Adverse effects of danazol prophylaxis on the lipid profiles of patients with hereditary angioedema

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Abstract:Hereditary angioedema (HAE) caused by C1-esterase inhibitor deficiency is an autosomal-dominant disease resulting from a mutation in the C1-inhibitor gene. HAE is characterized by recurrent attacks of intense, massive, localized subcutaneous edema involving the extremities, genitalia, face, or trunk, or submucosal edema of upper airway or bowels. These symptoms may be disabling, have a dramatic impact on quality of life, and can be life-threatening when affecting the upper airways. Because the manifestations and severity of HAE are highly variable and unpredictable, patients need individualized care to reduce the burden of HAE on daily life. Although effective therapy for the treatment of HAE attacks has been available in many countries for more than 30 years, until recently, there were no agents approved in the United States to treat HAE acutely. Therefore, prophylactic therapy is an integral part of HAE treatment in the United States and for selected patients worldwide. Routine long-term prophylaxis with either attenuated androgens or C1-esterase inhibitor has been shown to reduce the frequency and severity of HAE attacks. Therapy with attenuated androgens, a mainstay of treatment in the past, has been marked by concern about potential adverse effects. C1-esterase inhibitor works directly on the complement and contact plasma cascades to reduce bradykinin release, which is the primary pathologic mechanism in HAE. Different approaches to long-term prophylactic therapy can be used to successfully manage HAE when tailored to meet the needs of the individual patient.

Section: Experience With Attenuated Androgen Therapy In the Long-termmentioning

confidence: 99%

Hereditary Angioedema Caused By C1-Esterase Inhibitor Deficiency: A Literature-Based Analysis and Clinical Commentary on Prophylaxis Treatment Strategies

Gower

Busse

Aygören‐Pürsün

et al. 2011

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“…Side effects may include weight gain, acne, virilization, altered libido, menstrual irregularities, headaches, depression, fatigue, lipid abnormalities, hypertension, cholestasis, increased liver enzymes, peliosis hepatitis, and hepatocellular adenomas[2,8,59,69-73]. To review the published safety data on these agents, we performed a literature search and identified articles that included an evaluation of the safety of long-term attenuated androgen therapy in HAE (Table 2)[59-62,70,72-76].…”

Section: Experience With Attenuated Androgen Therapy In the Long-termmentioning

confidence: 99%

“…Additional serious adverse effects such as hypertension, lipid abnormalities, cystitis, hematuria, and liver disease, including adenomas and carcinoma, have also been associated with attenuated androgen therapy[59,60,62,70,73-75,80,81]. In 1 study, patients who received long-term prophylaxis for HAE with danazol were at a higher risk for developing abnormally low levels of high-density lipoprotein and high levels of low-density lipoprotein when compared with patients not taking attenuated androgens and healthy control subjects[73].…”

Section: Experience With Attenuated Androgen Therapy In the Long-termmentioning

confidence: 99%

“…In 1 study, patients who received long-term prophylaxis for HAE with danazol were at a higher risk for developing abnormally low levels of high-density lipoprotein and high levels of low-density lipoprotein when compared with patients not taking attenuated androgens and healthy control subjects[73]. Liver disease, ranging from increased transaminases to adenomas and peliolosis hepatitis, has been reported with androgen use and warrants vigilant monitoring of liver function[59,60,62,75,82].…”

Section: Experience With Attenuated Androgen Therapy In the Long-termmentioning

confidence: 99%

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Hereditary Angioedema Caused By C1-Esterase Inhibitor Deficiency: A Literature-Based Analysis and Clinical Commentary on Prophylaxis Treatment Strategies

Gower¹,

Busse²,

Aygören‐Pürsün³

et al. 2011

Self Cite

Hereditary angioedema (HAE) caused by C1-esterase inhibitor deficiency is an autosomal-dominant disease resulting from a mutation in the C1-inhibitor gene. HAE is characterized by recurrent attacks of intense, massive, localized subcutaneous edema involving the extremities, genitalia, face, or trunk, or submucosal edema of upper airway or bowels. These symptoms may be disabling, have a dramatic impact on quality of life, and can be life-threatening when affecting the upper airways. Because the manifestations and severity of HAE are highly variable and unpredictable, patients need individualized care to reduce the burden of HAE on daily life. Although effective therapy for the treatment of HAE attacks has been available in many countries for more than 30 years, until recently, there were no agents approved in the United States to treat HAE acutely. Therefore, prophylactic therapy is an integral part of HAE treatment in the United States and for selected patients worldwide. Routine long-term prophylaxis with either attenuated androgens or C1-esterase inhibitor has been shown to reduce the frequency and severity of HAE attacks. Therapy with attenuated androgens, a mainstay of treatment in the past, has been marked by concern about potential adverse effects. C1-esterase inhibitor works directly on the complement and contact plasma cascades to reduce bradykinin release, which is the primary pathologic mechanism in HAE. Different approaches to long-term prophylactic therapy can be used to successfully manage HAE when tailored to meet the needs of the individual patient.

“…Androgens have proven very useful, but they are not effective in everyone, cannot be used in children or pregnant women, and have a great many side effects that, although generally mild, preclude their use in some people[9]. Furthermore, they regularly induce weight gain and alterations in blood lipids that may predispose patients taking them for decades to atherosclerosis and cardiovascular disease[10]. None of these prophylactic drugs are effective as acute therapy and it is clear that new, more-specific agents are needed.…”

mentioning

confidence: 99%

Recombinant and Plasma-Purified Human C1 Inhibitor for the Treatment of Hereditary Angioedema

Frank¹

2010

BackgroundAgents for prophylaxis of hereditary angioedema (HAE) have been available in the United States for several decades, but their usefulness is limited by side effects and they cannot be used at all in some patients. No agents have been available in the United States to specifically treat acute attacks. HAE types I and II are associated with low functional levels of C1 inhibitor, and evidence accumulated over decades suggests that intravenous infusion of C1 inhibitor is useful for terminating angioedema attacks and for prophylaxis.Key PointsC1 inhibitor derived from pooled human plasma has been available for decades in Europe, and 2 preparations have been recently introduced into the United States. Both have been efficacious in carefully controlled double-blind studies. One preparation, Cinryze, was approved by the U.S. Food & Drug Administration (FDA) for prophylaxis of HAE attacks in October 2008, and the second, Berinert, was approved by the FDA for treatment of acute attacks in October 2009. A third preparation, the recombinant human C1 inhibitor Rhucin, is completing clinical trials. Although not yet approved by the FDA, preliminary results made available suggest that Rhucin, too, is effective in terminating attacks of HAE.ConclusionsAmericans will now have access to effective acute and prophylactic treatments with C1 inhibitor for hereditary angioedema.