Antidiarrheal and Cardio-Depressant Effects of Himalaiella heteromalla (D.Don) Raab-Straube: In Vitro, In Vivo, and In Silico Studies

Himalaiella heteromalla (D.Don) Raab-Straube is a commonly used remedy against various diseases. Crude extract and fractions of H. heteromalla were investigated for a gastrointestinal, bronchodilator, cardiovascular, and anti-inflammatory activities. H. heteromalla crude extract (Hh.Cr) relaxed spontaneous contractions and K+ (80 mM)-induced contraction in jejunum tissue dose-dependently. The relaxation of K+ (80 mM) indicates the presence of Ca++ channel blocking (CCB) effect, which was further confirmed by constructing calcium response curves (CRCs) as they caused rightward parallel shift of CRCs in a manner comparable to verapamil, so the spasmolytic effect of Hh.Cr was due to its CCB activity. Application of Hh.Cr on CCh (1 µM) and K+ (80 mM)-induced contraction in tracheal preparation resulted in complete relaxation, showing its bronchodilator effect mediated through Ca++ channels and cholinergic antagonist activity. Application of Hh.Cr on aortic preparations exhibited vasorelaxant activity through angiotensin and α-adrenergic receptors blockage. It also showed the cardio suppressant effect with negative chronotropic and inotropic response in paired atrium preparation. Similar effects were observed in in vivo models, i.e., decreased propulsive movement, wet feces, and inhibition of edema formation.

A150 INFLIXIMAB INDUCED EOSINOPHILIC PNEUMONITIS IN AN ADOLESCENT

Background Infliximab is used to induce and maintain remission of inflammatory bowel disease (IBD). Pulmonary abnormalities in IBD are rare, but comprise airway, parenchymal and interstitial lung complications. Pulmonary adverse effects reported after Infliximab include tuberculosis reactivation, invasive aspergillosis, interstitial pneumonitis, pulmonary oedema and alveolar hemorrhage. Aims Four cases previously reported associate Infliximab to eosinophilic pneumonitis. However, this is the first in pediatrics. Methods Case report of an adolescent female with IBD and a rare adverse reaction to Infliximab Results Our patient was diagnosed with ulcerative pancolitis, Mayo 2, initially treated with 5-ASA. Five months into therapy she was switched to azathioprine and Infliximab (10mg/kg every 8 weeks) due to worsening disease. She attained and maintained clinical and biochemical remission for the next 1.5 years. Azathioprine was stopped at the patient’s request. One month later, she presented with cough and nasal congestion but was afebrile. Peripheral eosinophilia was noted. Salbutamol and steroid inhalers were started, without improvement. She was admitted to hospital due to progressive cough, shortness of breath, and wheezing. Physical examination was otherwise unremarkable. Pulmonary function test showed FVC of 69%, FEV1 of 45% with bronchodilator effect of 12% and a FEV1/FVC of 59. Her blood work showed eosinophilia (4.42 x109/L) and an elevated IgE (4596 ug/L). Serum-specific IgE for Aspergillus was positive; but skin testing was negative. An X-ray showed marked bilateral interstitial thickening in the mid and lower zones. Chest CT showed extensive bronchiectasis with bronchial mucous plugging. A bronchoscopy with bronchoalveolar lavage (BAL) reported marked eosinophilia, negative for mycobacterium, bacterial and fungal growth. Other infectious and autoimmune etiologies were ruled out. She responded successfully to high-dose prednisone (50 mg/day). At discharge, symptoms had improved, and her pulmonary function tests were normal (FEV1 of 95% predicted and FEV1/FVC 84). Upon steroid taper, she relapsed in pulmonary symptoms, eosinophilia, as well as a flare of her IBD. Reinduction with steroids resolved her symptoms and eosinophilia. Due to her loss of response to Infliximab and pulmonary, she was switched to Vedolizumab with good response. After stopping Infliximab her lung function improved significantly (FVC of 96% predicted and FEV1 of 98% predicted) and has remained so. Peripheral eosinophilia dropped to 0.2 x109/L. Her IBD is currently in remission without any respiratory symptoms. Conclusions Eosinophilic pneumonitis can be a complication of Infliximab. Our patient had a delayed presentation of respiratory symptoms, 16 months after a satisfactory response to Infliximab. Although responsive to steroids, she ultimately needed to be switched to another immunosuppressive agent. Funding Agencies None

Exploring the sites and kinetics of bronchodilator response to β-2 agonists in asthma

Background We previously documented, in asthma patients, three different profiles of bronchodilation induced by short acting β-2 mimetics (SABA), characterized by dilation up to central, pre-acinar and intra-acinar airways assessed by ventilation distribution tests and associated with no change, increase and decrease of fractional exhaled nitric oxide (FENO) respectively. Aim To investigate the dynamics of these profiles over the entire SABA action period, assuming that airways bronchodilation could exhibit varying kinetics due to differences in the distribution of β-2 receptors in both the central and peripheral human airways. Methods FENO, FEV1, and the slope (S) of He and SF6 phase III (single-breath test) were measured in asthma patients before, and up to six hours after SABA inhalation (salbutamol 400µg). SHe and SSF6 decrease reflects pre- and intra-acinar obstruction relief respectively. Results 30 asthma patients (12F/18M, age: 45±18 years) were divided into groups with positive (NO+, n=9), negative (NO-, n=11) and no (NO=, n=10) FENO acute change. In the NO- group, FEV1 increased for up to four hours, whereas FENO, SHe and SF6 decreased in the early phase only. In stark contrast, in the NO+ group, FEV1 increased in the early phase only while the FENO increase and the SHe decrease lasted for up to four hours. Conclusion This study documents various profiles of SABA-induced bronchodilation in asthma patients, differing both by sites and dynamics of the bronchodilator process. So, detailed understanding of the bronchodilator effect of β2-agonists in asthma should not solely be limited to studying their impact on FEV1.

Androgen Effects on the Adrenergic System of the Vascular, Airway, and Cardiac Myocytes and Their Relevance in Pathological Processes

Introduction. Androgen signaling comprises nongenomic and genomic pathways. Nongenomic actions are not related to the binding of the androgen receptor (AR) and occur rapidly. The genomic effects implicate the binding to a cytosolic AR, leading to protein synthesis. Both events are independent of each other. Genomic effects have been associated with different pathologies such as vascular ischemia, hypertension, asthma, and cardiovascular diseases. Catecholamines play a crucial role in regulating vascular smooth muscle (VSM), airway smooth muscle (ASM), and cardiac muscle (CM) function and tone. Objective. The aim of this review is an updated analysis of the role of androgens in the adrenergic system of vascular, airway, and cardiac myocytes. Body. Testosterone (T) favors vasoconstriction, and its concentration fluctuation during life stages can affect the vascular tone and might contribute to the development of hypertension. In the VSM, T increases α1-adrenergic receptors (α1-ARs) and decreases adenylyl cyclase expression, favoring high blood pressure and hypertension. Androgens have also been associated with asthma. During puberty, girls are more susceptible to present asthma symptoms than boys because of the increment in the plasmatic concentrations of T in young men. In the ASM, β2-ARs are responsible for the bronchodilator effect, and T augments the expression of β2-ARs evoking an increase in the relaxing response to salbutamol. The levels of T are also associated with an increment in atherosclerosis and cardiovascular risk. In the CM, activation of α1A-ARs and β2-ARs increases the ionotropic activity, leading to the development of contraction, and T upregulates the expression of both receptors and improves the myocardial performance. Conclusions. Androgens play an essential role in the adrenergic system of vascular, airway, and cardiac myocytes, favoring either a state of health or disease. While the use of androgens as a therapeutic tool for treating asthma symptoms or heart disease is proposed, the vascular system is warmly affected.

Efficacy of Nebulized Magnesium Sulphate in the Treatment of Acute Bronchial Asthma Compared to Nebulized Salbutamol: A Randomized Control Trial

Background: Nebulized salbutamol is commonly used in treatment of asthma in children. The use of nebulized MgSO4 is one of the different treatment options available during acute exacerbation. Objective: To compare the efficacy of nebulized MgSO4 with nebulized salbutamol in the treatment of acute asthma in children. Materials and method: This randomized controlled study was conducted in Dhaka Medical College Hospital between January to December 2016. Children of 7-12 years with acute exacerbation of asthma were randomized into study group-A (MgSO4 group, n=30) and control group-B (Salbutamol group, n=30). Children of both groups were treated with serial nebulization thrice at 20 minute intervals by either 2.4 ml (4% MgSO4, 96 mg) or salbutamol (0.15 mg/kg minimum 2.5 mg) with 2.5 ml of isotonic normal saline. Results: The mean final PEFR were not different between the two groups (275.0±41.42 L/min in MgS04 group and 263±36.17 L/min in salbutamol group). The increase in PEF was statistically significant and comparable in both groups (by 35.1% in the MgS04 group and by 42.1% in the salbutamol group). Fischl score improvement was comparable and significant in both groups (4.31 to 0.43 in MgS04 group and 4.29 to 0.76 in salbutamol group). Statistically significant increase in oxygen saturation and reduction of heart rate was found in MgS04 group without any side effects. Nebulized MgSO4 was found having significant bronchodilator effect which is comparable to salbutamol. Conclusion: Nebulized MgS04 was found equally effective as nebulized salbutamol in the treatment of severe acute asthma in children. Bangladesh J Child Health 2020; VOL 44 (1) :24-29

Airway smooth muscle adapting in dynamic conditions is refractory to the bronchodilator effect of a deep inspiration

Airway smooth muscle (ASM) is continuously strained during breathing at tidal volume. Whether this tidal strain influences the magnitude of the bronchodilator response to a deep inspiration (DI) is not clearly defined. The present in vitro study examines the effect of tidal strain on the bronchodilator effect of DIs. ASM strips from sheep tracheas were mounted in organ baths and then subjected to stretches (30% strain), simulating DIs at varying time intervals. In between simulated DIs, the strips were either held at a fixed length (isometric) or oscillated continuously by 6% (length oscillations) to simulate tidal strain. The contractile state of the strips was also controlled by adding either methacholine or isoproterenol to activate or relax ASM, respectively. Although the time-dependent gain in force caused by methacholine was attenuated by length oscillations, part of the acquired force in the oscillating condition was preserved postsimulated DIs, which was not the case in the isometric condition. Consequently, the bronchodilator effect of simulated DIs (i.e., the decline in force postsimulated versus presimulated DIs) was attenuated in oscillating versus isometric conditions. These findings suggest that an ASM operating in a dynamic environment acquired adaptations that make it refractory to the decline in contractility inflicted by a larger strain simulating a DI.

Shortening of airway smooth muscle is modulated by prolonging the time without simulated deep inspirations in ovine tracheal strips

The shortening of airway smooth muscle (ASM) is greatly affected by time. This is because stimuli affecting ASM shortening, such as bronchoactive molecules or the strain inflicted by breathing maneuvers, not only alter quick biochemical processes regulating contraction but also slower processes that allow ASM to adapt to an ever-changing length. Little attention has been given to the effect of time on ASM shortening. The present study investigates the effect of changing the time interval between simulated deep inspirations (DIs) on ASM shortening and its responsiveness to simulated DIs. Excised tracheal strips from sheep were mounted in organ baths and either activated with methacholine or relaxed with isoproterenol. They were then subjected to simulated DIs by imposing swings in distending stress, emulating a transmural pressure from 5 to 30 cmH2O. The simulated DIs were intercalated by 2, 5, 10, or 30 min. In between simulated DIs, the distending stress was either fixed or oscillating to simulate tidal breathing. The results show that although shortening was increased by prolonging the interval between simulated DIs, the bronchodilator effect of simulated DIs (i.e., the elongation of the strip post- vs. pre-DI) was not affected, and the rate of re-shortening post-simulated DIs was decreased. As the frequency with which DIs are taken increases upon bronchoconstriction, our results may be relevant to typical alterations observed in asthma, such as an increased rate of re-narrowing post-DI. NEW & NOTEWORTHY The frequency with which patients with asthma take deep inspirations (DIs) increases during bronchoconstriction. This in vitro study investigated the effect of changing the time interval between simulated DIs on airway smooth muscle shortening. The results demonstrated that decreasing the interval between simulated DIs not only decreases shortening, which may be protective against excessive airway narrowing, but also increases the rate of re-shortening post-simulated DIs, which may contribute to the increased rate of re-narrowing post-DI observed in asthma.