The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform

Marco Cicardi - One of the best experts on this subject based on the ideXlab platform.

  • recombinant human c1 esterase inhibitor conestat alfa for prophylaxis to prevent attacks in adult and adolescent patients with hereditary Angioedema
    Expert Review of Clinical Immunology, 2018
    Co-Authors: Anna Valerieva, Sonia Caccia, Marco Cicardi
    Abstract:

    ABSTRACTIntroduction: Hereditary Angioedema (HAE) due to C1 inhibitor (C1-INH) deficiency is a debilitating and potentially lethal disease. Management includes on-demand treatment of Angioedema and...

  • Angioedema due to bradykinin dysregulation
    The Journal of Allergy and Clinical Immunology: In Practice, 2018
    Co-Authors: Marco Cicardi, Bruce L Zuraw
    Abstract:

    Angioedema is an acute swelling of the deeper layers of the skin or mucosa resulting from a transient increase in vascular permeability. Angioedema can occur in the absence or presence of hives, be hereditary or acquired, and be caused by various potential mediators, including histamine and bradykinin. Bradykinin-mediated Angioedema can be difficult to diagnose but is responsible for a disproportionate percentage of the serious morbidity and mortality associated with Angioedema. Our understanding of the basic biology of Angioedema has dramatically expanded over recent years. The classification of Angioedema has correspondently undergone major changes. Optimal management of patients with Angioedema requires that an accurate diagnosis be established and that treatment be tailored to the patient's specific form of Angioedema. In this article, we review the biology of bradykinin-mediated Angioedema as well as the clinical approach to the evaluation of Angioedema with a focus on bradykinin-mediated Angioedema. Recognizing how the underlying pathophysiology and mechanisms of bradykinin dysregulation contribute to Angioedema can help guide the clinical approach to the patient.

  • Diagnosis, Course, and Management of Angioedema in Patients With Acquired C1-Inhibitor Deficiency
    'Elsevier BV', 2017
    Co-Authors: Andrea Zanichelli, Chiara Suffritti, G.m. Azin, L. Maggioni, S. Caccia, F. Perego, R. Vacchini, Marco Cicardi
    Abstract:

    Background: Acquired Angioedema due to C1-inhibitor deficiency (C1-INH-AAE) is a rare disease with no prevalence data or approved therapies. Objective: To report data on patients with C1-INH-AAE followed at Angioedema Center, Milan (from 1976 to 2015). Methods: Diagnostic criteria included history of recurrent Angioedema without wheals; decreased C1-INH antigen levels and/or functional activity of C1-INH and C4 antigen less than 50% of normal; late symptom onset (>40 years); no family history of Angioedema and C1-INH deficiency. Results: In total, 77 patients (58% females; median age, 70 years) were diagnosed with C1-INH-AAE and 675 patients with hereditary Angioedema due to C1-INH deficiency (C1-INH-HAE) (1 patient with C1-INH-AAE/8.8 patients with C1-INH-HAE). Median age at diagnosis was 64 years. Median time between symptom onset and diagnosis was 2 years. Sixteen patients (21%) died since diagnosis, including 1 because of laryngeal edema. Angioedema of the face was most common (N = 63 [82%]), followed by abdomen (N = 51 [66%]), peripheries (N = 50 [65%]), and oral mucosa and/or glottis (N = 42 [55%]). Forty-eight of 71 patients (68%) had autoantibodies to C1-INH. In total, 56 patients (70%) used on-demand treatment for Angioedema including intravenous pdC1-INH 2000 U (Berinert, CSL Behring, Marburg, Germany) (N = 49) and/or subcutaneous icatibant 30 mg (Firazyr, Shire; Milano, Italy) (N = 27). Eventually, 8 of 49 patients receiving pdC1-INH became nonresponsive; all had autoantibodies. Thirty-four patients received long-term prophylaxis with tranexamic acid (effective in 29) and 20 with androgens (effective in 8). Conclusions: The incidence of C1-INH-AAE was 1 for every 8.8 patients with C1-INH-HAE. Thirty percent of the deaths were related to the disease. Treatments approved for C1-INH-HAE are effective in C1-INH-AAE, although with minimal differences

  • Novelties in the Diagnosis and Treatment of Angioedema.
    Journal of investigational allergology & clinical immunology, 2016
    Co-Authors: Marco Cicardi, Chiara Suffritti, Francesca Perego, Sonia Caccia
    Abstract:

    Angioedema is defined as local, noninflammatory, self-limiting edema that is circumscribed owing to increased leakage of plasma from the capillaries located in the deep layers of the skin and the mucosae. Two mediators, histamine and bradykinin, account for most cases of Angioedema. Angioedema can occur with wheals as a manifestation of urticaria, and this form is frequently allergic. In the present review, we discuss nonallergic Angioedema without wheals, which can be divided into 3 acquired and 4 hereditary forms. Histamine is the mediator in acquired Angioedema of unknown etiology (idiopathic histaminergic acquired Angioedema), whereas in other forms the main mediator is bradykinin. Angioedema can be caused by C1-inhibitor deficiency (C1-INH-hereditary Angioedema and C1-INH-acquired Angioedema), mutations in coagulation factor XII (FXII-hereditary Angioedema), and treatment with angiotensin-converting enzyme inhibitors (ACEI-acquired Angioedema). Etiology remains unclear in acquired Angioedema (idiopathic nonhistaminergic acquired Angioedema) and in 1 type of hereditary Angioedema (hereditary Angioedema of unknown origin). Several treatments are licensed for hereditary C1-INH deficiency. Plasma-derived and recombinant C1-INHs, the bradykinin receptor blocker icatibant, and the plasma kallikrein inhibitor ecallantide have been approved for on-demand treatment to reverse Angioedema symptoms. Attenuated androgen and plasma-derived C1-INH are approved for prophylaxis.

  • presentation diagnosis and treatment of Angioedema without wheals a retrospective analysis of a cohort of 1058 patients
    Journal of Internal Medicine, 2015
    Co-Authors: Marta Mansi, Andrea Zanichelli, Chiara Suffritti, Anna Coerezza, Romualdo Vacchini, C Stieber, Sven Cichon, Marco Cicardi
    Abstract:

    Background The first classification of Angioedema without wheals was recently reported and comprises different forms of the disease distinguished by aetiology, mediator of oedema and inheritance. Methods In total, 1725 consecutive patients with Angioedema without wheals were examined at our centre between 1993 and 2012. We excluded from the analysis 667 patients because of incomplete data or because Angioedema was related to a specific factor. Results According to the new classification of Angioedema, the 1058 patients included in this analysis were diagnosed with hereditary (HAE; n = 377) or acquired Angioedema (AAE; n = 681). The former group included HAE with C1-inhibitor (C1-INH) deficiency (C1-INH-HAE; n = 353) and HAE with normal C1-INH levels (n = 24), of which six had a factor XII mutation (FXII-HAE) and 18 had disease of unknown origin (U-HAE). The AAE group included disease with C1-INH deficiency (C1-INH-AAE; n = 49), AAE related to angiotensin-converting enzyme inhibitor treatment (n = 183), idiopathic histaminergic (IH-AAE; n = 379) and idiopathic nonhistaminergic Angioedema (InH-AAE; n = 70). We compared hereditary and AAE with uncertain aetiopathogenesis: the FXII-HAE and U-HAE groups pooled (FXII/U-HAE) versus InH-AAE. The median age at onset of FXII/U-HAE and InH-AAE was 26 and 38 years, respectively. In addition, 56% of patients with FXII/U-HAE and 81% of those with InH-AAE reported more than five attacks per year (median duration of 48 h). The location of Angioedema in patients with FXII/U-HAE versus those with InH-AAE was the following: face, 70% versus 86%; tongue, oral cavity or larynx, 55% versus 68%; limbs, 70% versus 56%; and gastrointestinal mucosa, 50% versus 20%. Prophylaxis with tranexamic acid was effective in all six patients with U-HAE and in 37 of 38 with InH-AAE who were started on this treatment. Conclusion Our findings in this cohort of patients with Angioedema provide new information on the clinical characteristics, diagnosis and treatment of this disease.

Nancy J Brown - One of the best experts on this subject based on the ideXlab platform.

  • dipeptidyl peptidase iv inhibitor use associated with increased risk of ace inhibitor associated Angioedema
    Hypertension, 2009
    Co-Authors: Nancy J Brown, Stuart Byiers, David Carr, Mario Maldonado, Barbara Ann Warner
    Abstract:

    Dipeptidyl peptidase-IV (DPP-IV) inhibitors decrease degradation of the incretins. DPP-IV inhibitors also decrease degradation of peptides, such as substance P, that may be involved in the pathogenesis of angiotensin-converting enzyme (ACE) inhibitor-associated Angioedema. This study tested the hypothesis that DPP-IV inhibition affects risk of clinical Angioedema, by comparing the incidence of Angioedema in patients treated with the DPP-IV inhibitor vildagliptin versus those treated with comparator in Phase III randomized clinical trials. Prospectively defined Angioedema-related events were adjudicated in a blinded fashion by an internal medicine adjudication committee and expert reviewer. Concurrent ACE inhibitor or angiotensin receptor blocker exposure was ascertained from case report forms. Study drug exposure was ascertained from unblinded data from phase III studies. Odds ratios and 95% confidence intervals comparing Angioedema risk in vildagliptin-treated and comparator-treated patients were calculated for the overall population and for patients taking ACE inhibitors or angiotensin receptor blockers, using both an analysis of pooled data and a meta-analysis (Peto method). Overall, there was no association between vildagliptin use and Angioedema. Among individuals taking an ACE inhibitor, however, vildagliptin use was associated with an increased risk of Angioedema (14 confirmed cases among 2754 vildagliptin users versus 1 case among 1819 comparator users: odds ratio 4.57 [95% confidence interval 1.57 to 13.28]) in the meta-analysis. Vildagliptin use may be associated with increased risk of Angioedema among patients taking ACE inhibitors, although absolute risk is small. Physicians confronted with Angioedema in a patient taking an ACE inhibitor and DPP-IV inhibitor should consider this possible drug-drug interaction.

  • dipeptidyl peptidase iv in angiotensin converting enzyme inhibitor associated Angioedema
    Hypertension, 2008
    Co-Authors: James Brian Byrd, Karine Touzin, Saba Sile, James V Gainer, John H Nadeau, Albert Adam, Chang Yu, Nancy J Brown
    Abstract:

    Angioedema is a potentially life-threatening adverse effect of angiotensin-converting enzyme inhibitors. Bradykinin and substance P, substrates of angiotensin-converting enzyme, increase vascular permeability and cause tissue edema in animals. Studies indicate that amino-terminal degradation of these peptides, by aminopeptidase P and dipeptidyl peptidase IV, may be impaired in individuals with angiotensin-converting enzyme inhibitor–associated Angioedema. This case-control study tested the hypothesis that dipeptidyl peptidase IV activity and antigen are decreased in sera of patients with a history of angiotensin-converting enzyme inhibitor–associated Angioedema. Fifty subjects with a history of angiotensin-converting enzyme inhibitor–associated Angioedema and 176 angiotensin-converting enzyme inhibitor–exposed control subjects were ascertained. Sera were assayed for angiotensin-converting enzyme activity, aminopeptidase P activity, aminopeptidase N activity, dipeptidyl peptidase IV activity, and antigen and the ex vivo degradation half-lives of bradykinin, des-Arg 9 -bradykinin, and substance P in a subset. The prevalence of smoking was increased and of diabetes decreased in case versus control subjects. Overall, dipeptidyl peptidase IV activity (26.6±7.8 versus 29.6±7.3 nmol/mL per minute; P =0.026) and antigen (465.8±260.8 versus 563.1±208.6 ng/mL; P =0.017) were decreased in sera from individuals with angiotensin-converting enzyme inhibitor–associated Angioedema compared with angiotensin-converting enzyme inhibitor–exposed control subjects without Angioedema. Dipeptidyl peptidase IV activity (21.5±4.9 versus 29.8±6.7 nmol/mL per minute; P =0.001) and antigen (354.4±124.7 versus 559.8±163.2 ng/mL; P =0.003) were decreased in sera from cases collected during angiotensin-converting enzyme inhibition but not in the absence of angiotensin-converting enzyme inhibition. The degradation half-life of substance P correlated inversely with dipeptidyl peptidase IV antigen during angiotensin-converting enzyme inhibition. Environmental or genetic factors that reduce dipeptidyl peptidase IV activity may predispose individuals to Angioedema.

Konrad Bork - One of the best experts on this subject based on the ideXlab platform.

  • classification diagnosis and approach to treatment for Angioedema consensus report from the hereditary Angioedema international working group
    Allergy, 2014
    Co-Authors: Marco Cicardi, Aleena Banerji, Jonathan A. Bernstein, Konrad Bork, Murat Bas, Teresa Caballero, Henriette Farkas, Werner Aberer, A S Grumach, Allen P Kaplan
    Abstract:

    Angioedema is defined as localized and self-limiting edema of the subcutaneous and submucosal tissue, due to a temporary increase in vascular permeability caused by the release of vasoactive mediator(s). When Angioedema recurs without significant wheals, the patient should be diagnosed to have Angioedema as a distinct disease. In the absence of accepted classification, different types of Angioedema are not uniquely identified. For this reason, the European Academy of Allergy and Clinical Immunology gave its patronage to a consensus conference aimed at classifying Angioedema. Four types of acquired and three types of hereditary Angioedema were identified as separate forms from the analysis of the literature and were presented in detail at the meeting. Here, we summarize the analysis of the data and the resulting classification of Angioedema.

  • hereditary Angioedema caused by missense mutations in the factor xii gene clinical features trigger factors and therapy
    The Journal of Allergy and Clinical Immunology, 2009
    Co-Authors: Konrad Bork, Jochen Hardt, Karin Wulff, Gunther Witzke, Petra Staubach
    Abstract:

    Background Hereditary Angioedema caused by mutations in the factor XII gene is a recently described disease entity that occurs mainly in women. It differs from hereditary Angioedema caused by C1 inhibitor deficiency. Objective To assess the clinical symptoms, factors triggering acute attacks, and treatments of this disease. Methods Thirty-five female patients with hereditary Angioedema and the factor XII mutations p.Thr309Lys and p.Thr309Arg who came from 13 unrelated families were studied. The observation period was 8.4 years on average (range, 2-26 years). Results Patients had on average 12.7 ± 7.9 Angioedema attacks per year. Recurrent facial swellings occurred in all patients; skin swellings other than facial, abdominal pain attacks, tongue swellings, and laryngeal edema occurred less frequently. Some factors that triggered Angioedema attacks were trauma, physical pressure, and emotional stress. Clinical symptoms started mainly after intake of oral contraceptives (17 women) or pregnancy (3 women). Exacerbation of the symptoms occurred after oral contraceptive use (8 women), pregnancy (7 women), hormone replacement therapy (3 women), intake of angiotensin-converting enzyme inhibitors (2 women), and an angiotensin 1 receptor blocker (1 woman). Effective treatments included C1 inhibitor concentrate for Angioedema attacks (6 women) and, for prophylaxis, progesterone (8 women), danazol (2 women), and tranexamic acid (1 woman). No difference between mutation p.Thr309Arg and p.Thr309Lys was found. Conclusions Facial swelling is a cardinal symptom of this condition. Estrogens may have a great influence, but this influence is highly variable. Various treatment options are available.

  • Disease expression in women with hereditary Angioedema.
    American Journal of Obstetrics and Gynecology, 2008
    Co-Authors: Laurence Bouillet, Konrad Bork, Anette Bygum, Hilary Longhurst, Teresa Caballero, Henriette Farkas, Isabelle Boccon-gibod, Christophe Bucher, Christian Drouet, Christian Massot
    Abstract:

    OBJECTIVE: Fluctuations in sex hormones can trigger Angioedema attacks in women with hereditary Angioedema. Combined oral contraceptive therapies, as well as pregnancy, can induce severe attacks. The course of Angioedema may be very variable in different women. STUDY DESIGN: Within the PREHAEAT project launched by the European Union, data on 150 postpubertal women with hereditary Angioedema were collected in 8 countries, using a patient-based questionnaire. RESULTS: Puberty worsened the disease for 62%. Combined oral contraceptives worsened the disease for 79%, whereas progestogen-only pills improved it for 64%. During pregnancies, 38% of women had more attacks, but 30% had fewer attacks. Vaginal delivery was usually uncomplicated. Attacks occurred within 48 hours in only 6% of cases. Those more severely affected during menses had more symptoms during pregnancies, suggesting a hormone-sensitive phenotype for some patients. CONCLUSION: The course of Angioedema in women with C1 inhibitor deficiency is affected by physiologic hormonal changes; consequently, physicians should take these into account when advising on management.

  • Hereditary Angioedema with normal C1 inhibitor: clinical symptoms and course.
    The American Journal of Medicine, 2007
    Co-Authors: Konrad Bork, Jochen Hardt, Georg Dewald
    Abstract:

    PURPOSE: A new type of hereditary Angioedema was described recently. It was characterized by recurrent bouts of Angioedema in various organs and normal C1 inhibitor and was observed mainly in women. Our aim was to conduct a detailed study of the clinical features of this condition. METHODS: A total of 138 patients with hereditary Angioedema and normal C1 inhibitor who belonged to 43 unrelated families were examined through the use of standardized questionnaires. RESULTS: A majority of patients with hereditary Angioedema and normal C1 inhibitor had skin swellings (92.8%), tongue swellings (53.6%), and abdominal pain attacks (50%). Laryngeal edema (25.4%) and uvular edema (21.7%) also were frequent, whereas edema episodes of other organs were rare (3.6%). Facial swellings and tongue involvement occurred considerably more frequently compared with hereditary Angioedema caused by C1 inhibitor deficiency. The number of patients with recurrent edema of only 1 organ was higher than in classic hereditary Angioedema. The number of patients with disease onset in adulthood was significantly higher in hereditary Angioedema with normal C1 inhibitor compared with classic hereditary Angioedema. Erythema marginatum was not observed. A subgroup of patients from families with coagulation factor XII mutations showed the same symptoms as the other patients. CONCLUSIONS: Hereditary Angioedema with normal C1 inhibitor levels shows a characteristic pattern of clinical symptoms. The main clinical features include skin swellings, tongue swellings, and abdominal pain attacks. There are many differences in the clinical symptoms and course of disease between this type of hereditary Angioedema and classic hereditary Angioedema caused by a genetic C1 inhibitor deficiency.

  • hereditary Angioedema with normal c1 inhibitor activity including hereditary Angioedema with coagulation factor xii gene mutations
    Immunology and Allergy Clinics of North America, 2006
    Co-Authors: Konrad Bork
    Abstract:

    Recurrent Angioedema of the skin is a commonly diagnosed clinical symptom that can be found in various clinical entities [1,2]. Some types of Angioedema of the skin are associated with episodes of upper airway obstruction that may be life threatening. Death by asphyxiation from laryngeal edema is well known in hereditary Angioedema (HAE) due to C1 inhibitor deficiency [3,4] and in recurrent Angioedema induced by angiotensinconverting enzyme (ACE) inhibitors [5–9]. Therefore, it is important to determine the exact type of Angioedema in each patient. In many patients Angioedema is associated with urticaria. If relapsing urticaria occurs simultaneously or alternately with Angioedema, both conditions are assumed to be symptoms of the same disease. This assumption is true in chronic idiopathic urticaria/Angioedema, IgE-mediated reactions (to foods, drugs, insect toxins, and other substances), serum sickness, urticaria/Angioedema induced by aspirin and nonsteroidal anti-inflammatory drugs (NSAIDS) or azo dyes and benzoates, and in reactions caused by substances that induce direct histamine release from mast cells. Recurrent Angioedema may occur in patients without urticaria. In these cases various disease entities due to a number of different pathogenetic mechanisms have to be considered. Recurrent Angioedema without urticaria can be due to an inherited or acquired C1 inhibitor deficiency [10–13] or may be induced by ACE inhibitors. HAE due to C1 inhibitor deficiency is not associated with urticaria, whereas ACE inhibitors may cause recurrent Angioedema alone or in association with urticaria. Other types of Angioedema without urticaria

Georg Kojda - One of the best experts on this subject based on the ideXlab platform.

  • Therapeutic efficacy of icatibant in Angioedema induced by angiotensin-converting enzyme inhibitors: a case series.
    Annals of Emergency Medicine, 2010
    Co-Authors: Murat Bas, Henning Bier, Jens Greve, Thomas K. Hoffmann, Klaus Stelter, Thomas Stark, Georg Kojda
    Abstract:

    Study objective The pathophysiology of angiotensin-converting enzyme inhibitor (ACEi)–induced Angioedema most likely resembles that of hereditary Angioedema, ie, it is mainly mediated by bradykinin-induced activation of vascular bradykinin B2 receptors. We hypothesize that the bradykinin B2 receptor antagonist icatibant might be an effective therapy for ACEi-induced Angioedema. Methods Eight patients with acute ACEi-induced Angioedema were treated with a single subcutaneous injection of icatibant. The outcome was assessed by the time to first improvement of symptoms, complete symptom relief, and drug safety. In addition, we retrospectively assessed the clinical course of 47 consecutive patients of our clinic with ACEi-induced Angioedema. Results First symptom improvement after icatibant injection occurred at a mean time of 50.6 minutes (standard deviation [SD] 21 minutes) and complete relief of symptoms at 4.4 hours (SD 0.8 hours). No patient received tracheal intubation, other drug treatment, tracheotomy, or a second icatibant injection. There were no adverse effects except erythema occurring at the injection site. In the historical comparison group treated with methylprednisolone and clemastine, the mean time to complete relief of symptoms was 33 hours (SD 19.4 hours). Some of these patients received a tracheotomy (3/47), were intubated (2/47), or received a second dose of methylprednisolone (12/47). Conclusion Although sample size limits the external validity of our results, the substantial decrease of time to complete symptom relief suggests that this new treatment is likely effective as a pharmacotherapeutic approach to treat ACEi-induced Angioedema.

  • nonallergic Angioedema role of bradykinin
    Allergy, 2007
    Co-Authors: Volker Adams, Tatsiana Suvorava, Tim Niehues, T. K. Hoffmann, Georg Kojda
    Abstract:

    Angioedema is an underestimated clinical problem. Many cases are nonallergic reactions, e.g. bradykinin-induced Angioedema caused by genetic defects and angiotensin-converting enzyme (ACE) inhibitors. This difference is crucial for successful therapy, in particular when complete emergency care is not available. Five important forms of nonallergic Angioedema can be distinguished: hereditary (HAE), acquired (AAE), renin-angiotensin-aldosterone system (RAAS)-blocker-induced (RAE), pseudoallergic Angioedema (PAE) and idiopathic Angioedema (IAE). Some Angioedema are present in the larynx and may cause death. A vast majority of nonallergic Angioedema are RAE, particularly those caused by ACE inhibitors. It appears important to emphasize that in 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 usually treated by a conservative clinical approach using artificial ventilation, glucocorticoids and antihistamines. Today, a plasma pool C1-esterase inhibitor (C1-INH) concentrate is the therapy of choice in HAE. The current pharmacotherapy of nonallergic Angioedema is not satisfactory, thus requiring the 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 Angioedema.

H. Farkas - One of the best experts on this subject based on the ideXlab platform.

  • Oral Plasma Kallikrein Inhibitor for Prophylaxis in Hereditary Angioedema
    New England Journal of Medicine, 2018
    Co-Authors: E. Aygoren-pursun, A. Bygum, V. Grivcheva-panovska, M. Magerl, J. Graff, O. Fain, A. Huissoon, T. Kinaciyan, Urs Steiner, H. Farkas
    Abstract:

    BACKGROUND: Hereditary Angioedema is a life-threatening illness caused by mutations in the gene encoding C1 inhibitor (also called C1 esterase inhibitor) that lead to overactivation of the kallikrein-bradykinin cascade. BCX7353 is a potent oral small-molecule inhibitor of plasma kallikrein with a pharmacokinetic and pharmacodynamic profile that may help prevent Angioedema attacks. METHODS: In this international, three-part, dose-ranging, placebo-controlled trial, we evaluated four doses of BCX7353 (62.5 mg, 125 mg, 250 mg, and 350 mg once daily) for the prevention of Angioedema attacks over a 28-day period. Patients with type I or II hereditary Angioedema with a history of at least two Angioedema attacks per month were randomly assigned to BCX7353 or placebo. The primary efficacy end point was the number of confirmed Angioedema attacks. Key secondary end points included Angioedema attacks according to anatomical location and quality of life. RESULTS: A total of 77 patients underwent randomization, 75 received BCX7353 or placebo, and 72 completed the trial. The rate of confirmed Angioedema attacks was significantly lower among patients who received BCX7353 at daily doses of 125 mg or more than among those who received placebo, with a 73.8% difference at 125 mg (P

  • Oral plasma kallikrein inhibitor for prophylaxis in hereditary Angioedema
    'Massachusetts Medical Society', 2018
    Co-Authors: E. Aygoren-pursun, A. Bygum, V. Grivcheva-panovska, M. Magerl, J. Graff, U.c. Steiner, O. Fain, A. Huissoon, T. Kinaciyan, H. Farkas
    Abstract:

    BACKGROUND Hereditary Angioedema is a life-threatening illness caused by mutations in the gene encoding C1 inhibitor (also called C1 esterase inhibitor) that lead to over-activation of the kallikrein-bradykinin cascade. BCX7353 is a potent oral small-molecule inhibitor of plasma kallikrein with a pharmacokinetic and pharmacodynamic profile that may help prevent Angioedema attacks. METHODS In this international, three-part, dose-ranging, placebo-controlled trial, we evaluated four doses of BCX7353 (62.5 mg, 125 mg, 250 mg, and 350 mg once daily) for the prevention of Angioedema attacks over a 28-day period. Patients with type I or II hereditary Angioedema with a history of at least two Angioedema attacks per month were randomly assigned to BCX7353 or placebo. The primary efficacy end point was the number of confirmed Angioedema attacks. Key secondary end points included Angioedema attacks according to anatomical location and quality of life. RESULTS A total of 77 patients underwent randomization, 75 received BCX7353 or placebo, and 72 completed the trial. The rate of confirmed Angioedema attacks was significantly lower among patients who received BCX7353 at daily doses of 125 mg or more than among those who received placebo, with a 73.8% difference at 125 mg (P<0.001). Significant benefits with respect to quality-of-life scores were observed in the 125-mg and 250-mg dose groups (P<0.05). Gastrointestinal adverse events, predominantly of grade 1, were the most commonly reported adverse events, particularly in the two highest BCX7353 dose groups. CONCLUSIONS Once-daily oral administration of BCX7353 at a dose of 125 mg or more resulted in a significantly lower rate of attacks of hereditary Angioedema than placebo. Mild gastrointestinal symptoms were the principal side effect. (Funded by BioCryst Pharmaceuticals; APeX-1 ClinicalTrials.gov number, NCT02870972)