Inhaled Corticosteroids Alone and in Combination With Long-Acting ß2 Receptor Agonists to Treat Reduced Lung Function in Preterm-Born Children: A Randomized Clinical Trial.

Importance: Decreases in future lung function are a hallmark of preterm birth, but studies for management of decreased lung function are limited. Objective: To determine whether 12 weeks of treatment with inhaled corticosteroids (ICS) alone or in combination with long-acting ß2 agonists (LABA) improves spirometry and exercise capacity in school-aged preterm-born children who had percent predicted forced expiratory volume in 1 second (%FEV1) less than or equal to 85% compared with inhaled placebo treatment. Design, Setting, and Participants: A double-blind, randomized, placebo-controlled trial was conducted to evaluate ICS and ICS/LABA against placebo. Preterm-born children (age, 7-12 years; gestation ≤34 weeks at birth) who did not have clinically significant congenital, cardiopulmonary, or neurodevelopmental abnormalities underwent spirometry, exercise testing, and measurement of fractional exhaled nitric oxide before and after treatment. A total of 144 preterm-born children at the Children's Hospital for Wales in Cardiff, UK, were identified and enrolled between July 1, 2017, and August 31, 2019. Interventions: Each child was randomized to 1 of 3 cohorts: fluticasone propionate, 50 µg, with placebo; fluticasone propionate, 50 µg, with salmeterol, 25 µg; or placebo inhalers, all given as 2 puffs twice daily for 12 weeks. Children receiving preexisting ICS treatment underwent washout prior to randomization to ICS or ICS/LABA. Main Outcomes and Measures: The primary outcome was between-group differences assessed by adjusted pretreatment and posttreatment differences of %FEV1 using analysis of covariance. Intention-to-treat analysis was conducted. Results: Of 144 preterm-born children who were identified with %FEV1 less than or equal to 85%, 53 were randomized. Treatment allocation was 20 children receiving ICS (including 5 with prerandomization ICS), 19 children receiving ICS/LABA (including 4 with prerandomization ICS), and 14 children receiving placebo. The mean (SD) age of children was 10.8 (1.2) years, and 29 of the randomized children (55%) were female. The posttreatment %FEV1 was adjusted for sex, gestation, bronchopulmonary dysplasia, intrauterine growth restriction, pretreatment corticosteroid status, treatment group, and pretreatment values. Posttreatment adjusted means for %FEV1, using analysis of covariance, were 7.7% (95% CI, -0.27% to 15.72%; P = .16) higher in the ICS group and 14.1% (95% CI, 7.3% to 21.0%; P = .002) higher in the ICS/LABA group compared with the placebo group. Active treatment decreased the fractional exhaled nitric oxide and improved postexercise bronchodilator response but did not improve exercise capacity. One child developed cough when starting inhaler treatment; no other adverse events reported during the trial could be attributed to the inhaler treatment. Conclusions and Relevance: The results of this randomized clinical trial suggest that combined ICS/LABA treatment is beneficial for prematurity-associated lung disease in children. Trial Registration: EudraCT number: 2015-003712-20.

Role of nitric oxide, bradykinin B2 receptor, and TRPV1 in the airway alterations caused by simvastatin in rats.

Dry cough has been reported in patients receiving statin therapy. However, the underlying mechanism or other possible alterations in the airways induced by statins remain unknown. Thus, the aim of this study was to evaluate whether simvastatin promotes alterations in airways, such as bronchoconstriction and plasma extravasation, as well as the mechanism involved in these events. Using methods to detect alterations in airway resistance and plasma extravasation, we demonstrated that simvastatin [20 mg/kg, intravenous (i.v.)] caused plasma extravasation in the trachea (79.8 + 14.8 µg/g/tissue) and bronchi (73.3 + 8.8 µg/g/tissue) of rats, compared to the vehicle (34.2 + 3.6 µg/g/tissue and 29.3 + 5.3 µg/g/tissue, respectively). NG-nitro-L-arginine methyl ester (L-NAME, 30 mg/kg, intraperitoneal), a nitric oxide (NO) synthase inhibitor, Icatibant [HOE 140, 10 nmol/50 µl, intratracheal (i.t.)], a bradykinin B2 antagonist, and capsazepine (100 nmol/50 µl, i.t.), a TRPV1 antagonist, attenuated simvastatin-induced plasma extravasation. Simvastatin (5, 10 and 20 mg/kg) did not cause bronchoconstriction per se, but exacerbated the bronchoconstrictive response to bradykinin (30 nmol/kg, i.v.), a B2 agonist (0.7 + 0.1 ml/H2O), or capsaicin (30 nmol/kg, i.v.), a TRPV1 agonist (0.8 + 0.1 ml/H2O), compared to the vehicle (0.1 + 0.04 ml/H2O and 0.04 + 0.01 ml/H2O, respectively). The bronchoconstriction elicited by bradykinin (100 nmol/kg, i.v.) in simvastatin non-treated rats was inhibited by L-NAME. The exacerbation of bronchoconstriction induced by bradykinin or capsaicin in simvastatin-treated rats was inhibited by L-NAME, HOE 140 or capsazepine. These results suggest that treatment with simvastatin promotes the release of bradykinin, which, via B2 receptors, releases NO that can then activate the TRPV1 to promote plasma extravasation and bronchoconstriction.

Evaluation of the efficacy and safety of icatibant and C1 esterase/kallikrein inhibitor in severe COVID-19: study protocol for a three-armed randomized controlled trial.

BACKGROUND: SARS-CoV-2, the virus that causes COVID-19, enters the cells through a mechanism dependent on its binding to angiotensin-converting enzyme 2 (ACE2), a protein highly expressed in the lungs. The putative viral-induced inhibition of ACE2 could result in the defective degradation of bradykinin, a potent inflammatory substance. We hypothesize that increased bradykinin in the lungs is an important mechanism driving the development of pneumonia and respiratory failure in COVID-19. METHODS: This is a phase II, single-center, three-armed parallel-group, open-label, active control superiority randomized clinical trial. One hundred eighty eligible patients will be randomly assigned in a 1:1:1 ratio to receive either the inhibitor of C1e/kallikrein 20 U/kg intravenously on day 1 and day 4 plus standard care; or icatibant 30 mg subcutaneously, three doses/day for 4 days plus standard care; or standard care alone, as recommended in the clinical trials published to date, which includes supplemental oxygen, non-invasive and invasive ventilation, antibiotic agents, anti-inflammatory agents, prophylactic antithrombotic therapy, vasopressor support, and renal replacement therapy. DISCUSSION: Accumulation of bradykinin in the lungs is a common side effect of ACE inhibitors leading to cough. In animal models, the inactivation of ACE2 leads to severe acute pneumonitis in response to lipopolysaccharide (LPS), and the inhibition of bradykinin almost completely restores the lung structure. We believe that inhibition of bradykinin in severe COVID-19 patients could reduce the lung inflammatory response, impacting positively on the severity of disease and mortality rates. TRIAL REGISTRATION: Brazilian Clinical Trials Registry Universal Trial Number (UTN) U1111-1250-1843. Registered on May/5/2020.

Management of hereditary angioedema in Japan: Focus on icatibant for the treatment of acute attacks.

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.

[Use of simulation in healthcare for therapeutic training of the parents of children with hereditary angioedema]. / Utilisation de la simulation en santé pour l'éducation thérapeutique des parents d'enfants souffrant d'un angio-œdème héréditaire.

BACKGROUND: C1INH-deficiency hereditary angioedema (HAE) is characterized by recurrent episodes of potentially severe oedema. Icatibant for SC injection will soon be approved for use in children and it is necessary to train parents in recognising severe episodes of AOH and in the technique for injection of icatibant. Simulation in healthcare (SH) is a set of educational methods for improving skills in a safe environment. We wished to assess the feasibility of a therapeutic training session (TTS) involving scripted scenarios for the parents of children with HAE. PATIENTS AND METHODS: The TTS session included pre- and post-training testing on AOH, two scenarios (calling emergency services for lingual AO; gastrointestinal AO) involving actors and a volunteer parent, a workshop for learning the SC injection technique, and a satisfaction questionnaire. We analysed the answers on the questionnaire and noted down parents' verbatim observations during debriefing sessions. RESULTS: Eight parents from 5 families took part in this session. Parents rated their overall satisfaction as 9.3/10. The parents commented that during the simulations, they felt "in the thick of it" and that they "experienced stress while viewing the scenes", thus attesting to the realism and relevance of the simulated scenarios. DISCUSSION: This session met the parents' expectations in terms of being able to cope and having adequate know-how, based on both the simulations and the level of knowledge acquired. The main limitation lay in the parents' difficulty in confronting certain situations reminiscent of traumatic past experiences. TTS shares many common features with SH for the parents of sick children. The place of the latter in TTS must be evaluated.

Effect of bradykinin on rats with thromboangiitis obliterans through PI3K/Akt signaling pathway.

OBJECTIVE: To explore the effect of bradykinin on rats with thromboangiitis obliterans (TAO) through the phosphatidylinositol 3-hydroxy kinase/protein kinase B (PI3K/Akt) signaling pathway. MATERIALS AND METHODS: The female Wistar rats were injected with lauric acid via the femoral artery to establish the TAO model, and they were randomly divided into control group (healthy rats), model group (TAO rats) and bradykinin group (TAO rats injected with bradykinin B2 receptor-specific inhibitor). The control was set in each group before the operation. The level of serum bradykinin in each group was detected via enzyme-linked immunosorbent assay (ELISA), and the reactive oxygen species (ROS) level, Caspase-3 activity and PI3K/Akt protein concentration in vascular tissues were measured via ELISA, Western blotting, ROS assay, and Caspase-3 activity assay, respectively. Moreover, the specific therapeutic mechanism of bradykinin was analyzed. RESULTS: In control group, the intima of the lower extremity venous tissues was smooth, the extima had no evident changes, and there was no inflammatory cell invasion around the arteries and veins. In model group, there was massive inflammatory cell invasion into the lower extremity venous tissues. In bradykinin group, fibrosis and atrophy occurred in venous tissues, the extima was thickened without fibrosis, and there was phagocytosis of neutrophils and mononuclear macrophages around the arteries and veins, as well as massive inflammatory infiltration. The PI3K/Akt protein concentration in lower extremity venous tissues was the highest in control group and the lowest in bradykinin group, and there were statistically significant differences (p<0.01). At 24 h after administration of doxorubicin (DOX), the level of ROS in lower extremity venous tissues was higher in bradykinin group than that in model group (p<0.05), and it was also higher in model group than that in control group (p<0.05). Besides, the activity of Caspase-3 in lower extremity venous tissues was significantly increased in bradykinin group compared with that in model group and control group, while it was slightly higher in model group than that in control group (p<0.05). CONCLUSIONS: The low expression of bradykinin can promote TAO in rats by the mechanism that it inhibits the PI3K/Akt signaling pathway to raise the oxidative stress level, thereby aggravating TAO.

The bradykinin system in stress and anxiety in humans and mice.

Pharmacological research in mice and human genetic analyses suggest that the kallikrein-kinin system (KKS) may regulate anxiety. We examined the role of the KKS in anxiety and stress in both species. In human genetic association analysis, variants in genes for the bradykinin precursor (KNG1) and the bradykinin receptors (BDKRB1 and BDKRB2) were associated with anxiety disorders (p < 0.05). In mice, however, neither acute nor chronic stress affected B1 receptor gene or protein expression, and B1 receptor antagonists had no effect on anxiety tests measuring approach-avoidance conflict. We thus focused on the B2 receptor and found that mice injected with the B2 antagonist WIN 64338 had lowered levels of a physiological anxiety measure, the stress-induced hyperthermia (SIH), vs controls. In the brown adipose tissue, a major thermoregulator, WIN 64338 increased expression of the mitochondrial regulator Pgc1a and the bradykinin precursor gene Kng2 was upregulated after cold stress. Our data suggests that the bradykinin system modulates a variety of stress responses through B2 receptor-mediated effects, but systemic antagonists of the B2 receptor were not anxiolytic in mice. Genetic variants in the bradykinin receptor genes may predispose to anxiety disorders in humans by affecting their function.

Self-administration of icatibant in acute attacks of Type I hereditary angioedema: A case report and review of hereditary angioedema.

Hereditary angioedema (HAE) is a rare group of genetic disease characterized by non-itchy swelling of subcutaneous and submucosal tissues of the extremities, genitalia, gastrointestinal tract, and upper airways, which can be life threatening. Moreover, unpredictability and recurrence of HAE attacks significantly affect patients' quality of life. Short- and long-term prophylaxis is used to decrease the severity and frequency of attacks, but during severe or potentially severe acute episodes, treatment with C1-INH replacement or icatibant is mandatory. Icatibant is a selective bradykinin B2 receptor antagonist that has been licensed for self-administration at home, resulting in earlier treatment of the attack and quicker recovery, less emergency admittance with a significant improvement of patients' quality of life, and decrease of health care costs. The authors present a case of a young woman, affected by Type I HAE, who has been successfully treated with icatibant on demand at home, resulting in reduction of emergency admissions and improvement of quality of life. The authors also review the different types HAE, their clinical aspects, diagnosis, and management.

Effect of the bradykinin 1 receptor antagonist SSR240612 after oral administration in Mycobacterium tuberculosis-infected mice.

The role, if any, played by the kinin system in tuberculosis infection models, either in vivo or in vitro, was investigated. The effects of Mycobacterium tuberculosis infection on C57BL/6 wild type, B1R-/-, B2R-/- and double B1R/B2R knockout mice were evaluated. Immunohistochemistry analysis was carried out to assess B1R and B2R expression in spleens and lungs of M. tuberculosis-infected mice. In addition, in vitro experiments with M. tuberculosis-infected macrophages were performed. The in vivo effects of HOE-140 and SSR240612 on the mice model of infection were also evaluated. Infected B2R-/- mice exhibited increased splenomegaly, whereas decreased spleen weight in infected double B1R/B2R knockout mice was observed. The bacterial load, determined as colony-forming units, did not differ in the spleens and lungs of the studied mouse strains. Importantly, immunohistochemical analysis revealed that B1R was upregulated in both spleens and lungs of infected mice. M. tuberculosis-infected macrophages incubated with SSR240612, alone or in combination with des-Arg9-BK, for four days, displayed a marked inhibitory effect on CFU counts. However, the pre-incubation of the selective B1R (des-Arg9-BK and SSR240612) and B2R (BK and HOE-140) agonists and antagonists, respectively, did not significantly affect the bacterial loads. A statistically significant reduction in the CFU of M. tuberculosis in lungs and spleens of animals treated with SSR240612, but not with HOE-140, was observed. Further efforts should be pursued to clarify whether or not SSR240612 might be considered an option for the treatment of tuberculosis.

The relevance of kalikrein-kinin system via activation of B2 receptor in LPS-induced fever in rats.

PURPOSE: This study evaluated the involvement of endogenous kallikrein-kinin system and the bradykinin (BK) B1 and B2 receptors on LPS- induced fever and the POA cells involved in this response. MATERIAL AND METHODS: Male Wistar rats received either i.v. (1 mg/kg), i.c.v. (20 nmol) or i.h. (2 nmol) injections of icatibant (B2 receptor antagonist) 30 or 60 min, respectively, before the stimuli. DALBK (B1 receptor antagonist) was given either 15min before BK (i.c.v.) or 30 min before LPS (i.v.). Captopril (5 mg/kg, sc.,) was given 1 h prior LPS or BK. Concentrations of BK and total kininogenon CSF, plasma and tissue kallikrein were evaluated. Rectal temperatures (rT) were assessed by telethermometry. Ca++ signaling in POA cells was performed in rat pup brain tissue microcultures. RESULTS: Icatibant reduced LPS fever while, captopril exacerbated that response, an effect abolished by icatibant. Icatibant (i.h.) reduced fever to BK (i.h.) but not that induced by LPS (i.v.). BK increased intracellular calcium concentration in neurons and astrocytes. LPS increased levels of bradykinin, tissue kallikrein and total kininogen. BK (i.c.v.) increased rT and decreased tail skin temperature. Captopril potentiated BK-induced fever an effect abolished by icatibant. DALBK reduced the fever induced by BK. BK (i.c.v.) increased the CSF PGE2concentration. Effect abolished by indomethacin (i.p.). CONCLUSIONS: LPS activates endogenous kalikrein-kinin system leading to production of BK, which by acting on B2-receptors of POA cells causes prostaglandin synthesis that in turn produces fever. Thus, a kinin B2-receptor antagonist that enters into the brain could constitute a new and interesting strategy to treat fever.

Subcutaneous Icatibant for the Treatment of Hereditary Angioedema Attacks: Comparison of Home Self-Administration with Administration at a Medical Facility.

BACKGROUND: Hereditary angioedema (HAE) is a life-threatening disorder characterized by recurrent angioedema. Icatibant, a subcutaneous bradykinin-B2-receptor antagonist, is an effective on-demand therapy. Data outside the United States suggest that self-administration is tolerated and patient-preferred compared with administration by health care professionals at medical facilities (HCP-administration). OBJECTIVE: A prospective, multicenter study was conducted in the United States to compare icatibant self-administration and HCP-administration. METHODS: Subjects 18 years or older with type I or II HAE were recruited. The first 2 HAE attacks after enrollment were treated at medical facilities. Subjects were instructed by a health care professional on self-administration during icatibant treatment for the second HAE attack. Icatibant was self-administered for all subsequent attacks. For each treated HAE attack, efficacy, safety, and tolerability data were recorded. RESULTS: Nineteen patients with HAE received icatibant for 79 distinct HAE attacks. Mean attack duration was significantly shorter with self-administration (n = 50; 547 ± 510 minutes) than with HCP-administration (n = 29; 968 ± 717 minutes; P = .006). Mean time to treatment was significantly shorter with self-administration (143 ± 226 minutes) than with HCP-administration (361 ± 503 minutes; P < .0001). Shorter times to treatment were associated with shorter time from treatment to symptom resolution (r = 0.35; P = .02). Improvements in visual analog scale score and patient symptom score from pretreatment to 4 hours postinjection were comparable between self-administration and HCP-administration. There were no serious adverse events or discontinuations due to adverse events with self-administration or HCP-administration. CONCLUSIONS: Icatibant self-administration shortened attack duration and time to treatment, with no difference in safety or local tolerability compared with HCP-administration. These findings support icatibant as an effective on-demand option for home-based treatment.

Icatibant as acute treatment for hereditary angioedema in adults.

INTRODUCTION: Hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) is a rare disease, characterized by recurrent, unpredictable episodes of cutaneous and/or mucosal edema. Bradykinin, released by the activation of the contact system, binds to bradykinin B2 receptors on the endothelial cell surface to enhance vascular permeaility, which leads to angioedema. AREAS COVERED: C1-INH-HAE therapy is aimed at the inhibition of bradykinin release, as well as at the blockage of its effects mediated by its receptor. Three controlled trials, three open-label extensions, and two open-label studies, and a prospective, observational study have confirmed the safety and efficacy of the bradykinin B2 receptor antagonist, icatibant administered as acute treatment for HAE attacks in adult patients with C1-INH-HAE. Expert commentary: The ready-to-use, pre-filled syringes of icatibant can be self-administered easily, effectively, safely and, importantly, conviently. - This has resulted in patients being able to quickly treat an attack and realize a dramatic change for the better in their lives.

Prophylaxis in hereditary angioedema (HAE) with C1 inhibitor deficiency.

Hereditary angioedema (HAE) is a rare congenital disorder characterized by recurrent episodes of subcutaneous or submucosal edema. Laryngeal manifestations can be life-threatening. In the majority of cases, the disease can be adequately treated with an on-demand approach--in some cases, however, short- or long-term prophylaxis is indicated. Attenuated androgens used to be the drugs of choice, but they are associated with considerable side effects and no longer commercially available in the German-speaking countries of the EU. They are currently being replaced by more effective and more tolerable agents such C1-inhibitors, the kallikrein inhibitor ecallantide, and the B2 receptor antagonist icatibant, which have recently obtained market authorization. These new drugs have had a major impact, especially on the indications and procedures for long-term prophylaxis. According to the most recent international consensus papers and our own experience, self-administered C1-inhibitors are now the first option for long-term prophylactic therapy. The decision for prophylaxis should no longer be based on single parameters such as the frequency of attacks but on adequate overall disease control including quality of life. More drugs are currently being developed, which may lead to further changes in the treatment algorithms of HAE.

Bradykinin Impairs and HOE 140 does not Protect Rat Hindlimb Skeletal Muscle Against Tourniquet-induced Reperfusion Injury.

BACKGROUND: Bradykinin (BK) is used in different tissues. Dose-dependent studies have demonstrated that low doses protect against ischemia/reperfusion (I/R) injury while higher doses lead to adverse effects. Although the beneficial effects of BK infusion were observed in myocardium, its role on the I/R impact in skeletal muscle (SM) has not been fully clarified. OBJECTIVE: This study was carried out to evaluate the effects of BK, administered in the hindlimbs of rats subjected to I/R. METHODS: The study design included three experimental groups: Group 1 control (saline), Group 2 (bradykinin), and Group 3 (HOE 140, a BK2 receptor blocker). In all three groups, rats were subjected to hindlimb ischemia for a total of 2 h followed by continuous 4 h of reperfusion with pharmacological interventions. The methods include analysis of enzymes (lactate dehydrogenase-LDH and creatinine phosphokinase-CPK), cell membrane marker of injury (malondialdeyde-MDA), recruitment of neutrophils (myeloperoxidase-MPO), and apoptosis index (immunohistochemistry TUNEL in situ peroxidase dead end). RESULTS: Except for the apoptotic index, all parameters studied were shown to be elevated in the reperfusion group intervened with BK. The blocking of BK2 receptors by HOE 140 did not affect the I/R injury. CONCLUSION: After 2 h of total ischemia, infusion of bradykinin during 4 h of reperfusion, worsened the I/R injury in the hindlimb skeletal muscle.

[Bradykinin-induced angioedema: Definition, pathogenesis, clinical presentation, diagnosis and therapy]. / Bradykinininduzierte Angioödeme: Definition, Pathogenese, Klinik, Diagnose und Therapie.

The incidence of bradykinin-induced angioedema is considerably lower than that of histamine-induced forms; however, the same is true for the clinician's knowledge of this condition. Bradykinin-induced angioedemas include hereditary angioedema (HAE), as well as acquired forms induced by drugs or antibody formation, e.g., during the course of oncologic disease. Drug-induced forms affect almost exclusively the head and neck region, and are thus important for the otorhinolaryngologist. Clear differentiation between histamine-induced angioedema (e. g., connected to allergy/urticaria) and bradykinin-induced angioedema is essential for selection of the specific treatment and may be lifesaving. Antihistamines and cortisone derivatives have no relevant effect in bradykinin induced-angioedema, whereas blood-derived C1 esterase inhibitor and bradykinin receptor 2 antagonists represent effective therapeutic options--both for acute and prophylactic treatment.

The cough reflex is upregulated by lisinopril microinjected into the caudal nucleus tractus solitarii of the rabbit.

We have previously shown that cough potentiation induced by intravenous administration of the AT1 receptor antagonist losartan is lower than that induced by the ACE inhibitor lisinopril in anesthetized and awake rabbits. Since losartan and lisinopril cross the blood-brain barrier, their central action on the cough reflex can be hypothesized. Mechanical stimulation of the tracheobronchial tree and citric acid inhalation were used to induce cough reflex responses in pentobarbital sodium-anesthetized, spontaneously breathing rabbits. Bilateral microinjections (30-50 nl) of losartan (5mM), lisinopril (1mM), bradykinin (0.05 mM), HOE-140 (0.2mM, a bradykinin B2 receptor antagonist) and CP-99,994 (1mM, an NK1 receptor antagonist) were performed into the caudal nucleus tractus solitarii, the predominant site of termination of cough-related afferents. Lisinopril, but not losartan increased the cough number. This effect was reverted by HOE-140 or CP-99,994. Cough potentiation was also induced by bradykinin. The results support for the first time a central protussive action of lisinopril mediated by an accumulation of bradykinin and substance P.

Analysis of characteristics associated with reinjection of icatibant: Results from the icatibant outcome survey.

PURPOSE: Phase 3 icatibant trials showed that most hereditary angioedema (HAE) (C1 inhibitor deficiency) acute attacks were treated successfully with one injection of icatibant, a selective bradykinin B2 receptor antagonist. We conducted a post hoc analysis of icatibant reinjection for HAE type I and II attacks in a real-world setting by using data from the Icatibant Outcome Survey, an ongoing observational study that monitors the safety and effectiveness of icatibant treatment. METHODS: Descriptive retrospective analyses of icatibant reinjection were performed on Icatibant Outcome Survey data (February 2008 to December 2012). New attacks were defined as the onset of new symptoms after full resolution of the previous attack. Potential associations between the patient and attack characteristics and reinjection were explored by using logistic regression analysis. RESULTS: Icatibant was administered for 652 attacks in 170 patients with HAE type I or II. Most attacks (89.1%) were treated with a single icatibant injection. For attacks that required two or three injections, the second injection was given a median of 11.0 hours after the first injection, with 90.4% of second injections administered ≥6 hours after the first injection. Time to resolution and attack duration were significantly longer for two or three injections versus one icatibant injection (p < 0.0001 and p < 0.05, respectively). Multivariate logistic regression analysis identified sex, attack severity, and laryngeal attacks as significantly correlated with reinjection (all p ≤ 0.05). These factors did not remain predictors for reinjection when two outlier patients with distinct patterns of icatibant use were excluded. CONCLUSIONS: In this real-world setting, most HAE attacks resolved with one icatibant injection. There was no distinct profile for patients or attacks that required reinjection when outliers with substantially different patterns of use were excluded. Because new attacks were not distinguished from the recurrence of symptoms, reinjection rates may be slightly higher than shown here. Clinical trial identifier: NCT01034969.

Icatibanto para o tratamento da crise aguda moderada ou grave do angioedema hereditário / Icatibant for the treatment of the moderate or severe acute crisis of hereditary angioedema

CONTEXTO: O angioedema hereditário (AEH) é uma doença genética caracterizada pela deficiência quantitativa ou qualitativa do inibidor de C1-INH, uma enzima inibidora das proteases da classe das serpinas. O C1-INH inibe as esterases e sem a inibição, a ativação do sistema do complemento encontra-se exacerbada, o que acarreta crises de edema. Os quadros mais graves de AEH podem causar o óbito por edema de laringe e asfixia ou intensa dor abdominal. Estima-se que sua prevalência seja aproximadamente de 1:50.000, acometendo diferentes grupos étnicos. EVIDÊNCIAS CIENTÍFICAS: O relatório enviado pelo demandante foi considerado inadequado. Foi realizada nova busca nas bases de dados primárias Medline e Cochrane para ensaios clínicos randomizados. As evidências foram classificadas seguindo a escala de JADAD. Foram elaborados novos modelos de custo-efetividade e nova análise do impacto orçamentário. Não foi identificada uma comparação direta e a heterogeneidade dos ensaios não permitiu uma comparação indireta entre os medicamentos Berinert® e Firazyr®, ambos significativamente superiores ao placebo para redução no tempo de resposta clínica. Um ensaio demonstrou superioridade do Firazyr® em relação ao ácido tranexâmico para redução no tempo de resposta clínica. O desfecho não foi mensurado da mesma forma entre os estudos, limitando as conclusões deste relatório. DECISÃO: PORTARIA Nº 33, de 14 de julho de 2015 - Torna pública a decisão de não incorporar o icatibanto para o tratamento da crise aguda moderada ou grave do angioedema hereditário no âmbito do Sistema Único de Saúde - SUS.