Medical Literature - 2004

Biological effects of C1 inhibitor

Davis AE,3rd 9/2004 Drug News & Perspectives

C1 inhibitor is a serine proteinase inhibitor (serpin) that regulates activation of both the complement and contact systems. Regulation of complement system activation takes place through inactivation of the classical pathway proteases, C1r and C1s, the lectin pathway protease, MASP2, and perhaps via inhibition of alternative pathway activation by reversible binding to C3b. Regulation of contact system activation takes place through inactivation of plasma kallikrein and coagulation factor XIIa. Deficiency of C1 inhibitor results in hereditary angioedema, which is characterized by recurrent episodes of localized angioedema of the skin, gastrointestinal mucosa or upper respiratory mucosa. A variety of clinical, in vitro and animal experiments indicate that the mediator of increased vascular permeability in hereditary angioedema is bradykinin. Animal models suggest that in addition to its utility in therapy of hereditary angioedema, C1 inhibitor may prove useful in a variety of other diseases including septic shock, reperfusion injury, hyperacute transplant rejection, traumatic and hemorrhagic shock, and the increased vascular permeability associated with thermal injury, interleukin-2 therapy and cardiopulmonary bypass. The therapeutic effect in these disease models very likely results from a combination of complement system activation, contact system activation and perhaps from other activities of C1 inhibitor. These other activities include a direct interaction with endotoxin, which may help to prevent endotoxic shock and an interaction with selectin molecules on endothelial cells, which may serve both to concentrate C1 inhibitor at sites of inflammation and to inhibit the transmigration of leukocytes across the endothelium. [References: 113].


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Canadian 2003 International Consensus Algorithm For the Diagnosis, Therapy, and Management of Hereditary Angioedema

Bowen T, Cicardi M, Farkas H, Bork K, Kreuz W, Zingale L, Varga L, Martinez-Saguer I, Aygören-Pürsün E, Binkley K, Zuraw B, Davis A 3rd, Hebert J, Ritchie B, Burnham J, Castaldo A, Menendez A, Nagy I, Harmat G, Bucher C, Lacuesta G, Issekutz A, Warrington R, Yang W, Dean J, Kanani A, Stark D, McCusker C, Wagner E, Rivard GE, Leith E, Tsai E, MacSween M, Lyanga J, Serushago B, Leznoff A, Waserman S, de Serres J. 09/2004 J Allergy Clin Immunol.

C1 inhibitor deficiency (hereditary angioedema [HAE]) is a rare disorder for which there is a lack of consensus concerning diagnosis, therapy, and management, particularly in Canada. European initiatives have driven the approach to managing HAE with 3 C1-INH Deficiency Workshops held every 2 years in Hungary starting in 1999, with the third Workshop having recently been held in May 2003. The European Contact Board has established a European HAE Registry that will hopefully advance our knowledge of this disorder. The Canadian Hereditary Angioedema Society/Société d’Angioédème Héréditaire du Canada organized a Canadian International Consensus Conference held in Toronto, Ontario, Canada, on October 24 to 26, 2003, to foster consensus between major European and North American HAE treatment centers. Papers were presented by investigators from Europe and North America, and this consensus algorithm approach was discussed. There is a paucity of double-blind placebo-controlled trials in the treatment of HAE, making levels of evidence to support the algorithm less than optimal. Enclosed is the consensus algorithm approach recommended for the diagnosis, therapy, and management of HAE and agreed to by the authors of this article. This document is only a consensus algorithm approach and requires validation. As such, participants agreed to make this a living 2003 algorithm (ie, a work in progress) and agreed to review its content at future international HAE meetings. The consensus, however, has strength in that it was arrived at by the meeting of patient-care providers along with patient group representatives and individual patients reviewing information available to date and reaching agreement on how to approach the diagnosis, therapy, and management of HAE circa 2003. Hopefully evidence to support approaches to the management of HAE will approach the level of meta-analysis of randomized controlled trials in the near future.

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Erythema marginatum and hereditary angioedema

Starr JC, Brasher GW, Rao A, Posey D 10/2004 South.Med.J.

OBJECTIVE: To search for anaphylatoxin activity in plasma during episodes of erythema marginatum, and to evaluate the histology of erythema marginatum by electron microscopy and immunohistologic techniques.

METHODS: Plasma samples were studied for C5a activity by granulocyte aggregation, and C3 conversion by immunoelectrophoresis. A skin biopsy of erythema marginatum was done, and the tissue stained with a rabbit antibody to bradykinin.

RESULTS: No plasma anaphylatoxin was found. Dense deposits of bradykinin were discovered in stromal tissue and lining endothelial cells.

CONCLUSIONS: Bradykinin may be important in the causality of the erythema marginatum associated with hereditary angioedema.


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Hereditary and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond

Agostoni A, Aygoren-Pursun E, Binkley KE, Blanch A, Bork K, Bouillet L, et al 9/2004 Journal of Allergy & Clinical Immunology

Hereditary angioedema (HAE), a rare but life-threatening condition, manifests as acute attacks of facial, laryngeal, genital, or peripheral swelling or abdominal pain secondary to intra-abdominal edema. Resulting from mutations affecting C1 esterase inhibitor (C1-INH), inhibitor of the first complement system component, attacks are not histamine-mediated and do not respond to antihistamines or corticosteroids. Low awareness and resemblance to other disorders often delay diagnosis; despite availability of C1-INH replacement in some countries, no approved, safe acute attack therapy exists in the United States. The biennial C1 Esterase Inhibitor Deficiency Workshops resulted from a European initiative for better knowledge and treatment of HAE and related diseases. This supplement contains work presented at the third workshop and expanded content toward a definitive picture of angioedema in the absence of allergy. Most notably, it includes cumulative genetic investigations; multinational laboratory diagnosis recommendations; current pathogenesis hypotheses; suggested prophylaxis and acute attack treatment, including home treatment; future treatment options; and analysis of patient subpopulations, including pediatric patients and patients whose angioedema worsened during pregnancy or hormone administration. Causes and management of acquired angioedema and a new type of angioedema with normal C1-INH are also discussed. Collaborative patient and physician efforts, crucial in rare diseases, are emphasized. This supplement seeks to raise awareness and aid diagnosis of HAE, optimize treatment for all patients, and provide a platform for further research in this rare, partially understood disorder.

Sep;114(3 Suppl):S51-131

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Hereditary angioedema: the rewards of studying a rare disease

Frank MM 7/2004 Journal of Allergy & Clinical Immunology


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Icatibant: HOE 140, JE 049, JE049

2004 Drugs in R & D

Icatibant [HOE 140, JE 049] is a potent, specific and selective peptidomimetic bradykinin beta2-receptor antagonist. It has a modified peptide structure, and is the first bradykinin receptor antagonist to act on the guinea-pig trachea without demonstrating agonist effects. Icatibant was originated by Hoechst Marion Roussel (now Sanofi-Aventis). Jerini is seeking a partner for development and marketing of icatibant for the treatment of refractory ascites in liver cirrhosis, angioedema and burns. In August 2004, Aventis merged with Sanofi-Synthelabo to form Sanofi-Aventis.Icatibant has shown an excellent safety profile in phase I studies. In December 2003, Jerini demonstrated positive results in the phase IIa study. Results obtained were statistically significant and clinically relevant. At the BIO 2004 International Annual Convention (BIO-2004) [San Francisco, CA, USA; 6-9 June 2004], Jerini reported plans to initiate phase IIb trials in this indication in the second half of 2004. Positive results from an icatibant formulation comparative study, in patients with acute attacks of hereditary angioedema, were announced in August 2004; IV and SC formulations showed no difference in efficacy and safety. It was announced in September 2004 by Jerini that a pivotal study, known as For Angioedema Subcutaneous Treatment (FAST) 1, had been initiated in the US and Canada. The protocol of a European study, to be known as FAST 2, is to be submitted to the authorities in September 2004. Jerini expects to launch the product in 2006. The US FDA granted icatibant, for the treatment of hereditary angioedema, fast-track designation in July 2004. In January 2003, the European Agency for the Evaluation of Medicinal Products granted icatibant orphan drug status in Europe for the treatment of angioedema. In November 2003, Jerini announced that effective December 2003, icatibant had orphan drug status in the US for the same indication. [References: 26].


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Sex hormones in hereditary angioneurotic oedema

Visy B, Fust G, Varga L, Szendei G, Takacs E, Karadi I, et al 4/2004 Clin.Endocrinol.(Oxf)

OBJECTIVE: The fluctuations in sex hormone levels at the beginning of adolescence, in the perimenopausal period, during pregnancy or during the use of oral contraceptives can precipitate oedematous attacks in hereditary angioneurotic oedema (HANO). Attacks usually disappear after the onset of menopause. This study was undertaken to establish any relationship between the serum levels of sex hormones and the incidence of HANO attacks.

PATIENTS AND MEASUREMENTS: Serum levels of LH, FSH, progesterone, oestradiol, testosterone, PRL and SHBG were measured in 78 patients [mean age 30.3 years (range 4-70 years)] with HANO. A questionnaire was used to explore the medical history of adult patients to characterize the evolution and the characteristics of attacks.

RESULTS: The number of attacks was significantly higher [odds ratio (OR) 6.36 (1.31-30.81); P = 0.022] in females with high progesterone levels (> or = 4 nmol/l), irrespective of age, menstrual cycle and danazol dose. The OR was even higher [13.4 (2.2-81.4); P = 0.005] when only subcutaneous attacks were considered. Multiple logistic regression analysis demonstrated a significantly lower attack frequency during 1-year follow-up in patients with a higher (40 nmol/l) SHBG level (OR 0.25 (0.07-0.90); P = 0.034). This difference existed independently of age and danazol dose.

CONCLUSION: In view of these results, the monitoring of progesterone and SHBG levels can prove useful in the prediction of attacks in hereditary angioneurotic oedema.


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


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