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C1 Inhibitor Functional Activities in Hereditary Angioedema Plasma of Patients under Therapy with Attenuated Androgens

C1 Inhibitor Functional Activities in Hereditary Angioedema Plasma of Patients under Therapy with... © 1984 S. K arger A G . Basel Schweiz. Ges. Derm. Vener., 65. Jahresvers.. Bern 1983 0011 -9 0 7 5 84 1695-0301 S 2.75/0 Dermatológica 169: 301-304 (1984) C I Inhibitor Functional Activities in Hereditary Angioedema Plasma of Patients under Therapy with Attenuated Androgens P.J. Späth“. B. Wüthrichb, R. Bit tier' “Zcntrallabordes Blutspendedienstes. Schweizerisches Rotes Kreuz. Bern. Schweiz; bDermatologische Klinik. Universitätsspital Zürich, Schweiz Key Words. Hereditary angioedema • Cl inhibitor function ■ Attenuated androgens • Danazol • Stanozolol Abstract. The effects of therapy with danazol or stanozolol on complement component C4 and on Cl inhibitor concentrations and functions in 6 patients suffering from the com­ mon form of hereditary angioedema are described. Whereas the mean C4 concentration was found within the normal range, the therapy with attenuated androgens resulted in a subnor­ mal mean of Cl inhibitor concentration, but an almost normal mean of functional activity. Three different types of hereditary angio­ with albumin. Approximately 15% o f HAE edema (HAE) can be distinguished [7], The are of the variant form. common form concerns patients with The high mortality of the disease (30%) 5-30% of normal serum concentrations of requires a long-term prophylactic treatment the regulatory protein Cl inhibitor (Cl- of HAE attacks. For the long-term manage­ INH). The protein synthesized is indistin­ ment of HAE antifibrinolytic agents and im­ guishable from Cl-IN H of healthy individu­ peded androgens such as danazol or stanoz­ als. In serum of patients suffering from the olol are used. In a recently published study two variant forms of the disease functionally the long-term treatment with danazol of pa­ inactive proteins are synthesized. The CI- tients with the common form of the disease INH serum concentration found in one of resulted in minimal changes o f levels of C 1 - the variant forms is normal or elevated. The INH, although serum concentrations of the second and very rare type of the variant fourth component of complement (C4) be­ forms is characterized by a markedly elevat­ came normal and patients asymptomatic [5]. ed concentration ofan inhibitor with poor or The aim of this study was to analyze no functional activity that forms a complex whether stanozolol, a less well described and Spath Wüthrich/Büller a less expensive therapeutic agent, had an ef­ Cl-IN H concentration of 0.07 ± 0.03 g/1 fect on Cl-IN H and C4 concentration com­ was also far below the normal range parable to the effect of danazol. In addition, (0.1 1-0.26 g/1). In contrast to the diminished mean of Cl-IN H concentration, the mean the effect of both danazol and stanozolol on the functional activity of C l-IN H was C4 concentration of 0.20 ± 0.067 g/1 was studied. within the normal range. In the common form of the disease the serum concentration of C l-IN H should re­ flect the level of functional activity. As long Patients and Methods as a close relationship between C l-IN H 3 men and 3 women with the diagnosis of the com- function and C4 concentration is accepted, mon form of HAE. made on the basis of clinical history the results presented above, which are simi­ as well as on serologic findings, were investigated. The lar to observations of others, made a linear women were under therapy with danazol (Danairol") relationship of C l-IN H concentration and during the whole study. 2 of the men were managed al­ function doubtful. Therefore, C l-IN H func­ ternatively with danazol and stanozolol (Stromba1 '). I man was under therapy with stanozolol for the whole tional activities were measured in plasma study. The usual minimal maintenance dosage was for probes of the patients. danazol 200 mg/day and for stanozolol 5 mg/day. The The mean C l-IN H functional activity in cumulative total of months of therapy with danazol is the group of patients managed by danazol now 183 and with stanozolol 64 months, respectively. was 68 ± 32% of normal, and in the group Cl-IN H and C4 concentrations were determined by radial immunodiffusion or by nephelomctry, respective­ of patients under therapy with stanozolol it ly. To estimate the Cl-IN H function, a simple immu­ was 75 ± 34%, respectively. Thus, the C l- nodiffusion technique was used [6]. The functional ac­ INH functional activities corresponded bet­ tivity was calculated as described [4], but on the ordinate ter to concentrations of C'4 than concentra­ corrected values of immunologically detectable O r tions of C l-IN H did. Using the Behrens- concentrations were plotted. C l r values were corrected by a correction factor. This factor adjusted the Cl r con­ Fischer statistics, no significant difference in centration of individual samples to be tested to 100%. mean values of C l-IN H concentrations and functions of the groups of danazol- or sta- nozolol-treated patients could be detected. Results These results indicated similar effects of dan­ azol and stanozolol on C l-IN H concentra­ A divergence of C l-IN H and C4 concen­ tions and functions as well as on C4 levels in trations in serum samples of HAE patients patients suffering from the common form of under therapy with danazol was found. The HAE. mean C4 concentration of0.15 ± 0.046 g/1 Plots of Cl-IN H concentrations and func­ was within the normal range (0.14-0.35 g/1). tions of individual samples also indicated In contrast, the mean Cl-IN H level similar relationships of these two parame­ was reduced to approximately 30% ters in plasma samples from patients under (0.06 ± 0.018 g/1) of the level of a serum therapy with danazol and stanozolol (fig. 1). pool of 50 healthy blood donors. Similar ob­ With 1 exception. C l-IN H concentrations servations were made by others too [1-3. 5], as low as 0.07 g/1 were still high enough to Under therapy with stanozolol the mean ascertain a functional activity within the 303 Functional C'l-IN H in H A E Fig. 1. Relation ol'Cl-INH concentrations and functions in 42 individual plasma samples from 5 patients under therapy with danazol (a) and in 21 individual plasma samples from 3 patients under treatment with stanozolol (b). The Cl -1NH concentrations were measured immunochemically. the Cl -INH functional activities as described. The open triangle represents Cl -INH concentration and function in a plasma sample of a patient who had an abscess on his neck at that time. The horizontal lines represent the under and the upper limit of normal range ol'C l-IN l I function. The vertical line indicates the lower limit of normal range ol'Cl-IN H concentration. normal range. Concentrations ranging from cient to maintain normal functional activity 0.04 to 0.07 g/1 could be associated with and homeostasis. Even concentrations functional levels of 10-130%. around 0.05 g/1, corresponding to only 25% of concentration of a plasma pool of 50 healthy blood donors, allow functional lev­ Discussion els around 50%. The correctness of measure­ ment o l'C l-IN H functional activities was supported by the almost complete absence Danazol orstanozolol therapy of patients of HAE attacks under both therapies. If a t­ suffering from the common form of HAE re­ tacks w'ere noted, they were never severe. sulted in almost normal concentrations of C4 and in an unexpected relationship of CI - The results presented may help to explain why patients affected by HAE can be free of INH concentrations and functions inde­ attacks for longer intervals. pendent of the attenuated androgen used. If a close relationship between C4 concentra­ tion and C l-IN H functional activity is ac­ cepted, this relationship could explain how markedly reduced Cl -INH concentration in References plasma of patients under therapy with dan­ I Agostoni. A.: Cicardi. M .; Martignoni. C.: Berga- azol or stanozolol can be associated with a maschini. L.; Marasini. B.: Danazol and stanozolol C4 concentration within the normal range. in long-term prophylactic treatment of hereditary Thus, under both therapiesCl-IN H concen­ angioedema. .1. Allergy clin. Immunol. 65: 75-79 trations of 0.07 g/1 seemed still to be suffi­ (1980). 304 Späth/W üthrich/Bütler 2 Ballogh, Z .; Whaley, K .: Hereditary angioedema: its tion in human serum and its use for the diagnosis of pathogenesis and management. Scott, med. J. 25: hereditary angioedema. Clin. Immunol. Immuno- 187-195 (1980). pathol. 15: 465-471 (1980). 3 Rosen, F.S.; Bcyler, A.: Hereditary angioneurotic 7 Zimmerman, H.P.; Wüthrich, B.: Späth, P.: Here­ edema and its correction with androgen therapy. ditäres Angioödem. Ein klinischer und immunolo­ Birth Defects 16: 499-507 (1980). gischer Beitrag anhand von 8 eigenen Fällen unter 4 Späth, P.J.; Bütler, R.; Nydegger, U.E.: Compara­ Langzeitbehandlung mit Androgenen. Schweiz, tive analysis of Cl -inhibitor (Cl -INH) function ver­ med. Wschr. 113: 876-884 (1983). sus concentration in patients with hereditary angio­ edema (HAE) and other immunological disorders. Immunobiology 160: 144 (1981). 5 Wüthrich, B.; Grob, P.J.: Hereditäres Angioödem: Komplementprofil unter einer Langzeitbehandlung Dr. P.J. Späth, mit Danazol. Dermatológica 160: 167-174 (1980). Zentrallabor des Blutspendedienstes. 6 Ziccardi, R.J.; Cooper, N.R.: Development of an Schweizerisches Rotes Kreuz, immunochemical test to assess Cl -inactivator func­ CH-3000 Bern 22 (Switzerland) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Dermatology Karger

C1 Inhibitor Functional Activities in Hereditary Angioedema Plasma of Patients under Therapy with Attenuated Androgens

Späth, P.J.; Wüthrich, B.; Bütler, R.
Dermatology , Volume 169 (5): 4 – Jan 1, 1984
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Publisher
Karger
Copyright
© 1984 S. Karger AG, Basel
ISSN
1018-8665
eISSN
1421-9832
DOI
10.1159/000249616
Publisher site
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Abstract

© 1984 S. K arger A G . Basel Schweiz. Ges. Derm. Vener., 65. Jahresvers.. Bern 1983 0011 -9 0 7 5 84 1695-0301 S 2.75/0 Dermatológica 169: 301-304 (1984) C I Inhibitor Functional Activities in Hereditary Angioedema Plasma of Patients under Therapy with Attenuated Androgens P.J. Späth“. B. Wüthrichb, R. Bit tier' “Zcntrallabordes Blutspendedienstes. Schweizerisches Rotes Kreuz. Bern. Schweiz; bDermatologische Klinik. Universitätsspital Zürich, Schweiz Key Words. Hereditary angioedema • Cl inhibitor function ■ Attenuated androgens • Danazol • Stanozolol Abstract. The effects of therapy with danazol or stanozolol on complement component C4 and on Cl inhibitor concentrations and functions in 6 patients suffering from the com­ mon form of hereditary angioedema are described. Whereas the mean C4 concentration was found within the normal range, the therapy with attenuated androgens resulted in a subnor­ mal mean of Cl inhibitor concentration, but an almost normal mean of functional activity. Three different types of hereditary angio­ with albumin. Approximately 15% o f HAE edema (HAE) can be distinguished [7], The are of the variant form. common form concerns patients with The high mortality of the disease (30%) 5-30% of normal serum concentrations of requires a long-term prophylactic treatment the regulatory protein Cl inhibitor (Cl- of HAE attacks. For the long-term manage­ INH). The protein synthesized is indistin­ ment of HAE antifibrinolytic agents and im­ guishable from Cl-IN H of healthy individu­ peded androgens such as danazol or stanoz­ als. In serum of patients suffering from the olol are used. In a recently published study two variant forms of the disease functionally the long-term treatment with danazol of pa­ inactive proteins are synthesized. The CI- tients with the common form of the disease INH serum concentration found in one of resulted in minimal changes o f levels of C 1 - the variant forms is normal or elevated. The INH, although serum concentrations of the second and very rare type of the variant fourth component of complement (C4) be­ forms is characterized by a markedly elevat­ came normal and patients asymptomatic [5]. ed concentration ofan inhibitor with poor or The aim of this study was to analyze no functional activity that forms a complex whether stanozolol, a less well described and Spath Wüthrich/Büller a less expensive therapeutic agent, had an ef­ Cl-IN H concentration of 0.07 ± 0.03 g/1 fect on Cl-IN H and C4 concentration com­ was also far below the normal range parable to the effect of danazol. In addition, (0.1 1-0.26 g/1). In contrast to the diminished mean of Cl-IN H concentration, the mean the effect of both danazol and stanozolol on the functional activity of C l-IN H was C4 concentration of 0.20 ± 0.067 g/1 was studied. within the normal range. In the common form of the disease the serum concentration of C l-IN H should re­ flect the level of functional activity. As long Patients and Methods as a close relationship between C l-IN H 3 men and 3 women with the diagnosis of the com- function and C4 concentration is accepted, mon form of HAE. made on the basis of clinical history the results presented above, which are simi­ as well as on serologic findings, were investigated. The lar to observations of others, made a linear women were under therapy with danazol (Danairol") relationship of C l-IN H concentration and during the whole study. 2 of the men were managed al­ function doubtful. Therefore, C l-IN H func­ ternatively with danazol and stanozolol (Stromba1 '). I man was under therapy with stanozolol for the whole tional activities were measured in plasma study. The usual minimal maintenance dosage was for probes of the patients. danazol 200 mg/day and for stanozolol 5 mg/day. The The mean C l-IN H functional activity in cumulative total of months of therapy with danazol is the group of patients managed by danazol now 183 and with stanozolol 64 months, respectively. was 68 ± 32% of normal, and in the group Cl-IN H and C4 concentrations were determined by radial immunodiffusion or by nephelomctry, respective­ of patients under therapy with stanozolol it ly. To estimate the Cl-IN H function, a simple immu­ was 75 ± 34%, respectively. Thus, the C l- nodiffusion technique was used [6]. The functional ac­ INH functional activities corresponded bet­ tivity was calculated as described [4], but on the ordinate ter to concentrations of C'4 than concentra­ corrected values of immunologically detectable O r tions of C l-IN H did. Using the Behrens- concentrations were plotted. C l r values were corrected by a correction factor. This factor adjusted the Cl r con­ Fischer statistics, no significant difference in centration of individual samples to be tested to 100%. mean values of C l-IN H concentrations and functions of the groups of danazol- or sta- nozolol-treated patients could be detected. Results These results indicated similar effects of dan­ azol and stanozolol on C l-IN H concentra­ A divergence of C l-IN H and C4 concen­ tions and functions as well as on C4 levels in trations in serum samples of HAE patients patients suffering from the common form of under therapy with danazol was found. The HAE. mean C4 concentration of0.15 ± 0.046 g/1 Plots of Cl-IN H concentrations and func­ was within the normal range (0.14-0.35 g/1). tions of individual samples also indicated In contrast, the mean Cl-IN H level similar relationships of these two parame­ was reduced to approximately 30% ters in plasma samples from patients under (0.06 ± 0.018 g/1) of the level of a serum therapy with danazol and stanozolol (fig. 1). pool of 50 healthy blood donors. Similar ob­ With 1 exception. C l-IN H concentrations servations were made by others too [1-3. 5], as low as 0.07 g/1 were still high enough to Under therapy with stanozolol the mean ascertain a functional activity within the 303 Functional C'l-IN H in H A E Fig. 1. Relation ol'Cl-INH concentrations and functions in 42 individual plasma samples from 5 patients under therapy with danazol (a) and in 21 individual plasma samples from 3 patients under treatment with stanozolol (b). The Cl -1NH concentrations were measured immunochemically. the Cl -INH functional activities as described. The open triangle represents Cl -INH concentration and function in a plasma sample of a patient who had an abscess on his neck at that time. The horizontal lines represent the under and the upper limit of normal range ol'C l-IN l I function. The vertical line indicates the lower limit of normal range ol'Cl-IN H concentration. normal range. Concentrations ranging from cient to maintain normal functional activity 0.04 to 0.07 g/1 could be associated with and homeostasis. Even concentrations functional levels of 10-130%. around 0.05 g/1, corresponding to only 25% of concentration of a plasma pool of 50 healthy blood donors, allow functional lev­ Discussion els around 50%. The correctness of measure­ ment o l'C l-IN H functional activities was supported by the almost complete absence Danazol orstanozolol therapy of patients of HAE attacks under both therapies. If a t­ suffering from the common form of HAE re­ tacks w'ere noted, they were never severe. sulted in almost normal concentrations of C4 and in an unexpected relationship of CI - The results presented may help to explain why patients affected by HAE can be free of INH concentrations and functions inde­ attacks for longer intervals. pendent of the attenuated androgen used. If a close relationship between C4 concentra­ tion and C l-IN H functional activity is ac­ cepted, this relationship could explain how markedly reduced Cl -INH concentration in References plasma of patients under therapy with dan­ I Agostoni. A.: Cicardi. M .; Martignoni. C.: Berga- azol or stanozolol can be associated with a maschini. L.; Marasini. B.: Danazol and stanozolol C4 concentration within the normal range. in long-term prophylactic treatment of hereditary Thus, under both therapiesCl-IN H concen­ angioedema. .1. Allergy clin. Immunol. 65: 75-79 trations of 0.07 g/1 seemed still to be suffi­ (1980). 304 Späth/W üthrich/Bütler 2 Ballogh, Z .; Whaley, K .: Hereditary angioedema: its tion in human serum and its use for the diagnosis of pathogenesis and management. Scott, med. J. 25: hereditary angioedema. Clin. Immunol. Immuno- 187-195 (1980). pathol. 15: 465-471 (1980). 3 Rosen, F.S.; Bcyler, A.: Hereditary angioneurotic 7 Zimmerman, H.P.; Wüthrich, B.: Späth, P.: Here­ edema and its correction with androgen therapy. ditäres Angioödem. Ein klinischer und immunolo­ Birth Defects 16: 499-507 (1980). gischer Beitrag anhand von 8 eigenen Fällen unter 4 Späth, P.J.; Bütler, R.; Nydegger, U.E.: Compara­ Langzeitbehandlung mit Androgenen. Schweiz, tive analysis of Cl -inhibitor (Cl -INH) function ver­ med. Wschr. 113: 876-884 (1983). sus concentration in patients with hereditary angio­ edema (HAE) and other immunological disorders. Immunobiology 160: 144 (1981). 5 Wüthrich, B.; Grob, P.J.: Hereditäres Angioödem: Komplementprofil unter einer Langzeitbehandlung Dr. P.J. Späth, mit Danazol. Dermatológica 160: 167-174 (1980). Zentrallabor des Blutspendedienstes. 6 Ziccardi, R.J.; Cooper, N.R.: Development of an Schweizerisches Rotes Kreuz, immunochemical test to assess Cl -inactivator func­ CH-3000 Bern 22 (Switzerland)

Journal

Dermatology – Karger

Published: Jan 1, 1984

Keywords: Danazol; Stanozolol; Hereditary angioedema; C1 inhibitor function; Attenuated androgens

There are no references for this article.