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1.
Brasília; CONITEC; nov. 2023.
Não convencional em Português | BRISA/RedTESA | ID: biblio-1538318

RESUMO

INTRODUÇÃO: O angioedema hereditário (AEH) é classificado como uma doença genética ultrarrara, potencialmente fatal e subdiagnosticada. É uma imunodeficiência primária do sistema complemento, e foi classificado como um erro inato da imunidade em decorrência da deficiência de inibidor de C1 esterase (C1-INH), proteína que controla as vias de ativação do complemento. A alteração do C1-INH leva ao aumento da produção de bradicinina que, por sua vez, causa vasodilatação, aumento da permeabilidade dos vasos e extravasamento de plasma. O AEH não tem cura, porém há opções terapêuticas para a profilaxia e controle das crises agudas. Conforme o atual PCDT de AEH, o tratamento das crises agudas com deficiência de C1-INH é realizado em ambiente hospitalar, com uso de plasma fresco congelado, caso exista o risco de asfixia para o paciente. O plasma fresco congelado não foi testado em ensaios clínicos quanto à sua eficácia e segurança nas crises de AEH, e sua administração oferece não apenas a reposição do C1-INH, mas também os substratos nos quais esse inibidor atua, podendo agravar o quadro, além da possibilidade de ocorrência de reações transfusionais e transmissão de patógenos. PERGUNTAS DE PESQUISA: O acetato de icatibanto é efetivo no tratamento de crises de angioedema hereditário em pacientes com 2 anos ou mais comparado ao plasma fresco congelado para redução de comparecimento à emergência, redução do tempo de internação em terapia intensiva, melhora da qualidade de vida, mortalidade e eventos adversos? O demandante externo elaborou a seguinte pergunta de pesquisa: Qual a eficácia, efetividade e segurança de icatibanto no tratamento de pacientes adultos com crises agudas de AEH com deficiência de C1-INH. EVIDÃ


Assuntos
Humanos , Angioedema Hereditário Tipos I e II/tratamento farmacológico , Antagonistas de Receptor B2 da Bradicinina/uso terapêutico , Sistema Único de Saúde , Brasil , Análise Custo-Benefício/economia
2.
J Dermatol ; 50(11): 1473-1477, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37381768

RESUMO

We evaluated the safety, efficacy, and pharmacokinetics of subcutaneous weight-adjusted icatibant for the treatment of acute hereditary angioedema attacks in Japanese pediatric patients. Two patients (aged 10-13 and 6-9 years) received icatibant for a total of four attacks. Each attack was abdominal and/or cutaneous and was treated with a single icatibant injection. Mild or moderate injection-site reactions were the only adverse events reported. Time to onset of symptom relief was 0.9-1.0 h. Icatibant was rapidly absorbed, with a pharmacokinetic profile consistent with previous studies. Simulated exposure levels were consistent with non-Japanese pediatric patients. These results support the safety and efficacy of icatibant in Japanese pediatric patients.


Assuntos
Angioedemas Hereditários , Antagonistas de Receptor B2 da Bradicinina , Criança , Humanos , Angioedemas Hereditários/tratamento farmacológico , Bradicinina/análogos & derivados , População do Leste Asiático , Injeções Subcutâneas , Resultado do Tratamento , Adolescente , Antagonistas de Receptor B2 da Bradicinina/farmacocinética , Antagonistas de Receptor B2 da Bradicinina/uso terapêutico
3.
Orphanet J Rare Dis ; 17(1): 399, 2022 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-36324138

RESUMO

Hereditary angioedema (HAE) is a rare autosomal dominant genetic disease characterized by repetitive subcutaneous or submucosal angioedema, activation of the kinin system, and increased vascular permeability. C1-inhibitor (C1-INH) deficiency, the main mechanism of HAE pathogenesis, occurs when abnormal activation of plasma kallikrein, bradykinin, and factor XII, or mutation of genes such as SERPING1 cause quantitative or functional C1-INH defects. Although androgens are not approved for HAE treatment in many countries, they are widely used in China and Brazil to reduce the frequency and severity of HAE attacks. The long-term adverse effects of androgen treatment are concerning for both physicians and patients. Virilization, weight gain, acne, hirsutism, liver damage, headache, myalgia, hematuria, menstrual disorders, diminished libido, arterial hypertension, dyslipidemia, and anxiety/depression are commonly observed during long-term treatment with androgens. These adverse effects can affect the quality of life of HAE patients and often lead to treatment interruption, especially in women and children. In-depth studies of the pathogenesis of HAE have led to the approval of alternative treatment strategies, including plasma-derived C1 inhibitor, recombinant human C1 inhibitor, plasma Kallikrein inhibitor (ecallantide; lanadelumab), and bradykinin B2 receptor antagonist (icatibant), some of which have achieved satisfactory results with mostly non-serious side effects. Therefore, a new standard of medical care may expand possibilities for the management of HAE in emerging countries.


Assuntos
Angioedemas Hereditários , Criança , Humanos , Feminino , Angioedemas Hereditários/tratamento farmacológico , Angioedemas Hereditários/prevenção & controle , Androgênios/uso terapêutico , Calicreína Plasmática , Qualidade de Vida , Proteína Inibidora do Complemento C1/uso terapêutico , Antagonistas de Receptor B2 da Bradicinina/uso terapêutico
4.
Acta Clin Croat ; 61(Suppl 1): 99-103, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36304798

RESUMO

Angioedema is a form of allergic mediated by histamine and non-allergic mediated by bradykinin and can be lethal if not recognized and treated promptly. This case demonstrates the proper diagnosis of and intervention in rapid onset severe angioedema. A 68-year-old male came to the emergency department with a complaint of dyspnea that started two hours before. He had type II diabetes, chronic kidney disease and several different antihypertensive medications, including an ACE inhibitor for hypertension. During physical examination, the patient was hypertensive, tachycardic, tachypnoic, and edematous. During his stay in the ED he was treated with a combination of corticosteroids, antihistamines and epinephrine, but the patient's edema and dyspnea worsened and his oxygen saturation started to deteriorate with a progression of skin edema. Intubation was not possible due to the large edema of the tongue, so a tracheotomy was done. An ampule of icatibant was administered and rapid regression of the edema, along with the stabilization of the patient's vital signs, followed after five minutes. The patient was discharged home after five days with a recommendation of discontinuing the ACE inhibitor. While non-hereditary angioedema is not a rare condition, emergency physicians should be adequately educated about it.


Assuntos
Angioedema , Diabetes Mellitus Tipo 2 , Hipertensão , Masculino , Humanos , Idoso , Antagonistas de Receptor B2 da Bradicinina/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Angioedema/diagnóstico , Angioedema/etiologia , Angioedema/terapia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Hipertensão/tratamento farmacológico , Dispneia/tratamento farmacológico
5.
Allergy Asthma Proc ; 43(2): 148-154, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35317892

RESUMO

Background: Patients' satisfaction is important for the success of the management of chronic diseases. Objective: Our aim was to evaluate the satisfaction level of the patients with hereditary angioedema (HAE) for icatibant treatment. Methods: Patients with HAE C1 esterase inhibitor (C1-INH) were evaluated by using a questionnaire that included details of their icatibant-treated attacks. Patients' demographic and clinical features were collected from their medical records and personal attack diaries. The visual analog scale was used for determining the attack severity. Results: Of the total 161 patients with HAE C1-INH, 91% had HAE type I and were included in the study. Patients reported a median (interquartile range [IQR]) attacks of 2 (0.5-3) per month and 16 (4.5-36) attacks per year. The median (IQR) frequency of attacks treated with icatibant was 6 (0-20) per year. The mean ± standard deviation (SD) duration of treatment with icatibant was 3 ± 2.3 years. The self-administration rate was 91.3%. The mean ± SD time to administration and time to onset of symptom resolution were 1.6 ± 1.1 hours and 1.7 ± 1.3 hours, respectively. There was a correlation between the time to administration and time to onset of symptom resolution (r = 0.566; p < 0.0001). A total of 125 patients (77%) reported that they were very satisfied or satisfied with icatibant. No correlation was observed between the satisfaction level and the attack sites; however, the patients with more severe attacks were more satisfied with icatibant (p < 0.0001). A total of 52 patients reported 74 mild local reactions. Systemic reactions were not observed. Conclusion: The current real-life study showed that icatibant was safe and effective. Moreover, the patients' satisfaction level with icatibant was high. We believe that the availability of icatibant should be encouraged during HAE attacks because it enables patients to be more involved in their disease management.


Assuntos
Angioedemas Hereditários , Bradicinina , Angioedemas Hereditários/diagnóstico , Angioedemas Hereditários/tratamento farmacológico , Bradicinina/análogos & derivados , Bradicinina/uso terapêutico , Antagonistas de Receptor B2 da Bradicinina/uso terapêutico , Proteína Inibidora do Complemento C1/uso terapêutico , Humanos , Resultado do Tratamento
6.
Nat Med ; 28(1): 39-50, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-35064248

RESUMO

Immune dysregulation is an important component of the pathophysiology of COVID-19. A large body of literature has reported the effect of immune-based therapies in patients with COVID-19, with some remarkable successes such as the use of steroids or anti-cytokine therapies. However, challenges in clinical decision-making arise from the complexity of the disease phenotypes and patient heterogeneity, as well as the variable quality of evidence from immunotherapy studies. This Review aims to support clinical decision-making by providing an overview of the evidence generated by major clinical trials of host-directed therapy. We discuss patient stratification and propose an algorithm to guide the use of immunotherapy strategies in the clinic. This will not only help guide treatment decisions, but may also help to design future trials that investigate immunotherapy in other severe infections.


Assuntos
Anticoagulantes/uso terapêutico , COVID-19/terapia , Inativadores do Complemento/uso terapêutico , Glucocorticoides/uso terapêutico , Fatores Imunológicos/uso terapêutico , Imunomodulação , Inibidores de Proteínas Quinases/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , Azetidinas/uso terapêutico , Bradicinina/análogos & derivados , Bradicinina/uso terapêutico , Antagonistas de Receptor B2 da Bradicinina/uso terapêutico , COVID-19/imunologia , Dexametasona/uso terapêutico , Combinação de Medicamentos , Inibidores do Fator Xa/uso terapêutico , Heparina/uso terapêutico , Humanos , Hidrocortisona/uso terapêutico , Mesilato de Imatinib/uso terapêutico , Imunização Passiva , Interferon beta-1a/uso terapêutico , Interferon beta-1b/uso terapêutico , Interferon gama/uso terapêutico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Sistema Calicreína-Cinina , Piperidinas/uso terapêutico , Purinas/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , SARS-CoV-2 , Sulfonamidas/uso terapêutico , Soroterapia para COVID-19
7.
Clin Exp Immunol ; 206(3): 378-383, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34586637

RESUMO

Acquired angioedema due to C1-inhibitor (C1-INH) deficiency (AAE-C1-INH) is rare and is associated with underlying lymphoproliferative diseases. C1-INH deficiency may be due to neoplastic over-consumption of C1-INH and the generation of anti-C1-INH autoantibodies. Uncovering an occult malignancy can lead to earlier oncology referral and improvement of angioedema after treatment of the underlying lymphoproliferative disorder. We characterized seven patients with C1-INH-AAE that highlights the importance of recognizing the association between C1-INH-AAE and underlying malignancy. In acute attacks, patients may be resistant to C1-INH therapy due to the presence of anti-C1-INH autoantibodies or rapid complement consumption, and may respond better to icatibant or ecallantide, which directly affect bradykinin. Treatment of the underlying malignancy also improves AAE-C1-INH symptoms and supports the role of lymphoproliferative B cells in AAE-C1-INH pathophysiology. Monitoring levels of C4, C1-INH function and level, and C1q may be predictive of AAE-C1-INH control and be used as surrogates for treatment efficacy. With close monitoring, low-dose danazol can be effective for long-term prophylaxis. Annual evaluation in AAE-C1-INH is recommended if an underlying malignancy is not found, as angioedema may precede the development of malignancy by several years. Our single-center study has aided in standardization of comprehensive AAE-C1-INH diagnosis, treatment, and monitoring strategies towards future therapeutic clinical trials.


Assuntos
Angioedema/patologia , Proteína Inibidora do Complemento C1/genética , Angioedema Hereditário Tipos I e II/genética , Transtornos Linfoproliferativos/patologia , Idoso , Angioedema/genética , Anti-Inflamatórios não Esteroides/uso terapêutico , Autoanticorpos/imunologia , Bradicinina/análogos & derivados , Bradicinina/uso terapêutico , Antagonistas de Receptor B2 da Bradicinina/uso terapêutico , Proteína Inibidora do Complemento C1/imunologia , Complemento C1q/antagonistas & inibidores , Complemento C1q/metabolismo , Feminino , Humanos , Transtornos Linfoproliferativos/genética , Masculino , Pessoa de Meia-Idade , Peptídeos/uso terapêutico , Estudos Retrospectivos
8.
Allergy Asthma Proc ; 42(2): 108-117, 2021 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-33581742

RESUMO

Background: Novel subcutaneous (SC) prophylactic therapies are transforming the treatment landscape of hereditary angioedema (HAE). Although questions are being raised about their cost, little attention has been paid to the cost and quality of life (QoL) impact of using on-demand-only medications. Objective: We assessed the overall economic burden of on-demand-only treatment for HAE and compared patient QoL with patients who received novel SC prophylactic therapies. Methods: US Hereditary Angioedema Association members were invited to complete an anonymous online survey to profile attack frequency, treatment use, and the presence of comorbidities as well as economic and socioeconomic variables. We modeled on-demand treatment costs by using net pricing of medications in 2018, indirect patient and caregiver costs, and attack-related direct billed costs for emergency department admissions, physician office visits, and/or hospitalizations. QoL was assessed by using the Angioedema Quality of Life questionnaire. Results: A total of 1225 patients (31.4%) responded. Of these, 737 adults with HAE (type I or II) met the inclusion criteria and completed the survey. Per patient/year direct costs associated with modeled on-demand-only treatment totaled $363,795, with additional indirect socioeconomic costs of $52,576 per patient/year. The greatest improvement in QoL was seen in patients who used novel SC prophylactic therapies, with a 59.5% (p < 0.01) improvement in median impairment scores versus on-demand-only treatment. In addition, patients who used novel SC prophylactic therapies reported a 77% reduction in the number of attacks each year when compared with those who used on-demand-only treatment. Conclusion: Our real-world patient data showed the cost and QoL burden of HAE treatment with on-demand-only therapy. Use of novel SC prophylaxis can lead to sizeable reductions in attack frequency and statistically significant and clinically relevant improvements in QoL. These data could be useful to clinicians and patients as they consider therapy options for patients with HAE.


Assuntos
Angioedemas Hereditários/tratamento farmacológico , Angioedemas Hereditários/prevenção & controle , Anti-Inflamatórios não Esteroides/administração & dosagem , Quimioprevenção , Proteína Inibidora do Complemento C1/administração & dosagem , Custos de Medicamentos/estatística & dados numéricos , Qualidade de Vida , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Angioedemas Hereditários/economia , Anti-Inflamatórios não Esteroides/economia , Anti-Inflamatórios não Esteroides/uso terapêutico , Anticorpos Monoclonais Humanizados/economia , Anticorpos Monoclonais Humanizados/uso terapêutico , Bradicinina/análogos & derivados , Bradicinina/economia , Bradicinina/uso terapêutico , Antagonistas de Receptor B2 da Bradicinina/economia , Antagonistas de Receptor B2 da Bradicinina/uso terapêutico , Quimioprevenção/economia , Quimioprevenção/métodos , Estudos de Coortes , Proteína Inibidora do Complemento C1/economia , Proteína Inibidora do Complemento C1/uso terapêutico , Progressão da Doença , Esquema de Medicação , Feminino , Inquéritos Epidemiológicos , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Peptídeos/economia , Peptídeos/uso terapêutico , Proteínas Recombinantes/economia , Proteínas Recombinantes/uso terapêutico , Autorrelato , Resultado do Tratamento , Estados Unidos , Adulto Jovem
9.
Allergol Int ; 70(1): 45-54, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32919903

RESUMO

Hereditary angioedema (HAE) is characterized by unpredictable, recurring and painful swelling episodes that can be disabling or even life-threatening. Awareness of HAE has progressively grown worldwide, and options for treatment of acute attacks and prevention of future attacks continue to expand; however, unmet needs in diagnosis and treatment remain. In Japan, recognition of HAE within the medical community remains low, and numerous obstacles complicate diagnosis and access to treatment. Importance of timely treatment of HAE attacks with on-demand therapies is continually demonstrated; recommended agents per the WAO/EAACI treatment guidelines published in 2018 include C1 inhibitor (C1-INH) concentrate, ecallantide, and icatibant. In Japan, multiple factors contribute to delayed HAE treatment (potentially leading to life-threatening consequences), including difficulties in finding facilities at which C1-INH agents are readily available. Recognition of challenges faced in Japan can help promote efforts to address current needs and expand access to effective therapies. Icatibant, a potent, selective bradykinin B2 receptor antagonist, has demonstrated inhibition of various bradykinin-induced biological effects in preclinical studies and has shown efficacy in treating attacks in various clinical settings (e.g. clinical trials, real-world studies), and HAE patient populations (e.g. with C1-INH deficiency, normal C1-INH). Icatibant was approved in Japan for the treatment of HAE attacks in September 2018; its addition to the HAE treatment armamentarium contributes to improved patient care. In Japan, disease awareness and education campaigns are warranted to further advance the management of HAE patients in light of the unmet needs and the emerging availability of modern diagnostic approaches and therapies.


Assuntos
Angioedemas Hereditários/epidemiologia , Angioedemas Hereditários/terapia , Angioedemas Hereditários/diagnóstico , Angioedemas Hereditários/etiologia , Bradicinina/administração & dosagem , Bradicinina/efeitos adversos , Bradicinina/análogos & derivados , Bradicinina/uso terapêutico , Antagonistas de Receptor B2 da Bradicinina/administração & dosagem , Antagonistas de Receptor B2 da Bradicinina/efeitos adversos , Antagonistas de Receptor B2 da Bradicinina/uso terapêutico , Proteína Inibidora do Complemento C1/genética , Gerenciamento Clínico , Progressão da Doença , Suscetibilidade a Doenças , Humanos , Japão , Guias de Prática Clínica como Assunto , Vigilância em Saúde Pública , Resultado do Tratamento
11.
J Clin Pharmacol ; 61(4): 555-564, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33091166

RESUMO

Elevated bradykinin levels are responsible for the development of clinical symptoms in patients with hereditary angioedema (HAE). Icatibant is a bradykinin type 2 receptor antagonist indicated for the acute treatment of HAE attacks. A population modeling and simulation approach was used to examine sources of variability impacting icatibant pharmacokinetics (PK) and provide guidance on icatibant dosing in pediatric patients with HAE. An exposure-response analysis was performed for the time to onset of symptom relief (TOSR). Data from 141 adults (133 healthy, 8 with HAE) who received subcutaneous icatibant 30 mg and 31 pediatric patients with HAE who received 0.4 mg/kg (capped at 30 mg) were included in the analysis. Icatibant PK was described by a 2-compartment model with linear elimination. Complete absorption of icatibant was expected within 1 hour of dosing. The apparent clearance and central volume of distribution were 15.4 L/h and 20.4 L, respectively. Icatibant PK was mainly dependent on body weight. The mean TOSR was very short (1.38 hours). A flat exposure-response was observed, confirming that the relationship plateaued at the level of exposure observed in pediatric patients. Simulations confirmed that weight band-based dosing regimens (10 mg [12-25 kg], 15 mg [26-40 kg], 20 mg [41-50 kg], 25 mg [51-65 kg], and 30 mg [>65 kg]) resulted in exposure similar to the 0.4-mg/kg dose. This analysis showed that icatibant undergoes rapid absorption, reaches levels required for therapeutic response, and promptly relieves HAE symptoms. A weight band-based dosing regimen is appropriate in pediatric patients with HAE.


Assuntos
Angioedemas Hereditários/tratamento farmacológico , Antagonistas de Receptor B2 da Bradicinina/farmacocinética , Antagonistas de Receptor B2 da Bradicinina/uso terapêutico , Bradicinina/análogos & derivados , Adolescente , Adulto , Peso Corporal , Bradicinina/farmacocinética , Bradicinina/uso terapêutico , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Adulto Jovem
13.
Iran J Immunol ; 17(3): 226-235, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32996899

RESUMO

BACKGROUND: Hereditary angioedema (HAE) is a rare genetic potentially life-threatening disease characterized by episodic non-pruritic subcutaneous and submucosal edema attacks in different parts of the body. OBJECTIVE: To assess the status of Romanian HAE patients after the recent introduction of a new therapy through a nationwide program. METHODS: This cross-sectional observational study included patients from the Romanian HAE Registry. RESULTS: The study included 84 patients with HAE type I (91.7%) and type II (8.3%). The mean delay in diagnosis was 2.4 years in children and 16.7 years in adults (p=0.019). Stress and tiredness were the most frequent trigger factors. The majority of the HAE episodes involved subcutaneous (89.3%), abdominal (77.4%), genital (51.2%), facial (41.7%), and laryngeal (39.3%) symptoms during the preceding 12 months. One or several misdiagnoses were reported in 83.33% patients and 44.1 % of the patients were subjected to or proposed unnecessary surgery during abdominal episodes. Plasma-derived C1-INH (pdC1-INH) and recombinant C1-INH (rhC1-INH) were respectively used in 10 (11.9%) and 13 (15.5%) of the HAE patients for life-threatening attacks over the past 12 months. Forty-three (51.19%) patients practiced home treatment with subcutaneous injection of the bradykinin B2-receptor antagonist for acute HAE attacks. CONCLUSION: The significantly lower delay observed in children suggests an improvement in the awareness of C1-INH-HAE among physicians in recent years. The management of HAE in Romania has been somewhat enhanced as the majority of HAE patients have recently gained access to pdC1-INH, rhC1-INH, and bradykinin B2-receptor antagonist.


Assuntos
Antagonistas de Receptor B2 da Bradicinina/uso terapêutico , Proteína Inibidora do Complemento C1/genética , Angioedema Hereditário Tipos I e II/diagnóstico , Adulto , Criança , Proteína Inibidora do Complemento C1/uso terapêutico , Estudos Transversais , Diagnóstico Tardio , Quimioterapia Combinada , Edema , Feminino , Angioedema Hereditário Tipos I e II/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Romênia , Adulto Jovem
15.
FASEB J ; 34(6): 7265-7269, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32359101

RESUMO

As of April 20, 2020, over time, the COVID-19 pandemic has resulted in 157 970 deaths out of 2 319 066 confirmed cases, at a Case Fatality Rate of ~6.8%. With the pandemic rapidly spreading, and health delivery systems being overwhelmed, it is imperative that safe and effective pharmacotherapeutic strategies are rapidly explored to improve survival. In this paper, we use established and emerging evidence to propose a testable hypothesis that, a vicious positive feedback loop of des-Arg(9)-bradykinin- and bradykinin-mediated inflammation â†’ injury â†’ inflammation, likely precipitates life threatening respiratory complications in COVID-19. Through our hypothesis, we make the prediction that the FDA-approved molecule, icatibant, might be able to interrupt this feedback loop and, thereby, improve the clinical outcomes. This hypothesis could lead to basic, translational, and clinical studies aimed at reducing COVID-19 morbidity and mortality.


Assuntos
Betacoronavirus , Antagonistas de Receptor B2 da Bradicinina/uso terapêutico , Bradicinina/análogos & derivados , Infecções por Coronavirus/fisiopatologia , Modelos Biológicos , Peptidil Dipeptidase A/fisiologia , Pneumonia Viral/fisiopatologia , Receptores Virais/fisiologia , Enzima de Conversão de Angiotensina 2 , Bradicinina/farmacologia , Bradicinina/fisiologia , Bradicinina/uso terapêutico , Antagonistas de Receptor B2 da Bradicinina/farmacologia , COVID-19 , Ensaios de Uso Compassivo , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Dispneia/etiologia , Dispneia/fisiopatologia , Retroalimentação Fisiológica/efeitos dos fármacos , Humanos , Inflamação , Uso Off-Label , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Receptores da Bradicinina/efeitos dos fármacos , Receptores da Bradicinina/fisiologia , SARS-CoV-2 , Tratamento Farmacológico da COVID-19
16.
Allergol Int ; 69(2): 268-273, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31672405

RESUMO

BACKGROUND: Hereditary angioedema (HAE) is a genetic disease characterized by recurrent swelling episodes affecting the skin, gastrointestinal mucosa, and upper respiratory tract. METHODS: A phase 3, single-arm, open-label study was performed to evaluate a selective bradykinin B2 receptor antagonist, icatibant, for the treatment of acute attacks in Japanese patients with HAE Type I or II. After the onset of an acute attack, icatibant 30 mg was administered by the patient or a healthcare professional via subcutaneous injection in the abdomen. RESULTS: Eight patients who had an attack affecting the skin (n = 4), abdomen (n = 3), or larynx (n = 1) were treated with icatibant (3 of the injections were self-administered). The median time to onset of symptom relief was 1.75 h (95% confidence interval, 1.00-2.50), and all patients had symptom relief within 5 h after administration. The time to maximum plasma concentration of icatibant was 1.79 h, and the maximum plasma concentration was 405 ng/ml. Seven patients experienced an injection site reaction, and 3 patients had adverse events (2 patients had a worsening or repeat HAE attack 29.0 and 18.3 h after icatibant administration, respectively, and 1 had headache). CONCLUSIONS: Although the number of patients is small, the efficacy and tolerability of icatibant for acute attacks were demonstrated in Japanese patients with HAE, regardless of self-administration or administration by healthcare professional.


Assuntos
Angioedemas Hereditários/tratamento farmacológico , Anti-Inflamatórios não Esteroides/uso terapêutico , Antagonistas de Receptor B2 da Bradicinina/uso terapêutico , Bradicinina/análogos & derivados , Doença Aguda , Adulto , Bradicinina/farmacocinética , Bradicinina/uso terapêutico , Antagonistas de Receptor B2 da Bradicinina/farmacocinética , Progressão da Doença , Feminino , Humanos , Injeções Subcutâneas , Japão , Masculino , Pessoa de Meia-Idade , Autoadministração , Resultado do Tratamento
17.
Int Immunopharmacol ; 78: 106081, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31835086

RESUMO

Angioedema (AE) occurring during ACE inhibitor therapy (ACEi-AE) is a rare complication involving between 0.1 and 0.7% of treated patients. AE can also complicate other therapeutic regimens that block the renin-angiotensin aldosterone system. Other drugs, such as immune suppressors, some type of antidiabetics or calcium antagonists, can increase the likelihood of ACEi-AE when associated to ACEi. There is a clear ethnic predisposition, since African-Americans or Hispanics show a higher prevalence of this condition compared to Caucasians. At least in African-Americans the genetic predisposition accounts for a general higher prevalence of AE, independently from the cause. People that experience ACEi-AE may have some recurrence when they are switched to an angiotensin-receptor blocker (ARB); however, epidemiological studies on large cohorts have shown that angiotensin receptor blockers (ARB) do not increase the likelihood of AE compared to other antihypertensives. Clinical manifestations consist of edema of face, lips, tongue, uvula and upper airways, requiring intubation or tracheotomy in severe cases. Attacks last for 48-72 h and require hospital admission in most cases. Intestinal involvement with sub-occlusive symptoms has also been reported. The pathogenesis of ACEi-AE depends mainly on a reduced catabolism and accumulation of bradykinin, which is normally metabolized by ACE. Genetic studies have shown that some single nucleotide polymorphisms at genes encoding relevant molecules for bradykinin metabolism and action may be involved in ACEi-AE, giving a basis for the ethnic predisposition. Treatment of ACEi-AE is still a matter of debate. Corticosteroids and antihistamines do not show efficacy. Some therapeutic attempts have shown some efficacy for fresh frozen plasma or C1 inhibitor concentrate infusion. Interventional studies with the specific bradykinin receptor antagonist icatibant have shown conflicting results; there might be a different ethnic predisposition to icatibant efficacy which has been proven in caucasian but not in black patients.


Assuntos
Angioedema/induzido quimicamente , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Bradicinina/imunologia , Hipertensão/tratamento farmacológico , Peptidil Dipeptidase A/metabolismo , Negro ou Afro-Americano , Angioedema/epidemiologia , Angioedema/imunologia , Angioedema/terapia , Antagonistas de Receptores de Angiotensina/administração & dosagem , Transfusão de Componentes Sanguíneos/métodos , Bradicinina/análogos & derivados , Bradicinina/metabolismo , Bradicinina/uso terapêutico , Antagonistas de Receptor B2 da Bradicinina/uso terapêutico , Proteína Inibidora do Complemento C1/uso terapêutico , Feminino , Humanos , Masculino , Plasma , Recidiva , Sistema Renina-Angiotensina/efeitos dos fármacos , Fatores de Risco , Fatores Sexuais
18.
Oncol Rep ; 42(6): 2521-2527, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31638249

RESUMO

It has been reported recently that bradykinin (BK) is involved in the regulation of various processes in cancer cells. However, its role and underlying mechanism of action in cervical cancer (CC) are still unknown. In the present study, it was revealed that BK promoted proliferation, migration, and invasion of CC cells, whereas bradykinin B2 receptor antagonist HOE140 had the inverse effect. Furthermore, it was confirmed that overexpression of bradykinin B2 receptor (B2R) facilitated the proliferation, migration, and invasion of BK­treated CC cells, while knockdown of B2R had the opposite effect. Mechanistically, the present results revealed that the BK/B2R­induced biological function of CC cells occured by activating STAT3 signaling pathways, and that knockdown of B2R or B2R antagonist had the opposite effects. Moreover, it was demonstrated that BK/B2R facilitated CC cell migration and invasion by upregulating the expression of the STAT3­regulated products MMP2 and MMP9, while downregulating the expression of the pro­apoptotic protein cleaved caspase­9. Thus, the present findings revealed that BK promoted CC cell proliferation, migration, and invasion by binding to B2R via STAT3 signaling pathways.


Assuntos
Antagonistas de Receptor B2 da Bradicinina/farmacologia , Bradicinina/metabolismo , Receptor B2 da Bradicinina/metabolismo , Fator de Transcrição STAT3/metabolismo , Neoplasias do Colo do Útero/patologia , Antagonistas de Receptor B2 da Bradicinina/uso terapêutico , Caspase 9/metabolismo , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Células HeLa , Humanos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Invasividade Neoplásica/prevenção & controle , Receptor B2 da Bradicinina/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/genética
19.
West J Emerg Med ; 20(4): 587-600, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31316698

RESUMO

Angioedema is defined by non-dependent, non-pitting edema that affects several different sites and is potentially life-threatening due to laryngeal edema. This narrative review provides emergency physicians with a focused overview of the evaluation and management of angioedema. Two primary forms include histamine-mediated and bradykinin-mediated angioedema. Histamine-mediated forms present similarly to anaphylaxis, while bradykinin-mediated angioedema presents with greater face and oropharyngeal involvement and higher risk of progression. Initial evaluation and management should focus on evaluation of the airway, followed by obtaining relevant historical features, including family history, medications, and prior episodes. Histamine-mediated angioedema should be treated with epinephrine intramuscularly, antihistaminergic medications, and steroids. These medications are not effective for bradykinin-mediated forms. Other medications include C1-INH protein replacement, kallikrein inhibitor, and bradykinin receptor antagonists. Evidence is controversial concerning the efficacy of these medications in an acute episode, and airway management is the most important intervention when indicated. Airway intervention may require fiberoptic or video laryngoscopy, with preparation for cricothyrotomy. Disposition is dependent on patient's airway and respiratory status, as well as the sites involved.


Assuntos
Angioedema/etiologia , Angioedema/terapia , Serviço Hospitalar de Emergência , Manuseio das Vias Aéreas , Algoritmos , Anti-Inflamatórios não Esteroides/uso terapêutico , Fatores de Coagulação Sanguínea/uso terapêutico , Bradicinina/análogos & derivados , Bradicinina/metabolismo , Bradicinina/uso terapêutico , Antagonistas de Receptor B2 da Bradicinina/uso terapêutico , Broncodilatadores/uso terapêutico , Epinefrina/uso terapêutico , Glucocorticoides/uso terapêutico , Histamina/metabolismo , Antagonistas dos Receptores Histamínicos/uso terapêutico , Humanos , Peptídeos/uso terapêutico , Plasma , Urticária/etiologia
20.
Expert Opin Biol Ther ; 19(6): 517-526, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30912460

RESUMO

INTRODUCTION: Hereditary angioedema due to C1-INH deficiency (C1-INH-HAE) is a rare disease with unpredictable, self-limiting and localized swelling episodes involving the cutaneous and subcutaneous tissues. In the last decade, the spectrum of the possibilities to control the disease has considerably changed with the development of biologic therapies making necessary a careful evaluation of the differences among current and emerging treatments to properly optimize the management of patients. AREAS COVERED: This review serves to summarize the literature regarding the use of biologics for the treatment of C1-INH-HAE. Medications already available on the market and new drugs in different phases of development are addressed. EXPERT OPINION: The advent of biologic therapies dramatically improved the lives of patients with C1-INH-HAE although further improvement is still needed. Whether this is cost/effective will be answered in the next years when we will see if these major advances will benefit the majority of the patients.


Assuntos
Angioedemas Hereditários/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Angioedemas Hereditários/genética , Anticorpos Monoclonais/uso terapêutico , Antagonistas de Receptor B2 da Bradicinina/uso terapêutico , Proteína Inibidora do Complemento C1/metabolismo , Proteína Inibidora do Complemento C1/uso terapêutico , Fator XII/imunologia , Terapia Genética , Humanos , Calicreínas/antagonistas & inibidores , Calicreínas/metabolismo , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/uso terapêutico
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