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Current Pharmaceutical Biotechnology Jun 2024The objective of the reported work was to develop Montelukast sodium (MS) solid lipid nanoparticles (MS-SLNs) to ameliorate its oral bio-absorption. Herein, the...
INTRODUCTION
The objective of the reported work was to develop Montelukast sodium (MS) solid lipid nanoparticles (MS-SLNs) to ameliorate its oral bio-absorption. Herein, the highpressure homogenization (HPH) principle was utilized for the fabrication of MS-SLNs.
METHOD
The study encompasses a 23 full factorial statistical design approach where mean particle size (Y1) and percent entrapment efficiency (Y2) were screened as dependent variables while, the concentration of lipid (X1), surfactant (X2), and co-surfactant (X3) were screened as independent variables. The investigation of MS-SLNs by DSC and XRD studies unveiled the molecular dispersion of MS into the SLNs while TEM study showed the smooth surface of developed MSSLNs. The optimized MS-SLNs exhibited mean particle size (MPS) = 115.5 ± 1.27 nm, polydispersity index (PDI) = 0.256 ± 0.04, zeta potential (ζ) = -21.9 ± 0.32 mV and entrapment efficiency (EE) = 90.97 ± 1.12 %. The In vivo pharmacokinetic study performed in Albino Wistar rats revealed 2.87-fold increments in oral bioavailability.
RESULTS
The accelerated stability studies of optimized formulation showed good physical and chemical stability. The shelf life estimated for the developed MS-SLN was found to be 22.38 months.
CONCLUSION
At the outset, the developed MS-SLNs formulation showed a significant increment in oral bioavailability and also exhibited excellent stability in exaggerated storage conditions.
PubMed: 38918978
DOI: 10.2174/0113892010300965240612054349 -
European Journal of Pharmacology Jun 2024Cysteinyl leukotrienes (CysLTs) are central to the pathophysiology of asthma and various inflammatory disorders. Leukotriene receptor antagonists (LTRAs) effectively... (Review)
Review
Cysteinyl leukotrienes (CysLTs) are central to the pathophysiology of asthma and various inflammatory disorders. Leukotriene receptor antagonists (LTRAs) effectively treat respiratory conditions by targeting cysteinyl leukotriene receptors, CysLT and CysLT subtypes. This review explores the multifaceted effects of LTs, extending beyond bronchoconstriction. CysLT receptors are not only present in the respiratory system but are also crucial in neuronal signaling pathways. LTRAs modulate these receptors, influencing downstream signaling, calcium levels, inflammation, and oxidative stress (OS) within neurons hinting at broader implications. Recent studies identify novel molecular targets, sparking interest in repurposing LTRAs for therapeutic use. Clinical trials are investigating their potential in neuroinflammation control, particularly in Alzheimer's disease (AD) and Parkinson's diseases (PD). However, montelukast, a long-standing LTRA since 1998, raises concerns due to neuropsychiatric adverse drug reactions (ADRs). Despite widespread use, understanding montelukast's metabolism and underlying ADR mechanisms remains limited. This review comprehensively examines LTRAs' diverse biological effects, emphasizing non-bronchoconstrictive activities. It also analyses plausible mechanisms behind LTRAs' neuronal effects, offering insights into their potential as neurodegenerative disease modulators. The aim is to inform clinicians, researchers, and pharmaceutical developers about LTRAs' expanding roles, particularly in neuroinflammation control and their promising repurposing for neurodegenerative disease management.
PubMed: 38909933
DOI: 10.1016/j.ejphar.2024.176755 -
Molecular Medicine Reports Aug 2024Montelukast and zafirlukast, cysteinyl leukotriene receptor antagonists (LTRAs), trigger apoptosis and inhibit cell proliferation of triple‑negative breast cancer...
Differential effects of montelukast and zafirlukast on MDA‑MB‑231 triple‑negative breast cancer cells: Cell cycle regulation, apoptosis, autophagy, DNA damage and endoplasmic reticulum stress.
Montelukast and zafirlukast, cysteinyl leukotriene receptor antagonists (LTRAs), trigger apoptosis and inhibit cell proliferation of triple‑negative breast cancer MDA‑MB‑231 cells. By contrast, only zafirlukast induces G/G cell cycle arrest. The present study compared the effects of these drugs on proteins regulating cell proliferation, apoptosis, autophagy, and endoplasmic reticulum (ER) and oxidative stress using reverse transcription‑quantitative PCR, western blotting and flow cytometry. The expression of proliferating markers, Ki‑67 and proliferating cell nuclear antigen, was decreased by both drugs. Zafirlukast, but not montelukast, decreased the expression of cyclin D1 and CDK4, disrupting progression from G to S phase. Zafirlukast also increased the expression of p27, a cell cycle inhibitor. Both drugs decreased the expression of anti‑apoptotic protein Bcl‑2 and ERK1/2 phosphorylation, and increased levels of the autophagy marker LC3‑II and DNA damage markers, including cleaved PARP‑1, phosphorylated (p)‑ATM and p‑histone H2AX. The number of caspase 3/7‑positive cells was greater in montelukast‑treated cells compared with zafirlukast‑treated cells. Montelukast induced higher levels of the ER stress marker CHOP compared with zafirlukast. Montelukast activated PERK, activating transcription factor 6 (ATF6) and inositol‑requiring enzyme type 1 (IRE1) pathways, while zafirlukast only stimulated ATF6 and IRE1 pathways. GSK2606414, a PERK inhibitor, decreased apoptosis mediated by montelukast, but did not affect zafirlukast‑induced cell death. The knockdown of CHOP by small interfering RNA reduced apoptosis triggered by montelukast and zafirlukast. In conclusion, the effects on cell cycle regulator proteins may contribute to cell cycle arrest caused by zafirlukast. The greater apoptotic effects of montelukast may be caused by the higher levels of activated caspase enzymes and the activation of three pathways of ER stress: PERK, ATF6, and IRE1.
Topics: Humans; Sulfides; Cyclopropanes; Quinolines; Apoptosis; Acetates; Endoplasmic Reticulum Stress; Cell Line, Tumor; Autophagy; Sulfonamides; Indoles; Female; DNA Damage; Phenylcarbamates; Tosyl Compounds; Cell Proliferation; eIF-2 Kinase; Endoribonucleases; Cell Cycle Checkpoints; Transcription Factor CHOP; Cell Cycle; Leukotriene Antagonists; Protein Serine-Threonine Kinases
PubMed: 38904207
DOI: 10.3892/mmr.2024.13265 -
Frontiers in Pharmacology 2024We describe the case of a 10-year-old boy with asthma (AS), accompanied by allergic rhinitis (AR), food allergy (FA), and combined attention-deficit/hyperactivity...
Omalizumab in combination with subcutaneous immunotherapy for the treatment of multiple allergies associated with attention-deficit/hyperactivity disorder: a case report and a literature review.
We describe the case of a 10-year-old boy with asthma (AS), accompanied by allergic rhinitis (AR), food allergy (FA), and combined attention-deficit/hyperactivity disorder (ADHD), who was treated at Shanghai Renji Hospital on 11 July 2020. The efficiency of the previous treatment with salmeterol/ticlosone was poor. Treatment with montelukast sodium resulted in development of neurological symptoms. Treatment with omalizumab in combination with subcutaneous immunotherapy (SCIT) was then initiated in our department based on anti-asthmatic therapy. Symptoms of asthma were completely controlled, and FA and AR symptoms improved. The treatment regimen led to a significant improvement in ADHD symptoms and the overall quality of life of the patient. The literature search was done in the PubMed database using "attention deficit/hyperactivity disorder/ADHD" and "asthma" as keywords, and we identified 47 relevant articles. In conclusion, our results show that treating asthma with omalizumab in combination with salmeterol/ticlosone and SCIT is efficient in controlling symptoms of multiple allergies and may lead to the improvement in ADHD symptoms and the overall quality of life of pediatric patients with ADHD. While current studies suggest that allergic diseases are closely related to ADHD, there is still a lack of studies or case reports of complete treatment protocols to provide clinical clues for management of the disease.
PubMed: 38887551
DOI: 10.3389/fphar.2024.1367551 -
The Journal of Asthma : Official... Jun 2024Eosinophil-derived neurotoxin (EDN) is an important biomarker of eosinophilic inflammation. This study evaluated Montelukast treatment response according to EDN...
Eosinophil-derived neurotoxin (EDN) is an important biomarker of eosinophilic inflammation. This study evaluated Montelukast treatment response according to EDN concentration in children with perennial allergic rhinitis (PAR). Fifty-two children with PAR were recruited and took a combination of Montelukast (5mg) and Levocetirizine (5mg) "Mont/Levo Group" or only Montelukast (5mg) "Mont Group" for 4 weeks. All caregivers were instructed to record rhinitis symptoms for 4 weeks. EDN was measured before and after treatment. Daytime nasal symptom scores (DNSS) significantly decreased in both the Mont/Levo ( = 0.0001; n = 20) and Mont Group ( < 0.0001; n = 20), but there were no significant differences between the two groups. EDN concentration also significantly decreased after treatment in both groups ( < 0.0001 and < 0.001, respectively). For secondary analysis, children with a high initial EDN concentration (EDN ≥ 53 ng/mL) were placed in the "High EDN Group", while those with a lower initial EDN concentration (EDN < 53 ng/mL) were put in the "Low EDN Group". Both groups experienced significant reductions in DNSS after either treatment regimen ( < 0.0001 and = 0.0027, respectively) but the High EDN Group had greater reductions. EDN concentrations in the High EDN Group decreased significantly from either treatment ( < 0.0001). We found that children with AR and a high serum EDN concentration may respond well to Montelukast treatment. A therapeutic strategy using EDN concentrations in patients with AR to evaluate therapeutic response may help improve quality of care.
PubMed: 38884630
DOI: 10.1080/02770903.2024.2370002 -
The Journal of Rheumatology Jun 2024Rituximab (RTX) is a monoclonal antibody often used in patient treatment of malignancies and several rheumatological disorders, including vasculitides. It has become an...
Rituximab (RTX) is a monoclonal antibody often used in patient treatment of malignancies and several rheumatological disorders, including vasculitides. It has become an essential component of many treatment protocols; however, is commonly associated with hypersensitivity infusion reactions..
PubMed: 38879194
DOI: 10.3899/jrheum.2024-0116 -
Clinical Pediatrics Jun 2024Montelukast by inhibiting leukotriene receptors in the bladder can prevent the activation of mast cells. We investigated the effectiveness of Montelukast in reducing the...
Montelukast by inhibiting leukotriene receptors in the bladder can prevent the activation of mast cells. We investigated the effectiveness of Montelukast in reducing the symptoms of children with bladder pain syndrome (BPS). In this randomized clinical trial, children were allocated into groups of intervention (Montelukast and oxybutynin) and the control (oxybutynin). At the beginning and after 14 days, questions from mothers of children about their urinary condition were asked about the frequency of nocturnal enuresis, frequent urination, urinary incontinence, urinary urgency, and their pain severity. There was no significant difference between two groups in terms of frequency of nocturnal enuresis, frequent urination, urinary incontinence, and urinary urgency. Regarding the frequency of pain distribution, the frequency of pain-free people in the Montelukast group was higher than control group (84.4% vs 56.3%, = .023). The results showed that adding Montelukast to oxybutynin has a significant decrease in pain in children with BPS.
PubMed: 38864166
DOI: 10.1177/00099228241260119 -
Results in Chemistry Dec 2023γ-Hydroxyalkenals, 4-hydroxynonenal (HNE) and phospholipid esters of 4-hydroxy-8-oxooctenoic acid (HOOA-PL), are produced from the alkyl and carboxyl termini of...
Cysteinyl leukotriene-like metabolites are generated in retinal pigment epithelial cells through glutathionylation/reduction of an oxidatively truncated fragment of arachidonate.
γ-Hydroxyalkenals, 4-hydroxynonenal (HNE) and phospholipid esters of 4-hydroxy-8-oxooctenoic acid (HOOA-PL), are produced from the alkyl and carboxyl termini of arachidonyl phospholipids by radical-induced oxidative cleavage. Metabolism of HNE by Michael addition of glutathione (GSH) followed by reduction of the aldehyde carbonyl produces a GSH derivative of 1,4-dihydroxynonane (DHN)-GSH. Analogous biochemistry was anticipated to produce a GSH derivative of 5,8-dihydroxyoctanoic acid (DHOA-GSH) that has structural and functional similarity to the cysteinyl leukotriene (LT)C. We now report that exposure of human retinal pigment epithelial cells to CoCl, an in vitro model of hypoxia-induced oxidative stress, generates DHOA-GSH and two products of its peptidolysis, DHOA-CysGly and DHOA-Cys that resemble LTD and LTE. Identification of these metabolites was confirmed by unambiguous chemical syntheses that also provided a heavy isotope labeled quantitative standard C N-DHOA-GSH. The availability of pure samples of these arachidonate metabolites will enable assessment of their biological activities, and testing the hypothesis that øLTs promote pathological inflammation by serving as LT receptor agonists. Because LT biosynthetic enzymes, e.g., 5-lipoxygenase, are not involved in the generation of øLTs in vivo, inhibitors of LT biosynthesis, e.g., Zileuton, are not expected to prevent the generation of øLTs. On the other hand, if øLTs are leukotriene receptor agonists, then the therapeutic effects of leukotriene receptor antagonist drugs, e.g., Montelukast, may include inhibition not only of LT-induced but also øLT-induced LT receptor activation and signaling.
PubMed: 38855016
DOI: 10.1016/j.rechem.2023.100995 -
The Journal of Allergy and Clinical... Jun 2024The benefits and harms of adding antileukotrienes to H1-antihistamines for the management of urticaria (hives, itch, and/or angioedema) remain unclear.
BACKGROUND
The benefits and harms of adding antileukotrienes to H1-antihistamines for the management of urticaria (hives, itch, and/or angioedema) remain unclear.
OBJECTIVE
We sought to systematically synthesize the treatment outcomes of antileukotrienes in combination with H1-antihistamines versus H1-antihistamines alone for acute and chronic urticaria.
METHODS
As part of updating American Academy of Allergy, Asthma & Immunology and American College of Allergy, Asthma, and Immunology Joint Task Force on Practice Parameters urticaria guidelines, we searched MEDLINE, Embase, CENTRAL, LILACS, WPRIM, IBECS, ICTRP, CBM, CNKI, VIP, Wanfang, FDA, and EMA databases from inception to December 18, 2023 for randomized controlled trials (RCTs) evaluating antileukotrienes and H1-antihistamines versus H1-antihistamines alone in patients with urticaria. Paired reviewers independently screened citations, extracted data, and assessed risk of bias. Random effects models pooled effect estimates for urticaria activity, itch, wheal, sleep, quality of life, and harms. The GRADE approach informed certainty of evidence ratings. Open Science Framework registration: https://osf.io/h2bfx/.
RESULTS
Thirty-four RCTs enrolled 3,324 children and adults. Compared to H1-antihistamines alone, the combination of a leukotriene receptor antagonist (LTRA) with H1-antihistamines probably modestly reduces urticaria activity (mean difference: -5.04, 95%CI -6.36 to -3.71; 7-day Urticaria Activity Score) with moderate certainty. We made similar findings for itch and wheal severity, and quality of life. Adverse events were probably not different between groups (moderate certainty), however, no RCT reported on neuropsychiatric adverse events.
CONCLUSION
Among patients with urticaria, adding LTRAs to H1-antihistamines probably modestly improves urticaria activity with little to no increase in overall adverse events. The added risk of neuropsychiatric adverse events in this population with LTRAs is small and uncertain.
PubMed: 38852861
DOI: 10.1016/j.jaci.2024.05.026 -
Aesthetic Plastic Surgery Jun 2024Capsular contracture (CC) remains a very common complication and the main cause of reoperation following a mammary implant surgery. Leukotrienes play an important role...
BACKGROUND
Capsular contracture (CC) remains a very common complication and the main cause of reoperation following a mammary implant surgery. Leukotrienes play an important role in the inflammatory cascade linked to the development of the periprosthetic capsule. The aim of this paper is to evaluate the incidence of recurrence of capsular contracture in female patients who underwent a secondary mammary augmentation due to this etiology, with and without treatment with leukotriene inhibitors during postoperative care.
MATERIAL AND METHODS
Sixty-four women submitted to a secondary mammary augmentation due to CC were evaluated retrospectively. Out of these patients, 20 (31%) were treated with Montelukast for 3 months. The remaining 44 (69%) did not receive antileukotriene. The presence of capsular contracture was measured using the Baker classification and magnetic resonance imaging a year after postoperative care. The median follow-up period was 15 months.
RESULTS
The patients receiving Montelukast (n = 20) presented a 15% CC rate (n = 1). The women that did not receive antileukotriene therapy (n = 44) presented a 16% CC rate (n = 7).
CONCLUSION
The results of our study show that treatment with Montelukast for 3 months after the operation is associated with lower rates of capsular contracture when compared to patients that did not receive the treatment.
LEVEL OF EVIDENCE III
This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
PubMed: 38849548
DOI: 10.1007/s00266-024-04122-x