Prematta et al The prevention of HAE attacks should begin with practical measures, which include avoidance of trauma and other interventions. Some medications can predispose an HAE patient to increased episodes of angioedema – these include estrogens and ACE inhibitors, which both should be avoided in patients with HAE. Patients are also likely to do better if conditions like gastritis and Helicobacter pylori infections are treated (Rais et al 1999; Visy et al 2007). Long-term prophy- laxis for patients with HAE has been achieved in some cases with antiﬁbrinolytics, C1-INH and attenuated androgens. Epsilon-aminocaproic acid (EACA) is an antiﬁbrinolytic agent used to treat HAE, and doses of 8–10 g per day have been shown to reduce frequency and severity of HAE attacks. Side effects of this medication include muscle discomfort, postural hypotension, sedative properties, and menstrual discomfort that is caused by the clotting of menstrual blood. In addition to these side effects is the theoretical risk of thrombophilia (Frank et al 1976). A contraindication to the use of EACA is a history of thrombosis and epilepsy. In countries outside the US, tranexamic acid has also been used as prophylaxis, but is not approved for use in the US. Attenuated androgens have also been used as prophylaxis for acute attacks of HAE. Danazol is the attenuated androgen most often prescribed to treat HAE, and is used in adults at doses of 50–200 mg 1 to 3 times daily and in some cases every other day therapy is effective. Once it has been initi- ated, its dose can often be titrated down slowly as tolerated in order to minimize its side effects. Some of these side effects include masculinization, acne, voice deepening, hirsutism, weight gain, and anxiety. This medication can also affect the liver, so liver function tests must be monitored. Additionally, danazol can slow growth in children and is contraindicated during pregnancy due to the possibility of masculinization of a female fetus. While attenuated androgens have been shown to be an effective agent, they do have signiﬁcant dose-related side effects that can limit their use (Hosea et al 1980). In many countries C1-INH is used for the treatment of acute HAE attacks; however, C1-INH is not yet approved in some countries, including the US. Thus, there are limited treatment options for acute HAE attacks in these areas, but several other products are being studied in clinical trials that may soon be available (Table 1). One such product is a recombinant human C1-INH (rhC1-INH) (Rhucin®; Pharming, Leiden, The Netherlands). This product is made by the introduction of a human C1-INH gene into rabbits. Speciﬁcally, the C1-inhibitor gene construct is under the milk-speciﬁc casein promoter for expression in rabbit milk. This recombinant C1-INH is then secreted into rabbit milk and is puriﬁed. Initial studies show that infusion of 100 units per kg body weight (U/kg) of this product is effective in ter- minating acute attacks of HAE with initiation of improvement recorded at a median time of 0.5 hours after infusion. How- ever, the half-life of this product is 3 hours, which is shorter than the reported half-life of C1-INH concentrate, which is 36–48 hours. The shorter half-life of recombinant C1-INH is due to differences in glycosylation of this product. The pos- sible beneﬁts of recombinant C1-INH include its theoretical reduced risk of viral transmission and that its production is not dependent on plasma donations. One drawback includes the potential for allergic reactions to rabbit proteins. Also, the short half-life raises concern for relapses of acute HAE attacks, although no relapses were reported in recent studies (van Doorn et al 2005; Choi et al 2007). Ecallantide® (Dyax Corp., Cambridge, MA, USA) is another product currently being studied for the treatment of acute HAE attacks. Decreased levels of C1-INH are believed to allow increased activation of the kallikrein cascade leading to an increase in bradykinin as a mechanism of angioedema. Ecallantide is a recombinant protein produced by the Pichia pastoris strain of yeast. It acts as a direct kallikrein inhibitor, blocking its action and preventing the downstream forma- tion of bradykinin. It can be administered intravenously or subcutaneously. A recent randomized, double-blind, placebo- controlled clinical trial was conducted which demonstrated that the median time from infusion to the beginning of effect was 30.5 minutes. Patients in the study received a dose ranging Table 1 A comparison of developing treatments for acute hereditary angioedema attacks in the US Method of production Mechanism of action Half-life Infusion method Berinert P® Plasma concentrate C1-inhibitor 36–48 h iv Cinryze® Plasma concentrate C1-inhibitor 20–92 h iv Rhucin® Recombinant protein C1-inhibitor 3 h iv Ecallantide® Recombinant protein Kallikrein inhibitor 1–4 h Subcutaneous Icatibant® Synthetic peptide Bradykinin-2 receptor antagonist 1–4 h Subcutaneous Abbreviation: h, hours; iv, intravenous. FDA status Pending FDA approval Pending FDA approval Was not FDA approved Pending resubmission to the FDA Was not approved by the FDA 976 Therapeutics and Clinical Risk Management 2008:4(5)