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Allergy 2007: 62: 842–856 ! 2007 The Authors Journal compilation ! 2007 Blackwell Munksgaard Nonallergic angioedema: role of bradykinin Angioedema is an underestimated clinical problem. Many cases are nonallergic M. Bas1, V. Adams2, T. Suvorava3, reactions, e.g. bradykinin-induced angioedema caused by genetic defects and T. Niehues4, T. K. Hoffmann1, angiotensin-converting enzyme (ACE) inhibitors. This difference is crucial for successful therapy, in particular when complete emergency care is not avail- 1Hals-, Nasen- und Ohrenklinik, Universit!tsklinikum able. Five important forms of nonallergic angioedema can be distinguished: D"sseldorf, D"sseldorf; 2Herzzentrum Leipzig GmbH, hereditary (HAE), acquired (AAE), renin-angiotensin-aldosterone system Universit!tsklinikum Leipzig, Leipzig; 3Institut f"r (RAAS)-blocker-induced (RAE), pseudoallergic angioedema (PAE) and idio- Pharmakologie undKlinische Pharmakologie, pathic angioedema (IAE). Some angioedema are present in the larynx and may Universit!tsklinikum D"sseldorf, D"sseldorf; 4Klinikf"r Kinder-Onkologie, -H!matologie und - cause death. A vast majority of nonallergic angioedema are RAE, particularly Immunologie, Universit!tsklinikum D"sseldorf, those caused by ACE inhibitors. It appears important to emphasize that in D"sseldorf, Germany patients with complete intolerance to RAAS-blockers, cessation of RAAS-blockers is likely to be associated with increased cardiovascular risk. Currently,there is no published algorithm for diagnosis and treatment. Angioedema is Key words: allergy; angioedema; angiotenin II receptor usually treated by a conservative clinical approach using artificial ventilation, type 1 antagonists; angiotensin-converting enzyme glucocorticoids and antihistamines. Today, a plasma pool C1-esterase inhibitor inhibitors; bradykinin; C1-INH; ecallantide; icatibant.
(C1-INH) concentrate is the therapy of choice in HAE. The current phar- Georg Kojda PharmD, PhD macotherapy of nonallergic angioedema is not satisfactory, thus requiring the Institut f"r Pharmakologie und Klinische identification of effective agents in clinical trials. Recently, several new drugs were developed: a recombinant C1-INH, a kallikrein inhibitor (ecallantide) and a specific bradykinin-B2-receptor antagonist (icatibant). According to currently available reports, these drugs may improve the treatment of kinin-induced Accepted for publication 14 April 2007 Angioedema is a swelling of the mucosa and/or submu- IAE). A vast majority of these forms of angioedema are cosa of the skin which may impair breathing and is induced by increased bradykinin levels (2) and are the potentially life-threatening (1). Swelling of the head-and- focus of this review. In contrast, many angioedema must neck regions, particularly in the pharynx and the larynx, be classified as IAE. For example, patients with chronic often require emergency treatment and several days of urticaria develop nonallergic angioedema in the absence hospitalization. Other manifestation locations are the of drug therapy or C1-INH deficiency (3). Pseudoallergic gastrointestinal tract, the gential region or the extremities.
angioedema is a different form of drug-induced nonaller- Beside the well-known forms of allergic angioedema, gic angioedema and is mediated by a so-called pseudo- many forms of nonallergic angioedema are known and a allergic process which is presumably linked to the vast majority of these are caused by increased plasma and mechanism of action of the triggering drug. For example, tissue concentrations of bradykinin. Thus, these forms of the pseudoallergic reaction to aspirin is thought to be a angioedema share a similar pathophysiology.
result of the inhibition of cyclo-oxygenase and subse-quently increased generation of cysteinyl-leukotrienes (4).
Forms of angioedema Epidemiology of angioedema In general, angioedema can be allergic or nonallergic,which basically means immunoglobulin (Ig) E-mediated In people with HAE, heterozygous C1-INH deficiency or not IgE-mediated, respectively. Nonallergic angioede- results in autosomal-dominant inheritance with an inci- ma might be caused by hereditary disposition or is of dence of 1:50 000 and there are no differences depending iatrogenic origin, and can be divided into five different on ethnic groups or sex (5). In contrast, AAE is a rare types (Fig. 1): hereditary (HAE), acquired (AAE), condition (6, 7). The incidence of RAE induced by ACEi RAAS-blocker-induced (RAE), pseudoallergic angioede- has been estimated with great variety which is most likely ma (PAE) and idiopathic angioedema (unknown cause, due to race differences. For example, in white Caucasians,

Nonallergic angioedema Figure 1. Different forms of angioedema (HAE: hereditaryangioedema, PAE: pseudoallergic angioedema, RAE: RAAS-blocker-induced angioedema, AAE: acquired angioedema).
the frequency of ACEi-induced angioedema is reported to mouse chromosome 7 (16). It is expressed in several range between 0.1% and 0.7% (1, 2, 5, 8, 9), while Black tissues like kidney, blood vessels, pancreas, gut salivary, people show a much greater susceptibility (10). In fact, a spleen, adrenal and neutrophils (17–20). From a cardio- recent meta-analysis investigating adverse reactions to vascular viewpoint, the kallikrein-kinin system is thought drugs used in cardiovascular medicine found a relative to antagonize the effects of the RAAS, and is closely risk of 3.0 for the development of ACEi-induced angi- related to this system (Fig. 2). The functional coupling oedema among Black compared to White people (11).
between the two systems is illustrated by angiotensin- Based on roughly 6.5 million users of ACEi in converting enzyme (ACE) whose two active sites are able Germany and on an average frequency of angioedema to generate angiotensin II from angiotensin I and to of 0.3%, approximately 20 000 cases of ACEi-induced degrade kinins into inactive peptides (21, 22).
angioedema will be expected to occur. Thus, the calcu-lated incidence approaches 1 : 4000 demonstrating that Bradykinin receptors and signal transduction ACEi-induced angioedema, which represents the majorityof RAEs, appears to be much more frequent than HAE Kinin receptors are cell surface, G-protein-coupled re- (12). Interestingly, AT-1-blockers appear to induce RAE ceptors of the seven-transmembrane family. So far, two but with a lower frequency than ACEi (2) and this subtypes of the receptor – the bradykinin receptor type 1 estimation has been confirmed in large clinical trials (13).
(BKR-1) and the BKR type 2 (BKR-2) – are identified, There are no data on the epidemiology of angioedema based on their pharmacological properties (23–26) and on caused by pseudoallergic reactions to drugs.
expression cloning (27–29). The human BKR-2 gene islocated on chromosome 14q32 (30), whereas the BKR-1has been mapped to chromosome 14q32.1–q32.2 (31). At Bradykinin in the human body the amino acid level, the BKR-1 and the BKR-2 shareonly 36% sequence homology (29). The BKR-1 is The kallikrein-kinin system synthesized in a variety of different organs de novo The discovery of the kallikrein-kinin system dates back to following tissue injury (31, 32), whereas the BKR-2 is 1909, when Abelous and Bardier demonstrated the constitutively expressed in a larger number of tissues (33).
hypotensive effect of urine (14). Kinins are pharmaco- Bradykinin is thought to be one of the most potent logically active peptides released into body fluids and into vasodilatators, as it is capable to liberate three important tissues as a result of the enzymatic action of kallikreins on endothelium-derived vasodilatory mediators: NO, pro- kininogens. Kinins are a family of peptides, including stacyclin (PGI2) and endothelium-derived hyperpolariz- bradykinin, kallidin and methionyl-lysyl-bradykinin, of ing factor (EDHF; 34). It is generally accepted that the which kallidin and methionyl-lysyl-bradykinin are con- activation of the BKR-2 on endothelial cells leads to an verted very rapidly into bradykinin via the action of activation of phospholipase C gamma via a transient aminopeptidases present in the plasma and urine (15).
Tissue kallikrein (EC, which differs signifi- increased formation of inositol 1,4,5-triphosphate (IP3) cantly from plasma kallikrein, is encoded by the KLK1 and diacylglycerol (35, 36). As a consequence of an gene located on human chromosome 19q13.2–q13.4 and elevated IP3 concentration, intracellular calcium rises by

Scheme of the connection between the renin-angio- Detrimental and beneficial effects of activation of tensin-aldosterone system and the kallikrein-kinin system.
BKR-2 in humans.
activates protein kinase A leading to an acute increase ofNO due to a phosphorylation of eNOS at Ser1179 (40).
Physiological actions of bradykinin Much progress in understanding the physiological roleof kinins has been made in the 1980s, when differ-ent selective antagonists of BKR-1 and BKR-2 werediscovered (26). More recently, the development ofC1-INH- and BKR-2-transgenic mice provided import-ant knowledge concerning the role of kinins in vivo (41,42). The effect of bradykinin on vascular permeabilitywas demonstrated by targeted disruption of C1-INH(42). Bradykinin was shown to dilate peripheral andcoronary vessels, may decrease arterial blood pressurein normotensive animals, and exert antithrombogenic,antiproliferative and antifibrogenic effects (Fig. 4; 33,43–47).
Scheme of the mechanisms of action of bradykinin- Cardiovascular actions of bradykinin are believed to be induced activation of vascular endothelial cells. Mediators such mainly mediated by the activation of BKR-2 on endot- as nitric oxide and prostacyclin act in an autocrine and para- helial cells leading to the release of NO, PGI2 and EDHF crine manner.
(48–52) and to the liberation of tissue plasminogenactivator (53). Bradykinin is also shown to be involved liberalization from internal stores or by an increased in the cardioprotective effect of preconditioning on Ca2+ influx (37), finally leading to an activation of the myocardial ischaemia/reperfusion injury (54). It can Ca2+-sensitive endothelial nitric oxide synthase (eNOS).
reduce the infarct area (55, 56) and has a growth In addition, the elevated intracellular Ca2+ activates the inhibitory effect to cardiomyocytes (57, 58). Additionally, Ca2+-sensitive phospholipase A2, which hydrolyses mem- kinins can evoke contractions of human bronchi smooth brane phospholipids liberating arachidonic acid, which is muscles (59), suggesting that bradykinin mediates dry the rate-limiting step in the synthesis of PGI2 (38).
cough induced by ACEi. Indeed, experimental data Beside these calcium-regulated signalling pathways, suggest that bradykinin might be a key substance in the recent studies also explored the importance of signalling pathomechanism of coughs associated with ACE inhib- pathways depending on phosphorylation. Ju and col- itors (60, 61). In addition, local accumulation of bradyk- leagues demonstrated that bradykinin activates tyrosine inin may lead to the activation of proinflammatory kinase 2 (Tyk2) of the Janus-activated kinase (JAK) peptides and local release of histamine, inducing a cough family, resulting in subsequent tyrosine phosphorylation reflex hypersensivity (62).
and nuclear translocation of STAT3 (39). Using similar The kallikrein-kinin system also plays an important approaches, it could be demonstrated that bradykinin also role in handling sodium and water metabolism. The Nonallergic angioedema natriuretic and diuretic effects of endogenous kinins are underlying mechanisms were extensively discussed and documented by several approaches, including BKR-2 reviewed previously (9, 83). Briefly, disrupted inhibition gene inactivation in transgenic mice: these animals are by C1-INH deficiency of the serine proteases C1s and C1r prone to salt-sensitive hypertension (63, 64). However, promotes activation of the complement system. In addi- this effect of bradykinin could not be confirmed in tion, the inhibition by C1-INH of two proteases of the another knockout strain (64). There is compelling evi- coagulation system, namely factor XIIa (Hagemann dence linking bradykinin to pathophysiological processes factor) and kallikrein appears important. As discussed that induce tissue damage and inflammation, hyperaemia, above, the kallikrein activity is a major player in the leakage of plasma proteins, bone resorption induced by synthesis of bradykinin. In particular, the vasodilator inflammation and pain; besides, many of these activities activities of bradykinin and its potency to promote and follow stimulation of BKR-1 (65–71). Bradykinin is also induce increased vascular permeability are well consistent involved in the production of pain and hyperalgesia by with its putative role in the pathophysiology of angi- direct activation of BKR-2 receptors on primary nonmy- elinated sensory neurones and thus participates in the According to our current knowledge, a deficiency of direct pain response (65). When inflammation is pro- C1-INH due to genetic defects plays a causal role in HAE longed, BKR-1, which are not expressed in healthy tissues (9). The human C1-INH gene has been mapped to to a significant degree, also play an important role in the chromosome 11 (11q12–q13.1; 5). Two variants of HAE maintenance of hyperalgesia. In vivo evidence for this was have been described: HAE type 1 with decreased C1-INH obtained in BKR-1 knockout mice which exhibited a levels and functional deficiency (85% of cases) and HAE reduced inflammatory response and hypoalgesia (72, 73).
type 2 with normal protein concentration but a functional Transgenic mice with overexpression of BKR-1 devel- defect (15% of cases; 84). Recently, a first case of oped exacerbated paw oedema, induced by polysaccha- homozygous C1-INH deficiency with the mutation c.
1576T>G was reported (85). Targeted disruption of C1- lipopolysaccharide-induced endotoxic shock, supporting INH in mice resulted in increased vascular permeability the notion that BKR-1 plays an important role in as evidenced i.v. injection of Evans blue in the tail and modulating inflammatory responses (74).
this was reversed by treatment with human C1-INH (42).
Finally, bradykinin has been shown to increase the Other data obtained with this transgenic mouse strain release of insulin from pancreatic b-cells through the provided strong additional evidence for a crucial involve- increase of intracellular calcium in response to hypergly- ment of BKR-2 in the pathogenesis of angioedema. For caemia (75, 76) and enhance insulin-dependent glucose example, increased vascular permeability was strongly transport (77). Other data revealed that bradykinin reduced by treatment with the BKR-2 antagonist icatib- released locally can regulate the uptake and availability ant or by simultaneous homozygous disruption of the of glucose in target tissues independently of the release of insulin (78, 79). These data suggest that decreaseddegradation of bradykinin contribute to the beneficial Acquired angioedema effects of ACEi in cardiovascular patients, such asreduced complications related to diabetes and a reduction AAE develops on the basis of nongenetic C1-INH of new cases of diabetes type 2 (80).
deficiency, which primarily affects adults or elderlypatients (9). This might be a result of various conditions,including severe illness such as malignancies. Patients Pathophysiology of bradykinin-induced angioedema with lymphoproliferative diseases may develop angioede-ma associated with decreased C1-INH plasma levels and Hereditary angioedema activity (7, 86). In contrast to HAE where the synthesis of In 1882, Heinrich Irena¨us Quincke described an acute and C1-INH is defective, AAE is characterized by large clearly circumscribed oedema. Although other case reports on such oedema had already been published, it (autoantibodies) consuming the C1q molecules and sub- was his real reward having accurately described this sequently C1-INH (87). Thus, C1q levels are normal in disease and separated it from urticaria (81). Today, the HAE, but decreased in AAE. In addition, C4 levels are so-called Quincke oedema is synonymous with angioede- low and C3 levels are normal in AAE. Other diseases such ma, and is still used to describe a circumscribed oedema as hepatocellular carcinoma and liver cirrhosis might be without urticaria and/or pruritus.
associated with decreased C1-INH plasma concentration It is known that the serine protease inhibitor (serpin) or activity, but subsequent angioedema has not been C1-INH has a variety of biological activities (82). Of described (88, 89). There is also a report on a lymphoma- these, the disrupted inhibition by C1-INH deficiency of associated angioedema with a normal plasma concentra- several proteases of the complement and the contact tion of C1-INH (90), and a recent characterization of a system and of kallikrein appear to be of particular new C1-INH mutation, leading to strong inhibition of importance for the development of angioedema. The monocyte C1-INH secretion (91).
treatment in severely ill cardiovascular patients who developed RAE. However, new s.c. drugs emerging to An essential component of the RAAS is ACE (carboxyp- treat angioedema (see below) are being evaluated in HAE eptidase, kininase 2, EC, an enzyme with two but not in RAE.
major proteolytic tasks: generation of angiotensin II anddegradation of bradykinin. In addition, ACE also Factors triggering angioedema attacks degrades substance P (92, 93). Treatment with ACEiincreases the plasma levels of bradykinin and the biolo- Numerous factors have been reported by patients with gical activity of bradykinin is crucially involved in the HAE as triggers or inducers of angioedema attacks.
actions of ACEi. For example, it has been shown that These include exposure to cold, mechanical trauma, tissue permanent blockade of BKR-2 by icatibant (formerly compression, prolonged sitting or standing, certain foods Hoe 140) halved the reduction of blood pressure induce- (e.g. eggs), infections, concomitant diseases, contact to able with captopril in hypertensive patients (94). ACEi- pesticides or chemicals either directly or via new products induced angioedema are perhaps caused by decreased or clothes, excitement/stress and certain drugs, such as degradation of bradykinin (95). Interestingly, combined ACEi and oestrogens (9). However, these anecdotic inhibitors of neutral endopeptidase and ACE, such as reports have never been systematically investigated and omapatrilat showed a dramatic fourfold increase of appear to depend on the patient!s individual character- angioedema when compared to the ACEi enalapril istics. One exception is the use of contraceptive oestro- (2.17% vs 0.68%; 96). Bradykinin might also be involved gens and hormone replacement therapy with oestrogens.
in dry cough, a typical side effect of ACE inhibitors (93).
It has been shown that some female HAE patients AT-1-blockers appear to induce angioedema with a respond to physiologically (first manifestation after lower frequency than ACEi (2, 13). Again, these angi- menarche, menstrual cycle and pregnancy) and/or oedema appear to be caused by bradykinin. It was shown pharmacologically increased serum oestrogen (contra- recently that AT-1-blockers increase bradykinin levels in ceptive oestrogen/gestagen combinations and hormone hypertensive patients (97). This effect was associated with replacement therapy with oestrogen) with an increased an increased ratio of bradykinin and its degradation frequency of attacks (104, 105). Other researchers found product BK1-7, suggesting that AT-1-blockers may similar cases in men and women after antiandrogenic inhibit ACE by a mechanism different from ACE- treatment with cyproterone (106). Likewise, a significant inhibitors. The circulating levels of angiotensin II increase correlation between the attack frequency and serum in response to AT-1-blocker therapy, because these drugs progesterone levels was evident in 44 female HAE interrupt the physiological feedback mechanism regula- patients, but not in the 34 male patients of this study ting angiotensin II synthesis by the release of renin (98).
cohort (107).
At the same time, all other AT-1 receptors are also The molecular mechanisms of triggering factors are blocked, leaving much room for the activation of largely unknown. One exception is the use of ACEi in angiotensin II type 2 receptors, which, in turn, might HAE patients, which further raises plasma and tissue inhibit the degradation of bradykinin by inhibition of bradykinin (see above). Thus, it is not surprising that ACE or of neutral endopeptidase (97). However, previous HAE patients sensitively respond to ACEi with an animal studies showed the stimulation of angiotensin II increase of their attack frequency (108, 109). A similar type 2 receptors might actually stimulate bradykinin mechanism is probably driving angioedema attacks in production so further studies are required to justify the cardiovascular patients without HAE. However, import- hypothesis given above (99). Nevertheless, AT-1-blockers ant questions remain to be clarified. For example, why do should be used with caution in patients who have only <1% of the patients taking ACEi develop experienced ACEi-induced angioedema (100).
angioedema, while bradykinin levels are increased in all ACEi and AT-1-blockers are widely used as level I ACEi-patients? Furthermore, what is the reason that evidence drugs to treat hypertension, myocardial infarc- some patients develop angioedema within a few days after tion, heart failure and type I diabetic nephropathy (101– starting the ACEi therapy, whereas others have their first 103). The beneficial effects of these drugs in heart failure attack after years of uneventful treatment (110)? and after a myocardial infarction include improvements It might be speculated that a variety of endogenous in survival, the rate of hospitalization, symptoms, cardiac factors counterbalance angioedema-inducing biological performance, neurohormonal levels and reverse remod- activities of bradykinin. In contrast, other factors might elling (101, 102). Thus, in patients who develop RAE, the create a tissue environment that disrupts this balance and cessation of RAAS-blocker therapy is, over the long term, induces angioedema. As many of the above-mentioned likely to be more important problem than is angioedema triggering factors are associated with an activation of itself. The availability of an easy-to-use oral or s.c. stand- inflammatory pathways, it appears promising to look for by medication which can be self-administered whenever an association between inflammatory plasma markers and an attack is recognized by the patient might be a the development of angioedema. Recent findings may promising future approach to maintain RAAS-blocker shed some light on such potential trigger factors. In a Nonallergic angioedema Figure 5. Plasma levels of (A) C-reactive protein and (B) fibrinogen in patients with RAAS)-blocker-induced caused by ACEi andpatients with angioedema of unknown cause [data adopted from Ref. (111)].
cohort of 43 non-HAE male and female patients suffering from an acute angioedema attack, 25 were taking ACEiand their attack completely resolved following drug initial emergency care cessation, while the other 18 cases showed no physical,biochemical or genetic signs allowing classification of their Monitoring vital functionsRating angioedema status attack and were thus assigned to the group of IAE.
Supplying OxygenEmergency pharmacotherapy Determination of acute-phase proteins during the acute Intubation, tracheotomy attack revealed striking differences between these two groups (Fig. 5). Patients on ACEi treatment had strik-ingly and significantly increased plasma levels ofC-reactive protein and of fibrinogen (111).
if needed laryngoscopy It should be added that in all these ACEi-treated patients, the levels of acute-phase proteins returned to normal as measured 3–6 months after the attack. Fur-thermore, the determination of acute-phase proteins in 21cardiovascular patients treated with ACEi who never experienced angioedema showed normal values as well.
A subsequent laboratory investigation showed not only potent in vitro vasodilator effects of fibrinogen in human artery rings, but also a strong potentiation of the Figure 6. Algorithm for the diagnosis of angioedema.
vasodilatory efficacy of bradykinin (M. Bas and G.
Kojda, unpublished results). Taken together, these resultsmay point to a contribution of the inflammatory process patient!s family history and current medications should to the pathophysiology of angioedema. However, it is still be performed.
not clear whether or not acute-phase proteins are truly A detailed physical examination should reveal whether the swelling is itchy or painful, which indicates allergicangioedema or inflammatory conditions, respectively.
Signs of urticaria usually exclude nonallergic angioede-ma. Blood measurements must include the determination Basic principles of diagnosis of C1-INH activity, and, eventually, C1-INH concentra- One of the most important procedures to diagnose tion and markers of inflammation (e.g. C-reactive oedema (see Fig. 6) is to separate allergic from nonaller- protein, leucocyte count). A reduced activity of plasma gic angioedema and to exclude other pathologies such as C1-INH is indicative of either hereditary or AAE, and infection, inflammation, tumours and diseases of large should be examined further, e.g. by genotyping or salivary glands. These procedures usually follow the determination of accompanying diseases such as lym- initial emergency care, e.g. monitoring of vital functions, phoma (please see "Case report: Acquired angioedema!).
determination of the status of angioedema, intubation, In some assumed drug-induced cases (ACEi), it might oxygen supply and pharmacotherapy with antihistamines, also be helpful to determine serum ACE activity. As for nebulized adrenaline and corticosteroids (1, 9). Beside a diagnostic imaging procedures, ultrasound visualization of the oedema region is usually sufficient, but uncertain laryngoscopy, several blood measurements, some imaging cases and/or abdominal pain should undergo magnetic procedures and an extensive anamnesis focusing on the

Figure 7. (A) ACEi-induced angioedema of the tongue. (B) Supraglottic laryngeal oedema caused on AT-1 R-blocker. (C) Hereditaryangioedema of the left hand. (D) Typical dermal efflorescence in HAE.
A first suspicion of HAE is given by mucosal tine 2 mg), i.v. glucocorticoids (e.g. methylprednisolone swellings and/or unclear abdominal pain in patients at 250–1000 mg) and/or adrenaline inhalation. The appli- a young age and those with a family history, a lack of cation of antihistamines in nonallergic angioedema may concomitant drug therapy and the absence of urticaria work in IAE but is ineffective and hence superfluous in as well. Following eventually necessary emergency RAE, AAE and PAE (2). This therapy is due to the fact treatment, the diagnostic procedure for HAE (type 1 that in an emergency situation – a patient with poten- and type 2) requires the measurement of both C1-INH tially life-threatening dyspnoea – the doctor may not be serum concentration and function (112). Furthermore, able to entirely exclude an allergic background. Simi- plasma levels of the complementary factor C4 in the larly, glucocorticoids are not proven to be effective in serum are reduced in a vast majority of the cases. This kinine-induced angioedema (108). However, glucocortic- factor is frequently reduced to approximately 25% of oids still belong to the standard for treatment of the normal value during the acute episode of angioede- angioedema (114). Principally, this medication should ma (81, 113). Furthermore, other rare conditions, such lead to a decrease in mucosal swelling. However, a as Crohn!s disease of the mouth and lips, facial clinical study showing a beneficial effect in patients with cellulitis and the superior vena cava syndrome should angioedema is lacking. It also has to be considered that be excluded (5). An illustration of different manifesta- this medication is used "off label! and may induce adverse tions of bradykinin-induced angioedema is depicted in effects, e.g. increased blood pressure. Thus, consequent monitoring of blood pressure and pulse are required.
Inhaled adrenaline may also be effective in laryngealoedema or other severe forms, but this is not based on Current treatment of angioedema evidence and adrenaline inhalation is not labelled for thisindication.
Basic emergency treatment In case of a progressive course of pharyngolaryngeal Depending on the symptoms and clinical findings, angioedema, it may be necessary to temporarily bypass emergency treatment consists of oxygen application, the airflow via intubation or tracheotomy. During the pharmacotherapy, intubation and, in severe cases, a acute angioedema episode, it is technically difficult to tracheotomy (84). Currently, in most medical institu- insert a ventilation tube and thus this attempt should be tions, pharmacotherapy of acute pharyngolaryngeal performed in the presence of an experienced head-and- angioedema consists of i.v. antihistamines (e.g. clemas- neck surgeon able to quickly perform a tracheotomy.
Nonallergic angioedema In cases with extensive cervical swelling it might be antihypertensive drugs. As described above, AT-1-block- difficult to identify the trachea and thus an emergency ers should not be used routinely to replace the much more coniotomy (between the cricoid and thyroid cartilage) commonly used ACEi (please see "Case report: RAAS- might become necessary. Taken together, the current blocker-induced angioedema!) (100, 119, 120). For exam- pharmacotherapy of acute nonallergic angioedema is not ple, the patient described in the RAE case below received satisfactory, thus requiring the identification of effective amlodipin to replace candesartan, and this might be agents in clinical trials.
sufficient, as long-acting dihydropyridines have beneficialeffects on the prognosis of patients with hypertension(103). However, this is strikingly different in patients with Hereditary and acquired angioedema a history of myocardial infarction or heart failure (101), As extensively reviewed recently (84), both types of where no equally effective drug is available. One possible angioedema are characterized by C1-INH deficiency, and approach to treat such patients in the future would be to usually respond rapidly to treatment with therapeutic provide a safe and easy-to-use stand-by medication which C1-INH, which is currently the "gold standard! of can be self-administered whenever an attack is scented by pharmacotherapy. It is not available in the USA, where the patient.
HAE is treated with the alkylated androgens stanazololand danzol (see Case report AAE). This i.v. substitutiontherapy with C1-INH concentrate derived from human Case report: Acquired angioedema plasma pools might also be used to prevent acuteangioedema attacks (9). Although there is theoretical A 65-year-old female patient with a history of surgically risk of infection with viruses such as HIV, the product has treated Morbus Crohn presented at the emergency been proved to be safe, as there is not one known case of department of the university hospital in Duesseldorf, viral infection despite many million applications. How- Germany, with recurrent angioedema located on her right ever, in view of the uncomfortable i.v. application route arm, hips and legs. A detailed diagnostic procedure this approach may be difficult to manage for the patient revealed a strongly decreased C1-INH activity (27%, (9). In contrast, drugs such as danazol (see Case report norm: 70–100) but no mutations in the C1-INH gene.
AAE) and tranexamic acid are available in oral form, and Other abnormal laboratory findings were: increased C- are used as a preventive pharmacotherapy to reduce the reactive protein of 1.3 mg/dl (norm: <0.5), increased frequency of attacks.
fibrinogen of 471–530 mg/dl (norm: 180–350) and in- Tranexamic acid is a fibrinolytic drug used for short- creased alkaline phosphatase of 120 U/l (norm: 35–104).
and long-term prophylactic pharmacotherapy in HAE, as Further examinations were carried out to look for it can reduce the number and severity of attacks in HAE lymphoproliferative diseases which have been reported to (113). Tranexamic acid is structurally related to the induce C1-INH deficiency (see above). Computerized amino acid, lysin and saturates lysin-binding regions in tomography showed no signs of splenomegaly or abnor- plasminogen by forming a reversible complex. This mal lymph nodes, and blood leucocyte counts were inhibits the binding of plasminogen and plasmin to fibrin, normal. A bone marrow biopsy revealed an infiltration disturbs the proteolytic activity of plasmin and subse- with a non-Hodgkin lymphoma. Histology showed a quently inhibits fibrinolysis (115). An accompanying 20% CD20- and CD43-positive infiltration and a cell effect of this action of tranexamic acid is the reduced population expressing CD23 and CD38. A bone marrow consumption of C1-INH, and this effect is used in the B-cell non-Hodgkin lymphoma was diagnosed. A specific treatment of HAE (9, 113). The potency of tranexamic treatment was not necessary, but the patient was advised acid in preventive pharmacotherapy in HAE patients is to return for further bone marrow biopsy and to avoid reported to be low, particularly among children (113, ACEi. Her acute angioedema attacks were treated with 116). Its important side effects include gastrointestinal C1-INH concentrate and danazol (200 mg/day) was symptoms, such as nausea, vomiting, diarrhoea and rare prescribed to prevent further attacks. Her repeatedly cases of thrombotic/embolic events (117, 118). In addi- measured C1-INH plasma concentration after 20 months tion, visual impairment and vertigo have been noted after of danazol therapy was 0.11 g/l (norm: 0.17–0.44) and long-term use of tranexamic acid. An annual fundoscopy C1-INH activity was 34% (norm: 70–100). Despite this is a recommended check for any impairment of visual apparent lack of a danazol-effect on C1-INH concentra- function, including retina tumours (113).
tion and activity, the patient experienced no furtherangioedema attacks. The non-Hodgkin lymphoma didnot progress after that.
RAE is basically treated as described in the section Basic Emergency treatment (see above). Furthermore, theimmediate cessation of RAAS-blockers is mandatory.
Angioedema might be the first sign of a lymphoprolif- Later on, the RAAS-blockers need to be replaced by other erative disease, as was evident in the present case. In this case, successful treatment with danazol, a steroid which blood pressure was 130/80 mmHg, and he was still taking stimulates the synthesis of C1-INH, and of C4 and phenprocoumon (INR 3,1), sotalol mite (160 mg b.i.d.), which is capable of reducing the frequency of angioede- l-thyroxine (150 mg daily) and tamsulosin (0.4 mg daily).
ma attacks in AAE (121), was successful. The drug is available in several European countries and in the USA (20 mg/day) was initiated. A routine laboratory investi- but no longer in Germany. In the USA, danazol and its gation on admission showed increased values of fibrin- congeneer, stanozolol, are widely used to treat angi- ogen (549 mg/dl; norm: 180–350) and leucocytes (11 900/ oedema, including acute attacks in children. Interest- ll; norm: 4000–11 000/ll). All other routinely determined ingly, this case also disputes the assumed mechanism of values were normal.
action of danazol and indicates that an increase of The patient was again treated with 250 mg i.v. meth- C1-INH concentration and activity are accompanied by ylprednisolone, 2 mg i.v. clemastine, 5 mg nebulized other yet unknown activities which interrupt the path- adrenaline and oxygen supply and recovered within ophysiology of angioedema. For example, in women, 24 h. On being discharged, he was advised to avoid both danazol induces deprivation of oestrogen, a well-known types of RAAS-blockers, ACEi and AT-1-blockers.
trigger of angioedema. Another interpretation is that Subsequently, candesartan was replaced by 5 mg/day danazol is not the underlying cause for the cessation of amlodipin, 50 mg/day triamterene and 25 mg/day hydro- angioedema. It is known that angioedema might not occur for many months despite continuously decreasedplasma C1-INH (9). However, long-term use of danazol may induce rare but severe side effects, e.g. liver diseasessuch as hepatic necrosis or cholestasis, adenomas and This case demonstrates that RAE can include severe eventually carcinomas (9, 122). Of the many other side laryngeal oedema, which can induce life-threatening effects, some may result from oestrogen deprivation in breathing impairment eventually requiring tracheotomy (110). Furthermore, this case is an example for recurrentRAE when an ACEi was replaced by an AT-1-blocker.
In a large controlled clinical trial the frequency ofangioedema induced by captopril (0.5%) was higher than Case report: RAAS-blocker-induced angioedema that induced by a valsartan (0.2%) (13). However, A 62-year-old male patient presented to the emergency department with dyspnoea and diffuse swelling of his might be more susceptible to angioedema induced by tongue that had developed within a few hours. Transnasal AT-1-blockers (see section RAAS-blocker-induced angi- flexible endoscopy revealed an oedema of the hypophar- oedema), although previous investigations on this matter ynx. He had no known history of allergies. He was taking do not support this view (99, 123). Thus, further clinical enalapril (5 mg daily) for the past 7 years to treat studies are necessary to estimate this risk more accurately.
hypertension (admission blood pressure 130/80 mmHg).
However, it appears necessary to precisely inform about Furthermore, the patient was wearing an atrial pacema- this potentially life-threatening side effect, including a ker, had an operation with aortic valve replacement clear information for patients. Finally, this case matches 7 years ago and was suffering from hypothyroidism.
similar cases registered worldwide and support the Additional prescription drugs are: phenprocoumon (INR 2,7), sotalol mite (160 mg b.i.d.), l-thyroxin (150 mg caution in patients with previous ACEi-induced angi- daily), tamsulosin (0.4 mg daily). Laboratory values on oedema (124).
admission showed a low increase of the acute phaseproteins CRP (0.8 mg/dl; norm: <0.5) and fibrinogen(370 mg/dl; norm: 180–350). All other routinely deter- Special considerations in paediatric treatment of mined values were normal.
The patient was treated with 250 mg i.v. methylpredn- isolone, 2 mg i.v. clemastine, 5 mg nebulized adrenaline In children, the main cause of kinin-induced angioedema and oxygen supply. He recovered within 24 h despite his is HAE. Insufficient C1-INH function as a result of severe hypopharyngeal oedema. On discharge, he was autoimmunity is also rare in children. It is likely that advised to avoid enalapril and other ACEi. Instead, HAE is under-diagnosed in childhood and adolescence.
therapy with 5 mg amlodipin was initiated to treat his It is estimated that 85% of the patients with HAE show symptoms before they are 20 years old. In contrast, only After 24 months, the patient returned, but with a 35% are diagnosed at that age. The clinical diagnosis of supraglottic laryngeal angioedema, accompanied by dys- HAE is difficult in children because they may present with pnoea and dysphonia. In the meantime, his antihyper- symptoms that are very common in childhood. Among tensive medication was changed from amlodipine to these symptoms is: abdominal pain, swelling of the 12.5 mg/day of AT-1-blocker candesartan. His admission extremities, difficulties to swallow, hoarseness or acute Nonallergic angioedema dyspnoea. Unless there is a positive family history, these convenient for the use in long-term prophylaxis. Choices symptoms are not immediately recognized as symptoms to C1-INH include antifibrinolytic agents like tranexa- of HAE, and, therefore, there is a diagnostic delay.
mic or !-aminocaproic acid or danazol. The antifibrin- Evidence for treatment relies mainly on data from a few olytic agents appear not to be an alternative because registries that report their paediatric data or consensus they cause adverse effects like myalgias and myonecrosis, conferences (9, 84, 113).
abdominal pain, hypotension and thromboses. In astudy by a Hungarian group, 26 children from 1 to15 years of age are reported (9, 116). Of them, 11 Education of parents and the patients (once they are adolescents) children were put on long-term prophylaxis with 1–2 g First of all, medical education is of key importance. If tranexamic acid because of frequent or life-threatening the parents are informed about the disease early diag- attacks. This proved to be ineffective in eight of the 11 nosis will be possible and unnecessary operations like and, therefore, the remaining eight children where put appendectomy in case of intra-abdominal oedema will be on danazol 100–200 mg/day, which the authors report to avoided. This point cannot be stressed enough, because be effective and without serious side effects (with the in our own experience, unnecessary operations have been exception of one girl with a delayed menarche). How- performed although parents knew about the diagnosis of ever, this series reports only a small number of children HAE in their children but not about their possible (n = 8) and the potential long-term side effects of manifestations. Avoidance of oral contraceptives in androgens in children (premature epiphysial closure with adolescent girls should be a part of counselling.
growth arrest, liver damage and hepatocellular adenoma, An important part in the education of patients is the development of secondary sexual characteristics, hirsu- knowledge of and contact with patient initiatives, in itism and many more) make many paediatricians very particular self-regulating communities which can be cautious about their use.
easily identified by their web pages. Parents need to be In conclusion, appropriate education of patients and provided with emergency lots of C1-INH concentrate for parents is mandatory. C1-INH concentrate has been their home refrigerator and their family doctor needs to shown to be effective and save children with acute be well informed about the disease. Moreover, parents attacks and for short-term prophylaxis as well. Man- and patients need to carry medical information cards agement of long-term prophylaxis is difficult. Both with information about the diagnosis in different antifibrinolytic agents and attenuated androgens cannot be recommended, although both are used where C1-INH concentrate is not available. Therefore, the devel-opment of new drugs is particularly important for Treatment of acute attacks children, who need long-term prophylactic pharmaco- Acute HAE attacks are successfully treated by infusion of 10–30 units C1-INH concentrate/kg body weight, usually500–1000 units. If this is not effective within 30–60 min,another 500–1000 units are to be administered. This Future directions – new treatment options treatment is usually effective within <2 h, save and welltolerated. Any swelling in the head-and-neck area, Significant adverse reactions, an uncomfortable route of unexplained hoarseness or dyspnoea or acute abdominal administration (i.v. infusion) and the lack of a proven pain should be treated with C1-INH promptly.
preventive pharmacotherapy may affect the quality of lifeof patients with HAE. These call for new options to treatHAE as also AAE and RAE. Fortunately, there are three Short-term prophylaxis new pharmacotherapeutic options which are currently Short-term prophylaxis is achieved by the infusion of investigated in clinical trials (Fig. 8): (1) recombinant 500–1000 units within 30–60 min before a planned inter- C1-INH, (2) the kallikrein inhibitor ecallantide and (3) vention. It should be done in any surgical procedure, the BKR-2-antagonist icatibant.
dental intervention or trauma in the head-and-neckregion.
Recombinant human C1-INH (rhC1-INH; Pharming Long-term prophylaxis Group, Leiden, the Netherlands) is extracted from the In children, systematic data from large cohorts and raw milk of transgenic rabbits. The gene-encoding controlled or randomized studies are lacking. There are human C1-INH is functionally linked to an extra bovine no established criteria when to initiate long-term pro- milk-specific promotor sequence (alpha-S1 casein) in the phylaxis. Once it is initiated, it is very difficult to rabbit DNA, thus leading to the secretion of C1-INH discontinue and is then usually given lifelong. As into the milk. rhC1-INH is expected to act in HAE the C1-INH is a plasma product and expensive, it is not same way as native C1-INH: it inhibits factor XIIa and

In addition, a prolongation of aPTT was observed. Thisis not surprising, as kallikrein and the Hagemann factor(factor XIIa), which autoactivate one another, are initialplayers in the clotting cascade. This action of ecallantidemight be a matter of concern and might cause significantinteractions with commonly used drugs, such as aspirinor heparin. However, it was suggested that prolongationof aPTT by ecallantide is not likely to represent anincreased risk of bleeding (126). Another concern even-tually limiting the use of ecallantide is the formation ofantibodies as well as the occurrence of anaphylacticreaction against this protein. Both events were observedduring treatment with ecallantide in a HAE patient, andmay rise safety concerns in terms of hypersensitivityreactions (127).
Target for new drugs to treat bradykinin-induced kallikrein, and blocks the formation of bradykinin Icatibant (Jerini AG, Berlin, Germany) is a synthetic (Fig. 8). Nevertheless, the half-life of rhC1-INH is decapeptide (MW: 1304.6 Da) with a similar structure approximately 3 h which is much shorter than the than bradykinin, but with five nonproteinogenic amino half-life of native C1-INH (125). rhC1-INH is currently acids. It is a potent, specific and selective BKR-2 tested in phase III trials on humans as listed in the web antagonist that does not interact with other peptide register of the U.S. National Institute of Health (http:// receptors, e.g. angiotensin II, substance P and neurokinin; accessed 16 April 2007). In con- A (128). Intranasal single-dose administration of icatib- trast to the plasma pool C1-INH, which is still the ant, at doses up to 500 lg and prior to kinin challenge, therapy of choice, the use of rhC1-INH will reduce the proved to inhibit bradykinin-induced symptoms in a small but significant risk for the transmission of diseases dose-dependent manner (129). Icatibant has been admin- elicited by contaminations of human plasma with so far istered so far to more than 1350 subjects in phase I–III unknown pathogens, such as viruses and prions. The trials (A. G. Jerini, personal communication). In an open- virtual unlimited availability of recombinant proteins label, proof-of-concept, phase II study, icatibant was such as rhC1-INH may also reduce the still immense administered either i.v. (0.4–0.8 mg/kg) or s.c. (30–40 mg) costs for C1-INH therapy.
to 15 HAE patients with 20 attacks (130) . Symptomintensity significantly decreased within 4 h after theadministration of icatibant, and a recent case report of treatment of HAE with icatibant supports these results Ecallantide (DX-88, Dyax Corp., Cambridge, MA, USA) is a recombinant 60 amino acid protein that Icatibant caused no treatment-related serious adverse specifically inhibits the plasma kallikrein. By blocking events or withdrawals. Local rapidly disappearing kallikrein, the formation of bradykinin from its precur- cutaneous reactions (erythema) occur following s.c.
sor high-molecular kininogen is downregulated (Fig. 7), injection (131). However, the upcoming results of two suggesting that ecallantide roughly mimicks the physio- double-blind, randomized phase III studies (FAST 1 logical actions of C1-INH. However, there are many and 2) have to be awaited before the safety profile of differences to the biological activity of C1-INH. For icatibant can be further determined. In these studies, example, although ecallantide potently inhibits plasma the efficacy of a single s.c. dose (30 mg) of icatibant in kallikrein, it shows a much less inhibitory activity moderate-to-severe HAE attacks of the skin or the against C1r, C1s, plasmin, factor XIIa and factor XIa abdomen was tested. The primary efficacy end point (126). Ecallantide has been tested in several phase I and was the time to the onset of symptom relief assessed by phase II trials, and is currently in a phase III trial for the patient using a visual analogue scale. The secondary treating HAE. In a phase II trial in 48 patients with end points of the double-blind, either placebo-con- HAE administered i.v. DX-88 significantly improved trolled (FAST 1) or tranexamic acid-controlled (FAST symptoms compared to placebo (126). The primary end 2), randomized multicentre study included the response point was the proportion of patients reporting a signi- rate (the rate of onset of symptom relief within 4 h ficant improvement 4 h after the administration. Overall, after application), the time to the complete alleviation ecallantide is described to be well tolerated. Some of symptoms, and the safety and tolerability of treat- reported side effects were dizziness, fatigue, headache, ment. The results of these recently finished studies have nausea, vomiting and elevations of the liver function test.
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Evolution, 56(7), 2002, pp. 1331–1339 WITHIN- AND BETWEEN-POPULATION VARIATION FOR WOLBACHIA-INDUCED REPRODUCTIVE INCOMPATIBILITY IN A HAPLODIPLOID MITE F. VALA,1,2 A. WEEKS,3 D. CLAESSEN,4 J. A. J. BREEUWER,5 AND M. W. SABELIS6 Institute for Biodiversity and Ecosystem Dynamics, University of Amsterdam, P.O. Box 94084, 1090 GB Amsterdam, The Netherlands

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NUEVAS FORMAS DE CREAR julio-agosto de 2004 julio-agosto de 2004 Revista de la OMPI/ Revista de la OMPI/ A primera vista, el olor del césped particular de un producto pueden Marcas tridimensionales y Las empresas deben prestar especial recién cortado, el color lila, el grito de adquirir un carácter distintivo y con- formas de productos atención a la descripción y a la repre-