ecallantide and icatibant

Hereditary angioedema due to C1-esterase inhibitor deficiency (C1-INH-HAE) is a rare autosomal dominant disease. In the last decade, new drugs and new indications for old drugs have played a role in the management of C1-INH-HAE. This review examines current therapy for C1-INH-HAE and provides a brief summary of drugs that are under development. Increased knowledge of the pathophysiology of C1-INH-HAE has been crucial for advances in the field, with inhibition of the kallikrein-kinin system (plasma kallikrein, activated factor XII) as a key area in the discovery of new drugs, some of which are already marketed for treatment of C1-INH-HAE. Pharmacological treatment is based on 3 pillars: treatment of acute angioedema attacks (on-demand treatment), short-term (preprocedure) prophylaxis, and long-term prophylaxis. The 4 drugs that are currently available for the treatment of acute angioedema attacks (purified plasma-derived human C1 esterase inhibitor concentrate, icatibant acetate, ecallantide, recombinant human C1 esterase inhibitor) are all authorized for self-administration, except ecallantide. Purified plasma-derived human C1 esterase inhibitor concentrate is the treatment of choice for short-term prophylaxis. Tranexamic acid, danazol, intravenous and subcutaneous nanofiltered purified plasma-derived human C1 esterase inhibitor concentrate, and lanadelumab can be used for long-term prophylaxis. New drugs are being investigated, mainly as long-term prophylaxis, and are aimed at blocking the kallikrein-kinin system by means of antiprekallikrein, antikallikrein, and anti-activated FXII action.

Topics: Angioedemas, Hereditary; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Complement C1 Inhibitor Protein; Humans; Kallikrein-Kinin System; Peptides; Recombinant Proteins

Topics: Angioedemas, Hereditary; Antibodies, Monoclonal, Humanized; Biological Therapy; Bradykinin; Complement C1 Inhibitor Protein; Humans; Kallikreins; Peptides; Receptor, Bradykinin B2; Recombinant Proteins

Hereditary angioedema is a rare genetic disorder caused by deficiency of C1 esterase inhibitor (C1-INH) and characterized by recurrent episodes of severe swelling that affect the limbs, face, intestinal tract and airway. Since laryngeal oedema can be life-threatening as a result of asphyxiation, correct diagnosis and management of hereditary angioedema is vital. Hereditary angioedema attacks are mediated by bradykinin, the production of which is regulated by C1-INH. Hereditary angioedema therapy relies on treatment of acute attacks, and short- and long-term prophylaxis. Acute treatment options include C1-INH concentrate, icatibant and ecallantide. Self-administration of treatment is recommended and is associated with increased quality of life of patients with hereditary angioedema. Advances in diagnosis and management have improved the outcomes and quality of life of patients with hereditary angioedema.

Topics: Bradykinin; Complement C1 Inhibitor Protein; Disease Progression; Factor XII; Hereditary Angioedema Types I and II; Humans; Kallikreins; Peptides; Quality of Life

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

Hereditary angioedema is characterized by severe, episodic edema of the subcutaneous and mucosal tissue. The disease carries significant morbidity and mortality due to involvement of the gastrointestinal tract and upper airway. Recent advances in the treatment of hereditary angioedema include new techniques used to isolate and purify human-derived C1 inhibitor, the production of a recombinant form of C1 inhibitor, and the development of drugs that target the kallikrein-kinin pathway. This paper reviews the mechanisms, efficacy, and adverse reactions associated with these medications.

Topics: Angioedemas, Hereditary; Bradykinin; Complement C1 Inhibitor Protein; Humans; Peptides

Hereditary angioedema (HAE) is a rare genetic disease defined by recurrent attacks of edema, causing a substantial burden for patients, with morbidity, mortality, and reduced quality of life. This burden is increased by delayed diagnosis, inappropriate treatment, and suboptimal follow-up and patient education. Several novel therapeutics have recently been approved or are currently under evaluation for prevention of HAE attacks.

Topics: Angioedemas, Hereditary; Bradykinin; Bradykinin B2 Receptor Antagonists; Complement C1 Inhibitor Protein; Humans; Kallikreins; Peptides; Recombinant Proteins

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

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

Hereditary angioedema (HAE) is a rare congenital disorder characterized by recurrent episodes of subcutaneous or submucosal edema. Laryngeal manifestations can be life-threatening. In the majority of cases, the disease can be adequately treated with an on-demand approach--in some cases, however, short- or long-term prophylaxis is indicated. Attenuated androgens used to be the drugs of choice, but they are associated with considerable side effects and no longer commercially available in the German-speaking countries of the EU. They are currently being replaced by more effective and more tolerable agents such C1-inhibitors, the kallikrein inhibitor ecallantide, and the B2 receptor antagonist icatibant, which have recently obtained market authorization. These new drugs have had a major impact, especially on the indications and procedures for long-term prophylaxis. According to the most recent international consensus papers and our own experience, self-administered C1-inhibitors are now the first option for long-term prophylactic therapy. The decision for prophylaxis should no longer be based on single parameters such as the frequency of attacks but on adequate overall disease control including quality of life. More drugs are currently being developed, which may lead to further changes in the treatment algorithms of HAE.

Topics: Androgens; Bradykinin; Bradykinin B2 Receptor Antagonists; Complement C1 Inhibitor Protein; Drug Monitoring; Evidence-Based Medicine; Hereditary Angioedema Types I and II; Humans; Peptides; Treatment Outcome

Hereditary angioedema (HAE) is a rare autosomal dominant disorder characterized by recurrent attacks of self-limiting tissue swelling. The management of HAE has transformed dramatically with recently approved therapies in the United States. However, there is lack of awareness among physicians about these new modalities. The aim of this review is to update the practicing physician about various therapeutic options available for HAE patients. An exhaustive literature search of PubMed and OVID was performed to develop this article. Management of HAE is traditionally classified into treatment of acute attacks or on-demand therapy, short-term (preprocedural) prophylaxis, and long-term prophylaxis. Newer therapies include C1 esterase inhibitor (C1-INH) and contact system modulators, namely, ecallantide and icatibant. Recombinant C1-INH, which is available in Europe, is awaiting approval in the United States. C1-INH concentrate is approved for prophylaxis as well as on-demand therapy while ecallantide and icatibant are approved for acute treatment only. Effective HAE management further includes patient education, reliable access to specific medications, and regular follow-up to monitor therapeutic response and safety.

Topics: Angioedemas, Hereditary; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Complement C1 Inhibitor Protein; Humans; Peptides; Practice Guidelines as Topic

Hereditary angioedema (HAE) due to C1 inhibitor (C1-INH) deficiency is a rare genetic disease characterized by recurrent swellings of the subcutaneous and submucosal tissues that can manifest as cutaneous edema, abdominal pain and laryngeal edema with airway obstruction. These symptoms have a significant impact on patients' quality of life. The reduction in C1-INH function leads to uncontrolled activation of the contact system and generation of bradykinin, the mediator of increased vascular permeability and edema formation. In the past, few treatment options were available; however, several new therapies with proven efficacy have recently become available to treat and prevent HAE attacks, such as plasma-derived and recombinant C1-INHs that replace the deficient protein, bradykinin receptor antagonist (icatibant) that blocks bradykinin activity and kallikrein inhibitor (ecallantide) that prevents bradykinin release. Such therapies can improve disease outcome. This article reviews the therapeutic management of HAE, which involves the treatment of acute attacks and prophylaxis.

Topics: Angioedemas, Hereditary; Bradykinin; Disease Management; Hereditary Angioedema Types I and II; Humans; Peptides; Treatment Outcome

Hereditary angioedema (HAE) is a rare type of angioedema caused by a quantitative or functional deficit of C1 inhibitor (C1 INH) that leads to excess production of bradykinin, which can result in acute localized swelling attacks in the skin or mucous membranes of the mouth, head and neck, extremities, gastrointestinal (GI) tract, genitals, trunk, and larynx. Angioedema in the respiratorytract maycause airway obstruction; severe abdominal pain, vomiting, or diarrhea may occur in the GI tract. Patients with HAE may be diagnosed and managed by HAE specialists or by primary care physicians depending on individual circumstances. Proper treatment requires differentiation from other forms of angioedema. Patients with HAE who are managed appropriately with medications that treat and prevent atttacks may have a lower risk of death from laryngeal edema and a better quality of life. Less frequent attacks may allow them to attend work, school, and leisure activities more regularlyand be free of the pain and disfigurement of HAE attacks moreoften.

Topics: Algorithms; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Chromosomes, Human, Pair 11; Complement C1 Inhibitor Protein; DNA Mutational Analysis; Hereditary Angioedema Types I and II; Humans; Peptides; Plasma

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

To review the pharmacology, pharmacokinetics, clinical trials, and safety of icatibant, a recently approved bradykinin B(2) receptor antagonist for treatment of acute attacks of hereditary angioedema (HAE).. Articles indexed in MEDLINE (1948-June 2012), International Pharmaceutical Abstracts (1970-May 2012), and Cumulative Index to Nursing and Allied Health Literature (1981-June 2012) were identified using the search terms icatibant, bradykinin B(2) receptor antagonist, and hereditary angioedema. Additional references were identified from the reference lists of the articles identified.. English-language articles were reviewed.. Icatibant was evaluated in 3 Phase 3 clinical trials and found to be a safe and effective option for treatment of acute HAE. Icatibant was compared to placebo in 2 clinical trials (FAST-1 and FAST-3) and to tranexamic acid in the FAST-2 trial. Patients receiving icatibant in FAST-1 did not experience a significant improvement in median time to clinically significant relief of the index symptom (p = 0.14), whereas patients receiving icatibant in FAST-3 experienced a significant improvement in median time to at least 50% reduction in symptom severity (p < 0.001). When icatibant was compared to tranexamic acid in FAST-2, the median time to clinically significant relief of the index symptom was shorter for patients receiving icatibant (p < 0.001). The most common adverse events associated with the administration of icatibant were injection-site reactions, which were mild to moderate and transient. These data suggest that icatibant is a safe and effective treatment for acute attacks of HAE. Although direct comparisons of recently approved alternatives for treatment of acute attacks are lacking, there are administration advantages of icatibant over other agents. Additionally, the cost of icatibant is comparable to that of the C1 esterase inhibitor Berinert and less expensive than ecallantide.. Available efficacy data support that icatibant should be considered a safe and effective treatment for acute attacks of HAE. Additionally, limited treatment options for this rare condition, ease of administration, and comparable cost profile support its consideration for formulary inclusion.

Topics: Angioedemas, Hereditary; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Bradykinin Receptor Antagonists; Clinical Trials, Phase III as Topic; Complement C1 Inhibitor Protein; Humans; Peptides; Tranexamic Acid

Hereditary angioedema (HAE) is a rare disorder generally caused by a deficit in the activity of C1-esterase inhibitor (C1-INH). Symptoms manifest as recurrent episodes of nonallergic, nonpruritic, and nonpitting edema. Attacks commonly occur on the extremities, trunk, genitalia, abdomen, or head and neck--the latter 2 locations are associated with the greatest morbidity and mortality. In the United States, there has been a considerable void in effective HAE treatments and emergency management guidelines. Clinical outcomes using agents such as fresh-frozen plasma, attenuated androgens (danazol), or plasmin inhibitors (aminocaproic acid) have not been ideal. Recent years have seen progress with US Food and Drug Administration (FDA) approval of several products for acute HAE treatment. Plasma concentrate of C1-INH has long been the treatment of choice in many parts of the world, and a pasteurized formula received FDA approval in October 2009 for treating attacks. Ecallantide, a plasma kallikrein inhibitor, and icatibant, a bradykinin receptor antagonist, were approved in December 2009 and August 2011, respectively, for treatment of acute attacks. A recombinant C1-INH product is in late development stages for treating acute attacks. These new treatments provide symptom relief within hours, dramatically shorten attack duration, and decrease mortality from airway compromise. For the first time, US physicians have rapid-acting and highly effective treatments for managing acute HAE attacks.

Topics: Angioedemas, Hereditary; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Complement C1 Inhibitor Protein; Complement Inactivating Agents; Emergency Treatment; Humans; Peptides; Practice Guidelines as Topic; United States

The 2 most commonly encountered primary immunodeficiency syndromes in adult practice are antibody deficiency disorders and hereditary angioedema.Immunologic therapy for these disorders has significantly improved patient management. Therapy with immunoglobulin leads to improvement in overall quality of life. With increasing survival rates and decreasing levels of life-threatening infections in patients with primary antibody deficiencies, disease complications are more commonly encountered. Treatment of these complications with monoclonal antibody therapy seems promising and is likely to increase in the future. More recently,several additional agents have become available, including novel drugs targeted at different elements of the disease process.

Topics: Adrenergic beta-Antagonists; Anemia, Hemolytic, Autoimmune; Angioedemas, Hereditary; Bradykinin; Complement C1 Inactivator Proteins; Complement C1 Inhibitor Protein; Cost-Benefit Analysis; Delayed Diagnosis; Disease Transmission, Infectious; Filtration; Granuloma; Home Infusion Therapy; Humans; Hypersensitivity, Delayed; Hypersensitivity, Immediate; Immunization, Passive; Immunoglobulin G; Immunoglobulins; Immunologic Deficiency Syndromes; Infections; Kallikreins; Nanotechnology; Peptides; Purpura, Thrombocytopenic, Idiopathic; Quality Control; Quality of Life; Recombinant Proteins; Self Administration; Technology, Pharmaceutical

The aim of treatment of hereditary angioedema (HAE) due to C1 esterase inhibitor deficiency (HAE-C1-INH) is either treating acute attacks or preventing attacks by using prophylactic treatment. For treating acute attacks, plasma-derived C1 inhibitor (C1-INH) concentrates, a bradykinin B2 receptor antagonist, and a recombinant human C1-INH are available in Europe. In the United States, a plasma-derived C1-INH concentrate, a bradykinin B2 receptor antagonist, and a plasma kallikrein inhibitor have been approved. Fresh frozen plasma is also available for treating acute attacks. Short-term prophylactic treatment focuses on C1-INH and attenuated androgens. Long-term prophylactic treatments include attenuated androgens such as danazol, stanozolol, and oxandrolone, antifibrinolytics, and a plasma-derived C1-INH concentrate. Plasma-derived C1-INH and a bradykinin B2 receptor antagonist are permitted for self-administration and home therapy. The number of management options has increased considerably within the last few years, thus helping to diminish the burden of HAE.

Topics: Angioedemas, Hereditary; Bradykinin; Complement C1 Inhibitor Protein; Danazol; Disease Management; Humans; Oxandrolone; Peptides; Plasma; Recombinant Proteins; Stanozolol

Hereditary angioedema (HAE) is a potentially life-threatening autosomal dominant disease characterized by recurrent episodes of oedema, commonly occurring in the skin, abdomen, and upper respiratory tract. After many years during which limited treatment options were available, a range of newer therapies with proven efficacy have been approved in Europe by the European Commission for the treatment of HAE attacks. However, due to differing legislation and financial restrictions, these treatment options are not available in all countries. Home therapy and self-administration of treatment are recommended in order to minimize the burden of disease upon the patient, with the ideal treatment option being effective, well-tolerated, and easy to prepare and administer. Recently, the Hereditary Angioedema International Working Group (HAWK) consensus recommended early, on-demand treatment for HAE. This article reviews the current treatment options available, and considers the need for treatment guidelines to recommend the appropriate therapy.

Topics: Airway Obstruction; Angioedemas, Hereditary; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Complement C1 Inhibitor Protein; Costs and Cost Analysis; Europe; Health Knowledge, Attitudes, Practice; Hospitalization; Humans; Insurance Coverage; Insurance, Pharmaceutical Services; Legislation, Drug; Peptides; Practice Guidelines as Topic; Practice Patterns, Physicians'; Self Administration

Hereditary Angioedema (HAE) is a rare disease characterized by recurrent, self-limiting episodes of swelling. New therapies have recently emerged and are now available; however, many physicians are not aware of the new medications, and their indications and contraindications.. To update allergists and primary care physicians on new advances in HAE therapies.. A PubMed literature search was used to develop this manuscript.. English language peer-reviewed angioedema articles were selected. High quality Phase II and III placebo-controlled clinical trials were reviewed and summarized.. Until 2008, therapy for HAE consisted of symptom relief with narcotics, hydration and fresh frozen plasma (FFP). Androgens and FFP are frequently used despite multiple, significant side effects. Newer therapies include C1-inhibitor--both human plasma derived and recombinant--as well as contact system modulators such as ecallantide and icatibant. All of these products can be used for treatment of acute attacks of HAE, and C1-inhibitors can also be used for prophylaxis.. New, disease-specific therapies have recently emerged which are more efficacious, are proven to work by placebo-controlled studies, have minimal adverse effects, and can be utilized for the treatment of HAE.

Topics: Androgens; Angioedemas, Hereditary; Bradykinin; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Complement C1 Inhibitor Protein; Databases, Bibliographic; Drug Administration Schedule; Humans; Narcotics; Peptides; Placebos; Plasma; Recombinant Proteins

To review and update the management and understanding of hereditary angioedema (HAE), while integrating insights into pediatric subtleties that exist in practice.. Major advances have recently been made in HAE treatment. Ecallantide (a kallikrein inhibitor approved for use in the United States in December 2009) and icatibant (a selective bradykinin B2 receptor antagonist approved for use in the United States in August 2011) represent novel subcutaneous therapies for acute HAE exacerbations. Recombinant human C1 esterase inhibitor (C1INH) serves as a promising future alternative to current mainstay acute and prophylactic treatment with plasma-derived C1INH. Recent guidelines have outlined new algorithms for short-term and long-term prophylaxis against HAE exacerbations.. The evolving standard of care for HAE management involves not only treatment of acute exacerbations but also individualized patient preference-sensitive short-term and long-term prophylaxis. Updated international consensus guidelines provide useful protocols, whereas recent clinical reviews have raised awareness of HAE. Further advances will likely focus on improving patient access to convenient acute and prophylactic treatment with C1INH.

Topics: Adolescent; Algorithms; Angioedemas, Hereditary; Bradykinin; Bradykinin Receptor Antagonists; Child; Child, Preschool; Complement C1 Inhibitor Protein; Evidence-Based Medicine; Female; Humans; Infant; Kallikreins; Male; Peptides; Practice Guidelines as Topic; Treatment Outcome; United States

Hereditary angioedema (HAE) is characterized by acute attacks of edema with multiple localizations, the laryngeal angioedema being the most potentially lethal. In HAE, C1-INH impairments cause episodic increase in kallikrein activity leading to attacks of angioedema. Several therapies have recently become available to treat or to prevent HAE attacks, and others are under evaluation for this indication. Plasma-derived C1-INH, bradykinin receptor antagonists (icatibant), kallikrein inhibitors (ecallantide), or recombinant C1-INH is authorized on the market for HAE attack therapy or prophylaxis. Some of these compounds can be used exclusively to treat HAE attacks, whereas others can also be used as prophylactic therapies. Such therapies, although not available worldwide, can improve disease outcome due to their different mechanisms of action.

Topics: Angioedemas, Hereditary; Bradykinin; Bradykinin Receptor Antagonists; Clinical Trials as Topic; Complement C1 Inhibitor Protein; Disease Progression; Humans; Kallikreins; Peptides; Recombinant Proteins

Hereditary angioedema is an episodic swelling disorder with autosomal dominant inheritance. Attacks are characterized by nonpitting edema of external or mucosal body surfaces. Patients often present with swelling of the extremities, abdominal pain, and swelling of the mouth and throat, which can at times lead to asphyxiation. The disease is caused by a mutation in the gene encoding the complement C1-inhibitor protein, which leads to unregulated production of bradykinin. Long-term therapy has depended on the use of attenuated androgens or plasmin inhibitors but in the US there was, until recently, no specific therapy for acute attacks. As well, many patients with hereditary angioedema in the US were either not adequately controlled on previously available therapies or required doses of medications that exposed them to the risk of serious adverse effects. Five companies have completed or are currently conducting phase III clinical trials in the development of specific therapies to terminate acute attacks or to be used as prophylaxis. These products are based on either replacement therapy with purified plasma-derived or recombinant C1-inhibitor, or inhibition of the kinin-generating pathways with a recombinant plasma kallikrein inhibitor or bradykinin type 2 receptor antagonist. Published studies thus far suggest that all of these products are likely to be effective. These new therapies will likely lead to a totally new approach in treating hereditary angioedema.

Topics: Acute Disease; Adrenergic beta-Antagonists; Androgens; Antifibrinolytic Agents; Bradykinin; Bradykinin Receptor Antagonists; Complement C1 Inhibitor Protein; Danazol; Hereditary Angioedema Type III; Hereditary Angioedema Types I and II; Hormone Antagonists; Humans; Kallikreins; Peptides; Tranexamic Acid

To determine when newer agents, such as C1 esterase inhibitor protein (C1-INH), should be considered as prophylaxis to decrease hereditary angioedema (HAE) attacks as an alternative to androgens, which have significant adverse events.. A literature review (PubMed, Google, and Ovid), guideline review, expert panel meeting, and group discussion were performed to decide when prophylaxis is indicated.. Articles addressing HAE therapy published in the peer-reviewed literature were selected.. The retrieved studies demonstrate that C1-INH is effective and that the half-life makes it attractive for prophylactic use. The short half-lives of ecallantide, icatibant, and recombinant human C1-INH limit their use as prophylactic agents. Patients with severe anxiety, more than 1 attack per month, rapid progression of attacks, limited access to health care, more than 10 days lost from work or school per year, previous laryngeal swelling, more than 3 emergency department visits per year, more than 1 hospitalization per year, previous intubation, previous intensive care unit care, significant compromise in quality of life, or narcotic dependency should be considered for androgen or C1-INH prophylaxis therapy.. Patients with HAE with frequent attacks, severe attacks, past laryngeal attacks, excessive loss of work or school, significant anxiety, and poor quality of life should be considered for C1-INH prophylaxis, especially those who fail, are intolerant of, have adverse reactions to, or are not candidates for androgen therapy.

Topics: Androgens; Angioedemas, Hereditary; Bradykinin; Bradykinin Receptor Antagonists; Clinical Trials as Topic; Complement C1 Inactivator Proteins; Complement C1 Inhibitor Protein; Humans; Kallikreins; Mortality; Peptides

Hereditary angioedema is a rare genetic disorder, manifested by recurrent edema leading to disfigurement, organ dysfunction and life-threatening respiratory impairment that may become fatal. The hallmark of HAE is C1 esterase inhibitor deficiency, but recent evidence points at bradykinin as the main mediator that causes hyperpermeability of small vasculature, leading to accumulation of edema fluid. Current therapeutic options for HAE are limited, and consist of drugs, replacement therapy, and supportive treatment. In view of many disadvantages of the current therapeutic modalities, new approaches to the treatment of HAE are now being offered. This review summarizes our experience with a new line of medications developed for the treatment of acute exacerbations and prophylaxis of HAE--icatibant: bradykinin receptor antagonist, ecallantide: kallikrein inhibitor, and two C1 INH preparations: Berinert-P, human plasma-derived concentrate, and Rhucin: novel recombinant C1-INH produced in transgenic rabbits. Preliminary results of these studies are encouraging and may bring new hope to the patients with this distressing condition. The exact number of HAE patients in Israel is unknown and because patients are treated individually and comprehensive laboratory assessment is partial, many cases might be missed or not treated according to accepted guidelines. We offer a new specialty center for HAE patients, addressing the medical and psychosocial needs of patients and their families.

Topics: Abdominal Pain; Angioedemas, Hereditary; Bradykinin; Bradykinin Receptor Antagonists; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Kallikreins; Male; Multicenter Studies as Topic; Nausea; Peptides; Treatment Outcome

To provide an overview on the current status of emerging therapies for hereditary angioedema (HAE) in the United States.. Summary statements were obtained from each pharmaceutical company regarding their agent.. Each agent is undergoing or has completed phase 3, double-blind, placebo-controlled trials.. Berinert P, a purified, virus-inactivated, human plasma-derived C1 inhibitor (C1-INH) concentrate, is being investigated in 2 international, multicenter, prospective trials. Experience with this agent in Europe and Canada indicates it is effective and safe. Cinryze is a nanofiltered C1-INH replacement therapy demonstrated to be effective and safe in acute and prophylactic arms of a phase 3, double-blind, placebo-controlled study. Rhucin, a recombinant human C1-INH replacement therapy from transgenic rabbits, has been shown to be effective and safe in phase 2 and phase 2/3 studies, with an additional phase 3 study ongoing. DX-88 or ecallantide, a potent and specific inhibitor of plasma kallikrein, achieved all primary and secondary efficacy end points in a placebo-controlled, double-blind, phase 3 study, with a second phase 3 study ongoing. Icatibant, a potent and specific peptidomimetic bradykinin 2 receptor antagonist, was studied in 2 phase 3 trials: FAST 1 (For Angioedema Subcutaneous Treatment) did not achieve statistical significance for the primary end point but did so for secondary end points, whereas FAST 2 achieved statistical significance for primary and secondary end points.. The future treatment of HAE in the United States appears promising based on progress being made in drug development for this orphan disease.

Topics: Adrenergic beta-Antagonists; Angioedemas, Hereditary; Animals; Animals, Genetically Modified; Attention; Bradykinin; Clinical Trials, Phase III as Topic; Complement C1 Inhibitor Protein; Controlled Clinical Trials as Topic; Filtration; Global Health; Humans; Kallikreins; Nanoparticles; Peptides; Rabbits; Recombinant Proteins; Treatment Outcome

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

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

Hereditary angioedema (HAE) is a rare C1-inhibitor (C1-INH) deficiency disease. Low levels of functional C1-INH can lead to recurrent attacks of severe swelling occurring in areas such as the limbs, face, gastrointestinal tract, and throat. These attacks are both painful and disabling and, if not treated promptly and effectively, can result in hospitalization or death. Agents targeting the specific physiologic pathway of HAE attacks can offer improved outcomes with limited side effects compared with nonspecific therapies. However, these treatments display varying efficacy in HAE patients, including the need to redose or seek additional care if the treatment does not resolve symptoms effectively.. To analyze the expected cost and utility per HAE attack when treated on-demand with HAE therapies indicated for the treatment of acute attacks.. A decision-tree model was developed using TreeAge Pro software. Four on-demand HAE treatments were included: ecallantide, icatibant, plasma-derived (pd)C1-INH, and recombinant human (rh)C1-INH. The model uses probabilities for redosing, self-administration versus health care provider administration, and risk of hospitalization. Costs within the model consisted of the HAE treatments and associated health care system expenses. Nonattack baseline utility and attack utility were implemented for effectiveness calculations; time to attack resolution was considered as well. Effectiveness and overall costs per attack were calculated and used to estimate cost per quality-adjusted life-year (QALY). Variability and ranges in cost-effectiveness were determined using probabilistic sensitivity analyses. Finally, a budget impact model for a health plan with 1 million covered lives was also developed.. The base case model outputs show costs and calculated effectiveness per attack at $12,905 and 0.806 for rhC1-INH, $14,806 and 0.765 for icatibant, $14,668 and 0.769 for pdC1-INH, and $21,068 and 0.792 for ecallantide, respectively. Cost per QALY was calculated using 26.9 attacks per person-year, leading to results of $420,941 for rhC1-INH, $488,349 for icatibant, $483,892 for pdC1-INH, and $689,773 for ecallantide. Sensitivity analyses demonstrate that redose rates (from 3% for rhC1-INH to 44% for icatibant) are a primary driver of variability in cost-effectiveness. Annual health plan costs from the budget impact model are calculated as $6.94 million for rhC1-INH, $7.97 million for icatibant, $7.90 million for pdC1-INH, and $11.33 million for ecallantide.. Accounting for patient well-being and additional cost components of HAE attacks generates a better estimation of cost-effectiveness than drug cost alone. Results from this model indicate that rhC1-INH is the dominant treatment option with lower expected costs and higher calculated effectiveness than comparators. Further analyses reinforce the idea that low redose rates contribute to improved cost-effectiveness.. Funding support was contributed by Pharming Healthcare. Relan and Adams are employed by Pharming Healthcare. Tyson and Magar are employed by AHRM, which received fees to perform the analysis and develop the manuscript. Bernstein reports grants, personal fees, and nonfinancial support from Shire, CSL Behring, and Pharming Healthcare; grants and personal fees from Biocryst; and nonfinancial support from HAEA, unrelated to this study.

Topics: Angioedemas, Hereditary; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Complement C1 Inhibitor Protein; Cost-Benefit Analysis; Decision Trees; Humans; Models, Economic; Peptides; Quality-Adjusted Life Years; Recombinant Proteins; Treatment Outcome

Hereditary autoinflammatory diseases are caused by gene mutations of the innate immune pathway, e.g. nucleotide receptor protein 3 (NLRP3). Here, we report a four-generation family with cold-induced urticarial rash, arthralgia, chills, headache and malaise associated with an autosomal-dominant inheritance. Genetic studies identify a substitution mutation in gene F12 (T859A, resulting in p.W268R) which encodes coagulation factor XII (FXII). Functional analysis reveals enhanced autocatalytic cleavage of the mutated protein and spontaneous FXII activation in patient plasma and in supernatant of transfected HEK293 cells expressing recombinant W268R-mutated proteins. Furthermore, we observe reduced plasma prekallikrein, cleaved high molecular weight kininogen and elevated plasma bradykinin. Neutrophils are identified as a local source of FXII. Interleukin-1β (IL-1β) is upregulated in lesional skin and mononuclear donor cells exposed to recombinant mutant proteins. Treatment with icatibant (bradykinin-B2-antagonist) or anakinra (interleukin-1-antagonist) reduces disease activity in patients. In conclusion, our findings provide a link between contact system activation and cytokine-mediated inflammation.

Topics: Adult; Blood Coagulation; Bradykinin; Cold Temperature; Factor XII; Female; HEK293 Cells; Hereditary Autoinflammatory Diseases; Humans; Inflammation Mediators; Interleukin 1 Receptor Antagonist Protein; Interleukin-1beta; Kininogen, High-Molecular-Weight; Male; Middle Aged; Mutation; Neutrophils; NLR Family, Pyrin Domain-Containing 3 Protein; Pedigree; Phenotype; Plasma Kallikrein; Recombinant Proteins; Skin

In this paper, we raise the hypothesis that Methylene Blue may be a treatment option for Corona Virus Disease of 2019 specially when combined with Non Steroid Anti-Inflammatory Drugs. In previous publications including ours, the role of kininogen system has been postulated. A correlation between clinical findings of the disease and this mechanism has been drawn to denote a pivotal role of kininogen-kallikrein system in pathophysiology of the disease. Therein the possible role of Icatibant, Ecallantide and Aprotinin in the treatment of this disease has been raised. Here we want to emphasize on an important post-receptor mechanism of bradykinin that is Nitric Oxide. We came to this aim because we found out how access to these novel treatment nominees may be expensive and unaffordable. For this reason we are focusing on possible role of an old albeit "mysterious" drug namely Methylene Blue. This medication may abort effects of Bradykinin by inhibition of Nitric Oxide synthase inhibitor and promote oxygen saturation while it is inexpensive and ubiquitously accessible. Clinical studies cannot be over emphasized.

Topics: Angiotensin-Converting Enzyme 2; Aprotinin; Bradykinin; COVID-19 Drug Treatment; Cytokines; Humans; Kininogens; Methylene Blue; Models, Theoretical; Nitric Oxide; Nitric Oxide Synthase; Peptides; Renin-Angiotensin System

Ever-expanding armamentarium of treatments for hereditary angioedema (HAE) are associated with various adverse effects, issues with vascular access, or lack of self-administration.. To understand patients' impressions and confidence in their past and present treatments, and identifying adverse events while also directly asking patients to reveal their hope for the future of HAE management and treatments.. After institutional review board approval, all subjects with laboratory-confirmed HAE were mailed a survey that they completed and returned to the researchers, and data were collected and entered into a secure online web application for surveys. Medication confidence data were summarized and expressed as means, medians, standard deviations, and quartiles by using a 5-point Likert scale. Analyses were performed by using statistical software.. Of 150 surveys, 38 (25.3%) were completed. Among 36 subjects, 27 (75.0%) were female subjects, and the mean age was 50.1 years. Cinryze and Berinert (both C1-esterase inhibitors) had the highest median scores (5.0) for patient confidence, followed by ecallantide (4.5), icatibant (4.0), and androgens (2.0). For Cinryze, 64.3% selected it as the most effective and 57.1% tolerated it best. For Berinert, 50% of the subjects found it to be most effective and 59.1% tolerated it best. Some subjects listed androgens as most effective (33.3%) or best tolerated (16.7%), and many reported that this class caused the most adverse effects (44.4%). Among those who answered, 50% preferred a noninvasive method of administration, such as oral (24%), subcutaneous (18%), or not intravenous (8%) routes.. Determining patient predilections and the reasoning behind them can be valuable for determining specific therapies to achieve each individual's personal goals.

Topics: Adolescent; Adult; Androgens; Angioedemas, Hereditary; Bradykinin; Drug Administration Routes; Female; Forecasting; Humans; Male; Middle Aged; Patient Satisfaction; Peptides; Surveys and Questionnaires

Real-world data on usage and associated outcomes with hereditary angioedema (HAE)-specific medications introduced to the United States (US) market since 2009 are very limited. The purpose of this retrospective study was to evaluate real-world treatment patterns of HAE-specific medications in the US and to assess their impact on healthcare resource utilization (HCRU). This analysis used IMS PharMetrics PlusTM database records (2006-2014) of patients with HAE, ≥1 insurance claim for an HAE-specific medication, and continuous insurance enrollment for ≥3 months following the first HAE prescription claim.. Of 631 total patients, 434 (68.8%) reported C1-INH(IV) use; 396 (62.8%) reported using ecallantide and/or icatibant. There were 306 episodes of prophylactic use of C1-INH(IV) (defined by continuous refills averaging ≥1500 IU/week for ≥13 weeks) in 155 patients; use of ≥1 on-demand rescue medication was implicated during 53% (163/306) of those episodes. Sixty-eight (20.2%) of 336 C1-INH(IV) users eligible for the HCRU analysis were hospitalized at least once, and 191 (56.8%) visited the emergency department (ED). Eighteen patients (5.4%) had a central venous access device (CVAD); of these, 5 (27.7%) required hospitalization and 14 (77.7%) had an ED visit. The adjusted relative risk of hospitalization and/or ED visits for patients with a CVAD was 2.6 (95% CI: 0.17, 39.23) compared to C1-INH(IV) users without a CVAD.. Despite widespread availability of modern HAE medications in the US, we identified a subset of patients requiring long-term prophylaxis who continue to be burdened by frequent rescue medication usage and/or complications related to the use of CVADs for intravenous HAE medication.

Topics: Angioedemas, Hereditary; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Bradykinin B2 Receptor Antagonists; Complement C1 Inhibitor Protein; Complement Inactivating Agents; Humans; Patient Acceptance of Health Care; Peptides; Retrospective Studies; United States

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

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

Hereditary angioedema (HAE) is a potentially life-threatening inherited disease characterized by attacks of skin swelling, severe abdominal pain, and upper airway swelling. Attacks typically begin in childhood, but the appropriate diagnosis is often missed. Attacks do not respond to epinephrine, antihistamines, or glucocorticoids. Recently, many effective drugs have been approved for treatment of adults with HAE, and the Medical Advisory Board of the HAE Patient's Association has developed and reported treatment recommendations for adults. Only 1 medication is approved for treatment of children <12 years of age, and there are no reported consensus recommendations for treatment of young children in the United States. The 11-member Medical Advisory Board, with extensive experience in the treatment of children, in concert with the leaders of the HAE Patient's Association, has developed these consensus recommendations to help in recognition, diagnosis, treatment of attacks, and prophylaxis of children with HAE.

Topics: Adolescent; Angioedemas, Hereditary; Anti-Inflammatory Agents, Non-Steroidal; Antifibrinolytic Agents; Bradykinin; Child; Complement C1 Inactivator Proteins; Complement C1 Inhibitor Protein; Danazol; Genetic Testing; Humans; Patient Care Team; Patient Education as Topic; Peptides; Recombinant Proteins; Tranexamic Acid

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

Hereditary angioedema (HAE) is a rare genetic syndrome caused by a deficiency in functional C1 inhibitor that results in recurrent episodes of nonpruritic swelling of the hands, feet, arms, legs, trunk, face, genitalia, bowels, and larynx beginning in childhood or adolescence and continuing throughout the patient's lifetime. Treatment for acute HAE attacks in the United States has been transformed by new therapies that inhibit the underlying mechanisms of angioedema- notably ecallantide, a potent and specific inhibitor of plasma kallikrein, and icatibant, a selective bradykinin receptor antagonist. These treatments, combined with safer formulations of plasma-derived C1 esterase inhibitor concentrate for HAE prophylaxis and acute treatment, have greatly improved the quality of life for people with HAE, many of whom can now lead fairly normal lives. This article reviews the current therapeutic landscape for HAE, including treatment for acute angioedema attacks, short- and long-term HAE prophylaxis, and home-based therapy.

Topics: Adolescent; Angioedemas, Hereditary; Bradykinin; Child; Clinical Trials as Topic; Cost of Illness; Female; Humans; Male; Peptides; Pregnancy; Secondary Prevention; Treatment Outcome; United States; Young Adult

Angioedema owing to hereditary deficiency of C1 inhibitor (HAE) is a rare, life-threatening, disabling disease. In the last 2 years, the results of well-designed and controlled trials with existing and new therapies for this condition have been published, and new treatments reached the market. Current guidelines for the treatment for HAE were released before the new trials and before the new treatments became available and were essentially based on observational studies and expert opinion. To provide evidence-based HAE treatment guidelines supported by the new studies, a conference was held in Gargnano del Garda, Italy, from September 26 to 29, 2010. The meeting hosted 58 experienced HAE expert physicians, representatives of pharmaceutical companies and representatives of HAE patients' associations. Here, we report the topics discussed during the meeting and evidence-based consensus about management approaches for HAE in adult/adolescent patients.

Topics: Angioedemas, Hereditary; Bradykinin; Bradykinin Receptor Antagonists; Complement C1 Inactivator Proteins; Complement C1 Inhibitor Protein; Humans; Kallikreins; Peptides

Hereditary angioedema (HAE) is a rare, potentially life-threatening autosomal dominant disease characterized by recurrent angioedema attacks that affect the skin, gastrointestinal tract, and airway, including the larynx. Pharmacologic developments in HAE treatment have culminated in the recent introduction of 4 new HAE-specific therapies in the United States.. In light of these new therapeutic options, this commentary outlines historical US HAE therapy choices, discusses the potential effect of the 4 recently approved HAE treatments, and considers strategies for optimizing their use in line with international treatment recommendations.. Treatment options for HAE in the United States have been limited to attenuated androgens and antifibrinolytic agents for long-term prophylaxis and FFP and supportive therapy for the management of acute attacks. The 4 new therapies that have recently become available (ie, 2 plasma-derived C1 esterase inhibitor (C1-INH) concentrates, the kallikrein inhibitor ecallantide, and the bradykinin β(2)-antagonist icatibant) have provided an opportunity to change routine HAE treatment. In 2009, despite the availability of 2 of the new treatments (ie, the plasma-derived C1-INH concentrates), a large survey of US physicians suggested that wide variability still existed in the treatment of patients with HAE. Since this survey was undertaken, clinical experience with all 4 new treatments has increased significantly, and because 3 of these agents (ie, 2 plasma-derived C1-INH concentrates and icatibant) can be self-administered by trained patients, physicians can now provide individualized care that is proven effective and more aligned with international guidance.

Topics: Angioedemas, Hereditary; Bradykinin; Bradykinin B2 Receptor Antagonists; Complement C1 Inhibitor Protein; Disease Management; Humans; Kallikreins; Peptides; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; United States

Hereditary angioedema due to C1 inhibitor (C1 esterase inhibitor) deficiency (types I and II HAE-C1-INH) is a rare disease that usually presents during childhood or adolescence with intermittent episodes of potentially life-threatening angioedema. Diagnosis as early as possible is important to avoid ineffective therapies and to properly treat swelling attacks. At a consensus meeting in June 2011, pediatricians and dermatologists from Germany, Austria, and Switzerland reviewed the currently available literature, including published international consensus recommendations for HAE therapy across all age groups. Published recommendations cannot be unconditionally adopted for pediatric patients in German-speaking countries given the current approval status of HAE drugs. This article provides an overview and discusses drugs available for HAE therapy, their approval status, and study results obtained in adult and pediatric patients. Recommendations for developing appropriate treatment strategies in the management of HAE in pediatric patients in German-speaking countries are provided.Conclusion Currently, plasma-derived C1 inhibitor concentrate is considered the best available option for the treatment of acute HAE-C1-INH attacks in pediatric patients in German-speaking countries, as well as for short-term and long-term prophylaxis.

Topics: Adolescent; Adult; Androgens; Anti-Inflammatory Agents, Non-Steroidal; Antifibrinolytic Agents; Austria; Bradykinin; Child; Complement C1 Inactivator Proteins; Complement C1 Inhibitor Protein; Complement Inactivating Agents; Disease Progression; Germany; Hereditary Angioedema Types I and II; Humans; Peptides; Recombinant Proteins; Switzerland

Topics: Adrenergic beta-Antagonists; Bradykinin; Complement C1 Inactivator Proteins; Complement C1 Inhibitor Protein; Disease Progression; Hereditary Angioedema Types I and II; Humans; Peptides; Recombinant Proteins; Spain

Hereditary angio-oedema (HAE) is a rare genetic disease caused by deficiency of complement C1 inhibitor. It is characterised by recurrent episodes of subcutaneous or submucosal oedema typically involving the extremities, bowel, face or larynx. Within the latest years it has become evident that the active mediator of HAE attacks is an increased level of bradykinin and various new treatment modalities have been developed. The aim of this paper is to give an update from the Danish HAE Comprehensive Care Centre on current treatment possibilities and address some of the challenges when diagnosing HAE.

Topics: Adult; Angioedemas, Hereditary; Bradykinin; Bradykinin B2 Receptor Antagonists; Complement C1 Inactivator Proteins; Complement C1 Inhibitor Protein; Complement Inactivating Agents; Diagnosis, Differential; Erythema; Female; Humans; Kallikreins; Laryngeal Edema; Peptides; Receptor, Bradykinin B2; Recombinant Proteins

Topics: Angioedemas, Hereditary; Bradykinin; Bradykinin B2 Receptor Antagonists; Complement C1 Inhibitor Protein; Complement Inactivating Agents; Humans; Kallikreins; Peptides; Self Administration

Topics: Acute Disease; Angioedemas, Hereditary; Bradykinin; Bradykinin B2 Receptor Antagonists; Complement C1 Inhibitor Protein; Complement Inactivating Agents; Humans; Kallikreins; Peptides

Hereditary angioedema (HAE) is an autosomal dominant disease associated with episodic attacks of nonpitting edema that may affect any external or mucosal body surface. Attacks most often affect the extremities, causing local swelling, the GI tract, leading to severe abdominal pain, and the mouth and throat, at times causing asphyxiation. Most patients with HAE have low levels of the plasma serine protease inhibitor C1 inhibitor. The edema in these patients is caused by unregulated generation of bradykinin. Effective chronic therapy of patients with impeded androgens or plasmin inhibitors has been available for decades, but in the United States, we do not have therapy for acute attacks. Five companies have completed or are in the process of conducting phase 3 clinical trials, double-blind, placebo-controlled studies of products designed to terminate acute attacks or to be used in prophylaxis. Two companies, Lev Pharmaceuticals and CSL Behring, have preparations of C1 inhibitor purified from plasma that have been used in Europe for decades (trade names Cinryze and Berinert P, respectively). One company, Pharming, has developed a recombinant C1 inhibitor preparation. One company, Dyax, is testing a kallikrein inhibitor (ecallantide), and one company, Jerini, is completing testing of a bradykinin type 2 receptor antagonist (Icatibant). Although little has been published thus far, all of these products may prove effective. It is likely that HAE treatment will change dramatically within the next few years.

Topics: Angioedemas, Hereditary; Bradykinin; Bradykinin Receptor Antagonists; Clinical Trials, Phase III as Topic; Complement C1 Inhibitor Protein; Controlled Clinical Trials as Topic; Double-Blind Method; Humans; Kallikreins; Peptides; Recombinant Proteins; United States

1 Kinin B(2) receptor antagonists or tissue kallikrein (t-KK) inhibitors prevent oedema formation and associated sequelae in caerulein-induced pancreatitis in the rat. We have now further investigated the mechanism of kinin generation in the pancreas. 2 Kinins were elevated in the pancreatic tissue already before oedema formation became manifest. Peak values (421+/-59 pmol g(-1) dry wt) were reached at 45 min and remained elevated for at least 2 h; a second increase was observed at 24 h. Pretreatment with the B(2) receptor antagonist icatibant abolished kinin formation, while post-treatment was ineffective. 3 Total kininogen levels were very low in the pancreas of controls, but increased 75-fold during acute pancreatitis. This increase was absent in rats that were pretreated with icatibant. 4 During pancreatitis, t-KK-like and plasma kallikrein (p-KK)-like activity in the pancreas, as well as trypsinogen activation peptide (TAP) increased significantly. Icatibant pretreatment further augmented t-KK about 100-fold, while p-KK was significantly attenuated; TAP levels remained unaffected. 5 Endogenous protease inhibitors (alpha(1)-antitrypsin, alpha(2)-macroglobulin) were low in normal tissues, but increased 45- and four-fold, respectively, during pancreatitis. This increase was abolished when oedema formation was prevented by icatibant. 6 In summary, oedema formation is initiated by t-KK; the ensuing plasma protein extravasation supplies further kininogen and active p-KK to the tissue. Concomitantly, endogenous protease inhibitors in the oedema fluid inhibit up to 99% of active t-KK. Our data thus suggest a complex interaction between kinin action and kinin generation involving positive and negative feedback actions of the inflammatory oedema.

Topics: Acute Disease; alpha 1-Antitrypsin; alpha-Macroglobulins; Animals; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Ceruletide; Edema; Enzyme Activation; Female; Kininogens; Kinins; Pancreas; Pancreatitis; Plasma Kallikrein; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Serine Proteinase Inhibitors; Tissue Kallikreins; Trypsinogen