Montelukast reduces seizures in pentylenetetrazol-kindled mice

Cysteinyl leukotrienes (CysLTs) have been implicated in seizures and kindling; however, the effect of CysLT receptor antagonists on seizure frequency in kindled animals and changes in CysLT receptor expression after pentylenetetrazol (PTZ)-induced kindling have not been investigated. In this study, we evaluated whether the CysLT1 inverse agonist montelukast, and a classical anticonvulsant, phenobarbital, were able to reduce seizures in PTZ-kindled mice and alter CysLT receptor expression. Montelukast (10 mg/kg, sc) and phenobarbital (20 mg/kg, sc) increased the latency to generalized seizures in kindled mice. Montelukast increased CysLT1 immunoreactivity only in non-kindled, PTZ-challenged mice. Interestingly, PTZ challenge decreased CysLT2 immunoreactivity only in kindled mice. CysLT1 antagonists appear to emerge as a promising adjunctive treatment for refractory seizures. Nevertheless, additional studies are necessary to evaluate the clinical implications of this research.

Effects of Interleukin-13 and Montelukast on the Expression of Zonula Occludens-1 in Human Podocytes

PURPOSE: The aim of this study was to investigate whether pathologic changes in zonula occludens-1 (ZO-1) are induced by interleukin-13 (IL-13) in the experimental minimal-change nephrotic syndrome (MCNS) model and to determine whether montelukast, a leukotriene receptor antagonist, has an effect on ZO-1 restoration in cultured human podocytes. MATERIALS AND METHODS: Human podocytes cultured on bovine serum albumin-coated plates were treated with different doses of IL-13 and montelukast and then examined for distribution using confocal microscopy and for ZO-1 protein levels using Western blotting. RESULTS: ZO-1 was internalized and shown to accumulate in the cytoplasm of human podocytes in an IL-13 dose-dependent manner. High doses (50 and 100 ng/mL) of IL-13 decreased the levels of ZO-1 protein at 12 and 24 h (both p<0.01; n=3), which were significantly reversed by a high dose (0.5 microM) montelukast treatment (p<0.01; n=3). CONCLUSION: Our results suggest that IL-13 alters the expression of ZO-1, and such alterations in the content and distribution of ZO-1 may be relevant in the pathogenesis of proteinuria in the MCNS model.

Effects of Interleukin-13 and Montelukast on the Expression of Zonula Occludens-1 in Human Podocytes

PURPOSE: The aim of this study was to investigate whether pathologic changes in zonula occludens-1 (ZO-1) are induced by interleukin-13 (IL-13) in the experimental minimal-change nephrotic syndrome (MCNS) model and to determine whether montelukast, a leukotriene receptor antagonist, has an effect on ZO-1 restoration in cultured human podocytes. MATERIALS AND METHODS: Human podocytes cultured on bovine serum albumin-coated plates were treated with different doses of IL-13 and montelukast and then examined for distribution using confocal microscopy and for ZO-1 protein levels using Western blotting. RESULTS: ZO-1 was internalized and shown to accumulate in the cytoplasm of human podocytes in an IL-13 dose-dependent manner. High doses (50 and 100 ng/mL) of IL-13 decreased the levels of ZO-1 protein at 12 and 24 h (both p<0.01; n=3), which were significantly reversed by a high dose (0.5 microM) montelukast treatment (p<0.01; n=3). CONCLUSION: Our results suggest that IL-13 alters the expression of ZO-1, and such alterations in the content and distribution of ZO-1 may be relevant in the pathogenesis of proteinuria in the MCNS model.

Effect of zafirlukast on capsular contracture around silicone implants in rats / Efeito do zafirlukast na contratura capsular ao redor de implantes de silicone em ratos

PURPOSE: To evaluate the effect of zafirlukast on capsular contracture around silicone implants by measuring the pressure within the implant, using a rat experimental model. METHODS: Forty adult female Wistar rats were used. Each one received two silicone implants, one with smooth-surface and the other with textured-surface. They were randomly divided into four groups (n=10). The rats of control group I were sacrificed after the implants. The remaining animals were subjected to a daily regimen of intra-peritoneal injection for a period of 90 days and they were distributed as follows: control group II received 0.9 percent physiological saline solution; experimental group I received zafirlukast 1.25 mg/kg; and experimental group II received zafirlukast 5 mg/kg. The measurement of intra-implant pressure of control group I was determined on the surgery day and in other groups on the ninetieth day, after being sacrificed. RESULTS: In the evaluation of textured implants there was an increase of internal pressure in the control group II, and there was no increase in the experimental groups. Compared to the controls there were not significant differences in smooth implants. CONCLUSION: Zafirlukast reduced the risk of developing capsular contracture around silicone implants with textured surface.

OBJETIVO: Avaliar o efeito do zafirlukast na contratura capsular ao redor de implantes de silicone, através da aferição da pressão intra-implante, utilizando-se um modelo experimental de ratos. MÉTODOS: Quarenta ratos fêmeas Wistar foram utilizados. Cada um recebeu dois implantes de silicone, sendo um com superfície lisa e outro texturizada. Foram divididos aleatoriamente em quatro grupos (n=10). Os ratos do grupo controle I foram sacrificados após o implante. O restante dos animais foi submetido a um regime diário de injeção intraperitoneal por um período de 90 dias e foram distribuídos: grupo controle II recebeu solução salina fisiológica 0,9 por cento, grupo experimental I recebeu zafirlukast 1,25 mg/kg, e grupo experimental II recebeu zafirlukast 5 mg/kg. O grupo controle II recebeu solução salina; grupo experimental I, 1,25 mg/kg/dia de zafirlukast; grupo experimental II, 5mg/kg/dia de zafirlukast. A aferição da pressão intra-implante do grupo controle I foi averiguada no dia do ato operatório, e nos outros grupos no nonagésimo dia, após serem sacrificados. RESULTADOS: Na avaliação dos implantes texturizados houve aumento da pressão interna no grupo controle II e, não se observou aumento nos grupos experimentais. Na comparação com os controles não foram observadas diferenças significativas nos implantes lisos. CONCLUSÃO: O Zafirlukast reduziu o risco de desenvolver contratura capsular em torno de implantes de silicone com superfície texturizada.

Up-regulation of BLT2 is critical for the survival of bladder cancer cells

The incidence rates of urinary bladder cancer continue to rise yearly, and thus new therapeutic approaches and early diagnostic markers for bladder cancer are urgently needed. Thus, identifying the key mediators and molecular mechanisms responsible for the survival of bladder cancer has valuable implications for the development of therapy. In this study, the role of BLT2, a receptor for leukotriene B4 (LTB4) and 12(S)-hydroxyeicosatetraenoic acid (HETE), in the survival of bladder cancer 253J-BV cells was investigated. We found that the expression of BLT2 is highly elevated in bladder cancer cells. Also, we observed that blockade of BLT2 with an antagonist or BLT2 siRNA resulted in cell cycle arrest and apoptotic cell death, suggesting a role of BLT2 in the survival of human bladder cancer 253J-BV cells. Further experiments aimed at elucidating the mechanism by which BLT2 mediates survival revealed that enhanced level of reactive oxygen species (ROS) are generated via a BLT2-dependent up-regulation of NADPH oxidase members NOX1 and NOX4. Additionally, we observed that inhibition of ROS generation by either NOX1/4 siRNAs or treatment with an ROS-scavenging agent results in apoptotic cell death in 253J-BV bladder cancer cells. These results demonstrated that a 'BLT2-NOX1/4-ROS' cascade plays a role in the survival of this aggressive bladder cancer cells, thus pointing to BLT2 as a potential target for anti-bladder cancer therapy.

Leukotrienes are not essential for the efficacy of a heterologous vaccine against Mycobacterium tuberculosis infection

Leukotrienes are reported to be potent proinflammatory mediators that play a role in the development of several inflammatory diseases such as asthma, rheumatoid arthritis and periodontal disease. Leukotrienes have also been associated with protection against infectious diseases. However, the role of leukotrienes in Mycobacterium tuberculosis infection is not understood. To answer this question, we studied the role of leukotrienes in the protective immune response conferred by prime-boost heterologous immunization against tuberculosis. We immunized BALB/c mice (4-11/group) with subcutaneous BCG vaccine (1 x 10(5) M. bovis BCG) (prime) followed by intramuscular DNA-HSP65 vaccine (100 µg) (boost). During the 30 days following the challenge, the animals were treated by gavage daily with MK-886 (5 mg·kg-1·day-1) to inhibit leukotriene synthesis. We showed that MK-886-treated mice were more susceptible to M. tuberculosis infection by counting the number of M. tuberculosis colony-forming units in lungs. The histopathological analysis showed an impaired influx of leukocytes to the lungs of MK-886-treated mice after infection, confirming the involvement of leukotrienes in the protective immune response against experimental tuberculosis. However, prime-boost-immunized mice treated with MK-886 remained protected after challenge with M. tuberculosis, suggesting that leukotrienes are not required for the protective effect elicited by immunization. Protection against M. tuberculosis challenge achieved by prime-boost immunization in the absence of leukotrienes was accompanied by an increase in IL-17 production in the lungs of these animals, as measured by ELISA. Therefore, these data suggest that the production of IL-17 in MK-886-treated, immunized mice could contribute to the generation of a protective immune response after infection with M. tuberculosis.

Antileukotrienes in the treatment of asthma and allergic rhinitis

OBJETIVO: Comparar os antagonistas de leucotrienos (ARLT) aos outros grupos de medicamentos utilizados para tratar a asma e a rinite alérgica. FONTES DOS DADOS: MEDLINE, LILACS e Biblioteca Cochrane. Palavras chaves: leucotrienos, antileucotrienos, tratamento da asma, tratamento da rinite alérgica, asma e rinite alérgica. Procurou-se agrupar os principais trabalhos e revisões sobre o assunto. SíNTESE DOS DADOS: Os ARLT são mais eficazes do que placebo e potencializam os efeitos dos corticosteróides inalados. A associação de corticosteróides inalados com agentes beta2 agonistas de longa duração (LABA) é mais eficaz do que a associação de cortiscoteróides inalados + ARLT. Embora pareça racional o uso de ARLT na crise aguda de asma e rinite alérgica, mais estudos são necessários para comprovar esse benefício. Os ARLT promovem redução no tempo de hospitalização e no número de crises de sibilância em lactentes com bronquiolite viral aguda pelo vírus respiratório sincicial e na sibilância recorrente após bronquiolite viral aguda. Os ARLT são menos eficazes que os corticosteróides intranasais no manejo da rinite alérgica. Os ARLT são eficazes na asma induzida por exercício (AIE), embora não constituam a primeira linha de tratamento. CONCLUSÃO: Estudos controlados e randomizados mostram que os corticosteróides inalados são as drogas de escolha para o tratamento da asma persistente e rinite alérgica. :Não existem evidências suficientes para recomendar o uso de ARLT como medicamento de primeira linha (monoterapia) em crianças com asma (nível I). Nas crianças que não podem usar corticosteróides inalados, os ARLT podem ser uma alternativa (nível II).

OBJECTIVE: To compare leukotriene antagonists (LTA) to other groups of drugs used in asthma and allergic rhinitis treatment. SOURCES: MEDLINE, LILACS and Cochrane Library. Keywords: leukotrienes, antileukotrienes, asthma treatment, allergic rhinitis treatment, asthma and allergic rhinitis. An attempt was made to group the main studies and reviews about this topic. SUMMARY OF THE FINDINGS: LTA are more efficient than placebo and enhance the effects of inhaled corticosteroids. The association of inhaled corticosteroids with long-acting beta2-agonists is more efficient than the association of inhaled corticosteroids + LTA. Although use of LTA in acute asthma attacks and allergic rhinitis seems reasonable, more studies are needed to confirm this benefit. LTA reduce hospitalization time and the number of wheezing attacks in infants with acute viral bronchiolitis caused by respiratory syncytial virus, as well as recurrent wheezing after acute viral bronchiolitis. LTA are less efficient than intranasal corticosteroids for allergic rhinitis management. LTA are efficient in exercise-induced asthma, although they are not the first-line treatment. CONCLUSIONS: Controlled and randomized studies show that inhaled corticosteroids are the drugs of choice to treat persistent asthma and allergic rhinitis. There is not enough evidence to recommend the use of LTA as first-line drug (monotherapy) in children with asthma (level I). For children who cannot use inhaled corticosteroids, LTA may be a good alternative (level II).

Montelukast in pediatric asthma management.

Leukotriene modifiers (receptor antagonist and biosynthesis inhibitor) represent the first mediator specific therapeutic option for asthma. Montelukast, a leukotriene receptor antagonist is the only such agent approved for use in pediatric patients. Montelukast modifies action of leukotrienes, which are the most potent bronchoconstrictors, by blocking Cysteinyl leukotriene receptors. Systemic drug like mountelukast can reach lower airways and improves the peripheral functions which play a crucial role in the evolution of asthma. Review of existing literature showed that montelukast compared to placebo has proven clinical efficacy in better control of day time asthma symptoms, percentage of symptom free days, need for rescue drugs and improvement in FEV 1. Studies also demonstrated improvement in airway inflammation as indicated by reduction in fractional exhaled nitric oxide, a marker of inflammation. Studies comparing low dose inhaled corticosteroids (ICS) with montelukast are limited in children and conclude that it is not superior to ICS. For moderate to severe persistent asthma, montelukast has been compared with long acting beta agonists (LABA) as an add-on therapy to ICS, montelukast was less efficacious and less cost-effective. It has beneficial effects in exercise induced asthma and aspirin-sensitive asthma. Montelukast has onset of action within one hour. Patient satisfaction and compliance was better with montelukast than inhaled anti-inflammatory agents due to oral, once a day administration. The recommended doses of montelukast in asthma are- children 1-5 years: 4 mg chewable tablet, children 6-14 years: 5mg chewable tablet, ADULTS: 10mg tablet; administered once daily. The drug is well tolerated. Based on the presently available data montelukast may be an alternative treatment for mild persistent asthma as monotherapy where ICS cannot be administered. It is also an alternative to LABA as an add-on therapy to ICS for moderate to severe persistent asthma. The other indications for use of montelukast include: allergic rhinitis, exercise induced bronchoconstriction and aspirin-induced asthma.

Drug therapy of childhood asthma.

Drug therapy is used to prevent and control asthma, and also to reduce the frequency and severity of its exacerbations, and reverse airflow obstruction. Asthma medications are thus categorized into two general classes--bronchodilators (relievers) and anti-inflammatory drugs (preventers). Short acting beta2-agonists is the therapy of choice for relief of acute symptoms and prevention of exercise induced bronchospasm (EIB). Corticosteroids are the most potent and effective anti-inflammatory medication currently available. Inhaled form is used in the long-term control of asthma. Systemic corticosteroids are used to gain prompt control of the disease when initiating long-term therapy. Long acting bronchodilator used concomitantly with anti-inflammatory medications for long-term control of symptoms, especially nocturnal symptoms. Ipratropium bromide may provide some additive benefit to inhaled beta2-agonists in severe exacerbations. Sustained release theophylline is a mild to moderate bronchodilator used principally as adjuvant to inhaled corticosteroids for prevention of nocturnal asthma. Leukotriene modifiers may be considered as an alternative therapy to inhaled corticosteroids or cromolyn or nedocromil.

Asthma--the changing face of drug therapy.

Until the recent introduction of long acting beta 2-agonists and the leukotriene antagonists, the drug treatment of asthma had remained largely unchanged for a quarter century. Recent studies have demonstrated the efficacy of the long acting beta 2-agonists in the management of asthma in children and highlighted their value as an adjunct to inhaled corticosteroids. The leukotriene antagonists are an important new class of drug therapy which target a specific area of asthma pathogenesis. Whilst they have been shown to be effective for asthma, their exact role in the clinical situation remains to be established. Recent guidelines have emphasised the important role of inflammation in persistent asthma and recommended the early institution of anti-inflammatory treatment. Many patients remain uncontrolled despite high doses of anti-inflammatory agents including oral corticosteroids. Recent experience with other immunomodulatory agents such as cyclosporin, methotrexate and intravenous immunoglobulin has highlighed their potential as steroid sparing agents. With improved understanding of asthma pathogenesis the potential for specific targeted therapies has become evident. Monoclonal antibodies to IgE and certain cytokines are being investigated as possible treatments for asthma. Similarly, preliminary studies of selective phosphodiesterase inhibitors in asthmatic individuals have been encouraging. Other potential therapies include platelet-activating factor receptor antagonists, tryptase inhibitors and prostaglandin E analogs. The continued development of such targeted treatments should ensure a greater diversity of therapeutic options for the management of asthma in the new millennium.