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1.
Anticancer Res ; 42(7): 3717-3724, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35790293

RESUMO

BACKGROUND/AIM: An association between leukotriene receptor antagonists (LTRA) and cancer has been previously reported, but the relationship between LTRA use and cancer prevention remains controversial. This study aimed to clarify the cancer-preventive effect of LTRA in Japanese patients with bronchial asthma. PATIENTS AND METHODS: We obtained information from a large populationbased medical information database to analyze data on patients who were newly diagnosed with bronchial asthma between 2006 and 2015. Eligible participants were patients who were prescribed an LTRA for at least 30 days (LTRA users) and those who were not using LTRA (LTRA non-users) during the objective period. LTRA users and LTRA non-users were matched 1:1 using propensity scores. RESULTS: The 1:1 propensity score matching of LTRA users and LTRA nonusers facilitated the inclusion of 3,744 participants each, in these two subgroups. The results of the Cox proportional hazards model after adjustment for covariates showed no significant difference in the cancer risk between LTRA users and non-users [adjusted hazard ratio (HR)=0.83, 95% confidence interval (CI)=0.59-1.16]. The subgroup analysis showed no significant difference in the cancer risk between the LTRA low-cumulative dose group and LTRA non-users, or between the LTRA medium-cumulative dose group and LTRA non-users. In contrast, the LTRA high-cumulative dose group had a significantly lower risk of developing cancer compared with LTRA non-users (adjusted HR=0.57, 95% CI=0.33-0.98). CONCLUSION: LTRA use may prevent cancer in patients with bronchial asthma.


Assuntos
Asma , Neoplasias , Asma/complicações , Asma/tratamento farmacológico , Asma/epidemiologia , Bases de Dados Factuais , Humanos , Antagonistas de Leucotrienos/uso terapêutico , Neoplasias/epidemiologia , Neoplasias/prevenção & controle , Estudos Retrospectivos
2.
Pharmacol Res ; 181: 106280, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35661709

RESUMO

Asthma is a major respiratory disorder characterised by chronic inflammation and airway remodelling. It affects about 1-8% of the global population and is responsible for over 461,000 deaths annually. Until recently, the pharmacotherapy of severe asthma involved high doses of inhaled corticosteroids in combination with ß-agonist for prolonged action, including theophylline, leukotriene antagonist or anticholinergic yielding limited benefit. Although the use of newer agents to target Th2 asthma endotypes has improved therapeutic outcomes in severe asthmatic conditions, there seems to be a paucity of understanding the diverse mechanisms through which these classes of drugs act. This article delineates the molecular and immunomodulatory mechanisms of action of new antiasthmatic agents currently being trialled in preclinical and clinical studies to remit asthmatic conditions. The ultimate goal in developing antiasthmatic agents is based on two types of approaches: either anti-inflammatory or bronchodilators. Biologic and most small molecules have been shown to modulate specific asthma endotypes, targeting thymic stromal lymphopoietin, tryptase, spleen tyrosine kinase (Syk), Janus kinase, PD-L1/PD-L2, GATA-3, and CD38 for the treatment and management of Th2 endotype asthma.


Assuntos
Antiasmáticos , Asma , Produtos Biológicos , Corticosteroides , Antiasmáticos/farmacologia , Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Humanos , Antagonistas de Leucotrienos
3.
Allergol Immunopathol (Madr) ; 50(3): 125-131, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35527666

RESUMO

BACKGROUND: No studies are comparing the impact of the add-on leukotriene-receptor antagonist (LTRA) with a step-up dose of inhaled corticosteroids (ICS) in partly controlled asthma patients with asthma control test (ACT) score ˂ 23. OBJECTIVE: To study the effect of LTRA add-on therapy in comparison to a step-up to medium dose of ICS in partially controlled asthma. METHODS: An open-labeled randomized controlled trial was conducted in asthma subjects with partly controlled asthma who had been in regular receipt of low dose ICS. All subjects were assessed for asthma using ACT, daytime and nighttime symptoms, rate of relievers used, spirometry, and impulse oscillometry (IOS) at 3 and 6 months. Subjects were randomized to receive daily oral LTRA 10 mg or step-up medium dose of ICS. RESULTS: Between June 2020 and January 2021, 50 participants were enrolled, all patients completing the study. After treatment, mean ACT scores were increased to more than 23 indicating well-controlled asthma in both groups, control being sustained throughout the whole 6-month study period (P ˂ 0.001). Within each group, ACT scores were improved by a minimal clinical important difference (MCID) ≥ 3 points at 6 months, compared to baseline values. There were significant decreases in nighttime and daytime symptoms, and the numbers of rescue relievers used in 4 weeks in both groups compared to baseline (P ˂ 0.001). CONCLUSIONS: LTRA add-on therapy in partially controlled asthma patients is comparable with step-up to medium dose of ICS/LABA as regards asthma control.


Assuntos
Antiasmáticos , Asma , Administração por Inalação , Corticosteroides/uso terapêutico , Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Quimioterapia Combinada , Humanos , Antagonistas de Leucotrienos/uso terapêutico , Leucotrienos/uso terapêutico
4.
Prostaglandins Other Lipid Mediat ; 161: 106649, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35595009

RESUMO

BACKGROUND: Arachidonic acid (AA), which is metabolized via the cyclooxygenase (COX) and the lipoxygenase (LOX) pathways, was found to be associated with venous thromboembolism (VTE). Metabolites of the LOX pathway include cysteinyl (Cys) Leukotrienes (LT), potent proinflammatory mediators, which have also been implicated in cardiovascular disease. OBJECTIVE: The purpose of this study was to examine if cysteinyl leukotriene receptor blockade by montelukast, lowers the risk of VTE. METHODS: We conducted a retrospective cohort study examining VTE risk among COPD patients from the United States Department of Veterans Affairs. We use propensity score matching and Cox survival models to estimate the hazard ratio comparing montelukast exposure to non-exposure. Montelukast exposure was associated with a 15.9% reduction in risk of VTE compared to those unexposed (HR= 0.841; 95% CI= (0.758-0.934)). CONCLUSION: The results of this study demonstrate that targeting LTs might be beneficial for VTE prophylaxis using the clinically available LT inhibitor, montelukast. Importantly, further research on LTs is warranted to fully understand and validate this relationship.


Assuntos
Quinolinas , Tromboembolia Venosa , Acetatos/farmacologia , Acetatos/uso terapêutico , Ciclopropanos , Humanos , Antagonistas de Leucotrienos/farmacologia , Antagonistas de Leucotrienos/uso terapêutico , Leucotrienos , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Receptores de Leucotrienos/metabolismo , Estudos Retrospectivos , Sulfetos , Tromboembolia Venosa/tratamento farmacológico , Tromboembolia Venosa/prevenção & controle
5.
Congenit Anom (Kyoto) ; 62(4): 161-168, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35538631

RESUMO

For leukotriene receptor antagonists (LTRAs), especially pranlukast, safety data during pregnancy is limited. Therefore, we conducted a prospective, two-centered cohort study using data from teratogen information services in Japan to clarify the effects of LTRA exposure during pregnancy on maternal and fetal outcomes. Pregnant women who being counseled on drug use during pregnancy at two facilities were enrolled. The primary outcome of this study was major congenital anomalies. The incidence of major congenital anomalies in women exposed to montelukast or pranlukast during the first trimester of pregnancy was compared with that of controls. Logistic regression analysis was performed to analyze the effects of maternal LTRA use during the first trimester of pregnancy on major congenital anomalies. The outcomes of 231 pregnant women exposed to LTRAs (montelukast n = 122; pranlukast n = 106; both n = 3) and 212 live births were compared with those of controls. The rate of major congenital anomalies in the LTRA group was 1.9%. Multivariable logistic regression analysis revealed that LTRA exposure was not a risk factor for major congenital anomalies (adjusted odds ratio, 0.78; 95% confidence interval, 0.23-2.05; p = 0.653). In addition, no significant difference was detected in stillbirth, spontaneous abortion, preterm birth, and low birth weight between the two groups. The present study revealed that montelukast and pranlukast were not associated with the risk of major congenital anomalies. Our findings suggest that LTRAs could be safely employed for asthma therapy during pregnancy.


Assuntos
Aborto Espontâneo , Nascimento Prematuro , Aborto Espontâneo/epidemiologia , Acetatos , Cromonas , Estudos de Coortes , Ciclopropanos , Feminino , Humanos , Recém-Nascido , Japão/epidemiologia , Antagonistas de Leucotrienos/efeitos adversos , Gravidez , Resultado da Gravidez/epidemiologia , Primeiro Trimestre da Gravidez , Nascimento Prematuro/tratamento farmacológico , Estudos Prospectivos , Quinolinas , Sulfetos
6.
J Immunol ; 208(10): 2331-2342, 2022 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-35470258

RESUMO

Cysteinyl leukotrienes (CysLTs) have been defined as central mediators of inflammation. Despite our extensive understanding of these bioactive lipid mediators in the pathogenesis of diseases such as asthma, allergic rhinitis, and even neurological disorders, information regarding the eye is markedly lacking. As a result, this study examined the expression profiles of two major CysLT receptors, CysLT1 and CysLT2, in the cornea using experimental mouse models of Pseudomonas aeruginosa-induced keratitis with contrasting outcomes: susceptible C57BL/6 (B6) and resistant BALB/c. Postinfection, disparate levels of CysLT receptors were accompanied by distinct expression profiles for select proinflammatory and anti-inflammatory cell surface markers detected on macrophages and polymorphonuclear neutrophils between the two strains. Further, inhibition of either CysLT receptor converted the disease response of both strains, where corneal perforation was prevented in B6 mice, and BALB/c mice fared significantly worse. In addition, receptor antagonist studies revealed changes in inflammatory cell infiltrate phenotypes and an influence on downstream CysLT receptor signaling pathways. Although the B6 mouse model highlights the established proinflammatory activities related to CysLT receptor activation, results generated from BALB/c mice indicate a protective mechanism that may be essential to disease resolution. Further, basal expression levels of CysLT1 and CysLT2 were significantly higher in uninfected corneas of both mouse strains as opposed to during infection, suggestive of a novel role in homeostatic maintenance within the eye. In light of these findings, therapeutic targeting of CysLT receptors extends beyond inhibition of proinflammatory activities and may impact inflammation resolution, as well as corneal surface homeostasis.


Assuntos
Asma , Ceratite , Animais , Asma/tratamento farmacológico , Inflamação/tratamento farmacológico , Antagonistas de Leucotrienos/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Receptores de Leucotrienos/genética
9.
J Asthma ; 59(6): 1231-1236, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-33974467

RESUMO

OBJECTIVE: Despite the availability of various treatment options, a large proportion of patients with asthma have uncontrolled asthma in the United States. Consequently, the economic burden of suboptimal asthma control is anticipated to substantially grow in the next 20 years, adversely impacting patients' quality of life. Therefore, there is an urgent need for effective treatments to achieve and maintain asthma control. The Global Initiative for Asthma recommends tiotropium as a controller medication for patients with asthma aged ≥6 years, based on evidence from several randomized controlled trials. However, more real-world data on the effectiveness of tiotropium are required to establish a broad picture of its use in everyday clinical practice. METHODS: Herein, we present 3 case reports of patients diagnosed with uncontrolled or fixed obstructive asthma not responding to inhaled corticosteroids (ICS) or ICS + long-acting ß2-agonists (LABAs) and/or leukotriene receptor antagonists (LTRAs). RESULTS: All 3 patients were prescribed tiotropium, irrespective of their age. Tiotropium improved lung function and quality of life, as indicated by the forced expiratory volume in 1 s/forced vital capacity ratio and the Asthma Control Test score. Furthermore, the addition of tiotropium reduced the use of rescue medication. CONCLUSIONS: Hence, the results from these case reports highlight that tiotropium could be an effective and safe add-on treatment option for patients across a range of age groups with uncontrolled or fixed obstructive asthma receiving prior ICS or ICS + LABA and/or LTRA therapy.


Assuntos
Asma , Administração por Inalação , Corticosteroides/uso terapêutico , Quimioterapia Combinada , Humanos , Antagonistas de Leucotrienos , Qualidade de Vida , Brometo de Tiotrópio/efeitos adversos
10.
Aesthet Surg J ; 42(5): 483-494, 2022 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-34618886

RESUMO

BACKGROUND: Capsular contracture (CC) is the most common long-term complication of breast surgery with prosthesis. Leukotriene receptor antagonists (LRAs) have been tested as a potential treatment; however, mixed results have been observed. OBJECTIVES: The aim of this study was to undertake a meta-analysis to clarify the treatment and prophylactic capabilities of LRAs in the management of CC. METHODS: A systematic literature search of the most popular English-language databases was performed to identify relevant primary publications. We included all studies that used the Baker scale to evaluate the treatment and preventive capabilities of LRAs. RESULTS: Six eligible studies were included based on predefined inclusion and exclusion criteria, totalling 2276 breasts, of which 775 did not receive LRAs and 1501 did. Final pooled results showed that LRAs could help manage CC with a risk difference (RD) of -0.38 with a corresponding 95% CI of -0.69 to -0.08, showing statistical significance at a Z value of 2.48, P = 0.01. Subgroup analysis based on the type of drug showed that only montelukast yielded statistical significance (RD = -0.27, 95% CI = -0.51 to -0.03, Z = 2.20, P = 0.03). Zafirlukast did not seem to influence CC. Further subgroup analysis based on treatment timing showed that prophylaxis was ineffective and only treatment for ongoing CC yielded statistically significant improvements. CONCLUSIONS: The current meta-analysis proved that LRAs could be used in the management of CC. Only treatment for ongoing CC showed statistically significant improvements. Montelukast seemed to be more efficient with a safer profile for adverse effects, whereas zafirlukast yielded no statistically significant results.


Assuntos
Implante Mamário , Implantes de Mama , Neoplasias da Mama , Contratura , Implante Mamário/efeitos adversos , Implantes de Mama/efeitos adversos , Neoplasias da Mama/etiologia , Contratura/induzido quimicamente , Contratura/tratamento farmacológico , Feminino , Humanos , Contratura Capsular em Implantes/etiologia , Contratura Capsular em Implantes/prevenção & controle , Antagonistas de Leucotrienos/uso terapêutico
11.
J Asthma ; 59(4): 780-786, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-33577360

RESUMO

OBJECTIVE: Several therapeutic agents have been assessed for the treatment of COVID-19, but few approaches have been proven efficacious. Because leukotriene receptor antagonists, such as montelukast have been shown to reduce both cytokine release and lung inflammation in preclinical models of viral influenza and acute respiratory distress syndrome, we hypothesized that therapy with montelukast could be used to treat COVID-19. The objective of this study was to determine if montelukast treatment would reduce the rate of clinical deterioration as measured by the COVID-19 Ordinal Scale. METHODS: We performed a retrospective analysis of COVID-19 confirmed hospitalized patients treated with or without montelukast. We used "clinical deterioration" as the primary endpoint, a binary outcome defined as any increase in the Ordinal Scale value from Day 1 to Day 3 of the hospital stay, as these data were uniformly available for all admitted patients before hospital discharge. Rates of clinical deterioration between the montelukast and non-montelukast groups were compared using the Fisher's exact test. Univariate logistic regression was also used to assess the association between montelukast use and clinical deterioration. A total of 92 patients were analyzed, 30 who received montelukast at the discretion of the treating physician and 62 patients who did not receive montelukast. RESULTS: Patients receiving montelukast experienced significantly fewer events of clinical deterioration compared with patients not receiving montelukast (10% vs 32%, p = 0.022). Our findings suggest that montelukast associates with a reduction in clinical deterioration for COVID-19 confirmed patients as measured on the COVID-19 Ordinal Scale. CONCLUSIONS: Hospitalized COVID-19 patients treated with montelukast had fewer events of clinical deterioration, indicating that this treatment may have clinical activity. While this retrospective study highlights a potential pathway for COVID-19 treatment, this hypothesis requires further study by prospective studies.


Assuntos
Asma , COVID-19 , Deterioração Clínica , Quinolinas , Acetatos/uso terapêutico , Asma/tratamento farmacológico , COVID-19/tratamento farmacológico , Ciclopropanos , Humanos , Antagonistas de Leucotrienos/uso terapêutico , Estudos Prospectivos , Quinolinas/uso terapêutico , Estudos Retrospectivos , SARS-CoV-2 , Sulfetos , Resultado do Tratamento
12.
Allergol. immunopatol ; 50(3): 125-131, 2022. ilus, graf, tab
Artigo em Inglês | IBECS | ID: ibc-203459

RESUMO

Background No studies are comparing the impact of the add-on leukotriene-receptor antagonist (LTRA) with a step-up dose of inhaled corticosteroids (ICS) in partly controlled asthma patients with asthma control test (ACT) score ˂ 23.Objective To study the effect of LTRA add-on therapy in comparison to a step-up to medium dose of ICS in partially controlled asthma.Methods An open-labeled randomized controlled trial was conducted in asthma subjects with partly controlled asthma who had been in regular receipt of low dose ICS. All subjects were assessed for asthma using ACT, daytime and nighttime symptoms, rate of relievers used, spirometry, and impulse oscillometry (IOS) at 3 and 6 months. Subjects were randomized to receive daily oral LTRA 10 mg or step-up medium dose of ICS.Results Between June 2020 and January 2021, 50 participants were enrolled, all patients completing the study. After treatment, mean ACT scores were increased to more than 23 indicating well-controlled asthma in both groups, control being sustained throughout the whole 6-month study period (P ˂ 0.001). Within each group, ACT scores were improved by a minimal clinical important difference (MCID) ≥ 3 points at 6 months, compared to baseline values. There were significant decreases in nighttime and daytime symptoms, and the numbers of rescue relievers used in 4 weeks in both groups compared to baseline (P ˂ 0.001).Conclusions LTRA add-on therapy in partially controlled asthma patients is comparable with step-up to medium dose of ICS/LABA as regards asthma control (AU)


Assuntos
Humanos , Corticosteroides/uso terapêutico , Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Administração por Inalação , Combinação de Medicamentos , Antagonistas de Leucotrienos/uso terapêutico , Leucotrienos/uso terapêutico
13.
Int Immunopharmacol ; 103: 108412, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34942461

RESUMO

Levocetirizine, a third-generation antihistamine, and montelukast, a leukotriene receptor antagonist, exhibit remarkable synergistic anti-inflammatory activity across a spectrum of signaling proteins, cell adhesion molecules, and leukocytes. By targeting cellular protein activity, they are uniquely positioned to treat the symptoms of COVID-19. Clinical data to date with an associated six-month follow-up, suggests the combination therapy may prevent the progression of the disease from mild to moderate to severe, as well as prevent/treat many of the aspects of 'Long COVID,' thereby cost effectively reducing both morbidity and mortality. To investigate patient outcomes, 53 consecutive COVID-19 test (+) cases (ages 3-90) from a well-established, single-center practice in Boston, Massachusetts, between March - November 2020, were treated with levocetirizine and montelukast in addition to then existing protocols [2]. The data set was retrospectively reviewed. Thirty-four cases were considered mild (64%), 17 moderate (32%), and 2 (4%) severe. Several patients presented with significant comorbidities (obesity: n = 22, 41%; diabetes: n = 10, 19%; hypertension: n = 24, 45%). Among the cohort there were no exclusions, no intubations, and no deaths. The pilot study in Massachusetts encompassed the first COVID-19 wave which peaked on April 23, 2020 as well as the ascending portion of the second wave in the fall. During this period the average weekly COVID-19 case mortality rate (confirmed deaths/confirmed cases) varied considerably between 1 and 7.5% [37]. FDA has approved a multicenter, randomized, placebo-controlled, Phase 2 clinical trial design, replete with electronic diaries and laboratory metrics to explore scientific questions not addressed herein.


Assuntos
Acetatos/uso terapêutico , COVID-19/tratamento farmacológico , Cetirizina/uso terapêutico , Ciclopropanos/uso terapêutico , Antagonistas não Sedativos dos Receptores H1 da Histamina/uso terapêutico , Antagonistas de Leucotrienos/uso terapêutico , Quinolinas/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , Sulfetos/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
14.
Am J Otolaryngol ; 43(1): 103227, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34563805

RESUMO

BACKGROUND: Chronic rhinosinusitis (CRS) in the setting of Aspirin Exacerbated Respiratory Disease (AERD) have high rate of treatment failure and disease recurrence. OBJECTIVE: Evaluate the long-term effect of zileuton on sinonasal outcomes in patients with AERD. METHODS: AERD patients were reviewed and divided into two cohorts, depending if they were treated with zileuton during their clinical course. Demographic data, 22-item sinonasal outcome test (SNOT-22), Lund-Kennedy (LK) endoscopy score, duration of treatment, and number of sinus surgeries performed were collected. RESULTS: 40 AERD patients were included, with follow-up duration up to 10 years (avg of 5.2 years). All patients were treated with topical saline and budesonide irrigations, intranasal steroid spray, and montelukast. 19 patients had uncontrolled sinus disease requiring multiple steroid tapers and were switched from montelukast to zileuton (cohort 1, 47.5%) at some point in their treatment. 21 patients (cohort 2, 52.5%) never needed zileuton. The average duration of treatment with zileuton was 6 years. Patients who required zileuton had a worse SNOT-22 (32.1 vs 19, p = 0.117), worse LK score (8.1 vs 7.5, p = 0.504), and higher average number of surgeries (1.9 vs 1.6, p = 0.343). The outcomes in the zileuton cohort trended toward improvement, however these did not reach statistical significance with an improved SNOT-22 from 32.1 to 27.4 (p = 0.617) and LK score from 7.9 to 6.2 (p = 0.092); The addition of zileuton significantly lowered the number of surgeries needed to an average of 0.5 (p < 0.0001). CONCLUSION: Zileuton may help decrease the number of sinus surgeries needed in AERD.


Assuntos
Asma Induzida por Aspirina/tratamento farmacológico , Hidroxiureia/análogos & derivados , Antagonistas de Leucotrienos/uso terapêutico , Rinite/tratamento farmacológico , Sinusite/tratamento farmacológico , Adulto , Idoso , Anti-Inflamatórios não Esteroides/efeitos adversos , Aspirina/efeitos adversos , Asma Induzida por Aspirina/complicações , Doença Crônica , Feminino , Humanos , Hidroxiureia/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Rinite/induzido quimicamente , Índice de Gravidade de Doença , Sinusite/induzido quimicamente , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
16.
Cell Mol Life Sci ; 79(1): 40, 2021 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-34971430

RESUMO

Leukotrienes are pro-inflammatory lipid mediators generated by 5-lipoxygenase aided by the 5-lipoxygenase-activating protein (FLAP). BRP-201, a novel benzimidazole-based FLAP antagonist, inhibits leukotriene biosynthesis in isolated leukocytes. However, like other FLAP antagonists, BRP-201 fails to effectively suppress leukotriene formation in blood, which limits its therapeutic value. Here, we describe the encapsulation of BRP-201 into poly(lactide-co-glycolide) (PLGA) and ethoxy acetalated dextran (Ace-DEX) nanoparticles (NPs), aiming to overcome these detrimental pharmacokinetic limitations and to enhance the bioactivity of BRP-201. NPs loaded with BRP-201 were produced via nanoprecipitation and the physicochemical properties of the NPs were analyzed in-depth using dynamic light scattering (size, dispersity, degradation), electrophoretic light scattering (effective charge), NP tracking analysis (size, dispersity), scanning electron microscopy (size and morphology), UV-VIS spectroscopy (drug loading), an analytical ultracentrifuge (drug release, degradation kinetics), and Raman spectroscopy (chemical attributes). Biological assays were performed to study cytotoxicity, cellular uptake, and efficiency of BRP-201-loaded NPs versus free BRP-201 to suppress leukotriene formation in primary human leukocytes and whole blood. Both PLGA- and Ace-DEX-based NPs were significantly more efficient to inhibit leukotriene formation in neutrophils versus free drug. Whole blood experiments revealed that encapsulation of BRP-201 into Ace-DEX NPs strongly increases its potency, especially upon pro-longed (≥ 5 h) incubations and upon lipopolysaccharide-challenge of blood. Finally, intravenous injection of BRP-201-loaded NPs significantly suppressed leukotriene levels in blood of mice in vivo. These results reveal the feasibility of our pharmacological approach using a novel FLAP antagonist encapsulated into Ace-DEX-based NPs with improved efficiency in blood to suppress leukotriene biosynthesis.


Assuntos
Antagonistas de Leucotrienos/farmacologia , Leucotrienos , Nanopartículas/química , Animais , Feminino , Voluntários Saudáveis , Humanos , Leucotrienos/biossíntese , Leucotrienos/metabolismo , Masculino , Camundongos
17.
Aging (Albany NY) ; 13(24): 25670-25693, 2021 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-34919533

RESUMO

Autophagy is an important cellular mechanism for maintaining cellular homeostasis, and its impairment correlates highly with age and age-related diseases. Retinal pigment epithelial (RPE) cells of the eye represent a crucial model for studying autophagy, as RPE functions and integrity are highly dependent on an efficient autophagic process. Cysteinyl leukotriene receptor 1 (CysLTR1) acts in immunoregulation and cellular stress responses and is a potential regulator of basal and adaptive autophagy. As basal autophagy is a dynamic process, the aim of this study was to define the role of CysLTR1 in autophagy regulation in a chronobiologic context using the ARPE-19 human RPE cell line. Effects of CysLTR1 inhibition on basal autophagic activity were analyzed at inactive/low and high lysosomal degradation activity with the antagonists zafirlukast (ZTK) and montelukast (MTK) at a dosage of 100 nM for 3 hours. Abundances of the autophagy markers LC3-II and SQSTM1 and LC3B particles were analyzed in the absence and presence of lysosomal inhibitors using western blot analysis and immunofluorescence microscopy. CysLTR1 antagonization revealed a biphasic effect of CysLTR1 on autophagosome formation and lysosomal degradation that depended on the autophagic activity of cells at treatment initiation. ZTK and MTK affected lysosomal degradation, but only ZTK regulated autophagosome formation. In addition, dexamethasone treatment and serum shock induced autophagy, which was repressed by CysLTR1 antagonization. As a newly identified autophagy modulator, CysLTR1 appears to be a key player in the chronobiological regulation of basal autophagy and adaptive autophagy in RPE cells.


Assuntos
Autofagia/efeitos dos fármacos , Células Epiteliais/metabolismo , Receptores de Leucotrienos/efeitos dos fármacos , Epitélio Pigmentado da Retina/efeitos dos fármacos , Acetatos/farmacologia , Western Blotting , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Fenômenos Cronobiológicos , Ciclopropanos/farmacologia , Humanos , Indóis/farmacologia , Antagonistas de Leucotrienos/farmacologia , Estresse Oxidativo/fisiologia , Fenilcarbamatos/farmacologia , Quinolinas/farmacologia , Epitélio Pigmentado da Retina/citologia , Epitélio Pigmentado da Retina/metabolismo , Sulfetos/farmacologia , Sulfonamidas/farmacologia
18.
Pak J Pharm Sci ; 34(5(Supplementary)): 1923-1928, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34836861

RESUMO

This study investigated the effect of solid dispersions (SD) on solubility and release of Zafirlukast (ZA) by physical mixture (PM), solvent evaporation (SE) and kneading method (KM) with Eudragit EPO (EPO) as binary component and Poloxamer 188 (P188) and Poloxamer 407 (P407) as ternary components. The binary and ternary systems caused an increase of 322 folds and 356 folds in aqueous solubility of ZA, respectively. Formulations were characterized for solubility, FTIR, PXRD, DSC, SEM and dissolution studies. P407 was found to be an excellent solubility booster in combination with EPO. It was concluded that solubility and dissolution rate of ZA increased significantly when SD of the ZA was prepared by solvent evaporation method (1:7 ratio) using 15% P407 as ternary component.


Assuntos
Excipientes/química , Indóis/química , Antagonistas de Leucotrienos/química , Fenilcarbamatos/química , Poloxâmero/química , Ácidos Polimetacrílicos/química , Sulfonamidas/química , Portadores de Fármacos , Composição de Medicamentos , Liberação Controlada de Fármacos , Indóis/administração & dosagem , Antagonistas de Leucotrienos/administração & dosagem , Fenilcarbamatos/administração & dosagem , Solubilidade , Sulfonamidas/administração & dosagem
19.
Pak J Pharm Sci ; 34(5): 1791-1803, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34803017

RESUMO

A simple and sensitive stability-indicating HPLC-UV method was developed and validated for the determination of montelukast in the development of chewable tablet formulation. Chromatographic separation was achieved using Atlantis® T3 3µm C18 (4.6mmID X 10cm) analytical column. The mobile phase was consisted of KH2PO4 (0.05mM)-ACN-TEA (450:550:1.33, v/v/v) adjusted to pH 2.0 with orthophosphoric acid. The analysis was run at a flow rate of 1.5 mL/min with detection wavelength at 255nm. Method validation was performed in accordance with ICH guideline. Stress degradation studies, comprising of acid and alkali hydrolysis (1M HCl and 1M NaOH), oxidative degradation (3% H2O2), photo degradation and heat degradation, were performed. The standard calibration curve was linear from 0.0025 - 0.375mg/mL. The LOD and LLOQ were 0.01µg/mL and 0.04µg/mL. Stress degradation result shows that montelukast sodium was sensitive to photo degradation, oxidation and acid hydrolysis. Oxidative degradation kinetic study of montelukast sodium followed first order reaction, with r2 =0.9877, apparent degradation rate constant, k= 0.1066 h-1, t1/2= 6.6151 hr and t90% = 1.0118hr. In conclusion, HPLC-UV method was successfully developed and validated for determination of montelukast sodium in chewable tablet formulation.


Assuntos
Acetatos/química , Cromatografia Líquida de Alta Pressão/métodos , Ciclopropanos/química , Antagonistas de Leucotrienos/química , Quinolinas/química , Sulfetos/química , Estabilidade de Medicamentos , Oxirredução , Comprimidos/química , Raios Ultravioleta
20.
Int J Mol Sci ; 22(21)2021 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-34769111

RESUMO

Characterization of new pharmacological targets is a promising approach in research of neurorepair mechanisms. The G protein-coupled receptor 17 (GPR17) has recently been proposed as an interesting pharmacological target, e.g., in neuroregenerative processes. Using the well-established ex vivo model of organotypic slice co-cultures of the mesocortical dopaminergic system (prefrontal cortex (PFC) and substantia nigra/ventral tegmental area (SN/VTA) complex), the influence of GPR17 ligands on neurite outgrowth from SN/VTA to the PFC was investigated. The growth-promoting effects of Montelukast (MTK; GPR17- and cysteinyl-leukotriene receptor antagonist), the glial cell line-derived neurotrophic factor (GDNF) and of two potent, selective GPR17 agonists (PSB-16484 and PSB-16282) were characterized. Treatment with MTK resulted in a significant increase in mean neurite density, comparable with the effects of GDNF. The combination of MTK and GPR17 agonist PSB-16484 significantly inhibited neuronal growth. qPCR studies revealed an MTK-induced elevated mRNA-expression of genes relevant for neuronal growth. Immunofluorescence labelling showed a marked expression of GPR17 on NG2-positive glia. Western blot and RT-qPCR analysis of untreated cultures suggest a time-dependent, injury-induced stimulation of GPR17. In conclusion, MTK was identified as a stimulator of neurite fibre outgrowth, mediating its effects through GPR17, highlighting GPR17 as an interesting therapeutic target in neuronal regeneration.


Assuntos
Acetatos/farmacologia , Ciclopropanos/farmacologia , Antagonistas de Leucotrienos/farmacologia , Crescimento Neuronal/efeitos dos fármacos , Quinolinas/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Sulfetos/farmacologia , Animais , Animais Recém-Nascidos , Técnicas de Cocultura , Avaliação Pré-Clínica de Medicamentos , Feminino , Masculino , Regeneração Nervosa/efeitos dos fármacos , Crescimento Neuronal/genética , Ratos
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