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BMC Chemistry Mar 2024Montelukast sodium (MLK) and Levocetirizine dihydrochloride (LCZ) are widely prescribed medications with promising therapeutic potential against COVID-19. However,...
Four chemometric models enhanced by Latin hypercube sampling design for quantification of anti-COVID drugs: sustainability profiling through multiple greenness, carbon footprint, blueness, and whiteness metrics.
Montelukast sodium (MLK) and Levocetirizine dihydrochloride (LCZ) are widely prescribed medications with promising therapeutic potential against COVID-19. However, existing analytical methods for their quantification are unsustainable, relying on toxic solvents and expensive instrumentation. Herein, we pioneer a green, cost-effective chemometrics approach for MLK and LCZ analysis using UV spectroscopy and intelligent multivariate calibration. Following a multilevel multifactor experimental design, UV spectral data was acquired for 25 synthetic mixtures and modeled via classical least squares (CLS), principal component regression (PCR), partial least squares (PLS), and genetic algorithm-PLS (GA-PLS) techniques. Latin hypercube sampling (LHS) strategically constructed an optimal validation set of 13 mixtures for unbiased predictive performance assessment. Following optimization of the models regarding latent variables (LVs) and wavelength region, the optimum root mean square error of cross-validation (RMSECV) was attained at 2 LVs for the 210-400 nm spectral range (191 data points). The GA-PLS model demonstrated superb accuracy, with recovery percentages (R%) from 98 to 102% for both analytes, and root mean square error of calibration (RMSEC) and prediction (RMSEP) of (0.0943, 0.1872) and (0.1926, 0.1779) for MLK and LCZ, respectively, as well bias-corrected mean square error of prediction (BCMSEP) of -0.0029 and 0.0176, relative root mean square error of prediction (RRMSEP) reaching 0.7516 and 0.6585, and limits of detection (LOD) reaching 0.0813 and 0.2273 for MLK and LCZ respectively. Practical pharmaceutical sample analysis was successfully confirmed via standard additions. We further conducted pioneering multidimensional sustainability evaluations using state-of-the-art greenness, blueness, and whiteness tools. The method demonstrated favorable environmental metrics across all assessment tools. The obtained Green National Environmental Method Index (NEMI), and Complementary Green Analytical Procedure Index (ComplexGAPI) quadrants affirmed green analytical principles. Additionally, the method had a high Analytical Greenness Metric (AGREE) score (0.90) and a low carbon footprint (0.021), indicating environmental friendliness. We also applied blueness and whiteness assessments using the high Blue Applicability Grade Index (BAGI) and Red-Green-Blue 12 (RGB 12) algorithms. The high BAGI (90) and RGB 12 (90.8) scores confirmed the method's strong applicability, cost-effectiveness, and sustainability. This work puts forward an optimal, economically viable green chemistry paradigm for pharmaceutical quality control aligned with sustainable development goals.
PubMed: 38500132
DOI: 10.1186/s13065-024-01158-7 -
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 -
Pharmaceuticals (Basel, Switzerland) Jan 2024Montelukast (MTK), a potent antagonist of cysteinyl leukotriene receptor 1, has shown therapeutic promise for the treatment of neuropsychiatric disorders. Delirium, a...
Montelukast (MTK), a potent antagonist of cysteinyl leukotriene receptor 1, has shown therapeutic promise for the treatment of neuropsychiatric disorders. Delirium, a common complication in critically ill patients, lacks effective treatment. This study aims to explore the impact of pre-intensive care unit (ICU) MTK use on in-hospital delirium incidence and, subsequent, prognosis in critically ill patients. A retrospective cohort study (n = 6344) was conducted using the MIMIC-IV database. After propensity score matching, logistic/Cox regression, E-value sensitivity analysis, and causal mediation analysis were performed to assess associations between pre-ICU MTK exposure and delirium and prognosis in critically ill patients. Pre-ICU MTK use was significantly associated with reduced in-hospital delirium (OR: 0.705; 95% CI 0.497-0.999; = 0.049) and 90-day mortality (OR: 0.554; 95% CI 0.366-0.840; = 0.005). The association was more significant in patients without myocardial infarction (OR: 0.856; 95% CI 0.383-0.896; = 0.014) and could be increased by extending the duration of use. Causal mediation analysis showed that the reduction in delirium partially mediated the association between MTK and 90-day mortality (ACME: -0.053; 95% CI -0.0142 to 0.0002; = 0.020). In critically ill patients, MTK has shown promising therapeutic benefits by reducing the incidence of delirium and 90-day mortality. This study highlights the potential of MTK, beyond its traditional use in respiratory disease, and may contribute to the development of novel therapeutic strategies for delirium.
PubMed: 38256958
DOI: 10.3390/ph17010125 -
Antioxidants (Basel, Switzerland) Sep 2023Overweight and obesity prevalence has increased worldwide. Apart from conventional approaches, people also resort to botanical supplements for reducing body weight,...
Overweight and obesity prevalence has increased worldwide. Apart from conventional approaches, people also resort to botanical supplements for reducing body weight, although several adverse events have been associated with these products. In this context, the present study aimed at evaluating the toxicity of -based products and shedding light on the mechanisms involved. The suspected hepatotoxic reactions related to -containing products collected within the Italian Phytovigilance System (IPS) were examined. Then, an in vitro study was performed to evaluate the possible mechanisms responsible for the liver toxicity, focusing on the modulation of oxidative stress and Nrf2 expression. From March 2002 to March 2022, the IPS collected eight reports of hepatic adverse reactions related to , which exclusively involved women and were mostly severe. The causality assessment was probable in three cases, while it was possible in five. In the in vitro experiments, a low cytotoxicity of was observed. However, its combination with montelukast greatly reduced cell viability, increased the intracellular ROS levels, and affected the cytoplasmic Nrf2 expression, thus suggesting an impairment of the antioxidant and cytoprotective defenses. Overall, our results support the safety concerns about -containing supplements and shed light on the possible mechanisms underpinning its hepatotoxicity.
PubMed: 37760074
DOI: 10.3390/antiox12091771 -
Frontiers in Medicine 2023Pityriasis rubra pilaris (PRP) is a rare inflammatory skin disorder characterized by hyperkeratotic follicular papules, orange-red scaling plaques with islands of...
Pityriasis rubra pilaris (PRP) is a rare inflammatory skin disorder characterized by hyperkeratotic follicular papules, orange-red scaling plaques with islands of sparing and palmoplantar keratoderma. While spontaneous resolution occurs in some cases, treatment can be challenging for others. The use of biologics in PRP management has gained attention in recent studies, although their high costs and potential side effects present limitations. We present a case of a 71-year-old patient with treatment-resistant PRP who showed significant improvement through optimized adalimumab treatment. Considering the emerging role of phospholipase A2 in PRP pathogenesis, montelukast was added, further enhancing the therapeutic response. By maintaining montelukast and prolonging the adalimumab interval to 3 and 4 weeks, effective dose optimization was achieved without PRP relapse. This case report highlights the potential for adalimumab dose optimization by shortening the initial treatment interval for increased effectiveness and lengthening the interval during the maintenance phase to conserve medication doses. Montelukast appears to assist in sustaining clinical outcomes during interval prolongation, necessitating further investigation through additional studies.
PubMed: 38098840
DOI: 10.3389/fmed.2023.1295777 -
Minerva Medica Aug 2023
PubMed: 37534834
DOI: 10.23736/S0026-4806.23.08711-6 -
Cureus Feb 2024Allergic rhinitis (AR) is increasingly prevalent in India, affecting a significant portion of the population and adversely impacting their quality of life. This...
INTRODUCTION
Allergic rhinitis (AR) is increasingly prevalent in India, affecting a significant portion of the population and adversely impacting their quality of life. This nationwide survey aimed to explore the perceptions and clinical preferences of Indian physicians regarding the perceived prevalence, common symptoms, and various available treatments for AR.
METHODS
This cross-sectional, observational, digital questionnaire-based survey was conducted from September 2022 to March 2023, involving physicians sharing insights on prevalence rates, diagnostic approaches, medication preferences, and immunotherapy practices in AR management.
RESULTS
A total of 1608 physicians participated in this survey. The majority of physicians (n=684, 42.5%) reported that the prevalence of AR in routine clinical practice is between 21 and 40%. Physicians also noted a substantial burden of AR with asthma (n=626, around 40%). Total IgE count was reported as a mandatory test for the diagnosis of AR by 47.5% of physicians (n=764). For the management of mild cases of seasonal or perennial AR, 980 (60.9%) physicians preferred fexofenadine as an oral antihistamine of choice. Fluticasone furoate was the preferred intranasal corticosteroid (INCS) option (67.1% of physicians (n=1079)), for the management of patients with moderate to severe AR, the most recommended duration of INCS therapy was two to four months (40.9% of physicians). Doctors recommended a montelukast and antihistamine combination in mild AR (n=152, 9.5%), mild AR not responding to antihistamine alone (n=291, 18.1%), moderate to severe AR along with INCS (n=252, 15.7%), and AR with mild asthma (n=74, 4.6%). The majority of physicians (n=1512, 75.6%) preferred using fexofenadine in combination with montelukast for the management of AR. The majority of physicians (n=839, 52.2%) opined that the efficacy rate of oral montelukast-fexofenadine was 60-90% in the management of mild-moderate AR. Around 55.3% of physicians (n=889) had not used immunotherapy in their clinical practice.
CONCLUSION
These observations offer a holistic view of how Indian physicians perceive the management of AR, a condition highly prevalent in India and often associated with asthma. It also highlights the treatment strategies employed in their day-to-day clinical practice.
PubMed: 38550471
DOI: 10.7759/cureus.55032 -
AACE Clinical Case Reports 2024Patients with systemic mastocytosis are at high risk of developing osteoporosis and fractures. Herein, we report a case of hip fragility fracture in a patient with...
BACKGROUND/OBJECTIVE
Patients with systemic mastocytosis are at high risk of developing osteoporosis and fractures. Herein, we report a case of hip fragility fracture in a patient with indolent systemic mastocytosis and normal bone density.
CASE REPORT
A 48-year-old man experienced a left femoral neck fracture after a fall. After a dose of oxycodone/hydromorphone postoperatively, he developed an anaphylactic reaction. Previously, he experienced a few other episodes of flushing, dizziness, and syncope precipitated by stress and alcohol. His examination was notable for pink and brown macules on his chest, back, arms, and legs. His laboratory test revealed a markedly elevated tryptase level of 171 ng/mL (<11 ng/mL). Treatment including cetirizine, montelukast, and ranitidine controlled his symptoms. His bone density test result was normal. Ten months after hip surgery, his c-terminal telopeptide of collagen type 1 and bone-specific alkaline phosphatase levels significantly increased. The bone scan demonstrated diffusely increased radiotracer uptake throughout the osseous structures. Given high bone turnover and the prior hip fracture, he received zoledronic acid yearly for 3 years, and no further fractures have occurred.
DISCUSSION
The case is unusual as the fracture occurred despite normal bone density and significant osteosclerosis, which was previously considered protective against fractures. Additionally, rather than the spine, the fracture occurred in the hip, which is an uncommon site for mastocytosis-induced fractures.
CONCLUSION
Mastocytosis is a rare cause of osteoporosis, and it is important to keep this condition in the differential diagnosis of osteoporosis, particularly when the fracture presentation is atypical.
PubMed: 38303771
DOI: 10.1016/j.aace.2023.10.003 -
Drug Metabolism and Disposition: the... May 2024This study investigated an association between the cytochrome P450 (CYP) 2C8*3 polymorphism with asthma symptom control in children and changes in lipid metabolism and...
The Cytochrome P450 (CYP) 2C8*3 Variant (rs11572080) is Associated with Improved Asthma Symptom Control in Children and Altered Lipid Mediator Production and Inflammatory Response in Human Bronchial Epithelial Cells.
This study investigated an association between the cytochrome P450 (CYP) 2C8*3 polymorphism with asthma symptom control in children and changes in lipid metabolism and pro-inflammatory signaling by human bronchial epithelial cells (HBECs) treated with cigarette smoke condensate (CSC). CYP genes are inherently variable in sequence and while such variations are known to produce clinically relevant effects on drug pharmacokinetics and pharmacodynamics, the effects on endogenous substrate metabolism and associated physiological processes are less understood. In this study, CYP2C8*3 was associated with improved asthma symptom control among children: Mean asthma control scores were 3.68 [n=207] for patients with one or more copies of the CYP2C8*3 allele vs. 4.42 [n=965] for CYP2C8*1/*1 (p=0.0133). , CYP2C8*3 was associated with an increase in montelukast 36-hydroxylation and a decrease in linoleic acid (LA) metabolism despite lower mRNA and protein expression. Additionally, CYP2C8*3 was associated with reduced mRNA expression of interleukin-6 (IL-6) and C-X-C motif chemokine ligand 8 (CXCL-8) by HBECs in response to CSC, which was replicated using the soluble epoxide hydrolase inhibitor, AUDA. Interestingly, 9(10)- and 12(13)-DiHOME, the hydrolyzed metabolites of 9(10)- and 12(13)-EpOME, increased the expression of IL-6 and CXCL-8 mRNA by HBECs. This study reveals previously undocumented effects of the CYP2C8*3 variant on the response of HBECs to exogenous stimuli. These findings suggest a role for CYP2C8 in regulating the EpOME:DiHOME ratio leading to a change in cellular inflammatory responses elicited by environmental stimuli that exacerbate asthma.
PubMed: 38772712
DOI: 10.1124/dmd.124.001684 -
Minerva Surgery Jun 2024
Topics: Humans; Cyclopropanes; Sulfides; Quinolines; Acetates; Rhinitis, Allergic; Drugs, Chinese Herbal; Leukotriene Antagonists; Female; Male; Adult; Capsules; Drug Therapy, Combination; Treatment Outcome
PubMed: 37851008
DOI: 10.23736/S2724-5691.23.10038-4