# I. INTRODUCTION

sthma is the most common chronic disease of childhood and its prevalence has substantially increased worldwide, particularly in pre-school children (Masoli et al., 2004). According to many investigators asthma prevalence is above 10% in most developed countries & expected to be twice in 2020 (Movahedy, 2000;Tepas et al., 2001, Liu et al., 2004,  Lodrup et al., 2006).

In children, asthma is the most common cause of school absence, affecting children's educational potential and adversely affecting a child's quality of life (Rance and Trent, 2005) and associated with significant morbidity and economic burden (Global Strategy for Asthma Management and Prevention, 1995).

The diagnosis of asthma is based on recurrence of symptoms remission and symptom responsiveness to bronchodilator and/or antiinflammatory agents (Bradley and Katie, 2009). Wheezing in infancy is found to be an important risk factor for the development of asthma (Csonka, 2001). It is generally recommended that below the age of 3 years, three or more wheezing episodes should be diagnosed asthma (Anon, 1992). Among children older than 3 years, the diagnosis of asthma becomes progressively more clear & beyond 6 years of age the definition of the National Heart, Lung and Blood Institute becomes logical which states that: asthma is primarily a disease of air way inflammation in which eosinophils, mast cells and release of inflammatory mediators as cytokines and leukotrienes from these cells are prominent, producing recurrent episodes of cough & wheeze often associated with increased bronchial hyperresponsiveness & reversible airway limitation (Barnett et al., 1997; Anon, 1998).


# A

The main purpose of asthma treatment is allowing the child to have a life with normal pulmonary function. Pulmonary function tests (PFTs) are used to determine asthma severity along with clinical symptoms and medication requirements. Normal lung function is one of the goals of asthma management in international guidelines, which includes forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and peak


# In children, preventive treatment has become the cornerstone of management of asthma & emphasis

The two classes of drugs most commonly used for childhood asthma, namely the ?2-agonist bronchodilators and inhaled corticosteroids, have both come under increasing inspection (Lipworth, 1993;Nishima et al., 2005).

As the development of tolerance resulting from continuous use of ?2-agonists is of concern and the risk of adverse systemic effects with inhaled corticosteroids, particularly in children require high dosages. In addition, ensuring adequate compliance with inhaled therapy continues to be a major difficulty. For these reasons, an orally active, once-daily, disease-modifying drug with additional bronchodilator properties would provide a major advance for managing young patients with asthma (Warner, 2001). Leukotriene antagonists have witnessed a favorable preference in asthma management of children as they target a specific site in the inflammation cascade of asthma ( Riccioni et al., 2004).

in health care has moved from treatment in acute illness to prevention and control of chronic conditions (Bateman et al., 2008).

Drugs stated in the global international asthma (GINA 2006) as prophylactic medications are: slowrelease theophylline, long acting beta2 agonist, ketotifen, oral corticosteroids, inhaled corticosteroids, and nedocromil, cromoglycate, & leukotriene modifiers (Paulo et al., 2003).

Montelukast is an oral leukotriene receptor antagonist, licensed as add on therapy for the treatment of 6 years or older patients , with mild to moderate asthma inadequately controlled on 'as required' shortacting beta2-agonists and inhaled corticosteroids and for prophylaxis of asthma in which the predominant component is exercise-induced broncho-constriction (Rabe and Schmidt, 2001).

Montelukast is recommended for use in 2 to 4 year age group for whom long acting beta2-agonists such as salmeterol are unlicensed or those poorly controlled on short-acting beta2-agonists and inhaled corticosteroids. Montelukast may offer an alternative to theophylline as add-on therapy in asthma poorly controlled by short acting beta2-agonists and inhaled corticosteroids alone (Naomi et al., 2006).

Montelukast is given orally & is palatable by children in its formulations thus drug delivery and compliance should be better than for inhaled Therapeutic and Some Biochemical Studies of Montelukast and Ketotifen of Children with Mild Asthma the present study was to compare the efficacy and safety of montelukast & ketotifen as controller in the treatment mild persistent asthmatic children.


# II. Review of Literture

Asthma 1.1 : Definition

The latest definition as stated by GINA 2009 of asthma; asthma is a chronic inflammatory disorder of airway in which many cells and cellular elements play a role. The chronic inflammation is associated with airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and cough particularly at night and early morning (Figure 1-1). The main physiological feature of asthma is episodic airway obstruction characterized expiratory airflow limitation (GINA, 2006). The various pathophysiologic mechanisms and clinical manifestations of asthma make it difficult to formulate a clear-cut definition. However, the whole concept of asthma definition as a distinct disease has been challenged (Silverman & Wilson, 1997). It has been proposed that asthma is probably not "a single disease, but rather a complex of multiple separate syndromes that overlap (Wenezel, 2006).

Asthma is much more likely to involve acute and severe episodes in children than in adults & tend to develop in a few days or even hours. Asthma is often initiated by a viral infection, and prompt, effective treatment is necessary to prevent frequent visits to the emergency department or readmissions to hospital (Levison, 1991). Respiratory syncytial virus (RSV) is the most important cause of viral lower respiratory tract illness in infants and children worldwide and is responsible for over 120000 annual hospitalizations in infants in the US alone (Chávez-Bueno et al., 2006). The diagnosis may be more difficult in children than in adults, since young children are unable to undergo pulmonary function and bronchial provocation test (Pellegrino et al., 2005).

The interplay and interaction between airway inflammation and clinical symptoms and pathophysiology of asthma.


# : Types of Asthma and Their Clinical Features

There are three forms of asthma known, for all of which the underlying causes have not been entirely elucidated. 1. Allergic asthma: Also known as extrinsic asthma may begin during childhood and persist into adulthood. It is linked to an immune response, as is the case with allergic reactions (Barnes, 2000). 2. Non-allergic asthma: referred to as intrinsic asthma is considered late-onset asthma, presenting typically during adulthood. It is triggered by factors unrelated to allergies and the resulting symptoms at typically during adulthood. It is triggered by factors unrelated to allergies and the resulting symptoms at least partially reversible with medication are not associated with an allergic reaction, meaning it is not considered an immune response (Asthma and Allergy Foundation of America, 2002). 3. Occupational asthma: is typically associated with exposure to fumes, gases, and dust or other substances harmful to the airways while working, causing onset, or recurrence of asthmatic symptoms. Occupational asthma can be either allergic or non-allergic in nature, and can be more prevalent in persons with a previous family history of allergies or asthma (Malo and Chan-Yeung, 2009). Typical symptoms are similar across all forms of asthma and generally include wheezing, shortness of breath, chest tightness, coughing, as well as potential runny nose, nasal congestion and eye irritation, depending on the severity and form of the asthma attack. Severity of this disease varies by the individual, and requires equally diverse treatment options that meet the medical needs of each asthmatic (Diette et al., 2004).


# : Prevalence of asthma

Asthma is a common affliction of the population, present throughout the ages. The history of asthma is still not well defined but can occur at any time & it is principally a pediatric disease, with most patients being diagnosed by 5 years of age & up to 50% of children having symptoms by 2 years of age (NHLB, 1997).

In the US & in other western industrialized countries, the prevalence of asthma in children has reached epidemic proportion & that the rate in children younger than 5years has increased 16%. About 30-70% children with asthma will improve markedly or become symptom free by early childhood; however chronic disease persists in about 30-40% of patients & generally 5% or less develops severe chronic disease (Gustafsson et al., 2006).


# : Causes of asthma

Although the causes of asthma are not completely understood, but the following are factors related to asthma occurrence:


# Global Journal of Medical Research Volume XII Issue X Version I ear 2012 Y

Therapeutic and Some Biochemical Studies of Montelukast and Ketotifen of Children with Mild Asthma 1.4.1 : Genetic Genetic linkage has been identified in loci containing major genes that can influence atopy and asthma (Cookson and Moffatt, 2000). Several asthma and allergy susceptibly genes have been identified through genome-wide linkage analysis (Holloway and Koppelman, 2007).


# : Gender

The ratio of asthma prevalence is twice the amount of male to female up to 13 -14 years of age. The ratio then progressively reverses to a 2:1 ratio for woman to man (Schatz and Camargo, 2003). The reason might be that the lung size is smaller in males than females at a younger age but is larger in adulthood (Martinez et al., 1995).


# : Age

In most children, asthma develops before age 5 years, and, in more than half, asthma develops before they age 3 years.

Among infants, 20% have wheezing with only upper respiratory tract infections (URTIs), and 60% no longer have wheezing by age 6 years. Many of these children were called "transient wheezers" (Martinez et al., 1995;Castro-Rodriguez, 2000). They tend to have no allergies, although their lung function is often abnormal.

These findings have led to the idea that they have small lungs. Children, in whom wheezing begins early, in conjunction with allergies, are more likely to have wheezing when they are aged 6-11 years. Similarly, children in whom wheezing begins after age 6 years often have allergies, and the wheezing is more likely to continue when they are aged 11 years (Lemnaske et al., 2005).


# 1.4.4: Environment

The role of the exposure to environmental allergens in asthma development is not fully understood. The levels of exposure to house-dust mite, cat and dog dander were not related to childhood asthma, although sensitization to mite and cat allergens was associated with indoor allergen exposure (Lau et al., 2000). Other epidemiologic studies have found that early exposure to dogs and cats may protect a child against allergic sensitization or the development of asthma (Gern et al., 2004), although other studies do not suggest such relation (Remes et al., 2001).


# 1.4.5: Tobacco smoke

Exposure to tobacco smoke increases the risk of asthma in children who have atopic dermatitis & aggravates symptoms of asthma, increases bronchial irritability and decreases pulmonary airflow rates (Murray and Morrison, 1989).

Studies of lung function after birth have shown that maternal smoking during pregnancy has a negative influence on lung development (Martinez et al., 1995) & Parents of all such children should therefore be encouraged not to smoke. Passive and active smoking is associated with a reduced therapeutic response to corticosteroids reducing the likelihood of asthma being controlled (Strachan et al., 1996; Withers et al., 1998).

Active smokers have more severe asthma symptoms, accelerated decline in lung function and impaired shortterm therapeutic responses to corticosteroids (Strachan   et al., 1996; Chalmers et al., 2002). The highest proportion of asthma related admissions to hospital are from smoking individuals (Thomson et al., 2004). 1.4.6: Infections The interaction between atopy and viral infections is complex. Reduced lung function and increased markers of inflammation observed before virus infection in the asthmatic patients with high levels of total IgE may be a risk factor for an adverse response to infection with rhinovirus (Zambrano et al., 2003).

Viruses have been shown to be potent triggers of asthma exacerbations, and the inability to restrict the symptoms of rhinovirus infections in the upper respiratory tract may be considered an indicator of asthma at all ages (Corne et al., 2002). On the contrary to this, population-based studies assessing infections exposure in children for viruses have found that exposure to infectious agents protects against asthma (Yazdanbakhsh and Wahyuni, 2005). Most infants and young children who continue to have a persistent wheeze and asthma have high immunoglobulin E (IgE) production and eosinophilic immune responses in the airways and in circulation at the time of the first viral URTI. They also have early IgE-mediated responses to local aeroallergens.


# 1.4.7: Other causes of asthma

Oral antibiotics are frequently prescribed for upper and lower respiratory tract infections in children. Findings from epidemiologic studies have supported an association between antibiotic use in the first year of life and asthma development in early childhood (Kozyrskyj and Becker, 2005;Marra et al., 2006). Evidence for this comes from that antibiotic administration causes altered intestinal flora, impaired barrier function, diminished Th-1 immune responses, and allergic airway disease, increased risk of childhood asthma.


# 1.5: Mechanism of asthma

The airway constriction that is characteristic of asthma is influenced by a number of physiological and environmental factors, including increased bronchial contractility, altered permeability of the bronchial mucosa, humeral and cellular mediators of inflammation, dysfunctional neural regulation and exposure to environmental stimuli as allergens (Phillips   et al., 1980). It involves several inflammatory cells and multiple mediators that result in characteristic pathophysiological change (Busse and Lemanske, 2001;Tattersfield, 2002).


# 1.5.1: Airway inflammation in Asthma

Airway inflammation in asthma is persistent even though symptoms are episodic, and relationship between the severity asthma and inflammatory intensity of asthma is not clearly established (Bousquet et al., 2000;Cohn, 2004).


# 1.5.1.1: Inflammatory mediators

Inflammatory cells such as eosinophils, lymphocytes, and mast cells are abundant in asthmatic lungs. Multiple cytokines, including leukotrienes, have been found in bronchoalveolar lavage fluid of asthmatics. IgE antibodies are also linked to progression of lung disease (Busse and Lemanske, 2001).

Other constituent airway cells, such as fibroblasts, endothelial cells, and epithelial cells, that contributes to the chronicity of the disease. Finally, cellderived mediators influence smooth muscle tone and produce structural changes and remodeling of the airway (Busse et al., 1993;Henderson, 1994). Structural cells of the airways also produce inflammatory mediators, and contributed to the persistence of inflammation in various ways.

Inhaled antigen activates mast cells and Th2 cells in the airway. They in turn induce the production of mediators of inflammation (such as histamine and leukotrienes) and cytokines including interleukin-4 and interleukin-5. Interleukin-5 travels to the bone marrow and causes terminal differentiation of eosinophils (Figure 1-2). Circulating eosinophils enter the area of allergic inflammation and begin migrating to the lung by rolling, through interactions with selectins, and eventually adhering to endothelium through the binding of integrins to members of the immunoglobulin super family of adhesion proteins: vascular-cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1). As the eosinophils enter the matrix of the airway through the influence of various chemokines and cytokines, their survival is prolonged by interleukin-4 and granulocyte-macrophage colonystimulating factor (GM-CSF). On activation, the eosinophil releases inflammatory mediators, such as leukotrienes and granule proteins, to injure airway tissues. In addition, eosinophils can generate GM-CSF to prolong and potentiate their survival and contribution to persistent airway inflammation (Busse et al., 1993).

In addition, generation of Th2 cytokines (e.g., interleukin-4 (IL-4), IL-5, and IL-13) could also explain the overproduction of IgE, presence of eosinophils, and development of airway hyperresponsiveness. There also may be a reduction in a subgroup of lymphocytes, regulatory T cells, which normally inhibit Th2 cells, as well as an increase in natural killer (NK) cells that release large amounts of Th1 and Th2 cytokines (Akbari et al.,


# 2006).

T -lymphocytes, along with other airway resident cells, also can determine the development and degree of airway remodeling. Although it is an oversimplification of a complex process to describe asthma as a Th2 disease, recognizing the importance of no. families of cytokines and chemokines has advanced our understanding of the development of airway inflammation (Barnes, 2002; Zimmermann et al., 2003). 1.5.1.2: Immunoglobulin E IgE is the antibody responsible for activation of allergic reactions and is important to the pathogenesis of allergic diseases and the development and persistence of inflammation. IgE attaches to cell surfaces via a specific high-affinity receptor. The mast cell has large numbers of IgE receptors; these, when activated by interaction with antigen, release a wide variety of mediators to initiate acute bronchospasm and also to release pro-inflammatory cytokines to perpetuate underlying airway inflammation (Sporik et al., 2001;Boyce, 2003). Other cells, basophils, dendritic cells, and lymphocytes also have high-affinity IgE receptors.

The development of monoclonal antibodies against IgE has shown that the reduction of IgE is  A clinical diagnosis of asthma may be prompted by symptoms such as episodic short breathlessness, wheezing, cough and chest tightness (Levy et al., 2006). Episodic symptoms after an incidental allergen exposure, seasonal variability of symptom recurrence and positive family history of asthma and atopic disease are also helpful diagnostic guide.

The following categories of symptoms are highly suggestive of a diagnosis of asthma: frequent episode of wheeze (more than once in month), activity induce cough or wheeze, nocturnal cough in period without viral infection, absence of seasonal variation of wheeze, symptoms persist after age 3 years (Guilbert et  al., 2006).

Di Lorenzo et al., (1997) reported that there is an interrelationship of the allergen type, total serum IgE, eosinophil and bronchial hyperresponsiveness suggesting that all three may play a role in the development of bronchial asthma in rhinitis patients.

The mean serum IgE levels and peripheral eosinophil counts were nearly of the same range in controls and vasomotor rhinitis (VMR) cases. In allergic rhinitis (AR) the serum IgE levels were elevated during the acute symptoms, in associated sinonasal polyposis and fungal involvement. However, the peripheral blood eosinophil counts were not elevated in AR patients. In patients of rhinitis with asthma, the IgE levels and peripheral eosinophil counts were both elevated.

The measure of allergic status is of importance in order to establish the risk factors that can cause asthma symptoms in individual patients. The presence of allergens is measured by measure of IgE in serum (GINA, 2007). There are different techniques for the detection of airflow limitation in the patient with asthma, of these methods is the use of spirometry (Enright et al., 1994). 1.6.2.1: Forced expiratory volume in one second (FEV1) Spirometry is the most frequently performed pulmonary function test and is an essential tool for the diagnosis and follow-up of respiratory diseases (Vandervoode et al., 2008).

The Forced Expiratory Volume in 1 second (FEV1) and the Forced Vital Capacity (FVC) are routinely used for this measure (Pellegrino 2005). The FEV1, which is the volume exhaled in the first second of expiration obtained from spirometry, is the measurement of lung volume during the execution of a forced expiratory maneuver.

The procedures and interpretation of FEV1 and Forced Vital Capacity (FVC) have been well codified (American Thoracic Society Statement, 1991; American Thoracic Society. Standardization of spirometry, 1995). Many lung diseases can result in a reduction of FEV1, thus a useful assessment of airflow limitation is the ratio of FEV1 to FVC. This ratio is usually greater than 0.75 to 0.80, but less suggests airflow limitation (Pellegrino et  al., 2005).

The ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) may be more sensitive than FEV1 alone as an indicator of pediatric asthma severity (Carlos et al., 2010). An FEV1/FVC >80% indicates well-controlled asthma in children aged 5-11 years.


# 1.6.2.2: Peak Expiratory Flow

The measure of Peak Expiratory Flow (PEF), using a peak flow meter, is important in both the diagnosis and the monitoring of asthma (American Thoracic Society Statement, 1991; U.S. Department of Health and Human Services, 1992; Smith et al., 1992; American Thoracic Society, 1994; National Asthma Education and Prevention Program Expert Panel Report Number II 1997) although, The utility of PEF to detect the presence of airflow limitation is not particularly good, since the variability of PEF among individuals is very large (+30 percent) (Pennock et al., 1983). However, PEF is a very useful method of monitoring changes or trends in the patient's lung function.

1.6.2.3: Exhaled nitric oxide levels Levels of exhaled nitric oxide and carbon monoxide can also be used as "noninvasive" markers of airway inflammation (Kharitonov et al., 1997). The levels of nitric oxide have been shown to be increased in asthma severity (Brindicci et al., 2007).


# 1.7: Growth in asthmatic children

In 1940, Cohen observed that there was an association between asthma and growth inhibition, and that the persistence of allergic symptoms caused a retardation in stature and bone maturation.

Since then, many studies about the relationship between asthma and growth were carried out, and it is now known that, regardless of treatment, moderate and severe asthma cause a delay in the puberty stretch, which is caught up later on regarding adult height (Hauspie et al., 1977;Preece et al., 1986).

Early onset, duration and severity of the disease, chest deformity, hypoxemia, chronic anorexia, use of corticosteroids, and socioeconomic level are factors under study as potentially responsible for growth retardation, but the results have been conflicting (Cowan et al., 1998).

Morbid processes also interfere with growth. Acute illnesses can cause its temporary arrest, and its posterior recovery will depend on how favorable the environmental, nutritional and socioeconomic conditions will be (Mata et al., 1971; Floud et al., 1990). As for chronic diseases, depending on the affected organs and systems, on the severity and duration of the disease, recovery may not occur at all (Mitchell et al., 1995).

Growth charts show the weight status categories used with children and teens (Table 1-1). All children with asthma must follow allergen avoidance measures. These will vary from child to child, depending on known triggers.

A child's asthma can improve or worsen with time, and frequent follow up with a specialist is necessary to step up or step down the treatment. A general principle is to start with a higher grade of treatment, and step down as the asthma comes under control.  (Travers et al., 2004). Oral corticosteroids given early during an acute asthma exacerbation (i.e., within 45 minutes of the onset of symptoms) reduce the likelihood of hospital admission (Rowe et al., 2004). In addition, oral corticosteroids are more effective than inhaled or nebulized corticosteroids in children hospitalized with severe acute asthma (Edmonds et al.,  2004 Smith et al., 2004).

Although theophylline is not widely used in the treatment of childhood asthma, there is some improvement of symptoms and lung function with the use of intravenous theophylline in children hospitalized with a severe asthma attack. However, this therapy does not reduce the length of stay or the need for additional bronchodilator treatment, and it is not recommended for routine use (Mitra et al., 2004).


# Beta2 -agonist

In an acute asthma exacerbation, inhaled beta 2 agonists are a mainstay of treatment. Administration of an inhaled beta 2 agonist via a metered-dose inhaler with a spacer device is equally as effective as nebulized therapy (Cates et al., 2003).

There is no evidence to support the use of oral or intravenous beta 2 agonists in the treatment of acute asthma (Travers et al., 2004). There is some evidence that high-dose nebulized beta 2 agonists administered every 20 minutes for six doses may be more effective than low-dose beta 2 agonists in treating severe acute asthma in children (Schuh et al., 1989).


# Corticosteriod

Oral corticosteroids are more effective than inhaled or nebulized corticosteroids in children hospitalized with severe acute asthma (Smith et al., 2004). There is no evidence that intravenous corticosteroids are any more effective than oral corticosteroids in children (Adapted from National Asthma Education and Prevention Program, 2002).

A systematic review of additional studies in the emergency department-including three pediatric studies-demonstrated that inhaled corticosteroids in high doses reduce hospital admission rates in patients with acute asthma. However, there is insufficient evidence that inhaled corticosteroids alone are as effective as systemic steroids (Edmonds et al., 2004). Theophylline Although theophylline is not widely used in the treatment of childhood asthma, there is some improvement of symptoms and lung function with the use of intravenous theophylline in children hospitalized with a severe asthma attack. However, this therapy does not reduce the length of stay or the need for additional bronchodilator treatment, and it is not recommended for routine use (Mitra et al., 2004 The cysteinyl leukotrienes (LTC 4, LTD 4, and LTE4) are products of arachidonic acid metabolism and are released from various cells, including mast cells and eosinophils. These eicosanoids bind to cysteinyl leukotriene (CysLT) receptors. (Afridi et al., 1998). The cyslt type-1 (CysLT1) receptor is found in the human airway (including airway smooth muscle cells and airway macrophages) and on other proinflammatory cells (including eosinophils). CysLTs have been correlated with the pathophysiology of asthma and allergic rhinitis. In asthma, leukotriene-mediated effects include airway edema, smooth muscle contraction, and altered cellular activity associated with the inflammatory process (Owen et al., 2000).The action of Leukotrienes can be blocked through either of the two specific mechanisms: 1) Inhibition of leukotriene production.

2) Antagonism of leukotriene binding to cellular receptors. Montelukast and Zafirlukast have been reported as leukotriene receptor antagonists of leuktriene D and E, which are components of slow reacting substance of anaphylaxis (Dockhornm et al., 2000). These drugs are not indicated for acute exacerbations but are recommended for prophylaxis and chronic treatment of asthma in adults and in children.


# 1.9.2.2.1: Montelukast

Montelukast is a specific leukotriene receptor antagonist that has been shown to be effective in children with mild persistent asthma (Garcia et al., 2005) and is recommended as a preventative agent for this group of children for the treatment of asthma (Wenzel, 1998;GINA, 2003;British Thoracic Society, 2003).  The molecular structure of montelukast.
The chemical structure of montelukast is 2-[1- [[(1R)-1-[3-[(E)-2-(7-chloroquinolin-2-yl)ethenyl] phenyl]- 3-[2-(2-hydroxypropaphenyl] propyl]sulfanylmethyl]cyclop

# Mechanism of action of montelukast

Montelukast binds with high affinity and selectivity to the cyslt1 receptor (Aharony, 1998). Montelukast inhibits physiologic actions of LTD 4 at the cyslt 1 receptor without any agonist activity (Anon, 1998;   Horwitz et al., 1998). This results in a reduction in bronchoconstriction, mucous secretion, vascular permeability and eosinophils recruitment. It also inhibits both early and late stage bronchoconstriction, implying both an anti-inflammatory and bronchodilatory action (Anon, 1999).


# Pharmacokinetics of Montelukast Absorption

Montelukast is rapidly absorbed following oral administration. After administration of the 10-mg filmcoated tablet to fasted adults, the mean peak montelukast plasma concentration (Cmax) is achieved in 3 to 4 hours (Tmax) & achieved at 2 hours after fasted administration of the 4mg chewable tablet to 2 to 5 year olds [Singulair, 2001]. The mean oral bioavailability is 64%. The C max found not be influenced by a standard meal in the morning (Cheng et al., 1996).

Montelukast administration once daily in the evening was based on comprehensive studies and no data indicate a greater benefit with administration in the evening as compared with dosing at any other time of day were found (Pajaron-Fernandez, 2006).

Maximal therapeutic response is achieved after the first dose & the half-life is reported between 2.7 to 7 hours (Knorr et al., 1999). Montelukast as 4 mg oral granule formulation found to be bioequivalent to the 4mg chewable tablet when administered to adults in the fasted state & the co-administration of the oral granule formulation with apple sauce shown not to have a clinically significant effect on the pharmacokinetics of montelukast (Knorr et al., 2001).

In a study comparing the pharmacokinetics of a 4-mg dose of montelukast oral granules in patients between 6 to 24 months old to the 10-mg in adults observed that the estimated AUC ratio of pediatric to adult 10 mg film were similar (Migoya et al, 2004).

Studies comparing the pharmacokinetics of montelukast within gender indicated that montelukast had similar kinetics in males & females (Singulair, 2001).


# Distribution

Montelukast is more than 99% bound to plasma proteins & the steady-state volume of distribution of montelukast averages 8-11 liters (Zhao et al., 1997).

Studies in rats with radiolabelled montelukast indicate minimal distribution across the blood-brain barrier & concentrations of radiolabelled material at 24 hours post dose were minimal in all other tissues (Chiba et al., 1997).


# Metabolism

Montelukast is extensively metabolized & studies performed in adults and children with therapeutic doses of montelukast, showed that plasma concentrations of metabolites of montelukast were undetectable at steady state (Chiba et al., 1997). In vitro studies using human liver microsomes indicate that cytochromes P450 3A4, 2A6 and 2C9 are involved in the metabolism of montelukast.


# Elimination

The plasma clearance of montelukast averages 45 ml/ min in healthy adults. Following an oral dose of radiolabel led montelukast, 86% of the radioactivity was recovered in 5-day fecal collections and <0.2% was recovered in urine. Although, studies on bioavailability of oral montelukast indicated that montelukast and its metabolites are excreted almost exclusively via the bile, however, no dosage adjustment is necessary for the elderly or mild to moderate hepatic insufficiency (Balani   et al., 1997). In spite of unavailability of pharmacokinetic studies in patients with renal impairment & since montelukast and its metabolites are eliminated by the biliary route thus no dose adjustment is required in patients with renal impairment.


# Adverse-effects

In clinical trials in children, the majority of the reported adverse effects found to be mild and included headache, ear infection, nausea, abdominal pain and pharyngitis & the incidence of these adverse effects was not higher than with placebo . It was found, in some patients receiving oral corticosteroids and Zafirlukast that reductions in steroid dose were associated with Churg-Strauss syndrome (Knoell et al., 1998) & they thought this may be due to reduced steroid dosage and not related to Zafirlukast. However, similar phenomenon has been reported with montelukast (Singulair, 2001).


# Precautions

Montelukast is metabolized extensively by CYP 3A4, therefore caution should be exercised especially in children when it is administered with inducers of CYP3A4 such as phenytoin, phenobarbital and rifampicin (Singulair, 2001).

Montelukast crosses the placenta and is excreted in breast milk therefore should not be prescribed to pregnant and lactating women, due to lack of controlled trials (Van Adelsberg, 2005).

Efficacy of montelukast in the management of asthma in children there is a growing body of evidence indicating that leukotriene modulators, such as leukotriene-receptor antagonists play an important role as first-line therapy in patients with mild to severe asthma (Riccioni et al., 2004;Bisgaard et al., 2005;Laitinen et al., 2005;Barclay, 2005).

Montelukast in mild & moderate persistent asthma compared with placebo; Several comparative studies in pediatric patients have been conducted in different age groups (Knorr et al., 1998; Knorr et al.,   2000) & showed significant improvements in multiple parameters of asthma control with montelukast as day time & night time asthma symptoms, need for betaagonist or oral corticosteroids; physician global evaluations and peripheral blood eosinophils (Stelmach   et al., 2002; Becker et al., 2004). In other randomized controlled trial comparing montelukast with inhaled fluticasone in 6-14 year old children with mild persistent asthma montelukast was comparable to fluticasone in increasing the percentage of asthma rescue free days but the secondary end points including FEV1, beta 2-agonist use, and quality of life improved significantly more in fluticasone treatment group (Garcia et al., 2006). However, the acceptance, convenience and adherence of the patient and parent to the treatment were better with montelukast than ICS owing to its easy and simple oral once daily administered montelukast which was found to be advantageous over ICS. In another randomized controlled trial showed that the response of montelukast & inhaled corticosteroid vary within subjects owing to pharmacogentic factors (Szefler et al., 2005).

Montelukast compared to long-acting ?2agoinst (LABA as add on therapy to inhaled corticosteroids (ICS) in adults; A study conducted among children revealed that add on therapy with montelukast plus low-dose budesonide was more effective than the addition of LABA or doubling the dose budesonide for controlling exhaled nitric oxide in 


# Montelukast

in excercise-induced bronchoconstriction; A study showed that following 8 weeks treatment with montelukast, asthma symptom score and FEV1 significantly improved in patients with excercised-induced bronchoconstriction. Montelukast was found to attenuate immediate and late phase response to exercise challenge in asthmatic children (Melo et al., 2003;Payaron et al., 2006).

Montelukast in the treatment of seasonal and perennial allergic rhinitis; it was evaluated in a number of randomized double blind trials compared to antihistamines. The effect of montelukast 10 mg was compared with loratidine, pseudoephedrine, cetrizine in children & adult patients were equivalent in the improving symptoms of rhinitis and quality of life index (Mucha et al., 2006; Watanasomsiri et al., 2008).

However the night sleep quality montelukast was significantly superior to cetrizine (Chen et al., 2006).

Montelukast in aspirin-induced asthma; the cysteinyl leukotrienes are the leading mediators of the airway reaction that occurs in persons with aspirinsensitive asthma after exposure to aspirin (O'Byrne et al., 1997). Leukotriene receptor antagonist found to be able to prevent this reaction (Drazen and Austen, 1999) and is considered the treatment of choice for these patients (Wenzel et al., 1998;Mehta, 2000).


# Other uses of montelukast

Apart from asthma other coming up roles for montelukast include chronic urticaria (Sanada, 2005) cystic fibrosis (Stelmach et al., 2004), migraine (Brandes  et al., 2004), eosinophilic gastroenteritis (Quack, 2005), vernal keratoconjuctivitis (Lambiase, 2003), antitussive effects in cough variant asthma (Toshiyuki et al., 2010)  and in atopic dermatitis (Mohammad et al., 2008). 1.9.2.2.2: Ketotifen Ketotifen has the properties of the anti¬histamines in addition to a stabilizing action on mast cells analogous to that of sodium cromoglycate. It is given orally as prophylactic management of asthma, and also used in the treatment of allergic conditions such as rhinitis and conjunctivitis. Ketotifen is taken orally in dose equivalent to 1mg of Ketotifen twice a daily with food (Parafitt, 1999).

Chemical structure of ketotifen is 4-(1-Methyl-4piperidylidene)-4H-benzo [4,5]  The molecular structure of ketotifen.


# Mechanism of action

Ketotifen is a relatively selective, noncompetitive histamine antagonist (H1-receptor) and mast cell stabilizer. Ketotifen inhibits the release of mediators from mast cells involved in hypersensitivity reactions. Decreased chemotaxis and activation of eosinophils has also been demonstrated. Ketotifen also inhibits cAMP phosphodiesterase (Castillo et al., 1991).

Properties of ketotifen which may contribute to its antiallergic activity and its ability to affect the underlying pathology of asthma include inhibition of the development of airway hyper-reactivity associated with activation of platelets by PAF (Platelet Activating Factor), inhibition of PAF-induced accumulation of eosinophils and platelets in the airways, suppression of the priming of eosinophils by human recombinant cytokines and antagonism of bronchoconstriction due to leukotrienes. Ketotifen inhibits of the release allergic mediators such as histamine, leukotrienes C4 and D4 (SRS-A) and PAF (Morita et al., 1990; Schoch, 2003).


# Pharmacokinetic of ketotifen Absorption

Following oral administration absorption is at least 60%. The rate of absorption is rapid with an absorption half-life of 1 hour. Bioavailability is about 50% due to a large first pass effect (Ketotifen, 2000).

The rate absorption of two formulation syrup and oral tablet study showed a significantly more rapid rate of absorption as assessed by Tmax than oral tablet and no significant differences were observed in the extent of absorption between dosages forms (Grahnén, 1992). Bioavailability is not affected by the intake of food (Yagi et al., 2002).


# Metabolism and Elimination

Ketotifen is extensively metabolized to the inactive ketotifen-N-glucuronide and the pharmacologically active nor-ketotifen. Clearance of the drug from plasma is biphasic, with a half-life of distribution of 3 hours and a half-life of elimination of 22 hours in adults. Children exhibit a similar pattern of elimination. The pattern of metabolism in children is the same as in adults, but the clearance is higher in children. Children over the age of 3 years therefore require the same daily dosage regimen as adults. In infants aged less than 3 years, however, the dosage must be adjusted, since the mean levels of the drug in infants are higher than those found in children, when the same dose is given. Children have a faster clearance of ketotifen than adults and would therefore require a higher dose per kilogram body weight to give comparable steady-state levels (McFadyen et al., 1997).


# Precautions

Ketotifen may cause in some people drowsy, dizzy but usually disappear spontaneously with continued medication or less alert than they are normally, excited, irritable, or nervous or to have trouble in sleeping. These are symptoms of central nervous system stimulation and are especially likely to occur in children.

For patients with diabetes, the syrup form of this medicine may affect blood sugar levels. As ketotifen may lower the seizure threshold it should be used with caution in patients with a history of epilepsy.

Efficacy of ketotifen in treatment of asthma in children In a randomized placebo-controlled trial, ketotifen has been studied in mild-to-moderate asthma. Various trials showed benefit from 10 to 12 weeks of therapy when Ketotifen was given twice a day & significant improvement in PEFR, FEV 1 parameters was observed after 14 weeks of therapy (Kabra et  Asthmatic children receiving ketotifen were more likely to reduce concomitant medications and had significant improvement over time in asthma scores and mean flows at 75%, 50%, and 25% of vital capacity. They also had a significantly increased incidence of dry mouth and significant weight gain compared to those receiving placebo (Simons et al., 2001).

In pollen-induced asthma and rhino conjunctivitis, ketotifen appeared to have good protective properties (Broberger et al., 1985).In perennial rhinitis & idiopathic anaphylaxis in children, Ketotifen was shown to be effective (Fokkens and   Scadding, 2004; Ditto et al., 1997).For the temporary prevention of ocular itching due to allergic conjunctivitis and nasal allergic rhino conjunctivitis, ketotifen showed good efficacy (Crampton, 2003) & useful also in the management of HIV-associated malnutrition (Ockenga, 1996). 2-Patients who demonstrated FEV1>80%.

Parents of the children were informed about the aim of the study, medications used, planning of treatment strategy including dose, timing, duration of treatment & the parameters that will be taken to assess the efficacy & safety of the treatment. Each child parent is asked to visit the hospital with their child at monthly interval which was considered as visits (first, second, third and fourth). Also they are instructed not to use any medication of asthma before informing us, other than ? 2agonist (salbutamol) in case they have attacked of acute bronchoconstriction.


# 2.2.2: Questionnaire

A structured questionnaire containing information about case history of each child was prepared for each child to be enrolled in the study (Appendix 2-1).


# Global Journal of Medical Research Volume XII Issue X Version I ear 2012 Y

Therapeutic and Some Biochemical Studies of Montelukast and Ketotifen of Children with Mild Asthma


# 2.2.3: Allocation of study patients

The 102 patients whom were diagnosed as having mild persistent asthma were randomly allocated to receive medications under clinical evaluation for 16 weeks as follows:

Group I: patients who received Montelukast: included 40 patients received montelukast orally; each night for a period of sixteen weeks. For those children aged 2-5 years, 4mg granules in the evening was given and for those children aged 6-12 years, 5mg chewable tablet in the evening was given. The chewable tablets or granule are instructed to be taken after evening meal at regular interval (mostly at 9 p.m.). Chewable tablet is instructed to be taken directly with adequate water. Granules instructed to be taken either directly in the mouth, or mixed with a spoonful of cold or room temperature soft food. The parents were instructed to give the full dose within 15 minutes after opening the drug sachet for 16 weeks, during this period a patient instructed to take ?2-agonist when wheezing attack occur.

Group II: patients who received Ketotifen oral syrup included 36 patients as oral syrup. One milligram every night at regular interval (at 9 p.m.) throughout period of 16 weeks, during this period a patient instructed to take ? 2 -agonist when wheezing attack occurs.

Group III: control group included 26 patients whom (neither received montelukast nor ketotifen medication) but they were instructed to have only ? 2adrenergic agonists during wheezing attack throughout period of 16 weeks at which the study was conducted.

Follow up chart was prepared for each child enrolled in the study. This chart contains detailed information about observations of child asthmatic symptoms or adverse-effects seen during time of study (Appendix 2-2).


# 2.2.4: Inclusion criteria

The inclusion criteria of patients selection was based on clinical history that included:

? Asthmatic children between ages of 2 years to 12 years. ? Patient's responses to nebulizer beta-agonist.

? Presence of persistent wheezing, chest tightness and persistent cough at night and/or early morning (mild persistent asthma). These symptoms were confirmed by physical examination and spirometry (FEV1>80% and FVC ratio).


# 2.2.5: Exclusive criteria

The exclusion criteria included, children: ? Patients under age of 2 years and more than 12 years. ? Presence with persistent moderate and sever of (FEV1 <80%). Spirometry was performed in the hospital. Each child underwent measurement of FEV1 & FVC by minispirometry for those children under 6 years and chest operator (spirometry) for those children 6 -12 years. The FVC and FEV1 values were recorded before and then every 4 week interval throughout the sixteen weeks of the treatment protocol for each child participated in the study.

The process of measurement of FEV1 & FVC by A-Minispirometry was performed as following:

1-Quietness and relaxation were given to the child in order to get corrected measurement. 2-The child was educated how to use minispirometry and how it will aid in the treatment of the asthma. For hematological analysis: 1 ml of the collected blood samples was introduced into tube containing EDTA anticoagulant & immediately used for preparation of blood smear for eosinophil percentage.


# 2.3.3.1: Estimation of esionophil percentage

Immediately after obtaining blood samples from the patient, a thin layer of blood smear was prepared & stained as follows: 1-The slide was left for at least 30 seconds in absolute methanol. 2-The stain (Leishmen stain) was drained onto the slides & left for 2 minutes. 3-A aliquot of the buffer solution was added onto the slides & then gently mixed with the stain without touching the surface of the blood film on the slide. 4-The slides were left for 3 min then rinsed with distilled water for 30 seconds & then dried. 5-Then, the slides were examined under oil immersion microscopically.


# 2.3.3.2: Determination of Serum IgE Procedure

1. The required reagents removed from the refrigerator and allow them to come to room temperature for at least 30 minutes. 2. One "IgE" strip and one "IgE" SPR used for each sample, control or calibrator to be tested. 3. The selected "IgE" test code was specified & identified by "S1", and tested in duplicate. 4. Each sample was then centrifuged. 5. The calibrator, control & samples were mixed by a vortex to improve result reproducibility. 6. 100 µL of calibrator, sample or control was drawn by pipette into the sample well. 7. The SPRs and strips inserted into the instrument.

The color labels would be checked with assay code on the SPRs and the reagent strips match. 8. The assay was initiated as directed in the operator manual. All assay steps were performed automatically by the instrument. Wait 30 minutes for completed of assay.

9. After assay is completed, the result of samples were read and recorded and then the SPRs and strips from instrument were removed.


# 2.3.4: Measurements of weight to age percentile

Weight to age percentile was estimated of each asthmatic child before starting treatment & thereafter at each visit corresponding to other parameters of drug evaluations taken in the study.


# 2.3.5: Effect of different treatment on liver function enzymes

From the 5ml blood samples taken, 3-4 ml of the remaining was left to clot at room temperature for 10-15mint then put it in centrifuged at 3000 rpm for three minutes. The separated serum by pipette and divided into two part, one part put in special tube of (Flexor instrument) used for the determination of liver enzymes test as serum alkaline phosphatase, serum aspartate aminotransferase (AST), serum alanine transaminase(ALT), and other part for serum IgE. These measurements were performed by using commercially available kits and manual measurement performed before treatment as a baseline and after each visit of treatment (Henderson et al., 2000; Scherwin, 2003).


# 2.3.5.1: Determination of Alkaline Phosphatase:

Procedure: the following procedure was held at 37? C using wave length 405 nm.

Read against reagent blank. At each visit parents were asked about any adverse experienced after using each medication. These experiences were recorded on the diary chart.


# 2.4: Statistical analysis

Data were analyzed using the statistically package social sciences (SPSS) version 16.0. Paired sample t-test was used to compare between mean values of parameters (FEV1, FVC, asthma symptoms, eosinophils percentage, serum IgE, weight to age percentile, serum ALP, serum ALT and serum AST after different time. Analysis of variance (ANOVA) was used for comparing the mean of different parameters used for evaluation of treatments between the treated groups. Chi square t -test was used for categorical variance in this study. P value < 0.05 was considered statistically significant.


# IV. Results

One hundred and two patients involved in the study were those who reported enough symptoms to fulfill the criteria of mild persistent asthma that included, number of attack wheezing, coughing, sleeping disturbances per week & their predicted FEV1 was >80% (Table1-2). The distribution of children under study to the treatment groups are shown in (Figure 3-1).

Distributions of asthmatic children in the treatment groups.   ? Different letters means significant differences (P<0.05) between two variables.

? Same letters means that no significant differences (P>0.05) between two variables. In this study, two age groups were distributed notably 2 -5.12 years & 6-12 years old children (Table 3- 1). The mean ±SD of age of participated children were (6.04 ±3.2), (5.25±2.4) and (6.33±2.67) years old in montelukast, ketotifen & control group respectively. The distribution of asthma in children within two age groups showed that the asthma distribution were 52.94% in preschool children at 2-5.12 years of age & 47.06% in school children aged 6-12 years (Figure 3-3). No significant differences were found between these 2 age groups (Table 3- The table  shows that within 102 asthmatic children involved in the study, children with positive history of allergic rhinitis & atopic dermatitis constituted 74.50% and 15.70% respectively and 9.8% of them had a history of both allergic rhinitis and atopic dermatitis, these differences are significantly between positive and negative allergy.  Parent's history of allergic rhinitis & asthma constituted 96% to the distribution of asthma in the studied children, (Table 3-3). Among this percentage, mother's & fathers history of asthma & allergic rhinitis contributed to 68% and 28% respectively to the distribution of asthma within the asthmatic children.

Parent's history of allergic rhinitis found to be associated more 74% with asthma distribution in the studied children than the parent's history of asthma 22% and that the relation of maternal history of allergic rhinitis was more 56% connected with asthma distribution in the children than their paternal history of allergic rhinitis 18% as shown in (Figure 3-4). There is significant deference between the role of allergic rhinitis and asthma in parents.  With asthma (%)


# 3.5: Effect of montelukast on pulmonary function tests

Montelukast produced significant improvement in the FEV1 & FVC from the first visit of treatment to the end of the study period, when compared to the FEV1 & FVC measurement before starting treatment as shown in (Table 3-4). Comparing the FEV1 measurement of the patients after montelukast treatment with those measurements in control group showed that improvement in FEV1 measurements started to be significant gradually started from the first visit to last visit of treatment as shown in (Table 3-5). When the effects of montelukast treatment on FEV1 measurements was compared to those in ketotifen group patients, the improvement was not significant after the first visit of treatment but improvement became significant from the second visit to last visit of treatment.

Concerning comparison of FVC measurement of the patients after treatment with montelukast with those in control group showed significant improvement in the FVC from first visit to last visit of treatment. However, when compared the FVC value in the patients of montelukast group were compared to those patients in ketotifen group was significantly improved after the third and fourth visit (Table 3-5). Treatment once daily with montelukast produced significant improvement in asthma symptoms compared to pretreatment parameters that included attacked no. of wheezing, coughing and nocturnal awakening per week as shown in (Table 3-6). The significant reduction in number of wheezing per week was noticed from the first visit ongoing to the end of treatment period compared to those recorded before starting treatment.

A significant reduction was found in the tendency of sleeping disturbance/ week from the first visit of once daily montelukast treatment to last visit when compare to those before treatment (Table 3-6).

Coughing / week was also significantly reduced, compared to pretreatment from the first visit to last visit of treatment. Comparison of improvement in asthma symptoms between montelukast with ketotifen treated group and control group patients, showed significant reduction in wheezing attack /week from first visit of treatment to last visit (Table 3-7). Similar significant reduction was found between montelukast group with ketotifen & control group patients in the cough attacks per week from first visit to last visit of treatment (Table 3- 7). Nocturnal sleeping disturbance was reduced significant treatment when compared with ketotifen and control group as seen in the (Table 3-   Comparison between eosinophils percentage in montelukast treated patients with those in control group yielded high significant differences at the first to last visits of treatment, whereas when compared with those in ketotifen group patients, showed no significant differences after the first visit of treatment but later on, Although no significant difference were found between the IgE levels in serum of patients in both montelukast & ketotifen treated for three visits of treatment but the differences became significantly reduced at the 4th visit of treatment in favor of montelukast group patients (Table 3-11). Once daily treatment of patients with montelukast resulted in significant elevation in ALP activity from first visits to last visit of treatment compared to pretreatment activity (Table 3-12).


# Montelukast

However when the activities of ALP in montelukast group patients was compared to those in control group, no significant elevation was found after the first & second visit of treatment but the elevation became significant after the third & the fourth visit of treatment (Table 3-13), whereas no significant elevation was found between the activity of ALP in patients treated with montelukast compared to those in ketotifen treated patients (Table 3-13).


# 3.9.2: Effect of montelukast on the activity of Alanine transaminase(ALT)

No significant differences in the serum activity of ALT was found in the patients after the first and second visit of montelukast treatment when compared with those before treatment, whereas a significant reduction in serum activity of ALT appeared after the third and fourth visit after montelukast treatment (Table 3


# -12).

When ALT activity was compared between montelukast treated patients with those in ketotifen & control group patients, there were no significant difference with each of the two groups until the fourth visit were a significant difference was found when compared with ketotifen & control group (Table 3-13).


# 3.9.3: Effect of montelukast on the activity of serum Aspartate aminotransferase (AST)

Montelukast once daily treatment produced highly significant elevation in AST activity, compared to those pretreatment values starting from the first visit to the last visit after treatment (Table 3 -12).

When the activity of serum AST in montelukasttreated patients was compared to those in ketotifen & control patients, there were no significant differences between the activity of AST in montelukast-treated patients with those in the ketotifen-treated & control group patients (Table 3-13).  When the effects of ketotifen treatment on FEV1 values was compared to those in patients in control group, the improvement in FEV1 was not significant until the last visit (Table 3-5). However, the FVC values in the patients in ketotifen group were not significantly different from those in control group throughout study period. Ketotifen effects on pulmonary function tests are compared with those of montelukast in section (3.5).


# 3.11: Effects of ketotifen on clinical symptoms of asthmatic children

All the clinical symptoms of asthma (wheezing, sleeping disturbances and coughing) were significantly improved starting from the first visit after ketotifen treatment to the end of study period when compared to pretreatment assessments (Table 3 -15). Comparison between ketotifen & montelukast effect on improvement on asthma symptoms are outlined in section (3.6). While, when wheezing in ketotifen treated patients was compared with those in control group, no significant differences were noticed for 2 visits but thereafter, significant reduction occurred i.e. at the third & fourth visits (table 3-7).

Sleeping disturbances was not reduced significantly in the first visit after ketotifen treatment compared to control but started to reduce significantly from the second visit ongoing to the fourth visit (Table 3- 7). No significant reduction in coughing was observed for 3 visits &then at last visit coughing was reduced significant (Table 3-7).


# 3.12: Effect of ketotifen on eosinophils percentage

Ketotifen did not produced significant reduction in the eosinophils percentage until at the four visits of treatment produced significant reduction when compared with those before treatment (Table 3-16). When the effects of ketotifen treatment on eosinophils percentage was compared to those patients in control group, no significant difference were found (Table 3-9). Comparison with montelukast is outlined in section (3.7).


# 3.13: Effect of ketotifen on the serum IgE levels

Ketotifen treatment caused no significant differences in serum IgE levels when compared to those before starting treatment for 3 visits & a significant reduction was observed at the fourth visit (Table 3-17). In section (3.8), a comparison between ketotifen & montelukast effects on serum IgE was illustrated. A gradual significant elevation in ALP activities was observed from the first visit to the end of treatment period with ketotifen when compared with those before starting treatment (Table 3 -18). Whereas, when the activity of ALP in ketotifen group patients was compared to those in montelukast (section 3.9.2) & in control group patients, no significant differences was observed throughout study period (Table 3-13).

3.14.2: Effect of ketotifen on the activity of ALT Ketotifen treatment did not produce significant differences in ALT activity when compared with those before treatment throughout the period of study (Table 3 -18).Whereas, when the activity of ALT in ketotifen group patients compared to those montelukast and control groups, no significant differences were observed until at fourth visit of treatment).


# 3.14.3: Effect of ketotifen on the activity of AST

Treatment of patients with ketotifen did not produced significant differences in serum asparate transaminase activity throughout period of study when compared with those before treatment (Table 3-18). When AST activity was compared with those of control patients, a significant elevation was shown from the second visit & thereafter to the end of treatment period. The comparison with montelukast effects on AST activity were elucidated in section (3.9.3).


# 3.15: Pulmonary function test in control group

Table (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) reveals the pulmonary function tests in control group patients whom were only kept on ?2 agonist intermittent treatment. No significant differences were shown in FEV1 and FVC values throughout period of study when compared with those before treatment. 


# NS

The comparison between pulmonary function tests (FEV1 & FVC) in montelukast or ketotifen treated patients with control group patients were clarified in sections 3.5 and 3.10 respectively.


# 3.16: Clinical symptoms of control patients

The episodic wheezing, cough & nocturnal sleep disturbances were not significant different throughout study period when compared with those before treatment (Table 3  


# 3.17: Eosinophils percentage in control group

In (Table 3-21) eosinophils percentage were shown increased significantly starting at the second to the last visit of study period when compared with those before treatment. In sections 3.7 and 3.12, comparisons between control group & montelukast group patients were demonstrated respectively. Estimation of activity of serum alkaline phosphatase in control patients showed no significant difference throughout period of study when compared with those before treatment (Table 3-22). The comparisons with montelukast & ketotifen group patients were outlined in sections 3.9.1 & 3.14.1 respectively.


# 3.18.2: Serum Alanine transaminase (ALT) activity

Significant elevation in the serum activity of ALT in control group patients were shown from the first visit to the last visit of study period when compared with those before starting treatment (Table 3 -22). Sections (3.9.2) & (3.14.2) reviewed the comparison between control group patients with those of montelukast & ketotifen patients respectively.


# 3.18.3: Serum Aspartate aminotransferase (AST) activity

Estimation of AST activity in control patients exhibited no significant difference throughout period of study when compared with those before treatment (Table [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22], and the comparison between control, montelukast & ketotifen group patients were elucidated in sections 3.9.3 & 3.14.3 respectively. A significant increase of weight percentile was observed after montelukast once daily treatment from the first visit and ongoing throughout the treatment period when compared with those before treatment as shown in (Table3-23). When the effects of montelukast treatment were compared with those of ketotifen group, no significant differences were seen throughout period of study, table 3-24. While when compared with those of control group, significant difference was found at the second visit of treatment & thereafter. Table (3 -25) show significant gradual increase of weight percentile starting from the first visit and to last period of study after ketotifen treatment. When the effects of treatment of ketotifen was compared with those of control group, no significant difference were seen at the first visit, however significant difference were started to appear from the second visit to last visit of treatment.


# 3.19.3: Weigh-age percentile of control group patients

Table  show that significant reduction from the first visit and ongoing throughout period of study in weight-age percentile of the asthmatic children. 


# 3.20: Adverse effects of montelukast treatment on asthmatic children

Adverse effects associated with montelukast treatment are shown in (Table 3-27). These adverseeffects were observed in 25 patients out of the 40 patients enrolled in montelukast group. Agitation (28%), nasal irritation and skin rash each constituted 13% while 2.5% of them showed lip edema. 


# 3.21: Adverse effects of ketotifen treatment on asthmatic children

Nasal irritation, skin rashes, increase appetite and sedation effects were shown in 32 out of 36 patients after ketotifen treatment and all were disappeared after drug discontinuation (Table 3-28). 


# V. DISCUSSION

The present study was designed to determine the ef¬ficacy and safety of montelukast and ketotifen as controller treatment in asthmatic children.

In the present study, the children distributed to preschool children and school children according to their age which were between 2 to 12 years and most children diagnosed with asthma according to the criteria of mild persistent asthma were preschool children (5.25±2.4 years) although no significant differences were shown between these groups which was inconsistent to those reported by (Martinez et al., 1995;Castro-Rodriguez, 2000;Uyan et al., 2003;Davis, 2009) as that asthma prevalence were higher in preschool children. This difference is most probably related to the small number of patients observed in this trial.

In this trial, both sexes were found affected although the distribution by sex revealed a ratio of 1.55:1 (male/female) but it is very close to those ratios (1.6:1 & 1.55:1) found in other studies (Carr et al., 1992;   Beasley, 2002; Alexander, 2005). The predominance of boys over girls in this study was significant and similar documentations about the predominance of male sex until adolescence over female has been reported by others as well (Martinez et al., 1995, Sundell, 2006) which has been attributed to differences in the structure & function relationship of the lung & airways, where girls


# Global Journal of Medical Research Volume XII Issue X Version I ear 2012 Y

Therapeutic and Some Biochemical Studies of Montelukast and Ketotifen of Children with Mild Asthma have airways that are more proportionate to the size of their lungs, while the airways of boys are proportionately smaller, compared to lung size (Davis, 2009).

Extensive epidemiologic researches have established links between patient's own history of atopy to asthma (Volcheck, 2004; Jonathan and Spergel, 2010). These links were observed also in this trial as 90.2% of the children had previous history of atopy which was significant and it was distributed as 74.5% to allergic rhinitis and 15.7% to atopic dermatitis and only 9.8% had no history of both atopy and it is obvious that history of allergic rhinitis was more related to asthma distribution in the studied children than history of atopic dermatitis, a similar correlation was also reported by (Leynaert, 2000) that rhinitis constituted 10.8% to the prevalence of asthma in the studied population versus 3.6% to 5% and to other study that showed of allergic rhinitis was 61.6% among individuals with asthma versus 6% among non-asthmatic (control) subjects (Alsamarai et al., 2009).

Basically, the factors that are associated with asthma are of two types: host factors & enviromental factors (Sunyer et al., 1997) so that the 9.8% of the asthmatic children in our study with no previousd history of atopy is probably related to enviromental& other factors which are numerous that tend to iniate asthma pathology& exacerbate symptoms which are important in the development, occurance, perpetution of asthma symptoms in children (Spork, 1990;Sundell, 2006).

Association between asthma & family history proposed that in families where neither parent had asthma nor allergic rhinitis, 6% of the children has asthma & that in families where one parent had asthma, 20% of the children had asthma whereas in families where both parents had asthma, 60% of the children had asthma (Hederos, 2007) and as well, in the present study we found that among the 102 asthmatic children, 96% of them, their parents had history of asthma and/or allergic rhinitis, which is also similar to those observed by (Kilpelainen et al., 2001), 1325 children at 7 years of age that the highest prevalence of atopic disease among children was in those with both parents had an identical type of atopic disease with 72% risk, and the lowest among children of parents without an atopic disease (10%).

Our finding of association of mother's history of atopy (68%) that was higher to asthma development in the children than father's history of atopy (26%) is found to be inconsistent with those reported in a survy of asthma prevalence among 1021 asthmatic children that 29.7% of them had mothers with history of asthma or rhinitis or allergy and 22.4% having father's with history of asthma or rhinitis or allergy (Svanes et al., 1999). asthma (Kilpelainen et al., 2001; Wickens et al., 2002;   Pallasaho, 2006).

The primary efficacy endpoint taken in this trial as one of the diagnostic test for pulmonary function was the change from baseline in FEV1 & FVC values.

Highly significant improvement in FEV1 value was obtained after once daily montelukast treatment of the asthmatic children & montelukast resulted in an increase in FEV1 value from the baseline by > 50%, >70%, >80%, & >90% at the first, second, third & fourth visit after treatment respectively which means that the asthmatic children have better ability to exhale air from their lungs, although the post-treatment values still did not reach the mean FEV1 value of (mean1.11 L/sec ) according to height in normal healthy child (Polgar and Weng, 1979). Similar finding was reported by (Jarvis and Markham, 2000;Meyer et al., 2003;Becker et al., 2004;Fall and Kope?, 2010).

In spite of significant improvement in FVC value from the first visit after treatment until the end of the study period, but the percent of increase from baseline value determined was only 22%, 41%, 48% & 50% after the first, second, third & fourth visits respectively of montelukast once daily treatment although it was still less than the mean value (1.12 L )in a normal child of according to height (Polgar and Weng, 1979). This means that montelukast treatment produced better expelling in the lung's air volume in the asthmatic children & that a greater volume over the time course of the FVC test is expelled but less than it would be expelled in a normal healthy individual.

However, when we determined the FEV1/FVC ratio which represents the percent of the lung size (FVC) that can be exhaled in one second; we find that this ratio is greater than 90% from the first visit after montelukast treatment & forward. Thus it is obvious that once daily montelukast treatment for 16 weeks had resulted in a significant improvement in pulmonary function because this ratio indicate that the children can breathe out 90% of the inhaled air in the lungs in one second.

This study involved not only evaluation of improvements in lung function test (FEV1 & FVC) before & after montelukast treatment as controller therapy of mild persistent asthma in children for a period of 16 weeks but also comparing montelukast efficacy with control group & ketotifen.

The finding that once-daily treatment with montelukast as compared with control, significantly improved multiple efficacy end points (FEV1 & FVC) from the first visit & thereafter over the 16 -weeks period in the studied children indicates its high efficacy in maintaining better breathing capacity in these asthmatic children. This result is also confirmed by findings of Furthermore the history of allergic rhinitis was the most frequently reported type of parental atopy in our study which has also been reported by other's as parental history of allergic rhinitis was the strongest risk factor for (Noonan et al., 1998; whom obtained 40-80% improvement in FEV1 when montelukast administered once daily for 3 weeks &of other findings. Furthermore, our results showed the superiority of montelukast over ketotifen in improving FEV1 that started to be significantly gradually better from the second visit & thereafter ongoing to the fourth visit after treatment. This reveal the greater potency of montelukast in performing better pulmonary function in these children with mild persistent asthma and it might be explained on the fact that although both drugs exhibited anti-inflammatory effect but revealed that leukotrienes ( LTC4,D4,E4 ) had great involvement than histamine in the pathophysiology of mild persistent asthma in children under this investigation as shown by the greater efficacy of the antileukoterine, montelukast over ketotifen as antihistaminic drug. The result of our study is corroborative with other studied (Nicosia et al., 2001;Riccioni et al., 2002;Capra, 2006;Capra et al., 2007; Peters-Golden and Henderson, 2007) that support the greater role of leukotrienes in mediating bronchocostriction, mucous secretion, with a subsequent reduction in airway inflammation (Harmanci, 2007).

Our finding also confirm the greater role of leukoterines over histamine in mediating asthma symptoms as administration of ketotifen for 12 weeks produced no significant improvement , compared to control, in FEV1 until 16 weeks after treatment where as FVC values did not differed significantly from those of control over the 16 weeks of once daily ketotifen treatment.

In spite of the significant improvement noticed in the FEV1 values in the asthmatic children when they are compared before & after ketotifen treatment from the first visit & onward to the end of the study period but the extend & level of significance was much less than those obtained in montelukast treated group children. Besides that the FVC values was improved only significantly from baseline values after 16 weeks of ketotifen treatment confirm the lower efficacy of ketotifen in ameliorating symptoms of asthma in children involved in the present study. Indeed the percentage change in FEV1 from baseline, was 9.6 %, 13.25%, 18.44% & 25.2% after the first, second, third & fourth visit respectively of ketotifen once daily treatment and is clearly less than those produced after montelukast treatment thus illuminating the importance of leukotriene antagonists in the treatment of asthma. Indeed, the asthmatic children that were placed on ketotifen therapy were 42 but as the study period was going on, 6 of them quit taking ketotifen & visiting the hospital for further evaluation of the therapy as they found no obvious relieve of their asthma symptoms & thus we followed up investigation only 36 patients to the end of study period & all the data that are stated in all the evaluations were those of only the 36 patients stayed to the of the trial.

Studies comparing montelukast with other antihistaminic agents as ketotifen, loratidine, the benefits of anti-histaminic drug in relieving asthmatic symptoms but they also pointed out the preference of montelukast over antihistaminic agents as antiinflammatory pharmacotherapy reversing brochoconstriction & reducing airways inflammation through their ability to reach lower airways and improves the peripheral functions thus play a crucial role in the evolution of asthma (Anon, 1999; Pajaron-Fernandez, 2006; Walia et al., 2006). This predominance of montelukast over ketotifen can be explained by that leukotrienes in the airways contributes more to the physiological and pathological changes of asthma (more potent than acetylcholine and histamine as contractile agonists of human airways (Barnes et al., 1984; Drazen and   Austen, 1999) plus that referring to earlier reports which stated that cysteinyl-leukoterines are approximately 100-10000 times as potent on molecular basis than histamine in causing constriction of the airways (Wiess, 1982;Weiss, 1983;Smith, 1985).

Patients with asthma often become wheezy at night with an overnight fall in forced expiratory flow rates (Montplaisir et al., 1982). They also sleep less well, become more hypoxaemic during the night, and have more irregular breathing during sleep than do healthy people of similar age (Catterall, 1983) therefore one of the aims of asthma pharmacotherapy is subjected toward relieving in both day & night asthma symptoms.

Montelukast by virtue of its antiinflammatory, bronchodilating effects (Anon, 1999; Pajaron-Fernandez, 2006) caused significant improvement in pulmonary function that contributed very well in ameliorating asthma symptoms from which, the asthmatic children complain adding heavy burden on their health & performance by reducing their physical activity & school attendance. The significant reduction in the attack wheezing, sleep disturbance & coughing frequencies shown after montelukast once daily treatment , compared to pretreatment symptoms in this trial through the first visit to the fourth visit after treatment, indicates its powerful anti-inflammatory effect through inhibition of cysteinyl leukoterines thus reducing bronchial hyperresponsiveness, mucus secretion & inflammation of the airways since cysteinyl leukoterines have been shown to be abundant in bronchi of asthmatic patients as well as in nasal fluids of patients with allergic & seasonal rhinitis (Walker and Sheik, 2002) and their inhibition will be a key factor in relieving asthma day & night symptoms (Pullerits et al., 1999;Pullerits et al., 2002) as shown in this study.

A linear relationship was noticed between improvement in FEV1, FVC values simultaneously with the reduction in asthma symptoms, from the first visit after montelukast once daily treatment, compared to fexofenadine in the treatment of asthma have outlined As compared to control group, montelukast also showed significant higher potency in reducing wheezing, sleeping disturbances & coughing from the first visit & ongoing to the last visit suggesting an optimal asthma control is being achieved in these asthmatic children & support what has been claimed in its pharmacokinetic study that its action starts within days after treatment (Paige, 1998). Whereas salbutamol (control group) effect by activating ?2-adrenoceptors and hence cause direct relaxation of bronchial smooth muscles (Stahl et al., 2003) was so weak that was un able to produced any significant improvement in neither pulmonary function nor in asthma symptoms throughout the study period. Honestly, the asthmatic children involved as control were 44 but as no good response they got from this ?-2 agonist therefore, 18 of them gave up this medication & 26 were remained to continue this trial as a comparison group & data included in this study were of those remains 26 patients only.

Montelukast was found to be superior to ketotifen in reducing wheezing & coughing from the first to the fourth visit after treatment as there were significant reducing both of these symptoms, although reduction in sleep disturbance started to be significantly from those in ketotifen treated group after two visits & thereafter. These results demonstrate that both ketotifen & montelukast are effective in relieving asthma symptoms through their inhibition of histamine & leukotrienes inflammatory effects and since ketotifen is known to cause sedation (Shakya, 2003)   (Anon, 2003) and further supported by others (Knorr, 1998). Likewise, significant differences in eosinophils percentage were found between montelukast treated group & those of control group from the first visit ongoing to the fourth visit of treatment which also postulated that montelukast significantly reduced peripheral blood eosinophils by 4% compared The significant differences seen, in the present study, between montelukast & control group comes from the fact that eosinophils percentage was elevated in control group in contrast to those in montelukast treated group, owing to the nature of inflammatory process & severity of asthma that was not controlled by salbutamol in the control group patients besides that salbutamol lacks anti-inflammatory effects (Oriol et al., 2008). Although no significant differences in eosinophils percentage was obtained between montelukast & ketotifen group patients after 4 weeks of daily treatment by either drug, but the differences became significant after 8 weeks & ongoing to the 16 weeks of treatment. This, of course would be related to the insignificant reduction in eosinophils percentage throughout 12 weeks of the ketotifen once daily treatment & that the difference became only significant after 16 weeks of ketotifen treatment, compared to control group by 27.25% only.

These findings are consistent with those reported in patients with allergic rhinitis (Philip et al., 2002) who found that montelukast reduced peripheral blood eosinophils by 16.9% from control whereas loratidine (an H1 antihistamine similar to ketotifen) did not reduced eosinophils percentages.

An explanation for these differences can be related to the great accusation about the greater role of leukotrienes (Chipps, 2004) over histamine (Barnes et al., 1984;Drazen and Austen, 1987) to the pathophysiology of asthma that elucidated montelukast potency over ketotifen in asthma therapy. Our results coincide with other studies that clearly demonstrated that treating subjects with allergic asthma had more response to antileukoterins than to antihistamine (Wiqar et al., 2008).

Besides this, we notice that the studied children had previous history of allergic rhinitis & a correlation between the degree of bronchial hyper responsiveness (a cardinal feature of asthma) and peripheral blood eosinophilia has been observed in subjects who exhibited a dual response following allergen challenge (Horn et al., 1975) and it was clarified when allergic rhinitis is associated with bronchial asthma, the eosinophil values was increased above the normal indicating relation between asthma & allergic rhinitis (Chowdary et al., 2003).

Among the most sensitive and widely used liver enzymes are the aminotransferases. aspartate aminotransferase (AST or SGOT) and alanine aminotransferase (ALT or SGPT) and Alkaline phosphatase (ALP) (Nyblom et al., 2006).

Treatment with montelukast was associated by elevation in activity of ALP from the first visit & forward compared to pretreatment values. Such finding has to a 3.7% increase in eosinophils of the control group (Ramsay,1997;Schmitt-Grohé et al., 2002;Bisgaard, 2004). been reported only in a case report (Incecik et al., 2007).The elevation of ALP seen after montelukast treatment is most probably related to a cholestatic &/or hepatocyte injury (Sarah and Corathers 2006) and according to montelukast pharmacokinetics studies, (Paige , 1998), montelukast undergoes extensive metabolism in the liver by the cytochrome P450 enzyme system, and is almost exclusively excreted with its metabolites into the bile (Schoors et al., 1995; Cheng et  al., 1996; Chiba et al., 1997) leading to elevated ALP activity in blood. Although we found a dramatic increase in ALP activity after montelukast treatment but these were not significantly higher than those of control group patients until after the third and fourth visit of treatment. Such results must require special attention & necessitates recommendation for ALP continuous monitoring after prolonged treatment with montelukast, although the values of ALP still are less than those expected in such age group children since up to 500 U/L are considered within normal range in these growing age children (Butch et al., 1989) but we assume that the study period was not so long for accusing such high elevation to developmental period in the children.

It seems that montelukast caused asymptomatic hepatotoxic effect although, no pathophysiologic mechanism has been proven to explain our result or the others reported with similar drugs but immunologically induced hypersensitivity reaction, hepatoto metabolites, drug reactions, or unexplained idiosyncratic responses may be involved (Reinus et al., 2000;Goldstein et al., 2004).

Although review of all reported cases of leukotriene modifier-induced hepatitis revealed that hepatic toxicity may develop within weeks or as late as 13 months after start of therapy. With the increasing use of these drugs, coupled with monitoring of liver function, more asymptomatic cases may become apparent. Serial liver function testing has been recommended for patients receiving zileuton (Montvale, 2002) but not for those receiving zafirlukast or montelukast (Reinus et al., 2000;Montvale, 2002). On the basis of our cases and literature review, we recommend that liver function be tested within 4 weeks of initiation of therapy with any leukotriene modifier and that testing be repeated at 3, 6, and 12 month.

Similarly, ketotifen induced gradually significant elevation in ALP activity from the first visit and onward, compared to pretreatment values which correspondence to those findings with montelukast in this study since no significant differences were noticed between both groups. This finding has not been published elsewhere with the use of ketotifen even for a longer period as for 28 weeks (Volovitz et al., 1988) for 32 weeks (Canny et al., 1997) for 36 weeks (Shakya et  al., 2003; Govil and Mirsa, 1992). Logical explanation for this finding is most likely related to its physicochemical properties & that might induce hepatobilary toxicity especially when given for such prolonged period as in our study. Besides this, ketotifen has known to inhibit hepatic microsomal enzymes that add impact on many drug interactions & drug toxicity (Grahnén et al., 1992).

ALT serves as a fairly specific indicator of liver status. Our results indicate that montelukast had no significant adverse-effect on the liver for two consecutive visits after treatment compared to pretreatment values but after 3 rd & 4 th visits, a significant reduction in ALT activity was shown indicating that its harmless effect on liver.

On the other hand, the ALT activity in the control group shown to increase from the first visit & onward although still it is less than the upper normal limit of 40 U/L (Behrman et al., 2003) & so a significant differences were found between montelukast & control group at the last visit. The elevation in ALT activity is shown correlated with asthma severity and has been attributed to insufficient gas exchange and subsequent liver hypoxia and liver cell damage (Carlos et al., 2001).

An elevation in AST seen after montelukast treatment beginning from the first visit after treatment & forward when compared to pretreatment activity is as has been proposed an indication of liver damage as such results were also reported after montelukast treatment (Khan and Hashmi, 2008).

Ketotifen once daily treatment for 16 weeks had no significant effects on ALT & AST activity compared to pretreatment values & when compared to those pretreatment values throughout study period indicating lack of hepatotoxic effect but when compared with control group a significant elevation was found at the third visit in ALT and after the second visit & onward in AST values. This may be because these values were at the first place higher in ketotifen group patients than in those of control group patients.

Similarly no significant differences were noticed between ketotifen & montelukast group in AST values throughout study period but significant differences were noticed until the fourth visit after treatment in ALT values. This is because ALT activity was reduced in montelukast group but not in ketotifen group.

Estimation of IgE level provides evidence in support of atopy (Chowdary, 2003). In our study we observed a significant reduction in specific IgE values following montelukast treatment which indicates that montelukast was highly effective in attenuating the pathological events associated with IgE-mediated inflammation since it reduced the IgE values from the first visit of treatment & further more reduction thereafter was persisted until the end of the trial when compared to pretreatment value although a study by (Stelmach et  al., 2002) revealed that children required high doses of pharmacokinetic profile since ketotifen is, as montelukast, extensively metabolized in liver to active (nor ketotifen) & inactive metabolites (N-glucuronide) montelukast to reduce IgE levels significantly & proposed that perhaps long-term treatment with montelukast will be beneficial to asthma patients to


# Global Journal of Medical Research Volume XII Issue X Version I ear 2012 Y

Therapeutic and Some Biochemical Studies of Montelukast and Ketotifen of Children with Mild Asthma decrease IgE levels. We observed that there was a correlation between reduction in specific IgE levels & eosinophils percentage since these two factors contributes to hypersensitivity reactions as well as asthma (Sunyer et al., 1997) however, no significant correlation between the clinical response to montelukast and serum IgE levels was observed after treatment with montelukast for four weeks by (Cai et al., 2006). Ketotifen showed to be less effective than montelukast in inhibiting this immunoglobulin as no significant differences was obtained after ketotifen treatment for 3 visits & only became significant after the fourth visit. Similar finding was also reported for lack of ketotifen effect on IgE values in asthmatic children & for inhaled steroids also by (Turktas et al., 1996). The low potency of ketotifen in reducing IgE levels indicates that treatment with ketotifen can inhibit mast cells to degranulate in a non-mediated IgE fashion (Castillo et  al., 1991). Another proposed explanation is that ketotifen has no affect on the mast receptor expression for IgE & therefore, the possible mechanism of action of ketotifen could be directed toward the interior of, rather than the exterior of the plasmatic membrane (Castillo et al., 1987).

It has been found that montelukast was more effective in children with higher blood levels of eosinophil cationic protein in their pretreatment blood sample than do children with no response (Kopriva et al., 2003) which may be explained as that montelukast has high influence on IgE-mediated hypersensitivity condition (Tug et al., 2009) & as the children in our study had previous history of atopy coupled with their family's history of atopy therefore montelukast produced satisfactory response in the studied children.

It has been postulated that when decision is made to start regular anti-inflammatory prophylactic treatment, it is based not only on the results of pulmonary function tests, asthma symptoms, bronchodilator requirement, but must be also on the evaluation of the inflammatory markers such as IgE (Fahy, 2000) & that is why use of medication that reduce IgE levels has been considered as effective therapy of asthma (Bradley, 2004). Thus according to our results we can see that montelukast possessed higher efficacy & potency in ameliorating the allergic manifestations in asthma pathogenesis in the studied children than did ketotifen although no significant differences were shown between these 2 groups for 3 visits until the last visit but still we can observe there is fluctuations in IgE values after ketotifen treatment whereas montelukast produced a steep reduction in IgE values starting from the first through the last visit after treatment.

Montelukast treatment was associated with agitation which was recognized in 28 % of patients out of 40 children. This adverse CNS stimulation effects was also reported following montelukast treatment by others (Brunlöf et al., 2008; Manali and Wood, 2009;  Wallerstedt et al., 2009). Although conflicting results was also stated that montelukast treatment was associated with depressive modes (Dukes and Aronson, 2000). Anyhow, in the absence of confirmed studies concerning these diverse CNS effects, we could not postulate a hypothesis for it, but reviewing montelukast pharmacodynamics with its ability to traverse blood brain barrier (Pardridge, 1999;PRICE, 2000). The documentation of presence of Cyst LTs receptors in the dorsal root ganglia (Evans, 2002;Gennaro et al., 2004). plus that a recent article elucidated potency of montelukast in the prevention of tumor cell migration through both cerebral and peripheral capillaries (Nozaki et al., 2010) gives an indication for a role of montelukast in brain biochemistry.

Thus, from the adverse-effects recorded in the patients in our trial & with those proposed effects of montelukast on the brain we do believe that montelukast in some patients under unusual circumstances can cause neurological disturbances or modulation of excitatory &/ or inhibitory neurotransmission in the brain leading those above mentioned adverse-effects. Of course, these entire mentioned hypotheses are just speculation & certainly require serious attention & approval.

The other adverse-effects (nasal irritation, skin rashes & lip edema) have been also recorded in other studies (Knorr et al., 2001; Minciullo et al., 2004;  McEvoy, 2007; Brunlöf et al., 2008). Although numerous studies indicated that montelukast is well tolerated with a safety profile similar both in adult and pediatric populations (Dempsey, 2000) and demonstrated no clinical or laboratory difference in adverse effects versus placebo (Lagos and Marshall, 2007;Bisgaard et al., 2009;Giudice et al., 2009).

Apart from agitation, these adverse-effects are considered mild & unfortunately are expected with any medication especially with a drug that interfere with components of hypersensitivity (Fall and Kopec, 2010 ;Mastalerz and Kumik, 2010).

Ultimately, these adverse-effects were subsided within times after drugwithdrawal, but still they require special attention and may necessitate drug discontinuation.

However, more serious adverse-effects have been published following montelukast treatment as swelling of the face, tongue, lips, eyes, hands, feet, ankles, or lower legs but none of these, other than lip Adverse-effects with montelukast treatment were experienced in 19 out of 40 children and ranged from agitation (28%) to lip edema (2.5%). edema, were observed in the children under the present trial.

An interesting adverse-effect is that 8% of the children had increased appetites. Such finding has not been reported previously and is considered in our opinion a positive outcome. In the mean while, with the absence of postulated hypothesis for this effect we may explain this on the basis that those children either had relieved from asthma symptoms & returned back turn normal appetite (caught up) or that montelukast may stimulate appetite, same as antihistamines, since it can access brain but still it remains unexplainable for the present time & might worth more extensive investigation.

Sedation was experienced in 47% of children enrolled in ketotifen treatment group which was persisted up to 4 weeks after drug discontinuation. This adverse-effect accompanied with ketotifen treatment considered common adverse-effect of ketotifen as other H1-antihistamines (Caps, 1991;Katzung, 2004;Schwartzer et al., 2004). The reason is that H1antihistamines owing to their chemical structure which is derived from the same stem of anticholinergic, antimuscarinic, antidepressants, and antipsychotics agent (Emanuel, 1999; Church et al., 2010) and so they have poor receptor selectivity and often interact with receptors of other biologically active amines causing antimuscarinic, anti-?-adrenergic and antiserotonin effects (Govil and Mirsa, 1992;Martin and Romer, 1993). As first generation H1-antihistamines readily penetrate the blood-brain barrier (Yanai et al., 1995;  Yanai et al., 1999; Okamura et al., 2000; Szefler et al.,   2005)  & have tendency to interfere with neurotransmission by histamine at central nervous system -H1-receptors so that they causes potential sedation, drowsiness, and somnolence (Holgate et al.,   2003; Casale et al., 2003) although this was not followed by impaired performance (Barbier and Bradbury, 2007).

The increase in appetite that was experienced by 30% (within 36 children) of patients in ketotifen group is also well known adverse-effect associated with ketotifen treatment that lead ultimately to weigh gain as was found in our trail (Tantichaiyakul and Preutthipan, 2010). The reason for ketotifen causing increase in appetite is attributed to various factors and anticholinergic effects are among one of these (Nematia et al., 2006) but studies have related weight gain following ketotifen treatment in patients with elevated TNF-? infected with HIV & AIDs to the ability of ketotifen to inhibit the release of TNF-? (Ockenga et al.,  1996; Nevzorova et al., 2001). Interestingly sedation & increase appetite effects were disappeared after one month of ketotifen withdrawal.

Skin rashes that was experienced in 8.3% after ketotifen treatment was considered minor as it subsided within 4 days after treatment & nasal irritation that was experienced in 5.5 % of ketotifen group patients could be due to sequences of antihistaminic effects of this Since long time ago & so far, considerable studies have proposed that asthma causes growth retardation (Abrams, 2001;Cohen et al., 2004) whereas other studies states the opposite & presume that growth retardation is related to asthma severity (Ismail et  al., 2006). In the present study, although the mean weight percentile of the 102 children was within the range of healthy weight (5th percentile to less than the 85th percentile) but this does not reflect the absence of asthma burden.

The significant increase in weight percentile shown after the first visit of montelukast treatment and onward when compared to those before treatment & to those of control group patient from the second visit & onward indicates that montelukast had positive outcome on improvement of pulmonary function and suppressed exacerbations of asthma symptoms in the studied children as that these children, more likely resumed better appetite that ultimately caused the steady significant increase of weight, a phenomena referred to as caught up effect and indeed 8% of children experienced increase appetite. To our knowledge, such finding has not been reported previously with montelukast but on the contrary researches have showed no influence of montelukast on weight in children (Garcia et al., 2006; Becker et al., 2006) this finding requires more investigation.

Similarly, ketotifen showed gradually slow increase in weight starting from the first visit to the last visit after treatment compared to those before starting treatment. Such finding has also been stated previously since ketotifen has a property of stimulating appetite that is associated with weight gain (Tantichaiyakul and Preutthipan, 2010). This property is related to its chemical structure which is derived from cyproheptadine, a serotonin and histamine antagonist known to be primarily indicated for increasing appetite & body weight (Grant et al., 1990;Nemati et al., 2006 ).

Similar results are reported by (Herbarth et al., 1993) furthermore the role of ketotifen in inhibiting TNF? that was associated with gained weight in subjects (+ 2.7 kg) after ketotifen treatment has been postulated (Ockenga et al., 1996). The insignificant differences between montelukast & ketotifen effects on weight gain percentile throughout study period reflects the efficacy of both drugs in improving pulmonary function & relieving asthma symptoms that eventually lead to weight gain.

On the contrary, control group children showed significant reduction in their weight at the first visit to the end of treatment protocol. Such finding coincided with those denoting the negative influence of asthma on body linear growth and that growth retardation could be drug and although it disappeared after three weeks of drug withdrawal but from medical safety point, it should not be ignored & however require follow up.

normalized by controlling the allergy (Martin et al., 1981;  Solé et al., 1991; Neville et al., 1996; Ismail et al., 2006). 


# Global Journal of


# VI. Recommendation

The followings are recommendations for further investigation extracted from the core of the present study:

? Use of montelukast in the treatment of mild persistent asthma in children. 
1![Figure 1-1:](image-2.png "Figure 1")
![effective in asthma treatment (Castro-Rodriguez et al., 2000; Busse and Lemanske, 2001; Holgate et al., 2005).These clinical observations further support the importance of IgE to asthma.](image-3.png "")
12![Figure 1-2 : Airway inflammation (Cohn et al., 2004). Vascular-cell adhesion molecule 1 (VCAM-1) Intercellular adhesion molecule 1 (ICAM-1) Granulocyte-macrophage colony-stimulating factor (GM -CSF) Monocyte chemotactic protein (MCP-1) Macrophage inflammatory protein (MIP-1?)](image-4.png "Figure 1 - 2 :")
6![Physical examination 1.6.2: Measurement of Air Flow Limitation Measurement of lung function provides an assessment of the severity of airway limitation, its reversibility and variability and provides confirmation of the diagnosis of asthma (BTS, 2007).](image-5.png "1. 6 :")
13![Figure 1-3 :](image-6.png "Figure 1 - 3 :")
3![. The molecular formula ropyl]acetic acid (Figure 1 of montelukast is C H CINNaO S and the molecular weight 608.17 (Patil et al., 2009).](image-7.png "- 3 )")
13![Figure 1-3 :](image-8.png "Figure 1 - 3 :")
![Other adverse-effects related to montelukast therapy are psychiatric disorders & hepatobiliary disorders (Khan and Hashmi, 2008). Montelukast has shown to cause transient elevation in ALT & AST activity (Marc et al., 2004; Incecik et al., 2007).](image-9.png "")
![Montelukast in viral-induced asthma; An efficacy study showed that montelukast effectively reduced viral induced asthma exacerbations in 2-5 year old patients with intermittent asthma over 12 months of treatment and also delayed the median time to first exacerbation by approximately 2 months (Bisgaard et al.; 2005). Montelukast granules have been evaluated in pediatric patients with asthma aged 6-24 month and 10-26 months in a randomized controlled trial & it was found to have a positive effect on lung function, airway inflammation and symptom scores in very young children with early childhood asthma (Van Adelsberg et al., 2005). The study concluded that montelukast 4mg granule was well tolerated over 6 weeks of treatment in children aged between 6-24 months with asthma (Migoya et al., 2004).Montelukast in recurrent & persistent asthma;The efficacy of montelukast compared to corticosteroids has been studied in the management of recurrent and persistent asthma in children & found corticosteroid superior to Montelukast (Williams et al.,2001; Karaman  et al., 2004; Garcia et al., 2006; Harmanci, 2007).](image-10.png "")
![Therapeutic and Some Biochemical Studies of Montelukast and Ketotifen of Children with Mild Asthma asthmatic children(Miraglia et al., 2007; Khan and   Hashmi, 2008).](image-11.png "")
![cyclohepta [1,2b]thiophen-10(9H)-one hydrogen fumarate with molecular formula of C19H19NOS.C4H4O4; C23H23NO5S shown in figure 1-4( Govil and Misra, 1992).](image-12.png "")
14![Figure 1-4 :](image-13.png "Figure 1 - 4 :")
![al., 2000; John and Sons, 2004). In a double-blind crossover trial, ketotifen given to a group of young asthmatic children, no useful prophylaxis against bronchoconstriction was shown (Groggins et al, 1981; Shakya et al, 2003) & compared to disodium cromoglycate, there was a significant improvement in morning PEFR on disodium cromoglycate compared with placebo whereas ketotifen (1 mg b.d.) did not (Monie et al., 1982; Croce et al., 1995).](image-14.png "")
1![Distribution of asthmatic children within different treatment groupsAmong the 102 asthmatic children participated this study, the distribution of asthma within boys & girls were 60.8% and 39.2% respectively, (Table3-1) and this differences were significant as shown in (Figure3-2).](image-15.png "1 :")
3![Figure 3-1 :](image-16.png "Figure 3")
32![Figure 3-2 Distribution of asthmatic children according to gender](image-17.png "Figure 3 - 2")
33![Figure 3 -3 Distribution of asthmatic children according to age](image-18.png "Figure 3 - 3")
3434![Figure 3-4 Relation of history of allergic rhinitis and atopic dermatitis to asthma in the asthmatic children](image-19.png "Figure 3 - 4 3 . 4 :")
35![Figure 3-5 Relation of family history with asthma in children](image-20.png "Figure 3 - 5")
7![Effect of montelukast of eosinophils percentageSignificant reduction in the eosinophils percentage found from the first visit to last visit of treatment when compared to pretreatment percentage (Table3-8).](image-21.png "7 :")
![pretreatment parameters suggesting the direct relationship between improvements in pulmonary Global Journal of Medical Research Volume XII Issue X Version I ear 2012 Y Therapeutic and Some Biochemical Studies of Montelukast and Ketotifen of Children with Mild Asthma function test & the relieve of asthma symptoms in the studied children in our trial.](image-22.png "")
1Weight Status CategoryPercentile RangeUnderweightLess than the 5th percentileHealthy weight5th percentile to less than the 85th percentileOverweight85th to less than the 95th percentileObeseEqual to or greater than the 95th percentile1.8: Classification of Asthma(Adapted from National Asthma Education andTo date, asthma severity has been classifiedPrevention Program; 2002).according to the frequency of symptoms in combination with lung function parameters such as forced expiratory volume in one second and peak expiratory flow. The1.8.1: Mild intermittent asthma These children have infrequent symptoms likestandard classification of asthma severity from thecough and wheeze --less than twice in one week. TheNational Institutes of Health consensus guidelineepisodes of asthma are short lived, and the child is well
1Asthma classification*Symptom frequencyLung function ?Mild intermittentDaytime: 2 days in a week or lessPEF or FEV 1 :Nighttime: 2 nights per month or less80 percent or more of predicted functionMild persistentDaytime: more than 2 days in a week, butPEF or FEV 1 :less than 1 time per day80 percent or more of predicted functionNighttime: more than 2 nights per monthModerate persistentDaytime: dailyPEF or FEV 1 :Nighttime: more than 1 night per week60 to 80 percent of predicted functionSevere persistentDaytime: continualPEF or FEV 1 :Nighttime: frequent60 percent or less of predicted functionPEF = peak expiratory flow.FEV 1 = forced expiratory volume in one second.*-Clinical features before treatment or adequate control.?-Lung function measurements are used only in patients older than five years.(Adapted from National Asthma Education and Prevention Program, 2002).1.9: Asthma treatments in childrenprevent exacerbations and to maintain normal lungThe current concept of asthma therapyfunction (Table 1-2).according to the Global Initiative for Asthma (1995) isbased on a stepwise approach, depending on disease1.9.1: Acute Therapyseverity, and the aim is to reduce the symptoms thatInhalation therapy is the cornerstone of asthmaresult from airway obstruction and inflammation, totreatment in all age of children. In an acute asthma
? Previous or family history of sensitivity tomontelukast and ketotifen.? Respiratory tract, cardiac and other disorders.? Patients who received drugs that include one ormore of the following:1-Beta-agonists(oralorlong-actingoranticholinergics) within 1 week.2-Corticosteroids within 1 month.3-Clarithromycin, erythromycin or azithromycin within1 month.4-Chlorpheniramine, diphenhydramine, within 2weeks.2.3: Evaluation of treatment: included2.3.1: Clinical evaluationsIn this study, the clinical evaluation of lungfunction test included: the forced expiratory volume inone second (FEV1) & forced vital capacity (FVC) whichwere measured before starting medication & at eachvisit after treatment (at monthly interval) by minisirometry& spirometry.
5-The nose of child was closed by clamp and askedto take deep breath, & then expired the whole airvolume into the instrument & the reading of FEV1 &FVC were recorded.2.3.2: Asthma symptomsAsthma symptoms included no. attack ofwheezing, cough frequency and reduction sleepdisturbance per week as outlined in Appendix 2 -2.2.3.3: Determination of esionophils percentage andSerum Immuneglobulin E (IgE)Blood samples (4-5ml) were obtained fromeach patient before drug administration & every 4 weeksafter drug administration in the treatment groups(montelukast &ketotifen) & at similar times for controlgroup.B-Chest operator -Function (spirometry):1-The weight of child was measured by electronicscale and recorded.2-The height of child was measured by stadiometerand recorded.3-For each patient, the following data [date, sex(male= 1; female=0), age, height, weight] wereregistered.4-The spacer was cleaned before and after eachexamination by odorless antiseptic.
2.3.5.2: Determination of aspartate aminotransferase(AST) or (GOT)Procedure: the following procedure was held at37? C using wave length 340 nm.Read against reagent blank.1-Reagent 1(240 µL) and 30 µl of sample was mixed,then wait for 4mint and 43 sec.2-60 µl of reagent R2 was added to the previous tubeand mix, waited 4 min 43 seconds.3-Mixed, and after 50 seconds incubation, thevariation of absorbance per mint(A/min) measuredduring 159 seconds. Calculation At 340 nm for a 1cm path light cuvette:ear 2012 YActivity (U\L) = -1746 * A\min2.3.6: Adverse experiences1-Reagent 1(200 µL) and 10 µl of sample was mixed, then wait for 43 sec. 2-50 µl of reagent 2 was added to the previous tube and mix, waited 4 min 43 seconds. 3-Then added 50 µL of reagent R2. 4-Mixed, and after 50 seconds incubation, the variation of absorbance per mint(A/mint) measured during 133 seconds. CalculationMedical Research Volume XII Issue X Version IAt 405 nm, with a 1 cm light path cuvette: Activity (U\L) = A/min * 1 402 2.4.2.2: Determination of Alanine transaminase (ALT) or (GPT) Procedure: the following procedure was held at 37? C using wave length 340 nm. Read against reagent blank.Global Journal of1-Reagent 1(240 µL) and 30 µl of sample was mixed,then wait for 4mint and 43 sec.2-60 µl of reagent R2 was added to the previous tubeand mix, waited 4 min 43 seconds.3-Mixed, and after 50 seconds incubation, thevariation of absorbance per mint (A/min) measuredduring 159 seconds.CalculationAt 340 nm for a 1 cm path light cuvette:Activity (U/L) = -1746 * A\min
3Treatment groupsMontelukastKetotifenControlTotaln (%)n (%)n(%)n(%)Number of subjects40 (39.2)36 (35.3)26 (25.5)102(100)GenderMale23(22.55)21(20.6)18(17.65)62(60.8) aFemale17(16.7)15(14.7)8(7.8)40(39.2) bAge2 -5.12 yrs20(19.6)20(19.6)14(13.73)54(52.94) a6-12 yrs20(19.6)16(15.69)12(11.76)48(47.06) aMean ±SD of total age of patients6.04 ±3.25.25±2.46.33±2.675.83±2.99
3AllergyPositive n (%)Negative n (%)Child with history of allergic rhinitis76 (74.50)26 (25.50)Child with history of atopic dermatitis16 (15.70)86 (84.30)Child with history of allergic rhinitis and atopic dermatitis10(9.8)-
3Parent HistoryWith asthmaTotal(%)With allergic rhinitis (%)(%)Child with maternal history125668Child with paternal history101828No any family history006Therapeutic and Some Biochemical Studies of Montelukast and Ketotifen of Children with Mild Asthma
3Visits after treatmentPulmonaryBeforePPfunctiontreatmentat first visitP Valueat 2 nd visitValueat 3 rd visitValueat 4 th visitparameterP ValuesMean± S.EMean± S.EMean ±S.EMean ±S.EMean ±S.EFEV10.347 ±0.0380.534 ±0.0430.0010.615 ±0.0410.0010.654 ±0.0560.0010.711 ±0.064 0.001(L/Sec)SSSS0.4790.5860.6790.722FVC±0.062±0.0930.001±0.1070.0010.71 ±0.1120.001±0.1140.001(L)SSSS
35Forced Expiratory Volume per second ( FEV1)
3ClinicalBeforeVisits After treatmentsymptomstreatmentPPat 4 th visitMean ±S.Eat first visitValueat 2 nd visitValueat 3 rd visitP ValueMeanP ValueMean± S.EMean ±S.EMean ±S.E±S.E0.077Wheezing2.45 ±0.09±0.0210.010.025 ±0.020.0010.05 ±0.020.0010±0.020.0001SSSSSleeping01 ±0.080.0011 ±0.070.0011 ±0.070.0011 ±0.0760.0001SSSS
3Cough1.6 ±0.0150.98 ±0.0190.010.775 ±0.020.0010.3 ±0.091E-060.25±0.061E-06S5SSSWheezingat first visitP Valueat 2 nd visitP Valueat 3 rd visitP Valueat 4 th visitMean± S.EMean ±S.EMean ±S.EMean ±S.EP Value
3
3Visits After treatmentBeforetreatmentPPat first visitValueat 2 nd visitValueat 3 rd visitP Valueat 4 th visitMeanP Value±S.EMean± S.EMean ±S.EMean ±S.EMean ±S.E6.71.2061.226±0.5452.202 ±0.2540.01±0.1690.003±0.1580.0021.2 ±0.150.001SSSSof treatment (Table 3 -9).Eosinophils percentagePPPat first visitValueat 2 nd visitValueat 3 rd visitValueat 4 th visitP ValueMean± S.EMean ±S.EMean ±S.EMean ±S.EMontelukKetotifen 0.066MontelukaKetotifen 0.01MontelukaKetotifen 0.001MontelukaKetotifen 0.001astNSstSstSstSControl0.002Control0.001Control0.001Control0.001SSSScontrol0.301Ketotifencontrol0.501Ketotifencontrol0.235Ketotifencontrol0.308KetotifenNSNSNSNSS: significant NS: not significant3.8: Effects of montelukast of the serum IgE levelsongoing to the last visit of once daily montelukastSerum IgE levels were reduced significantlytreatment when compared to pretreatment (Table 3-10).after treatment with montelukast from the first visit &
3Visits after treatmentBefore treatmentat first visitP Valueat 2 nd visitP Valueat 3 rd visitP Valueat 4 th visit±S.E MeanMean± S.EMean ±S.EMean ±S.EMean ±S.EP Value
3Serum IgE (IU/ml)
3Visits after treatmentSerumBefore treatmentat first visitat 2 nd visitat 3 rd visitat 4 th visitliver enzymesMean ±S.EMean± S.EP valueMean± S.EP valueMean± S.EP valueMean± S.EP value(U/L)
3Serum alkaline phosphatase
3Visits after treatmentatBeforeP3rdvisitat 4 th visittreatmentat first visitP ValueValueP ValueP Valuepulmonaryat 2 nd visitMeanMeanfunctionMean ±S.EMean ±S.EMean ±S.E±S.E±S.Etest0.4560.482FEV1(L\sec)0.385 ±0.023 0.422 ±0.0250.020.436 ±0.020.02S±0.020.01±0.020.001SSSS0.4270.570.59FVC L (L)±0.0290.51 ±0.035 0.2920.51 ±0.030.096±0.0280.061±0.030.01NSNSNSS
3Visits after treatmentBeforetreatmentat 2 nd visitclinical symptomMeanat first visitP valueMeanP valueat 3 rd visitP valueat 4 th visitP values±S.EMean ±S.E±S.EMean ±S.EMean ±S.EWheezin2.0561.190.68g±0.11.38 ±0.20.001±0.2040.0011.05 ±0.190.001±0.1340.001SSSS3±0.0Sleeping0.18 1±0.070.002810.0010±0.070.0010.0010.056±0.0.51 ±04SSS0.074SCough2.5 ±0.162.1 ±0.180.0061.4 ±0.1850.0011.5 ±0.290.0030.81 ±0.1680.003SSSS
3Visits After treatmentBeforePPtreatmentat first visitValueat 2 nd visitValueat 3 rd visitP Valueat 4 th visitP ValueMean ±S.EMean ±S.EMean ±S.EMean ±S.EMean ±S.E5.9684.3424.342±0.573.78 ± 0.48 0.3353.586 ±0.0720.107±0.3550.072±0.350.034NSNSNSS
3Visits After treatmentBeforetreatmentat first visitat 2 nd visitat 3 rd visitat 4 th visitMean ±S.EMean ±S.EP valueMean ±S.EP valueMean ±S.EP valueMean ±S.EP value602±48.9614.5 ±63.10.197459.31 ±42.60.178520.7 ±75.10.064388.7 ±48.20.026NSNSNSS3.14: Effect of ketotifen on serum liver enzymes activity 3.14.1: Effect of ketotifen on alkaline phosphatase (ALP) activity
3Visits After treatmentBeforePPserumtreatmentat first visitP Valueat 2 nd visitValueat 3 rd visitValueat 4 th visitP ValueliverMean ±S.EMean ±S.EMean ±S.EMean ±S.EMean ±S.Eenzymes(U/l)428.1ALP393.2 ± 14.99±22.1340.011433.1 ±21.560.004438.7 ±19.21 0.004440.2 ±20.3 0.004SSSS
3Visits After treatmentBeforepulmonarytreatmentat first visitP Valueat 2 nd visitP Valueat 3 rd visitP Valueat 4 th visitP ValuefunctiontestMean ±S.EMean ±S.EMean ±S.EMean ±S.EMean ±S.E0.410.40FEV1 (L\sec)±0.03±0.0390.3540.4 ±0.0290.5030.41 ±0.0330.3910.41 ±0.030.38NSNSNSNS0.490.499FVC (L)0.49±0.03±0.0420.20.488 ±0.030.184±0.0390.1530.52 ±0.0450.125NSNSNS
ear 2012YMedical Research Volume XII Issue X Version IGlobal Journal of
3Af ter treatmentC lini calB eforesy mptomstreatmenta t first visitP Valueat 2 nd v isitP Valueat 3 rd v isitP Valuea t 4th visitP ValueM ean ±S.EM ean ±S.EM ean ±S.EM ean ±S.EM ean ±S.E2.152.232.36Wh eezing2.31 ± 01332 ± 0.01240.103± 0.01430.381± 0.01780.483± 0.01520.574NSNSNSNS0.0384Sle eping0 ±00 ±00.0670 ±00.44± 0.03850.5420.07± 00.635NSNSNSNS2.232.582C ough2.5± 0.1692.5± 0.01770.1262.2± 0.01990.371± 0.01880.658± 0.01890.724NSNSNSN S
3After treatmentat firstBefore treatmentvisit Mean ±S.EP Valueat 2 nd visitP Value at 3 rd visitP Valueat 4 th visitP Value(Mean ±S.E)Mean ±S.EMean ±S.EMean ±S.E5.5 ±0.4965.56±0.4380.9115.97 ±0.420.0115.9 ±0.4780.0256.2 ±0.5430.037NSSSS3.18: Liver enzymes estimation in control group3.18.1: Serum alkaline phosphatase (ALP) activity
3After treatmentBeforetreatmentPPPat first visitP Value at 2 nd visitValueat 3 rd visitValueat 4 th visitValueLiverMeanenzymes (U\L)±S.EMean ±S.EMean ±S.EMean ±S.EMean ±S.E389.4389.2390.1397.2ALP±22.5±19.470.912390.4 ±18.70.863±26.950.765±23.560.625NSNSNSNSALT26.532.824±1.9731.9 ±1.580.00132.625 ±2.10.00433.93 ±2.240.004±2.210.039SSSS10.610.12AST±0.66±0.4870.63710.6 ±0.6310.4239.7 ±0.5410.45710.1 ±0.510.476NSNSNSNS3.19: Effect of montelukast and ketotifen on weightmeasurement3.19.1: Effect of montelukast on weight-age percentilesof asthmatic children
3weight toBeforeAfter treatmentagetreatmentat first visitPat 2 nd visitP valueat 3 rd visitP valueat 4 th visitP valuepercentile(mean ±(mean ±value(mean ±(mean ±(mean ±measuremS.E.)S.E.)S.E.)S.E.)S.E.)ent44.69±5.7353.1±5.30.00155.87±5.20.0058.3±5.040.00159.2±4.90.001S1SSS
3Weight to age percentile
3weight to ageBeforeAfter treatmentpercentiletreatmentat first visitP value at 2 nd visitP valueat 3 rd visitP value at 4 th visitP valuemeasurement(mean ±(mean ±(mean ±(mean ±(mean ±S.E.)S.E.)S.E.)S.E.)S.E.)44.44±5.748.8±5.70.01154.2±5.80.00259.2±5.80.00162.4±5.850.001SSSS
3PercentileBeforeAfter treatmentweight totreatmentat first visitPat 2 nd visitPat 3 rd visitPat 4 th visitPage(mean ± S.E.)(mean ±value(mean ±value(mean ±valu(mean ± S.EvalueS.E.)S.E.)S.E.)e36.34±5.935.5±6.10.00134.7±5.90.00132.6±5.70.0032.3±7.10.001SS1SS
3Adverse EffectsMontelukast (n=40)Disappearance of the adverse effectNo.%Agitation1128Within 2 month after drug withdrawalWithin one month of drug withdrawalNasal irritation513
3Adverse Effectsketotifen (n=36)Disappearance of adverse effectNo.%Sedation1747After 1 month of drug discontinuationincrease appetite1027.7After 1 month of drug discontinuationSkin rash38.3within 4 daysNasal irritation25.5After 3 weeks of drug discontinuation
ear 2012Y

			© 2012 Global Journals Inc. (US)
			© 2012 Global Journals Inc. (US) © 2012 Global Journals Inc. (US) Therapeutic and Some Biochemical Studies of Montelukast and Ketotifen of Children with Mild Asthma
			© 2012 Global Journals Inc. (US) © 2012 Global Journals Inc. (US)
		
		
			
			
			

				


* 
	
		Chronic Pulmonary Insufficiency in Children and Its Effects on Growth and Development
		
			SAAbrams
		
	
	
		J Nutr
		
			131
			
			2001
		
	




* 
	
		An etiological factor of bronchial asthma in a rural area of upper Punjab
		
			FHAfridi
		
		
			SIAhmad
		
		
			KHassan
		
		
			MAJaffery
		
		
			NIkram
		
		
			HAQureshi
		
	
	
		J Rawal Med Coll
		
			7
			2
			1998
		
		
			University of Texas Southwestern Medical Center at Dallas
		
	
	-5. thesis




* 
	
		The Relationship between Asthma and Allergic Rhinitis in the Iraqi Population
		
			AMAlsamarai
		
		
			AMAlwan
		
		
			AHAhmad
		
		
			MASalih
		
		
			JASalih
		
		
			MAAldabagh
		
		
			SAlturaihi
		
	
	
		Allergology Internation
		
			58
			
			2009
		
	




* 
	
		Lung function testing: Selection of reference values and interpretive strategies
	
	
		Am Rev Respir Dis
		
			144
			1202
			1991
			American Thoracic Society Statement
		
	




* 
	
		Standardization of spirometry. Update
	
	
		Am J Respir Crit Care Med
		
			152
			1107
			1995
			American Thoracic Society
		
	




* 
	
		
			Anon
		
		Montelukast (Singulair). New Medicines on the Market
				UKMI
		
			1998
		
	




* 
	
		Lukotriene antagonists: new drugs for asthma
		
			Anon
		
	
	
		MeReC Bull
		
			10
			1
			
			1999
		
	




* 
	
		Montelukast reduces peripheral blood eosinophilia but not tissue eosinophilia or symptoms in a patient with eosinophilic gastroenteritis and esophageal stricture
		
			Anon
		
	
	
		Ann Allergy Asthma Immunol
		
			90
			
			2003
		
	




* 
	
		Asthma: a follow up statement from an international paediatric asthma consensus group
		
			Anon
		
	
	
		Arch Dis Child
		
			67
			
			1992
		
	




* 
	
		Third international Pediatric Consensus Statement on the Management of Childhood Asthma
		
			Anonymous
		
	
	
		Pediatric Pulmonology
		
			25
			
			1998
		
	




* 
	
		
	
	
		Asthma and Allergy Foundation of America
		
			2002
		
	




* 
	
		Metabolic profiles of montelukast sodium (Singulair), a potent cysteinyl leukotriene1 receptor antagonist, in human plasma and bile
		
			SKBalani
		
		
			XXu
		
		
			VPratha
		
	
	
		Drug Metab Dispos
		
			25
			
			1997
		
	




* 
	
		Histaminergic Control of Sleep-Wake Cycles: Recent Therapeutic Advances for Sleep and Wake Disorders
		
			AJBarbier
		
		
			MJBradbury
		
	
	
		CNS & Neurological Disorders-Drug Targets
		
			6
			
			2007
		
	




* 
	
		Montelukast in intermittent mild asthma
		
			LBarclay
		
	
	
		Am J Respir Crit Care Med
		
			171
			
			2005
		
	




* 
	
		Asthma. ed 2 nd
		
			PGBarnes
		
	
	
		Martin Dunitz Ltd
		
			2000. November 21, 2005
		
	




* 
	
		Cytokine modulators as novel therapies for asthma
		
			PJBarnes
		
	
	
		Annu Rev Pharmacol Toxicol
		
			42
			
			2002
		
	




* 
	
		Comparative effects of inhaled leukoterine C4, leukoterine D4 and histamine in normal human subjects
		
			NCBarnes
		
		
			PJPiper
		
		
			JFCostello
		
	
	
		Thorax
		
			39
			7
			
			1984
		
	




* 
	
		Pharmacology of Leukotriene Receptor Antagonists
		
			DAharony
		
	
	
		Am J Respir Crit. Care Med
		
			1998
		
	




* 
	
		Intravenous versus oral corticosteroids in the management of acute asthma in children
		
			PLBarnett
		
		
			GLCaputo
		
		
			MBaskin
		
		
			NKuppermann
		
	
	
		Ann Emerg Med
		
			29
			
			1997
		
	




* 
	
		Statistical Analysis of Proposed Pediatric Asthma Screening Survey
		
			JCAlexander
		
		
			EDBateman
		
		
			SSHurd
		
		
			PJBarnes
		
		
			JBousquet
		
		
			J MDrazen
		
		
			MFitzgerald
		
		
			PGibson
		
		
			KOhta
		
		
			2005
		
	
	PhD 21




* 
	
		Global strategy for asthma management and prevention: GINA executive summary
		
			PO'byrne
		
		
			SEPedersen
		
		
			EPizzichini
		
		
			SSullivan
		
		
			SDWenzel
		
		
			SEZar
		
		
			HJ
		
	
	
		Europ Respir J
		
			31
			1
			
			2008
		
	




* 
	
		The burden of asthma with specific reference to the United States
		
			RBeasley
		
	
	
		Journal of Allergy and Clinical Immunology
		
			109
			Suppl5
			
			2002
		
	




* 
	
		Montelukast in asthmatic patients 6 years-14 years old with an FEV1 > 75%
		
			ABecker
		
		
			ASwern
		
		
			CATozzi
		
		
			QYu
		
		
			TReiss
		
		
			BKnorr
		
	
	
		Curr Med Res Opin
		
			20
			
			2004
		
	




* 
	
		Linear growth in prepubertal asthmatic children treated with montelukast, beclomethasone, or placebo: a 56-week randomized
		
			ABecker
		
		
			OKuznetsova
		
		
			JVermeulen
		
		
			ManuelESoto-Quiros
		
		
			BettyYoung
		
		
			FTReiss
		
		
			SBDass
		
		
			BKnorr
		
	
	
		Annal of Allergy, Asthma and Immunology
		
			96
			6
			
			2006
		
	




* 
	
		Nelson Textbook of Pediatrics
		
			RBehrman
		
		
			RKliegman
		
		
			HJenson
		
		
			2003
			Saunder
			2400
			Amsterdam
		
	
	17th ed




* 
	
		Pulmonary function tests in preschool children with asthma
		
			NBeydon
		
		
			IPin
		
		
			RMatran
		
		
			MChaussain
		
	
	
		Am J Resp Crit Care Med
		
			168
			6
			
			2003
		
	




* 
	
		
		
			HBisgaard
		
		
			-SZielen
		
		
			GarciaGarcia
		
		
			MLJohnston
		
		
			S LGilles
		
		
			LMenten
		
		
			JTozzi
		
		
			CAPolos
		
		
			P
		
		
			2004
		
	




* 
	
		Montelukast reduces asthma exacerbations in 2 to 5year old children with intermittent asthma
		
			HBisgaard
		
		
			SZielen
		
		
			MLGarcia-Garcia
		
		
			2005
		
	




* 
	
		
	
	
		Am J Respir Crit Care Med
		
			171
			
		
	




* 
	
		Safety and tolerability of montelukast in placebo-controlled pediatric studies and their open-label extensions
		
			HBisgaard
		
		
			SDavid
		
		
			LBMaria
		
		
			ATCarol
		
		
			NKReiss
		
		
			FTheodore
		
		
			BKnorr
		
		
			GertrudeN
		
	
	
		Pediatr Pulmonol
		
			44
			6
			
			2009
		
	




* 
	
		Asthma From bronchoconstriction to airway inflammation and remodeling
		
			JBousquet
		
		
			PKJeffery
		
		
			WWBusse
		
		
			JohnsonMVignola
		
	
	
		Am J Respir Crit Care Med
		
			161
			5
			
			2000
		
	




* 
	
		Mast cells: beyond IgE
		
			JABoyce
		
	
	
		J Allergy Clin Immunol
		
			111
			1
			
			2003
		
	




* 
	
		
		
			KatieBradley
		
	
	
		Blueprints PEDIATRICS. Pulmonology
		
			20
			297
			2009
		
	
	5th edition




* 
	
		Targeted anti-IgE Therapy for Patients With Moderate to Severe Asthma
		
			CEBradley
		
	
	
		Biotecnology Health Care
		
			
			2004
		
	




* 
	
		Montelukast for migraine prophylaxis: a patients with asthma of differing severity
		
			JLBrandes
		
		
			WHVisser
		
		
			MVFarmer
		
		
			2004
		
	




* 
	
		British guideline on the management of asthma
	
	
		Thorax
		
			58
			1
			
			2003
			British Thoracic Society
		
	
	Suppl




* 
	
		Ketotifen in pollen-induced asthma: a double blind placebo-controlled stud
		
			UBroberger
		
		
			Graft -Lonnevig
		
		
			GELilja
		
		
			Rylander
		
	
	
		Allergology
		
			26
			5
			
			1985
		
	




* 
	
		Individual case safety reports in children in commonly used drug groups -signal detection
		
			GBrunlöf
		
		
			TukukinoCarina
		
		
			SMWallerstedt
		
	
	
		BMC Clin Pharm
		
			8
			
			2008
		
	




* 
	
		
		
			WWBusse
		
		
			RFLemanske
		
	
	
		Asthma. N Engl J Med
		
			344
			5
			
			2001
		
	




* 
	
		Mechanism of airway inflammation in asthma
		
			WWBusse
		
		
			WFCalhoun
		
		
			JDSedgwick
		
	
	
		N Engl J Med
		
			147
			6
			
			1993
		
	
	Pt 2




* 
	
		Update to the British Guideline on the Management of Asthma
		
	
	
		BTS
		
			2007
		
	




* 
	
		Elevated alkaline phosphatase in kids
		
			AWButch
		
		
			TTGoodnow
		
		
			WSBrown
		
		
			AMcclellan
		
		
			GKessler
		
		
			MGScott
		
	
	
		Clin Chem
		
			35
			10
			
			1989
		
	




* 
	
		Relationship Between Urinary Cysteinyl Leukotriene E4 Levels and Clinical Response to Antileukotriene Treatment in Patients with Asthma
		
			CCai
		
		
			JYang
		
		
			HSuping
		
		
			ZMeiqian
		
		
			GWei
		
	
	
		LUNG
		
			185
			2
			
			2006
		
	




* 
	
		Effectiveness of Prophylactic inhaled steroids in childhood asthma: a systemic review of the literature
		
			CCalpin
		
		
			CMacarthur
		
		
			DStephens
		
		
			WFeldman
		
		
			PCParkin
		
	
	
		J Allergy Clin Immunol
		
			100
			
			1997
		
	




* 
	
		Does ketotifen have a steroid-sparing effect in childhood asthma
		
			ReismanJCanny
		
		
			HLevison
		
	
	
		Eur Respir J
		
			10
			
			1997
		
	




* 
	
		Immunologic and therapeutic aspects of ketotifen
		
			LPCaps
		
	
	
		Allergy
		
			11
			
			1991
		
	




* 
	
		Cysteinylleukotriene receptor antagonists: present situation and future opportunities
		
			VCapra
		
		
			Ambrosio
		
		
			MRiccioni
		
		
			GRovati
		
		
			GE
		
	
	
		Curr Med Chem
		
			13
			
			2006
		
	




* 
	
		Cysteinyl-leukotrienes and their receptors in asthma and other inflammatory diseases: critical update and emerging trends
		
			VCapra
		
		
			M DThompson
		
		
			ASala
		
		
			D ECole
		
		
			GFolco
		
		
			GERovati
		
	
	
		Med Res Re
		
			27
			
			2007
		
	




* 
	
		Comparison of racemic albuterol and levalbuterol for treatment of acute asthma
		
			JCCarl
		
		
			TRMyers
		
		
			HLKirchner
		
		
			CMKercsmar
		
	
	
		J Pediatr
		
			143
			
			2003
		
	




* 
	
		
	
	
		Headache
		
			44
			
			2004
		
	




* 
	
		The association between asthma, asthma therapeutic classes and hepatic enzyme elevation among adult HMO members
		
			CBrindicci
		
		
			KIto
		
		
			PJBarnes
		
		
			Sa ;Kharitonov
		
		
			ICarlos
		
		
			SSidney
		
		
			ELydick
		
		
			MichaelESorel
		
		
			DMark
		
	
	
		Comp Therap
		
			27
			2
			
			2007. 2001
		
	
	Differential flow analysis of exhaled nitric oxide in 50




* 
	
		Lung function measurement in the assessment of childhood asthma: recent important developments
		
			ECarlos
		
		
			-CagnaniBaena
		
		
			LeonardB
		
		
			2010
		
	




* 
	
		
	
	
		Curr Opin Allergy & Clin Immuno
		
			10
			2
			
		
	




* 
	
		Variations in asthma hospitalizations and deaths in New York City
		
			WCarr
		
		
			LZeitel
		
		
			KWeiss
		
	
	
		Am J Public Health
		
			82
			
			1992
		
	




* 
	
		First does no harm: managing antihistamine impairment in patients with allergic rhinitis
		
			TBCasale
		
		
			MSBlaiss
		
		
			EGelfand
		
		
			TGilmore
		
		
			PDHarvey
		
		
			IHindmarch
		
		
			FESimons
		
		
			DLSpangler
		
		
			SJSzefler
		
		
			TETerndrup
		
		
			SAWaldman
		
		
			JWeiler
		
		
			DFWong
		
	
	
		J Allergy Clin Immuno
		
			111
			5
			
			2003
		
	




* 
	
		IgE receptors and serum IgE in pollinosis. The influence of season and action of ketotifen
		
			J GCastillo
		
		
			MLSanz
		
		
			PMGamboa
		
		
			AOehling
		
	
	
		Allergol Immunopathol
		
			15
			
			1987
		
	




* 
	
		Mechanism of ketotifen action in hypersensitivity reactions. Its effect on cellular enzymatic activities
		
			JGCastillo
		
		
			AOehling
		
		
			PMGamboa
		
	
	
		J Investig Allergol Clin Immunol
		
			1
			5
			
			1991
		
	




* 
	
		A Clinical Index to Define: Risk of Asthma in Young Children with Recurrent Wheezing
		
			JACastro-Rodriguez
		
		
			CJHolberg
		
		
			ALWright
		
		
			FDMartinez
		
	
	
		Am J Respir Crit Care Med
		
			162
			4
			
			2000
		
	
	Pt 1




* 
	
		Holding chambers versus nebulisers for betaagonist treatment of acute asthma
		
			CCCates
		
		
			ABara
		
		
			JACrilly
		
		
			BHRowe
		
	
	
		Cochrane Database Syst
		
			3
			D000052
			2003
		
	




* 
	
		Ketotifen and nocturnal asthma
		
			JRCatterall
		
		
			PmaCalverley
		
		
			JTPower
		
		
			CMShapiro
		
	
	
		Thorax
		
			38
			
			1983
		
	




* 
	
		Influence of cigarette smoking on inhaled corticosteroid treatment in mild asthma
		
			GWChalmers
		
		
			KJMacleod
		
		
			SALittle
		
		
			LJThomson
		
		
			CPMcsharry
		
		
			NCThomson
		
	
	
		Thorax
		
			57
			
			2002
		
	




* 
	
		Respiratory syncytial virus bronchiolitis current and future strategies for treatment and prophylaxis
		
			SChávez-Bueno
		
		
			AMejías
		
		
			RCWelliver
		
	
	
		Treat Respir Med
		
			5
			6
			
			2006
		
	




* 
	
		
		
			HCheng
		
		
			JALeff
		
		
			RAmin
		
		
			1996
		
	




* 
	
		Pharmacokinetics, bioavailability, and safety of montelukast sodium (MK-0476) in healthy males and females
	
	
		Pharm Res
		
			13
			
		
	




* 
	
		Randomized placebo-controlled trial comparing montelukastand cetirizine for treating perennial allergic rhinitis in children aged 2-6 yr
		
			STChen
		
		
			KHLu
		
		
			HLSun
		
		
			WTChang
		
		
			KHLue
		
		
			MCChou
		
	
	
		Pediatr Allergy Immunol
		
			17
			
			2006
		
	




* 
	
		Hepatic microsomal metabolism of IgE and Eosinophils in Respiratory Allergy Patients
		
			MChiba
		
		
			XXu
		
		
			JANishime
		
		
			SKBalani
		
		
			JHLin
		
		
			1997
		
	




* 
	
		
	
	
		Indian J Allergy Asthma Immunol
		
			17
			1
			
		
	




* 
	
		Risk of first-generation H1 antihistamines: a GA2LEN position paper
		
			MKChurch
		
		
			MMaurer
		
		
			FerSimons
		
		
			CBindslev-Jensen
		
		
			JPCauwenberge
		
		
			Bousquet
		
	
	
		Allergy
		
			10
			
			2010
		
	




* 
	
		Asthma: Mechanism of disease persistence and progression
		
			LCohn
		
		
			JAElias
		
		
			GLChupp
		
	
	
		Annu Rev Immunol
		
			22
			
			2004
		
	




* 
	
		Anthropometry in children. Progress in allergic children as shown by increments in height, weight and maturity
		
			MBCohen
		
		
			RRWeller
		
		
			SCohen
		
	
	
		Am J Dis Child
		
			60
			
			1940
		
	




* 
	
		Genetics of asthma and allergic disease
		
			WOCookson
		
		
			MMoffatt
		
	
	
		Hum. Mol.Genet
		
			9
			
			2000
		
	




* 
	
		
		
			JMCorne
		
		
			CMarshall
		
		
			SSmith
		
		
			JSchreiber
		
		
			GSanderson
		
		
			STHolgate
		
		
			JohnstonSl
		
		
			2002
		
	




* 
	
		Frequency, severity, and duration of rhinovirus infections in asthmatic and non-asthmatic in cohort study
	
	
		Lancet
		
			359
			
		
	




* 
	
		Effect of asthma and its treatment on growth: four year follow-up of cohort of children from general practices in Taysid
		
			CCowan
		
		
			RGNeville
		
		
			GEThomas
		
		
			IKCrombie
		
		
			RAClark
		
		
			IWRicketts
		
	
	
		BMJ
		
			316
			
			1998
		
	




* 
	
		Comparison of ketotifen fumarate ophthalmic solution alone, desloratadine alone, and their combination for inhibition of the signs and symptoms of seasonal allergic rhinoconjunctivitis in the conjunctival allergen challenge model: a double-masked, placebo-and active-controlled trial
		
			HJCrampton
		
	
	
		Clin Ther
		
			25
			7
			
			2003
		
	




* 
	
		A double-blind, placebo-controlled comparison of sodium cromoglycate and ketotifen in the treatment of childhood asthma
		
			JCroce
		
		
			EBNegreiros
		
		
			JAMazzei
		
		
			GIsturiz
		
	
	
		Journal of Asthma
		
			50
			6
			
			1995
		
	




* 
	
		Management of the wheezing Toddler, diagnostic practice, therapy, and Predictors of symptom persistence. Academic Dissertation, university of Tampere
		
			PCsonka
		
	
	
		Medical School, Department of Pediatrics
		
			2001
		
	




* 
	
		Protective effect of histamine 1 and cyslt1 antagonist on allergen induced airway responses in atopic asthma
		
			BDavis
		
		
			2009
			Saskatoon
		
		
			Department of pharmacology, University of Saskatchewan
		
	
	Ph.D. thesis




* 
	
		Montelukast: a potent leukotriene D4 receptor antagonist, in humans
		
			OJDempsey
		
	
	
		Drug Metab Dispos
		
			76
			
			2000
		
	
	Postgrad Med J




* 
	
		Use of ketotifen in asthma
		
			BEChipps
		
	
	
		Allergy Clin Immunol
		
			4
			1
			
			2004
		
	




* 
	
		
		
			ECChowdary
		
		
			JJVinaykumar
		
		
			RatnaRao
		
		
			KRao
		
		
	




* 
	
		Relationship of physician estimate of underlying asthma severity to asthma outcomes
		
			GBDiette
		
		
			JAKrishnan
		
		
			LLWolfenden
		
		
			EASkinner
		
		
			DMSteinwachs
		
		
			AWWu
		
	
	
		Ann Allergy AsthmaImmunol
		
			2004
		
	




* 
	
		Nonspecific airway hyperresponsiveness in monosensitive sialian patients with allergic rhinitis: Its relationship to total serum IgE level and blood eosinophils during and out of the pollen season
		
			DiLorenzo
		
		
			GMansuetop
		
		
			MMelluso
		
		
			GMorici
		
		
			RamBabu
		
		
			VRangamani
		
		
			;
		
		
			EspositoPellitteri
		
		
			M
		
	
	
		Clin Exp Allergy
		
			27
			
			2003. 1997
		
	
	A study on Serum Norrito F




* 
	
		Pediatric idiopathic anaphylaxis: experience with22 patients
		
			AMDitto
		
		
			JKrasnick
		
		
			PAGreenberger
		
		
			KJKelly
		
		
			KMcgrath
		
		
			RPatterson
		
	
	
		J Allergy Clin Immunol
		
			100
			
			1997
		
	




* 
	
		Comparisonof the effects of intravenous and oral montelukast on airway function: a double blind, placebo controlled, three periods, cross over study in asthmatic patients
		
			RJDockhorn
		
		
			RABaumgartner
		
		
			JALeff
		
	
	
		Thorax
		
			55
			
			2000
		
	




* 
	
		Leukotrienes and airway responses
		
			JMDrazen
		
		
			AustenKf
		
	
	
		Am Rev Respir Dis
		
			136
			
			1999
		
	




* 
	
		Meyler's Side Effects of Drugs
		
			MNDukes
		
		
			JKAronson
		
		
			2000
			Elsevier
		
	
	14 ed.




* 
	
		
			FMDucharme
		
		
			DiSalvio
		
		
			F
		
		Anti
				
			2004
		
	




* 
	
		
	
	
		Cochrane Database Syst Rev
		
			4
			2314
		
	




* 
	
		Early use of inhaled corticosteroids in the emergency department treatment of acute asthma
		
			MLEdmonds
		
		
			CACamargoJr
		
		
			CVPollackJr
		
		
			BHRowe
		
	
	
		Cochrane Database Syst Rev
		
			4
			308
			2004
		
	




* 
	
		Histamine and the antiallergic antihistamines: a history of their discoveries
		
			MBEmanuel
		
	
	
		Clin Exp Allergy
		
			3
			
			1999. 1999
		
	
	Suppl




* 
	
		Physiologic measures: Pulmonary function test
		
			PLEnright
		
		
			MDLebowitz
		
		
			DWCockcroft
		
	
	
		Am J Respir Crit Care Med
		
			149
			S9
			1994
		
	




* 
	
		Cysteinyl leukotriene receptors
		
			JFEvans
		
	
	
		Prostaglandins Other Lipid Mediat
		
			
			2002
		
	




* 
	
		Reducing IgE level as a strategy for the treatment of asthma
		
			JVFahy
		
	
	
		Clin. Exp Allergy
		
			30
			1
			
			2000
		
	
	suppl




* 
	
		Status of leukotrienes in the pathophysiology of asthma. Necessity for antileukotrienes treatment
		
			AMFall
		
		
			AKopec
		
	
	
		Pneumonol Alergol Pol
		
			78
			1
			
			2010
		
	




* 
	
		Height, health and history: nutritional stature in the United Kingdom
		
			RFloud
		
		
			KWachter
		
		
			AGregory
		
		
			1990
			Cambridge University Press
			
			Cambridge
		
	




* 
	
		Perennial rhinitis in the under 4s: A difficult problem to treat safely and effectively. A comparison of intranasal fluticasone propionate and ketotifen in the treatment 93
		
			WJFokkens
		
		
			Gk ;Scadding
		
		
			ADGennaro
		
		
			CCarnini
		
		
			CBuccellati
		
		
			RBallerio
		
		
			SZarini
		
		
			FFumagalli
		
	
	
		The FASEB J
		
			4
			597
			2004. 2004
		
	
	Cysteinylleukotriene receptor activation in brain inflammatory reactions and cerebral edema formation: a role for transcellular biosynthesis of cysteinyl leukotrienes




* 
	
		Effects of dog ownership and genotype on immune development and atopy In infancy
		
			JEGern
		
		
			CLReardon
		
		
			SHoffjan
		
		
			DNicolae
		
		
			ZLi
		
		
			KARoberg
		
		
			WANeaville
		
	
	
		J Allergy Clin Immunol
		
			113
			2
			
			2004. 2004
		
	




* 
	
		Global strategy for asthma management and prevention
		
			Gina
		
	
	
		National Institutes of Health; Publication
		
			
			2003
		
	




* 
	
		
			Gina
		
		The global Initiative for Asthma Report: Global Strategy for Asthma Management & Prevention. Available on www.ginasthma. org
				
			2006
		
	




* 
	
		
		
			MMGiudice
		
		
			APezzulo
		
		
			CCapristo
		
		
			EAlterio
		
		
			SCaggiano
		
		
			DBenedictis
		
		
			AFCapristo
		
		
			2009
		
	




* 
	
		Leukotriene modifiers in the treatment of asthma in children
	
	
		Ther Adv Respir Dis
		
			3
			5
			
		
	




* 
	
		Management Segment. Chapter seven
	
	
		Global Strategy for Asthma Management and Prevention
				
			NIH Publication
			2006. January, 1995
			
		
	
	updated 2006)




* 
	
		Global Strategy for Asthma Management and Prevention
	
	
		Global Initiative for Asthma
		
			1995
		
	




* 
	
		NHLBI/WHO Workshop report
				
			
		
	




* 
	
		
		
			MFGoldstein
		
		
			JAnoia
		
		
			MBlack
		
		
			2004
		
	




* 
	
		Montelukast-induced hepatitis
	
	
		Ann Intern Med
		
			140
			
		
	




* 
	
		
		
			YCGovil
		
		
			PKMirsa
		
	
	
		Ketotifen. Indian pediatrics
		
			29
			
			1992
		
	




* 
	
		Pharmacokinetics of ketotiffn after oral administration to healthy male subjects
		
			AGrahnén
		
		
			Lönnebo
		
		
			EckernSBeck
		
		
			BDahlström
		
		
			BLindström
		
	
	
		Biopharmaceutics & Drug Disposition
		
			13
			
			1992
		
	




* 
	
		
		
			SMGrant
		
		
			KLGoa
		
		
			AFitton
		
		
			EMSorkin
		
		
			1990
		
	




* 
	
		Ketotifen A review of its pharmacodynamic and Pharmacokinetic properties and therapeutic use in asthma and allergic disorders
	
	
		Drugs
		
			40
			
		
	




* 
	
		Ketotifen in the prophylaxis of childhood asthma
		
			R CGroggins
		
		
			EJHiller
		
		
			ADMilner
		
		
			GMStokes
		
	
	
		Arch Dis Child
		
			56
			
			1981
		
	




* 
	
		Long term of 2-4-year-old children with perennial rhinitis
		
			TWGuilbert
		
		
			WJMorgan
		
		
			RSZeiger
		
		
			DTMauger
		
		
			SJBoehmer
		
		
			SJSzefler
		
	
	
		Pediatr Allergy Immunol
		
			15
			
			2006
		
	




* 
	
		Montelukas tcompared with fluticasone, control of asthma among 6 to 14 year old patients with mild asthma: The MOSAIC study
		
			MLGarcia
		
		
			UWahn
		
		
			LGilles
		
		
			ASwern
		
		
			CATozzi
		
		
			PPolos
		
	
	
		N Engl J Med
		
			116
			19
			
			2006
		
	
	Pediatrics




* 
	
		Poor asthma control in children: evidence from epidemiological surveys & implications for clinical practice
		
			PMGustafsson
		
		
			LWatson
		
		
			KJDavis
		
		
			KFRabe
		
	
	
		International Journal of Clinical Practice
		
			60
			
			2006
		
	




* 
	
		Montelukast: its role in the treatment of childhood asthma. Ther Clin
		
			KHarmanci
		
	
	
		Risk Manag
		
			3
			5
			
			2007
		
	




* 
	
		Maturational delay and temporal growth retardation in asthmatic boys
		
			RHauspie
		
		
			CSusanne
		
		
			FAlexander
		
	
	
		J Allergy Clin Immunol
		
			59
			
			1977
		
	




* 
	
		Asthma in young children, epidemiology, burden of asthma & effects of a parental information program
		
			CAHederos
		
		
			2007
			Stockholm
		
		
			Karolenka institute
		
	
	PhD thesis




* 
	
		Role of leukotrienes in asthma
		
			WRHendersonJr
		
	
	
		Ann Allergy
		
			72
			3
			
			1994
		
	




* 
	
		Fundamental of Clinical Chemistry, 5 th Ed
		
			ARHenderson
		
		
			DWMoss
		
		
			TEnzyme
		
	
	
		Burtis
		
			70
			2000
		
	




* 
	
		
			LHerbarth
		
		
			USuttmann
		
		
			MBallmaier
		
		
			FRohde
		
		
			HDeicher
		
		
			ISchedel
		
		Effects of ketotifen on HIV infected individuals International Conference on AIDS. Int Conf AIDS; 1993
				
			500
		
	




* 
	
		
		
			JWHolloway
		
		
			GHKoppelman
		
		
			2007
		
	




* 
	
		Identifying novel genes contributing to asthma pathogenesis
	
	
		Curr Opin Allergy Clin Immunol
		
			7
			
		
	




* 
	
		Consensus Group on New-Generation Antihistamines (CONGA): present status and recommendations
		
			STHolgate
		
		
			GWCanonica
		
		
			FESimons
		
		
			MTaglialatela
		
		
			MTharp
		
		
			HTimmerman
		
		
			KYanai
		
	
	
		Clin Exp Allergy
		
			33
			9
			
			2003
		
	




* 
	
		The anti-inflammatory effects of omalizumab confirm the central role of IgE in allergic inflammation
		
			SHolgate
		
		
			TCasale
		
		
			SWenzel
		
		
			JBousquet
		
		
			YDeniz
		
		
			CReisner
		
	
	
		J Allergy Clin Immunol
		
			2005
		
	




* 
	
		Total eosinophil percentagein the management of bronchial Asthma. New Engl
		
			BRHorn
		
		
			EDRobin
		
		
			JTheodore
		
		
			AVan Keseel
		
	
	
		J Med
		
			292
			
			1975
		
	




* 
	
		Histamine and asthma: an appraisal based on specific H1-receptor Antagonism
		
			PHHowarth
		
	
	
		Clin Exp Allergy
		
			20
			
			1990
		
	
	Suppl. 2




* 
	
		The role of leukotriene modifiers in the treatment of asthma
		
			RJHorwitz
		
		
			KAMcgill
		
		
			WWBusse
		
	
	
		Am J Respir Crit Care Med
		
			157
			
			1998
		
	




* 
	
		Probable montelukast-induced hepatotoxicity in a pediatric patient: Case report
		
			FIncecik
		
		
			YOnlen
		
		
			OSangun
		
		
			SAkoglu
		
	
	
		Ann Saudi Med
		
			27
			
			2007. 2010 Oct. 15
		
	
	serial online. cited




* 
	
		Ketotifen alone or as additional medication for long-term control of asthma and wheeze in children. NHS Evidencewomen's health
		
			W &John
		
		
			Sons
		
		
			2004
		
	




* 
	
		Epidemiology of Atopic Dermatitis and Atopic March in Children
		
			Jonathan
		
		
			Spergel
		
	
	
		Immunology and Allergy Clinics of North America
		
			30
			3
			2010
		
	




* 
	
		Ketotifen for asthma in children aged 5 to 15 years: a randomized placebo-controlled trial
		
			SKKabra
		
		
			RMPandey
		
		
			RSingh
		
		
			VSeth
		
	
	
		Annals of Allergy, Asthma and Immunology
		
			85
			
			2000
		
	




* 
	
		Histamine, serotonin and the ergot alkaloids
		
			BGKatzung
		
		Katzung BG,
		
			2004
			McGraw Hill
			
			New York
		
	
	Basic and clinical pharmacology. 9th ed




* 
	
		
			Ketotifen Fumarate (apo-Ketotifen
		
	
	
		CPS Compendium of pharmaceuticals and specialties
				
			LWelbanks
		
		Ottawa
		
			Canadian Pharmacists Association
			2000
			114
		
	
	35th ed




* 
	
		
		
			SAKhan
		
		
			ZYHashmi
		
		
			2008
		
	




* 
	
		
	
	
		Pak J Med Sci
		
			24
			3
			
		
	




* 
	
		Exhaled and nasal nitric oxide measurements: recommendations.The European Respiratory Society Task Force
		
			SKharitonov
		
		
			KAlving
		
		
			PBarnes
		
	
	
		Eur Respir. J
		
			10
			
			1997
		
	




* 
	
		Farm environment in childhood prevents the development of allergies
		
			MKilpelainen
		
		
			EOTerho
		
		
			HHelenius
		
		
			MKoskenvuo
		
	
	
		Clin Exp Allergy
		
			30
			
			2000
		
	




* 
	
		Validation of a new questionnaire on asthma, allergic rhinitis and conjunctivitis among young adults
		
			MKilpelainen
		
		
			EOTerho
		
		
			HHelenius
		
		
			MKoskenvuo
		
	
	
		Allergy
		
			56
			
			2001
		
	




* 
	
		Montelukast, a leukotriene receptor antagonist for the treatment of persistent asthma in children aged 2 to 5 years
		
			BKnorr
		
		
			LMFranchi
		
		
			HBisgaard
		
		
			JHVermeulen
		
		
			LeSouef
		
		
			PSantanello
		
		
			N
		
	
	
		Pediatrics
		
			108
			3
			E48
			2001
		
	




* 
	
		
		
			BKnorr
		
		
			HHNguyen
		
		
			GLKearns
		
		
			2001
		
	




* 
	
		Montelukast dose selection in children ages 2 to 5 years: comparison of population pharmacokinetics between children and adults
	
	
		J Clin Pharmacol
		
			41
			
		
	




* 
	
		Study of Growth in Prepubertal Asthmatics
		
			NFIsmail
		
		
			SMAly
		
		
			MOAbdu
		
		
			DNKafash
		
		
			CjhKelnar
		
	
	
		Indian J Pediatr
		
			73
			12
			
			2006
		
	




* 
	
		Effect of montelukast on lung function and esonophil in persistent asthma Adis International Limited, Mairangi Bay
		
			JarvisBMarkham
		
		
			A
		
		
			2000
			59
			
		
	




* 
	
		Evaluation of the safety profile of montelukast (MK-0476) in pediatric patients aged 2 to 5 years
		
			BKnorr
		
	
	
		J Allergy Clin Immunol
		
			105
			
			2000
		
	




* 
	
		
		
			BKnorr
		
		
			PLarson
		
		
			HHNguyen
		
		
			1999
		
	




* 
	
		Montelukast dose selection in 6-to 14-year-olds: comparison of single-dose pharmacokinetics in children and adults
	
	
		J Clin Pharmacol
		
			39
			
		
	




* 
	
		Montelukast for chronic asthma in 6-to 14-year-old children. A randomized double-blind trial
		
			BKnorr
		
	
	
		JAMA
		
			279
			
			1998
		
	




* 
	
		Montelukast (MK-0476) improves asthma over a 3 month treatment period in 2-to5-year-olds
		
			BKnorr
		
	
	
		Am J Resp & Critical Care Med
		
			161
			3
			A56
			2000
		
	




* 
	
		Early life exposure to antibiotics for non-respiratory infections is associated with asthma
		
			ALKozyrskyj
		
		
			ABBecker
		
	
	
		J Allergy Clin Immunol
		
			115
			S173
			2005
		
	




* 
	
		Prophylactic antiasthma drugs in Japan
		
			MKurosawa
		
	
	
		J Asthma
		
			27
			
			1990
		
	




* 
	
		in the management of allergic rhinitis
		
			JALagos
		
		
			GDMarshall
		
	
	
		Ther Clin Risk Manag
		
			3
			
			2007
		
	




* 
	
		Leukotriene E(4)-induced persistent eosinophilia and airway obstruction are reversed by zafirlukast in patients with asthma
		
			ALaitinen
		
		
			ALindqvist
		
		
			MHalme
		
		
			AAltraja
		
		
			LALaitinen
		
	
	
		J Allergy Clin Immunol
		
			115
			
			2005
		
	




* 
	
		Montelukast, a leukotriene receptor antagonist, in vernal keratoconjunctivitis associated with asthma
		
			ALambiase
		
		
			SBonini
		
		
			GRasi
		
		
			MCoassin
		
		
			ABruscolini
		
		
			SBonini
		
	
	
		Arch Ophthalmol
		
			121
			
			2003
		
	




* 
	
		Rhinovirus illnesses during infancy predict 100 subsequent childhood wheezing
		
			RFLemnaskeJr
		
		
			DJJackson
		
		
			REGangnon
		
	
	
		J Allergy Clin Immunol
		
			116
			3
			
			2005
		
	




* 
	
		Canadian consensus on the treatment of asthma in children
		
			HLevison
		
	
	
		Can Med Asso J
		
			1
			
			1991
		
	




* 
	
		Guidelines: diagnosis of respiratory diseases in primary care
		
			MLLevy
		
		
			MFletcher
		
		
			DBPrice
		
		
			THausen
		
		
			RJHalbert
		
		
			BPYawn
		
	
	
		Prim Care Respir J
		
			15
			1
			
			2006
		
	
	Respiratory Group (IPCRG)




* 
	
		Clinical pharmacology of corticosteroids in bronchial asthma
		
			BJLipworth
		
	
	
		Pharmacol Therap
		
			58
			
			1993
		
	




* 
	
		Nelson Textbook of Pediatrics
		
			AHLiu
		
		
			JDSpahn
		
		
			DMLeung
		
		Behraman RE, Kliegman RM, Jenson HB
		
			2004
			
		
	
	Childhood asthma. 17th ed. Philadelphia; WB Saunders




* 
	
		Asthma in every fifth child in Oslo, Norway: a 10-year follow up of a birth cohort study
		
			CkcLodrup
		
		
			GHaland
		
		
			DevulapalliCs
		
		
			MMunthe-Kaas
		
		
			MPettersen
		
		
			BGranum
		
		
			MLovik
		
		
			KHCarlson
		
	
	
		Allergy
		
			61
			
			2006
		
	




* 
	
		Agents Causing Occupational Asthma
		
			JMMalo
		
		
			MChan-Yeung
		
	
	
		J Allerg Clinin Immunol
		
			123
			3
			
			2009
		
	




* 
	
		Suicidality and montelukast
		
			PManali
		
		
			JMWood
		
		
			PostolacheTt
		
	
	
		Expert Opin Drug Saf
		
			3
			
			2009
		
	




* 
	
		
		
			MarcFGoldstein
		
		
			JamesAMartin
		
		
			B
		
		
			2004
		
	




* 
	
		Montelukast-Induced Hepatitis
	
	
		Annals of Internal Medicine
		
			140
			7
			
		
	




* 
	
		does antibiotic exposure during infancy lead to development of asthma A systematic review and met analysis
		
			FMarra
		
		
			LLynd
		
		
			MCoombes
		
	
	
		Chest
		
			129
			
			2006
		
	




* 
	
		The pharmacological properties of a new orally active antianaphylactic compound: Ketotifen a benzocyclo heptatiophen
		
			ULMartin
		
		
			DRomer
		
	
	
		Drug Res
		
			28
			
			1993
		
	




* 
	
		The effect on growth of childhood asthma
		
			AJMartin
		
		
			LILandau
		
		
			PDPhelan
		
	
	
		Acta Paediatr Scand
		
			70
			
			1981
		
	




* 
	
		Asthma and wheezing in the first six years of life. The Group Health Medical Associates
		
			FDMartinez
		
		
			ALWright
		
		
			LMTaussig
		
		
			CJHolberg
		
		
			MHalonen
		
		
			MorganWj
		
	
	
		N. Engl. J. Med
		
			332
			
			1995
		
	




* 
	
		The global burden of asthma: executive summary of the GINA Dissemination Committee report
		
			MMasoli
		
		
			DFabian
		
		
			SHolt
		
		
			RBeasley
		
	
	
		Allergy
		
			59
			
			2004
		
	




* 
	
		Antileukotriene drugs in the treatment of asthma
		
			LMastalerz
		
		
			JKumik
		
	
	
		Pol Arch Med
		
			2010
		
	




* 
	
		Infection and nutrition of children of a low socioeconomic rural community
		
			LMata
		
		
			JJUrrutia
		
		
			ALechitig
		
	
	
		Am J Clin Nutr
		
			24
			
			1971
		
	




* 
	
		
		
			LMcfadyen
		
		
			RMiller
		
		
			TMLudden
		
		
			1997
		
	




* 
	
		Ketotifen pharmacokinetics in children with atopic perennial asthma
	
	
		Euro J Clin Pharm
		
			52
			5
			
		
	




* 
	
		American Hospital Formulary Service. AHFS Drug Information
		
			GKMcevoy
		
		
			2007
			American Society of Health-System Pharmacists
			2755
			Bethesda, MD
		
	




* 
	
		Montelukast in childhood asthma
		
			NPMehta
		
	
	
		Indian Pediatr
		
			37
			12019
			2000
		
	




* 
	
		Exercise induced bronchoconstriction in children: montelukast 120 attenuates the immediate phase and late phase responses
		
			REMelo
		
		
			DSole
		
		
			CKNaspitz
		
	
	
		J Allergy Clin Immunol
		
			111
			
			2003
		
	




* 
	
		Validity of body mass index compared with other body-composition screening indexes for the assessment of body fatness in children and adolescents
		
			ZMei
		
		
			LMGrummer-Strawn
		
		
			APietrobelli
		
		
			AGoulding
		
		
			MIGoran
		
		
			WHDietz
		
	
	
		Amer J Clin Nutr
		
			
			2002
		
	




* 
	
		Response to montelukast among subgroups of children aged 2 to 14 years with asthma
		
			KAMeyer
		
		
			JMArduino
		
		
			NCSantanello
		
	
	
		J Allergy Clin Immunol
		
			111
			
			2003
		
	




* 
	
		
		
			EMigoya
		
		
			GLKearns
		
		
			AHartford
		
		
			2004
		
	




* 
	
		Pharmacokinetics of montelukast in asthmatic patients 6 to 24 months old
	
	
		J Clin Pharmacol
		
			44
			
		
	




* 
	
		Noncompliance and treatment failure in children with asthma
		
			HMilgrom
		
		
			BBender
		
		
			LAckerson
		
		
			PBowry
		
		
			BSmith
		
		
			BRand
		
	
	
		J Allergy Clin Immunol
		
			98
			
			1996
		
	




* 
	
		Montelukast-Induced Generalized Urticaria
		
			PLMinciullo
		
	
	
		Ann Pharmacother
		
			38
			6
			
			2004
		
	




* 
	
		Levels of cysteinyl leukotriene receptor mRNA in human peripheral leukocytes: significantly higher levels of Cysteinyl leukotriene receptor 2 mRNA in eosinophils
		
			HMita
		
		
			MHasegawa
		
		
			HSaito
		
		
			KAkiyama
		
	
	
		Clin Exp Allergy
		
			31
			11
			
			2001
		
	




* 
	
		Nutritional status of children with congenital heart disease
		
			IMMitchell
		
		
			RWLogan
		
		
			JcsPollack
		
		
			MpgJamieson
		
	
	
		Br Heart J
		
			73
			
			1995
		
	




* 
	
		Intravenous aminophylline for acute severe asthma in children over 2 years using inhaled bronchodilators
		
			AMitra
		
		
			DBassler
		
		
			FMDucharme
		
	
	
		Cochrane Database Syst Rev
		
			4
			D001276
			2004
		
	




* 
	
		Montelukast use in atopic dermatitis has been evaluated in many clinical trials
		
			MohammadSEhlayel
		
		
			BAbdulbari
		
	
	
		Curr Pediatr Res
		
			12
			1 & 2
			
			2008
		
	




* 
	
		A double-Blind clinical trial of ketotifen and disodium cromoglycate in bronchial asthma
		
			AMonie
		
		
			SPeter
		
		
			LDavid
		
		
			AGerald
		
		
			HDBrian
		
	
	
		British Journal of Diseases
		
			76
			
			1982
		
	




* 
	
		Nocturnal asthma: features of attacks, sleep and breathing patterns
		
			JMontplaisir
		
		
			JWalsh
		
		
			JLMalo
		
	
	
		Am Rev Respir Dis
		
			125
			
			1982
		
	




* 
	
		Accolate tablets (zafirlukast). Physicians' Desk Reference Medical Economics
		
			NJMontvale
		
		
			2002
			
		
	




* 
	
		Ketotifen inhibits PAF-induced actin polymerization in a human eosinophilic leukemia cell line
		
			MMorita
		
		
			STsuruta
		
		
			KJMori
		
		
			MMayumi
		
		
			HMikawa
		
	
	
		ERJ
		
			3
			10
			
			1990
		
	




* 
	
		Asthma, prevention, diagnosis and treatment for general physicians.Tehran Prevention and Disease
		
			MMovahedy
		
		
			2000
		
	
	Control Center: 2




* 
	
		Comparison of montelukast and pseudoephedrine in the treatment of allergic rhinitis
		
			SMMucha
		
		
			MNaclerio
		
		
			RMBaroody
		
		
			FM
		
	
	
		Arch Otolaryngol Head Neck Surg
		
			132
			
			2006
		
	




* 
	
		Eosinophil chemotaxis inhibited by 5 lipoxygenase blockade and leukotriene receptor antagonism
		
			NMMunoz
		
		
			IDouglas
		
		
			DMayer
		
		
			AHerrnreiter
		
		
			XZhu
		
		
			ARLeff
		
	
	
		Am. J. Respir. Crit. Care Med
		
			155
			4
			
			1997
		
	




* 
	
		Passive smoking by asthmatics: its greater effect on boys than on girls and older than on younger children
		
			ABMurray
		
		
			BJMorrison
		
	
	
		Pediatrics
		
			84
			
			1989
		
	




* 
	
		Guidelines for the diagnosis and management of asthma. National Heart, Lung, and Blood Institute
	
	
		National Asthma Education and Prevention Program Expert Panel Report Number
		
			2
			
			1997
		
	
	National Institutes of Health




* 
	
		Randomized Open-Label Comparative Study of Montelukast versus Theophylline Added to Inhaled Corticosteroid in Asthmatic Children
		
			KNaomi
		
		
			KToshio
		
		
			YasuheiOAkihiro
		
		
			M A
		
	
	
		Allergology International
		
			55
			
			2006
		
	




* 
	
		Effect of Ketotifen and Cyproheptadine on Appetite and Weight Changes in Mice
		
			MNematia
		
		
			BHabibi
		
		
			Asld
		
		
			KSharifia
		
	
	
		Iranian Journal of Pharmaceutical Sciences
		
			2
			3
			
			2006
		
	




* 
	
		Asthma and growth -cause for concern Asthma & Growth in Tayside Children
		
			RGNeville
		
		
			CMccowan
		
		
			GThomas
		
		
			IKCrombie
		
	
	
		Ann Hum Biol
		
			23
			
			1996
		
	




* 
	
		Changes in biochemical inflammation markers in evaluation of the effectiveness of basic chemotherapy in bronchial asthma
		
			VANevzorova
		
		
			EVProsekova
		
		
			Bi
		
		
			PALukianov
		
		
			ShestoskaiaIu
		
		
			VArzamastseva
		
		
			AI
		
	
	
		Ter Arkh
		
			73
			
			2001
		
	




* 
	
		Leukotrienes as mediators of asthma
		
			SNicosia
		
		
			VCapra
		
		
			GRovati
		
	
	
		Pulm. Pharmacol. Ther
		
			14
			
			2001
		
	




* 
	
		Pediatric Asthma
		
			SNishima
		
		
			KFurusho
		
		
			AMorikawa
		
		
			HMochizuki
		
		
			TAkasaka
		
	
	
		Allergy & Immunology
		
			18
			1
			
			2005
		
	




* 
	
		Montelukast, a potent leukotriene receptor antagonist, causes dose-related improvements in chronic asthma
		
			MJNoonan
		
		
			PChervinsky
		
		
			PBrandon
		
		
			MZhang
		
		
			JKundu
		
		
			SMcburney
		
		
			J
		
	
	
		Eur Respir J
		
			11
			
			1998
		
	




* 
	
		Cysteinyl Leukotriene Receptor Antagonists Inhibit Tumor Metastasis by Inhibiting Capillary Permeability
		
			MNozaki
		
		
			MYoshikawa
		
		
			KIshitani
		
		
			HKobayashi
		
		
			KHoukin
		
		
			KImai
		
	
	
		Keio J Med
		
			59
			1
			
			2010
		
	




* 
	
		The AST/ALT ratio as an indicator of cirrhosis in patients with PBC
		
			HNyblom
		
		
			EBjörnsson
		
		
			MSimrén
		
		
			FAldenborg
		
		
			SAlmer
		
		
			ROlsson
		
	
	
		Liver Int
		
			26
			7
			
			2006. september
		
	




* 
	
		Antileukotrienes in the treatment of asthma
		
			PMO'byrne
		
		
			EIsrael
		
		
			JMDrazen
		
	
	
		Ann Intern Med
		
			127
			
			1997
		
	




* 
	
		Ketotifen in HIVinfected patients: effects on body weight and release of TNF-?
		
			FOckenga
		
		
			URohde
		
		
			LSüttmann
		
		
			MHerbarth
		
		
			SBallmaier
		
		
			ISchedel
		
	
	
		Europ J Clinic Pharm
		
			5
			3
			
			1996
		
	




* 
	
		Functional neuroimaging of cognition impaired by a classical antihistamine, d-chlorpheniramine
		
			NOkamura
		
		
			KYanai
		
		
			MHiguchi
		
		
			JSakai
		
		
			RIwata
		
		
			TIdo
		
		
			HSasaki
		
		
			TWatanabe
		
		
			MItoh
		
	
	
		Br J Pharmacol
		
			129
			1
			
			2000
		
	




* 
	
		Effects of salbutamol on exhaled breath condensate biomarkers in acute lung injury: prospective analysis
		
			ROriol
		
		
			SGómez-Ollés
		
		
			Maria-Jesús
		
		
			CXavier
		
		
			MMark
		
		
			JDJoan
		
		
			RM
		
	
	
		Critical Care
		
			12
			3
			
			2008
		
	




* 
	
		Additive bronchoprotective and bronchodilator effects with single doses of salmeterol and montelukast in asthmatic patients receiving inhaled
		
			JOwen
		
		
			A MDempsey
		
		
			JSWilson
		
	
	
		Corticosteroids. Chest
		
			117
			
			2000
		
	




* 
	
		Montelukast: a selective leukotriene receptor Antagonist
		
			DPaige
		
	
	
		Pediatric Pharmacotherapy
		
			4
			10
			
			1998
		
	




* 
	
		Montelukast administered in the morning or evening to prevent exercise-induced bronchoconstriction in children
		
			MPajaron-Fernandez
		
		
			SGarcia-Rubia
		
		
			MSanchez-Solis
		
		
			Garcia-Marcos
		
		
			L
		
	
	
		Pediatr Pulmonol
		
			41
			
			2006
		
	




* 
	
		Prevalence and determinants of respiratory symptoms, asthma, chronic bronchitis and allergic sensitization in Helsinki: A comparison
		
			PPallasaho
		
		
			2006
		
		
			Faculty of Medicine, Department of Pulmonary Medicine University of Helsinki
		
	
	PhD thesis




* 
	
		Martindale The Complete Drug Reference
		
			KParafitt
		
		
			1999
			Royal Pharmaceutical Society
			
			London
		
	
	32 nd edition




* 
	
		Blood-brain barrier biology and methodology
		
			WMPardridge
		
	
	
		J Neurovirol
		
			5
			
			1999
		
	




* 
	
		HPLC Determination of Montelukast and Bambuterol
		
			SPatil
		
		
			YVPore
		
		
			BSKuchekar
		
		
			AManei
		
		
			KhireVg
		
	
	
		Indian J Pharm Sci
		
			71
			1
			
			2009
		
	




* 
	
		
		
			AMPaulo
		
		
			AMCamargos
		
		
			ProfetaSc
		
		
	




* 
	
		
		
			HPayaron -Fernandez
		
		
			Garcia-Rubia
		
		
			2006
		
	




* 
	
		Interpretative strategies for lung function tests
		
			RPellegrino
		
		
			RViegi
		
		
			VBrusasco
		
		
			ROCrapo
		
		
			FBurgos
		
		
			RCasaburi
		
	
	
		Eur. Respir J
		
			26
			
			2005
		
	




* 
	
		Pulmonary function testing
		
			BEPennock
		
		
			JJCottrell
		
		
			RMRodgers
		
	
	
		Arch Intern Med
		
			143
			2123
			1983
		
	




* 
	
		
		
			MPeters-Golden
		
		
			JHenderson
		
		
			W R
		
		
			2007
		
	




* 
	
		
		
			Leukotrienes
		
	
	
		N. Engl. J. Med
		
			357
			
		
	




* 
	
		Metabolic and cardiovascular side effects of the beta 2-adrenoceptor agonist's salbutamol and rimiterol
		
			P JPhillips
		
		
			AVedig
		
		
			P LJones
		
		
			MGChapman
		
		
			MCollins
		
		
			J EDwards
		
		
			T CSmeaton
		
		
			Duncan B M
		
	
	
		Br J Clin Pharmacol
		
			9
			5
			
			1980
		
	




* 
	
		Montelukast in Seasonal Allergic Rhinitis
		
			GPhilip
		
		
			KMalmstrom
		
		
			FCHampel
		
		
			SFWeinstein
		
		
			CFLaforce
		
		
			PHRatner
		
	
	
		Clin Exp Allergy
		
			32
			
			2002
		
	




* 
	
		The Functional Development of Respiratory System-From Period Of Gestation To Adulthood
		
			GPolgar
		
		
			T RWeng
		
	
	
		Amer Rev Respir Dis
		
			120
			3
			1979. September
		
	




* 
	
		The growth of children with chronic paediatric disease
		
			MAPreece
		
		
			CMLaw
		
		
			PswDavies
		
	
	
		Clin Endocrinol Metabol
		
			15
			
			1986
		
	




* 
	
		Tolerability of montelukast
		
			DPrice
		
	
	
		Drugs
		
			59
			
			2000
		
	
	suppl 1




* 
	
		Randomized controlled study comparing a leukotriene receptor antagonist and a nasal glucocorticoid in seasonal allergic rhinitis
		
			TPullerits
		
		
			LPraks
		
		
			BESkoogh
		
		
			RAni
		
		
			JLotvall
		
	
	
		Am J Resp Crit Care Med
		
			159
			6
			
			1999
		
	




* 
	
		Comparison of a nasal glucocorticoid, antileukotriene and a combination of anti leukotriene and anti histamine in the treatment of seasonal allergic rhinitis
		
			TPullerits
		
		
			LPraks
		
		
			VRistioja
		
		
			JLotvall
		
	
	
		J Allergy Clin Immunol
		
			109
			6
			
			2002
		
	




* 
	
		Eosinophilic gastroenteritis in a young girl-long term remission under montelukast
		
			IQuack
		
		
			LSellin
		
		
			NJBuchner
		
		
			DTheegarten
		
		
			LCRump
		
		
			BFHenning
		
	
	
		BMC Gastroenterol
		
			18
			24
			2005
		
	




* 
	
		Pharmacological treatment of asthma today
		
			KFRabe
		
		
			DTSchmidt
		
	
	
		Eur Respir J
		
			18
			
			2001
		
	
	Suppl 34




* 
	
		A Canadian multicenter study with Zaditen (ketotifen) in the treatment of bronchial asthma in children age 5-17 years
		
			ARackham
		
		
			CABrown
		
		
			RKChandra
		
	
	
		J Allergy Clin Immunol
		
			84
			
			1989
		
	




* 
	
		Profile of a primary care practice asthma program
		
			KRance
		
		
			Sa
		
	
	
		J of ped. Health Care
		
			19
			1
			
			2005
		
	




* 
	
		
		
			CFRamsay
		
		
			CIVan Kan
		
		
			RBNieman
		
		
			JWang
		
		
			JhjmVan Krieken
		
		
			LnaWillems
		
		
			1997
		
	




* 
	
		Severe liver injury after treatment with the leukotriene receptor antagonist zafirlukast
		
			JFReinus
		
		
			SPersky
		
		
			JSBurkiewicz
		
		
			DQuan
		
		
			NMBass
		
		
			TJDavern
		
	
	
		Ann Intern Med
		
			133
			
			2000
		
	




* 
	
		Effect of the two different leukotriene receptor antagonists, montelukast and zafirlukast, on quality of life: a 12-week randomized study
		
			GRiccioni
		
		
			R DVecchia
		
		
			DiIlio
		
		
			C
		
		
			D'orazio N
		
	
	
		Allergy Asthma Proc
		
			25
			
			2004a
		
	




* 
	
		Update of the leukotriene modulators for the treatment of asthma
		
			GRiccioni
		
		
			DiIlio
		
		
			C
		
		
			DOrazio
		
		
			N
		
	
	
		Expert Opinion on Investigational Drugs
		
			2004b
		
	




* 
	
		The role of antileukotrienes in the treatment of asthma
		
			GRiccioni
		
		
			FSantilli
		
		
			NOrazio
		
		
			SSensi
		
		
			RSpoltore
		
		
			DeBenedictis
		
	
	
		Int. J. Immunopathol. Pharmacol
		
			15
			
			2002
		
	




* 
	
		Early emergency department treatment of acute asthma with systemic Therapeutic and Some Biochemical Studies of Montelukast and Ketotifen of Children with Mild Asthma corticosteroids
		
			BHRowe
		
		
			CSpooner
		
		
			FMDucharme
		
		
			JABretzlaff
		
		
			GWBota
		
	
	
		Cochrane Database Syst Rev
		
			4
			2178
			2004
		
	




* 
	
		The effectiveness of montelukast for the treatment of anti-histamine-resistant chronic urticaria
		
			SSanada
		
		
			TTanaka
		
		
			YKameyoshi
		
		
			MHide
		
	
	
		Arch Dermatol Res
		
			26
			
			2005
		
	




* 
	
		Focus on Diagnosis: The Alkaline Phosphatase Level: Nuances of a Familiar Test
		
			SarahD
		
		
			Corathers
		
	
	
		Pediatrics in Revie
		
			27
			
			2006
		
	




* 
	
		The relationship of sex to asthma prevalence, health care utilization, and medications in a large managed care organization
		
			MSchatz
		
		
			CACamargo
		
	
	
		Ann. Allergy Asthma Immunol
		
			91
			
			2003
		
	




* 
	
		Liver function Clinical Chemistry: Theory,Analysis, Correlation, 4 th Ed
		
			JScherwin
		
		Kaplan L.A., Pesce A.J., Kazmierczak S.C., Mosby inc
		
			2003
			492
			St Louis USA
		
	




* 
	
		Anti-inflammatory effects of montelukast in mild cystic fibrosis An Allergy Asthma Immunol
		
			SSchmitt-Grohé
		
		
			OEickmeier
		
		
			RSchubert
		
		
			CBez
		
		
			Zielen
		
		
			2002
			89
			
		
	




* 
	
		Single dose pharmacokinetics, safety and tolerability of MK-0476, a new leukotriene D4 receptor antagonist, in healthy volunteers
		
			DFSchoors
		
		
			DeSmet
		
		
			MReiss
		
		
			T
		
	
	
		Br J Clin Pharmacol
		
			40
			
			1995
		
	




* 
	
		
		
			CSchoch
		
	
	
		Journal of Ocular Pharmacology and Therapeutics. Journal of Ocular Pharmacology and Therapeutics
		
			19
			1
			
			2003
		
	




* 
	
		Ketotifen alone or as additional medication for longterm control of asthma and wheeze in children
		
			GSchwartzer
		
		
			DBassler
		
		
			AMitra
		
		
			FMDuchame
		
		
			JForster
		
	
	
		Cochrane Database Syst Rew
		
			D001384
			2004
		
	




* 
	
		Efficacy and tolerability of Ketotifen in Nepalese asthmatic children
		
			KNShakya
		
		
			PJoshi
		
		
			APiya
		
		
			MirBaral
		
	
	
		Kathmandu University Medical Journal
		
			4
			4
			
			2003
		
	




* 
	
		Serum eosinophilic cationic protein and blood eosinophil percentage for the prediction of the presence of airways inflammation in chil¬dren with wheezing
		
			MDShields
		
		
			VBrown
		
		
			ECStevenson
		
	
	
		Clin.Exp.Allergy
		
			29
			
			1999
		
	




* 
	
		Asthma-time for a change of name
		
			MSilverman
		
		
			NWilson
		
	
	
		Archi Dis Child
		
			77
			
			1997
		
	




* 
	
		Montelukast added to budesonide in children with persistent asthma: a randomized, double-blind, crossover study
		
			FESimons
		
		
			JRVilla
		
		
			BWLee
		
		
			AMTeper
		
		
			BLyttle
		
		
			GAristizabal
		
	
	
		J Pediatr
		
			138
			
			2001
		
	




* 
	
		Paediatric 4mg Chewable Tablets. Summary of Product Characteristics
		
			Singular
		
		
			January (2001
			MSD Ltd
		
	




* 
	
		The effects of inhaled leukoterine D4 in humans
		
			LJSmith
		
	
	
		Am J. Respir Dis
		
			131
			3
			
			1985
		
	




* 
	
		Doença alérgica e sua repercussão sobre o crescimento
		
			DSolé
		
		
			DmfScalabrin
		
		
			FSano
		
		
			MCMallozi
		
		
			CKNaspitz
		
		
			AMSpínola-Castro
		
	
	
		J Pediatr (RJ)
		
			67
			
			1991
		
	
	Abstract




* 
	
		Association of asthma with serum IgE and skin test reactivity to allergens among children living at high
		
			RSporik
		
		
			JMIngram
		
		
			WPrice
		
		
			JHSussman
		
		
			RWHonsinger
		
		
			TAPlatts-Mills
		
	
	
		Am. J. Respir. Crit. Care Med
		
			164
			8
			
			2001
		
	




* 
	
		Formoterol used as needed improves health related quality of life in asthmatic patients uncontrolled with inhaled corticosteroids
		
			EStahl
		
		
			SDirkje
		
		
			KlasPostma
		
		
			Svensson
		
	
	
		Respiratory medicine
		
			97
			9
			
			2003
		
	




* 
	
		Randomized double-blind trial of the effect of treatment with montelukast on bronchial hyperresponsiveness and serum eosinophilic cationic protein (ECP), soluble interleukin 2 receptor (sIL-2R), IL-4, and soluble intercellular adhesion molecule 1(sICAM-1) in children with asthma
		
			IStelmach
		
		
			JJerzynska
		
		
			PAKuna
		
	
	
		J Allergy Clin Immunol
		
			109
			
			2002
		
	




* 
	
		Effect of montelukast on lung function and clinical symptoms in patients with cystic fibrosis
		
			IStelmach
		
		
			AKorzeniewska
		
		
			KSmejda
		
		
			IJarosz
		
		
			WStelmach
		
	
	
		Pneumonol Alergol Pol
		
			72
			
			2004
		
	




* 
	
		Incidence and prognosis of asthma and wheezing illness from early childhood to age 33 in a national British cohort
		
			DPStrachan
		
		
			BKButland
		
		
			AndersonHr
		
	
	
		BMJ
		
			312
			
			1996
		
	




* 
	
		Asthma and allergies: The role of the home environment
		
			JSundell
		
		
			BKolarik
		
		
			KNaydenov
		
		
			MLarsson
		
		
			HLEngman
		
		
			CGBornehag
		
	
	
		Public Health Sciences
		
			2
			
			2006
		
	




* 
	
		The Spanish Group of the European Respiratory Health Survey. Risk factors for asthma in young adults
		
			JSunyer
		
		
			JMAnto
		
		
			MKogevinas
		
		
			MABarcelo
		
		
			JBSoriano
		
		
			ATobias
		
	
	
		Eur Respir J
		
			10
			
			1997
		
	




* 
	
		Childhood environment and adult atopy: results from the European Community Respiratory Health Survey
		
			CSvanes
		
		
			DJarvis
		
		
			SChinn
		
		
			PBurney
		
	
	
		J Allergy Clin Immunol
		
			103
			
			1999
		
	




* 
	
		Characterization of within-subject responses to fluticasone and montelukast in childhood asthma
		
			SJSzefler
		
		
			BRPhillips
		
		
			FDMartinez
		
	
	
		J Allergy Clin Immunol
		
			115
			
			2005
		
	




* 
	
		Ketotifen versus Inhaled Budesonide for Controlling Childhood Asthma
		
			PTantichaiyakul
		
		
			APreutthipan
		
	
	
		J Med Assoc Thai
		
			5
			
			2010
		
	




* 
	
		
		
			AETattersfield
		
		
			AJKnox
		
		
			JRBritton
		
		
			IPHall
		
	
	
		Asthma. Lancet
		
			360
			9342
			
			2002
		
	




* 
	
		Essentionals, Nelson Textbook of Pediatrics
		
			ECTepas
		
		
			DTUmetsu
		
		Behraman RE, Kliegman RM, Jenson H
		
			2001
			
			Saunders
		
	
	Immunology and allergy. 4th ed. Philadelphia




* 
	
		
	
	
		The Childhood Asthma Management Program Research Group
		
			2000
		
	




* 
	
		Long-term effects of budesonide or nedocromil in children with asthma
	
	
		N Engl J Med
		
			343
			
		
	




* 
	
		Asthma and cigarette smoking
		
			NCThomson
		
		
			RChaudhuri
		
		
			ELivingston
		
	
	
		Eur. Respir J
		
			24
			
			2004
		
	




* 
	
		Antitussive Effects of the Leukotriene Receptor Antagonist Montelukast in Patients with Cough Variant Asthma and Atopic
		
			KToshiyuki
		
		
			FMasaki
		
		
			OHaruhiko
		
		
			NYasuto
		
		
			NSatoshi
		
		
			IYoshihisa
		
	
	
		Cough Allergology International
		
			59
			
			2010
		
	




* 
	
		Intravenous beta2-agonists for acute asthma in the emergency department
		
			ATravers
		
		
			APJones
		
		
			KKelly
		
		
			SJBarker
		
		
			CACamargo
		
		
			BHRowe
		
		
			2004
		
	




* 
	
		
	
	
		Cochrane DatabaseSyst Rev
		
			4
			D002988
		
	




* 
	
		Relationship between the IL-12B Promoter Polymorphism and Allergic Rhinitis, Familial Asthma, Serum Total IgE, and Eosinophil Level in Asthma Patients
		
			ETug
		
		
			UOzbey
		
		
			TTug
		
		
			HYuce
		
	
	
		J Investig Allergol Clin Immunol
		
			19
			1
			
			2009
		
	




* 
	
		Effects of inhaled steroid treatment on serum eosinophilic cationic protein (ECP) and low affinity receptor for IgE (Fc epsilon RII/sCD23) in childhood bronchial asthma
		
			ITürkta?
		
		
			SDemirsoy
		
		
			Koç
		
		
			NGökçora
		
		
			SElbeg
		
	
	
		Arch Dis Child
		
			75
			
			1996
		
	




* 
	
		Prevalence of asthma and allergy disorder among children in Duzce
		
			PAUyan
		
		
			AGozukara
		
	
	
		Turkey. The International Journal of epidemiology
		
			1
			1
			
			2003
		
	




* 
	
		International consensus report on diagnosis and treatment of asthma
		
			1992
			PHHS Publicatio
			4
			
			Washington D.C
		
		
			U.S. Department of Health and Human Services
		
	
	U.S. Government Printing Office




* 
	
		Safety, tolerability, and exploratory efficacy of montelukast in 6-to 24-month-old patients with asthma
		
			JVan Adelsberg
		
		
			JMoy
		
		
			LXWei
		
		
			CATozzi
		
		
			BKnorr
		
		
			TFReiss
		
	
	
		Curr Med Res Opin
		
			21
			
			2005
		
	




* 
	
		Forced vital capacity and forced expiratory volume in six seconds as predictors of reduced total ling capacity
		
			JVandervoode
		
		
			SVerbanck
		
		
			DSchuermans
		
		
			LBroekaert
		
		
			DDevroey
		
		
			JKartounian
		
		
			WVincken
		
	
	
		Euro Respir J
		
			31
			
		
	




* 
	
		One year treatment with salmeterol compared with beclomethasone in children with asthma. The Dutch Paediatric Asthma Study Group
		
			AAVerberne
		
		
			CFrost
		
		
			RJRoorda
		
		
			HVan Der Laag
		
		
			KFKerrebijn
		
	
	
		Am J Respir Crit Care Med
		
			156
			
			1997
		
	




* 
	
		Efficacy and safety of ketotifen in young children with asthma
		
			BVolovitz
		
		
			IVarsano
		
		
			J CCumella
		
		
			LJaber
		
	
	
		J Allergy and Clinical Immunology
		
			81
			3
			
			1988
		
	




* 
	
		Does rhinitis lead to asthma. Evidence for theone-airway hypothesis
		
			GWVolcheck
		
	
	
		Postgrad Med
		
			115
			
			2004
		
	




* 
	
		Montelukast in pediatric asthma management
		
			MWalia
		
		
			RLodha
		
		
			SKKabra
		
		
			2006
			Indian J Pediatrics
		
	




* 
	
		
		
			WalkerSheik
		
		
			ARhinitis
		
	
	
		BMJ
		
			324
			403
			2002
		
	




* 
	
		Montelukast and psychiatric disorders in children
		
			SMWallerstedt
		
		
			GBrunlöf
		
		
			ASundström
		
		
			ALEriksson
		
	
	
		Pharmacoepidemiol Drug Saf
		
			18
			9
			
			2009
		
	




* 
	
		The role of leukotriene receptor antagonists in the treatment of chronic asthma in childhood
		
			OJWarner
		
	
	
		Allergy
		
			56
			
			2001
		
	
	Suppl 66




* 
	
		Asian pacific journal of allergy and immunology
		
			AWatanasomsiri
		
		
			OPoachanukoon
		
		
			PVichyanond
		
		
			2008
			26
			
		
	




* 
	
		Airway constriction in normal human produced by inhalation of leukoterine D. potency, time course, & effect of aspirin therapy
		
			JWWeiss
		
	
	
		JAMA
		
			249
			20
			
			1983
		
	




* 
	
		Antileukotriene drugs in the management of asthma
		
			SEWenzel
		
	
	
		JAMA
		
			280
			
			1998
		
	




* 
	
		Asthma: defining of the persistent adult phenotypes
		
			SEWenezel
		
	
	
		The Lancet
		
			368
			
			2006
		
	




* 
	
		Bronchoconstrictor effects of leukoterine C in human bronchi
		
			JWWiess
		
	
	
		Science
		
			216
			4542
			
			1982
		
	




* 
	
		Farm residence and exposures and the risk of allergic diseases in New Zealand children
		
			KWickens
		
		
			JMLane
		
		
			PFitzharris
		
		
			RSiebers
		
		
			GRiley
		
		
			JDouwes
		
		
			TSmith
		
		
			JCrane
		
	
	
		Allergy
		
			57
			
			2002
		
	




* 
	
		Grant Medical College
		
			AWiqar
		
		
			AltafLShaikh
		
		
			Patel
		
		
			SKamal
		
		
			RajatSaini
		
		
			KiranSaha
		
		
			Chulki
		
		
			2008
		
	
	Ph.D thesis
	Recent advances in the management of allergy and asthma




* 
	
		The natural history of respiratory symptoms in a cohort of adolescents
		
			NJWithers
		
		
			LLow
		
		
			STHolgate
		
		
			JBClough
		
	
	
		Am. J. Respir Crit Care Med
		
			158
			
			1998
		
	




* 
	
		Pharmacokinetics of ketotifen fumarate after intravenous, intranasal, oral and rectal administration in rabbits
		
			NYagi
		
		
			YTaniuch
		
		
			KHamada
		
		
			JISudo
		
		
			HSekikawa
		
	
	
		Biolog and Pharmac Bullet
		
			25
			12
			
			2002
		
	




* 
	
		with epinastine, a secondgeneration antihistamine
		
			KYanai
		
		
			JHRyu
		
		
			TWatanabe
		
		
			RIwata
		
		
			TIdo
		
		
			MAsakura
		
		
			RMatsumura
		
		
			MItoh
		
	
	
		Meth Find Exp Clin Pharmacol
		
			17
			
			1995
		
	
	Suppl C




* 
	
		New findings in pharmacological effects Therapeutic and Some Biochemical Studies of Montelukast and Ketotifen of Children with Mild Asthma induced by antihistamines: from PET studies to knock-out mice
		
			KYanai
		
		
			NOkamura
		
		
			MTagawa
		
		
			MItoh
		
		
			TWatanabe
		
	
	
		Clin Exp Allergy
		
			29
			3
			
			1999
		
	
	Suppl




* 
	
		The role of helminthes infections in protection from atopic disorders
		
			Yazdanbakhsh MWahyuni
		
		
			S
		
	
	
		Curr Opin Allergy Clin Immunol
		
			5
			
			2005
		
	




* 
	
		Experimental rhinovirus challenges in adults with mild asthma: Response to infection in relation to IgE
		
			JCZambrano
		
		
			HTCarper
		
		
			GPRakes
		
		
			JPatrie
		
		
			DDMurphy
		
		
			TAPlatts-Mills
		
		
			JMGwaltneyJr
		
		
			TKHatley
		
		
			AMOwens
		
		
			PWHeymann
		
	
	
		J Allergy Clin Immunol
		
			111
			5
			
			2003
		
	




* 
	
		Pharmacokinetics and bioavailability of montelukast sodium (MK-0476) in healthy young and elderly volunteers
		
			JJZhao
		
		
			JDRogers
		
		
			SDHolland
		
	
	
		Biopharm Drug Dispos
		
			18
			
			1997
		
	




* 
	
		
			NZimmermann
		
		
			GKHershey
		
		
			PSFoster
		
		
			MERothenberg
		
		Chemokines in asthma: cooperative interaction between chemokines and IL
				
			2002
		
	




* 
	
		
	
	
		J Allergy Clin Immunol
		
			111
			2