icatibant and Angioedema

Angioedema (AE) occurring during ACE inhibitor therapy (ACEi-AE) is a rare complication involving between 0.1 and 0.7% of treated patients. AE can also complicate other therapeutic regimens that block the renin-angiotensin aldosterone system. Other drugs, such as immune suppressors, some type of antidiabetics or calcium antagonists, can increase the likelihood of ACEi-AE when associated to ACEi. There is a clear ethnic predisposition, since African-Americans or Hispanics show a higher prevalence of this condition compared to Caucasians. At least in African-Americans the genetic predisposition accounts for a general higher prevalence of AE, independently from the cause. People that experience ACEi-AE may have some recurrence when they are switched to an angiotensin-receptor blocker (ARB); however, epidemiological studies on large cohorts have shown that angiotensin receptor blockers (ARB) do not increase the likelihood of AE compared to other antihypertensives. Clinical manifestations consist of edema of face, lips, tongue, uvula and upper airways, requiring intubation or tracheotomy in severe cases. Attacks last for 48-72 h and require hospital admission in most cases. Intestinal involvement with sub-occlusive symptoms has also been reported. The pathogenesis of ACEi-AE depends mainly on a reduced catabolism and accumulation of bradykinin, which is normally metabolized by ACE. Genetic studies have shown that some single nucleotide polymorphisms at genes encoding relevant molecules for bradykinin metabolism and action may be involved in ACEi-AE, giving a basis for the ethnic predisposition. Treatment of ACEi-AE is still a matter of debate. Corticosteroids and antihistamines do not show efficacy. Some therapeutic attempts have shown some efficacy for fresh frozen plasma or C1 inhibitor concentrate infusion. Interventional studies with the specific bradykinin receptor antagonist icatibant have shown conflicting results; there might be a different ethnic predisposition to icatibant efficacy which has been proven in caucasian but not in black patients.

Topics: Angioedema; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Black or African American; Blood Component Transfusion; Bradykinin; Bradykinin B2 Receptor Antagonists; Complement C1 Inhibitor Protein; Female; Humans; Hypertension; Male; Peptidyl-Dipeptidase A; Plasma; Recurrence; Renin-Angiotensin System; Risk Factors; Sex Factors

Acquired angioedema with C1-inhibitor deficiency is a rare and peculiar entity belonging to the spectrum of bradykinin angioedemas. It usually occurs in subjects over 60 years old, and is mostly associated with a B-cell lymphoid hemopathy or a monoclonal gammopathy. The diagnosis relies on at least one angioedema episode, lasting more than 24 h, and on the decrease of functional C1-inhibitor. Low C1q is observed in 90% of patients, and an anti C1-inhibitor antibody is found in 50% of patients. The treatment of severe attacks relies on icatibant or C1-inhibitor perfusions. Long term prophylaxis in patients with frequent attacks requires treatment of the associated hemopathy if so. In case of idiopathic angioedema, tranexamic acid and danazol may be used, provided that there is-no thrombophilia; as well as rituximab as second-line treatment. Inhibitors of kallikrein still need to be evaluated in this therapeutic indication.

Topics: Angioedema; Angioedemas, Hereditary; Bradykinin; Chemoprevention; Comorbidity; Diagnosis, Differential; Diagnostic Techniques and Procedures; France; Hematologic Diseases; Humans; Internal Medicine; Middle Aged; Reference Standards; Rituximab; Societies, Medical; Tranexamic Acid

Angioedema (AE) caused by angiotensin-converting enzyme inhibitors (ACEIs) requires prompt and appropriate management, but current treatment options are limited to symptomatic treatment. Icatibant is a bradykinin receptor antagonist approved for hereditary AE treatment. Some recent studies showed a potential role for icatibant on ACEI-induced AE while others have shown no promising effect. This meta-analysis of randomized controlled trials (RCTs) was conducted to provide evidence for the use of icatibant in the treatment of ACEI-induced AE.. Relevant RCTs that examined the effects of icatibant for ACEI-induced AE were retrieved from EMBASE, PubMed and Cochrane Library (Central). Included articles for the meta-analysis were assessed using the Cochrane risk of bias tool. For meta-analysis, the pooled mean differences (MD) with 95% CIs and the pooled relative risk (RR) with 95% CIs were calculated using RevMan 5.3. The systematic review was performed in accordance with the PRISMA statement.. A total of 234 records were identified after searching the databases. In total, three RCTs involving 179 patients were included in the meta-analysis. The three RCTs had a low risk of bias and the characteristics of the participants and the outcome measures were similar among the RCTs. Treatment with icatibant shortened the time to achieve complete resolution of ACEI-induced AE symptoms compared to placebo or conventional treatments. However, the difference was not statistically significant (MD: -7.77 hours; 95% CI: -25.18-9.63 hours). There were no differences between groups in terms of drug-related adverse effects, apart from the reactions at the site of injection (RR: 1.35; 95% CI: 0.53-3.45).. This meta-analysis evaluated the effectiveness and tolerability of icatibant therapy for ACEI-induced AE, but the benefit of icatibant therapy over placebo or conventional treatment strategies could not be shown.

Topics: Angioedema; Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Humans; Randomized Controlled Trials as Topic

Angioedema is defined by non-dependent, non-pitting edema that affects several different sites and is potentially life-threatening due to laryngeal edema. This narrative review provides emergency physicians with a focused overview of the evaluation and management of angioedema. Two primary forms include histamine-mediated and bradykinin-mediated angioedema. Histamine-mediated forms present similarly to anaphylaxis, while bradykinin-mediated angioedema presents with greater face and oropharyngeal involvement and higher risk of progression. Initial evaluation and management should focus on evaluation of the airway, followed by obtaining relevant historical features, including family history, medications, and prior episodes. Histamine-mediated angioedema should be treated with epinephrine intramuscularly, antihistaminergic medications, and steroids. These medications are not effective for bradykinin-mediated forms. Other medications include C1-INH protein replacement, kallikrein inhibitor, and bradykinin receptor antagonists. Evidence is controversial concerning the efficacy of these medications in an acute episode, and airway management is the most important intervention when indicated. Airway intervention may require fiberoptic or video laryngoscopy, with preparation for cricothyrotomy. Disposition is dependent on patient's airway and respiratory status, as well as the sites involved.

Topics: Airway Management; Algorithms; Angioedema; Anti-Inflammatory Agents, Non-Steroidal; Blood Coagulation Factors; Bradykinin; Bradykinin B2 Receptor Antagonists; Bronchodilator Agents; Emergency Service, Hospital; Epinephrine; Glucocorticoids; Histamine; Histamine Antagonists; Humans; Peptides; Plasma; Urticaria

Non-hereditary angioedema (AE) with normal C1 esterase inhibitor (C1INH) can be presumably bradykinin- or mast cell-mediated, or of unknown cause. In this systematic review, we searched PubMed, EMBASE, and Scopus to provide an overview of the efficacy of different treatment options for the abovementioned subtypes of refractory non-hereditary AE with or without wheals and with normal C1INH. After study selection and risk of bias assessment, 61 articles were included for data extraction and analysis. Therapies were described for angiotensin-converting enzyme inhibitor-induced AE (ACEi-AE), for idiopathic AE, and for AE with wheals. Described treatments consisted of ecallantide, icatibant, C1INH, fresh frozen plasma (FFP), tranexamic acid (TA), and omalizumab. Additionally, individual studies for anti-vitamin K, progestin, and methotrexate were found. Safety information was available in 26 articles. Most therapies were used off-label and in few patients. There is a need for additional studies with a high level of evidence. In conclusion, in acute attacks of ACEi-AE and idiopathic AE, treatment with icatibant, C1INH, TA, and FFP often leads to symptom relief within 2 h, with limited side effects. For prophylactic treatment of idiopathic AE and AE with wheals, omalizumab, TA, and C1INH were effective and safe in the majority of patients.

Topics: Angioedema; Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Humans; Omalizumab; Progestins; Tranexamic Acid; Treatment Outcome

Angiotensin-converting enzyme inhibitor (ACEI)-induced angioedema can occur at any point during therapy and, when severe, can require mechanical ventilation. Standard agents for anaphylactic reactions have limited efficacy for bradykinin-mediated angioedema and, therefore, agents approved for hereditary angioedema are increasingly prescribed for these patients.. This systematic review critically evaluates evidence describing the off-label use of fresh frozen plasma (FFP), prothrombin complex concentrate (PCC), complement 1 esterase inhibitor (C1-INH), icatibant, and ecallantide for treatment of ACEI-induced angioedema.. A PubMed search was conducted and articles were cross-referenced for additional citations. All full-text clinical trials, case series, and case reports published in the English language describing pharmacologic treatment of ACEI-induced angioedema were included. Thirty-seven publications detailing FFP, PCC, and regimens approved for hereditary angioedema, including icatibant, ecallantide, and C1-INH, are reviewed extensively.. While findings of decreased time to symptom resolution or a cessation in symptom progression have been reported with each of these therapies, additional data showing clinically relevant implications, such as reduced intensive care unit length of stay or avoidance of mechanical ventilation, are warranted, especially when taking cost into consideration. FFP has limited evidence demonstrating a benefit for treatment of ACEI-induced angioedema without consistent dosing strategies. However, given its wide availability and low potential for adverse reactions, FFP therapy may be reasonable. Of the novel agents traditionally used for hereditary angioedema, icatibant has the highest level of evidence and has been reported to be successful in limiting the progression of angioedema.

Topics: Angioedema; Angiotensin-Converting Enzyme Inhibitors; Blood Coagulation Factors; Bradykinin; Complement C1 Inactivator Proteins; Humans; Off-Label Use; Peptides; Plasma

The bradykinin B2 receptor antagonist icatibant is effective in angiotensin-converting enzyme inhibitor-induced angioedema. The drug is not approved officially for this indication and has to be administered in an emergency situation off-label. Corticosteroids or antihistamines do not seem to work in this condition. The effectiveness of C1-esterase-inhibitor in angiotensin-converting enzyme-induced angioedema must be verified in a double-blind study.

Topics: Angioedema; Bradykinin; Bradykinin B2 Receptor Antagonists; Diagnosis, Differential; Drug-Related Side Effects and Adverse Reactions; Emergency Medical Services; Epiglottis; Humans; Off-Label Use; Renin; Tongue; Urticaria

Angioedema is a potentially life-threatening occurrence that is encountered by critical care providers. The mechanistic understanding of angioedema syndromes has improved in recent years, and novel medications are available that improve outcomes from these syndromes. This clinically focused review will describe the underlying genetics, pathophysiology, classification and treatment of angioedema syndromes, with an emphasis on the novel pharmacologic agents that have recently become available for acute treatment.. A MEDLINE search was conducted with the MeSH terms angioedema, acquired angioedema, hereditary angioedema type III, and angiotensin converting enzyme inhibitor-induced angioedema.. Selected publications describing angioedema, clinical trials, diagnosis, management, and genetics were retrieved (reviews, guidelines, clinical trials, case series), and their bibliographies were also reviewed to identify relevant publications.. Data from the relevant publications were reviewed, summarized and the information synthesized.. The data obtained were used to describe the current state of diagnosis and management of various angioedema syndromes.. Angioedema is a life-threatening syndrome with multiple subtypes, each with a distinct pathophysiology. We present an evidence-based approach to the diagnosis and suggested management of various subtypes of angioedema. Securing the airway remains the most important intervention, followed by administration of both established and more novel pharmacologic interventions based on disease pathology.

Topics: Airway Management; Angioedema; Bradykinin; Bradykinin B2 Receptor Antagonists; Complement C1 Inactivator Proteins; Complement C1 Inhibitor Protein; Critical Care; Humans; Kallikreins; Peptides; Recombinant Proteins

To evaluate the place in therapy of fresh frozen plasma (FFP), C1 esterase concentrate (C1-INH), ecallantide, and icatibant in the management of angiotensin-converting enzyme inhibitor-induced angioedema (ACEI-IA).. A literature search was performed using PubMed (1946 through August 2015) and Embase (<1966 through August 2015). References from identified articles were reviewed.. Consensus papers, practice guidelines, case reports/series, clinical trials, and meeting abstracts published in English and involving humans were included.. No medications are currently Food and Drug Administration-approved for managing ACEI-IA. Emerging evidence suggests that FFP and medications approved for management of acute attacks of hereditary angioedema, another bradykinin-mediated event, may be effective for use in ACEI-IA. Positive efficacy results were reported with FFP and C1-INH while mixed results have been seen with ecallantide. Off-label icatibant has the most evidence supporting its use in ACEI-IA with rapid symptom resolution (10 minutes to 6 hours) and avoidance of intubation and tracheotomy in several cases. These agents were well-tolerated in ACEI-IA.. ACEI-IA is typically a self-limiting event. First-line therapies include ACEI discontinuation, observation, and supportive medications (eg, corticosteroids, antihistamines, and epinephrine). Symptom progression can be life-threatening and may require interventions such as tracheotomy and intubation. Off-label use of FFP and medications approved for hereditary angioedema have resulted in rapid resolution of symptoms and avoidance of intubation. Among these agents, icatibant has the most supporting evidence and has been incorporated into practice guidelines and algorithms as a second-line agent for serious life-threatening ACE-IA.

Topics: Angioedema; Angioedemas, Hereditary; Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Complement C1s; Humans; Off-Label Use; Peptides; Plasma; United States

The published evidence on pharmacologic approaches to the management of angiotensin-converting enzyme inhibitor (ACEI)-induced angioedema is reviewed.. Angioedema is a serious, potentially life-threatening adverse effect of ACEI use. Although the underlying mechanism is not fully understood, excess bradykinin produced through a complex interplay between the kallikrein-kinin and renin-angiotensin-aldosterone systems is thought to play a major role. The nonallergic nature of the reaction renders traditional therapies (corticosteroids and antihistamines) ineffective because those agents do not modify the proposed pathophysiology. Fresh frozen plasma (FFP) provides kinase II, a protein that breaks down bradykinin. Case reports support FFP as a treatment for ACEI-induced angioedema, but no formal evaluations have been completed to date. Both ecallantide and complement 1 esterase (C1) inhibitor concentrate reduce bradykinin production through upstream inhibition of kallikrein. C1 inhibitor concentrate has been used successfully to manage ACEI-induced angioedema in a few reported cases, but robust supportive studies are lacking. Conversely, ecallantide has been evaluated in multiple randomized trials but has not been shown to offer advantages over traditional therapies. The use of icatibant, a direct antagonist of bradykinin B2 receptors, was reported to be beneficial in several case reports and in a small Phase II study, safely and rapidly reducing symptoms of ACEI-induced angioedema. An ongoing Phase III trial (NCT01919801) will better define the role of icatibant in the management of ACEI-induced angioedema.. FFP, C1 inhibitor, and icatibant appear to be safe and effective therapeutic options for the management of ACEI-induced angioedema, whereas it appears ecallantide should be avoided.

Topics: Angioedema; Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Complement C1 Inhibitor Protein; Disease Management; Humans; Plasma

Angioedema is defined as local, noninflammatory, self-limiting edema that is circumscribed owing to increased leakage of plasma from the capillaries located in the deep layers of the skin and the mucosae. Two mediators, histamine and bradykinin, account for most cases of angioedema. Angioedema can occur with wheals as a manifestation of urticaria, and this form is frequently allergic. In the present review, we discuss nonallergic angioedema without wheals, which can be divided into 3 acquired and 4 hereditary forms. Histamine is the mediator in acquired angioedema of unknown etiology (idiopathic histaminergic acquired angioedema), whereas in other forms the main mediator is bradykinin. Angioedema can be caused by C1-inhibitor deficiency (C1-INH-hereditary angioedema and C1-INH-acquired angioedema), mutations in coagulation factor XII (FXII-hereditary angioedema), and treatment with angiotensin-converting enzyme inhibitors (ACEI-acquired angioedema). Etiology remains unclear in acquired angioedema (idiopathic nonhistaminergic acquired angioedema) and in 1 type of hereditary angioedema (hereditary angioedema of unknown origin). Several treatments are licensed for hereditary C1-INH deficiency. Plasma-derived and recombinant C1-INHs, the bradykinin receptor blocker icatibant, and the plasma kallikrein inhibitor ecallantide have been approved for on-demand treatment to reverse angioedema symptoms. Attenuated androgen and plasma-derived C1-INH are approved for prophylaxis.

Topics: Angioedema; Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Complement C1 Inhibitor Protein; Humans

Angioedema (AE) is characterized by nonpitting edema of the dermis and subcutaneous layers. The most common sites of involvement are the tongue, lips, face, and throat; however, swelling can also occur in the extremities, genitalia, and viscera. Life-threatening airway swelling can also occur. AE may be allergic or nonallergic. The overall lifetime incidence of AE is reported to be as high as 15%.. This article summarizes the etiology, pathophysiology, and current treatment of several forms of nonallergic AE (including hereditary, acquired, and idiopathic AE) and focuses on angiotensin-converting enzyme inhibitor-induced angioedema (ACEi-AE), which is responsible for 30%-40% of all AE seen in United States emergency departments.. Although the triggers, which are primary biologic mechanisms, and treatments for ACEi-AE may differ from those of the hereditary and acquired forms of AE, the clinical effects of ACEi-AE are mediated through a shared pathway, the kallikrein-kinin system. Thus, although current therapeutic options for ACEi-AE are limited, recent advances in the treatment of hereditary AE (HAE) appear promising for improving the outcomes of patients with ACEi-AE.. New HAE medications that correct imbalances in the kallikrein-kinin system may prove safe and efficacious in the treatment of ACEi-AE.

Topics: Adrenergic beta-Antagonists; Angioedema; Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Complement C1 Inhibitor Protein; Endoscopy; Humans; Incidence; Intubation, Intratracheal; Kallikreins; Peptides; Risk Factors

Angiotensin-converting enzyme (ACE) inhibitor-related angioedema (AE) may be fatal in the absence of specific treatment. No consensus for this side effect currently exists. Also, the French national reference centre for angioedema (CREAK) decided to establish recommendations, developed by an expert group and proposed at a national meeting. A scientific committee conducted a comprehensive literature review and worked out with proposals. These proposals were submitted to a vote to the expert panel of CREAK at a national meeting. Proposals that had received the majority were retained. Diagnosis of ACE inhibitor-related AE is based on clinical events. Regarding the severity of the disease, this diagnosis has to be put forward in any patient currently treated with or who has been treated with ACE inhibitors in the previous 6 months. The diagnosis is important because AE does not respond to usual treatment of histamine-induced AE (antihistamines, corticosteroids, and epinephrine), but only to specific treatment of bradykinin-induced AE, as antagonists of bradykinin or concentrates of C1 inhibitor. The subsequent use of ACE is strictly contra-indicated. A report to pharmacovigilance centres of every case is essential. These recommendations should improve the standardization of the management of ACE inhibitor-related AE.

Topics: Adrenergic beta-Antagonists; Angioedema; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Bradykinin Receptor Antagonists; Dipeptidyl-Peptidase IV Inhibitors; France; Humans; Immunosuppressive Agents

Angioedema is a serious complication of renin-angiotensin system inhibitor therapy. The incidence is 0.1-0.7%. It consists of nonpitting edema and involves the face and lips. In severe cases, it extends to pharyngeal and laryngeal structures.. Decreased degradation of bradykinin and its metabolites is thought to be a culprit. When the angiotensin-converting enzyme is inhibited, bradykinin metabolism is dependent on degradation by neutral endopeptidase, dipeptidyl peptidase IV, and aminopeptidase P. When these enzymes are inhibited, as in treatment of diabetes or in transplant recipients, the incidence of angioedema increases significantly. African-Americans, people over 65, women, and those with a history of smoking are especially at risk. A fiberoptic laryngeal examination should be performed in all patients. Patients with rapid progression of symptoms are at risk for airway compromise. Supportive treatment with steroids and antihistamines is not very effective. Recently, icatibant, a bradykinin receptor antagonist, has been used to successfully shorten the resolution of edema.. Trauma of the airway, especially during difficult intubation, may precipitate severe angioedema. In cases with laryngeal involvement, fiberoptic intubation may be necessary. After the episode of angioedema, lifetime discontinuation of all renin-angiotensin inhibitors may be warranted.

Topics: Anesthesia; Angioedema; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Enzyme Inhibitors; Humans; Intubation, Intratracheal; Kallikrein-Kinin System; Laryngoscopy; Renin-Angiotensin System; Risk Factors

HOE-140/ Icatibant is a selective, competitive antagonist to bradykinin (BK) against its binding to the kinin B2 receptor. Substitution of five non-proteogeneic amino acid analogues makes icatibant resistant to degradation by metalloproteases of kinin catabolism. Icatibant has clinical applications in inflammatory and vascular leakage conditions caused by an acute (non-controlled) production of kinins and their accumulation at the endothelium B2 receptor. The clinical manifestation of vascular leakage, called angioedema (AE), is characterized by edematous attacks of subcutaneous and submucosal tissues, which can cause painful intestinal consequences, and life-threatening complications if affecting the larynx. Icatibant is registered for the treatment of acute attacks of the hereditary BK-mediated AE, i.e., AE due to C1 inhibitor deficiency.. This review discusses emerging knowledge on the kinin system: kinin pharmacological properties, biochemical characteristics of the contact phase and kinin catabolism proteases. It underlines the responsibility of the kinins in AE initiation and the potency of icatibant to inhibit AE formation by kinin-receptor interactions.. Icatibant antagonist properties protect BK-mediated AE patients against severe attacks, and could be developed for use in inflammatory conditions. More studies are required to confirm whether or not prolonged and frequent applications of icatibant could result in the impairment of the cardioprotective effect of BK.

Topics: Angioedema; Animals; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Bradykinin B2 Receptor Antagonists; Humans; Kinins

Bradykinin has been implicated to contribute to allergic inflammation and the pathogenesis of allergic conditions. It binds to endothelial B(1) and B(2) receptors and exerts potent pharmacological and physiological effects, notably, decreased blood pressure, increased vascular permeability and the promotion of classical symptoms of inflammation such as vasodilation, hyperthermia, oedema and pain. Towards potential clinical benefit, bradykinin has also been shown to exert potent antithrombogenic, antiproliferative and antifibrogenic effects. The development of pharmacologically active substances, such as bradykinin receptor blockers, opens up new therapeutic options that require further research into bradykinin. This review presents current understanding surrounding the role of bradykinin in nonallergic angioedema and other conditions seen by allergists and emergency physicians, and its potential role as a therapeutic target.

Topics: Angioedema; Animals; Biomedical Research; Bradykinin; Complement C1 Inhibitor Protein; Humans; Mice; Vasodilator Agents

Angioedema is an oedematous swelling of the mucosa or submucosa of the skin. Acute angioedema represents a clinical emergency when the pharynx or larynx are involved and breathing of the patient is impaired. For rapid and effective treatment it is necessary to differentiate between allergic and non-allergic angioedema. Three of the five subforms of non-allergic angioedema are mediated by bradykinin: renin-angiotensin-aldosterone system (RAAS)-blocker-induced angioedema (RAE), hereditary angioedema (HAE) and acquired angioedema (AAE). Antihistamines, corticosteroids and adrenalin can be used to treat allergic angioedema but are ineffective in acute attacks of non-allergic angioedema. In these events the bradykinin-B2-receptor antagonist icatibant (in HAE, or RAE) or C1-INH concentrate (in HAE, or AAE) are therapeutic options for rapid alleviation of acute angioedema. The following article gives an overview of the diagnostics and treatment in the emergency situation of "acute angioedema", especially if swelling of the head-and-neck region is present.

Topics: Acute Disease; Adrenal Cortex Hormones; Angioedema; Bradykinin; Emergency Medical Services; Epinephrine; Histamine Antagonists; Humans; Lung Diseases, Obstructive

C1 inhibitor deficiency is a rare syndrome clinically characterized by recurrent episodes of swelling of subcutaneous tissue or angioedema. It can involve the skin, upper respiratory airways and abdomen. There are two main types: hereditary and acquired. Angioedema can involve practically any part of the cutaneous surface, it can cause lethal laryngeal edema and can present as gastrointestinal obstruction. The attacks can be triggered, in general, by trauma, drugs or infections. Diagnosis is confirmed by decreased serum levels of C4 and absence or marked decrease of the level or function of C1 inhibitor. Commonly employed drugs for prophylaxis and treatment of these patients include anabolic steroids, antifibrinolytic agents, and infusion of C1 inhibitor concentrate. Fresh frozen plasma is an option to be considered for short term prophylaxis or treatment of the acute attack. It is convenient to know this syndrome as it is a potentially life-threatening disease. Diagnosis of this rare syndrome is based on clinical features and characteristic alterations of laboratory tests. The acute attack should be treated as quickly as possible. Prophylactic therapy is indicated in certain circumstances (dental procedures, oral surgery).

Topics: Adolescent; Adult; Aminocaproic Acid; Angioedema; Bradykinin; Child; Child, Preschool; Complement C1 Inhibitor Protein; Complement C4; Danazol; Disease Management; Estrogens; Female; Humans; Intraoperative Complications; Male; Middle Aged; Serine Proteinase Inhibitors; Tranexamic Acid

Hereditary angioedema, an autosomal dominant disorder, presents clinically as recurrent episodes of swelling. It results from either deficient production or function of C1 inhibitor. Acquired angioedema is associated with lymphoproliferative or autoimmune disease. Conventionally attenuated androgens and antifibrinolytics have been used for prophylaxis, both for the long term and presurgically. Fresh frozen plasma and plasma-derived C1 inhibitor concentrate have been used primarily for treatment of acute attacks. All have drawbacks in side effects or potential for infection transmission. New treatments (recombinant C1 inhibitor, icatibant, DX-88, and for acquired angioedema, rituximab) so far show good safety profiles. Early data suggest these may be effective treatment alternatives. The efficacy of current treatment and the potential held by newer agents that target specific elements in complement or kinin pathways are examined. Some agents are likely to have a wider role in treatment of other, more common, forms of angioedema.

Topics: Androgens; Angioedema; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antifibrinolytic Agents; Autoimmune Diseases; Blood Component Transfusion; Bradykinin; Chromosome Disorders; Complement C1 Inactivator Proteins; Complement C1 Inhibitor Protein; Complement System Proteins; Humans; Kinins; Lymphoproliferative Disorders; Peptides; Plasma; Rituximab; Serpins

ACE-inhibitor induced angioedema is a non-allergic drug-related side effect. Inhibited bradykinin degradation leads to an unphysiological enhanced bradykinin plasma level with vascular leakage and, consequently, to angioedema. ACE-inhibitor induced angioedema develop rapidly in the head and neck region. Typical sites of manifestation are lips, tongue, and larynx. Novel pharmacotherapies may allow a causal treatment of the ACE-inhibitor induced angioedema in the future.

Topics: Adrenal Cortex Hormones; Algorithms; Angioedema; Angioedemas, Hereditary; Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Bradykinin Receptor Antagonists; Forecasting; Histamine Antagonists; Humans; Laryngeal Edema; Laryngoscopy; Magnetic Resonance Imaging; Time Factors; Tomography, X-Ray Computed

Angiotensin-converting enzyme inhibitor-related angioedema is a well documented condition, which seems to occur in up to 1% of treated patients. It represents a problem for both the clinician and the patient: for the clinician, the diagnosis may be difficult due to its peculiar clinical characteristics, whereas for the misdiagnosed patient the delay prolongs a potentially dangerous situation. If the drug is not discontinued, the attacks tend to become worse and even life-threatening. There are now evidences that increased levels of bradykinin have an important role in the pathophysiology of attacks and, moreover, there are genetic factors that render certain individuals susceptible to angiotensin-converting enzyme inhibitor-related angioedema. In this review, the authors analyse the pathogenetic mechanism, the clinical presentation, the management and future perspectives of research on this condition.

Topics: Angioedema; Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Humans

The kallikrein-kinin system is an endogenous metabolic cascade, triggering of which results in the release of vasoactive kinins (bradykinin-related peptides). This complex system includes the precursors of kinins known as kininogens and mainly tissue and plasma kallikreins. The pharmacologically active kinins, which are often considered as either proinflammatory or cardioprotective, are implicated in many physiological and pathological processes. The interest of the various components of this multi-protein system is explained in part by the multiplicity of its pharmacological activities, mediated not only by kinins and their receptors, but also by their precursors and their activators and the metallopeptidases and the antiproteases that limit their activities. The regulation of this system by serpins and the wide distribution of the different constituents add to the complexity of this system, as well as its multiple relationships with other important metabolic pathways such as the renin-angiotensin, coagulation, or complement pathways. The purpose of this review is to summarize the main properties of this kallikrein-kinin system and to address the multiple pharmacological interventions that modulate the functions of this system, restraining its proinflammatory effects or potentiating its cardiovascular properties.

Topics: Angioedema; Angiotensin-Converting Enzyme Inhibitors; Animals; Aprotinin; Bradykinin; Bradykinin B2 Receptor Antagonists; Cardiovascular Diseases; Complement C1 Inactivator Proteins; Complement C1 Inhibitor Protein; Humans; Inflammation; Kallikrein-Kinin System; Kallikreins; Kidney Diseases; Kinins; Neprilysin; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Pyridines; Randomized Controlled Trials as Topic; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Serpins; Thiazepines

The B. We sought to test the hypothesis that a bradykinin B. Patients with ACE inhibitor-associated angioedema (defined as swelling of lips, tongue, pharynx, or face during ACE inhibitor use and no swelling in the absence of ACE inhibitor use) were enrolled at Vanderbilt University Medical Center from October 2007 through September 2015 and at Massachusetts General Hospital in 2012. C1 inhibitor deficiency and patients with bowel edema only were excluded. Patients were randomized within 6 hours of presentation to subcutaneous icatibant 30 mg or placebo at 0 and 6 hours later. Patients assessed severity of swelling using a visual analog scale serially following study drug administration or until discharge.. Thirty-three patients were randomized and 31 received treatment, with 13 receiving icatibant and 18 receiving placebo. One patient randomized to icatibant did not complete the visual analog scale and was excluded from analyses. Two-thirds of patients were black and two-thirds were women. Time-to-resolution of symptoms was similar in placebo and icatibant treatment groups (P = .19 for the primary symptom and P > .16 for individual symptoms of face, lip, tongue, or eyelid swelling). Frequency of administration of H1 and H2 blockers, corticosteroids, and epinephrine was similar in the 2 treatment groups. Time-to-resolution of symptoms was similar in black and white patients.. This study does not support clinical efficacy of a bradykinin B

Topics: Adult; Aged; Angioedema; Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Bradykinin B2 Receptor Antagonists; Double-Blind Method; Female; Humans; Male; Middle Aged; Treatment Outcome

Angioedema induced by treatment with angiotensin-converting-enzyme (ACE) inhibitors accounts for one third of angioedema cases in the emergency room; it is usually manifested in the upper airway and the head and neck region. There is no approved treatment for this potentially life-threatening condition.. In this multicenter, double-blind, double-dummy, randomized phase 2 study, we assigned patients who had ACE-inhibitor-induced angioedema of the upper aerodigestive tract to treatment with 30 mg of subcutaneous icatibant, a selective bradykinin B2 receptor antagonist, or to the current off-label standard therapy consisting of intravenous prednisolone (500 mg) plus clemastine (2 mg). The primary efficacy end point was the median time to complete resolution of edema.. All 27 patients in the per-protocol population had complete resolution of edema. The median time to complete resolution was 8.0 hours (interquartile range, 3.0 to 16.0) with icatibant as compared with 27.1 hours (interquartile range, 20.3 to 48.0) with standard therapy (P=0.002). Three patients receiving standard therapy required rescue intervention with icatibant and prednisolone; 1 patient required tracheotomy. Significantly more patients in the icatibant group than in the standard-therapy group had complete resolution of edema within 4 hours after treatment (5 of 13 vs. 0 of 14, P=0.02). The median time to the onset of symptom relief (according to a composite investigator-assessed symptom score) was significantly shorter with icatibant than with standard therapy (2.0 hours vs. 11.7 hours, P=0.03). The results were similar when patient-assessed symptom scores were used.. Among patients with ACE-inhibitor-induced angioedema, the time to complete resolution of edema was significantly shorter with icatibant than with combination therapy with a glucocorticoid and an antihistamine. (Funded by Shire and the Federal Ministry of Education and Research of Germany; ClinicalTrials.gov number, NCT01154361.).

Topics: Aged; Angioedema; Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Bradykinin B2 Receptor Antagonists; Clemastine; Double-Blind Method; Drug Therapy, Combination; Female; Glucocorticoids; Histamine H1 Antagonists; Humans; Injections, Subcutaneous; Male; Middle Aged; Prednisolone; Time Factors

The pathophysiology of angiotensin-converting enzyme inhibitor (ACEi)-induced angioedema most likely resembles that of hereditary angioedema, ie, it is mainly mediated by bradykinin-induced activation of vascular bradykinin B2 receptors. We hypothesize that the bradykinin B2 receptor antagonist icatibant might be an effective therapy for ACEi-induced angioedema.. Eight patients with acute ACEi-induced angioedema were treated with a single subcutaneous injection of icatibant. The outcome was assessed by the time to first improvement of symptoms, complete symptom relief, and drug safety. In addition, we retrospectively assessed the clinical course of 47 consecutive patients of our clinic with ACEi-induced angioedema.. First symptom improvement after icatibant injection occurred at a mean time of 50.6 minutes (standard deviation [SD] 21 minutes) and complete relief of symptoms at 4.4 hours (SD 0.8 hours). No patient received tracheal intubation, other drug treatment, tracheotomy, or a second icatibant injection. There were no adverse effects except erythema occurring at the injection site. In the historical comparison group treated with methylprednisolone and clemastine, the mean time to complete relief of symptoms was 33 hours (SD 19.4 hours). Some of these patients received a tracheotomy (3/47), were intubated (2/47), or received a second dose of methylprednisolone (12/47).. Although sample size limits the external validity of our results, the substantial decrease of time to complete symptom relief suggests that this new treatment is likely effective as a pharmacotherapeutic approach to treat ACEi-induced angioedema.

Topics: Angioedema; Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Clemastine; Female; Humans; Injections, Subcutaneous; Male; Methylprednisolone; Middle Aged; Retrospective Studies; Time Factors; Treatment Outcome

In hereditary angioedema, bradykinin is assumed to be the most important mediator of edema formation.. To assess whether the selective bradykinin receptor-2 antagonist Icatibant is effective in acute edema attacks of hereditary angioedema.. In this uncontrolled pilot study, 15 patients with 20 attacks were treated with Icatibant. The attacks were analyzed by using a standardized and validated visual analog scale measurement and compared with historical data of untreated attacks. Plasma bradykinin concentration was measured before and 4 hours after intravenous Icatibant treatment.. Symptom intensity decreased within 4 hours after administration of Icatibant; the median time to onset of symptom relief was 1.50, 1.42, and 1.13 hours in the intravenous groups and 0.58 and 0.45 hours in the subcutaneous groups, respectively. The median difference in the 10-cm visual analog scale 4 hours after start of treatment was 4.11 cm (95% CI, 1.72-6.07). Compared with untreated attacks, Icatibant treatment reduced the mean (SD) time to onset of symptom relief by 97% from 42 +/- 14 to 1.16 +/- 0.95 hours (all groups combined). Median bradykinin concentration was 7-fold above the norm during acute attacks at 48.5 pmol/L and decreased to 18.0 pmol/L 4 hours after Icatibant infusion or injection.. Icatibant was effective in treating acute attacks of hereditary angioedema.. This is the first report demonstrating the clinical usefulness of antagonizing bradykinin binding to bradykinin receptor-2 in hereditary angioedema.

Topics: Acute Disease; Adult; Angioedema; Bradykinin; Bradykinin B2 Receptor Antagonists; Female; Genetic Diseases, Inborn; Humans; Male; Middle Aged; Pilot Projects

Topics: Acute Disease; Angioedema; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Bradykinin B2 Receptor Antagonists; Humans; Middle Aged

C1-inhibitor (C1INH) concentrates and the selective bradykinin B2 receptor antagonist icatibant are approved only for treating hereditary angioedema with C1INH deficiency. Yet, they are regularly prescribed off label in other types of bradykinin-mediated angioedema including angiotensin-converting enzyme inhibitor (ACEi)-related and undetermined angioedema. We conducted a retrospective chart review of inpatient prescriptions of C1INH concentrates and icatibant between 2016 and 2020 in the University Hospital of Angers. The first outcome was the proportion of prescriptions with explicit indication. Then, we determined the compliance of prescriptions with European Medicines Agency approvals and the French bradykinin-mediated angioedema reference center guidelines. Finally, we estimated the economic impact of inappropriate prescribing. The therapeutic indication was explicit in 90.4% of prescriptions (n = 66/73). Only 17.8% of prescriptions were for hereditary angioedema with C1INH deficiency, while 31.5% were for ACEi-related and 28.7% for undetermined angioedema. However, most off-label prescriptions were consistent with the French bradykinin-mediated angioedema reference center guidelines (73.3%). We estimated that 13% of drug expenditures were potentially excessive. The predominance of off-label prescriptions may be explained by the infrequency of hereditary angioedema and the absence of approved alternatives in other types of bradykinin-mediated angioedema. Most attacks were related to ACEis. Epinephrine was rarely prescribed as first-line therapy in attacks of unknown origin. Given the high prices of these drugs, we advocate the development of a readily available management algorithm of angioedema to reduce inappropriate prescriptions in our center. In addition, we think that the drug prescription circuit should be redesigned to ensure the traceability of prescribed vials in the dispensing areas.

Topics: Angioedema; Angioedemas, Hereditary; Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Humans; Off-Label Use; Prescriptions; Retrospective Studies

Acquired angioedema due to C1-inhibitor (C1-INH) deficiency (AAE-C1-INH) is rare and is associated with underlying lymphoproliferative diseases. C1-INH deficiency may be due to neoplastic over-consumption of C1-INH and the generation of anti-C1-INH autoantibodies. Uncovering an occult malignancy can lead to earlier oncology referral and improvement of angioedema after treatment of the underlying lymphoproliferative disorder. We characterized seven patients with C1-INH-AAE that highlights the importance of recognizing the association between C1-INH-AAE and underlying malignancy. In acute attacks, patients may be resistant to C1-INH therapy due to the presence of anti-C1-INH autoantibodies or rapid complement consumption, and may respond better to icatibant or ecallantide, which directly affect bradykinin. Treatment of the underlying malignancy also improves AAE-C1-INH symptoms and supports the role of lymphoproliferative B cells in AAE-C1-INH pathophysiology. Monitoring levels of C4, C1-INH function and level, and C1q may be predictive of AAE-C1-INH control and be used as surrogates for treatment efficacy. With close monitoring, low-dose danazol can be effective for long-term prophylaxis. Annual evaluation in AAE-C1-INH is recommended if an underlying malignancy is not found, as angioedema may precede the development of malignancy by several years. Our single-center study has aided in standardization of comprehensive AAE-C1-INH diagnosis, treatment, and monitoring strategies towards future therapeutic clinical trials.

Topics: Aged; Angioedema; Anti-Inflammatory Agents, Non-Steroidal; Autoantibodies; Bradykinin; Bradykinin B2 Receptor Antagonists; Complement C1 Inhibitor Protein; Complement C1q; Female; Hereditary Angioedema Types I and II; Humans; Lymphoproliferative Disorders; Male; Middle Aged; Peptides; Retrospective Studies

Topics: Angioedema; Angioedemas, Hereditary; Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Humans; N-Methyl-3,4-methylenedioxyamphetamine

Topics: Angioedema; Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents, Non-Steroidal; Antifibrinolytic Agents; Blood Transfusion; Bradykinin; Humans

A potential complication after intravenous administration of recombinant tissue plasminogen activators (rtPAs) for thrombolysis in acute ischaemic stroke is orolingual angioedema, with an incidence of 0.4%-7.9%. In the herewith reported case, we discuss potential links between a history of sarcoidosis and the occurrence of orolingual angioedema after rtPA administration. Sarcoidosis is often accompanied by an elevated ACE level. In contrast, low ACE levels appear to play a role in the pathomechanism currently assumed to trigger angioedema, that is, the activation of the bradykinin and complement pathways. Medication with ACE inhibitors is considered a risk factor for angioedema. Based on these considerations, the patient was also treated with icatibant, a bradykinin B2-receptor antagonist, which has been found useful in recent publications on treating orolingual angioedema after intravenous lysis in ischaemic stroke.

Topics: Angioedema; Bradykinin; Computed Tomography Angiography; Female; Humans; Infarction, Middle Cerebral Artery; Infusions, Intravenous; Intubation, Intratracheal; Lip; Middle Aged; Recombinant Proteins; Sarcoidosis; Thrombolytic Therapy; Tissue Plasminogen Activator; Tongue; Treatment Failure

Tratamiento del angioedema orolingual inducido por alteplasa mediante icatibant.

Topics: Angioedema; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Fibrinolytic Agents; Humans; Male; Middle Aged; Mouth Diseases; Tissue Plasminogen Activator; Tongue Diseases

Severe orolingual angioedema is a life-threatening complication of alteplase treatment for acute ischemic stroke that occurs during alteplase infusion or in the first 2 hours afterward. Currently, there are no proven therapies, although glucocorticoids, antihistamines, and adrenaline are sometimes used. Intubation is required if significant airway compromise supervenes. The incidence is .2%-5.1%, and risk factors include treatment with angiotensin-converting enzyme inhibitors and total insular infarcts. Here we report a case of alteplase-induced severe angioedema, which resolved briskly following icatibant treatment.

Topics: Angioedema; Bradykinin; Bradykinin B2 Receptor Antagonists; Fibrinolytic Agents; Humans; Infarction, Posterior Cerebral Artery; Male; Middle Aged; Thrombolytic Therapy; Tissue Plasminogen Activator; Treatment Outcome

Topics: Angioedema; Bradykinin; Emergency Medical Services; Female; Humans; Middle Aged; Stroke; Tissue Plasminogen Activator; Treatment Outcome

Angioedema (AE) is a potentially life-threatening event. We investigated the etiology of AE, with the emphasis on bradykinininduced angioedema treatment in emergency medicine.. The retrospective study included 237 patients with AE, who were examined and treated in two hospitals (group A and B) in Croatia from 2009 to 2016. The location and duration of AE, data about chronic diseases and treatment, potential causative agents (food, drugs, insect bites and chemicals), physical examination data and the subsequent treatment were analyzed.. There was no statistical difference regarding age or comorbidities but there was a statistically significant difference in etiology between the groups (Chi-square, P=0.03). Renin-angiotensin-aldosterone system (RAAS) blocker induced AE was the main cause of emergency attendance in group A (37.5%) and among the leading causes in group B (18.8%). Bradykinin-induced AE (hereditary angioedema (HAE) and RAAS-AE) were the leading causes in a total of 75 (31.5%) patients. RAAS-AE was treated with glucocorticoids and antihistamines. HAE attacks in both groups (2/7 patients, 1.5/6%) were treated with specific therapy. Other causes of AE in groups A/B were insect bites (15/23 patients, 13.5/20%), use of antibiotics/analgetics (11/17 patients, 9/15%), gastroesophageal reflux disease (10/11 patients, 8/9%), neoplasms (5/6 patients, 4/5%) and idiopatic (32/31 patients, 26.5/26%). 21% of patients were hospitalized.. Bradykinin-mediated AE was the main cause of emergency attendance associated with AE. Advances in the treatment of HAE, with case reports of patients with RAAS-AE treated with C1 esterase inhibitor concentrate or bradykinin receptor antagonist, may prove to be a new, reliable and efficacious therapy option.

Topics: Adult; Aged; Angioedema; Angioedemas, Hereditary; Bradykinin; Bradykinin Receptor Antagonists; Complement C1 Inhibitor Protein; Complement C1s; Croatia; Emergency Medicine; Female; Gastroesophageal Reflux; Hospitalization; Hospitals; Humans; Incidence; Insect Bites and Stings; Male; Middle Aged; Neoplasms; Prevalence; Renin-Angiotensin System; Retrospective Studies

Topics: Aged, 80 and over; Angioedema; Angioedemas, Hereditary; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Bradykinin B2 Receptor Antagonists; Complement C1 Inactivator Proteins; Female; Humans; Immunologic Factors; Lymphoma; Male; Middle Aged; Paraproteinemias; Peptides; Rituximab; Treatment Outcome

Article chosen Bas M, Greve J, Stelter K, et al. A Randomized Trial of Icatibant in ACE-Inhibitor-Induced Angioedema. N Engl J Med 2015;372:418-25. doi:10.1056/NEJMoa1312524.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Angioedema; Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Double-Blind Method; Emergency Service, Hospital; Female; Histamine Antagonists; Humans; Male; Middle Aged; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Steroids

The Icatibant Outcome Survey (IOS) is an observational study monitoring safety and effectiveness of icatibant in the real-world setting. We analyzed safety data from 3025 icatibant-treated attacks in 557 patients (enrolled between July 2009 and February 2015). Icatibant was generally well tolerated. Excluding off-label use and pregnancy, 438 patients (78.6%) did not report adverse events (AEs). The remaining 119 (21.4%) patients reported 341 AEs, primarily gastrointestinal disorders (19.6%). Of these, 43 AEs in 17 patients (3.1%) were related to icatibant. Serious AEs (SAEs) occurred infrequently. A total of 143 SAEs occurred in 59 (10.6%) patients; only three events (drug inefficacy, gastritis, and reflux esophagitis) in two patients were considered related to icatibant. Notably, no SAEs related to icatibant occurred in patients with cardiovascular disease, nor in those using icatibant at a frequency above label guidelines. Additionally, no major differences were noted in AEs occurring in on-label vs off-label icatibant users.

Topics: Adolescent; Angioedema; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Cardiovascular Diseases; Female; Gastrointestinal Diseases; Humans; Male; Off-Label Use; Time Factors; Treatment Outcome

Icatibant is used to treat acute hereditary angioedema with C1 inhibitor deficiency types I/II (C1-INH-HAE types I/II) and has shown promise in angioedema due to acquired C1 inhibitor deficiency (C1-INH-AAE). Data from the Icatibant Outcome Survey (IOS) were analysed to evaluate the effectiveness of icatibant in the treatment of patients with C1-INH-AAE and compare disease characteristics with those with C1-INH-HAE types I/II. Key medical history (including prior occurrence of attacks) was recorded upon IOS enrolment. Thereafter, data were recorded retrospectively at approximately 6-month intervals during patient follow-up visits. In the icatibant-treated population, 16 patients with C1-INH-AAE had 287 attacks and 415 patients with C1-INH-HAE types I/II had 2245 attacks. Patients with C1-INH-AAE versus C1-INH-HAE types I/II were more often male (69 versus 42%; P = 0·035) and had a significantly later mean (95% confidence interval) age of symptom onset [57·9 (51·33-64·53) versus 14·0 (12·70-15·26) years]. Time from symptom onset to diagnosis was significantly shorter in patients with C1-INH-AAE versus C1-INH-HAE types I/II (mean 12·3 months versus 118·1 months; P = 0·006). Patients with C1-INH-AAE showed a trend for higher occurrence of attacks involving the face (35 versus 21% of attacks; P = 0·064). Overall, angioedema attacks were more severe in patients with C1-INH-HAE types I/II versus C1-INH-AAE (61 versus 40% of attacks were classified as severe to very severe; P < 0·001). Median total attack duration was 5·0 h and 9·0 h for patients with C1-INH-AAE versus C1-INH-HAE types I/II, respectively.

Topics: Adult; Aged; Aged, 80 and over; Angioedema; Angioedemas, Hereditary; Bradykinin; Disease Progression; Female; Follow-Up Studies; Humans; Male; Middle Aged; Phenotype; Retrospective Studies; Severity of Illness Index; Surveys and Questionnaires; Treatment Outcome

Patients suffering from bradykinin-induced angioedema show recurrent swelling of subcutaneous and submucosal structures. Increased bradykinin levels lead to an increase in vascular permeability and edema formation. Current therapy consists of B2 bradykinin receptor antagonists, C1-esterase-inhibitor (C1-INH) concentrate, or the kallikrein inhibitor ecallantide. In most cases the treatment of acute attacks is sufficient. Prophylactic therapy is recommended only in severe cases. C1-INHc has been shown a safe and efficient option. Its effect on the quality of life has not yet been analyzed.. Patients with inadequate disease control despite an "on-demand therapy" including C1-INHc and/or the B2 receptor antagonist icatibant were switched to long-term prophylaxis consisting in an individual dose of intravenous C1-INHc (Cinryze). None of the patients had been previously treated with ecallantide. Disease-specific quality-of-life questionnaires and patient records were used for evaluation. Disease control, quality of life, adverse events, and administered dosage per month were compared for 6 months on on-demand therapy and the following 6 months under prophylactic therapy.. Data of seven patients with hereditary angioedema (HAE) and one patient with acquired angioedema were evaluated. Prophylactic therapy with Cinryze led to a significant and clinically relevant reduction in the overall attack frequency from 6.7 to 2.3 per month without relevant side effects. The frequency of severe attacks was reduced by 89% and quality of life significantly improved.. Prophylaxis with Cinryze led to a significantly improved quality of life in our cohort of patients with high-frequency bradykinin-induced angioedema attacks that were not sufficiently treated with on-demand medication.

Topics: Adult; Aged; Angioedema; Bradykinin; Bradykinin B2 Receptor Antagonists; Complement C1 Inactivator Proteins; Complement C1 Inhibitor Protein; Drug Substitution; Female; Humans; Male; Middle Aged; Peptides; Premedication; Prospective Studies; Quality of Life; Surveys and Questionnaires

Angioedema is a deep intradermal or sub-cutaneous edema, which can be mediated by histamine, bradykinin or mixture of both components. The aims of this review are to describe the clinical approach and diagnosis of non-hereditary bradykinin-mediated angioedema induced by drugs such as: angiotensin-converting inhibitor, sartan, gliptins, rapamycin or some thrombolytic reagents and renin inhibitors. Furthermore, we will discuss the drug management of these angioedema, which is mainly based on C1 inhibitor concentrate or icatibant administration.

Topics: Angioedema; Bradykinin; Bradykinin B2 Receptor Antagonists; Complement C1 Inhibitor Protein; Humans

Angioedema is a localized, sudden, transient, and often recurrent swelling of the deeper layers of the skin or mucosa with no epidermal component. It is caused by vasoactive substances that produce a transient increase in endothelial permeability. Angioedema involving the laryngeal components is a life-threatening situation for the patient,and it is a challenge for the emergency medicine physician to rapidly achieve a safety airway. Most cases of laryngeal angioedema are induced by histamine release; but 10% are bradykinin induced, which does not respond to the conventional algorithm of treating allergic induced angioedema. We present a case report of an angiotensin converting enzyme (ACE) inhibitor–induced laryngeal angioedema alleviated only after treatment with the new bradykinin receptor inhibitor medication icatibant which was licensed only for use in hereditary angioedema. We reviewed the literature for the use of icatibant in acquired drug-induced angioedema; and because of the similar pathogenesis between the hereditary angioedema and the ACE inhibitor–induced angioedema,we propose an algorithm for careful use of icatibantin life-threatening angioedema in the emergency department.

Topics: Aged; Angioedema; Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Bradykinin B2 Receptor Antagonists; Female; Humans; Laryngeal Edema

Acute, drug-induced angioedema may not respond to standard therapies, because the pathogenetic mechanism that induces the pathology is not always mediated by histamine but, in certain instances, by bradykinin. A case of angioedema is reported here, in which allergic etiology was excluded by the non-response to antihistamines. Considering the clinical history (repeated use of drugs) and the ineffectiveness of standard therapy, it was decided to administer a beta2 receptor antagonist, icatibant. After 20 minutes, the patient reported a subjective improvement. The only form of angioedema for which this type of medication is licensed is the hereditary deficiency of C1 inhibitor. The use of icatibant for the treatment of other types of angioedema (which can also be life-saving if the airway is involved) is off label. The off-label use of a drug is allowed in the absence of a viable alternative therapy, if there is scientific evidence in the literature and if the prescriber takes responsibility. The case here reported draws attention to this therapeutic problem and underlines the fact that a life-threatening emergency can justify the use of icatibant.

Topics: Aged; Angioedema; Anti-Allergic Agents; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Bradykinin B2 Receptor Antagonists; Female; Humans; Off-Label Use

Angiotensin II receptor antagonists have been proposed as a replacement therapy after the occurrence of either an angiotensin converting enzyme (ACE) inhibitor-induced angioedema or cough. However, recent studies indicate that angioedema is associated with elevated bradykinin levels in a small fraction of patients treated with angiotensin-II-receptor blockers, suggesting a common pathophysiological mechanism. To date, a standard treatment for angiotensin II receptor blocker-induced angioedema does not exist.. We present a case series of patients admitted to our hospital due to angioedema induced by an angiotensin II receptor blocker. The patients were either treated with either icatibant (n = 3) or prednisolone-21-hydrogen succinate/clemastine (n = 5). Both patient groups were compared with an untreated patient cohort (n = 3). All patients were previously diagnosed with essential hypertonia.. Icatibant was an effective therapy for angiotensin II receptor blocker-induced angioedema. Full symptom recovery was achieved after 5 to 7 hours, whereas symptom remission occurred within 27 to 52 and 24 to 54 hours in patients treated with Solu-Decortin prednisolone/clemastine and untreated patients, respectively. The recovery time for icatibant was similar to that described in previous studies regarding the therapeutic efficacy of icatibant for the treatment of hereditary angioedema and patients suffering from angiotensin converting enzyme inhibitor-induced angioedema.. Icatibant is a safe and effective substance for the treatment of angiotensin II receptor blocker-induced angioedema. Although the pathophysiology of angiotensin II receptor blocker-induced angioedema remains unclear, it appears to be associated with the bradykinin pathway.

Topics: Angioedema; Angiotensin Receptor Antagonists; Bradykinin; Bradykinin B2 Receptor Antagonists; Clemastine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Essential Hypertension; Female; Follow-Up Studies; Glucocorticoids; Histamine H1 Antagonists; Humans; Hypertension; Injections, Intravenous; Male; Prednisolone; Retrospective Studies; Treatment Outcome

No specific drugs are licensed for the treatment of ACE inhibitor (ACEI)-acquired angioedema (ACEI-AAE). Icatibant, an antagonist of the B2 receptor of bradykinin, is a potential treatment for this condition; however, its use in this setting is poorly documented. We report here clinical outcomes of 13 patients with ACEI-AAE treated with icatibant, in a real-life setting. Thirteen patients on ACEI seen in an Emergency Department (ED) with angioedema involving face, lips or the upper airways were analyzed. Angioedema due to known causes other than ACEI treatment was excluded. Initially, all patients received standard therapy (antihistamine, corticosteroids and epinephrine). Due to the lack of response and a worsening severity of symptoms, all patients received one subcutaneous injection of icatibant (30 mg/mL). Following icatibant treatment, all patients experienced improvement in the symptoms. The median time from onset of clinical symptoms to injection of icatibant was 3 h (IQR 2.5-5.5 h). Symptom relief was reported at 30 min (IQR 27.5-70 min). A complete resolution of symptoms was observed at 5 h (IQR 4-7 h). Ten patients had previously experienced angioedema attacks. The Median time to complete resolution of the previous attacks was higher (54 h; IQR 33-63 h), than after icatibant (p = 0.002) therapy. No patients required tracheal intubation or tracheotomy, and all patients were discharged within 24 h. No adverse events were reported. Before discharge, all patients were instructed to discontinue ACEI, and to take a different antihypertensive agent. This case series supports the efficacy of icatibant in improving symptoms of ACEI-AAE.

Topics: Aged; Aged, 80 and over; Angioedema; Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Bradykinin B2 Receptor Antagonists; Emergency Service, Hospital; Female; Humans; Injections, Subcutaneous; Male; Middle Aged

Sporadic and familiar forms of non-histaminergic angioedema and normal C1 inhibitor encompass a group of disorders possibly caused by bradikinin. We aimed to study the subgroups of hereditary angioedema with FXII mutation (FXII-HAE), unknown genetic defect (U-HAE) and idiopathic non-histaminergic acquired angioedema (InH-AAE). We screened the F12 locus in our cohort and delineated the clinical, laboratory and genetic features. Four families carried the p.Thr309Lys mutation in F12 gene. Haplotyping confirmed the hypothesis of a common founder. Six families were affected by U-HAE and 13 patients by sporadic InH-AAE. C4 levels were significantly lower in FXII-HAE than in InH-AAE. In the FXII-HAE group, none had attacks exclusively in high estrogenic states; acute attacks were treated with icatibant. Prophylaxis with tranexamic acid reduced the attack frequency in most patients. Our study provides new data on the diagnosis, clinical features and treatment of non-histaminergic angioedema, underlying the role of the screening for F12 mutations.

Topics: Adolescent; Adult; Aged; Angioedema; Angioedemas, Hereditary; Antifibrinolytic Agents; Bradykinin; Bradykinin B2 Receptor Antagonists; Cohort Studies; Complement C4; Factor XII; Female; Genetic Predisposition to Disease; Genetic Testing; Humans; Italy; Male; Middle Aged; Pedigree; Polymorphism, Single Nucleotide; Tranexamic Acid; Young Adult

Angioedema occurs in up to 2% of those taking angiotensin-converting enzyme (ACE) inhibitors. Upper airway angioedema may potentially require endotracheal intubation or cricothyrotomy, and is usually unresponsive to adrenaline. The bradykinin receptor antagonist icatibant is proven to be effective in the treatment of acute attacks of hereditary angioedema, and has also been reported effective in the treatment of angioedema associated with ACE inhibitors.. To describe the use of icatibant for ACE inhibitor-associated airway angioedema.. We treated 13 consecutive emergency department (ED) patients, who had not improved with adrenaline and/or corticosteroids, with icatibant 30 mg subcutaneously for ACE inhibitor-associated upper respiratory tract angioedema according to an agreed protocol.. Four patients were intubated in the ED either before or after receiving icatibant; three of these were extubated within 24 h of treatment. Eight patients received early icatibant and did not require intubation. The time from onset of airway angioedema to ED presentation ranged from 1 h to 3 days (median 4 h); from ED presentation to receiving icatibant, from 30 minutes to 3 days (median 3 h); and to onset of symptom improvement after icatibant, 15 minutes to 7 h (median 2 h). One patient received a second dose of icatibant.. All patients improved after receiving icatibant, consistent with its bradykinin receptor blocking mechanism. Icatibant rapidly reversed symptoms, and appeared to avert the need for intubation or expedite extubation. Timely use of icatibant in ACE inhibitor-associated angioedema may avert the need for invasive airway procedures and intensive care unit admission.

Topics: Adult; Aged; Aged, 80 and over; Angioedema; Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Bradykinin B2 Receptor Antagonists; Clinical Decision-Making; Emergency Service, Hospital; Female; Humans; Intubation, Intratracheal; Larynx; Male; Middle Aged; Oropharynx

Topics: Aged; Angioedema; Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Bradykinin B2 Receptor Antagonists; Female; Humans; Remission Induction

Idiopathic angioedema is defined as localized swelling of the cutaneous and mucosal tissue that occurs in episodes without a clear etiology. It can be problematic to treat when the underlying pathophysiology is not well understood.. To identify successful treatments of idiopathic angioedema reported in the literature.. A literature search was performed using PubMed. Published case reports and articles discussing treatment of idiopathic angioedema were used in the formulation of this review. In addition, 2 case reports are provided.. Although there are no approved treatments for idiopathic angioedema, several medications used for the treatment of hereditary angioedema, such as bradykinin receptor antagonists (icatibant), kallikrein inhibitors (ecallantide), and C1 inhibitors, were successful in 10 patients. Anti-IgE monoclonal antibody (omalizumab) proved successful in 5 patients. The most widely used and successful medication was tranexamic acid (154 patients).. Despite an unknown etiology, this article highlights viable treatment options for idiopathic angioedema. More clinical trials and better markers identifying the cause of angioedema are needed.

Topics: Adolescent; Angioedema; Antibodies, Anti-Idiotypic; Bradykinin; Female; Humans; Peptides; Tranexamic Acid

Topics: Adult; Angioedema; Bradykinin; Bradykinin B2 Receptor Antagonists; Humans; Male; N-Methyl-3,4-methylenedioxyamphetamine; Treatment Outcome

We present a case of a 75-year-old woman treated with an ACE inhibitor, who presented with angio-oedema of the tongue and had difficulty speaking. No symptoms of anaphylaxis or urticaria were present. The patient was treated intravenously with antihistamine and glucocorticoid in combination with adrenaline inhalations. After 6 h in the hospital the swelling progressed, and the patient was admitted to the intensive care unit and treated with one injection of icatibant-a bradykinin receptor antagonist. The patient reported subjective relief after 20-30 min and the swelling resolved within 2 h. Although the angio-oedema was potentially life threatening, the patient avoided intubation and mechanical ventilation. ACE inhibitor-induced angio-oedema is most likely caused by an accumulation of bradykinin and substance P. Consequently, a bradykinin receptor antagonist is the rational treatment of choice instead of antiallergic medications, which have no proven efficacy in this condition.

Topics: Aged; Angioedema; Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Bradykinin Receptor Antagonists; Diagnosis, Differential; Female; Humans; Tongue

Topics: Adult; Aged; Angioedema; Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Bradykinin B2 Receptor Antagonists; Female; Humans; Lip; Male; Tongue

Topics: Aged; Angioedema; Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Bradykinin B2 Receptor Antagonists; Drug Synergism; Everolimus; Female; Humans; Quinapril; Remission Induction; Sirolimus; Tetrahydroisoquinolines; TOR Serine-Threonine Kinases

Topics: Angioedema; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Face; Humans; Male; Middle Aged

The prevalence of acquired angioedema (AAE) is hitherto unknown and, to date, less than 200 patients have been reported worldwide. AAE is associated with lymphoproliferative conditions and autoantibodies against C1 inhibitor (C1INH). Rituximab (RTX) is increasingly used in the treatment of AAE patients.. A nationwide study of AAE patients was performed in Denmark. Clinical features, associated disorders, treatments and outcomes were registered.. Eight AAE patients were identified. The diagnostic delay was on average 1 year and 8 months. Patients were treated with C1INH concentrate or icatibant on demand. Six patients were diagnosed with a clonal B-cell disorder during follow-up, on average 2.5 years after the first swelling. Two patients had monoclonal B-cell lymphocytosis (MBL). Two patients received RTX.. AAE is a rare condition occurring in less than 10% of patients with C1INH deficiency in Denmark. AAE is highly associated with haematologic disorders, and we recommend yearly follow-up visits with clinical examination and blood tests including flow cytometry to diagnose B-cell conditions at an early stage. We report 2 patients with AAE and associated MBL, which is a benign expansion of clonal B lymphocytes. MBL can be the precursor of chronic lymphocytic leukaemia or is associated with non-Hodgkin's lymphoma. If angioedema is poorly controlled with standard treatment regimens, we suggest treatment of the associated haematologic disorder. Based on a review of the literature and our own data, we recommend therapy with RTX, especially in patients with anti-C1INH autoantibodies.

Topics: Adrenergic beta-Antagonists; Aged; Aged, 80 and over; Angioedema; Antibodies, Monoclonal, Murine-Derived; Autoantibodies; B-Lymphocytes; Bradykinin; Cohort Studies; Complement C1 Inactivator Proteins; Complement C1 Inhibitor Protein; Denmark; Female; Humans; Lymphocytosis; Male; Middle Aged; Rituximab

ACE-inhibitor is an antihypertensive drug which is increasingly used to treat a wide range of medical conditions. A known adverse reaction is angio-oedema of the head and neck, which can become fatal when the upper airway is involved, causing asphyxia. We present a Caucasian man, who developed severe angio-oedema of the tongue and floor of the mouth. He was successfully treated with complement C1-concentrate causing the swelling to regress within 20 min. This treatment option can be an effective alternative to bradykinin antagonists, which might not be available in the emergency room, or more invasive measures like intubation or emergency airway puncture.

Topics: Angioedema; Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Complement C1; Diagnosis, Differential; Humans; Male; Middle Aged; Palate, Soft; Tongue

Angioedema related to the use of angiotensin-converting enzyme inhibitors (AE-ACEi) has, so far, been treated with antiallergic drugs with questionable results. Because angioedema in this setting is likely related to increased levels of bradikinin, we decided to use icatibant, a bradikinin receptor antagonist licensed for use in hereditary angioedema, in a patient with AE-ACEi. In the same patient, the time to resolution of the angioedema during previous attacks was about 2 days when classic antiallergic drug regimens were used; when icatibant was used, this time shortened to 10 hours. Icatibant is a promising drug in the treatment of AE-ACEi.

Topics: Aged; Angioedema; Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Bradykinin Receptor Antagonists; Humans; Lisinopril; Male

Topics: Adrenergic beta-Antagonists; Adult; Angioedema; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Diagnosis, Differential; Face; Female; Humans; Periodicity; Treatment Outcome

We present the case of a 28-year-old female with a previous diagnosis of C1 esterase inhibitor deficiency presenting for dental extractions under general anaesthesia. Following prophylaxis with a new bradykinin receptor 2 antagonist (icatibant), surgery was carried out uneventfully with an unremarkable postoperative course.

Topics: Adult; Anesthesia, General; Angioedema; Angioedemas, Hereditary; Bradykinin; Bradykinin B2 Receptor Antagonists; Complement C1s; Female; Humans; Molar, Third; Monitoring, Intraoperative; Oral Surgical Procedures; Perioperative Care; Preoperative Care

Topics: Angioedema; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Bradykinin B2 Receptor Antagonists; Humans; Injections, Subcutaneous; Male; Middle Aged; Receptor, Bradykinin B2

Icatibant, a bradykinin B2 receptor antagonist, is an established treatment for acute attacks of hereditary angioedema (HAE) with C1-inhibitor (C1-INH) deficiency. We describe our experience with icatibant in eight patients with angioedema because of acquired C1-INH deficiency (AAE). Forty-eight moderate-to-severe attacks were treated with subcutaneous icatibant 30 mg; two moderate attacks resolved without treatment. The median (range) duration of treated attacks (onset to complete resolution) was 9.33 (1.67-39.00) h; durations of the untreated attacks were 72 and 96 h. Symptom improvement following icatibant treatment occurred in 0.5 (0.25-2.10) h and complete resolution in 6.75 (0.50-30.75) h. A single icatibant injection achieved complete symptom resolution in 47 attacks; one facial attack required a second injection. One peripheral attack responded less quickly than other treated attacks. Five patients reported transient injection site reactions. Icatibant appeared to provide effective symptom relief and was generally well tolerated.

Topics: Adrenergic beta-Antagonists; Aged; Aged, 80 and over; Angioedema; Autoantibodies; Autoimmune Diseases; Bradykinin; Bradykinin B2 Receptor Antagonists; Complement C1 Inhibitor Protein; Female; Humans; Male; Middle Aged; Treatment Outcome

Icatibant is a selective bradykinin 2 receptor antagonist, currently licensed for use in hereditary angioedema. Its benefit in ACE inhibitor angioedema is yet to be fully established. A handful of preliminary case reports suggest that it may be of benefit in reducing both symptom severity and possible hospital or intensive care admission. To date, there are no case reports of the usage of Icatibant in the emergency department in the UK. Here we report our experience of Icatibant in a 62-year-old gentleman presenting with severe oral, pharyngeal and laryngeal oedema while on an ACE inhibitor.

Topics: Adrenergic beta-Antagonists; Angioedema; Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Bradykinin B2 Receptor Antagonists; Epiglottis; Humans; Intubation, Intratracheal; Male; Middle Aged; Ramipril; Tongue; Vocal Cords

Topics: Adrenergic beta-Antagonists; Angioedema; Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Bradykinin Receptor Antagonists; Humans

Topics: Adult; Angioedema; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Female; Humans

Topics: Angioedema; Bradykinin; Bradykinin Receptor Antagonists; Face; Female; Humans; Middle Aged

Topics: Aged, 80 and over; Angioedema; Bradykinin; Humans; Male

Angiotensin-converting enzyme (ACE) inhibitors block the catalysis of angiotensin I to angiotensin II and also the breakdown of bradykinin. ACE inhibitor-induced angioedema is mediated by inhibited bradykinin degradation leading to enhanced bradykinin plasma levels. The efficacy of currently used standard treatments with antiallergic drugs is questionable. A patient with acute ACE inhibitor-induced angioedema was treated with icatibant, a specific bradykinin B2 receptor antagonist approved for the treatment of hereditary angioedema. A single subcutaneous injection of 30 mg icatibant resulted in a rapid onset of symptom relief and a remarkable shortening of duration of the attack.

Topics: Adrenergic beta-Antagonists; Aged; Angioedema; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Bradykinin; Bradykinin B2 Receptor Antagonists; Deglutition Disorders; Humans; Male; Mouth; Respiratory Sounds

Topics: Adrenergic beta-Antagonists; Angioedema; Bradykinin; Complement C1 Inhibitor Protein; Erythema; Hereditary Angioedema Types I and II; Humans; Male; Middle Aged; Treatment Outcome

We are reporting the case of a bradykinin-mediated angioedema, secondary to the angiotensin converting enzyme inhibitors, which delayed treatment could have unfavorably influence the vital prognostic of the patient. Initially, the patient had an isolated edema of the superior lip. Prehospital treatment included methylprednisolone, hydroxyzine and epinephrine. The patient was subsequently taken to the emergency department. His situation deteriorated. An edema of the cheeks and the tongue appeared. The transfer of the patient to an emergency department, specializing in kinin angioedema was organized, in order for the patient to receive specific treatments. After a subcutaneous injection of icatibant, the situation improved very rapidly, with a regression of the edema. This observation is consistent with the early use of the specific therapeutic in bradykinin-mediated angioedema. Any delay in administering the treatment can negatively impact the prognostic. The availability of such treatments should therefore be organized during the prehospital phase.

Topics: Angioedema; Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents; Bradykinin; Emergency Medical Services; Histamine H1 Antagonists; Humans; Hydroxyzine; Hypertension; Lip; Male; Methylprednisolone; Middle Aged

A 78 year-old woman with life-threatening angiotensin-converting enzyme inhibitor (ACE-i) induced angioedema was unresponsive to conventional treatment with corticosteroids, antihistamines and epinephrine. She was successfully treated with icatibant licensed for treatment of hereditary angioedema knowing that both conditions involve bradykinin induced activation of bradykinin B2 receptors. Randomised, controlled trials are warranted to document the efficacy of icatibant in ACE-i angioedema.

Topics: Adrenergic beta-Antagonists; Aged; Angioedema; Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Enalapril; Female; Humans

Topics: Adrenergic beta-Antagonists; Adult; Angioedema; Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Bradykinin B2 Receptor Antagonists; Humans; Male

Activation of bradykinin-mediated B2 receptor has been shown to play an important role in the onset of angioedema associated with C1 inhibitor deficiency. This finding has led to the development of novel therapeutic drugs such as the B2 receptor antagonist icatibant. However, it is unclear whether other receptors expressed on endothelial cells contribute to the release of kinins and vascular leakage in these patients. The recognition of their role may have obvious therapeutic implications.. Our aim was to investigate the involvement of B1 and gC1q receptors in in vitro and in vivo models of vascular leakage induced by plasma samples obtained from patients with C1 inhibitor deficiency.. The vascular leakage was evaluated in vitro on endothelial cells by a transwell model system and in vivo on rat mesentery microvessels by intravital microscopy.. We observed that the attack phase plasma from C1 inhibitor-deficient patients caused a delayed fluorescein-labeled albumin leakage as opposed to the rapid effect of bradykinin, whereas remission plasma elicited a modest effect compared with control plasma. The plasma permeabilizing effect was prevented by blocking the gC1q receptor-high-molecular-weight kininogen interaction, was partially inhibited by B2 receptor or B1 receptor antagonists, and was totally prevented by the mixture of the 2 antagonists. Involvement of B1 receptor was supported by the finding that albumin leakage caused by attack phase plasma was enhanced by IL-1beta and was markedly reduced by brefeldin A.. Our data suggest that both B1 receptor and gC1q receptor are involved in the vascular leakage induced by hereditary and acquired angioedema plasma.

Topics: Adrenergic beta-Antagonists; Angioedema; Animals; Antibodies, Monoclonal; Blood Vessels; Bradykinin; Bradykinin B1 Receptor Antagonists; Brefeldin A; Capillary Permeability; Cell Line, Tumor; Complement C1 Inhibitor Protein; Hereditary Angioedema Types I and II; Humans; Immunologic Factors; Interleukin-1beta; Male; Membrane Glycoproteins; Protein Synthesis Inhibitors; Rats; Rats, Inbred WKY; Receptor, Bradykinin B1; Receptors, Complement

Heterozygosity for C1 inhibitor (C1INH) deficiency results in hereditary angioedema. Disruption of the C1INH gene by gene trapping enabled the generation of homozygous- and heterozygous-deficient mice. Mating of heterozygous-deficient mice resulted in the expected 1:2:1 ratio of wild-type, heterozygous, and homozygous-deficient offspring. C1INH-deficient mice showed no obvious phenotypic abnormality. However, following injection with Evans blue dye, both homozygous and heterozygous C1INH-deficient mice revealed increased vascular permeability in comparison with wild-type littermates. This increased vascular permeability was reversed by treatment with intravenous human C1INH, with a Kunitz domain plasma kallikrein inhibitor (DX88), and with a bradykinin type 2 receptor (Bk2R) antagonist (Hoe140). In addition, treatment of the C1INH-deficient mice with an angiotensin-converting enzyme inhibitor (captopril) increased the vascular permeability. Mice with deficiency of both C1INH and Bk2R demonstrated diminished vascular permeability in comparison with C1INH-deficient, Bk2R-sufficient mice. These data support the hypothesis that angioedema is mediated by bradykinin via Bk2R.

Topics: Angioedema; Animals; Bradykinin; Bradykinin Receptor Antagonists; Capillary Permeability; Complement C1 Inactivator Proteins; Disease Models, Animal; Heterozygote; Homozygote; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptor, Bradykinin B2; Receptors, Bradykinin