Selective Bradykinin B2 Receptor Antagonist Research Articles

Large Predominance of Off-Label Prescriptions of C1-Inhibitor Concentrates and Icatibant in a Real-Life Setting: A Retrospective Clinical Study.

C1-inhibitor (C1INH) concentrates and the selective bradykinin B2 receptor antagonist icatibant are approved only for treating hereditary angioedema with C1INH deficiency. Yet, they are regularly prescribed off label in other types of bradykinin-mediated angioedema including angiotensin-converting enzyme inhibitor (ACEi)-related and undetermined angioedema. We conducted a retrospective chart review of inpatient prescriptions of C1INH concentrates and icatibant between 2016 and 2020 in the University Hospital of Angers. The first outcome was the proportion of prescriptions with explicit indication. Then, we determined the compliance of prescriptions with European Medicines Agency approvals and the French bradykinin-mediated angioedema reference center guidelines. Finally, we estimated the economic impact of inappropriate prescribing. The therapeutic indication was explicit in 90.4% of prescriptions (n=66/73). Only 17.8% of prescriptions were for hereditary angioedema with C1INH deficiency, while 31.5% were for ACEi-related and 28.7% for undetermined angioedema. However, most off-label prescriptions were consistent with the French bradykinin-mediated angioedema reference center guidelines (73.3%). We estimated that 13% of drug expenditures were potentially excessive. The predominance of off-label prescriptions may be explained by the infrequency of hereditary angioedema and the absence of approved alternatives in other types of bradykinin-mediated angioedema. Most attacks were related to ACEis. Epinephrine was rarely prescribed as first-line therapy in attacks of unknown origin. Given the high prices of these drugs, we advocate the development of a readily available management algorithm of angioedema to reduce inappropriate prescriptions in our center. In addition, we think that the drug prescription circuit should be redesigned to ensure the traceability of prescribed vials in the dispensing areas.

The Icatibant Outcome Survey: 10 years of experience with icatibant for patients with hereditary angioedema.

In patients with hereditary angioedema (HAE), bradykinin causes swelling episodes by activating bradykinin B2 receptors. Icatibant, a selective bradykinin B2 receptor antagonist, is approved for on-demand treatment of HAE attacks. The Icatibant Outcome Survey (IOS; NCT01034969) is an ongoing observational registry initiated in 2009 to monitor the effectiveness/safety of icatibant in routine clinical practice. As of March 2019, 549 patients with HAE type 1 or 2 from the IOS registry had been treated of 5995 total attacks. This article reviews data published from IOS over time which have demonstrated that the effectiveness of icatibant in a real-world setting is comparable to efficacy in clinical trials; one dose is effective for the majority of attacks; early treatment (facilitated by self-administration) leads to faster resolution and shorter attack duration; effectiveness/safety of icatibant has been shown across a broad range of patient subgroups, including children/adolescents and patients with HAE with normal C1 inhibitor levels; and tolerability has been demonstrated in patients aged ≥65 years. Additionally, this review highlights how IOS data have provided valuable insights into patients' diagnostic journeys and treatment behaviours across individual countries. Such findings have helped to inform clinical strategies and guidelines to optimise HAE management and limit disease burden. This research was sponsored by Takeda Development Center Americas, Inc. Takeda Development Center Americas, Inc., provided funding to Excel Medical Affairs for support in writing and editing this manuscript.

A case of hereditary angioedema due to C1-inhibitor deficiency with recurrent abdominal pain diagnosed 40 years after the occurrence of the initial symptom

Hereditary angioedema due to C1-inhibitor deficiency (HAE-C1-INH) is a rare disease, which induces an acute attack of angioedema mediated by bradykinin. HAE-C1-INH can cause serious abdominal pain when severe edema develops in the gastrointestinal tract. However, because it takes a long time, 13.8 years on average in Japan, from the occurrence of the initial symptom to the diagnosis due to low awareness of the disease, undiagnosed HAE-C1-INH patients sometimes undergo unnecessary surgical procedures for severe abdominal pain. We herein present a 56-year-old patient with HAE-C1-INH, who underwent numerous abdominal operations. He frequently needed hospitalization with the administration of opioid due to severe abdominal pain. However, after he was accurately diagnosed with HAE-C1-INH at 55 years of age, he could start self-administration for an acute attack with icatibant, a selective bradykinin B2 receptor antagonist. Consequently, he did not need hospitalizing for ten months after the beginning of the treatment. A series of an accurate diagnosis and appropriate treatment for HAE-C1-INH improved his quality of life. Thus, HAE-C1-INH should be considered, when we meet patients with unidentified recurrent abdominal pain. This case highlights significance of an early diagnosis and appropriate treatment for HAE-C1-INH.

Receptor mechanism of infarct-limiting effect of adaptation to normobaric hypoxia

The aim of the study was to investigate the involvement of bradykinin, cannabinoid and vanilloid (TRPV1 channel) receptors in the implementation of the infarct-limiting effect of chronic normobaric hypoxia (CNH). Materials and methods . The study was performed on male Wistar rats ( n = 117) weighing 250–300 g. Adaptation to CNH was modeled for 21 days at 12% pO 2 , 0.3% pCO 2 and normal atmospheric pressure. A day after adaptation of rats to CNH coronary artery occlusion (45 min) and reperfusion (2 h) was performed. In the study the following compounds were used: selective cannabinoid CB1 receptor antagonist rimonabant (1 mg/kg), selective cannabinoid CB2 receptor antagonist AM630 (2.5 mg/kg), selective bradykinin B2 receptor antagonist HOE140 (50 μg/kg), and vanilloid receptor (TRPV1 channel) antagonist capsazepine (3 mg/kg). All antagonists were administered 15 min before coronary artery occlusion. Results. Adaptation to normobaric hypoxia promoted the formation of the pronounced infarct-limiting effect. The blockade of B2 receptor eliminated the infarct-limiting effect of CNH. Blockade of cannabinoid or vanilloid receptors did not affect the infarct-limiting effect of CNH. Conclusion . The infarct-limiting effect of CNH depends on the activation of B2 receptor, and the adaptive increase in cardiac tolerance to ischemia/reperfusion does not depend on cannabinoid or vanilloid receptors.

Type 2 hereditary angioedema treated with acute exacerbation with icatibant: A case report

Hereditary angioedema (HAE) is a rare autosomal dominant disorder caused by genetic deficiency or decreased function of C1-es terase inhibitor. It is characterized by swelling of subcutaneous and submucosal tissues of the extremities, gastrointestinal tract, and upper airways which can be life-threatening. Thus, early recognition and treatment of the disease are important. Short- and long-term prophylaxes are used to decrease the severity and frequency of attacks. Icatibant is a selective bradykinin B2-receptor antago nist, earlier treatment of acute attacks and hospital admission. The authors present a case of 47-year-old woman who was diag nosed with type II HAE, danazol as a long term. Her symptoms improved dramatically after drug treatment. The unpredictability and recurrence of HAE attacks could have a negative impact on social life and quality of life. This case shows that timely and proper treat ment could improve quality of life and reduce morbidity and mortality. (Allergy Asthma Respir Dis 2021;9:180-183)

Efficacy, pharmacokinetics, and safety of icatibant for the treatment of Japanese patients with an acute attack of hereditary angioedema: A phase 3 open-label study

BackgroundHereditary angioedema (HAE) is a genetic disease characterized by recurrent swelling episodes affecting the skin, gastrointestinal mucosa, and upper respiratory tract. MethodsA 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. ResultsEight 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). ConclusionsAlthough 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.

Bradykinin increases blood pressure in endotoxemic rats

Despite the knowledge about the mechanisms triggered by bradykinin (BK), mainly its hypotensive effect, several aspects of biological effects of this peptide remain unclear, such as its release and action in endotoxemia. The main hypothesis of this study was that blood pressure responses to BK are impaired in experimental models of sepsis. Female Wistar rats (200–280 g) received intraperitoneal (i.p.) injections of sterile saline (1 ml/kg), or lipopolysaccharide (LPS; 1 mg/kg), and were anesthetized at 6, 24, 48, or 72 h after for direct measurement of the mean arterial pressure (MAP). The hypotensive effect of intravenous (i.v.) BK (6, 20 and 60 nmol/kg), and acetylcholine (ACh; 60 nmol/kg) were assessed before and after the treatment with prazosin (0.5 mg/kg i.v.), HOE 140 (20 nmol/kg s.c.), [Leu8]des‐Arg9‐BK (100 nmol/kg, i.v.), losartan (15 mg/kg, i.v.), Y‐27632 (0.1 mg/kg, i.v.), or indomethacin (10 mg/kg i.v.). We also evaluated the influence of endotoxemia on BK‐ and ACh‐induced vasodilation in the in vitro perfused mesenteric vascular bed obtained from both control and LPS 24 h groups. Moreover, the expression of bradykinin B2 and angiotensin II AT1 receptors, and the phosphorylated MYPT‐1 subunit of myosin phosphatase (pMYPT‐1) was detected by Western blotting in homogenates of resistance mesenteric arteries. In spite of the lack of changes in the MAP, and the hypotensive effects induced by BK and ACh remained unaltered in the LPS groups, LPS‐treated animals presented hematological evidence of systemic inflammation (i.e. leukocytosis, high levels of nitrate + nitrite), compared with the control group. Although endotoxemia have not changed the hypotensive effects induced by BK and ACh, BK‐induced hypotension in LPS treated animals (both 24 h and 48 h groups) was followed by an immediate and sustained pressor effect. For instance, the MAP increased by 9 ± 2, 18 ± 5, and 24 ± 3 mm Hg in the control group, and by 29 ± 4, 42 ± 3, and 56 ± 4 mm Hg in the LPS 24 h group, after administration of 6, 20, and 60 nmol/kg BK, respectively. This hypertensive response to BK was not reduced by the selective antagonist of the alpha‐1 adrenergic receptor prazosin, nor by the antagonist of the BK B1 receptor [Leu8]des‐Arg9‐BK, but it was vanished by HOE‐140, a selective BK B2 receptor antagonist, and losartan, an angiotensin II AT1 receptor antagonist. We also found that the hypertensive effect of angiotensin II (60 nmol/kg) was enhanced from 52 ± 5 mm Hg in control animals to 75 ± 3 mm Hg in the LPS 24 h group, an event that was fully prevented by HOE‐140. Although the cyclooxygenase inhibitor indomethacin has not had any influence on BK effects, the Rho‐associated kinase (ROCK) inhibitor Y‐27632 avoided the enhanced hypertensive effect of BK in LPS‐treated animals. Western blotting analysis revealed that B2 and AT1 receptors, and pMYPT‐1, were significantly increased in resistance arteries at 24 h after LPS, compared with samples from control animals. Notably, perfused mesenteric vascular bed obtained from the LPS 24 h group also displayed pressor responses to BK. These results disclose that in spite of the typical hypotension produced by BK in healthy animals, administration of BK in endotoxemic rats produces a biphasic effect, which is characterized by a hypotension followed by a sustained rise in blood pressure. The pressor effect of BK, induced by endotoxemia, appears to be mediated by both bradykinin B2 and angiotensin II AT1 receptors and is fully dependent on activation of ROCK.Support or Funding InformationCNPq (448738/2014‐7). This study was approved by CEUA/UFSC (PP00566).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Oxidative stress in the optic nerve and cortical visual area of steptozotocin-induced diabetic Wistar rats: Blockade with a selective bradykinin B1 receptor antagonist

The role of bradykinin B1 receptors on the oxidative stress as measured by the levels of Na+/K+ ATPase activity, malondialdehyde (MDA) and glutathione (GSH) in male Wistar rat optic nerve and visual cortex area 1 and 4weeks after STZ treatment was studied. Rats were divided into 4 groups (n=6–7): 1. Controls (non-diabetics); 2. Diabetics (65mg/kg streptozotocin, STZ); 3. Diabetics injected with B1 antagonist R-954 (2mg/Kg) during the last 3days of a one week period; 4. Diabetics injected with B1 antagonist R-954 (2mg/Kg) during the last 3days of a 4week period. The results showed that plasma glucose levels increased by up to 4 fold in diabetic rats 1 or 4weeks following the STZ treatment. R-954 treatment did significantly decrease blood glucose levels. Levels of MDA was increased in the plasma of the 1 and 4week diabetic animals whereas the GSH levels were decreased. Both markers returned to normal following R-954 treatment. Na+/K+ ATPase activity significantly decreased in the optic nerve and visual cortex of diabetic rats at 1 and 4weeks but returned to normal following R-954 treatment. MDA levels increased markedly at 1 and 4weeks compared with control levels in the optic nerve but slightly in the visual cortex and returned to control levels in both tissues following R-954 treatment. GSH levels decreased in both tissues at 1 and 4weeks compared with control levels. Following administration of the selective BKB1R antagonist R-954, the levels of GSH returned to normal in both tissues of the 1 and 4week diabetic animals. These results showed that the inducible BKB1 receptors are associated with the oxidative stress in the optic nerve and cortical visual area of diabetic rats and suggested that BKB1-R antagonist R-954 could have a beneficial role in the treatment of diabetic retinopathy.

Role of selective blocking of bradykinin receptor subtypes in attenuating allergic airway inflammation in guinea pigs

The present study was designed to evaluate the potential role of bradykinin antagonists (R-715; bradykinin B1 receptor antagonist and icatibant; bradykinin B2 receptor antagonist) in treatment of allergic airway inflammation in comparison to dexamethasone and montelukast. R-715 as dexamethasone significantly decreased peribronchial leukocyte infiltration, bronchoalveolar lavage fluid (BALF) albumin and interleukin 1β as well as serum OVA-specific IgE level. Also, R-715 like montelukast significantly decreased BALF cell count (total and eosinophils). Icatibant showed negative results. The current findings suggest that selective bradykinin B1 receptor antagonists may have the therapeutic potential for the treatment of allergic airway inflammation.

Human Urinary Kallidinogenase Promotes Angiogenesis and Cerebral Perfusion in Experimental Stroke.

Angiogenesisis a key restorative mechanism in response to ischemia, and pro-angiogenic therapy could be beneficial in stroke. Accumulating experimental and clinical evidence suggest that human urinary kallidinogenase (HUK) improves stroke outcome, but the underlying mechanisms are not clear. The aim of current study was to verify roles of HUK in post-ischemic angiogenesis and identify relevant mediators. In rat middle cerebral artery occlusion (MCAO) model, we confirmed that HUK treatment could improve stroke outcome, indicated by reduced infarct size and improved neurological function. Notably, the 18F-FDG micro-PET scan indicated that HUK enhanced cerebral perfusion in rats after MCAO treatment. In addition, HUK promotespost-ischemic angiogenesis, with increased vessel density as well as up-regulated VEGF andapelin/APJ expression in HUK-treated MCAO mice. In endothelial cell cultures, induction of VEGF and apelin/APJ expression, and ERK1/2 phosphorylation by HUK was further confirmed. These changes were abrogated by U0126, a selective ERK1/2 inhibitor. Moreover, F13A, a competitive antagonist of APJ receptor, significantly suppressed HUK-induced VEGF expression. Furthermore, angiogenic functions of HUK were inhibited in the presence of selective bradykinin B1 or B2 receptor antagonist both in vitro and in vivo. Our findings indicate that HUK treatment promotes post-ischemic angiogenesis and cerebral perfusion via activation of bradykinin B1 and B2 receptors, which is potentially due to enhancement expression of VEGF and apelin/APJ in ERK1/2 dependent way.

Treatment of HAE Attacks in the Icatibant Outcome Survey: An Analysis of Icatibant Self-Administration versus Administration by Health Care Professionals

Background: Icatibant, a selective bradykinin B2 receptor antagonist for the treatment of acute hereditary angio-oedema (HAE) attacks in adults, can be administered by health care professionals (HCPs) or self-administered. This analysis compared characteristics and outcomes of acute HAE attacks treated with self-administered and HCP-administered icatibant in a real-world setting. Methods: The Icatibant Outcome Survey (Shire, Zug, Switzerland; NCT01034969) is an international observational study monitoring the safety and effectiveness of icatibant treatment. Descriptive retrospective analyses were performed (February 2008 to December 2012). Results: Icatibant was used in 652 attacks in 170 patients with HAE type I/II. Most icatibant injections were self-administered (431/652, 68.5%). The proportion of self-treated attacks increased over time (40.3% in 2009 vs. 89.7% in 2012). The median time to administration was significantly shorter in self- versus HCP-treated attacks (1.5 vs. 2.4 h; p = 0.016). Earlier treatment (<2 h after onset) was significantly associated with a shorter median time to resolution (2.5 vs. 5.0 h; p = 0.032) and attack duration (3.0 vs. 14.0 h; p < 0.0001), regardless of administration method. Patients self-administered icatibant for attacks of all severities; overall, 34.7% of severe and 30.2% of very severe attacks were HCP treated. Logistic regression analysis did not find use of long-term prophylaxis, attack location or gender to be predictive for self-administration. Conclusions: The proportion of HAE attacks treated with self-administered icatibant increased over time. Patients successfully self-administered icatibant for a wide variety of HAE attacks, demonstrating that icatibant is generally well tolerated and effective for self-administration. Self-administration of icatibant provides a complementary option to HCP administration, enabling optimization of patient care.

A Randomized Trial of Icatibant in ACE-Inhibitor–Induced Angioedema

BackgroundAngioedema induced by treatment with angiotensin-converting–enzyme (ACE) inhibitors accounts for one third of angioedema cases in the emergency room; it is usually manifested in the upper airway and the head and neck region. There is no approved treatment for this potentially life-threatening condition.MethodsIn this multicenter, double-blind, double-dummy, randomized phase 2 study, we assigned patients who had ACE-inhibitor–induced angioedema of the upper aerodigestive tract to treatment with 30 mg of subcutaneous icatibant, a selective bradykinin B2 receptor antagonist, or to the current off-label standard therapy consisting of intravenous prednisolone (500 mg) plus clemastine (2 mg). The primary efficacy end point was the median time to complete resolution of edema.ResultsAll 27 patients in the per-protocol population had complete resolution of edema. The median time to complete resolution was 8.0 hours (interquartile range, 3.0 to 16.0) with icatibant as compared with 27.1 hours (interquartile range, 20.3 to 48.0) with standard therapy (P=0.002). Three patients receiving standard therapy required rescue intervention with icatibant and prednisolone; 1 patient required tracheotomy. Significantly more patients in the icatibant group than in the standard-therapy group had complete resolution of edema within 4 hours after treatment (5 of 13 vs. 0 of 14, P=0.02). The median time to the onset of symptom relief (according to a composite investigator-assessed symptom score) was significantly shorter with icatibant than with standard therapy (2.0 hours vs. 11.7 hours, P=0.03). The results were similar when patient-assessed symptom scores were used.ConclusionsAmong patients with ACE-inhibitor–induced angioedema, the time to complete resolution of edema was significantly shorter with icatibant than with combination therapy with a glucocorticoid and an antihistamine. (Funded by Shire and the Federal Ministry of Education and Research of Germany; ClinicalTrials.gov number, NCT01154361.)

Muscle hyperalgesia induced by peripheral P2X3 receptors is modulated by inflammatory mediators

ATP, via activation of P2X3 receptors, has been highlighted as a key target in inflammatory hyperalgesia. Therefore, the aim of this study was to confirm whether the activation of P2X3 receptors in the gastrocnemius muscle of rats induces mechanical muscle hyperalgesia and, if so, to analyze the involvement of the classical inflammatory mediators (bradykinin, prostaglandins, sympathetic amines, pro-inflammatory cytokines and neutrophil migration) in this response. Intramuscular administration of the non-selective P2X3 receptor agonist α,β-meATP in the gastrocnemius muscle of rats induced mechanical muscle hyperalgesia, which, in turn, was prevented by the selective P2X3 and P2X2/3 receptors antagonist A-317491, the selective bradykinin B1-receptor antagonist Des-Arg9-[Leu8]-BK (DALBK), the cyclooxygenase inhibitor indomethacin, the β1- or β2-adrenoceptor antagonist atenolol and ICI 118,551, respectively. Also, the nonspecific selectin inhibitor fucoidan. α,β-meATP induced increases in the local concentration of the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin 1β (IL-1β), which were reduced by bradykinin antagonist. Finally, α,β-meATP also induced neutrophil migration. Together, these findings suggest that α,β-meATP induced mechanical hyperalgesia in the gastrocnemius muscle of rats via activation of peripheral P2X3 receptors, which involves bradykinin, prostaglandins, sympathetic amines, pro-inflammatory cytokines release and neutrophil migration. It is also indicated that bradykinin is the key modulator of the mechanical muscle hyperalgesia induced by P2X3 receptors. Therefore, we suggest that P2X3 receptors are important targets to control muscle inflammatory pain.

36 Prevention of Invasive Airway Management in Drug-Induced Angioedema Using Icatibant

Angioedema occurs in 0.1 to 1.0% of patients taking Angiotensin Converting Enzyme Inhibitors (ACEI) or Angiotensin Receptor Blockers (ARB). Standard supportive care with drug discontinuation, epinephrine, antihistamines, and corticosteroids is recommended. Some cases progress to life threatening oral edema requiring invasive airway management (IAM), such as endotracheal intubation, cricothyrotomy, or tracheotomy. Icatibant, a selective bradykinin B2 receptor antagonist, has been used off-label in ACEI/ARB-associated angioedema to prevent tracheotomy. Icatibant has an average wholesale price of $9,606 per dose, limiting administration to patients experiencing airway compromise. The primary outcome of this study was to evaluate whether icatibant can abort IAM in life-threatening ACEI/ARB-associated oral angioedema. The secondary purpose was to evaluate patient outcome and cost. A retrospective review was performed of ten months of pre- and post-implementation of a criteria-based protocol using a 30 mg subcutaneous dose of icatibant for life-threatening ACEI/ARB- associated oral angioedema with attending emergency physician-documented imminent IAM. This included all patients who presented to the Ohio State University Wexner Medical Center University Hospital emergency department (ED), a tertiary care academic center, or University Hospital East ED, an inner city teaching hospital, with angioedema and secondarily ACEI/ARB-associated angioedema based on an admission or discharge ICD-9 diagnosis code of 995.1, and ACEI or ARB home medication use within 24 hours. Pre-implementation review was from January 1, 2011 to October 31, 2011 and post-implementation review was from May 1, 2013 to February 28, 2014. Outcome data included number of patients with IAM, patient length of stay (LOS), and total hospital cost. Total ED visits during each review period were approximately 96,000. In the pre-implementation period, 93 patients with a diagnosis of angioedema were identified, of whom 42 were associated with ACEI and two with ARB use (47% of angioedema patients and 0.04% of all ED visits). Eighteen drug-associated patients were admitted with six (6 of 44, 13.6%) receiving either endotracheal intubation (4 cases), cricothyrotomy (1 case), or tracheotomy (1 case). LOS ranged from 2 to 16 days and averaged 7.7 days, with an associated hospital cost of $17,878 + $24,482. In the post-implementation period, there were 143 cases of angioedema, of which 63 were associated with ACEI and three with ARB use (46% of angioedema patients and 0.07% of all ED patients). Thirty-two drug-associated patients were admitted and one (non-icatibant) standard supportive care patient received IAM with a LOS of 6 days and hospital cost of $15,137. Icatibant was used in seven of the drug-associated patients (10.6%), none of whom subsequently required IAM. Length of stay for icatibant patients averaged 0.5 days with a total hospital cost of $5,951 + $1,575. None of the icatibant patients had any reported side effects or adverse reactions. Visible angioedema decrease occurred within one hour in all cases. The use of icatibant in ACEI/ARB-associated angioedema patients with imminent invasive airway management was associated with a reduction in invasive airway management, length of stay, and total hospital cost, compared to standard supportive care.

The bradykinin B1 receptor antagonist BI113823 reverses inflammatory hyperalgesia by desensitization of peripheral and spinal neurons.

Bradykinin is a neuropeptide released after tissue damage which plays an important role in inflammatory pain. The up-regulation of the bradykinin B1 receptor in response to inflammation makes it an attractive target for drug development. Aim was to investigate if the selective B1 receptor antagonist BI113823 reduces inflammation-induced mechanical hyperalgesia and if the effect is mediated via peripheral and/or spinal B1 receptor antagonism. Electrophysiological recordings of peripheral afferents and spinal neurons were combined with behavioural experiments to better understand the underlying mechanisms of B1 receptor antagonism. Experiments were performed 24 h after injection of complete Freund's adjuvant (CFA) or saline into the paw of Wistar rats. A gene expression analysis for the B1 receptor was performed in different tissues. BI113823 was administered orally or intrathecally to assess effects on CFA-induced hyperalgesia. Peripheral afferents of the saphenous nerve as well as spinal wide dynamic range (WDR) and nociceptive-specific (NS) neurons were recorded, and mechanosensitivity was measured before and after BI113823 administration. BI113823 reduced CFA-induced mechanical hyperalgesia when administered orally or intrathecally. An increased B1 receptor gene expression was found in peripheral and spinal neural tissue. BI113823 significantly reduced mechanosensitivity of peripheral afferents and spinal NS neurons, but had no effect on WDR neurons. The selective bradykinin B1 receptor antagonist BI113823 reduces CFA-induced mechanical hyperalgesia which is mediated via antagonism of peripheral as well as spinal bradykinin B1 receptors. The selective modulation of CFA-sensitized spinal NS neurons by BI113823 could be a promising property for the treatment of inflammatory pain.

Icatibant in the treatment of Angiotensin-converting enzyme inhibitor-induced angioedema.

We describe the case of a 75-year-old woman who presented with massive tongue and lip swelling secondary to angiotensin-converting enzyme inhibitor-induced angioedema. An awake fibre-optic intubation was performed because of impending airway obstruction. As there was no improvement in symptoms after 72 hours, the selective bradykinin B2 receptor antagonist icatibant (Firazyr) was administered and the patient's trachea was successfully extubated 36 hours later. To our knowledge this is the first documented case of icatibant being used for the treatment of angiotensin-converting enzyme inhibitor-induced angioedema in the United Kingdom and represents a novel therapeutic option in its management.

Activity of Bradykinin B2 Receptor Is Regulated by Long-Chain Polyunsaturated Fatty Acids

The molecular and cellular mechanisms by which long-chain polyunsaturated fatty acids (LCPUFA) exert their beneficial effects on cardiovascular health remain obscure. While both LCPUFA and bradykinin (BK) signaling pathway play a role in the cardiovascular system, any direct link between the two is yet to be established. Using picosecond time-resolved fluorescence microscopy and a genetically engineered bradykinin B2 receptor (B2R) sensor (B2K-CC), we detected LCPUFA-induced conformational responses in the B2R similar to those caused by its cognate ligand, BK. The selective B2R antagonist (HOE-140) blocked the eicosapentaenoic acid (EPA, C20∶5, n-3) induced conformational response of the B2K-CC. Further analysis suggests that LCPUFA are capable of direct, B2R-dependent activation of extracellular ligand-regulated kinases (ERK). From a wide range of fatty acids studied, varying in chain length, saturation, and position of double bonds, EPA, docosahexaenoic (DHA, C22∶6, n-3), docosadienoic (DDA, C22∶2, n-6), and dihomo-gamma linoleic (DGLA, C20∶3, n-6) fatty acids caused the highest ERK phosphorylation. EPA or DHA dependent ERK phosphorylation was inhibited by the selective B2R antagonist. We show that LCPUFA stimulates downstream signaling by B2R such as B2R-dependent phosphorylation and expression regulation of endothelial nitric-oxide synthase (eNOS). Further analysis indicated that LCPUFA also alters levels of the eNOS transcription factor, kruppel-like factor 2 (KLF2). Moreover we show that EPA increases membrane fluidity on the same time scale as B2R conformational response, suggesting that partitioning of LCPUFA into bilayer is a primary step required for receptor activation. In summary our data show that LCPUFA activate B2R receptor at nanomolar concentrations suggesting a novel molecular mechanism by which fatty acids may affect the cardiovascular system.

An update on hereditary angioedema

To review and update the management and understanding of hereditary angioedema (HAE), while integrating insights into pediatric subtleties that exist in practice. Major advances have recently been made in HAE treatment. Ecallantide (a kallikrein inhibitor approved for use in the United States in December 2009) and icatibant (a selective bradykinin B2 receptor antagonist approved for use in the United States in August 2011) represent novel subcutaneous therapies for acute HAE exacerbations. Recombinant human C1 esterase inhibitor (C1INH) serves as a promising future alternative to current mainstay acute and prophylactic treatment with plasma-derived C1INH. Recent guidelines have outlined new algorithms for short-term and long-term prophylaxis against HAE exacerbations. The evolving standard of care for HAE management involves not only treatment of acute exacerbations but also individualized patient preference-sensitive short-term and long-term prophylaxis. Updated international consensus guidelines provide useful protocols, whereas recent clinical reviews have raised awareness of HAE. Further advances will likely focus on improving patient access to convenient acute and prophylactic treatment with C1INH.

Bradykinin- and lipopolysaccharide-induced bradykinin B2 receptor expression, interleukin 8 release and “nitrosative stress” in bronchial epithelial cells BEAS-2B: Role for neutrophils

Bradykinin-induced interleukin (IL)-8 release should potentially activate neutrophils releasing myeloperoxidase (MPO) and subsequently generating “nitrosative stress”.We studied bradykinin-induced expression of bradykinin B2 receptor and bradykinin- and lipopolysaccharide (LPS)-induced IL-8 release, MPO (marker of neutrophil activation) and 3-nitrotyrosine (3-NT; marker of “nitrosative stress”) production in human bronchial epithelial cells BEAS-2B alone or in co-culture with human neutrophils.We evaluated B2 receptor protein expression in BEAS-2B cells by immunostainings and Western blot analysis, and measured respectively bradykinin- or LPS-induced IL-8 release in BEAS-2B cells and bradykinin- and/or LPS-induced MPO and 3-NT production in BEAS-2B cells co-cultured with human neutrophils by ELISA. In addition, we evaluated bradykinin- and/or LPS-induced 3-NT formation in BEAS-2B cells co-cultured with human neutrophils by immunocytochemistry.Bradykinin up-regulates B2 receptor expression (P<0.05) and stimulate IL-8 release (P<0.001) in BEAS-2B cells. Either the selective bradykinin B2 receptor antagonist HOE 140 or the selective bradykinin B1 receptor antagonist Lys-(des-Arg9, Leu8)-bradykinin alone halved IL-8 release and the combination of both drugs suppressed this effect. In BEAS-2B cells co-cultured with human neutrophils bradykinin increased MPO release and 3-NT production compared to BEAS-2B cells with human neutrophils (P<0.001), and the addition of LPS in BEAS-2B cells with human neutrophils and bradykinin induced a further dramatically increase of MPO release and 3-NT formation (P<0.001).Bradykinin and LPS provoked “nitrosative stress”, potentially mediated by IL-8, in bronchial epithelium co-cultured with neutrophils suggesting a role for bradykinin in the amplification of chronic airway inflammation via production of “nitrosative stress”.

Blockade of early and late retinal biochemical alterations associated with diabetes development by the selective bradykinin B1 receptor antagonist R-954

The chronic hyperglycemia measured alongside diabetes development is associated with significant long-term damage and failure of various organs. In the present study it was shown that hyperglycemia induced early and long term increases in nitric oxide (NO) levels, kallikrein activity and vascular capillary permeability measured as plasma extravasation, and decreases of Na/K ATPase activity in diabetic rat retina 4 and 12 weeks after streptozotocin (STZ) injection. Treatment of the animals for 5 consecutive days with a novel selective bradykinin B1 receptor (BKB1-R) antagonist R-954 (2mg/kgs.c) at the end of the 4 and 12 week periods highly reduced NO, kallikrein and capillary permeability and increased Na/K ATPase activity in the retina. These results suggest that the BKB1-R receptor subtype is over-expressed during the streptozotocin-induced development of diabetes in rat retina as evidenced by the inhibitory effects of the BKB1-R antagonist R-954 on NO, kallikrein and vascular permeability increases as well as Na/K ATPase decreases. The beneficial role of the BKB1-R antagonist R-954 for the treatment of the diabetic retinopathy is also suggested.