Histamine Challenge Research Articles

Quantitative assessment of skin swelling using optical coherence tomography.

Preclinical and clinical studies suggest that optical coherence tomography (OCT) is a useful tool to visualize inflammatory conditions. The objective of this study was to evaluate the usefulness of combining OCT and various image processing techniques for quantitative assessment of histamine-induced tissue swelling. Both time-domain and frequency-domain OCT were used on a mouse ear model. The ear thickness and volume before and after histamine challenge were determined from pixel locations in 2D scans and voxel number counting in 3D scans. Swelling kinetics was analyzed on 3D contour mapping. Microvessel network was visualized using speckle decorrelation analysis. OCT images showed that the thickness and volume changes were histamine dose and contact time dependent. The 3D mapping showed that the histamine-induced swelling spread slowly and directionally. OCT data indicated that microvessel opening and vessel dilation occurred prior to tissue swelling. OCT is a robust and quantitative non-invasive imaging tool for assessing skin swelling.

Inspiratory and Expiratory Flow Changes, Voice Symptoms and Laryngeal Findings during Histamine Challenge Tests

Objective: The aim of this study was to analyse the associations between the spirometry parameter changes in relation to laryngeal finding changes and self-reported voice and throat symptom changes among patients undergoing a histamine challenge test. Patients and Methods: Thirty adult patients with a chronic cough underwent a histamine challenge test. Videolaryngostroboscopy and voice and throat symptoms were assessed using a visual analogue scale immediately before and after the challenge test. Correlations between the relative changes in spirometry values in relation to the change in vocal fold oedema and redness and self-reported voice and throat symptom changes during the challenge test were assessed. Results: A correlation between the relative change in inspiratory and expiratory air flow values and the change in voice and throat symptoms during the histamine challenge test was found. The vocal fold oedema, visible on videolaryngostroboscopy, caused by the histamine challenge did not significantly affect the spirometry air flow values. Conclusion: The relative changes in inspiratory and expiratory air flow and voice and throat symptoms during the histamine challenge test correlated. The vocal fold oedema caused by the histamine challenge, visible on videolaryngostroboscopy, did not significantly affect the spirometry air flow values.

Patterns of bronchial hyperreactivity in patients of congestive heart failure

Abstract Objectives To study the incidence of bronchial hyperreactivity in patients of congestive heart failure. Methods 50 subjects were divided into two groups. Group A was apparently healthy people taken as controls. Group B included patients of congestive heart failure. Both groups were then further subjected to spirometry followed by histamine bronchoconstriction test if FEV1/FVC > 85%. Results 1 subject out of 25 in group A as compared to 18 out of 25 in group B showed a fall in FEV1 of more than 20% on histamine challenge test. Hence the difference in bronchial hyperreactivity in both groups was statistically significant (p Conclusion 72% of the patients of congestive heart failure demonstrated bronchial hyperreactivity whereas the incidence in normal controls was only 4%.

The contribution of an asthma diagnostic consultation service in obtaining an accurate asthma diagnosis for primary care patients: results of a real-life study

Previous studies showed that general practitioners have problems in diagnosing asthma accurately, resulting in both under and overdiagnosis. To support general practitioners in their diagnostic process, an asthma diagnostic consultation service was set up. We evaluated the performance of this asthma diagnostic consultation service by analysing the (dis)concordance between the general practitioners working hypotheses and the asthma diagnostic consultation service diagnoses and possible consequences this had on the patients’ pharmacotherapy. In total 659 patients were included in this study. At this service the patients’ medical history was taken and a physical examination and a histamine challenge test were carried out. We compared the general practitioners working hypotheses with the asthma diagnostic consultation service diagnoses and the change in medication that was incurred. In 52% (n = 340) an asthma diagnosis was excluded. The diagnosis was confirmed in 42% (n = 275). Furthermore, chronic rhinitis was diagnosed in 40% (n = 261) of the patients whereas this was noted in 25% (n = 163) by their general practitioner. The adjusted diagnosis resulted in a change of medication for more than half of all patients. In 10% (n = 63) medication was started because of a new asthma diagnosis. The ‘one-stop-shop’ principle was met with 53% of patients and 91% (n = 599) were referred back to their general practitioner, mostly within 6 months. Only 6% (n = 41) remained under control of the asthma diagnostic consultation service because of severe unstable asthma. In conclusion, the asthma diagnostic consultation service helped general practitioners significantly in setting accurate diagnoses for their patients with an asthma hypothesis. This may contribute to diminish the problem of over and underdiagnosis and may result in more appropriate treatment regimens.

Study of pH Stability of R-Salbutamol Sulfate Aerosol Solution and Its Antiasthmatic Effects in Guinea Pigs.

Currently, all commercial available nebulized salbutamol in China is in its racemic form. It is known that only R-salbutamol (eutomer) has therapeutic effects, while S-salbutamol (distomer) may exacerbate asthma after chronic use. Therefore, it is an unmet clinical need to develop R-salbutamol as a nebulized product that is more convenient for young and old patients. In our study, a stable aerosol solution of R-salbutamol sulfate was established, and its antiasthmatic effects were confirmed. The decomposition rate and racemization effect of the R-salbutamol sulfate solution were evaluated over a pH range from 1 to 10 (except pH=7, 8) at 60°C. The aerodynamic particle size of the R-salbutamol sulfate solution and commercial RS-salbutamol sulfate solution were both tested in vitro by Next-Generation Impactor (NGI) in 5°C. Laser diffractometer was used to characterize the droplet-size distribution (DSD) of both solutions. We next conducted an in vivo animal study to document the antiasthmatic effect of R-salbutamol aerosol sulfate solution and determine the relationship to RS-salbutamol. The results showed that the R-salbutamol sulfate solution was more stable at pH 6. In vitro comparison studies indicated that there was no distribution difference between R-salbutamol sulfate solution and the commercial RS-salbutamol solution. The animal results showed that R-salbutamol was more potent than RS-salbutamol against the same dose of histamine challenge. Unlike commercial RS-salbutamol, which was acidified to a pH of 3.5 to extend bench life but may cause bronchoconstriction in asthmatic patients, the neutralized R-salbutamol solution was more suitable for clinic use.

Laryngeal Mucosal Reaction during Bronchial Histamine Challenge Test Visualized by Videolaryngostroboscopy

To examine the changes in the larynx, as well as self-reported voice and throat symptoms, among patients undergoing a histamine challenge test. Thus, to understand the possible clinical effects of histamine on the larynx. Controlled, open prospective study. Thirty adult patients with prolonged cough and suspicion of bronchial asthma underwent a histamine challenge test. Videolaryngostroboscopy was performed immediately before and after the challenge. Voice and throat symptoms immediately before and after the challenge test were assessed using a visual analog scale. Videolaryngostroboscopy after exposure showed significant increases in edema (P < 0.001) as well as redness (P < 0.001) of the vocal folds after the exposure. Self-reported voice complaints increased significantly for 8 of 11 symptoms. A moderate positive correlation was found between the increase in edema of the vocal folds and reported heartburn/regurgitation symptoms (r = 0.42, P < 0.05). Atopy, asthma, nasal symptoms, or bronchial hyperreactivity during the histamine challenge test were not associated with laryngeal reactions. According to the results, the laryngeal mucosal reaction during a histamine challenge test can be objectively visualized. Videolaryngostroboscopy findings, together with an increase in self-reported voice and throat symptoms, show that histamine has potential effects on vocal folds. The mucosal reaction seems to be pronounced among patients with reflux symptoms, probably reflecting the permeability features of the vocal folds.

Respiratory Symptoms, Lung Function Impairment, and Chronic Respiratory Diseases Among Crop Farmers: Assessment by Job Exposure Matrices

Objective: To evaluate the prevalence of chronic respiratory symptoms, lung function impairment, and chronic obstructive respiratory diseases in crop farmers. Our objective is to then examine their relation to exposure duration, and to explore the usefulness of job exposure matrices as tools for exposure assessment, and predictors for respiratory health impairment. Methods: A cross-sectional study was performed, including 50 males (mean age: 45.4±10.7 years) employed as crop farmers (duration of exposure: 21.6±9.7 years) and 50 male office workers as a control group (mean age: 44.1±9.8 years) matched for age, smoking habits, and socioeconomic status. Methods of evaluating examined subjects included the completion of a questionnaire on respiratory symptoms in the last 12 months (cough, phlegm, dyspnoea, wheezing, chest tightness, and nasal symptoms), spirometry and histamine challenge (provocative concentration producing a 20% fall in forced expiratory volume in 1 second [FEV1]: ≤8 mg/mL), as well as use of job exposure matrices. Results: Crop farmers had a significantly higher prevalence of cough (29.4%), phlegm (16.7%), and wheezing (11.9%), than the control group (p&lt;0.05). All spirometric parameters (forced vital capacity [FVC], FEV1, FEV1/FVC%, maximal expiratory flow (MEF) at 75%, 50%, and 25%) were lower in crop farmers compared to the control patients, but statistical significance was confirmed only for MEF at 25%, 50%, and 25–75% (p=0.021, p=0.011, and p=0.003, respectively). The prevalence of bronchial hyperresponsiveness, asthma, and chronic obstructive pulmonary disease was higher in crop farmers but without statistical significance. JEM were useful tools for exposure assessment and predictors of factors for asthma and COPD development. Conclusion: The results suggest that occupational exposure among crop farmers is associated with a higher prevalence of respiratory symptoms, lung function impairment, and a higher prevalence of chronic respiratory diseases.

The use of 4.5% hypertonic saline challenge test in diagnosing asthma in children with chronic recurrent cough

Background The 4.5% hypertonic saline (HS) challenge test hasseveral benefits compared to histamine challenge test as gold stan-dard. Saline is an inexpensive non-pharmacological substancewhich is relatively safe. Its mechanism in inducing bronchospasmresembles that of asthma. Moreover, it can easily be made in amodest medical laboratory.Objective To determine the ability of 4.5% HS challenge test com-pared to histamine challenge test in diagnosing asthma in childrenwith chronic recurrent cough (CRC).Methods This study was a diagnostic test on children with CRCaged 6 to 14 years, conducted in outpatient clinic of Department ofChild Health, Cipto Mangunkusumo Hospital, Jakarta. All subjectsunderwent lung function tests. Subjects whose FEV 1 was &lt;80% werediagnosed as asthmatic and underwent the 4.5% HS challenge testonly. Those whose FEV 1 was 80% underwent the histamine chal-lenge test followed by the 4.5% HS challenge test one or two weekslater. Test results were expressed as positive or negative. Based onthe results, we calculated the sensitivity, specificity, predictive val-ues, and likelihood ratios of the 4.5% HS challenge test.Results Forty-five subjects, consisting of 22 boys and 23 girls,were enrolled. The average age of subjects was 9 years old. Atopichistory in the family or in subjects themselves was found in 80% ofsubjects. Eight subjects had FEV 1 of &lt;80%. Forty-four subjectswere diagnosed with asthma based on a baseline FEV 1 of &lt;80%or a positive histamine provocation test. Thirty-seven subjects hada positive 4.5% HS challenge test; all had asthma. Sensitivity andspecificity of the 4.5% HS challenge test were 84.1% and 100.0%,respectively; the positive and negative predictive values were100.0% and 12.5%, respectively. The positive likelihood ratio wasinfinite and negative likelihood ratio was 0.16.Conclusion The 4.5% hypertonic saline challenge test can be usedas an alternative bronchial provocation test in diagnosing asthma inchildren with CRC. Further study with larger sample size is neededfor widespread usage.

Is spirometry essential in diagnosing asthma? Yes.

Asthma is a disease that is often hard to diagnose because many patients have no signs or symptoms and have a normal lung function between attacks. Impaired lung function during a histamine challenge test is the reference test, but is not acceptable to many patients, especially to children. A history of certain symptoms also has sufficient diagnostic value for the diagnosis of asthma. Both the British and Dutch guidelines allow indication of a diagnosis of asthma without further additional testing when certain signs and symptoms are present.1,2 So for these patients spirometry …

Effect of Heat Shock Treatment on Endothelial Cell Integrity after Histamine Challenge

Endothelial cells and endothelial cell integrity play a central role in circulatory homeostasis. Our previous study indicated that heat shock treatment reduces protein leakage and attenuates the hypotension caused by anaphylactic shock. Also, heat shock treatment maintains cerebral vascular permeability, while the blood brain barrier is opened by high osmotic stress. In this study we investigated the potential mechanism by which heat shock protein 72 (Hsp72), the major product after heat shock, maintains cellular integrity of cultured histamine-induced human umbilical vein endothelial cells (HUVECs) upon challenge by histamine. Tight junction proteins (ZO-1 and occludin) and a cytoskeleton component (F-actin) were evaluated by an immunocytochemical study. The immunochemical density of ZO-1 and occludin was clearly decreased in the non-heated cells after histamine challenge, and associated with the proportional decline of F-actin. The adverse phenomenon was prevented in the heated cells in which Hsp72 was significantly over-expressed. It was further demonstrated that Hsp72 could be exclusively coimmunoprecipitated with ZO-1 or occludin in heated cells. In conclusion, histamine-induced conformational alteration of HUVECs is attenuated by previous heat shock treatment, and the Hsp72-mediated preservation of tight junction proteins, as well as cytoskeletal structure, could be the possible mechanism of action.

A histamine-independent itch pathway is required for allergic ocular itch

Non-histaminergic TRPA1 neural pathway is required for the development of allergic ocular itch. Pharmacological inhibition of TRPA1 channel can lead to novel therapeutic strategies to treat ocular itch in severe allergic conjunctivitis.

Relationship between the response to allergen, histamine and hypertonic saline nasal challenge and subjective reactivity to irritants in subjects with seasonal allergic rhinitis

Background Patients with seasonal allergic rhinitis (SAR) may have symptoms triggered by environmental changes and irritants exposure in the absence of allergen. It is hypothesized that level of hyperreactivity in mixed rhinitis is related the inflammation in the late phase response, stimulation of sensory nerves and transient receptor potential (TRP) channels. The study was done to compare subjective and objective response to the low-dose allergen, histamine and hypertonic saline challenge, with subjective responsiveness to common irritants.

Joint incidence of asthma and rhinitis in macedonia.

The concept of “united airways disease”, based on many similar features and mutual interactions in the pathogenesis of asthma (A) and rhinitis (R), has led to an integral approach to their management. We conducted this study to determine the quantity of the problem of joint incidence of A and R in R. Macedonia, and, perhaps to obtain information on a potential causative effect of the two diseases.Three hundred eighty six patients, who presented with wheezing and/or upper respiratory symptoms at the Pulmology and Allergy Clinic, Skopje, were included during a period of 48 months. The presence of bronchial hyperreactivity – BHR (positive histamine challenge), atopy (prick test to seasonal or perennial inhaled allergens), rhinitis symptoms (such as nasal secretion and obstruction) and X-ray of paranasal sinuses was registered by a specially designed questionnaire. R was diagnosed in 106 of the subjects (27.5%), and A in 280 (72.5%). Among the patients with A, co-incidence with R was found in 219 (76.5%). Including X-ray of paranasal sinuses to the diagnostic protocol increased this percentage to over 90% (256 patients). From the 219 patients with A and R together, 127 (57.99%) had positive atopy. On the other hand, 19 (18.0%) of the rhinitis-only patients had positive BHR without asthma symptoms. The follow up of the rhinitis patients with positive BHR revealed 4 patiets who developed asthma within 36 months, but this was also the case with 2 of the subjects with R and negative BHR. In conclusion, the co-incidence of A and R in our material is 78.21%, or 91.4% (including sinusitis); a greater co-existence of A and R is found in atopic patients. The patients with allergic R are at high risk for developing A and should be monitored in the future and the R symptoms should be adequately treated in order to minimize the risk for developing asthma.

Clemastine Confers Neuroprotection and Induces an Anti-Inflammatory Phenotype in SOD1(G93A) Mouse Model of Amyotrophic Lateral Sclerosis.

Mutations in the Cu(2+)/Zn(2+) superoxide dismutase 1 (SOD1) gene underlie 14-23 % of familial and 1-7 % of sporadic cases of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease characterized by a specific loss of motor neurons in the brain and spinal cord. Neuroinflammation and oxidative stress are emerging as key players in the pathogenesis of ALS, thus justifying the interest in glial cells and particularly microglia, in addition to motor neurons, as novel therapeutic approaches against ALS. Recently, histamine was proven to participate in the pathogenesis of neuroinflammatory and neurodegenerative diseases, and particularly, microglia was shown to be sensitive to the histamine challenge mainly through histamine H1 receptors. Clemastine is a first-generation and CNS-penetrant H1 receptor antagonist considered as a safe antihistamine compound that was shown to possess immune suppressive properties. In order to investigate if clemastine might find promising application in the treatment of ALS, in this work, we tested its action in the SOD1(G93A) mouse model which is extensively used in ALS preclinical studies. We demonstrated that chronic clemastine administration in SOD1(G93A) mice reduces microgliosis, modulates microglia-related inflammatory genes, and enhances motor neuron survival. Moreover, in vitro, clemastine is able to modify several activation parameters of SOD1(G93A) microglia, and particularly CD68 and arginase-1 expression, as well as phospho-ERK1/2 and NADPH oxidase 2 levels. Being clemastine a drug already employed in clinical practice, our results strongly encourage its further exploitation as a candidate for preclinical trials and a new modulator of neuroinflammation in ALS.

P54 Which Secondary Care Asthma Patients Are Most Likely To Overestimate Their Control? A Cross-sectional Study

Introduction Asthma is a global health issue affecting 300 million people worldwide; with increasing prevalence and morbidity and preventable mortality. Despite advances in management the number of asthma related deaths has not improved. Asthma is a heterogeneous condition, with a variety of clusters of clinical presentations and courses, objective measures and treatment responses. A common feature of asthma is the under-reporting of poor symptom control by patients and under-recognition by clinicians. Poor asthma control in the preceding 12-months prior to admission has been linked to asthma related deaths. The significance of measuring asthma control independently from asthma severity has been demonstrated. However, considerable differences in perceived and actual control are apparent. There is a need to identify patient groups at risk of under-reporting symptoms and not recognising poor control. Aim To establish which patient features are associated with overestimation of disease control. Setting Secondary care consultant led asthma clinic. Population 108 patients recruited over 10 weeks. Measures Objective measures of disease severity were mapped against perceived symptom control using the Asthma Control Test; age, gender, co-morbidities, medications, induced sputum, lung function, IgE, blood eosinophil, histamine challenge test, exhaled nitric oxide, ECG CXR, smoking status and BMI. Analysis Significant associations between patient groups and perceptions of symptom control are described. Results 61 (56.6%) of patients had difficult asthma according to BTS guidance. 95 (88.0%) had poorly controlled asthma, with 70 (64.8%) of these perceiving adequate control of symptoms. All patients with good perceived and actual control of symptoms; 13 (12.0%), had never smoked. 85.5% of patients who did not recognise their symptoms prevalence were overweight, obese or morbidly obese. All patients with raised IgE or blood eosinophillia had poorly controlled asthma; though 58.6% of this group perceived good control. Conclusion This single centre cross-sectional study suggests smokers, overweight patients and those with inflammation predominant asthma are most likely to under-report severity. These findings are in keeping with the cluster analyses of Haldar and Moore. Further work is required to follow-up these patients to establish if poor perception of symptoms changes over time, or is associated with future asthma attack frequency.

P210 Airways Resistance In Bronchial Challenge Testing

Introduction Measurement of airways resistance is an alternative to spirometry to assess airflow obstruction. This can be measured by the interrupter technique (RInt) using a hand held device. We wished to know how RInt compared to forced expiratory volume in 1 second (FEV1) during a histamine challenge test. Methods Twenty-nine (13 male) patients, aged 48.9 (SD 15.3) years, referred for a histamine challenge test were enrolled. Patients had measurement of RInt then FEV1 after administration of saline and following doubling concentrations of histamine from 0.06 mg/ml to 8 mg/ml. Extrapolation of the log dose-response curve was undertaken to calculate the concentration (Provocation Concentration – PC) causing an increase airways resistance of 20, 40, 60, 80, 100, 120, 140 and 160% (RInt PC1.2 to RInt PC2.6) and a reduction in FEV1 by 20% (FEV1 PC20). The number of patients with a negative challenge (i.e. PC > 8 mg/ml histamine) was calculated for FEV1 and each change in airway resistance. Patients assessed their procedure provoked symptoms of breathlessness, dizziness and tiredness on a 100 mm visual analogue scale. Results Geometric (SD) PC20 for FEV1 was 1.87 (0.5) mg/ml with 11 patients having a negative challenge. A RInt PC2.0 had the best agreement with FEV1 PC20 (Kappa 0.39 (p = 0.024)). There is a significant negative correlation between RInt and FEV1 (r = -0.94). The respective mean (SD) breathlessness, dizziness and tiredness scores for RInt were 26(4) mm, 18(3) mm, 22(4) mm and for spirometry were 40(4) mm, 27(5) mm, 31(5)mm. There was a significant (p Conclusion RInt was tolerated better than spirometry. A doubling of airways resistance had the best agreement with PC20 FEV1.

Airways resistance in bronchial challenge testing

Introduction: Measurement of airways resistance is an alternative to spirometry to assess airflow obstruction. This can be measured by the interrupter technique (RInt) using a handheld device. We wished to know how RInt compared to forced expiratory volume in 1 s (FEV1) during a histamine challenge test. Methods: Twenty-nine (13 male) patients, aged 48.9 (SD 15.3) years, referred for a histamine challenge test, were enrolled. Patients had measurement of RInt then FEV1 after administration of saline and following doubling concentrations of histamine from 0.06 to 8 mg/ml. Extrapolation of the log dose–response curve was undertaken to calculate the concentration (provocation concentration, PC) causing an increase airways resistance of 20, 40, 60, 80, 100, 120, 140 and 160% (RInt PC1.2 to RInt PC2.6) and a reduction in FEV1 by 20% (FEV1 PC20). The number of patients with a negative challenge (i.e. PC > 8 mg/ml histamine) was calculated for FEV1 and each change in airway resistance. Patients assessed their procedure-provoked symptoms of breathlessness, dizziness and tiredness on a visual analogue scale. Results: Geometric (SD) PC20 for FEV1 was 1.87 (0.5) mg/ml with 11 patients having a negative challenge. A RInt PC20 had the best agreement with FEV1 PC20 [Kappa 0.39 (p = 0.024)]. There is a significant negative correlation between RInt and FEV1 (r = −0.94). The respective mean (SD) breathlessness, dizziness and tiredness scores for RInt were 26 (4) mm, 18 (3) mm, 22 (4) mm and for spirometry were 40 (4) mm, 27 (5) mm, 31 (5) mm. There was a significant (p < 0.05) difference for breathlessness. Conclusion: RInt was tolerated better than spirometry. A doubling of airways resistance had the best agreement with PC20 FEV1.

The inverse agonist propranolol confers no corticosteroid-sparing activity in mild-to-moderate persistent asthma.

The murine asthma model shows that switching off airway β2 receptors with an inverse agonist may confer anti-inflammatory effects as well as corticosteroid-sparing activity. We have assessed for any corticosteroid-sparing effects of propranolol, an inverse agonist, added to low-dose inhaled corticosteroid (ICS) compared with higher dose ICS. A randomized double-blind placebo-controlled cross-over trial in mild-to-moderate persistent asthmatic patients was performed. After a run-in (2 weeks) on hydrofluoroalkane-beclometasone dipropionate (HFA-BDP) at 100 μg/day (HFA-BDP100), patients received randomized treatments (4 weeks) with propranolol at 80 mg/day plus HFA-BDP at 100 μg/day compared with placebo plus HFA-BDP at 400 μg/day (HFA-BDP400). Propranolol was up-titrated to 80 mg/day over the initial 2 weeks. Tiotropium was co-administered until 5 days before each histamine challenge (the primary outcome). Sixteen patients completed the study [mean age, 38 years; forced expiratory volume in 1 s (FEV1), 86.4%; histamine provocative concentration causing a 20% fall in FEV1 (PC20), 1.39 mg/ml; ICS dose, 406 μg/day]. Histamine PC20 was unchanged by adding propranolol to HFA-BDP100 compared with baseline (HFA-BDP100) {0.17 doubling dilution (dd) difference [95% confidence interval (CI): -0.58 to 0.92]}, but there was a significant improvement with HFA-BDP400 compared with both baseline [1.05 dd (95% CI: 0.43-1.66); P=0.02], and propranolol+HFA-BDP100 [0.88 dd (95% CI: 0.45-1.30); P=0.006]. Significant improvements were also observed with HFA-BDP400 for exhaled nitric oxide, blood eosinophils, serum eosinophilic cationic protein and asthma quality-of-life questionnaire symptoms compared with propranolol+HFA-BDP100. Salbutamol recovery post-challenge was partially blunted by propranolol (median prolongation 5 min; P=0.002). Domiciliary evening FEV1 also fell with propranolol+HFA-BDP100 [mean reduction from baseline 0.22 litres (95% CI: 0.10-0.34); P=0.012], whereas Asthma Control Questionnaire remained unchanged. In conclusion, the inverse agonist propranolol produced no improvements when given with low-dose ICS, whereas further significant improvements in airway hyper-responsiveness and inflammation were demonstrated with higher dose ICS. Thus, propranolol does not confer corticosteroid-sparing activity in persistent asthma.

A randomised trial evaluating the effects of the TRPV1 antagonist SB705498 on pruritus induced by histamine, and cowhage challenge in healthy volunteers.

BackgroundTransient receptor potential vanilloid type 1 (TRPV1) is a non-selective cation channel widely expressed in skin tissues, and peripheral sensory nerve fibres. Activation of TRPV1 releases neuropeptides; the resulting neurogenic inflammation is believed to contribute to the development of pruritus. A TRPV1 antagonist has the potential to perform as an anti-pruritic agent. SB705498 is a TRPV1 antagonist that has demonstrated in vitro activity against cloned TRPV1 human receptors and when orally administered has demonstrated pharmacodynamic activity in animal models and clinical studies.ObjectivesTo select a topical dose of SB705498 using the TRPV1 agonist capsaicin; to confirm engagement of the TRPV1 antagonistic action of SB705498 and assess whether the dose selected has an effect on itch induced by two challenge agents.MethodsA clinical study was conducted in 16 healthy volunteers to assess the effects of 3 doses of SB705498 on skin flare induced by capsaicin. Subjects with a robust capsaicin response were chosen to determine if the selected topical formulation of SB705498 had an effect on challenge agent induced itch.ResultsFollowing capsaicin challenge the greatest average reduction in area of flare was seen for the 3% formulation. This dose was selected for further investigation. Itch intensity induced by two challenge agents (cowhage and histamine) was assessed on the Computerised Visual Analogue Scale. The difference in average itch intensity (Weighted Mean Over 15 Mins) between the 3% dose of SB705498 and placebo for the cowhage challenge was −0.64, whilst the histamine challenge showed on average a −4.65 point change.ConclusionsThe 3% topical formulation of SB705498 cream was clinically well tolerated and had target specific pharmacodynamic activity. However there were no clinically significant differences on pruritus induced by either challenge agent in comparison to placebo. SB705498 is unlikely to be of symptomatic benefit for histaminergic or non-histaminergic induced itch.Trial RegistrationClinicalTrials.gov NCT01673529

The inhibitory effect of simvastatin and aspirin on histamine responsiveness in human vascular endothelial cells

Statins and aspirin deliver well-established cardiovascular benefits resulting in their increased use as combined polypills to decrease risk of stroke and heart disease. However, the direct endothelial effect of combined statin/aspirin cotreatment remains unclear. Histamine is an inflammatory mediator that increases vascular permeability, and so we examined the effect of treating human umbilical vein endothelial cells (HUVECs) for 24 h with 1 μM simvastatin and 100 μM aspirin on histamine responsiveness. Subsequent histamine (1 μM) challenge increased intracellular calcium (Ca(2+)i) concentration, an effect that was significantly inhibited by combined simvastatin/aspirin pretreatment but not when then the compounds were given separately, even at 10-fold higher concentrations. In contrast, the Ca(2+)i mobilization response to ATP challenge (10 μM) was not inhibited by combined simvastatin/aspirin pretreatment. The H1 receptor antagonist pyrilamine significantly inhibited both histamine-induced Ca(2+)i mobilization and extracellular signal-regulated kinase (ERK) activation, whereas ranitidine (H2 receptor antagonist) was without effect. However, combined simvastatin/aspirin pretreatment failed to decrease H1 receptor protein expression ruling out receptor downregulation as the mechanism of action. Histamine-induced ERK activation was also inhibited by atorvastatin pretreatment, while simvastatin further inhibited histamine-induced vascular endothelial cadherin phosphorylation as well as altered HUVEC morphology and inhibited actin polymerization. Therefore, in addition to the known therapeutic benefits of statins and aspirin, here we provide initial cellular evidence that combined statin/aspirin treatment inhibits histamine responsiveness in HUVECs.