Leukotriene Research Articles

The peroxisome: an up-and-coming organelle in immunometabolism.

Peroxisomes are essential metabolic organelles, well known for their roles in the metabolism of complex lipids and reactive ionic species. In the past 10 years, peroxisomes have also been cast as central regulators of immunity. Lipid metabolites of peroxisomes, such as polyunsaturated fatty acids (PUFAs), are precursors for important immune mediators, including leukotrienes (LTs) and resolvins. Peroxisomal redox metabolism modulates cellular immune signaling such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation. Additionally, peroxisomal β-oxidation and ether lipid synthesis control the development and aspects of the activation of both innate and adaptive immune cells. Finally, peroxisome number and metabolic activity have been linked to inflammatory diseases. These discoveries have opened avenues of investigation aimed at targeting peroxisomes for therapeutic intervention in immune disorders, inflammation, and cancer.

A Comprehensive Review on Ulcer and Their Treatment.

A peptic ulcer is a lesion (sore) on the stomach lining, or duodenum. Peptic ulcers are probably a twentieth-century condition. The ulcer disease continues to be a significant source of worldwide morbidity and mortality. The Gastrointestinal ulcers and duodenal ulcers are considered the two most extreme types of peptic ulcers. Peptic ulcers are found to be caused by an excess of violent factors including Hydrochloric acid (HCL) pepsin, refluxed bile leukotrienes (LT), reactive oxygen species (ROS) and protective factors, these include mucus-bicarbonate barrier functions, prostaglandins (PGs), mucosal blood flow, cell regeneration and migration, non-enzymatic and enzymatic and certain growth factors. The primary cause of peptic ulcer disease is pylori infection and the use of NSAIDs. This review article underscores the importance of a multidisciplinary approach in the management of ulcers to improve patient outcomes and quality of life.

Effect of Temperature and Humidity on the Allegro-inflammatory Factors and Allergic Rhinitis-related Behavior.

Allergic rhinitis (AR) is an allergic disease induced by the T helper 2 (TH2) lymphocyte immune response, where its mediators are the primary cause of clinical symptoms. Environmental factors are the primary determinants of the allergic response in genetically susceptible individuals. This study investigates the effects of climate conditions (warm, cold, humid, and dry) on allergic rhinitis. AR models were created in mice under 4 different conditions. We investigated AR-related behavior (sneezing and nose rubbing), as well as total immunoglobulin E (IgE), histamine, interleukin-4 (IL-4), leukotriene (LT) B4 and LTC4 levels, and gene expression of CysLT1R, HRH1, and MUC5a. Nose rubbing, histamine levels, and the expression of MUC5a and HRH1 were increased in AR models in cold conditions, and sneezing was increased in AR models kept in dry conditions. LTB4 and LTC4 levels and the expression of CysLT1R in AR models kept in a wet environment also significantly increased compared with the control group. The levels of total IgE and IL-4 showed no significant changes. Air temperature and humidity affect AR pathophysiology, and weather conditions can be essential in controlling AR.

The roles of eicosanoids in myocardial diseases.

Myocardial disease, the abnormalities of the cardiac muscle, is the leading cause of death in humans. Eicosanoids represent a large spectrum of lipid mediators with critical roles in physiological and pathophysiological conditions. Arachidonic acid (AA) is the major resource of eicosanoids and is metabolized via cyclooxygenases (COXs), lipoxygenases (LOXs), and cytochrome P450 (CYP) enzymes producing a diverse family of lipid mediators called eicosanoids, including prostanoids, leukotrienes (LTs), epoxyeicosatrienoic acids (EETs), dihydroxyeicosatetraenoic acid (diHETEs), eicosatetraenoic acids (ETEs), and lipoxins (LXs). Beyond the well-established roles of eicosanoids in inflammation and vascular biology, a growing body of evidence showed that eicosanoids, especially CYP450 derived eicosanoids EETs, are preventive and therapeutic targets for many of the myocardial diseases. EETs not only ameliorate the cardiac injury and remodeling in different pathological models, but also attenuate subsequent hemodynamic disturbances and cardiac dysfunction. EETs have direct and indirect protective properties in the myocardium, and thus relieve dietetic cardiomyopathy and inflammatory cardiomyopathy. Moreover, EETs are capable to attenuate the ischemic cardiomyopathy, including the myocardial infarction and cardiac ischemic reperfusion injury. Multiple biological events and signaling networks are targeted during the myocardial protection of EETs, these are including mitochondria hemostasis, angiogenesis, oxidative stress, inflammatory response, metabolic regulation, endoplasmic reticulum (ER) stress and cell death. Additionally, eicosanoids from COX and LOX also have important roles in some of the myocardial diseases, such as cardiac hypertrophy and ischemic heart disease. This chapter summarizes the physiological and pathophysiological significance, and the signal mechanisms of the eicosanoids, especially the EETs, in myocardial diseases.

KAAACI Allergic Rhinitis Guidelines: Part 1. Update in Pharmacotherapy

The prevalence of allergic rhinitis (AR) and the socioeconomic burden associated with the medical cost and quality of life (QOL) of AR have progressively increased. Therefore, practical guidelines for the appropriate management of AR need to be developed based on scientific evidence while considering the real-world environment, values, and preferences of patients and physicians. The Korean Academy of Asthma, Allergy and Clinical Immunology revised clinical guidelines of AR to address key clinical questions of the management of AR. Part 1 of the revised guideline covers the pharmacological management of patients with AR in Korea. Through a meta-analysis and systematic review, we made 4 recommendations for AR pharmacotherapy, including intranasal corticosteroid (INCS)/intranasal antihistamine (INAH) combination therapy, oral antihistamine/INCS combination therapy, leukotriene receptor antagonist treatment in AR patients with asthma, and prophylactic treatment for patients with pollen-induced AR. However, all recommendations are conditional because of the low or very low evidence of certainty. Well-designed and strictly executed randomized controlled trials are needed to measure and report appropriate outcomes.

The role of leukotriene inhibition using a 5-lipoxygenase (5-LO) inhibitor in a joint contracture model

PurposeArthrofibrosis is a common inflammatory complication of joint trauma and surgery. 5lipoxygenase (5-LO) is a key enzyme involved in inflammation. Inhibition of 5-LO has been shown to reduce inflammation in heart and lung models but has not been examined in a joint contracture model.MethodsTwenty-six rats underwent joint contracture. Six rats served as non-surgical controls. A 5-LO inhibitor, caffeic acid (CA), suspended in 10% ethanol was orally administered to 14 rats and ethanol without CA to the remaining 12 rats daily for 21 days. Leukotriene B4 (LTB4) levels were measured, both systemically and locally. 5-LO levels in the posterior capsule were quantified by measuring the ratio of the length of the posterior capsule demonstrating 5-LO immunostaining to the total length of the capsule.ResultsJoint contracture was successfully achieved in all rats who underwent manipulation. Levels of 5- LO measured in the posterior capsule were significantly increased in the animals who underwent surgery (56%/44–64) compared to the non-surgical control animals (7%/4–9). LTB4 levels were found to be significantly lower in the non-surgical control animals (107.79 ± 34.08 pg/ml) compared to all surgical animals (157.6 ± 55.3 pg/ml).ConclusionSurgical intervention resulted in increased 5-LO activity of the synovial surface of the posterior capsule and increased LTB4 levels in the patellar tendon—fat pad. Oral administration of the 5LO inhibitor, CA, was ineffective at reducing systemic and local LTB4 levels and preventing knee joint contracture. Inhibiting 5-LO activity may still be effective in preventing arthrofibrosis and warrants further investigation.

Leukotrienes in the atherosclerotic cardiovascular diseases — a systematic review

Introduction: The role of inflammation in the pathogenesis of atherosclerotic diseases is strongly suggested. There are multiple studies indicating the possibility of a pathophysiological connection between atherosclerotic changes and leukotrienes (LTs) — the products of arachidonic acid metabolism. The goal of this systematic review, performed in line with the PRISMA statement, was to investigate the potential role of LTs in the pathophysiology of atherosclerotic cardiovascular diseases (CVD). Material and methods: The MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews were searched to identify the potentially eligible studies. Publications that contained information on any type of LTs identified in blood or urine were included in the review. A database search identified 2082 records. Reliable LTs identification in patients with CVD was used in 30 publications. Results: Stable and acute forms of coronary artery disease are characterized by the overproduction of different types of LTs. The level of LTB4 and LTC4 in the blood is elevated in patients with cerebral ischemia. Patients with acute and chronic peripheral artery disease have elevated levels of LTE4 in urine. Conclusions: The findings of this systematic review show that there is a clear tendency to indicate the association of cardiovascular atherosclerotic diseases with increased production of LTs. This dependency detailed characteristic remains unclear and the question on the impact of elevated leukotrienes on clinical atherosclerotic disease manifestations is still open.

Highly potent and selective 5-lipoxygenase inhibition by new, simple heteroaryl-substituted catechols for treatment of inflammation

5-Lipoxygenase (LO) catalyzes the first steps in the formation of pro-inflammatory leukotrienes (LT) that are pivotal lipid mediators contributing to allergic reactions and inflammatory disorders. Based on its key role in LT biosynthesis, 5-LO is an attractive drug target, demanding for effective and selective inhibitors with efficacy in vivo, which however, are still rare. Encouraged by the recent identification of the catechol 4-(3,4-dihydroxyphenyl)dibenzofuran 1 as 5-LO inhibitor, simple structural modifications were made to yield even more effective and selective catechol derivatives. Within this new series, the two most potent compounds 3,4-dihydroxy-3′-phenoxybiphenyl (6b) and 2-(3,4-dihydroxyphenyl)benzo[b]thiophene (6d) potently inhibited human 5-LO in cell-free (IC506b and 6d = 20 nM) and cell-based assays (IC506b = 70 nM, 6d = 60 nM). Inhibition of 5-LO was reversible, unaffected by exogenously added substrate arachidonic acid, and not primarily mediated via radical scavenging and antioxidant activities. Functional 5-LO mutants expressed in HEK293 cells were still prone to inhibition by 6b and 6d, and docking simulations revealed distinct binding of the catechol moiety to 5-LO at an allosteric site. Analysis of 5-LO nuclear membrane translocation and intracellular Ca2+ mobilization revealed that these 5-LO-activating events are hardly affected by the catechols. Importantly, the high inhibitory potency of 6b and 6d was confirmed in human blood and in a murine zymosan-induced peritonitis model in vivo. Our results enclose these novel catechol derivatives as highly potent, novel type inhibitors of 5-LO with high selectivity and with marked effectiveness under pathophysiological conditions.

Leukotriene Receptor Antagonists and Risk of Neuropsychiatric Entities: A Meta-Analysis of Observational Studies

Leukotriene receptor antagonists (LTRAs) are commonly prescribed to patients with allergic diseases. Several case reports and pharmacovigilance studies have indicated that LTRAs might increase the risk of neuropsychiatric (NP) entities. However, the results are mixed in observational studies. Thus, the association between LTRAs and NP entities remains controversial. To quantitatively evaluate the NP risk with LTRAs based on current observational studies to provide a reference for clinical practice. We systematically reviewed the literature in Medline, Embase, Web of Science, Cochrane Library, Scopus, and PsycINFO. A meta-analysis of observational studies that investigated the association between LTRA use and the risk of NP entities was performed. Odds ratios (OR) with 95% confidence intervals (CI) were used to measure the effect; heterogeneity was evaluated using I-squared (I2) statistics. Subgroup and sensitivity analyses were conducted to assess bias. Eleven articles were included in the primary analysis. No significant association was found between LTRA use and NP entities (OR: 1.08, 95% CI: 0.93-1.24, I2= 93.7%). In patients with allergic rhinitis (AR), a mildly increased NP risk was found (OR: 1.099, 95% CI: 1.004-1.202). The association between LTRA use and NP entities was not significant in patients with asthma (OR: 1.06, 95% CI: 0.90-1.26). LTRAs increased the risk of NP entities in a single study using data from an asthma clinic (OR: 9.00, 95% CI: 1.20-69.50), but not in studies from databases (OR: 1.07, 95% CI: 0.93-1.23). At the population level, LTRAs and NP entities were unrelated. However, the association may exist in particular groups (eg, patients with AR or NP history). Subject-specific studies are required to further examine the relationship between LTRAs and NP entities and identify the underlying mechanisms.

Effect of School Integrated Pest Management or Classroom Air Filter Purifiers on Asthma Symptoms in Students With Active Asthma: A Randomized Clinical Study

To determine if environmental control measures (1) school-wide integrated pest management (IPM) program and/or (2) use of high-efficiency particulate air (HEPA) filter purifiers in inner city elementary school classrooms would reduce asthma morbidity in students with active asthma.Forty-one inner city elementary schools in the Northeastern United States were recruited for this study. There were 236 students with active, physician-diagnosed asthma randomized to IPM (by school) and/or HEPA filter purifiers (by classroom). Physician-diagnosed asthma was defined as the child having had unscheduled doctor visits, hospitalization, corticosteroid bursts, symptoms, or controller medication use in the past year. Fifty seven percent of the children were Hispanic and 24% were Black. Mean age was 8.1 years, 48% female, mean FEV1 97% to 99.7% predicted at randomization. Forty-fifty percent of the children were using short acting β agonists alone and the rest were on inhaled corticosteroids and/or leukotriene modifiers. The study was conducted during the school years 2015 to 2020.All students with active physician-diagnosed asthma had a screening visit with questionnaires, skin testing, and spirometry as well as 2 follow-up visits with the same assessments during the year. Baseline environmental assessment for a panel of allergens (mouse, rat, dust mite, cockroach, cat, dog, Alternaria alternate, and Aspergillus fumigatus) were conducted at the schools by collecting a 1-week air sample, immediately followed by vacuum–settled dust samples from each students’ primary classroom and in the participants homes. The allergens were analyzed using a multiplex assay (MARIA, Indoor Biotechnologies). Follow-up environmental assessment after randomization took place once each winter and spring during the school year.The allocation to free standing classroom HEPA filter purifiers, active or sham, was blinded to the participants and those assessing the outcomes. The IPM program consisted of application of rodenticide, sealing entry points, trap placement, targeted cleaning, and brief educational handouts for the school staff. Infestation was assessed every 3 months and IPM reapplied as needed. Trained pest management specialists providing the school-wide IPM program were unblinded, but the student participants and trial investigators remained blinded throughout the trial.Four groups of 59 students each were randomized using a factorial design to either intervention alone, both interventions together, or neither for the entire school year. Classroom and home allergen and particle levels at randomization were balanced between the 4 groups.The asthma-related health outcomes of the students were assessed by parent survey at baseline and every 2 months until the end of the school year. The primary outcome was the number of symptom-days with asthma during a 2-week period assessed over the 10 months of randomization. Prespecified secondary outcomes were school absences, Composite Asthma Severity Index score, healthcare utilization, and spirometry measurements.Ninety eight percent of the classrooms had detectable levels of mouse allergen and 26% of the participants were sensitized to mouse allergen. More than 90% of baseline classroom allergen levels for cockroach, rat, Alternaria, Aspergillus and dust mite were undetectable.Use of the school-wide IPM program resulted in a mean of 1.5 symptom-days with asthma during a 2-week period versus 1.9 symptom-days for no IPM; use of HEPA filter purifiers resulted in a mean of 1.6 symptom-days with asthma versus 1.8 symptom-days for sham HEPA filter purifiers; neither comparison was statistically significant. Other prespecified secondary outcomes, including healthcare utilization or missed school days because of asthma also did not differ significantly between the intervention groups. The HEPA filter purifiers significantly reduced mouse and dog allergens in the classrooms. The IPM program did not significantly reduce concentrations of any of the allergens or particles measured. A post hoc exploratory analysis found a statistically significant association of reduction in asthma symptoms with the school wide IPM program but only for a limited time (mid-November to February).In an inner-city population of elementary school students with active asthma, use of a school-wide IPM program or HEPA filter purifiers in the classrooms did not significantly reduce symptom-days with asthma.It is possible that these children had asthma that was too mild to see a significant difference in these environmental interventions. Also unclear is whether resources to perform environmental control measures are best used at the school level or at home. As an accompanying editorial notes, “as allergen sensitization is related to the pathogenesis and pathophysiology of childhood asthma,” allergen avoidance should still be a basic tenet of treatment and worth continued investigation.URL: www.pediatrics.org/cgi/doi/10.1542/peds.10.1001/jama.2021.11559

RWD83 Real-World Treatment Patterns in Chronic Spontaneous Urticaria in the United States

Treatment of chronic spontaneous urticaria (CSU) in the US is a stepwise approach recommended by local guidelines. First line: non-sedating H1-antihistamines (ns-H1AH); 2nd line & 3rd line: increased licensed dose ns-H1AH or change of H1AH or add H2-antihistamines (H2AH) or leukotriene inhibitor (LTRA) or sedating H1AH or doxepin; 4th line: add omalizumab or cyclosporine. Rescue medication with short-course oral corticosteroids (OCS), in case of exacerbations. The objective of the study was to assess real-world treatment patterns in adult patients with CSU.

Peripheral blood leukotriene B4 and E4 as biomarkers in Alzheimer’s disease

AbstractBackgroundWe showed recently that use of leukotriene receptor antagonists, typically used in asthma therapy, was associated with preserved executive function among people with Alzheimer’s disease (AD) dementia. The aim of this study was to determine if leukotriene B4 (LTB4) and E4 (LTE4) would be associated with longitudinal changes in cognitive performance and cerebrovascular disease markers in people with AD.MethodParticipants with clinical AD or mild cognitive impairment were identified from the Ontario Neurodegenerative Disease Research Initiative. LTB4 and LTE4 were extracted from fasting serum and quantified using ultra‐high performance liquid chromatography‐tandem mass spectrometry (UPLC‐MS/MS). Concentrations below the limit of detection were imputed using quantile regression imputation of left‐censored data. Cognition was assessed using composite scores for executive function (Trails Making Test B, Symbol Digit Modalities Test, Stroop switching task, and verbal fluency) and memory (Rey Auditory Verbal Learning Test and Brief Visuospatial Memory Test). White matter hyperintensities (WMH), lacunes, and perivascular spaces (PVS) were quantified using T2‐weighted structural magnetic resonance imaging (MRI). Longitudinal associations between baseline LTB4 or LTE4 and cognition and imaging markers at baseline and 1‐year‐follow‐up were assessed using mixed‐effects linear regression models, controlling for baseline demographic factors, medication use, and vascular comorbidities. Findings were corrected for multiple comparisons using a 5% false discovery rate.ResultAmong 158 participants (mean age = 69.22 years, 51% female, mean education = 14.61 years), higher baseline concentrations of LTB4 were not associated with performance in executive function or memory over time nor with changes in WMH, lacunes, or PVS over time. Higher baseline concentrations of LTE4 were associated with better performance in memory over time (β = 0.153 [95% CI = 0.026, 0.287]; however, this finding did not survive correction for multiple comparisons (adjusted p = 0.260; Table 1).ConclusionIn a group of patients with AD, higher LTB4 and LTE4 in serum were not associated with changes in cognitive performance nor markers of cerebrovascular disease. These findings suggest very little potential for serum leukotrienes as biomarkers for cognitive decline of cerebrovascular disease progression in AD.

만성 두드러기의 기능의학적 치료

Urticaria is a disease that causes recurrent hives and wheals, and is classified into acute and chronic (6 weeks or longer) according to the duration of the disease. If the cause of chronic urticaria is unknown, it is called chronic spontaneous urticaria (CSU), and 50% of CSU is caused by an autoimmune mechanism. CSU treatment removes triggers and avoids exacerbating factors. Medications include antihistamines, leukotriene receptor antagonists, omalizumab, cyclosporine. In case of acute exacerbation, steroids are prescribed. As an alternative treatment, drugs for autoimmune diseases are used. We hope that a more fundamental and integrated functional medicinal treatment will be realized through access to and management of 7 major clinical imbalances in functional medicine, including heavy metals, persistant organic pollutants, infections, intestinal microbiomes abnormalities, and food hypersensitivities (food immunoglobulin E & immunoglobulin G test) as triggers of CSU.

Longitudinal changes in the prevalence of adult asthma: An epidemiological survey among Japanese salaried employees and their dependents using healthcare insurance claim from 1999 to 2019

BackgroundInformation on changes in asthma prevalence and the treatment status for asthma is used as basic information for taking medical and administrative measures against asthma. However, this information among adults is relatively limited. MethodsTo elucidate changes in the prevalence of asthma and treatment status over time among Japanese adults, health insurance claim data from some health insurance societies covering salaried employees and their dependents were studied longitudinally. Claim data from FY1999 to 2007 were obtained from two health insurance societies, and data from FY 2011 to 2019 were obtained from three different health insurance societies, and changes in standardized asthma prevalence among subjects aged 20–59 years, proportion of asthma patients prescribed ICS, leukotriene receptor antagonist (LTRA), and LABA, and the mean number of acute asthma exacerbations per year were analyzed. ResultsThe prevalence of asthma increased from 1.6% in 1999 to 3.0% in 2007 and 2.9% in 2011 to 4.6% in 2019. Increased trends in asthma prevalence from 2011 to 2019 were more noticeable in subjects in their 50s than those in their 20s for both sexes. The number of emergency visits related to asthma was 1.5 per year in 1999, which decreased to 0.8 per year in 2019. The proportion of people prescribed all anti-asthma medications (ICS, LTRA, and LABA) increased over time. ConclusionsThe prevalence of adult asthma among Japanese salaried employees and their dependents has increased over the last 20 years, suggesting more attention should be paid to the prevention of this disease in adults.

Effect of "joint treatment of lung and intestine" with moxibustion on lung function and airway inflammation in asthmatic rats

To investigate the role of moxibustion of "Feishu" (BL13)，"Tianshu" (ST25) for asthma by simultaneously treating lung and intestine (i.e., treating both lung and intestine at the same time) in asthmatic rats. A total of 48 SD rats were randomly divided into normal, model, lung treatment and joint-treatment of lung and intestine (joint-treatment) groups, with 12 rats in each. The asthma model was established by subcutaneous (bilateral back and inguinal regions) and intraperitoneal injection of mixture solution of albumin and Aluminium Hydroxide gel (on day 1st, and 9th) and followed by inhalation of atomized 1% ovalbumin (on day 15th, 20 min each time, once daily for 1 week). Moxibustion was applied to bilateral BL13 for rats of the lung treatment group or bilateral BL13 and ST25 for rats of the joint-treatment group. One hour after the intervention, the rats in the later three groups were separately given nebulized 1% ovalbumin solution inhalation for 20 min. The treatments were conducted once daily for 14 consecutive days. After intervention, the lung functions including the forced expiratory flow 25% (FEF 25%), maximal mid-expiratory flow (MMEF), dynamic lung compliance (Cdyn), forced expiratory volume/ forced vital capacity (FEV/FVC), peak expiratory flow (PEF), and lung resistance (RL) were measured by using a small animal lung function detector, and pathological changes and collagen deposition in the lung tissues were observed by H.E. and Masson staining, separately. The levels of interleukin (IL)-17, IL-4, IL-13, IL-33, IL-5, leukotriene (LT) and thymic stromal lymphocyte (TSLP) in the lung tissue were measured by ELISA. Compared with the normal group, the FEF 25%, MMEF， Cdyn， FEV/FVC and PEF were significantly decreased (P<0.05, P<0.01)， and the pulmonary RL, collagen deposition, and contents of IL-17, IL-4, IL-13, IL-33, IL-5, TSLP and LT were notably increased (P<0.05, P<0.01) in the model group. After intervention, the MMEF and Cdyn in the lung treatment group, PEF, MMEF, Cdyn, FEV/FVC, FEF 25% in the joint-treatment group, were markedly increased (P<0.05, P<0.01), whereas the collagen deposition, IL-17, IL-4 and TSLP in both the lung treatment and joint-treatment groups, RL, IL-13, IL-33, IL-5 and LT in the joint-treatment group were considerably down-regulated (P<0.05, P<0.01). The effects of the joint treatment were apparently superior to those of lung treatment in down-regulating the contents of TSLP and LT (P<0.05, P<0.01). H.E. staining showed thickened alveolar wall, infiltration of a large number of inflammatory cells in the bronchus of the model group, which was relatively milder in the joint-treatment group. "Joint treatment of lung and intestine" with moxibustion is superior to "lung treatment" alone in ameliorating the lung function and mitigating airway inflammation in rats with asthma.

Leukotriene Antagonist Use is Associated With Lower Systolic Blood Pressure in Adults

Chronic kidney disease (CKD) is an increasingly prevalent and progressive disorder that affects many adults in the United States. This disorder is associated with significant healthcare costs, morbidity, and mortality as CKD leads to kidney failure and increased cardiovascular risk. With most forms of CKD, inflammation plays a central role in the progression of kidney and cardiovascular disease (CVD).1 The severity of CKD correlates with the number of kidney macrophages promoting the induction of chronic inflammation, tubular injury, and fibrosis.

Adverse Drug Reactions (ADRs) of Montelukast in Children.

To obtain more insight into the safety profile of montelukast for children with asthma, allergic rhinitis and sleep-related breathing disorders. We retrospectively studied all adverse drug reactions to montelukast among 385 children 6 months or older in six tertiary centers over a two-year period. A total of 89.6% were asthmatic, 50% had allergic rhinitis and 13.6% had sleep-related breathing disorders; Singulair was the most common type of montelukast used (67.9%). This study reported a high prevalence of adverse drug reactions among 123 patients (31.9%), predominantly in those aged 4-9 years (52.8%), followed by adolescents (24.4%) and toddlers (22.8%). Two (ADRs) were reported in 9.8% of the children, while three or more were reported in 5.5%. Sleep disturbance was the most common (ADRs), affecting 15.1% of participants (overlap was common; 5.5% of children experienced sleep difficulties, 4.4% experienced sleep interruption and decreased sleep, and 1.82% experienced nightmares), followed by agitation (10.4%), pain (9.4%) and hyperactivity (6.8%). No serious (ADRs) were reported. Eleven percent of families faced difficulties in purchasing montelukast, and only 57% of families had insurance. Misconceptions were common (9.8% reported it to be a steroid, while 30.6% believed it to be a bronchodilator). Although 81% of the families believed it was an effective and preventive medication, 5.3% stopped the drug due to concern about side effects, especially agitation (3%) and nightmares (0.6%). These data demonstrate that montelukast is effective, but the associated adverse neuropsychiatric drug reactions are more prevalent than those reported in the literature. In particular, sleep disturbance, agitation, pain and hyperactivity were observed. Pediatricians should be aware of such (ADRs). Misconceptions about montelukast are still common, and parental counseling and urgent epidemiological studies are needed to quantify the risk for management plans.

Significance of modern antihistamines in the treatment of patients with allergic rhinitis

Allergic rhinitis (AR) is one of the most common diseases in the world, which is based on immunoglobulin E (IgE) – mediated inflammation that develops after contact with various allergens. About 40 % of people suffer from various allergic diseases, every 3 rd inhabitant of the Earth has symptoms of allergic rhinitis and every 10 th has bronchial asthma. The early phase of allergen binding to IgE antibodies occurs within a few minutes after contact, the late phase develops after 4–6 hours. In addition to the airborne pathway of penetration, contact with the allergen is possible through the skin and mucous membranes, gastrointestinal tract, with parenteral administration of drugs. Taking into account the etiotropic factor, there are year-round allergic rhinitis (CAR) and seasonal (SAR). By the nature of the course, intermittent and persistent allergic rhinitis are distinguished. The most basic symptoms of allergic rhinitis include: sneezing, rhinorrhea, nasal congestion, itching, decreased sense of smell. Treatment includes antihistamines, intranasal steroids, leukotriene receptor antagonists and immunotherapy. To date, antihistamines of the second generation are recommended and widely used for the treatment of patients with allergic rhinitis, the main representative of which is levocetirizine (levocetirizine dihydrochloride). The purpose of the work is an analytical review of the results of clinical trials of levocetirizine for allergic rhinitis. The article discusses in detail the prevalence, etiology and pathogenesis, classification of the disease, treatment regimens for patients with allergic rhinitis, and provides two own clinical observations. Based on the data of a number of studies, the advantages of using antihistamines of the second generation in allergic rhinitis have been demonstrated, expanding not only the possibilities of treating patients, but also preventing the transition of the disease into a chronic process.

Cysteinyl leukotriene receptor 1 is dispensable for osteoclast differentiation and bone resorption.

Cysteinyl leukotriene receptor 1 (CysLTR1) is a G protein-coupled receptor for the inflammatory lipid mediators cysteinyl leukotrienes, which are involved in smooth muscle constriction, vascular permeability, and macrophage chemokine release. The Cysltr1 gene encoding CysLTR1 is expressed in the macrophage lineage, including osteoclasts, and the CysLTR1 antagonist Montelukast has been shown to suppress the formation of osteoclasts. However, it currently remains unclear whether CysLTR1 is involved in osteoclast differentiation and bone loss. Therefore, to clarify the role of CysLTR1 in osteoclastogenesis and pathological bone loss, we herein generated CysLTR1 loss-of-function mutant mice by disrupting the cysltr1 gene using the CRISPR-Cas9 system. These mutant mice had a frameshift mutation resulting in a premature stop codon (Cysltr1 KO) or an in-frame mutation causing the deletion of the first extracellular loop (Cysltr1Δ105). Bone marrow macrophages (BMM) from these mutant mice lost the intracellular flux of calcium in response to leukotriene D4, indicating that these mutants completely lost the activity of CysLTR1 without triggering genetic compensation. However, disruption of the Cysltr1 gene did not suppress the formation of osteoclasts from BMM in vitro. We also demonstrated that the CysLTR1 antagonist Montelukast suppressed the formation of osteoclasts without functional CysLTR1. On the other hand, disruption of the Cysltr1 gene partially suppressed the formation of osteoclasts stimulated by leukotriene D4 and did not inhibit that by glutathione, functioning as a substrate in the synthesis of cysteinyl leukotrienes. Disruption of the Cysltr1 gene did not affect ovariectomy-induced osteoporosis or lipopolysaccharide-induced bone resorption. Collectively, these results suggest that the CysLT-CysLTR1 axis is dispensable for osteoclast differentiation in vitro and pathological bone loss, while the leukotriene D4-CysTR1 axis is sufficient to stimulate osteoclast formation. We concluded that the effects of glutathione and Montelukast on osteoclast formation were independent of CysLTR1.

Eosinophil depletion with benralizumab is associated with attenuated mannitol airway hyperresponsiveness in severe uncontrolled eosinophilic asthma

Airway hyperresponsiveness (AHR) and eosinophilia are hallmarks of persistent asthma. We investigated whether eosinophil depletion with benralizumab might attenuate indirect mannitol AHR in severe uncontrolled asthma using a pragmatic open-label design. After a 4-week run-in period with provision of usual inhaled corticosteroids and/or long-acting β-agonist (baseline), adults with mannitol-responsive uncontrolled severe eosinophilic asthma received 3 doses of open-label benralizumab 30 mg every 4 weeks, followed by 16 weeks' washout after the last dose. The primary outcome was doubling difference (DD) in provocative dose of mannitol required to decrease FEV1 by 10% (PD10) at the end point after 12 weeks, powered at 90% with 18 patients required to detect 1 DD. Secondary outcomes included measures assessed by the asthma control questionnaire and mini-asthma quality of life questionnaire. Twenty-one patients completed 12 weeks' benralizumab therapy at the end point at week 12. Mean (SEM) age was 53 (4) years, and FEV1 80.2% (4.1%) inhaled corticosteroid dose was 1895 (59) μg, with 12 receiving long-acting muscarinic antagonist and 13 leukotriene receptor antagonists. Improvement in AHR was significant by 8 weeks, with a mean 2.1 DD (95% confidence interval 1.0, 3.3; P< .01) change in PD10 at week 12, while mean changes in asthma control questionnaire and mini-asthma quality of life questionnaire were significant by week 2 and sustained over 12 weeks, both exceeding the minimal important difference. Peripheral blood eosinophils were depleted by 2 weeks (439 to 6 cells/μL). No significant improvement occurred in lung function after 12 weeks. Domiciliary peak flow and symptoms also improved with benralizumab. Eosinophil depletion results in clinically meaningful attenuated AHR in severe uncontrolled asthma patients.