Leukotriene receptor antagonists as adjuvant therapy of antihistamines in chronic urticaria: a systematic review and meta-analysis.

Certain guidelines recommend a second-generation H1-antihistamine (AH) as first-line treatment for patients with chronic urticaria (CU). However, some patients show insufficient response to a standard dose of this therapy and might benefit from adding leukotriene receptor antagonists (LTA). Therefore, we aimed to perform a systematic review and meta-analysis comparing LTA plus antihistamines with antihistamines alone. We performed a systematic review and meta-analysis, searching PubMed, EMBASE, and Cochrane Central for randomized clinical trial (RCT) data comparing LTA plus AH treatment to AH alone in patients with CU. Statistical analysis was performed using R Studio 4.3.2. Heterogeneity was assessed with I2 statistics. Three studies comprising 234 patients with urticaria were included. The mean age was 37.23 years in the leukotriene antagonist + antihistamines (LTA + AH) group and 39.14 years in the antihistamines (AH) group. Follow-up ranged from 2 to 18 months between studies. There was no statistically significant difference between groups in terms of TSS level (SMD: -74.82; 95% CI: -222.66 to 73.02; P = 0.32; I2 = 98%), neither in terms of pruritus (MD: -0.07; 95% CI: -0.42 to 0.28; P = 0.70; I2 = 74%). After sensitivity analysis, with the systematic exclusion of each study from the grouped estimates, the result for TSS level did not change. These findings suggest that leukotriene receptor antagonists with antihistamines do not have better outcomes than antihistamines alone regarding TSS and pruritus in patients with CU.

Comparison of treatment efficacy of omega-3 fish oil and montelukast in ovalbumin-protease-induced allergic rhinitis model in rats.

OBJECTIVES: Montelukast is a well-known leukotriene receptor antagonist commonly used in treating allergic rhinitis and asthma. Omega-3 fatty acid is also known as an antiallergic and immunomodulator molecule. This study aimed to elucidate the efficacy of systemic montelukast and omega-3 fatty acid treatment in allergic rhinitis models in Wistar Hannover rats. METHODS: This research was conducted on 28 healthy Wistar Hannover rats weighing 250-350 g. After establishing the allergic rhinitis model, nasal symptoms were observed and scored, and the nasal mucosa of all rats was investigated histologically. Light microscopy was utilized to evaluate the degree of ciliary loss, goblet cell hyperplasia, vascular congestion, vascular proliferation, inflammatory cell infiltration, eosinophil infiltration, and hypertrophy in chondrocytes. RESULTS: As a result of the analysis of the data obtained from the study, it was determined that typical allergic rhinitis symptoms such as nasal scratching and sneezing were significantly reduced in the rats in the montelukast and omega-3 treated group, and these symptoms did not increase after repeated intranasal OVA-protease applications. Histological examinations after fish oil treatment did not reveal typical inflammatory changes in allergic rhinitis. None of the rats in the montelukast and omega-3 groups had any increase in goblet cells, whereas 14.3% of the rats in the control group and 28.6% of the rats in the allergic rhinitis group had mild increase. Last but not least, 71.4% of rats in the allergic rhinitis group had a moderate increase. The difference between the groups was statistically significant (p < 0.001). CONCLUSION: Regarding the outcomes of this research, it was observed that w-3 fatty acids had antiallergic effects, both histopathological and clinical, in the allergic rhinitis model. We believe that further randomized controlled trials incorporating larger cohorts are warranted to verify the use of omega-3 fatty acids in treating allergic rhinitis. The level of evidence of this article is Level 2.

Cysteinyl leukotriene induces eosinophil extracellular trap formation via cysteinyl leukotriene 1 receptor in a murine model of asthma.

PURPOSE: Eosinophils are one of the main cells responsible to the inflammatory response in asthma by the release of inflammatory molecules such as cytokines, reactive oxygen species (ROS), cytotoxic granule, eosinophil extracellular trap (EET), and lipid mediators as cysteinyl leukotriene (cysLT). The interconnections between these molecules are not fully understood. Here, we attempted to investigate the cysLT participation in the mechanisms of EET formation in an asthma model of OVA challenge. MATERIALS AND METHODS: Before intranasal challenge with OVA, BALB/cJ mice were treated with a 5-lipoxygenase-activating protein (FLAP) inhibitor (MK-886), or with a cysLT1 receptor antagonist (MK-571) and the lung and bronchoalveolar lavage fluid (BALF) were analyzed. RESULTS: We showed that OVA-challenged mice treated with MK-886 or MK-571 had a decrease in inflammatory cells, goblet cells hyperplasia, and eosinophil peroxidase (EPO) activity in the airway. However, only OVA-challenged mice treated with MK-571 had an improvement in lung function. Also, treatments with MK-886 or MK-571 decreased Th2 cytokines levels in the airway. Moreover, we observed that OVA-challenged mice treated with MK-886 or MK-571 had a decrease in EET formation in BALF. We also verified that EET release was not due to cell death because the cell viability remained the same among the groups. CONCLUSION: We revealed that the decrease in cysLT production or cysLT1 receptor inhibition by MK-886 or/and MK-571 treatments, respectively reduced EET formation in BALF, showing that cysLT regulates the activation process of EET release in asthma.

Eficacia y seguridad de la combinación de fexofenadina con montelukast en el tratamiento de la rinitis alérgica / Efficacy and safety of combined therapy of fexofenadine and montelukast for the treatment of allergic rhinitis

El propósito de este trabajo fue revisar la literatura científica que evalúa la eficacia y seguridad de las monoterapias de fexofenadina y montelukast, la terapia combinada (fija o en asociación) de montelukast - fexofenadina, así como de montelukast con otros antihistamínicos de segunda generación en el tratamiento de la rinitis alérgica. Se realizó una estrategia de búsqueda bibliográfica de múltiples etapas, en donde se identificaron estudios basados en ensayos clínicos y estudios no aleatorizados (ensayo controlado no aleatorizado, controlado antes-después, de series de tiempo interrumpidas, con controles históricos, de cohorte, de casos y controles, estudio transversal, y series de casos) en pacientes con rinitis alérgica, en las bases de datos MEDLINE/ PubMed, Scopus, Web of Science, Biblioteca Cochrane, Redalyc y Colección BVS y debido a la cantidad de resultados obtenidos se incluyó la búsqueda en Hinari. Con base en esta revisión se concluye que las combinaciones de antihistamínicos de segunda generación y antagonistas de leucotrienos y, en particular, la combinación fija de fexofenadina ­ montelukast es eficaz, segura y favorece la adherencia al tratamiento, y a largo plazo también ayuda a alcanzar el objetivo terapéutico.

The purpose of this work was to review the scientific literature that evaluates the efficacy and safety of monotherapies of fexofenadine and montelukast, the combined therapy (fixed-dose or separate drug combinations) of montelukast-fexofenadine, as well as the use of montelukast together with other second-generation antihistamines in the treatment of allergic rhinitis. A multistage literature search strategy was designed, including clinical trials and non-randomized studies (non-randomized controlled trial, controlled before-after study, interrupted time series study, historical control study, cohort study, case-control study, crosssectional study, and case series) evaluating patients with allergic rhinitis. The databases MEDLINE/PubMed, Scopus, Web of Science, Cochrane Library, Redalyc, BVS Collection, and, due to the number of results obtained, Hinari were included. Based on this review, the conclusion is that the combinations of secondgeneration antihistamines with leukotriene antagonists and, in particular, the fixed combination of fexofenadine-montelukast are effective, safe and promote treatment adherence. In the long term, they also help achieve therapeutic goals.

Tratamento da UCE refratária aos anti-histamínicos e na impossibilidade do omalizumabe, nos adultos / Treatment of CSU refractory to antihistamines and in the impossibility of omalizumab therapy in adults

Há o empenho contínuo de especialistas no desenvolvimento de tratamentos resolutivos ou eficazes nos controles das doenças, no entanto, a entidade urticária crônica espontânea (UCE), quando refratária à primeira linha de tratamento, os anti-histamínicos, apresenta um prognóstico desfavorável. Existe um arsenal de medicamentos biológicos disponíveis já consolidados como eficazes e seguros, porém eventualmente nos defrontamos com a inacessibilidade a estes medicamentos, devido aos custos dos mesmos e aos trâmites necessários para dar início ao tratamento. Tais fatos fundamentam a discussão sobre terapias alternativas com outros fármacos, visando manter o manejo adequado da doença e a qualidade de vida dos pacientes.

Specialists have made a continuous effort for the development of effective treatments for disease control; however, chronic spontaneous urticaria (CSU), when refractory to the first line of treatment, ie, antihistamines, has an unfavorable prognosis. There are biological medicines available, which have been consolidated as effective and safe, but we are occasionally faced with a lack of access to these medicines due to their costs and the necessary procedures to start treatment. Such facts support the discussion about alternative therapies with other drugs, aiming at maintaining the adequate management of the disease and the quality of life of patients.

Reacciones adversas a montelukast: de la teoría a la práctica. Serie de casos / Adverse drug reactions of montelukast: from theory to practice. Case report

El montelukast se utiliza ampliamente en el tratamiento de sibilancias recurrentes y/o asma. Están descritas numerosas reacciones adversas medicamentosas (RAM) en niños relacionadas con montelukast; se destacan las neuropsiquiátricas. Realizamos un estudio observacional, retrospectivo, descriptivo, sobre RAM relacionadas con montelukast. Entre enero de 2012 y diciembre de 2017, en la Unidad de Neumonología Pediátrica se trataron con Montelukast 348 pacientes; de ellos, 20 presentaron RAM. Los síntomas más frecuentes fueron insomnio (n = 7), hiperactividad (n = 4), pesadillas (n = 3), dolor abdominal (n = 2) y parestesias en extremidades (n = 2). Se presentaron desde días hasta meses tras iniciar el tratamiento, y desaparecieron tras su suspensión. Se destacan dos pacientes con parestesias en extremidades, síntoma no descrito antes en niños. El 5,7 % de los pacientes tratados con montelukast presentaron RAM que requirieron suspender el tratamiento. Los trastornos del sueño fueron los más frecuentes.

Montelukast is widely used in recurrent wheezing and/or asthma treatment. Several adverse drug reactions (ADRs) have been described in children related to montelukast. Neuropsychiatric reactions are one of the most important. We designed an observational, retrospective, descriptive study on ADRs related to montelukast in the Pediatric Pulmonology Unit, Hospital Universitario Miguel Servet, Zaragoza, Spain. Between January 2012 and December 2017, in the Pediatric Pulmonology Unit, 348 patients were treated with Montelukast; of them, 20 presented RAM. The main symptoms described were insomnia (n = 7), hyperactivity (n = 4), nightmares (n = 3), abdominal pain (n = 2) and paraesthesia in extremities (n = 2). They appeared from the first days to months after the start of treatment and disappeared after stopping it. Two patients presented limb paresthesia, not described previously in children. The 5.7 % of our patients treated with montelukast had ADRs that required treatment discontinuation. Sleep disorders were the most frequent.

Leukotriene receptor antagonist reduces inflammation and alveolar bone loss in a rat model of experimental periodontitis.

BACKGROUND: Leukotrienes (LTs) participate in the process of tissue damage in periodontal disease by leukocyte chemotaxis and osteoclastic activation. The activation of Cysteinyl-LT receptor is associated with increased expression of proinflammatory molecules and osteoclastogenesis. However, its implications on periodontal disease progression have not been studied. The present study evaluated the effect of the cysteinyl-LT receptor antagonist (montelukast [MT]) on ligature-induced experimental periodontitis (EP) in rats. METHODS: Adult male Wistar rats were subjected to bilateral ligature-induced periodontitis and orally treated with MT (at doses of 10 or 30 mg/kg/d, MT10, and MT30, respectively). Sham animals had the ligatures immediately removed and received placebo treatment. Sets of animals were euthanized 7, 14, or 21 days after ligature placement and the mandibles were removed for macroscopic evaluation of alveolar bone loss (ABL). In addition, histological analysis of periodontal tissues, myeloperoxidase (MPO) activity of gingival tissues, and periodontal tissue expression of collagen type I, RUNX2, RANK, RANKL, OPG, BLT1, Cys-LTR1, LTA4H, and LTC4S were also analyzed. RESULTS: MT significantly reduced ABL at 14 (MT10 and MT30) and 21 days (MT10) (P < 0.05), gingival MPO at 7 (MT10) and 14 days (MT30) (P < 0.05), LTA4H, BLT1 and LTC4S gene expression on day 14 day (MT30, P < 0.05) and increased RUNX2 expression on day 14 (MT30, P < 0.05). CONCLUSION: Systemic therapy with MT decreases periodontal inflammation and ABL in ligature-induced periodontitis in rats.

Effect of LTRA in L-ASA Challenge for Aspirin-Exacerbated Respiratory Disease Diagnosis.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) consists of asthma, chronic rhinosinusitis with polyps, and hypersensitivity to aspirin and/or nonsteroidal anti-inflammatory drugs (NSAIDs). Nasal Lysine Aspirin Challenge is an effective tool for the diagnosis of hypersensitivity to aspirin and/or NSAIDs in patients with AERD. However, there is no unified international consensus version to perform nasal provocation tests (NPTs). OBJECTIVE: To investigate the effect of a leukotriene receptor antagonist (LTRA), montelukast, on the lysine-acetylsalicylate (L-ASA) nasal challenge. METHODS: We included 86 patients divided into 3 samples: group A (AERD without LTRA), group B (AERD with LTRA), and the control group (NSAID-tolerant asthmatics). NPT with L-ASA was performed with 25 mg of L-ASA every 30 minutes 4 times followed by rhinomanometry and spirometric measurements and evaluation of symptoms using a novel clinical scale. RESULTS: In group A, 94.5% of patients (35 of 37) developed a positive response to NPT (drop >40% in total nasal flow), whereas only 46% of group B subjects (13 of 28) showed a positive response to the nasal challenge (P < .001). Control subjects did not show any response to the L-ASA challenge. A novel clinical score demonstrated accuracy in classifying the hypersensitivity to aspirin and/or NSAIDs when patients avoid LTRA (33 of 37). CONCLUSION: Patients with AERD without LTRA showed a greater positive response to the L-ASA challenge than those taking this drug; therefore, LTRA treatment should be discontinued before the challenge for optimal diagnostic accuracy.

Efeito tempo-dose-resposta do montelucaste no processo de reparo alveolar em camundongos 129Sv/Ev / Time-dose-response effect of Montelukast in the process of alveolar repair in 129Sv / Ev mice

Metabólitos do ácido araquidônico são conhecidos por exercerem importante papel nos processos inflamatórios e no metabolismo do tecido ósseo. No entanto, as ações pontuais, especialmente dos leucotrienos derivados da 5-lipoxigenase (5-LO) sobre o processo de reparo ósseo intramembranoso são pouco exploradas. O presente estudo tem como objetivo analisar os efeitos tempo-dose-resposta da droga montelucaste (MTK), potente antagonista dos receptores de cisteinil leucotrienos tipo 1 (CisLT1Rs), no curso do reparo alveolar pós-exodontia em camundongos 129Sv/Ev, bem como nos níveis plasmáticos de marcadores ósseos bioquímicos. Para tanto, foram utilizados 70 camundongos machos jovens divididos em quatro grupos, de acordo com o tratamento: C - Grupo Controle (não tratados); CV - Grupo Controle Veículo, 20 µL de solução fisiológica (SF) 0,9%; MTK2 ­2 mg/kg de MTK e MTK4 ­ 4 mg/kg de MTK. Os animais dos grupos CV, MTK2 e MTK4 foram tratados diariamente por via oral, iniciando 24 horas antes do procedimento cirúrgico, continuando até o final dos períodos experimentais de 7, 14 e 21 dias pós-operatórios. Ao final dos períodos determinados, os animais foram submetidos à eutanásia para coleta de sangue para análise bioquímica dos níveis de cálcio, fosfato, fosfatase ácida resistente ao tartarato (TRAP) total e fosfatase alcalina (FAL), coleta da maxila direita contendo os alvéolos dentários para serem analisados por meio de microtomografia computadorizada (microCT), e análise histopatológica. Os resultados obtidos foram submetidos à testes estatísticos considerando-se nível de confiança de 5%. Observou-se aumento do BV/TV para os animais tratados com MTK em relação aos grupos C e CV, tanto aos 14 dias quanto aos 21 dias, sendo maior no grupo MTK4 aos 14 dias em relação ao grupo MTK2. Do mesmo modo, os animais tratados com MTK em ambas doses apresentaram aumento significativo de Tb.Th em comparação aos grupos C e CV aos 21 dias. Chamou a atenção valores de BV/TV e Tb.Th significativamente reduzidos no grupo CV em comparação ao C, indicando um efeito negativo da manipulação do animal. Na análise histopatológica observou-se reparo ósseo precoce nos animais MTK2 e MTK4 em todos os períodos avaliados, em comparação aos do grupo C, bem como atraso no processo de reparo no grupo CV aos 21 dias. Quanto aos marcadores plasmáticos, observou-se aumento do cálcio no grupo MTK4 em relação ao grupo C aos 7 dias, e aos 21 dias também em relação ao grupo MTK2. Já o fosfato mostrouse significantemente elevado nos períodos de 7 e 21 dias no grupo MTK2 em relação aos demais grupos. FAL e TRAP total não apresentaram níveis plasmáticos significativamente diferentes comparando-se os grupos e períodos. Considerando os resultados obtidos, concluiu-se que o MTK exerceu efeito tempo-dose-dependente, acelerando o processo de reparo ósseo intramembranoso alveolar e interferindo nos níveis plasmáticos de cálcio e fosfato no presente modelo animal(AU)

Arachidonic acid metabolites are known to play an important role in inflammatory processes and in bone metabolism. However, the role of these products on alveolar bone repair post tooth extraction remains to be explored, especially leukotrienes, derived from 5-lipoxygenase (5-LO). The present study aims to analyze the time-doseresponse effects of the drug montelukast (MTK), a potent type 1 leukotriene cystenyl antagonist (CisLT1Rs), in the alveolar repair process after extraction in male 129Sv/Ev mice. For this purpose, 70 young male mice were used, divided into four groups: C - Control Group (no treatment); VC - Vehicle Control Group, treated with 20 µL of 0.9% SF; MTK2 - treated with 2mg / Kg of MTK and MTK4 - treated with 4mg / Kg of MTK. The animals of the CV, MTK2 and MTK4 groups were treated daily orally (V.O.), starting 24 hours before the surgical procedure, continuing until the end of the experimental periods of 7, 14 and 21 days postoperatively. At the end of the experimental periods, the animals were euthanized for blood collection for serum markers as calcium, phosphate, tartrate-resistant acid phosphate (TRAP) and alkaline phosphatasis (FAL), and to removal of the right maxilla containing the dental socket to be analyzed under computed microtomography (microCT) and histopathology. The results obtained were subjected to statistical tests considering a confidence level of 5%. Results revealed an increase in BV/TV for MTK vs. C and CV groups, in both 14 and 21 days time points. Of note, this increase was higher in MTK4 than in the MTK2 at 14 days. Considering Tb.Th, both MTK2 e MTK4 groups presented positive effects in the BV/TV and Tb.Th increase when compared to controls groups (C and CV) at 21 days. A decrease in BV/TV and Tb.Th was observed in CV compared to C, as a negative effect of animal manipulation. As observed in H&E sections, both MTK2 and MTK4 experimental groups presented an early bone repair in comparison with C group from 7 to 21 days. CV group presented a slight delayed bone healing compared to C. Levels of calcium was increased in MTK4 in comparison to C and MTK2 at 7 and 21 days. Phosphate was significantly elevated at 7 and 21 days in MTK2 in comparison to the other groups. Despite of beneficial effects on observed on morphological levels on sites of healing (microCT and HE), no significant changes were found for bone markers of remodeling in blood plasma (FAL and TRAP). Taken together, these results indicate that MTK induced early bone healing post tooth extraction in 129Sv/Ev mice. Thus, the inhibition of CysLT is suggested to exert a positive influence on intramembranous bone repair post tooth extraction(AU)

Clinical safety of zafirlukast treatment during acute inflammatory reaction in nile tilapia (Oreochromis niloticus) / Segurança clínica do tratamento com zafirlucaste durante a reação inflamatória aguda em tilápia do nilo (Oreochromis niloticus)

Little is known about the toxicity of immune modulators in fish. Zafirlukast is an anti-inflammatory that antagonizes cysteine leukotriene receptors (CysLTR1). Aiming to study immunomodulatory treatments on fish health, this study evaluated the clinical safety of oral zafirlukast treatment, through biochemical and hematological analyzes during acute inflammatory reaction in Nile tilapia (Oreochromis niloticus), induced by Aeromonas hydrophila bacterins. 72 young tilapias were randomly divided in 9 aquariums (100 L each, n=8) to compose the following treatments: T0 (control), T1 (Treatment with 250 µg zafirlukast) and T2 (Treatment with 500 µg zafirlukast). Eight animals were evaluated per treatment in three periods: six, 24 and 48 hours post-inoculation (HPI), blood collection was performed for hematological and serum biochemical evaluation. The study of hepatic and renal functionality revealed that treatment with both doses of zafirlukast did not result in changes in the circulating values of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, creatinine, triglycerides, cholesterol, and total protein, suggesting that the drug has not presented hepatotoxicity, as well as compromised liver and kidney functions. Tilapia submitted to treatment with 500 µg showed adverse hematological effects characterized by polycythemia associated with microcytosis. Therefore, oral treatment with zafirlukast has demonstrated clinical safety at a therapeutic dose of 250 µg in tilapia during acute aerocystitis, although hematological changes were observed in tilapia treated with overdose of this leukotriene blocker

Pouco se sabe sobre a toxicidade de imunomoduladores em peixes. Zafirlukast é um anti-inflamatório que antagoniza os receptores de leucotrienos cisteínicos (CysLTR1). Com o objetivo de estudar o efeito de tratamentos imunomoduladores sobre a saúde dos peixes, este estudo avaliou a segurança clínica do tratamento com zafirlucaste oral, por meio de análises bioquímicas e hematológicas durante reação inflamatória aguda em tilápia do Nilo (Oreochromis niloticus), induzida por bacterinas de Aeromonas hydrophila. Para tal, 72 tilápias jovens foram divididas aleatoriamente em 9 aquários (100 L cada, n=8) para compor os seguintes tratamentos: T0 (controle), T1 (Tratamento com 250 µg de zafirlucaste) e T2 (Tratamento com 500 µg de zafirlucaste). Oito animais foram avaliados por tratamento em três períodos: seis, 24 e 48 horas pós-inoculação (HPI), foi realizada coleta de sangue para avaliação hematológica e bioquímica sérica. O estudo da funcionalidade hepática e renal revelou que o tratamento com ambas as doses de zafirlucaste não resultou em alterações nos valores circulantes de aspartato aminotransferase (AST), alanina aminotransferase (ALT), fosfatase alcalina, creatinina, triglicerídeos, colesterol e proteína total, sugerindo que a droga não comprometeu as funções hepáticas e renais. As tilápias tratadas com 500 µg apresentaram efeitos hematológicos adversos caracterizados por policitemia associada a microcitose. Portanto, o tratamento oral com zafirlucaste demonstrou segurança clínica na dose de 250 µg em tilápias durante aerocistite aguda, embora alterações hematológicas tenham sido observadas em tilápias tratadas com sobredosagem deste bloqueador de leucotrieno.

Clinical safety of zafirlukast treatment during acute inflammatory reaction in nile tilapia (Oreochromis niloticus) / Segurança clínica do tratamento com zafirlucaste durante a reação inflamatória aguda em tilápia do nilo (Oreochromis niloticus)

Little is known about the toxicity of immune modulators in fish. Zafirlukast is an anti-inflammatory that antagonizes cysteine leukotriene receptors (CysLTR1). Aiming to study immunomodulatory treatments on fish health, this study evaluated the clinical safety of oral zafirlukast treatment, through biochemical and hematological analyzes during acute inflammatory reaction in Nile tilapia (Oreochromis niloticus), induced by Aeromonas hydrophila bacterins. 72 young tilapias were randomly divided in 9 aquariums (100 L each, n=8) to compose the following treatments: T0 (control), T1 (Treatment with 250 µg zafirlukast) and T2 (Treatment with 500 µg zafirlukast). Eight animals were evaluated per treatment in three periods: six, 24 and 48 hours post-inoculation (HPI), blood collection was performed for hematological and serum biochemical evaluation. The study of hepatic and renal functionality revealed that treatment with both doses of zafirlukast did not result in changes in the circulating values of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, creatinine, triglycerides, cholesterol, and total protein, suggesting that the drug has not presented hepatotoxicity, as well as compromised liver and kidney functions. Tilapia submitted to treatment with 500 µg showed adverse hematological effects characterized by polycythemia associated with microcytosis. Therefore, oral treatment with zafirlukast has demonstrated clinical safety at a therapeutic dose of 250 µg in tilapia during acute aerocystitis, although hematological changes were observed in tilapia treated with overdose of this leukotriene blocker(AU)

Pouco se sabe sobre a toxicidade de imunomoduladores em peixes. Zafirlukast é um anti-inflamatório que antagoniza os receptores de leucotrienos cisteínicos (CysLTR1). Com o objetivo de estudar o efeito de tratamentos imunomoduladores sobre a saúde dos peixes, este estudo avaliou a segurança clínica do tratamento com zafirlucaste oral, por meio de análises bioquímicas e hematológicas durante reação inflamatória aguda em tilápia do Nilo (Oreochromis niloticus), induzida por bacterinas de Aeromonas hydrophila. Para tal, 72 tilápias jovens foram divididas aleatoriamente em 9 aquários (100 L cada, n=8) para compor os seguintes tratamentos: T0 (controle), T1 (Tratamento com 250 µg de zafirlucaste) e T2 (Tratamento com 500 µg de zafirlucaste). Oito animais foram avaliados por tratamento em três períodos: seis, 24 e 48 horas pós-inoculação (HPI), foi realizada coleta de sangue para avaliação hematológica e bioquímica sérica. O estudo da funcionalidade hepática e renal revelou que o tratamento com ambas as doses de zafirlucaste não resultou em alterações nos valores circulantes de aspartato aminotransferase (AST), alanina aminotransferase (ALT), fosfatase alcalina, creatinina, triglicerídeos, colesterol e proteína total, sugerindo que a droga não comprometeu as funções hepáticas e renais. As tilápias tratadas com 500 µg apresentaram efeitos hematológicos adversos caracterizados por policitemia associada a microcitose. Portanto, o tratamento oral com zafirlucaste demonstrou segurança clínica na dose de 250 µg em tilápias durante aerocistite aguda, embora alterações hematológicas tenham sido observadas em tilápias tratadas com sobredosagem deste bloqueador de leucotrieno.(AU)

Targeting Leukotrienes as a Therapeutic Strategy to Prevent Comorbidities Associated with Metabolic Stress.

Leukotrienes (LTs) are potent lipid mediators that exert a variety of functions, ranging from maintaining the tone of the homeostatic immune response to exerting potent proinflammatory effects. Therefore, LTs are essential elements in the development and maintenance of different chronic diseases, such as asthma, arthritis, and atherosclerosis. Due to the pleiotropic effects of LTs in the pathogenesis of inflammatory diseases, studies are needed to discover potent and specific LT synthesis inhibitors and LT receptor antagonists. Even though most clinical trials using LT inhibitors or antagonists have failed due to low efficacy and/or toxicity, new drug development strategies are driving the discovery for LT inhibitors to prevent inflammatory diseases. A newly important detrimental role for LTs in comorbidities associated with metabolic stress has emerged in the last few years and managing LT production and/or actions could represent an exciting new strategy to prevent or treat inflammatory diseases associated with metabolic disorders. This review is intended to shed light on the synthesis and actions of leukotrienes, the most common drugs used in clinical trials, and discuss the therapeutic potential of preventing LT function in obesity, diabetes, and hyperlipidemia.

Fatores associados ao sexo para sibilância recorrente e asma / Sex-related factors for recurrent wheezing and asthma

Nas últimas décadas, consolidou-se o conhecimento da heterogeneidade de fatores associados à asma. Sexo, condições ambientais, genética, raça, obesidade, questões hormonais e imunológicas influenciam sintomas e resposta ao tratamento da asma. Associação entre asma e obesidade é observada em adultos e crianças e parece ser muito mais consistente no sexo feminino. As mulheres adultas também apresentam maior prevalência de asma em comparação aos homens, e têm três vezes mais chances de hospitalização, o que é mantido até a menopausa. Mulheres são mais afetadas quando expostas ao tabagismo passivo e ativo, e, nos meninos, a exposição intrauterina ao tabaco tem maior influência negativa no crescimento de vias aéreas. Homens e mulheres apresentam diferenças em relação ao envolvimento de pequenas vias aéreas. Os homens apresentaram mais aprisionamento aéreo induzido pela metacolina, enquanto as mulheres têm frações mais elevadas de óxido nítrico exalado. Mulheres apresentam maior diversidade de polimorfismos genéticos associados à asma. Quanto à resposta ao tratamento, homens respondem melhor funcionalmente, com aumento do VEF1, quando utilizam corticoides inalatórios. Meninos entre 2-9 anos respondem melhor aos antagonistas de leucotrienos, resposta que se inverte e passa a ser mais significativa em meninas entre 10-14 anos. O enfoque do manejo atual da sibilância recorrente e da asma deve levar em consideração aspectos individuais específicos, que variam entre homens e mulheres, e que impactam no tratamento e prognóstico da doença.

In recent decades, knowledge of the heterogeneity of asthma-related factors has been consolidated. Sex, environmental conditions, genetics, race, obesity, and hormonal and immunological factors influence symptoms and response to the treatment of asthma. The association between asthma and obesity is seen in adults and children and appears to be much more consistent in women. Adult women also have a higher prevalence of asthma compared to men and are three times more likely to be hospitalized, which persists until menopause. Women are more affected when exposed to passive and active smoking and, in boys, intrauterine tobacco exposure has a greater negative influence on airway growth. Men and women differ in terms of involvement of small airways. Men present with greater methacholine-induced air trapping, while women have higher fractions of exhaled nitric oxide. Women show a greater diversity of genetic polymorphisms associated with asthma. As for treatment response, men respond better functionally, with increased forced expiratory volume in 1 second (FEV1) when using inhaled corticosteroids. Boys aged 2-9 years respond better to leukotriene antagonists, a response that is then reversed and becomes more significant in girls aged 10-14 years. The current approach to recurrent wheezing and asthma must take specific aspects into account, which vary between men and women and impact the treatment and prognosis of the disease.

Informe diário de evidências COVID-19: busca realizada em 19 de maio de 2020 / COVID-19 daily evidence report: search conducted on May 19, 2020

O Informe Diário de Evidências é uma produção do Ministério da Saúde que tem como objetivo acompanhar diariamente as publicações científicas sobre tratamento farmacológico e vacinas para a COVID-19. Dessa forma, são realizadas buscas estruturadas em bases de dados biomédicas, referente ao dia anterior desse informe. Não são incluídos estudos pré-clínicos (in vitro, in vivo, in silico). A frequência dos estudos é demonstrada de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, coortes, entre outros). Para cada estudo é apresentado um resumo com avaliação da qualidade metodológica. Essa avaliação tem por finalidade identificar o grau de certeza/confiança ou o risco de viés de cada estudo. Para tal, são utilizadas ferramentas já validadas e consagradas na literatura científica, na área de saúde baseada em evidências. Cabe ressaltar que o documento tem caráter informativo e não representa uma recomendação oficial do Ministério da Saúde sobre a temática. Foram encontrados 19 artigos e 17 protocolos.

Exercise-Induced bronchoconstriction and therapeutic modulation in Iraqi Girls Intermediate School Students

EIB (Exercise-Induced Bronchoconstriction) describes the narrowing that accurs in the airway follow a short period of exercise. EIB is found in 8-10% of normal children population as occult bronchospasm during or after physical activities. The mecanisms of EIB are related to rapid ventilation and mouth brathing which cause beat and water loss during breathing leading to bronchoconstriction. Peak Expiratory Flow Rate (PEFR) measured pre and post-exercise in students aged 12-16 years in girl intrmediate school. Any female shows PEFR values reduction 15% after 6 minutes continuous free running considered as asthmatic patient, this give an incidence rate of asthmatic patient of 9% in female students in this age. Treatment of EIB, Zafirlukast treatment gives (85.7%) protection rate. While salbutamol inhalation gives a protection rate 88%. Only 66.6% of girls with EIB give an improvement in PEFR values after sodium cromoglycate treatment. A regular measurement of PEFR in school students appears to be a good indicator of EIB, while inhalation of salbutaol 15 minutes before exercise give a good protection against EIB attacks at least for 4 hours (AU)

Montelukast, Leukotriene Inhibitor, Reduces LPS-Induced Acute Lung Inflammation and Human Neutrophil Activation.

OBJECTIVES: Some pro-inflammatory lipids derived from 1 lipooxygenase enzyme are potent neutrophil chemoattractant, a cell centrally involved in acute respiratory distress syndrome (ARDS); a syndrome lacking effective treatment. Considering the beneficial effects of the leukotriene receptor inhibitor, montelukast, on other lung diseases, whether montelukast attenuates inflammation in a mouse model of ARDS, and whether it reduces LPS stimulated activation of human neutrophils was investigated. METHODS: Thirty-five C57Bl/6 mice were distributed into control (PBS)+24h, LPS+24h (10µg/mouse), control+48h, LPS+48h, and LPS 48h+Montelukast (10mg/kg). In addition, human neutrophils were incubated with LPS (1µg/mL) and treated with montelukast (10µM). RESULTS: Oral-tracheal administration of montelukast significantly attenuated total cells (P<.05), macrophages (P<.05), neutrophils (P<.01), lymphocytes (P<.001) and total protein levels in BAL (P<.05), as well as IL-6 (P<.05), CXCL1/KC (P<.05), IL-17 (P<.05) and TNF-α (P<.05). Furthermore, montelukast reduced neutrophils (P<.001), lymphocytes (P<.01) and macrophages (P<.01) in the lung parenchyma. In addition, montelukast restored BAL VEGF levels (P<.05). LTB4 receptor expression (P<.001) as well as NF-κB (P<.001), a downstream target of LPS, were also reduced in lung parenchymal leukocytes. Furthermore, montelukast reduced IL-8 (P<.001) production by LPS-treated human neutrophils. CONCLUSION: In conclusion, montelukast efficiently attenuated both LPS-induced lung inflammation in a mouse model of ARDS and in LPS challenged human neutrophils.

Daily inhaled corticosteroids or montelukast for preschoolers with asthma or recurrent wheezing: A systematic review.

BACKGROUND: Most international asthma guidelines recommend that children ≤5 years with asthma or recurrent wheezing be treated with daily low- moderate dose inhaled corticosteroids (ICS) as the preferred controller and leukotriene receptor antagonists (LTRA) as alternative therapy. There is no systematic review comparing the efficacy of ICS versus LTRA monotherapy in this age group. OBJECTIVE: To compare the efficacy of daily ICS versus LTRA in preschoolers with asthma or recurrent wheezing. METHODS: Randomized, prospective, controlled trials published by December 2017, with a minimum of 3-month therapy with daily ICS versus LTRA were identified. The co-primary outcomes were the number of wheezing episodes and daily symptom score. Secondary outcomes included unscheduled emergency visits, need of rescue systemic corticosteroids (SC), hospitalization for exacerbations, lung function, and adverse effects. RESULTS: Of 29 trials identified, six studies (n = 3204 patients, 62% males, age range: 6-54 months) met the inclusion criteria; two were at low risk of bias. Five pertained to children with asthma; one to those with recurrent wheezing. No outcomes were similarly reported in the six studies, preventing meta-analysis. Based on trials at lowest risk of bias and the largest open-labelled studies, ICS was associated with better control of symptoms and less exacerbations than LTRA. And also less need for rescue SC. Insufficient data of high quality prevented firm conclusions on other secondary outcomes. CONCLUSIONS: In preschoolers with asthma or recurrent wheezing, daily ICS appears more effective than daily LTRA for improving symptom control and decreasing exacerbations, particularly those requiring rescue SC, although the magnitude of benefit remains to be quantified.

Inhibition of 5-lipoxygenase alleviates graft-versus-host disease.

Leukotriene B4 (LTB4), a proinflammatory mediator produced by the enzyme 5-lipoxygenase (5-LO), is associated with the development of many inflammatory diseases. In this study, we evaluated the participation of the 5-LO/LTB4 axis in graft-versus-host disease (GVHD) pathogenesis by transplanting 5-LO-deficient leukocytes and investigated the effect of pharmacologic 5-LO inhibition by zileuton and LTB4 inhibition by CP-105,696. Mice that received allogeneic transplant showed an increase in nuclear 5-LO expression in splenocytes, indicating enzyme activation after GVHD. Mice receiving 5-LO-deficient cell transplant or zileuton treatment had prolonged survival, reduced GVHD clinical scores, reduced intestinal and liver injury, and decreased levels of serum and hepatic LTB4 These results were associated with inhibition of leukocyte recruitment and decreased production of cytokines and chemokines. Treatment with CP-105,696 achieved similar effects. The chimerism or the beneficial graft-versus-leukemia response remained unaffected. Our data provide evidence that the 5-LO/LTB4 axis orchestrates GVHD development and suggest it could be a target for the development of novel therapeutic strategies for GVHD treatment.

Position statement of the Brazilian Academy of Rhinology on the use of antihistamines, antileukotrienes, and oral corticosteroids in the treatment of inflammatory sinonasal diseases / Posicionamento da Academia Brasileira de Rinologia sobre o uso de anti-histamínicos, antileucotrienos e corticosteroides orais no tratamento de doenças inflamatórias nasossinusais

Abstract Introduction: Inflammatory conditions of the nose and paranasal sinuses are very prevalent in the general population, resulting in marked loss of quality of life in affected patients, as well as significant work, leisure, and social activity losses. These patients require specific and specialized treatment. A wide range of oral medications are available. Objective: The present document is aimed to clarify, for professionals treating patients with inflammatory sinonasal diseases, both specialists and general practitioners, specific oral therapies in noninfectious nasal inflammatory conditions. Methods: The methodology used to create this article included the search for the key words: oral corticosteroids, antihistamines, antileukotrienes, rhinitis, rhinosinusitis in the MEDLINE and EMBASE databases in the last 5 years. Since no relevant article was found for the text on the subject of interest in the last 5 years, the search was extended for another 5 years, and so on, according to the authors’ needs. Results: Relevant literature was found regarding the use of antihistamines, antileukotrienes and oral corticosteroids in these conditions. The Brazilian Academy of Rhinology emphasizes, after extensive discussion by the collegiate, key points in the treatment with these drugs. Conclusion: There is support in the literature for the use of these drugs; however, final considerations about the role of each of them have been made.

Resumo Introdução: As afecções inflamatórias do nariz e dos seios paranasais são muito prevalentes na população geral, causam acentuada perda de qualidade de vida dos pacientes afetados, geram perdas significativas das atividades de trabalho, lazer e sociais. Esses pacientes necessitam de tratamento específico e especializado e uma ampla gama de medicações orais está disponível. Objetivo: O presente documento tem por objetivo esclarecer àqueles que tratam das doenças nasossinusais inflamatórias, tanto especialistas quanto generalistas, sobre as terapêuticas orais nas afecções inflamatórias nasais não infecciosas. Método: A metodologia usada para elaboração deste artigo incluiu a busca das palavras chave: corticosteroides orais, anti-histamínicos, antileucotrienos, rinite, rinossinusite nos bancos de dados Medline e Embase nos últimos 5 anos. Como não foi achado artigo relevante para o texto sobre o assunto de interesse nos últimos 5 anos, a busca foi estendida por mais 5 anos, e assim por diante, de acordo com a necessidade dos autores. Resultados: Literatura relevante foi encontrada com relação ao uso dos anti-histamínicos, antileucotrienos e corticosteroides orais nessas afecções. A Academia Brasileira de Rinologia ressalta, após amplo debate do colegiado, pontos-chave no tratamento com esses medicamentos. Conclusão: Há respaldo na literatura para o uso desses medicamentos, entretanto considerações finais acerca do papel de cada deles foram feitas.

Position statement of the Brazilian Academy of Rhinology on the use of antihistamines, antileukotrienes, and oral corticosteroids in the treatment of inflammatory sinonasal diseases.

INTRODUCTION: Inflammatory conditions of the nose and paranasal sinuses are very prevalent in the general population, resulting in marked loss of quality of life in affected patients, as well as significant work, leisure, and social activity losses. These patients require specific and specialized treatment. A wide range of oral medications are available. OBJECTIVE: The present document is aimed to clarify, for professionals treating patients with inflammatory sinonasal diseases, both specialists and general practitioners, specific oral therapies in noninfectious nasal inflammatory conditions. METHODS: The methodology used to create this article included the search for the key words: oral corticosteroids, antihistamines, antileukotrienes, rhinitis, rhinosinusitis in the MEDLINE and EMBASE databases in the last 5 years. Since no relevant article was found for the text on the subject of interest in the last 5 years, the search was extended for another 5 years, and so on, according to the authors' needs. RESULTS: Relevant literature was found regarding the use of antihistamines, antileukotrienes and oral corticosteroids in these conditions. The Brazilian Academy of Rhinology emphasizes, after extensive discussion by the collegiate, key points in the treatment with these drugs. CONCLUSION: There is support in the literature for the use of these drugs; however, final considerations about the role of each of them have been made.