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1.
N Engl J Med ; 376(12): 1131-1140, 2017 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-28328347

RESUMO

BACKGROUND: Hereditary angioedema is a disabling, potentially fatal condition caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein. In a phase 2 trial, the use of CSL830, a nanofiltered C1 inhibitor preparation that is suitable for subcutaneous injection, resulted in functional levels of C1 inhibitor activity that would be expected to provide effective prophylaxis of attacks. METHODS: We conducted an international, prospective, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, phase 3 trial to evaluate the efficacy and safety of self-administered subcutaneous CSL830 in patients with type I or type II hereditary angioedema who had had four or more attacks in a consecutive 2-month period within 3 months before screening. We randomly assigned the patients to one of four treatment sequences in a crossover design, each involving two 16-week treatment periods: either 40 IU or 60 IU of CSL830 per kilogram of body weight twice weekly followed by placebo, or vice versa. The primary efficacy end point was the number of attacks of angioedema. Secondary efficacy end points were the proportion of patients who had a response (≥50% reduction in the number of attacks with CSL830 as compared with placebo) and the number of times that rescue medication was used. RESULTS: Of the 90 patients who underwent randomization, 79 completed the trial. Both doses of CSL830, as compared with placebo, reduced the rate of attacks of hereditary angioedema (mean difference with 40 IU, -2.42 attacks per month; 95% confidence interval [CI], -3.38 to -1.46; and mean difference with 60 IU, -3.51 attacks per month; 95% CI, -4.21 to -2.81; P<0.001 for both comparisons). Response rates were 76% (95% CI, 62 to 87) in the 40-IU group and 90% (95% CI, 77 to 96) in the 60-IU group. The need for rescue medication was reduced from 5.55 uses per month in the placebo group to 1.13 uses per month in the 40-IU group and from 3.89 uses in the placebo group to 0.32 uses per month in the 60-IU group. Adverse events (most commonly mild and transient local site reactions) occurred in similar proportions of patients who received CSL830 and those who received placebo. CONCLUSIONS: In patients with hereditary angioedema, the prophylactic use of a subcutaneous C1 inhibitor twice weekly significantly reduced the frequency of acute attacks. (Funded by CSL Behring; COMPACT EudraCT number, 2013-000916-10 , and ClinicalTrials.gov number, NCT01912456 .).


Assuntos
Proteína Inibidora do Complemento C1/administração & dosagem , Angioedema Hereditário Tipos I e II/prevenção & controle , Adulto , Proteína Inibidora do Complemento C1/efeitos adversos , Proteína Inibidora do Complemento C1/metabolismo , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Angioedema Hereditário Tipos I e II/classificação , Humanos , Injeções Subcutâneas , Masculino , Risco , Autoadministração , Índice de Gravidade de Doença
2.
Int Arch Allergy Immunol ; 179(3): 187-191, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30943491

RESUMO

BACKGROUND: The prevalence of peanut allergy (PA) is constantly on the rise. Atopic dermatitis (AD) is a major risk factor for developing food allergy. Some bath oils and skin creams used for treating AD contain peanut oil, and it has been suggested that exposure to peanut allergens through a disrupted skin barrier is a potential cause of PA. Our aim was to investigate whether application of peanut oil to irritated skin causes a systemic or respiratory allergic response to peanuts in an animal model. METHODS: BALB/c mice underwent epicutaneous sensitization with either peanut oil (PM, n = 9) or phosphate buffered solution (controls, n = 9) daily for 5 consecutive days. Ten days after the last exposure the mice were challenged with intranasal peanut protein for 5 consecutive days. Bronchial alveolar lavage fluid was collected for cellular studies and measurement of cytokine levels. Sera were collected for immunoglobulin E (IgE) measurement. RESULTS: Epicutaneous peanut oil sensitization increased leukocyte and eosinophil counts and interleukin-13 levels (p = 0.003, p = 0.0006 and p = 0.03, respectively), in addition to increasing total serum IgE (p = 0.03). CONCLUSIONS: The results suggest that topical application of peanut oil may play a role in the etiology of PA.


Assuntos
Alérgenos/administração & dosagem , Antígenos de Plantas/administração & dosagem , Hipersensibilidade a Amendoim , Óleo de Amendoim/administração & dosagem , Hipersensibilidade Respiratória , Administração Cutânea , Animais , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/imunologia , Feminino , Imunoglobulina E/sangue , Interleucina-13/imunologia , Interleucina-4/imunologia , Contagem de Leucócitos , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Camundongos Endogâmicos BALB C , Hipersensibilidade a Amendoim/sangue , Hipersensibilidade a Amendoim/imunologia , Hipersensibilidade Respiratória/sangue , Hipersensibilidade Respiratória/imunologia
3.
Pediatr Allergy Immunol ; 30(5): 562-568, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30993784

RESUMO

BACKGROUND: Attacks of hereditary angioedema (HAE) due to C1 esterase inhibitor deficiency (C1-INH-HAE) usually begin during childhood or adolescence. However, limited data are available regarding indications and modalities of treatment of children. This study evaluated recombinant human C1-INH (rhC1-INH) for HAE attacks in children. METHODS: This open-label, phase 2 study included children aged 2-13 years with C1-INH-HAE. Eligible HAE attacks were treated intravenously with rhC1-INH 50 IU/kg body weight (maximum, 4200 IU). The primary end-point was time to beginning of symptom relief (TOSR; ≥20 mm decrease from baseline in visual analog scale [VAS] score, persisting for two consecutive assessments); secondary end-point was time to minimal symptoms (TTMS; <20 mm VAS score for all anatomic locations). RESULTS: Twenty children (aged 5-14 years; 73 HAE attacks) were treated with rhC1-INH. Seventy (95.9%) of the attacks were treated with a single dose of rhC1-INH. Seven (35.0%) children were treated for four or more attacks. Overall, median TOSR was 60.0 minutes (95% confidence interval [CI], 60.0-65.0); data were consistent across attacks. Median TTMS was 122.5 minutes (95% CI, 120.0-126.0); data were consistent across attacks. No children withdrew from the study due to adverse events. No treatment-related serious adverse events or hypersensitivity reactions were reported; no neutralizing antibodies were detected. CONCLUSIONS: Recombinant human C1-INH was efficacious, safe, and well tolerated in children. Data support use of the same dosing regimen for HAE attacks in children (50 IU/kg; up to 4200 IU, followed by an additional dose, if needed) as is currently recommended for adolescents and adults.


Assuntos
Angioedemas Hereditários/tratamento farmacológico , Proteína Inibidora do Complemento C1/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Administração Intravenosa , Adolescente , Peso Corporal , Criança , Pré-Escolar , Protocolos Clínicos , Cálculos da Dosagem de Medicamento , Feminino , Humanos , Masculino , Resultado do Tratamento
4.
Lancet ; 390(10102): 1595-1602, 2017 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-28754491

RESUMO

BACKGROUND: Hereditary angio-oedema is a recurrent, oedematous disorder caused by deficiency of functional C1 inhibitor. Infusions of plasma-derived C1 esterase inhibitor deter attacks of hereditary angio-oedema, but the prophylactic effect of recombinant human C1 esterase inhibitor has not been rigorously studied. We aimed to assess the efficacy of recombinant human C1 esterase inhibitor for prophylaxis of hereditary angio-oedema. METHODS: We conducted this phase 2, multicentre, randomised, double-blind, placebo-controlled crossover trial at ten centres in Canada, the Czech Republic, Israel, Italy, Macedonia, Romania, Serbia, and the USA. We enrolled patients aged 13 years or older with functional C1-inhibitor concentrations of less than 50% of normal and a history of four or more attacks of hereditary angio-oedema per month for at least 3 months before study initiation. Patients were randomly assigned centrally (1:1:1:1:1:1), via an interactive response technology system with fixed allocation, to receive one of six treatment sequences. During each sequence, patients received intravenous recombinant human C1 esterase inhibitor (50 IU/kg; maximum 4200 IU) twice weekly, recombinant human C1 esterase inhibitor once weekly and placebo once weekly, and placebo twice weekly, each for 4 weeks with a 1 week washout period between crossover. All patients, investigators, and study personnel who participated in patient care were masked to group allocation during the study. The primary efficacy endpoint was the number of attacks of hereditary angio-oedema observed in each 4 week treatment period. Attack symptoms were recorded daily. The primary efficacy analysis was done in the intention-to-treat population. Safety was assessed in all patients who received at least one injection of study medication. This study is registered with ClinicalTrials.gov, number NCT02247739. FINDINGS: Between Dec 29, 2014, and May 3, 2016, we enrolled 35 patients, of whom 32 (91%) underwent randomisation (intention-to-treat population) and 26 (81%) completed the study. The mean number of attacks of hereditary angio-oedema over 4 weeks was significantly reduced with recombinant human C1 esterase inhibitor twice weekly (2·7 attacks [SD 2·4]) and once weekly (4·4 attacks [3·2]) versus placebo (7·2 attacks [3·6]), with mean differences of -4·4 attacks (p<0·0001) and -2·8 attacks (p=0·0004), respectively. We recorded adverse events in ten (34%) of 29 patients given twice-weekly recombinant human C1 esterase inhibitor, 13 (45%) of 29 patients given the once-weekly regimen, and eight (29%) of 28 patients given placebo. Headache (twice-weekly treatment) and nasopharyngitis (once-weekly treatment) were the most common adverse events. Two (7%) adverse events (fatigue and headache) were deemed possibly related to treatment with recombinant human C1 esterase inhibitor, but both resolved without additional treatment. No thrombotic or thromboembolic events, systemic allergic reactions (including anaphylaxis), or neutralising antibodies were reported. INTERPRETATION: Prophylaxis with recombinant human C1 esterase inhibitor provided clinically relevant reductions in frequency of hereditary angio-oedema attacks and was well tolerated. In view of the pharmacokinetic profile of recombinant human C1 esterase inhibitor, our results suggest that efficacy of C1-inhibitor replacement therapy might not be a direct function of plasma trough concentrations of C1 inhibitor. FUNDING: Pharming Technologies.


Assuntos
Angioedemas Hereditários/prevenção & controle , Proteína Inibidora do Complemento C1/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Adolescente , Adulto , Idoso , Angioedemas Hereditários/sangue , Proteína Inibidora do Complemento C1/efeitos adversos , Proteína Inibidora do Complemento C1/farmacocinética , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Masculino , Taxa de Depuração Metabólica/fisiologia , Pessoa de Meia-Idade , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/sangue , Proteínas Recombinantes/farmacocinética , Resultado do Tratamento , Adulto Jovem
5.
Isr Med Assoc J ; 20(4): 227-232, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29629730

RESUMO

BACKGROUND: Management of patients with hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) is evolving worldwide. Evaluating the Israeli experience may provide valuable insights. OBJECTIVES: To compare demographics and icatibant treatment patterns and outcomes in patients with C1-INH-HAE enrolled in the Icatibant Outcome Survey (IOS) in Israel with those in other countries. METHODS: The IOS is an ongoing observational study that prospectively monitors real-world icatibant safety/tolerability and treatment outcomes. RESULTS: By July 2016, 58 patients from Israel and 594 patients from other countries were enrolled. Median age at diagnosis (16.7 vs. 21.3 years, P = 0.036) and median delay between symptom onset and diagnosis (0.8 vs. 6.6 years, P = 0.025) were lower in Israel compared with other countries, respectively. Differences in attack severity were not significant (P = 0.156); however, during follow-up, Israeli patients were less likely to miss > 7 days of work/school due to C1-INH-HAE-related complications (P = 0.007). A trend was also shown in Israel for earlier time to treatment (median 0.5 vs. 1.3 hours, P = 0.076), attack duration was shorter (median 5.0 vs. 9.0 hours, P = 0.026), and patients more often self-administered icatibant (97.2% vs. 87.5%, P = 0.003), respectively. However, Israeli patients were less likely to treat attacks (P = 0.036). Whereas patients in Israel reported exclusive use of danazol for long-term prophylaxis, those in other countries used various agents, including C1-INH. CONCLUSIONS: Recognition of C1-INH-HAE and timeliness of icatibant treatment appear more favorable, and attack duration shorter, in Israel compared with other countries.


Assuntos
Angioedemas Hereditários/tratamento farmacológico , Anti-Inflamatórios não Esteroides/uso terapêutico , Bradicinina/análogos & derivados , Danazol/administração & dosagem , Autoadministração/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Angioedemas Hereditários/diagnóstico , Angioedemas Hereditários/fisiopatologia , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/efeitos adversos , Bradicinina/administração & dosagem , Bradicinina/efeitos adversos , Bradicinina/uso terapêutico , Diagnóstico Tardio , Feminino , Seguimentos , Humanos , Israel , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sistema de Registros , Índice de Gravidade de Doença , Inquéritos e Questionários , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
6.
Pediatr Allergy Immunol ; 28(4): 370-376, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28258590

RESUMO

BACKGROUND: The clinical expressions of hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) and its related burden may negatively affect patient quality of life. This study aimed to assess health-related quality of life (HRQoL) in children with C1-INH-HAE. METHODS: Children (N = 98: 34 C1-INH-HAE patients, 64 healthy controls) aged 3-18 years were recruited in Israel and Hungary. All individuals completed a demographic questionnaire, a disease activity and site questionnaire, and the Pediatric Quality of Life Inventory (PedsQL™) 4.0 Generic Core Scales (child self-report and maternal proxy report) to assess HRQoL. RESULTS: Among C1-INH-HAE patients, nine (26.5%) had 1-5 attacks/year, six (17.6%) had 6-18 attacks/year, eight (23.5%) had 25-60 attacks/year, and 11 (32.4%) were asymptomatic over the previous year. Children with C1-INH-HAE attacks demonstrated lower HRQoL than healthy control children across the total score, school, and psychosocial dimensions of the PedsQL™. The number of C1-INH-HAE attacks negatively correlated with the total HRQoL score (r = -0.48, p = 0.008), school-related HRQoL (r = -0.39, p = 0.02), and psychosocial HRQoL (r = -0.43, p = 0.01). Patients with multisite laryngeal, abdominal, and peripheral C1-INH-HAE attacks had a lower HRQoL compared with those who experienced solely peripheral attacks across the total score (p = 0.04), physical (p = 0.04), and school (p = 0.02) domains. There was no significant difference between asymptomatic C1-INH-HAE patients and healthy controls. CONCLUSIONS: Children with symptomatic C1-INH-HAE demonstrate impaired HRQoL compared with healthy controls. HRQoL was affected by the frequency and site of C1-INH-HAE attacks and mostly in the school and physical domains.


Assuntos
Angioedemas Hereditários/epidemiologia , Qualidade de Vida , Adolescente , Angioedemas Hereditários/genética , Criança , Pré-Escolar , Proteína Inibidora do Complemento C1/genética , Progressão da Doença , Feminino , Humanos , Hungria/epidemiologia , Israel/epidemiologia , Masculino , Instituições Acadêmicas , Inquéritos e Questionários
7.
Pediatr Allergy Immunol ; 28(7): 692-698, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28692169

RESUMO

BACKGROUND: The severe life-threatening characteristics of hereditary angioedema (HAE) with C1-inhibitor deficiency (C1-INH-HAE) can affect anxiety levels among pediatric patients. This emotional burden together with the physical restrictions of C1-INH-HAE may decrease children's health-related quality of life (HRQoL). OBJECTIVES: (i) To compare anxiety state and trait between children with C1-INH-HAE and healthy controls; (ii) to examine the relationship between the level of anxiety of children with C1-INH-HAE, their disease activity/affected sites and their HRQoL; and (iii) to predict the HRQoL of children with C1-INH-HAE based on their anxiety level and disease activity/affected sites METHODS: Thirty-three children with C1-INH-HAE (aged 5-18 years) and 52 healthy controls were recruited from Israel and Hungary. All children completed the State-Trait Anxiety Inventory for Children (STAIC), the Pediatric Quality of Life Inventory (Peds-QL) demographic questionnaire and a disease activity and site questionnaire . Disease activity was defined as the number of attacks in last year. RESULTS: Both anxiety state and trait were significantly higher among children with C1-INH-HAE as compared to the controls (44.74±10.56 vs 38.76±10.67, P<.01, 29.21±5.16 vs 25.23±4.09, P<.001 in comparison). Significant differences were found between C1-INH-HAE patients with HAE attacks, asymptomatic C1-INH-HAE patients, and healthy controls in both anxiety state (F56,2 =4.69, P=.001) and trait (F56,2 =9.06, P<.0001). A higher anxiety trait was correlated with the number of angioedema-affected sites (r=.52, P=.003). The presence of HAE attacks and higher anxiety trait predicted a lower HRQoL in children with C1-INH-HAE. CONCLUSIONS: C1-INH-HAE children have higher anxiety trait and state, which correlate with reduced HRQoL domains.


Assuntos
Angioedemas Hereditários/psicologia , Ansiedade/epidemiologia , Qualidade de Vida/psicologia , Adolescente , Criança , Pré-Escolar , Estudos Transversais , Progressão da Doença , Feminino , Humanos , Hungria , Israel , Masculino , Índice de Gravidade de Doença , Inquéritos e Questionários
8.
Clin Exp Pharmacol Physiol ; 44 Suppl 1: 64-69, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28466565

RESUMO

Aging is associated with altered decreased barrier function in the skin, which can lead to different types of immunoglobulin E (IgE)-mediated sensitization to environmental allergens. Yet, allergen-specific respiratory sensitization among the elderly is not well described. The aim of this study was to investigate the effect of aging on allergic pulmonary inflammation induced by epicutaneous sensitization of mechanically irritated skin in mice. For this purpose, 6-week-, 6-month-, and 18-month-old female BALB/c mice, underwent epicutaneous sensitization with ovalbumin (OVA) or phosphate buffered saline (PBS), followed by an inhaled OVA challenge. Blood OVA-specific IgE levels measured after epicutaneous sensitization, as well as, bronchial alveolar lavage fluids (BALF) leucocyte, eosinophil, and cytokine levels measured after OVA inhalation challenge were similar among the 6-week-old (young) and 6-month-old (adult) groups. However, significantly decreased levels of systemic OVA IgE, and BALF leukocyte, eosinophil and T helper cell type 2 cytokine levels, were measured after OVA inhalation challenge in elderly (18-month-old) mice compared to the other groups of mice. In addition, interleukin-10 (IL-10), a regulatory suppressor cytokine, was more abundant in the BALF of the elderly group after epicutaneous sensitization and inhalation challenge. Our results suggest that elderly mice have a reduced allergic response to induced sensitization with OVA, possibly regulated by increased IL-10 levels.


Assuntos
Envelhecimento/imunologia , Pulmão/imunologia , Ovalbumina/administração & dosagem , Pneumonia/prevenção & controle , Hipersensibilidade Respiratória/prevenção & controle , Pele/imunologia , Administração Cutânea , Fatores Etários , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Modelos Animais de Doenças , Eosinófilos/imunologia , Eosinófilos/metabolismo , Feminino , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Interleucina-10/imunologia , Interleucina-10/metabolismo , Pulmão/metabolismo , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Pneumonia/sangue , Pneumonia/imunologia , Hipersensibilidade Respiratória/sangue , Hipersensibilidade Respiratória/imunologia , Pele/metabolismo , Células Th2/imunologia , Células Th2/metabolismo
9.
Int Arch Occup Environ Health ; 88(4): 443-53, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25138777

RESUMO

PURPOSE: Lung inflammation from exposure to airborne particulate matter (PM) may be responsible for morbidity in asthma, but several studies using environmental monitoring data showed inconsistent results. Thus, the aim of this study was to evaluate the capability of induced sputum (IS) technology in order to biologically monitor PM in the lungs of urban asthmatic children. METHODS: We collected clinical, demographic, biological and environmental monitoring data on 136 children referred for asthma evaluations. The study participants were divided into two groups according to IS eosinophil counts of <3% (non-eosinophilic inflammation, n = 52) and ≥3% (eosinophilic inflammation, n = 84). RESULTS: The eosinophilic group displays significantly higher levels of fractional exhaled nitric oxide than the non-eosinophilic one (58.8 ± 47.5 vs 28.9 ± 34.2 ppm, p = 0.007). Particles (0-2.5 and 0-5 µm) comprised a strong risk factor for eosinophilic inflammation in IS (≥3%). Children with >80% of particles (0-2.5 µm) out of the total PM accumulated in the airways displayed the highest OR 10.7 (CI 2.052-56.4 p = 0.005) for an existing eosinophilic inflammation. Heme oxygenase-1 (HO-1) enzyme levels in IS positively correlated with % eosinophils and with particles in IS ranging between 2 and 3 µm. The level of HO-1 enzyme activity and FEV1/FVC in children with <3% eosinophils, but not ≥3%, was positively and significantly correlated, showing a protective effect of HO-1. CONCLUSION: Accumulation of PM involves oxidative stress pathways and is a risk factor for developing eosinophilic inflammation in asthmatic children. IS can biologically monitor this process.


Assuntos
Poluentes Atmosféricos/análise , Asma/etiologia , Monitoramento Ambiental/métodos , Pulmão , Material Particulado/análise , Escarro , Adolescente , Poluentes Atmosféricos/toxicidade , Testes Respiratórios , Criança , Eosinófilos/citologia , Feminino , Heme Oxigenase-1/imunologia , Humanos , Ferro/análise , Israel , Contagem de Leucócitos , Masculino , Óxido Nítrico/análise , Óxidos de Nitrogênio/análise , Estresse Oxidativo/efeitos dos fármacos , Material Particulado/toxicidade , População Urbana/estatística & dados numéricos
10.
Isr Med Assoc J ; 16(8): 487-90, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25269339

RESUMO

BACKGROUND: Chronic spontaneous urticaria (CSU) is a common, debilitating disease that is frequently resistant to standard therapy. Omalizumab, anti-immunoglobulin-E humanized monclonal antibody, was recently shown to be effective in treating resistant CSU. OBJECTIVES: To investigated the treatment of CSU with omalizumab in Israel. METHODS: We conducted a multicenter retrospective analysis of patients with refractory CSU treated with omalizuamb in Israel during 2012-2013. Complete improvement was defined as resolution of symptoms with no need for other medications, or satisfactory when patients' condition improved but required regular or intermittent doses of antihistamines. RESULTS: Forty-three patients received omalizumab off-label for refractory CSU. Their mean age was 45 +/- 12 years and CSU duration was 4.3 +/- 4 years. In this cohort, 98% were unsuccessfully treated with high dose H(1)-antihistamines, 88% with systemic glucocorticoids and 30% with cyclosporine and/ or other immune-modulators. Fourteen patients received only one injection of omalizumab, while the other 29 received on average of 4.3 +/- 3.2 injections; 30 patients received 150 mg/ month and 13 received 300 mg/month. Following omalizumab therapy, disease remitted within weeks in 86% of patients, of whom half achieved complete remission. The latter was associated with usage of high dose omalizumab, 300 mg/month vs. 150 mg/month (P = 0.02) and repeated therapy (i.e., multiple injections vs. a single injection) (P = 0.0005). CONCLUSIONS: Omalizumab is an effective and safe treatment for refractory CSU with rapid onset of action for inducing and maintaining remission. Treating CSU patients mandates an individual approach, because while low dose omalizumab will suffice for some patients others might need higher doses and prolonged therapy.


Assuntos
Anticorpos Anti-Idiotípicos , Anticorpos Monoclonais Humanizados , Antagonistas dos Receptores Histamínicos/uso terapêutico , Urticária , Adulto , Antialérgicos/administração & dosagem , Antialérgicos/efeitos adversos , Anticorpos Anti-Idiotípicos/administração & dosagem , Anticorpos Anti-Idiotípicos/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Doença Crônica , Relação Dose-Resposta a Droga , Resistência a Medicamentos , Sinergismo Farmacológico , Feminino , Humanos , Imunoglobulina E/imunologia , Injeções Subcutâneas , Israel , Masculino , Pessoa de Meia-Idade , Omalizumab , Estudos Retrospectivos , Índice de Gravidade de Doença , Resultado do Tratamento , Urticária/tratamento farmacológico , Urticária/imunologia , Urticária/fisiopatologia
11.
N Engl J Med ; 363(6): 532-41, 2010 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-20818888

RESUMO

BACKGROUND: Hereditary angioedema is characterized by recurrent attacks of angioedema of the skin, larynx, and gastrointestinal tract. Bradykinin is the key mediator of symptoms. Icatibant is a selective bradykinin B2 receptor antagonist. METHODS: In two double-blind, randomized, multicenter trials, we evaluated the effect of icatibant in patients with hereditary angioedema presenting with cutaneous or abdominal attacks. In the For Angioedema Subcutaneous Treatment (FAST) 1 trial, patients received either icatibant or placebo; in FAST-2, patients received either icatibant or oral tranexamic acid, at a dose of 3 g daily for 2 days. Icatibant was given once, subcutaneously, at a dose of 30 mg. The primary end point was the median time to clinically significant relief of symptoms. RESULTS: A total of 56 and 74 patients underwent randomization in the FAST-1 and FAST-2 trials, respectively. The primary end point was reached in 2.5 hours with icatibant versus 4.6 hours with placebo in the FAST-1 trial (P=0.14) and in 2.0 hours with icatibant versus 12.0 hours with tranexamic acid in the FAST-2 trial (P<0.001). In the FAST-1 study, 3 recipients of icatibant and 13 recipients of placebo needed treatment with rescue medication. The median time to first improvement of symptoms, as assessed by patients and by investigators, was significantly shorter with icatibant in both trials. No icatibant-related serious adverse events were reported. CONCLUSIONS: In patients with hereditary angioedema having acute attacks, we found a significant benefit of icatibant as compared with tranexamic acid in one trial and a nonsignificant benefit of icatibant as compared with placebo in the other trial with regard to the primary end point. The early use of rescue medication may have obscured the benefit of icatibant in the placebo trial. (Funded by Jerini; ClinicalTrials.gov numbers, NCT00097695 and NCT00500656.)


Assuntos
Angioedemas Hereditários/tratamento farmacológico , Antagonistas de Receptor B2 da Bradicinina , Bradicinina/análogos & derivados , Doença Aguda , Adulto , Bradicinina/administração & dosagem , Bradicinina/efeitos adversos , Bradicinina/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Injeções Subcutâneas , Análise de Intenção de Tratamento , Masculino , Estatísticas não Paramétricas , Ácido Tranexâmico/uso terapêutico
12.
Isr Med Assoc J ; 14(1): 70-2, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22624448

RESUMO

The prevalence of food allergy is increasing in both the pediatric and adult populations. While symptom onset occurs mostly during childhood, there are a considerable number of patients whose symptoms first begin to appear after the age of 18 years. The majority of patients with adult-onset food allergy suffer from the pollen-plant allergy syndromes. Many of them manifest their allergy after exercise and consuming food to which they are allergic. Eosinophilic esophagitis, an eosinophilic inflammation of the esophagus affecting individuals of all ages, recently emerged as another allergic manifestation, with both immediate and late response to the ingested food. This review provides a condensed update of the current data in the literature on adult-onset allergy.


Assuntos
Hipersensibilidade Alimentar/epidemiologia , Adulto , Idade de Início , Esofagite Eosinofílica/epidemiologia , Hipersensibilidade Alimentar/diagnóstico , Humanos , Prevalência
13.
Isr Med Assoc J ; 14(3): 180-3, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22675860

RESUMO

Defective immunological suppression can be a cause of the inflammation that leads to an allergic condition such as asthma. Suppressor regulatory T cells (Tregs) are essential for inducing and maintaining immunological tolerance to foreign and self-antigens, including allergens. Tregs are apparently altered in number and function in allergic asthmatic patients. Some treatments that ameliorate asthma symptoms lead to an increase in the number and functional impairment of Tregs, indicating that these cells play an important role in the anti-inflammatory effect of those medications.


Assuntos
Asma/fisiopatologia , Linfócitos T Reguladores/imunologia , Antiasmáticos/efeitos adversos , Asma/tratamento farmacológico , Humanos , Imunoterapia/efeitos adversos , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo
14.
Immunol Invest ; 40(6): 657-66, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21542720

RESUMO

Adenoid hypertrophy is the most common cause of upper airway obstruction and sleep-disordered breathing in children, yet its pathogenesis remains unclear. The identification of the novel helper T cell subsets, Th17 cells and regulatory T cells (Tregs) could provide new insight into our understanding of the mechanisms involved in the development of this condition. The purpose of this study is to evaluate the adenoidal lymphocyte subsets to describe the percentage of various lymphocyte subsets in hypertrophied adenoids and correlate them with symptom severity. Twenty consecutive children undergoing adenoidectomy were included, and lymphocytes were isolated from their adenoids. T cell subpopulations were detected by flow cytometry using a fluoresceinated monoclonal antibody directed against a number of cell markers (CD4+, CD8+, CD25+, FOXP3 IL17+, and others). We found a significant negative linear correlation between the Th17/Treg ratio and the patients' clinical scores (R = -0.71 p < 0.005). The correlation was independent of age and gender. Decreased ratios of Th17/Treg subpopulations may play a role in the pathogenesis of adenoid hypertrophy.


Assuntos
Tonsila Faríngea/imunologia , Hipertrofia/imunologia , Linfócitos T Reguladores/patologia , Células Th17/patologia , Adenoidectomia , Tonsila Faríngea/patologia , Tonsila Faríngea/cirurgia , Fatores Etários , Linfócitos B/patologia , Complexo CD3/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Contagem de Células , Criança , Pré-Escolar , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Hipertrofia/patologia , Lactente , Interferon gama/metabolismo , Interleucinas/metabolismo , Subpopulações de Linfócitos/metabolismo , Subpopulações de Linfócitos/patologia , Masculino , Caracteres Sexuais , Apneia Obstrutiva do Sono/diagnóstico , Inquéritos e Questionários , Linfócitos T Reguladores/metabolismo , Células Th17/metabolismo , Fator de Crescimento Transformador beta/metabolismo
15.
J Asthma ; 47(8): 849-52, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20846087

RESUMO

BACKGROUND: House dust mites (HDMs) are important causes of persistent allergic diseases, such as asthma and rhinitis. Various types of mites are found in the house dust of many countries, including Israel. OBJECTIVE: To evaluate the prevalence of sensitization to various HDMs in patients with perennial allergic rhinitis and asthma. METHODS: Sensitization of 117 patients with persistent rhinitis who attended the Allergy and Asthma Center in Tel Aviv (Israel) was evaluated by a skin prick test (SPT) using standardized allergenic extracts. The tested mites were Dermatophagoides farinae (DF), Dermatophagoides pteronyssinus (DP), Lepidoglyphus destructor (LD), Blomia tropicalis (BT), Tyrophagus putrescentiae (TP), Acarus siro (AS), Glycyphagus domesticus (GD), Blomia kulagini (BK), and Tetranychus urticae (TU). RESULTS: Most patients (n = 95, 81%) had a positive SPT to at least one mite extract. The three most frequent positive reactions were to DF (78%), DP (75%), and, unexpectedly, BT (77%). The correlation between DF and DP sensitization was higher than the correlation between DF or DP to BT (r = .78 versus r = .60, p < .05). Six patients had positive skin reactions to at least one mite species other than DF, DP or BT, mainly LD (n = 2, 2.1%) and BK (n = 4, 3.8%). CONCLUSIONS: The findings of this study identified the most ubiquitous mites to which Israeli patients with allergic rhinitis were sensitized and indicated the importance of BT as an allergen. Extracts of these mites may provide a more accurate diagnosis and effective treatment of respiratory diseases due to mite allergy in Israel and probably in other countries with similar climes.


Assuntos
Asma/imunologia , Ácaros/imunologia , Rinite Alérgica Perene/imunologia , Adolescente , Adulto , Animais , Asma/diagnóstico , Asma/epidemiologia , Feminino , Humanos , Imunização , Israel/epidemiologia , Masculino , Prevalência , Rinite Alérgica Perene/diagnóstico , Rinite Alérgica Perene/epidemiologia , Testes Cutâneos , Estatísticas não Paramétricas , Inquéritos e Questionários , Adulto Jovem
16.
Dermatology ; 221(4): 373-7, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-21099198

RESUMO

BACKGROUND: Ethyl chloride (EC) is usually used as a topical anesthetic spray agent. However, its antipruritic effects have never been studied, to the best of our knowledge. METHODS: A double-blind placebo-controlled prospective study. Overall, 51 healthy volunteers underwent a histamine skin prick test on both arms in order to trigger local pruritus. Thereafter, the affected areas were treated with an EC spray on one arm and a saline spray (placebo) on the other. Subjects as well as researchers were blind to which sprays were used. Subjects reported improvement in pruritus following EC/placebo and rated the intensity of pruritus by using a validated questionnaire and a visual analog scale. The flare and wheal reactions were measured in both arms before and following treatment with EC/placebo. RESULTS: Significant improvement in pruritus was reported more frequently following treatment with EC compared with placebo (84 vs. 16%; p < 0.0001). Significant reduction in pruritus intensity was reported immediately and 15 min following treatment with EC compared with placebo (p < 0.05). There was no significant difference between EC and placebo in terms of the flare and wheal reactions. CONCLUSIONS: EC is an effective antipruritic agent, and it does not change the wheal and flare reactions, making it ideal for treating pruritus secondary to allergy skin tests without masking their results.


Assuntos
Antipruriginosos/uso terapêutico , Cloreto de Etil/uso terapêutico , Prurido/tratamento farmacológico , Adulto , Método Duplo-Cego , Feminino , Histamina/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor , Testes de Irritação da Pele , Adulto Jovem
17.
Int J Ophthalmol ; 13(3): 509-512, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32309191

RESUMO

AIM: To evaluate the mechanism of which brimonidine tartrate 0.15% causes clinical hypersensitivity. METHODS: A prospective case-control study comparing 8 glaucoma patients with clinical hypersensitivity to brimonidine to a control group consisting 13 healthy volunteers. Blood samples were stimulated with brimonidine 0.15%, timolol 0.5% or brimonidine tartrate/timolol maleate 0.2%/0.5%. Premixed antibodies (CD63/FITC and aIgE/PE) were added for direct staining and whole-blood samples were lysed, fixed and analyzed by a flow cytometer. The basophil population was defined by high IgE cell expression. Degranulation was identified by the expression of the activation molecule CD63. RESULTS: Basophil activation was not significant when comparing percent of activated basophils of patients and healthy controls after exposure to brimonidine (2.58%, 2.45%, respectively, P=0.72). There was a significant suppression of basophil activation when a combination of brimonidine-timolol (0.87%) was compared to timolol (2.27%; P=0.012) and to brimonidine alone (2.58%; P=0.017). CONCLUSION: The results of our study do not support the hypothesis that brimonidine induces an immediate allergic reaction. Basophil activation was suppressed by the presence of ß-blockers in patients hypersensitive to brimonidine and in healthy individuals. This finding indicates that timolol suppress brimonidine drug reaction by a different mechanism.

19.
Isr Med Assoc J ; 11(2): 74-7, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19432033

RESUMO

BACKGROUND: Mite allergy is an indoor allergen responsible for most respiratory allergies in the western world. Environmental control can modify disease activity in these patients. OBJECTIVES: To examine the benefit of the Plasma Cluster device (Sharp, Japan) for inactivating and removing mites from the environment of patients diagnosed with either mite-sensitive perennial allergic rhinitis or mite-sensitive allergic asthma. METHODS: Patients with AR (n=30) or AA (n=10) were enrolled into a prospective open observational 8 week study. The first 2 weeks involved initial evaluation, the following 4 weeks consisted of active usage of the device, and the last 2 weeks were designated for follow-up. Symptom scores (recorded daily by patients and during visits by physicians) were recorded and analyzed. RESULTS: Patients with AR experienced a significant (P < 0.05) reduction in nasal discharge, post-nasal drip, nasal congestion, nasal itching, watery eyes, itchy eyes, headache, itchy ears, night disturbances and an improvement in general well-being during the last 2 days of the study compared to baseline. Patients with AA reported significant (P < 0.05) reduction in dyspnea, wheezing and the need to avoid dust mites. There was a significant (P < 0.05) improvement in mean peak expiratory flow rate at study closure compared to baseline. CONCLUSIONS: Short-term usage of the Plasma Cluster device resulted in considerable clinical improvement and increased peak expiratory flow rate in patients with AR or AA. The findings of this pilot study warrant longer and controlled studies to determine the value of this device in the treatment of various allergic disorders.


Assuntos
Ar Condicionado/instrumentação , Asma/prevenção & controle , Filtração/instrumentação , Pyroglyphidae , Rinite Alérgica Perene/prevenção & controle , Adulto , Animais , Asma/etiologia , Estudos de Coortes , Desenho de Equipamento , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Rinite Alérgica Perene/etiologia , Resultado do Tratamento , Ventilação/instrumentação , Adulto Jovem
20.
J Allergy Clin Immunol Pract ; 7(6): 1793-1802.e2, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30772477

RESUMO

BACKGROUND: For the prevention of attacks of hereditary angioedema (HAE), the efficacy and safety of subcutaneous human C1-esterase inhibitor (C1-INH[SC]; HAEGARDA, CSL Behring) was established in the 16-week Clinical Study for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1-Inhibitor Replacement Therapy (COMPACT). OBJECTIVE: To assess the long-term safety, occurrence of angioedema attacks, and use of rescue medication with C1-INH(SC). METHODS: Open-label, randomized, parallel-arm extension of COMPACT across 11 countries. Patients with frequent angioedema attacks, either study treatment-naive or who had completed COMPACT, were randomly assigned (1:1) to 40 IU/kg or 60 IU/kg C1-INH(SC) twice per week, with conditional uptitration to optimize prophylaxis (ClinicalTrials.gov registration no. NCT02316353). RESULTS: A total of 126 patients with a monthly attack rate of 4.3 in 3 months before entry in COMPACT were enrolled and treated for a mean of 1.5 years; 44 patients (34.9%) had more than 2 years of exposure. Mean steady-state C1-INH functional activity increased to 66.6% with 60 IU/kg. Incidence of adverse events was low and similar in both dose groups (11.3 and 8.5 events per patient-year for 40 IU/kg and 60 IU/kg, respectively). For 40 IU/kg and 60 IU/kg, median annualized attack rates were 1.3 and 1.0, respectively, and median rescue medication use was 0.2 and 0.0 times per year, respectively. Of 23 patients receiving 60 IU/kg for more than 2 years, 19 (83%) were attack-free during months 25 to 30 of treatment. CONCLUSIONS: In patients with frequent HAE attacks, long-term replacement therapy with C1-INH(SC) is safe and exhibits a substantial and sustained prophylactic effect, with the vast majority of patients becoming free from debilitating disease symptoms.


Assuntos
Angioedemas Hereditários/prevenção & controle , Proteína Inibidora do Complemento C1/administração & dosagem , Adolescente , Adulto , Idoso , Criança , Feminino , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
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