Medical Literature - 2006

Ecallantide (Dyax/Genzyme)

Lehmann A 3/2006 Expert Opinion on Biological Therapy

Ecallantide is one of a series of small-protein kallikrein inhibitors, identified through Dyax Corp’s phage display technology, that is being developed by Dyax and Genzyme as a potential subcutaneous treatment for hereditary angioedema (HAE). Dyax is also independently developing ecallantide for the reduction of peri-operative blood loss during cardiopulmonary bypass surgery. The company had expected to begin phase II clinical studies in coronary bypass graft patients in the first half of 2005; however, by October 2005, these trials had been delayed until partnership negotiations for the program were completed. A pivotal, phase III clinical trial of ecallantide in HAE began in December 2005.


Not available online.

Evaluation and management of angioedema of the head and neck

Bas M, Hoffmann TK, Kojda G 7/2006 Current Opinion in Otolaryngology & Head & Neck Surgery

PURPOSE OF REVIEW: Sudden occurrence of subcutaneous or submucosal swelling, the so-called angioedema, is an established and potentially life-threatening condition. Several forms of angioedema show a great variety of tissue localizations and different underlying mechanisms such as genetic mutations, allergic reactions and nonallergic reactions exist. Unfortunately, angioedema is often unrecognized and/or incorrectly treated. To change this situation, a better understanding of angioedema and possible therapeutic approaches appears necessary.

RECENT FINDINGS: Recent investigations have shed new light on the pathomechanism of nonallergic drug-induced angioedema and new therapeutic options targeting the kallikrein-kinin system have become available for patients in clinical trials. Furthermore, extensive clinical evaluations of commonly used inhibitors of the renin-angiotensin system have provided reliable data on the incidence of angioedema induced by these drugs. Accordingly, several thousand patients worldwide experience severe fatal attacks although timely medical care would have saved their lives.

SUMMARY: Current data suggest that the nonapetide bradykinin plays a crucial role in the pathogenesis of most forms of nonallergic angioedema, while histamine acts as the main biogenic mediator in allergic angioedema. Thus, correct diagnosis is crucial for effective treatment. Standard antiallergic drugs such as glucocorticoids and antihistamines are most probably ineffective in nonallergic angioedema forms. [References: 48].


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Hereditary angioedema

Sachse MM, Khachemoune A, Guldbakke KK, Kirschfink M 10/2006 Journal of Drugs in Dermatology: JDD

Hereditary angioedema (HAE) is a rare autosomal dominant disorder caused by a C1-inhibitor deficiency. It is characterized by potentially life-threatening recurrent episodes of angioedema of the skin and mucosa. Several recent studies have further elucidated the immunology of HAE implicating bradykinin, the key mediator of the contact system. This article reviews the pathophysiology, subtypes, and clinical features of HAE. Therapeutic approaches for various clinical situations (emergency and prophylactic regimens) are also discussed. [References: 48].


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Hereditary angioedema: causes, manifestations and treatment

Longhurst HJ, Bork K 12/2006 Br.J.Hosp.Med.


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Hereditary angioedema: the clinical syndrome and its management in the United States

Frank MM 11/2006 Annals of Allergy, Asthma, & Immunology

There have been important breakthroughs in the understanding and treatment of hereditary angioedema (HAE). An associated abnormality of the serum protein C1 inhibitor led to purified protein use to end attacks. Consideration of the endocrine functions led to rediscovery of impeded androgen use in disease prophylaxis. Considerations of pathophysiology led to introduction of epsilon aminocaproic and tranexemic acids in prophylaxis and to a resurgence in trials of new therapeutic agents. We have gone from a situation where it was not uncommon for patients to have a severe attack sometime in their lives that led to airway compromise and possible death to a situation where death from disease is highly unusual. Thus HAE is in many ways a success story of modern medicine. [References: 50].


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Novel pharmacotherapy of acute hereditary angioedema with bradykinin B2-receptor antagonist icatibant

Bas M, Bier H, Greve J, Kojda G, Hoffmann TK 12/2006 Allergy


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Novel therapies for hereditary angioedema

Zuraw BL 11/2006 N.Engl.J.Med.

Advances in our understanding of the molecular mechanisms underlying hereditary angioedema (HAE) have led to the development of new treatment modalities. Five new drugs for the treatment of HAE are currently undergoing clinical testing in the United States. These novel therapeutics can be divided into two groups: drugs that replace C1 inhibitor (C1INH) functional activity and drugs that abrogate the bradykinin-mediated increase in vascular permeability associated with HAE attacks. The first group includes two plasma-derived C1INH concentrates as well as a recombinant transgenic human C1INH protein, and the second group includes an engineered plasma kallikrein inhibitor as well as a B2 bradykinin receptor antagonist. This article reviews the rationale, development, and potential use of these novel therapeutics. [References: 64].


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Symptoms, course, and complications of abdominal attacks in hereditary angioedema due to C1 inhibitor deficiency

Bork K, Staubach P, Eckardt AJ, Hardt J 3/2006 The American Journal of Gastroenterologyy (Am.J.Gastroenterol.)

OBJECTIVES: Recurrent abdominal attacks belong to the cardinal and most distressing symptoms of hereditary angioedema (HAE) due to C1 inhibitor deficiency. They are characterized by crampy pain, but may include vomiting, diarrhea, and other features. Detailed clinical data about the symptoms and course of abdominal attacks have not been reported.

METHODS: We retrospectively observed a total of 33,671 abdominal attacks in 153 patients with HAE including a prospectively examined subgroup of 23 patients. Symptoms, course, frequency of attacks, and complications were analyzed.

RESULTS: The relation of mild, moderate, and severe attacks was 1:1.4:5.6 in the prospective part of the study. Extra-abdominal symptoms preceded the abdominal symptoms. The mean maximal pain score was 8.4 (range 1-10). Vomiting occurred in 73% (24,696) and diarrhea in 41% (13,682) of the attacks. Circulatory collapse accompanied 4.4% (1,468) of the attacks, with loss of consciousness (LOC) occurring in 2.2% (739). Nine patients could clearly distinguish two types of abdominal attacks: vomiting and diarrhea. Rare complications included tetany, hemorrhagic stools, and intussusception of the colon. In 28% (43) of the patients, recurrent abdominal attacks had started before the characteristic swelling of the skin had ever occurred. A model is proposed to classify the severity of the attacks and to describe the clinical course.

CONCLUSIONS: Abdominal attacks in HAE constitute a more disabling and complex syndrome than previously assumed. Our results add to the understanding of symptoms and course of HAE and may aid in the early recognition of an impending attack and improve clinical management.


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The therapeutic potential of a kallikrein inhibitor for treating hereditary angioedema

Levy JH, O'Donnell PS 9/2006 Expert Opin.Investig.Drugs

Hereditary angioedema (HAE) manifests as intermittent, painful attacks of submucosal oedema affecting the larynx, gastrointestinal tract or limbs. Currently, acute treatment is available in Europe but not USA, and requires intravenous administration of a pooled blood product. HAE is most likely caused by dysinhibition of the contact cascade, resulting in overproduction of bradykinin. DX-88 (ecallantide, Dyax Corp.) is a highly specific recombinant plasma kallikrein inhibitor that halts the production of bradykinin and can be dosed subcutaneously. In a placebo-controlled Phase II trial in patients with HAE, DX-88 resulted in significant improvement in symptoms compared with placebo. A Phase III trial is ongoing. This review explains the pathophysiology of HAE and the mechanism by which DX-88, a non-intravenous, nonplasma-derived therapy, might improve the disease, and discusses the clinical course of HAE and available treatments. Finally, it explores the potential value and efficacy of DX-88 in treating HAE. [References: 95].


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Funding for Canadian Hereditary Angioedema Network has been generously provided by unrestricted grants from:


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