an allergen-driven process that induces specific IgE and the activation of mast cells and basophils through the cross-linking of IgE receptors. However, it is clear that non-IgE-mediated pathways can induce symptoms indistinguishable from those of classic anaphylaxis, and their activation could explain the severity of IgE-mediated anaphylaxis. Indeed, mast cells and basophils can be activated by antibodies against IgE or their receptors, by molecules such as anaphylatoxins, or through G-coupled receptors. Some other allergens can induce antibodies of class IgG that can activate neutrophils to produce a molecule similar to histamine to induce anaphylaxis. Finally, some inflammatory mediators such as bradykinin or prostaglandin can also modulate mast cell and basophil activation as well as directly cause vasodilation and bronchoconstriction, resulting in anaphylaxis-like reactions.
Antonella Cianferoni

1676 related Products with: Non-IgE-mediated anaphylaxis.

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#33599139   2021/02/18 To Up

Kallikrein-1 Blockade Inhibits Aortic Expansion in a Mouse Model and Reduces Prostaglandin E2 Secretion From Human Aortic Aneurysm Explants.

Background Abdominal aortic aneurysm (AAA) is an important cause of mortality in older adults. The kinin B2 receptor agonist, bradykinin, has been implicated in AAA pathogenesis through promoting inflammation. Bradykinin is generated from high- and low-molecular-weight kininogen by the serine protease kallikrein-1. The aims of this study were first to examine the effect of neutralizing kallikrein-1 on AAA development in a mouse model and second to test how blocking kallikrein-1 affected cyclooxygenase-2 and prostaglandin E in human AAA explants. Methods and Results Neutralization of kallikrein-1 in apolipoprotein E-deficient () mice via administration of a blocking antibody inhibited suprarenal aorta expansion in response to angiotensin (Ang) II infusion. Kallikrein-1 neutralization decreased suprarenal aorta concentrations of bradykinin and prostaglandin E and reduced cyclooxygenase-2 activity. Kallikrein-1 neutralization also decreased protein kinase B and extracellular signal-regulated kinase 1/2 phosphorylation and reduced levels of active matrix metalloproteinase 2 and matrix metalloproteinase 9. Kallikrein-1 blocking antibody reduced levels of cyclooxygenase-2 and secretion of prostaglandin E and active matrix metalloproteinase 2 and matrix metalloproteinase 9 from human AAA explants and vascular smooth muscle cells exposed to activated neutrophils. Conclusions These findings suggest that kallikrein-1 neutralization could be a treatment target for AAA.
Corey S Moran, Erik Biros, Smriti M Krishna, Susan K Morton, Daniel J Sexton, Jonathan Golledge

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#33239231   2020/11/12 To Up

Hypothesis: Alpha-1-antitrypsin is a promising treatment option for COVID-19.

No definitive treatment for COVID-19 exists although promising results have been reported with remdesivir and glucocorticoids. Short of a truly effective preventive or curative vaccine against SARS-CoV-2, it is becoming increasingly clear that multiple pathophysiologic processes seen with COVID-19 as well as SARS-CoV-2 itself should be targeted. Because alpha-1-antitrypsin (AAT) embraces a panoply of biologic activities that may antagonize several pathophysiologic mechanisms induced by SARS-CoV-2, we hypothesize that this naturally occurring molecule is a promising agent to ameliorate COVID-19. We posit at least seven different mechanisms by which AAT may alleviate COVID-19. First, AAT is a serine protease inhibitor (SERPIN) shown to inhibit TMPRSS-2, the host serine protease that cleaves the spike protein of SARS-CoV-2, a necessary preparatory step for the virus to bind its cell surface receptor ACE2 to gain intracellular entry. Second, AAT has anti-viral activity against other RNA viruses HIV and influenza as well as induces autophagy, a known host effector mechanism against MERS-CoV, a related coronavirus that causes the Middle East Respiratory Syndrome. Third, AAT has potent anti-inflammatory properties, in part through inhibiting both nuclear factor-kappa B (NFκB) activation and ADAM17 (also known as tumor necrosis factor-alpha converting enzyme), and thus may dampen the hyper-inflammatory response of COVID-19. Fourth, AAT inhibits neutrophil elastase, a serine protease that helps recruit potentially injurious neutrophils and implicated in acute lung injury. AAT inhibition of ADAM17 also prevents shedding of ACE2 and hence may preserve ACE2 inhibition of bradykinin, reducing the ability of bradykinin to cause a capillary leak in COVID-19. Fifth, AAT inhibits thrombin, and venous thromboembolism and in situ microthrombi and macrothrombi are increasingly implicated in COVID-19. Sixth, AAT inhibition of elastase can antagonize the formation of neutrophil extracellular traps (NETs), a complex extracellular structure comprised of neutrophil-derived DNA, histones, and proteases, and implicated in the immunothrombosis of COVID-19; indeed, AAT has been shown to change the shape and adherence of non-COVID-19-related NETs. Seventh, AAT inhibition of endothelial cell apoptosis may limit the endothelial injury linked to severe COVID-19-associated acute lung injury, multi-organ dysfunction, and pre-eclampsia-like syndrome seen in gravid women. Furthermore, because both NETs formation and the presence of anti-phospholipid antibodies are increased in both COVID-19 and non-COVID pre-eclampsia, it suggests a similar vascular pathogenesis in both disorders. As a final point, AAT has an excellent safety profile when administered to patients with AAT deficiency and is dosed intravenously once weekly but also comes in an inhaled preparation. Thus, AAT is an appealing drug candidate to treat COVID-19 and should be studied.
Xiyuan Bai, Joseph Hippensteel, Alida Leavitt, James P Maloney, David Beckham, Cindy Garcia, Qing Li, Brian M Freed, Diane Ordway, Robert A Sandhaus, Edward D Chan

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#32824891   2020/08/19 To Up

In Vitro Modeling of Bradykinin-Mediated Angioedema States.

Kinins (peptides related to bradykinin, BK) are formed from circulating substrates, the kininogens, by the action of two proteases, the kallikreins. The only clinical application of a BK receptor ligand, the B receptor antagonist icatibant, is the treatment of the rare hereditary angioedema (HAE) caused by the deficiency of C1-esterase inhibitor (C1-INH). Less common forms of HAE (genetic variants of factor XII, plasminogen, kininogen) are presumably mediated by increased BK formation. Acquired forms of BK-mediated angioedema, such as that associated with angiotensin-I converting enzyme (ACE) inhibition, are also known. Antibody-based analytical techniques are briefly reviewed, and support that kinins are extremely short-lived, prominently cleared by ACE. Despite evidence of continuous activation of the kallikrein-kinin system in HAE, patients are not symptomatic most of the time and their blood or plasma obtained during remission does not generate excessive immunoreactive BK (iBK), suggesting effective homeostatic mechanisms. HAE-C1-INH and HAE-FXII plasmas are both hyperresponsive to fibrinolysis activation. On another hand, we suggested a role for the alternate tissue kallikrein-kinin system in patients with a plasminogen mutation. The role of the BK B receptor is still uncertain in angioedema states. iBK profiles under in vitro stimulation provide fresh insight into the physiopathology of angioedema.
François Marceau, Hélène Bachelard, Xavier Charest-Morin, Jacques Hébert, Georges E Rivard

2636 related Products with: In Vitro Modeling of Bradykinin-Mediated Angioedema States.

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#32358539   2020/05/01 To Up

The kallikrein-kinin pathway as a mechanism for auto-control of brown adipose tissue activity.

Brown adipose tissue (BAT) is known to secrete regulatory factors in response to thermogenic stimuli. Components of the BAT secretome may exert local effects that contribute to BAT recruitment and activation. Here, we found that a thermogenic stimulus leads to enhanced secretion of kininogen (Kng) by BAT, owing to induction of kininogen 2 (Kng2) gene expression. Noradrenergic, cAMP-mediated signals induce KNG2 expression and release in brown adipocytes. Conversely, the expression of kinin receptors, that are activated by the Kng products bradykinin and [Des-Arg9]-bradykinin, are repressed by thermogenic activation of BAT in vivo and of brown adipocytes in vitro. Loss-of-function models for Kng (the circulating-Kng-deficient BN/Ka rat) and bradykinin (pharmacological inhibition of kinin receptors, kinin receptor-null mice) signaling were coincident in showing abnormal overactivation of BAT. Studies in vitro indicated that Kng and bradykinin exert repressive effects on brown adipocyte thermogenic activity by interfering the PKA/p38 MAPK pathway of control of Ucp1 gene transcription, whereas impaired kinin receptor expression enhances it. Our findings identify the kallikrein-kinin system as a relevant component of BAT thermogenic regulation that provides auto-regulatory inhibitory signaling to BAT.
Marion Peyrou, Rubén Cereijo, Tania Quesada-López, Laura Campderrós, Aleix Gavaldà-Navarro, Laura Liñares-Pose, Elena Kaschina, Thomas Unger, Miguel López, Marta Giralt, Francesc Villarroya

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#32270933   // To Up

[Hereditary angioedema due to C1-esterase inhibitor deficiency : novel approaches].

Hereditary angioedema type 1 and 2 are due to a deficiency in C1--esterase inhibitor. This molecule inhibits the generation of bradykinin, a potent inflammatory mediator that increases vascular permeability. Upon accumulation of bradykinin, patients affected develop painful subcutaneous or submucosal edemas that last for several days. In case the upper airways are affected, there is risk of suffocation. This type of angioedema does not respond to antihistamines, cortico-steroids or epinephrine. Management of angioedema attacks consists in injecting C1-esterase inhibitor concentrate or icatibant, a bradykinin receptor B2 antagonist. Preventive measures aim at reducing the frequency and the severity of angioedema attacks. Inhibition of -plasma kallikrein by lanadelumab, a monoclonal antibody adminis-tered subcutaneously, is effective and well tolerated.
Florian Stehlin, Camillo Ribi

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#31994957   2020/03/19 To Up

Biological therapy in hereditary angioedema: transformation of a rare disease.

: Hereditary angioedema, a disabling condition, with high mortality when untreated, is caused by C1 inhibitor deficiency and other regulatory disorders of bradykinin production or metabolism. This review covers the remarkable progress made in biological therapies for this rare disorder.: Over the past 10 years, several evidence-based parenteral treatments have been licensed, including two plasma-derived C1 inhibitor replacement therapies and one recombinant C1 inhibitor replacement for acute treatment of angioedema attacks and synthetic peptides for inhibition of kallikrein or bradykinin B2 receptors, with oral small molecule treatments currently in clinical trial. Moreover, recent advances in prophylaxis by subcutaneous C1 inhibitor to restore near-normal plasma function or by humanized antibody inhibition of kallikrein have resulted in freedom from symptoms for a high proportion of those treated.: This plethora of treatment possibilities has come about as a result of recent scientific advances. Collaboration between patient groups, basic and clinical scientists, physicians, nurses, and the pharmaceutical industry has underpinned this translation of basic science into treatments and protocols. These in their turn have brought huge improvements in prognosis, quality of life and economic productivity to patients, their families, and the societies in which they live.
Hilary Longhurst, Henriette Farkas

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#31914894   // To Up

Neurons, Receptors, and Channels.

Here, I recount some adventures that I and my colleagues have had over some 60 years since 1957 studying the effects of drugs and neurotransmitters on neuronal excitability and ion channel function, largely, but not exclusively, using sympathetic neurons as test objects. Studies include effects of centrally active drugs on sympathetic transmission; neuronal action and neuroglial uptake of GABA in the ganglia and brain; the action of muscarinic agonists on sympathetic neurons; the action of bradykinin on neuroblastoma-derived cells; and the identification of M-current as a target for muscarinic action, including experiments to determine its distribution, molecular composition, neurotransmitter sensitivity, and intracellular regulation by phospholipids and their hydrolysis products. Techniques used include electrophysiological recording (extracellular, intracellular microelectrode, whole-cell, and single-channel patch-clamp), autoradiography, messenger RNA and complementary DNA expression, antibody injection, antisense knockdown, and membrane-targeted lipidated peptides. I finish with some recollections about my scientific career, funding, and changes in laboratory life and pharmacology research over the past 60 years.
David A Brown

2927 related Products with: Neurons, Receptors, and Channels.

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