Hereditary angioedema: therapeutic effect of danazol on C4 and C1 esterase inhibitors.

Fabiani JE1, Paulin P, Simkin G, Leoni J, Palombarani S, Squiquera L.

Abstract

Hereditary angioedema (HAE) is an inherited deficiency of C1 esterase inhibitor (C1 inh). The two types of genetic C1 inh deficiency are type I, which is quantitative, and type II, which is functional. For the purpose of the present study, four HAE patients were selected. None of them had received any androgenic therapy. The group included three type I and one type II cases. All patients that entered the protocol received danazol, 400 mg/day for 14 days. The complement system was evaluated by monitoring C4, hemolytic complement 50% (CH50), circulating immune complexes (CIC), and antigenic and functional C1 inh during the study. The level of complement factors at the beginning and at the end of this period demonstrated a statistically significant increase in C4 and CH50 and the disappearance of CIC, while C1 inh remained unmodified. These results suggest that the therapeutic effect of danazol may have two mechanisms of action: (1) promotion of C4 synthesis by anabolic effect resulting in an improvement of the complement system with the disappearance of CIC and (2) a minor increase in C1 inh level primarily due to the lack of its consumption.

http://www.ncbi.nlm.nih.gov/pubmed/2108593

[Hereditary angioedema. Effect of danazol on C4 and functional C1INH].

Fabiani JE, Paulin P, Simkin G, Leoni J, Palombarani S, Squiquera L.

Abstract

Hereditary angioedema (HAE) is an inherited deficiency of the inhibitor of C1 esterase (C1 inh). Two types of genetic C1 inh deficiency have been described, type I: quantitative, and type II: functional. For the purpose of the present study, 4 out of 51 HAE patients were selected. None of them had received any previous androgenic therapy. The group was integrated by two type I and one type II cases. All patients that entered in the protocol received 400 mg/day of danazol over 14 days. The complement system was evaluated by monitoring C4, Hemolytic complement 50% (CH50), Circulating Immune Complexes (CIC), and antigenic and functional C1 INH during the study. The level of the complement factors at the beginning and the end of this period demonstrated a statistically significant increase of C4 and CH50 and the disappearance of CIC, while C1INH remained unmodified. These results suggest that the therapeutic effect of Danazol may have two mechanisms of action: i. promotion of C4 synthesis by anabolic effect resulting in an improvement of the complement system with the disappearance of CIC, and ii, a minor increase of C1 inh level primarily due to the lack of its consumption.

http://www.ncbi.nlm.nih.gov/pubmed/2772500

Dear Dr. Aldallal, 

thank you very much for your answer. It seems to me that the facts known so far are somewhat unclear, maybe even contradictory. On the contrary to Fabiani et al. (1990), Pappalardo et al. (2003) demonstrated increased level of C1inh in HAE patients' serum. Later, Drouet et al. (2008) showed thet androgens increased activity of aminopeptidase P, what may contribute to aleviation of attacs. However, I could not find the explanatory molecular mechanism. Do you know about any other data? Thank you in advance!

http://www.ncbi.nlm.nih.gov/pubmed/12706530

http://www.ncbi.nlm.nih.gov/pubmed/?term=drouet+app+2008

Dear Dr Grodecka,

This is Christian Drouet; we introduced aminopeptidase P (APP) activity in many biological investigations on angioedema patients carrying SERPING1 or F12 varinats, or without any genetic defect (that is under nC1INH-HAE). We observed that APP is associated with increased severity risk in the context of C1Inh deficiency and in some other familial conditions where there is a strategic role for the catabolims of the B1R ligand in the development of the attacks (unpublished).

You can learn from prominent papers of Prof Albert Adam on the impact of membrane Aminopeptidase P in the kinin catabolism : PMID:21898657 ; PMID:18433037 ; PMID:11406494 ; PMID:10458510. Do you need papers,

From many observations on famiies carrying SERPING1 abnormalities, the severity is depending on a degree of low kinin catabolism, but not on a degree of contact phase control by C1Inh. In addition, most often C1Inh function is measured on C1s protease residual activity.

Best wishes

Christian

Dear prof. Drouet, 

thank you very much for your extensive answer, including the non.-published results.

If I could ask you a little bit more - have you included androgens (danazol) in some furhter experiments than were published in 2008? Thank you in advance! Lucie

Dear Lucie,

Since 2008, data on kinin catabolism have been collected from nearly 850 C1Inh deficient patients (under prophylaxis by danazol, tranexamic acid, C1Inh concentrate). They do confirm a consistent increase of APP activity, but not of CPN, ACE or DPPIV activities.

Besides, kinin forming activity is not strongly diminished in patients under danazol prophylaxis, compared to patients without danazol (unpublished). But we have to consider that all HAE patients exhibit an important kinin forming activity; a consistent reduction of kinin forming activity is observed under tranexamic acid prophylaxis (Defendi et al, 2013, PLoS ONE).

Best. Christian

Dear prof. Drouet, thank you very much for your answer.