RESUMO
Angioedema without concomitant urticaria is a well-known complication of treatment with the recombinant tissue-type plasminogen activator (r-tPA) alteplase and its genetically modified variant tenecteplase. It is potentially lethal when causing airway obstruction and can require intubation. The latest guideline for the early management of patients with acute ischemic stroke from the American Heart Association/American Stroke Association advises to treat this complication initially by interfering with the histamine pathway. This article aims to clarify the pathophysiological mechanism of r-tPA-induced angioedema and provides several arguments that this condition is primarily bradykinin-mediated and hence should be treated initially by intervening with the bradykinin pathway. Second, other-less frequently reported-adverse symptoms after r-tPA therapy and their proposed pathophysiological mechanisms leading to specific treatment are described. This manuscript describes the need for an update of the section "3.5 IV alteplase" from the American Heart Association/American Stroke Association guideline to treat this r-tPA-induced angioedema adequately and prevent potentially fatal outcomes.
Assuntos
Angioedema , Fibrinolíticos , Acidente Vascular Cerebral , Ativador de Plasminogênio Tecidual , Humanos , Angioedema/induzido quimicamente , Ativador de Plasminogênio Tecidual/efeitos adversos , Ativador de Plasminogênio Tecidual/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Fibrinolíticos/efeitos adversos , Fibrinolíticos/uso terapêutico , Bradicinina/uso terapêutico , Proteínas Recombinantes/uso terapêutico , AVC Isquêmico/tratamento farmacológicoRESUMO
Hereditary angioedema is a rare autosomal dominant condition characterized by episodes of swelling of the upper airway, intestines, and skin. The disorder is characterized by deficiency in C1 esterase inhibitor (C1-INH) or a decrease in functional C1-INH. Treatment options include on demand therapy (treatment of acute attacks), long-term prophylaxis, and short-term prophylaxis. Corticosteroids, epinephrine, and antihistamines are not effective for this form of angioedema. The high mortality in patients undiagnosed underscores a need for broader physician awareness to identify these patients and initiate therapy.
Assuntos
Angioedemas Hereditários , Humanos , Angioedemas Hereditários/diagnóstico , Angioedemas Hereditários/tratamento farmacológico , Angioedemas Hereditários/terapia , Bradicinina/análogos & derivados , Bradicinina/uso terapêutico , Proteína Inibidora do Complemento C1/uso terapêutico , Proteína Inibidora do Complemento C1/genética , Médicos de Atenção Primária , Atenção Primária à SaúdeAssuntos
Antagonistas de Receptores de Angiotensina , Inibidores da Enzima Conversora de Angiotensina , Bradicinina , Tratamento Farmacológico da COVID-19 , COVID-19 , Humanos , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Bradicinina/uso terapêutico , Bradicinina/análogos & derivados , Antagonistas de Receptores de Angiotensina/uso terapêutico , SARS-CoV-2RESUMO
BACKGROUND: Angioedema due to acquired C1-inhibitor deficiency is a very rare but serious disease, with an estimated prevalence of 1 per 500,000 persons. There are no approved therapies to treat or prevent angioedema swelling in patients with this condition. Deucrictibant is a specific, orally bioavailable, competitive antagonist of the bradykinin B2 receptor currently under investigation for hereditary angioedema. OBJECTIVE: Our aim was to assess the efficacy and safety of deucrictibant as acute and prophylactic treatment for angioedema due to acquired C1-inhibitor deficiency. METHODS: A 2-part, randomized, double-blind, placebo-controlled crossover study was conducted. In Part 1, 4 consecutive angioedema attacks were treated with 3 doses of deucrictibant (10 mg, 20 mg, and 30 mg) or placebo. In Part 2, deucricibant, 20 mg, or placebo was administered twice daily for 2 treatment periods of 8 weeks. RESULTS: Three patients were enrolled; of those 3 patients, 1 completed both study parts and 2 completed only Part 2. In Part 1, a reduction in attack severity was observed in the 3 attacks treated with deucrictibant as opposed to an increase in severity of the attack treated with placebo. In Part 2, the individual mean monthly attack rates were 2.0, 0.6, and 1.0 during the placebo period and 0.0 across all patients during treatment with deucrictibant. There were no severe adverse events and 1 self-limiting treatment-emergent adverse event (abdominal pain). CONCLUSIONS: Deucrictibant has the potential to effectively and safely treat and prevent angioedema attacks due to acquired C1-inhibitor deficiency.
Assuntos
Angioedema , Estudos Cross-Over , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Angioedema/tratamento farmacológico , Método Duplo-Cego , Idoso , Proteína Inibidora do Complemento C1/uso terapêutico , Adulto , Resultado do Tratamento , Antagonistas de Receptor B2 da Bradicinina/uso terapêutico , Bradicinina/análogos & derivados , Bradicinina/uso terapêuticoRESUMO
BACKGROUND: Angiotensin converting enzyme inhibitors (ACE-Is) prevent the breakdown of bradykinin and can lead to life threatening angioedema. Tranexamic acid is an antifibrinolytic that inhibits formation of precursors involved in bradykinin synthesis and, in case reports, has been described as a potential treatment for ACE-I angioedema. METHODS: This retrospective study included patients who presented to the emergency department (ED) from January 2018 to August 2021 with angioedema while taking an ACE-I. Patients who received tranexamic acid (treatment group) were compared with patients who did not receive tranexamic acid (control group). Primary outcome was length of stay (LOS). Secondary outcomes evaluated included ICU admissions, intubations, and safety events. RESULTS: A total of 262 patients were included in this study (73 treatment; 189 control). Overall, the median ED LOS was longer in the treatment group than controls (20.9 h vs 4.8 h, p < 0.001). ICU admission rates were higher in the treatment group (45% vs 16%, p < 0.001). More patients were intubated in the treatment group (12% vs 3%, p = 0.018). No difference was seen between the treatment group and the controls for return within 7 days, complications related to thrombosis, and death. In patients presenting with severe angioedema symptoms who were admitted to the hospital, median LOS was not different between the two groups (58.7 h vs 55.7 h, p = 0.61). CONCLUSIONS: Patients who received tranexamic acid had increased ED LOS, rates of ICU admission, and need for intubation. This finding may be related to the severity of presentation. Administration of tranexamic acid appears safe to use in ACE-I angioedema. Prospective randomized controlled studies should be considered to determine whether tranexamic acid is an effective treatment for ACE-I angioedema.
Assuntos
Angioedema , Ácido Tranexâmico , Humanos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Ácido Tranexâmico/uso terapêutico , Estudos Retrospectivos , Bradicinina/uso terapêutico , Estudos Prospectivos , Angioedema/induzido quimicamente , Angioedema/tratamento farmacológicoRESUMO
Hereditary angioedema (HAE) is typically caused by a deficiency of the protease inhibitor C1 inhibitor (C1INH). The absence of C1INH activity on plasma kallikrein and factor XIIa leads to overproduction of the vasoactive peptide bradykinin, with resulting angioedema. As the primary site of C1INH and prekallikrein production, the liver is recognized as an important therapeutic target in HAE, leading to the development of hepatic-focused treatment strategies such as GalNAc-conjugated antisense technology and gene modification. This report reviews currently available data on hepatic-focused interventions for HAE that have advanced into human trials. Donidalorsen is an investigational GalNAc3-conjugated antisense oligonucleotide that binds to prekallikrein mRNA in the liver and reduces the expression of prekallikrein. Phase 2 data with subcutaneous donidalorsen demonstrated a significant reduction in HAE attack rate compared with placebo. Phase 3 trials are underway. ADX-324 is a GalNAc3-conjugated short-interfering RNA being investigated in HAE. BMN 331 is an investigational AAV5-based gene therapy vector that expresses wild-type human C1INH and is targeted to hepatocytes. A single intravenous dose of BMN 331 is intended to replace the defective SERPING1 gene and enable patients to produce functional C1INH. A first-in-human phase 1/2 study is ongoing with BMN 331. NTLA-2002 is an investigational in vivo clustered regularly interspaced short palindromic repeats/Cas9-based therapy designed to knock out the prekallikrein-coding KLKB1 gene in hepatocytes; a phase 1/2 study is ongoing. Findings from these and other ongoing studies are highly anticipated with the expectation of expanding the array of treatment options in HAE.
Assuntos
Angioedemas Hereditários , Humanos , Angioedemas Hereditários/genética , Angioedemas Hereditários/prevenção & controle , Bradicinina/uso terapêutico , Bradicinina/metabolismo , Proteína Inibidora do Complemento C1/uso terapêutico , Fígado/metabolismo , Pré-CalicreínaRESUMO
Hereditary angioedema (HAE) and acquired C1-inhibitor deficiency (AAE-C1-INH) are orphan diseases. Berotralstat is a recently licensed long-term prophylaxis (LTP) and the first oral therapy for HAE patients. No approved therapies exist for AAE-C1-INH patients. This study is the first to report real-world clinical data of patients with AAE-C1-INH and HAE who received Berotralstat. All patients treated with Berotralstat were included in this retrospective, bi-centric study. Data was collected from patients' attack calendars and the angioedema quality of life (AE-QoL) and angioedema control test (AECT) questionnaires before treatment, and at 3, 6, and 12 months after treatment and was then analyzed. Twelve patients were included, 3 patients with AAE-C1-INH, 7 patients with HAE type I, and 2 patients with HAE-nC1-INH. One patient (HAE I) quit treatment. Berotralstat was associated with fewer attacks in all groups. After 6 months of treatment, a median decrease of attacks per month was noted for HAE type I patients (3.3 to 1.5) and AAE-C1-INH patients (2.3 to 1.0). No aerodigestive attacks were noted for AAE-C1-INH patients. For HAE-nC1-INH patients, a mean decrease from 3.8 to 1.0 was noted (3 months). For HAE I patients, the total AE-QoL lowered a mean of 24.1 points after 6 months, for HAE-nC1-HAE patients 8.0 points, and for AAE-C1-INH patients 13.7 points. AECT scores increased for HAE I patients (mean: 7.1), HAE-nC1-INH patients (9.0), and AAE-C1-INH patients (4.2) after 6 months. Patients with HAE, HAE-nC1-INH, and AAE-C1-INH treated with Berotralstat showed reduced angioedema attacks and improved AE-QoL and AECT scores.
Assuntos
Angioedema , Angioedemas Hereditários , Pirazóis , Humanos , Angioedemas Hereditários/tratamento farmacológico , Angioedemas Hereditários/prevenção & controle , Qualidade de Vida , Estudos Retrospectivos , Bradicinina/uso terapêutico , Angioedema/terapia , Proteína Inibidora do Complemento C1/uso terapêuticoRESUMO
SARS-CoV-2 binds to ACE2 receptors and enters cells. The symptoms are cough, breathlessness, loss of taste/smell and X-ray evidence of infiltrates on chest imaging initially caused by oedema, and subsequently by a lymphocytic pneumonitis. Coagulopathy, thrombosis and hypotension occur. Worse disease occurs with age, obesity, ischaemic heart disease, hypertension and diabetes.These features may be due to abnormal activation of the contact system. This triggers coagulation and the kallikrein-kinin system, leading to accumulation of bradykinin and its derivatives, which act on receptors B1R and B2R. Receptor activation causes cough, hypotension, oedema and release of the cytokine interleukin-6 (IL-6) which recruits lymphocytes. These effects are core features seen in early SARS CoV-2 infection. METHODS AND ANALYSIS: In this study, hypoxic patients with COVID-19 with symptom onset ≤7 days will be randomised to either a bradykinin inhibitor (icatibant) or placebo. Patients and investigators will be blinded. The primary outcome will be blood oxygenation, measured by arterial blood sampling. The secondary outcome will be cardiovascular status. Retinal imaging will be performed to assess vessel size. Blood samples will be taken for measurement of inflammatory analyses including IL-6. As a separate substudy, we will also take comparator blood inflammatory samples from a COVID-19-negative cohort. ETHICS AND DISSEMINATION: The study has received the following approvals: West Midlands-Edgbaston Research Ethics Committee. Medicines and Healthcare products Regulatory Agency has issued a clinical trial authorisation. Belfast Health and Social Care Trust is the study sponsor. Results will be made available to participants upon request and findings will be presented and published. TRIAL REGISTRATION NUMBER: NCT05407597.
Assuntos
COVID-19 , Hipotensão , Humanos , Bradicinina/uso terapêutico , Tosse , Edema , Interleucina-6 , SARS-CoV-2 , Resultado do Tratamento , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Arterial hypertension is the main preventable cause of premature mortality worldwide. Across Latin America, hypertension has an estimated prevalence of 25.5-52.5%, although many hypertensive patients remain untreated. Appropriate treatment, started early and continued for the remaining lifespan, significantly reduces the risk of complications and mortality. All international and most regional guidelines emphasize a central role for renin-angiotensin-aldosterone system inhibitors (RAASis) in antihypertensive treatment. The two main RAASi options are angiotensin-converting enzyme inhibitors (ACEis) and angiotensin II receptor blockers (ARBs). Although equivalent in terms of blood pressure reduction, ACEis are preferably recommended by some guidelines to manage other cardiovascular comorbidities, with ARBs considered as an alternative when ACEis are not tolerated. This review summarizes the differences between ACEis and ARBs and their place in the international guidelines. It provides a critical appraisal of the guidelines based on available evidence from randomized controlled trials (RCTs) and meta-analyses, especially considering that hypertensive patients in daily practice often have other comorbidities. The observed differences in cardiovascular and renal outcomes in RCTs may be attributed to the different mechanisms of action of ACEis and ARBs, including increased bradykinin levels, potentiated bradykinin response, and stimulated nitric oxide production with ACEis. It may therefore be appropriate to consider ACEis and ARBs as different antihypertensive drugs classes within the same RAASi group. Although guideline recommendations only differentiate between ACEis and ARBs in patients with cardiovascular comorbidities, clinical evidence suggests that ACEis provide benefits in many hypertensive patients, as well as those with other cardiovascular conditions.
Assuntos
Inibidores da Enzima Conversora de Angiotensina , Hipertensão , Humanos , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Antagonistas de Receptores de Angiotensina/farmacologia , Antagonistas de Receptores de Angiotensina/uso terapêutico , Bradicinina/farmacologia , Bradicinina/uso terapêutico , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Sistema Renina-AngiotensinaRESUMO
Angioedema is a well-recognized and potentially lethal complication of angiotensin-converting enzyme inhibitor (ACEi) therapy. In ACEi-induced angioedema, bradykinin accumulates due to a decrease in its metabolism by ACE, the enzyme that is primarily responsible for this function. The action of bradykinin at bradykinin type 2 receptors leads to increased vascular permeability and the accumulation of fluid in the subcutaneous and submucosal space. Patients with ACEi-induced angioedema are at risk for airway compromise because of the tendency for the face, lips, tongue, and airway structures to be affected. The emergency physician should focus on airway evaluation and management when treating patients with ACEi-induced angioedema.
Assuntos
Angioedema , Inibidores da Enzima Conversora de Angiotensina , Humanos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Bradicinina/uso terapêutico , Bradicinina/metabolismo , Angioedema/diagnóstico , Angioedema/etiologia , Angioedema/terapiaRESUMO
Bradykinin-mediated angioedema is a rare, non-allergic, potentially life-threatening disease. ACE inhibitor-induced angioedema and hereditary angioedema (HAE) are the two most common presentations. Therapeutic options, pathophysiology and diagnosis continue to be investigated, with considerable progress in HAE over the last few decades. For all patients with bradykinin-mediated angioedema, there are several medications that should be avoided or administered with caution. Some of the triggering medications are well known, while others are suspected or of unknown significance. A common denominator is that there is no approved therapy for bradykinin-mediated angioedema as a drug side effect. Some medications, such as tissue plasminogen activator, have a higher incidence of angioedema with potential airway compromise than ACE inhibitors, although this fact is widely underappreciated. In this review, we aim to summarize what is currently known and recommended about concomitant medication in HAE patients and the interaction of other bradykinin-influencing drugs.
Assuntos
Angioedema , Angioedemas Hereditários , Humanos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Bradicinina/uso terapêutico , Ativador de Plasminogênio Tecidual/efeitos adversos , Angioedema/induzido quimicamente , Angioedema/diagnóstico , Angioedemas Hereditários/diagnóstico , Proteína Inibidora do Complemento C1RESUMO
Angioedema is generally readily recognizable clinically and is characterized by localized nonpitting edema involving subcutaneous, submucosal, or deep dermal tissue caused by increased vascular permeability and extravasation of intravascular fluid. It can occur via a variety of mechanisms. A number of clinical conditions (masqueraders) are occasionally mistaken for angioedema. Clinical classification of the various angioedema forms begins with noting the presence or absence of concurrent urticaria or wheals. Pathogenesis can be considered through two broad categories: mast cell-mediated with release of vasoactive mediators causing angioedema usually associated with urticaria or in the context of an anaphylactic reaction; and bradykinin (BK)-driven, in which increased vascular permeability is mediated by BK. BK-mediated angioedema does not occur with urticaria, nor does it respond to antiallergic medications. The various forms of hereditary angioedema are included in this category, requiring specific tests of C4 and C1 inhibitor level and function to confirm the diagnosis. Angiotensin converting enzyme inhibitors, which impair the degradation of BK, account for up to a third of all patients with angioedema presenting to the emergency department. Finally, angioedema may occur by yet unknown mechanisms; under this circumstance, it is difficult to manage.
Assuntos
Angioedema , Angioedemas Hereditários , Urticária , Humanos , Angioedema/tratamento farmacológico , Urticária/diagnóstico , Urticária/tratamento farmacológico , Angioedemas Hereditários/tratamento farmacológico , Proteína Inibidora do Complemento C1/uso terapêutico , Bradicinina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêuticoRESUMO
INTRODUCTION: Severe dermal pain triggered by sweating stimuli, such as bathing, exercise, and mental stress, significantly affects patients' daily lives. The pathomechanism underlying the sweating-induced dermal pain remains poorly understood and there exists no standard treatment for such pain. This study aims to evaluate the effectiveness of icatibant as an analgesic, a bradykinin B2 receptor antagonist, in treating sweating-induced dermal pain, and to establish the role of bradykinin in pain induction. METHODS/DESIGN: A multicenter, exploratory, crossover, single-blinded, placebo-controlled randomized, comparative study will be conducted to evaluate the efficacy of subcutaneous icatibant injection (30 mg) in treating sweating-induced dermal pain. Ten patients will be enrolled and assigned randomly in a 1:1 ratio to either the icatibant-placebo or placebo-icatibant groups. The primary endpoint is the change in the visual analog scale scores for dermal pain induced by thermal load before and after treatment with icatibant or placebo. Secondary endpoints include changes in the duration of dermal pain, blood and plasma histamine levels, serum angiotensin-converting enzyme levels, and histological evaluation of skin tissue samples at the site of dermal pain. DISCUSSION: The effectiveness of icatibant against sweating-induced dermal pain would provide clear evidence for the involvement of the bradykinin-bradykinin B2 receptor pathway in the pathogenesis of this condition. This finding may contribute to a better understanding of the underlying mechanisms of dermal pain associated with sweating stimuli and has the potential to improve patients' quality of life by suggesting potential treatment options, specifically, using drugs that inhibit bradykinin or suppress its production.
Assuntos
Bradicinina , Qualidade de Vida , Humanos , Bradicinina/uso terapêutico , Estudos Cross-Over , Método Simples-Cego , Sudorese , Dor/tratamento farmacológicoRESUMO
INTRODUCTION: Intradialytic hypotension (IDH) is a common clinical complication and is associated with increased morbidity and mortality in patients undergoing maintenance hemodialysis (MHD). The pathogenesis of IDH has been attributed to the rapid reduction of plasma volume during hemodialysis and the inadequate compensatory mechanisms in response to hypovolemia, such as the lack of vasoconstriction. This may be due to the increased production of vasodilators, such as bradykinin. In this study we test the hypothesis that bradykinin B2 receptor blockade prevents intradialytic hypotension. METHODS: We performed a post-hoc analysis of a double-blind, placebo-controlled, randomized, 2 × 2 crossover clinical trial comparing the continuous infusion of icatibant, a bradykinin B2 receptor blocker, and placebo during hemodialysis. Icatibant or placebo was infused for 30 min before and during hemodialysis in 11 patients on MHD. RESULTS: Seven of the patients had IDH, defined as a reduction of systolic blood pressure equal to or greater than 20 mmHg during hemodialysis. Stratified analysis, based on the presence of IDH, revealed that icatibant prevented the decrease in blood pressure compared to placebo in patients with IDH [blood pressure at average nadir (2.5 h after hemodialysis): Placebo,114.3 ± 8.9 vs. icatibant, 125.6 ± 9.1 mmHg, mean ± S.E.M]. Icatibant did not affect blood pressure in the group of patients without IDH. CONCLUSION: Bradykinin B2 receptor blocker may prevent the occurrence of IDH. Further studies should evaluate the hemodynamic effects of icatibant during hemodialysis and the symptomatology associated with IDH.
Assuntos
Hipotensão , Receptores da Bradicinina , Humanos , Receptores da Bradicinina/uso terapêutico , Bradicinina/farmacologia , Bradicinina/uso terapêutico , Hipotensão/etiologia , Hipotensão/prevenção & controle , Diálise Renal/efeitos adversos , Pressão SanguíneaRESUMO
Hereditary angioedema, with or without deficient C1 inhibitor level or function, is a rare disease characterized by recurrent attacks of noninflammatory subcutaneous and/or submucosal edema. It may be life-threatening and substantially affects quality of life. Attacks may be spontaneous or induced, in a setting of emotional stress, by infections or physical trauma, in particular. As the key mediator is bradykinin, this angioedema does not respond to the usual treatments of mast cell-mediated angioedema (antihistamines, corticosteroids, adrenaline), which is much more frequent. Therapeutic management of hereditary angioedema first consists in treating severe attacks with a selective B2 bradykinin receptor antagonist or a C1 inhibitor concentrate. The latter or an attenuated androgen (danazol) can be used for short-term prophylaxis. Therapeutic solutions conventionally proposed for long-term prophylaxis (danazol, antifibrinolytics [tranexamic acid], C1 inhibitor concentrate) vary in efficacy and/or pose problems of safety or ease of use. Kallikrein inhibitors (subcutaneous lanadelumab, oral berotralstat) recently made available as disease-modifying treatment constitute an important advance in long-term prophylaxis of hereditary angioedema attacks. The advent of these new drugs is accompanied by a new ambition for patients: optimize control of the disease and thereby minimize its impact on quality of life.
Assuntos
Angioedema , Angioedemas Hereditários , Humanos , Angioedemas Hereditários/tratamento farmacológico , Danazol/uso terapêutico , Qualidade de Vida , Angioedema/tratamento farmacológico , Bradicinina/uso terapêuticoRESUMO
Angioedema without Urticaria: Medical History and Findings Abstract. Abstracts: We present the case of a woman with repeated attacks of angioedema without wheals. Given that there was no benefit from systemic steroid and antihistamines therapy, we interpretated the clinical picture as bradykinin- (and not histamine-) induced. Owing to the late onset and a negative family history, we suspected a case of angioedema due to acquired C1-INH deficiency. This hypothesis was later confirmed by specific hematological tests. We therefore started a specific prophylaxis and therapy in case of acute attacks.
Assuntos
Angioedema , Urticária , Feminino , Humanos , Angioedema/diagnóstico , Angioedema/tratamento farmacológico , Angioedema/etiologia , Urticária/diagnóstico , Urticária/tratamento farmacológico , Urticária/etiologia , Bradicinina/uso terapêuticoRESUMO
Chronic spontaneous urticaria (CSU) is primarily a T2-dominant disease with a complex genetic background. Skin mast cell activation can be induced not only via the IgE-FcεRI axis but also from several other distinct mechanisms, molecules, and receptors involved in CSU onset, persistence, and exacerbation. These include autoallergy, autoimmunity, central or peripheral neuroimmune dysregulation, activation of both extrinsic and intrinsic coagulation pathways, and microbial infections. Besides mast cells, recent reports suggest the active and direct involvement of basophils and eosinophils. Several biological characteristics or biomarkers have been linked with CSU's known endotypes and may help forecast therapeutic responses. The introduction of biologic therapy for CSU has been a major advance in the last 10 years. The cornerstone of angioedema (AE) pathogenesis is increased vascular permeability and plasma leakage into the deeper dermis and subcutis, either mediated by histamine or bradykinin (BK). C1-inhibitor deficiency, hereditary or acquired, is the primary cause of BK-mediated AE due to increased plasma BK concentration. Other complex conditions have been identified, with some likely involving contact system dysregulation and other putative mechanisms related to vascular endothelial dysfunction. The approval of multiple hereditary-AE-specific therapies for both prevention and acute attacks has revolutionized treatment of this disease. Any new knowledge of the pathogenesis of CSU and AE offers the opportunity to improve patient information, physician-patient communication, prediction of therapeutic responses, selection of precise tailor-made treatment for each patient, and exploration of novel treatment options for those who do not achieve disease control with current medications.
Assuntos
Angioedema , Angioedemas Hereditários , Urticária Crônica , Urticária , Humanos , Urticária/tratamento farmacológico , Angioedema/terapia , Bradicinina/uso terapêutico , Bradicinina/metabolismo , Comunicação , Gerenciamento Clínico , Doença CrônicaRESUMO
BACKGROUND: ACE inhibitor (ACEi) induced angioedema predominantly affects the upper aerodigestive tract. As ACEi induced angioedema is mediated by bradykinin, therapeutic response to antihistamines and glucocorticoids remains unsatisfactory. In bradykinin mediated hereditary angioedema, C1-esterase inhibitor (C1INH) is an effective and approved treatment since many years. Our aim was to evaluate the therapeutic effect of C1INH in ACEi induced angioedema. METHODS: We performed a double-blind, parallel-group, multicentre randomised placebo-controlled trial between December 2013 and September 2018. Eligible were adults with ACEi induced angioedema with airway obstruction. Participants were randomised 1:1 to single doses of either C1INH (20 IU/kg) or placebo (0.9% NaCl) i.v in addition to standard care (i.v. 500 mg prednisolone and 2.68 mg clemastine) i.v. Composite symptom scores were assessed at baseline and up to 48 h, at discharge and 1 week after discharge. Physician assessed time to complete oedema resolution (TCER) and time to onset of relief (TOR). RESULTS: 30 patients (16 C1INH, 14 placebo) were randomised and dosed. 25 (9 C1INH, 12 placebo) completed the study. TCER was 29.63 h ± 15.56 h in the C1INH and 17.29 h ± 10.40 h in the placebo arm (p = 0.0457). TORs were 4.13 h ± 3.38 h and 2.86 h ± 1.29 h for C1INH and placebo, respectively (p = 0.4443). There were no adverse events related to study medication. CONCLUSIONS: In the context of baseline application of steroids and antihistamines C1INH was inferior in the treatment of ACEi induced angioedema when compared to placebo with respect to time to complete resolution of symptoms. Eudra-CT Number: 2012-001670-28.
Assuntos
Angioedema , Angioedemas Hereditários , Adulto , Humanos , Proteína Inibidora do Complemento C1/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Bradicinina/uso terapêutico , Angioedema/induzido quimicamente , Angioedema/tratamento farmacológico , Angioedemas Hereditários/tratamento farmacológico , Angioedemas Hereditários/induzido quimicamenteRESUMO
Monoclonal antibodies (mAbs) have been shown to be effective and generally safe across a continually expanding list of therapeutic areas. We describe the advantages and limitations of mAbs as a therapeutic option compared with small molecules. Specifically, we discuss a novel mAb in the treatment of hereditary angioedema (HAE), a rare and potentially life-threatening condition characterized by recurrent unpredictable swelling attacks. HAE is mediated by dysregulation of plasma kallikrein activity leading to overproduction of bradykinin. Current prophylactic treatment for HAE includes androgens or replacement of the endogenous plasma kallikrein inhibitor, C1 inhibitor. However, there remains an unmet need for an effective, less burdensome treatment option. Lanadelumab is a fully human mAb targeting plasma kallikrein. Results from clinical trials, including a pivotal Phase 3 study and its ensuing open-label extension study, demonstrated that lanadelumab is associated with few treatment-related adverse events and reduced the rate of HAE attacks. This novel treatment option has the potential to significantly improve the lives of patients with HAE.
Assuntos
Angioedemas Hereditários , Anticorpos Monoclonais , Humanos , Anticorpos Monoclonais/uso terapêutico , Calicreína Plasmática , Angioedemas Hereditários/tratamento farmacológico , Angioedemas Hereditários/prevenção & controle , Resultado do Tratamento , Proteína Inibidora do Complemento C1/uso terapêutico , Bradicinina/uso terapêuticoRESUMO
C1-inhibitor (C1INH) concentrates and the selective bradykinin B2 receptor antagonist icatibant are approved only for treating hereditary angioedema with C1INH deficiency. Yet, they are regularly prescribed off label in other types of bradykinin-mediated angioedema including angiotensin-converting enzyme inhibitor (ACEi)-related and undetermined angioedema. We conducted a retrospective chart review of inpatient prescriptions of C1INH concentrates and icatibant between 2016 and 2020 in the University Hospital of Angers. The first outcome was the proportion of prescriptions with explicit indication. Then, we determined the compliance of prescriptions with European Medicines Agency approvals and the French bradykinin-mediated angioedema reference center guidelines. Finally, we estimated the economic impact of inappropriate prescribing. The therapeutic indication was explicit in 90.4% of prescriptions (n = 66/73). Only 17.8% of prescriptions were for hereditary angioedema with C1INH deficiency, while 31.5% were for ACEi-related and 28.7% for undetermined angioedema. However, most off-label prescriptions were consistent with the French bradykinin-mediated angioedema reference center guidelines (73.3%). We estimated that 13% of drug expenditures were potentially excessive. The predominance of off-label prescriptions may be explained by the infrequency of hereditary angioedema and the absence of approved alternatives in other types of bradykinin-mediated angioedema. Most attacks were related to ACEis. Epinephrine was rarely prescribed as first-line therapy in attacks of unknown origin. Given the high prices of these drugs, we advocate the development of a readily available management algorithm of angioedema to reduce inappropriate prescriptions in our center. In addition, we think that the drug prescription circuit should be redesigned to ensure the traceability of prescribed vials in the dispensing areas.